Azathioprine hypersensitivity in bullous pemphigoid

Volume 23 Number 1 July 1990

semide and potassium therapy continued unchanged. This regimen was maintainedfor 1 month and resultedin partial resolution of her symptoms with no untowardeffects. The captopril dosage was increased to 25 mg orallyevery8 hours. Onemonth later she notedpruritic areas on the extremities as wellas some hair thinning. She deniedany changesin her hair management or the use of nonprescription medications. Examination revealed a morbilliform rash in the antecubital and popliteal fossae. Scalp hairs could be easily removed by plucking. Captopril was decreased to 12.5 mg orally every 8 hours. The patientreturned 1monthlater withresolution of the rash and pruritus, but severe alopecia was now apparent. She had large areasofcompletehair loss, exposing an erythematous, boggy, nontender scalp. Remaining hair was easily removed with light traction. Captopril was stopped. A complete blood count, includingplateletsand differential, wasnormal, Results of thyroid function studies(T3 resinuptake, and levels ofT4 and thyroid-stimulating hormone) were normal. Spontaneous hair regrowth began I month after the captopril was stopped. The patient is nowbeingtreatedwithfurosemide andpotassium only and no longer haspruritus;her rash and alopecia haveresolved.

Discussion. Furosemide is also recognized to cause a variety of skin reactions including rash, pruritus, urticaria, purpura, photosensitivity, necrotizing angiitis, exfoliative dermatitis, and erythema multiforme. In the present caseit isnot known whetherthe captopril itselfor an unknown interaction with furosemide resulted in the alopecia. Her clinical course while she still took furosemide excluded hypersensitivity to thismedication alone and thus implicates captopril in someway. REFERENCES l. Vidt D, Bravo E, Fouad F. Captopril. N Engl J Med 1982;306:214-8. 2. Vlasses P, Conner D, Rotmensch H, et al. Double-blind comparison of captopril and enalapril in mild to moderate hypertension. J Am Coll CardioI1986;7:651-60. 3. Goodman LS, Gilman A. The pharmacological basis of therapeutics. 7th ed. New York: MacMillan Publishing Company, 1985:651-2. 4. Bennett D, ed.AMA drug evaluations. 5th ed.Philadelphia: WB Saunders, 1983:735-7.

Dialysis acne Eliyahu Fuchs, MD, and Velva Lynfield, MD Brooklyn. New York We would like to alert dermatologists to yet another rash associated withdialysis treatment of kidney failure. We recently sawa 51-year-old blackman with no previous history ofskin problems in whom increased facial oiliness and acneofthe faceand uppertrunk developed sev-

Brief communications 125 eral months after hemodialysis was begun for end-stage kidneydisease secondary to hypertension. Thelesions responded to a combination of benzoyl peroxide gel,erythromycin solution, and hydrocortisone cream. Because acneat this ageis unusual, wereviewed hismedications. At Brooklyn Veterans Administration Medical Center, dialysis patients are given the following medications: calcium carbonate, vitamins, and "malogen." "Malogen" turned out to be testosterone enanthate, given as an intramuscular injection, 200 mg weekly, to stimulate hematopoiesis. Because testosterone is acnegenic, we would expect acne to occur in other patients with kidney failure beingtreatedwithit. Indeed, the dialysis staffhad noted it in otherpatients but did not consult dermatologists.

Azathioprine hypersensitivity in bullous pemphigoid Daniel W. Collison, MD,a.* and Philip J. Dahlberg, MD,a and James D. Hogan, MDb LaCrosse, Wisconsin Azathioprine has been a useful adjunct to the immunosuppressive therapyfor bullous pemphigoid, primarily because ofits steroid-sparing effects.' Drugfever is occasionally caused by azathioprine.l but this has not been previously reported in a patient withbullous pemphigoid. Drughypersensitivity should be considered in the differentialdiagnosis offeverin the elderly, whoareoften taking multiple medications. Case report.A 65-year-old woman had a 2-month history of blistering, which was unresponsive to oral erythromycin and prednisone therapy. She hada history of osteoarthritis and was allergic to penicillin. Physical examination revealed intact and collapsed bullae and erosions involving the shins, anterior thighs, vaginal introitus, labia minora, umbilical and suprasacral areas, upper arms, and left buccalmucosa. Healing hypopigmented andhyperpigmented plaques were presenton the upper back andchest. Biopsy specimens obtainedfrom new lesions on the suprasacral area revealed subepidermal bullaeand, by directimmunofluorescence, depositsofC3, IgG,andIgM in a linearpatternat the basementmembrane zone.Bullous pemphigoid was diagnosed. Tetracycline (500 mg orally twice daily), niacinamide (500 mgorally twice daily), nystatin(500,000 units orally twicedaily), and topical betamethasone dipropionate ointment (once daily) were started.Topicalviscous lidocaine wasused to assist in urination. The patient reported minor improvement, but

