Citation for published version (APA): Linthorst Homan, M. W. (2012). Clinical and patient reported outcomes in vitiligo

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1 UvA-DARE (Digital Academic Repository) Clinical and patient reported outcomes in vitiligo Linthorst Homan, M.W. Link to publication Citation for published version (APA): Linthorst Homan, M. W. (2012). Clinical and patient reported outcomes in vitiligo General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam ( Download date: 21 Sep 2018

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3 Clinical and patient reported outcomes in vitiligo May Linthorst Homan

4 Clinical and patient reported outcomes in vitiligo ISBN: Layout and printing: Off Page, Cover: Violet Lotgering Publication of this thesis was financially supported by: ABBOTT Immunology, Actavis B.V., afdeling Dermatologie AMC, ALK-ABELLÓ B.V., Astellas Pharma BV, Eucerin, EuroTec BV, Fagron, Galderma, GlaxoSmithKline, Huidstichting Chanfleury van IJsselsteijn, Janssen, Landelijke Vereniging Voor Vitiligo Patiënten, Laser Vision, LEO Pharma BV, Louis Widmer, Medizorg, Mediq i.s.m. Pierre Fabre Dermo-Cosmétique, Pfizer bv, Stichting EIS, Stichting Nederlands Instituut voor Pigmentstoornissen, Tobrix, Universiteit van Amsterdam, Waldmann B.V., Will Pharma. Copyright 2012 by M. W. Linthorst Homan. All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, without prior permission of the author.

5 CLINICAL AND PATIENT REPORTED OUTCOMES IN VITILIGO ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad van doctor aan de Universiteit van Amsterdam op gezag van de Rector Magnificus prof. dr. D.C. van den Boom ten overstaan van een door het college voor promoties ingestelde commissie, in het openbaar te verdedigen in de Agnietenkapel op donderdag 11 oktober 2012, te uur door May Wijna Linthorst Homan geboren te Arnhem

6 Promotiecommissie Promotor: Co-promotor: Overige leden: Prof. dr. J.D.Bos Prof. dr. M.A.G. Sprangers Dr. J.P.W. van der Veen Dr. J. de Korte Prof. dr. N. van Geel Prof. dr. M.A. Grootenhuis Prof. dr. R.J. de Haan Prof. dr. R. Hoekzema Prof. dr. T. Nijsten Faculteit der Geneeskunde

7 Contents Chapter 1 General introduction and aims of the thesis 7 Chapter 2 Chapter 3 Chapter 4 Chapter 5 Chapter 6 Measurement properties of outcome measures for vitiligo: a systematic review 17 Digital Image Analysis versus clinical assessment to evaluate repigmentation after punch grafting in vitiligo 43 A randomised comparison of excimer laser versus narrow-band ultra violet B phototherapy after punch grafting in stable vitiligo patients 53 The burden of vitiligo: patient characteristics associated with quality of life 65 Characteristics of patients with universal vitiligo and health-related quality of life 81 Chapter 7 Impact of childhood vitiligo on adult life 91 Chapter 8 Summary and conclusions 105 Chapter 9 Samenvatting en conclusies 111 Addendum SF Skindex Bibliografie 129 Curriculum Vitae 133 Dankwoord 137

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9 1 General introduction and Aims of the thesis

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11 VITILIGO Vitiligo is a chronic skin disease, in which white skin patches arise due to loss of pigment-producing melanocytes. This skin disease is common in all races, regardless of age and sex and affects 0.5-1% of the world population. 1 The first signs of vitiligo can arise at any age but in 50% of the patients affected, the onset is before the age of 20 years. The most common clinical pattern is the so-called subtype generalized or non-segmental vitiligo. 2;3 The Vitiligo European Task Force (VETF) defines non-segmental vitiligo as an acquired chronic pigmentation disorder characterized by white patches, often symmetrical, which usually increase in size with time corresponding to a substantial loss of functioning epidermal and sometimes hair follicle melanocytes. 4 Other subtypes of vitiligo are localised types, such as segmental, focal and mucosal vitiligo. In some patients, depigmentation spreads over more than 80% of the whole body. This type of vitiligo is known as universal vitiligo. 2 Generally, vitiligo does not lead to significant physical morbidity, but vitiligo can have an impact on the quality of life of the patients. Many vitiligo patients, for instance, suffer from psychosocial distress and social stigmatization. 5-7 Because skin colour plays a major role in an individual s perception of health, wealth, worth and desirability, pigment disfigurement may influence social interactions, 8 and may even lead to social exclusion. It is for this reason, that vitiligo has been declared to be one of the major medical problems in India. 9;10 However, in Western-European countries vitiligo, although associated with other auto-immune diseases, 2 is often considered as a harmless, cosmetic skin disorder. The importance of treating vitiligo patients is therefore often underestimated. 7;11;12 It is important to recognize and to pay attention to the psychosocial impact of this disease INTRODUCTION TREATMENT OF VITILIGO Although vitiligo can as yet not be cured, several treatment options are available. These treatments are intended to reduce disease activity and/or induce repigmentation in existing vitiligo patches, and thereby to improve quality of life. Narrowband ultra violet B phototherapy (NB-UVB) was introduced in 1997 and is now widely accepted to be the most effective therapy for vitiligo. It has largely replaced the classical ultra violet A phototherapy combined with the photosensitizer psoralen (PUVA) which was less effective and had more sideeffects. 13 It is assumed that by its immunomodulating effect, NB-UVB inhibits disease activity and promotes melanocyte migration and proliferation. 14 In 2002, the 308-nm xenon chloride excimer laser (EL) was introduced as a treatment for vitiligo EL was reported to be more effective than NB-UVB treatment. 26;27 Another putative advantage of EL over NB-UVB would be the selective targeting which spares non-affected skin and reduces the cumulative UV dose. 9

