Autologous transplantation techniques for vitiligo: how to evaluate treatment outcome

ARTICLE

Auteur(s) : N.A.C. VAN GEEL, K. ONGENAE, Y.M.S.J. VANDER HAEGHEN, J.M. NAEYAERT

Department of Dermatology, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium

Article accepted on 18/11/2003

To date no single treatment exists to cure vitiligo. Therefore, many studies have been performed and are still ongoing to investigate the efficacy of several available and new treatment modalities. Among these, a lot of studies are concentrating on transplantation techniques for vitiligo [1-43]. In these surgical vitiligo trials a variety of assessment methods have been used to evaluate the response to therapy. Many of these evaluation methods rely on the subjective assessment of repigmentation by the investigator. Until now no attention has been devoted to this finding in medical literature. However, to allow an objective and reliable evaluation of results a consensus about an adequate scoring system is needed. It will enable accurate and appropriate data collection usable for both direct comparison and for pooling of treatment results from different clinical trials. Furthermore, interpretation of treatment results seems to vary widely between physicians and patients and should be of influence in determining a therapeutic consensus. To put all these different aspects into perspective in evaluating transplantation techniques for vitiligo, we will first describe the range of clinical evaluation methods used in vitiligo studies. To that end we conducted a systematic literature survey particularly concerning autologous transplantation methods. Secondly we investigate the clinical relevance of an achieved result for both physicians and patients, as the meaning of a ‘successful' treatment has never been investigated from the patients' point of view. To achieve this, a written questionnaire was sent to both dermatologists and vitiligo patients.

Materials and Methods

Data sources

Literature survey

The computerized bibliographical databases PubMed (National Library of Medicine, Indexed for Medline) and EMBASE (Elsevier Science BV, Amsterdam, The Netherlands) were screened for clinical vitiligo trials from January 1966 to March 2002. Furthermore, the reference list of the articles was also checked by intensive hand search. We included articles on surgical therapy for vitiligo including minipunch grafting, split-thickness grafting, epidermal blister grafting, cultured epidermal grafting, cultured melanocytes and non-cultured epidermal grafting. Methodological studies were excluded, as were studies reporting fewer than 5 patients, abstracts-only, correspondences, letters to the editor and editorials. Two investigators (NVG and KO) independently assessed the articles for inclusion or exclusion. Special attention was given to both evaluation methods and outcome parameters used in the selected studies. The influence of other interfering factors on treatment results such as skin type, type of vitiligo, surface of acceptor lesions, activity of disease and localisation of the lesions, were recorded.

Questionnaire

A questionnaire concerning vitiligo was sent in 2001 to all (n = 558) currently practicing Dutch (n = 269) and French-speaking (n = 289) dermatologists in Belgium. Although this questionnaire was meant to investigate the quality of life of vitiligo patients, only the answer to one particular question was analysed for this study. This question investigated the exact meaning of a successful treatment result'. Response alternatives included:
1. Achieving > 50% repigmentation
2. Achieving > 75% repigmentation
3. Achieving 100% repigmentation
4. Satisfaction of the patient, regardless of the achieved percentage of repigmentation
5. Improvement of cosmetic appearance
6. No more sunburn reactions in summer
This same question was also put to 152 vitiligo patients who were recorded in the patient database of the department of Dermatology, University Hospital Ghent. All participants were asked to complete the questionnaire and return it by mail in a preaddressed, stamped envelope. A written informed consent was obtained from all participants and the local ethical committee approved the study.

Results

Literature survey

Forty-three clinical vitiligo trials concerning surgical treatment modalities, published in 1966-2002, were selected (Table I) [1-43]. In all 43 selected studies, treatment was evaluated in terms of repigmentation capacity. None mentioned the measurement of quality of life as a second parameter.

Techniques to measure treatment response (Table I)

Thirty-five authors [1-5, 8-19, 21-27, 29, 31, 33-38, 41-43] showed no information at all about the measurement technique they used to evaluate treatment response, while 5 studies only mentioned the use of photographs for evaluation, without further specifications of the measurement technique [7, 28, 30, 32, 40]. In the studies of Boersma and Guerra et al. planimetric measurement was used based on photographs and transparent films respectively [20, 39], while the group of Hatchome mentioned the use of a microbalance' [6]. As interobserver variation can flaw accurate assessment, one study mentioned more than one observer evaluating the same patient to increase the reliability [43].

