CLINICAL AND PATIENT REPORTED OUTCOMES IN VITILIGO May Linthorst Homan
Clinical and patient reported outcomes in vitiligo ISBN: 978-94-6182-152-2 Layout and printing: Off Page, www.offpage.nl 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.
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 12.00 uur door May Wijna Linthorst Homan geboren te Arnhem
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
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-36 117 Skindex-29 125 Bibliografie 129 Curriculum Vitae 133 Dankwoord 137
1 GENERAL INTRODUCTION AND AIMS OF THE THESIS
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. 10 1 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. 15-25 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
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). 34-44 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
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. 46-48 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-29 50 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
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
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of male and female muslim patients in Iran. Gend Med 2006; 3: 124-30. 58. Aghaei S, Sodaifi M, Jafari P et al. DLQI scores in vitiligo: reliability and validity of the Persian version. BMC Dermatol 2004; 4: 8. 59. Zghal A, Zeglaoui F, Kallel L et al. [Quality of life in dermatology: Tunisian version of the Skindex-29]. Tunis Med 2003; 81: 34-7. 60. Belhadjali H, Amri M, Mecheri A et al. [Vitiligo and quality of life: a case-control study.]. Ann Dermatol Venereol 2007; 134: 233-6. 61. Mechri A, Amri M, Douarika AA et al. [Psychiatric morbidity and quality of life in Vitiligo: a case controlled study]. Tunis Med 2006; 84: 632-5. 62. 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: 373-4. 63. 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: 317-22. 64. 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: 524-9. 1 INTRODUCTION 15
3 PUNCH DIGITAL IMAGE ANALYSIS VERSUS CLINICAL ASSESSMENT TO EVALUATE REPIGMENTATION AFTER GRAFTING IN VITILIGO M.W. Linthorst Homan A. Wolkerstorfer M.A.G. Sprangers J.P.W. van der Veen J Eur Acad Dermatol Venereol. 2012 May 23. doi:10.1111/j.1468-3083.2012.04568.x.
3 SUMMARY Background: Repigmentation as a treatment outcome in vitiligo is not assessed in a standard way, making results of clinical trials hard to compare. Different types of repigmentation assessments after punch grafting have not been compared so far. Objective: To compare assessments of repigmentation by a digital image analysis system (DIAS) with those of clinical observers and patients after punch grafting for vitiligo. Methods: One vitiligo patch was selected in each patient (n=21). This patch was treated with the punch grafting technique. The grade of repigmentation (%) after 3 months was assessed by 1) DIAS; 2) 3 clinical observers and 3) the patient, scoring the grade of repigmentation on photographs. Physicians and patients also evaluated the global result on a 7-point scale. Results: There was an almost perfect agreement between the three clinical observers and the DIAS (ICC 0.83). As expected, variation was found between the clinical observers. Patients scores showed a moderate agreement with the DIAS (ICC 0.49) and a poor agreement with the physicians (ICC 0.28). Overall, the patients were more satisfied with the results than the physicians. Conclusions: Whereas the results of the digital and clinical assessments were comparable, patients ratings diverged. The DIAS can overcome the inevitable differences between observers, which are intrinsic to a visual grading method, and is advisable for clinical trials on vitiligo to objectively assess repigmentation in limited lesions. 44
INTRODUCTION Vitiligo is a chronic skin disease characterised by the development of depigmented macules, due to loss of melanocytes. Several treatment options are available; nonsurgical (e.g. local immunosuppressive treatments, phototherapy) and surgical therapies (e.g. punch grafting). 1 Reliable outcome measures are important to compare studies and to assess the changes over time. A variety of scoring systems is used to evaluate the treatment outcome in terms of repigmentation, 2 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. An objective measurement tool of repigmentation, such as a digital image analysis system (DIAS), 3-13 can overcome some of these limitations. To date DIAS has not been evaluated for the assessment of the outcome after punch grafting. The aim of this study was to compare assessments of repigmentation by computerised measurement (DIAS, objective scoring), different clinical observers (clinical scoring) and patients assessment as treatment outcome after punch grafting in vitiligo patients. MATERIALS AND METHODS 3 DIGITAL IMAGE ANALYSIS VS. CLINICAL ASSESSMENT Patients Consecutive adult vitiligo patients (18 years or older) of the Netherlands Institute of Pigment Disorders (NIPD), who were scheduled for punch grafting were invited to participate in the study. An informed consent form was signed before inclusion. As punch grafting is a routine treatment in the NIPD and treatment was given as part of routine medical care, approval by the local research ethics committee was not needed. Treatment In each patient one vitiligo patch was selected. This patch was treated with the punch grafting technique. 5 Prior to treatment and after three months, clinical photographs of the treated lesion were taken with a Canon Power Shot G6 digital camera. Conditions were standardised throughout the study, including the room, lighting, background and distance between camera and patient. Digital Image Analysis Objective measurement of the grade of repigmentation was performed with a digital image analysis system (DIAS). To assess the size of the vitiligo lesion, the contours of the lesion were copied on a transparent sheet before and after treatment. This technique has the advantage that the curvature of the body surface will not bias the measurement. Afterwards these sheets were scanned using a 45
3 predefined resolution. DIAS involved an application based on Matlab (Math works, Inc, Natik, MA, USA). By comparing pre- and post-treatment pictures we computed the relative surface showing repigmentation expressed as percentage of the selected vitiligo patch. Clinical assessment Three different observers (all dermatologists) evaluated the percentage of repigmentation on a 10-point scale (1-10%, 11-20%...-91-100%) by comparing the photographs on a computer monitor before and after treatment. The observers were additionally asked to give their opinion about the result of treatment on a 7-point scale (excellent - very good good - not good/ not bad - rather poor - poor - very poor). Patients assessment Patients were asked to assess the degree of repigmentation on a 10-point scale (1-10%, 11-20%...-91-100%) by comparing their own photographs, before and after treatment, on a computer monitor. The patients were additionally asked to give their opinion about the result of treatment on a 7-point scale (excellent - very good good - not good/ not bad - rather poor - poor - very poor). Statistical analysis The scores of digital image analysis, clinical and patients assessment were compared and correlations were calculated. To measure the inter-observer reliability between the three physicians and patients, we used the intra-class correlation (ICC) coefficient. We used the absolute agreement definition for all ICC models. 14 ICC values of 0.80 1.0, 0.60 0.80, and 0.40 0.60 are generally considered to indicate almost perfect, substantial, or moderate agreement, respectively. 15 We needed 21 photographs of patients with vitiligo to estimate the ICC with 0.15 accuracy and 95% certainty around the assumed point estimate of ICC= 0.80. All analyses were done using a Statistical Package for Social Sciences (SPSS) database, the SPSS for Windows version 12.01. RESULTS Patients Twenty-one adult patients with vitiligo (8 males/13 females) were included in this study. The mean age was 44.3 years (SD 14.7, Median 45.3). The body sites affected varied, including trunk (28.6%), leg (19.1%), feet (14.3%), arm (14.3%), hand (9.5%), wrist (9.5%) and face (4.8%). Digital, clinical and patients assessment The repigmentation scores provided by the DIAS, observers and patients as well as the scores of the 7-point scale are displayed per patient in Table 1. Agreement 46
Table 1. Scores of repigmentation (%) and 7-point scale. NA Not available Opinion patient Opinion observer 3 Opinion observer 2 Opinion observer 1 % DIAS % observer 3 % observer 2 % observer 1 % patient Gender Bodysite 1 F Arm 0-10% 0-10% 0-10% 0-10% 0-10% Very poor Very poor Poor Poor Not goodnot bad 2 F Hand 31-40% 0-10% 0-10% 0-10% 0-10% Very poor Rather poor Very poor 3 M Face 0-10% 0-10% 0-10% 0-10% 0-10% Very poor Very poor Very poor Rather good Not goodnot bad Rather good Rather poor Not goodnot bad 4 F Trunk NA 51-60% 21-30% 11-20% 31-40% 5 F Leg 61-70% 51-60% 31-40% 0-10% 41-50 Rather good Good Poor Very good Poor Poor Rather poor Not goodnot bad 6 M Arm 0-10% 21-30% 11-20% 0-10% 0-10% Not good -not bad 7 M Hand 11-20% 0-10% 0-10% 0-10% 0-10% Poor Poor Very poor 8 F Arm 0-10% 0-10% 0-10% 0-10% 0-10% Very poor Very poor Very poor Rather good 9 F Trunk NA 91-100% 81-90% 71-80% 91-100% Rather good Very good Rather good good 10 F Arm NA 21-30% 0-10% 0-10% 11-20% Rather poor Poor Very poor Rather good Good Not goodnot bad 11 F Arm 71-80% 51-60% 21-30% 11-20% 51-60% Rather good Rather good 12 F Trunk 51-60% 0-10% 0-10% 0-10% 0-10% Very poor Very poor Very poor Rather good 13 M Foot NA 11-20% 0-10% 0-10% 0-10% Poor Very poor Very poor Rather poor 14 F Leg 81-90% 71-80% 51-60% 0-10% 91-100% Rather good Good Poor good 15 M Trunk 71-80% 61-70% 31-40% 21-30% 51-60% Rather good Good Rather good Very good 16 M Foot 0-10% 0-10% 0-10% 0-10% 0-10% Very poor Very poor Very poor Poor Poor Good Not goodnot bad 17 F Trunk 41-50 21-30% 11-20% 0-10% 31-40% Rather poor Not goodnot bad 18 F Trunk 21-30% 11-20% 0-10% 0-10% 11-20% Poor Very poor Poor 19 M Leg 11-20% 51-60% 31-40% 0-10% 11-20% Rather good Good Very bad good 20 M Leg 0-10% 21-30% 0-10% 0-10% 0-10% Rather poor Very poor Very poor Poor 21 F Foot 0-10% 11-20% 0-10% 0-10% 0-10% Rather poor Very poor Very poor Rather poor 3 DIGITAL IMAGE ANALYSIS VS. CLINICAL ASSESSMENT 47
3 between clinical observers and DIAS was almost perfect for observers 1 and 2 (ICC 0.90 and 0.85 respectively), but moderate for observer 3 (ICC 0.47). Overall, the agreement between the three clinical observers combined (average rating) and DIAS was almost perfect (ICC 0.83) (Table 2). Patients on the other hand scored the degree of repigmentation in general higher than did the physicians or the DIAS (Table 1). Patients scores showed a moderate agreement with the DIAS (ICC 0.49) and a poor agreement with the physicians (ICC 0.28). Overall, the patients were more satisfied with the results than the physicians. For example, seven patients rated the change as very good and good whereas two of the three observers did not endorse these two top categories. DISCUSSION In this study we compared an objective digital assessment system with the more subjective assessment by physicians and patients of repigmentation after punch grafting for vitiligo. We found an almost perfect agreement between the clinical observers and the DIAS. However, there was a substantial variation among the clinical observers, a finding that is common for visual assessment. Consequently, clinical observers should be trained to calibrate their scoring of repigmentation. Conversely, DIAS does not introduce inter-rater and intra-rater observer variability. It is therefore a good objective assessment of repigmentation in vitiligo patches, thus enabling reliable cross-treatment and cross-study comparisons. DIAS has some limitations though. Firstly, on curved body surfaces, the DIAS has a certain degree of distortion resulting from the sloped surface, unless a transparent sheet is used to trace the lesion s contours, which we did. Furthermore, perifollicular repigmentation or other complex patterns are difficult to catch by using boundary tracing system. Moreover, for the evaluation of widespread vitiligo lesions DIAS is time consuming. For this treatment the VASI score 16 may be more appropriate. Furthermore, observers have to be trained to be able to use the DIAS which includes a learning curve. Without adequate training, DIAS might be subject to some intra-and interrater variability as well. 17 Finally, as the technique is time consuming, it is less feasible in daily practice. A limitation of our study is that we did not explore other, more complex, DIAS options (e.g. analysis of colour or ultraviolet photographs). These options could also overcome the difficulty in analyzing vitiligo areas of larger extension. In our study, patients scored the degree of repigmentation generally higher than the physicians or the DIAS, which may reflect wishful thinking and is in line with their higher treatment satisfaction as compared to physicians. It is important to include the patients assessment of the treatment outcome, because their satisfaction is the most important goal of the treatment. For atopic dermatitis a few self-assessment scoring systems have been developed, for example the patient oriented SCORAD. 18 These scoring systems can be used in daily clinical practice, 48
Table 2. ICC: Intraclass Correlation Coefficients, C.I: Confidence Interval ICC 95% C.I. Observer 1 vs DIAS 0.90 0.73 0.96 Observer 2 vs DIAS 0.85 0.63 0.94 Observer 3 vs DIAS 0.47 0.06 0.75 (Observer 1, 2 and 3) vs DIAS¹ 0.83 0.64 0.93 Patients vs DIAS ² 0.49 0.09 0.75 Patients vs (Observer 1, 2 and 3) ² 0.28-0,16 0.63 = model 3 (two-way fixed), single measure ¹ = model 2 (two-way random), single measure ² = model 1 (one-way random), single measure e.g. to screen patients for their need for (additional) care and in the context of research. For vitiligo, self-assessment instruments for treatment outcome have not been developed yet. Other methods of repigmentation scoring, such as point counting 19 have been proposed and may provide a simple alternative to measure the vitiligo surface area. Further research is needed to compare this method with DIAS. Although it was not an objective of our study to evaluate percentage of repigmentation after punch grafting, we noticed a remarkable variation of repigmentation. This is partly a result of the inclusion of locations that are known to react poorly to treatment, such as the feet. Moreover, intrinsic patient-related factors may be involved. 3 DIGITAL IMAGE ANALYSIS VS. CLINICAL ASSESSMENT From this study we can conclude that: 1. Clinical scoring in general is as adequate as digital image analysis, though interobserver variability can be great and training should be given to observers in the context of clinical trials. 2. Patients assessments of repigmentation differ from those of clinicians and are more positive as is their satisfaction with treatment (compared to those of physicians). 3. Digital image analysis is the most objective measure of repigmentation and for this reason could be regarded as the gold standard for assessing repigmentation in clinical research. Since the technique is complex and laborious, it is only feasible for monitoring limited areas of vitiligo. Acknowledgement: We thank B.L. Kallimanis King and Robert Lindeboom for the help with the statistical analyses of the data. 49
3 REFERENCE LIST 1. Njoo MD, Westerhof W. Vitiligo. Pathogenesis and treatment. Am J Clin Dermatol 2001; 2: 167-81. 2. Whitton ME, Pinart M, Batchelor J et al. Interventions for vitiligo. Cochrane Database Syst Rev 2010; CD003263. 3. 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: 150-5. 4. 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: 595-8. 5. Boersma BR, Westerhof W, Bos JD. Repigmentation in vitiligo vulgaris by autologous minigrafting: results in nineteen patients. J Am Acad Dermatol 1995; 33: 990-5. 6. Guerra L, Capurro S, Melchi F et al. Treatment of stable vitiligo by Timedsurgery and transplantation of cultured epidermal autografts. Arch Dermatol 2000; 136: 1380-9. 7. 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: 581-5. 8. 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: 1203-8. 9. 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: 23-9. 10. 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. 2012 Jun; 26(6): 690-5. 11. 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: 910-7. 12. 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: 133-7. 13. 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: 1105-11. 14. Shrout PE, Fleiss JL. Intraclass correlations: uses in assessing rater reliability. Psychol Bull 1979; 86: 420-8. 15. Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics 1977; 33: 159-74. 16. 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: 677-83. 17. Jagoe R, Steel JH, Vucicevic V et al. Observer variation in quantification of immunocytochemistry by image analysis. Histochem J 1991; 23: 541-7. 18. Stalder JF, Barbarot S, Wollenberg A et al. Patient-Oriented SCORAD (PO-SCORAD): a new self-assessment scale in atopic dermatitis validated in Europe. Allergy 2011; 66: 1114-21. 19. Aydin F, Senturk N, Sahin B et al. A practical method for the estimation of vitiligo surface area: a comparison between the point counting and digital planimetry techniques. Eur J Dermatol 2007; 17: 30-2. 50
4 A RANDOMISED COMPARISON OF EXCIMER LASER VERSUS NARROW-BAND ULTRA VIOLET B PHOTOTHERAPY AFTER PUNCH GRAFTING IN STABLE VITILIGO PATIENTS M.W. Linthorst Homan Ph. I. Spuls L. Nieuweboer-Krobotova J. de Korte M.A.G. Sprangers J.D. Bos A. Wolkerstorfer J.P.W. van der Veen J Eur Acad Dermatol Venereol. 2012 Jun;26(6):690-5.