12 1 Topical therapy with corticosteroids or calcineurin inhibitors can be considered for limited lesions, but is most effective in combination with phototherapy or natural sunlight. 28;29 Surgical therapies can be considered for stable vitiligo patches that are resistant or respond unsatisfactory to non-surgical therapies due to an insufficient remaining reservoir of melanocytes in these lesions. Melanocyte transplant techniques include suction blister grafting, split-thickness skin grafting, punch grafting and melanocyte cell suspension. In the Netherlands Institute for Pigment Disorders (NIPD) the autologous punch grafting technique is routinely used as a surgical therapy. This technique is relatively simple and has shown to be effective for stable localised and generalized vitiligo. 30 Punch grafting followed by either EL 31 or NB-UVB 32 was found to be effective in inducing repigmentation in vitiligo patients. The efficacy of EL versus NB-UVB after punch grafting in vitiligo patients has not been evaluated. OUTCOME MEASURES IN VITILIGO The aim of treatment is to induce repigmentation and to achieve a better quality of life. Good clinical measures are essential to measure the efficacy of a therapy in terms of repigmentation. The Vitiligo Area Scoring Index (VASI) 33 was introduced as a quantitative parametric score. The VASI is calculated using a formula that includes contributions from all body regions. A few years later, in the Vitiligo European Task Force (VETF), a system was proposed which combines analysis of extent, stage of disease (staging), and disease progression (spreading). 4 These two measurements are subjective clinical assessments. In addition, a variety of other scoring systems is in use to evaluate treatment outcome in terms of repigmentation, 3 making cross-study comparisons difficult. Moreover, most outcome measures rely on a subjective clinical assessment, which cannot exclude inter-observer bias and may therefore have limited accuracy and reproducibility. Only few studies use an objective measurement tool to score repigmentation, such as a digital image analysis system (DIAS) As it is digitally analyzed, this measurement can overcome most of the limitations mentioned. Subjective and objective repigmentation measurements after punch grafting have not been compared so far. Good measures of patient reported outcomes (PROs) are also essential to measure the efficacy of a therapy in terms of quality of life. 45 PROs are reports or assessments of any aspect of a patient s health status and/or treatment impact that come directly from the patient, without the interpretation of the responses by anyone else. 10

13 HEALTH RELATED QUALITY OF LIFE Health-related quality of life (HRQL) is a multi-dimensional construct which reflects the patients evaluation of the impact of a disease and/or treatment on their physical, psychological, and social functioning and well-being In vitiligo patients, HRQL can be assessed with generic questionnaires and/ or dermatology-specific HRQL questionnaires. Disease specific HRQL instruments are not yet available for vitiligo. Generic HRQL questionnaires can be used for all diseases. They allow comparisons with other medical conditions, not just skin diseases, as well as comparison with the general population. These questionnaires do not focus on all areas of a specific disease, but they give an overall description of quality of life. An example of a generic HRQL questionnaire is the widely used Medical Outcomes Study 36-item Short-Form General Health Survey (SF-36). 49 Dermatology-specific HRQL questionnaires are developed to assess impact on quality of life specific to skin diseases. With these questionnaires it is possible to make comparisons between different skin diseases. The Skindex and the Dermatology Life Quality Index (DLQI), 51 are widely used dermatology-specific HRQL questionnaires. Using a combination of a generic (such as the SF-36) and a dermatologyspecific HRQL questionnaire (such as the Skindex-29), a wide range of domains and aspects of quality of life can be assessed. Moreover, both types of instruments may measure different but complementary domains and aspects of patients health. 52;53 A number of studies has examined HRQL in patients with generalized vitiligo. 6;10;54-63 These studies used mainly dermatology-specific questionnaires and reported that in general, vitiligo had a negative impact on HRQL, particularly on psychosocial functioning. The patient-specific characteristics associated with HRQL have not been studied. Moreover, no data are available on the HRQL of patients with universal vitiligo or on the impact of childhood vitiligo on adult life. 1 INTRODUCTION AIMS OF THIS THESIS The aims of this thesis are first to investigate the clinical and patient reported outcomes (PROs) of vitiligo treatment (Chapter 2, 3 and 4), and second to gain insight into the health-related quality of life (HRQL) and other PROs in generalized and universal vitiligo and in adult patients who had vitiligo in childhood (Chapter 5, 6 and 7). As there are different outcome measures used in vitiligo research, it is necessary to know the quality and validity of these existing clinical measures. Improvement of the indicated imperfections in these clinical measures will lead to better decision making in patient care for vitiligo. In Chapter 2 a systematic review summarizing the available evidence of the measurement properties of clinician, patient and observer reported outcomes in vitiligo treatment is described. Chapter 3 describes a study comparing repigmentation rates as judged by computerised measurement, clinicians and patients after punch grafting in vitiligo patients. In 11

14 1 Chapter 4, the percentage of repigmentation is measured to compare the excimer laser with narrowband ultraviolet B phototherapy, as post-treatment regimens in vitiligo patients who underwent punch grafting. In Chapter 5, in order to draw a profile of vitiligo patients who suffer most and thereby need special attention, the burden of vitiligo is described. The generic and dermatology-specific HRQL in sociodemographically and clinically distinct subgroups of patients with generalized vitiligo is investigated. Furthermore, associations between HRQL and sociodemographic and clinical patient characteristics are explored. As little is known about universal vitiligo, we describe the characteristics of patients with universal vitiligo in Chapter 6. Moreover, these characteristics are compared with those of patients with generalized vitiligo. Furthermore, the HRQL of patients with universal vitiligo is compared with that of patients with generalized vitiligo. In Chapter 7 the social and psychosexual development and current HRQL of adult patients suffering from vitiligo since childhood are compared with those of a group of healthy controls. Moreover, these outcomes in patients reporting negative childhood experiences are compared with those of patients who do not report negative childhood experiences related to vitiligo. It is our hope that the results of this thesis will contribute to the improvement of the quality of care and the quality of life of patients with vitiligo. 12

