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Photo- und Photochemotherapie der Vitiligo
Abstract
Dieses Kapitel beschäftigt sich mit der Anwendung von Photochemotherapie und Phototherapie bei Vitiligo. Zunächst wird die Krankheit definiert und werden Differentialdiagnosen und assoziierte Phänomene beschrieben. Allgemeine therapeutische Maßnahmen und Alternativen zu phototherapeutischen Verfahren folgen. Den Hauptteil bildet die Beschreibung der praktischen Durchführung und Wirkung der Bestrahlungsbehandlung mit oder ohne Photosensibilisator sowie von kombinierten Therapieformen.
Ultraviolet radiation-based therapies of vitiligo are the most potent options for its treatment. This chapter shall provide detailed information about the role and application of phototherapeutic regimens. Initially, the disease will be defined and compared to other conditions in the differential diagnosis. The main portion of this chapter will concentrate on ultraviolet phototherapy and photochemotherapy. Adjunctive and combined therapeutic modalities are discussed, as well as alternative treatment options.
Seit Jahrzehnten stellen photo- und photochemotherapeutische Verfahren etablierte dermatologische Behandlungsregime dar. Die enge Verzahnung von dermatologischer, photobiologischer und photoimmunologischer Forschung mit strahlenphysikalischen und technischen Innovationen haben der Photodermatologie in den letzten Jahren wichtige Impulse gegeben, die sich rasch in der Therapie niedergeschlagen haben. Einerseits ist auf die Einführung neuer selektiver Spektren im UVB- und UVA-Bereich, z.B. auf die 311 nm-UVB-oder die UVA1-Phototherapie, andererseits auf neue Indikationen, z.B. die Behandlung von Bindegewebserkrankungen und der GvHD, hinzuweisen. Im Folgenden wird Neues und Bewährtes in der Photo(chemo)-therapie sowohl in Bezug auf klinische als auch auf wissenschaftliche Relevanz dargestellt.
Recent advances in the culturing of pigment cells from human beings have made it possible to begin the transplantation of autologous melanocytes into areas of skin that are hypopigmented. In a patient with piebaldism we were able to take pigment cells from a shave biopsy of the normally pigmented skin of the back, expand the cells in culture, and return them to an area devoid of pigment cells and get a perfect take. To grow the cells in culture we used 12-O-tetradecanoyl-phorbol-13-acetate (TPA) as well as cholera toxin and isobutylmethyl xanthine. At this time, one can substitute basic fibroblast growth factor for TPA. The procedure of using autologous pigment cell cultures opens the door for further advances in the treatment of patients who do not have melanocytes in certain areas of the skin, as seen in patients with vitiligo or piebaldism, or as a consequence of severe mechanical or thermal trauma.
An anticipated effect of khellin, related to its chemical structure, in the photochemotherapy of amelanosis has been investigated. In a double-blind clinical study, khellin has been orally administered to 30 vitiligo patients for 4 months with subsequent exposure to natural sunlight. At the end of the trial period, 5 patients out of 30 (16.6%) repigmented 90-100%; 7 cases (23.3%) repigmented 50-60% of the vitiliginous areas treated; 11 (36.6%) repigmented 25% or less, and 7 subjects (23.3%) showed negative response. 30 control subjects failed to repigment at all. The achieved repigmentation was stable after drug cessation for a period of 1 year. These data add a previously unreported effect for the non-psoralen compound, khellin, in the therapy of vitiligo.
Vitiligo vulgaris is a human disease that clinically is manifested by white spots on the skin. Histologically it affects the entire keratinocyte-Langerhans cell-melanocyte (KLM) unit. The melanocyte is destroyed. Keratinocytes exhibit vacuolar degeneration. The function of Langerhans cells is altered. White or depigmented skin has a muted capacity to respond to inflammatory or immune stimuli.The cause of vitiligo is not known. Genetic factors are involved in humans and in the two best studied animal models, mice and chickens. The disease in humans is not transmitted in any simple Mendelian fashion but seems to be polygenic.In chickens and mice, the melanocyte expresses an inherent defect that causes a suicidal death. In the chicken, the death of the melanocyte elicits a secondary immune reaction that accelerates the depigmenting process. In mice, no role for the immune system can be identified. In humans, vitiligo melanocytes express inherent defects when grown in culture. The immune system is activated by death of the melanocytes, and antibodies are produced. What role the antibodies have in accelerating the disease is not known.Vitiligo can be treated with a variety of methods, including applications of topical steroids or ingestion of psoralens and exposure to ultraviolet light. Although no cure is available at this time, repigmentation of much of the affected skin can be achieved. Therapy must be prescribed carefully and correctly. When done so, however, results are rewarding both for the patient and the physician.
