Evaluation of Methoxsalen in the Treatment of Vitiligo Irving D

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EVALUATION OF METHOXSALEN IN THE TREATMENT OF VITILIGO IRVING D. LONDON, M.D. Montgomery, Atabamo

The value of the psoralen compounds in theviolet light from a General Electric R.S. Sunlamp treatment of vitiligo has been documented inbulb. The amount of exposure was gradually in- this country since 1952 (1—6). Vitiligo is a dis-creased, based on the patient's tolerance. Another ease of unknown etiology in which the pigmentgroup was treated by topical application of one rarely if ever has been known to return spon-per cent methoxsalen paint over small patches of vitiligo followed by exposure to sunlight or sun- taneously to the involved areas (see p. 281).lamp. At first, both 8-methoxypsoralen (methox- No statistical analysis will be attempted in this salen) and 8-isoamylenoxypsoralen were usedpaper for several reasons. First, several patients together in capsules for oral administration andwere lost from view after several months of treat- mixed in a cream for topical use. Since 1955,ment. Some were seen at distant clinics and these only methoxsalen has been used, after Kanofrecords were not available during the preparation (5) found that this compound was as effectiveof this paper. A few patients had to stop taking when used alone as when combined with 8-the drug because of toxic reactions. Lastly, the isoamylenoxypsoralen. When methoxsalen, eithertechnics of administration of the psoralens were not always comparable. I shall, therefore, discuss applied topically or taken orally, is followed bynot statistics but the results in general of the exposure to gradually increasing doses of sun-various technies especially as they pertain to light or artificial ultraviolet light, gradual re-individual patients. pigmentation of vitiligo has been noticed in a varying proportion of cases. TOPICAL THERAPY The author became interested in this treatment for vitiligo in 1953 and has used these The intensity of sunlight in the deep South compounds, along with controlled exposure tomust be reckoned with in the topical application sunlight or ultraviolet light in approximatelyof methoxsalen to vitiligo. In practically all 40 patients. cases in which mcthoxsalcn lotion was applied to an exposed surface, such as hands, neck or METHODS face, burning and vesiculation followed the In 1953 and 1954 the first group of patients wasexposure to sunlight, after one or several treat- treated with both oral and topical administrationments. This was probably due not only to the of the mixed psoralens.* Approximately 15 pa-intensity of the measured therapeutic exposure tients received from two to six 10 mg. capsules ofbut also to additional casual exposures the pa- the mixed psoralens daily, divided into two ortient unsuspectingly received while out in the three doses. The one per cent cream was alsosun following treatment. The worst such case applied once daily to the lesions. The patientsoccurred in September, 1956. This was a white were instructed to expose themselves to increasing amounts of sunlight or ultraviolet light at leastmale, age 36, who had only one application of five times weekly. methoxsalen to the white spots on his hands. Since 1955 most of the patients were treated byFive to ten minutes later he exposed his hands the oral administration of methoxsalen, 20 mg.for only one minute to noonday sun. Severe, daily being taken two hours prior to carefullyintensive burning with the formation of large measured exposures to the mid-day sun or ultra-blisters on these areas resulted overnight. These Presented at the Brook Lodge Invitationalblisters persisted for fourteen days and the Symposium on the Psoralens, sponsored by thepatient required oral steroid therapy to clear Upjohn Company, Kalamazoo, Michigan, Marchthem. The patient admitted that he was out 27—28, 1958. *Themixed oral psoralens contained 10 mg.,of doors with his hands exposed to the sun the S-methoxypsnralen and 5 mg. 8-isoamylenoxy-afternoon following the mcthoxsalen lotion. psoralen. Bi-psoralen cream contained 0.75% Contact dermatitis, with or without blistering, S-methoxypsoralen and 0.25% 8-isoamylenoxypsoralen. has also been noticed in the colored patients 315 316 THE JOURNAL OF INVESTIGATIVE DERMATOLOGY