15 Reference List 1. Alikhan A, Felsten LM, Daly M et al. Vitiligo: a comprehensive overview Part I. Introduction, epidemiology, quality of life, diagnosis, differential diagnosis, associations, histopathology, etiology, and work-up. J Am Acad Dermatol 2011; 65: Njoo MD, Westerhof W. Vitiligo. Pathogenesis and treatment. Am J Clin Dermatol 2001; 2: Whitton ME, Pinart M, Batchelor J et al. Interventions for vitiligo. Cochrane Database Syst Rev 2010; CD Taieb A, Picardo M. The definition and assessment of vitiligo: a consensus report of the Vitiligo European Task Force. Pigment Cell Res 2007; 20: Porter J, Beuf AH, Nordlund JJ et al. Psychological reaction to chronic skin disorders: a study of patients with vitiligo. Gen Hosp Psychiatry 1979; 1: Kent G, Al Abadie M. Psychologic effects of vitiligo: a critical incident analysis. J Am Acad Dermatol 1996; 35: Ongenae K, Beelaert L, Van GN et al. Psychosocial effects of vitiligo. J Eur Acad Dermatol Venereol 2006; 20: Grimes PE. White patches and bruised souls: advances in the pathogenesis and treatment of vitiligo. J Am Acad Dermatol 2004; 51: S5-S7. 9. Chaturvedi SK, Singh G, Gupta N. Stigma experience in skin disorders: an Indian perspective. Dermatol Clin 2005; 23: Parsad D, Dogra S, Kanwar AJ. Quality of life in patients with vitiligo. Health Qual Life Outcomes 2003; 1: Njoo MD, Bossuyt PM, Westerhof W. Management of vitiligo. Results of a questionnaire among dermatologists in The Netherlands. Int J Dermatol 1999; 38: Ongenae K, Van GN, De SS et al. Management of vitiligo patients and attitude of dermatologists towards vitiligo. Eur J Dermatol 2004; 14: Westerhof W, Nieuweboer-Krobotova L. Treatment of vitiligo with UV-B radiation vs topical psoralen plus UV-A. Arch Dermatol 1997; 133: Wu CS, Lan CC, Wang LF et al. Effects of psoralen plus ultraviolet A irradiation on cultured epidermal cells in vitro and patients with vitiligo in vivo. Br J Dermatol 2007; 156: Choi KH, Park JH, Ro YS. Treatment of Vitiligo with 308-nm xenon-chloride excimer laser: therapeutic efficacy of different initial doses according to treatment areas. J Dermatol 2004; 31: Esposito M, Soda R, Costanzo A et al. Treatment of vitiligo with the 308 nm excimer laser. Clin Exp Dermatol 2004; 29: Hadi SM, Spencer JM, Lebwohl M. The use of the 308-nm excimer laser for the treatment of vitiligo. Dermatol Surg 2004; 30: Hofer A, Hassan AS, Legat FJ et al. Optimal weekly frequency of 308-nm excimer laser treatment in vitiligo patients. Br J Dermatol 2005; 152: Hofer A, Hassan AS, Legat FJ et al. The efficacy of excimer laser (308 nm) for vitiligo at different body sites. J Eur Acad Dermatol Venereol 2006; 20: Leone G, Iacovelli P, Paro VA et al. Monochromatic excimer light 308 nm in the treatment of vitiligo: a pilot study. J Eur Acad Dermatol Venereol 2003; 17: Ostovari N, Passeron T, Zakaria W et al. Treatment of vitiligo by 308-nm excimer laser: an evaluation of variables affecting treatment response. Lasers Surg Med 2004; 35: Spencer JM, Nossa R, Ajmeri J. Treatment of vitiligo with the 308-nm excimer laser: a pilot study. J Am Acad Dermatol 2002; 46: Taneja A, Trehan M, Taylor CR. 308-nm excimer laser for the treatment of localized vitiligo. Int J Dermatol 2003; 42: Baltas E, Csoma Z, Ignacz F et al. Treatment of vitiligo with the 308-nm xenon chloride excimer laser. Arch Dermatol 2002; 138: Zhang XY, He YL, Dong J et al. Clinical efficacy of a 308 nm excimer laser in the treatment of vitiligo. Photodermatol Photoimmunol Photomed 2010; 26: Hong SB, Park HH, Lee MH. Short-term effects of 308-nm xenon-chloride excimer laser and narrow-band ultraviolet B in the treatment of vitiligo: a comparative study. J Korean Med Sci 2005; 20: Casacci M, Thomas P, Pacifico A et al. Comparison between 308-nm monochromatic excimer light and narrowband UVB phototherapy ( nm) in the treatment of vitiligo - a multicentre controlled study. J Eur Acad Dermatol Venereol 2007; 21: Felsten LM, Alikhan A, Petronic-Rosic V. Vitiligo: a comprehensive overview Part II: treatment options and approach to treatment. J Am Acad Dermatol 2011; 65: Westerhof W, Nieuweboer-Krobotova L, Mulder PG et al. Left-right comparison study of the combination of fluticasone propionate and UV-A vs. either fluticasone propionate 1 INTRODUCTION 13

