An economic evaluation of the randomized controlled trial of topical corticosteroid and home-based narrowband ultraviolet B for active and limited vitiligo (the HI-Light Vitiligo Trial).

BACKGROUND: Economic evidence for vitiligo treatments is absent. OBJECTIVES: To determine the cost-effectiveness of (i) handheld narrowband ultraviolet B (NB-UVB) and (ii) a combination of topical corticosteroid (TCS) and NB-UVB compared with TCS alone for localized vitiligo. METHODS: Cost-effectiveness analysis alongside a pragmatic, three-arm, placebo-controlled randomized controlled trial with 9 months' treatment. In total 517 adults and children (aged ≥ 5 years) with active vitiligo affecting < 10% of skin were recruited from secondary care and the community and were randomized 1: 1: 1 to receive TCS, NB-UVB or both. Cost per successful treatment (measured on the Vitiligo Noticeability Scale) was estimated. Secondary cost-utility analyses measured quality-adjusted life-years using the EuroQol 5 Dimensions 5 Levels for those aged ≥ 11 years and the Child Health Utility 9D for those aged 5 to < 18 years. The trial was registered with number ISRCTN17160087 on 8 January 2015. RESULTS: The mean ± SD cost per participant was £775 ± 83·7 for NB-UVB, £813 ± 111.4 for combination treatment and £600 ± 96·2 for TCS. In analyses adjusted for age and target patch location, the incremental difference in cost for combination treatment compared with TCS was £211 (95% confidence interval 188-235), corresponding to a risk difference of 10·9% (number needed to treat = 9). The incremental cost was £1932 per successful treatment. The incremental difference in cost for NB-UVB compared with TCS was £173 (95% confidence interval 151-196), with a risk difference of 5·2% (number needed to treat = 19). The incremental cost was £3336 per successful treatment. CONCLUSIONS: Combination treatment, compared with TCS alone, has a lower incremental cost per additional successful treatment than NB-UVB only. Combination treatment would be considered cost-effective if decision makers are willing to pay £1932 per additional treatment success.

Randomized controlled trial of topical corticosteroid and home-based narrowband ultraviolet B for active and limited vitiligo: results of the HI-Light Vitiligo Trial.

BACKGROUND: Evidence for the effectiveness of vitiligo treatments is limited. OBJECTIVES: To determine the effectiveness of (i) handheld narrowband UVB (NB-UVB) and (ii) a combination of potent topical corticosteroid (TCS) and NB-UVB, compared with TCS alone, for localized vitiligo. METHODS: A pragmatic, three-arm, placebo-controlled randomized controlled trial (9-month treatment, 12-month follow-up). Adults and children, recruited from secondary care and the community, aged ≥ 5 years and with active vitiligo affecting < 10% of skin, were randomized 1 : 1 : 1 to receive TCS (mometasone furoate 0·1% ointment + dummy NB-UVB), NB-UVB (NB-UVB + placebo TCS) or a combination (TCS + NB-UVB). TCS was applied once daily on alternating weeks; NB-UVB was administered on alternate days in escalating doses, adjusted for erythema. The primary outcome was treatment success at 9 months at a target patch assessed using the participant-reported Vitiligo Noticeability Scale, with multiple imputation for missing data. The trial was registered with number ISRCTN17160087 on 8 January 2015. RESULTS: In total 517 participants were randomized to TCS (n = 173), NB-UVB (n = 169) and combination (n = 175). Primary outcome data were available for 370 (72%) participants. The proportions with target patch treatment success were 17% (TCS), 22% (NB-UVB) and 27% (combination). Combination treatment was superior to TCS: adjusted between-group difference 10·9% (95% confidence interval 1·0%-20·9%; P = 0·032; number needed to treat = 10). NB-UVB alone was not superior to TCS: adjusted between-group difference 5·2% (95% CI - 4·4% to 14·9%; P = 0·29; number needed to treat = 19). Participants using interventions with ≥ 75% expected adherence were more likely to achieve treatment success, but the effects were lost once treatment stopped. Localized grade 3 or 4 erythema was reported in 62 (12%) participants (including three with dummy light). Skin thinning was reported in 13 (2·5%) participants (including one with placebo ointment). CONCLUSIONS: Combination treatment with home-based handheld NB-UVB plus TCS is likely to be superior to TCS alone for treatment of localized vitiligo. Combination treatment was relatively safe and well tolerated but was successful in only around one-quarter of participants.