who have used the topical application. Onechild, age nine, became completely repigmented colored child, however, did have burning andand has continued to receive one or two capsules blistering of several spots on his face treateddaily for over one and one-half years without last year and now reports that without anyany harmful effect. Her pigmentation persists. further treatment the lesions have repigmented A white male, age 43, has been on methoxsalen and have remained so up to the present. Topicalfor three years with only several short breaks in methoxsalen therapy was used successfully inthe treatment. These breaks were necessitated two other colored patients whose lesions wereby a hernia operation two years ago and again under the clothing; one on the thighs, anotherby a short bout of influenza this past winter. on the chest. These patients did not have anyThis patient has had vitiligo for fifteen years. burn or vesiculation with their treatment. ThisHis lesions were scattered over the face, neck, observation, therefore, leads to the conclusionhands and body. He was mainly interested in that severe reactions are due to additionalobtaining a decent cosmetic appearance of the casual exposures to sunlight in uncovered areasleukodermic spots on his face and neck. The treated with topical methoxsalen. In general,vitiligo on these areas showed some repigmenta- topical psoralen therapy should be used withtion with typical perifollicular distribution of extreme caution in the Southern states on thethe melanin pigment within several weeks, and exposed surfaces of the body and with cautiouslycomplete repigmentation within four to five controlled sunlight or sunlamp therapy wheremonths. Since then there was some regression the lesions are on the areas covered by clothing.of the vitiligo when he was unable to take the drug or when he diminished it to one capsule RESPONSE TO ORAL THERAPY daily. With higher doses he becomes very nervous, About 35 patients were treated orally withupset and depressed. methoxsalen. Most of these patients showed some beginning repigmentation in two weeks TOXIC REACTIONS to two months after the onset of treatment. Those that showed no repigmentation in two In the early group, which consisted of about months failed to show any afterwards. Thefifteen patients, liver function studies were per- dorsa of the hands most often failed to showformed. One of these patients had a 2-plus eephalin flocculation test about two months repigmentation. The repigmentation was usually in the form of perifollicular ephelis-like lesionsafter commencing therapy, but had not had a or a filling-in of pigment from the periphery.prior test. This was not considered significant. With continuation of therapy, these maculesLiver function studies have not been performed became coalesced to form large patches of pig-in this investigation since 1954. ment which would eventually fill in the defect. Toxic reactions of mild to moderate degree As has been previously observed (8, 9), thewere noted with oral methoxsalen therapy from normal skin exposed to the sun or ultravioletthe beginning of this study. Two patients dis- light after methoxsalen tans excessively or be-continued oral treatment because of severe nausea comes hyperpigmented. In vitiligo the whiteand vomiting. In 1954, a white female, age 17, had persistent nausea and vomiting, lasting four or spots become surrounded by hyperpigmented areas making them become more prominent andfive days, after taking one capsule. A second patient noticed very little repigmentation after two bizarre in appearance, thereby causing many white women to stop the treatment. Anothermonths of therapy and because of the severe commonly noted finding with oral medication isnausea and vomiting on one capsule daily dis- the fact that this therapy has had to be continuedcontinued treatment. SeYeral patients discon- indefinitely because leaving the drug off or re-tinued methoxsalen because of severe nervous- ducing the dose produced a relapse of the vitiligo.ness. Three patients noticed erythema and itching Colored patients responded much better tofollowing oral methoxsalen therapy. the oral administration of the psoralens than In response to a recent questionnaire, the did the white patients. Children respondedfollowing reasons were noted for discontinuing faster and again more completely than adults.therapy: In this series were several colored children, ages 1. Toxic symptoms: severe nausea and vomit- five to 11 and one white child, age 11. One colored ing, nervousness, blistering and dermatitis. EVALUATION OF METHOXSALEN IN TREATING VITILIGO 317