16 1 or UV-A alone for the long-term treatment of vitiligo. Arch Dermatol 1999; 135: Boersma BR, Westerhof W, Bos JD. Repigmentation in vitiligo vulgaris by autologous minigrafting: results in nineteen patients. J Am Acad Dermatol 1995; 33: Nieuweboer-Krobotova L, Veen JPW. Excimer laser and minigrafting- combination therapy for vitiligo. Poster EADV P Ref Type: Pamphlet 33. Lahiri K, Malakar S, Sarma N et al. Repigmentation of vitiligo punch grafting and NB-UVB: a prospective study. Int J Dermatol 2006; 45: Hamzavi I, Jain H, McLean D et al. Parametric modeling of narrowband UV-B phototherapy for vitiligo using a novel quantitative tool: the Vitiligo Area Scoring Index. Arch Dermatol 2004; 140: van Geel N, Vander Haeghen Y, Ongenae K et al. A new digital image analysis system useful for surface assessment of vitiligo lesions in transplantation studies. Eur J Dermatol 2004; 14: Andreassi L, Pianigiani E, Andreassi A et al. A new model of epidermal culture for the surgical treatment of vitiligo. Int J Dermatol 1998; 37: Boersma BR, Westerhof W, Bos JD. Repigmentation in vitiligo vulgaris by autologous minigrafting: results in nineteen patients. J Am Acad Dermatol 1995; 33: Guerra L, Capurro S, Melchi F et al. Treatment of stable vitiligo by Timedsurgery and transplantation of cultured epidermal autografts. Arch Dermatol 2000; 136: Lepe V, Moncada B, Castanedo-Cazares JP et al. A double-blind randomized trial of 0.1% tacrolimus vs 0.05% clobetasol for the treatment of childhood vitiligo. Arch Dermatol 2003; 139: van Geel N, Ongenae K, De Mil M et al. Doubleblind placebo-controlled study of autologous transplanted epidermal cell suspensions for repigmenting vitiligo. Arch Dermatol 2004; 140: van Geel N, Ongenae K, Vander Haeghen Y et al. Subjective and objective evaluation of noncultured epidermal cellular grafting for repigmenting vitiligo. Dermatology 2006; 213: Linthorst Homan MW, Spuls PI, Nieuweboer- Krobotova L et al. A randomized comparison of excimer laser versus narrow-band ultraviolet B phototherapy after punch grafting in stable vitiligo patients. J Eur Acad Dermatol Venereol Bakis-Petsoglou S, Le Guay JL, Wittal R. A randomized, double-blinded, placebocontrolled trial of pseudocatalase cream and narrowband ultraviolet B in the treatment of vitiligo. Br J Dermatol 2009; 161: Cazzaniga S, Sassi F, Mercuri SR et al. Prediction of clinical response to excimer laser treatment in vitiligo by using neural network models. Dermatology 2009; 219: Fongers A, Wolkerstorfer A, Nieuweboer- Krobotova L et al. Long-term results of 2-mm punch grafting in patients with vitiligo vulgaris and segmental vitiligo: effect of disease activity. Br J Dermatol 2009; 161: Patrick DL, Burke LB, Powers JH et al. Patientreported outcomes to support medical product labeling claims: FDA perspective. Value Health 2007; 10 Suppl 2: S125-S Testa MA, Simonson DC. Assesment of quality-of-life outcomes. N Engl J Med 1996; 334: Finlay AY. Quality of life assessments in dermatology. Semin Cutan Med Surg 1998; 17: Finlay AY. Quality of life measurement in dermatology: a practical guide. Br J Dermatol 1997; 136: Aaronson NK, Muller M, Cohen PD et al. Translation, validation, and norming of the Dutch language version of the SF-36 Health Survey in community and chronic disease populations. J Clin Epidemiol 1998; 51: Chren MM, Lasek RJ, Flocke SA et al. Improved discriminative and evaluative capability of a refined version of Skindex, a quality-of-life instrument for patients with skin diseases. Arch Dermatol 1997; 133: Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)--a simple practical measure for routine clinical use. Clin Exp Dermatol 1994; 19: Chren MM, Lasek RJ, Quinn LM et al. Convergent and discriminant validity of a generic and a disease-specific instrument to measure quality of life in patients with skin disease. J Invest Dermatol 1997; 108: De Korte J, Mombers FM, Sprangers MA et al. The suitability of quality-of-life questionnaires for psoriasis research: a systematic literature review. Arch Dermatol 2002; 138: Kent G, al-abadie M. Factors affecting responses on Dermatology Life Quality Index items among vitiligo sufferers. Clin Exp Dermatol 1996; 21: Ongenae K, Van Geel N, De Schepper S et al. Effect of vitiligo on self-reported healthrelated quality of life. Br J Dermatol 2005; 152: Borimnejad L, Parsa YZ, Nikbakht-Nasrabadi A et al. Quality of life with vitiligo: comparison 14

17 of male and female muslim patients in Iran. Gend Med 2006; 3: Aghaei S, Sodaifi M, Jafari P et al. DLQI scores in vitiligo: reliability and validity of the Persian version. BMC Dermatol 2004; 4: Zghal A, Zeglaoui F, Kallel L et al. [Quality of life in dermatology: Tunisian version of the Skindex-29]. Tunis Med 2003; 81: Belhadjali H, Amri M, Mecheri A et al. [Vitiligo and quality of life: a case-control study.]. Ann Dermatol Venereol 2007; 134: Mechri A, Amri M, Douarika AA et al. [Psychiatric morbidity and quality of life in Vitiligo: a case controlled study]. Tunis Med 2006; 84: Parsad D, Pandhi R, Dogra S et al. Dermatology Life Quality Index score in vitiligo and its impact on the treatment outcome. Br J Dermatol 2003; 148: Kim dy, Lee JW, Whang SH et al. Quality of life for Korean patients with vitiligo: Skindex-29 and its correlation with clinical profiles. J Dermatol 2009; 36: Choi S, Kim DY, Whang SH et al. Quality of life and psychological adaptation of Korean adolescents with vitiligo. J Eur Acad Dermatol Venereol 2010; 24: INTRODUCTION 15