In the past, several authors described an association of vitiligo with autoimmune disorders and the presence of different tissue autoantibodies. A review of the literature showed large differences in the results. Therefore, 321 patients with vitiligo (male/female ratio 114/207) were examined to see whether the frequencies of associated diseases and phenomena (i.e. Koebner phenomenon, canities praecox, halo nevi, poliosis circumscripta), the number of pigmented lesions and the presence of autoantibodies are of significance in order to support (a) a subentity of childhood vitiligo and (b) whether there is a true predisposition or association of autoimmune or other diseases in this group of patients. The data confirm earlier results of a prevalence of thyroid disease and the presence of thyroid antibodies, whereas other diseases are a random event. 6.2% of the patients had congenital nevi compared with 2.8% in a normal healthy population. Based on the results of this study and the significant higher risk for development of melanomas in this patient group, an annual checkup is recommended.
Background:
Common treatments used for severe psoriasis include psoralen and ultraviolet A radiation (PUVA), methotrexate, ultraviolet B (UVB), and tar. These therapies are often used for prolonged periods and may be carcinogenic.
Methods:
For more than 13 years, the authors have prospectively determined the incidence of skin cancer and use of treatments for psoriasis in a 1380 patient cohort originally enrolled in a therapeutic trial of PUVA at 16 university centers.
Results:
Squamous cell carcinoma (SCC) developed in more than one fourth of patients exposed to high doses of PUVA. In this group, the standard morbidity ratio for these tumors was 83 (95% confidence interval [CI], 72-96) compared with the expected number of these tumors in the general population. High-level exposure to methotrexate is a significant independent risk factor for developing SCC (relative risk, 2.1 for high versus low or no exposure; 95% CI, 1.4-2.8). Metastatic disease developed in seven patients with SCC. No significant increase in the risk of SCC was associated with long term exposure to UVB or topical tar, and no substantial increase in the risk of basal cell carcinoma was noted in association with prolonged use of any of these treatments.
Conclusions:
Long term exposure to PUVA and methotrexate significantly increases the risk of SCC in patients with psoriasis. This risk should be considered in selection of treatment. The ultimate morbidity of these tumors is undetermined.
PUVA is known to be carcinogenic when used in the treatment of psoriasis. To date skin cancer has not been demonstrated after PUVA treatment of vitiligo. We report a patient in whom multiple squamous cell carcinomata and keratoses developed in vitiligo areas after a prolonged course of PUVA. PUVA therapy of vitiligo induces repigmentation of affected skin in some patients. An increased frequency of cutaneous neoplasms in depigmented areas is a potential hazard, as in these sites the photoprotective effect of melanin is lacking.
Of 18 severely afffected vitiligo patients who used 20% monobenzylether of hydroquinone (MBEH, Benoquin) as a depigmenting agent, 8 achieved complete depigmentation after 10 months or more of use and 3 dramatic but no complete hypopigmentation. The 3 patients with no results did not use MBEH for more than 4 months. Complications were frequent particularly among those who did well, but only 1 case of contact dermatitis limited therapy. All patients who depigmented fully were very pleased with their results. As depigmentation induced by MBEH is generally irreversible, MBEH use must be reserved for induction of complete depigmentation of severely affected vitiligo patients who cannot or do not choose to repigment and who can accept the permanence of never tanning. The history, histology and mechanism of MBEH depigmentation are discussed.
Local injection of physostigmine revealed that dermatomally distributed vitiligo was associated with a dysfunction of the sympathetic nerves in the affected skin and that non-dermatomally distributed vitiligo was not. These observations led to the hypothesis that the primary disturbance of dermatomally distributed vitiligo lies in the sympathetic nerves of the affected area and that non-dermatomally distributed vitiligo has its primary disturbance in the melanocyte itself, where an autoimmune mechanism is suspect. Results of therapy supported this hypothesis by showing that topical corticosteroid is effective only in the latter, while the former reacts to oral nialamide.
