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Table 1. 
Evaluation of First-Choice Therapies
Evaluation of First-Choice Therapies
Table 2. 
Mean Estimated Percentages of Patients With Vitiligo Who Achieved Repigmentation (>75%) Induced by First-Choice Therapies*
Mean Estimated Percentages of Patients With Vitiligo Who Achieved Repigmentation (>75%) Induced by First-Choice Therapies*
Table 3. 
Treatment Scheme for Vitiligo
Treatment Scheme for Vitiligo
Table 4. 
First-Choice Therapies in 302 Patients With Vitiligo Evaluated Over 6 Months
First-Choice Therapies in 302 Patients With Vitiligo Evaluated Over 6 Months
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Woolf  SH Practice guidelines: a new reality in medicine, I: recent developments. Arch Intern Med. 1990;1501811- 1818Article
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Woolf  SH Practice guidelines, a new reality in medicine, II: methods of developing guidelines. Arch Intern Med. 1992;152946- 952Article
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Woolf  SH Practice guidelines: a new reality in medicine, III: impact on patient care. Arch Intern Med. 1993;1532646- 2655Article
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Kenney  JA  JrGrimes  PE How we treat vitiligo. Cutis. 1983;32347- 348
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Antoniou  CKatsambas  A Guidelines for the treatment of vitiligo. Drugs. 1992;43490- 498Article
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Grimes  PE Vitiligo: an overview of therapeutic approaches. Dermatol Clin. 1993;11325- 338
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Drake  LADinehart  SMFarmer  ER  et al.  Guidelines of care for vitiligo: American Academy of Dermatology. J Am Acad Dermatol. 1996;35620- 626Article
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Eddy  DM The challenge. JAMA. 1990;263287- 290Article
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Evidence-Based Medicine Working Group, Evidence-based medicine: a new approach to teaching the practice of medicine. JAMA. 1992;2682420- 2425Article
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Sackett  DLRosenberg  WMGray  JAMHaynes  RBRichardson  WS Evidence based medicine: what it is and what it isn't. BMJ. 1996;31271- 72Article
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Ladhani  S The need for evidence-based management of skin diseases. Int J Dermatol. 1997;3617- 22Article
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Eddy  DM Clinical decision making: from theory to practice: guidelines for policy statements: the explicit approach. JAMA. 1990;2632239- 22402243Article
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Njoo  MDSpuls  PIBos  JDWesterhof  WBossuyt  PMM Nonsurgical repigmentation therapies in vitiligo: meta-analysis of the literature. Arch Dermatol. 1998;1341532- 1540
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Njoo  MDWesterhof  WBos  JDBossuyt  PMM A systematic review of autologous transplantation methods in vitiligo. Arch Dermatol. 1998;1341543- 1549
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Mosher  DBParrish  JAFitzpatrick  TB Monobenzylether of hydroquinone: a retrospective study of treatment of 18 vitiligo patients and a review of the literature. Br J Dermatol. 1977;97669- 679Article
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Thissen  MWesterhof  W Laser treatment for further depigmentation in vitiligo. Int J Dermatol. 1997;36386- 388Article
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Westerhof  WNieuweboer-Krobotova  LMulder  PGGlazenburg  EJ Left-right comparison study of the combination of fluticasone propionate and UV-A vs either fluticasone propionate and UV-A alone for the long-term treatment of vitiligo. Arch Dermatol. 1999;1351061- 1066Article
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Grimshaw  JMRussell  IT Effect of clinical guidelines on medical practice: a systematic review of rigorous evaluations. Lancet. 1993;3421317- 1322Article
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Grimshaw  JMRussell  IT Achieving health gain through clinical guidelines, I: developing scientifically valid guidelines. Qual Health Care. 1993;2243- 248Article
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Evidence-Based Dermatology: Original Contribution
December 1999

The Development of Guidelines for the Treatment of Vitiligo

Author Affiliations
 

DamianoAbeniMDMichaelBigbyMDPaoloPasquiniMD, MPHMoysesSkzloMDHywelWilliamsMSc, FRCP, PhD

Arch Dermatol. 1999;135(12):1514-1521. doi:10.1001/archderm.135.12.1514
Abstract

Objective  To develop and introduce evidence-based guidelines for the treatment of vitiligo in children and in adults.