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19 2 Measurement properties of outcome measures for vitiligo: a systematic review C. Vrijman M.W. Linthorst Homan J. Limpens J.P.W. van der Veen A. Wolkerstorfer C.B. Terwee Ph. I. Spuls Accepted for publication in Archives of Dermatology

20 2 SUMMARY Objective: To summarize and critically appraise the evidence on the measurement properties of clinician, patient and observer reported outcomes, measuring any construct of interest in patients with all types of vitiligo. Data sources: Electronic databases PubMed from 1948, OVID EMBASE from 1980 and CINAHL (EBSCOhost) from1982 up to July 2011 were searched. Study selection: Two authors independently screened all records for eligibility. For inclusion, the study population had to include vitiligo patients in which outcome measures were developed or evaluated on its measurement properties. The initial search retrieved 1249 records of which 14 articles met the inclusion criteria. Data extraction: Characteristics of the included instruments, study population and the results of the measurement properties were extracted. The COSMIN 4-point checklist combined with quality criteria for measurement properties was used to calculate the overall level of evidence per measurement property of each instrument. Independent extraction and assessment was done by two authors. Data synthesis: Eleven different measurement instruments were identified. Strong evidence was found for a positive internal consistency of the Dermatology Life Quality Index. For other instruments the evidence of measurement properties was limited or unknown. Conclusions: Recommendations on the use of specific outcome measures for vitiligo should be formulated with caution as current evidence is insufficient due to a low number of studies with a poor methodological quality and unclear clinical relevance. To recommend on outcome measures for vitiligo further research on measurement properties of clinical relevant outcome measures for vitiligo according to COSMIN quality criteria is needed. 18

21 INTRODUCTION Vitiligo is a common depigmenting cutaneous disorder (0.5-1% of the world population) in both children and adults and with no predilection of gender or ethnicity. 1-3 Two different types of vitiligo can be clinically distinguished: segmental and non-segmental vitiligo. 4 In both types the melanocytes are destroyed, resulting in loss of pigment from circumscribed areas of the skin. To measure disease severity, efficacy of therapies, impact on quality of life and to make comparisons between treatment outcomes feasible, good outcome measures are necessary. Besides, it is essential to differ between outcomes used for clinical practice and outcomes used for research and to achieve consensus on scoring systems. 5;6 Ideally, these outcome measures are clearly defined and have clinical and biological significance and are characterized by good measurement properties like reliability, validity and responsiveness. 7;8 It is crucial to know the quality of the current existing measures and improving the indicated imperfections in outcome measures will finally lead to better decision making in patient care. Research of measurement properties in dermatology is in its infancy. To date, most research of outcome measures has been done for psoriasis and atopic dermatitis, although a validated tool for evaluating the methodological quality was lacking Recently, the COnsensus-based Standards for the selection of health status Measurement INstruments (COSMIN), an instrument to evaluate the methodological quality of studies on measurement properties, has been developed. 8;13;14 Using COSMIN it is now possible to critically appraise and compare the quality of these studies. For vitiligo, many different outcome measures are used. In a systematic review of randomized controlled trials of interventions for vitiligo up to 2009, approximately 90 different outcome measures were identified. 15 These outcome measures are poorly standardized and have a lack of consensus and uniformity. The consensus report from the Vitiligo European Task Force in 2007 showed that besides the current lack of consensus on definition, there is also a lack of uniformity in methods of assessment, which makes it generally impossible to compare the outcomes of different studies. 4 The aim of this systematic review is to summarize and critically appraise the evidence on the measurement properties of clinician, patient and observer reported outcomes, measuring any construct of interest in patients with all types of vitiligo. 2 outcome measures for vitiligo METHODS Search strategy A medical librarian (JL) with experience in conducting searches for systematic reviews, undertook a systematic search of the electronic databases PubMed from 1948, OVID EMBASE from 1980 and CINAHL (EBSCOhost) from1982 up to July 2011 to identify studies on measurement properties for scoring vitiligo. 19

22 2 PubMed was chosen rather than OVID MEDLINE, because the clinimetric filter used, was developed and validated in this database. 16 The search in PubMed and OVID EMBASE consisted of Subject Headings (MeSH, SH) and free-text words for vitiligo, a clinimetric filter (combined with the Boolean operator AND ) was used. This validated, sensitive, clinimetric filter was used for PubMed and a provisional translation of this clinimetric filter for EMBASE (Terwee, personal communication). Animal studies were excluded by double negation, i.e. by using NOT ( animals [MeSH Terms] NOT humans [MeSH Terms]). In CINAHL, we searched only for vitiligo in title and abstract (Table 1). Reference Manager software (version 12.0) was used to manage and de-duplicate all identified references. Eligibility criteria Inclusion criteria Studies evaluating any construct of interest were eligible. For inclusion, the study population had to include at least one of the types of vitiligo patients, i.e. segmental or non-segmental vitiligo. If only a part of the study population included vitiligo patients, the study was considered eligible as well. The instruments under study needed to be all clinician, patient or observer reported outcome measures. The aim of the included study had to be the development of a measurement instrument or the evaluation of one or more of its measurement properties. Studies that focus only on interpretability, e.g. the determination of minimal important change, were also considered to be eligible. Besides, the study had to be published as a full text original article and no restrictions regarding languages were made. Exclusion criteria Studies where the measurement instruments are used as an endpoint without studying the measurement properties were not considered eligible. Table 1. Search approach in PubMed, EMBASE and CINAHL. Search component 1 PubMed EMBASE CINAHL Vitiligo clinimetric search filter ( AND ) animal filter ( NOT ) vitiligo[mh] OR vitiligo[tiab] validated sensitive clinimetric filter 16 ( animals [mesh] NOT humans [mesh]) vitiligo/ or vitiligo. tw,kw,ot. provisional clinimetric filter (Terwee, personal communication) (animal.hw. or nonhuman/) not human/ [MH] vitiligo OR TX vitiligo 1 The general approach is (vitiligo AND clinimetric filter) NOT (animal filter). Abbreviations and Commands: [mh], MH, / = subject headings (i.e. MeSH-terms in MEDLINE); [tiab],.tw., TX = textwords (word in title and abstract);.ot.=original title words;.kw.=authorsupplied keywords;.hw. = heading word; ND= not done. For further explanation, see text. Nd Nd 20

