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Cochrane Database of Systematic Reviews Review - Intervention

Interventions for hand eczema

Authors' declarations of interest

Version published: 26 April 2019 Version history

https://doi.org/10.1002/14651858.CD004055.pub2
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Background

Hand eczema is an inflammation of the skin of the hands that tends to run a chronic, relapsing course. This common condition is often associated with itch, social stigma, and impairment in employment. Many different interventions of unknown effectiveness are used to treat hand eczema.

Objectives

To assess the effects of topical and systemic interventions for hand eczema in adults and children.

Search methods

We searched the following up to April 2018: Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, AMED, LILACS, GREAT, and four trials registries. We checked the reference lists of included studies for further references to relevant trials.

Selection criteria

We included randomised controlled trials (RCTs) that compared interventions for hand eczema, regardless of hand eczema type and other affected sites, versus no treatment, placebo, vehicle, or active treatments.

Data collection and analysis

We used standard methodological procedures expected by Cochrane. Primary outcomes were participant‐ and investigator‐rated good/excellent control of symptoms, and adverse events.

Main results

We included 60 RCTs, conducted in secondary care (5469 participants with mild to severe chronic hand eczema). Most participants were over 18 years old. The duration of treatment was short, generally up to four months. Only 24 studies included a follow‐up period. Clinical heterogeneity in treatments and outcome measures was evident. Few studies performed head‐to‐head comparisons of different interventions. Risk of bias varied considerably, with only five studies at low risk in all domains. Twenty‐two studies were industry‐funded.

Eighteen trials studied topical corticosteroids or calcineurin inhibitors; 10 studies, phototherapy; three studies, systemic immunosuppressives; and five studies, oral retinoids. Most studies compared an active intervention against no treatment, variants of the same medication, or placebo (or vehicle). Below, we present results from the main comparisons.

Corticosteroid creams/ointments: when assessed 15 days after the start of treatment, clobetasol propionate 0.05% foam probably improves participant‐rated control of symptoms compared to vehicle (risk ratio (RR) 2.32, 95% confidence interval (CI) 1.38 to 3.91; number needed to treat for an additional beneficial outcome (NNTB) 3, 95% CI 2 to 8; 1 study, 125 participants); the effect of clobetasol compared to vehicle for investigator‐rated improvement is less clear (RR 1.43, 95% CI 0.86 to 2.40). More participants had at least one adverse event with clobetasol (11/62 versus 5/63; RR 2.24, 95% CI 0.82 to 6.06), including application site burning/pruritus. This evidence was rated as moderate certainty.

When assessed 36 weeks after the start of treatment, mometasone furoate cream used thrice weekly may slightly improve investigator‐rated symptom control compared to twice weekly (RR 1.23, 95% CI 0.94 to 1.61; 1 study, 72 participants) after remission is reached. Participant‐rated symptoms were not measured. Some mild atrophy was reported in both groups (RR 1.76, 95% CI 0.45 to 6.83; 5/35 versus 3/37). This evidence was rated as low certainty.

Irradiation with ultraviolet (UV) light: local combination ultraviolet light therapy (PUVA) may lead to improvement in investigator‐rated symptom control when compared to local narrow‐band UVB after 12 weeks of treatment (RR 0.50, 95% CI 0.22 to 1.16; 1 study, 60 participants). However, the 95% CI indicates that PUVA might make little or no difference. Participant‐rated symptoms were not measured. Adverse events (mainly erythema) were reported by 9/30 participants in the narrow‐band UVB group versus none in the PUVA group. This evidence was rated as moderate certainty.

Topical calcineurin inhibitors: tacrolimus 0.1% over two weeks probably improves investigator‐rated symptom control measured after three weeks compared to vehicle (14/14 tacrolimus versus 0/14 vehicle; 1 study). Participant‐rated symptoms were not measured. Four of 14 people in the tacrolimus group versus zero in the vehicle group had well‐tolerated application site burning/itching.

A within‐participant study in 16 participants compared 0.1% tacrolimus to 0.1% mometasone furoate but did not measure investigator‐ or participant‐rated symptoms. Both treatments were well tolerated when assessed at two weeks during four weeks of treatment.

Evidence from these studies was rated as moderate certainty.

Oral interventions: oral cyclosporin 3 mg/kg/d probably slightly improves investigator‐rated (RR 1.88, 95% CI 0.88 to 3.99; 1 study, 34 participants) or participant‐rated (RR 1.25, 95% CI 0.69 to 2.27) control of symptoms compared to topical betamethasone dipropionate 0.05% after six weeks of treatment. The risk of adverse events such as dizziness was similar between groups (up to 36 weeks; RR 1.22, 95% CI 0.80 to 1.86, n = 55; 15/27 betamethasone versus 19/28 cyclosporin). The evidence was rated as moderate certainty.

Alitretinoin 10 mg improves investigator‐rated symptom control compared with placebo (RR 1.58, 95% CI 1.20 to 2.07; NNTB 11, 95% CI 6.3 to 26.5; 2 studies, n = 781) and alitretinoin 30 mg also improves this outcome compared with placebo (RR 2.75, 95% CI 2.20 to 3.43; NNTB 4, 95% CI 3 to 5; 2 studies, n = 1210). Similar results were found for participant‐rated symptom control: alitretinoin 10 mg RR 1.73 (95% CI 1.25 to 2.40) and 30 mg RR 2.75 (95% CI 2.18 to 3.48). Evidence was rated as high certainty. The number of adverse events (including headache) probably did not differ between alitretinoin 10 mg and placebo (RR 1.01, 95% CI 0.66 to 1.55; 1 study, n = 158; moderate‐certainty evidence), but the risk of headache increased with alitretinoin 30 mg (RR 3.43, 95% CI 2.45 to 4.81; 2 studies, n = 1210; high‐certainty evidence). Outcomes were assessed between 48 and 72 weeks.

Authors' conclusions

Most findings were from single studies with low precision, so they should be interpreted with caution. Topical corticosteroids and UV phototherapy were two of the major standard treatments, but evidence is insufficient to support one specific treatment over another. The effect of topical calcineurin inhibitors is not certain. Alitretinoin is more effective than placebo in controlling symptoms, but advantages over other treatments need evaluating.

Well‐designed and well‐reported, long‐term (more than three months), head‐to‐head studies comparing different treatments are needed. Consensus is required regarding the definition of hand eczema and its subtypes, and a standard severity scale should be established.

The main limitation was heterogeneity between studies. Small sample size impacted our ability to detect differences between treatments.

PICOs

Population
Intervention
Comparison
Outcome

The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.

See more on using PICO in the Cochrane Handbook.

Treatments for hand eczema

Review question

We reviewed evidence on the effects of topical and systemic (oral or injected medicines that work throughout the entire body) treatments for hand eczema when compared against placebo (an identical but inactive treatment), no treatment, vehicle (inactive ingredients that help deliver an active treatment), or another treatment. We included 60 randomised trials (5469 participants) published up to April 2018.

Background

Hand eczema is an inflammation of the skin of the hands that can be caused by contact allergens (i.e. substances that cause an allergic reaction) such as rubber chemicals, but other external factors (e.g. irritants such as water or detergents) and atopic predisposition are often important triggers. Hand eczema can cause a reduction in quality of life leading to many work‐related problems. Various types of hand eczema exist, and different topical (creams, ointments, or lotions) and systemic treatments with unknown effectiveness can be used.

Study characteristics

Most participants were hospital outpatients over 18 years of age with mild to severe chronic hand eczema. Treatment was usually given for up to four months, and outcomes were mainly assessed after treatment. A large variety of treatments were studied and compared to no treatment, variants of the same medication, placebo, or vehicle. Twenty‐two studies were funded by pharmaceutical companies.

Key results

Limited data are available to support the best way of managing hand eczema due to varying study quality and inability to pool data from studies with similar interventions. Corticosteroid creams/ointments and phototherapy (irradiation with UV light) are the major treatment options, although comparisons between these options are lacking. Below, we present results for the main comparisons of interest.

Corticosteroid creams/ointments: clobetasol propionate foam probably increases participant‐rated good/excellent control of hand eczema when compared to vehicle (516 versus 222 per 1000), but the difference between groups was less clear for investigator‐rated control, and more adverse events were reported with clobetasol propionate (178 versus 79 per 1000) (all based on moderate‐certainty evidence).

Mometasone furoate cream used thrice weekly may slightly improve investigator‐rated good/excellent control compared to twice weekly treatment, and participant‐rated control was not measured. Mild skin thinning occurred in both groups, but cases were few (all based on low‐certainty evidence).

Irradiation with UV light: various types of irradiation (i.e. exposure to radiation) were compared. Local PUVA may improve investigator‐rated good/excellent control compared to narrow‐band UVB (400 versus 200 per 1000); however, we are uncertain of this finding because results also show that local PUVA may make little or no difference. Participant‐rated symptoms were not measured. Nine out of 30 participants in the narrow‐band UVB group reported adverse events (mainly redness) compared to none in the PUVA group (all based on moderate‐certainty evidence).

Topical calcineurin inhibitors: people receiving tacrolimus are probably more likely to achieve improved investigator‐rated good/excellent symptom control compared to those given vehicle (14/14 participants with tacrolimus compared to none with vehicle), but participant‐rated control of symptoms was not measured. Four of 14 people in the tacrolimus group versus zero in the vehicle group had well‐tolerated application site burning/itching. One small study compared tacrolimus to mometasone furoate, which were both well tolerated, but did not measure investigator‐ or participant‐rated control (all based on moderate‐certainty evidence).

Oral interventions: oral immunosuppressant (a drug that hinders the immune response) cyclosporin probably slightly improves investigator‐ or participant‐rated control of good/excellent symptoms compared to topical betamethasone cream (a corticosteroid). The risk of adverse events such as dizziness was similar between groups (all based on moderate‐certainty evidence).

The oral vitamin A derivative (retinoid) alitretinoin (10 mg) achieved investigator‐rated good/excellent symptom control in 307 compared to 194 participants per 1000 with placebo, and alitretinoin 30 mg achieved investigator‐rated control in 432 compared to 157 participants per 1000 with placebo. Similar results were shown for participant‐rated control (high‐certainty evidence). When the dosage of alitretinoin was increased to 30 mg, risk of headache was higher compared to placebo (74 versus 251 per 1000; high‐certainty evidence), but this probably does not differ between alitretinoin 10 mg and placebo (based on moderate‐certainty evidence).

Quality of the evidence

The quality of evidence was mainly moderate, with most analyses based on single studies that had small sample sizes; therefore, some results should be interpreted with care.

Authors' conclusions

Implications for practice

The results of this review cannot be used to inform clinical practice with regard to the best way of managing hand eczema, especially in the long term. Until such data are forthcoming, physicians will be tempted to use an array of treatments.

For the comparison of clobetasol propionate versus vehicle foam, the percentage of participants with self‐rated good/excellent control of symptoms probably improves with clobetasol propionate, but the effect is less clear for investigator‐rated symptoms (moderate‐quality evidence). Mometasone furoate cream thrice weekly may slightly improve investigator‐rated symptoms compared to twice weekly application (low‐quality evidence); participant‐rated control was not measured.

Tacrolimus ointment probably improves investigator‐rated good/excellent control of symptoms compared to vehicle foam (moderate‐quality evidence); participant‐rated control was not measured.

A relatively new systemic treatment (an oral retinoid called alitretinoin) for patients with severe chronic hand eczema showed clearance or almost clearance of about half the participants in three large RCTs (Fowler 2014; Ruzicka 2004, Ruzicka 2008). We found high‐quality evidence that relative to placebo, people who are given alitretinoin were more likely to achieve good symptom control (investigator or participant rated). The benefit became more apparent with increased dosage (10 mg versus 30 mg).

Local PUVA may lead to improvement compared to local narrow‐band UVB; however, the 95% confidence interval indicates that local PUVA might make little or no difference (moderate‐quality evidence). Participant‐rated control was not measured.

Oral cyclosporin probably slightly improves investigator‐/participant‐rated control of symptoms compared with topical betamethasone dipropionate (moderate‐quality evidence).

For the comparison tacrolimus 0.1% ointment versus mometasone furoate ointment, investigator‐rated symptoms and participant‐rated control was not measured.

Adverse events: adverse (long‐ and short‐term) effects of the interventions

  • Clobetasol propionate led to more adverse events (including application site burning/pruritus after intervention application, nasopharyngitis, and one incident of severe fissures) compared to vehicle foam (moderate‐quality evidence)

  • With regard to mometasone furoate cream used thrice weekly compared to twice weekly, mild atrophy was reported in both groups (low‐quality evidence)

  • When compared to local PUVA, adverse events (mainly erythema) were reported in the local narrow‐band UVB group only (moderate‐quality evidence)

  • With regard to tacrolimus ointment compared to mometasone furoate ointment, both treatments were well tolerated; none of the participants dropped out due to adverse events (moderate‐quality evidence)

  • When compared to vehicle foam, adverse events (well‐tolerated burning/itching at the application site) were reported in the group taking tacrolimus ointment only (moderate‐quality evidence)

  • The risk of adverse events such as dizziness was fairly similar between those taking oral cyclosporin and those taking topical betamethasone dipropionate (moderate‐quality evidence)

The 20 studies listed under Studies awaiting classification may alter the conclusions of the review once assessed.

Implications for research

The most important implication of this review is the need to conduct high‐quality RCTs of people with hand eczema to compare commonly used interventions by using simple outcome measures that can be understood by participants and clinicians.

  • E (Evidence): current evidence for managing hand eczema is mainly of low to moderate certainty and especially head‐to‐head trials are missing. Recently, head‐to‐head trials for different (systemic) treatments have been registered in trial registries (ISRCTN80206075; NCT03026907; NCT03026946), which might alter the outcomes of this review in the near future.

  • P (Population): people with chronic (longer than six months) moderate to severe hand eczema should be included in future trials. Subgroup analyses on participants with different variants of hand eczema are recommended, although lack of consensus regarding the classification of hand eczema is a major limitation. We need international consensus regarding the definition of (chronic) hand eczema and subgroups of hand eczema, based on morphology or aetiology. Subgroups of especial interest include participants with hyperkeratotic hand eczema and participants with recurrent vesicular hand eczema. Studies on acute hand eczema were not included in this review but may be of interest, especially in primary care settings. Not many children were included in these studies, and this is a potential subgroup of interest for future studies.

  • I (Intervention): all sources of treatment can be included, although we would recommend including the main interventions (topical corticosteroids, UV therapy, topical calcineurin inhibitors, acitretin, alitretinoin, and cyclosporin).

  • C (Comparison): head‐to‐head trials, in which different groups of commonly used interventions are compared, are highly desirable, for example, cyclosporin versus alitretinoin or UVA therapy versus topical corticosteroids. If an RCT includes placebo (or vehicle or inactive treatment) as the only comparator instead of an established treatment modality, this should be clearly and convincingly justified.

  • O (Outcome): at the moment, international consensus on a standard severity scale for hand eczema is lacking. Many of the scales used were not validated, and validation of commonly used scoring systems is needed. Alternatively, a simple global rating measure with, for example, photographic anchors is highly recommended (Charman 2005; Weistenhöfer 2010). We would like to recommend the same procedure as is currently ongoing in atopic dermatitis: Harmonising Outcome Measures for Eczema (HOME) (Schmitt 2010). The HOME group is a worldwide initiative with the aim of developing a consensus‐based set of core outcome domains for trials and clinical record keeping in atopic dermatitis. This is important, to allow comparison of data across trials ‐ one of the difficulties that we encountered in this review on interventions for hand eczema. Duration of remission, the way the disease is brought under control, adverse events, focus on patient‐reported outcomes, and simple outcome measures applicable to all participants are preferable. Hand eczema is known to influence quality of life; therefore quality of life should be an important outcome. In addition, trials should focus on economic consequences, since hand eczema is a common occupational disease. A major limitation of almost all reviewed trials is that no measure of effect size including precision is given. This is necessary to enable judgement of whether advantages of treatments are not only statistically significant but also meaningful.

  • T (Time stamp): our latest search was conducted in April 2018. Older studies focused mainly on topical corticosteroids, UV therapy, and irradiation, and more recent (namely, industry‐funded) studies focus on topical calcineurin inhibitors (pimecrolimus and tacrolimus) and alitretinoin. The included studies were predominantly of short duration. Future studies should have adequate treatment duration, preferably longer than three months, which in our opinion is the minimum duration required to document important data such as duration and frequency of disease relapse. Furthermore, studies on chronic hand eczema should include a follow‐up period of at least equal duration. Acute hand eczema, especially the allergic type, tends to respond quickly to treatment and needs only a short follow‐up, in which case a few weeks of treatment and follow‐up should be sufficient.

It is obvious in many of the reviewed trials that the approach to statistical analyses was limited. Several parametric and non‐parametric statistical procedures that are able to model both within (person and/or time) and between subject (treatment) factors simultaneously have been offered by most statistical packages for many years. A major limitation of many of the treatment comparisons is that they did not control for baseline variation. In addition, omnibus factorial designs (allowing contrasts to be specified a priori) reduce the type 1 error rate because they test several hypotheses at the same time. Post‐hoc comparisons would be necessary only should the data reveal surprising results. These analyses, of course, would have to be viewed in an explorative fashion. Future studies need to overcome said limitations.

Many deficiencies in trial reporting thus far can be avoided if all specialist dermatology journals adopt the CONSORT guidelines (Moher 2001), especially since many of the 'unclear' risks, turned out to be based on missing information in the report instead of flaws in the study design. All future studies should adhere to these guidelines. Future studies should ensure they are adequately powered to detect any differences between treatment groups and to reduce imprecision.

Practical recommendations for upcoming studies include the above‐mentioned recommendations on chronic hand eczema. Studies that are highly recommended include the comparison of phototherapy (e.g. bath‐PUVA) versus alitretinoin 30 mg in a large cohort of participants with chronic hand eczema with a duration of at least three months and follow‐up of at least equal length. This study is already registered (ISRCTN80206075), and results of this trial might influence the outcomes of this review in future updates.

Another recommendation would be to compare alitretinoin 30 mg to cyclosporin in participants with vesicular hand eczema and with hyperkeratotic hand eczema, since participants with vesicular hand eczema seemed to respond less to alitretinoin in the included trials on alitretinoin. This study design is already registered for vesicular hand eczema as well, and we are awaiting the results (NCT03026946). Other potential research options include comparison of a potent topical corticosteroid, since this is the mainstream of treatment, to alitretinoin 30 mg or to phototherapy. The comparative advantage over other treatments needs further evaluation, since the only study that did compare alitretinoin to another immunosuppressant (cyclosporin) was ended prematurely (NCT01231854).

Summary of findings

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Summary of findings for the main comparison. Corticosteroid creams/ointments: clobetasol propionate foam compared to vehicle foam for hand eczema

Corticosteroid creams/ointments: clobetasol propionate foam compared to vehicle foam for hand eczema

Patient or population: participants with moderate to severe hand eczema
Setting: secondary care with outpatients in Northern America
Intervention: clobetasol propionate 0.05% foam twice a day for 14 days
Comparison: vehicle/placebo foam twice a day for 14 days

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No. of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Assumed riska

Corresponding risk

Risk with vehicle foam

Risk with clobetasol propionate foam

Primary: investigator‐rated good/excellent control of symptoms

Follow‐up: day 15

Study population

RR 1.43
(0.86 to 2.40)

125
(1 RCT)

⊕⊕⊕⊝
Moderateb

‐

270 per 1000

386 per 1000
(232 to 648)

Primary: participants with self‐rated good/excellent control of symptoms

Follow‐up: day 15

Study population

RR 2.32
(1.38 to 3.91)

125
(1 RCT)

⊕⊕⊕⊝
Moderatec

NNTB 3 (95% CI 2 to 8)

222 per 1000

516 per 1000
(307 to 869)

Primary: adverse events ‐ at least 1 adverse event

Follow‐up: day 15

Study population

RR 2.24
(0.82 to 6.06)

125
(1 RCT)

⊕⊕⊕⊝
Moderatec

‐

79 per 1000

178 per 1000
(65 to 481)

Primary: adverse events ‐ any adverse event treatment‐related (application site pruritus)

Follow‐up: day 15

Study population

RR 1.02
(0.06 to 15.89)

125
(1 RCT)

⊕⊕⊕⊝
Moderated

‐

16 per 1000

16 per 1000
(1 to 252)

Secondary: reduction in severity, participant‐rated scoring

Follow‐up: day 15

Study population

RR 1.57
(1.21 to 2.04)

125
(1 RCT)

⊕⊕⊕⊝
Moderateb

NNTB 3 (95% CI 2 to 7)

524 per 1000

822 per 1000
(634 to 1000)

Secondary: reduction in severity, investigator‐rated scoring ‐ improvement at least 2 grades

Follow‐up: day 15

Study population

RR 1.47
(0.90 to 2.39)

125
(1 RCT)

⊕⊕⊕⊝
Moderateb

‐

286 per 1000

420 per 1000
(257 to 683)

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: confidence interval; NNTB: number needed to treat for an additional beneficial outcome; RCT: randomised controlled trial; RR: risk ratio.

Kircik 2013

GRADE Working Group grades of evidence.
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

aThe assumed risk is the mean control group risk.

bDowngraded by one level to moderate‐certainty evidence for imprecision. Small sample size and small number of events.

cDowngraded by one level to moderate‐certainty evidence for imprecision. Wide confidence interval with small sample size and small number of events.

dDowngraded by one level to moderate‐certainty evidence for imprecision. Summary effect contains both appreciable benefit and harm; wide confidence interval with small sample size and small number of events.

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Summary of findings 2. Corticosteroid creams/ointments: mometasone furoate cream 3 times/week versus 2 times/week for hand eczema

Corticosteroid creams/ointments: mometasone furoate cream thrice a week versus twice a week

Patient or population: people (all patch‐tested) with hand eczema > 6 months that had cleared upon daily treatment for a maximum of 9 weeks with mometasone furoate cream
Settings: secondary care with outpatients from hospitals in Denmark
Intervention: mometasone furoate cream 3 times/week up to 36 weeks

Comparision: mometasone furoate cream 2 times/week up to 36 weeks

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No. of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Assumed riska

Corresponding risk

Risk with mometasone furoatetwice a week

Risk with mometasone furoate thrice a week

Primary: investigator‐rated good/excellent control of symptoms
Follow‐up: 36 weeks

Study population

RR 1.23
(0.94 to 1.61)

72
(1 RCT)

⊕⊕⊝⊝
Lowb

‐

676 per 1000

831 per 1000
(635 to 1000)

Primary: participant‐rated good/excellent control of symptoms
Not measured

See comment

See comment

Not estimable

‐

See comment

No data available

Primary: adverse events
Follow‐up: 36 weeks

Study population

RR 1.76
(0.45 to 6.83)

72
(1 RCT)

⊕⊕⊝⊝
Lowc

‐

81 per 1000

143 per 1000
(36 to 554)

Secondary: investigator‐rated reduction in severity

Not measured

See comment

See comment

Not estimable

‐

See comment

No data available

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio.

Veien 1999

GRADE Working Group grades of evidence.
High certainty: further research is very unlikely to change our confidence in the estimate of effect.
Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low certainty: we are very uncertain about the estimate.

aThe assumed risk is the mean control group risk.

bDowngraded by two levels to low‐certainty evidence. Imprecision downgraded by one level: the event number was small as was the sample size. Downgraded one level for risk of bias, given the high risk of detection and performance bias.

cDowngraded by two levels to low‐certainty evidence. Imprecision downgraded by one level: the summary effect contains both appreciable benefit and harm; sample size was small as was the event rate. Downgraded one level for risk of bias, given the high risk of detection and performance bias.

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Summary of findings 3. Irradiation with UV light: local narrow‐band UVB compared to local PUVA for hand eczema

Irradiation with UV light: local narrow‐band UVB compared to local PUVA for hand eczema

Patient or population: people with hand eczema unresponsive to clobetasol propionate
Setting: secondary care with outpatients in the United Kingdom.
Intervention: local narrow‐band UVB twice weekly for 12 weeks
Comparison: immersion PUVA twice weekly for 12 weeks

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No. of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Assumed riska

Corresponding risk

Risk with local PUVA

Risk with local narrow‐band UVB

Primary: investigator‐rated good/excellent control of symptoms

Follow‐up: 12 weeks

Study population

RR 0.50
(0.22 to 1.16)

60
(1 RCT)

⊕⊕⊕⊝
Moderateb

‐

400 per 1000

200 per 1000
(88 to 464)

Primary: participant‐rated good/excellent control of symptoms

Not measured

See comment

See comment

Unable to estimate treatment effect

‐

See comment

No data reported

Primary: adverse events ‐ reported adverse events, mainly erythema

Follow‐up: 12 weeks

See comment

See comment

RR 19.00
(1.16 to 312.42)

60
(1 RCT)

⊕⊕⊕⊝
Moderatec

PUVA:

No adverse events reported (0/30)

Narrow‐band UVB:

9 out of 30 participants reported an adverse event, mainly erythema

Fisher's exact test  P = 0.0019

Secondary: investigator‐rated reduction in severity in mTLSSd

Follow‐up: 12 weeks

‐

‐

Unable to estimate treatment effect

43 (1 RCT)

⊕⊕⊕⊝
Moderatee

Reduction in mTLSS PUVA:

Median mTLSS of 8.5 (range 0 to 16) and 8 (range 3 to 15) for the left and right hand, to a median mTLSS 3 (range 0 to 13) and 3 (range 0 to 14) (n = 23)

Reduction mTLSS local narrow‐band UVB group:

Median mTLSS of 7 (range 0 to 16) and 8.5 (range 1 to 15) to a median mTLSS5 (range 0 to 11) and 4.5 (range 0 to 11) (n = 20)

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: confidence interval; mTLSS: modified total lesion symptom score; PUVA: oral psoralen combined with UVA; RCT: randomised controlled trial; RR: risk ratio; UV: ultraviolet.

2015

GRADE Working Group grades of evidence.
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

aThe assumed risk is the mean control group risk.

bDowngraded by one level to moderate‐certainty evidence for imprecision. Small sample size, small number of events, and high dropout rate.

cDowngraded by one level to moderate‐certainty evidence for imprecision. Wide confidence interval with small sample size, small number of events, and high dropout rate.

dThe Modified Total Lesion Symptom Score (mTLSS) is the sum of seven items (erythema, oedema, vesiculation, scaling, lichenification/hyperkeratosis, fissures, and pruritus/pain) scored on a 4‐point scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe). A high mTLSS represents severe hand eczema.

eDowngraded by one level to moderate‐certainty evidence for imprecision. Small sample size based on single study.

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Summary of findings 4. Topical calcineurin inhibitors: tacrolimus 0.1% ointment compared to mometasone furoate ointment for vesicular hand eczema

Topical calcineurin inhibitors: tacrolimus 0.1% ointment compared to mometasone furoate ointment for vesicular hand eczema

Patient or population: people with moderate to severe chronic relapsing dyshidrotic eczema on hands
Setting: secondary care setting at a single dermatology department in Germany
Intervention: topical calcineurin inhibitors tacrolimus 0.1% ointment twice daily during 4 weeks
Comparison: topical corticosteroid mometasone furoate ointment twice daily during 4 weeks

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No. of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Risk with mometasone furoate ointment

Risk with topical calcineurin inhibitor tacrolimus 0.1% ointment

Primary: investigator‐rated good/excellent control of symptoms ‐

Not measured

See comment

See comment

Not estimable

‐

See comment

Not measured

Primary: participant‐rated good/excellent control of symptoms ‐

Not measured

See comment

See comment

Not estimable

‐

See comment

Not measured

Primary: adverse events
Follow‐up: 2 weeks

See comment

See comment

Not estimable

16 pairs of hands (1 RCT)

⊕⊕⊕⊝
Moderatea

Within‐participant design

None of the participants dropped out because of adverse events

Secondary: investigator‐rated reduction in severity ‐ DASIb

Follow‐up: 2 weeks

See comment

See comment

Not estimable

16 pairs of hands (1 RCT)

⊕⊕⊕⊝
Moderatea

Within‐participant design

Tacrolimus group:

Mean DASI from 18 (SD 12.68) to 6.6 (SD 6.18)

Mometasone furoate group:

Mean DASI from 18.5 (SD 14.09) to 6.9 (SD 7.7)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; DASI: Dyshydrotic Eczema Area and Severity Index; RCT: randomised controlled trial; RR: risk ratio; SD: standard deviation.

Schnopp 2002

GRADE Working Group grades of evidence.
High certainty: further research is very unlikely to change our confidence in the estimate of effect.
Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low certainty: we are very uncertain about the estimate.

aDowngraded by one level to moderate‐certainty evidence for imprecision: small sample size in a single study and small number of events.

bDASI: Dyshydrotic Eczema Area and Severity Index is an assessment of severity combining objective (vesicles, erythema, and desquamation) and subjective (itch) evaluations on a scale from 0 (no eczema) to 60 (severe hand eczema).

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Summary of findings 5. Topical calcineurin inhibitors: tacrolimus 0.1% ointment versus vehicle for hand eczema

Topical calcineurin inhibitor tacrolimus 0.1% ointment compared to vehicle for hand eczema

Patient or population: people with moderate to severe nickel sulphate‐induced allergic contact dermatitis based on clinical history (hand eczema) and proven by patch testing, resistant to topical corticosteroids
Settings: secondary care setting in a single‐centre study in Italy
Intervention: topical calcineurin inhibitor tacrolimus 0.1% ointment twice daily for 2 weeks

Comparison: vehicle twice daily for 2 weeks

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No. of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Risk with vehicle

Risk with tacrolimus 0.1% ointment

Primary: investigator‐rated good/excellent control of symptoms

Follow‐up: 3 weeks

See comment

See comment

RR 29.00
(1.90 to 443.25)

28
(1 RCT)

⊕⊕⊕⊝
Moderatea

Unable to calculate assumed risk as no events in the control group ‐ 14/14 participants in the tacrolimus group had good/excellent control of symptoms.

Fisher's exact test P = 0.0001, NNTB 1, 95% CI 1 to 1

Primary: participant‐rated good/excellent control of symptoms
Not measured

See comment

See comment

Not estimable

‐

See comment

No data reported

Primary: adverse events ‐ burning/itching at application site

Follow‐up: 3 weeks

See comment

See comment

RR 9.00
(0.53 to 152.93)

28
(1 RCT)

⊕⊕⊕⊝
Moderatea

Unable to calculate assumed risk as no events in the control group ‐ 4/14 participants in the tacrolimus group had burning/itching at the application site.

Fisher's exact test P = 0.1129, RR 9.00, 95% CI 0.53 to 152.93

No data on "all adverse events"

Secondary: investigator‐rated reduction in severity ‐

Not measured

See comment

See comment

Not estimable

‐

See comment

No data reported

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; NNTB: number needed to treat for an additional beneficial outcome; RCT: randomised controlled trial; RR: risk ratio.

Pacor 2006

GRADE Working Group grades of evidence.
High certainty: further research is very unlikely to change our confidence in the estimate of effect.
Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low certainty: we are very uncertain about the estimate.

aDowngraded by one level to moderate‐certainty evidence for imprecision: very small sample size, low event rate, and very large confidence intervals.

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Summary of findings 6. Oral immunosuppressants: oral cyclosporin versus topical betamethasone dipropionate

Oral cyclosporin compared to topical betamethasone for patient with hand eczema

Patient or population: people with hand eczema, continuously for 6 months, significant disability, inadequate response to conventional treatment, confirmation by histopathology
Setting: secondary care setting at a single centre in Finland
Intervention: oral cyclosporin 3 mg/kg/d and placebo cream for 6 weeks
Comparison: topical betamethasone dipropionate 0.05% cream and placebo capsules for 6 weeks

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No. of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Assumed riska

Corresponding risk

Risk with topical betamethasone

Risk with oral cyclosporin

Primary: investigator‐ rated good/excellent control of symptomsb

Follow‐up: 6 weeks

Study population

RR 1.88
(0.88 to 3.99)

34
(1 RCT)

⊕⊕⊕⊝
Moderatec

‐

333 per 1000

627 per 1000
(293 to 1000)

Primary: participant‐rated good/excellent control of symptomsb

Follow‐up: 6 weeks

Study population

RR 1.25
(0.69 to 2.27)

34
(1 RCT)

⊕⊕⊕⊝
Moderatec

‐

500 per 1000

625 per 1000
(345 to 1000)

Primary: adverse events ‐ at least 1 adverse event

Follow‐up: 36 weeks

Study population

RR 1.22
(0.80 to 1.86)

55d
(1 RCT)

⊕⊕⊕⊝
Moderatec

Because of partial cross‐over design, a different number of participants is given for this outcome

556 per 1000

678 per 1000
(444 to 1000)

Secondary: investigator‐rated reduction in severityb

Follow‐up: 6 weeks

Mean investigator‐rated reduction in severity in total disease activity score after 6 weeks of treatment was 5.7

MD 0.30 higher
(2.50 lower to 3.10 higher)

‐

34
(1 RCT)

⊕⊕⊕⊝
Moderatec

‐

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; MD: mean difference; RCT: randomised controlled trial; RR: risk ratio.

Granlund 1996

GRADE Working Group grades of evidence.
High certainty: further research is very unlikely to change our confidence in the estimate of effect.
Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low certainty: we are very uncertain about the estimate.

aThe assumed risk is the mean control group risk.

bObserver‐rated disease activity score: grading 0 to 3 (0 = none, 1 = mild, 2 = moderate, 3 = severe) on erythema, scaling, infiltration, excoriation, crusting, and vesicles for both hands. A high score represents severe hand eczema.

cDowngraded by one level to moderate‐certainty evidence. Imprecision downgraded by one level: small sample size.

dThe number of participants varies between different outcomes because this is a cross‐over study, and adverse events were included from all different phases of the trial.

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Summary of findings 7. Oral retinoids: alitretinoin 30 mg versus placebo for hand eczema

Oral retinoids: alitretinoin 30 mg versus placebo for hand eczema

Patient or population: people with moderate to severe chronic hand eczema
Settings: secondary care with outpatients in an international multi‐centre setting
Intervention: oral retinoid alitretinoin 30 mg for 12 to 24 weeks

Comparison: oral placebo for 12 to 24 weeks

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No. of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Assumed riska

Corresponding risk

Risk with placebo

Risk with alitretinoin 30 mg

Primary: investigator‐rated good/excellent control of symptoms

Follow‐up: 48 weeks to 72 weeks

Study population

RR 2.75 (2.20 to 3.43)

1210
(2 RCTs)

⊕⊕⊕⊕
Highb

NNTB 4, 95% CI 3 to 5

157 per 1000

432 per 1000
(346 to 539)

Primary: participant‐rated good/excellent control of symptoms

Folluw‐up: 48 weeks to 72 weeks

Study population

RR 2.75
(2.18 to 3.48)

1210
(2 RCTs)

⊕⊕⊕⊕
Highb

NNTB 4, 95% CI 3 to 5

143 per 1000

394 per 1000
(312 to 498)

Primary: adverse events ‐ headache

Folluw‐up: 48 weeks to 72 weeks

Study population

RR 3.43
(2.45 to 4.81)

1210
(2 RCTs)

⊕⊕⊕⊕
Highb

All adverse events not stated in Ruzicka 2008

NNTH 6, 95% CI 4 to 11

74 per 1000

251 per 1000
(179 to 352)

Secondary: investigator‐rated reduction in severity in TLSSc and mTLSSd

See comment

See comment

Not estimable

‐

See comment

Only incomplete data reported; therefore we were unable to extract these data

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; NNTB: number needed to treat for an additional beneficial outcome; NNTH: number needed to treat for an additional harmful outcome; RCT: randomised controlled trial; RR: risk ratio.

Ruzicka 2008; Fowler 2014

GRADE Working Group grades of evidence.
High certainty: further research is very unlikely to change our confidence in the estimate of effect.
Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low certainty: we are very uncertain about the estimate.

aThe assumed risk is the mean control group risk.

bRelatively high number of dropouts, although analysed via intention‐to‐treat analysis. Risk of bias was low, the two included studies were consistent, and the evidence is applicable to patients with (moderate to) severe hand eczema. Risk of publication bias was considered low, although the studies were sponsored by a pharmaceutical company.

cThe total lesion symptom score (TLSS) is the sum of seven items (erythema, oedema, vesicles, desquamation, hyperkeratosis, fissures, and pruritus/pain) scored on a 4‐point scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe). A high TLSS represents severe hand eczema.

dThe modified total lesion symptom score (mTLSS) is the sum of seven items (erythema, oedema, vesiculation, scaling, lichenification/hyperkeratosis, fissures, and pruritus/pain) scored on a 4‐point scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe). A high mTLSS represents severe hand eczema.

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Summary of findings 8. Oral retinoids: alitretinoin 10 mg versus placebo for hand eczema

Oral retinoids: alitretinoin 10 mg versus placebo for hand eczema

Patient or population: people with moderate to severe chronic hand eczema
Settings: secondary care with outpatients in an international multi‐centre setting
Intervention: oral retinoid alitretinoin 10 mg for 12 to 24 weeks

Comparison: oral placebo for 12 to 24 weeks

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No. of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Assumed riska

Corresponding risk

Risk with placebo

Risk with alitretinoin

Primary: investigator‐rated good/excellent control of symptoms

Follow‐up: up to 48 weeks

Study population

RR 1.58 (1.20 to 2.07)

781
(2 RCTs)

⊕⊕⊕⊕
Highb

NNTB 11, 95% CI 6.3 to 26.5

194 per 1000

307 per 1000
(233 to 402)

Primary: participant‐rated good/excellent control of symptoms

Follow‐up: up to 48 weeks

Study population

RR 1.73
(1.25 to 2.40)

765
(2 RCTs)

⊕⊕⊕⊕
Highb

NNTB 9, 95% CI 6 to 20

144 per 1000

249 per 1000
(180 to 345)

Primary: all adverse events

Follow‐up: up to 48 weeks

Study population

RR 1.01

(0.66 to 1.55)

158
(1 RCT)

⊕⊕⊕⊝
Moderatec

NNTH 260, 95% CI ‐14.47 to 15.24

346 per 1000

350 per 1000

(228 to 537)

Secondary: investigator‐rated reduction in severity of TLSSd

Follow‐up: up to 48 weeks

See comment

See comment

‐

158
(1 RCT)

⊕⊕⊕⊝
Moderatec

Median % change in score from baseline (95% CI)

Placebo group:

‐25% (95% CI ‐42 to ‐14)

Aitretinoin 10 mg:

–59 (95% CI –73 to –33)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; NNTB: number needed to treat for an additional beneficial outcome; NNTH: number needed to treat for an additional harmful outcome; RCT: randomised controlled trial; RR: risk ratio; TLSS: total lesion symptom score.

Ruzicka 2004; Ruzicka 2008

GRADE Working Group grades of evidence.
High certainty: further research is very unlikely to change our confidence in the estimate of effect.
Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low certainty: we are very uncertain about the estimate.

aThe assumed risk is the mean control group risk.

b Both studies were at low risk of bias and results were precise.

cDowngraded by one level to moderate‐certainty evidence: imprecision downgraded by one level: small sample size.

dThe total lesion symptom score (TLSS) is the sum of seven items (erythema, oedema, vesicles, desquamation, hyperkeratosis, fissures, and pruritus/pain) scored on a 4‐point scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe). A high TLSS represents severe hand eczema.

Background

Please note that unfamiliar terms may be listed in Appendix 1 ('Glossary of medical terms').

Future research would involve comparing different treatment groups. Focus on subgroups would provide reliable evidence for informed decisions about which treatment is effective in managing hand eczema.

The overall quality of evidence was very low. Many trials included in this review, particularly older ones, were of low quality with methodological weaknesses in design (small studies, short duration) or were biased (not blinded, sponsored by pharmaceuticals). Most included participants with chronic hand eczema in secondary care settings; some included only specific subtypes of hand eczema, thereby limiting direct application of study findings. Most analyses were based on single studies of small sample size and imprecise results.

Description of the condition

Definition and epidemiology

Hand eczema is an inflammation of the skin (dermatitis) that is confined to the hands. Hand eczema is a common condition with a point prevalence varying between 1% and 5% in the general population. When mild cases are included, one‐year prevalence can reach 10% (Meding 2004; Thyssen 2010; Yngveson 2000). Thyssen et al conducted a review of seven epidemiological studies on hand eczema and concluded the median incidence rate of hand eczema was 5.5 cases/1000 person‐years. For women, the incidence rate of hand eczema was 9.6 cases/1000 person‐years, and for men, 4.0 cases/1000 person‐years (Thyssen 2010). A possible explanation for this sex difference is greater exposure of women to wet work, such as cleaning, nursing, and hair dressing, for example (Mollerup 2014; Nilsson 1985). The incidence of notified (i.e. usually more severe) occupation‐related cases is estimated to be above 0.7 per 1000 people per year, with much higher incidences (up to 1 in 100) in high‐risk populations such as hairdressers (Diepgen 2003). Decreased prevalence has been observed in Swedish adults and was attributed to a decline in occupational exposure to irritants (Meding 2002).

Over the years, several authors have proposed a workable definition of hand eczema, whereby different subtypes have been recognised (Menné 2000). Hand eczema can be classified according to aetiological (causative) factors, clinical‐morphological typology, or a combination of both (Coenraads 2012; Diepgen 2009a). However, due to multi‐causality, it is difficult to assess the influence of each causative factor; therefore only one aetiological diagnosis might be insufficient. The Danish Contact Dermatitis Group developed a classification system based on morphology with clear definitions for each classification and one or more aetiological diagnoses (Menné 2011). This might facilitate the classification of hand eczema and was demonstrated to be a useful tool in general practice (Johansen 2011). However, there is an obvious need for international consensus regarding the classification of subgroups of hand eczema.

In the current literature, different names can be used for the same subgroups, or the same name can be used for different subgroups. An example of this is vesicular hand eczema (Veien 2009): this might be called pompholyx, dyshidrotic eczema, dyshidrosis, or vesicular eczema; no consensus has been reached regarding the definition. The original definition of 'pompholyx' states "an eruption of vesicles and bullae on the palms, which is accompanied by pain and severe itching". Fox 1873 hypothesised that pompholyx was caused by sweating of the palms and introduced the term 'dyshidrosis' (hydrosis from sweating); both terms were used for the same clinical vesicular type. Later, Kutzner 1986 demonstrated that sweat glands are not altered in vesicular hand eczema and discussed the histological features of eczema. However, despite this evidence, the term 'dyshidrosis' is still used in current literature.

Hand eczema may be accompanied by similar skin changes on the feet.

Causes

In many people, hand eczema has more than one cause and both predisposing and external factors play a part. Being atopic (a tendency to develop asthma, hay fever, or eczema) is a major predisposing factor responsible for hand eczema; one‐third to one‐half of people with hand eczema can be considered atopic (Coenraads 1998; Meding 1990; Svensson 1988). The role of genetic factors, especially the association between filaggrin (FLG) mutations and hand eczema, is still under investigation (Heede 2016; Kaae 2012; Molin 2015).