Patients and Setting  Patients, residents, and dermatologists from the Department of Dermatology, Academic Medical Center, University of Amsterdam, and the Netherlands Institute for Pigmentary Disorders in Amsterdam.

Design  Scientific evidence obtained from 3 systematic reviews of the literature was combined with the results of 2 questionnaires and interviews of potential users of the guidelines, 3 internal expert meetings, and 1 local expert meeting, during which preliminary guidelines were presented and commented on. A final version of the guidelines was synthesized and disseminated among potential users. Six months after the introduction of these guidelines, their use was evaluated.

Results  Before the development of the guidelines, there was no uniformity in treatment selection, and there was a variability in estimates of treatment outcome. The meta-analysis showed class 3 corticosteroids and narrowband UV-B to be the most effective and safest therapies for localized and for generalized vitiligo, respectively. From another systematic review, it could be concluded that patients with segmental, stable, or lip-tip vitiligo could be successfully treated with most autologous transplantation methods. For vitiligo universalis, results of the systematic review showed that depigmentation using monobenzone or a Q-switched ruby laser was equally effective. The final version of the guidelines consisted of a treatment scheme together with detailed treatment protocols. Implementation of the guidelines was evaluated in 5 physicians. After the introduction of these guidelines, they were followed in most adult cases with vitiligo (71% of patients with localized vitiligo, 82% with generalized vitiligo, 100% with stable or segmental vitiligo, and 80% with universal vitiligo). In children with vitiligo, the physicians adhered to the guidelines for 52% of the cases.

Conclusions  Guidelines for the treatment of vitiligo can be successfully developed and disseminated for daily clinical practice. The results of the implementation of these guidelines should be confirmed in other centers involving more clinicians.

VITILIGO is a common idiopathic pigmentary skin disorder for which there is no definite cure available. Treatment for vitiligo aims to achieve repigmentation in the lesions and to stabilize the depigmenting process. Repigmentation leads to an improvement of the cosmetic appearance and of the skin tolerance for sunburns.1 Each year, many articles are published about the effectiveness and safety of various different repigmentation therapies. Because of the increasing clinical knowledge and literature, it is essential to create strategies that may facilitate therapeutic decision making.

There is a growing interest in the use of clinical guidelines for the practice of medicine. Guidelines contain systemati cally developed statements that assist the clinician in choosing the most appropriate therapy for a specific condition. Guidelines are regarded as tools to reduce inappropriate care, control geographic variations in practice patterns, and make the use of health care resources more effective.24 Several guidelines and review articles have been published on categories of vitiligo patients that should receive therapy and, if so, which treatment should be applied.58 Unfortunately, many of these recommendations were based on personal preferences. Some were the product of informal or formal institutional consensus meetings, which were at best supported by a limited number of references to the scientific literature.3 Personal and institutional experience can be misleading, since the number of observations is usually small and there are no controls. Furthermore, decisions about intervention made by patients and physicians are far from random; follow-up is usually limited, incomplete, and short-term; and memory can be highly selective. Consequently, there is a wide variation in the therapeutic histories of comparable patients.9

Since the early 1980s, more evidence-based guidelines are being developed. Evidence-based guidelines link recommendations directly to scientific evidence of effectiveness. Rules of evidence are emphasized over expert opinion in making recommendations.1012 Within this movement, the explicit method specifies the benefits, harms, and costs of potential interventions to derive explicit estimates of the probability of each outcome and compares the desirability of the outcomes from the patient's perspective. This approach enhances the accuracy and diminishes the subjectivity of treatment recommendations. When sufficient scientific proof is lacking, estimates may also be generated by expert opinion, provided that the source of the estimate is adequately documented.13

Many skin diseases, such as vitiligo, are chronic in nature and have an unknown cause. Therefore, the choice for treatment varies with certain patient and disease characteristics. Recent clinical evidence has shown that many traditional vitiligo treatments are ineffective or harmful, or have been replaced by more effective and less-toxic therapeutic modalities. A more systematic approach using practice guidelines can be valuable in the treatment of vitiligo, since it incorporates new information into existing strategies of therapeutic decision making.

In this article, we describe the development and implementation of evidence-based guidelines for the treatment of vitiligo at the Netherlands Institute for Pigmentary Disorders (NIPD) and the Department of Dermatology, Academic Medical Center, Amsterdam, the Netherlands.