4 SUMMARY Background: Ultraviolet radiation following punch grafting may stimulate the migration of melanocytes from the grafts into the vitiliginous skin, thereby increasing the rate of repigmentation. We compared the effects of the 308-nm xenon chloride excimer laser (EL) versus Narrow-Band Ultraviolet B (NB-UVB) after punch grafting in patients with vitiligo. Objective: The aims of this study were to evaluate 1) repigmentation (%), 2) treatment satisfaction and 3) patient preferences for EL versus NB-UVB therapy after punch grafting in vitiligo. Methods: Fourteen patients were treated with the punch grafting technique on two symmetrical vitiligo patches. Starting 1 week after the punch grafting, the vitiligo patches were treated twice a week during 3 months, with EL on one side and with NB-UVB on the other side. Repigmentation (%) was measured by a digital image analysis system. Patients satisfaction with and preference for treatment were also assessed. Results: Whereas both treatment modalities induced repigmentation, no statistically significant difference was found in grade of repigmentation after 3 months. With EL, 71.4% lower cumulative dose was reached. Patients were significantly more satisfied with NB-UVB and preferred it over EL. Conclusions: The choice between EL and NB-UVB cannot solely be based on repigmentation, but rather on other factors, such as patients preferences. However, given the lower UV dose of EL, we recommend its use in vulnerable populations, such as small children and patients with sun-damaged skin with a history of long-term UVB treatment. 54
INTRODUCTION Vitiligo is a common skin disorder, characterized by the appearance of milky white maculae, due to a loss of melanocytes. 1 Non-surgical and surgical therapies are available for vitiligo. Surgical therapies can be considered for stable vitiligo patches that are resistant or respond unsatisfactory to non-surgical therapies. In the Netherlands Institute for Pigment Disorders (NIPD) we routinely use the autologous punch grafting technique as a surgical therapy. This technique is relatively simple and has shown to be effective for stable localised and generalized vitiligo. 2 After punch grafting, we treat our patients with narrow band ultraviolet B (NB-UVB) to stimulate further repigmentation. Monotherapy with NB-UVB was introduced in 1997 as an effective treatment for generalized vitiligo, with better repigmentation and fewer adverse effects than topical photo chemotherapy (PUVA). 3 In 2002, the 308-nm xenon chloride excimer laser (EL) was introduced as a treatment for vitiligo. 4-14 In vitiligo EL treatment was compared with NB-UVB treatment. 15;16 A higher efficacy of EL was found as it produced more rapid repigmentation. Another advantage of EL over NB-UVB is selective targeting which spares non-affected skin and reduces the cumulative UV dose. Punch grafting followed by either EL 17 or NB-UVB 18 was found to be effective in inducing repigmentation in vitiligo patients. In these studies, repigmentation was assessed by independent investigators who rated photographs of the treated skin. To our knowledge, no studies have compared the efficacy of EL versus NB-UVB after punch grafting in vitiligo patients. The aim of this study was to evaluate percentage of repigmentation, treatment satisfaction and patient preferences regarding EL versus NB-UVB therapy as a post-treatment regimen in vitiligo patients who underwent punch grafting. 4 EXCIMER LASER VS NB-UVB AFTER PUNCH GRAFTING METHODS We employed a prospective, single blinded, randomized within-patient controlled study design. The trial was approved by the local research ethics committee and was recorded in the trial register (www.trialregister.nl, NTR789). Patients Consecutive adult patients (18 years or older) attending the NIPD, with stable generalized vitiligo were invited to participate in the study. Stable vitiligo was defined as no progression of existing lesions or no appearance of new lesions during the previous 6 months, absence of the Koebner phenomenon and a positive minigrafting test. 19 An additional inclusion criterion was the presence of two symmetrical vitiligo patches on the extremities or the trunk, to reduce exposure to sunlight Exclusion criteria included a history of hypertrophic scarring and/or keloid, allergic/phototoxic reaction (Lidocaine, Tegaderm, Suture strips, and sunlight), a personal or family history of skin cancer or photosensitivity and/or 55
photo toxicity disorders, Skin type I (according to Fitzpatrick classification I-VI), 20 pregnancy, use of medications known to cause photosensitivity and/or photo toxicity and other skin diseases that would impair evaluation of repigmentation or local immunosuppressive treatment within 6 weeks prior to enrolment. 4 Treatment Selection of treatment sites and randomization In each patient we selected two treatment areas that were similar in size, colour and body location. The site of treatment with EL and NB-UVB was randomly assigned with a randomization computer program (Graphpad Software Inc., La Jolla, CA, USA). Treatment allocation was blinded for the physicians, not for the patients. Punch grafting The two lesions were treated with punch grafts in the same distribution pattern. The punch grafting method consists of harvesting small 1.5 mm full thickness punch grafts from normally pigmented donor sites (such as hip, buttocks and outer thigh). These were subsequently transplanted to the two depigmented acceptor sites in which similar punches were taken and removed. The procedure was performed using local infiltration anaesthesia. The grafts were placed 5 mm apart and were covered with suture strips and a transparent adhesive tape (Tegaderm) during 7 days. The donor site was also covered with a transparent adhesive tape (Tegaderm). Lesions treated on the extremities were covered with an elastic bandage for 1 week to give compression and fixation on the grafted site. Post-treatment phototherapy After 7 days, the grafted areas were irradiated during 3 months with EL at one side and NB-UVB on the other side: twice a week, on non-consecutive days amounting to 24 treatments. Patients started their treatment at the beginning of September and the last treatment was given in July. 308-nm EL A 308-nm xenon chloride gas EL (Talos ; Wavelight Laser Technology AG, Erlangen, Germany; 308 nm, 10 or 20 mm spot size, 200 mw/ cm 2, 60 ns, 200 Hz) was used. The initial dose was 0.05 J/ cm 2, independent of the skin type. Sequential doses had an increment according to the manufacturer s guidelines, with a range of 0.025-0.10 J/ cm 2. Doses were not increased if there was erythema lasting for 24 hours or more. If painful erythema, such as burning, pain, or blistering developed, the treatment was withheld until this erythema disappeared. The subsequent dose was decreased by 0.05 J/ cm 2. Possible presence of painful erythema was checked by the treating dermatologist. The cumulative UV dose was measured at the end of the treatment. The eyes of the patient and nurse were protected by UV-blocking goggles during the treatment session. 56
UVB (311nm) phototherapy (NB-UVB) The treated vitiligo patches were locally irradiated based on our own guidelines for NB-UVB in vitiligo patients of the NIPD. The initial irradiation dose was 0.25 J/cm 2, independent of the skin type. Irradiation dose was increased by 50 mj/cm 2 each subsequent treatment when minimal erythema occurred in the lesions, which means an erythema vanishing within 24 hours. If the erythema was lasting for 24 hours or more the dose was held constant for the subsequent treatment. If painful erythema developed, the treatment was withheld until the painful erythema was relieved and the subsequent dose was decreased by 20%. The cumulative UV dose was measured at the end of the treatment. The eyes were protected by UVblocking goggles during the treatment. For both treatment modalities, the patients were asked to protect their skin from sun exposure during treatment and to apply sunscreen in case sun exposure of the treated skin was unavoidable. Assessment of therapy outcomes Repigmentation. Clinical photographs of the treated lesions were taken with a Canon Power Shot G6 digital camera, prior to punch grafting and after every six treatments with EL and NB-UVB. Conditions were standardized throughout the study, including the room, lighting, background and distance between camera and patient. Objective measurement of the grade of repigmentation was performed by a digital image analysis system. To assess the size of the vitiligo lesion the contours of the lesion were copied on a transparent sheet before and after treatment. This technique has the advantage that the curvature of the body surface will not bias the measurement. Afterwards these sheets were scanned using a predefined resolution. Digital image analysis involved an application based on Matlab (Math works, Inc, Natik, MA, USA). By comparing pre- and post-treatment pictures we computed the relative surface showing repigmentation expressed in percentages. Treatment satisfaction. A study-specific questionnaire consisting of two questions on satisfaction with each treatment modality: (i) How do you appreciate the results of punch grafting with the EL (or NB-UVB) and (ii) Would you recommend this treatment to other patients? Answers were given on a 7-point scale running from very good to very poor, and yes, certainly to no, certainly not respectively. Administration took place after 3 months treatment. Patient preference. A study-specific questionnaire consisting of two questions on preference: (i) If you will be treated again with punch grafting, which treatment do you prefer? and (ii) Can you report the reason for this preference? Optional answers to the first question were: EL, NB-UVB, I don t know, no preference. Optional answers to the second question were: more repigmentation, a faster rate of repigmentation, no colour difference, faster treatment, other. 4 EXCIMER LASER VS NB-UVB AFTER PUNCH GRAFTING 57
4 Statistical Analysis On the basis of the results of a pilot study, 17 including 20 patients, we estimated that EL would lead to 15% more repigmentation after 3 months than NB-UVB. A sample size of 16 patients would have a power of 80% with of 0.05 to detect this difference, assuming a standard deviation of 20%. Paired Student s t-test was used for the statistical evaluation of the differences in percentage of repigmentation. The Wilcoxon signed ranks test was used for the difference in patient satisfaction between the two treatment modalities. All analyses were conducted using SPSS (for Windows version 12.01; SPSS Inc., Chicago, IL, USA). The level of significance was set at P<0.05. RESULTS Patient characteristics A total of 16 patients were included in the study. Two of these patients did not finish the study (after 8 and 13 treatments) because of private problems unrelated to the study. These patients were not included in the statistical analysis. One patient only completed 21 out of the 24 treatments and another patient completed 22 treatments because of health problems unrelated to the vitiligo treatment. These patients were included in the statistical analysis. All participants gave informed consent. The 14 patients suitable for analyses consisted of nine female and five male patients, with a mean age of 44.2 years (SD 16.4, median 47.2) (Table 1). None of the patients experienced painful erythema during therapy and 3 months after the EL and NB-UVB. Repigmentation The mean degree of repigmentation attained after EL treatment was 31% compared to 38% for NB-UVB treatment [t (df = 13) = 2.11; P<0.06]. More than 75% repigmentation was obtained in two patients after EL versus three patients after NB-UVB. The cumulative UV dose for lesions treated with EL was 7.3 + 3.5 J/cm² and Table 1. Patients characteristics Gender Age Disease duration Skin type Male Female Median SD 1-5 years > 10 years I-III IV-VI N=14 % 5 9 47.2 16.4 4 10 4 10 35.7 64.3 28.6 71.4 28.6 71.4 58
for NB-UVB 25.6 + 11.6 J/cm². With EL 71.4% lower cumulative dose was reached (Table 2). For both treatment modalities, there was no further pigmentation of the punch grafts on the feet (n=3). Treatment satisfaction Seven patients (50%) reported to be satisfied with the results of EL treatment, whereas 11 (79%) patients indicated to be satisfied with the results of NB-UVB treatment [z (df=13)= 2.41; P=0.02]. Patients were found to be comparable with respect to recommending a treatment modality to another patient: eight patients vs. nine patients would recommend treatment with EL vs. NB-UVB. Moreover, three patients would possibly recommend either modality whereas two patients were not able to make a choice. Finally one patient would not recommend EL. Patient preference Seven patients (50%) preferred NB-UVB to EL because of more and more rapid repigmentation while two patients (14.3%) preferred EL because it was less time consuming. Five patients did not have a preference for treatment (35.7%). DISCUSSION To our knowledge, this is the first randomized controlled trial of EL versus NB-UVB treatment after punch grafting in vitiligo patients. Contrary to our expectation, EL did not result in a higher degree of repigmentation than NB-UVB, but rather led to comparable results. Interestingly patients favoured the NB-UVB treatment as they were more satisfied with it and preferred it over EL. Our results run counter to two previous studies that compared EL with NB-UVB in vitiligo patients who did not undergo punch grafting. In a group of eight vitiligo patients, Hong et al 15 found that EL was more effective than NB-UVB as it produced more rapid and profound repigmentation. Another study comparing EL with NB-UVB in 21 patients, also found that EL was more effective because of faster repigmentation. 16 In these studies, physicians assessed repigmentation based on clinical examination and evaluation of photographs. Conversely, we used a digital image analysis system, which is a more objective and reliable scoring method, perhaps explaining, in part, the difference in results. We noticed a remarkable dispersion of repigmentation irrespective of the type of phototherapy. This is partly a result of the inclusion of locations that are known to react poorly, such as the feet. However, it also indicates that intrinsic patientrelated factors may be more important than post-treatment procedures for the results of punch-grafting in vitiligo as was suggested recently. 21 As it is known that stability is a lesion-specific phenomenon in many patients, the area based variable status of stability may account for some variation in matched pairs. The used treatment doses merit attention. We treated our patients according to the NIPD guidelines and started with an initial dose of 0.25 J/cm² for the 4 EXCIMER LASER VS NB-UVB AFTER PUNCH GRAFTING 59
4 NB-UVB and 0.05 J/ cm² for EL. These dosages are within the wide range reported in the literature. For NB-UVB therapy initial doses range from 0.10 J/cm²-0.74 J/ cm² or 70% of the minimal erythema dose (MED). 3;14-16;22-26 For EL, initial doses are much lower and range from 0.05 J/ cm²- 0.60 J/ cm², depending on the body site, or 75% the MED. 4;5;7-10;12;14-16 Whereas we used the lowest reported initial dose of EL, we found this was warranted because most patients reported a mild shortlived erythema on the treatment day on both treated sites. Consequently, the comparable repigmentation induced by EL was achieved by a lower cumulative dose, i.e. 71.4% less than that of NB-UVB treatment. The choice for either EL or NB-UVB cannot be made on the percentage of repigmentation but needs to be based on other factors, such as patients preferences, cumulative dose, availability, ease of administration and costs. NB-UVB is the preferred choice of patients, and it is more feasible, less time consuming and cost-effective. However, the cumulative dose is substantially higher than that of EL, and it may affect surrounding tissue possibly resulting in long-term side effects, such as increased carcinogenicity. As we lack insight into Table 2. Treatment outcomes Repigmentation After excimer laser (%) Repigmentation After NB-UVB (%) Gender M/F Age Treated lesion Skin type (II-VI) 1 F 18,5 Arms V 84 95 2¹ F 18,8 Trunk IV 82 95 3 F 48,9 Arms IV 56 53 4 F 52,9 arms IV 11 17 5 M 37,9 Feet IV 1 5 6² F 63,8 Legs IV 65 93 7 F 42,7 Legs II 2 44 8 M 54,1 Trunk V 59 51 9 M 45,5 Feet IV 6 4 10 F 62,1 Trunk III 22 39 11 F 27,1 Trunk II 15 12 12 M 69,1 Legs II 17 19 13 M 50,0 Legs IV 5 7 14 F 27,0 Feet IV 5 4 Mean (SD) ¹ patient with 21 treatments, ² patient with 22 treatments 60
the prevalence and severity of long-term side effects of vitiligo treatment with EL or NB-UVB, future studies are needed on this point. A number of limitations of this study merit attention. Firstly, the sample size is relatively small. Our sample size analysis indicated that inclusion of 16 patients would be sufficient to achieve significant differences. However, as two patients dropped out of the study prematurely, we have results of 14 patients instead of the intended 16. This number appeared to be sufficient to draw clear conclusions as the percentage of repigmentation of EL was not higher but lower than that of NB-UVB, albeit insignificantly. More importantly, we found statistically significant differences between the treatment modalities with respect to patients treatment satisfaction. Secondly, this study only focused on short-term effects of 24 treatments. We therefore have no information on the effects of longer treatments or on long-term follow-up effects. Our study has a number of strengths. The within-patient study design where EL and NB-UVB were randomly allocated to skin patches at either side of the body, allowed for direct comparison between the two treatment modalities. An additional major strength is the objective and reliable assessment of the percentage of Cumulative dosis EL (J/cm2) Cumulative dosis NB-UVB (J/cm2) Difference in cumulative dosis (J/cm2) Patient Satisfaction EL Patient Satisfaction NB-UVB Treatment Preference 9.45 29.47 20.02 Very good Very good EL 5.69 16.73 11.04 Rather good Very good None 2.30 8.52 6.22 Rather good Very good NB-UVB 3.29 14.41 11.12 Not good- Not bad Good None 13.97 49.31 35.34 Bad Rather good NB-UVB 10.67 33.24 22.57 Rather good Good NB-UVB 8.91 37.75 28.84 Bad Good NB-UVB 2.94 13.23 10.29 Very good Very good None 10.50 36.17 25.67 Bad Bad None 4.41 14.11 9.70 Good Good None 5.20 23.68 18.48 Not good- Not bad Not good- Not bad NB-UVB 10.25 34.05 23.80 Good Good EL 6.56 23.83 17.27 Rather bad Rather good NB-UVB 8.40 23.90 15.50 7.32 (3.50) 25.60 (11.62) 18.27 (8.34) Not good not bad Not good not bad NB-UVB 4 EXCIMER LASER VS NB-UVB AFTER PUNCH GRAFTING 61