The most common external causes of hand eczema include contact with mild toxic agents or irritants (for instance, water and soaps). The resulting irritant contact dermatitis can be distinguished from allergic contact dermatitis, which is caused by skin contact with allergens. Allergic contact dermatitis is less common than irritant contact dermatitis, and it occurs only in persons who have developed a contact allergy to a specific substance such as rubber, nickel, or perfumes. Ingested allergens (e.g. nickel) may occasionally provoke hand eczema (Jensen 2006). Little evidence suggests that inhalation of house dust mites may increase the severity of vesicular hand eczema (Schuttelaar 2013). The relevance of psychosomatic factors remains speculative (Menné 2000). In many people with chronic hand eczema, a combination of the above‐mentioned factors plays a role. In addition, for several types of hand eczema, the cause is still unknown.

Impact

Itch is common among those with hand eczema. The itch caused by hand eczema can be intense, leading to sleep loss in the sufferer and in other family members. A vicious cycle of symptoms causing skin damage can develop, the so‐called itch/scratch/itch cycle. Cracks and blisters can be painful. Cracking, hyperkeratosis (callus‐like thickening), and inflexibility of the hands are also problematic and may limit mobility of the hands.

A visible skin disease can be a great burden and can lead to a social stigma. The hands are important organs of communication and expression; therefore any visible skin disease on the hands may result in major psychosocial problems (e.g. anxiety, low self‐esteem, social phobia).

Painful cracks and blisters, besides their negative effects on daily life outside work, can impede an individual's ability to carry out manual work, leading to significant disability and huge economic losses for both individuals and society. A systematic review estimated the mean annual total cost per hand eczema patient at between €1712 and €9792 (Politiek 2016). Hand eczema accounts for an estimated 90% of occupational skin disease. Patients have substantial use of sick leave due to their hand eczema. Studies in patients with chronic severe hand eczema have reported job loss up to 20% (Cvetkovski 2005). Quality of life assessments have shown an impact on daily life and on employment (Agner 2008; Moberg 2009). A comparison between the generic quality of life instrument Short Form Health Survey (SF‐36) and the skin‐related Dermatology Life Quality Index (DLQI) revealed slightly higher impact of hand eczema on women compared to men for specific sub‐items (Wallenhammar 2004). A comparison of physician‐rated versus participant‐rated assessments of severity showed a poor correlation, indicating that patients may evaluate several aspects of their hand eczema (including degree of erythema, vesicles, and fissures) differently from physicians (van Coevorden 2006).

Prognosis

Previous studies have suggested that hand eczema tends to run a chronic relapsing course, with the vast majority of people experiencing negative psychosocial consequences (Hald 2009; Meding 2005; Petersen 2014; Veien 2008).

Description of the intervention

Many diverse therapies are used to control the disease, such as:

  • skin protection measures, including gloves;

  • topical treatments (bland emollients, corticosteroid creams/ointments, calcineurin inhibitors, coal tar and derivatives, irradiation with ultraviolet (UV) light or X‐rays); and

  • systemic treatments (oral corticosteroids, oral retinoids, or other immunosuppressants such as cyclosporin).

The main groups of interventions covered by this review are topical corticosteroids, topical calcineurin inhibitors (immunomodulators), irradiation with UV light, and oral retinoids or systemic immunosuppressants.

Overall, after proper education and counselling, including the recommendation of emollients, application of topical corticosteroids remains the mainstream treatment for hand eczema (nationaleczema.org).

How the intervention might work

Theoretically, identifying and eliminating an allergic contact factor (e.g. nickel or rubber allergy) could result in cure of hand eczema, provided this is the sole cause. In clinical practice, however, such cases are rare, as hand eczema is often due to a combination of irritant and allergic contact exposure, as well as to endogenous factors.

This review deals with a great variety of interventions. Major types of interventions are topical corticosteroids, topical immunomodulators, irradiation with UV light, and oral retinoids.

Topical corticosteroids are the most frequently prescribed treatments for hand eczema (Soost 2012). They have overlapping mechanisms of action: like oral immunosuppressants (e.g. corticosteroids), they inhibit inflammation (anti‐inflammatory) and production of inflammatory substances (immunosuppressive) (Ahluwalia 1998; Sakuma 2001; Schleimer 1993).

Topical immunomodulators, such as tacrolimus and pimecrolimus, are non‐steroidal immunosuppressants that are more selective in their mode of action than corticosteroids. They inhibit the production of inflammatory substances in the body (such as synthesis and release of inflammatory cytokines from T‐lymphocytes, and release of inflammatory mediators from mast cells). Calcineurin is present during activation of T‐lymphocytes, and since tacrolimus and pimecrolimus block this step, they are called 'calcineurin inhibitors' (de Paulis 1992; Sakuma 2001).

Topical moisturisers or emollients can relieve dryness of the skin, can improve the skin barrier function, and can influence transepidermal water loss (depending on the composition of the emollient) (Lodén 2012b; Rawlings 2004). Moisturisers are available in various compositions such as oil‐in‐water, water‐in‐oil, lotions, gels, and emulsions, among others, and various adjuvants such as urea or salicylic acid can be added to reduce thickness and scaling of the skin.

Coal tar has been used to treat eczema since ancient times. It is claimed to increase epidermal differentiation and to up‐regulate various key barrier proteins such as filaggrin, thus improving the skin barrier function (McLean 2013; van den Bogaard 2013). Moreover coal tar suppresses the Th2 cytokine response (McLean 2013; van den Bogaard 2013).

Irradiation with UV light can be performed with different types of UVA and UVB, depending on the wavelength. UVA treatment overall is combined with a topical or oral agent (psoralen) to make the skin more sensitive to UVA. Examples of different types of phototherapy include broad‐spectrum UVB (280 to 315 nm), small‐spectrum UVB (311 to 313 nm, also known as TL‐01 or narrow‐band UVB), UVA‐1 (340 to 400 nm), and topical and oral psoralen combined with UVA (PUVA; 315 to 400 nm). UVA‐1 phototherapy can be used at high (HD; 130 J/cm²), medium (MD; 50 J/cm²), and low doses (LD; 10 J/cm²) (Hönigsmann 2003). The mechanism of photo(chemo)therapy is multi‐factorial. In general, UV light locally decreases the activity of the immune system and inhibits the quantity of inflammatory cells. It suppresses the antigen‐presenting function of the Langerhans cells and induction of apoptosis of T‐cells (Majoie 2009). In addition, photo(chemo)therapy results in an increase in the amount of stratum corneum; in other words, the skin gets thicker (Jekler 1990). Finally, UVB reduces the number of microbes on the skin, including Staphylococcus aureus (Faergemann 1987).

Oral retinoids are vitamin A derivatives. Retinoids are thought to interfere at different steps in the inflammatory process. They have immunomodulatory properties and interfere with the epidermal differentiation process in various ways (Blair 2016; Kislat 2014; Schmitt‐Hoffmann 2012). Both alitretinoin and acitretin are retinoids, although their mechanism of action is slightly different. Alitretinoin is thought to have anti‐inflammatory and immunomodulatory effects on the skin. Alitretinoin binds with high affinity to both retinoic acid receptor (RAR) and retinoid X receptor (RXR) and presents anti‐inflammatory and immunomodulatory activity, and acitretin binds only selectively to RAR, although both retinoids are thought to reduce inflammation (Blair 2016; Kislat 2014; Schmitt‐Hoffmann 2012).

Hand eczema is a chronic condition that might be accompanied by flares and might improve as a result of the natural course; therefore, we believe a minimum treatment duration of three months is required to document important data such as duration and frequency of disease relapse.

Why it is important to do this review

The high prevalence of hand eczema, along with its poor prognosis and associated disability with economic losses and impairment of quality of life, makes hand eczema an important disease to study from an individual and a societal perspective. This, coupled with the long list of diverse treatments of unknown effectiveness and several conflicting studies (Diepgen 2007; van Coevorden 2004b), suggests that a systematic review is needed. Even if methodological constraints do not permit sufficient clarification of existing conflicts to provide clear guidance in clinical practice, this review will be an important step in identifying research gaps and consequently providing directions for future research.

The plans for this review were published as a protocol "Interventions for hand eczema" (van Coevorden 2009). Differences between the review and the protocol are stated in the section Differences between protocol and review.

Objectives

To assess the effects of topical and systemic interventions for hand eczema in adults and children.

Methods

Criteria for considering studies for this review

Types of studies

We included randomised controlled trials (RCTs) of interventions for hand eczema regardless of hand eczema type and other affected localisations.

Types of participants

People (adults and children, occupational and non‐occupational) with the diagnosis of hand eczema, regardless of the underlying assumed cause, were eligible. We also included participants with other parts of the body affected in addition to the hand. The terms 'eczema' and 'dermatitis' were acceptable whenever they referred to the hands. Other terms such as 'pompholyx', 'dyshidrosis', and 'pulpitis' were also deemed acceptable. We included participants with different types of hand eczema, for example, chronic hand eczema, hyperkeratotic palmar (also know as tylotic) hand eczema, and vesicular eczema (also known as dyshidrotic hand eczema or pompholyx).

We included in this review studies that included participants with other diagnoses besides hand eczema only when we were able to obtain separate data for hand eczema participants.

Types of interventions

We included only studies comparing the intervention versus no treatment, placebo, vehicle, or other active treatments. We considered all types of interventions, except interventions to prevent hand eczema (primary prevention). We excluded studies that focused on prevention of hand eczema and studies that investigated integrated care programmes or educational programmes (non‐pharmacological interventions).

We considered studies comparing different interventions, for example, topical corticosteroids versus topical calcineurin inhibitors or oral cyclosporin versus topical corticosteroids, as most clinically relevant. For 'Summary of findings' tables, we included the following comparisons.

  • Mometasone furoate cream on different treatment schedules.

  • Local narrow‐band UVB versus local PUVA.

  • Tacrolimus 0.1% ointment versus vehicle.

  • Tacrolimus 0.1% ointment versus mometasone furoate ointment.

  • Oral cyclosporin versus topical betamethasone dipropionate.

  • Oral alitretinoin at 10 mg and 30 mg a day versus placebo.

When a study reported on treatment during a remission‐ or clearance‐induction phase for participants before they were randomised to a follow‐up or maintenance phase, we considered only the latter (randomised) phase for this review.

Types of outcome measures

We extracted the following primary and secondary outcomes from the included studies.

Primary outcomes

  • Percentage of participants with self‐rated good/excellent control of symptoms.

  • Percentage of participants with investigator‐rated good/excellent control of symptoms.

  • Adverse events: adverse effects (long‐ and short‐term) of the intervention. Long‐term adverse events are defined as adverse events occurring after completion of the treatment phase; short‐term adverse events occur during the treatment phase.

Secondary outcomes

  • Reduction in severity (participant‐rated).

  • Reduction in severity (investigator‐rated).

  • Time until relapse, defined as the number of days/weeks until the participant reported worsening of symptoms after initial response.

  • Dose reduction: reduction in treatment dose per time unit or cumulative prescribed treatment dose. For example, a decrease in daily topical medication, or a decrease in weekly photo irradiation.

We did not exclude studies from the review that did not include these outcomes.

We believe that three months is the minimum study duration required to document important data such as duration and frequency of disease relapse.

Search methods for identification of studies

We aimed to identify all relevant RCTs regardless of language or publication status (published, unpublished, in press, or in progress).

Electronic searches

The Cochrane Skin Information Specialist searched the following databases up to 19 April 2018, using strategies based on the draft strategy for MEDLINE presented in our published protocol (van Coevorden 2009).

  • Cochrane Skin Group Specialised Register (search strategy in Appendix 2).

  • Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 3), in the Cochrane Library (search strategy in Appendix 3).

  • MEDLINE via Ovid (from 1946) (search strategy in Appendix 4).

  • Embase via Ovid (from 1974) (search strategy in Appendix 5).

  • Allied and Complementary Medicine (AMED) via Ovid (from 1985) (search strategy in Appendix 6).

  • Latin American and Caribbean Health Science Information database (LILACS) (from 1982) (search strategy in Appendix 7).

  • Global Resource of Eczema Trials. Centre of Evidence Based Dermatology (accessed at http://www.greatdatabase.org.uk on 19 April 2018), using the following terms in the title of the records: hand* or finger* or palm or palms.

Trials registries

We (WAC and PJC) searched the following trials registries up to 21 April 2018, using the following search terms: hand and (eczema or dermatitis).

Searching other resources

Correspondence with authors

If we needed clarification regarding studies, we contacted study authors using the correspondence options stated in their papers (for studies published since 1999). If email addresses did not work, we tried to find recent publications by the same corresponding author with more recent contact data, or we searched Facebook, LinkedIn, and the Internet to connect with these authors. In addition, we tried to contact all authors of studies that included other dermatoses among hand eczema, to obtain separate data for hand eczema participants. We listed in the 'notes' section of the Characteristics of included studies tables whether we contacted study authors, and if they responded. We have not included in the review complete correspondence with all studies, but we have shown the relevant citations in the Characteristics of included studies tables. The full correspondence with study authors is available upon request.

References from published studies

We checked the bibliographies of included studies for further references to relevant trials.

Adverse events

We did not perform a separate search for adverse events. However, we did examine data on adverse events from the included studies.

Unpublished literature

We contacted authors and pharmaceutical companies in relation to ongoing trials that were recently completed according to the trial registries mentioned under Electronic searches. When results were published on the trial register websites, we included these in the results, and we tried to contact study authors for additional information if necessary.

Conference proceedings

We searched the conference proceedings of annual conferences of the European Academy of Dermatology and Venereology (EADV) from 2000 to 2011 for further relevant RCTs. Some were available from the JEADV; however, some others had to be obtained from the organisation itself, from which we requested the material on CD‐ROM.

Handsearching

We handsearched using the terms 'eczema', 'dermatitis', 'hand(s)', 'palmoplantar', and 'inflammatory' in 16 English, two German, one Italian, one French, and one Dutch dermatology journal (all journals 1977 through 2003). We searched the journals listed in Appendix 8.

Data collection and analysis

Selection of studies

Three review authors (PJC, JLB, and WAC) independently checked titles and abstracts identified from the searches. Three review authors (PJC, TD, and ÅS) conducted an additional handsearch. If it was clear that the study did not refer to a randomised controlled trial on hand eczema, we excluded it. We retrieved all potential trials as full‐text articles for further independent examination by two review authors (TD and ÅS). These two review authors decided which trials conformed to the inclusion criteria and resolved discrepancies by discussion in consensus meetings. We obtained missing data from the trial authors when possible. Whenever we found duplicate publications of the same trial, we used the paper with the most relevant data (usually we had a conference abstract and a full article) as the primary reference and listed the other publication in the additional references following the reference section.

Data extraction and management

Three review authors (PJC, TD, and ÅS) extracted data independently, using a standardised data extraction form. These review authors and future reviewers piloted the data extraction form during a meeting of the European Dermato‐Epidemiology Network, in July 2000. This form was based on a preceding systematic review of psoriasis interventions and was later updated according to Cochrane recommendations. We resolved discrepancies and uncertainties in a series of consensus meetings, which were led by one review author (PJC).

Two other review authors (JLB and WAC) entered into Review Manager 5.3 and checked the outcome data extracted from the included studies (RevMan).

Assessment of risk of bias in included studies

Two review authors (ÅS and TD) independently assessed the risk of bias in included studies following the domain‐based evaluation described in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions and, using the Cochrane risk of bias tool, assessed all included studies from the following aspects for potential risk of bias (Higgins 2011b).

  • Random sequence generation, which refers to selection bias due to inadequate generation of a randomised sequence.

  • Allocation concealment, which also refers to selection bias but due to inadequate concealment of the allocation sequence before assignment.

  • Blinding of participants and personnel, which refers to performance bias due to knowledge of intervention allocation by participants or personnel.

  • Blinding of outcome assessment, which refers to detection bias due to knowledge of intervention allocation by the outcome assessor.

  • Incomplete outcome data, which refers to the quantity, nature, or manner in which incomplete outcome data were handled.

  • Selective reporting, which refers to reporting bias due to selective reporting.

  • Other source of bias, which refers to any other types of bias not covered above, including inclusion of baseline comparisons, certainty of the diagnosis, and premature ending.

Whenever we encountered disagreement regarding assessment of risk of bias, we resolved this in a consensus meeting with a third review author (PJC or HW). Two review authors (JLB and WAC) assessed completed 'Risk of bias' forms and entered the data into RevMan.

Measures of treatment effect

We employed risk ratios (RR) with 95% confidence intervals (CIs) to measure the effect of a treatment for dichotomous outcomes. We expressed results as number needed to treat for an additional beneficial outcome (NNTB) when appropriate, along with different rates of baseline risk. We expressed results from analyses of continuous data as mean differences (MDs), along with CIs and respective P values. Whenever a small study (fewer than 30 participants) included zero events in one arm, we used Fisher's exact test to calculate the P value, and we provided numerical data for the numerator/denominator for each treatment (Grainge 2013). We calculated Fisher's exact test using GraphPad software (GraphPad).

We interpreted numerical data in charts and tables when possible. We tried to extract numerical data from graphical presentations by using a ruler, or we contacted study authors for recent trials if the data were unclear. For data that had been extracted from a graph, we added remarks.

For studies that exclusively presented median values for a particular outcome, we substituted the median for the mean, provided that data were not too skewed. When standard deviations were not available from a paper, we tried to calculate these from other available data. When confidence intervals were provided, we used the formula given in Chapter 7.7.3.2 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a).

For multi‐arm studies, we analysed each arm in comparison with placebo when possible.

Unit of analysis issues

Cluster randomised trials

We checked cluster randomised trials (groups of individuals instead of individuals randomised to intervention or control) for unit of analysis errors based on advice provided in Section 16.3.4 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011d).

Cross‐over studies

In cross‐over studies (with each participant allocated to a sequence of interventions, instead of to only one intervention), unit of analysis issues can arise when participants have been randomised to multiple treatments over multiple periods, or when there has been an inadequate washout period. We dealt with cross‐over studies by analysing only the first treatment period as a simple parallel‐group study.

Within‐participant studies (self‐controlled, left‐right designs)

Given that analysis of paired data was not possible with RevMan, we summarised the data from within‐participant studies in the text. The unit of analysis in within‐participant studies was one hand per participant, whereas in parallel‐group studies, the unit of analysis was per participant. Relevant data were presented in the analysis as "other data", in table format.

Studies with multiple arms

For studies including multiple arms (more than two) in the analyses, we plotted the different comparisons in different forest plots when possible.

Dealing with missing data

For trials published from 1999 onwards and with uncertainty, we tried to contact trial authors if we felt that this may yield essential additional information. In these cases, we contacted the first author or, when stated, the corresponding author of the article. For the current review, we did not make any assumption or imputation to missing data. We extracted all outcome data as they were reported in the original studies. We stated when authors were contacted and whether additional information was provided under Characteristics of included studies.

Assessment of heterogeneity

We had planned to explore reasons for heterogeneity amongst studies and, if necessary, to carry out sensitivity analyses to examine the effects of excluding study subgroups (e.g. children versus adults, atopic versus allergic contact hand eczema) or studies with high risk of bias.

Clinical heterogeneity (or clinical diversity) is considered as variability among participants, interventions, and outcomes. In future updates of this review, we plan to assess clinical heterogeneity by examining characteristics of the studies and similarity between types of participants, interventions, and outcomes. If studies were sufficiently similar, we achieved statistical pooling by using a weighted treatment effect.

We used random‐effects model meta‐analysis because of anticipated differences across studies in, amongst other things, the participant base included. Statistical heterogeneity was investigated with the I² test. If the I² statistic had been greater than 50%, reasons for heterogeneity in studies would have been explored.

Assessment of reporting biases

We planned on including statistical methods for detecting publication bias (e.g. Begg's funnel plots). However, funnel plots are recommended by the Cochrane Handbook for Systematic Reviews of Interventions, Section 10.4 (Higgins 2011c), when at least a substantial number of studies (10 or more) are included in the meta‐analysis. This was not feasible due to the heterogeneity of included studies. For reporting bias, we studied the study authors and institutions involved (pharmaceutical companies or not), funding, sponsorship of commercially available supplements, and, finally, conflicts of interest.

Data synthesis

When data permitted, we had planned to conduct statistical pooling, using a random‐effects model whenever studies appeared sufficiently similar.

Subgroup analysis and investigation of heterogeneity

We conducted no pre‐planned subgroup analyses in the current review, but in future updates, we will carry out analyses, if data permit, to examine the effects of including specific study subgroups (e.g. children versus adults, recurrent vesicular versus hyperkeratotic hand eczema).

Sensitivity analysis

We conducted no pre‐planned sensitivity analyses in this review, but for future updates, we will consider performing sensitivity analyses for pooled analysis involving only studies at low risk of bias.

'Summary of findings' tables

We included in the 'Summary of findings' tables all primary outcomes and the secondary outcome 'investigator‐rated reduction in severity' for the clinically most relevant studies (Ryan 2016). We assessed clinical relevance based on the clinical experiences of study authors. We tried to include studies from every group of interventions (topical corticosteroids, topical calcineurin inhibitors, UV therapy, and systemic treatments), and to keep the total number of included studies to a minimum. We therefore aimed to include studies that compared different groups of comparisons or studies that answered the questions that authors ask themselves on a regular basis in everyday practice. The 'Summary of findings' tables are based on the GRADE principles (GRADEPro, version 3.6.1). The GRADE approach is a sequential process that evaluates the quality of a body of evidence by considering the following domains.

  • Study limitations, which refers to risk of bias in either study design or conduct that could lead to biased estimation of treatment effect.

  • Inconsistency of results, which refers to unexplained heterogeneity of results.

  • Indirectness of evidence, which refers to directness of comparisons of target populations, interventions, comparators, and outcomes of the included studies compared to those of the planned PICO of the systematic review.

  • Imprecision, because results are generally imprecise when the study includes few participants, few events, or a wide confidence interval of the effect estimate.

  • Publication bias.

Randomised controlled trials (RCTs) began as high‐quality/certainty evidence, but If concerns were identified in the above domains, certainty was rated down by one or two levels depending on the severity of the concern. The GRADE approach completes assessments of the body of evidence by grading it in the high, moderate, low, or very low certainty category.

A duration of longer than three months was preferred for evaluating a clinically relevant effect. We considered interventions comparing different groups of interventions and studies providing different treatment regimens with regards to dosages or frequency as clinically most relevant. Therefore we included the following comparisons in the 'Summary of findings' tables.

Results

Description of studies

We included 60 RCTs on different interventions for hand eczema.

Results of the search

Our searches of the databases yielded 588 records (Electronic searches). Our searches of the trials registries identified six further studies. We therefore had a total of 594 records.

No duplicate records were identified, hence we screened 594 references. We excluded 493 records based on titles and abstracts. We obtained the full text of the remaining 101 records. We excluded 11 studies (Characteristics of excluded studies). We added 20 records to Characteristics of studies awaiting classification because we were unable to extract separate data on hand eczema patients. We identified eight ongoing studies (Characteristics of ongoing studies).

We included 60 studies reported in 62 references. For a further description of our screening process, see the study flow diagram (Figure 1).

Figure 1
Study flow diagram.

Study flow diagram.

Included studies

Details of the 60 included studies with a total of 5469 participants are summarised in the Characteristics of included studies table. We included studies published from May 1967 to April 2018, as well as unpublished data from studies registered in trial registries up to April 2018.

Design

Of the 60 RCTs, 18 were within‐participant studies (i.e. having a left‐right design, comparing one hand with the other) (Adams 2007; Baskan 2005; Cartwright 1987; Chu 2009; Faghihi 2008; Fairris 1984; Fairris 1985; Fredriksson 1975; Grattan 1991; Kemper 1998; King 1984; Lindelöf 1987; Möller 1983; Odia 1996; Schnopp 2002; Sezer 2007; Sheehan‐Dare 1989; Uggeldahl 1986). In total, 41 studies used a parallel‐group design. Fowler 2005 used a parallel‐group design but within each group chose a within‐participant design as well. Two of these parallel‐group studies used a cross‐over design (Burrows 1986; Granlund 1996), but they were parallel before cross‐over.

Participants

The original protocol stipulated diagnosis by a physician. Although only one of the identified studies stated this explicitly, all studies were based on participants being outpatients at hospitals. Therefore, we assumed that the diagnosis was established by a physician for all participants. Some studies included a specific subgroup of hand eczema, while others excluded these subgroups, for example, vesicular (or dyshidrotic) hand eczema was included by 11 studies (Adams 2007; Grattan 1991; Odia 1996; Pigatto 1990; Polderman 2003; Said 2010; Schnopp 2002; Sezer 2007; Sharma 2006; Sheehan‐Dare 1989; Tzaneva 2009), and vesicular hand eczema was excluded by three studies (Bleeker 1989; Chu 2009; Hordinsky 2010). The same was true for atopic dermatitis and atopic dermatitis on the hands: six studies targeted atopic eczema specifically (Bauer 2012; Fowler 2005; Lauriola 2011; NCT01231854; Veien 1995; Yousefi 2012), while six other studies excluded participants with characteristics of atopic eczema (Bleeker 1989; Burrows 1986; Chu 2009; Hordinsky 2010; Katsarou 2012; Lodén 2012a).

All studies were performed in a secondary setting and included participants who had hand eczema for at least several weeks to months; therefore the review did not include acute hand eczema.

The studies included participants with different grades of severity, and not all studies included a severity grade as an inclusion criterion. Moderate to severe hand eczema was included in the following studies: Baskan 2005; Kircik 2013; Krejci‐Manwaring 2008; Pacor 2006; Ruzicka 2004; Schnopp 2002; Tzaneva 2009; van Coevorden 2004a. Chu 2009 included only mild hand eczema. Mild to moderate hand eczema was included in Belsito 2004,Hordinsky 2010,Kucharekova 2003,Lauriola 2011, and Odia 1996. Cherill 2000,Fowler 2005,Hanifin 2004, and Uggeldahl 1986 included moderate hand eczema. Fowler 2014,NCT01231854, and Ruzicka 2008 included only severe hand eczema, and Bauer 2012 included moderate to very severe hand eczema. In two studies, the included severity was not completely clear (Veien 1995; Veien 1999).

Another inclusion criterion was poor response or resistance to conventional therapies such as topical corticosteroids (Adams 2007;Brass 2015; Cartwright 1987; Fairris 1984; Fairris 1985;Fowler 2014; Granlund 1996; King 1984; Lindelöf 1987; NCT01231854; Odia 1996; Pacor 2006; Ruzicka 2004; Ruzicka 2008; Sezer 2007; Sheehan‐Dare 1989; Sjövall 1987; Tzaneva 2009). Only one study included a minimally affected area of hand eczema (Bayerl 1999). Disabling hand eczema was an inclusion criterion in two studies (Granlund 1996; Grattan 1991).

Overall, children were not included as a study population. One study included participants between 1.5 and 70 years of age (Uggeldahl 1986), another study included participants at least 10 years of age (Boroujeni 2017), four studies included participants 12 years of age and older (Faghihi 2008; Jowkar 2011; Jowkar 2014; Kircik 2013), and one study had a minimum inclusion age of 16 years (Grattan 1991). The remaining studies included only adults. A few studies excluded older participants. Two studies used an upper age limit of 60 years (Jowkar 2011; Yousefi 2012), three studies 65 years (Agarwal 2013; Bleeker 1989; Fowler 2005), three studies 70 years (Granlund 1996; Ruzicka 2004; Uggeldahl 1986), and three studies 75 years (Fowler 2014; NCT01231854; Ruzicka 2008).

One study included female participants exclusively (Kaaber 1983). The remaining studies included both female and male participants. Pregnant or lactating women, or both, were excluded from about half of the studies (32 studies).

Overall, participants were in general good health, and studies often excluded systemic diseases such as diabetes and renal or hepatic disease.

Sample size calculation

A total of 5469 participants were enrolled. Most studies were relatively small (12 to 158 participants), and sample size calculations often were not stated. A large proportion of the 5469 participants were included in five trials (Belsito 2004; Fowler 2014; Hordinsky 2010; Ruzicka 2004; Ruzicka 2008). Twelve studies included fewer than 25 participants (Burrows 1986; Fairris 1984; Grattan 1991; Kemper 1998; King 1984; Lindelöf 1987; Odia 1996; Pigatto 1990; Schnopp 2002; Sezer 2007; Sharma 2006; Sjövall 1987). In 27 studies, between 25 and 50 participants were included (Baskan 2005; Bauer 2012; Bayerl 1999; Cartwright 1987; Cherill 2000; Faghihi 2008; Fairris 1985; Fredriksson 1975; Granlund 1996; Gupta 1993; Hanifin 2004; Jowkar 2011; Kaaber 1983; Katsarou 2012; Krejci‐Manwaring 2008; Kucharekova 2003; Lauriola 2011; Lodén 2012a; Odia 1996; Pacor 2006; Polderman 2003; Said 2010; Sheehan‐Dare 1989; Thestrup‐Pedersen 2001; Tzaneva 2009; Veien 1995; Whitaker 1996). Between 50 and 100 participants were included in eight studies (Bleeker 1989; Boroujeni 2017; Brass 2015; Fowler 2005; Jowkar 2014; Möller 1983; Uggeldahl 1986; Yousefi 2012). Between 100 and 500 participants were included in eight studies (Agarwal 2013; Belsito 2004; Bissonnette 2010; Hill 1998; Kircik 2013; Ruzicka 2004; van Coevorden 2004a; Veien 1999). Three studies included more than 500 participants (Fowler 2014; Hordinsky 2010; Ruzicka 2008).

NCT01231854 aimed to include 78 participants based on a sample size calculation; however the study was ended prematurely and included only 15 participants.

Setting

None of the studies were conducted in a primary care setting. As far as we know, all studies were conducted in a secondary care setting and included outpatients from hospitals. About half of the studies were conducted as multi‐centre studies, usually within the same country. Six studies were international multi‐centre studies (Belsito 2004; Bissonnette 2010; Cherill 2000; Hordinsky 2010; Ruzicka 2004; Ruzicka 2008).

Although most studies did not declare the country in which the study was conducted, we assumed that they were conducted in the hospitals of the investigators. Based on this assumption, most studies were conducted in North America and Europe. A substantial number of studies were conducted in the United Kingdom (Brass 2015; Burrows 1986; Cartwright 1987; Fairris 1984; Fairris 1985; Grattan 1991; Hill 1998; King 1984; Sheehan‐Dare 1989), Sweden (Bleeker 1989; Fredriksson 1975; Lindelöf 1987; Möller 1983; Sjövall 1987), Germany (Adams 2007; Bauer 2012; Bayerl 1999; Bissonnette 2010; NCT01231854; Odia 1996; Schnopp 2002), Denmark (Kaaber 1983; Thestrup‐Pedersen 2001; Veien 1995; Veien 1999), and the Netherlands (Kemper 1998; Kucharekova 2003; Polderman 2003; van Coevorden 2004a).

A few studies were conducted in other parts of the world, including Iran (Boroujeni 2017; Faghihi 2008; Jowkar 2011; Jowkar 2014; Yousefi 2012), India (Agarwal 2013; Sharma 2006), Turkey (Baskan 2005; Sezer 2007), Singapore (Said 2010), South Africa (Whitaker 1996), and Taiwan (Chu 2009).

Treatment duration

Overall the studies were of relatively short duration. One study had a duration of only one week (Gupta 1993). The treatment episode was less than one month in 22 studies (Belsito 2004; Bleeker 1989; Boroujeni 2017; Chu 2009; Faghihi 2008; Fowler 2005; Fredriksson 1975; Hill 1998; Jowkar 2011; Jowkar 2014; Kemper 1998; King 1984; Kircik 2013; Lauriola 2011; Lodén 2012a; Odia 1996; Pacor 2006; Polderman 2003; Schnopp 2002; Sharma 2006; Uggeldahl 1986; Yousefi 2012), and it was less than two months (eight weeks) in 12 studies (Adams 2007; Baskan 2005; Bauer 2012; Bayerl 1999; Cherill 2000; Grattan 1991; Kucharekova 2003; Lindelöf 1987; Said 2010; Sheehan‐Dare 1989; Sjövall 1987; Thestrup‐Pedersen 2001); nine studies had a treatment duration between two and four months (Brass 2015; Cartwright 1987; Fairris 1984; Fairris 1985; Katsarou 2012; Krejci‐Manwaring 2008; Pigatto 1990; Sezer 2007; van Coevorden 2004a).

Only 11 studies had a duration of active treatment longer than four months (Agarwal 2013; Bissonnette 2010; Fowler 2014; Hanifin 2004; NCT01231854; Ruzicka 2004; Ruzicka 2008; Tzaneva 2009; Veien 1995; Veien 1999; Whitaker 1996).

Studies with a cross‐over design had an active treatment phase of six weeks for both drugs (Burrows 1986; Granlund 1996), and Hordinsky 2010 had an active treatment phase of six weeks, followed by an open‐label phase.

The total duration of active treatment was unclear in two studies (Kaaber 1983; Möller 1983).

Follow‐up

Most studies did not include a follow‐up period. Only 24 studies included a follow‐up period (Baskan 2005; Cartwright 1987; Fairris 1984; Fairris 1985; Fowler 2014; Granlund 1996; Grattan 1991; Jowkar 2011; Krejci‐Manwaring 2008; Lindelöf 1987; NCT01231854; Pacor 2006; Polderman 2003; Ruzicka 2004; Ruzicka 2008; Said 2010; Schnopp 2002; Sezer 2007; Sharma 2006; Sheehan‐Dare 1989; Sjövall 1987; Tzaneva 2009; van Coevorden 2004a; Whitaker 1996). This period varied from a week to several months and involved scheduled visits or just a single follow‐up questionnaire. Veien 1999 clearly states that the treatment episode was 30 weeks, although data in the survival analyses suggest follow‐up to 250 days.

Two studies were ended prematurely (Burrows 1986; NCT01231854).

Interventions and comparisons

In most studies, an active intervention was compared to no treatment, variants of the same medication, or placebo (or vehicle). Very few studies compared two different classes of interventions: one study compared coal tar paste with a corticosteroid (Kemper 1998), one study phototherapy (PUVA) with X‐rays (Sheehan‐Dare 1989), one study phototherapy (UVA‐1) with a topical corticosteroid (Said 2010), two studies a calcineurin inhibitor with a corticosteroid (Katsarou 2012; Schnopp 2002), one study cyclosporin with a topical corticosteroid (Granlund 1996), and one study cromoglycate with a diet (Pigatto 1990). One study compared oral cyclosporin to oral alitretinoin (NCT01231854). We organised the remaining trials into the categories described below and provide details of the various dose regimens. Full details of interventions and comparisons for each included study are given in the Characteristics of included studies.

I. Skin protection measures, including gloves

These were not included in this review.

II. Topical treatments

A. Bland emollients

One study (Table 1) compared effects of two different emollients ‐ an emollient with ceramides (Locobase Repair) in 17 participants versus a regular petrolatum‐based emollient (Vaseline‐lanette) in 15 participants ‐ as adjuvants in the treatment of hand eczema over two months (Kucharekova 2003).

Open in table viewer
Table 1. Overview of studies on bland emollients: investigator‐rated good/excellent control

Study

Comparison

Investigator‐rated good/excellent control in RR (95% CI)

Comment

Kucharekova 2003

Ceramide‐containing emollient versus regular petrolatum‐based emollient

No data regarding the primary outcome investigator‐rated good/excellent control

‐

Chu 2009

E‐DO lotion versus vehicle lotion

E‐DO: 37 responders, 12 of whom responded to E‐DO only (19%), and 25 to both (39.7%)

Vehicle: 36 responders, 11 of whom responded to vehicle only (17.5%), and 25 to both (39.7%)

Investigator‐rated RR 1.06 (95% CI 0.54 to 2.10)

Within‐patient study

E‐DO is a trade/product name.

One within‐participant study compared an emollient with E‐DO lotion once daily to vehicle lotion. E‐DO claims to be a potential agent for revitalising skin cells to regain their moisture retention capacity and might improve wound healing and inhibition of Staphylococcus aureus and Propionibacterium acnes, according to the study authors (Chu 2009).

B. Corticosteroid creams or ointments

Nine studies evaluated topical corticosteroids as the main intervention (Bleeker 1989; Faghihi 2008; Fowler 2005; Gupta 1993; Kircik 2013; Lodén 2012a; Möller 1983; Uggeldahl 1986; Veien 1999).

Bleeker 1989 compared two topical corticosteroids to determine whether the less potent fluprednidene (Cortoderm) cream was as effective as the more potent betamethasone‐17‐valerate (Betnovate) cream. Each product was applied once daily, in the evenings, for a study period of three weeks. In both study groups, a specific emollient was used if required.

In a within‐participant study (Fowler 2005), the effectiveness of hydrocortisone butyrate (HB) 0.1% cream was compared with three other medium‐potency corticosteroid creams (fluticasone propionate 0.05% cream (FP), prednicarbate emollient 0.1% cream (PC), and mometasone furoate 0.1% cream (MF)) for treatment of chronic atopic and hand dermatitis. Participants were randomised to one of three treatment groups: HB versus FP, HB versus PC, or HB versus MF. Subsequently, participants applied twice‐daily HB to one hand, and FP, PC, or MF to the other hand, for a duration of two weeks.

A double‐blind within‐participant study investigated whether the addition of zinc sulphate to clobetasol cream is effective in the treatment of chronic hand eczema (Faghihi 2008). Forty‐seven participants were randomised and subsequently were treated twice daily with clobetasol + zinc sulphate cream on one hand and clobetasol 'only' cream on the other hand for two weeks.

In Gupta 1993, one group received betamethasone dipropionate polyacrylic film‐forming lotion (Occlucort) twice a day for seven days. The other group received a traditional betamethasone dipropionate (Diprosone) lotion, slightly thickened to resemble the consistency of the other product.

In Kircik 2013, participants received clobetasol propionate 0.05% foam or vehicle foam twice daily for a period of 15 days.

In a double‐blind randomised clinical trial (Lodén 2012a), twice‐daily application of betamethasone‐valerate 0.1% cream (BV group) was compared to once‐daily application of betamethasone‐valerate 0.1% cream in combination with once‐daily application of a moisturiser cream containing 5% urea (BV + M group). The study duration was two weeks. Both groups were allowed to use urea 5% cream for additional hand treatment.

A multi‐centre study was designed to investigate whether twice weekly application of a steroid was effective in keeping hand eczema, which had been brought into remission, under control (Möller 1983). To induce remission, 61 participants with symmetrical hand eczema of at least six months duration were treated with clobetasol propionate (Dermovate) cream twice weekly. Then, the 55 (out of 61) participants who were healed were included in a maintenance study and were followed for a mean period of 138 days (range 55 to 193 days); this occurred in the form of an RCT that compared one hand (receiving clobetasol (Dermovate) cream) with the other hand (receiving fluprednidene (Cortoderm) cream). When relapse occurred during the maintenance phase, the cream allocated to that hand could be applied more frequently; if this failed, the cream for the other (best) hand could be used temporarily. Participants were allowed to use an emollient (Essex cream) as needed.

Two strengths of the same topical corticosteroid were compared in a within‐participant design (Uggeldahl 1986). Forty‐six participants were treated twice daily with desonide (Tridesilon) cream 0.1% on one hand and desonide (Apolar) cream 0.05% on the other for two weeks. Participants had not been treated for eczema for at least one week before the study began.

The aim of one study was to compare mometasone (Elocon) ointment ("fatty cream") applied three times per week versus two times per week (Veien 1999). Initially, all participants were treated for three weeks with daily application of mometasone furoate to bring their dermatitis under control. This RCT investigated 106 participants whose dermatitis was brought under control. They were randomised to three parallel study groups for up to 36 weeks: treatment with mometasone furoate ointment once daily three times a week, treatment with mometasone furoate ointment once daily two times a week, and treatment with only emollients. In this study, in case of obvious bacterial infection, a course of oral antibiotics or potassium permanganate soaks, or both, was permitted. All participants were given an emollient to be used freely. Clinical evaluations were carried out after 3, 6, 12, 18, 24, and 30 weeks of maintenance treatment.

For an overview of the outcome 'Investigator‐rated good/excellent control' in these studies, see the additional tables section (Table 2).

Open in table viewer
Table 2. Overview of studies on topical corticosteroids: investigator‐rated good/excellent control

Study

Comparison of topical corticosteroids

Investigator‐rated good/excellent control in RR (95% CI)

Comment

Möller 1983

Intermittent clobetasol versus fluprednidene

Clobetasol better since 32/46 versus 14/46 hands remained in remission; investigator‐rated

Within‐patient study

Uggeldahl 1986

Desonide 0.1% versus desonide 0.05%

No data regarding the primary outcome investigator‐rated good/excellent control

Within‐patient study

Bleeker 1989

Fluprednidene versus betamethasone

RR 0.59 (95% CI 0.28 to 1.23); investigator‐rated

‐

Gupta 1993

Betamethasone film versus betamethasone lotion

RR 10.24 (95% CI 0.59 to 176.56); investigator‐rated

‐

Veien 1999

Mometasone 3 times/week versus mometasone 2 times/week

RR 1.23 (95% CI 0.94 to 1.61); investigator‐rated

‐

Fowler 2005

Hydrocortisone butyrate versus fluticasone propionate twice daily
Hydrocortisone butyrate versus prednicarbate emollient twice daily

Hydrocortisone butyrate 0.1% cream versus mometasone furoate twice daily

No data regarding the primary outcome investigator‐rated good/excellent control

Three parallel treatment groups Each group separately within‐patient

Faghihi 2008

0.05% clobetasol cream versus 0.05% clobetasol + zinc sulphate cream

Clobetasol + zinc sulphate better in terms of respectively scaling (25/47 versus 3/47), redness (41/47 versus 1/41), and lichenification (24/47 versus 7/47); investigator‐rated

Within‐patient study

Lodén 2012a

Betamethasone‐valerate 0.1% cream twice daily versus betamethasone‐valerate 0.1% cream once daily + urea 5% cream once daily

RR 0.75 (0.55 to 1.03); investigator‐rated

‐

Kircik 2013

Clobetasol propionate 0.05% foam twice daily versus vehicle foam twice daily

RR 1.43 (0.86 to 2.40); investigator‐rated

‐

CI: confidence interval.

RR: risk ratio.

C. Coal tar and derivatives

Kemper 1998 investigated the efficacy of coal tar paste (pix lithanthracis) compared to zinc oxide paste and betamethasone‐valerate. Nineteen participants with symmetrical hand eczema were included and were treated with coal tar paste on one hand and betamethasone‐valerate ointment 0.1% or zinc oxide paste on the other hand. Participants were instructed to wear gloves on both hands for protection and bandage. Clinical evaluation of the hands was carried out once a week, and at that same visit, the corresponding treatment was applied, again to the hands. Treatment duration was four weeks.

For an overview of the outcome 'Investigator‐rated good/excellent control' in this study, see the additional tables section (Table 3).

Open in table viewer
Table 3. Overview of studies on coal tar and derivatives: investigator‐rated good/excellent control

Study

Comparison

Investigator‐rated good/excellent control in RR (95% CI)

Comment

Kemper 1998

Coal tar paste versus betamethasone‐valerate or zinc oxide once a week

No data regarding the primary outcome investigator‐rated good/excellent control

Within‐patient study

D. Irradiation with UV light

Variations in UV phototherapy (UVA, UVB, PUVA) were investigated in 10 studies (Adams 2007; Bayerl 1999; Brass 2015; Grattan 1991; Polderman 2003; Said 2010; Sezer 2007; Sjövall 1987; Tzaneva 2009; van Coevorden 2004a).