METHODS

At the start of the project, a guideline-development group was composed, consisting of 1 main investigator (M.D.N), 2 staff members of the Department of Dermatology (W.W. and J.D.B.), a clinical epidemiologist (P.M.M.B.), a clinical librarian, and an external expert on pigmentary disorders who did not work at either of the 2 institutions.

An evaluation was made of the existing strategies for the treatment of vitiligo using a questionnaire and a structured interview. A meta-analysis of the literature was performed concerning the most currently studied and applied nonsurgical repigmentation therapies and the most current autologous transplantation methods and depigmentation therapies.

During a first internal meeting, the results of the evaluation of initial status and the results of the literature studies were presented. A draft of the guidelines was discussed. Subsequently, preliminary guidelines were developed and discussed in a second internal meeting. At a final expert meeting, the preliminary guidelines were revised. After its acceptance, the final version of the guidelines was disseminated. Their use was evaluated 6 months after the introduction.

RESULTS
EVALUATION OF THE TREATMENT POLICY BEFORE DEVELOPMENT OF THE GUIDELINES

The NIPD is a specialized national outpatient clinic for patients with pigmentary skin diseases. In 1997, 1951 new patients were seen at this institute. Of these, 8.3% (162/1951) were patients from the city of Amsterdam and its surrounding areas, and 91.7% (1789/1951) came from outside this region. Seven hundred forty-one patients with vitiligo were diagnosed in 1997 (38% of all diagnoses). In 1997, 5751 new patients visited the outpatient clinic of the Department of Dermatology of the Academic Medical Center of the University of Amsterdam. Patients came from the city of Amsterdam and its surrounding areas (65% [3738/5751]) as well as from outside this region (35% [2013/5751]). In 1997, 43 patients (0.7% of all diagnoses) were diagnosed as having vitiligo, of which 90% were referred to the NIPD. At the beginning of the study in September 1997, the NIPD consisted of 1 dermatologist and 2 residents. The Department of Dermatology comprised 9 dermatologists and 12 residents.

To detect variations in current treatment policy and disagreements in estimates of treatment outcome and adverse effects, an evaluation was made of the existing strategies for the treatment of vitiligo. The evaluation consisted of a questionnaire and a structured interview. An inventory was made of the therapy choices and regimens for the treatment of vitiligo using a questionnaire. All physicians were asked for their definition of a successful event in vitiligo therapy. Subsequently, all participants were interviewed by one of the investigators (M.D.N.) and asked to comment on their own therapy selection. For each therapeutic option, their opinion was solicited regarding the expected percentage of patients achieving a successful event and on the expected rates of adverse effects.

Of the 23 questionnaires sent, 14 were filled in and returned. Nine physicians (all from the Department of Dermatology) reported that they had too little experience with the treatment of vitiligo, since they had treated no more than 5 patients with vitiligo over the past year. These physicians did not complete the questionnaire.

The first-choice therapies of the remaining 14 respondents are listed in Table 1. The results show that the respondents were not unanimous in their selection of a first-choice therapy. For children younger than 12 years, topical corticosteroid therapy was chosen by 79% (11/14) of the respondents for localized vitiligo, 79% (11/14) for generalized vitiligo, and 86% (12/14) for stable vitiligo. In children with generalized vitiligo, phototherapeutic modalities, such as narrowband UV-B and oral psoralen–UV-A (PUVA), were prescribed by 14% (2/14) and 7% (1/14) of the respondents, respectively. Children with lip-tip vitiligo or universal vitiligo were not given any therapy by 79% (11/14) and 93% (13/14) of the physicians, respectively. Autologous transplantation methods were not chosen as first-choice therapy for children by any of the respondents.

For adults, topical corticosteroid therapy was prescribed by 64% (9/14) of the physicians for localized vitiligo, 71% (10/14) for generalized vitiligo, and 79% (11/14) for lip-tip vitiligo. In patients with generalized vitiligo, other treatment choices were narrowband UV-B therapy (14% [2/14]) and oral PUVA (7% [1/14]). In patients with stable vitiligo, most respondents (71% [10/14]) recommended autologous transplantation as the first-choice therapy. There was also no consensus regarding the therapy for patients with universal vitiligo; 64% (9/14) would offer depigmentation therapy, whereas 36% (5/14) would prescribe repigmentation therapy with oral PUVA.

