Nail Psoriasis and Quality-of-Life Measurement in Clinical Trials: Call for the Use of Nail-Specific Instruments

Nail involvement on fingers and/or toes is frequent in psoriasis, with 25% [1] to 41% [2] of patients affected. It is also a marker of increased disease severity of psoriasis and psoriasis arthritis [3‐5]. Clinically, it can manifest in symptoms such as pitting, nail plate crumbling, or nail thickening and uplifting [6]. Further signs include leukonychia, onychodystrophy, splinter hemorrhages, and oil drops. Nail psoriasis (NPso) comes with considerable patient burden over and above impairments due to other psoriasis symptoms [2, 7, 8]. Firstly, NPso is highly visible, especially when the fingers are affected, resulting in perceptions of stigma, self-consciousness, and social problems. As a consequence, patients often try to hide their nails from others. Secondly, NPso can interfere with walking and with activities involving the fingers, such as manual work, typing, or self-care; this results in impairments at work, during sporting activities, and in everyday life. Thirdly, like other psoriatic lesions, NPso can induce unpleasant sensations such as pain and itch.

Nails are considered a hard-to-treat location in psoriasis [1], especially when using topical treatment only. In recent years, targeted systemic treatments such as secukinumab have been shown to improve both clinical NPso severity and health-related quality of life (HRQoL) [9]. In a recent network meta-analysis, six biologics were compared in terms of probability of achieving complete clinical resolution of NPso about half a year after treatment initiation [10]. Outcomes differed greatly between medications, ranging from 0.8% for infliximab to 46.5% for ixekizumab. This comparison must be interpreted with caution because—as is typical for network analyses—the included studies were not completely comparable, regarding patient characteristics, outcome measures and others; the authors note that, for example, the effectiveness of infliximab was underestimated. However, the analysis shows that efficacious medication for NPso is available. Another recent meta-analysis [11] found tofacitinib and ixekizumab to effectively reduce clinical severity of NPso. Again, comparability was limited due to the different endpoints and outcome instruments used, with some studies even having to be excluded from the meta-analysis for this reason. This underlines the benefits of using uniform outcome measures across trials.

One of the main objectives of psoriasis and NPso treatment, if not the primary objective, is to reduce patient burden. This is why outcomes that should be measured in clinical NPso trials also include HRQoL, which is a multi-dimensional construct covering the impact of disease and treatment on different areas of the patient’s life [12]. This typically includes physical, emotional, and social impairments as well as functional limitations in everyday life. Standardized HRQoL questionnaires either focus on the effect of a specific disease (like psoriasis) or disease group (like skin diseases), or on patients in general (generic HRQoL) and must be evaluated for reliability, validity, and responsiveness before being used in clinical trials [13]. Including HRQoL as a trial endpoint is all the more important as clinical severity and quality of life are associated, but far from redundant [14].

However, assessment methods designed for use in skin psoriasis are not sufficiently sensitive to spot the impact of NPso, which is true for both clinical severity and HRQoL instruments. Clinical severity of psoriasis is most commonly measured with the Psoriasis Area and Severity Index (PASI), which weighs by affected body surface area in head, upper limbs, trunk, and lower limbs without nails being considered separately [15]. Nail affection can thus account for a very small increase in PASI scores only. NPso severity is therefore measured with nail-specific instruments like the Nail Psoriasis Severity Index (NAPSI) [16] or the NAPPA Clinical Assessment of Severity (NAPPA-CLIN) [17].

For HRQoL measurement, the skin-specific Dermatology Life Quality Index (DLQI) [18] is the instrument used most commonly in clinical studies on psoriasis [19]. In addition, the Psoriasis Index of Quality of Life (PSORIQoL) questionnaire has been developed for the measurement of psoriasis-specific HRQoL impairment [20]. Neither DLQI nor PSORIQoL fully reflect nail-specific problems such as difficulties working with one’s hands.

Not using nail-specific instruments in patients with NPso can have a number of negative consequences. First, patient burden, and thus the need for clinical action, may be underestimated if the specific effects of NPso account for a large part of the patient’s HRQoL impairment. Second, treatment effects will be underestimated if the intervention in question specifically benefits the nails and thereby improves nail-specific HRQoL impairments. Third, treatment effects will be overestimated if the intervention mainly improves skin, but not nail symptoms. Neglecting nail-specific impairment can thus lead to suboptimal treatment decisions.

This is why we believe that in clinical practice, NPso-specific HRQoL instruments should be used both in patients with NPso only and in those with both nail and skin symptoms, and that the extra effort for adding these instruments is warranted. In clinical studies that include patients with NPso, nail-specific instruments should be added as a secondary endpoint. If the main target of an intervention is actually NPso improvement, clinical trials need not exclude patients with both nail and body psoriasis in order to specifically assess the effect on NPso as long as all items of the HRQoL instruments are specific to nail impairments (which is the case for both instruments described below).

In order to detect validated questionnaires for the measurement of HRQoL in people with NPso, we conducted a PubMed/Medline search combining search terms on NPso (Fig. 1). The search was conducted on November 30th, 2020. We found two instruments: The Nail Psoriasis Quality of Life Scale (NPQ10) [21] and the Nail Assessment in Psoriasis and Psoriatic Arthritis–Quality of Life (NAPPA-QOL) [17].

In order to get an overview of how HRQoL is measured in randomized controlled trials (RCTs) on NPso, we also conducted a PubMed/Medline search on January 12th, 2021 (see Fig. 2). We selected studies that either included only patients with NPso or analyzed patients with NPso as a subgroup of the study population, as only in such studies is the use of nail-specific HRQoL instruments considered reasonable, and that assessed HRQoL with any instrument. From the included studies, we extracted information on HRQoL instruments as well as information on any other patient-reported outcome measures used.