4 repigmentation. Moreover, we asked patients systematically about their satisfaction with and preference for either treatment. Whereas these questions needed to be tailored to the study treatments, they were, by definition, study-specific and unstandardized. However, they were simple and straightforward. In conclusion, both EL and NB-UVB achieve comparable degrees of repigmentation after punch grafting, whereas patients were significantly more satisfied with the results of NB-UVB treatment and preferred it more than EL. However, given the large variation in results, we strongly recommend shared decision making by the dermatologist and the patient, on the treatment modality of choice. In vulnerable populations, such as small children and patients with sun damaged skin and/or with a history of long-term UVB treatment, EL should be given serious consideration because of its lower UV dose. REFERENCE LIST 1 Njoo MD, Westerhof W. Vitiligo. Pathogenesis and treatment. Am J Clin Dermatol 2001; 2: 167-81. 2 Boersma BR, Westerhof W, Bos JD. Repigmentation in vitiligo vulgaris by autologous minigrafting: results in nineteen patients. J Am Acad Dermatol 1995; 33: 990-5. 3 Westerhof W, Nieuweboer-Krobotova L. Treatment of vitiligo with UV-B radiation vs topical psoralen plus UV-A. Arch Dermatol 1997; 133: 1525-8. 4 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: 284-92. 5 Esposito M, Soda R, Costanzo A et al. Treatment of vitiligo with the 308 nm excimer laser. Clin Exp Dermatol 2004; 29: 133-7. 6 Hadi SM, Spencer JM, Lebwohl M. The use of the 308-nm excimer laser for the treatment of vitiligo. Dermatol Surg 2004; 30: 983-6. 7 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: 981-5. 8 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: 558-64. 9 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: 531-7. 10. 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: 152-6. 11. Spencer JM, Nossa R, Ajmeri J. Treatment of vitiligo with the 308-nm excimer laser: a pilot study. J Am Acad Dermatol 2002; 46: 727-31. 12. Taneja A, Trehan M, Taylor CR. 308-nm excimer laser for the treatment of localized vitiligo. Int J Dermatol 2003; 42: 658-62. 13. Baltas E, Csoma Z, Ignacz F et al. Treatment of vitiligo with the 308-nm xenon chloride excimer laser. Arch Dermatol 2002; 138: 1619-20. 14. 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: 138-42. 15. 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: 273-8. 16. Casacci M, Thomas P, Pacifico A et al. Comparison between 308-nm monochromatic excimer light and narrowband UVB phototherapy (311-313 nm) in the treatment of vitiligo - a multicentre controlled study. J Eur Acad Dermatol Venereol 2007; 21: 956-63. 17. Nieuweboer-Krobotova L, Veen JPW. Excimer laser and minigrafting- combination therapy for vitiligo. Poster EADV P08.140. 2005. Ref Type: Pamphlet 18. Lahiri K, Malakar S, Sarma N et al. Repigmentation of vitiligo punch grafting and NB-UVB: a prospective study. Int J Dermatol 2006; 45: 649-55. 19. Falabella R, Arrunategui A, Barona MI et al. The minigrafting test for vitiligo: detection of 62
stable lesions for melanocyte transplantation. J Am Acad Dermatol 1995; 32: 228-32. 20. Fitzpatrick TB. The validity and practicality of sun-reactive skin types I through VI. Arch Dermatol 1988; 124: 869-71. 21. Wind B, Meesters A, Kroon M et al. Punchgraft testing in vitiligo; effects of UVA, NB-UVB and 632.8 nm Helium-Neon laser on the outcome. J Eur Acad Dermatol Venereol 2010. 22. El Mofty M, Mostafa W, Esmat S et al. Narrow band Ultraviolet B 311 nm in the treatment of vitiligo: two right-left comparison studies. Photodermatol Photoimmunol Photomed 2006; 22: 6-11. 23. Kanwar AJ, Dogra S, Parsad D et al. Narrowband UVB for the treatment of vitiligo: an emerging effective and well-tolerated therapy. Int J Dermatol 2005; 44: 57-60. 24. Nicolaidou E, Antoniou C, Stratigos AJ et al. Efficacy, predictors of response, and longterm follow-up in patients with vitiligo treated with narrowband UVB phototherapy. J Am Acad Dermatol 2007; 56: 274-8. 25. Scherschun L, Kim JJ, Lim HW. Narrow-band ultraviolet B is a useful and well-tolerated treatment for vitiligo. J Am Acad Dermatol 2001; 44: 999-1003. 26. Nicolaidou E, Antoniou C, Stratigos A et al. Narrowband ultraviolet B phototherapy and 308-nm excimer laser in the treatment of vitiligo: a review. J Am Acad Dermatol 2009; 60: 470-7. 4 EXCIMER LASER VS NB-UVB AFTER PUNCH GRAFTING 63
5 THE BURDEN OF VITILIGO: PATIENT CHARACTERISTICS ASSOCIATED WITH QUALITY OF LIFE M.W. Linthorst Homan Ph. I. Spuls J. de Korte J.D. Bos M.A.G. Sprangers J.P.W. van der Veen J Am Acad Dermatol. 2009; 61(3): 411-20
5 SUMMARY Background: Vitiligo is commonly regarded as a harmless cosmetic skin problem in Western societies, and the importance of treating vitiligo patients is often underestimated. Objective: To determine the clinical and sociodemographic variables that adversely affect the quality of life in adult patients with generalized vitiligo so that these variables can be considered in the treatment and care. Methods: A total of 245 adult patients with generalized vitiligo completed two quality of life questionnaires (the Medical Outcomes Study 36-Item Short-form General Health Survey and the Skindex-29). Physicians assessed sociodemographic and clinical characteristics of these patients. Results: Dark skin type, vitiligo located on the chest, and treatment in the past appeared to have an adverse impact on the psychosocial domains of the quality of life. Moreover, itch was reported by 20% of the patients in this study. Limitations: Psychiatric comorbidity was not evaluated in the analyses. Conclusion: Generalized vitiligo is a serious skin disorder with an adverse impact on the emotional state, comparable with that in other major skin diseases. 66
INTRODUCTION Millions of men and women worldwide have vitiligo. The most common clinical variety is the so-called non-segmental or generalized vitiligo, 1 in which scattered milky-white skin patches may appear all over the body because of loss of functional melanocytes. Many patients with vitiligo experience psychosocial distress and social stigmatization. 2-4 Because skin color plays a major role in an individual s perception of health, wealth, worth and desirability, pigmentary disfigurements may influence social interactions. 5 Vitiligo may even lead to social exclusion in certain societies. Therefore, vitiligo is considered to be one of the major medical problems in India. 6;7 However, in Western-European countries, although associated with other autoimmune diseases, 8 vitiligo is often considered as a harmless, cosmetic skin disorder, whereby the importance of treating vitiligo patients is often underestimated. 4;9;10 Nevertheless, it is important to recognize and to deal with the psychosocial impact of this disease. 7 We evaluated the burden of vitiligo taking a broad range of factors into account in order to compile a profile of vitiligo patients who suffer most and require special medical care. One way of evaluating the burden of a disease is by measuring the healthrelated quality of life (HRQL), i.e. using standardized questionnaires to measure the impact of the disease on the physical, the psychological and the social functioning and the well-being of the patient. 11;12 A number of studies has examined HRQL in patients with vitiligo. 3;7;13-20 These studies focused mainly on specific questionnaires in dermatology and reported that, in general, vitiligo had an adverse impact on HRQL, particularly on psychosocial functioning. There are no studies in vitiligo in which a combination of a generic and a dermatology-specific HRQL questionnaire was used. A wide range of domains and aspects of quality of life can be assessed by using this combination. Moreover, both types of instruments may measure different, but complementary domains and aspects of patients health, 21;22 and the use of a generic HRQL questionnaire, such as the Medical Outcomes Study 36-Item Short-form General Health Survey (SF-36), allows comparisons with other medical conditions, not just skin diseases. The first aim of this study was to determine the generic and the dermatologyspecific HRQL in sociodemographically and clinically distinct subgroups of patients with generalized vitiligo. The second aim was to investigate associations between HRQL and sociodemographic and patient clinical characteristics to include these characteristics in the treatment and care of patients with generalized vitiligo. 5 THE BURDEN OF VITILIGO METHODS Patients All consecutive adult patients (age >18 years) with generalized vitiligo, referred to the Netherlands Institute of Pigment Disorders (NIPD) from January to December 2006, were invited to participate in the study. Patients who did not 67
speak or read Dutch, who were mentally and/or physically unable to complete the study questionnaires, or who had an additional skin disease were excluded. Patients provided informed written consent. Medical ethics approval was sought, but was considered not to be required by the medical ethics committee (in the Netherlands approval is only required for self-report questionnaires containing intrusive items). 5 Measures Outcome Measures. Generic Quality of life: The SF-36. This widely used questionnaire consisted of 36 items forming 8 domains or scales: physical functioning; social functioning; role physical (limitations in usual role activities due to physical problems); role emotional (limitations in usual role activities due to emotional problems); bodily pain; mental health; vitality; and general health perceptions. We used the validated Dutch translation of the SF-36. 23 The questions referred to the previous 4 weeks. A score from 0 to 100 was calculated for each scale, with higher scores indicating better quality of life. Two summary scores were calculated; the Physical Component Summary (PCS) and the Mental Component Summary (MCS), by adding weighted combinations of the 8 scales. The summary scores were converted to standardized T scores that had a mean of 50 and a standard deviation (SD) of 10. A summary score of 50 (SD 10) reflected an average quality of life of the general population. 23;24 Dermatology-specific quality of life: Skindex-29. This questionnaire consisted of 29 items forming 3 scales: symptoms (e.g. itch, pain and irritation), emotions (e.g. worry, shame, embarrassment, frustration and depression), and functioning (e.g. sleep, social life, social isolation, sexuality, work and hobbies). The questions referred to the previous week; scores were given on a 5-point scale, from never to all the time. Scale scores and a sum score were calculated on a 100-point scale, with lower scores indicating a better quality of life. 25 Independent measures. The sociodemographic data included age and sex. The clinical data included duration of disease, vitiligo disease activity, 26 treatment history, treatment effect, current treatment, symptoms (sunburn and/or itch on the depigmented areas as distinct symptoms), comorbidity, smoking, skin type 27, affected body sites and extent of the disease (in percent). These data were collected using a study-specific questionnaire and dermatologic examination was performed by the physician at the first consultation at the NIPD (Appendix). Statistical analysis A descriptive analysis was carried out to assess the characteristics of the sample. Age was dichotomized in lower (younger) versus higher (older) age rather than the median age of the total group. The means of the scale scores and the summary scores of the SF-36 and the Skindex-29 were calculated according to the guidelines of these questionnaires. Effect sizes (d), measuring the strength of these associations, were calculated by dividing the difference between the 68
mean scores of each group by the pooled SD for those means. Following Cohen recommendations, effect sizes of 0.20, 0.50 and 0.80 were considered to be small, moderate and large, respectively. 28 First, univariate associations were calculated using analysis of variance. The outcome variables were the PCS and the MCS of the SF-36, and the scales and sum score of the Skindex-29. Independent variables were the sociodemographic and clinical characteristics. Effect sizes were calculated for statistically significant associations with two groups (P<0.01). In case of significant associations, we further analyzed the extent to which the two groups differed with respect to sociodemographic and clinical characteristics, using independent t tests. The independent variables that were univariately associated with the outcome variables (P<0.10) were entered into a multiple linear regression model. A level of significance was set at P less than 0.01. All statistical analyses were carried out using software (SPSS, Version 12.01 for Windows, SPSS Inc, Chicago, IL). RESULTS Patient characteristics In all, 248 adult patients with generalized vitiligo were eligible for the study from January 1 until December 31, 2006. Almost all the patients participated in the study, except 3 patients: two patients refused to participate and one patient did not complete the questionnaires. The age of the 245 patients (response rate=98.8%) included in this study ranged from 18 to 74 years (median 40.2, SD 12.6). The sociodemographic and clinical characteristics are presented in Table 1. 5 THE BURDEN OF VITILIGO Description of generic and dermatology-specific HRQL The means and the SD of the SF-36 and the Skindex-29 are presented in Table 2. SF-36 scores from an age- and sex-matched Dutch reference population without chronic illness were available and presented as well. 23 In our study population the PCS was 54.4 (SD 8.6) and the MCS was 46.3 (SD 11.2), indicating that the physical quality of life was higher, but the mental quality of life was lower than that of the reference population. For the Skindex-29 no comparable reference data from a healthy Dutch population were available. The mean scale scores of the Skindex- 29 were 13.9 (symptoms), 35.9 (emotions), and 16.7 (functioning). These scores indicated that symptoms were adversely influenced mildly, and that emotions and functioning were influenced moderately, with the most adverse impact on the emotional domain. Univariate associations Generic HRQL. The results of the univariate analysis are presented in Table 3. The PCS score of the SF-36 (P<0.01) with small to moderate effect sizes showed that an older age, a fair skin type and comorbidity were all associated with a low physical quality of life. No differences were found in sociodemographic and clinical 69
Table 1. Patient characteristics Study population N=245 % Gender Male female 110 135 44.9 55.1 5 Age 1 Disease duration Mean <40 years > 40 years < 1 year 1-5 year > 5 years 41.4 (SD 12.6) 121 124 42 91 112 49.4 50.6 17.1 37.1 45.7 Disease activity 2 Stable vitiligo Active vitiligo 76 169 31 69 Treatment history Treated patients Untreated patients 116 129 47.3 52.7 Effective treatment 3 Yes No 42 74 17.1 30.2 Current treatment Yes No 18 227 7.3 92.7 Symptoms (Itch and sunburn) Patients with - Itch - Sunburn - Itch and sunburn Patients without symptoms 23 104 26 92 9.4 42.4 10.6 37.6 Patients with co-morbidity Non-dermatological Dermatological 44 15 18.0 6.1 Smoking Yes No, never No, not anymore 65 124 56 26.5 50.6 22.9 Skin type I-III IV-VI 183 62 74.7 25.3 Localisation 4 Face Hands Arms Genitals Legs Chest/Trunk Feet Back Neck 199 175 149 144 131 124 105 89 86 81.2 71.4 60.8 58.8 53.5 50.6 42.9 36.3 35.1 Extension in % 1-5% 6-10% 11-15% 16-25% 26 >% 172 42 16 9 6 70.2 17.1 6.5 3.7 2.4 1 Median age was 40.15, therefore age < 40 y and > 40 y was used in univariate and multivariate analyses. 2 Stable: no expansion of existing lesions or appearance of new lesions during the previous 6 months 3 effective: stabilization and/or repigmentation 4 More options possible; >100% 70
Table 2. Medical Outcomes Study 36-Item Shortform General Health Survey and the Skindex-29 scale mean scores. SF-36 Mean (SD) Reference population N=307 (SD) Effect size* Physical functioning 90.7 (16.2) 89.1 (16.3) 0.09 Role physical 86.3 (28.3) 81.6 (30.3) 0.15 Bodily pain 84.2 (22.3) 75.3 (22.9) 0.38 General health 72.2 (19.1) 73.6 (19.6) 0.07 Vitality 64.6 (19.4) 67.7 (19.4) 0.16 Social functioning 81.3 (23.3) 84.2 (22.5) 0.12 Role emotional 81.3 (33.9) 85.5 (29.9) 0.13 Mental health 72.8 (18.1) 76.2 (18.2) 0.18 Physical Component Summary Score (PCS) 54.4 (8.6) 51.5 (8.5) 0.29 Mental Component Summary Score (MCS) 46.3 (11.2) 49.4 (10.3) 0.30 Skindex-29 Emotions 35.9 (23.6) N/A Functioning 16.7 (19.5) N/A Symptoms 13.9 (14.6) N/A Sum score 22.8 (17.1) N/A 5 THE BURDEN OF VITILIGO PCS/ MCS of 50 (SD 10) reflects an average quality of life of the general population *: Effect size of 0.20, 0.50, and 0.80 were considered to be small, moderate and large respectively N/A: Not available characteristics between patients older or younger than 40 years and patients with or without comorbidity. Further analysis showed that patients with dark skin (type IV-VI) differed significantly from patients with fair skin (type I-III) in two variables: those with dark skin reported fewer symptoms of sunburn and vitiligo on the genitals was present in only a small percentage (P<0.01). None of the independent variables were statistically significantly associated with the MCS. Dermatology-specific HRQL. Women reported having more emotional problems with their vitiligo than did men (P<0.01) in the Skindex-29. Further analysis indicated that women had vitiligo on the chest more often (P<0.01). Patients who had treatment in the past had significantly higher scores on the emotions and functioning scale of the Skindex-29 and a significantly higher sum score (P<0.01) with moderate effect sizes (range 0.46-0.56). No differences were found in sociodemographic and clinical characteristics between patients who had treatment in the past and those without any treatment in the past. Although vitiligo is generally considered to be a skin disease with cosmetic effects only, 53% of the patients reported to have sunburn and 20% reported to have itch on the depigmented areas. Of the 44 patients with itch (who had 71