During the interviews, it appeared that most respondents (12 of 14) regarded "more than 75% repigmentation" as a cosmetically acceptable level of repigmentation. Therefore, this was defined as a successful event of vitiligo therapy. Table 2 shows that physicians working at the NIPD are generally more optimistic toward treatment outcome than those working at the Department of Dermatology. The expected rates of adverse effects were more or less consistent among the respondents (results not shown). Many respondents questioned whether therapy-induced repigmentations were permanent. They did not agree on the maximum recommended dosage for phototherapies in view of the long-term carcinogenic risks.

SYSTEMATIC REVIEW OF THE LITERATURE

We have performed a meta-analysis and a systematic review of the available literature (last update, December 1997) on the most applied forms of nonsurgical repigmentation therapy and autologous transplantation methods, respectively, with regard to both effectiveness and safety. The methods and results of these studies have been reported elsewhere.14,15 In addition, a systematic review was performed on the effectiveness and safety of depigmentation therapies for vitiligo (M.D.N., W.W., J.D.B., and P.M.M.B., unpublished study, 1987). Data sources consisted of computerized searches of bibliographic databases (using MEDLINE [National Library of Medicine, Bethesda, Md] and EMBASE [Elsevier Science BV, Amsterdam, the Netherlands), a complementary manual literature search, and contacts with researchers and pharmaceutical firms. Predefined selection criteria were applied to both randomized controlled trials (RCTs) and nonrandomized controlled trials. Two investigators (M.D.N. and W.W.) independently assessed the articles for inclusion. When there was a disagreement, a third investigator (P.M.M.B.) was consulted. A preliminary search revealed that only a minor number of RCTs had been performed on vitiligo therapies. Therefore, analysis was also performed on the available patient series. Because comparative or placebo-controlled trials can contain a description of at least 2 patient series, the total number of patient series could exceed the total number of studies included.

META-ANALYSIS OF NONSURGICAL REPIGMENTATION THERAPIES

Sixty-three studies were found on therapies for localized vitiligo. Of these, 10 of 11 RCTs and 29 of 110 patient series were included. One hundred seventeen studies on therapies for generalized vitiligo were found. Of these 10 of 22 RCTs and 46 of 231 patient series were included. Most studies were excluded because they described combination therapies or an obsolete drug or dosage scheme and because there were inadequate or insufficient data on effectiveness.

Among RCTs on localized vitiligo, the pooled odds ratio vs placebo for topical class 3 corticosteroid therapy was 14.32 (95% confidence interval [CI], 2.45-83.72). In the patient series, topical class 3 and class 4 corticosteroid therapies had the highest mean success rates (56%; 95% CI, 50%-62%; and 55%; 95% CI, 49%-61%, respectively). Topical methoxsalen (8-MOP; ICN, Costa Mesa, Calif) therapy had the highest proportion of patients developing phototoxic reactions (58%; 95% CI, 51%-65%), followed by trioxsalen therapy (39%; 95% CI, 23%-56%) and unsubstituted psoralen therapy (25%; 95% CI, 12%-38%). Atrophy was the most common adverse effect for local corticosteroid therapy, occurring most commonly in patients receiving treatment with intralesional corticosteroids (33%; 95% CI, 22%-43%), followed by patients treated with class 4 corticosteroids (14%; 95% CI, 10%-18%) and class 3 corticosteroids (2%; 95% CI, 1%-5%).

In the RCTs on generalized vitiligo, the odds ratio vs placebo for treatment with oral 8-methoxsalen and sunlight was 23.37 (95% CI, 1.33-409.93), and for treatment with oral unsubstituted psoralen and sunlight it was 19.87 (95% CI, 2.37-166.32); for treatment with oral trioxsalen and sunlight the pooled odds ratio was 3.75 (95% CI, 1.24-11.29). In the series, the best mean success rates were reported for narrowband UV-B (63%; 95% CI, 50%-76%), broadband UV-B (57%; 95% CI, 29%-82%), and oral methoxsalen and UV-A (51%; 95% CI, 46%-56%) therapies. Treatment with oral methoxsalen and UV-A was associated with the highest rates of adverse effects, including nausea and vomiting in 29% (95% CI, 24%-35%) and phototoxic reactions in 25% (95% CI, 20%-30%) of the cases. No adverse effects were reported with narrowband or broadband UV-B therapy.

