Background
Epidermolysis bullosa (EB) is a heterogeneous group of inherited mucocutaneous fragility disorders. Four major types of EB are differentiated by their ultrastructural plane of skin separation: EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB) and Kindler EB (KEB) [
1].
Recessive DEB (RDEB) encompasses a number of distinct subtypes that all result from biallelic mutations in
COL7A1, the gene encoding type VII collagen, the major component of anchoring fibrils at the dermal-epidermal junction [
2,
3]. Severe RDEB (RDEB-S) is associated with marked mucocutaneous blistering, chronic wounds, scarring, impaired nutrition and growth, anaemia and, among other complications, development of aggressive cutaneous squamous cell carcinomas (SCCs), the main cause of death in early adulthood [
4‐
7]. Intermediate RDEB (RDEB-I) presents with less severe generalized skin fragility and scarring, also with internal complications and SCC but occuring later and less frequently [
4,
5,
7]. Inversa RDEB (RDEB-Inv) usually manifests as generalized blistering early in life but, over time, develops a predilection for flexural sites such as axillae, groins and genitals, with marked intra-oral and oesophageal involvement [
8]. The rare pruriginosa form is usually dominantly inherited but can be recessive (RDEB-Pru) [
9]. Individuals progressively develop extremely itchy skin with characteristic prurigo-like nodules or plaques, usually starting on the lower legs but with more generalized spread in some cases.
Itch is common in all forms of EB [
10‐
12] and causes significant distress [11,13−16]. Pruritus in RDEB tends to be more severe than in other EB types [
11] with similar intensity to itch associated with atopic dermatitis, chronic urticaria and nodular prurigo [
13]. Factors that exacerbate EB itch include healing of wounds, skin infections, dry skin, heat, sweating and stress [
11,
14,
15]. EB-associated itch negatively impacts on quality of life and sleep, [
11,
14] and scratching contributes to skin damage [
16]. Interventions include emollients, topical corticosteroids, antihistamines, neuropathic pain medicines and neurokinin-1 receptor antagonists although these generally have limited efficacy [
12,
17,
18].
The precise mechanisms of EB pruritus are poorly understood but are likely multifactorial including acute and chronic wounds, dysregulated inflammation, impaired skin barrier function and a possible neural mechanism [
19‐
24]. Varied aetiology may partly explain the poor responsiveness of EB itch to standard treatments [
11]. This, in conjunction with distress caused by itch and the consequences of scratching worsening blistering, highlights the need for further studies into pathomechanisms of EB-associated itch and development of effective therapies.
The Prospective Epidermolysis Bullosa Longitudinal Evaluation Study (PEBLES) is a register study which has recruited children and adults with RDEB from the United Kingdom London EB reference centres since late 2014. It records detailed participant information including subjective, objective, laboratory and health economic data. The aim of PEBLES is to delineate, in detail, the natural history of different RDEB subtypes to inform prognostication and identify robust and meaningful endpoints for future clinical trials. Here, we present PEBLES data relating to itch and the impact it has on individuals with RDEB.
Discussion
In our study, we used the LIS to explore different elements of itch in a cohort of 50 participants with RDEB aged 8 years and above. To our knowledge, this is the second and largest study using the LIS in EB [
14].
Itch frequency in our cohort was high with occurrence in the preceding month in 227 (93%) of 243 reviews from 50 participants. This concurs with previous studies that demonstrated frequent self-reported itch in 85% (n = 83), [
10] 100% (n = 6) [
14,
28] and 100% (n = 5) [
11] of individuals with RDEB, although these studies did not break down by RDEB subtype [
11,
14,
15,
28].
Our finding that participants with RDEB-Pru reported itch episode duration of over 2 h in almost half of reviews supports the clinical phenotype of RDEB-Pru where greater itch duration causes increased scratching and resultant lichenified prurigo-like skin changes. The shorter itch duration in RDEB-S participants may reflect that they tend to have more skin wounds and therefore more pain, which may be a more prevalent or distressing symptom, thereby reducing the relative perception of itch.
Itch severity and distress were high across all RDEB groups and significantly greater in RDEB-S compared to RDEB-I (p = 0.023 and p = 0.023, respectively). Although previous studies have highlighted correlations between EB severity and pruritus and that EB-associated itch is distressing for patients, [11,13−15] our study is the first to quantify this in different RDEB subtypes. Consequences of itch were greatest in RDEB-Pru likely reflecting the itch severity, frequency and duration in this group.
Circumstances associated with high itch occurrence included being in a hot environment and when sweating, in keeping with a previous study using the LIS in a small sample (n = 13) of DEB patients [
14] and in two other studies using a questionnaire [
11] or semi-structured interview [
15]. Our cohort also associated being stressed out with itching, a factor identified in one study, [
11] but less so with changes in weather except in RDEB-S. Our data demonstrated less itch occurrence in a cold environment and on contact with air, consistent with previous reports [
11,
14]. Having dry skin has been identified as a factor increasing itch in EB [
11,
15] but this is not specifically questioned in the LIS.