Table 3. Univariate associations of health-related quality of life and sociodemographic and clinical variables SF-36 Variable PCS P-value d MCS P-value Emotions P-value Gender M F 55.5 52.8 0.02 31.8 39.3 0.01* 5 Age (years) Disease duration < 40 >40 <1 year 1-5 years >5 years 55.9 52.1 0.01* 0.45 44.9 47.8 0.05 38.8 33.1 29.0 36.1 38.4 0.06 0.09 Disease activity Active Stable Treatment history Treated Untreated 42.7 29.8 0.01* Co-morbidity With Without 48.8 55.1 0.01* 0.64 43.6 46.9 0.09 Symptoms With Without Skin type I-III IV-VI 54.8 51.4 0.01* 0.37 47.3 43.3 0.02 31.8 48.1 0.01* Vitiligo chest yes no 53.0 54.9 0.09 45.0 47.7 0.06 40.1 31.6 0.01* Vitiligo arms yes no Vitiligo feet yes no Extension 1-5% 6-10% 11-15% 16-25% 26>% 46.4 47.9 40.5 42.6 53.3 0.09 Only variables with a P-value < 0.10 are shown in this table. d: effect size.* P-value < 0.01, effect size was calculated only for P-values <0.01. nondermatologic comorbidities), 5 patients had a history of thyroid dysfunction, but none of the patients had a history of diabetes. HRQL was statistically significantly more impaired in patients with skin type IV-VI (P<0.01) on the emotions (d=0.68) and functioning (d=0.64) scale and the sum score (d= 0.67). Furthermore, patients with generalized vitiligo on the chest had significantly higher scores on the emotions and functioning scales and sum score (P<0.01), with small to moderate effect sizes (range 0.37-0.52). Further analysis indicated that 71.8% of these patients were female with vitiligo on several body sites. In 23.3% of these patients more than 10% of the body area was depigmented. 72
Skindex-29 d Functioning P-value d Symptoms P-value d 0.32 0.56 10.9 15.4 20.1 14.7 21.2 21.3 12.6 0.02 0.02 0.01* 0.46 16.1 12.0 0.03 Sum score P-value d 20.5 24.6 17.4 22.4 25.1 21.4 25.7 27.5 18.5 0.06 0.04 0.07 0.01* 0.54 5 THE BURDEN OF VITILIGO 16.7 9.3 0.01* 0.54 0.68 13.4 26.6 0.01* 0.64 19.7 31.7 0.01* 0.67 0.37 21.6 11.8 0.01* 0.52 16.0 11.8 0.02 26.7 18.8 0.01* 0.48 18.9 13.5 0.03 19.6 14.6 0.05 13.8 20.2 32.2 26.3 20.2 0.01* 20.9 23.5 35.9 31.0 23.8 0.01* Finally, patients in the category of 11% to 15% of the skin area depigmented had most impairment on the functioning scale and the sum score (P<0.01). However, this finding must be viewed with caution because 11% to 15% of the skin area was depigmented in only 16 patients (6.5%). Multivariate associations Generic quality of life. In a multiple linear regression model, with the PCS and the MCS as outcome variables and demographic and clinical variables (P<0.10) as independent variables, a weak linear association was found (R²=17.2% for PCS and R²= 10.2% for MCS). Age, comorbidity and skin type were statistically significantly associated with the PCS (P<0.01). Patients who were older than 40 years, those 73
Table 4. Multivariate regression analysis of HRQL and socio-demographic and clinical variables. 5 Variable R² (%)¹ PCS P SF-36 R² (%)¹ Intercept 65.8 0.01 42.1 0.01 Gender 2.5-2.0 0.08 Age 7.5-3.3 0.01 1.7 3.2 0.03 Disease duration <1 year vs >5 years <1 year vs 1-5 years MCS Disease activity Treatment history Co-morbidity 12.7-5.4 0.01 3.6-4.4 0.02 Symptoms P Skin type 16.5-4.0 0.01 5.9-3.4 0.04 Vitiligo chest 17.2 1.5 0.20 7.2 2.9 0.07 Vitiligo arms Vitiligo feet Extension 1-5% vs >25% 1-5% vs 16-25% 1-5% vs 11-25% 1-5% vs 6-10 % 10.2 8.4-1.1-4.5 2.2 0.07 0.79 0.14 0.28 ¹ Indicates the amount of variation in each dependent variable that can be accounted for by the independent factor. P value <0.01 with comorbidity, and those with dark skin had poorer physical functioning on the SF-36. None of the independent variables were statistically significantly associated with the MCS (Table 4). Dermatology-specific quality of life. Treatment history and skin type were independently associated with the emotions (R²=21.0%, P<0.01) and functioning (R²=23.9, P<0.01) scale and the sum score of the Skindex-29 (R²= 23.3, P<0.01). Patients with dark skin (skin type IV-VI) and those who had treatment in the past had significantly more impairment in psychosocial functioning. Furthermore, vitiligo on the chest was significantly associated with the functioning scale (P<0.01). For the symptoms scale, logically, the symptoms itch and or sunburn were significantly associated (R²= 10.0, P<0.01). 74
R² (%)¹ Skindex-29 Emotions Functioning Symptoms Sum score P R² (%)¹ P R² (%)¹ P R² (%)¹ 36.6 0.01 7.3 0.43 19.5 0.01 16.5 0.04 2.5 5.2 0.08 1.4 2.2 0.31 3.9-5.1 0.06 5.4 4.4 4.2 0.27 0.30 3.1 3.4 0.7 0.34 0.84 3.7 2.6 1.9 P 0.40 0.54 4.3 5.1 0.05 4.5 3.4 0.14 11.5-10.2 0.01 8.2-6.5 0.01 2.1-3.5 0.06 9.8-6.8 0.01 19.6 15.9 0.01 16.6 13.1 7.8 6.8 0.01 0.01 18.6 11.4 0.01 5 THE BURDEN OF VITILIGO 21.0-6.0 0.04 21.8-7.0 0.01 8.8-3.0 0.97 22.0-5.5 0.02 22.0-0.6 0.81 22.0 2.5 0.36 23.9 3.0 7.7 10.7 4.7 0.70 0.24 0.04 0.16 23.3-0.6 5.4 7.7 1.0 0.92 0.33 0.07 0.73 DISCUSSION Our results showed that adult patients with generalized vitiligo had a low mental HRQL (MCS), comparable with that of patients with other skin diseases such as eczema, 29;30 psoriasis, 30-33 and hand eczema. 34 For unknown reasons, the PCS score in the vitiligo group as a whole appeared to be higher than that in the healthy reference population (effect size 0.29), although older age, comorbidity, and a fair skin type were associated with relatively lower scores on the PCS. Measurement with the dermatology-specific Skindex-29 showed that patients with generalized vitiligo had mostly emotional problems. The severity of these emotional problems was comparable with that of patients with psoriasis, 25;35 eczema, 25 chronic hand dermatitis, 36 and acne. 37;38 Our results further showed that generalized vitiligo particularly had an impact on the HRQL of patients with dark skin (skin type IV-VI), patients with vitiligo on the chest, and patients who had treatment in the past. Skin type was the only clinical patient characteristic that was independently associated with both generic and dermatology-specific HRQL. 75
5 We studied a large sample of patients with an almost equal sex distribution and with a broad variation in ethnic background in contrast to the other reported HRQL studies in patients with vitiligo. One quarter of the participating patients in the current study had dark skin. These patients originated from Suriname, India, Morocco, Turkey, Curacao, Indonesia, China or Afghanistan. Porter and Beuf 39 reported the effect of race on the reaction to impaired appearance and found that race was not significantly associated with overall self-esteem and the degree of disturbance by vitiligo. In contrast, in our study population, patients with dark skin reported more HRQL impairment than patients with fair skin. Surprisingly, the presence of generalized vitiligo on the face and the hands was not associated with impaired generic and dermatology-specific HRQL. In a recent study on coping and stigmatization in vitiligo, Schmid-Ott et al. 40 also reported that the location of vitiligo does not play a critical role in the overall stigmatization experience. Unexpectedly, we found a statistically significant association between vitiligo on the chest and the emotion and functioning scale and the sum score of the Skindex-29. Patients with vitiligo on the chest were predominantly women in whom more than 10% of the body area was depigmented. These women may feel ashamed to wear clothes that expose the affected site and also in sexual relationships when vitiligo is present on the breasts. An intriguing finding in this study was that patients who had effective treatment in the past (mostly patients with long-lasting vitiligo), reported a worse HRQL as compared with patients who had no effective treatment in the past (mostly patients with recently developed vitiligo). An explanation for this may be that the latter group was more optimistic about the possibility of improvement. The group that already had treatment and sought medical advice again, may predominantly consist of relatively dissatisfied patients with a low degree of acceptance of their disease. Higher sensitivity to sunburn is a widely recognized symptom of vitiligo. Schmid- Ott et al. 40 reported that vitiligo only rarely involved itch. This finding is in contrast to our results; 20% of our study population had vitiligo-associated pruritus. This pruritus could not be explained by comorbidity such thyroid disease or diabetes mellitus. However, itch as a symptom of vitiligo requires further investigations. The majority of the studies on HRQL in vitiligo patients used the Dermatology Life Quality Index. 13;14;16;18-20 It was pointed out in all these studies that vitiligo had a negative impact on psychosocial functioning. To date, Skindex-29-data in vitiligo may be obtained from 3 studies. Firstly, Sampogna et al. 35 investigated the association between poor HRQL and psychiatric morbidity in 32 patients with vitiligo. Psychiatric morbidity was strongly associated with poorer HRQL in the scales emotions and functioning. Secondly, Rumpf et al. 41 used the Skindex-29 in 333 patients with vitiligo to validate a self-administered version of the Pictorial Representation of Illness Measure. Significant correlations were found with the Skindex-29 scales emotions and functioning. Finally, Zghal et al. 17 translated the Skindex-29 in Tunisian and used it in 20 patients with vitiligo. In this study, uncovered areas, particularly the face, were found to be bothersome 76
by all the patients. The highest scores, meaning a relatively low HRQL, in patients with vitiligo were found on the emotional and functioning scales. These results corroborate the results of our study. To our knowledge, this is the first study reporting both generic and dermatologyspecific quality of life in a large multiracial group of patients with vitiligo. As we are a national referral center for pigment disorders, it may be argued that we see a selected population of patients with vitiligo with a relatively high burden of the disease and that our study population may not reflect the impact of the disease in the larger community of people with vitiligo who do not seek care. Nevertheless, many of our patients (52.7%) did not receive any treatment elsewhere and many dermatologists in our country do not treat vitiligo at all. 9 Further longitudinal studies are necessary to obtain additional insight into the stability of the associations found in this study and to evaluate the influence of medical and/or psychological interventions in patients with an impaired HRQL. CONCLUSIONS The results of this study showed that generalized vitiligo is a serious skin disorder with an impact on emotional life comparable with that in other major skin diseases. Moreover, vitiligo is associated with itch in 20% of the patients. Quality of life is mostly affected in dark-skinned patients. Vitiligo on the hands and the face did not appear to be a major determinant for the HRQL. 5 THE BURDEN OF VITILIGO Acknowledgement: We thank R. de Haan, J. Binnekade, and P. Nieuwkerk for their contribution in the statistical analyses of the data and E. Hull and B.Tank for reviewing the manuscript. REFERENCES LIST 1. Whitton ME, Ashcroft DM, Barrett CW et al. Interventions for vitiligo. Cochrane Database Syst Rev 2006; CD003263. 2. 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: 73-7. 3. Kent G, Al Abadie M. Psychologic effects of vitiligo: a critical incident analysis. J Am Acad Dermatol 1996; 35: 895-8. 4. Ongenae K, Beelaert L, Van Geel N et al. Psychosocial effects of vitiligo. J Eur Acad Dermatol Venereol 2006; 20: 1-8. 5. Grimes PE. White patches and bruised souls: advances in the pathogenesis and treatment of vitiligo. J Am Acad Dermatol 2004; 51: S5-S7. 6. Chaturvedi SK, Singh G, Gupta N. Stigma experience in skin disorders: an Indian perspective. Dermatol Clin 2005; 23: 635-42. 7. Parsad D, Dogra S, Kanwar AJ. Quality of life in patients with vitiligo. Health Qual Life Outcomes 2003; 1: 58. 8. Njoo MD, Westerhof W. Vitiligo. Pathogenesis and treatment. Am J Clin Dermatol 2001; 2: 167-81. 9. Njoo MD, Bossuyt PM, Westerhof W. Management of vitiligo. Results of a questionnaire among dermatologists in The Netherlands. Int J Dermatol 1999; 38: 866-72. 10. Ongenae K, Van Geel N, De Schepper S et al. Management of vitiligo patients and attitude of dermatologists towards vitiligo. Eur J Dermatol 2004; 14: 177-81. 11. Finlay AY. Quality of life assessments in dermatology. Semin Cutan Med Surg 1998; 17: 291-6. 12. Finlay AY. Quality of life measurement in dermatology: a practical guide. Br J Dermatol 1997; 136: 305-14. 77
5 13. Kent G, al-abadie M. Factors affecting responses on Dermatology Life Quality Index items among vitiligo sufferers. Clin Exp Dermatol 1996; 21: 330-3. 14. Ongenae K, Van Geel N, De Schepper S et al. Effect of vitiligo on self-reported health-related quality of life. Br J Dermatol 2005; 152: 1165-72. 15. Borimnejad L, Parsa YZ, Nikbakht-Nasrabadi A et al. Quality of life with vitiligo: comparison of male and female muslim patients in Iran. Gend Med 2006; 3: 124-30. 16. Aghaei S, Sodaifi M, Jafari P et al. DLQI scores in vitiligo: reliability and validity of the Persian version. BMC Dermatol 2004; 4: 8. 17 Zghal A, Zeglaoui F, Kallel L et al. [Quality of life in dermatology: Tunisian version of the Skindex-29]. Tunis Med 2003; 81: 34-7. 18. Belhadjali H, Amri M, Mecheri A et al. [Vitiligo and quality of life: a case-control study.]. Ann Dermatol Venereol 2007; 134: 233-6. 19 Mechri A, Amri M, Douarika AA et al. [Psychiatric morbidity and quality of life in Vitiligo: a case controlled study]. Tunis Med 2006; 84: 632-5. 20 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: 373-4. 21 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: 103-7. 22 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: 1221-7. 23 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: 1055-68. 24 Ware JE, Jr., Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care 1992; 30: 473-83. 25 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: 1433-40. 26 Njoo MD, Das PK, Bos JD et al. Association of the Kobner phenomenon with disease activity and therapeutic responsiveness in vitiligo vulgaris. Arch Dermatol 1999; 135: 407-13. 27 Fitzpatrick TB. The validity and practicality of sun-reactive skin types I through VI. Arch Dermatol 1988; 124: 869-71. 28 Cohen J. Statistical power analysus for the behavioral sciences. Hillsdale, NJ : Lawrence Erlbaum Associates, 1988. 29 Holm EA, Wulf HC, Stegmann H et al. Life quality assessment among patients with atopic eczema. Br J Dermatol 2006; 154: 719-25. 30 Lundberg L, Johannesson M, Silverdahl M et al. Health-related quality of life in patients with psoriasis and atopic dermatitis measured with SF-36, DLQI and a subjective measure of disease activity. Acta Derm Venereol 2000; 80: 430-4. 31 Shikiar R, Willian MK, Okun MM et al. The validity and responsiveness of three quality of life measures in the assessment of psoriasis patients: results of a phase II study. Health Qual Life Outcomes 2006; 4: 71. 32 Wahl A, Moum T, Hanestad BR et al. The relationship between demographic and clinical variables, and quality of life aspects in patients with psoriasis. Qual Life Res 1999; 8: 319-26. 33 Wahl A, Hanestad BR, Wiklund I et al. Coping and quality of life in patients with psoriasis. Qual Life Res 1999; 8: 427-33. 34 Wallenhammar LM, Nyfjall M, Lindberg M et al. Health-related quality of life and hand eczema- -a comparison of two instruments, including factor analysis. J Invest Dermatol 2004; 122: 1381-9. 35 Sampogna F, Picardi A, Chren MM et al. Association between poorer quality of life and psychiatric morbidity in patients with different dermatological conditions. Psychosom Med 2004; 66: 620-4. 36 Fowler JF, Ghosh A, Sung J et al. Impact of chronic hand dermatitis on quality of life, work productivity, activity impairment, and medical costs. J Am Acad Dermatol 2006; 54: 448-57. 37 Lasek RJ, Chren MM. Acne vulgaris and the quality of life of adult dermatology patients. Arch Dermatol 1998; 134: 454-8. 38 Jones-Caballero M, Chren MM, Soler B et al. Quality of life in mild to moderate acne: relationship to clinical severity and factors influencing change with treatment. J Eur Acad Dermatol Venereol 2007; 21: 219-26. 39 Porter JR, Beuf AH. Racial variation in reaction to physical stigma: a study of degree of disturbance by vitiligo among black and white patients. J Health Soc Behav 1991; 32: 192-204. 40 Schmid-Ott G, Kunsebeck HW, Jecht E et al. Stigmatization experience, coping and sense of coherence in vitiligo patients. J Eur Acad Dermatol Venereol 2007; 21: 456-61. 41 Rumpf HJ, Lontz W, Uesseler S. A selfadministered version of a brief measure of suffering: first aspects of validity. Psychother Psychosom 2004; 73: 53-6. 78
Appendix 1. Study specific questionnaire Gender and age Disease duration VIDA score (Vitiligo disease activity score) Treatment history Treatment effect Current treatment Symptoms Other skin disease in history (not present at the moment of inclusion) Medical history Smoking Dermatologic examination Skin type (according to Fitzpatrick classification I-VI) 27 Affected body sites Extension of the disease (Rule of 9: a lesion with the size of the patient s hand palm will correspond with 1% of the body surface area (BSA)). < 1 year 1-5 year > 5 years Active for the last 6 weeks = +4 Active for the last 3 months = +3 Active for the last 6 months = +2 Active for the last 1 year = +1 Stable for at least 1 year = 0 Stable for at least 1 year and repigmentation=-1 UVB(311nm) phototherapy PUVA Local therapy Minigrafting Other None Stabilisation and/or repigmentation UVB(311nm) phototherapy PUVA Local therapy Minigrafting Other None Itch Sunburn Itch and sunburn Alopecia areata Psoriasis Eczema Other Thyroid dysfunction Diabetes Mellitus Reumatic arthritis Other Yes No, never No, not anymore I-III IV-VI Face Neck Arms Hands Legs Feet Back Trunk Genital area 1-5% 6-10 11-15% 16-25 26> 5 THE BURDEN OF VITILIGO 79
6 CHARACTERISTICS OF PATIENTS WITH UNIVERSAL VITILIGO AND HEALTH- RELATED QUALITY OF LIFE M.W. Linthorst Homan M.A.G. Sprangers J. de Korte J.D. Bos J.P.W. van der Veen A short version of this chapter is published as a letter to the editor in: Arch Dermatol. 2008; 144(8): 1062-4