2. The treatment was too prolonged and incontinued indefinitely to maintain repigmenta- most instances had to be continued indefinitely.tion. 3. Many patients, especially women, objected Colored children have uniformly shown a to the hyperpigmentation surrounding thegood response, with a more rapid onset of benefit vitiliginous areas which made these areas moreand more complete end result. prominent during the early stages of therapy Oral mcthoxsalcn therapy is recommended and during the summers. for patients who arc practical and patient, and who will be satisfied with a reasonable cosmetic DIscussIoN rcpigmcntation of the face and neck. The pa- In 1955, in discussing Elliott's paper (7) attient with generalized vitiligo who wants to the Southern Medical Association meeting inrcpigmcnt all the affected areas should be dis- Houston, the writer raised the question of thecouraged from beginning or attempting treat- recurrence of vitiligo in the healed areas and thement. necessity of continuing treatment indefinitely The toxic effects of mcthoxsalcn include severe with oral mcthoxsalcn therapy. It is now com-nausea and vomiting, severe nervousness, de- monly noted that dcpigmcntation follows dis-pression, and dermatitis with blistering. continuation or decreasing the oral dosage of The reasons given by patients for discontinu- the methoxsalcn. ing therapy were: (a) severe toxic symptoms, In reviewing two recent papers on topical or(b) slowness of rcpigmcntation, (c) the prolonged combined therapy, it is noted that George andtreatment that is necessary, and (d) the bizarre Burks (4), and Sheldon et at. (6) speak of "cures."accentuation of the vitiligo because of surround- Complete rcpigmcntation took place in George'sing hypcrpigmcntation. group in two of eleven patients in from two weeks REFERENCES to two months and in Sheldon's group in four of twenty-five patients in about four months.1. SERLA, M.: Treatment of vitiligo, correspond- ence. Arch. Dermat. &Syph.,65: 358, 1952. All these patients received topical therapy; some2. SIDI, E. AND Boununols-GAvARDIN, J.: The also took oral mcthoxsalen. Neither paper men- treatment of vitiligo with Ammi majus Linn.J. Invest.Dermat., 18: 391, 1952. tions dcpigmcntation occurring when therapy3.LERNEE,A. B., DENTON, C. R. AND FITZ- stopped. In the present survey, three patients PATRIcK, T. B.: Clinical and experimental had complete rcpigmcntation which has per- studies with 8-methoxypsoralen in vitiligo. J.Invest.Dermat., 20: 299, 1953. sisted for six months to one year following topical4. Gotoi, W. M. AND BURK5, J. W., JR.: Treat- treatment. It is therefore probable that topical ment of vitiligo with psoralen derivates. therapy is more efficacious and longer-lasting Arch. Dermat. &Syph.,71: 14, 1955. 5.KANOF,N. B.: Melanin formation in vitilig- than oral methoxsalcn, despite the fact that inous skin under the influence of external dermatitis may result from the topical applica- applications of 8-methoxypsoralen. J.Invest. Dermat., 24:5, 1955. tions. 6.SHELDON,S. A.,HARRELL,E. R. AND CuRTIs, A.C.: Resultsin the treatment of vitiligo 5UMMARY AND cONcLUsIONs with8-methoxypsoralen. Arch. Dermat. & Syph.,74:9, 1956. Topical therapy of vitiligo with mcthoxsalen 7.ELLIOTT,J.A., JR.:Thetreatment of vitiligo should be used with great caution on the exposed with8-methoxypsoralen. South. M. J., 49: 691,1956. surfaces of patients residing in the Southern 8. LERNER,A.B.: Potentiation of suntanning states. This treatment may be applied with less throughingestion of 8-methoxypsoralen. J. danger on the covered areas of the body. Topical Invest.Dermat., 25:1,1956. 9.FITZPATRICK,T.B., HoPKINs,C.E., BLICKEN- therapy results in longer lasting repigmentation sTAFF, D. D. AND SWIFT, S.: Augmented pigmentation and other responses of normal of vitiligo. human skin to solar radiation following oral Repigmcntation on oral therapy will commence administration of 8-methoxypsoralen. J. within two months, if at all. Medication must be Invest.Dermat., 25:187, 1955.