The ISA score did not show significant differences between RDEB subtypes or age despite a larger surface area of skin blistering and wounds seen in RDEB-S compared to other subtypes [
29]. Although other studies have shown that larger wounds are associated with increased itch, [
11,
30] greater self-assessed disease severity, and worse quality of life, [
10] itch is prevalent in all types of EB [
10] and ISA has only been quantified in one study and not by RDEB subtype [
14]. Our results suggest that itch may not be confined to wounds.
Despite high itch frequency, severity and distress in all RDEB subtypes, only 61% of the reviews in our study included medications for itch suggesting a lack of efficacy or satisfaction with these treatments. Emollients and topical corticosteroids reported on medication review but not as itch treatment in the LIS suggests use for other indications (e.g. dry skin, overgranulated wounds). Other studies report similar or an even lower proportion of individuals using medications for itch, with antihistamines being most common [
12,
27]. Additionally, patient-reported satisfaction with itch medication was modest. As itch is one of the biggest problems and top priorities for EB patients and caregivers, [
15,
28,
31,
32] this suggests that effective itch treatment remains a significant unmet need in EB.
Few clinical trials in EB have evaluated pruritus as a primary or secondary outcome. Studies of mesenchymal stromal cell infusions in RDEB have demonstrated reduced itch as a secondary endpoint [
33‐
35] and a recent randomised, double-blind, placebo-controlled trial of calcipotriol in DEB wounds found a statistically significant fall in itch scores [
36]. Another phase 2 randomised, double-blind, placebo-controlled trial of the neurokinin 1 receptor antagonist, serlopitant, included itch reduction as a primary endpoint in different types of EB; although not reaching statistical significance, results showed a trend for greater itch score reduction in the treatment arm [
17]. Encouragingly, two clinical trials are underway specifically to address itch in EB; pregabalin in RDEB (NCT 03928093), and topical cannabinol in different types of EB (NCT 04908215).
Different modalities have been used in DEB pruriginosa in individual cases or small series including thalidomide, [
37] ciclosporin, [
38,
39] intravenous immunoglobulin, [
40] topical ketamine and amitriptyline gel with oral mirtazapine [
41] and oral janus kinase inhibitors [
42,
43]. Recent reports have demonstrated encouraging responses with omalizumab anti-immunoglobulin E monoclonal antibody, [
44] and dupilumab against interleukin 4 and interleukin 13 [
45‐
49]. As yet, however, there have been no formal clinical trials in DEB pruriginosa presumably due to its rarity and the inherent difficulties for sufficient statistical powering.
Interestingly, correlation between the iscorEB itch scores and LIS severity and frequency was generally poor across different RDEB subtypes. Similarly, total iscorEB scores showed strong correlations only in RDEB-I for itch frequency, distress and consequences, and RDEB-Inv for itch severity, distress, consequences and ISA. In general, iscorEB total score and LIS subdomains did not correlate in RDEB-S; this may reflect the greater global severity of this subtype whereby the specific contribution made by the different elements of pruritus captured in the LIS are overshadowed by other iscorEB components. Similarly, total QOLEB scores correlated strongly only for RDEB-Inv itch severity, distress, consequences and ISA, but not in RDEB-S suggesting that the contribution of itch to total disease burden captured by QOLEB is minor compared to other facets of the disease. These results suggest that future clinical trials in RDEB where itch is a potential outcome measure should include specific itch measurement tools, such as LIS, rather than relying on more global scoring systems to detect changes.
Limitations of our study include the lack of validation for using LIS under 18 years, the exclusion of children under 8 years who were not asked to complete LIS, and incomplete data for some reviews, especially for ISA. The rarity of RDEB-Pru also meant that the number of participants and reviews was limited which constrained calculations of statistical significance.
Conclusions
Our study details the specific nature of itch in a large cohort of different RDEB subtypes using the LIS. It demonstrates that individuals with RDEB-S have greater itch frequency, severity and distress than those with RDEB-I, and that RDEB-Pru in particular is associated with high itch severity, duration, frequency, distress and consequences. These differences highlight the limitations of grouping all RDEB patients together when analysing itch. The relatively low frequency of itch medication might indicate lack of efficacy and highlights the need for more effective therapies in EB.
The poor correlation between specific LIS subdomains and disease severity score (iscorEB) and quality of life (QOLEB) for individuals with RDEB-S are counter to previous self-reported studies evaluating itch but may indicate that its impact is dwarfed in these measures by other elements contributing to disease severity.
The data presented here are the largest to date looking specifically at itch in different subtypes of EB and may serve as comparator control data for future clinical trials where the rarity of RDEB makes adequate powering of studies with placebo controls challenging.
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