The results of this study allowed us to conclude that class 3 corticosteroids and UV-B were the most effective and safest therapies for localized and for generalized vitiligo, respectively.

SYSTEMATIC REVIEW OF AUTOLOGOUS TRANSPLANTATION METHODS

Sixty-three studies were found, of which 16 reported on minigrafting, 13 on split-thickness skin grafting, 15 on grafting of epidermal blisters, 17 on grafting of cultured melanocytes, and 2 on grafting of noncultured epidermal suspension. Of these, 39 patient series were included in our analysis. Autologous transplantation methods were performed in cases of stable and segmental vitiligo. Patients with lesions on sites that did not respond to nonsurgical therapies, such as lips, hands, feet, fingers (so-called lip-tip vitiligo), and genital areas, were also treated with these methods.

The highest mean success rates were achieved with split-thickness skin (87%; 95% CI, 82%-91%) and epidermal blister (87%; 95% CI, 83%-90%) grafting. The average success rate for 5 culturing techniques varied from 13% to 53%. However, for 4 of the 5 culturing methods, fewer than 20 patients were reported. Minigrafting had the highest rate of adverse effects. Scar formation of the donor site occurred in 40% of the cases (95% CI, 34%-47%), and cobblestoning appearance of the grafts at the acceptor site was seen in 27% of the cases (95% CI, 21%-33%). Nevertheless, minigrafting was shown to be the easiest, fastest, and least expensive method.

Because no comparative controlled trials were included, the treatment recommendations for transplantation should be viewed with caution. Split-thickness skin or epidermal blister grafting can be recommended as the most effective and safest techniques. No definite conclusions can be drawn with regard to the effectiveness of culturing techniques, since only a small number of patients have been studied. The choice of transplantation method also depends on disease characteristics as well as on the availability of specialized personnel and equipment.

SYSTEMATIC REVIEW OF DEPIGMENTATION THERAPIES FOR VITILIGO UNIVERSALIS

Two studies were found on therapy with monobenzone. One was a case report and had to be excluded. The second was an open retrospective study of 18 patients.16 One patient dropped out of this study. Eight (47%; 95% CI, 23%-72%) of the remaining 17 patients who were treated with monobenzone achieved 100% depigmentation.

Only 1 study was found on depigmentation therapy using the Q-switched ruby laser.17 In 3 (38%; 95% CI, 9%-76%) of 8 patients who received treatment with the Q-switched ruby laser, 100% depigmentation was observed.

Burning, erythema, contact dermatitis, and pruritus occurred most commonly in patients who were treated with depigmenting cream. Patients who were treated with laser therapy experienced pain in 50% of the cases and erythema in all cases. These adverse effects disappeared after 2 or 3 days.

Treatment recommendations regarding the most effective and safest depigmenting therapy for vitiligo universalis can only be made with caution, since only 1 study has been found for the 2 different modalities. For now, no large differences in the levels of effectiveness can be inferred from the 2 trials included in the analysis. One may prefer the use of a cream over laser therapy, since cream is less expensive and easier to apply. A major disadvantage, however, is that bleaching with cream may take months or years to result in evident signs of depigmentation. In contrast, laser therapy is faster, and it is possible to treat larger areas of residual pigment at once, but one must keep in mind that patients with a negative Koebner phenomenon will not respond to laser therapy.

THE DEVELOPMENT OF PRELIMINARY GUIDELINES

Nine dermatologists and 12 residents from the Department of Dermatology, 1 dermatologist and 1 resident from the NIPD, and an independent clinical epidemiologist participated in the first internal meeting. During this meeting, the results of the questionnaires, interviews, and literature studies were presented and discussed.

Based on the results of the questionnaire, the literature studies, and the first internal meeting, preliminary guidelines for the treatment of vitiligo were synthesized. These guidelines were distributed by internal mail to all potential users (staff dermatologists and residents of both target institutions).

In the second internal meeting, which was attended by the same personnel as the first, participants gave their comments on the preliminary guidelines. At the same time, a draft of the preliminary guidelines was mailed to the external expert for critical review.