It is proposed that non-dermatomally distributed vitiligo be referred to as Type A and dermatomally distributed vitiligo as Type B.
We have performed a retrospective study of 59 patients with vitiligo who received PUVA therapy from 1972 to 1986. Sixteen patients had generalized vitiligo and 43 vitiligo in four locations (focal vitiligo). In both groups there were repigmentation in 44% of the patients. Half of the repigmented patients had improved more than 50%. None developed hypertrichosis, actinic keratosis, lentigines, or skin cancer within the observation period. Regardless of the results of PUVA therapy half of the patients thought PUVA was an acceptable therapy.
At present, there is no universally effective drug for vitiligo therapy; there are, however, various therapeutic modalities that may be beneficial. Therapeutic regimens used to treat vitiligo include psoralens and ultraviolet A light (PUVA), topical corticosteroids, fluorouracil locally applied with skin abrasion, a variety of surgical techniques to transplant autologous melanocytes from pigmented skin to nonpigmenting areas, a new photochemotherapeutic regimen using oral khellin with UVA phototherapy, and a recently proposed treatment with oral phenylalanine in combination with UVA exposure. PUVA and topical corticosteroids are the 2 most frequently used modalities. The use of effective sunscreens with a high sun protection factor (SPF) is of help in preventing the vitiliginous areas from burning and normal skin from becoming tanned. Cosmetic camouflage is also useful to disguise the white areas of skin. Finally, depigmentation should be considered in patients with greater than 50% cutaneous involvement who fail to respond or are unwilling to undergo treatment. The selection of patients for therapy should take into consideration the patient's motivation, the psychological impact of the disease and the clinical presentation of vitiligo, and should weigh the risks and benefits of prolonged therapy.
The therapeutic uses of naturally occurring psoralens in modern-day medicine (8-methoxypsoralen (8-MOP), 5-methoxypsoralen (5-MOP), 4,5',8-trimethylpsoralen, and a few other synthetic psoralens) have evolved through five stages of development. (1) In the historical period (2000 BC to 1930 AD), the pigment-stimulating properties of naturally occurring plants containing psoralens were described anecdotally. (2) The second period (1930-1960) dealing with the chemistry of psoralens involved extraction, identification of their structure, synthesis, and the relationship between chemical structure and their photoreactivity and pigment-stimulating properties. The treatment of vitiligo with oral and topical 8-MOP became popular. (3) In the third period (1960-1974), we witnessed a new beginning and the growth of basic science studies and clinical investigations into various biological properties of psoralens including action spectrum studies, mutagenesis and carcinogenesis studies, in vitro and in vivo photoreactivity studies of various psoralens with DNA, RNA, proteins, and pharmacological and toxicological studies in vitiligo patients undergoing long-term therapy for repigmentation. (4) The fourth period (1974-1988) is recognized as the period of photochemotherapy and the development of the science of photomedicine which established the therapeutic effectiveness of psoralens in combination with newly developed UV irradiation systems that emitted high-intensity UVA radiation in the treatment of severe psoriasis, mycosis fungoides, and over 16 other skin diseases. The effectiveness of PUVA (psoralen + UVA) was confirmed by well controlled clinical trials in thousands of patients, both in the USA and in European countries. Combination therapy with oral retinoids and PUVA contributed to greater effectiveness and long-term safety of psoralen photochemotherapy. (5) In the fifth period (1989 and beyond), psoralens are now emerging as photochemoprotective agents against non-melanoma skin cancers and as immunologic modifiers in the management of certain patients with disorders of circulating T-cells using new techniques of photopheresis. In the final analysis, perhaps the application of pharmacological and therapeutic concepts and principles of using psoralens in combination with UVA has contributed to the development of a new science of photomedicine in which the interaction between basic scientists, photobiologists, and physicians has produced both basic and new clinical knowledge for the care and control of human suffering.