6 SUMMARY Background: Little is known about universal vitiligo, a rare type of vitiligo in which more than 80% of the skin is depigmented. Objective: To describe characteristics and health related quality of life (HRQL) of patients with universal vitiligo and to compare these with the characteristics and HRQL of patients with generalized vitiligo. Methods: Eligible patients were mailed questionnaires on socio-demographic and clinical characteristics and generic and dermatology specific HRQL. The results were compared with those of a matched comparison group of patients with generalized vitiligo. Results: A total of 55 patients with universal vitiligo completed the questionnaires. In them, the number of family members with vitiligo and the prevalence of reported co-morbidities were significantly higher than in patients with generalized vitiligo. Rheumatoid arthritis and alopecia areata were reported in 15% and 7% respectively (universal vitiligo) versus 3% and 0% (generalized vitiligo). Patients with universal vitiligo reported poorer physical HRQL on the SF-36 compared to patients with generalized vitiligo. There was no significant difference in dermatology specific HRQL between patients with universal and generalized vitiligo. Conclusions: Universal vitiligo is characterized by an extreme clinical presentation with (sub) total depigmentation, a strong familial expression of the disease and high prevalence of co-morbidity, such as thyroid dysfunction and rheumatoid arthritis. Surprisingly, HRQL is comparable to what is found in general vitiligo except for poorer functioning in daily life and physical HRQL, which probably reflects co-morbidity. 82
INTRODUCTION Vitiligo is a chronic skin disease affecting approximately 1% of the world population. The most common type is generalized vitiligo, 1 in which depigmented scattered macules may occur over the entire body in a symmetrical distribution pattern. In some patients, depigmentation spreads over more than 80% of the whole body. This type of vitiligo is known as universal vitiligo. 2 Little is known about universal vitiligo. We do not know whether patient characteristics differ from those in the more common types of vitiligo. Moreover, nothing is known about health-related quality of life (HRQL) in these patients. As patients with universal vitiligo are nearly completely depigmented, they may judge their appearance more favourably as compared to patients with generalized vitiligo, in whom scattered white maculae, often located on exposed areas such as the face and hands, appear to be more noticeable. But since the body surface area is (sub) totally depigmented, sunburn could be a bigger problem in patients with universal vitiligo. The aims of this study to describe characteristics and HRQL of patients with universal vitiligo and to compare these with the characteristics and HRQL of patients with generalized vitiligo. METHODS Patients Study population: Universal vitiligo The inclusion criteria for participation in the study were: (i) having universal vitiligo, diagnosed at the Netherlands Institute of Pigment Disorders (NIPD) between 1994 (the year of the opening of the institute) and 2006; (ii) age 18 years or older at the time of completing the questionnaires; (iii) ability to read and understand the Dutch language of the questionnaires. Eligible patients were mailed a package, containing information about the study, an informed consent form, a questionnaire booklet with a questionnaire on patient characteristics, and 2 quality of life questionnaires and a stamped return envelope. Patients were asked to sign the informed consent form and to return this with the completed questionnaires. In case a patient did not respond, the patient was reminded by phone with a maximum of 3 follow-up calls. Patients who did not want to participate in the study were asked to return a short form asking about the reason for declining study participation. Comparison group: Generalized vitiligo A cohort of 245 adult patients (18 years or older) with generalized vitiligo, referred to the NIPD from January to December 2006, served as a comparison group. Each patient with universal vitiligo was matched for age and sex with 2 patients of the comparison group. 6 UNIVERSAL VITILIGO AND HEALTH-RELATED QUALITY OF LIFE 83
Measures Patient characteristics Sociodemographic and clinical patient characteristics were collected with a questionnaire. The sociodemographic data included age and sex. The clinical data comprised age at onset of the vitiligo, treatment history, comorbidity, family history, symptoms, and skin type. 3 6 Health-related quality of life (HRQL) Generic Quality of life: the Medical Outcomes Study 36-item Short-Form General Health Survey (SF-36). This widely used questionnaire consists of 36 items forming eight domains or scales: physical functioning; social functioning; role physical (limitations in usual role activities due to physical problems); role emotional (limitations in usual role activities due to emotional problems); bodily pain; mental health; vitality; and general health perceptions. 4 We used the validated Dutch translation of the SF-36. 5 The questions refer to the previous 4 weeks. A score from 0 to 100 is calculated for each scale, with higher scores indicating better quality of life. Two summary scores can be calculated; the Physical Component Summary (PCS) and the Mental Component Summary (MCS), by adding weighted combinations of the eight scales. The summary scores are converted to standardized T scores that have a mean of 50 and a standard deviation (SD) of 10. A summary score of 50 (SD 10) reflects an average quality of life of the general population. Dermatology-specific quality of life: Skindex-29. This questionnaire consists of 29 items forming three scales: symptoms (e.g. itch, pain and irritation), emotions (e.g. worries, shame, embarrassment, frustration and depression), and functioning (e.g. sleep, social life, social isolation, sexuality, work and hobbies). The questions refer to the previous week; scores are given on a 5-point scale, from never to all the time. Scale scores and a sum score are calculated on a 100-point scale, with lower scores indicating better quality of life. 6 Statistical analysis To detect a priori differences between respondents and non-respondents, age and sex were compared using a ²-test and a t-test, respectively. The characteristics of patients with universal vitiligo were compared with those of generalized vitiligo, using a t-test or ²-tests. The means of the scale scores and the summary scores of the SF-36 and the Skindex-29 of patients with universal vitiligo were compared with those of patients with generalized vitiligo, using t-tests. Effect sizes were calculated. 7 An effect size of 0.3 can be considered as clinically important. 8 The level of significance was set at P<0.05. All statistical analyses were carried out using SPSS version 12.01 for Windows. 84
RESULTS Patient characteristics A total of 65 patients were eligible for this study. Six patients did not want to participate in the study, and 4 patients did not respond. The 55 patients included in this study (response rate: 85%) ranged from 22 to 77 years (median age: 52 years). The respondents and non-respondents did not differ significantly with respect to age and sex. Patient characteristics and P values are presented in Table 1. Comparison to patients with generalized vitiligo Almost half of the patients with universal vitiligo already had vitiligo before the age of 15 years, while in the majority of patients with generalized vitiligo the disease started from the age of 31 years (P<0.05). Patients with universal vitiligo reported significantly more comorbidities than the patients with generalized vitiligo Table 1. Patient characteristics Gender Age Age at onset Treatment history Male Female Median SD 0-15 years 16-30 year 31> years Treated patients Untreated patients Universal vitiligo N=55 % 13 42 51.7 12.8 26 17 12 38 17 24 76 47 31 22 69 31 General Vitiligo N=110 % P-value¹ 36 74 50.9 11.6 7 18 85 54 56 33 67 6 16 77 49 51 0.31 0.57 0.01 0.02 6 UNIVERSAL VITILIGO AND HEALTH-RELATED QUALITY OF LIFE Co-morbidity With Without 37 18 67 33 27 83 25 76 0.01 Common co-morbidities Thyroid disease Reumatoid artritis Diabetes Mellitus Alopecia areata 11 8 4 4 20 15 7 7 12 3 3 0 11 3 3 0 0.17 0.01 0.33 0.02 Vitiligo in the familiy Yes (Of which universal vitiligo) No 26 (13) 29 47 (24) 53 38 72 35 66 0.05 Symptoms Patients with symptoms - Itch - Sunburn - Itch and sunburn Patients without symptoms 3 21 8 23 6 38 15 42 10 50 15 35 9 46 14 32 0.84 0.54 1.00 0.27 Skintype I-III IV-VI 41 14 75 26 85 25 77 23 0.85 ¹ Significance level: P<0.05 85
6 (P<0.05). The most frequently mentioned comorbidities were thyroid dysfunction, rheumatoid arthritis, diabetes mellitus and alopecia areata. Patients with universal vitiligo seemed to experience rheumatoid arthritis more often (15%) than patients with generalized vitiligo (3%, P<0.05). Furthermore, alopecia areata was reported in 4 patients with universal vitiligo, whereas none of the patients with generalized vitiligo reported this comorbidity (P<0.05). Patients with universal vitiligo reported to have more family members (47%) with vitiligo than patients with generalized vitiligo (35%, P<0.05). Of the family members of patients with universal vitiligo, 24% also had universal vitiligo. Generic and dermatology-specific HRQL Table 2 shows the results of HRQL outcomes. Statistically significant differences were seen in the Physical Functioning, Bodily Pain, General Health domains and in the Physical Component Summary of the SF-36 with a poorer physical HRQL in patients with universal vitiligo. Scores on the Functioning scale of the Skindex- 29 were significantly higher in patients with universal vitiligo, indicating more functional impairment in these patients compared with patients with generalized vitiligo (P<0.05). The effect sizes of these statistically significant results can be considered clinically important. DISCUSSION To our knowledge, this is the first study focusing on patient characteristics and HRQL of patients with universal vitiligo. According to the literature, the prevalence of universal vitiligo within the whole population of vitiligo patients ranges from 0-5%-9.0%. 9-12 In our institute (NIPD), approximately 1% of the newly referred vitiligo patients are diagnosed with universal vitiligo. This percentage is based on our annual reports. A family history of vitiligo was reported in a relatively high percentage of the patients with universal vitiligo (47%). In our control group of patients with generalized vitiligo the percentage was 35%, which is in close agreement with several other studies in vitiligo, 11;13;14 while other studies report even lower percentages. 9;15;16 A recent study on multiple affected family members in generalized vitiligo showed that familial vitiligo is characterized by higher frequencies of autoimmune thyroid disease, rheumatoid arthritis and other autoimmune diseases. 17 Although we did not find higher frequencies of autoimmune disease in patients with a family history of vitiligo, we did find a difference in comorbidity in the two clinical subtypes of vitiligo: more patients with universal vitiligo reported to have rheumatoid arthritis and alopecia areata, in comparison to patients with generalized vitiligo. In our group of patients with generalized vitiligo, the presence of concurrent rheumatoid arthritis is in agreement with data from the literature. 17 The literature shows a high variability in the prevalence alopecia areata associated with generalized vitiligo, ranging from 0.3%-16%. 10;18-22 In our study, none of the 86
Table 2. Health related quality of life Universal vitiligo Generalized vitiligo SF-36¹ Mean (SD) Mean (SD) P-value² Effect size³ Physical functioning 80.2 (24.0) 87.9 (20.0) 0.03 0.35 Role physical 74.6 (38.3) 84.8 (29.1) 0.06 0.30 Bodily pain 70.3 (27.7) 81.5 (24.1) 0.01 0.43 General health 64.4 (23.3) 71.3 (19.8) 0.05 0.32 Vitality 61.0 (22.1) 67.0 (18.8) 0.07 0.29 Social functioning 77.1 (26.4) 84.3 (21.8) 0.06 0.30 Role emotional 78.8 (39.2) 84.3 (31.1) 0.33 0.16 Mental health 71.4 (19.4) 75.4 (16.8) 0.17 0.22 Physical Component Summary Score (PCS) 48.0 (11.6) 52.4 (9.9) 0.01 0.40 Mental Component Summary Score (MCS) 46.7 (11.5) 48.5 (10.0) 0.29 0.17 Skindex-29 4 Emotions 31.0 (28.2) 34.4 (21.1) 0.39 0.14 Functioning 22.5 (26.2) 15.2 (18.7) 0.04 0.32 Symptoms 19.3 (20.2) 14.3 (13.6) 0.06 0.29 Sum score 24.7 (22.3) 21.7 (15.5) 0.32 0.16 ¹ SF-36: Higher scores indicate better HRQL ² Significance level: P<0.05 ³ Effect size of 0.20, 0.50, and 0.80 were considered to be small, moderate and large respectively 4 Skindex-29: Lower scores indicate better HRQL 6 UNIVERSAL VITILIGO AND HEALTH-RELATED QUALITY OF LIFE patients with generalized vitiligo reported to have alopecia areata. The high prevalence of both rheumatoid arthritis and alopecia areata in universal vitiligo is a new finding. In 47% of the patients with universal vitiligo depigmentation started before the age of 15. This is in agreement with a Dutch epidemiological study involving 1061 patients with generalized vitiligo. 14 However, in our comparison group of patients with generalized vitiligo, first signs of the disease started in the majority of patients from the age of 31 years. We have to take into account that the comparison group consists of merely adult new referrals, leading to a selection bias in favour of lateonset vitiligo. As patients with universal vitiligo are often completely depigmented, sunburn could be a big problem. However, patients with universal vitiligo did not report to have more symptoms of sunburn than patients with general vitiligo. This might be due to the fact that most of our patients with universal vitiligo were treated with bleaching agents to reduce cosmetically disturbing remnants of normal 87
6 pigmentation in the face. We always instruct these patients to avoid sun exposure in order to prevent repigmentation. In general, patients with universal vitiligo reported poorer physical HRQL on the SF-36 as compared to patients with generalized vitiligo. This might be due to the higher amount of reported comorbidities. Measurement with the dermatologyspecific Skindex-29 revealed that patients with universal vitiligo reported more impairment in the Functioning scale compared to patients with generalized vitiligo. Both universal and generalized vitiligo patients reported emotional problems. The severity of these emotional problems was comparable to what has been found in patients with other skin diseases such as psoriasis, 6;23;24 chronic hand dermatitis 25 and acne. 26;27 CONCLUSIONS Our results suggest that universal vitiligo represents the high end of the spectrum in generalized vitiligo. This is represented by an extreme clinical presentation with (sub) total depigmentation, a strong familial expression of the disease and high prevalence of comorbidity, such as thyroid dysfunction, rheumatoid arthritis and alopecia areata. HRQL is comparable to what is found in generalized vitiligo except for poorer functioning in daily life and physical HRQL, which probably reflects comorbidity. REFERENCE LIST 1. Whitton ME, Ashcroft DM, Barrett CW et al. Interventions for vitiligo. Cochrane Database Syst Rev 2006; CD003263. 2. Njoo MD, Westerhof W. Vitiligo. Pathogenesis and treatment. Am J Clin Dermatol 2001; 2: 167-81. 3. Fitzpatrick TB. The validity and practicality of sun-reactive skin types I through VI. Arch Dermatol 1988; 124: 869-71. 4. Ware JE, Jr., Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care 1992; 30: 473-83. 5. 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: 1055-68. 6. 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: 1433-40. 7. Cohen J. Statistical power analysus for the behavioral sciences. Hillsdale, NJ : Lawrence Erlbaum Associates, 1988. 8. Revicki DA, Cella D, Hays RD et al. Responsiveness and minimal important differences for patient reported outcomes. Health Qual Life Outcomes 2006; 4: 1-5. 9. Dogra S, Parsad D, Handa S et al. Late onset vitiligo: a study of 182 patients. Int J Dermatol 2005; 44: 193-6. 10. Liu JB, Li M, Yang S et al. Clinical profiles of vitiligo in China: an analysis of 3742 patients. Clin Exp Dermatol 2005; 30: 327-31. 11. Schallreuter KU, Lemke R, Brandt O et al. Vitiligo and other diseases: coexistence or true association? Hamburg study on 321 patients. Dermatology 1994; 188: 269-75. 12. Alkhateeb A, Fain PR, Thody A et al. Epidemiology of vitiligo and associated autoimmune diseases in Caucasian probands and their families. Pigment Cell Res 2003; 16: 208-14. 13. Barona MI, Arrunategui A, Falabella R et al. An epidemiologic case-control study in a population with vitiligo. J Am Acad Dermatol 1995; 33: 621-5. 88
14. Westerhof W, Bolhaar B, Menke HE et al. Resultaten van een enquete onder vitiligo patiënten. Ned Tijdschr Dermatol Venereol 1996; 6: 100-5. 15. Handa S, Dogra S. Epidemiology of childhood vitiligo: a study of 625 patients from north India. Pediatr Dermatol 2003; 20: 207-10. 16. Hu Z, Liu JB, Ma SS et al. Profile of childhood vitiligo in China: an analysis of 541 patients. Pediatr Dermatol 2006; 23: 114-6. 17. Laberge G, Mailloux CM, Gowan K et al. Early disease onset and increased risk of other autoimmune diseases in familial generalized vitiligo. Pigment Cell Res 2005; 18: 300-5. 18. Demis DJ, Weiner MA. Alopecia universalis, onychodystrophy, and total vitiligo. Arch Dermatol 1963; 88: 195-201. 19. Gopal KV, Rama Rao GR, Kumar YH et al. Vitiligo: a part of a systemic autoimmune process. Indian J Dermatol Venereol Leprol 2007; 73: 162-5. 20. Ro BI. Alopecia areata in Korea (1982-1994). J Dermatol 1995; 22: 858-64. 21. Sharma VK, Kumar B, Dawn G. A clinical study of childhood alopecia areata in Chandigarh, India. Pediatr Dermatol 1996; 13: 372-7. 22. Sharma VK, Dawn G, Kumar B. Profile of alopecia areata in Northern India. Int J Dermatol 1996; 35: 22-7. 23. Sampogna F, Picardi A, Chren MM et al. Association between poorer quality of life and psychiatric morbidity in patients with different dermatological conditions. Psychosom Med 2004; 66: 620-4. 24. de Korte J, Van Onselen J, Kownacki S et al. Quality of care in patients with psoriasis: an initial clinical study of an international disease management programme. J Eur Acad Dermatol Venereol 2005; 19: 35-41. 25. Fowler JF, Ghosh A, Sung J et al. Impact of chronic hand dermatitis on quality of life, work productivity, activity impairment, and medical costs. J Am Acad Dermatol 2006; 54: 448-57. 26. Lasek RJ, Chren MM. Acne vulgaris and the quality of life of adult dermatology patients. Arch Dermatol 1998; 134: 454-8. 27. Jones-Caballero M, Chren MM, Soler B et al. Quality of life in mild to moderate acne: relationship to clinical severity and factors influencing change with treatment. J Eur Acad Dermatol Venereol 2007; 21: 219-26. 6 UNIVERSAL VITILIGO AND HEALTH-RELATED QUALITY OF LIFE 89