Outcome parameters of treatment results (Table I)

The most important parameter in evaluating treatment in vitiligo is undoubtedly the amount of repigmentation. However, 20 different final scoring systems were used in our 43 selected reports to evaluate repigmentation capacity. In 14 studies (33%) repigmentation was recorded as an exact percentage [5, 10, 11, 16, 20, 22, 23, 25, 28-31, 39, 41]. Ten studies (23%) used this parameter in a broader, less-defined sense, varying from ‘more than 75% repigmentation' to less than 30%, 31-50, 51-75, 76-90 and 91-100%' [17-19, 21, 24, 34, 36-38, 42]. Eleven authors (26%) only stated the presence or absence of repigmentation or acceptance of the graft [4, 6, 7, 12-14, 27, 32, 33, 40, 43]. Four other studies (9%) qualified repigmentation as ‘zero', ‘partial' or ‘complete' [3, 8, 9, 35] and 3 (7%) mentioned the presence of poor', moderate', fair', good' or excellent' results [1, 2, 15]. In one study results are classified on a grading scale from 0 to 3, of which grade 0 means no response and grade 3 almost complete response [26].

Confounding factors on treatment results (Table I)

Factors that may have an influence on the treatment outcome include skin type, type of vitiligo, disease activity, treated surface area and the localisation of the lesions and should therefore be taken into account when evaluating therapy results.
Twenty-eight of 43 articles (65%) did not mention the skin type of their patient population at all [1-4, 6, 7, 9, 11-13, 16, 18-22, 24, 26, 27, 29, 30, 32-34, 37, 38, 42, 43], whereas the type of vitiligo (focal, segmental or generalised) was noted in 88% [3-15, 17-22, 24-30, 32-43] of the cases (n = 38), but 17 out of 43 trials (40%) [1, 2, 4, 7-9, 12, 14, 17, 21, 26, 27, 32, 33, 36, 37, 43] did not define the specific anatomical localisations of the treated lesions.
There has been an attempt to adequately describe disease activity in 23 (53%) reports [1-4, 8, 9, 12, 14, 16, 17, 19, 20, 22, 26, 27, 29, 30, 33-35, 37, 39, 40]. Unfortunately, the definition of an active' or stable' vitiligo varies strongly among them. The cut off point of no further progression of lesions' is made from 3 months to 3 years. Besides, it is not always clear whether a positive regression (repigmentation) is classified as stable or active disease.
The treated surface area, being an important confounding factor in evaluating transplantation techniques, was only estimated in 15 studies (35%) [5, 8, 10, 11, 14, 17, 20, 28-30, 34, 37, 39, 41, 43].

Questionnaire survey

Eighty-six percent (230/269) of Dutch speaking dermatologists, 75% of French-speaking dermatologists (216/289) and 66% of the vitiligo patients (101/152) completed the questionnaire. Vitiligo patients involved in the study were over 18 years of age, formally diagnosed as having vitiligo by a dermatologist of the Department of Dermatology, Ghent University Hospital. The results of the questionnaire are given in Table II.

For 78% of all questionned Belgian dermatologists the definition of a successful treatment' is when the patient is satisfied, regardless of the achieved percentage of repigmentation'. Twenty-one percent found only a complete repigmentation to be considered as success. Note that more than one answer was allowed. As indicated in Table II, vitiligo patients often define a successful treatment as a ‘full repigmentation' or an ‘esthetical improvement' (48.5% in both cases). Only 32% considers a repigmentation of more than 75%' as a success. It is also remarkable that one third of the vitiligo patients mentioned a decrease in sun sensitivity as an important criterium, while only 18% of the Dermatologists reported this.