In order to evaluate the efficacy of topical khellin the vitiligo macules of one side only were painted in 41 patients with a 2% solution of khellin in acetone and propylene glycol (90 and 10%, respectively) and exposed to sunlight for a period of 4 months with 3 weekly applications and with exposure times up to 90 min. The macules of the other side were treated in 36 of the 41 patients with acetone and propylene glycol only and sun-exposed with the same schedule, while in the remaining 5 patients they were neither treated with khellin or placebo nor sun-exposed. No significant difference was evidenced between the khellin and placebo-treated sides: no excellent result (repigmentation more than 75% of the affected area) was found, and good results (repigmentation more than 50%) were found in 24.9% of khellin- plus sunlight-treated macules and in 22.3% of placebo- plus sunlight-treated macules.
Thirty‐six patients with vitiligo were treated with oral 5‐methoxypsoralen (5‐MOP) and subsequently exposed to UVA irradiation. The patients were treated once or twice weekly over a period of 2–10 months, taking 40–60 mg of 5‐MOP 2 hours before exposure to UVA light. The amount of exposure to UVA light was slowly increased according to the patient's tolerance.
Eleven (31%) patients showed remarkable repigmentation of the areas of vitiligo within six months. Overall, 78% of the patients showed effective repigmentation. Areas of vitiligo on the face and trunk were more responsive to treatment than those on the distal part of limbs. Adverse effects due to the drug included 2 patients with nausea and 1 patient with headache. It is suggested that treatment with systemic 5‐MOP is effective, safe, and useful in selected cases of vitiligo.
The placenta should be an excellent source of factors which might be efficacious in the treatment of vitiligo. Proof, however, for that hypothesis is lacking. Numerous claims have been made about Melagenina. It would appear to be nontoxic if we were to assume that the medication does not contain infectious agents. The ease of application certainly is of value for patients with vitiligo who wish to try some therapy for their disease. Practically, it is very costly to travel to Cuba and to export Melagenina. The cost of shipping on airplanes plus import duties make the price very high. Unfortunately, the inconvenience of the travel and the costs cannot necessarily be offset by the claims to efficacy. The biochemistry, assays for biological activity and the pharmacology studies as reported do not stand up to rigorous and acceptable scientific standards. The medication clearly needs further and intensive study. Now that the barriers between countries are being dismantled, it is hoped that the Cuban team will be able to travel to other laboratories outside of Cuba where they can continue animal studies as well as studies on melanocytes growing in culture. In addition, it is hoped that they will be able to share more about the pharmacology, the chemistry, the isolation and other chemical properties of the medication. These results can be published and will stand up to scrutiny by the world's medical and scientific community. Until that time, patients and their physicians must recognize the uncertain quality of the claims as well as the high financial cost and potential risk of using Melagenina either within or outside of Cuba.
L-Phenylalanine is a promising agent for the treatment of vitiligo when taken orally and followed with ultraviolet light (UVA) irradiation. Of 13 children so treated, 3 experienced repigmentation of all vitiliginous areas, 6 showed 50% to 90% improvement, and 4 failed to respond. None of the children experienced side effects during the treatment.
Cyclosporin A is a potent immunosuppressive drug with almost a decade of clinical use. Due to its lack of bone marrow toxicity, it has assumed a leading role in organ transplant surgery. Likewise, it has shown remarkable efficacy in psoriasis and has shown potential usefulness in other dermatologic diseases, most of which are thought to have an autoimmune T-cell-mediated pathogenesis. There are many other inflammatory skin conditions in which T lymphocytes represent a majority of the cellular infiltrates, and theoretically such disorders may be responsive to CsA. Diseases such as lichen planus, allergic contact dermatitis, photoallergy, and vitiligo are potential areas of further study. The potential use of topical and intralesional CsA also warrants further clinical evaluation. There are reports of topical CsA showing effectiveness for alopecia areata and nickel contact sensitivity. Griffiths et al. treated six psoriatic patients with 2% CsA ointment twice daily for 4 weeks. The response to placebo or CsA at the end of the study was similar in all patients. Notably, there was no measured systemic absorption and no change in blood pressure or renal function. We had similar unimpressive results in several patients treated with a 10% solution of CsA; minimal to no response was seen. Of great benefit would be an effective topical preparation without systemic absorption or toxicity. Future studies will need to carefully evaluate the vehicle used and the strength of topical CsA employed. The role of CsA in dermatologic disease still needs much investigation, both at the clinical and basic science levels. The studies to date show dramatic and exciting results. Indeed, CsA may well represent a major advance in the understanding and treatment of psoriasis. However, the decision to use CsA for nonfatal diseases such as psoriasis will require a careful balance between efficacy and toxicity. If long-term side effects can be avoided or kept within reasonably safe, acceptable limits, CsA holds great promise for the treatment of psoriasis. It may at times be used as an acute intervention, with a relatively large, initial dose for a short period of time to quickly clear severe psoriasis. This could be followed by either a reduction to a lower and safer maintenance dose or a program of other treatments. Cyclosporin A may also prove useful alone in very low doses or in combination therapy, as with UVB or PUVA. Optimal dosing protocols are currently under investigation.