Among the 182 publications found with the search terms, 45 were articles on RCTs in patients with NPso. Of these, eight reported on HRQoL outcomes. One of these eight studies had to be excluded as no full text was available [22]. The remaining seven papers (Table 2) reported on five different studies. Publication dates ranged from 2009 to 2020. Between one and three different HRQoL instruments were used in each study. The skin-specific DLQI was used in four studies, two of which used this instrument as the only HRQoL measure (the REACH and the BELIEVE study [23, 24]). A third study used only generic (i.e., not disease-specific) HRQoL instruments in addition to the DLQI, namely the EQ-5D and the SF-36 (the CRYSTAL study [25]). The fourth study added the EQ-5D and the NAPPA-QOL to the DLQI (the TRANSFIGURE study [9, 26]). The remaining RCT was reported in two papers, one of which presented results of the NPQ10 [27] and the other presented results of the NPQ10 and the NAPPA-QOL as HRQoL outcomes [28].

The two trials using NPso-specific HRQoL instruments revealed that the use of adalimumab and secukinumab improved HRQoL [9, 26‐28] (Table 3). As this was only a secondary objective in these studies, the scope of reporting on HRQoL differed. While for one study baseline values were reported [27, 28], the TRANSFIGURE study [9, 26] only reported relative improvement without giving baseline values. The latter trial also assessed skin-related and generic HRQoL, for which similar improvement was found.

These findings show that in the majority of RCTs evaluating NPso treatments, no HRQoL findings were reported. If they are reported, this is mostly based on instruments that are not NPso specific. The findings further show that if HRQoL is evaluated, the assessment is not consistent across RCTs. As a consequence, outcomes are only comparable between a subset of trials, which hinders interpretability, but also hampers meta-analyses and indirect comparisons of treatments. With the last-named analysis, one can compare the effectiveness of two different interventions even though they have not been assessed in a head-to-head trial [10, 29]. This is possible if both treatments have been tested against the same, third, intervention, which then serves as a common comparator. However, a common outcome parameter is also needed—for example, nail-specific HRQoL.

In the TRANSFIGURE study [9, 26], the Nail Assessment in Psoriasis and Psoriatic Arthritis–Patient Benefit Index (NAPPA-PBI) [17] has been used in addition to the NAPPA-QOL. This instrument assesses the importance of specific treatment goals from the perspective of patients with NPso, and also evaluates the extent to which these goals have been achieved by NPso treatment. The weighted global score indicates the treatment benefit as perceived by the individual patient, which can complement the data on HRQoL improvement as treatment needs can differ widely from one patient to another [7].

The findings of our literature search match that of a systematic review conducted in 2015 (published in 2018, [30]) that aimed to identify both clinical and patient-reported NPso outcome measures used in RCTs. They found that HRQoL was assessed in 43% of the included studies, mainly using the DLQI, but also the NPQ10 and the NAPPA-QOL. The authors advocate the development of core outcome sets for NPso, that is, a consensus-derived set of outcomes to be measured and reported in research and/or practice. They suggest this could be done in the context of the International Dermatology Outcome Measures (IDEOM) initiative [31]. IDEOM has recommended HRQoL as a core domain to be measured in all psoriasis clinical trials, and the manifestation ‘nail psoriasis’ as ‘important, but not required’ [32]. They did not specify how HRQoL shall be measured, leaving this to future IDEOM working groups; as of May 2021, no such consensus on how to assess HRQoL in psoriasis trials has been published yet.

An earlier systematic review performed in 2009 (published in 2010, [33]) aimed to describe the use of clinical and patient-reported outcome measures in a broader range of NPso study types. It showed that use of patient-reported outcome measures was rare in clinical studies and case reports. As the NPQ10 had first been published in that same year, and the NAPPA-QOL even later, it is not surprising that the review found no use of nail-specific HRQoL instruments; this illustrates the positive development in this field within the last decade.

HRQoL impairment due to NPso is an important outcome in both clinical care and research. It should be measured with standardized patient questionnaires for which there is evidence of good psychometric properties including reliability, validity, and responsiveness; ideally, these questionnaires should be NPso-specific in order to capture the distinct impairments that come with this condition. In addition, generic and skin-specific questionnaires can be used, especially if comparison with other disease groups, for example, people with psoriasis but without nail affection, is required.

Different instruments have been used in NPso trials. A consensus on instruments to be used for the measurement of generic, skin-specific, and NPso-specific HRQoL in future research would greatly improve comparability between trials. For both NPso-specific HRQoL instruments available to date, the NPQ10 and the NAPPA-QOL, good internal consistency and convergent validity have been demonstrated, and both have successfully been used in clinical trials. Both tools have unique advantages: The NAPPA-QOL allows for HRQoL evaluation in different dimensions, has demonstrated responsiveness to change, and is available in 18 country-specific language versions. The NPQ10 is only half as long as the NAPPA-QOL; its test-retest reliability has been supported (in 15 patients), while evaluation of this psychometric property is still pending for the NAPPA-QOL.

Further research is needed for both instruments, in particular on NPQ10 responsiveness and test-retest reliability in a larger sample, and on test-retest reliability of the NAPPA-QOL. For both tools, we also recommend investigation of structural validity and measurement invariance using Item Response Theory methods, and of content validity using qualitative methods [34]. We would not recommend the development of a new measure unless future research finds that both instruments have severe shortcomings. Instead, we advocate consensus finding on use of one of these two existing instruments as the standard tool to evaluate nail-specific HRQoL in NPso trials.