THE FINAL VERSION OF THE GUIDELINES

Comments from the staff members and the residents of both institutions and comments from the external expert were incorporated in a new draft of the guidelines. The final version was then synthesized in the form of a treatment scheme (Table 3). Recommendations regarding first and alternatives choices were given according to the age of the patient, clinical type, severity of disease, and disease activity. Recommendations on the minimum and maximum treatment duration were made during a consensus meeting with a smaller group of experts, consisting of members of the guideline development group, an expert on phototherapeutic therapies, and a photobiologist. When sufficient scientific evidence was lacking, recommendations on the selection of therapy and dosage schemes were made during this same consensus meeting.

For children younger than 12 years, treatment with class 3 topical corticosteroids (eg, fluticasone propionate or betamethasone valereate) was recommended as the first-choice therapy. This choice was made regardless of the clinical type. When no repigmentation was observed after 6 months, localized UV-B therapy or topical PUVA therapy could be prescribed and the "skin-saving principle" applied (ie, parts of the body where no lesions were present [especially the face] should be shielded during treatments). Additionally, parts of the body that had repigmented satisfactorily during the course of the therapy should, if possible, be shielded during subsequent treatments (eg, trousers should be worn). In children, genital areas should always be protected during UV exposures. Treatment with topical corticosteroid may be combined with UV-A radiation. In a recent left-right comparative study, it was shown that the combined treatment with fluticasone and UV-A led to a higher repigmentation grade than treatment with either fluticasone or UV-A alone.18 A facial tanner or a sun bed may be used as the UV-A source.

In adult patients, treatment choice was guided by clinical type. Patients with only localized vitiligo could be treated with class 3 corticosteroids combined with UV-A therapy. If there is no response after 6 months, localized UV-B or topical PUVA therapy could be given as an alternative. Narrowband UV-B therapy was recommended as the most effective and safest therapy for generalized vitiligo. A minimum treatment duration of 6 months was recommended for narrowband UV-B therapy. Responsive patients could be given this treatment for a maximum of 24 months. After the first course of 1 year, a resting period of 3 months was recommended to minimize the annual cumulative dose of UV-B.

The therapy selected as the first choice for segmental, stable, or lip-tip vitiligo was autologous transplantation. In the NIPD, split-thickness skin grafting and minigrafting are performed on a routine basis for these conditions. For patients who do not desire a surgical intervention, alternatives may be considered.

In patients with extensive areas of depigmentation (>80%) and/or disfiguring lesions on the face who do not respond to repigmentation therapies, depigmentation of the residual melanin should be considered. During and upon completion of the therapy, patients are permanently at risk for acquiring sunburn from acute solar irradiation. Patients should therefore be advised to minimize sun exposure and to apply broad-spectrum sunscreens. The use of a potent bleaching cream and/or laser therapy (eg, the Q-switched ruby laser) is considered to be the cornerstone of depigmentation therapy for these patients.

In all cases, advice regarding the use of camouflage and sunblocking agents should always be given. If necessary, psychological counseling may be recommended.

These guidelines were distributed together with detailed treatment protocols (not included in this article).

DISSEMINATION AND IMPLEMENTATION OF THE FINAL VERSION OF THE GUIDELINES

The guidelines were mailed to all potential users. A copy of the guidelines was placed on the desk of every treatment room as a reminder. The guidelines were incorporated into the specific dermatological treatment protocol index to which every dermatologist and resident has access. Furthermore, the guidelines were presented and commented on during an internal meeting and again during a local symposium on pigmentary disorders. The implementation of the guidelines was discussed once a week during regular staff meetings and their use was encouraged.

EVALUATION

After 6 months, use of the guidelines was evaluated by means of a questionnaire. Since during this period almost all patients with vitiligo had been referred to the NIPD for treatment, evaluation of the use of the guidelines took place primarily at the NIPD. The second questionnaire was also sent to physicians working at the Department of Dermatology; physicians were asked to evaluate whether dissemination and implementation of the guidelines had also succeeded there.

Information was obtained from NIPD patient record forms regarding the therapy given to patients with vitiligo between June 1998 and January 1999. In addition, in individual cases the reasons for not adhering to the guidelines were noted.

In the questionnaire, all physicians were asked to indicate whether they were familiar with the guidelines and how many new patients with vitiligo they saw during the past 6 months. They were also asked to indicate what sources of information they used to make a first choice of therapy. All physicians were also asked to give their opinion regarding the context and content of the guidelines and their usefulness in daily practice.

Twenty-three questionnaires were sent to the physicians working at both institutions. In the introduction period, 2 new part-time staff members and 1 new resident were employed at the Department of Dermatology and at the NIPD, respectively.