Identifying key components for a psychological intervention for people with vitiligo - a quantitative and qualitative study in the United Kingdom using web-based questionnaires of people with vitiligo and healthcare professionals.

BACKGROUND: Psychological interventions are recommended as part of routine management of vitiligo. However, the development and effectiveness of such interventions have been rarely addressed. This study aimed to identify key components for a psychological intervention for people with vitiligo. This is the first time perspectives of people with vitiligo, and healthcare professionals (HCPs) have been directly explored to inform intervention content and delivery. OBJECTIVES: To identify 1. which psychological difficulties are highlighted that can be targeted by an intervention; 2. what is important in terms of intervention content and delivery. METHODS: Web-based questionnaires containing both quantitative and qualitative items were completed by people with vitiligo and HCPs. Questionnaires collected data from people with vitiligo on demographics, clinical features, psychological difficulties and priority areas for psychological interventions, including ideas on delivery and content. HCPs questionnaires collected data on psychological difficulties reported, use of psychological interventions and suitability within health services. Quantitative data were analysed using descriptive statistics, and qualitative data utilized thematic framework analysis. RESULTS: A total of 100 people with vitiligo (66% female, 92% Caucasian) and 39 HCPs (54% dermatologists) participated. Key areas of difficulty were the impact of vitiligo, coping, issues with appearance/body image and the sun, and medical interactions. Vitiligo on sensitive sites was associated with more psychological impact. Interventions directed at increasing acceptance, confidence and self-esteem, as well as managing embarrassment, were important. These issues could be managed through interventions such as cognitive behavioural therapy, mindfulness and acceptance and commitment therapy. Both people with vitiligo and HCPs favoured individual interventions. CONCLUSION: Vitiligo has significant impact, requiring ongoing psychosocial support. There is a strong need for a psychoeducational intervention with focus on acceptance and managing social impact. The results of this study are the first steps to informing the development of a patient-centred psychological intervention.

The prevalence of psychological comorbidity in people with vitiligo: a systematic review and meta-analysis.

BACKGROUND: Vitiligo is a chronic disorder causing skin depigmentation with global prevalence varying from 0·2% to 1·8%. U.K. guidelines recommend assessment of psychological state during clinical evaluation of vitiligo. However, the prevalence of psychological comorbidity in people with vitiligo has not been described. OBJECTIVES: To establish the prevalence of psychological symptoms or disorders in people with vitiligo and describe the outcome measures used. METHODS: We performed a comprehensive search of MEDLINE, Embase, CINAHL and PsycINFO to identify observational studies assessing the prevalence of psychological symptoms or disorders (December 2016). DerSimonian and Lard random-effects models were used to estimate the overall pooled prevalence. RESULTS: We identified 29 studies with 2530 people with vitiligo. Most studies included a measure of either depression (n = 25) or anxiety (n = 13). The commonest tools were the Hospital Anxiety and Depression Scale and the Centre for Epidemiology Studies Depression Scale. Ten studies provided information on 13 other psychological outcomes. Pooled prevalence using depression-specific and anxiety-specific questionnaires was 0·29 [95% confidence interval (CI) 0·21-0·38] and 0·33 (95% CI 0·18-0·49), respectively. Prevalence was lower for clinically diagnosed depression (0·21, 95% CI 0·15-0·28) and anxiety (0·15, 95% CI 0·06-0·24). When nonspecific tools were used the prevalence remained similar for depression (0·27, 95% CI 0·08-0·46) but increased for anxiety (0·46, 95% CI 0·39-0·52). High heterogeneity was observed. CONCLUSIONS: A range of psychological outcomes are common in people with vitiligo. The prevalence of anxiety was influenced by type of screening tool, suggesting the need for validation of psychological outcome screening tools in the field of dermatology.

Generating new evidence, improving clinical practice and developing research capacity: the benefits of recruiting to the U.K. Dermatology Clinical Trials Network's STOP GAP and BLISTER trials.