Said 2010 compared the efficacy of topical betamethasone‐valerate 0,1% cream twice daily to UVA‐1 phototherapy thrice weekly for six weeks. Twenty‐four participants with chronic vesicular hand eczema were treated with phototherapy, and 23 participants were treated with topical corticosteroids.

Treatment with a portable UVB phototherapy unit, to be used at home, was compared with treatment by non‐specific topical treatment in a study among 48 participants with occupational hand dermatitis (Bayerl 1999). It seems that the UVB‐treated group also applied this non‐specific topical treatment. The UVB‐treated group irradiated their hands at home five days per week for eight weeks according to a predetermined dosage scheme.

Two studies compared oral PUVA with topical bath PUVA: van Coevorden 2004a and Tzaneva 2009.

Tzaneva 2009 compared oral PUVA versus bath PUVA. Immediately after immersion for 15 minutes, the hands and feet were exposed to UVA irradiation. The irradiation doses in both groups were increased depending on the degree of erythematous response. Treatment was given three to four times a week until complete clearance, or over a maximum period of 20 weeks. After clearing, participants were maintained on PUVA twice weekly for two weeks and then once weekly for another four weeks.

van Coevorden 2004a compared a randomised controlled parallel study of oral PUVA phototherapy whereby the hands were irradiated by participants themselves at home with bath PUVA; the hands were soaked in a psoralen (trioxsalen) solution followed by UVA in the clinic. The aim was to demonstrate equal clinical efficacy, assuming that costs for home treatment would be substantially lower. Treatment was given for 10 weeks, and there was follow‐up after the end of treatment for another eight weeks. Emollients were allowed in both groups.

Sezer 2007 compared UVA with UVB: 12 participants received local narrow‐band UVB three times a week on one hand and local PUVA on the other hand for nine weeks. The initial dose was 150 mJ/cm² for each participant. A 20% increasing dose schedule was used until a final dose of 2000 mJ/cm² was reached versus local PUVA three times a week during nine weeks on 12/15 contralateral hands. The initial dose of psoralen plus UVA irradiation was 1.0 J/cm² with an increase of 0.5 J/cm² in every second session until a final dose of 7.5 J/cm² was achieved.

Brass 2015 compared the efficacy of narrow‐band UVB with localised PUVA. Sixty participants received immersion PUVA or narrow‐band UVB twice a week for 12 weeks.

Studies that employed UVA treatment were Adams 2007 and Grattan 1991.

A within‐participant study compared the effectiveness of middle‐dose UVA‐1 irradiation to topical cream PUVA therapy (Adams 2007). UVA‐1 is a newer form of UV therapy that contains only long‐wavelength UVA‐1 radiation (340 to 400 nm) and thus reduces the risk of burning. Participants with chronic relapsing dyshidrotic hand eczema received one treatment modality on one hand and one treatment modality on the other hand. Treatment was given three times a week during a period of five weeks (middle‐dose UVA‐1 irradiation three times a week during five weeks (cumulative dose of 600 J/cm²) versus local 8‐MOP‐cream‐PUVA irradiation three times a week during five weeks (cumulative dose of 17.4 J/cm²)). 8‐MOP‐crème was applied 30 minutes before the start of irradiation. Grattan 1991 used topical PUVA three times weekly for eight weeks versus UVA (with placebo psoralen paint). The PUVA treatment was performed by applying a liquid ("paint") containing methoxypsoralen to one hand. On the contralateral hand, an inactive paint was applied, whereupon both hands were irradiated with UVA. Moisturisers were allowed on both hands, and both hands received a small fraction of UVB from UVA lamps.

Polderman 2003 used UVA‐1 (long‐wavelength UV radiation) irradiation 40 J/cm² on the hands five times weekly for three weeks versus placebo (simulated blue light). Emollients seem to have been allowed in both groups.

Sjövall 1987 used UVB irradiation only on the hands four times a week for eight weeks in six participants versus a placebo for UVB (filtered light) on the hands four times a week for eight weeks in six participants versus hand UVB followed by whole‐body UVB + UVA four times a week during eight weeks in six participants. Their 'ordinary topical treatment' was permitted in all groups. Emollients were allowed in both groups.

For an overview of studies with UV therapy, see Table 4.

Open in table viewer
Table 4. Overview of studies on irradiation with UV light: investigator‐rated good/excellent control

Study

Comparison

Investigator‐rated good/excellent control in RR (95% CI)

Comment

Bayerl 1999

UVB versus no UVB

No data regarding the primary outcome investigator‐rated good/excellent control

‐

Sjövall 1987

Local UVB versus placebo

RR 2.0 (95% CI 0.26 to 15.6)

‐

Sjövall 1987

Local UVB hand versus whole body + hand UVB

RR 2.2 (95% CI 0.83 to 5.8)

‐

Sjövall 1987

Local UVB hand versus whole body versus placebo

RR 3.67 (95% CI 0.90 to 14.97)

‐

van Coevorden 2004a

Oral PUVA versus topical bath PUVA

No data regarding the primary outcome investigator‐rated good/excellent control

‐

Grattan 1991

Topical PUVA versus UVA

No data regarding the primary outcome investigator‐rated good/excellent control

Within‐patient study

Polderman 2003

UVA‐1 versus placebo

No data regarding the primary outcome investigator‐rated good/excellent control

‐

Brass 2015

Local NB‐UVB versus topical PUVA

RR 0.50 (95% CI 0.22 to 1.16)

‐

Sezer 2007

Local NB‐UVB versus topical PUVA

NB‐UVB was effective in 2/12 hands and topical PUVA was effective in 1/12 hands

Within‐patient study

Tzaneva 2009

Oral PUVA versus bath PUVA

No data regarding the primary outcome investigator‐rated good/excellent control

‐

Adams 2007

UVA‐1 versus topical cream PUVA

No data regarding the primary outcome investigator‐rated good/excellent control

Within‐patient study

Said 2010

Local UVA‐1 versus topical betamethasone‐valerate cream

No data regarding the primary outcome investigator‐rated good/excellent control

‐

CI: confidence interval.

RR: risk ratio.

NB‐UVB: narrow‐band ultraviolet B.

PUVA: psoralen + ultraviolet A.

UVB: ultraviolet B.

UVA‐1: a subtype of ultraviolet A.

E. Irradiation with X‐rays (ionising radiation)

X‐rays/radiotherapy/Grenz rays were studied in five publications (Cartwright 1987; Fairris 1984; Fairris 1985; King 1984; Lindelöf 1987). One study compared conventional superficial radiotherapy to UV phototherapy (Sheehan‐Dare 1989). All these studies used within‐participant designs (i.e. comparing one hand with the contralateral hand).

Two of these studies used superficial X‐rays 300 Rad as active treatment (Fairris 1984; King 1984).

King 1984 included 20 participants and treated one hand with three fractionated doses of 100 Rad (i.e. a total of 300 Rad) at 45 kV given at one‐week intervals; Fairris 1984 treated participants with a combination of topical therapy and superficial X‐ray therapy, and assessed them at 6, 9, and 18 weeks after the start of X‐ray therapy. One hand was treated with 100 Rad at 50 kV on three occasions at intervals of 21 days (i.e. total 300 Rad), and the other hand with placebo. Participants continued treatment with tar paste or steroid ointments on both hands throughout the trial.

Lindelöf 1987 gave six fractionated doses of 3 Gy at one‐week intervals for six weeks. Placebo therapy was achieved by allowing the apparatus to hum without emitting radiation.

In Cartwright 1987, one hand was irradiated three times with 3 Gy of Grenz rays (total 900 Rad), and the contralateral hand was treated in an exactly similar manner with sham radiation. Treatments were repeated at 21‐day intervals for a total of three visits. Evaluations were performed by the doctor and the participant at 3, 6, 9, 12, 15, and 18 weeks after initial treatment.

One study compared superficial X‐ray and Grenz ray irradiation (Fairris 1985). Both radiation therapies were given in three divided doses at 21‐day intervals. One hand received 1 Gy of conventional superficial X‐ray 50 kV, the other 3 Gy of Grenz ray 10 kV.

One study compared X‐ray irradiation to UV phototherapy (Sheehan‐Dare 1989). Superficial X‐ray irradiation (0.9 Gy at 50 kV administered on three occasions at 21‐day intervals) on one hand was compared with topical PUVA therapy (three times a week for six weeks) on the contralateral hand in 25 participants. Assessments were performed before and at 6, 9, and 18 weeks after the start of treatment.

For an overview of studies including irradiation with X‐rays, see Table 5.

Open in table viewer
Table 5. Overview of studies on X‐rays (ionising radiation): investigator‐rated good/excellent control

Study

Comparison

Investigator‐rated good/excellent control in RR (95% CI)

Comments

King 1984

X‐rays 300 rad versus placebo

No difference after 6 months. Grenz ray effective in 11/15 hands versus 8/15 hands with placebo.

Within‐patient study

Fairris 1984

X‐rays 300 rad versus placebo

No data regarding the primary outcome investigator‐rated good/excellent control

Within‐patient study

Lindelöf 1987

Grenz rays 1800 rad versus placebo

No data regarding the primary outcome investigator‐rated good/excellent control

Within‐patient study

Cartwright 1987

Grenz rays 300 rad versus placebo

No data regarding the primary outcome investigator‐rated good/excellent control

Within‐patient study

Fairris 1985

X‐rays 1 Gy versus Grenz rays 3 Gy

No data regarding the primary outcome investigator‐rated good/excellent control

Within‐patient study

Sheehan‐Dare 1989

X‐rays versus PUVA

No data regarding the primary outcome investigator‐rated good/excellent control

Within‐patient study

CI: confidence interval.

Grenz rays: a type of X‐rays (ionising radiation).

Gy: Gray, a unit of radiation dose.

RR: risk ratio.

F. Topical calcineurin inhibitors

Tacrolimus was studied in four papers (Katsarou 2012; Krejci‐Manwaring 2008; Pacor 2006; Schnopp 2002). Pimecrolimus was evaluated in three papers (Bauer 2012; Belsito 2004; Hordinsky 2010), as well as in two conference abstracts (Baskan 2005; Cherill 2000).

Topical tacrolimus 0.1% ointment (FK506) twice daily was compared with the topical corticosteroid mometasone furoate 0.1% ointment in a within‐participant design (Schnopp 2002). Participants were encouraged to use emollients in addition. Treatment duration was four weeks, and treatment was followed by a washout period of two weeks. Tacrolimus ointment 0.1% twice daily during four weeks versus mometasone furoate 0.1% ointment twice daily was also used in Katsarou 2012 (with tapering mometasone furoate dose in the mometasone arm of the trial).

Katsarou 2012 compared topical tacrolimus 0.1% twice daily for 30 days and once daily for 31 to 90 days in 15 participants to mometasone furoate ointment twice daily for one week, once daily during week two and week three, once daily three times a week for weeks four and five, and once daily two times a week during the rest of the study (for 90 days) in 15 participants.

Two studies addressed tacrolimus ointment versus vehicle (Krejci‐Manwaring 2008; Pacor 2006).

Twice‐daily application of tacrolimus ointment was compared to its vehicle to study its effectiveness in keeping hand eczema in remission (Krejci‐Manwaring 2008). Remission was induced after a three‐week taper of prednisone. Simultaneous to the prednisone taper, participants started with tacrolimus or its vehicle for a total treatment duration of 12 weeks.

The aim of another trial was to evaluate the efficacy of 0.1% tacrolimus ointment for nickel sulphate‐induced allergic contact dermatitis of the hands (Pacor 2006). Participants were randomised to twice‐daily treatment with either 0.1% tacrolimus ointment or its vehicle during 14 days.

Five of our included studies addressed the use of pimecrolimus cream: Baskan 2005; Bauer 2012; Belsito 2004; Cherill 2000; Hordinsky 2010.

A large multi‐centre study with 294 participants compared twice‐daily application of pimecrolimus 1% cream to twice‐daily application of vehicle in a three‐week study (Belsito 2004). In both groups, the evening application was followed by six‐hour occlusion. Time to relapse was compared between pimecrolimus 1% cream and vehicle in a randomised controlled parallel study (Bauer 2012). Before commencement, participants with atopic hand eczema used mometasone furoate for one to three weeks until symptoms had cleared. This was followed by an eight‐week maintenance period with pimecrolimus versus vehicle cream. Another published abstract reporting a placebo‐controlled randomised trial comparing pimecrolimus 1% cream with vehicle over eight weeks found pimecrolimus to be effective in suppressing all clinical signs of hand eczema apart from vesiculation (Baskan 2005). Only limited data could be extracted from one study comparing pimecrolimus 1% cream (with or without occlusion) to vehicle because this study was published as a conference abstract (Cherill 2000). In a large multi‐centre study (Hordinsky 2010), 652 adults were randomised to pimecrolimus 1% or vehicle cream twice daily with overnight occlusion for six weeks.

For an overview of studies including topical calcineurin inhibitors, see Table 6.

Open in table viewer
Table 6. Overview of studies on topical calcineurin inhibitors: investigator‐rated good/excellent control

Study

Comparison

Investigator‐rated good/excellent control in RR (95% CI)

Comments

Schnopp 2002

Tacrolimus ointment versus mometasone furoate

No data regarding the primary outcome investigator‐rated good/excellent control

Within‐patient study

Katsarou 2012

Tacrolimus ointment versus mometasone furoate

No data regarding the primary outcome investigator‐rated good/excellent control

Improvement was reported separately for subcategories of clinical signs

Krejci‐Manwaring 2008

Tacrolimus ointment versus vehicle

No data regarding the primary outcome investigator‐rated good/excellent control

‐

Pacor 2006

Tacrolimus ointment versus vehicle

RR 29.0 (95% CI 1.9 to 443.25)

‐

Belsito 2004

Pimecrolimus cream versus vehicle

RR 1.53 (95% CI 0.99 to 2.36)

‐

Hordinsky 2010

Pimecrolimus cream versus vehicle

RR 1.28 (95% CI 0.99 to 1.66)

‐

Bauer 2012

Pimecrolimus cream versus vehicle

No data regarding the primary outcome investigator‐rated good/excellent control

‐

Baskan 2005

Pimecrolimus cream versus vehicle

No data regarding the primary outcome investigator‐rated good/excellent control

‐

Cherill 2000

Pimecrolimus cream versus vehicle

No data regarding the primary outcome investigator‐rated good/excellent control

‐

CI: confidence interval.

RR: risk ratio.

G. Other topical interventions

Two antibacterial agents ‐ clioquinol cream and fusidic acid cream ‐ each combined with a corticosteroid (betamethasone‐valerate) were compared in a multi‐centre study on 120 hand eczema participants with confirmed or suspected secondary infection of their eczema (Hill 1998). The unblinded study had a duration of four weeks.

One study investigated urea cream (Fredriksson 1975), that is, Aquacare HP cream, a moisturising emulsion containing multi‐sterols, phospholipids, and fatty diols (pH 6), twice a day (morning and evening) for four weeks, versus control of Calmurid cream containing betaine and lactic acid (pH 3), twice a day for four weeks.

Bexarotene, a novel type of retinoid, was evaluated in 55 participants by a three‐arm unblinded (phase I to II open label) study lasting 22 weeks (Hanifin 2004). The intervention was bexarotene 1% gel applied in a stepwise accumulation every two weeks from once every other day to three times daily (bexarotene only group). Comparators were bexarotene application in combination with mometasone furoate (B + MF group) and in combination with hydrocortisone (B + HC group). All three groups used emollients.

One study compared topical furpalmate‐containing cream (0.3%) with a topical corticosteroid (hydrocortisone acetate 0.5%) twice a day (Lauriola 2011).

Jowkar 2014 studied the efficacy of topical fumaric acid 5% cream twice daily compared to triamcinolone 0.1% cream twice daily in 92 participants.

Three studies investigated herbal topical treatments: one study compared a 2% oil extract of Nigella sativa L. to betamethasone ointment 0.1% and Eucerin (Yousefi 2012). Nigella sativa L. (family Ranunculaceae) is an annual flowering plant that grows in south and southwest Asia, of which the seeds can be used as spice. Another study compared a cream with 4% Fumaria parviflora Lam. twice daily to vehicle cream (Jowkar 2011). Fumaria parviflora Lam. extract (family Papaveraceae) is a Persian herbal medicine that is called 'Shahtareh' in Iran. The plants were dried, and from them an abstract was made for the cream. Finally, twice‐daily application with an oil‐in‐water emulsion‐based herbal cream containing fenugreek seeds 5%, marshmallow 5%, chamomile 5%, and walnut leaves 5% was compared with twice‐daily application of the topical steroid fluocinolone acetonide cream 2%, in the study of Boroujeni 2017.

In a within‐participant study, pulsed direct iontophoresis on one hand was compared with no iontophoresis on the contralateral hand (Odia 1996), in which one of the participants' hands received pulsed direct current iontophoresis, 20 times 15 minutes each during three weeks in 20 hands, or as a control, no iontophoresis on contralateral hands for three weeks. Both hands received steroid‐free tar solution and zinc paste.

For an overview of other topical interventions, see Table 7.

Open in table viewer
Table 7. Overview of studies on other topical interventions: investigator‐rated good/excellent control

Study

Comparison

Investigator‐rated good/excellent control in RR (95% CI)

Comments

Hill 1998

Betamethasone‐valerate + clioquinol versus betamethasone‐valerate + fusidic acid

RR 1.03 (95% CI 0.74 to 1.43)

‐

Fredriksson 1975

Aquacare HP cream versus calmurid cream containing betaine and lactic acid

No data regarding the primary outcome investigator‐rated good/excellent control

Within‐patient study

Odia 1996

Iontophoresis versus no iontophoresis

No data regarding the primary outcome investigator‐rated good/excellent control

Within‐patient study

Boroujeni 2017

Herbal cream containing fenugreek seeds 5%, marshmallow 5%, chamomile 5%, and walnut leaves 5% versus fluocinolone acetonide cream 2% twice daily

No data regarding the primary outcome investigator‐rated good/excellent control

‐

Hanifin 2004

Bexarotene 1% gel versus bexarotene with either mometasone furoate or hydrocortisone

RR 0.85 (95% CI 0.40 to 1.80) for bexarotene only versus B + MF; 1.83 (95% CI 0.61 to 5.53) for bexarotene only versus B + HC; and 2.15 (95% CI 0.67 to 6.89) for B + MF versus B + HC

‐

Jowkar 2014

Fumaric acid 5% cream versus triamcinolone 0.1% cream

No data regarding the primary outcome investigator‐rated good/excellent control

‐

Lauriola 2011

Furpalmate versus hydrocortisone acetate cream

RR 0.90 (95% CI 0.76 to 1.07)

‐

Jowkar 2011

4% Fumaria Parviflora Lam cream versus vehicle cream twice daily

No data regarding the primary outcome investigator‐rated good/excellent control

‐

Yousefi 2012

Nigella sativa L. versus betamethasone ointment versus Eucerin

No data regarding the primary outcome investigator‐rated good/excellent control

‐

B: bexarotene 1% gel.

CI: confidence interval.

Fumaria Parviflora Lam: Fumaria Parviflora Lamarck.

HC: hydrocortisone.

MF: mometasone furoate.

Nigella sativa L: Nigella sativa Linne.

RR: risk ratio.

III. Systemic treatments

A. Oral corticosteroids

We identified no RCTs addressing oral corticosteroids.

B. Immunosuppressants

We found two publications on cyclosporin (Granlund 1996), but these studies were based on the same trial, which had three phases. Oral cyclosporin 3 mg/kg/d and placebo cream for six weeks was compared with topical betamethasone dipropionate 0.05% cream and placebo capsules identical to cyclosporin. This was a cross‐over trial, in which participants who failed to respond to their intervention in phase I were crossed over to the alternative intervention. The use of own emollients was allowed in both groups.

Agarwal 2013 investigated a low dose of azathioprine combined with topical clobetasol 0.05% cream compared to topical clobetasol 0.05% cream alone during 24 weeks.

NCT01231854 compared the effects of oral cyclosporin 2.7 to 4.0 mg/kg to those of alitretinoin 30 mg/d during 24 weeks. Please see Table 8.

Open in table viewer
Table 8. Overview of studies on immunosuppressants: investigator‐rated good/excellent control

Study

Comparison

Investigator‐rated good/excellent control in RR (95% CI)

Comments

Granlund 1996

Oral cyclosporin versus topical betamethasone

RR 1.88 (95% CI 0.88 to 3.99)

‐

Agarwal 2013

Oral azathioprine and clobetasol propionate 0.05% cream twice daily versus topical clobetasol propionate 0.05% cream twice daily

RR 2.33 (95% CI 1.61 to 3.38)

‐

NCT01231854

Oral cyclosporin versus alitretinoin

RR 1.50 (95% CI 0.35 to 6.40)

Study terminated prematurely and included 15 participants only

CI: confidence interval.

RR: risk ratio. 

C. Oral retinoids

We identified six studies evaluating oral retinoids (Bissonnette 2010; Fowler 2014; NCT01231854; Ruzicka 2004; Ruzicka 2008; Thestrup‐Pedersen 2001). Ruzicka 2004 had previously been presented in part as a conference abstract (Larsen 2003, listed under Ruzicka 2004).

Three studies investigated the effect of 10 mg oral alitretinoin (Bissonnette 2010; Ruzicka 2004; Ruzicka 2008)

Two large multi‐centre studies compared a total of four different oral doses of a novel retinoid (alitretinoin) with placebo capsules (Ruzicka 2004; Ruzicka 2008). In Ruzicka 2004, three groups, each receiving respectively, 10, 20, or 40 mg per day, were compared with a placebo group. The trial lasted 12 weeks. The other study (Ruzicka 2008; also known as Benefit of Alitretinoin in Chronic Hand Eczema or BACH study) compared two groups receiving, respectively, oral alitretinoin 10 or 30 mg once daily versus placebo up to 24 weeks. In both studies, participants were allowed to use a standard emollient.

The large multicenter study of Fowler 2014 compared alitretinoin 30 mg/d to placebo in 596 participants with severe chronic hand eczema. The treatment duration was 24 weeks, and afterwards participants were followed up for a substantial period of time.

NCT01231854 aimed to compare the effectiveness and safety of 30 mg alitretinoin to cyclosporin during 24 weeks in 78 participants.

In Bissonnette 2010, 117 participants suffering from chronic hand eczema were included who had been successfully treated with alitretinoin in an earlier study (Ruzicka 2008), and who had relapsed within the 24‐week observation period after treatment. These 117 relapsed participants were randomised to receive their previous treatment or placebo in a 2:1 ratio. A total of 73 participants were included who had been treated with 30 mg alitretinoin in the previous BACH study (Ruzicka 2008). No other topical or systemic medication for hand eczema was allowed during the treatment period. Dose reductions of study medication were not allowed.

Thestrup‐Pedersen 2001 compared acitretin given orally at 30 mg daily for eight weeks to placebo capsules given for eight weeks. Both groups were allowed to use topical emollients.

For an overview of studies on oral retinoids, see Table 9.

Open in table viewer
Table 9. Overview of studies on oral retinoids: investigator‐rated good/excellent control

Study

Comparison

Investigator‐ or participant‐rated good/excellent control in RR (95% CI)

Comments

Thestrup‐Pedersen 2001

Oral acitretin versus placebo

No data regarding the primary outcome investigator‐rated good/excellent control

‐

Ruzicka 2004

Oral alitretinoin (20 mg and 40 mg) versus placebo

40 mg
Participant‐rated
RR 3.51 (95% CI 1.80 to 6.82)
Investigator‐rated
RR 1.97 (95% CI 1.3 to 3.0)

20 mg
Participant rated
RR 2.74 (95% CI 1.37 to 5.46)
Investigator‐rated
RR 1.49 (95% CI 0.94 to 2.34)

‐

Ruzicka 2008; Fowler 2014

Oral alitretinoin 30 mg versus placebo

30 mg
Participant‐rated
RR 2.75 (95% CI 2.18 to 3.48)
Investigator‐rated
RR 2.75 (95% CI 2.20 to 3.43)

‐

Ruzicka 2004; Ruzicka 2008

Oral alitretinoin 10 mg versus placebo

10 mg

Participant‐rated
RR 1.73 (95% CI 1.25 to 2.40)

Investigator‐rated
RR 1.58 (95% CI 1.20 to 2.07)

‐

Bissonnette 2010

Re‐treatment with oral alitretinoin (30 mg and 10 mg) versus placebo

30 mg
Investigator‐rated
RR 9.55 (95% CI 2.51 to 36.27)

10 mg
Investigator‐rated
RR 4.76 (95% CI 0.70 to 32.25)

‐

CI: confidence interval.

RR: risk ratio.

D. Other oral interventions

This group included six studies (Table 10) ‐ one on triethylenetetramine (Burrows 1986), two on disulphiram (Kaaber 1983; Sharma 2006), one comparison of a low‐nickel diet versus oral treatment with disodium cromoglycate (Pigatto 1990), one on oral ranitidine (Veien 1995), and one on evening primrose oil (Whitaker 1996).

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Table 10. Overview of other oral interventions: investigator‐rated good/excellent control

Study

Comparison

Investigator‐rated good/excellent control in RR (95% CI)

Comments

Burrows 1986

Oral triethylenetetramine versus placebo

Trientine was effective in 6/20 participants versus 10/20 in the placebo group

Unclear whether participant‐ or investigator‐rated

Kaaber 1983

Oral tetraethylthiuram disulphide versus placebo

Investigator‐rated

RR 2.95 (95% CI 0.71 to 12.34)

‐

Pigatto 1990

Oral disodium cromoglycate without dietary restriction versus a low‐nickel diet

No data regarding the primary outcome investigator‐rated good/excellent control

‐

Sharma 2006

Low‐nickel diet and disulphiram versus a normal diet and placebo

Investigator‐rated

RR 9.09 (95% CI 1.40 to 58.91)

‐

Veien 1995

Ranitidine versus placebo

RR 2.22 (95% CI 1.20 to 4.10)

Unclear whether participant‐ or investigator‐rated

Whitaker 1996

Oral gamma‐linoleic acid (GLA; evening primrose oil) versus placebo

No data regarding the primary outcome investigator‐rated good/excellent control

CI: confidence interval.

RR: risk ratio.

Three studies aimed specifically to intervened on the imputed role of nickel allergy in hand eczema, and included exclusively nickel‐sensitive participants (Burrows 1986; Kaaber 1983; Sharma 2006).

Burrows 1986 compared oral triethylenetetramine (Trientine) 300 mg daily for six weeks to placebo and was designed as a cross‐over study, but this trial was terminated prematurely (23 participants had been included) because of literature reports on teratogenicity in rats.

Kaaber 1983 compared oral tetraethylthiuram disulphide 50 mg/d first week, increasing to 200 mg/d for at least six weeks, to placebo, and was performed in 30 nickel‐sensitive (patch test‐positive) women with pompholyx‐type hand eczema. Half of the participants (n = 15) received tetraethylthiuram disulphide (Antabuse) with gradually increasing dosage (up to 20 mg/d) for "at least six weeks"; probably this maximum dose was given for six weeks. The other 15 women received placebo tablets. Both groups were allowed to use a topical corticosteroid (desoximethasone) and emollients.

Twenty‐one nickel‐sensitive participants (proven by means of patch testing) with vesicular hand eczema were included in a single‐blinded trial and were randomised into two treatment groups (Sharma 2006); a low‐nickel diet in combination with disulphiram was compared with a normal diet in combination with placebo.

Pigatto 1990 compared a low‐nickel diet in eight participants to oral disodium cromoglycate (DSCG) 1500 to 2000 mg three times a day in nine participants to no treatment in seven participants for a period of three months; however this last group was not randomised and therefore was not included in the analyses.

Veien 1995 compared oral ranitidine 300 mg twice daily to placebo tablets in a trial of probably 16 weeks. Both groups were allowed to use betamethasone cream/ointment and emollients.

Evening primrose oil (GLA ‐ gamma linolenic acid) 50 mg in 20 participants was compared to placebo capsules in 19 participants for 16 weeks (Whitaker 1996). Both groups were allowed to use unlimited qualities of emollients and a limited amount of group III corticosteroids. Participants were followed up for eight weeks after the end of treatment, resulting in a total study duration of 24 weeks.

For an overview, see Table 10.

Outcomes

The 60 included RCTs reported diverse outcomes. About half of these studies (n = 33) included our primary outcome good/excellent control either participant‐ or investigator‐rated, although not all included reproducible data. Almost all studies reported our primary outcome 'adverse events' (n = 55). There was substantial heterogeneity between the studies in terms of outcome measures, duration, and timing of outcome assessments.

Most studies used a scale to score the (change in) severity of hand eczema or the rate of clearance. However, many different scoring systems were composed to score different items on different scales, and some did, while others did not, include the affected area. Most scoring systems were unnamed, non‐validated, and self‐created, and combined objective and subjective scores; in these cases, we provided a narrative account of study results and did not attempt quantitative analyses.

The Hand Eczema Severity Index (HECSI) is an assessment of the clinical severity of hand eczema that includes the extent and severity of hand eczema. The hands are divided into five areas (fingertips, fingers, palms, backs of hands and wrists). For each of these areas, the intensity of the six following clinical signs is scored on a grade from 0 (no skin changes) to 3 (severe changes): erythema, induration/papulation, vesicles, fissures, scaling, and oedema were graded on this scale. Moreover, the affected area for each is scored from 0 to 4 (0 = 0%; 1 = 1% to 25%; 2 = 26% to 50%; 3 = 51% to 75%; 4 = 76% to 100%) for the extent of clinical symptoms. Finally, the scores given for each extent location are multiplied by the total sum of the intensity of each clinical feature, resulting in a score of 0 (no hand eczema symptoms) to a maximum severity score of 360 points (very severe hand eczema). Scores above 28 represent severe hand eczema. This is a validated scoring system with excellent agreement for both interobserver and intraobserver reliability (Held 2005). Four studies used the HECSI (Agarwal 2013; Bauer 2012; NCT01231854; Yousefi 2012); three studies awaiting classification (EUCTR2005‐005793‐75‐DE; IRCT201112018263N1; NCT01950494), as well as six ongoing studies, included this outcome parameter (IRCT2014012916412N1; ISRCTN80206075; NCT02664805; NCT03026907; NCT03026946; PACTR201704002194318).

The Dyshydrotic Eczema Area and Severity Index (DASI) is an assessment of severity combining objective (vesicles, erythema, and desquamation) and subjective (itch) evaluations. Each item has to be assessed on a scale ranging from 0 to 3 (0 = absent, 1 = mild, 2 = moderate, 3 = severe), and the grading must be representative for all affected areas. The severity grading is multiplied by a number representative of the total affected area. DASI score = (Vesicles + Erythema + Desquamation + Itch) × Area score points. This results in a DASI ranging from 0 to 60. A DASI score between 0 and 15 represents mild dyshidrotic eczema, 16 to 30 is moderate, and between 31 and 60 represents severe dyshidrotic eczema. The DASI was first described by Odia (Odia 1996). It was used as primary outcome in five studies (Adams 2007; Odia 1996; Polderman 2003; Said 2010; Schnopp 2002); however, this regularly used instrument is not validated.

The Hand Eczema Area and Severity Score (HEAS) is used to assess clinical severity, corrected for the percentage of affected skin area (Simons 1997). The score ranges from 0 (no hand eczema) to 96 (very severe hand eczema) points. Two studies used the HEAS score, although this score is not validated for hand eczema (Chu 2009; Kucharekova 2003).

The Hand Eczema Extent Score (HEES) is a simple clinical score that is not validated (Meding 1989). The HEES scores only the extent of the presence of eczema signs on different locations of the hands, without including intensity of the lesions, with a range of 0 (no hand eczema) to 74 (very severe hand eczema) points. One study included the HEES (Lodén 2012a).

The Total Lesion Symptom Score (TLSS) is the sum of seven items (erythema, oedema, vesicles, desquamation, hyperkeratosis, fissures, and pruritus/pain) scored on a 4‐point scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe). The TLSS was used in Ruzicka 2004, and afterwards a slightly modified version (modified Total Lesion Symptom Score ‐ mTLSS) was used in Ruzicka 2008, Bissonnette 2010, Fowler 2014, and Brass 2015; the seven items were erythema, oedema, vesiculation, scaling, lichenification/hyperkeratosis, fissures, and pruritus/pain. A high mTLSS represents severe hand eczema. The mTLSS relates to the Physician Global Assessment, and a photographic guide has been developed to train observers.

Some studies used scoring systems derived and validated for atopic dermatitis. For example, the validated Eczema Area and Severity Index (EASI) was used (Jowkar 2011;Jowkar 2014), and this scoring system was adjusted to a Hand Eczema Area and Severity Index (HEASI) score (Hanifin 2004). NCT01231854 included the validated SCORing Atopic Dermatitis (SCORAD) next to the HECSI for participants with atopic hand eczema.

The Hand Eczema Area and Severity score is adapted from the well known EASI. The HEASI is calculated by (sum of severity scores for signs) × (involved hand area integer), whereby for the area, 1 = < 10% involvement, 2 = 10% to 29%, 3 = 30% to 49%, 4 = 50% to 69%, 5 = 70% to 89%, and 6 = 90% to 100%. Severity score is 0 = none, 1 = mild, 2 = moderate, 3 = moderately severe, and 4 = severe for the following signs: erythema, scaling, oedema, lichenification, vesiculation, and fissuring.

Investigator and Physician Global assessments (PGA and IGA) or variants of this scoring system (such as the Investigator's Static Global Assessment (ISGA)) were used in different studies, on a 4‐ or 5‐point scale for both hands overall (Bauer 2012; Belsito 2004; Bissonnette 2010; Bleeker 1989; Brass 2015; Cartwright 1987; Chu 2009; Fairris 1984; Fairris 1985; Fowler 2014; Grattan 1991; Gupta 1993; Hill 1998; Hordinsky 2010; King 1984; Kircik 2013; Krejci‐Manwaring 2008; Kucharekova 2003; Lauriola 2011; NCT01231854; Pacor 2006; Ruzicka 2004; Ruzicka 2008; Sheehan‐Dare 1989; Sjövall 1987). In general, a low IGA or PGA score represents well‐controlled hand eczema, whereas a high score represents severe hand eczema. PGA scores have been extensively studied and compared to, for example, HECSI and HEAS (Coenraads 2005; Van Der Valk 2013).

Itch was scored as subjective parameter in most studies (Agarwal 2013; Bayerl 1999; Bleeker 1989; Boroujeni 2017; Brass 2015; Cherill 2000; Chu 2009; Faghihi 2008; Fowler 2005; Fowler 2014; Granlund 1996; Gupta 1993; Hanifin 2004; Hill 1998; Hordinsky 2010; Jowkar 2014; Katsarou 2012; Kemper 1998; Kircik 2013; Krejci‐Manwaring 2008; Kucharekova 2003; Lauriola 2011; Lindelöf 1987; Odia 1996; Pacor 2006; Pigatto 1990; Polderman 2003; Ruzicka 2004; Ruzicka 2008; Schnopp 2002; Sezer 2007; Sharma 2006; Thestrup‐Pedersen 2001; Uggeldahl 1986; van Coevorden 2004a; Veien 1995).

Ten studies included quality of life as an outcome parameter; especially more recent studies and studies in trial registries included quality of life. The extensively studied and validated Dermatology Life Quality Index (DLQI from Finlay 1994) was used in seven studies (Bauer 2012; Brass 2015; Chu 2009; Kircik 2013; Lodén 2012a; Ruzicka 2004; Yousefi 2012). The DLQI contains 10 questions regarding the impact of skin conditions and their treatment on participants' lives, which are answered on a scale ranging from 0 (not at all) to 3 (very much). A total DLQI score between 0 and 1 represents no or minimal effect at all on a participant's life. A DLQI score of 10 or greater represents significant impact on life quality, whereas a score over 21 represents an extremely large effect on quality of life. A change in DLQI score of at least 4 points is considered clinically relevant in inflammatory skin conditions (Basra 2008; Basra 2015).

Another quality of life questionnaire that was used is the Eczema Disability Index (EDI) (Granlund 1996). The EDI includes 15 questions representing different dimensions of quality of life on a scale from 0 (not at all) to 6 (very much). The Skindex‐29 was used by one study (Fowler 2014). Finally the Skindex‐17 was used in another study (NCT01231854). The Skindex‐17 is a dermatological health‐related quality of life instrument that is derived from the Skindex‐29 and includes only 17 items instead of 29, and a 3‐point scale for answers instead of a 5‐point scale. A high score on the Skindex represents the huge impact of a skin condition on quality of life.

Economic losses such as sick days or out‐of‐pocket expenses were rarely registered as outcome parameters and were not included as outcome parameters before 2004. NCT01231854 and Brass 2015 contained an extensive cost‐effectiveness analysis based on the EQ‐5D. In addition, out‐of‐pocket expenses were registered in NCT01231854. van Coevorden 2004a registered travel expenses and time off work for participants. Two studies included the influence of hand eczema on work impairment with the Work Productivity and Activity Impairment Questionnaire (WPAI) (Kircik 2013; NCT01231854).

Cosmetic acceptability was considered as another outcome parameter in four studies (Fowler 2005; Fredriksson 1975; Kucharekova 2003; Lauriola 2011).

One of our secondary outcomes was 'dose reduction' ‐ reduction in treatment dose per time unit or cumulative prescribed treatment dose. None of the included studies provided reproducible data regarding this outcome.

Funding

For many older studies, it is unclear who funded the study. More recent studies often declared funding for the study or clearly stated relationships with pharmaceutical companies. In total, 22 studies were funded by pharmaceutical industries or were (co‐)authored by employees of pharmaceutical companies (Bauer 2012; Belsito 2004; Bissonnette 2010; Bleeker 1989; Cherill 2000; Chu 2009; Fowler 2005; Fowler 2014; Granlund 1996; Gupta 1993; Hill 1998; Hordinsky 2010; Kircik 2013; Krejci‐Manwaring 2008; Lodén 2012a; Möller 1983; Ruzicka 2004; Ruzicka 2008; Uggeldahl 1986; Veien 1995; Veien 1999; Whitaker 1996). Thirteen studies were sponsored by governmental organisations, universities, or hospitals (Baskan 2005; Brass 2015; Faghihi 2008; Jowkar 2011; Jowkar 2014; Katsarou 2012; NCT01231854; Pacor 2006; Schnopp 2002; Sharma 2006; Tzaneva 2009; van Coevorden 2004a; Yousefi 2012).

Excluded studies

The excluded studies are summarised under Characteristics of excluded studies. The 11 excluded studies comprised studies that were excluded for different reasons such as:

Ongoing studies

The search yielded eight ongoing studies whose content we have summarised under Characteristics of ongoing studies:

Three studies are focused on topical treatments.

  • NCT02664805: comparing the efficacy of twice daily applications of LEO 124249 ointment with LEO 124249 ointment vehicle for up to eight weeks for treatment of chronic hand eczema.

  • IRCT2014012916412N1: comparing the efficacy of pumpkin ointment twice daily with betamethasone ointment twice daily, and almond ointment twice daily and Eucerin ointment twice daily.

  • IRCT2017070922965N10: evaluating the effect of topical atorvastatin as adjuvant therapy for treatment of hand eczema.

One study is examining palmar botulinum toxin injections.

  • PACTR201704002194318: evaluating the efficacy and tolerability of botulinum toxin type A for treatment of hand eczema.

Four are exploring systemic treatments.

  • JPRN‐UMIN000003326: determining the effect of olopatadine on itching in hand eczema.

  • ISRCTN80206075: comparing alitretinoin 30 mg with PUVA twice weekly as first‐line treatment for severe chronic hand eczema.

  • NCT03026946: comparing the efficacy of alitretinoin 30 mg and cyclosporine for treatment for severe recurrent vesicular hand eczema.

  • NCT03026907: comparing alitretinoin 30 mg with azathioprine in severe non‐hyperkeratotic hand eczema.

Data from ongoing trials that have been completed at the time of the next update will be included in the review, if those results are available.

Studies awaiting classification

We added 20 records to Characteristics of studies awaiting classification. These include a lot of studies on different topical treatments such as hand creams and sanitisers for the treatment of hand eczema that were listed in different trial registries and, although they seem completed, results have never been posted and we were unable to obtain these results.

This section also contains studies that included different dermatoses among hand eczema, but for which we were unable to obtain separate data for hand eczema despite contacting the study investigator.

Risk of bias in included studies

Many studies were at high or unclear risk of bias in one or more components of trial design. We assessed only six studies as having low risk of bias in all components of trial design (Baskan 2005; Bauer 2012; Fowler 2005; Lindelöf 1987; Pacor 2006; Ruzicka 2004). Eight studies had only one unclear risk of bias with remaining domains rated as low risk (Bissonnette 2010; Fairris 1984; Fairris 1985; Fowler 2014; Kircik 2013; Ruzicka 2008; Sheehan‐Dare 1989; Yousefi 2012). We rated 29 studies as having high risk of bias in at least one domain (Adams 2007; Agarwal 2013; Bayerl 1999; Brass 2015; Burrows 1986; Cartwright 1987; Fredriksson 1975; Hanifin 2004; Hill 1998; Jowkar 2014; Katsarou 2012; Kemper 1998; King 1984; Krejci‐Manwaring 2008; Kucharekova 2003; Lauriola 2011; Möller 1983; NCT01231854; Odia 1996; Pigatto 1990; Said 2010; Schnopp 2002; Sharma 2006; Sjövall 1987; Thestrup‐Pedersen 2001; Tzaneva 2009; van Coevorden 2004a; Veien 1995; Veien 1999).

Further information can be found in the risk of bias tables for each included study and in Figure 2 and Figure 3.

Figure 2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figure 3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

Randomisation procedure

We judged the procedure as adequate (low risk of bias) when the allocation sequence was able to protect against biased allocation of comparison groups. If no details were given about the methods of sequence generation (i.e. if there was doubt about the adequacy of sequence generation), we judged studies as having unclear risk. We considered systematic methods that allow biased allocations, such as alternation or assignment based on day of admission, as inadequate (high risk of bias). References to a lottery system, throwing dice, or using a computer programme were considered as adequate (low risk of bias).

The randomisation procedure was unclear in 22 studies. For 25 studies, we judged the randomisation procedure as adequate based on the article (Adams 2007; Bauer 2012; Bayerl 1999; Cartwright 1987; Fairris 1984; Fairris 1985; Fowler 2014; Hanifin 2004; Hordinsky 2010; Kaaber 1983; Katsarou 2012; Kemper 1998; Kircik 2013; Krejci‐Manwaring 2008; Lindelöf 1987; Lodén 2012a; NCT01231854; Polderman 2003; Ruzicka 2004; Ruzicka 2008; Sezer 2007; Sheehan‐Dare 1989; Tzaneva 2009; van Coevorden 2004a; Yousefi 2012). For 13 studies, we were unable to base judgement on the article, but personal communication with study authors clarified that the randomisation procedure was adequate (Agarwal 2013; Baskan 2005; Bissonnette 2010; Brass 2015; Fowler 2005; Jowkar 2014; Kucharekova 2003; Pacor 2006; Schnopp 2002; Sharma 2006; Thestrup‐Pedersen 2001; Veien 1995; Veien 1999). In total, we judged the randomisation procedure as adequate in 38 studies.