Autologous minigrafting has been reported as an effective method for repigmenting diverse types of stable leukoderma. A group of 22 patients with localized vitiligo, 17 segmental and five focal, who are under treatment with this method, are described. Thirteen patients attained a 90% to 100% repigmentation, two others achieved a partial improvement, and five patients had a positive test area indicating the possibility of repigmentation by means of this procedure. Only two patients had a negative test with minigrafts and, consequently, they were left untreated. Autologous minigrafting is suggested as an alternative for treating localized vitiligo, particularly when other medical therapeutic attempts have failed in repigmenting this often refractory condition.
Twenty-eight patients with vitiligo were treated with a new photochemotherapeutic regimen using khellin, a furanochromone, as photosensitizer, together with ultraviolet A (UVA) irradiation. Twenty-five patients received khellin orally and three patients were treated with topical khellin. Treatments were given three times weekly. As opposed to psoralens, khellin did not induce skin phototoxicity with UVA but it induced repigmentation similar to psoralens. The treatment success strongly depended on the number of treatments. More than 70% repigmentation was achieved in 41% of the patients who had received 100 to 200 treatments. This success rate is comparable to the rate obtained with psoralens. Seven patients experienced a mild elevation of liver transaminases within the early treatment phase and their treatments were discontinued. No long-term internal organ or skin toxicity was observed. The major advantage of khellin is that it does not lead to phototoxic skin erythema and thus can be considered safe for home treatment. Because of its photochemistry it may be considered less hazardous than psoralens regarding mutagenicity and carcinogenicity.
Khellin, whose chemical structure closely resembles that of psoralen, is reported to be an efficient drug for treating vitiligo when combined with ultraviolet A irradiation. Photobiological activity on yeast is found to be much lower than that of bifunctional psoralens such as 5-methoxypsoralen. In vitro experiments reveal that khellin is a poor photosensitizer. It behaves as a monofunctional agent with respect to DNA photoaddition. It does not photoinduce cross-links in DNA in vitro or in Chinese hamster cells in vivo. This behavior may explain the low photogenotoxicity in yeast and the lack of phototoxic erythemal response when treating vitiligo with khellin.
Vitiligo provides a model system for studying chronic actinic damage in skin devoid of melanin pigments and thereby permits assessment of their photoprotective function. Our study comprised 23 patients with a mean age of 67 years having stable, long-lasting vitiligo on light-exposed body regions. The vitiliginous and normally pigmented, light-exposed skin was examined clinically for manifestations of chronic actinic damage. In 11 patients skin biopsies were obtained from vitiliginous and adjacent pigmented skin for qualitative and quantitative histological comparison. Our study did not reveal evidence for a significant increase of chronic actinic damage in skin devoid of melanin pigments. These results are in agreement with the rareness of reported skin cancer in vitiligo.
Recently, favourable results have been reported from oral L-phenylalanine (Phe) combined with UVA/sunlight irradiation (Phe-UVA) in the treatment of vitiligo. In the present pilot study vitiligo patients were treated on a thrice weekly scheme of 50 mg Phe.kg-1 body weight and exposed to sunlight as a source of UVA. An observed 81% response on the skin disorder correlates with earlier figures; 43% responded within 3 months. The self-controlled treatment includes the risk of over-irradiation, as possibly happened with one patient. The repigmentation was predominantly of follicular pattern. The assumption that Phe plays a central biochemical regulatory role in melanin, catecholamine and antibody synthesis forms an attractive challenge for the explanation of repigmentation and requires further investigation.