Clinical trials may benefit clinical practice in three ways: firstly, clinicians may change their practice according to the new trial evidence; secondly, clinical processes can improve when working on a trial; and thirdly, research capacity is increased. We held a meeting to present and discuss the results of two large multicentre randomized controlled trials delivered through the U.K. Dermatology Clinical Trials Network. Investigators gave reflections on how the trials had changed their clinical practice. The STOP GAP trial showed that prednisolone and ciclosporin are equally effective as first-line systemic treatment for pyoderma gangrenosum. The final decision of which treatment to use should be based on the different adverse event profiles of the two drugs in relation to comorbidities, along with age, disease severity and patient preference. The BLISTER trial showed that starting people with pemphigoid on doxycycline produces acceptable short-term effectiveness and a superior safety profile to oral corticosteroids. Recruiting to these trials has led to the development of new specialist clinics with improved documentation. It has increased the profile of participating departments and embedded research in the department's activities. Helping to design and run these trials has also allowed trial staff to develop new skills in research design, which has been beneficial for career development. These and other benefits of recruiting to the trials are summarized here. We hope that these reflections will inspire wider involvement in clinical research.

Validation of the Vitiligo Noticeability Scale: a patient-reported outcome measure of vitiligo treatment success.

BACKGROUND: Patient-reported outcome measures are rarely used in vitiligo trials. The Vitiligo Noticeability Scale (VNS) is a new patient-reported outcome measure assessing how 'noticeable' vitiligo patches are after treatment. The noticeability of vitiligo after treatment is an important indicator of treatment success from the patient's perspective. OBJECTIVES: To evaluate the construct validity, acceptability and interpretability of the VNS. METHODS: Clinicians (n = 33) and patients with vitiligo (n = 101) examined 39 image pairs, each depicting a vitiligo lesion pre- and post-treatment. Using an online questionnaire, respondents gave a global assessment of treatment success and a VNS score for treatment response. Clinicians also estimated percentage repigmentation of lesions (< 25%; 25-50%; 51-75%; > 75%). Treatment success was defined as 'yes' on global assessment, a VNS score of 4 or 5, and > 75% repigmentation. Agreement between respondents and the different scales was assessed using kappa (κ) statistics. RESULTS: Vitiligo Noticeability Scale scores were associated with both patient- and clinician-reported global treatment success (κ = 0·54 and κ = 0·47, respectively). Percentage repigmentation showed a weaker association with patient- and clinician-reported global treatment success (κ = 0·39 and κ = 0·29, respectively). VNS scores of 4 or 5 can be interpreted as representing treatment success. Images depicting post-treatment hyperpigmentation were less likely to be rated as successful. CONCLUSIONS: The VNS is a valid patient-reported measure of vitiligo treatment success. Further validation of the VNS is required, using larger sets of clinical pre- and post-treatment images, affecting a wider range of anatomical sites.

Evidence-based management of vitiligo: summary of a Cochrane systematic review.

Vitiligo affects around 1% of the world's population. Despite it being relatively common, there is still no effective treatment. The objective of this study was to update the Cochrane systematic review of randomized clinical trials (RCTs) to evaluate the efficacy of treatments for vitiligo. We carried out searches of a range of databases to October 2013 for RCTs of interventions for vitiligo regardless of language or publication status. At least two reviewers independently assessed study eligibility and methodological quality and extracted data using data extraction forms approved by the Cochrane Skin Group. Our primary outcomes of interest were quality of life, > 75% repigmentation and adverse effects. We retrieved 96 studies, of which 39 were new studies, with an overall total of 4512 participants. Repigmentation was assessed in all studies, although only five reported on all three of our primary outcomes. Regarding our two secondary outcomes, six studies measured cessation of spread but none assessed long-term permanence of repigmentation at 2 years' follow-up. Most of the studies evaluated combination treatments, which generally showed better repigmentation than monotherapies. Of the new studies, seven were surgical interventions. The majority of the studies had fewer than 50 participants. The quality of the studies was poor to moderate at best. Very few studies specifically included children or participants with segmental vitiligo. Five years after the last update of this review, there are still important variations in study design and outcome measures in clinical trials for vitiligo, limiting the evidence for the efficacy of different therapeutic options. The best evidence from individual trials showed short-term benefit from topical corticosteroids and various forms of ultraviolet radiation combined with topical preparations. Long-term follow-up and patient-rated outcomes should be incorporated into study design, and more studies should assess psychological interventions.