Concealment of allocation

We judged this as adequate (low risk of bias) when clinicians and participants were unaware of future allocations before participants gave consent to the study. Examples of these include randomisation by a third party or use of sequentially numbered, opaque, sealed envelopes. We judged this as unclear risk of bias if insufficient details are given about methods of allocation concealment. We judged the allocation inadequate (high risk of bias) when there was a possibility of knowledge of the next assignment, so when investigators could have successfully guessed the allocation before the participant gave consent.

Of the above‐mentioned 38 studies with an appropriate randomisation procedure, concealment of allocation was adequate in 25 (Adams 2007; Agarwal 2013; Baskan 2005; Bauer 2012; Bayerl 1999; Fowler 2005; Fowler 2014; Jowkar 2014; Kircik 2013; Krejci‐Manwaring 2008; Kucharekova 2003; Lindelöf 1987; Lodén 2012a; NCT01231854; Pacor 2006; Polderman 2003; Ruzicka 2004; Ruzicka 2008; Schnopp 2002; Sharma 2006; Thestrup‐Pedersen 2001; van Coevorden 2004a; Veien 1995; Veien 1999; Yousefi 2012).

For eight studies, concealment of allocation was clear, but the randomisation procedure was unclear (Fredriksson 1975; Granlund 1996; Grattan 1991; Gupta 1993; Jowkar 2011; King 1984; Möller 1983; Uggeldahl 1986).

In total, in 33 studies the method used to conceal allocation was judged as adequate. In the remaining 27 studies, it is unclear if allocation was concealed.

Blinding

Performance bias

Performance bias refers to systematic differences between groups in the care provided, or in exposure to factors other than the interventions of interest (Higgins 2011a). After enrolment into the study, blinding of participants and site staff can reduce the risk that knowledge of which intervention was received, rather than the intervention itself, affects outcomes. Effective blinding can also ensure that the compared groups receive similar amounts of attention, ancillary treatment, and diagnostic investigation. With regards to performance bias, blinding of participants and of study personnel was judged separately. Use of identical looking study and control drugs (vehicle or placebo) was considered an adequate method of blinding, if the study was double‐blind.

If study authors made every attempt to blind the study to the best of their abilities, we judged the study as low risk. When, for example, the radiographer was the only person aware of treatment allocation but the study could not have been done in another way, we judged this as low risk of bias because we considered this the best possible way to minimise the risk of performance bias.

For 27 studies, both participants and staff were blinded in an adequate manner (Baskan 2005; Bauer 2012; Bissonnette 2010; Cartwright 1987; Chu 2009; Faghihi 2008; Fowler 2014; Fredriksson 1975; Granlund 1996; Grattan 1991; Gupta 1993; Jowkar 2011; Jowkar 2014; King 1984; Kircik 2013; Krejci‐Manwaring 2008; Lindelöf 1987; Lodén 2012a; NCT01231854; Pacor 2006; Ruzicka 2004; Ruzicka 2008; Sheehan‐Dare 1989; Thestrup‐Pedersen 2001; Veien 1995; Whitaker 1996; Yousefi 2012). Seven studies were only participant‐blinded (Fairris 1984; Fairris 1985; Fowler 2005; Kaaber 1983; Möller 1983; Polderman 2003; Uggeldahl 1986). Nine studies had unclear risk of blinding (Belsito 2004; Bleeker 1989; Boroujeni 2017; Brass 2015; Burrows 1986; Cherill 2000; Hordinsky 2010; Lauriola 2011; Sezer 2007).

For 17 studies, no blinding of participants was attempted, so the risk of performance bias was considered high (Adams 2007; Agarwal 2013; Bayerl 1999; Hanifin 2004; Hill 1998; Katsarou 2012; Kemper 1998; Kucharekova 2003; Odia 1996; Pigatto 1990; Said 2010; Schnopp 2002; Sharma 2006; Sjövall 1987; Tzaneva 2009; van Coevorden 2004a; Veien 1999). Some studies claimed a double‐blind design but this was not feasible because participants had to follow lifestyle interventions such as a low‐nickel diet (e.g. Pigatto 1990; Sharma 2006), or because treatment groups received completely different treatment such as whole‐body irradiation versus local radiation (e.g. Sjövall 1987).

Detection bias

'Detection bias' refers to systematic differences between groups in how outcomes are determined. Blinding of outcome assessors reduces the risk that knowledge of which intervention was received, rather than the intervention itself, affects outcome measurement (Higgins 2011a). We judged the procedure as having low risk of bias for detection when the outcome assessor was unaware of the allocation. When an article states only that the study was investigator‐blinded or double‐blinded, we considered this as too little information by which to judge the risk of bias and concluded that risk was unclear. We judged low risk of detection bias for studies that used independent observers, that received study drugs packed and dispensed by a third party, or that described another adequate method used to blind the observer.

The observer was blinded in an adequate manner in 30 studies (Agarwal 2013; Baskan 2005; Bauer 2012; Bissonnette 2010; Brass 2015; Fairris 1984; Fairris 1985; Fowler 2005; Granlund 1996; Grattan 1991; Gupta 1993; Jowkar 2011; Jowkar 2014; Katsarou 2012; King 1984; Kircik 2013; Krejci‐Manwaring 2008; Kucharekova 2003; Lindelöf 1987; Lodén 2012a; NCT01231854; Odia 1996; Pacor 2006; Polderman 2003; Ruzicka 2004; Ruzicka 2008; Schnopp 2002; Sheehan‐Dare 1989; Tzaneva 2009; Veien 1995).

Ten studies made no attempt to blind the observer (Adams 2007; Bayerl 1999; Hanifin 2004; Hill 1998; Kemper 1998; Said 2010; Sharma 2006; Thestrup‐Pedersen 2001; van Coevorden 2004a; Veien 1999). For the remaining 20 studies, it is unclear whether the observer was truly blinded.

Incomplete outcome data

We tried to minimise the quantity of missing data by contacting all study authors from 1999 forward. We contacted them through personal communication by email, letters, or social media features such as LinkedIn. We asked questions with regard to uncertainty in the assessment of risks of bias or trial design. We also tried to search other sources such as trial registries, which may provide additional information with regards to study design, or we compared the study to similar studies done by the same authors.

We judged attrition bias as low risk in 50 studies (Baskan 2005; Bauer 2012; Belsito 2004; Bissonnette 2010; Bleeker 1989; Boroujeni 2017; Burrows 1986; Cherill 2000; Chu 2009; Faghihi 2008; Fairris 1984; Fairris 1985; Fowler 2005; Fowler 2014; Fredriksson 1975; Granlund 1996; Grattan 1991; Gupta 1993; Hill 1998; Hordinsky 2010; Jowkar 2011; Kaaber 1983; Katsarou 2012; Kircik 2013; Kucharekova 2003; Lauriola 2011; Lindelöf 1987; Lodén 2012a; Möller 1983; NCT01231854; Odia 1996; Pacor 2006; Pigatto 1990; Polderman 2003; Ruzicka 2004; Ruzicka 2008; Said 2010; Schnopp 2002; Sezer 2007; Sharma 2006; Sheehan‐Dare 1989; Sjövall 1987; Thestrup‐Pedersen 2001; Tzaneva 2009; Uggeldahl 1986; van Coevorden 2004a; Veien 1995; Veien 1999; Whitaker 1996; Yousefi 2012). We judged attrition bias as unclear in two studies (Agarwal 2013; Hanifin 2004), and as high in eight studies (Adams 2007; Bayerl 1999; Brass 2015; Cartwright 1987; Jowkar 2014, Kemper 1998; King 1984; Krejci‐Manwaring 2008).

Loss to follow‐up and intention‐to‐treat (ITT) analysis

We judged the risk of attrition bias (incomplete outcome bias) as adequate (low risk of bias) when more than 80% of participants were followed up and analysed in the groups to which they were originally randomised. In addition, we considered an intention‐to‐treat (ITT) analysis as having low risk of bias for the attrition bias. When more than 20% of participants dropped out and no ITT analysis was carried out, we considered the study element to have high risk of bias.

A total of 13 studies reported no dropouts (Cherill 2000; Faghihi 2008; Fredriksson 1975; Katsarou 2012; Lauriola 2011; Lodén 2012a; Odia 1996; Pacor 2006; Pigatto 1990; Schnopp 2002; Sharma 2006; Thestrup‐Pedersen 2001; Veien 1999).

Despite loss of participants during follow‐up, data were analysed according to the ITT analysis principle in 14 studies (Bauer 2012; Belsito 2004; Bissonnette 2010; Chu 2009; Fowler 2014; Granlund 1996; Hill 1998; Hordinsky 2010; Kircik 2013; Polderman 2003; Ruzicka 2004; Ruzicka 2008; van Coevorden 2004a; Veien 1995). NCT01231854 included an ITT analysis but included only 14 of the 78 planned participants due to early termination.

For 23 studies, at least 80% of participants were followed up and were included in the analyses (Agarwal 2013; Baskan 2005; Bleeker 1989; Boroujeni 2017; Burrows 1986; Fairris 1984; Fairris 1985; Fowler 2005; Grattan 1991; Gupta 1993; Jowkar 2011; Kaaber 1983; Kucharekova 2003; Lindelöf 1987; Möller 1983; Said 2010; Sezer 2007; Sheehan‐Dare 1989; Sjövall 1987; Tzaneva 2009; Uggeldahl 1986; Whitaker 1996; Yousefi 2012).

The highest dropout rates were, respectively, 40%, 39%, 37%, and 37% (Cartwright 1987 ; Krejci‐Manwaring 2008; Kemper 1998; Jowkar 2014). Eight studies analysed less than 80% (Adams 2007; Bayerl 1999; Brass 2015; Cartwright 1987; Jowkar 2014, Kemper 1998; King 1984; Krejci‐Manwaring 2008).

For one study, it is unclear how many participants were analysed because the text states that less than 80% finished the protocol; however all participants seem to have been analysed without mention of ITT analyses (Hanifin 2004).

Selective reporting

We found a total 38 studies that we judged as having low risk of bias (Adams 2007; Agarwal 2013; Baskan 2005; Bauer 2012; Bayerl 1999; Belsito 2004; Bissonnette 2010; Bleeker 1989; Brass 2015; Fairris 1984; Fairris 1985; Fowler 2005; Fowler 2014; Granlund 1996; Hanifin 2004; Jowkar 2011; Jowkar 2014; Katsarou 2012; King 1984; Krejci‐Manwaring 2008; Kucharekova 2003; Lindelöf 1987; NCT01231854; Odia 1996; Pacor 2006; Pigatto 1990; Ruzicka 2004; Schnopp 2002; Sezer 2007; Sheehan‐Dare 1989; Sjövall 1987; Thestrup‐Pedersen 2001; Tzaneva 2009; Uggeldahl 1986; van Coevorden 2004a; Veien 1999; Whitaker 1996; Yousefi 2012). We judged 17 studies as having unclear risk of reporting bias (Boroujeni 2017; Burrows 1986; Cartwright 1987; Cherill 2000; Chu 2009; Faghihi 2008; Grattan 1991; Gupta 1993; Hill 1998; Hordinsky 2010; Kaaber 1983; Kircik 2013; Lodén 2012a; Polderman 2003; Ruzicka 2008; Said 2010; Sharma 2006), and five as having high risk of reporting bias (Fredriksson 1975; Kemper 1998; Lauriola 2011; Möller 1983; Veien 1995). High risk of bias was assigned whenever we found severe discrepancies between the Materials and Methods section and the study protocol and Results section, when the stated primary outcome was neglected (Fredriksson 1975), and when significance levels were reached on subscores or on other scores, or were not stated at all (Kemper 1998; Lauriola 2011; Möller 1983). For example, Fredriksson 1975 used an unclear severity scale ranging from 0 to 5 and did not state the results of this outcome at all.

Many, especially older studies, did not register before commencement of the trial, so that the correspondence between actually reported outcomes and outcomes intended to be reported could not be assessed for most included studies. We found trial registration for 13 studies (Adams 2007; Bauer 2012; Bissonnette 2010; Brass 2015; Chu 2009; Fowler 2014; Hordinsky 2010; Jowkar 2011; Kircik 2013; Lodén 2012a; Ruzicka 2008; NCT01231854; Yousefi 2012), and we found discrepancies in Chu 2009,Hordinsky 2010, Kircik 2013,Lodén 2012a, and Ruzicka 2008 with regards to additional or missing outcome parameters. We found no major discrepancies between protocol and report in eight studies (Adams 2007; Bauer 2012; Bissonnette 2010; Brass 2015; Fowler 2014; Jowkar 2011; NCT01231854; Yousefi 2012), although one study was registered two years after the recruitment start date (Yousefi 2012).

For the other studies, we examined discrepancies between the Materials and Methods section and the Results section and noted no major discrepancies in most (Agarwal 2013; Baskan 2005; Bayerl 1999; Belsito 2004; Bleeker 1989; Fairris 1984; Fairris 1985; Fowler 2005; Granlund 1996; Hanifin 2004; Jowkar 2014; Katsarou 2012; King 1984; Krejci‐Manwaring 2008; Kucharekova 2003; Lindelöf 1987; Odia 1996; Pacor 2006; Pigatto 1990; Schnopp 2002; Sezer 2007; Sheehan‐Dare 1989; Sjövall 1987; Thestrup‐Pedersen 2001; Tzaneva 2009; Uggeldahl 1986; van Coevorden 2004a; Veien 1999; Whitaker 1996), although in some studies we did find severe discrepancies, mainly involving missing information (Fredriksson 1975; Kemper 1998; Lauriola 2011; Möller 1983; Veien 1995).

Other potential sources of bias

Baseline comparison for severity of disease and diagnostic certainty

When assessing other potential sources of bias, we considered several aspects, namely, baseline balance for severity of disease and/or participants, diagnostic certainty, and whether the study was completed or ended prematurely.

Diagnostic certainty, meaning that the diagnosis was confirmed by a physician, was applicable to almost all studies. We judged this as low risk in all but one study (Said 2010).

For within‐participant studies, we considered a baseline comparison dispensable. This was true for 18 within‐participant studies (i.e. having a left‐right design, comparing one hand with the other) (Adams 2007; Baskan 2005; Cartwright 1987; Chu 2009; Faghihi 2008; Fairris 1984; Fairris 1985; Fredriksson 1975; Grattan 1991; Kemper 1998; King 1984; Lindelöf 1987; Möller 1983; Odia 1996; Schnopp 2002; Sezer 2007; Sheehan‐Dare 1989; Uggeldahl 1986). For three studies, we found significant differences at baseline and therefore declared them as having unclear risk of bias (Granlund 1996; Hill 1998; Krejci‐Manwaring 2008). Sixteen studies did not state baseline comparisons (Agarwal 2013; Bayerl 1999; Boroujeni 2017; Burrows 1986; Cherill 2000; Kaaber 1983; Kucharekova 2003; Lauriola 2011; Lodén 2012a; Pigatto 1990; Polderman 2003; Said 2010; Sharma 2006; Sjövall 1987; Thestrup‐Pedersen 2001; Tzaneva 2009), and these were unclear in three studies (Bleeker 1989; Jowkar 2011; Whitaker 1996). For the remaining studies, baseline comparisons were clearly stated (Adams 2007; Bauer 2012; Belsito 2004; Bissonnette 2010; Brass 2015; Fowler 2005; Fowler 2014; Gupta 1993; Hanifin 2004; Hordinsky 2010; Jowkar 2014; Katsarou 2012; Kircik 2013; NCT01231854; Pacor 2006; Ruzicka 2004; Ruzicka 2008; van Coevorden 2004a; Veien 1995; Veien 1999; Yousefi 2012).

Studies ending prematurely

Two studies were ended prematurely (Burrows 1986; NCT01231854). Burrows 1986 ended because teratogenicity in rats was reported during the study, and NCT01231854 ended because the investigator‐initiated study was unable to include the planned number of participants. For this, we judged high risk of bias.

In total, we judged the risk of other potential sources of bias as high in two studies, unclear in 21 studies, and low in the remaining 37 studies.

Effects of interventions

See: Summary of findings for the main comparison Corticosteroid creams/ointments: clobetasol propionate foam compared to vehicle foam for hand eczema; Summary of findings 2 Corticosteroid creams/ointments: mometasone furoate cream 3 times/week versus 2 times/week for hand eczema; Summary of findings 3 Irradiation with UV light: local narrow‐band UVB compared to local PUVA for hand eczema; Summary of findings 4 Topical calcineurin inhibitors: tacrolimus 0.1% ointment compared to mometasone furoate ointment for vesicular hand eczema; Summary of findings 5 Topical calcineurin inhibitors: tacrolimus 0.1% ointment versus vehicle for hand eczema; Summary of findings 6 Oral immunosuppressants: oral cyclosporin versus topical betamethasone dipropionate; Summary of findings 7 Oral retinoids: alitretinoin 30 mg versus placebo for hand eczema; Summary of findings 8 Oral retinoids: alitretinoin 10 mg versus placebo for hand eczema

In the text below, where it has been possible to calculate an effect size, we have reported these with 95% confidence intervals. If no data were available for these analyses, we removed the result from this section and mentioned this in Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8, Table 9, and Table 10 for the primary outcome investigator‐rated good/excellent control.

We considered statistical pooling, but the studies were too heterogeneous in terms of design, types of particular treatment compared, assessment of outcomes, duration of the trial, and presentation of data. The exceptions were two studies that compared 10 mg alitretinoin as active treatment versus placebo (Ruzicka 2004; Ruzicka 2008), along with studies regarding topical calcineurin inhibitors with regard to adverse events (Bauer 2012; Belsito 2004; Hordinsky 2010). Beside results of the pooled analysis, these studies also reported heterogeneity statistics. We considered, for example, pooling Brass 2015 and Sezer 2007, although treatment intensity (twice weekly versus thrice weekly) and study duration were too different. Moreover, only limited information was available on Brass 2015. Finally, Sezer 2007 was a within‐participant study, and Brass 2015 was a parallel‐group study.

In the additional tables section, we have tabulated the primary outcome investigator‐rated good/excellent control for the different categories of interventions, that is, corticosteroids, irradiation with UV light, and irradiation with X‐rays (respectively, Table 2Table 4 and Table 5).

I. Skin protection measures, including gloves

We identified no randomised controlled trials.

II. Topical treatments

Comparison 1. Bland emollients: ceramide‐containing emollients

A comparison was made between an emollient with ceramides (Locobase Repair) in 17 participants versus a regular petrolatum‐based emollient (Vaseline‐lanette) in 15 participants (Kucharekova 2003). Results were mainly depicted in graphic presentation (bar diagrams), and exact numbers cannot be extracted.

Primary outcome: adverse events

One participant in the ceramide group experienced an exacerbation of hand dermatitis, as did two participants in the comparison group (risk ratio (RR) 0.44, 95% confidence interval (CI) 0.04 to 4.39; P = 0.49; Analysis 1.1). This showed no clear difference between groups.

Comparison 2. Bland emollients: emollient E‐DO versus vehicle
Primary outcome: percentage of participants with self‐rated good/excellent control at week 4

Chu 2009 conducted a within‐participant study. After four weeks, the percentage of hands with a self‐rated reduction of at least 50% on the participants' global assessment (PaGA) was 34.92% (22 hands) in the E‐DO group, and 36.51% (23 hands) in the vehicle group (reported as 'other data'; see Analysis 2.1).

Primary outcome: percentage of participants with investigator‐rated good/excellent control at week 4

We identified one within‐participant study on E‐DO (Chu 2009). After four weeks, 12 (19.0%) hands responded to E‐DO only, 11 (17.5%) responded to vehicle only, and 25 (39.7%) responded to both. The overall response rate was 37 (58.73%) E‐DO hands and 36 (57.14%) vehicle hands (reported as 'other data'; see Analysis 2.2). Also see Table 1.

Primary outcome: adverse events

At least one adverse event was reported by 19.4% of participants; 12 occurred on the E‐DO hand (17.9%), and eight (11.9%) on the vehicle hand. Prurirtus was recorded for six E‐DO hands and for two vehicle hands (reported as 'other data'; see Analysis 2.3). No serious adverse events were reported.

Comparison 3. Corticosteroid creams or ointments: fluprednidene acetate cream versus betamethasone‐valerate

For an overview of studies on topical corticosteroids for the outcome investigator‐rated good/excellent control, see the additional tables section (Table 2). That overview presents only the primary outcomes as defined according to our protocol (i.e. participant‐ or investigator‐rated good or excellent control); consequently, this does not necessarily reflect the primary outcome that may be stated in the study report.

The point estimates (RRs) and confidence intervals (CIs), if available, are based on the per‐protocol evaluation of participants, and are not based on an ITT analysis, unless stated otherwise. We considered statistical pooling, but the studies were too heterogeneous in terms of design, types of corticosteroid, assessment of outcomes, and presentation of data.

Primary outcome: percentage of participants with investigator‐rated good/excellent control (healed) after three weeks of treatment

In a parallel study (Bleeker 1989), 14 out of 38 participants in the betamethasone group healed, as did 8 of 37 in the fluprednidene group. There was no clear difference between groups (RR 0.59, 95% CI 0.28 to 1.23; Analysis 3.1;Table 2).

Primary outcome: adverse events

Eight participants in the betamethasone group and seven in the fluprednidene group reported adverse events such as redness, smarting, swelling, irritation, or dryness (RR 0.90, 95% CI 0.36 to 2.23; Analysis 3.2), showing no clear differences between groups.

Secondary outcome: reduction in severity, investigator‐rated scoring improvement > 50% after three weeks

After three weeks of treatment, 23 of 38 participants in the betamethasone group and 27 of 37 participants in the fluprednidene group showed improvement greater than 50% (Bleeker 1989). There were no clear differences between groups (RR 1.21, 95% CI 0.87 to 1.67; Analysis 3.3).

Comparison 4. Corticosteroid creams/ointments: betamethasone‐dipropionate film‐forming lotion versus betamethasone‐dipropionate thick lotion

For this comparison, we found only one relevant trial (Gupta 1993).

Primary outcome: percentage of participants with investigator‐rated good/excellent control of symptoms at day 7

Five of the 28 people in the betamethasone‐dipropionate film‐forming lotion group achieved good/excellent symptom control compared to zero of 26 in the control group. Fisher's exact test results in a P value of 0.051 (Analysis 4.1; Table 2).

Primary outcome: adverse events

No clear difference was found in relation to the occurrence of at least one adverse event (RR 1.33, 95% CI 0.33 to 5.44; Analysis 4.2).

In the betamethasone‐dipropionate film‐forming lotion group, two participants had stinging at the application site, one stinging in the eyes when opening the bottle close to the face, and one a "melting" feeling during the sauna visit compared to no application site reactions in the control group (Fisher's exact test P = 0.11). In the thickened lotion group, one participant experienced headache (probably not related to the study drug), and two had an exacerbation of hand eczema, compared to none in the control group (Fisher's exact test P = 1.00 and 0.49; also see Analysis 4.2). Zero events were reported in one of the arms for all of these three subgroups, and the confidence interval around the point of estimate was wide.

Secondary outcome: reduction in severity, investigator‐rated scoring (not specified), and in overall severity at day 7

At day 7, 23 out of 28 participants in the film‐forming group improved compared to 10 out of 26 participants in the thickened lotion group. There may be a difference between corticosteroid creams/ointments in favour of the betamethasone‐dipropionate film‐forming lotion at day 7 (RR 2.30, 95% CI 1.35 to 3.93; number needed to treat for an additional beneficial outcome (NNTB) 2, 95% CI 1 to 5; Analysis 4.3).

Secondary outcome: reduction in severity, investigator‐rated global improvement, of eczema

The global comparison between treatments at day 7 showed improved eczema in 23 of 28 participants treated with polyacrylic film‐forming lotion versus 18 of 26 participants treated with thickened lotion (RR 1.19, 95% CI 0.87 to 1.62; Analysis 4.4), indicating no clear difference in improvement between the two treatments.

Comparison 5. Corticosteroid creams/ointments: clobetasol propionate cream versus intermittent fluprednidene acetate cream
Primary outcome: percentage of participants with investigator‐rated good/excellent control

No relapses were observed in 32 of 46 (70%) hands treated with clobetasol propionate cream and in 14 of 46 (30%) hands treated with fluprednidene acetate cream (Möller 1983). This is reported as 'other data'; see Analysis 5.1 and Table 2.

Primary outcome: adverse events

Adverse events occurred in four participants treated with clobetasol and in three participants treated with fluprednidene (reported as 'other data' in Analysis 5.2). One participant reported an adverse event from both glucocorticoids.

Comparison 6. Corticosteroid creams/ointments: clobetasol propionate foam 0.05% versus vehicle foam

This comparison included one study of 125 participants (Kircik 2013).

Primary outcome: percentage of participants with investigator‐rated good/excellent control at day 15

In the clobetasol group, 38.7% (24/62 participants) had an Investigator Static Global Assessment (ISGA) score of 0 or 1 versus 27% (17/63 participants) in the vehicle group. There was no clear difference between groups (RR 1.43, 95% CI 0.86 to 2.40; Analysis 6.1;summary of findings Table for the main comparison; Table 2).

Primary outcome: percentage of participants with self‐rated good/excellent control at day 15

At the end of the study on day 15, 51.6% (32/62 participants) in the clobetasol group graded their hand eczema as clear or almost clear versus 22.2% (14/63 participants) in the vehicle group using the subject's global assessment (SGA). The relative risk of 2.32 favours clobetasol propionate foam over vehicle (RR 2.32, 95% CI 1.38 to 3.91; NNTB 3, 95% CI 2 to 8; Analysis 6.2; summary of findings Table for the main comparison).

Primary outcome: adverse events

Adverse events were reported in 18% (11/62) of participants in the clobetasol propionate foam group and in 8% (5/63) of those in the vehicle foam group (RR 2.24, 95% CI 0.82 to 6.06; Analysis 6.3; summary of findings Table for the main comparison). One participant reported application site burning/pruritus after clobetasol foam application. Three participants in the clobetasol group reported nasopharyngitis compared to one participant in the control group (RR 3.05, 95% CI 0.33 to 28.52; Analysis 6.3). No serious adverse events were reported in the clobetasol propionate foam group, and one participant in the vehicle group discontinued due to severe fissures (RR 0.34, 95% CI 0.01 to 8.16; Analysis 6.3). The wide confidence interval in this case could in part be the result of zero events in the clobetasol propionate foam group.

Secondary outcome: reduction in severity, participant‐rated scoring, at day 15

At the end of treatment, 51 out of 62 participants (82.3%) had at least one grade improvement in SGA score, compared to 33 out of 63 participants (52.4%) in the vehicle group (RR 1.57, 95% CI 1.21 to 2.04; NNTB 3, 95% CI 2.2 to 7; Analysis 6.4; summary of findings Table for the main comparison). This difference is statistically significant, but we have reduced confidence in it is clinical significance due to small sample size and limitation in study design.

Secondary outcome: reduction in severity, investigator‐rated scoring, at day 15

In Kircik 2013, 26 out of 62 participants (41.9%) in the clobetasol group versus 18 out of 63 (28.6%) in the control group improved by two grades or more in ISGA score. There was no clear difference between groups (RR 1.47, 95% CI 0.90 to 2.39; Analysis 6.5).

In total, 45 participants (72.6%) in the clobetasol group versus 38 (60.3%) in the control group improved by at least one grade in ISGA score after 15 days of treatment. Again, there was no clear difference between groups (RR 1.20, 95% CI 0.94 to 1.55; Analysis 6.5).

Comparison 7. Corticosteroid creams/ointments: desonide cream 0.1% versus desonide cream 0.05%

Two strengths of the same topical corticosteroid were compared in a study using a within‐participant (left/right) design (Uggeldahl 1986). Forty‐six participants were treated twice daily with desonide (Tridesilone) cream 0.1% on one hand and desonide (Apolar) cream 0.05% on the other hand. These participants had not been treated for eczema for at least one week before the study. The duration of the study was only 14 days.

Primary outcome: adverse events

Two participants reported stinging upon application of desonide 0.05% cream (reported as 'other data'; Analysis 7.1).

Comparison 8. Corticosteroid creams/ointments: intermittent treatment with topical mometasone furoate at different frequencies (long term)

Veien 1999 included participants with chronic hand eczema that had cleared upon daily treatment for a maximum of 9 weeks with mometasone furoate cream.

Primary outcome: percentage of participants with investigator‐rated good/excellent control

Mometasone furoate 3 times/week versus mometasone furoate 2 times/week

For this subgroup, we found only one relevant trial (n = 72) (Veien 1999). Among participants treated with mometasone three times a week, 29 out of 35 (83%) had no recurrences, compared to 25 out of 37 (68%) of those treated with mometasone two times a week. Mometasone furoate cream used thrice weekly may slightly improve investigator‐rated good/excellent control of symptoms when compared to twice weekly application; however, the 95% confidence interval does include 1 (RR 1.23, 95% CI 0.94 to 1.61; Analysis 8.1; summary of findings Table 2Table 2).

Mometasone furoate 3 times/week versus emollients only

For this subgroup, we found only one relevant trial (n = 69) (Veien 1999). We noted a clear difference between corticosteroid creams/ointments: mometasone furoate cream 3 times weekly versus no steroids (RR 3.13, 95% CI 1.75 to 5.59; NNTB 2, 95% CI 1 to 3; Analysis 8.2;Table 2), but the difference may not be clinically significant due to imprecision of results caused by small sample size and limitations in study design/conduct.

Mometasone furoate 2 times/week versus emollients only

For this subgroup, we found only one relevant trial (n = 71) (Veien 1999). There was a statistically significant difference between corticosteroid creams/ointments: mometasone furoate cream 2 times weekly versus no steroids (RR 2.55, 95% CI 1.40 to 4.67; NNTB 2, 95% CI 2 to 5; Analysis 8.2), i.e. mometasone furoate twice a week was better than emollient only, but again, the difference may not be clinically significant due to imprecision of results caused by small sample size and limitations in study design/conduct.

Primary outcome: adverse events

Mometasone furoate 3 times/week versus mometasone furoate 2 times/week

In 10 participants, mild skin atrophy was noted at some point during the study. In five participants, atrophy disappeared during the study, and five participants had mild atrophy at the end of the study. The difference between groups was not clear (RR 1.76, 95% CI 0.45 to 6.83; Analysis 8.3; summary of findings Table 2).

Comparison 9. Corticosteroid creams/ointments: 0.05% clobetasol and 2.5% zinc sulphate cream versus 0.05% clobetasol cream

Faghihi 2008 investigated whether zinc sulphate added to clobetasol cream is effective in the treatment of chronic hand eczema (n = 47 hands).

Primary outcome: percentage of participants with investigator‐rated good/excellent control

After eight weeks, 25 out of 47 hands (53%) treated with clobetasol + zinc sulphate cream were clear from scaling compared to three hands (6%) treated with clobetasol cream alone (presented as 'other data' in Analysis 9.1;Table 2). Regarding erythema, 41 hands (87%) treated with clobetasol + zinc sulphate cream were clear after eight weeks compared to one hand (2%) treated with clobetasol cream alone (reported as 'other data' in Analysis 9.1). Last, 24 hands (51%) treated with clobetasol + zinc sulphate cream and seven hands (15%) treated with clobetasol cream alone were clear of lichenification (reported as 'other data' in Analysis 9.1). Absence of scaling, redness, and/or lichenification was seen as investigator‐rated good/excellent control. An overall assessment of good/excellent control was not possible.

Primary outcome: adverse events

Treatments were well tolerated and no significant adverse events were reported or observed by participants in both groups. Trial authors concluded that treatments were generally well tolerated (no exact data given).

Comparison 10. Corticosteroid creams/ointments: betamethasone‐valerate 0.1% cream twice daily versus betamethasone‐valerate 0.1% cream and urea 5% cream

Lodén 2012a compared the application of betamethasone‐valerate 0.1% cream twice daily versus the application of betamethasone‐valerate 0.1% cream in the morning and a moisturiser containing urea 5% cream in the evening.

Primary outcome: percentage of participants with investigator‐rated good/excellent control (cleared)

For this outcome, we found only one relevant trial (Lodén 2012a; n = 44). Clearance was defined as a score ≤ 3 on the HEES. There was no clear difference between betamethasone‐valerate 0.1% cream (15 out of 22) and urea 5% cream (20 out of 22) (RR 0.75, 95% CI 0.55 to 1.03; Analysis 10.1;Table 2).

Secondary outcome: reduction in severity, participant‐rated

For this outcome, we found only one relevant trial (Lodén 2012a; n = 44). The average reduction in VAS (mm) was 36.3 in the betamethasone‐valerate 0.1% cream (BV) twice daily treatment group compared with 54.0 in the betamethasone‐valerate and urea (BV + M) group. The mean difference with regards to the VAS score was ‐17.70, although the relatively wide confidence interval did borderline include zero; therefore the results should be interpreted with caution (mean difference (MD) ‐17.70, 95% CI ‐35.42 to 0.02; Analysis 10.2).

Secondary outcome: reduction in severity, investigator‐rated

For this outcome, we found only one relevant trial (Lodén 2012a; n = 44). After two weeks, the average reduction in HEES was 12.5 (standard deviation (SD) 13.9) in the BV group compared to 10.5 (SD 9.0) in the BV + M group. There was no clear difference between groups (MD 2.00, 95% CI ‐4.92 to 8.92; Analysis 10.3).

Comparison 11. Topical others: coal tar paste versus betamethasone‐valerate ointment 0.1% versus zinc oxide paste

In an unblinded randomised within‐participant study (Kemper 1998), the efficacy of pix lithanthracis (coal tar paste) compared to zinc oxide paste and betamethasone‐valerate was investigated (n = 19). Also see Table 3.

Primary outcome: adverse events

Six participants dropped out because they experienced problems with wearing gloves (the specific type of problem is not identified). One participant dropped out due to pompholyx as a result of allergy to 5% pix lithanthracis (reported as 'other data' in Analysis 11.1).

Comparison 12. Irradiation with UV light: UVB versus no UVB

For the phototherapy studies (UVA, UVB, PUVA), pooling was considered for two studies with data comparing UVB with no UVB or placebo (Bayerl 1999; Sjövall 1987); however, we found these studies too heterogeneous in terms of design, outcome assessment, and presentation of data to do so.

Treatment with a portable UVB phototherapy unit, to be used at home, was compared to no UVB treatment in a study among 48 participants with occupational hand dermatitis (Bayerl 1999).

Primary outcome: adverse events

In both groups, two participants showed an exacerbation. Other adverse events were stinging and burning sensations in some participants, which limited the increase in UVB therapy (RR 1.00, 95% CI 0.15 to 6.53; Analysis 12.1).

Comparison 13. Irradiation with UV light: whole body UVB versus placebo or local UVB hands
Primary outcome: percentage of participants with investigator‐rated good/excellent control (cleared)

Local UVB hands alone versus placebo

For this subgroup, we found only one relevant trial. Three groups were compared in a trial of 18 participants with chronic hand eczema, and data for 10 participants were available (Sjövall 1987). Among participants receiving local UVB, two cleared, while in the group receiving filtered light (placebo UVB), one participant cleared (RR 2.00, 95% CI 0.26 to 15.62; Analysis 13.1;Table 4), but the confidence interval for the RR did not indicate clear differences between groups.

Whole‐body UVB + local UVB hands versus placebo

For this subgroup, we found only one relevant trial (Sjövall 1987; n = 10). Five out of five participants in the whole‐body UVB group showed good symptom control compared to one in the control group (RR 3.67, 95% CI, 0.90 to 14.97; Analysis 13.1;Table 4). However, the confidence interval around the effect estimate was wide and imprecise.

Whole‐body UVB + local UVB hands versus local UVB hands alone

Five participants in the whole‐body UVB irradiation group had good symptom control compared to two in the control group, but due to the small sample size, the intervention group did not demonstrate clear advantage over the group given local UVB of the hands alone (RR 2.20, 95% CI 0.83 to 5.84; Analysis 13.1;Table 4).

Primary outcome: adverse events

Adverse events were not seen in either group.

Secondary outcome: time until relapse (low score = better outcome)

A postal follow‐up questionnaire three months after completion of treatment asked participants about the course of their hand dermatitis: the number of weeks in remission was presented in a descriptive way. In the local UVB group, two participants were still in remission after 15 weeks. The other three participants relapsed after 1 to 12 weeks (median 5 weeks). In the UVB local + whole‐body group, all participants relapsed within 3 to 10 weeks (median 6 weeks). The participant in the placebo group who had reached remission relapsed after three weeks. This difference was not statistically significant for local UVB hands alone versus placebo (MD 4.10, 95% CI ‐3.25 to 11.45); for whole‐body UVB + local UVB hands versus placebo (MD 0.50, 95% CI ‐4.98 to 5.98); nor for whole body UVB + local UVB hands versus local UVB hands alone (MD ‐3.60, 95% CI ‐9.68 to 2.48) (Analysis 13.2).

Comparisons 14 and 15. Irradiation with UV light: local narrow‐band UVB versus local PUVA

For this outcome, we found two relevant trials (Sezer 2007, n = 24; and Brass 2015, n = 60). Brass 2015 was a parallel‐group study that investigated local narrow‐band UVB twice weekly compared to local PUVA twice weekly over a period of 12 weeks. Sezer 2007 studied local narrow‐band UVB thrice weekly for nine weeks compared to local PUVA thrice weekly in a left‐right study.

Primary outcome: percentage of participants with investigator‐rated good/excellent control (clearance) in UVB versus PUVA

In Brass 2015, six out of 30 participants treated with narrow‐band UVB improved compared to 12 out of 30 participants on local PUVA after 12 weeks (RR 0.50, 95% CI 0.22 to 1.16; Analysis 14.1;summary of findings Table 3; Table 4).

In Sezer 2007, two out of 12 hands treated with UVB cleared (17%). On the PUVA‐treated side, one hand cleared (8%), as presented in Analysis 15.1 and in Table 4.

Primary outcome: adverse events

Brass 2015 reported no serious treatment‐related adverse events. An adverse event (mainly erythema) was reported in nine participants treated with local narrow‐band UVB and in none of the participants treated with local PUVA (Fisher's exact test P = 0.0019; RR 19.00, 95% CI 01.16 to 312.42; Analysis 14.2; summary of findings Table 3).

In Sezer 2007, one participant dropped out because of an exacerbation of eczema in both hands (unclear from which group). Palmar hyperpigmentation due to PUVA was observed in three participants (see Analysis 15.2).

Secondary outcome: reduction in severity, investigator‐rated, by local narrow‐band UVB versus local PUVA

The data for Brass 2015 were not reproducible; however in the PUVA group, the mTLSS was reduced from a median of 8.5 (range 0 to 16) and 8 (range 3 to 15) for the left and right hand, to a median of 3 (range 0 to 13) and 3 (range 0 to 14) (n = 23). In the local narrow‐band UVB group, the median mTLSS was reduced from 7 (range 0 to 16) and 8.5 (range 1 to 15) to 5 (range 0 to 11) and 4.5 (range 0 to 11) after 12 weeks of treatment (n = 20) (summary of findings Table 3).

We identified Sezer 2007 as the only relevant trial for this comparison (Sezer 2007, n = 24). For both treatments, researchers observed a marked clinical improvement in nine out of 12 hands (75%). The difference in total clinical scores between irradiation with UV light, local narrow‐band UVB, and local PUVA was not clear (see Analysis 15.3).

Comparison 16. Irradiation with UV light: oral PUVA versus topical bath PUVA

Two studies investigated oral PUVA and bath PUVA (Tzaneva 2009; van Coevorden 2004a); however because the designs of these studies were substantially different, and because van Coevorden 2004a mainly focused on the at‐home versus hospital‐based version, we did not pool these studies. Also see Table 4.

Primary outcome: adverse events

van Coevorden 2004a included only adverse events that constituted a reason to discontinue. From the oral/home PUVA group, three participants dropped out because of adverse events (nausea). From the hospital/bath PUVA group, one dropped out because of adverse events (burn). There were no clear differences between groups (nausea Fisher's exact test P = 0.1180; RR 7.18, 95% CI 0.38 to 136.71; burn Fisher's exact test P = 1.00; RR 0.34, 95% CI 0.01 to 8.26; Analysis 16.1).

In Tzaneva 2009, investigators gave oral PUVA (8‐methoxypsoralen capsules) to 14 participants and topical bath PUVA therapy with 8‐methoxypsoralen to 13 participants. Erythema occurred in 10 participants (71%) in the oral PUVA group, and in eight participants (62%) in the bath PUVA group (Fisher's exact test P = 0.49; RR 1.16, 95% CI 0.67 to 2.00; Analysis 16.1). In the oral PUVA group, 10 participants reported nausea (Fisher's exact test P = 0.0002; RR 19.60, 95% CI 1.26 to 304.14; number needed to treat for an additional harmful outcome (NNTH) 1, 95% CI 1 to 2), five reported dizziness (Fisher's exact test P = 0.04; RR 10.27, 95% CI 0.62 to 169.16), and three reported headache (Fisher's exact test P = 0.22; RR 6.53, 95% CI 0.37 to 115.49). Adverse events were observed most often at the beginning of therapy and improved during subsequent treatments. None of these adverse events led to dropouts.

With the exception of 'erythema', all other subgroups in this outcome had zero events in one of the arms, which could have been responsible in part for the wide confidence interval around the point of estimate, and for which FIsher's exact test was used.

Secondary outcome: reduction in severity, investigator‐rated improvement, in mean eczema scores at week 10

For this outcome, we found only one relevant trial (van Coevorden 2004a, n = 158). At the end of the treatment phase (10 weeks) in the home PUVA group, 56/78 participants (72%) showed improvement (mean 3.3, SD 3.8) versus 49/80 participants (61%) in the hospital/bath PUVA group (mean 2.5, SD 3.4) (MD 0.80, 95% CI ‐0.33 to 1.93; Analysis 16.2).

Secondary outcome: reduction in severity, investigator‐rated improvement, in mean scores at week 18 (low score = better outcome)

For this outcome, we found only one relevant trial (van Coevorden 2004a, n = 158). At eight weeks after the treatment phase, the reduction in mean score from baseline was 3.1 (SD 4.05) versus 2.7 (SD 3.4), respectively; there was no clear difference between irradiation with UV light: oral PUVA and topical bath PUVA (MD 0.40, 95% CI ‐0.77 to 1.57; Analysis 16.3).

Comparison 17. Irradiation with UV light: topical PUVA versus UVA

In a 16‐week within‐participant (left‐right) study, topical PUVA was compared with UVA (Grattan 1991) in 15 participants (n = 30 hands).

Primary outcome: adverse events

Only one participant who completed the study experienced a burning sensation on the back of his PUVA‐treated hand (see Analysis 17.1). Probably two participants had to be withdrawn due to exacerbation of eczema ‐ one from each group (see Analysis 17.1).

Comparison 18. Irradiation with UV light: UVA‐1 versus betamethasone‐valerate 0.1% cream

Irradation with UVA‐1 three times a week was compared to topical betamethasone‐valerate 0.1% twice a day over a six‐week period in 47 participants (Said 2010).

Primary outcome: adverse events

Tolerance of both treatments was good. The only adverse event noted was post‐phototherapy pigmentation, which occurred in 18 of the 24 participants treated with UVA‐1 compared to none of the participants in the control group (Fisher's exact test P = 0.0001; RR 35.52, 95% CI 2.26 to 557.08; NNTH 1, 95% CI 1 to 2; Analysis 18.1). Zero events in the control group is likely to explain the wide confidence interval.