We correlated the level of vitiligo antibodies to the extent of depigmentation in thirty-two patients with vitiligo. Vitiligo antibodies were assayed by protein A-sepharose immunoprecipitation method. Antibodies were present in four of eight (50%) patients with minimal vitiligo (less than 2% body surface involved), in nine of ten (90%) patients with moderate vitiligo (2 to 5% surface involved), and in thirteen of fourteen (93%) patients with more extensive disease (greater than 5% surface involved). The level of vitiligo antibodies in the three groups expressed as a binding index was 2.9% +/- 2.03, 5.6% +/- 2.92, and 8.0% +/- 3.03 SD, respectively. These results suggest that there is a relation between the incidence and level of vitiligo antibodies and the extent of depigmentation in vitiligo.
To determine the long-term cutaneous side-effects of oral photochemotherapy (PUVA), we examined 95 patients, 59 with psoriasis and 36 with mycosis fungoides (MF). These comprised 80% and 69% respectively of the patients with these disorders treated with PUVA in our department from 1977 to 1985. Two psoriatic patients had squamous carcinomas, both of whom had received high cumulative UVA doses and also methotrexate concurrently with PUVA. Six patients with MF had actinic keratoses. The mean age of these patients (69 years) was significantly greater than the mean age of the patients without actinic keratoses (54 years), but there was no significant difference in their cumulative UVA doses. No patients developed basal cell carcinomas or malignant melanoma. ‘PUVA lentigines’ were found in 46% of the patients. They were most frequent in patients currently being treated and in those who had received high cumulative UVA doses, but persisted for up to 7 years after discontinuing therapy.
Seventy-one patients had yearly ophthalmological examinations, or a single examination at least 3 months after commencing PUVA, This examination included retinal function tests to detect any subclinical visual impairment. Five of these patients had cataract prior to PUVA therapy, and were significantly older (mean age 71 years) than those without cataract (mean age 53 years). Three patients (mean age 61 years) developed new lens opacities whilst receiving PUVA. However, none of these patients was considered to have cataract as none had impairment of visual acuity due to lens opacity. No patients without lens opacity developed evidence of subclinical visual impairment.
The administration of phenylalanine (Phe) combined with UVA exposure was found to be effective in vitiligo. Phe is an amino acid which constitutes part of the daily dietary protein, and when orally administered in a dose of 50 mg/kg body weight, it results in an elevated plasma level. Since peak concentrations of Phe in the blood are reached between 30 and 45 min after ingestion, UVA exposure was administered at this time. After 4 months (32 treatments) reasonable repigmentation preferentially occurred in the skin area of subcutaneous fat (adipose tissue). Apart from the repigmentation of hypo-pigmented macules, vitiligo patients can tolerate more sun than usual, especially at the vitiliginous lesion, and they experience no sunburn as a result of Phe-UVA therapy. Normal skin also tans very well.
The treatment of vitiligo is still unsatisfactory in many patients. The only two methods that have been evaluated in numerous patients are classic psoralen-light therapy and local treatment with potent fluorinated corticosteroids. These two methods in addition to some more recent therapies that have still been insufficiently investigated are reviewed in light of the data in the newer literature.
Repigmentation has been observed under the influence of topically administered Efudix cream in 3 patients with vitiligo of symmetrical acral type. No response has been received in 2 patients with segmental vitiligo treated in the same way. Recurrence of vitiligo was seen in 1 patient. Histologic and electron microscopic characterization of recolonized melanocytes is described. The significance of topical 5-fluorouracil treatment in vitiligo is discussed.
.— Oral trimethylpsoralen was given to 12 children with different clinical types of vitiligo in a dosage of 5–10 mg daily, followed by exposure to sunlight. The response to this therapy was favourable. Vitiligo areata responded the best as compared to the other types. No cutaneous or systemic side effects were seen. Trimethylpsoralen is therefore recommended for the treatment of vitiligo in children.
In the present study 46 patients with severe psoriasis maintained on long-term PUVA therapy have been followed up to 6 1/2 years after the initiation of treatment. Repeated ophthalmological examinations were performed in order to detect any early sign of lens changes. No ocular side effects attributed to the photochemotherapy were revealed during this period. Continued use of appropriate eye shielding is recommended and also routines to remind patients to actually wear their protective glasses.