7 IMPACT OF CHILDHOOD VITILIGO ON ADULT LIFE M.W. Linthorst Homan J. de Korte M.A. Grootenhuis J.D. Bos M.A.G. Sprangers J.P.W. van der Veen Br J Dermatol. 2008; 159(4): 915-20
7 SUMMARY Background: The onset of vitiligo occurs before the age of 20 years in 50% of patients. Having a chronic disease in childhood can impede a child s health related quality of life (HRQL). Objective: Firstly, to compare the social and psychosexual development and current HRQL of young adult patients with childhood vitiligo with those of a group of healthy controls. Secondly, to compare these outcomes in patients reporting negative childhood experiences with those of patients not reporting negative childhood experiences. Methods: Eligible patients were mailed questionnaires on (i) sociodemographic and clinical characteristics, (ii) social and psychosexual development, (iii) generic and dermatology-specific HRQL, (iv) presence of negative childhood experiences related to vitiligo, (v) specification of these negative experiences and (vi) patients recommendations for further care. Results: A total of 232 patients with vitiligo completed the questionnaires. Social and psychosexual development and generic HRQL in young adult patients with childhood vitiligo were not different from those of healthy controls. However, patients reporting negative childhood experiences reported significantly more problems in social development than those not reporting negative experiences. Furthermore, negative childhood experiences were significantly associated with more HRQL impairment in early adulthood. Conclusions: Reporting negative experiences from childhood vitiligo appears to be associated with HRQL impairment in young adults with vitiligo. 92
INTRODUCTION Vitiligo is a chronic skin disease, characterized by the appearance of white depigmented maculae due to loss of melanocytes. This acquired pigment disorder is common in all races, regardless of age and sex. The onset of the disease may vary from early infancy to old age. In 50% of patients affected, the onset is before the age of 20 years. 1;2 Having a chronic disease in childhood can impede a child s health-related quality of life (HRQL). 3 Childhood, particularly adolescence, is characterized by rapid psychological and social development, and by emotional vulnerability. Negative experiences may have an impact on childhood development and adult life. 4 The visibility of vitiligo may induce such experiences, depending on the location and the extent of the disease, the age of the child, and its individual capacities and social environment. 5 The fulfilment of age-specific developmental tasks and the achievement of developmental milestones, such as making friends outside the family and forming sexual relationships, are of great importance to the ability to adjust to adult life. 6-8 No knowledge exists on psychosocial development and current HRQL of adult patients with childhood vitiligo. The first aim of this study was to compare the social and psychosexual development and current HRQL of adult patients with childhood vitiligo with those of a group of healthy controls. The second aim was to compare these outcomes in patients reporting negative childhood experiences with those of patients not reporting negative childhood experiences related to vitiligo. MATERIALS AND METHODS 7 IMPACT OF CHILDHOOD VITILIGO ON ADULT LIFE Study population The inclusion criteria for participation in the study were: (i) having general vitiligo in childhood (<15 years) diagnosed at the Netherlands Institute of Pigment Disorders between 1994 and 2006; (ii) age 18-30 years at the time of completing the study questionnaires (norm data of the Course of Life questionnaire were available for young adults aged 18-30 years 7 ); (iii) ability to read and understand Dutch. Eligible patients were mailed a package containing study information, an informed consent form, a questionnaire booklet and a stamped return envelope. Patients were asked to return a signed informed consent form together with the completed questionnaires. In case a patient did not respond, the patient was reminded by phone with a maximum of three follow-up calls. Patients who did not want to participate were asked to return a short form asking about their age, sex and reason for declining study participation. Medical ethics approval was not required as in the Netherlands approval is only required for self-report questionnaires containing intrusive items. 93
7 Measures The questionnaire booklet included the following seven measures: Sociodemographic and clinical characteristics A study-specific questionnaire addressing sociodemographic and clinical patient characteristics. Social and psychosexual development Two scales of the Course of Life questionnaire 6 : (i) social development; (ii) psychosexual development. These scales investigate developmental stages of young adults, aged 18-30 years, grown up with a chronic disease. For each item, the answers were scored with a no (1) or yes (2), with a higher score indicating the accomplishment of more developmental tasks. A comparison group for the Course of Life questionnaire was recruited through general practitioners in a former study and consisted of 508 healthy controls, 239 (47%) men and 269 (53%) women. The median age of this comparison group was 23.8 (range 18.0-30.9). 7 Generic health-related quality of life The Dutch version of the SF-36 was used. 9 10 This questionnaire consists of 36 items forming eight domains or scales and two summary scores. The questions refer to the previous 4 weeks. A score from 0 to 100 was calculated for each scale, with higher scores indicating a better quality of life. We selected 201 respondents, with matching ages (16-25 years), from a Dutch reference population (1742 persons without chronic illness). 10 Dermatology-specific health-related quality of life The Skindex-29, a dermatology-specific HRQL questionnaire, consists of 29 items forming three scales: Symptoms, Emotions, and Functioning. The questions refer to the previous week; scores are given on a five-point scale, from never to all the time. Scale scores and an overall or summary score are calculated on a 100-point scale, with lower scores indicating a better quality of life. 11 Presence of negative childhood experiences related to vitiligo A question was asked on negative experiences during childhood related to vitiligo: Did you have negative experiences related to vitiligo in your childhood? (Yes/No). If answered yes, we asked subjects to describe these negative experiences. We did not give a definition for negative experiences; patients could determine what they considered to be a negative experience from their vitiligo. The question was used to divide two distinct subgroups: patients who indicated to have had negative experiences from vitiligo during childhood (yes) versus those who did not (no). Specification of negative experiences A study-specific questionnaire, consisting of 21 questions assessing experiences related to vitiligo during the primary and secondary school period. Questions were based on the clinical experience of the authors, including dermatologists 94
and psychologists. Patients were asked retrospectively whether vitiligo during childhood was considered to account for specific social discomfort. Scores were given on a five-point scale, from never to all the time. Higher scores indicate that vitiligo during childhood was considered to account for more social discomfort. Patients recommendations for further care A set of five questions asked for respondents recommendation for further care. Scores were given on a five-point scale, from never to all the time. Higher scores indicate requirement of more (psychosocial) support. We pilot-tested the questionnaires in four vitiligo patients for breadth of coverage and clarity. Patients found the questionnaires comprehensive and clear. Statistical analysis Descriptive analyses were performed to assess the characteristics of the sample. To detect a priori differences between respondents and non-respondents, age and gender were compared using a ²-test and a Student s t-test respectively. Comparison of patients with healthy controls The mean scores of the social and psychosexual development scale and SF-36 scale scores of patients were compared to those of a group of healthy controls using Student s t-tests. Effect sizes (d) were calculated by dividing the difference between the mean scores of each group by the pooled standard deviation (SD) for those means. Following Cohen s recommendations, effect sizes of 0.20, 0.50 and 0.80 were considered to be small, moderate and large, respectively. 12 Comparison of patients with and without negative experiences Patients who indicated to have had negative experiences were compared with those who did not. To detect a priori differences betweens these subgroups, sociodemographic and clinical patient characteristics were compared using Student s t-tests and ²-tests. P<0.05 indicated statistical significance. For the social and psychosexual development scales, the SF-36 and the Skindex-29, the means of these groups were compared using Student s t-tests. Effect sizes were calculated. The answers on specification of negative experiences and patients recommendations were dichotomised into never-seldom-sometimes versus oftenalways. The percentages of patients in the latter category were compared between the two groups, using ²-tests. P<0.01 indicated statistical significance. 7 IMPACT OF CHILDHOOD VITILIGO ON ADULT LIFE 95
RESULTS Patients characteristics The questionnaire booklet was sent to 306 patients. A total of 232 patients completed and returned the booklet (response rate 76%). The median age of these 232 patients was 21.3 years (range 18-28); one third (32.3%) was male (Table 1). Nine of 74 patients returned the non-response form. These non-respondents reported that they were not interested, did not have time, or did not feel like participating in the study. The respondents and non-respondents did not differ significantly with respect to age and gender (data not shown). 7 Comparison of patients with healthy controls The mean social and psychosexual development scores of patients did not differ significantly from those of the healthy controls (Table 2). Additionally, none of the SF-36 mean scores differed significantly from those of the healthy controls (Table 3). Comparison of patients with and without negative experiences Patients A total of 91 (40.1%) patients reported negative experiences of their vitiligo during childhood (Table 1). Patients reporting negative experiences reported more frequently (P<0.05) that they had vitiligo on their feet, arms, and genitals. The most commonly reported negative experiences are shown in Table 4. Social and psychosexual development Patients who reported to have had negative childhood experiences scored significantly lower (P<0.01, d=0.38) on the domain social development than patients who did not report negative experiences (Table 2). Generic and dermatology specific health-related quality of life Patients with negative childhood experiences reported significantly poorer HRQL in all the domains of the SF-36 and the Skindex-29 (P<0.01). The effect sizes for the scales of the SF-36 were moderate (0.42-0.77) and those of the Skindex-29 were moderate to large (0.44-1.04) (Table 5). Specification of negative experiences Shame towards peers was the most common negative experience during primary and secondary school (52.8% and 56.0%, respectively), followed by avoidance of intimacy and/or social activities and tendency to do things alone (Table 6). Questions on avoidance of treatment and absence from school did not seem to be relevant (P >0.12). Patients recommendations for further care Patients both with and without negative experiences reported a requirement for more information about the disease and its treatment (55.1% and 43.6%, respectively). Patients with negative experiences of their vitiligo during childhood reported that they would have required more personal coaching, contact with fellow sufferers, and psychological support (P<0.01) (Table 7). 96
Without negative experiences N=136² (%) P-Value Table 1. Patient characteristics. Total N=232 (%) With negative experiences N=91¹ (%) 0.08 Gender male female 75 (32.3) 157 (67.7) 23 (25.3) 68 (74.7) 51 (37.5) 85 (62.5) 0.08 Age Mean (SD) Median 21.6 (2.7) 21.3 22.0 (2.5) 21.7 21.4 (2.7) 20.9 0.83 Age at onset 1-5 year 6-10 year 10-15 years 67 (28.9) 105 (45.3) 58 (25.0) 25 (27.5) 44 (48.4) 21 (23.1) 40 (29.4) 61 (44.9) 35 (25.7) 0.85 Treatment history Untreated patients Treated patients 22 (9.5) 210 (90.5) 8 (8.8) 83 (91.2) 13 (9.6) 123 (90.4) 0.65 Current treatment Yes No 40 (17.4) 190 (82.6) 17 (18.7) 74 (81.3) 21 (15.4) 115 (84.6) 0.45 Symptoms (itch and sunburn) Patients with symptoms - Itch - Sunburn - Itch and sunburn Patients without symptoms 14 (6.0) 51 (22.0) 7 (3.0) 159 (68.5) 8 (8.8) 21 (23.1) 2 (2.2) 59 (64.8) 6 (4.4) 29 (21.3) 4 (2.9) 97 (71.3) 0.54 Comorbidity Thyroid disease³ Rheumatic arthritis Diabetes Mellitus 11 (4.9) 3 (1.3) 5 (2.5) 7 (7.7) 2 (2.2) 2 (2.2) 4 (2.8) 1 (0.7) 3 (2.1) 0.43 0.01 0.01 0.05 0.07 0.76 0.07 0.68 0.35 Localization 4 Legs Feet Arms Genitals Hands Chest/Trunk Face Back Neck 171 (74.0) 162 (70.1) 157 (68.0) 150 (64.9) 143 (61.9) 130 (56.3) 125 (54.1) 90 (39.0) 61 (26.4) 71 (78.0) 75 (82.4) 72 (79.1) 68 (74.7) 64 (70.3) 53 (58.2) 57 (62.6) 38 (41.8) 27 (29.7) 97 (72.4) 84 (62.7) 82 (61.2) 82 (61.2) 77 (57.5) 74 (55.2) 66 (49.3) 51 (38.1) 31 (23.1) 7 1, 2: five missing values 3: Hypothyroid: nine patients (n=6 with negative experiences, n=3 without) Hyperthyroid: two patients (n=1 with negative experiences, n=1 without) 4: Multiple options possible; totals exceed 100% IMPACT OF CHILDHOOD VITILIGO ON ADULT LIFE 97
Table 2. Social and psychosexual development. Social development Psycho-sexual development Study population Mean ± SD 21.26 ± 2.25 21.06 ± 2.42 7.25 ± 1.16 7.17 ± 1.13 Healthy controls P-value/ Mean ± SD Effect size* 0.32/ 0.09 0.39/ 0.07 With negative experiences Mean ± SD Without negative experiences Mean ± SD 20.74 ± 2.33 21.59 ± 2.11 7.34 ± 1.08 7.20 ± 1.22 P-value/ Effect size 0.01/ 0.38 0.35/ 0.12 7 * Effect sizes of 0.20, 0.50 and 0.80 were considered to be small, moderate and large, respectively Table 3. Results of the SF-36 and the reference population. SF-36 Reference Total group (SD) population (SD) P-value Effect size* Physical functioning 94.3 (12.3) 94.2 (9.6) 0.93 0.01 Role physical 87.6 (27.8) 88.3 (25.4) 0.79 0.03 Bodily pain 84.8 (20.6) 82.5 (19.1) 0.24 0.11 General health 75.1 (22.2) 77.9 (17.2) 0.15 0.16 Vitality 66.7 (20.1) 70.6 (15.7) 0.03 0.25 Social functioning 87.9 (20.6) 87.8 (18.1) 0.96 0.00 Role emotional 83.3 (32.7) 83.7 (30.4) 0.90 0.01 Mental health 75.8 (18.5) 77.8 (14.2) 0.22 0.14 Physical Component Score (PCS) 54.9 (7.0) 54.8 (6.5) 0.88 0.01 Mental Component Score (MCS) 48.1 (10.7) 49.0 (8.8) 0.35 0.10 * Effect size of 0.20, 0.50, and 0.80 were considered to be small, moderate and large respectively Table 4. Examples of negative experiences. Negative experiences n (%) Teased at school 31 (34) Negative self-image 30 (33) To be stared at 20 (22) Feelings of shame 18 (20) Difficulties in choosing clothing 11 (12) Avoidance of sport activities 9 (10) Inconvenient questions by strangers 6 (6.6) 98
Table 5. Results of the SF-36 and Skindex-29. SF-36 Patients with negative experiences in the past (SD) Patients without negative experiences in the past (SD) P-value Effect size* Physical functioning 90.3 (16.2) 96.9 (7.7) 0.01 0.52 Role physical 78.3 (34.8) 93.8 (19.9) 0.01 0.55 Bodily pain 79.3 (22.5) 88.5 (18.5) 0.01 0.45 General health 68.5 (24.7) 79.5 (19.3) 0.01 0.50 Vitality 59.5 (21.8) 71.5 (17.5) 0.01 0.61 Social functioning 80.1 (24.7) 93.1 (15.5) 0.01 0.63 Role emotional 74.0 (38.7) 89.5 (26.5) 0.01 0.47 Mental health 67.4 (21.0) 81.2 (14.2) 0.01 0.77 Physical Component Score (PCS) 53.1 (8.0) 56.1 (6.0) 0.01 0.42 Mental Component Score (MCS) 43.8 (12.4) 50.9 (8.4) 0.01 0.67 Skindex-29 Total 20.6 (15.4) 7.4 (10.4) 0.01 1.00 Symptoms 9.1 (11.3) 4.5 (9.3) 0.01 0.44 Emotions 33.6 (23.1) 12.9 (16.0) 0.01 1.04 Functioning 16.5 (17.2) 4.6 (10.4) 0.01 0.84 * Effect size of 0.20, 0.50, and 0.80 were considered to be small, moderate and large respectively DISCUSSION To our knowledge, this is the first study focusing on developmental milestones, negative experiences during childhood and HRQL in young adult patients with childhood vitiligo. We found that the social and psychosexual development during childhood and current generic HRQL in young adult patients in whom vitiligo was diagnosed in early childhood were not different from a group of healthy controls. However, patients reporting negative experiences of their vitiligo during childhood reported significantly more problems in social development. Surprisingly their psychosexual development appeared to be comparable to that of healthy controls. Furthermore, negative childhood experiences were significantly associated with more HRQL impairment in early adulthood, as measured by the generic SF-36 and the dermatology-specific Skindex-29. The generic HRQL is even comparable to that of patients with atopic eczema, a far more symptomatic disease. 13 Reporting negative childhood experiences has a large relevance for dermatology-specific HRQL as the effect sizes were predominantly large. Special attention is warranted for patients with vitiligo on feet, arms and genitals, who seem to be at risk for negative experiences. 7 IMPACT OF CHILDHOOD VITILIGO ON ADULT LIFE 99