Comparison 19. Irradiation with UV light: UVA‐1 versus placebo

UVA‐1 irradiation for three weeks in 15 participants with dyshidrotic hand eczema was compared with placebo (simulated blue light) in 13 participants (Polderman 2003).

Primary outcome: adverse events

Apart from some minor erythemal reactions, no adverse events occurred. Three of 13 participants in the placebo group dropped out after two weeks because of exacerbation, but no clear differences was identified between groups (Fisher's exact test P = 0.2258; RR 0.13, 95% CI 0.01 to 2.22; Analysis 19.1). Zero events in the intervention group is likely to explain the wide confidence interval.

Secondary outcome: reduction in severity of itch, participant‐rated decrease in VAS, at week 3 (higher score = greater reduction)

For this outcome, we found only one relevant trial (Polderman 2003, n = 28). Although there was a notable difference between irradiation with UV light: UVA‐1 (mean 2.31, SD 2.01) and placebo (mean ‐1.37, SD 4.05) with regards to VAS scores for itch (MD 3.68, 95% CI 1.25 to 6.11; Analysis 19.2), we have low confidence about the strength of the finding due to limited sample size (i.e. imprecision).

Secondary outcome: reduction in severity, investigator‐rated improvement in DASI, at week 3 (higher score = greater reduction)

In the same group of participants (Polderman 2003), the severity score on the Dyshydrotic eczema Area and Severity Index (DASI) decreased in the UVA‐1 group (mean 8.67, SD 6.72) compared to the placebo group (mean ‐0.38, SD 8.87) in week 3 (MD 9.05, 95% CI 3.15 to 14.95; Analysis 19.3).

Comparison 20. Irradiation with UV light: PUVA versus UVA‐1

In a within‐participant study, the effectiveness of middle‐dose UVA‐1 irradiation was compared with topical cream PUVA therapy in 15 participants with chronic relapsing dyshidrotic hand eczema (Adams 2007).

Primary outcome: adverse events

Burning occurred in three participants in the topical cream PUVA group and in one participant in the UVA‐1 group, and increased pruritus occurred in five participants in the topical PUVA group versus three in the UVA‐1 group (Analysis 20.1).

Comparison 21. Irradiation with X‐rays (ionising radiation)

Among trials evaluating the effects of ionising radiation (X‐rays), we considered pooling the results of four studies comparing X‐rays with placebo irradiation (Cartwright 1987; Fairris 1984; King 1984; Lindelöf 1987), but dosages, presentation of results, and follow‐up times were considered too heterogeneous in most cases. Moreover, all these studies used a within‐participant design (i.e. comparing one hand versus the contralateral hand). Superficial X‐ray irradiation on one hand was compared with topical PUVA on the contralateral hand in 25 participants (Sheehan‐Dare 1989). Also see Table 5.

Comparison 21A. Irradiation with X‐rays: X‐rays versus placebo
Primary outcomes: percentage of participants with investigator‐rated good/excellent control

After one month in seven out of 15 participants, hands treated with X‐rays were categorised as showing good response (defined as 'clear' or 'nearly clear'), whereas all 15 placebo‐treated hands were categorised as showing poor response (defined as 'partly clear', 'no change', or 'relapse') (King 1984; see Analysis 21.1 and Table 5). After three months, ten irradiated hands and six placebo‐treated hands were categorised as showing good response (see Analysis 21.1), and after six months there was a good response in 11 irradiated and eight placebo‐treated hands (see Analysis 21.1). There were no clear differences between groups.

Primary outcome: adverse events

No systemic or local adverse events were noted.

Comparison 21B. Irradiation with X‐rays: Grenz ray

The effect of 3 Gy Grenz ray therapy six times in weekly intervals was investigated in within‐participant studies (Lindelöf 1987; 24 participants, 48 hands in a within‐participant design; Cartwright 1987; 30 participants, 60 hands in a within‐participant design).

Primary outcome: adverse events

Six participants had hyperpigmentation in treated hands, and no participants in the placebo group experienced adverse events (see Analysis 21.2); however, there is no clear difference between groups.

Comparison 21C. Irradiation with X‐rays: X‐rays versus Grenz rays

A within‐participant study on 25 participants compared superficial X‐ray and Grenz ray irradiation (Fairris 1985).

Primary outcome: adverse events

Fairris 1985 reported no adverse events from either therapy.

Comparison 22. Topical calcineurin inhibitors: tacrolimus ointment versus mometasone furoate

An overview of all of the studies on topical calcineurin inhibitors can be found in Table 6.

The current comparison included two studies (Schnopp 2002, n = 16; Katsarou 2012, n = 30).

Primary outcome: adverse events

Both treatments were well tolerated. None of the participants in Schnopp 2002 dropped out because of adverse events.

Katsarou 2012 investigated adverse events but did not report any.

Secondary outcome: reduction in severity, investigator‐rated

Although the reduction in mean DASI equalled improvement in scores for both treatments after two weeks, no clear difference was found between groups. The mean DASI score was reduced from 18 (SD 12.68) to 6.6 (SD 6.18) in the tacrolimus group, and from 18.5 (SD 14.09) to 6.9 (SD 7.7) in the mometasone furoate group, respectively (Schnopp 2002; see Analysis 22.1 and summary of findings Table 4).

Comparison 23. Topical calcineurin inhibitors: tacrolimus 0.1% ointment versus vehicle cream

Two studies addressed this comparison (Krejci‐Manwaring 2008, n = 32; Pacor 2006, n = 28).

Primary outcome: percentage of participants with investigator‐rated good/excellent control (remarkable improvement/complete remission)

Pacor 2006: In the tacrolimus group, complete remission at the end of treatment was observed in six participants (6/14), and remarkable improvement in eight participants (8/14). Treatment with vehicle cream did not lead to remarkable improvement (0/14) and led to only mild improvement in 4 of 14 participants (Fisher's exact test P = 0.0001; RR 29.00, 95% CI 1.90 to 443.25; NNTB 1, 95% CI 1 to 1; Analysis 23.1; summary of findings Table 5Table 6). Zero events in the control group is likely to explain the wide confidence interval.

Primary outcome: adverse events

In Krejci‐Manwaring 2008, researchers observed one case of each of the following adverse events: acute contact dermatitis at the site of the necklace, flare of atopic dermatitis on the foot, acne‐like rash on the face, leg cramps, and worsening of hand dermatitis. Stinging was not reported.

In Pacor 2006, four participants (4/14) in the tacrolimus group experienced transient burning and itching at the application site, which was well tolerated (Fisher's exact test P = 0.1129; RR 9.00, 95% CI 0.53 to 152.93; Analysis 23.2; summary of findings Table 5).

RR given above is based on zero events in one arm, which is likely to explain the wide confidence interval.

Comparison 24. Topical calcineurin inhibitors: pimecrolimus 1% cream versus vehicle

Five of the included studies addressed this comparison: Belsito 2004 (n = 294), Hordinsky 2010 (n = 652), Bauer 2012 (n = 36), Cherill 2000 (n = 48), and Baskan 2005 (n = 25).

Primary outcome: percentage of participants with investigator‐rated good/excellent control (clear or almost clear) with pimecrolimus cream versus vehicle at three weeks

For this subgroup, we found only one relevant trial (Belsito 2004, n = 294). In all, 42 of 151 versus 26 of 143 participants had good investigator‐rated symptom control in intervention and control groups, respectively. The favourable outcome for pimecrolimus was borderline because the confidence interval includes 1 and therefore should be interpreted with care (RR 1.53, 95% CI 0.99 to 2.36; NNTB 10, 95% CI 5 to 1111; Analysis 24.1). When the subgroups were analysed based on aetiology, we did not find significant differences for irritant, allergic, or endogenous hand eczema (Analysis 24.1;Table 6).

Primary outcome: percentage of participants with investigator‐rated good/excellent control (clear or almost clear) with pimecrolimus cream versus vehicle at six weeks

For this subgroup, we found only one relevant trial (Hordinsky 2010, n = 652). Treatment success (IGA score 0 = clear and 1 = almost clear) was achieved in 97 of 325 participants (29.8%) in the pimecrolimus cream 1% group and in 76 of 327 participants in the vehicle group. Favourable outcomes for pimecrolimus were borderline significant because the confidence interval included 1 and should be interpreted with care (RR 1.28, 95% CI 0.99 to 1.66; Analysis 24.1).

Primary outcome: adverse events

Bauer 2012, Belsito 2004, and Hordinsky 2010 reported adverse events (Analysis 24.2). Hordinsky 2010 found no clear differences between groups in terms of treatment‐related erythema or irritation (RR 0.56, 95% CI 0.30 to 1.06; n = 652); itching (RR 0.89, 95% CI 0.52 to 1.53; n = 652); warmth, stinging, and burning (RR 0.82, 95% CI 0.52 to 1.29; n = 652); or herpes simplex infection (RR 0.60, 95% CI 0.15 to 2.51; n = 652). No adverse events were stated in Cherill 2000 and Baskan 2005.

Secondary outcome: reduction in severity, participant‐rated

For pruritus relief between pimecrolimus 1% and vehicle, we found only one relevant trial (Hordinsky 2010, n = 652). There appears to be greater pruritus relief in the intervention group (pimecrolimus 1% cream) than in the vehicle group (RR 1.15, 95% CI 1.06 to 1.25; NNTB 9, 95% CI 6 to 22; Analysis 24.3); however, benefit relative to the control group appears to be marginal.

Secondary outcome: time until relapse

Time to relapse was compared between pimecrolimus 1% cream and vehicle in Bauer 2012 (n = 36). Time to relapse did not differ significantly between groups according to the trial authors (pimecrolimus: 39.35 days; vehicle: 33.19 days); this was represented in a survival graph. We were unable to reproduce these analyses.

Comparison 25. Topical antibacterial agents: betamethasone‐valerate/clioquinol cream versus betamethasone‐valerate/fusidic acid
Primary outcomes: percentage of participants with investigator‐rated good/excellent control (intention‐to‐treat) after four weeks

For this outcome, we found one relevant trial (Hill 1998, n = 120). In the ITT analysis, 34 of 62 participants (54.8%) in the betamethasone‐valerate/clioquinol group and 31 of 58 (53,4%) in the betamethasone‐valerate/fusidic acid group had a good response (RR 1.03, 95% CI 0.74 to 1.43; Analysis 25.1;Table 7).

Primary outcome: adverse events

In the clioquinol group, 11 of 62 participants experienced adverse events versus nine of 58 participants in the fusidic acid group (RR 1.14, 95% CI 0.51 to 2.56; Analysis 25.2). Several other adverse events were observed, including chest infection (1/62 versus 0/58), application‐related irritation (5/62 versus 5/58), deterioration of eczema (4/62 versus 4/58), eye watering (1/62 versus 0/58), hands coloured yellow (1/62 versus 0/58), hands feeling thick (0/62 versus 1/58), and vesicle on the hands (0/62 versus 1/58), but none of these showed between‐group differences (Analysis 25.2).

As shown above, quite a few subgroups under this outcome had zero events in one of the arms; this is likely to explain the wide 95% confidence interval.

Comparison 26. Topical retinoids: bexarotene 1% gel versus bexarotene with corticosteroids
Primary outcomes: percentage of participants with investigator‐rated good/excellent control (> 90% clearance on physician response rates)

Treatment success (> 90% clearance) was achieved by 39% in the bexarotene only group, by 46% in the B + MF group, and by 21% in the B + HC group.

Bexarotene only versus bexarotene + mometasone

For this subgroup, we found only one relevant trial (Hanifin 2004, n = 41). There was no clear difference between topical retinoids: bexarotene 1% gel and bexarotene with mometasone (RR 0.85, 95% CI 0.40 to 1.8; Analysis 26.1;Table 7).

Bexarotene only versus bexarotene + hydrocortisone

For this subgroup, we found only one relevant trial (Hanifin 2004, n = 42). There was no clear difference between topical retinoids: bexarotene 1% gel and bexarotene with hydrocortisone (RR 1.83, 95% CI 0.61 to 5.53; Analysis 26.1;Table 7).

Bexarotene + mometasone versus bexarotene + hydrocortisone

For this subgroup, we found only one relevant trial (Hanifin 2004, n = 27). There was no clear difference between topical retinoids: bexarotene 1% gel and mometasone versus bexarotene with hydrocortisone (RR 2.15, 95% CI 0.67 to 6.89; Analysis 26.1;Table 7).

Primary outcome: adverse events

Forty‐one participants (75%) had one or more adverse events during the study, of whom 27 (49%) had one or more events possibly related to the study drugs. The bexarotene group had irritation/rash in eight participants; stinging/burning in two; and dermatitis flare in five. The B + MF group had irritation/rash in four participants and stinging/burning in four participants. The B + HC group had irritation/rash in four participants; stinging/burning in four participants, and dermatitis flare in zero participants (which is likely to explain the wide 95% confidence interval). None of the adverse events occurred significantly more often in a study or control group (Analysis 26.2; Analysis 26.3).

Secondary outcome: reduction in severity, investigator‐rated: > 90% and > 50% reduction in hand eczema area and severity index (HEASI)

The percentage with > 90% reduction in Hand Eczema Area and Severity Index (HEASI) score in the bexarotene only group was 36%, in the B + MF group 38%, and in the B + HC group 14%. But there was no clear difference between groups according to the study authors. For > 50% reduction in HEASI, the percentages were, respectively, 79%, 85%, and 64%.

Bexarotene only versus bexarotene + mometasone

For this subgroup, we found only one relevant trial (Hanifin 2004, n = 41). There was no clear difference between topical retinoids: bexarotene 1% gel and bexarotene with mometasone (RR 0.93, 95% CI 0.69 to 1.26; Analysis 26.4).

Bexarotene only versus bexarotene + hydrocortisone

For this subgroup, we found only one relevant trial (Hanifin 2004, n = 42). There was no clear difference between topical retinoids: bexarotene 1% gel and bexarotene with hydrocortisone (RR 1.22, 95% CI 0.79 to 1.89; Analysis 26.4).

Bexarotene + mometasone versus bexarotene + hydrocortisone

For this subgroup, we found only one relevant trial (Hanifin 2004, n = 27). There was no clear difference between topical retinoids: bexarotene 1% gel and mometasone versus bexarotene with hydrocortisone (RR 1.32, 95% CI 0.84 to 2.07; Analysis 26.4).

Comparison 27. Other topical agents: calmurid versus Aquacare

A within‐participant study compared topical Aquacare HP cream to a calmurid cream (Fredriksson 1975).

Primary outcome: adverse events

In the calmurid group, 13 participants experienced a burning sensation upon application compared to no adverse events in the Aqua HP group (see Analysis 27.1).

Comparison 28. Fumaric acid 5% cream versus triamcinolone 0.1% cream

This study compared topical fumaric acid twice daily to triamcinolone cream twice daily for four weeks in 58 participants (Jowkar 2014).

Primary outcome: adverse events

Erythema and pruritus were noted in two participants in each treatment group (RR 0.93, 95% CI 0.14 to 6.18; Analysis 28.1).

Comparison 29. Furpalmate 0.3% cream versus hydrocortisone acetate 0.5% cream
Primary outcome: percentage of participants with investigator‐rated and/or self‐rated good/excellent control (complete remission)

For this outcome, we found only one relevant trial (Lauriola 2011, n = 40). In the study report, treatments were shown to be equally effective in "curing" or "improving" hand dermatitis after 14 days. In the furpalmate group, 18 of 20 participants (90%) were cured or improved after 14 days, and this occurred in 20 of 20 participants in the hydrocortisone group (100%) (RR 0.90, 95% CI 0.76 to 1.07; Analysis 29.1;Table 7).

Comparison 30. Fumaria parviflora versus vehicle cream

Studies using a parallel‐group design compared use of 2% Nigella sativa L. (family Ranunculaceae) ointment (a traditional medicine) twice daily with 0.1% betamethasone ointment twice daily and with Eucerin cream twice daily in 60 participants over four weeks (Yousefi 2012, n = 60).

A parallel‐group study (Jowkar 2011, n = 44) compared the effect of an extract of 4% Fumaria parviflora Lam. cream twice a day versus vehicle cream (placebo) twice daily in 44 participants for four weeks.

Primary outcome: adverse events

Yousefi 2012 reported no adverse events for treatment with Nigella sativa L. and Eucerin cream.

In Jowkar 2011, one participant dropped out due to development of redness and papules in the Fumaria parviflora Lam. cream group (RR 3.00, 95% CI 0.13 to 69.87; Analysis 30.1). Zero events in the vehicle group is likely to explain the wide confidence interval and Fisher's exact test results with a P value of 1.00.

III. Systemic treatments

We identified no randomised controlled trials on oral corticosteroids.

Comparison 31. Oral immunosuppressants: oral azathioprine and topical clobetasol propionate versus topical clobetasol propionate only

Agarwal 2013 compared oral azathioprine with topical clobetasol propionate 0.05% cream to topical clobetasol propionate 0.05% cream alone in 108 participants; 91 participants completed the trial.

Primary outcome: percentage of participants with investigator‐rated good/excellent control

After eight weeks, 36.95% in the clobetasol only group had a good response (defined as 75% improvement in signs and symptoms) versus 73.3% in the clobetasol with additional azathioprine 50 mg group (RR 1.98, 95% CI 1.31 to 3.01; NNTB 3, 95% CI 2 to 6; Analysis 31.1). After 24 weeks, 39.13% in the clobetasol only group improved, as did 91.1% in the clobetasol and azathioprine group (RR 2.33, 95% CI 1.61 to 3.38; NNTB 2, 95% CI 1 to 3; Analysis 31.1; Table 8).

Primary outcome: adverse events

No adverse events that would require reduction of dosage or discontinuation of treatment were reported.

Secondary outcomes: reduction in severity, investigator‐rated (higher score = greater reduction)

This was measured by the hand eczema severity index (HECSI): after 24 weeks, 64.66% in the control group showed improvement, as did 91.29% in the intervention group (MD 10.79, 95% CI 4.77 to 16.81; Analysis 31.2).

Secondary outcome: reduction in severity of itch, participant‐rated (higher score = greater reduction)

After 24 weeks, the itch score difference was 6.04 (SD 2.35) in the intervention group, and 4.56 (SD 2.26) in the control group (MD 1.48, 95% CI 0.53 to 2.43; Analysis 31.3). This is a participant‐rated outcome, measured on a numerical scale from 0 to 10.

Comparison 32. Oral immunosuppressants: oral cyclosporin versus topical betamethasone dipropionate
Primary outcome: percentage of participants with investigator‐rated good/excellent control

Overall assessment of good/very good efficacy was 60% in the cyclosporin group and 31% in the betamethasone group (Granlund 1996). There was no apparent difference between groups (RR 1.88, 95% CI 0.88 to 3.99; n = 34; Analysis 32.1; summary of findings Table 6; Table 8).

Primary outcome: percentage of participants with self‐rated good/excellent control

One study addressed this (Granlund 1996, n = 34; the original randomised number was n = 41, but seven people left the study early; hence data were available for only 34 people). Overall assessment of good/very good efficacy was 60% in the cyclosporin group and 48% in the betamethasone group; the difference between groups was unclear (RR 1.25, 95% CI 0.69 to 2.27; Analysis 32.2; summary of findings Table 6).

Primary outcome: adverse events

"Some kind of adverse event" occurred in 19 of 28 participants on cyclosporin and in 15 of 27 participants in the betamethasone group (RR 1.22, 95% CI 0.80 to 1.86; Analysis 32.3; summary of findings Table 6). In the cyclosporin group, one participant experienced dizziness, vomiting, and facial oedema versus zero events in the control group (Fisher's exact test P = 1.00; RR 2.90, 95% CI 0.12 to 68.15; Analysis 32.3). In the betamethasone group, one participant had insomnia versus zero events in the cyclosporin group (Fisher's exact test P = 0.49; RR 0.32, 95% CI 0.01 to 7.57; Analysis 32.3) (Granlund 1996). Two people in the cyclosporin group had an increase in serum creatinine of greater than 30% versus zero events in the betamethasone group (Fisher's exact test P = 0.49; RR 4.83, 95% CI 0.24 to 96.16; Analysis 32.3). Zero events in some of the above analyses is likely to explain the wide 95% confidence interval.

The number of participants in this section is different from that in the other sections because in the publication, adverse events in the run‐in and cross‐over phases are combined.

Secondary outcome: reduction in severity, investigator‐rated total disease activity score (six weeks; higher score = greater reduction)

For this outcome, we found only one relevant trial (n = 34) (Granlund 1996).

The mean total decrease in total disease activity score was 6.0 (SD 4.3) in the cyclosporin group and 5.7 (SD 4.0) in the betamethasone group (MD 0.30, 95% CI ‐2.50 to 3.10; Analysis 32.4; summary of findings Table 6).

Comparison 33. Oral immunosuppressants: oral cyclosporin versus alitretinoin

NCT01231854 compared cyclosporin to alitretinoin but was ended prematurely due to inability to include the total number of participants. According to the sample size calculation, 78 participants should have been included; however, only 15 participants were included and 14 were analysed.

Primary outcome: percentage of participants with investigator‐rated good/excellent control (IGA) after 24 weeks

In the cyclosporin group, three out of seven participants (42.9%) reached complete or nearly complete clearance of hand eczema according to the Investigator Global Assessment (IGA), as did two out of seven participants (28.6%) in the alitretinoin group, after 24 weeks. There was no apparent difference between groups (Fisher's exact test P = 1.00; RR 1.50, 95% CI 0.35 to 6.40; Analysis 33.1; Table 8).

Primary outcomes: percentage of participants with participant‐rated good/excellent control (PGA) after 24 weeks

In the cyclosporin group, four out of seven participants (57.1%) reached complete or nearly complete clearance of hand eczema according to the Patient Global Assessment (PGA), as did two out of seven participants (28.6%) in the alitretinoin group. There was no apparent difference between groups (Fisher's exact test P = 0.59; RR 2.00, 95% CI 0.53 to 7.60; Analysis 33.2).

Primary outcome: adverse events

Six adverse events were documented, of which two were possibly related to the use of cyclosporin (fatigue, bone ache, dry lips in one participant, and exacerbation of atopic eczema in another participant). No serious adverse events were recorded throughout the trial. At least one adverse event occurred in 3 of 7 cyclosporin participants and in 2 of 7 alitretinoin participants (Fisher's exact test P = 1.00; RR 1.50, 95% CI 0.35 to 6.40; Analysis 33.3).

Secondary outcome: time until relapse

None of the participants relapsed during the 24 weeks of follow‐up (0 of 7 versus 0 of 7).

Comparison 34. Oral retinoids: acitretin versus placebo

Oral acitretin was compared with placebo capsules in a study that enrolled 29 participants with hyperkeratotic dermatitis of the palms (Thestrup‐Pedersen 2001). Fourteen participants were allocated to 30 mg acitretin once daily for eight weeks, and 15 participants received identical looking placebo capsules. This study did not provide useable data for analysis, as only subscale mean score was available, without SD.

Primary outcome: adverse events

No adverse events were reported and all biochemical parameters were within normal limits in both groups.

Secondary outcome: reduction in severity, investigator rated, after four and eight weeks

Trial authors used a score system composed of subscales with hyperkeratosis, fissures, scaling, itch, and redness. After four weeks of treatment, a 51% reduction in all symptoms was seen in the acitretin group compared to a 9% reduction in the placebo group. No further improvement was seen after eight weeks of treatment (Thestrup‐Pedersen 2001). No reproducible data were given.

Secondary outcome: reduction in severity, participant‐rated number of participants with improvement in itch

After eight weeks of treatment, itch was reduced by 41% in the acitretin group compared to 19% in the placebo group (Thestrup‐Pedersen 2001). No reproducible data were given.

Comparison 34A. Oral retinoids: alitretinoin versus placebo

Four studies investigated the effect of oral alitretinoin: Bissonnette 2010,Fowler 2014,Ruzicka 2004, and Ruzicka 2008.

Primary outcome: percentage of participants with investigator‐rated good/excellent control (clear or almost clear) at week 12, at week 24, or at end of treatment

In Ruzicka 2004 and Ruzicka 2008, clearance or almost clearance of eczema occurred more often in all groups treated with alitretinoin compared to placebo after 12 weeks. Fowler 2014 studied this after 24 weeks.

Alitretinoin 40 mg versus placebo

For this subgroup, we found only one relevant trial (Ruzicka 2004, n = 159). There might be a difference between groups, as 43 out of 81 participants in the 40 mg group had clear or almost clear status for PaGA compared to 21 of 78 in the placebo group (RR 1.97, 95% CI 1.30 to 3.00; NNTB 4, 95% CI 2 to 9; Analysis 34.1; Table 9).

Alitretinoin 30 mg versus placebo

For this subgroup, we found two relevant trials (Ruzicka 2008, n = 614; Fowler 2014, n = 596). There was a clear difference between alitretinoin 30 mg and placebo, and the alitretinoin group was 2.75 times more likely to achieve symptom‐clear status compared to the placebo group (RR 2.75, 95% CI 2.20 to 3.43; NNTB 4, 95% CI 3 to 5; Analysis 34.1; summary of findings Table 7; Table 9).

Alitretinoin 20 mg versus placebo

For this subgroup, we found only one relevant trial (Ruzicka 2004, n = 158). There was no clear difference between groups, as 32 out of 80 participants in the 20 mg group had clear or almost clear status for PaGA, compared to 21 of 78 in the placebo group (RR 1.49, 95% CI 0.94 to 2.34; Analysis 34.1; Table 9).

Alitretinoin 10 mg versus placebo

For this subgroup, we found two relevant trials (n = 781). According to both studies (Ruzicka 2004; Ruzicka 2008), alitretinoin 10 mg was more effective for this outcome (respectively, 39% and 28%) compared to placebo (RR 1.58, 95% CI 1.20 to 2.07; NNTB 11, 95% CI 6.3 to 26.5; Analysis 34.1; summary of findings Table 8; Table 9). There might be a difference between groups, but we are uncertain of the strength of the evidence due to imprecision of the estimates.

Primary outcome: percentage of participants with self‐rated good/excellent control (clear or almost clear) with PaGA at week 12, at week 24, or at end of treatment

Ruzicka 2004 shows that for all doses of alitretinoin, statistically significantly more participants rated their eczema as clear or almost clear compared to those given placebo.

Alitretinoin 40 mg versus placebo

For this subgroup, we found only one relevant trial (Ruzicka 2004, n = 147). Of 74 participants in the 40 mg group, we judged that 32 had clear or almost clear status for PaGA compared to nine of 73 in the placebo group (RR 3.51, 95% CI 1.80 to 6.82; NNTB 3, 95% CI 2 to 6; Analysis 34.5). There might be a difference between groups, but we are uncertain of the strength of the evidence due to imprecision of the estimates.

Alitretinoin 30 mg versus placebo

For this subgroup, we found two relevant trials (Ruzicka 2008, n = 614; Fowler 2014, n = 596). There might be a difference in the study of Ruzicka 2008: 163 out of 409 participants in the 30 mg group were judged as having clear or almost clear status for PaGA after 200 days or at the end of treatment, compared to 31 of 205 in the placebo group (RR 2.64, 95% CI 1.87 to 3.72; Analysis 34.5), but we are uncertain of the strength of the evidence due to imprecision of the estimates.

Pooling the data for alitretinoin 30 mg (heterogeneity statistics: Chi² test = 0.11, P = 0.74; I² = 0) gives an effect estimate that clearly favours the intervention group and demonstrates that the alitretinoin group was 2.75 times more likely to achieve improvement relative to the placebo group (RR 2.75, 95% CI 2.18 to 3.48; NNTB 4, 95% CI 3 to 5; Analysis 34.5; summary of findings Table 7).

Alitretinoin 20 mg versus placebo

For this subgroup, we found only one relevant trial (Ruzicka 2004, n = 147). Of 74 participants in the 20 mg group, 25 were judged to have clear or almost clear status for PaGA compared to 9 of 73 in the placebo group (RR 2.74, 95% CI 1.37 to 5.46; NNTB 5, 95% CI 3 to 13; Analysis 34.5). There might be a difference between groups, but we are uncertain of the strength of the evidence due to imprecision of the estimates.

Alitretinoin 10 mg versus placebo

For this subgroup, we found two relevant trials (n = 765). Both studies found that 10 mg alitretinoin was more effective (respectively, 29% and 24% clear or almost clear) than placebo (Ruzicka 2004; Ruzicka 2008). Pooling these data for 10 mg alitretinoin (heterogeneity statistics: Chi² test = 0.89, P = 0.35; I² = 0) shows there might be a difference between groups, but we are uncertain of the strength of the evidence due to imprecision of the estimate (RR 1.73, 95% CI 1.25 to 2.40; NNTB 9, 95% CI 6 to 20; Analysis 34.5; summary of findings Table 8).

Primary outcome: adverse events

Studies listed in detail the adverse events observed; headache was one of the most frequent events (22 in 40 mg group, eight in 20 mg group, four in 10 mg group, and seven in the placebo group in Ruzicka 2004; and 87 of 296 and 81 of 409 participants using alitretinoin 30 mg in Fowler 2014 and Ruzicka 2008, respectively). There was no clear difference between groups for 10 mg (Analysis 34.6), 20 mg (Analysis 34.7), or 40 mg (Analysis 34.9) versus placebo. However, the 30 mg versus placebo subgroup comparison produced a few notable between‐group differences (Analysis 34.8), specifically for the following adverse events: headache (RR 3.43, 95% CI 2.45 to 4.81; NNTH 6, 95% CI 4 to 11), flushing (RR 7.28, 95% CI 2.05 to 25.86; NNTH 25, 95% CI 17 to 50), erythema (RR 5.79, 95% CI 2.09 to 16.06; NNTH 25, 95% CI 14 to 100), nausea (RR 3.82, 95% CI 1.67 to 8.76; NNTH 27, 95% CI 18 to 56), elevated blood triglycerides (RR 7.05, 95% CI 1.89 to 26.28; NNTH 33, 95% CI 20 to 50), vomiting (RR 8.00, 95% CI 1.01 to 63.57; NNTH 50, 95% CI 23 to 250), and tinnitus (RR 4.33, 95% CI 1.25 to 15.05; NNTH 33, 95% CI 17 to 100). With the exception of headache, we have limited confidence in the clinical significance of the differences mentioned above because in most of these analyses, the number of events was too small; hence, this reduced the precision of the effect estimates. Limitations in the quality of the trial further compromised our confidence in this finding.

Some of the outcomes above had zero events in one arm, which is likely to explain the wide 95% confidence interval. These outcomes are dry lips, fatigue, rigours, tonsillitis, and elevated blood triglycerides.

Secondary outcome: reduction in severity, investigator‐rated, in total lesion symptom score

Ruzicka 2004 observed a higher median % reduction in total lesion symptom score for all doses of alitretinoin compared to placebo: 25% in the placebo group (stated 95% CI ‐42 to ‐14) versus 52% in the 20 mg group (stated 95% CI ‐73 to ‐42) and 71% in the 40 mg group (stated 95% CI ‐80 to ‐44; Analysis 34.10). The difference between alitretinoin and placebo was apparent for both doses according to study authors (Analysis 34.10). There was also reporting of a decrease in extent of disease in all groups, but no details were given. We have plotted these data (Analysis 34.11) based on the medians. Because the original data were not available to us, we were unable to assess whether the data were skewed; therefore, it is uncertain whether the medians are close to the means.

Alitretinoin 40 mg versus placebo

For this subgroup, we found only one relevant trial (Ruzicka 2004, n = 159). Only median data were available; hence, we reported these as 'other data' in a table (Analysis 34.11). The median of the alitretinoin group is evidently higher than that of the placebo group; however, we are unsure of the clinical importance of the observed difference.

Alitretinoin 20 mg versus placebo

For this subgroup, we found only one relevant trial (Ruzicka 2004, n = 158). Only median data were available; hence, we reported these as 'other data' in a table (Analysis 34.11). Similar to the previous analysis, the median of the alitretinoin group is evidently higher than that of the placebo group; however, we are unsure of the clinical importance of the observed difference.

Alitretinoin 10 mg versus placebo

For this subgroup, we found only one relevant trial (Ruzicka 2004, n = 158). Only median data were available; hence, we reported these as 'other data' in a table (Analysis 34.11). The median of the alitretinoin group is evidently higher than that of the placebo group, as in the previous analysis, and we are unsure of the clinical importance of the observed difference.

Secondary outcome: reduction in severity, investigator‐rated, in modified total lesion symptom score

Fowler 2014: the modified total lesion symptom score showed a change of ‐53.99% in the alitretinoin 30 mg group after 24 weeks and a change of ‐29.86% in the placebo group. For the mean difference in reduction, these numbers were inverted, so the mean difference in reduction of severity was 24.13 (MD 24.13, 95% CI 17.87 to 30.39; Analysis 34.12).

Ruzicka 2008: the median reduction in the modified total lesion symptom score was 75% in the 30 mg group and 56% in the 10 mg group, compared to 39% in the placebo group (Analysis 34.10).

Secondary outcome: time to relapse

Fowler 2014 included a follow‐up phase up to 48 weeks after end of treatment. The median time to relapse after end of treatment was 83.0 weeks, with a 95% CI of 48.3 to 83.0, according to trial authors.

For Ruzicka 2008, the median time to relapse was 5.5 months for alitretinoin 30 mg, 6.2 months for alitretinoin 10 mg, and 5.4 months for placebo.

Comparison 35. Oral retinoids: re‐treatment with alitretinoin versus placebo

In Bissonnette 2010, 117 participants with chronic hand eczema were successfully treated with alitretinoin in an earlier study (Ruzicka 2008); 24 withdrew.

Primary outcome: percentage of participants with investigator‐rated good/excellent control (clear or almost clear)

Alitretinoin 30 mg versus placebo

For this subgroup, we found only one relevant trial (Bissonnette 2010, n = 73). A total of 39 out of 49 participants (80%) who were re‐treated with 30 mg alitretinoin were rated as 'clear' or 'almost clear' according to the PGA, compared to 2 of 24 participants (8%) who were re‐treated with placebo. There appears to be a large effect favouring the intervention group (RR 9.55, 95% CI 2.51 to 36.27; NNTB 1, 95% CI 1 to 2; Analysis 35.1; Table 9); however, we have limited confidence in this finding due to the small sample size and risk of bias in the study itself.

Alitretinoin 10 mg versus placebo

For this subgroup, we found only one relevant trial (Bissonnette 2010, n = 31). Ten out of 21 participants were cleared or almost cleared again under re‐treatment with 10 mg alitretinoin in comparison to 1 out of 10 participants who were re‐treated with placebo (10%) (RR 4.76, 95% CI 0.70 to 32.25; Analysis 35.1; Table 9). In the group that was re‐treated with placebo, 9 out of 13 participants (69%) responded again.

Primary outcome: adverse events

Headache was the most frequently reported adverse event in the 30 mg group; 7 of 50 participants reported headache in the intervention group compared with zero events in the placebo group (Fisher's exact test P = 0.0129; RR 13.82, 95% CI 0.81 to 235.45; Analysis 35.3). None of the participants in the alitretinoin 10 mg group or in the placebo group reported headache. Adverse events occurred similarly in both groups (Analysis 35.2; Analysis 35.3). Three serious adverse events were reported: one case of acute cardiac failure with fatal outcome in the 10 mg group, which was not related to the study drug; one case of aortic aneurysm and one case of coronary artery disease (both in the 30 mg group) were assessed as having a remote relationship to the study drug.

Comparison 36. Other oral interventions: oral triethylenetetramine versus placebo

Burrows 1986 (n = 23) studied oral triethylenetetramine versus placebo and included exclusively nickel‐sensitive participants.

Primary outcome: percentage of participants with investigator‐ and participant‐rated good/excellent control

We found one study for this outcome (Burrows 1986), including 23 participants in a cross‐over design, of which 20 were analysed. Because the data before cross‐over are not available, rather than analysing the post‐cross‐over data, we have presented them in a table for the readers' review (Analysis 36.1; Table 10). This outcome was based on a global assessment (improved/no change/deterioration) by participant and doctor, probably by consensus, and included both phases of the cross‐over study.

Primary outcome: adverse events

None of the participants in Burrows 1986 reported adverse events; however, this trial was ended prematurely due to increased teratogenicity among rats who received trientine.

Comparison 37. Other oral interventions: tetraethylthiuram disulfide (TETDS) versus placebo

Kaaber 1983 studied oral tetraethylthiuram disulfide (TETDS) versus placebo in 24 nickel‐sensitive participants.

Primary outcome: percentage of participants with investigator‐rated good/excellent control during treatment period

For this outcome, we found only one relevant trial (Kaaber 1983, n = 24). Among participants receiving the active compound, 5 out of 11 'healed' versus 2 out of 13 in the placebo group. Analysis 37.1 shows no clear difference between the two groups in that the 95% CI includes 1 and is wide (Fisher's exact test P = 0.1819; RR 2.95, 95% CI 0.71 to 12.34). Also see Table 10.

Primary outcome: adverse events

In the group receiving tetraethylthiuram disulphide, hepatic toxicity was experienced in two participants (Fisher's exact test P = 0.48; RR 5.00, 95% CI 0.26 to 96.13; Analysis 37.2) and headache in one (Fisher's exact test P = 1.00; RR 3.00, 95% CI 0.13 to 68.26; Analysis 37.2). Two participants had mild acne, but it is not clear to which group they were assigned. In the intervention group, there was one case of discontinuation due to depression and one case of discontinuation due to dyspepsia, whereas neither event occurred in the control group (Fisher's exact test P = 1.00; Analysis 37.2). There were zero events in placebo group for all of the above subgroups; this is likely to explain the wide 95% confidence intervals.

Comparison 38. Other oral interventions: low‐nickel diet (LND) and disulphiram versus normal diet and placebo

Sharma 2006 (n = 21) compared a low‐nickel diet combined with disulphiram versus a normal diet and placebo and included exclusively nickel‐sensitive participants.

Primary outcomes: percentage of participants with self‐rated good/excellent control (clearance of eczema) after four weeks

For this outcome, we found only one relevant trial (Sharma 2006, n = 21). Ten of the 11 participants in the LND group reached good/excellent control compared to 1 of 10 in the control group (Fisher's exact test P = 0.0003; RR 9.09, 95% CI 1.40 to 58.91; NNTB 1, 95% CI 1 to 2; Analysis 38.1).

Primary outcome: adverse events

Three out of 11 participants treated with disulphiram experienced a metallic taste (Fisher's exact test P = 0.2143; RR 6.42, 95% CI 0.37 to 110.71; Analysis 38.2), and two had mild drowsiness (Fisher's exact test P = 0.4762; RR 4.58, 95% CI 0.25 to 85.33; Analysis 38.2 ). Three participants treated with disulphiram showed mild elevation of liver enzymes (Fisher's exact test P = 0.2143; RR 6.42, 95% CI 0.37 to 110.71; Analysis 38.2).

Comparison 39. Other oral interventions: oral evening primrose oil versus placebo
Secondary outcome: reduction in severity, investigator‐rated score at week 24

For this outcome we only found one relevant trial (Whitaker 1996, n = 34) on oral gamma‐linoleic acid (GLA, evening primrose oil, Epogam). Mean and SD of the evening primrose oil group is 18 ± 12.37, and for the placebo group is 30.4 ± 23.36. There was no clear difference between the oral interventions (MD ‐12.40, 95% CI ‐25.46 to 0.66, Analysis 39.1).

Comparison 40. Other oral interventions: ranitidine versus placebo
Primary outcome: percentages of participants with self‐ and/or investigator‐rated good/excellent control (clearance / marked alleviation)

For this outcome, we found only one relevant trial (Veien 1995, n = 47). Although it is not clear whether this was participant‐ or investigator‐rated, 17 out of 23 with ranitidine cleared or were markedly improved versus 8 out of 24 receiving placebo (RR 2.22, 95% CI 1.20 to 4.10; NNTB 2, 95% CI 2 to 7; Analysis 40.1; Table 10).

Primary outcome: adverse events

No adverse events were reported in the ranitidine or placebo group.

Comparison 41. Other oral interventions: disodium cromoglycate diet (DSCG) versus low‐nickel diet

For this comparison, we found one study (Pigatto 1990), which included 16 participants in three different treatment groups (disodium cromoglycate diet (DSCG) versus low‐nickel diet versus a non‐randomised control for eight participants who did not give consent for the study and were only followed up). Because participants were not randomised, this subgroup is deleted from the review.

Primary outcomes: number of participants with self‐rated good/excellent control of itch after three months

For this outcome, we found only one relevant trial (n = 16) (Pigatto 1990). The numbers of events in the disodium cromoglycate and low‐nickel groups were 5 of 8 and 1 of 8, respectively (Fisher's exact test P = 0.1189; RR 5.00, 95% CI 0.74 to 33.78; Analysis 41.1).

Discussion

Summary of main results

Hand eczema is a common condition. In light of the high prevalence of hand eczema, it is striking that the results of all 60 identified randomised controlled trials (RCTs) are based on approximately 5469 participants, whereby about half of them (n = 2893) were enrolled in five RCTs: three on the oral retinoid alitretinoin (Fowler 2014; Ruzicka 2004; Ruzicka 2008), and two on the topical calcineurin inhibitor pimecrolimus (Belsito 2004; Hordinsky 2010).

Although many systematic reviews focus on a single treatment modality or its closely related variants, we have tried to include all interventions in this review in an attempt to determine which therapy would reflect current standard treatment and the extent to which there is evidence for its effectiveness. The wide range of available treatments underlines the fact that there does not seem to be a single candidate for standard therapy. Topical corticosteroids and ultraviolet (UV) phototherapy are the major treatment options for chronic hand eczema, although in this review, we found little strong or consistent evidence that one intervention for hand eczema should be recommended over the other.

About half of the studies (n = 33) included our primary outcome of good/excellent control of symptoms rated by participants or by investigators. The definition of good/excellent control varied across studies because a wide variety of outcome measures were used. Most studies included the primary outcome adverse events (n = 55). None of the adverse events were life‐threatening, and most were mild (local irritation with stinging, erythema, and burning).

Of the nine trials on topical corticosteroids, each dealt with a different type of steroid. The duration of six studies was rather short, namely, one week (Gupta 1993), two weeks (Faghihi 2008; Fowler 2005; Kircik 2013; Lodén 2012a; Uggeldahl 1986), and three weeks (Bleeker 1989). Treatment in Veien 1999 lasted up to 36 weeks, and treatment duration in Möller 1983 is unknown. Three trials compared two different corticosteroids. The comparators used in the remaining trials were the same corticosteroids as those used for the intervention, the same treatment but in a different vehicle, or a different dosage, or they were applied at a different frequency or were combined with zinc sulphate or urea, or consisted of vehicle alone.

Based on one study (125 participants), which compared clobetasol propionate foam with vehicle, clobetasol probably improves participant‐rated good/excellent symptom control more than vehicle; however, the difference between groups on observer‐rated scales is less clear (moderate‐certainty evidence) (Kircik 2013). Another study (72 participants) compared mometasone furoate cream used thrice weekly compared to twice weekly, and mometasone furoate cream used thrice weekly may slightly improve investigator‐rated good/excellent control of symptoms (low‐certainty evidence); participant‐rated symptoms were not measured (Veien 1999). See summary of findings Table for the main comparison and summary of findings Table 2.