23 Studies, in which two measurement instruments are compared to each other without a validation of one explicit instrument, were also considered not eligible because it is often unclear which instrument of the two compared instruments is validated in these studies. Studies, in which the instrument of interest was used in the validation process of another instrument, randomized controlled trials or other longitudinal studies in which indirect evidence for responsiveness might be found, were excluded. They were excluded because it is often difficult to interpret the evidence for validity or responsiveness provided in these studies as no hypotheses about the validity or responsiveness of the instrument of interest are formulated and tested in these studies. Selection Two authors (CV, MLH) independently screened initially all records on title and abstract in which a study was excluded if it did not refer to a study population of vitiligo patients, or did not study measurement properties. Full text copies of the selected articles were obtained and the reference lists of these articles were also screened for eligibility by both authors. The final selection was based on the assessment of the full-text articles by two independent authors as well. A study was included if the above described inclusion criteria were met. Disagreements were solved by discussion. If necessary a third independent author (PS) was consulted to reach consensus. Evaluation of methodological quality of the included studies The methodological quality analysis of the included studies was performed using the COSMIN 4-point checklist. 13 The measurement properties were divided over three domains: reliability, validity and responsiveness. 17;18 (etable 1) The COSMIN checklist consists of nine boxes with 5-18 items concerning methodological standards on how each measurement property should be assessed. Except sample size, each item was scored on a 4-point rating scale (i.e. poor, fair, good, excellent ). An overall methodological quality score of a study was determined for each measurement property separately, by taking the lowest rating of any item in a box ( worst score counts ). Methodological quality scores for different studies were rated separately and were not combined. Data extraction The following information was extracted from the included articles by two authors independently (CV, MLH): (1) characteristics of the included instruments, (2) characteristics of the included study population in which the measurement properties were assessed (number of patients, percentage of vitiligo patients in the study population, mean age, gender, setting, country, language) and (3) results of the measurement properties. Interpretability was extracted by information on floor or ceiling effects or minimal important change (MIC) or minimal important difference (MID) As there is no consensus of core domains for outcomes measures for vitiligo, the Food and Drug Administration (FDA) qualification of clinical outcome 2 outcome measures for vitiligo 21

24 2 assessments was used to categorize the outcome measures ( gov/drugs/newsevents/ucm htm, accessed November 2011). There is a differentiation of clinician reported outcomes (CRO), patient reported outcomes (PRO) and observer reported outcomes (ORO). CRO was defined as outcomes assessed or reported by physician or other clinician, PRO was defined as outcomes assessed or reported by patients and ORO was defined as outcomes reported by other observers than clinicians or patients, for instance assessed by a computer. Data synthesis quality assessment Besides the methodological quality of the studies, the quality of the measurement properties of included instruments was evaluated as well. The results of the measurement properties were rated with the quality criteria for measurement properties. 22 (etable 2) The overall evidence for separate measurement properties of the instruments was determined by combining the results of different studies adjusted for their methodological quality. The level of evidence was rated as strong, moderate, limited, conflicting or unknown as proposed by the Cochrane Back Review Group, with an additional weight for sample size since this was not used in the evaluation of the methodological quality of the studies. 23 (etable 3) RESULTS Results of the electronic literature search Figure 1 summarizes the selection process for all studies. The initial search retrieved 1249 records from the three databases searched. After exclusion of duplicates 1161 articles remained. After screening for eligibility on title and abstract, 19 records were selected of which the references yielded no additional publications. With full text 15 articles were identified that met the inclusion criteria. One article was additionally excluded as this article 24 was a duplicate of an earlier published original article. 25 Therefore, 14 articles remained for analysis. The main reasons for exclusion in the full-text selection are represented in Figure 1. No systematic reviews about measurement properties of scorings systems for vitiligo were found. Description of the included studies The 14 articles evaluating the measurement properties of 11 different instruments were published between 1996 and Characteristics of the included instruments are shown in Table 2 and characteristics of the included study populations are shown in Table 3. In four studies the study population consisted of vitiligo patients as well as patients with other skin diseases, whereas 10 studies had a study population consisting solely of vitiligo patients. The methodological quality according to the COSMIN checklist is summarized in Table 4. The results of the measurement properties are shown in etable 4 and Table 5 summarizes the evidence on the measurement properties of the different instruments. The following instruments were evaluated as described below. 22