Table 6. Specification of negative experiences. 7 PRIMARY SCHOOL Vitiligo (Always-often) lead to With negative experiences (%) Without negative experiences (%) P-value Feelings of shame towards peers 52.8 8.3 0.01 Avoidance of intimacy 23.6 2.3 0.01 Avoidance of social activities 21.3 0.8 0.01 Tendency to do things alone 15.9 0.8 0.01 Avoidance of sport activities 14.6 0.8 0.01 Conflicts with parents 5.6 0.8 0.08 Avoidance of treatment 3.4 1.5 0.65 Absence from school 3.4 0.0 0.12 SECONDARY SCHOOL Feelings of shame towards peers 56.0 10.4 0.01 Tendency to do things alone 38.5 3.0 0.01 Avoidance of intimacy 34.1 3.7 0.01 Avoidance of social activities 24.2 0.0 0.01 Avoidance of sport activities 23.1 2.2 0.01 Conflicts with parents 9.9 0.0 0.01 Avoidance of treatment 4.4 3.0 0.85 Absence from school 2.2 0.0 0.32 Table 7. Patients recommendations for further care. Vitiligo (Always-often) lead to With negative experiences (%) Without negative experiences (%) P-value Demand for information about the disease and treatment 55.1 43.6 0.13 Demand for personal coaching/advice of the dermatologist 56.2 37.8 0.01 Contact with fellow sufferers 21.6 2.2 0.01 Psychological support 15.6 1.5 0.01 Support of a social worker 7.9 0.7 0.02 Most patients in our study population would have liked more information and guidance by their physicians. Unfortunately, physicians do not regularly offer support. Porter et al. 14 found that patients with vitiligo are emotionally distressed by the disease and two thirds of the patients reported feelings of embarrassment. However, they received little support from their physicians. Moreover, Ongenae et al. 15 and Njoo et al. 16 reported that vitiligo is often considered as just a cosmetic skin disorder 100
by physicians and they found that most dermatologists do not offer active treatment for vitiligo. Our findings show that dermatologists should be alert to these concerns of their patients. Awareness of and responsiveness to these important issues need to be integral components of medical education and training. This study has various limitations. Firstly, the two scales of the Course of Life questionnaire and the social discomfort questionnaire are retrospective, and enquire about current perceptions of past experiences. The extent to which negative experiences actually occurred in the past cannot be answered easily and would require prospective study designs. Secondly, the focus of our study was the perception of negative experiences in the past. Localization, skin type and extent of the disease at present could also have influenced the outcomes of this study. Thirdly, the gender distribution is not representative for the general vitiligo population, as women are predominant in this study group. In future research it might be important to develop a disease-specific questionnaire with the aid of patients with vitiligo to obtain more insight into the detailed experiences of patients both during childhood and thereafter. The most important finding of this study is that reporting negative experiences from vitiligo in childhood appears to be significantly associated with HRQL impairment in young adults with vitiligo. We suggest that young adults with vitiligo could be screened for HRQL impairment by the following simple question: Did you have negative experiences from vitiligo in daily life during childhood? We recommend physicians to provide more guidance to their patients with vitiligo, especially those who report negative experiences. REFERENCES LIST 1. Njoo MD, Westerhof W. Vitiligo. Pathogenesis and treatment. Am.J.Clin.Dermatol. 2001; 2: 167-81. 2. Whitton ME, Ashcroft DM, Barrett CW et al. Interventions for vitiligo. Cochrane.Database. Syst.Rev. 2006; CD003263. 3. Beattie PE, Lewis-Jones MS. A comparative study of impairment of quality of life in children with skin disease and children with other chronic childhood diseases. Br.J.Dermatol. 2006; 155: 145-51. 4. Haavet OR, Straand J, Saugstad OD et al. Illness and exposure to negative life experiences in adolescence: two sides of the same coin? A study of 15-year-olds in Oslo, Norway. Acta Paediatr. 2004; 93: 405-11. 5. Hill-Beuf A, Porter JD. Children coping with impaired appearance: social and psychologic influences. Gen.Hosp.Psychiatry 1984; 6: 294-301. 6. Grootenhuis MA, Stam H, Destree-Vonk A et al. Levensloop Vragenlijst voor Jong- Volwassenen. [Course of life questionnaire for young adults]. Gedrag en gezondheid 2003; 31: 336-50. 7. Stam H, Grootenhuis MA, Last BF. The course of life of survivors of childhood cancer. Psychooncology. 2005; 14: 227-38. 8. Last BF, Grootenhuis MA, Destree- Vonk A et al. De ontwikkeling van een levensloopvragenlijst voor jong-volwassenen (LVJV) [The development of a course of life questionnaire for young adults]. Gedrag en gezondheid 2000; 12: 213-25. 9. Ware JE, Jr., Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med.Care 1992; 30: 473-83. 10. 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: 1055-68. 11. Chren MM, Lasek RJ, Flocke SA et al. Improved discriminative and evaluative capability of a refined version of Skindex, a quality-of-life 7 IMPACT OF CHILDHOOD VITILIGO ON ADULT LIFE 101
instrument for patients with skin diseases. Arch.Dermatol. 1997; 133: 1433-40. 12. Cohen J. Statistical power analysis for the behavioral sciences. Hillsdale, NJ : Lawrence Erlbaum Associates, 1988. 13. Holm EA, Wulf HC, Stegmann H et al. Life quality assessment among patients with atopic eczema. Br.J.Dermatol. 2006; 154: 719-25. 14. 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: 73-7. 15. Ongenae K, Van Geel N, De Schepper S et al. Management of vitiligo patients and attitude of dermatologists towards vitiligo. Eur.J.Dermatol. 2004; 14: 177-81. 16. Njoo MD, Bossuyt PM, Westerhof W. Management of vitiligo. Results of a questionnaire among dermatologists in The Netherlands. Int.J.Dermatol. 1999; 38: 866-72. 7 102
8 SUMMARY AND CONCLUSIONS
8 The first part of this thesis included three studies on clinical and patient reported outcomes in the treatment of vitiligo. In the second part, the focus was on healthrelated quality of life (HRQL) and other patient reported outcomes in vitiligo. The general introduction in Chapter 1 provided a brief overview of the aetiology, pathogenesis and current treatment options for vitiligo as well as of clinical and patient reported outcomes used in vitiligo research. In the absence of a consensus on well-defined, quantitative, outcome measures, it is difficult to pool and to compare the results of clinical studies in vitiligo. Therefore, in Chapter 2, a systematic review was presented on the properties of clinician, patient and observer reported outcomes measures. These properties were summarized and critically appraised. Electronic databases MEDLINE, EMBASE and CINAHL were searched. 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 was used to calculate the overall level of evidence per measurement property of each instrument. Fourteen studies involving 11 measurement instruments met the inclusion criteria. It appeared that recommendations on the use of specific outcome measures for vitiligo should be formulated with caution: current evidence is insufficient due to the low number of studies, their relatively poor methodological quality, and unclear clinical relevance. Strong evidence was found for a good internal consistency of the quality of life questionnaire Dermatology Life Quality Index (DLQI). For other instruments the evidence of measurement properties was limited or unknown. In order to be able to recommend on outcome measures for vitiligo, further research on measurement properties of clinically relevant outcome measures for vitiligo according to COSMIN quality criteria is needed. In Chapter 3 repigmentation of vitiligo lesions after punch grafting was assessed in three ways, and the results of these assessments were compared with each other. In 21 patients, one specific vitiligo patch was selected. This patch was treated with the punch grafting technique. The grade of repigmentation (%) after 3 months was assessed by i) a digital image analysis system (DIAS), ii) 3 clinical observers and iii) patients themselves scoring the grade of repigmentation by photographs of the lesions. Physicians and patients also evaluated the global result on a 7-point scale. The scores of DIAS, clinical and patients assessment were compared and correlations were calculated with the use of the intra-class correlation (ICC) coefficient. ICC values of 0.80 1.0, 0.60 0.80, and 0.40 0.60 are generally considered to indicate almost perfect, substantial, or moderate agreement, respectively. We found an almost perfect agreement between the three clinical observers and the DIAS (ICC 0.83). However, there was a large variation between the three clinical observers which is not uncommon in visual assessment. Patients scores showed a moderate agreement with the DIAS (ICC 0.49) and a poor agreement with the physicians (ICC 0.28). Overall, the patients were more satisfied with the results than the physicians. 106
The DIAS can overcome the inevitable differences between observers, such as inter-rater and intra-rater variability, inherent in visual grading. Therefore, it appeared to be a good objective tool for the assessment of repigmentation in vitiligo patches, thereby enabling reliable cross-treatment and cross-study comparisons. However, this technique is complex and laborious. Therefore, it was suggested that the DIAS should be used in clinical trials in which only a small number of lesions needs to be evaluated. Phototherapy following punch grafting may stimulate the migration of melanocytes from the grafts into the vitiliginous skin, thereby increasing the rate of repigmentation. In Chapter 4 we described a prospective, single blinded, randomized within-patient controlled study comparing the effects of phototherapy using the 308-nm xenon chloride excimer laser (EL) versus Narrow Band UVB (NB-UVB) treatment after punch grafting in vitiligo patients. Fourteen patients were treated with the punch grafting technique on two symmetrical vitiligo patches. Starting 1 week after the punch grafting, the vitiligo patches were treated twice a week during 3 months, with EL on one side and with NB-UVB on the other side. Repigmentation (%) was measured by a DIAS. Patients satisfaction with- and preference for treatment were also assessed. Contrary to our expectations, EL did not result in a higher degree of repigmentation as compared to NB-UVB; results were comparable. However, with EL, a 71.4% lower cumulative dose was reached compared to NB-UVB. Interestingly, patients favoured the NB-UVB treatment as they were more satisfied with it and preferred it over EL. The choice between EL and NB-UVB cannot solely be based on repigmentation, but rather on other factors, such as patients preferences. Given the lower UV dose of EL, we recommend its use in selected patient groups, such as small children and patients with sun-damaged skin and/or a history of long-term UVB treatment. In Western societies, vitiligo is often regarded as a harmless cosmetic skin problem. As a consequence, the relevance of treating vitiligo patients is often underestimated. In Chapter 5 we described a study estimating the burden of vitiligo in a large cohort of vitiligo patients by measuring their health-related quality of life (HRQL) with two questionnaires; the generic, 36-item Short-Form General Health Survey (SF-36) and the dermatology-specific questionnaire, the Skindex-29. The SF-36 is a widely used questionnaire. It consists of 36 items forming eight domains or scales. Two summary scores were calculated; the Physical Component Summary (PCS) and the Mental Component Summary (MCS). The Skindex-29 consists of 29 items forming three scales (symptoms, emotions and functioning). All consecutive adult patients (age >18 years) with generalized vitiligo, referred to the Netherlands Institute of Pigment Disorders (NIPD) from January to December 2006, were invited to participate in the study. A total of 245 adult patients with generalized vitiligo (response rate=98.8%) completed the two quality of life questionnaires. Physicians assessed sociodemographic and clinical 8 SUMMARY AND CONCLUSIONS 107
8 characteristics of these patients. A descriptive analysis was carried out to assess the characteristics of the sample. Our results indicated that adult patients with generalized vitiligo have a MCS score lower than that of the general population and comparable to that of patients with other skin diseases, such as atopic eczema, psoriasis and hand eczema. Measurement with the dermatology-specific Skindex-29 revealed that in patients with generalized vitiligo, scores on the emotions scale were higher (which means more problems in emotional life) than scores on the symptoms and functioning scale. Scores on the emotions scale were also comparable to that of patients with psoriasis, atopic eczema, chronic hand dermatitis and acne. Moreover, vitiligo appeared to be associated with itch in 20% of the patients. Unexpectedly, localization of vitiligo on visible areas, like hands and face, did not appear to be a major determinant for loss of HRQL, whereas localization on the chest, especially in women, was associated with lower HRQL. Furthermore, and not unexpectedly, generalized vitiligo particularly affected patients with a dark skin (skin type IV-VI). In fact, skin type was the only clinical patient characteristic that was independently associated with both generic and dermatology-specific loss of HRQL. Further longitudinal studies are needed to obtain additional insight into the stability of the associations found in this study, and in order to evaluate the efficacy of medical and/or psychological interventions in patients with an impaired HRQL. In Chapter 6 a retrospective cohort study focusing on patient characteristics and HRQL of patients with universal vitiligo was presented. The characteristics and the HRQL of 55 patients with universal vitiligo were compared with those of 110 patients with generalized vitiligo. Patients with universal vitiligo reported a higher percentage of affected family members compared to patients with generalized vitiligo (47% versus 35%). Moreover, patients with universal vitiligo reported significantly more comorbidity like rheumatoid arthritis (15%) and alopecia areata (7%) than patients with generalized vitiligo (3% and 0% respectively). Surprisingly, the impact on HRQL was comparable to what was found in generalized vitiligo except for poorer functioning in daily life and physical HRQL, which possibly reflects the difference in comorbidity as described above. In half of the patients, vitiligo starts before the age of 20 years. Having a chronic disease in childhood could impede a child s well-being and development. In Chapter 7, data on developmental milestones, negative experiences during childhood and HRQL in young adult patients suffering from vitiligo since childhood, were compared to data from healthy controls. Furthermore, outcomes in patients reporting disease-related negative childhood experiences were compared with those from patients not reporting negative childhood experiences. Eligible patients were mailed questionnaires on (i) sociodemographic and clinical characteristics, (ii) social and psychosexual development (two scales of the Course of Life questionnaire), (iii) generic (SF-36) and dermatology-specific 108
(Skindex-29) HRQL, (iv) presence of negative childhood experiences related to vitiligo, (v) specification of these negative experiences, and (vi) patients recommendations for further care. A total of 232 patients with vitiligo completed the questionnaires. We found that the social and psychosexual development during childhood and current generic HRQL in young adult patients in whom vitiligo was diagnosed in early childhood were not different from a group of healthy controls. However, patients reporting negative vitiligo-related experiences during childhood reported significantly more problems in social but not in psychosexual development. The most important finding of this study was that the report of negative vitiligo-related experiences in childhood appeared to be significantly associated with HRQL impairment in young adults with vitiligo. We suggest that young adults with vitiligo should be screened for HRQL impairment by the following simple question: Did you have negative experiences from vitiligo in daily life during childhood? We recommend physicians to provide more guidance to their vitiligo patients, especially those who report negative experiences. 8 SUMMARY AND CONCLUSIONS 109
9 SAMENVATTING EN CONCLUSIES
9 Het eerste deel van dit proefschrift bestaat uit drie studies over klinische en patient reported outcomes voor de behandeling van vitiligo. In het tweede deel lag de nadruk op kwaliteit van leven en andere patient reported outcomes in vitiligo. De introductie in hoofdstuk 1 bevat een overzicht van de etiologie, pathogenese en behandelopties voor vitiligo en van de klinische en patient reported outcomes in vitiligo onderzoek. Omdat er geen consensus is voor goed gedefinieerde, kwantitatieve uitkomst parameters, is het moeilijk om de resultaten van klinische studies bij vitiligo te vergelijken. Daarom is in hoofdstuk 2 een systematische review beschreven over de eigenschappen van klinische, patiënt en waarnemer gebonden uitkomstmaten. Deze eigenschappen zijn samengevat en kritisch beoordeeld. Er werd gezocht in de elektronische databases MEDLINE, EMBASE and CINAHL. De COnsensusbased Standards for the selection of health status Measurement INstruments (COSMIN), een instrument om methodologische kwaliteit van studies over meeteigenschappen te evalueren, was gebruikt om de algemene level of evidence per instrument te beoordelen. Veertien studies, met daarin 11 meetinstrumenten, voldeden aan de inclusie criteria. Het bleek dat aanbevelingen voor het gebruik van specifieke uitkomstmaten voor vitiligo met voorzichtigheid geformuleerd moeten worden: het huidige bewijs is onvoldoende door het beperkt aantal studies, hun relatief zwakke methodologische kwaliteit, en de onduidelijke relevantie. Sterke aanwijzingen werden gevonden voor een goede interne consistentie van de kwaliteit van leven vragenlijst Dermatology Life Quality Index (DLQI). Voor de andere instrumenten was het bewijs van de meeteigenschappen gelimiteerd of onbekend. Meer onderzoek is nodig naar meeteigenschappen van klinisch relevante uitkomstmaten voor vitiligo volgens de COSMIN kwaliteitscriteria. In hoofdstuk 3 werd de repigmentatie van vitiligo laesies na punch grafting beoordeeld op drie manieren, en de resultaten van deze beoordelingen werden met elkaar vergeleken. Eén specifieke vitiligo laesie werd geselecteerd bij 21 patiënten. Deze laesie werd behandeld met de punch grafting methode. De repigmentatie (%) werd beoordeeld na 3 maanden door i) een digital image analyse systeem (DIAS), ii) 3 artsen en iii) de patiënten zelf, aan de hand van foto s van de behandelde vitiligo laesie. Artsen en patiënten vulden ook een 7-punt schaal vragenlijst in met een evaluatie van het eindresultaat. De scores van de DIAS, van de artsen en van de patiënten werden vergeleken en de correlaties werden berekend met de intra-class correlation (ICC) coëfficiënt. ICC waarden van 0.80 1.0, 0.60 0.80, en 0.40 0.60 betekenen respectievelijk een bijna perfecte, substantiële, of matige overeenkomst. Wij vonden een bijna perfecte overeenkomst tussen de drie artsen en de DIAS (ICC 0.83). Echter, er was een grote variatie tussen de drie artsen onderling, hetgeen niet ongebruikelijk is bij visuele beoordeling. Patiënten scores liet een matige overeenkomst zien met de DIAS (ICC 0.49) en een slechte met die van de artsen (ICC 0.28). Over het algemeen waren de patiënten meer tevreden met de resultaten dan de artsen. 112