The 10 trials on UV phototherapy were too heterogeneous for pooling. Three studies provided UVB as the main intervention, three gave UVA‐1, and six used oral psoralen combined with UVA (PUVA) as the main intervention or comparator. Other comparators included no treatment, placebo, UVB, the same treatment as the intervention but at different sites, UVA, and topical betamethasone‐valerate cream. One study had a treatment duration of less than one month (Polderman 2003), five had a treatment duration of less than two months (Adams 2007; Bayerl 1999; Grattan 1991; Said 2010; Sjövall 1987), three had a treatment duration of two to four months (Brass 2015; Sezer 2007; van Coevorden 2004a), and one had a treatment duration greater than four months (Tzaneva 2009).

In one of the studies comparing local narrow‐band UVB to local PUVA, results showed that PUVA may lead to an improvement in investigator‐rated good/excellent symptom control (60 participants), but the 95% confidence interval indicates that local PUVA might make little or no difference (moderate‐certainty evidence). Participant‐rated symptoms were not measured (Brass 2015). See summary of findings Table 3.

The topical calcineurin inhibitors were studied in nine RCTs, and almost all studies compared tacrolimus or pimecrolimus to vehicle. Based on one small study comparing tacrolimus over two weeks to vehicle, investigator‐rated good/excellent symptom control is probably more likely to be achieved in those treated with tacrolimus (14/14 participants in the tacrolimus group versus zero people in the vehicle group), but participant‐rated good/excellent control of symptoms was not measured (28 participants) (moderate‐certainty evidence) (Pacor 2006). Tacrolimus was compared to mometasone in a within‐participant trial but did not measure investigator‐ or participant‐rated good/excellent symptoms (Schnopp 2002). See summary of findings Table 4 and summary of findings Table 5.

Three studies assessed immunosuppressants, which were compared against a steroid or a retinoid. In one cross‐over RCT comparing oral cyclosporin to topical betamethasone dipropionate, cyclosporin probably slightly improves participant‐ or investigator‐rated good/excellent control of symptoms (34 participants) (moderate‐certainty evidence) (Granlund 1996). See summary of findings Table 6.

A relatively new treatment option is oral alitretinoin, which has been compared with placebo in three large trials, with a total enrolment of 1947 participants (Fowler 2014; Ruzicka 2004; Ruzicka 2008). These trials investigated, in addition to other dosages, a daily dosage of 10 mg. Ruzicka 2004 and Ruzicka 2008 were considered sufficiently equivalent to pool the data for 10 mg daily, which showed that alitretinoin was more effective than placebo in both investigator‐ and participant‐rated good/excellent control of symptoms (high‐certainty evidence). Even larger risk ratios were observed when a higher dosage of alitretinoin (30 mg) was compared to placebo for both outcomes (Fowler 2014; Ruzicka 2008) (high‐certainty evidence). See summary of findings Table 7 and summary of findings Table 8.

Oral alitretinoin has not yet been compared to other treatment modalities such as corticosteroids or UV phototherapy. Unfortunately, the study that was expected to further clarify the position of systemic treatments with retinoids or systemic immunosuppressants (alitretinoin versus cyclosporin) in the treatment of hand eczema was ended prematurely (NCT01231854). Although this study shows low risk of bias in all other domains, it included only 15 of the required 78 participants.

Adverse events were reported by 55 of the 60 studies; they were generally mild and similar between groups. Mild atrophy was reported with mometasone furoate thrice weekly or twice weekly (low‐certainty evidence), but more adverse events (e.g. application site burning/pruritus after intervention application, nasopharyngitis, one incident of severe fissures) were noted when clobetasol propionate foam was compared to vehicle placebo (moderate‐certainty evidence). In the study comparing local narrow‐band UVB to local PUVA, only the narrow‐band UVB group reported adverse events (mainly erythema) (moderate‐certainty evidence). When tacrolimus was compared to vehicle, well‐tolerated burning/itching was reported only in the tacrolimus group (moderate‐certainty evidence). With systemic treatment, the risk of adverse events with oral cyclosporin compared to topical betamethasone was similar, and dizziness was reported (moderate‐certainty evidence). The occurrence of headaches and flushing was similar when alitretinoin 10 mg was compared to placebo (moderate‐certainty evidence), but risk of headache was greater with alitretinoin 30 mg than with placebo (high‐certainty evidence).

Overall completeness and applicability of evidence

We included 60 RCTs with a total of 5469 participants. Overall, studies included adults of both genders in general good health, which in our opinion is applicable to an important part of the hand eczema population, since hand eczema can be related to occupation.

The applicability of evidence is limited by several methodological weaknesses of the included studies; one of the most prominent of these is the varied definition of hand eczema. Furthermore, the definition of hand eczema was different in almost all trials. Studies defined 'chronic hand eczema' as duration longer than six months or longer than three months, or did not include a minimal duration of disease at all. We intended to conduct subgroup analyses, but a minority of the trials defined subgroups (e.g. Ruzicka 2004 and Ruzicka 2008 did include subgroups). In general, it is not clear which participants had hyperkeratotic hand eczema or vesicular hand eczema, and clinical experience suggests that the clinical subtype might influence treatment success. Without logical and comprehensive definitions of hand eczema with clear diagnostic criteria for hand eczema and its subgroups, RCTs are seriously flawed, which is one of the main pitfalls of this review.

Furthermore, in this review, we found a wide range of severity scoring systems for hand eczema, which prevented meaningful data pooling.

Finally, some studies, especially older studies, did collect useable data with regard to the effectiveness of treatment but did not report these data (Fredriksson 1975). Since these were all single‐study results, which could not have been pooled anyway, we do not believe that this influenced the overall completeness of the evidence.

Of all treatment categories, the largest number of studies focus on topical steroids (nine RCTs) and UV therapy (10 RCTs). Nevertheless, most trials do not include one of these treatments as a comparator. In fact, most trials provide placebo, vehicle, or a variant of the intervention as a comparator, making it difficult to draw conclusions on the comparative advantages of different treatments. We did identify some ongoing studies, for example, ISRCTN80206075,NCT03026907, and NCT03026946; results of these trials might eventually help to fill some of the gaps. With regard to phototherapy, it is difficult to compare different studies because different treatment regimens were used. Although in daily practice the treatment regimens are highly dependent on patient skin type and on the occurrence of adverse events, it might be challenging to align treatment protocols. Topical steroids were assessed in nine studies, although different treatment regimens were not investigated intensively, nor was the strength of different corticosteroids. Topical calcineurin inhibitors were investigated in nine studies. Topical calcineurin inhibitors were compared with placebo and with active treatment (topical corticosteroids), although this last comparator might have been used more often. Alitretinoin was examined in well‐designed studies with a substantial number of participants. Other oral treatments such as cyclosporin, methotrexate, or acitretin were barely/not investigated, which is a severe shortcoming in the overall completeness of evidence.

With regard to outcomes, our primary outcomes percentage of participants with investigator‐rated and/or self‐rated good/excellent control of symptoms and/or adverse events were reported in most of the included studies. However, the secondary outcome dose reduction was not stated in any of the included studies. Moreover, various studies did not report on time until relapse.

The enrolled participants had typical long‐standing eczema. Studies included overall chronic hand eczema with long‐lasting disease and included patients in secondary care settings; therefore acute eczema is not included in these studies. Consequently, the results are less applicable for the primary care setting. This review included participants of all ages; however, most of the included studies did not include children. Only four studies included participants under the age of 16 years and did not provide separate results for this subgroup; therefore, the results of this review may not be applicable to children. With regard to external validity, these studies were conducted all over the world, supporting the generalisability of the results.

The objective of this Cochrane Review was to assess the effects of topical and systemic interventions for hand eczema in adults and children. Because of the above‐mentioned implications, it is difficult to answer our review question with a single answer. As stated before, we cannot comment on children based on the included studies, which mainly include adults. However, this review does provide a clear overview of different studies on potential topical and systemic interventions for adult patients with chronic hand eczema. A pitfall is the lack of head‐to‐head studies, which makes it impossible to know whether one treatment is favoured over another.

Quality of the evidence

We found some serious limitations in the quality of reporting and aimed to discuss these according to the GRADE considerations(study limitations, consistency of effect, imprecision, indirectness, and publication bias).

Limitations in study design and implementation

We included only RCTs in this review. Overall, the older studies had more shortcomings with regard to risk of bias, and we judged them as having 'high' or 'unclear' risk of bias with regard to allocation concealment, blinding, and/or loss to follow‐up. Frequent shortcomings included missing information on randomisation and blinding, no justification of the number of participants, and no analysis of dropouts. Studies that were conducted more recently had an overall low or unclear risk of bias for most of the risks (allocation concealment, blinding, intention‐to‐treat analysis, and selective reporting of outcomes), although they sometimes were sponsored by pharmaceutical industries. Over a third of the studies used a within‐participant design (left‐right studies). Although these studies show strengths in terms of power to obtain statistically significant results with small numbers of participants, this is done at the expense of problems in interpreting studies finding no difference in effect. This might be a consequence of cross‐contamination of topical interventions, possible systemic effects of topical preparations, or both. In general, we consider the body of evidence in this review as having 'unclear risk of bias'.

As a consequence, we downgraded evidence only for one of our main comparisons (mometasone furoate cream three times per week versus two times per week; summary of findings Table 2), as we considered the included study to be at high risk of detection and performance bias (Veien 1999).

Indirectness of evidence

Overall the included studies were of relatively small sample size and short duration. Although hand eczema usually has a chronically relapsing course, less than half of the studies had a duration longer than three months, which in our opinion is the minimum duration required to document important data such as duration and frequency of disease relapse. Therefore, this is considered as a form of indirectness. This review analysed the efficacy of many different interventions, of which various included a placebo. Moreover, because the number of studies comparing different groups of interventions (e.g. corticosteroids, oral retinoids, phototherapy) is limited and the number of participants for each intervention is limited (with the exception of alitretinoin), the evidence is mostly indirect. Overall, participants in a secondary care setting with chronic eczema were included. As mentioned above, the definition of 'chronic hand eczema' was not always clear; this could be defined as having a minimal duration of six weeks to six months. Some studies included participants with specific subtypes of hand eczema such as recurrent vesicular hand eczema, whereas others excluded this subgroup. We were unable to pool the data for different subgroups of hand eczema, for example, to focus on hyperkeratotic palmar hand eczema, since the data for specific subgroups often were not stated. A wide range of outcome parameters was presented, most of which were not validated. Some studies used a validated outcome measure such as the Hand Eczema Severity Index (HECSI), whereas most created their own non‐validated, un‐named scoring system. Another limitation arose from the comparators used: most interventions were compared to an inactive placebo, which is less effective than standard treatment in most settings. We decided not to downgrade the evidence in our main comparisons for indirectness, as we judged this to be a less serious concern than imprecision (see below).

Consistency of results

It is difficult to judge the consistency of the results because we were unable to pool the study results for most of the outcomes assessed because only a single study was available, or because of clinical heterogeneity in interventions (and co‐interventions), treatment duration, comparison groups, and outcomes measured or reported. As a direct consequence of the overwhelming diversity in study characteristics (i.e. clinical heterogeneity), most of the comparisons are based on single studies, hence making it difficult for the review authors to draw any firm conclusions with confidence. We can interpret this review only as a scoping review. Hence, we could not downgrade any evidence for inconsistency.

Imprecision of results

Most of the analyses are based on a single study of small sample size, and often with low event rates (in some cases, zero events), and the 95% confidence interval of effect estimates was often very wide, resulting in a low‐precision assessment. Hence, we downgraded most of the outcomes included in the summary of findings tables for imprecision because we believe the small sample size means there was not enough power to detect any differences between groups. The effectiveness outcomes in two of our main comparisons comparing alitretinoin 10 mg or 30 mg versus placebo were not downgraded for imprecision because the analyses included two studies equalling a larger sample size, and the results had fairly narrow 95% confidence intervals, which did not include one showing high‐certainty evidence supporting the effectiveness of alitretinoin (see summary of findings Table 7 and summary of findings Table 8).

Probability of publication bias

We did not produce funnel plots due to insufficient numbers of included trials for all given outcomes. Publication bias may especially be present in the wide range of studies on different moisturisers to treat hand eczema: we did find various registered trials in trial registries that were not (yet) published. Contact with study authors in some cases revealed that the results were minimal and would not be published, or study authors did not respond to our writings at all. In other cases, study authors were not at liberty to disclose results but referred us to pharmaceutical sponsors, who often remained unresponsive.

Potential biases in the review process

We acknowledge that there was potential for bias at all stages of the review process, but we made various attempts to restrict the level of bias.

We comprehensively searched for randomised controlled trials from a wide range of databases to avoid the risk of publication bias, and we used clinically relevant outcome measures. We tried to compare respective trial registrations with published trials to ascertain whether there was lack of correspondence between what was intended to be an outcome and actually reported outcomes. We attempted to be as inclusive as possible in our search strategy and included studies reported in languages other than English. The different language backgrounds of review authors enabled us to include Dutch ‐ Kemper 1998 ‐ and German articles ‐ Adams 2007; Bayerl 1999. We translated a Turkish article to minimise language bias (Baskan 2005). Nevertheless, the studies included in this review were predominantly conducted in European or North American countries and were published in European or American journals.

The authors of this review independently assessed the eligibility of studies for inclusion in this review; two other review authors extracted data and assessed risk of bias to minimise the potential for additional bias beyond that detailed in the 'Risk of bias in included studies’ tables. Discrepancies between review authors were resolved by discussion to reach consensus. However, we acknowledge that our assessments may occasionally have been subjective, for example, in the case of the not‐blinded radiographers (Cartwright 1987; Fairris 1984; Fairris 1985; King 1984). Therefore, readers may not agree with all of our decisions.

Review authors who were involved as trialists for certain studies were not involved in selection, assessment, and data extraction for those studies. Pieter‐Jan Coenraads was involved in the studies of Ruzicka 2004, Ruzicka 2008, and van Coevorden 2004a. Thomas L Diepgen was involved in the studies of Bauer 2012 and Ruzicka 2008 (Declarations of interest).

The authors of this review are aware that some differences between protocol and review (see Differences between protocol and review) may have been a source of bias. The protocol was published in 2009, and Cochrane guidance has since developed. Such differences include changing adverse events to a primary outcome, adding a time point of a minimum of three months for measuring outcomes such as relapse, changing the way measures of treatment effect are expressed, and making changes to the literature search. We tried to not make these decisions based on the data we had extracted, but rather on the new Cochrane guidance.

We judged a lot of studies to have unclear risk of bias, especially with regard to selection bias, since a substantial number of studies did not describe the way allocation concealment and sequence generation were performed. To obtain more clarity on this matter, we contacted all authors from studies published after 1999 by email or through other forms of social media such as LinkedIn. Study authors with a personal or professional relation to one of the authors of this review may have been reached more easily and might have been more prone to respond to our requests. Therefore, these studies may have been judged more often as having low risk of bias. For studies pre‐1999 and for reports for which study authors were unresponsive, we had less information and had to deal with more ambiguity, which we were unable to resolve; this may have contributed to some bias in assessments of these studies, and these studies were more often judged as having unclear risk of bias.

The time frame for the studies included in this review inevitably shows that there is a time trend in treatments that are evaluated: earlier studies tend to focus on corticosteroids, UV phototherapy, or X‐rays, and more recent trials evaluate the effects of novel medicaments such as oral retinoids and topical calcineurin inhibitors.

The fact that 20 studies have not yet been incorporated into this review may be a source of potential bias.

Agreements and disagreements with other studies or reviews

This Cochrane Review studies a wide range of treatments that have been evaluated by RCTs since 1967. Within the same time frame, many uncontrolled and non‐randomised controlled studies have been published. van Coevorden 2004b conducted a review to describe study design and the quality of studies on hand eczema, covering the time period from 1977 up to 2003. These review authors included 90 studies, of which 44 were case series, 15 non‐randomised controlled trials, and 31 RCTs. In total, 11 different categories of treatment were found, and most trials studied ultraviolet irradiation (n = 32) or corticosteroids (n = 13). This review concluded that the overall quality of reporting on hand eczema was poor, and most hand eczema trials were not considered adequate to guide clinical practice. Since the current Cochrane Review was conducted in part by the same review authors and incorporated the same RCTs, it is not surprising that the results and conclusions of both reviews overlap. However, since we tried to obtain more information by contacting authors in this Cochrane Review, and since we sought additional published and unpublished data, we had fewer uncertainties with regard to the quality of evidence. We also included RCTs that were conducted after 2003, and in general these studies are of better quality than the older studies. We maintain that the overall quality of reporting in hand eczema is low, and that there is a need for well‐designed head‐to‐head studies of adequate duration, reported according to the CONSORT guidelines.

Over the years, various groups have composed guidelines for the management of (chronic) hand eczema (Veien 2003; Diepgen 2007; Diepgen 2009b; English 2009; Lynde 2010; Menné 2011). These guidelines have in common that they all acknowledge the lack of RCTs. All guidelines recommend topical corticosteroids as one of the first steps in pharmacological treatment for all types of hand eczema. Thereafter, the guidelines recommend different steps, in which the subtype of hand eczema can be a leading factor, usually starting with topical treatments (e.g. more potent or prolonged use of corticosteroids or calcineurin inhibitors).

For severe hand eczema that is unresponsive to topical treatment, basically all guidelines recommend a treatment regimen with tar, phototherapy, and systemic (oral) treatment (acitretin, alitretinoin, cyclosporin, corticosteroids, or others). Since alitretinoin was recently licensed for the treatment of hand eczema in Europe and Canada (not yet in the United States), the more recent guidelines include this treatment option for severe chronic hand eczema (Diepgen 2009b; English 2009; Lynde 2010; Menné 2011).

English 2009 published a consensus statement on the management of chronic hand eczema in the view of general practitioners and dermatologists. The authors did not conduct a systematic review but based their statement on a mix of clinical experience and a variety of RCTs and non‐RCTs on hand eczema and atopic dermatitis. In general, they advise a skin protection programme and topical treatment with corticosteroids or calcineurin inhibitors in a primary care setting whenever possible. For referrals to secondary care (dermatologist), PUVA, cyclosporin, azathioprine, and alitretinoin are preferred treatment options for hyperkeratotic and vesicular hand eczema, with emphasis on the importance of patient preference and local availability. Furthermore, PUVA (also in our review a well‐studied intervention) is recommended for hyperkeratotic hand eczema. Methotrexate and mycophenolate are recommended after failure of other systemic interventions; however, this recommendation is not supported because of lack of RCTs examining these interventions.

The German Dermatologic Society stresses the importance of education and prevention (Diepgen 2009b). Topical corticosteroids, topical calcineurin inhibitors, and iontophoresis are the first treatment steps. For moderate to severe hand eczema, highly potent corticosteroids, UV therapy, and alitretinoin are recommended, while other systemic treatment options such as cyclosporin are the final resort. This recommendation is based largely on the fact that alitretinoin is registered for the treatment of hand eczema, while cyclosporin is an off‐label therapy.

The Canadian guideline states that treatment of hand eczema can be difficult and unsatisfactory (Lynde 2010). Researchers distinguish three important clinical types: irritant contact dermatitis, allergic contact dermatitis, and atopic hand eczema. This guideline provides a clear flow diagram for acute hand eczema and chronic hand eczema, which is divided into mild, moderate, and severe. Topical corticosteroids are the mainstream of treatment, and phototherapy is recommended for moderate chronic hand eczema unresponsive to topical corticosteroids. For severe cases that are unresponsive to potent topical corticosteroids, phototherapy and alitretinoin are recommended. When this is insufficient as well, cyclosporin can be considered. Because the comparative study NCT01231854 was ended prematurely, we do not know whether alitretinoin should be preferred over cyclosporin.

Danish guidelines state that treatment for hand eczema should be tailored to the individual and that skin care education is very important (Menné 2011). They classify hand eczema into six different clinical types: chronic fissured hand eczema, recurrent vesicular hand eczema, hyperkeratotic palmar hand eczema, pulpitis, interdigital eczema, and nummular hand eczema. Furthermore, they distinguish between mild/moderate hand eczema and severe hand eczema. Mild/moderate hand eczema should be treated with topical corticosteroids, potentially in rotation with calcineurin inhibitors. For severe hand eczema, a step‐up with topical corticosteroids and "possibly potassium permanganate baths" for vesicular hand eczema and "silver nitrate solutions" for hyperkeratotic eczema is recommended. However, our review did not find evidence for these treatment options. If topical treatment is insufficient, a further step‐up regimen is recommended with tar, phototherapy, and systemic treatment (acitretin, alitretinoin, cyclosporin, corticosteroids, or others), although the guideline does not given an order of priority and does not make further recommendations regarding the different subtypes of hand eczema.

The American Academy of Dermatology has published guidelines on the use of topical glucocorticoids ‐ the mainstay of treatment for hand eczema (Drake 1996). The British Photodermatology Group developed a guideline on phototherapy and included a comment on the use of phototherapy in hand eczema (Halpern 2000). Although the evidence for topical PUVA over oral PUVA is scarce, this group suggests a commonsense approach, which is not contradictory to the findings of this review.

The studies included in this review regarding alitretinoin did find an increase in the number of participants reporting headache while taking alitretinoin compared to placebo with a high level of evidence (Bissonnette 2010; Ruzicka 2004; Ruzicka 2008), which is in line with multiple daily life studies that have reported headache as a well known side effect of alitretinoin (Diepgen 2012; Augustin 2016).

Overall, we can conclude that most guidelines do not give a single recommendation based on the current literature, which is consistent with the main finding of this review.

Study flow diagram.
Figures and Tables -
Figure 1

Study flow diagram.

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Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Comparison 1 Bland emollients: ceramide‐containing emollient versus regular petrolatum‐based emollient, Outcome 1 Primary: adverse events: exacerbation resulting in dropout.
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Analysis 1.1

Comparison 1 Bland emollients: ceramide‐containing emollient versus regular petrolatum‐based emollient, Outcome 1 Primary: adverse events: exacerbation resulting in dropout.

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Study

Group ‐ within‐participant study

Total number of events

Total number of pairs of hands analysed

Chu 2009

Emollient E‐DO

22

67

Chu 2009

Vehicle

23

67

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Analysis 2.1

Comparison 2 Bland emollients: emollient E‐DO versus vehicle, Outcome 1 Primary: percentage of participants with self‐rated good/excellent control at week 4.

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Study

Group‐ within‐participant study

Event number

Total number of pairs of hands randomised

Chu 2009

Emollient E‐DO

37

67

Chu 2009

Vehicle

36

67

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Analysis 2.2

Comparison 2 Bland emollients: emollient E‐DO versus vehicle, Outcome 2 Primary: percentage of participants with investigator‐rated good/excellent control at week 4.

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Study

Group ‐ within‐participant study

Event number

Total number of hands pairs of analysed

At least 1 adverse event

Chu 2009

Emollient E‐DO

12

67

Chu 2009

Vehicle

8

67

Pruritus

Chu 2009

Emollient E‐DO

6

67

Chu 2009

Vehicle

2

67

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Analysis 2.3

Comparison 2 Bland emollients: emollient E‐DO versus vehicle, Outcome 3 Adverse events.

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Comparison 3 Corticosteroid creams/ointments: fluprednidene versus betamethasone, Outcome 1 Primary: investigator‐rated good/excellent control of symptoms after 3 weeks of treatment.
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Analysis 3.1

Comparison 3 Corticosteroid creams/ointments: fluprednidene versus betamethasone, Outcome 1 Primary: investigator‐rated good/excellent control of symptoms after 3 weeks of treatment.

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Comparison 3 Corticosteroid creams/ointments: fluprednidene versus betamethasone, Outcome 2 Primary: number of participants with at least 1 adverse event.
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Analysis 3.2

Comparison 3 Corticosteroid creams/ointments: fluprednidene versus betamethasone, Outcome 2 Primary: number of participants with at least 1 adverse event.

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Comparison 3 Corticosteroid creams/ointments: fluprednidene versus betamethasone, Outcome 3 Secondary: investigator‐rated improvement > 50% after 3 weeks.
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Analysis 3.3

Comparison 3 Corticosteroid creams/ointments: fluprednidene versus betamethasone, Outcome 3 Secondary: investigator‐rated improvement > 50% after 3 weeks.

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Study

Group

Number of participants with good/excellent control

Total number of participants

Gupta 1993

B‐film forming lotion

5

28

Gupta 1993

B‐thick lotion

0

26

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Analysis 4.1

Comparison 4 Corticosteroid creams/ointments: betamethasone‐dipropionate film‐forming lotion versus betamethasone‐dipropionate thick lotion, Outcome 1 Primary: investigator‐rated good/excellent control of symptoms at day 7.

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Comparison 4 Corticosteroid creams/ointments: betamethasone‐dipropionate film‐forming lotion versus betamethasone‐dipropionate thick lotion, Outcome 2 Primary: adverse events.
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Analysis 4.2

Comparison 4 Corticosteroid creams/ointments: betamethasone‐dipropionate film‐forming lotion versus betamethasone‐dipropionate thick lotion, Outcome 2 Primary: adverse events.

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Comparison 4 Corticosteroid creams/ointments: betamethasone‐dipropionate film‐forming lotion versus betamethasone‐dipropionate thick lotion, Outcome 3 Secondary: investigator‐rated reduction (not specified) in severity at day 7.
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Analysis 4.3

Comparison 4 Corticosteroid creams/ointments: betamethasone‐dipropionate film‐forming lotion versus betamethasone‐dipropionate thick lotion, Outcome 3 Secondary: investigator‐rated reduction (not specified) in severity at day 7.

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Comparison 4 Corticosteroid creams/ointments: betamethasone‐dipropionate film‐forming lotion versus betamethasone‐dipropionate thick lotion, Outcome 4 Secondary: investigator‐rated global improvement in eczema.
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Analysis 4.4

Comparison 4 Corticosteroid creams/ointments: betamethasone‐dipropionate film‐forming lotion versus betamethasone‐dipropionate thick lotion, Outcome 4 Secondary: investigator‐rated global improvement in eczema.

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Study

Group ‐ within‐participant study

Event number

Total number of pairs of hands analysed

Möller 1983

Clobetasol

32

46

Möller 1983

Flupredniden

14

46

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Analysis 5.1

Comparison 5 Corticosteroids creams/ointments: clobetasol propionate versus flupredniden acetate, Outcome 1 Primary: percentage of participants with investigator‐rated good/excellent control.

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Study

Group ‐ within‐participant study

Event number

Total number of pairs of hands analysed

At least 1 adverse event

Möller 1983

Clobetasol

4

46

Möller 1983

Flupredniden

3

46

Burning sensation

Möller 1983

Clobetasol

2

46

Möller 1983

Flupredniden

2

46

Reversible atrophy

Möller 1983

Clobetasol

1

46

Möller 1983

Flupredniden

0

46

Brittle skin

Möller 1983

Clobetasol

1

46

Möller 1983

Flupredniden

1

46

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Analysis 5.2

Comparison 5 Corticosteroids creams/ointments: clobetasol propionate versus flupredniden acetate, Outcome 2 Adverse events.

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Comparison 6 Corticosteroids creams/ointments: clobetasol propionate foam 0.05% versus vehicle, Outcome 1 Primary: percentage of participants with investigator‐rated good/excellent control at day 15.
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Analysis 6.1

Comparison 6 Corticosteroids creams/ointments: clobetasol propionate foam 0.05% versus vehicle, Outcome 1 Primary: percentage of participants with investigator‐rated good/excellent control at day 15.

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Comparison 6 Corticosteroids creams/ointments: clobetasol propionate foam 0.05% versus vehicle, Outcome 2 Primary: percentage of participants with self‐rated good/excellent control at day 15.
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Analysis 6.2

Comparison 6 Corticosteroids creams/ointments: clobetasol propionate foam 0.05% versus vehicle, Outcome 2 Primary: percentage of participants with self‐rated good/excellent control at day 15.

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Comparison 6 Corticosteroids creams/ointments: clobetasol propionate foam 0.05% versus vehicle, Outcome 3 Primary: adverse events.
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Analysis 6.3

Comparison 6 Corticosteroids creams/ointments: clobetasol propionate foam 0.05% versus vehicle, Outcome 3 Primary: adverse events.

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Comparison 6 Corticosteroids creams/ointments: clobetasol propionate foam 0.05% versus vehicle, Outcome 4 Secondary: reduction in severity, participant‐rated scoring at day 15.
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Analysis 6.4

Comparison 6 Corticosteroids creams/ointments: clobetasol propionate foam 0.05% versus vehicle, Outcome 4 Secondary: reduction in severity, participant‐rated scoring at day 15.

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Comparison 6 Corticosteroids creams/ointments: clobetasol propionate foam 0.05% versus vehicle, Outcome 5 Secondary: reduction in severity, investigator‐rated scoring at day 15.
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Analysis 6.5

Comparison 6 Corticosteroids creams/ointments: clobetasol propionate foam 0.05% versus vehicle, Outcome 5 Secondary: reduction in severity, investigator‐rated scoring at day 15.

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Study

Group ‐ within‐participant study

Event number

Total number of pairs of hands analysed

Uggeldahl 1986

Desonide cream 0.1%

0

50

Uggeldahl 1986

Desonide cream 0.05%

2

50

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Analysis 7.1

Comparison 7 Corticosteriods creams/ointments: desonide cream 0.1% versus desonide cream 0.05%, Outcome 1 Adverse events.

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Comparison 8 Corticosteroid creams/ointments: mometasone furoate cream 3 times/week versus 2 times/week versus no steroids, Outcome 1 Primary: investigator‐rated good/excellent control.
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Analysis 8.1

Comparison 8 Corticosteroid creams/ointments: mometasone furoate cream 3 times/week versus 2 times/week versus no steroids, Outcome 1 Primary: investigator‐rated good/excellent control.

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Comparison 8 Corticosteroid creams/ointments: mometasone furoate cream 3 times/week versus 2 times/week versus no steroids, Outcome 2 Primary: investigator‐rated good/excellent control.
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Analysis 8.2

Comparison 8 Corticosteroid creams/ointments: mometasone furoate cream 3 times/week versus 2 times/week versus no steroids, Outcome 2 Primary: investigator‐rated good/excellent control.

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Comparison 8 Corticosteroid creams/ointments: mometasone furoate cream 3 times/week versus 2 times/week versus no steroids, Outcome 3 Primary: adverse events.
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Analysis 8.3

Comparison 8 Corticosteroid creams/ointments: mometasone furoate cream 3 times/week versus 2 times/week versus no steroids, Outcome 3 Primary: adverse events.

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Study

Group ‐ within‐participant study

Event number

Total number of pairs of hands analysed

Scaling

Faghihi 2008

Clobetasol cream

3

47

Faghihi 2008

Clobetasol cream Clobetasol & Zinc sulphate cream

25

47

Redness

Faghihi 2008

Clobetasol cream

1

47

Faghihi 2008

Clobetasol cream Clobetasol & Zinc sulphate cream

41

47

Lichenification

Faghihi 2008

Clobetasol cream

7

47

Faghihi 2008

Clobetasol cream Clobetasol & Zinc sulphate cream

24

47

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Analysis 9.1

Comparison 9 Corticosteroid creams/ointments: clobetasol and zinc sulphate cream versus clobetasol cream, Outcome 1 Primary outcome: percentage of participants with investigator‐rated good/excellent control.

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Comparison 10 Corticosteroid creams/ointments: betamethasone‐valerate 0.1% cream versus urea 5% cream, Outcome 1 Primary: investigator‐rated good/excellent control of symptoms.
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Analysis 10.1

Comparison 10 Corticosteroid creams/ointments: betamethasone‐valerate 0.1% cream versus urea 5% cream, Outcome 1 Primary: investigator‐rated good/excellent control of symptoms.

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Comparison 10 Corticosteroid creams/ointments: betamethasone‐valerate 0.1% cream versus urea 5% cream, Outcome 2 Secondary: participant‐rated reduction in severity (bigger reduction in severity = better outcome).
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Analysis 10.2

Comparison 10 Corticosteroid creams/ointments: betamethasone‐valerate 0.1% cream versus urea 5% cream, Outcome 2 Secondary: participant‐rated reduction in severity (bigger reduction in severity = better outcome).

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Comparison 10 Corticosteroid creams/ointments: betamethasone‐valerate 0.1% cream versus urea 5% cream, Outcome 3 Secondary: investigator‐rated reduction in severity (bigger reduction in severity = better outcome).
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Analysis 10.3

Comparison 10 Corticosteroid creams/ointments: betamethasone‐valerate 0.1% cream versus urea 5% cream, Outcome 3 Secondary: investigator‐rated reduction in severity (bigger reduction in severity = better outcome).

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Study

Group ‐ within‐participant study

Event number

Total number of pairs of hands analysed

Kemper 1998

Betamethasone valerate 0.1% cream

0

19

Kemper 1998

Coal tar paste

1

19

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Analysis 11.1

Comparison 11 Topical others: coal tar versus betamethasone‐valerate, Outcome 1 Primary outcome: adverse events.

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Comparison 12 Irradiation with UV light versus no UVB, Outcome 1 Primary: adverse events ‐ exacerbation.
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Analysis 12.1

Comparison 12 Irradiation with UV light versus no UVB, Outcome 1 Primary: adverse events ‐ exacerbation.

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Comparison 13 Irradiation with UV light: whole‐body UVB versus placebo or local UVB hands, Outcome 1 Primary: investigator‐rated good/excellent control of symptoms by UVB hand vs whole‐body UVB vs placebo.
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Analysis 13.1

Comparison 13 Irradiation with UV light: whole‐body UVB versus placebo or local UVB hands, Outcome 1 Primary: investigator‐rated good/excellent control of symptoms by UVB hand vs whole‐body UVB vs placebo.

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Comparison 13 Irradiation with UV light: whole‐body UVB versus placebo or local UVB hands, Outcome 2 Secondary: time until relapse depicted in weeks of remission.
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Analysis 13.2

Comparison 13 Irradiation with UV light: whole‐body UVB versus placebo or local UVB hands, Outcome 2 Secondary: time until relapse depicted in weeks of remission.

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Comparison 14 Irradiation with UV light: local narrow‐band UVB versus local PUVA, Outcome 1 Primary: investigator‐rated good/excellent control of symptoms in UVB vs PUVA.
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Analysis 14.1

Comparison 14 Irradiation with UV light: local narrow‐band UVB versus local PUVA, Outcome 1 Primary: investigator‐rated good/excellent control of symptoms in UVB vs PUVA.

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Comparison 14 Irradiation with UV light: local narrow‐band UVB versus local PUVA, Outcome 2 Primary: adverse events ‐ reported adverse event, mainly erythema.
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Analysis 14.2

Comparison 14 Irradiation with UV light: local narrow‐band UVB versus local PUVA, Outcome 2 Primary: adverse events ‐ reported adverse event, mainly erythema.

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Study

Group ‐ within‐participant study

Event number

Total number of pairs of hands analysed

Sezer 2007

NB‐UVB

2

12

Sezer 2007

Local PUVA

1

12

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Analysis 15.1

Comparison 15 Irradiation with UV light: local narrow‐band UVB versus local PUVA, Outcome 1 Primary: investigator‐rated good/excellent control of symptoms in UVB vs PUVA.

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Study

Group ‐ within‐participant study

Event number

Total number of pairs of hands analysed

Palmar hyperpigmentation

Sezer 2007

NB‐UVB

0

12

Sezer 2007

Local PUVA

3

12

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Analysis 15.2

Comparison 15 Irradiation with UV light: local narrow‐band UVB versus local PUVA, Outcome 2 Primary: adverse events.

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Study

Group ‐ within‐participant study

Event number

Total number of pairs of hands analysed

Sezer 2007

NB‐UVB

9

12

Sezer 2007

Local PUVA

9

12

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Analysis 15.3

Comparison 15 Irradiation with UV light: local narrow‐band UVB versus local PUVA, Outcome 3 Secondary: investigator‐rated improvement by local narrow‐band UVB vs local PUVA.

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Comparison 16 Irradiation with UV light: oral PUVA versus topical bath PUVA, Outcome 1 Primary: adverse events.
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Analysis 16.1

Comparison 16 Irradiation with UV light: oral PUVA versus topical bath PUVA, Outcome 1 Primary: adverse events.

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Comparison 16 Irradiation with UV light: oral PUVA versus topical bath PUVA, Outcome 2 Secondary: investigator‐rated reduction in severity at week 10 (bigger reduction in severity = better outcome).
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Analysis 16.2

Comparison 16 Irradiation with UV light: oral PUVA versus topical bath PUVA, Outcome 2 Secondary: investigator‐rated reduction in severity at week 10 (bigger reduction in severity = better outcome).

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Comparison 16 Irradiation with UV light: oral PUVA versus topical bath PUVA, Outcome 3 Secondary: investigator‐rated reduction in severity at week 18 (bigger reduction in severity = better outcome).
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Analysis 16.3

Comparison 16 Irradiation with UV light: oral PUVA versus topical bath PUVA, Outcome 3 Secondary: investigator‐rated reduction in severity at week 18 (bigger reduction in severity = better outcome).

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Study

Group ‐ within‐participant study

Event number

Total number of pairs of hands analysed

Discontinuation due to adverse events

Grattan 1991

Topical PUVA

1

15

Grattan 1991

UVA

1

15

Burning

Grattan 1991

Topical PUVA

1

15

Grattan 1991

UVA

0

15

Exacerbation of eczema

Grattan 1991

Topical PUVA

1

15

Grattan 1991

UVA

0

15

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Analysis 17.1

Comparison 17 Irradiation with UV light: topical PUVA versus UVA, Outcome 1 Primary: adverse events.

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Comparison 18 Irradiation with UV light: UVA‐1 versus topical betamethasone valerate 0.1% cream, Outcome 1 Primary: adverse events ‐ hyperpigmentation.
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Analysis 18.1

Comparison 18 Irradiation with UV light: UVA‐1 versus topical betamethasone valerate 0.1% cream, Outcome 1 Primary: adverse events ‐ hyperpigmentation.

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Comparison 19 Irradiation with UV light: UVA‐1 versus placebo, Outcome 1 Primary: adverse events ‐ discontinuation because of exacerbation.
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Analysis 19.1

Comparison 19 Irradiation with UV light: UVA‐1 versus placebo, Outcome 1 Primary: adverse events ‐ discontinuation because of exacerbation.

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Comparison 19 Irradiation with UV light: UVA‐1 versus placebo, Outcome 2 Secondary: participant‐rated reduction in severity on VAS for itch (week 3, bigger reduction in severity = better outcome).
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Analysis 19.2

Comparison 19 Irradiation with UV light: UVA‐1 versus placebo, Outcome 2 Secondary: participant‐rated reduction in severity on VAS for itch (week 3, bigger reduction in severity = better outcome).

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Comparison 19 Irradiation with UV light: UVA‐1 versus placebo, Outcome 3 Secondary: investigator‐rated reduction in severity on dyshidrotic eczema area and severity index (DASI) (week 3, bigger reduction in severity = better outcome).
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Analysis 19.3

Comparison 19 Irradiation with UV light: UVA‐1 versus placebo, Outcome 3 Secondary: investigator‐rated reduction in severity on dyshidrotic eczema area and severity index (DASI) (week 3, bigger reduction in severity = better outcome).

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Study

Group ‐ within‐participant study

Event number

Total number of pairs of hands analysed

Burning

Adams 2007

PUVA

3

11

Adams 2007

UVA‐1

1

11

Itching

Adams 2007

PUVA

5

11

Adams 2007

UVA‐1

3

11

Figures and Tables -
Analysis 20.1

Comparison 20 Irradiation with UV light: PUVA versus UVA‐1, Outcome 1 Primary: adverse events.

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Study

Group ‐ within‐participant study

Event number

Total number of pairs of hands analysed

after 1 month

King 1984

Grenz Ray

7

15

King 1984

Placebo

0

15

after 3 months

King 1984

Grenz Ray

10

15

King 1984

Placebo

6

15

after 6 months

King 1984

Grenz Ray

11

15

King 1984

Placebo

8

15

Hyperkeratotic eczema after 6 months

King 1984

Grenz Ray

4

8

King 1984

Placebo

2

6

Pompholyx after 6 months

King 1984

Grenz Ray

7

7

King 1984

Placebo

6

7

Chronic palmar eczema after 6 months

King 1984

Grenz Ray

11

15

King 1984

Placebo

0

15

Figures and Tables -
Analysis 21.1

Comparison 21 Irradiation with Grenz ray, Outcome 1 Primary: investigator‐rated improvement good/excellent control.

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Study

Group ‐ within‐participant study

Event number

Total number of pairs of hands analysed

Cartwright 1987

Grenz

1

30

Cartwright 1987

Placebo

0

30

Lindelöf 1987

Grenz

5

24

Lindelöf 1987

Placebo

0

24

Figures and Tables -
Analysis 21.2

Comparison 21 Irradiation with Grenz ray, Outcome 2 Primary: adverse events ‐ hyperpigmentation.

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Study

Group ‐ within‐participant study

Mean

SD

Total number of pairs of hands analysed

Schnopp 2002

Tacrolimus

6.6

6.18

8

Schnopp 2002

Mometasone

6.9

7.7

8

Figures and Tables -
Analysis 22.1

Comparison 22 Topical calcineurin inhibitors: tacrolimus 0.1% ointment versus mometasone furoate, Outcome 1 Secondary: reduction in investigator‐rated severity ‐ DASI.

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Comparison 23 Topical calcineurin inhibitors: tacrolimus 0.1% ointment versus vehicle, Outcome 1 Primary: investigator‐rated good/excellent control of symptoms.
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Analysis 23.1

Comparison 23 Topical calcineurin inhibitors: tacrolimus 0.1% ointment versus vehicle, Outcome 1 Primary: investigator‐rated good/excellent control of symptoms.

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Comparison 23 Topical calcineurin inhibitors: tacrolimus 0.1% ointment versus vehicle, Outcome 2 Primary: adverse events burning/itching at application site.
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Analysis 23.2

Comparison 23 Topical calcineurin inhibitors: tacrolimus 0.1% ointment versus vehicle, Outcome 2 Primary: adverse events burning/itching at application site.

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Comparison 24 Topical calcineurin inhibitors: pimecrolimus 1% cream versus vehicle, Outcome 1 Primary: investigator‐rated good/excellent control of symptoms pimecrolimus cream vs vehicle.
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Analysis 24.1

Comparison 24 Topical calcineurin inhibitors: pimecrolimus 1% cream versus vehicle, Outcome 1 Primary: investigator‐rated good/excellent control of symptoms pimecrolimus cream vs vehicle.

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Comparison 24 Topical calcineurin inhibitors: pimecrolimus 1% cream versus vehicle, Outcome 2 Primary: adverse events.
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Analysis 24.2

Comparison 24 Topical calcineurin inhibitors: pimecrolimus 1% cream versus vehicle, Outcome 2 Primary: adverse events.

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Comparison 24 Topical calcineurin inhibitors: pimecrolimus 1% cream versus vehicle, Outcome 3 Secondary: participant‐rated reduction in severity pruritus relief between pimecrolimus 1% and vehicle.
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Analysis 24.3

Comparison 24 Topical calcineurin inhibitors: pimecrolimus 1% cream versus vehicle, Outcome 3 Secondary: participant‐rated reduction in severity pruritus relief between pimecrolimus 1% and vehicle.