Vitiligo is refractory to most therapeutic modalities. To assess the efficacy of a variety of PUVA therapies, we enrolled 596 subjects in a prospective study, and 230 were followed for up to 55 months. Various psoralen derivatives and dosage schedules were used. Each subject was examined at yearly intervals for therapeutic response and evidence of chronic PUVA toxicity. At 4 years after therapeutic inception, 29 (13%) developed lesions in remaining vitiliginous macules. Clinically, hyperkeratotic macules and hyperkeratotic, lichenoid, and telangiectatic papules were discerned. Histologic examination of these lesions revealed them to be actinic and lichenoid keratoses, verruca vulgaris, and hyperkeratosis with either hyperplasia or atrophy. No tumors were present. In perilesional skin, dermal collagen and elastic tissue degeneration, much greater in degree than reported in psoriatic skin, was observed. In this group of PUVA-treated patients, no increased risk of carcinoma was apparent during the follow-up period.
In 28 patients with vitiligo, 5% fluorouracil cream was applied daily to vitiliginous lesions under occlusive dressings, following an epidermal abrasion on the first day. The treated lesions became completely eroded after seven to nine days of treatment at which time treatment was stopped. Epithelialization then occurred within ten days. Repigmentation first began one to two weeks after epithelialization and occurred in all the treated lesions within two months. Eighteen (64%) of the 28 patients showed complete or almost complete repigmentation in all treated spots and five patients (18%) showed partial repigmentation. The remaining five patients (18%), including two patients with segmental vitiligo, showed no response. Of 23 patients who showed complete or partial repigmentation, three patients had recurrence of vitiligo within one year. No systemic toxicity was observed in this series of patients.
The efficacy of topical 8-methoxypsoralen (8-MOP) in varying concentrations and vehicles was assessed in 73 vitiligo patients. The response rates in different anatomic sites were also assessed. Seven patients (9%) had 100% repigmentation; 26 (36%) had 50% or greater repigmentation, 29 (40%) had some degree of pigment return, but less than 50%; 11 (15%) had no repigmentation. Results suggest that neither concentration of drug nor vehicle is a crucial factor for inducing repigmentation of vitiliginous patches on the face, trunk, and extremities. Low-dose 8-MOP (0.1%) was as effective as high dose 8-MOP (0.5%, 1%), while causing fewer side effects. However, when treating recalcitrant areas (distal extremities), 1% 8-MOP may be the most efficacious preparation for topical photochemotherapy. A phototoxic response preceded repigmentation in all cases. The following responses were obtained for the various anatomic sites treated: 56% of facial lesions; 35% of trunk areas; 36% of the extremities, and 13% of the recalcitrant areas had greater than 50% repigmentation.
Neuropeptide and neuronal marker immunoreactivity was studied in skin biopsies from lesional and marginal areas in 12 patients with vitiligo, and in seven normal controls. The vitiligo was active in seven, static in two, and of unknown activity in three. Antibodies against general neuronal marker PGP 9.5 (PGP 9.5), substance P (SP), calcitonin gene-related peptide (CGRP), vasoactive intestinal polypeptide (VIP), and neuropeptide Y (NPY), were used. The epidermis, dermo-epidermal junction, papillary and reticular dermis, and appendages, were assessed semiquantitatively for reactivity with each antibody. Staining with PGP 9.5 in the upper dermis was assessed quantitatively by image analysis. An increase in reactivity against NPY antibody was seen in five of 10 cases (three with active vitiligo) in the marginal areas, and in three of 12 subjects (all with active vitiligo) in the lesional vitiligo areas. VIP antibody reactivity showed a minimal increase in the marginal and lesional vitiligo areas (in two cases each, both of whom had active vitiligo). SP and CGRP reactivities did not differ from normal. PGP 9.5 staining was minimally increased at the dermo-epidermal junction and lower Malpighian layer in biopsies from marginal areas in three of 10 subjects (all with active vitiligo). Quantitative analysis of PGP 9.5 reactivity in the upper dermis showed no difference between vitiligo and normal biopsies. These findings support the concept of neuronal or neuropeptide involvement in vitiligo, and in particular suggest that NPY may have a role in the pathogenesis of the disease.