Discussion

At the moment there is absolutely no uniformity in the assessment of treatment outcome in surgical vitiligo trials. So far a specific index for the severity assessment of vitiligo has not been described. For other skin diseases such as acne vulgaris, eczema, mycosis fungoides and psoriasis, special criteria have been developed for measuring the severity and treatment response over time [e.g. Psoriasis Assessment and Severity Index (PASI)] [44-47]. To reach general consensus for evaluation of vitiligo patients and their treatment there is an urgent need for a Vitiligo Assessment and Severity Index as well. Therefore, both assessment methods, evaluation of influencing factors and quality of life need to be standardized.
Our literature survey demonstrates that 20 different outcome parameters have been used in the 43 included vitiligo studies. These differences will result in incompatible and non-comparable data (Table I). Secondly, as most methods have been based on visual assessment, a high inter- and intraobserver variability may be suspected, leading to a highly subjective outcome. Currently only 3 reports mention the use of a more objective measurement tool, being a planimetric measurement by a digital image analysis system and a measurement by microbalance' [6, 20, 39]. Depending on the exact system used, photographic image analysis may be considered a far more objective tool than visual assessment, although it may underestimate the real affected surface. Indeed, this technique flattens' the body contours so that a three-dimensional object is quantified in two dimensions. To overcome this problem, the use of tracing lesions (point counting grids) on a transparent sheet will probably be the more appropriate, albeit time-consuming method.
Current methods to roughly assess the involved body surface contain both ‘the rule of nine' — and the ‘flat hand = 1%' — method. The first assumes that the total body surface area comprises 9% for head/ neck, each arm, anterior and posterior leg, and the four trunk quadrants, leaving 1% for the genitalia. In the second method a flat hand represents 1% of the total body surface area. Both methods are very subjective and based on visual assessment. A high inter- and intraobserver variability in the calculation of the body surface area among clinicians has therefore already been demonstrated in several psoriasis studies [48, 49].Recently the so-called Dermatological Global Assessment (DGA) [50] system has been developed and allows a much more detailed description of the disease extent spread over 7 specific body parts on a scale of 0-4.
Influencing factors on treatment outcome may be of importance in the interpretation of treatment effectiveness. Previous observations demonstrated that darker skin types (Fitzpatrick skin type IV or more) may have a better therapeutic response to autologous transplantation techniques [51]. Furthermore, it is known that different vitiligo types may respond better than others. Segmental vitiligo with the presence of poliosis for example is difficult to treat by conservative treatment, but is a good indication for surgical intervention.
Regarding anatomical localisation it is known that hands and feet are poorly responding areas, while repigmentation on the face and trunk can be very satisfying. Unfortunately, 17 (40%) of the selected vitiligo studies in our literature survey used an ‘overall repigmentation-score' as the crucial measured endpoint, without further specification of the localisation. In our opinion it is mandatory to evaluate each anatomical region separately.
No one evaluated the improvement in quality of life additional to repigmentation capacity with regards to treatment outcome in transplantation studies. However to measure quality of life, a multidimensional concept has been developed by Finlay et al. [52] that encompasses the physical, social and psychological well-being of an individual. In 1989 Kent et al. [53] used this questionnaire for vitiligo patients. Quality of Life assessment is an interesting additional tool in the evaluation of treatment outcome because the percentage of repigmentation alone may not always be a good indicator of patient satisfaction. A good repigmentation of a small but well exposed area (e.g. face, hands) may be more satisfying to a patient than good repigmentation on large but totally covered areas of the body. Besides, the time that treatment results remain present is, for some patients at least, as relevant as the repigmentation capacity of the treatment itself. This could be a useful clinical outcome parameter as well in terms of quality of life.
When one has reached general agreement on both assessment method and scoring system for adequate treatment evaluation one may question how to weight the achieved results? In other words what constitutes a successful improvement' in vitiligo in the view of dermatologists as well as vitiligo patients? The questionnaire survey demonstrated that repigmentation of more than 75% is a successful result for only 32% of vitiligo patients, as they mainly consider complete repigmentation or an improvement of their cosmetic appearance as a success. For 78% of all questionned Belgian dermatologists the definition of a successful treatment' is when the patient is satisfied, regardless of the achieved percentage of repigmentation'. Our results differ therefore from a previous survey among Dutch dermatologists [54], where most dermatologists (66%) defined a successful treatment as over 75% repigmentation was achieved'. Among them only 15% regarded a therapy as being successful if the patient was satisfied, regardless of the achieved percentage of repigmentation'. They did however not investigate the meaning of a successful treatment' among vitiligo patients.