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Comparison 25 Topical antibacterial agents: betamethasone‐valerate/clioquinol cream versus betamethasone‐valerate/fusidic acid, Outcome 1 Primary: investigator‐rated good/excellent control of symptoms (intention‐to‐treat).
Figures and Tables -
Analysis 25.1

Comparison 25 Topical antibacterial agents: betamethasone‐valerate/clioquinol cream versus betamethasone‐valerate/fusidic acid, Outcome 1 Primary: investigator‐rated good/excellent control of symptoms (intention‐to‐treat).

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Comparison 25 Topical antibacterial agents: betamethasone‐valerate/clioquinol cream versus betamethasone‐valerate/fusidic acid, Outcome 2 Primary: adverse events.
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Analysis 25.2

Comparison 25 Topical antibacterial agents: betamethasone‐valerate/clioquinol cream versus betamethasone‐valerate/fusidic acid, Outcome 2 Primary: adverse events.

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Comparison 26 Topical retinoids: bexarotene 1% gel versus bexarotene with corticosteroids, Outcome 1 Primary: investigator‐rated good/excellent control of symptoms (> 90% clearance).
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Analysis 26.1

Comparison 26 Topical retinoids: bexarotene 1% gel versus bexarotene with corticosteroids, Outcome 1 Primary: investigator‐rated good/excellent control of symptoms (> 90% clearance).

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Comparison 26 Topical retinoids: bexarotene 1% gel versus bexarotene with corticosteroids, Outcome 2 Primary: adverse events bexarotene vs bexarotene + mometasone.
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Analysis 26.2

Comparison 26 Topical retinoids: bexarotene 1% gel versus bexarotene with corticosteroids, Outcome 2 Primary: adverse events bexarotene vs bexarotene + mometasone.

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Comparison 26 Topical retinoids: bexarotene 1% gel versus bexarotene with corticosteroids, Outcome 3 Primary: adverse events bexarotene vs bexarotene + hydrocortisone.
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Analysis 26.3

Comparison 26 Topical retinoids: bexarotene 1% gel versus bexarotene with corticosteroids, Outcome 3 Primary: adverse events bexarotene vs bexarotene + hydrocortisone.

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Comparison 26 Topical retinoids: bexarotene 1% gel versus bexarotene with corticosteroids, Outcome 4 Secondary: investigator‐rated reduction in severity (> 50% reduction in hand eczema area and severity index (HEASI)).
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Analysis 26.4

Comparison 26 Topical retinoids: bexarotene 1% gel versus bexarotene with corticosteroids, Outcome 4 Secondary: investigator‐rated reduction in severity (> 50% reduction in hand eczema area and severity index (HEASI)).

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Study

Group ‐ within‐participant study

Event number

Total number of pairs of hands analysed

Fredriksson 1975

Aquacare

0

30

Fredriksson 1975

Calmurid

13

30

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Analysis 27.1

Comparison 27 Other topical agents: calmurid versus aquacare, Outcome 1 Primary: adverse events: burning.

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Comparison 28 Other topical agents: fumaric acid 5% cream verus triamcinolone 0.1% cream, Outcome 1 Primary: adverse events.
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Analysis 28.1

Comparison 28 Other topical agents: fumaric acid 5% cream verus triamcinolone 0.1% cream, Outcome 1 Primary: adverse events.

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Comparison 29 Other topical agents: furpalmate 0.3% cream versus hydrocortisone acetate 0.5% cream, Outcome 1 Primary: investigator‐rated good/excellent control of symptoms.
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Analysis 29.1

Comparison 29 Other topical agents: furpalmate 0.3% cream versus hydrocortisone acetate 0.5% cream, Outcome 1 Primary: investigator‐rated good/excellent control of symptoms.

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Comparison 30 Other topical agents: Fumaria parviflora versus vehicle cream, Outcome 1 Primary: adverse events: discontinuation due to erythema and papules.
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Analysis 30.1

Comparison 30 Other topical agents: Fumaria parviflora versus vehicle cream, Outcome 1 Primary: adverse events: discontinuation due to erythema and papules.

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Comparison 31 Oral immunosuppressants: oral azathioprine with topical clobetasol propionate versus topical clobetasol propionate, Outcome 1 Primary: percentage of participants with investigator‐rated good/excellent control.
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Analysis 31.1

Comparison 31 Oral immunosuppressants: oral azathioprine with topical clobetasol propionate versus topical clobetasol propionate, Outcome 1 Primary: percentage of participants with investigator‐rated good/excellent control.

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Comparison 31 Oral immunosuppressants: oral azathioprine with topical clobetasol propionate versus topical clobetasol propionate, Outcome 2 Secondary: investigator‐rated reduction in severity (bigger reduction in severity = better outcome).
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Analysis 31.2

Comparison 31 Oral immunosuppressants: oral azathioprine with topical clobetasol propionate versus topical clobetasol propionate, Outcome 2 Secondary: investigator‐rated reduction in severity (bigger reduction in severity = better outcome).

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Comparison 31 Oral immunosuppressants: oral azathioprine with topical clobetasol propionate versus topical clobetasol propionate, Outcome 3 Secondary: participant‐rated reduction in severity (bigger reduction in severity = better outcome).
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Analysis 31.3

Comparison 31 Oral immunosuppressants: oral azathioprine with topical clobetasol propionate versus topical clobetasol propionate, Outcome 3 Secondary: participant‐rated reduction in severity (bigger reduction in severity = better outcome).

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Comparison 32 Oral immunosuppressants: oral cyclosporin versus topical betamethasone dipropionate, Outcome 1 Primary: investigator‐rated very good or good efficacy.
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Analysis 32.1

Comparison 32 Oral immunosuppressants: oral cyclosporin versus topical betamethasone dipropionate, Outcome 1 Primary: investigator‐rated very good or good efficacy.

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Comparison 32 Oral immunosuppressants: oral cyclosporin versus topical betamethasone dipropionate, Outcome 2 Primary: participant‐rated very good or good efficacy.
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Analysis 32.2

Comparison 32 Oral immunosuppressants: oral cyclosporin versus topical betamethasone dipropionate, Outcome 2 Primary: participant‐rated very good or good efficacy.

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Comparison 32 Oral immunosuppressants: oral cyclosporin versus topical betamethasone dipropionate, Outcome 3 Primary: adverse events.
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Analysis 32.3

Comparison 32 Oral immunosuppressants: oral cyclosporin versus topical betamethasone dipropionate, Outcome 3 Primary: adverse events.

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Comparison 32 Oral immunosuppressants: oral cyclosporin versus topical betamethasone dipropionate, Outcome 4 Secondary: investigator‐rated reduction in severity in total disease activity score (6 weeks; bigger reduction in severity = better outcome).
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Analysis 32.4

Comparison 32 Oral immunosuppressants: oral cyclosporin versus topical betamethasone dipropionate, Outcome 4 Secondary: investigator‐rated reduction in severity in total disease activity score (6 weeks; bigger reduction in severity = better outcome).

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Comparison 33 Oral immunosuppressants: oral cyclosporin versus alitretinoin, Outcome 1 Primary: investigator‐rated good/excellent control (IGA) after 24 weeks.
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Analysis 33.1

Comparison 33 Oral immunosuppressants: oral cyclosporin versus alitretinoin, Outcome 1 Primary: investigator‐rated good/excellent control (IGA) after 24 weeks.

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Comparison 33 Oral immunosuppressants: oral cyclosporin versus alitretinoin, Outcome 2 Primary: participant‐rated good/excellent control (PGA) after 24 weeks.
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Analysis 33.2

Comparison 33 Oral immunosuppressants: oral cyclosporin versus alitretinoin, Outcome 2 Primary: participant‐rated good/excellent control (PGA) after 24 weeks.

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Comparison 33 Oral immunosuppressants: oral cyclosporin versus alitretinoin, Outcome 3 Primary: adverse events.
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Analysis 33.3

Comparison 33 Oral immunosuppressants: oral cyclosporin versus alitretinoin, Outcome 3 Primary: adverse events.

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Comparison 34 Oral retinoids: alitretinoin versus placebo, Outcome 1 Primary: investigator‐rated good/excellent control of symptoms.
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Analysis 34.1

Comparison 34 Oral retinoids: alitretinoin versus placebo, Outcome 1 Primary: investigator‐rated good/excellent control of symptoms.

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Comparison 34 Oral retinoids: alitretinoin versus placebo, Outcome 2 Primary: investigator‐rated good/excellent control of symptoms hyperkeratotic eczema.
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Analysis 34.2

Comparison 34 Oral retinoids: alitretinoin versus placebo, Outcome 2 Primary: investigator‐rated good/excellent control of symptoms hyperkeratotic eczema.

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Comparison 34 Oral retinoids: alitretinoin versus placebo, Outcome 3 Primary: investigator‐rated good/excellent control of symptoms pompholyx.
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Analysis 34.3

Comparison 34 Oral retinoids: alitretinoin versus placebo, Outcome 3 Primary: investigator‐rated good/excellent control of symptoms pompholyx.

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Comparison 34 Oral retinoids: alitretinoin versus placebo, Outcome 4 Primary: investigator‐rated good/excellent control of symptoms fingertip.
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Analysis 34.4

Comparison 34 Oral retinoids: alitretinoin versus placebo, Outcome 4 Primary: investigator‐rated good/excellent control of symptoms fingertip.

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Comparison 34 Oral retinoids: alitretinoin versus placebo, Outcome 5 Primary: participant‐rated investigator‐rated good/excellent control of symptoms.
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Analysis 34.5

Comparison 34 Oral retinoids: alitretinoin versus placebo, Outcome 5 Primary: participant‐rated investigator‐rated good/excellent control of symptoms.

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Comparison 34 Oral retinoids: alitretinoin versus placebo, Outcome 6 Primary: adverse events alitretinoin 10 mg vs placebo.
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Analysis 34.6

Comparison 34 Oral retinoids: alitretinoin versus placebo, Outcome 6 Primary: adverse events alitretinoin 10 mg vs placebo.

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Comparison 34 Oral retinoids: alitretinoin versus placebo, Outcome 7 Primary: adverse events alitretinoin 20 mg vs placebo.
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Analysis 34.7

Comparison 34 Oral retinoids: alitretinoin versus placebo, Outcome 7 Primary: adverse events alitretinoin 20 mg vs placebo.

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Comparison 34 Oral retinoids: alitretinoin versus placebo, Outcome 8 Primary: adverse events alitretinoin 30 mg vs placebo.
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Analysis 34.8

Comparison 34 Oral retinoids: alitretinoin versus placebo, Outcome 8 Primary: adverse events alitretinoin 30 mg vs placebo.

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Comparison 34 Oral retinoids: alitretinoin versus placebo, Outcome 9 Primary: adverse events alitretinoin 40 mg vs placebo.
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Analysis 34.9

Comparison 34 Oral retinoids: alitretinoin versus placebo, Outcome 9 Primary: adverse events alitretinoin 40 mg vs placebo.

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Study

Alitretinoin 40 mg

Ruzicka 2004

Median of % change from baseline: ‐70.5% (95% CI ‐44 to ‐80).

Ruzicka 2004

Significant more reduction than placebo (P < 0.001; Kruskal‐Wallis test).

Alitretinoin 30 mg

Ruzicka 2008

Median of % change from baseline: ‐75%

Ruzicka 2008

Significant more reduction than placebo (P < 0.001; Kruskal‐Wallis test).

Alitretinoin 20 mg

Ruzicka 2004

Median of % change from baseline: ‐52 (95% CI ‐42 to ‐73)

Ruzicka 2004

Significant more reduction than placebo (P < 0.01; Kruskal‐Wallis test).

Alitretinoin 10 mg

Ruzicka 2004

Median of % change from baseline: ‐25% (95% CI ‐14 to ‐42)

Ruzicka 2004

Significant more reduction than placebo (P < 0.01; Kruskal‐Wallis test).

Ruzicka 2008

Median of % change from baseline: ‐56%

Ruzicka 2008

Significant more reduction than placebo (P < 0.01; Kruskal‐Wallis test).

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Analysis 34.10

Comparison 34 Oral retinoids: alitretinoin versus placebo, Outcome 10 Secondary: investigator‐rated reduction in severity in total lesion symptom score.

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Study

Group

Median

SD

N

Alitretinoin 40 mg vs placebo

Ruzicka 2004

Alitretinoin 40 mg

70.5

81.407

81

Ruzicka 2004

Placebo

25.0

62.13

78

Alitretinoin 20 mg vs placebo

Ruzicka 2004

Alitretinoin 20 mg

52.0

80.9

80

Ruzicka 2004

Placebo

25.0

62.13

78

Alitretinoin 10 mg vs placebo

Ruzicka 2004

Alitretinoin 10 mg

59.0

89.892

80

Ruzicka 2004

Placebo

25.0

62.13

78

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Analysis 34.11

Comparison 34 Oral retinoids: alitretinoin versus placebo, Outcome 11 Secondary: investigator‐rated reduction in severity in total lesion symptom score.

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Comparison 34 Oral retinoids: alitretinoin versus placebo, Outcome 12 Secondary: reduction in severity, investigator‐rated in modified total lesion symptom score (bigger reduction in severity scored negative = better outcome).
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Analysis 34.12

Comparison 34 Oral retinoids: alitretinoin versus placebo, Outcome 12 Secondary: reduction in severity, investigator‐rated in modified total lesion symptom score (bigger reduction in severity scored negative = better outcome).

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Comparison 35 Oral retinoids: re‐treatment alitretinoin versus placebo, Outcome 1 Primary: investigator‐rated good/excellent control of symptoms.
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Analysis 35.1

Comparison 35 Oral retinoids: re‐treatment alitretinoin versus placebo, Outcome 1 Primary: investigator‐rated good/excellent control of symptoms.

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Comparison 35 Oral retinoids: re‐treatment alitretinoin versus placebo, Outcome 2 Primary: adverse events 10 mg vs placebo.
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Analysis 35.2

Comparison 35 Oral retinoids: re‐treatment alitretinoin versus placebo, Outcome 2 Primary: adverse events 10 mg vs placebo.

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Comparison 35 Oral retinoids: re‐treatment alitretinoin versus placebo, Outcome 3 Primary: adverse events 30 mg vs placebo.
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Analysis 35.3

Comparison 35 Oral retinoids: re‐treatment alitretinoin versus placebo, Outcome 3 Primary: adverse events 30 mg vs placebo.

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Study

Group ‐ within‐participant study

Event

Total number of participants analysed

Burrows 1986

Trientine

6

20

Burrows 1986

Placebo

10

20

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Analysis 36.1

Comparison 36 Other oral interventions: oral triethylenetetramine versus placebo, Outcome 1 Primary: investigator‐ and/or participant‐rated improvement.

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Comparison 37 Other oral interventions: oral tetraethylthiuram disulfide (TETDS) versus placebo, Outcome 1 Primary: investigator‐rated good/excellent control of symptoms during treatment period.
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Analysis 37.1

Comparison 37 Other oral interventions: oral tetraethylthiuram disulfide (TETDS) versus placebo, Outcome 1 Primary: investigator‐rated good/excellent control of symptoms during treatment period.

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Comparison 37 Other oral interventions: oral tetraethylthiuram disulfide (TETDS) versus placebo, Outcome 2 Primary: adverse events.
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Analysis 37.2

Comparison 37 Other oral interventions: oral tetraethylthiuram disulfide (TETDS) versus placebo, Outcome 2 Primary: adverse events.

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Comparison 38 Other oral interventions: low‐nickel diet (LND) + disulphiram versus normal diet + placebo, Outcome 1 Primary: investigator‐rated good/excellent control of symptoms after 4 weeks.
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Analysis 38.1

Comparison 38 Other oral interventions: low‐nickel diet (LND) + disulphiram versus normal diet + placebo, Outcome 1 Primary: investigator‐rated good/excellent control of symptoms after 4 weeks.

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Comparison 38 Other oral interventions: low‐nickel diet (LND) + disulphiram versus normal diet + placebo, Outcome 2 Primary: adverse events.
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Analysis 38.2

Comparison 38 Other oral interventions: low‐nickel diet (LND) + disulphiram versus normal diet + placebo, Outcome 2 Primary: adverse events.

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Comparison 39 Other oral interventions: oral evening primrose oil versus placebo, Outcome 1 Secondary: investigator‐rated reduction in severity score at week 24 (bigger reduction in severity = better outcome).
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Analysis 39.1

Comparison 39 Other oral interventions: oral evening primrose oil versus placebo, Outcome 1 Secondary: investigator‐rated reduction in severity score at week 24 (bigger reduction in severity = better outcome).

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Comparison 40 Other oral interventions: oral ranitidine versus placebo, Outcome 1 Primary: participant‐ and investigator‐rated good/excellent control of symptoms.
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Analysis 40.1

Comparison 40 Other oral interventions: oral ranitidine versus placebo, Outcome 1 Primary: participant‐ and investigator‐rated good/excellent control of symptoms.

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Comparison 41 Other oral interventions: disodium cromoglycate diet (DSCG) versus low‐nickel diet, Outcome 1 Primary: participant‐rated good/excellent control of symptoms (itch) after 3 months of itch in DSCG versus diet.
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Analysis 41.1

Comparison 41 Other oral interventions: disodium cromoglycate diet (DSCG) versus low‐nickel diet, Outcome 1 Primary: participant‐rated good/excellent control of symptoms (itch) after 3 months of itch in DSCG versus diet.

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Summary of findings for the main comparison. Corticosteroid creams/ointments: clobetasol propionate foam compared to vehicle foam for hand eczema

Corticosteroid creams/ointments: clobetasol propionate foam compared to vehicle foam for hand eczema

Patient or population: participants with moderate to severe hand eczema
Setting: secondary care with outpatients in Northern America
Intervention: clobetasol propionate 0.05% foam twice a day for 14 days
Comparison: vehicle/placebo foam twice a day for 14 days

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No. of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Assumed riska

Corresponding risk

Risk with vehicle foam

Risk with clobetasol propionate foam

Primary: investigator‐rated good/excellent control of symptoms

Follow‐up: day 15

Study population

RR 1.43
(0.86 to 2.40)

125
(1 RCT)

⊕⊕⊕⊝
Moderateb

‐

270 per 1000

386 per 1000
(232 to 648)

Primary: participants with self‐rated good/excellent control of symptoms

Follow‐up: day 15

Study population

RR 2.32
(1.38 to 3.91)

125
(1 RCT)

⊕⊕⊕⊝
Moderatec

NNTB 3 (95% CI 2 to 8)

222 per 1000

516 per 1000
(307 to 869)

Primary: adverse events ‐ at least 1 adverse event

Follow‐up: day 15

Study population

RR 2.24
(0.82 to 6.06)

125
(1 RCT)

⊕⊕⊕⊝
Moderatec

‐

79 per 1000

178 per 1000
(65 to 481)

Primary: adverse events ‐ any adverse event treatment‐related (application site pruritus)

Follow‐up: day 15

Study population

RR 1.02
(0.06 to 15.89)

125
(1 RCT)

⊕⊕⊕⊝
Moderated

‐

16 per 1000

16 per 1000
(1 to 252)

Secondary: reduction in severity, participant‐rated scoring

Follow‐up: day 15

Study population

RR 1.57
(1.21 to 2.04)

125
(1 RCT)

⊕⊕⊕⊝
Moderateb

NNTB 3 (95% CI 2 to 7)

524 per 1000

822 per 1000
(634 to 1000)

Secondary: reduction in severity, investigator‐rated scoring ‐ improvement at least 2 grades

Follow‐up: day 15

Study population

RR 1.47
(0.90 to 2.39)

125
(1 RCT)

⊕⊕⊕⊝
Moderateb

‐

286 per 1000

420 per 1000
(257 to 683)

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: confidence interval; NNTB: number needed to treat for an additional beneficial outcome; RCT: randomised controlled trial; RR: risk ratio.

Kircik 2013

GRADE Working Group grades of evidence.
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

aThe assumed risk is the mean control group risk.

bDowngraded by one level to moderate‐certainty evidence for imprecision. Small sample size and small number of events.

cDowngraded by one level to moderate‐certainty evidence for imprecision. Wide confidence interval with small sample size and small number of events.

dDowngraded by one level to moderate‐certainty evidence for imprecision. Summary effect contains both appreciable benefit and harm; wide confidence interval with small sample size and small number of events.

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Summary of findings for the main comparison. Corticosteroid creams/ointments: clobetasol propionate foam compared to vehicle foam for hand eczema
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Summary of findings 2. Corticosteroid creams/ointments: mometasone furoate cream 3 times/week versus 2 times/week for hand eczema

Corticosteroid creams/ointments: mometasone furoate cream thrice a week versus twice a week

Patient or population: people (all patch‐tested) with hand eczema > 6 months that had cleared upon daily treatment for a maximum of 9 weeks with mometasone furoate cream
Settings: secondary care with outpatients from hospitals in Denmark
Intervention: mometasone furoate cream 3 times/week up to 36 weeks

Comparision: mometasone furoate cream 2 times/week up to 36 weeks

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No. of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Assumed riska

Corresponding risk

Risk with mometasone furoatetwice a week

Risk with mometasone furoate thrice a week

Primary: investigator‐rated good/excellent control of symptoms
Follow‐up: 36 weeks

Study population

RR 1.23
(0.94 to 1.61)

72
(1 RCT)

⊕⊕⊝⊝
Lowb

‐

676 per 1000

831 per 1000
(635 to 1000)

Primary: participant‐rated good/excellent control of symptoms
Not measured

See comment

See comment

Not estimable

‐

See comment

No data available

Primary: adverse events
Follow‐up: 36 weeks

Study population

RR 1.76
(0.45 to 6.83)

72
(1 RCT)

⊕⊕⊝⊝
Lowc

‐

81 per 1000

143 per 1000
(36 to 554)

Secondary: investigator‐rated reduction in severity

Not measured

See comment

See comment

Not estimable

‐

See comment

No data available

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio.

Veien 1999

GRADE Working Group grades of evidence.
High certainty: further research is very unlikely to change our confidence in the estimate of effect.
Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low certainty: we are very uncertain about the estimate.

aThe assumed risk is the mean control group risk.

bDowngraded by two levels to low‐certainty evidence. Imprecision downgraded by one level: the event number was small as was the sample size. Downgraded one level for risk of bias, given the high risk of detection and performance bias.

cDowngraded by two levels to low‐certainty evidence. Imprecision downgraded by one level: the summary effect contains both appreciable benefit and harm; sample size was small as was the event rate. Downgraded one level for risk of bias, given the high risk of detection and performance bias.

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Summary of findings 2. Corticosteroid creams/ointments: mometasone furoate cream 3 times/week versus 2 times/week for hand eczema
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Summary of findings 3. Irradiation with UV light: local narrow‐band UVB compared to local PUVA for hand eczema

Irradiation with UV light: local narrow‐band UVB compared to local PUVA for hand eczema

Patient or population: people with hand eczema unresponsive to clobetasol propionate
Setting: secondary care with outpatients in the United Kingdom.
Intervention: local narrow‐band UVB twice weekly for 12 weeks
Comparison: immersion PUVA twice weekly for 12 weeks

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No. of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Assumed riska

Corresponding risk

Risk with local PUVA

Risk with local narrow‐band UVB

Primary: investigator‐rated good/excellent control of symptoms

Follow‐up: 12 weeks

Study population

RR 0.50
(0.22 to 1.16)

60
(1 RCT)

⊕⊕⊕⊝
Moderateb

‐

400 per 1000

200 per 1000
(88 to 464)

Primary: participant‐rated good/excellent control of symptoms

Not measured

See comment

See comment

Unable to estimate treatment effect

‐

See comment

No data reported

Primary: adverse events ‐ reported adverse events, mainly erythema

Follow‐up: 12 weeks

See comment

See comment

RR 19.00
(1.16 to 312.42)

60
(1 RCT)

⊕⊕⊕⊝
Moderatec

PUVA:

No adverse events reported (0/30)

Narrow‐band UVB:

9 out of 30 participants reported an adverse event, mainly erythema

Fisher's exact test  P = 0.0019

Secondary: investigator‐rated reduction in severity in mTLSSd

Follow‐up: 12 weeks

‐

‐

Unable to estimate treatment effect

43 (1 RCT)

⊕⊕⊕⊝
Moderatee

Reduction in mTLSS PUVA:

Median mTLSS of 8.5 (range 0 to 16) and 8 (range 3 to 15) for the left and right hand, to a median mTLSS 3 (range 0 to 13) and 3 (range 0 to 14) (n = 23)

Reduction mTLSS local narrow‐band UVB group:

Median mTLSS of 7 (range 0 to 16) and 8.5 (range 1 to 15) to a median mTLSS5 (range 0 to 11) and 4.5 (range 0 to 11) (n = 20)

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: confidence interval; mTLSS: modified total lesion symptom score; PUVA: oral psoralen combined with UVA; RCT: randomised controlled trial; RR: risk ratio; UV: ultraviolet.

2015

GRADE Working Group grades of evidence.
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

aThe assumed risk is the mean control group risk.

bDowngraded by one level to moderate‐certainty evidence for imprecision. Small sample size, small number of events, and high dropout rate.

cDowngraded by one level to moderate‐certainty evidence for imprecision. Wide confidence interval with small sample size, small number of events, and high dropout rate.

dThe Modified Total Lesion Symptom Score (mTLSS) is the sum of seven items (erythema, oedema, vesiculation, scaling, lichenification/hyperkeratosis, fissures, and pruritus/pain) scored on a 4‐point scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe). A high mTLSS represents severe hand eczema.

eDowngraded by one level to moderate‐certainty evidence for imprecision. Small sample size based on single study.

Figures and Tables -
Summary of findings 3. Irradiation with UV light: local narrow‐band UVB compared to local PUVA for hand eczema
Navigate to table in Review
Summary of findings 4. Topical calcineurin inhibitors: tacrolimus 0.1% ointment compared to mometasone furoate ointment for vesicular hand eczema

Topical calcineurin inhibitors: tacrolimus 0.1% ointment compared to mometasone furoate ointment for vesicular hand eczema

Patient or population: people with moderate to severe chronic relapsing dyshidrotic eczema on hands
Setting: secondary care setting at a single dermatology department in Germany
Intervention: topical calcineurin inhibitors tacrolimus 0.1% ointment twice daily during 4 weeks
Comparison: topical corticosteroid mometasone furoate ointment twice daily during 4 weeks

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No. of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Risk with mometasone furoate ointment

Risk with topical calcineurin inhibitor tacrolimus 0.1% ointment

Primary: investigator‐rated good/excellent control of symptoms ‐

Not measured

See comment

See comment

Not estimable

‐

See comment

Not measured

Primary: participant‐rated good/excellent control of symptoms ‐

Not measured

See comment

See comment

Not estimable

‐

See comment

Not measured

Primary: adverse events
Follow‐up: 2 weeks

See comment

See comment

Not estimable

16 pairs of hands (1 RCT)

⊕⊕⊕⊝
Moderatea

Within‐participant design

None of the participants dropped out because of adverse events

Secondary: investigator‐rated reduction in severity ‐ DASIb

Follow‐up: 2 weeks

See comment

See comment

Not estimable

16 pairs of hands (1 RCT)

⊕⊕⊕⊝
Moderatea

Within‐participant design

Tacrolimus group:

Mean DASI from 18 (SD 12.68) to 6.6 (SD 6.18)

Mometasone furoate group:

Mean DASI from 18.5 (SD 14.09) to 6.9 (SD 7.7)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; DASI: Dyshydrotic Eczema Area and Severity Index; RCT: randomised controlled trial; RR: risk ratio; SD: standard deviation.

Schnopp 2002

GRADE Working Group grades of evidence.
High certainty: further research is very unlikely to change our confidence in the estimate of effect.
Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low certainty: we are very uncertain about the estimate.

aDowngraded by one level to moderate‐certainty evidence for imprecision: small sample size in a single study and small number of events.

bDASI: Dyshydrotic Eczema Area and Severity Index is an assessment of severity combining objective (vesicles, erythema, and desquamation) and subjective (itch) evaluations on a scale from 0 (no eczema) to 60 (severe hand eczema).

Figures and Tables -
Summary of findings 4. Topical calcineurin inhibitors: tacrolimus 0.1% ointment compared to mometasone furoate ointment for vesicular hand eczema
Navigate to table in Review
Summary of findings 5. Topical calcineurin inhibitors: tacrolimus 0.1% ointment versus vehicle for hand eczema

Topical calcineurin inhibitor tacrolimus 0.1% ointment compared to vehicle for hand eczema

Patient or population: people with moderate to severe nickel sulphate‐induced allergic contact dermatitis based on clinical history (hand eczema) and proven by patch testing, resistant to topical corticosteroids
Settings: secondary care setting in a single‐centre study in Italy
Intervention: topical calcineurin inhibitor tacrolimus 0.1% ointment twice daily for 2 weeks

Comparison: vehicle twice daily for 2 weeks

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No. of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Risk with vehicle

Risk with tacrolimus 0.1% ointment

Primary: investigator‐rated good/excellent control of symptoms

Follow‐up: 3 weeks

See comment

See comment

RR 29.00
(1.90 to 443.25)

28
(1 RCT)

⊕⊕⊕⊝
Moderatea

Unable to calculate assumed risk as no events in the control group ‐ 14/14 participants in the tacrolimus group had good/excellent control of symptoms.

Fisher's exact test P = 0.0001, NNTB 1, 95% CI 1 to 1

Primary: participant‐rated good/excellent control of symptoms
Not measured

See comment

See comment

Not estimable

‐

See comment

No data reported

Primary: adverse events ‐ burning/itching at application site

Follow‐up: 3 weeks

See comment

See comment

RR 9.00
(0.53 to 152.93)

28
(1 RCT)

⊕⊕⊕⊝
Moderatea

Unable to calculate assumed risk as no events in the control group ‐ 4/14 participants in the tacrolimus group had burning/itching at the application site.

Fisher's exact test P = 0.1129, RR 9.00, 95% CI 0.53 to 152.93

No data on "all adverse events"

Secondary: investigator‐rated reduction in severity ‐

Not measured

See comment

See comment

Not estimable

‐

See comment

No data reported

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; NNTB: number needed to treat for an additional beneficial outcome; RCT: randomised controlled trial; RR: risk ratio.

Pacor 2006

GRADE Working Group grades of evidence.
High certainty: further research is very unlikely to change our confidence in the estimate of effect.
Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low certainty: we are very uncertain about the estimate.

aDowngraded by one level to moderate‐certainty evidence for imprecision: very small sample size, low event rate, and very large confidence intervals.

Figures and Tables -
Summary of findings 5. Topical calcineurin inhibitors: tacrolimus 0.1% ointment versus vehicle for hand eczema
Navigate to table in Review
Summary of findings 6. Oral immunosuppressants: oral cyclosporin versus topical betamethasone dipropionate

Oral cyclosporin compared to topical betamethasone for patient with hand eczema

Patient or population: people with hand eczema, continuously for 6 months, significant disability, inadequate response to conventional treatment, confirmation by histopathology
Setting: secondary care setting at a single centre in Finland
Intervention: oral cyclosporin 3 mg/kg/d and placebo cream for 6 weeks
Comparison: topical betamethasone dipropionate 0.05% cream and placebo capsules for 6 weeks

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No. of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Assumed riska

Corresponding risk

Risk with topical betamethasone

Risk with oral cyclosporin

Primary: investigator‐ rated good/excellent control of symptomsb

Follow‐up: 6 weeks

Study population

RR 1.88
(0.88 to 3.99)

34
(1 RCT)

⊕⊕⊕⊝
Moderatec

‐

333 per 1000

627 per 1000
(293 to 1000)

Primary: participant‐rated good/excellent control of symptomsb

Follow‐up: 6 weeks

Study population

RR 1.25
(0.69 to 2.27)

34
(1 RCT)

⊕⊕⊕⊝
Moderatec

‐

500 per 1000

625 per 1000
(345 to 1000)

Primary: adverse events ‐ at least 1 adverse event

Follow‐up: 36 weeks

Study population

RR 1.22
(0.80 to 1.86)

55d
(1 RCT)

⊕⊕⊕⊝
Moderatec

Because of partial cross‐over design, a different number of participants is given for this outcome

556 per 1000

678 per 1000
(444 to 1000)

Secondary: investigator‐rated reduction in severityb

Follow‐up: 6 weeks

Mean investigator‐rated reduction in severity in total disease activity score after 6 weeks of treatment was 5.7

MD 0.30 higher
(2.50 lower to 3.10 higher)

‐

34
(1 RCT)

⊕⊕⊕⊝
Moderatec

‐

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; MD: mean difference; RCT: randomised controlled trial; RR: risk ratio.

Granlund 1996

GRADE Working Group grades of evidence.
High certainty: further research is very unlikely to change our confidence in the estimate of effect.
Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low certainty: we are very uncertain about the estimate.

aThe assumed risk is the mean control group risk.

bObserver‐rated disease activity score: grading 0 to 3 (0 = none, 1 = mild, 2 = moderate, 3 = severe) on erythema, scaling, infiltration, excoriation, crusting, and vesicles for both hands. A high score represents severe hand eczema.

cDowngraded by one level to moderate‐certainty evidence. Imprecision downgraded by one level: small sample size.

dThe number of participants varies between different outcomes because this is a cross‐over study, and adverse events were included from all different phases of the trial.

Figures and Tables -
Summary of findings 6. Oral immunosuppressants: oral cyclosporin versus topical betamethasone dipropionate
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Summary of findings 7. Oral retinoids: alitretinoin 30 mg versus placebo for hand eczema

Oral retinoids: alitretinoin 30 mg versus placebo for hand eczema

Patient or population: people with moderate to severe chronic hand eczema
Settings: secondary care with outpatients in an international multi‐centre setting
Intervention: oral retinoid alitretinoin 30 mg for 12 to 24 weeks

Comparison: oral placebo for 12 to 24 weeks

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No. of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Assumed riska

Corresponding risk

Risk with placebo

Risk with alitretinoin 30 mg

Primary: investigator‐rated good/excellent control of symptoms

Follow‐up: 48 weeks to 72 weeks

Study population

RR 2.75 (2.20 to 3.43)

1210
(2 RCTs)

⊕⊕⊕⊕
Highb

NNTB 4, 95% CI 3 to 5

157 per 1000

432 per 1000
(346 to 539)

Primary: participant‐rated good/excellent control of symptoms

Folluw‐up: 48 weeks to 72 weeks

Study population

RR 2.75
(2.18 to 3.48)

1210
(2 RCTs)

⊕⊕⊕⊕
Highb

NNTB 4, 95% CI 3 to 5

143 per 1000

394 per 1000
(312 to 498)

Primary: adverse events ‐ headache

Folluw‐up: 48 weeks to 72 weeks

Study population

RR 3.43
(2.45 to 4.81)

1210
(2 RCTs)

⊕⊕⊕⊕
Highb

All adverse events not stated in Ruzicka 2008

NNTH 6, 95% CI 4 to 11

74 per 1000

251 per 1000
(179 to 352)

Secondary: investigator‐rated reduction in severity in TLSSc and mTLSSd

See comment

See comment

Not estimable

‐

See comment

Only incomplete data reported; therefore we were unable to extract these data

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; NNTB: number needed to treat for an additional beneficial outcome; NNTH: number needed to treat for an additional harmful outcome; RCT: randomised controlled trial; RR: risk ratio.

Ruzicka 2008; Fowler 2014

GRADE Working Group grades of evidence.
High certainty: further research is very unlikely to change our confidence in the estimate of effect.
Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low certainty: we are very uncertain about the estimate.

aThe assumed risk is the mean control group risk.

bRelatively high number of dropouts, although analysed via intention‐to‐treat analysis. Risk of bias was low, the two included studies were consistent, and the evidence is applicable to patients with (moderate to) severe hand eczema. Risk of publication bias was considered low, although the studies were sponsored by a pharmaceutical company.

cThe total lesion symptom score (TLSS) is the sum of seven items (erythema, oedema, vesicles, desquamation, hyperkeratosis, fissures, and pruritus/pain) scored on a 4‐point scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe). A high TLSS represents severe hand eczema.

dThe modified total lesion symptom score (mTLSS) is the sum of seven items (erythema, oedema, vesiculation, scaling, lichenification/hyperkeratosis, fissures, and pruritus/pain) scored on a 4‐point scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe). A high mTLSS represents severe hand eczema.

Figures and Tables -
Summary of findings 7. Oral retinoids: alitretinoin 30 mg versus placebo for hand eczema
Navigate to table in Review
Summary of findings 8. Oral retinoids: alitretinoin 10 mg versus placebo for hand eczema

Oral retinoids: alitretinoin 10 mg versus placebo for hand eczema

Patient or population: people with moderate to severe chronic hand eczema
Settings: secondary care with outpatients in an international multi‐centre setting
Intervention: oral retinoid alitretinoin 10 mg for 12 to 24 weeks

Comparison: oral placebo for 12 to 24 weeks

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No. of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Assumed riska

Corresponding risk

Risk with placebo

Risk with alitretinoin

Primary: investigator‐rated good/excellent control of symptoms

Follow‐up: up to 48 weeks

Study population

RR 1.58 (1.20 to 2.07)

781
(2 RCTs)

⊕⊕⊕⊕
Highb

NNTB 11, 95% CI 6.3 to 26.5

194 per 1000

307 per 1000
(233 to 402)

Primary: participant‐rated good/excellent control of symptoms

Follow‐up: up to 48 weeks

Study population

RR 1.73
(1.25 to 2.40)

765
(2 RCTs)

⊕⊕⊕⊕
Highb

NNTB 9, 95% CI 6 to 20

144 per 1000

249 per 1000
(180 to 345)

Primary: all adverse events

Follow‐up: up to 48 weeks

Study population

RR 1.01

(0.66 to 1.55)

158
(1 RCT)

⊕⊕⊕⊝
Moderatec

NNTH 260, 95% CI ‐14.47 to 15.24

346 per 1000

350 per 1000

(228 to 537)

Secondary: investigator‐rated reduction in severity of TLSSd

Follow‐up: up to 48 weeks

See comment

See comment

‐

158
(1 RCT)

⊕⊕⊕⊝
Moderatec

Median % change in score from baseline (95% CI)

Placebo group:

‐25% (95% CI ‐42 to ‐14)

Aitretinoin 10 mg:

–59 (95% CI –73 to –33)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; NNTB: number needed to treat for an additional beneficial outcome; NNTH: number needed to treat for an additional harmful outcome; RCT: randomised controlled trial; RR: risk ratio; TLSS: total lesion symptom score.

Ruzicka 2004; Ruzicka 2008

GRADE Working Group grades of evidence.
High certainty: further research is very unlikely to change our confidence in the estimate of effect.
Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low certainty: we are very uncertain about the estimate.

aThe assumed risk is the mean control group risk.

b Both studies were at low risk of bias and results were precise.

cDowngraded by one level to moderate‐certainty evidence: imprecision downgraded by one level: small sample size.

dThe total lesion symptom score (TLSS) is the sum of seven items (erythema, oedema, vesicles, desquamation, hyperkeratosis, fissures, and pruritus/pain) scored on a 4‐point scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe). A high TLSS represents severe hand eczema.

Figures and Tables -
Summary of findings 8. Oral retinoids: alitretinoin 10 mg versus placebo for hand eczema
Navigate to table in Review
Table 1. Overview of studies on bland emollients: investigator‐rated good/excellent control

Study

Comparison

Investigator‐rated good/excellent control in RR (95% CI)

Comment

Kucharekova 2003

Ceramide‐containing emollient versus regular petrolatum‐based emollient

No data regarding the primary outcome investigator‐rated good/excellent control

‐

Chu 2009

E‐DO lotion versus vehicle lotion

E‐DO: 37 responders, 12 of whom responded to E‐DO only (19%), and 25 to both (39.7%)

Vehicle: 36 responders, 11 of whom responded to vehicle only (17.5%), and 25 to both (39.7%)

Investigator‐rated RR 1.06 (95% CI 0.54 to 2.10)

Within‐patient study

E‐DO is a trade/product name.
Figures and Tables -
Table 1. Overview of studies on bland emollients: investigator‐rated good/excellent control
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Table 2. Overview of studies on topical corticosteroids: investigator‐rated good/excellent control

Study

Comparison of topical corticosteroids

Investigator‐rated good/excellent control in RR (95% CI)

Comment

Möller 1983

Intermittent clobetasol versus fluprednidene

Clobetasol better since 32/46 versus 14/46 hands remained in remission; investigator‐rated

Within‐patient study

Uggeldahl 1986

Desonide 0.1% versus desonide 0.05%

No data regarding the primary outcome investigator‐rated good/excellent control

Within‐patient study

Bleeker 1989

Fluprednidene versus betamethasone

RR 0.59 (95% CI 0.28 to 1.23); investigator‐rated

‐

Gupta 1993

Betamethasone film versus betamethasone lotion

RR 10.24 (95% CI 0.59 to 176.56); investigator‐rated

‐

Veien 1999

Mometasone 3 times/week versus mometasone 2 times/week

RR 1.23 (95% CI 0.94 to 1.61); investigator‐rated

‐

Fowler 2005

Hydrocortisone butyrate versus fluticasone propionate twice daily
Hydrocortisone butyrate versus prednicarbate emollient twice daily

Hydrocortisone butyrate 0.1% cream versus mometasone furoate twice daily

No data regarding the primary outcome investigator‐rated good/excellent control

Three parallel treatment groups Each group separately within‐patient

Faghihi 2008

0.05% clobetasol cream versus 0.05% clobetasol + zinc sulphate cream

Clobetasol + zinc sulphate better in terms of respectively scaling (25/47 versus 3/47), redness (41/47 versus 1/41), and lichenification (24/47 versus 7/47); investigator‐rated

Within‐patient study

Lodén 2012a

Betamethasone‐valerate 0.1% cream twice daily versus betamethasone‐valerate 0.1% cream once daily + urea 5% cream once daily

RR 0.75 (0.55 to 1.03); investigator‐rated

‐

Kircik 2013

Clobetasol propionate 0.05% foam twice daily versus vehicle foam twice daily

RR 1.43 (0.86 to 2.40); investigator‐rated

‐

CI: confidence interval.