The in vitro effect of Anapsos, a water based extract of the naturally occurring fern Polypodium leucotomos (calagualine), on human leukocyte fractions was investigated. Calagualine inhibited interleukin-2 secretion and concanavalin A (Con A) stimulated proliferation of T-lymphocytes in a concentration dependent manner. In contrast, a greatly enhanced secretion of IL-1 alpha, IL-1 beta and tumor necrosis factor alpha was induced suggesting a stimulation of monocytes and dendritic cells also present in this system. Endotoxin induced stimulation was excluded. Also in the absence of Con A, calagualine stimulated cytokine production. The presented data show for the first time that calagualine exerts an immunomodulating effect on leukocyte fractions, paving the way for further detailed studies related to possible clinical efficacy.
Thirty-three patients with the depigmentation disorder vitiligo were successfully treated with a new topical application of pseudocatalase, calcium and short-term UVB light exposure. First repigmentation occurred in the majority of cases after 2-4 months. Complete repigmentation on the face and dorsum of the hands appeared in 90% of the group. In all patients, active depigmentation was arrested. None of them developed new lesions during treatment. No recurrence of the disease was observed during a 2-year follow-up. The rationale for this pilot study originated from a recent understanding of vitiligo at the molecular level. The involved epidermis produces hydrogen peroxide due to defective tetrahydrobiopterin recycling and increased monoamine oxidase A activity, whereupon catalase is inactivated. In addition, calcium homeostasis is perturbed in the affected skin. The substitution for insufficient catalase by a pseudocatalase together with calcium and UVB exposure lead to effective repigmentation.
There is a long-standing controversy over whether melanocytes in vitiligo lesions are actually lost or are still present but inactivated. Resolving this matter is essential for understanding the underlying pathology and for the development of treatment. Standard methods of detecting melanocytes are based on active melanin synthesis. However, it is possible that inactive melanocytes remain in the lesions. There are no methods presently available to detect such dormant melanocytes. Using a panel of one polyclonal and 17 monoclonal antibodies directed against melanocytic cells (largely selected by the European Organisation for Research and Treatment of Cancer Melanoma Group for diagnostic and therapeutic purposes), we investigated the absence or inactivation of melanocytes in vitiligo by immunohistochemistry. Results using this panel of antibodies on frozen skin sections suggest that melanocytes are indeed absent in the lesions. However, in epidermal split-skin preparations, residual staining was occasionally observed. To determine whether the staining obtained was due to degenerated melanocytes, confocal laser scanning microscopy was used. Immunofluorescent staining using the antibody NKI-beteb confirmed this to be the case. The results presented here strongly suggest that melanocytes are indeed lost in vitiligo lesions.
Patients with vitiligo have circulating antibodies directed in part to pigment cell antigens with MWs of approximately 90, 75, and 40-45 kDs. These antigens are denominated VIT 90, VIT 75, and VIT 40, respectively. To further characterize these “vitiligo” antigens, we examined their relation to antigens defined by a panel of 25 monoclonal antibodies (moab) to pigment cell antigens. We found by immunoprecipitation and SDS-PAGE analysis of 125I labelled, detergent soluble, human melanocyte macromolecules, that 24 (83%) of 29 patients with vitiligo had antibodies to one or more vitiligo antigens vs. 2 (7%) of 28 control individuals. Seventeen of the 25 moabs did not react with any labelled antigen in the same lysate. Of the remaining eight moabs, only four precipitated an antigen that co-migrated with one of the vitiligo antigens. Moab TA99, HMSA-5, and TMH-1 (all directed to the 75 kD tyrosinase-related protein [TRP1]) co-migrated with VIT 75. Moab W6/32 (directed to class I HLA antigen) co-migrated with VIT 40. Immunodepletion studies with vitiligo antibodies selectively depleted the antigen defined by W6/32 but not the antigen defined by TA99 and HMSA-5, indicating that VIT 75 was not the 75 kD tyrosinase-related protein. The vitiligo antigens were easily labelled by the lactoperoxidase technique but poorly labelled with 35S-methionine, suggesting they are expressed on the cell surface.
These studies indicate that VIT 90 and VIT 75 differ from antigens defined by currently available moabs to pigment cell antigens. VIT 40 appears to share a cross-reactive epitope, or be tightly bound to, class I HLA antigen.