Eighteen staff members and residents of the Department of Dermatology had seen fewer than 5 patients with vitiligo during the introduction period. These physicians did not report responses regarding the context and content of the guidelines. However, all 18 physicians reported that they were familiar with the guidelines.

The questionnaire was completed by 2 respondents from the Department of Dermatology and by 3 respondents from the NIPD. All 5 reported that they used the guidelines during therapeutical decision making. They also agreed that the guidelines gave clear directions for which patient group and clinical types the treatments were recommended. Treatment recommendations as presented in the guidelines were found to be reader-friendly and comprehensive. Furthermore, the responding physicians believed that the objectives were clearly defined and that dosage schemes were adequately adapted for clinical use. Finally, they found that circumstances in which exceptions might be made and patients' preferences were clearly defined in the treatment protocols that were attached to the guidelines.

In the introduction period, 302 vitiligo patients had visited the NIPD (Table 4). Among them were 44 children younger than 12 years with vitiligo. The clinical type of their vitiligo is shown in Table 4. In 23 cases (52%), therapy with class 3 corticosteroids and UV-A was the first choice, which is in accord with the guidelines. In 18 children, localized narrowband UV-B therapy was prescribed. The reasons for not adhering to the guidelines in these cases were "fast stabilization required" (n = 14) and "on specific request of the parents" (n = 4). Three patients (1 was aged 9 years and 2 were aged 11 years) received autologous transplantation by minigrafting technique because they had localized and stable vitiligo patches.

There were 258 adults patients with vitiligo. Of the 21 patients with localized vitiligo, the guidelines were followed in the treatment of 15 patients (71%); 3 were given localized narrowband UV-B therapy (all on specific request of the patient), and 3 did not desire therapy. Two hundred seven patients had generalized vitiligo, of whom 82% (170/207) received treatment with narrowband UV-B, according the guidelines. In 33 patients, class 3 corticosteroids plus UV-A therapy was prescribed because patients specifically requested this therapy (n = 11) or because they found the distance to the hospital too great (n = 13), lacked time (n = 2), or wanted only to treat facial lesions (n = 7). The remaining 4 patients with generalized vitiligo did not wish to be treated. There were 21 patients with segmental and stable vitiligo, all of whom received autologous transplantation, a choice that was in accord with the guidelines. There was 1 patient with lip-tip vitiligo who did not want any treatment. Five adult patients were diagnosed as having vitiligo universalis, 4 of whom (80%) had started with depigmentation therapy and 1 of whom did not desire depigmentation therapy.

COMMENT

The successful introduction of clinical guidelines depends on the strategies for developing, disseminating, and implementing these guidelines in daily practice.19 The introduction of guidelines for the treatment of vitiligo, as described in this study, has taken in account all 3 crucial stages. Guidelines are more likely to achieve the desired health effects if they are consistent with the available scientific evidence or, in the absence of such evidence, with the best clinical judgments.20 Compliance with guidelines has been shown to be enhanced if these guidelines are developed and adopted by those who will use them.21 Therefore, we linked scientific evidence from 3 literature studies with the results of 2 questionnaires and interviews among the potential users of the guidelines, 3 internal expert meetings, and 1 local expert meeting, during which the guidelines were presented and commented on. After the guidelines were accepted and introduced in daily practice, the final version was evaluated.

The results of the first questionnaire showed that there was no uniformity in treatment choices and in estimates of treatment outcome. In view of the potential long-term carcinogenic risks of UV-B and oral PUVA, many physicians asked the guideline development group to come up with recommendations on the maximum treatment duration for these phototherapeutic modalities. The literature review therefore focused on clinical trials in which the percentage of repigmentation, adverse effect profiles, and treatment duration were all adequately reported and analyzed. The best available evidence is delivered by RCTs and summarized in systematic reviews and meta-analyses.11 However, our own systematic reviews of the available literature showed that only a small number of properly designed RCTs have been performed for both nonsurgical repigmentation therapies and autologous transplantation methods in vitiligo. The systematic review of depigmentation therapies in vitiligo showed that no RCT has yet been performed. In such analyses, calculated weighted estimates on treatment outcome and safety from uncontrolled studies cannot be considered as measures of effectiveness, since these studies are prone to selection bias. Such summary estimates should therefore be interpreted with caution. Furthermore, only a few studies were found on the treatment of vitiligo in children. In most trials, both children and adults were included in the study and treatment outcomes were not analyzed separately. Recommendations for children could therefore not be entirely evidence-based. The additional input from experts that was generated during the internal and expert meetings was needed to develop explicit guidelines.