The Eczema Priority Setting Partnership: a collaboration between patients, carers, clinicians and researchers to identify and prioritize important research questions for the treatment of eczema.

BACKGROUND: Eczema is a common condition, yet there are uncertainties regarding many frequently used treatments. Knowing which of these uncertainties matter to patients and clinicians is important, because they are likely to have different priorities from those of researchers and funders. OBJECTIVES: To identify the uncertainties in eczema treatment that are important to patients who have eczema, their carers and the healthcare professionals (HCPs) who treat them. METHODS: An eczema Priority Setting Partnership was established, including patients, HCPs and researchers. Eczema treatment uncertainties were gathered from patients and clinicians, and then prioritized in a transparent process, using a methodology advocated by the James Lind Alliance. RESULTS: In the consultation stage 493 participants (including 341 patients/carers) made 1070 submissions, of which 718 were uncertainties relating to the treatment of eczema. Treatment uncertainties with more than one submission were grouped into 52 'indicative uncertainties', which were then ranked by 514 participants (including 399 patients/carers). The top 14 treatment uncertainties were prioritized for research. The first four were common to patients/carers and HCPs (shared uncertainties): (i) the best and safest way of using topical steroids (including frequency of application, potency, length of time, alternation with other topical treatments and age limits); (ii) the long-term safety of topical steroids; (iii) the role of food allergy tests; and (iv) the most effective and safe emollients in treating eczema. The remaining 10 of the top 14 uncertainties comprised the next five highest ranked uncertainties for patients and the next five highest ranked uncertainties for HCPs. At a workshop involving 40 participants (patients, HCPs and researchers), shared uncertainties were formulated into possible research questions. CONCLUSIONS: The top 14 treatment uncertainties around the treatment of eczema provide guidance for researchers and funding bodies to ensure that future research answers questions that are important to both clinicians and patients.

Which outcomes should we measure in vitiligo? Results of a systematic review and a survey among patients and clinicians on outcomes in vitiligo trials.

BACKGROUND: Relevant and reliable outcomes play a crucial role in the correct interpretation and comparison of the results of clinical trials. There is a lack of consensus around methods of assessment and outcome measures for vitiligo, which makes it difficult to compare results of randomized controlled trials (RCTs) and perform meta-analysis. OBJECTIVES: To describe the heterogeneity in outcome measures used in published RCTs of vitiligo treatments, and to report the most desirable outcomes from patients' and clinicians' perspectives. METHODS: We conducted a systematic review of outcome measures used in RCTs as well as a survey of the most desirable outcomes identified by patients and clinicians as part of a Vitiligo Priority Setting Partnership. RESULTS: Outcomes from 54 eligible trials were analysed and compared with outcomes suggested by patients and clinicians. In the systematic review, 25 different outcomes were reported. Only 22% of trials had clearly stated primary outcome measures. Repigmentation was the most frequently reported outcome in 96% of trials and was measured using 48 different scales. Only 9% of trials assessed quality of life. Thirteen per cent measured cessation of spreading of the disease and 17% of studies reported patients' opinions and satisfaction with the treatment. In contrast, out of 438 suggestions made by patients and clinicians, cosmetically acceptable repigmentation (rather than percentage of repigmentation) was the most desirable outcome (68%), followed by cessation of spread of vitiligo (15%), quality of life (8%) and maintenance of repigmentation (4%). CONCLUSIONS: We propose that future vitiligo trials should include repigmentation, cosmetic acceptability of results, global assessment of the disease, quality of life, maintenance of repigmentation, stabilization of vitiligo and side-effects. International consensus among clinicians, researchers and patients is needed to establish an agreed core outcome set for future vitiligo trials.

A randomized trial of methotrexate vs. azathioprine for severe atopic eczema: a critical appraisal.