Conclusion

This study emphasizes that there is no uniformity in assessment systems for treatment outcome in vitiligo studies concerning autologous transplantation methods. As a comprehensive, useful and standardized tool is lacking, further research is indicated to quantify the effectiveness of different treatment modalities. The definition of important parameters, such as disease activity, should be precisely defined and universally agreed upon. However, till that time, to prevent the use of inaccurate or inappropriate data, the achieved results should be interpreted with caution.
Both specialist and patient should know that several factors such as skin type and localisation of the lesions may have an influence on treatment outcome. Secondly, one should keep in mind that the clinical significance of an achieved treatment result is often different for therapist and patient. The long-term goal should be to develop a golden standard' that is useful in monitoring treatment efficacy objectively. A combination of both a clinical and a psychological evaluation is probably the most appropriate assessment. n

Acknowledgements. This research project was supported by a grant from the “Bijzonder Onderzoeksfonds” number 01108101 (Ghent University, Belgium) for NvG and a grant from the Fonds Wetenschappelijk Onderzoek (Ghent University, Belgium) for KO.
We would like to thank David Njoo, dermatologist in training (Department of Dermatology, Academic Medical Center, University of Amsterdam) for the Embase data screening.

References

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Figure 1. Ectopic nail of medium plantar area of right foot. Figure 2. Terminal germinal matrix stained with toluidine blue. Relapsing and painful horny excrescence of the sole: a case of ectopic plantar nail 1 Department of Dermatology, University of Sassari, V. le S. Pietro 43, Sassari, 07100, Italy 2 Department of Biomedical Sciences, Section of Human Anatomy, V. le S. Pietro 43, Sassari, 07100, University of Sassari, Italy 3 Department of Plastic Surgery, University of Sassari, V. le S. Pietro 43, Sassari, 07100, Italy The ectopic nail is an extra nail, rarely observed. This anomaly is mostly congenital and more rarely acquired, for example after trauma (inoculation of nail matrix) [1]. It has been observed mainly in Japan and almost 45 cases are reported [2]. A 43-year-old female without personal and family history of traumas, acquired and congenital dermatopathies, presented with a horny excrescence of the sole of the foot, complaining about pain during walking. The patient noticed the lesion about five years earlier. Her father presented a well developed bifid thumb. Physical examination revealed a keratotic cone, 8 × 6 mm, surrounded by a well defined sulcus in the right foot plantar area (Fig. 1). The lesion had an intradermic implant base and an antero-posterior orientation. Ultrasonic examination showed a well defined echodense area, protruding from the skin surface, and deepening 5 mm into subcutis. Radiography did not reveal foot bone anomalies. The lesion was surgically removed. The histological examination of a specimen section stained with haematoxylin and eosin revealed well-developed nail components: a keratogenic area of the nail matrix, a nail bed and a nail plate, formed by squamous cells faintly stained by eosin. The nail plate appeared developed mainly parallel to skin surface. The underlying dermis did not present any inflammatory process. In semithin sections stained with toluidine blue, flat and layered keratinocytes with a fusiform nucleus were present in the germinal matrix (Fig. 2). They fitted together and their cytoplasm was strongly stained by toluidine blue. These cells represent the ventral part of nail plate and become onychocytes, losing their nucleus, in the dorsal and finally in the distal nail plate. In the sterile nail matrix, epithelial squamous cells have a eosinophilic cytoplasm with keratohyalin granules. These cells form part of the nail bed. Matrix cells are characterized by a globose, hyperchromic nucleus and by light, poorly eosinophilic cytoplasm. Diagnosis was ectopic plantar nail. This deformity affects mainly hand digits, in particular the fifth, and very rarely the foot. Normal nail growth depends on the underlying phalanx. In fact, in the anonychia or micronychia, the phalanx is hypoplastic or atrophic at X-ray examination. The true ectopic nail differs from other corneous formations, like foot clavus and wart, for its clinical and histopathological aspects. The ectopic nail can grow with a vertical orientation to the skin surface, like the tooth or the fetal nail, or with an horizontal orientation, like terminal normal nail. The orientation can be modified after trauma, like foot pressure. n References 1. Guéro S. Pathologie congénitale de l'ongle. In: Dumontier C. L'ongle. Amsterdam: Elsevier; 2000; 27: 121-8. 2. Tomita K, Inoue K, Ichikawa H, Shirai S. Congenital ectopic nails. Plast Reconstr Surg 1997; 100: 1497-9.