25 Medline (n=521) Embase (n=419) Cinahl (n=309) 2 Articles retrieved by search strategy (n=1161) Articles selected based on title and abstract (n=19) Exclude duplicates (n=88) outcome measures for vitiligo Reference list (n=0) Articles selected based on full text (n=14) Main reason for exclusion: - Other skin diseases, e.i. non-vitiligo patients (n=1) - Studies not published as a full text original article (n=2) - Studies using the measurement instrument as an endpoint without studying the measurement properties (n=1) - Double publication (n=1) Articles included in review (n=14) : - Clinician reported outcomes (n=3) - Patient reported outcomes (n=8) - Observer reported outcomes (n=3) Figure 1. Flowchart of the search and selection. n = number of articles; i.e = id est (that is) Evaluated instruments for vitiligo Clinician reported outcomes Vitiligo European Task Force (VETF) assessment. The VETF assessment was evaluated on the measurement error. The evidence was rated as unknown since there was only one study 26 with a poor methodological quality. No information on the interpretability was found since there was no information reported regarding floor and ceiling effects or regarding minimal important change (MIC) or minimal important difference (MID). 23

26 Table 2. Characteristics of the included instruments. 2 Instrument Construct of interest Studies Clinician reported outcomes Vitiligo European Task Force (VETF)-assessment Extent of disease Stage of disease Spreading of disease Taieb et al Vitiligo Area Scoring Index (VASI) Surface of lesions Hamzavi et al Point counting Surface of lesions Aydin et al Patient reported outcomes Skindex-29 Health related Quality of life Nijsten et al Zghal et al Skindex-16 Health related Quality of life AlGhamdi et al Skindex-teen Health related Quality of life Smidt et al Dermatology life quality index score (DLQI) Health related Quality of life Aghaei et al Kent et al Patient Benefit Index (PBI) Benefit of therapy Augustin et al Pictorial Representation of Illness Measure (PRISM) Representation of illness and perception of suffering Rumpf et al Observer reported outcomes Digital image analysis system (DIAS) Surface of lesions Van Geel et al Image analysis technique Repigmentation of lesions Nugroho et al Fadzil et al 1 HRQoL= Health related quality of life 24

27 Description System which combines analysis of extent, stage of disease (staging) and disease progression (spreading). Extent is evaluated using the rule of 9. Staging is based on cutaneous and hair pigmentation in vitiligo patches and disease is staged 0-4 on the largest macule in each body region except hands and feet which are assessed separately and globally as one unique area. Assessment of spreading is based on Wood s lamp examination of the same largest macule in each body area. VASI=Σ(all body sites) [hand units] X [residual depigmentation] The body was divided into 5 separate and mutually exclusive regions: hands, upper extremities (excluding hands), trunk, lower extremities (excluding the feet) and feet. The face and neck areas were not included in the overall evaluation. One hand unit which encompasses the palm plus the volar surface of all the digits is approximately 1% of the total body surface area and was used as a guide to estimate the baseline percentage of vitiligo involvement of the body. For all affected hand units the extent of the residual depigmentation was estimated to the nearest of the following percentages: 0, 10%, 25%, 50%, 75%, 90% or 100%. Borders of vitiligo lesions are marked on a transparent sheet. This transparent grid set was superimposed to cover the entire lesion projection area randomly. The number of intersection hitting the lesions was counted. The total area of the lesion was estimated by multiplying 0.1 cm 2 by the number of points. 2 outcome measures for vitiligo HRQoL 1 questionnaire for skin disease: 29 questions in 3 domains (Emotions, Symptoms and Functioning) with a 5-point scale (total score range 0-100, 0=best quality of life, 100= worst quality of life) HRQoL questionnaire for skin disease: 16 questions in 3 domains (Emotions, Symptoms and Functioning) with a 5-point scale (total score range 0-100, 0=best quality of life, 100= worst quality of life) HRQoL questionnaire for adolescents with skin disease. 22 questions in 2 domains (Psychosocial functioning and Physical symptoms) with a 5-point scale. (total score not specified) HRQoL questionnaire: 10 questions with a 4-point scale (score 0-3) Total score 30 (0=best quality of life, 30=worst quality of life) Includes weighting of individual benefits by patients needs in the therapy of vitiligo. Needs prior to therapy (PNQ) and benefits achieved by therapy (PPQ) are converted to weighted index value, the PBI. PBI=Σ (PNQ/ΣPNQ)PBQ Self-administered measurement. Sheet of paper with a fixed disk at the bottom right hand corner representing the subject self. Individuals were asked to imagine that the paper represents his/her life as it is at the moment. A second disk is used to represent the disease and subjects are asked where to put the disk in his/her life at the moment. Outcome measure is the distance between the centers of the two disks, called self-illness separation (SIS). DIAS for surface measurement of vitiligo lesions. Digital photographs copied on a transparent sheet. The surface measurement of the transparent sheet is done with a simple image processing program in Matlab (The Math Works. Inc.3 Apple Hill Drive, Natick, MA , USA). This result in 3D lesions surface measurements. Objective digital skin image technique to monitor progression of repigmentation over shorter time period of 6 weeks. The technique is based on principal component analysis and independent component analysis which convert red, green and blue skin images into images that represent skin areas due to melanin and haemoglobin. 25

28 2 Table 3 Characteristics of the included study populations. % Gender Study Instrument N 1 vitiligo Mean age 3 (M/F) 4 Setting Country Language Clinician reported outcomes English 10 European countries % NR 2 NR Hospital VETFassessment Taieb et al, Pigment Cell Res /13 Hospital Canada English 47 (±12.7) (range 23-77) VASI % Hamzavi et al, Arch Dermatol % 31.6 (±17.7) NR Hospital Turkey English Point counting Aydin et al, Eur J Dermatol 2007 Patient reported outcomes NR NR Hospital Italy Italian 6% Skindex Nijsten et al, Dermatology 2009 Skindex % 38(±1) 31/29 Hospital Tunis French Zghal et al, Tun Med 2003 Saudi Arabia Arabic Cases: hospital Controls: population + hospital Cases: 172/166 Controls: 177/163 Cases: (±10.73) Controls: (±11.03) Skindex % AlGhamdi et al, Int J Soc Derm /109 Hospital USA English 15.3(±1.4) (range ) Skindex-teen % Smidt et al, Arch Dermatol 2010 DLQI % 28.3 (±11.09) 27/43 Hospital Iran Persian Aghaei et al, BMC Derm 2004 English United Kingdom DLQI % 46.6 (range 16-81) 150/464 Vitiligo society Kent et al, Clin Exp Derm 1996 PBI % NS NS Vitiligo society Germany German Augustin et al, Dermatology