AIM: Schram et al. aimed to compare the efficacy and safety of methotrexate vs. azathioprine in adults with severe atopic eczema. SETTING AND DESIGN: This single-blind, parallel-group (ratio 1 : 1), randomized controlled trial was conducted in a secondary care setting in the Netherlands between July 2009 and December 2010. STUDY EXPOSURE: Patients with severe atopic eczema were randomly assigned in a 1 : 1 ratio to receive either methotrexate (10-22·5 mg weekly) or azathioprine (1·5-2·5 mg kg(-1) daily) for 12 weeks, followed by a 12-week follow-up period. OUTCOMES: The outcome measures comprised various eczema severity measures including: SCORing of Atopic Dermatitis index (SCORAD); Investigator Global Assessment (IGA); Patient Global Assessment (PGA); Eczema Area and Severity Index (EASI); and Patient-Oriented Eczema Measurement (POEM). Further outcomes included a visual analogue scale of itch and sleeplessness; Skindex-17; serum levels of thymus and activation-regulated chemokine; quantity of topical corticosteroids used; and the number of courses of rescue medication (oral prednisolone) used. PRIMARY OUTCOME MEASURE: The primary outcome was the mean change in SCORAD after 12 weeks of treatment. RESULTS: Forty-five patients were screened and 42 of these were included in the trial. At week 12, patients in the methotrexate group had a mean ± SD relative reduction in SCORAD of 42 ± 18% compared with 39 ± 25% in the azathioprine group (P = 0·52). Proportions of patients achieving at least mild disease and reductions in impact on quality of life and symptoms were similar in both groups at weeks 12 and 24. No statistically significant differences were found in the number and severity of adverse events. Abnormalities in blood count were more common in the azathioprine group but no serious adverse events occurred in either group. CONCLUSIONS: Schram et al. conclude that both methotrexate and azathioprine achieved clinically relevant improvement and were safe in the short term. They also conclude that both treatments are appropriate treatment options for severe atopic eczema in adult populations.

Acne, isotretinoin and suicide attempts: a critical appraisal.

AIM: Sundström et al. (BMJ 2010; 341: c5812) aimed to assess suicide risk before, during and after isotretinoin treatment. HYPOTHESIS: People with severe acne may be at higher risk of attempted suicide regardless of exposure to isotretinoin. SETTING AND DESIGN: This retrospective cohort study from Sweden linked a patient register of isotretinoin users (1980-1989) or patients identified through specified pharmacies (1986-1989) to hospital discharges and a register of causes of death (1980-2001). STUDY EXPOSURE: The study exposure was isotretinoin, identified from a register of named patients given isotretinoin (special application to the Medical Products Agency) or patients prescribed isotretinoin in a dermatology clinic with 'clinic approval' to prescribe the medication without individual application. OUTCOMES: The outcomes were recorded suicide attempts (identified using ICD-8 and ICD-9 codes E950-E958, ICD-10 codes Y6-64); accidents with unclear intent and an 'external cause' (ICD-8 and ICD-9 codes E980-E988 and ICD-10 codes Y10-Y34) and deaths with underlying causes. PRIMARY OUTCOME MEASURE: Standardized incidence ratio (SIR) of suicide rates compared with the general population 3 years before, during and up to 15 years after completion of treatment with isotretinoin. RESULTS: The cohort included 5756 people. During the 21-year follow-up period, 128 (2·2%) had a hospital admission for a suicide attempt. For all attempts, the SIR [95% confidence interval (CI)] increased from 0·99 (0·65-1·44) 3 years prior to treatment to 1·57 (0·86-2·63) in the year before treatment, increasing to 1·78 (1·04-2·85) within 6 months after starting treatment and decreasing to 1·04 (0·74-1·43) 3 years following treatment. For first suicide attempts, the SIR (95% CI) increased from 0·89 (0·54-1·37) 3 years prior to treatment to 1·36 (0·65-2·50) in the year before treatment, increasing to 1·93 (1·08-3·18) within 6 months of treatment and decreasing to 0·97 (0·64-1·40) 3 years following treatment. Twelve (38%) of 32 patients who attempted suicide prior to treatment made a further attempt or committed suicide at some stage during follow up. Of the 14 who attempted suicide during or within 6 months of treatment, 10 (71%) made a further attempt during follow up. CONCLUSIONS: Sundström et al. (BMJ 2010; 341: c5812) conclude that there was an increased risk of suicide attempts up to 6 months after the end of treatment with isotretinoin and advise close monitoring for up to a year after completing a course of treatment. Patients with a history of suicide attempts before treatment made fewer new attempts at suicide than those where suicidality was observed in connection with treatment, suggesting that patients with severe acne with a history of attempted suicide should not automatically be refused isotretinoin treatment. The authors also state that suicide risk was already rising prior to treatment and that the additional risk cannot therefore be attributed to isotretinoin use.