De DIAS kan de onvermijdelijke verschillen tussen beoordelaars helpen voorkomen, zoals de variabiliteit tussen verschillende en in dezelfde beoordelaars, die inherent is aan visuele beoordeling. Daarom blijkt DIAS een goede objectieve maat voor de repigmentatie score van vitiligo laesies, waarbij het mogelijk wordt om betrouwbare vergelijkingen te maken tussen verschillende studies. Echter, deze techniek is complex en tijdintensief. Daarom adviseren we de DIAS te gebruiken voor die klinische trials waarbij het volstaat om slechts een klein aantal laesies te beoordelen. Fototherapie na punch grafting kan de migratie van melanocyten vanuit de punch grafts naar de omringende vitiligohuid stimuleren en daardoor kan de repigmentatie toenemen. In Hoofdstuk 4 beschreven we een prospectieve, enkel geblindeerde, gerandomiseerde, binnen de patiënt gecontroleerde studie om de effecten te vergelijken van de 308-nm xenon chloride excimer laser (EL) versus de Narrow Band UVB (NB-UVB) behandeling na punch grafting in vitiligo patiënten. Veertien patiënten werden behandeld met de punch grafting techniek in twee symmetrische vitiligo laesies. Een week na de punch grafting werden de vitiligo laesies tweemaal per week gedurende 3 maanden behandeld met EL aan de ene kant en met NB-UVB aan de andere kant. Repigmentatie (%) werd gemeten met behulp van de DIAS. Patiëntentevredenheid met en voorkeur voor de behandeling werden ook onderzocht. De EL en de NB-UVB gaven vergelijkbare repigmentatie. Met de EL werd er een 71.4% lagere cumulatieve dosis (J/cm 2 ) bereikt vergeleken met NB-UVB. Een interessante bevinding was dat patiënten een voorkeur hadden voor NB-UVB behandeling, omdat ze meer tevreden waren met deze behandeling vergeleken met de EL. De keuze tussen EL en NB-UVB kan niet alleen gebaseerd worden op de repigmentatie, maar mede ook op andere factoren, zoals patiëntenvoorkeur. Omdat dat de EL een lagere UV dosis geeft, adviseren wij dit te gebruiken in geselecteerde patiënten groepen, zoals bij kleine kinderen en bij patiënten met een door de zon beschadigde huid en/of met een voorgeschiedenis van langdurige UVB behandeling. In westerse landen wordt vitiligo vaak gezien als een onschuldige, cosmetische huidziekte. Daardoor wordt de noodzaak tot behandeling vaak onderschat. In hoofdstuk 5 beschrijven we een studie naar de last van vitiligo in een groot cohort van vitiligo patienten door de Kwaliteit van Leven (KvL) te meten met twee vragenlijsten: de generieke, de SF 36 ( 36-item Short-Form General Health Survey ) en de dermatologie specifieke vragenlijst, de Skindex-29. De SF-36 is een wereldwijd gebruikte vragenlijst. Deze bestaat uit 36 vragen die 8 domeinen of schalen vormen. Twee samenvattende scores werden berekend; de Physical Component Summary (PCS) en de Mental Component Summary (MCS). De Skindex-29 bestaat uit 29 vragen welke 3 schalen vormen (symptomen, emoties en functioneren). Alle achtereenvolgende volwassen patiënten (leeftijd >18 jaar) met vitiligo vulgaris, die werden verwezen naar de Stichting Nederlands Instituut voor Pigmentstoornissen (SNIP) van januari tot en met december 2006, werden 9 SAMENVATTING EN CONCLUSIES 113
9 uitgenodigd om aan de studie deel te nemen. In totaal voltooiden 245 patiënten met vitiligo vulgaris (respons=98.8%) de twee KvL vragenlijsten. Artsen noteerden de demografische en klinische karakteristieken van deze patiënten. Onze resultaten tonen aan dat volwassen patiënten met vitiligo vulgaris een lagere MCS score hebben vergeleken met de algemene bevolking, maar een vergelijkbare score met die van patiënten met andere huidziekten, zoals atopisch eczeem, psoriasis en handeczeem. De resultaten van de dermatologie specifieke Skindex-29 toonden aan dat bij patiënten met vitiligo vulgaris de scores van de emotieschaal hoger waren dan van de symptomen en/of functioneren schaal. De scores van de emotieschaal waren ook vergelijkbaar met die van patiënten met psoriasis, atopisch eczeem, chronisch handeczeem en acne. Bovendien bleek vitiligo geassocieerd met jeuk bij 20% van de patiënten. Tegen de verwachting in bleek dat de lokalisatie van vitiligo op zichtbare plaatsen zoals handen en gezicht geen belangrijke determinant voor verlies van KvL was, terwijl locatie op de borst, speciaal bij vrouwen, geassocieerd was met een verminderde KvL. Tevens, wel verwacht, had vitiligo vooral invloed op patiënten met een donkere huid (huidtype IV-VI). Het huidtype was de enige klinische patiëntenkarakteristiek die onafhankelijk was geassocieerd met zowel generieke als dermatologie specifieke verlies van kwaliteit van leven. Longitudinale studies zijn nodig om verder inzicht te verkrijgen in de stabiliteit van de associaties die gevonden zijn in deze studie, en om de effectiviteit van medische en/of psychologische interventies te evalueren bij patiënten met een verminderde KvL. In hoofdstuk 6 wordt een retrospectieve cohort studie gepresenteerd over patiënten karakteristieken en KvL bij patiënten met vitiligo universalis. De karakteristieken en KvL van 55 patiënten met vitiligo universalis werden vergeleken met die van 110 patiënten met vitiligo vulgaris. Patiënten met vitiligo universalis rapporteerden een hoger percentage van familieleden met vitiligo vergeleken patiënten met vitiligo vulgaris (47% versus 35%). Bovendien vermeldden patiënten met vitiligo universalis significant meer comorbiditeiten zoals reumatoïde artritis (15%) en alopecia areata (7%) dan patiënten met vitiligo vulgaris (3% en 0% respectievelijk). Verassend was dat de impact op KvL vergelijkbaar was met de KvL van patiënten met vitiligo vulgaris, behalve voor het functioneren in het dagelijks leven en de Physical Component Score, deze waren slechter bij patiënten met vitiligo universalis. Dit hangt mogelijk mede samen met het verschil in comorbiditeit, zoals hierboven beschreven. Bij de helft van de patiënten begint vitiligo voor de leeftijd van 20 jaar. Een chronische ziekte in de jeugd kan het welzijn en de ontwikkeling van het kind belemmeren. In hoofdstuk 7 werden de gegevens van ontwikkeling in mijlpalen, negatieve ervaringen in de jeugd en KvL bij jong volwassenen patiënten die vitiligo hebben sinds de jeugd, vergeleken met gezonde personen. Tevens werden de uitkomsten van patiënten die ziektegerelateerde negatieve jeugdervaringen hadden gemeld, vergeleken met die van patiënten zonder ziekte gerelateerde negatieve jeugdervaringen. 114
Patiënten kregen vragenlijsten toegestuurd betreffende (i) demografische en klinische karakteristieken, (ii) sociale and psychosexuele ontwikkeling (twee schalen van de Course of Life vragenlijst), (iii) generieke (SF-36) en dermatologiespecifieke (Skindex-29) KvL, (iv) aanwezigheid van negatieve jeugd ervaringen gerelateerd aan vitiligo, (v) specificatie van deze negatieve ervaringen en, (vi) aanbevelingen van patiënten voor het bevorderen van de zorg. In totaal 232 patiënten met vitiligo vulden de vragenlijsten in. We vonden dat de sociale en psychosexuele ontwikkeling gedurende de jeugd en huidige generieke KvL in jong volwassen patiënten bij wie vitiligo was gediagnosticeerd in de vroege jeugd, niet verschillend was ten opzichte van de groep van gezonde personen. Patiënten met een negatieve vitiligo-gerelateerde ervaring gedurende de jeugd vermeldden significant meer problemen in sociale maar niet in psychosexuele ontwikkeling. De meest belangrijke bevinding van deze studie was dat het rapporteren van negatieve vitiligo gerelateerde ervaringen in de jeugd significant geassocieerd was met verminderde KvL bij jong volwassen patiënten met vitiligo. We suggereren dat jong volwassenen met vitiligo gescreend moeten worden voor KvL vermindering door hen de volgende simpele vraag voor te leggen: Heeft u in uw jeugd nare ervaringen gehad vanwege uw vitiligo? We adviseren aan artsen meer begeleiding te geven aan vitiligo patiënten, vooral bij hen die negatieve ervaringen vermelden. 9 SAMENVATTING EN CONCLUSIES 115
& SF-36
& SF-36 119
& 120
& SF-36 121
& 122
& SF-36 123
& SKINDEX-29
& 126
& SKINDEX-29 127
& BIBLIOGRAFIE
Linthorst Homan MW, Wolkerstorfer A, Sprangers MA, van der Veen JP. Digital image analysis vs. clinical assessment to evaluate repigmentation after punch grafting in vitiligo. J Eur Acad Dermatol Venereol. 2012 May 23, doi: 10.1111/ j.1468-3083.2012.04568 Linthorst Homan MW, Spuls PI, Nieuweboer-Krobotova L, de Korte J, Sprangers MA, Bos JD, Wolkerstorfer A, van der Veen JP. A randomized comparison of excimer laser versus narrow-band ultraviolet B phototherapy after punch grafting in stable vitiligo patients. J Eur Acad Dermatol Venereol. 2012 Jun;26(6):690-5. Linthorst Homan MW, Spuls PI, de Korte J, Bos JD, Sprangers MA, van der Veen JP. The burden of vitiligo: patient characteristics associated with quality of life. J Am Acad Dermatol. 2009 Sep;61(3):411-20. Linthorst Homan MW, de Korte J, Grootenhuis MA, Bos JD, Sprangers MA, van der Veen JP. Impact of childhood vitiligo on adult life. Br J Dermatol. 2008 Sep;159(4):915-20. Linthorst Homan MW, Sprangers MA, de Korte J, Bos JD, van der Veen JP. Characteristics of patients with universal vitiligo and health-related quality of life. Arch Dermatol. 2008 Aug;144(8):1062-4. Baarslag HJ, Koopman MM, Hutten BA, Linthorst Homan MW, Büller HR, Reekers JA, van Beek EJ. Long-term follow-up of patients with suspected deep vein thrombosis of the upper extremity: survival, risk factors and post-thrombotic syndrome. Eur J Intern Med. 2004 Dec;15(8):503-507. PubMed PMID: 15668085. Vrijman C, Linthorst Homan MW, Limpens J, van der Veen JP, Wolkerstorfer A, Terwee CB, Spuls PhI. Measurement properties of outcome measures for vitiligo: a systematic review. Accepted for pubication in Archives of Dermatology. & BIBLIOGRAFIE 131
& CURRICULUM VITAE
May Linthorst Homan werd geboren op 19 februari 1978 te Arnhem. In 1996 behaalde ze haar diploma aan het Stedelijk Gymnasium te Arnhem. Omdat ze was uitgeloot voor de studie geneeskunde is ze van 1996-1997 in Parijs Frans gaan studeren aan de Université Paris-Sorbonne. Aansluitend startte ze in 1997 met de studie geneeskunde aan de Vrije Universiteit te Amsterdam. Tijdens de doctoraalfase was zij betrokken bij wetenschappelijk onderzoek naar trombose op de afdeling Vaculaire Geneeskunde in het Academisch Medisch Centrum te Amsterdam onder begeleiding van professor dr. H.R. Büller en professor dr. M.M. Levi. In 2002 tot 2004 volgde zij haar coschappen in regio Noord-Holland, een keuze coschap kindergeneeskunde in Paramaribo, Suriname en het oudste coschap op de afdeling dermatologie van het Academisch Medisch Centrum te Amsterdam. Aansluitend werd het artsexamen in 2004 cum laude afgelegd. Daarna heeft ze gedurende vier maanden gewerkt als ANIOS interne geneeskunde in ziekenhuis Hilversum voordat zij in april 2005 begon als ANIOS dermatologie in de Stichting Nederlands Instituut voor Pigmentstoornissen in combinatie met wetenschappelijk onderzoek, wat geleid heeft tot dit proefschrift. In oktober 2007 startte ze haar eerste helft van de opleiding tot dermatoloog in het Onze Lieve Vrouwe Gasthuis, te Amsterdam onder begeleiding van professor dr. R. Hoekzema en professor dr. J.D. Bos en het laatste deel in het Academisch Medisch Centrum onder begeleiding van dr. J. Mekkes. Eind november 2012 verwacht ze de opleiding af te ronden. Vanaf april 2013 zal zij werkzaam zijn als fellow dermatologie in Dermatologisch Centrum Isala te Zwolle. May is getrouwd met Daan Beetsma en samen hebben zij een zoon Matthijs en een dochter Anna. Eind december 2012 verwachten zij hun derde kindje. & CURRICULUM VITAE 135
& DANKWOORD
HEEL VEEL DANK AAN Professor J.D. Bos, mijn promotor. Voor de mogelijkheid te promoveren en de begeleiding daarvan, voor de mogelijkheid tot dermatoloog opgeleid te worden, voor het vertrouwen en de ruime tijd die u mij gaf om het proefschrift af te ronden en voor de nuttige en inspirerende besprekingen de laatste maanden voorafgaand aan de promotie. Professor Mirjam Sprangers, mijn promotor. Voor jouw waardevolle begeleiding, voor jouw snelle, heldere, gedetailleerde en zeer zinvolle commentaar op de vele versies van de artikelen (anders was mijn proefschrift er niet in deze vorm geweest) en voor de bijzondere en gezellige middag die we samen achter jouw computer hebben gewerkt aan hoofdstuk 4. Wietze van der Veen, mijn co-promotor. Voor de mogelijkheid tot promotie onderzoek binnen de SNIP, voor je adviezen en voor je kritische beoordeling van de manuscripten. & John de Korte, mijn co-promotor. Voor je kritische commentaar op en de adviezen voor, in het bijzonder, de kwaliteit van leven onderzoeken. De leden van de promotiecommissie: Professor dr. N. van Geel, Professor dr. M.A. Grootenhuis, Professor dr. R.J. de Haan, Professor dr. R. Hoekzema, Professor dr. T. Nijsten. Voor uw deelname aan de commissie en de tijd die u hebt vrijgemaakt voor het beoordelen van mijn manuscript. Professor Rick Hoekzema. En ook voor de mogelijkheid voor de zeer leerzame en leuke opleiding in het OLVG die ik nooit had willen missen. Professor Martha Grootenhuis. En ook voor de fijne samenwerking en het realiseren van een interessant hoofdstuk 7. Professor Rob de Haan. En ook voor de begeleiding van de statistische analyse van hoofdstuk 5. Inge Oskam en Heleen Sterneberg-Vos, mijn paranimfen. Voor de bijzondere en dierbare vriendschap en dat jullie aan mijn zijde staan op 11 oktober. Vitiligo patiënten die betrokken waren bij de onderzoeken. Voor de vrijwillige en vaak enthousiaste deelname aan de verschillende studies. Violet. Voor het mooie ontwerp van de cover van mijn proefschrift. Phyllis Spuls. Voor je hulp bij het opzetten van een aantal studies, voor de kritische beoordelingen daarvan en voor je steun in mijn onderzoekstraject. 138
Charlotte Vrijman. Voor de mogelijkheid die jij mij gaf mee te werken aan de systematic review zodat het mogelijk werd mijn promotie af te ronden en voor de gezellige samenwerking. Albert Wolkerstorfer. Voor je goede adviezen en hulp bij de klinische studies. Inka Nieuweboer-Krobotová. Voor je hulp bij het behandelen van patiënten voor de studie excimer laser vs NB-UVB. Robert Lindeboom, Bellinda King, Jan Binnekade en Pythia Nieuwkerk. Voor de onmisbare hulp bij de statistische analyses. De SNIPpers : Bernice, Carmen, Alisa, Mijke, Linda, Mireille, Daphne. Voor jullie ondersteuning bij mijn onderzoek en de fijne, leuke en gezellige samenwerking. Bas, Mandy, Marjan, Pina, Elian en Lidian. Voor de tips en adviezen bij het afronden van het proefschrift. Sanna, Anna-Christa, Willemijn, Wendy en Marieke. Voor jullie adviezen voor en de leuke gesprekken over allerlei promotie voorbereidingen. Marjolein. Voor het enthousiasme voor de dermatologie dat jij in Suriname aan mij hebt overgebracht. Alle overige (oud- en huidige) collega arts assistenten. Voor de leuke opleidingstijd die we samen hadden/ hebben. Alle stafleden, verpleegkundigen en baliemedewerkers van de afdeling dermatologie OLVG en AMC. Voor de fijne en gezellige samenwerking. Jan Mekkes. Voor de leerzame en leuke opleidingstijd in het AMC. Robert. Voor al je technische hulp en het oplossen van alle computerproblemen. Marja en Mariska. Voor alle ondersteunende hulp. Alle sponsoren. Voor de financiële ondersteuning voor het drukken van dit proefschrift. Eric Ullmann. Voor de waardevolle gesprekken en de enorme stimulans de afgelopen jaren. Vele andere vrienden en familieleden hier niet bij name genoemd. Voor de interesse en belangstelling de afgelopen jaren. Papa en Mama. Voor ALLES! Papa, en ook voor je hulp bij de voorbereidingen van het proefschrift. & DANKWOORD Daan, Matthijs en Anna. Omdat jullie zo lief zijn en mij zo gelukkig maken! Jullie zijn mijn allergrootste geluk! 139
STELLINGEN Zoals bij zoveel ziekten, wordt bij vitiligo veel onderzoek gedaan naar nieuwe behandelingen zonder gebruik te maken van degelijke parameters. (dit proefschrift) Bij behandeling van vitiligo valt op dat de behandelaars regelmatig minder tevreden zijn over de effectiviteit dan de patiënt zelf. (dit proefschrift) Vitiligo gaat met meer symptomen gepaard dan alleen pigmentverlies. (dit proefschrift) Patiënten met vitiligo universalis hebben, tegen de verwachting in, gemiddeld genomen niet meer verlies van kwaliteit van leven dan vitiligo patiënten met minder uitgebreide vitiligo. (dit proefschrift) Vitiligo op kinderleeftijd heeft invloed op kwaliteit van leven wanneer zij volwassenen zijn. (dit proefschrift) It is important to have a catchy name for your questionnaire. (Andrew Finlay) Het niet vergoeden van de behandeling van C2 varices (klinisch relevante en klachten veroorzakende varices) draagt niet bij tot verbetering van de kwaliteit van zorg en zal ook niet leiden tot kostenbesparing. Marktwerking in de zorg leidt tot een markt waarin de zorg niet werkt. Als U dan toch in de directe zon wilt of moet zijn, vermijd die dan in ieder geval wanneer Uw schaduw korter is dan Uzelf. (J.D.Bos) It always seems impossible until it is done. (Nelson Mandela) Succes dient niet alleen gemeten te worden aan de hoogten die zijn bereikt, maar ook aan de obstakels die zijn overwonnen.