RR: risk ratio.
Figures and Tables -
Table 2. Overview of studies on topical corticosteroids: investigator‐rated good/excellent control
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Table 3. Overview of studies on coal tar and derivatives: investigator‐rated good/excellent control

Study

Comparison

Investigator‐rated good/excellent control in RR (95% CI)

Comment

Kemper 1998

Coal tar paste versus betamethasone‐valerate or zinc oxide once a week

No data regarding the primary outcome investigator‐rated good/excellent control

Within‐patient study
Figures and Tables -
Table 3. Overview of studies on coal tar and derivatives: investigator‐rated good/excellent control
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Table 4. Overview of studies on irradiation with UV light: investigator‐rated good/excellent control

Study

Comparison

Investigator‐rated good/excellent control in RR (95% CI)

Comment

Bayerl 1999

UVB versus no UVB

No data regarding the primary outcome investigator‐rated good/excellent control

‐

Sjövall 1987

Local UVB versus placebo

RR 2.0 (95% CI 0.26 to 15.6)

‐

Sjövall 1987

Local UVB hand versus whole body + hand UVB

RR 2.2 (95% CI 0.83 to 5.8)

‐

Sjövall 1987

Local UVB hand versus whole body versus placebo

RR 3.67 (95% CI 0.90 to 14.97)

‐

van Coevorden 2004a

Oral PUVA versus topical bath PUVA

No data regarding the primary outcome investigator‐rated good/excellent control

‐

Grattan 1991

Topical PUVA versus UVA

No data regarding the primary outcome investigator‐rated good/excellent control

Within‐patient study

Polderman 2003

UVA‐1 versus placebo

No data regarding the primary outcome investigator‐rated good/excellent control

‐

Brass 2015

Local NB‐UVB versus topical PUVA

RR 0.50 (95% CI 0.22 to 1.16)

‐

Sezer 2007

Local NB‐UVB versus topical PUVA

NB‐UVB was effective in 2/12 hands and topical PUVA was effective in 1/12 hands

Within‐patient study

Tzaneva 2009

Oral PUVA versus bath PUVA

No data regarding the primary outcome investigator‐rated good/excellent control

‐

Adams 2007

UVA‐1 versus topical cream PUVA

No data regarding the primary outcome investigator‐rated good/excellent control

Within‐patient study

Said 2010

Local UVA‐1 versus topical betamethasone‐valerate cream

No data regarding the primary outcome investigator‐rated good/excellent control

‐

CI: confidence interval.

RR: risk ratio.

NB‐UVB: narrow‐band ultraviolet B.

PUVA: psoralen + ultraviolet A.

UVB: ultraviolet B.

UVA‐1: a subtype of ultraviolet A.
Figures and Tables -
Table 4. Overview of studies on irradiation with UV light: investigator‐rated good/excellent control
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Table 5. Overview of studies on X‐rays (ionising radiation): investigator‐rated good/excellent control

Study

Comparison

Investigator‐rated good/excellent control in RR (95% CI)

Comments

King 1984

X‐rays 300 rad versus placebo

No difference after 6 months. Grenz ray effective in 11/15 hands versus 8/15 hands with placebo.

Within‐patient study

Fairris 1984

X‐rays 300 rad versus placebo

No data regarding the primary outcome investigator‐rated good/excellent control

Within‐patient study

Lindelöf 1987

Grenz rays 1800 rad versus placebo

No data regarding the primary outcome investigator‐rated good/excellent control

Within‐patient study

Cartwright 1987

Grenz rays 300 rad versus placebo

No data regarding the primary outcome investigator‐rated good/excellent control

Within‐patient study

Fairris 1985

X‐rays 1 Gy versus Grenz rays 3 Gy

No data regarding the primary outcome investigator‐rated good/excellent control

Within‐patient study

Sheehan‐Dare 1989

X‐rays versus PUVA

No data regarding the primary outcome investigator‐rated good/excellent control

Within‐patient study

CI: confidence interval.

Grenz rays: a type of X‐rays (ionising radiation).

Gy: Gray, a unit of radiation dose.

RR: risk ratio.
Figures and Tables -
Table 5. Overview of studies on X‐rays (ionising radiation): investigator‐rated good/excellent control
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Table 6. Overview of studies on topical calcineurin inhibitors: investigator‐rated good/excellent control

Study

Comparison

Investigator‐rated good/excellent control in RR (95% CI)

Comments

Schnopp 2002

Tacrolimus ointment versus mometasone furoate

No data regarding the primary outcome investigator‐rated good/excellent control

Within‐patient study

Katsarou 2012

Tacrolimus ointment versus mometasone furoate

No data regarding the primary outcome investigator‐rated good/excellent control

Improvement was reported separately for subcategories of clinical signs

Krejci‐Manwaring 2008

Tacrolimus ointment versus vehicle

No data regarding the primary outcome investigator‐rated good/excellent control

‐

Pacor 2006

Tacrolimus ointment versus vehicle

RR 29.0 (95% CI 1.9 to 443.25)

‐

Belsito 2004

Pimecrolimus cream versus vehicle

RR 1.53 (95% CI 0.99 to 2.36)

‐

Hordinsky 2010

Pimecrolimus cream versus vehicle

RR 1.28 (95% CI 0.99 to 1.66)

‐

Bauer 2012

Pimecrolimus cream versus vehicle

No data regarding the primary outcome investigator‐rated good/excellent control

‐

Baskan 2005

Pimecrolimus cream versus vehicle

No data regarding the primary outcome investigator‐rated good/excellent control

‐

Cherill 2000

Pimecrolimus cream versus vehicle

No data regarding the primary outcome investigator‐rated good/excellent control

‐

CI: confidence interval.

RR: risk ratio.
Figures and Tables -
Table 6. Overview of studies on topical calcineurin inhibitors: investigator‐rated good/excellent control
Navigate to table in Review
Table 7. Overview of studies on other topical interventions: investigator‐rated good/excellent control

Study

Comparison

Investigator‐rated good/excellent control in RR (95% CI)

Comments

Hill 1998

Betamethasone‐valerate + clioquinol versus betamethasone‐valerate + fusidic acid

RR 1.03 (95% CI 0.74 to 1.43)

‐

Fredriksson 1975

Aquacare HP cream versus calmurid cream containing betaine and lactic acid

No data regarding the primary outcome investigator‐rated good/excellent control

Within‐patient study

Odia 1996

Iontophoresis versus no iontophoresis

No data regarding the primary outcome investigator‐rated good/excellent control

Within‐patient study

Boroujeni 2017

Herbal cream containing fenugreek seeds 5%, marshmallow 5%, chamomile 5%, and walnut leaves 5% versus fluocinolone acetonide cream 2% twice daily

No data regarding the primary outcome investigator‐rated good/excellent control

‐

Hanifin 2004

Bexarotene 1% gel versus bexarotene with either mometasone furoate or hydrocortisone

RR 0.85 (95% CI 0.40 to 1.80) for bexarotene only versus B + MF; 1.83 (95% CI 0.61 to 5.53) for bexarotene only versus B + HC; and 2.15 (95% CI 0.67 to 6.89) for B + MF versus B + HC

‐

Jowkar 2014

Fumaric acid 5% cream versus triamcinolone 0.1% cream

No data regarding the primary outcome investigator‐rated good/excellent control

‐

Lauriola 2011

Furpalmate versus hydrocortisone acetate cream

RR 0.90 (95% CI 0.76 to 1.07)

‐

Jowkar 2011

4% Fumaria Parviflora Lam cream versus vehicle cream twice daily

No data regarding the primary outcome investigator‐rated good/excellent control

‐

Yousefi 2012

Nigella sativa L. versus betamethasone ointment versus Eucerin

No data regarding the primary outcome investigator‐rated good/excellent control

‐

B: bexarotene 1% gel.

CI: confidence interval.

Fumaria Parviflora Lam: Fumaria Parviflora Lamarck.

HC: hydrocortisone.

MF: mometasone furoate.

Nigella sativa L: Nigella sativa Linne.

RR: risk ratio.
Figures and Tables -
Table 7. Overview of studies on other topical interventions: investigator‐rated good/excellent control
Navigate to table in Review
Table 8. Overview of studies on immunosuppressants: investigator‐rated good/excellent control

Study

Comparison

Investigator‐rated good/excellent control in RR (95% CI)

Comments

Granlund 1996

Oral cyclosporin versus topical betamethasone

RR 1.88 (95% CI 0.88 to 3.99)

‐

Agarwal 2013

Oral azathioprine and clobetasol propionate 0.05% cream twice daily versus topical clobetasol propionate 0.05% cream twice daily

RR 2.33 (95% CI 1.61 to 3.38)

‐

NCT01231854

Oral cyclosporin versus alitretinoin

RR 1.50 (95% CI 0.35 to 6.40)

Study terminated prematurely and included 15 participants only

CI: confidence interval.

RR: risk ratio. 
Figures and Tables -
Table 8. Overview of studies on immunosuppressants: investigator‐rated good/excellent control
Navigate to table in Review
Table 9. Overview of studies on oral retinoids: investigator‐rated good/excellent control

Study

Comparison

Investigator‐ or participant‐rated good/excellent control in RR (95% CI)

Comments

Thestrup‐Pedersen 2001

Oral acitretin versus placebo

No data regarding the primary outcome investigator‐rated good/excellent control

‐

Ruzicka 2004

Oral alitretinoin (20 mg and 40 mg) versus placebo

40 mg
Participant‐rated
RR 3.51 (95% CI 1.80 to 6.82)
Investigator‐rated
RR 1.97 (95% CI 1.3 to 3.0)

20 mg
Participant rated
RR 2.74 (95% CI 1.37 to 5.46)
Investigator‐rated
RR 1.49 (95% CI 0.94 to 2.34)

‐

Ruzicka 2008; Fowler 2014

Oral alitretinoin 30 mg versus placebo

30 mg
Participant‐rated
RR 2.75 (95% CI 2.18 to 3.48)
Investigator‐rated
RR 2.75 (95% CI 2.20 to 3.43)

‐

Ruzicka 2004; Ruzicka 2008

Oral alitretinoin 10 mg versus placebo

10 mg

Participant‐rated
RR 1.73 (95% CI 1.25 to 2.40)

Investigator‐rated
RR 1.58 (95% CI 1.20 to 2.07)

‐

Bissonnette 2010

Re‐treatment with oral alitretinoin (30 mg and 10 mg) versus placebo

30 mg
Investigator‐rated
RR 9.55 (95% CI 2.51 to 36.27)

10 mg
Investigator‐rated
RR 4.76 (95% CI 0.70 to 32.25)

‐

CI: confidence interval.

RR: risk ratio.
Figures and Tables -
Table 9. Overview of studies on oral retinoids: investigator‐rated good/excellent control
Navigate to table in Review
Table 10. Overview of other oral interventions: investigator‐rated good/excellent control

Study

Comparison

Investigator‐rated good/excellent control in RR (95% CI)

Comments

Burrows 1986

Oral triethylenetetramine versus placebo

Trientine was effective in 6/20 participants versus 10/20 in the placebo group

Unclear whether participant‐ or investigator‐rated

Kaaber 1983

Oral tetraethylthiuram disulphide versus placebo

Investigator‐rated

RR 2.95 (95% CI 0.71 to 12.34)

‐

Pigatto 1990

Oral disodium cromoglycate without dietary restriction versus a low‐nickel diet

No data regarding the primary outcome investigator‐rated good/excellent control

‐

Sharma 2006

Low‐nickel diet and disulphiram versus a normal diet and placebo

Investigator‐rated

RR 9.09 (95% CI 1.40 to 58.91)

‐

Veien 1995

Ranitidine versus placebo

RR 2.22 (95% CI 1.20 to 4.10)

Unclear whether participant‐ or investigator‐rated

Whitaker 1996

Oral gamma‐linoleic acid (GLA; evening primrose oil) versus placebo

No data regarding the primary outcome investigator‐rated good/excellent control

CI: confidence interval.

RR: risk ratio.
Figures and Tables -
Table 10. Overview of other oral interventions: investigator‐rated good/excellent control
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Comparison 1. Bland emollients: ceramide‐containing emollient versus regular petrolatum‐based emollient

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Primary: adverse events: exacerbation resulting in dropout Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected
Figures and Tables -
Comparison 1. Bland emollients: ceramide‐containing emollient versus regular petrolatum‐based emollient
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Comparison 2. Bland emollients: emollient E‐DO versus vehicle

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Primary: percentage of participants with self‐rated good/excellent control at week 4 Show forest plot

Other data

No numeric data

2 Primary: percentage of participants with investigator‐rated good/excellent control at week 4 Show forest plot

Other data

No numeric data

3 Adverse events Show forest plot

Other data

No numeric data

3.1 At least 1 adverse event

Other data

No numeric data

3.2 Pruritus

Other data

No numeric data
Figures and Tables -
Comparison 2. Bland emollients: emollient E‐DO versus vehicle
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Comparison 3. Corticosteroid creams/ointments: fluprednidene versus betamethasone

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Primary: investigator‐rated good/excellent control of symptoms after 3 weeks of treatment Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

2 Primary: number of participants with at least 1 adverse event Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

3 Secondary: investigator‐rated improvement > 50% after 3 weeks Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected
Figures and Tables -
Comparison 3. Corticosteroid creams/ointments: fluprednidene versus betamethasone
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Comparison 4. Corticosteroid creams/ointments: betamethasone‐dipropionate film‐forming lotion versus betamethasone‐dipropionate thick lotion

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Primary: investigator‐rated good/excellent control of symptoms at day 7 Show forest plot

Other data

No numeric data

2 Primary: adverse events Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

2.1 At least 1 adverse event

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.2 Application site reaction

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.3 Headache

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.4 Exacerbation eczema leading to withdrawal

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3 Secondary: investigator‐rated reduction (not specified) in severity at day 7 Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

4 Secondary: investigator‐rated global improvement in eczema Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected
Figures and Tables -
Comparison 4. Corticosteroid creams/ointments: betamethasone‐dipropionate film‐forming lotion versus betamethasone‐dipropionate thick lotion
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Comparison 5. Corticosteroids creams/ointments: clobetasol propionate versus flupredniden acetate

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Primary: percentage of participants with investigator‐rated good/excellent control Show forest plot

Other data

No numeric data

2 Adverse events Show forest plot

Other data

No numeric data

2.1 At least 1 adverse event

Other data

No numeric data

2.2 Burning sensation

Other data

No numeric data

2.3 Reversible atrophy

Other data

No numeric data

2.4 Brittle skin

Other data

No numeric data
Figures and Tables -
Comparison 5. Corticosteroids creams/ointments: clobetasol propionate versus flupredniden acetate
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Comparison 6. Corticosteroids creams/ointments: clobetasol propionate foam 0.05% versus vehicle

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Primary: percentage of participants with investigator‐rated good/excellent control at day 15 Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

2 Primary: percentage of participants with self‐rated good/excellent control at day 15 Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

3 Primary: adverse events Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

3.1 Discontinuation due to adverse events (fissures)

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3.2 At least 1 adverse event

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3.3 Any adverse event treatment‐related (application site pruritus)

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3.4 Nasopharyngitis

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

4 Secondary: reduction in severity, participant‐rated scoring at day 15 Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

5 Secondary: reduction in severity, investigator‐rated scoring at day 15 Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

5.1 Improvement at least 2 grades

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

5.2 Improvement at least 1 grade

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]
Figures and Tables -
Comparison 6. Corticosteroids creams/ointments: clobetasol propionate foam 0.05% versus vehicle
Navigate to table in Review
Comparison 7. Corticosteriods creams/ointments: desonide cream 0.1% versus desonide cream 0.05%

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Adverse events Show forest plot

Other data

No numeric data
Figures and Tables -
Comparison 7. Corticosteriods creams/ointments: desonide cream 0.1% versus desonide cream 0.05%
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Comparison 8. Corticosteroid creams/ointments: mometasone furoate cream 3 times/week versus 2 times/week versus no steroids

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Primary: investigator‐rated good/excellent control Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

1.1 Mometasone furoate 3 times/week vs mometasone furoate 2 times/week

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2 Primary: investigator‐rated good/excellent control Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

2.1 Mometasone furoate 3 times/week vs emollient and ointment only

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.2 Mometasone furoate 2 times/week vs emollient and ointment only

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3 Primary: adverse events Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

3.1 Mild atrophy

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]
Figures and Tables -
Comparison 8. Corticosteroid creams/ointments: mometasone furoate cream 3 times/week versus 2 times/week versus no steroids
Navigate to table in Review
Comparison 9. Corticosteroid creams/ointments: clobetasol and zinc sulphate cream versus clobetasol cream

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Primary outcome: percentage of participants with investigator‐rated good/excellent control Show forest plot

Other data

No numeric data

1.1 Scaling

Other data

No numeric data

1.2 Redness

Other data

No numeric data

1.3 Lichenification

Other data

No numeric data
Figures and Tables -
Comparison 9. Corticosteroid creams/ointments: clobetasol and zinc sulphate cream versus clobetasol cream
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Comparison 10. Corticosteroid creams/ointments: betamethasone‐valerate 0.1% cream versus urea 5% cream

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Primary: investigator‐rated good/excellent control of symptoms Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

2 Secondary: participant‐rated reduction in severity (bigger reduction in severity = better outcome) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

3 Secondary: investigator‐rated reduction in severity (bigger reduction in severity = better outcome) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected
Figures and Tables -
Comparison 10. Corticosteroid creams/ointments: betamethasone‐valerate 0.1% cream versus urea 5% cream
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Comparison 11. Topical others: coal tar versus betamethasone‐valerate

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Primary outcome: adverse events Show forest plot

Other data

No numeric data
Figures and Tables -
Comparison 11. Topical others: coal tar versus betamethasone‐valerate
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Comparison 12. Irradiation with UV light versus no UVB

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Primary: adverse events ‐ exacerbation Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected
Figures and Tables -
Comparison 12. Irradiation with UV light versus no UVB
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Comparison 13. Irradiation with UV light: whole‐body UVB versus placebo or local UVB hands

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Primary: investigator‐rated good/excellent control of symptoms by UVB hand vs whole‐body UVB vs placebo Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

1.1 Local UVB hands alone vs placebo

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

1.2 Whole‐body UVB + local UVB hands vs placebo

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

1.3 Whole body UVB + local UVB hands versus local UVB hands alone

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2 Secondary: time until relapse depicted in weeks of remission Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

2.1 Local UVB hands alone vs placebo (high score = better outcome)

1

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

2.2 Whole‐body UVB + local UVB hands vs placebo (high score = better outcome)

1

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

2.3 Whole‐body UVB + local UVB hands vs local UVB hands alone (high score = better outcome)

1

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]
Figures and Tables -
Comparison 13. Irradiation with UV light: whole‐body UVB versus placebo or local UVB hands
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Comparison 14. Irradiation with UV light: local narrow‐band UVB versus local PUVA

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Primary: investigator‐rated good/excellent control of symptoms in UVB vs PUVA Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

2 Primary: adverse events ‐ reported adverse event, mainly erythema Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected
Figures and Tables -
Comparison 14. Irradiation with UV light: local narrow‐band UVB versus local PUVA
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Comparison 15. Irradiation with UV light: local narrow‐band UVB versus local PUVA

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Primary: investigator‐rated good/excellent control of symptoms in UVB vs PUVA Show forest plot

Other data

No numeric data

2 Primary: adverse events Show forest plot

Other data

No numeric data

2.1 Palmar hyperpigmentation

Other data

No numeric data

3 Secondary: investigator‐rated improvement by local narrow‐band UVB vs local PUVA Show forest plot

Other data

No numeric data
Figures and Tables -
Comparison 15. Irradiation with UV light: local narrow‐band UVB versus local PUVA
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Comparison 16. Irradiation with UV light: oral PUVA versus topical bath PUVA

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Primary: adverse events Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

1.1 Nausea leading to dropout

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

1.2 Burn leading to dropout

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

1.3 Erythema

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

1.4 Dizziness

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

1.5 Nausea

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

1.6 Headache

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2 Secondary: investigator‐rated reduction in severity at week 10 (bigger reduction in severity = better outcome) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

3 Secondary: investigator‐rated reduction in severity at week 18 (bigger reduction in severity = better outcome) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected
Figures and Tables -
Comparison 16. Irradiation with UV light: oral PUVA versus topical bath PUVA
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Comparison 17. Irradiation with UV light: topical PUVA versus UVA

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Primary: adverse events Show forest plot

Other data

No numeric data

1.1 Discontinuation due to adverse events

Other data

No numeric data

1.2 Burning

Other data

No numeric data

1.3 Exacerbation of eczema

Other data

No numeric data
Figures and Tables -
Comparison 17. Irradiation with UV light: topical PUVA versus UVA
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Comparison 18. Irradiation with UV light: UVA‐1 versus topical betamethasone valerate 0.1% cream

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Primary: adverse events ‐ hyperpigmentation Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected
Figures and Tables -
Comparison 18. Irradiation with UV light: UVA‐1 versus topical betamethasone valerate 0.1% cream
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Comparison 19. Irradiation with UV light: UVA‐1 versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Primary: adverse events ‐ discontinuation because of exacerbation Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

2 Secondary: participant‐rated reduction in severity on VAS for itch (week 3, bigger reduction in severity = better outcome) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

3 Secondary: investigator‐rated reduction in severity on dyshidrotic eczema area and severity index (DASI) (week 3, bigger reduction in severity = better outcome) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected
Figures and Tables -
Comparison 19. Irradiation with UV light: UVA‐1 versus placebo
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Comparison 20. Irradiation with UV light: PUVA versus UVA‐1

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Primary: adverse events Show forest plot

Other data

No numeric data

1.1 Burning

Other data

No numeric data

1.2 Itching

Other data

No numeric data
Figures and Tables -
Comparison 20. Irradiation with UV light: PUVA versus UVA‐1
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Comparison 21. Irradiation with Grenz ray

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Primary: investigator‐rated improvement good/excellent control Show forest plot

Other data

No numeric data

1.1 after 1 month

Other data

No numeric data

1.2 after 3 months

Other data

No numeric data

1.3 after 6 months

Other data

No numeric data

1.4 Hyperkeratotic eczema after 6 months

Other data

No numeric data

1.5 Pompholyx after 6 months

Other data

No numeric data

1.6 Chronic palmar eczema after 6 months

Other data

No numeric data

2 Primary: adverse events ‐ hyperpigmentation Show forest plot

Other data

No numeric data
Figures and Tables -
Comparison 21. Irradiation with Grenz ray
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Comparison 22. Topical calcineurin inhibitors: tacrolimus 0.1% ointment versus mometasone furoate

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Secondary: reduction in investigator‐rated severity ‐ DASI Show forest plot

Other data

No numeric data
Figures and Tables -
Comparison 22. Topical calcineurin inhibitors: tacrolimus 0.1% ointment versus mometasone furoate
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Comparison 23. Topical calcineurin inhibitors: tacrolimus 0.1% ointment versus vehicle

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Primary: investigator‐rated good/excellent control of symptoms Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

2 Primary: adverse events burning/itching at application site Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

2.1 Burning/itching at application site

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]
Figures and Tables -
Comparison 23. Topical calcineurin inhibitors: tacrolimus 0.1% ointment versus vehicle
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Comparison 24. Topical calcineurin inhibitors: pimecrolimus 1% cream versus vehicle

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Primary: investigator‐rated good/excellent control of symptoms pimecrolimus cream vs vehicle Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.1 Primary: investigator‐rated clear or almost clear pimecrolimus cream vs vehicle 3 weeks

1

294

Risk Ratio (M‐H, Random, 95% CI)

1.53 [0.99, 2.36]

1.2 Primary: investigator‐rated clear or almost clear pimecrolimus cream vs vehicle 6 weeks

1

652

Risk Ratio (M‐H, Random, 95% CI)

1.28 [0.99, 1.66]

1.3 Primary: investigator‐rated clear or almost clear pimecrolimus cream vs vehicle 3 weeks irritant hand eczema

1

185

Risk Ratio (M‐H, Random, 95% CI)

1.7 [0.93, 3.10]

1.4 Primary: investigator‐rated clear or almost clear pimecrolimus cream vs vehicle 3 weeks allergic hand eczema

1

49

Risk Ratio (M‐H, Random, 95% CI)

1.33 [0.30, 5.96]

1.5 Primary: investigator‐rated clear or almost clear pimecrolimus cream vs vehicle 3 weeks endogenous hand eczema

1

134

Risk Ratio (M‐H, Random, 95% CI)

1.32 [0.75, 2.33]

2 Primary: adverse events Show forest plot

3

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

2.1 Discontinuation because of adverse event

2

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.2 Application site reaction

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.3 At least 1 adverse event

2

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.4 Serious adverse event (not related to study)

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.5 Treatment‐related adverse event

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.6 Erythema or irritation

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.7 Itching

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.8 Warmth, stinging, burning

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.9 Herpes simplex virus infection

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3 Secondary: participant‐rated reduction in severity pruritus relief between pimecrolimus 1% and vehicle Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected
Figures and Tables -
Comparison 24. Topical calcineurin inhibitors: pimecrolimus 1% cream versus vehicle
Navigate to table in Review
Comparison 25. Topical antibacterial agents: betamethasone‐valerate/clioquinol cream versus betamethasone‐valerate/fusidic acid

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Primary: investigator‐rated good/excellent control of symptoms (intention‐to‐treat) Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

2 Primary: adverse events Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

2.1 At least 1 adverse event

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.2 Chest infection

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.3 Irritation associated with application

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.4 Deterioration of eczema

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.5 Eyes watering

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.6 Hands coloured yellow

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.7 Hands felt thick

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.8 Vesicle on hand

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]
Figures and Tables -
Comparison 25. Topical antibacterial agents: betamethasone‐valerate/clioquinol cream versus betamethasone‐valerate/fusidic acid
Navigate to table in Review
Comparison 26. Topical retinoids: bexarotene 1% gel versus bexarotene with corticosteroids

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Primary: investigator‐rated good/excellent control of symptoms (> 90% clearance) Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

1.1 Bexarotene only (A) vs bexarotene + mometasone (B)

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

1.2 Bexarotene only (A) vs bexarotene + hydrocortisone (B)

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

1.3 Bexarotene + mometasone (A) vs bexarotene + hydrocortisone (B)

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2 Primary: adverse events bexarotene vs bexarotene + mometasone Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

2.1 Irritation/rash

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.2 Stinging/burning

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.3 Exacerbation of dermatitis

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3 Primary: adverse events bexarotene vs bexarotene + hydrocortisone Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

3.1 Irritation/rash

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3.2 Stinging/burning

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3.3 Exacerbation of dermatitis

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

4 Secondary: investigator‐rated reduction in severity (> 50% reduction in hand eczema area and severity index (HEASI)) Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

4.1 Bexarotene (A) only vs bexarotene + mometasone (B)

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

4.2 Bexarotene (A) only vs bexarotene + hydrocortisone (B)

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

4.3 Bexarotene + mometasone (A) vs bexarotene + hydrocortisone (B)

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]
Figures and Tables -
Comparison 26. Topical retinoids: bexarotene 1% gel versus bexarotene with corticosteroids
Navigate to table in Review
Comparison 27. Other topical agents: calmurid versus aquacare

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Primary: adverse events: burning Show forest plot

Other data

No numeric data
Figures and Tables -
Comparison 27. Other topical agents: calmurid versus aquacare
Navigate to table in Review
Comparison 28. Other topical agents: fumaric acid 5% cream verus triamcinolone 0.1% cream

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Primary: adverse events Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected
Figures and Tables -
Comparison 28. Other topical agents: fumaric acid 5% cream verus triamcinolone 0.1% cream
Navigate to table in Review
Comparison 29. Other topical agents: furpalmate 0.3% cream versus hydrocortisone acetate 0.5% cream

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Primary: investigator‐rated good/excellent control of symptoms Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected
Figures and Tables -
Comparison 29. Other topical agents: furpalmate 0.3% cream versus hydrocortisone acetate 0.5% cream
Navigate to table in Review
Comparison 30. Other topical agents: Fumaria parviflora versus vehicle cream

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Primary: adverse events: discontinuation due to erythema and papules Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected
Figures and Tables -
Comparison 30. Other topical agents: Fumaria parviflora versus vehicle cream
Navigate to table in Review
Comparison 31. Oral immunosuppressants: oral azathioprine with topical clobetasol propionate versus topical clobetasol propionate

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Primary: percentage of participants with investigator‐rated good/excellent control Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

1.1 Week 8

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

1.2 Week 24

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2 Secondary: investigator‐rated reduction in severity (bigger reduction in severity = better outcome) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

2.1 Week 4

1

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

2.2 Week 8

1

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

2.3 Week 12

1

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

2.4 Week 24

1

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

3 Secondary: participant‐rated reduction in severity (bigger reduction in severity = better outcome) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

3.1 Week 4

1

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

3.2 Week 8

1

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

3.3 Week 12

1

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

3.4 Week 24

1

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]
Figures and Tables -
Comparison 31. Oral immunosuppressants: oral azathioprine with topical clobetasol propionate versus topical clobetasol propionate
Navigate to table in Review
Comparison 32. Oral immunosuppressants: oral cyclosporin versus topical betamethasone dipropionate

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Primary: investigator‐rated very good or good efficacy Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

2 Primary: participant‐rated very good or good efficacy Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

3 Primary: adverse events Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

3.1 At least 1 adverse event

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3.2 Discontinuation due to dizziness, vomiting, and facial oedema

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3.3 Discontinuation due to severe insomnia

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3.4 Increase in serum creatinine > 30%

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

4 Secondary: investigator‐rated reduction in severity in total disease activity score (6 weeks; bigger reduction in severity = better outcome) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected
Figures and Tables -
Comparison 32. Oral immunosuppressants: oral cyclosporin versus topical betamethasone dipropionate
Navigate to table in Review
Comparison 33. Oral immunosuppressants: oral cyclosporin versus alitretinoin

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Primary: investigator‐rated good/excellent control (IGA) after 24 weeks Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

2 Primary: participant‐rated good/excellent control (PGA) after 24 weeks Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

3 Primary: adverse events Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected
Figures and Tables -
Comparison 33. Oral immunosuppressants: oral cyclosporin versus alitretinoin
Navigate to table in Review
Comparison 34. Oral retinoids: alitretinoin versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Primary: investigator‐rated good/excellent control of symptoms Show forest plot

3

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.1 Alitretinoin 40 mg vs placebo

1

159

Risk Ratio (M‐H, Random, 95% CI)

1.97 [1.30, 3.00]

1.2 Alitretinoin 30 mg vs placebo

2

1210

Risk Ratio (M‐H, Random, 95% CI)

2.75 [2.20, 3.43]

1.3 Alitretinoin 20 mg vs placebo

1

158

Risk Ratio (M‐H, Random, 95% CI)

1.49 [0.94, 2.34]

1.4 Alitretinoin 10 mg vs placebo

2

781

Risk Ratio (M‐H, Random, 95% CI)

1.58 [1.20, 2.07]

2 Primary: investigator‐rated good/excellent control of symptoms hyperkeratotic eczema Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.1 Alitretinoin 40 mg vs placebo hyperkeratotic eczema

1

131

Risk Ratio (M‐H, Random, 95% CI)

2.61 [1.61, 4.23]

2.2 Alitretinoin 30 mg vs placebo hyperkeratotic eczema

1

519

Risk Ratio (M‐H, Random, 95% CI)

3.94 [2.60, 5.97]

2.3 Alitretinoin 20 mg vs placebo hyperkeratotic eczema

1

136

Risk Ratio (M‐H, Random, 95% CI)

1.72 [1.02, 2.90]

2.4 Alitretinoin 10 mg vs placebo hyperkeratotic eczema

2

662

Risk Ratio (M‐H, Random, 95% CI)

2.05 [1.47, 2.86]

3 Primary: investigator‐rated good/excellent control of symptoms pompholyx Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

3.1 Alitretinoin 40 mg vs placebo pompholyx

1

37

Risk Ratio (M‐H, Random, 95% CI)

1.66 [0.58, 4.72]

3.2 Alitretinoin 30 mg vs placebo pompholyx

1

166

Risk Ratio (M‐H, Random, 95% CI)

2.04 [1.06, 3.91]

3.3 Alitretinoin 20 mg vs placebo pompholyx

1

38

Risk Ratio (M‐H, Random, 95% CI)

0.9 [0.26, 3.08]

3.4 Alitretinoin 10 mg vs placebo pompholyx

2

197

Risk Ratio (M‐H, Random, 95% CI)

1.30 [0.70, 2.39]

4 Primary: investigator‐rated good/excellent control of symptoms fingertip Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

4.1 Alitretinoin 40 mg vs placebo fingertip

1

51

Risk Ratio (M‐H, Random, 95% CI)

1.77 [0.81, 3.86]

4.2 Alitretinoin 30 mg vs placebo fingertip

1

297

Risk Ratio (M‐H, Random, 95% CI)

2.49 [1.59, 3.89]

4.3 Alitretinoin 20 mg vs placebo fingertip

1

53

Risk Ratio (M‐H, Random, 95% CI)

1.18 [0.50, 2.77]

4.4 Alitretinoin 10 mg vs placebo fingertip

2

330

Risk Ratio (M‐H, Random, 95% CI)

1.51 [0.99, 2.29]

5 Primary: participant‐rated investigator‐rated good/excellent control of symptoms Show forest plot

3

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

5.1 Alitretinoin 40 mg vs placebo

1

147

Risk Ratio (M‐H, Random, 95% CI)

3.51 [1.80, 6.82]

5.2 Alitretinoin 30 mg vs placebo

2

1210

Risk Ratio (M‐H, Random, 95% CI)

2.75 [2.18, 3.48]

5.3 Alitretinoin 20 mg vs placebo

1

147

Risk Ratio (M‐H, Random, 95% CI)

2.74 [1.37, 5.46]

5.4 Alitretinoin 10 mg vs placebo

2

765

Risk Ratio (M‐H, Random, 95% CI)

1.73 [1.25, 2.40]

6 Primary: adverse events alitretinoin 10 mg vs placebo Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

6.1 All adverse events

1

158

Risk Ratio (M‐H, Random, 95% CI)

1.01 [0.66, 1.55]

6.2 Headache

2

781

Risk Ratio (M‐H, Random, 95% CI)

1.10 [0.38, 3.19]

6.3 Dry lips

2

781

Risk Ratio (M‐H, Random, 95% CI)

0.50 [0.05, 4.66]

6.4 Flushing

2

781

Risk Ratio (M‐H, Random, 95% CI)

1.16 [0.28, 4.70]

6.5 Dry mouth

2

781

Risk Ratio (M‐H, Random, 95% CI)

1.98 [0.53, 7.44]

6.6 Erythema

2

781

Risk Ratio (M‐H, Random, 95% CI)

1.11 [0.33, 3.71]

6.7 Eczema

2

781

Risk Ratio (M‐H, Random, 95% CI)

0.80 [0.38, 1.68]

6.8 Conjunctivitis

1

158

Risk Ratio (M‐H, Random, 95% CI)

0.49 [0.05, 5.27]

6.9 Eye pruritus

1

158

Risk Ratio (M‐H, Random, 95% CI)

0.98 [0.06, 15.32]

6.10 Fatigue

1

158

Risk Ratio (M‐H, Random, 95% CI)

2.93 [0.12, 70.75]

6.11 Rigors

1

158

Risk Ratio (M‐H, Random, 95% CI)

2.93 [0.12, 70.75]

6.12 Tonsilitis

2

781

Risk Ratio (M‐H, Random, 95% CI)

0.51 [0.15, 1.70]

6.13 Pharyngitis

2

781

Risk Ratio (M‐H, Random, 95% CI)

0.82 [0.44, 1.54]

6.14 Influenza

1

623

Risk Ratio (M‐H, Random, 95% CI)

1.23 [0.39, 3.86]

6.15 Nausea

1

623

Risk Ratio (M‐H, Random, 95% CI)

1.63 [0.45, 5.88]

6.16 Elevated blood creatinine kinase

2

781

Risk Ratio (M‐H, Random, 95% CI)

1.43 [0.73, 2.80]

6.17 Elevated blood triglycerides

2

781

Risk Ratio (M‐H, Random, 95% CI)

1.03 [0.56, 1.88]

7 Primary: adverse events alitretinoin 20 mg vs placebo Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

7.1 All adverse events

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

7.2 Headache

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

7.3 Dry lips

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

7.4 Flushing

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

7.5 Dry mouth

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

7.6 Erythema

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

7.7 Eczema

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

7.8 Conjunctivitis

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

7.9 Eye pruritus

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

7.10 Fatigue

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

7.11 Rigors

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

7.12 Tonsilitis

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

7.13 Pharyngitis

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

8 Primary: adverse events alitretinoin 30 mg vs placebo Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

8.1 Headache

2

1210

Risk Ratio (M‐H, Random, 95% CI)

3.43 [2.45, 4.81]

8.2 Dry lips

1

614

Risk Ratio (M‐H, Random, 95% CI)

1.88 [0.63, 5.59]

8.3 Flushing

2

1210

Risk Ratio (M‐H, Random, 95% CI)

7.28 [2.05, 25.86]

8.4 Dry mouth

1

614

Risk Ratio (M‐H, Random, 95% CI)

2.51 [0.55, 11.33]

8.5 Erythema

2

1210

Risk Ratio (M‐H, Random, 95% CI)

5.79 [2.09, 16.06]

8.6 Eczema

1

614

Risk Ratio (M‐H, Random, 95% CI)

0.65 [0.29, 1.46]

8.7 Pharyngitis

2

1210

Risk Ratio (M‐H, Random, 95% CI)

0.82 [0.49, 1.36]

8.8 Influenza

2

1210

Risk Ratio (M‐H, Random, 95% CI)

1.17 [0.45, 3.06]

8.9 Nausea

2

1210

Risk Ratio (M‐H, Random, 95% CI)

3.82 [1.67, 8.76]

8.10 Elevated blood creatinine kinase

1

614

Risk Ratio (M‐H, Random, 95% CI)

1.63 [0.54, 4.93]

8.11 Elevated blood triglycerides

2

1210

Risk Ratio (M‐H, Random, 95% CI)

7.05 [1.89, 26.28]

8.12 Dizziness

1

596

Risk Ratio (M‐H, Random, 95% CI)

2.0 [0.61, 6.57]

8.13 Upper respiratory tract infection

1

596

Risk Ratio (M‐H, Random, 95% CI)

1.54 [0.78, 3.04]

8.14 Sinusitis

1

596

Risk Ratio (M‐H, Random, 95% CI)

0.89 [0.35, 2.27]

8.15 Rash

1

596

Risk Ratio (M‐H, Random, 95% CI)

1.5 [0.54, 4.16]

8.16 Vomiting

1

596

Risk Ratio (M‐H, Random, 95% CI)

8.00 [1.01, 63.57]

8.17 Arthralgia

1

596

Risk Ratio (M‐H, Random, 95% CI)

1.2 [0.37, 3.89]

8.18 Depression

1

596

Risk Ratio (M‐H, Random, 95% CI)

2.33 [0.61, 8.94]

8.19 Laceration

1

596

Risk Ratio (M‐H, Random, 95% CI)

13.0 [0.74, 229.73]

8.20 Tinnitus

1

596

Risk Ratio (M‐H, Random, 95% CI)

4.33 [1.25, 15.05]

8.21 Cough

1

596

Risk Ratio (M‐H, Random, 95% CI)

2.25 [0.70, 7.23]

8.22 Hypertriglceridaemia

1

596

Risk Ratio (M‐H, Random, 95% CI)

6.0 [0.73, 49.53]

9 Primary: adverse events alitretinoin 40 mg vs placebo Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

9.1 All adverse events

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

9.2 Headache

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

9.3 Dry lips

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

9.4 Flushing

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

9.5 Dry mouth

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

9.6 Erythema

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

9.7 Eczema

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

9.8 Conjunctivitis

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

9.9 Eye pruritus

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

9.10 Fatigue

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

9.11 Rigors

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

9.12 Tonsilitis

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

9.13 Pharyngitis

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

10 Secondary: investigator‐rated reduction in severity in total lesion symptom score Show forest plot

Other data

No numeric data

10.1 Alitretinoin 40 mg

Other data

No numeric data

10.2 Alitretinoin 30 mg

Other data

No numeric data

10.3 Alitretinoin 20 mg

Other data

No numeric data

10.4 Alitretinoin 10 mg

Other data

No numeric data

11 Secondary: investigator‐rated reduction in severity in total lesion symptom score Show forest plot

Other data

No numeric data

11.1 Alitretinoin 40 mg vs placebo

Other data

No numeric data

11.2 Alitretinoin 20 mg vs placebo

Other data

No numeric data

11.3 Alitretinoin 10 mg vs placebo

Other data

No numeric data

12 Secondary: reduction in severity, investigator‐rated in modified total lesion symptom score (bigger reduction in severity scored negative = better outcome) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected
Figures and Tables -
Comparison 34. Oral retinoids: alitretinoin versus placebo
Navigate to table in Review
Comparison 35. Oral retinoids: re‐treatment alitretinoin versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Primary: investigator‐rated good/excellent control of symptoms Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

1.1 Alitretinoin 30 mg vs placebo

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

1.2 Alitretinoin 10 mg vs placebo

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2 Primary: adverse events 10 mg vs placebo Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

2.1 Any adverse event

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.2 Treatment‐related adverse event

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.3 Nasopharyngitis

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.4 Influenza

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.5 Erythema

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.6 Eczema

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.7 Dermatitis

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.8 Dry lips

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.9 Cheilitis

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.10 Dry mouth

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.11 Elevated triglycerides

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.12 High cholesterol

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.13 High triglycerides

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3 Primary: adverse events 30 mg vs placebo Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

3.1 Any adverse event

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3.2 Treatment‐related adverse event

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3.3 Treatment‐related serious adverse event

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3.4 Nasopharyngitis

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3.5 Rhinitis

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3.6 Bronchitis

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3.7 Upper respiratory tract infection

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3.8 Influenza

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3.9 Erythema

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3.10 Eczema

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3.11 Dermatitis

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3.12 Dry skin

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3.13 Headache

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3.14 Dry lips

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3.15 Nausea

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3.16 Cheilitis

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3.17 Dry mouth

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3.18 Elevated creatinine

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3.19 TSH high

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3.20 TSH low

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3.21 High cholesterol

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3.22 High triglycerides

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]
Figures and Tables -
Comparison 35. Oral retinoids: re‐treatment alitretinoin versus placebo
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Comparison 36. Other oral interventions: oral triethylenetetramine versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Primary: investigator‐ and/or participant‐rated improvement Show forest plot

Other data

No numeric data
Figures and Tables -
Comparison 36. Other oral interventions: oral triethylenetetramine versus placebo
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Comparison 37. Other oral interventions: oral tetraethylthiuram disulfide (TETDS) versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Primary: investigator‐rated good/excellent control of symptoms during treatment period Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

2 Primary: adverse events Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

2.1 Discontinuation due to depression

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.2 Discontinuation due to dyspepsia

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.3 Hepatic toxicity

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.4 Headache requiring dose reduction

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]
Figures and Tables -
Comparison 37. Other oral interventions: oral tetraethylthiuram disulfide (TETDS) versus placebo
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Comparison 38. Other oral interventions: low‐nickel diet (LND) + disulphiram versus normal diet + placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Primary: investigator‐rated good/excellent control of symptoms after 4 weeks Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

2 Primary: adverse events Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

2.1 Metallic taste

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.2 Drowsiness

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.3 Elevation of liver enzymes

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]
Figures and Tables -
Comparison 38. Other oral interventions: low‐nickel diet (LND) + disulphiram versus normal diet + placebo
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Comparison 39. Other oral interventions: oral evening primrose oil versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Secondary: investigator‐rated reduction in severity score at week 24 (bigger reduction in severity = better outcome) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected
Figures and Tables -
Comparison 39. Other oral interventions: oral evening primrose oil versus placebo
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Comparison 40. Other oral interventions: oral ranitidine versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Primary: participant‐ and investigator‐rated good/excellent control of symptoms Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected
Figures and Tables -
Comparison 40. Other oral interventions: oral ranitidine versus placebo
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Comparison 41. Other oral interventions: disodium cromoglycate diet (DSCG) versus low‐nickel diet

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Primary: participant‐rated good/excellent control of symptoms (itch) after 3 months of itch in DSCG versus diet Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected
Figures and Tables -
Comparison 41. Other oral interventions: disodium cromoglycate diet (DSCG) versus low‐nickel diet
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