Six months after their introduction, the dissemination of the guidelines had succeeded both in the Department of Dermatology and at the NIPD. All 23 participating physicians were familiar with the guidelines. However, implementation was only partly successful, since only 5 of these physicians had treated a substantial number of patients with vitiligo during this period (>5 patients). These 5 physicians considered the guidelines to be an easy, practical, and useful tool for making a specific treatment choice.

Analysis of first treatment choices made for 302 new patients with vitiligo revealed that the guidelines were followed for most adults (n = 258). In children with vitiligo, the physicians adhered to the guidelines for 52% of the cases. This relatively low compliance rate compared with adults may be explained by the way that the treatment scheme was formulated for children (ie, no further distinction was made in the several clinical types or the disease activity). The effectiveness and safety of narrowband UV-B therapy for children with generalized vitiligo is currently being investigated. In the future, the data from this trial could lead to an evidence-based adjustment of the treatment scheme for children.

The finding that the guidelines were not followed in all cases confirms the general belief that guidelines should not be regarded as rigid criteria, but that they are intended to be flexible. Guidelines should guide action in most cases. Depending on the patient, the setting, the circumstances, or other factors, any part of the guidelines can and should be adjusted to fit individual needs.22 Quantitative measures of patient preferences also need to be further investigated for patients with vitiligo, in a manner similar to that previously described by Zug et al23 for patients with psoriasis.

The results of this study show that clinical guidelines for the treatment of vitiligo can be successfully developed and disseminated for daily clinical practice. Implementation of these guidelines was only partly successful, however, since the number of physicians using the guidelines was low. Therefore, the results of the implementation of these guidelines should be confirmed in other centers involving more physicians who see more patients with vitiligo. Guidelines are not static and should regularly be updated to take into account changes in medical knowledge and practice and particularly the results of randomized trials and meta-analyses. Future studies in vitiligo treatment should also focus on the permanency of therapy-induced repigmentations and on the long-term risk-benefit ratios of the different modalities.

Editor's Comment

This clinical practice guideline is a systemically developed protocol to assist dermatologists and their patients in making decisions about the appropriate treatment for vitiligo. The following questions should be asked in evaluating the guidelines: Are the recommendations valid? What are the recommendations? Will the recommendations help you in caring for your patients? Please see: Hayward RS, Wilson MC, Tunis SR, Bass EB, Guyatt G, for the Evidence-Based Medicine Working Group. Users' guides to the medical literature, VIII: how to use clinical practice guidelines, A: are the recommendations valid? (JAMA. 1995;274:570-574) and Wilson MC, Hayward RS, Tunis SR, Bass EB, Guyatt G, for the Evidence-Based Medicine Working Group. Users' guides to the medical literature, VIII: How to use clinical practice guidelines, B: what are the recommendations and will they help you in caring for your patients? (JAMA. 1995;274:1630-1632) for details on how to evaluate and use clinical practice guidelines.—Michael Bigby, MD, Editor

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Article Information

A cooperative effort of the Clinical Epidemiology Unit of the Istituto Dermopatico dell'Immacolata–Istituto di Recovero e Cura a Carattere Scientifico (IDI-IRCCS) and the Archives of Dermatology

Accepted for publication August 17, 1999.

This project was supported by a grant from the Commission for Guidelines for Clinical Practice, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.

This work was presented at the Second Stichting Nederlands Instituut voor Pigmentstoornissen Symposium, Amsterdam, November 21, 1997.

We thank S. Pavel, PhD, the external referent who critically reviewed the preliminary version of the guidelines. We also thank Hélène Dyserinck, clinical librarian, for her assistance with the bibliographical database searches and Phylis Spuls, MD, for her help at various stages of this work.

Corresponding author: M. D. Njoo, MD, Netherlands Institute for Pigmentary Disorders, Instituut voor Wetenschappelÿk Onderzoek Building, Academic Medical Center, Meibergdreef 35, 1105 AZ Amsterdam, the Netherlands (e-mail: m.d.njoo@amc.uva.nl).

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