29 PRISM % 41.8 (±10.6) 93/250 Vitiligo society Germany German Rumpf et al, Psychoher Psychosom 2004 Observer reported outcomes DIAS % 29.4 (range 15-51) 4/6 Hospital Belgium Dutch Van Geel et al, Eur J Dermatol % NR NR NS Malaysia Malay Image analysis technique Nugroho et al, IEEE % NR NR Hospital Malaysia Malay Image analysis technique Fadzil et al, J Med Engin Techn N=number of patients 2 NR= not reported 3 Mean age with ±standard deviation and/or range 4 M/F=male/female 2 outcome measures for vitiligo 27

30 2 Table 4. Methodological quality of each study per measurement property and instrument. Criterion validity Responsiveness Construct validity Translation Structural validity Content validity Measurement error Internal consistency Reliability Study Clinical reported outcomes Taieb, et al (VETF-assessment) poor Hamzavi, et al (VASI) fair Aydin, et al (point counting) fair fair Patient reported outcomes Nijsten,et al (Skindex-29) poor Zghal, et al (Skindex-29) poor Alghamdi, et al (Skindex-16) poor poor fair fair Smidt, et al (Skindex-teen) excellent fair poor excellent fair Aghaei, et al (DLQI) good good fair Kent, et al (DLQI) good poor Augustin, et al (PBI) poor poor Rumpf, et al (PRISM) poor Observer reported outcomes Van Geel, et al (DIAS) fair poor poor Nugroho, et al (Image analysis technique) poor Fadzil, et al (Image analysis technique) 28

31 Vitiligo Area Scoring Index (VASI). Criterion validity is the only evaluated measurement property of the VASI. The evidence for the criterion validity was rated as unknown as only one study 27 with a poor methodological quality was found. No information on the interpretability was found. Point counting. There is limited evidence for a positive reliability of the point counting method as one study 28 with fair methodological quality showed a correlation coefficient >0.70. No other measurement properties were evaluated. No information on the interpretability was reported. Patient reported outcomes Skindex-29. For the Skindex-29 the internal consistency and criterion validity were evaluated. For both measurement properties the evidence was rated as unknown as for both properties one study was found with a poor methodological quality. 29;30 No information regarding floor or ceiling effects or MIC or MID was found. Skindex-16. The internal consistency, content validity and construct validity were evaluated by one study. 31 For the internal consistency and content validity the evidence is unknown due to a poor methodological quality of the study. Limited evidence was rated for positive construct validity and positive results of the Arabic translation due to fair methodological quality of the study. No information on interpretability was reported. Skindex-teen. One study 32 evaluated the Skindex teen on internal consistency, reliability, content validity, structural validity and responsiveness. For the internal consistency, structural validity, reliability and responsiveness limited positive evidence was rated, while for content validity the evidence was rated as unknown due to a poor methodological quality of the study. No information on the interpretability was reported. Dermatology Life Quality Index (DLQI) score. The internal consistency and construct validity were evaluated for the DLQI. 25;33 Strong evidence was found for positive internal consistency, whereas moderate evidence was rated for positive construct validity. The evidence of a positive Persian translation was rated as limited due to a fair methodological quality of the study. No information on interpretability was found. Patient Benefit Index (PBI). There was one study 34 which evaluated both internal consistency and construct validity. For both measurement properties the evidence was rated as unknown since the methodological quality of the study was poor. Missing items were not clearly described while distributional characteristics of the PBI were well described. It showed a right skewed distribution with a mean of 1.03 and marked floor effects, particularly only few values above the threshold of 1 were observed (SD=1.13;median=0.61, IQR= n=711) with respect to all therapies. Consequently, only slight patient-defined benefit was attained for the majority of patients under therapy. Pictorial Representation of Illness Measure (PRISM). The construct validity of the PRISM was evaluated in one study. 35 Since the methodological 2 outcome measures for vitiligo 29

32 Table 5. Quality of measurement properties per instrument 2 Instrument Internal Consistency Reliability Measurement Error Content Validity Clinician reported outcomes VETF-assessment na na? na VASI na na na na Point counting na + na na Patient reported outcomes Skindex-29? na na na Skindex-16? na na? Skindex-teen + + na? DLQI +++ na na na PBI? na na na PRISM na na na na Observer reported outcomes DIAS na na? na Image analysis technique na na na na na = no information available Rating: +++ or --- = strong evidence positive/negative result, ++ or -- = moderate evidence positive/negative result, + or - = limited evidence positive/negative result, +/- = conflicting evidence,? = unknown, due to poor methodological quality, na = no information available quality of the study was poor, the evidence for construct validity was rated as unknown. No other measurement property was evaluated and no information on interpretability was found. Observer reported outcomes Digital Image Analysis System (DIAS). For the DIAS the measurement error and criterion validity were evaluated by van Geel et al. 36 For the measurement error fair methodological quality was found but no MIC was defined. As a result, the evidence for the quality of the measurement error was rated as unknown as well as the evidence for the criterion validity, due to a poor methodological quality. No information on interpretability was found. Image analysis technique. Two studies evaluated the construct validity of the image analysis technique. 37;38 However, the evidence of the construct validity was rated as unknown since both studies have a poor methodological quality. No information on the interpretability was found. 30