From the Dermatology Service, Brooklyn Veterans Administration Medical Center. No reprints available.

From the Departments of Internal Medicine,' andDermatology," The Gundersen Clinic, Noreprints available, *Current address: Department ofDermatology, Henry Ford Hospital, Detroit, Michigan.

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Brief communications

Journal of the American Academy of Derm atology

Azathioprine use: Iidiiillllllllllillililllllll!!I!

39

Fig. 1. Graph of patient's temperature . Bar at top indicates periodsofazathioprinetherapy.

symptoms flared after 1 month. Tetracycline was discontinued and oral azathioprine, 50 mg twice daily, was started. W ith this regimen, the bullous pemphigoid improved. Nine days after starting azathioprine, she had intermittent chills,fever(upt039° C), malaise, headaches,a nd blurred vision. The symptoms predictably occurred several hours after azathioprine ingestion; blurred visionand headache occurred first.She came to the emergency department 14 days later with partie. ularlyseveresymptoms.Shedeniedothers ymptom sofinfection. On examin ation, her temperature was initially 36.1 0 C and rose to 39.4 0 C (orally) during an episode of rigors. Th ere were shallow erosions of the left buccal mucosa but no bullae or erosions elsewhere. The WBC count was 6600 cells/rnm' with 17% band forms and 73% neutrophils. Multiphasic serum a nalyses a nd results of ur inalysis were normal. The patient was admitted for evaluation of fever of unknown origin. Th e differential diagnosis included drug fever and sepsis. Azathioprine was discont inued, but niacinam ide and topical bctamethasone dipropionate ointment were continued. Bacte rial cultures were obtained from the blood (drawn during rigors), from a pharyngeal swabbing, a nd from ur ine a nd stool samples. Fever swings persisted until 24 hours after the last azathioprine dose (Fig. I). During the next 72 hours, the patient had no symptoms and remained afebrile. Results of serial physical exam inations were normal and bacteriologic cultures were negative. To testthe diagnosis of drug fever, the patient was ch allenged again with 50 mg doses of azathioprine given 12 hours a part. Two hours after the first dose, she had a headache and blurred vision, which persisted throughout the day. Her temperature steadily rose above the baseline established during the previous 3 days (Fig. I). Ten hours after she received a second dose of az athioprine, rigors and fever (38,8 0 C) developed. Azathioprine was discontinu ed. Fe-

vel', headache, and blurred vision resolved during the next 14 hours. She continued niacinamide therapy as an outpat ient and had no further bullae. Discussion. Azathioprine (Imuran) is a purine analog that inhibitsboth RNA and DNA synthesis. It is the most widelyusedimmunosuppressive agent in dermatology;its use dates to 1969whenWolffand Schreiner' reported its efficacy in the treatment of pemphigus vulgaris. Greaves et al.' first described azathioprine treatment of bullous pemphigoid. Bullous pemphigoid is responsive to corticosteroids,but the doses required may exacerbate or induce fluid retention, cardiac failure, electrolyteabnormalities, diabetes, osteoporosis, cataracts, hypertension, bleeding, and other complications. I The steroid-sparingeffectofazathioprine may help prevent these complications that are of particular gravity in the elderly, the group most likely to contract bullous pemphigoid. Azathioprine-induced fever in bullouspemphigoidhas not been previously reported. Our patient's fevercurveis typical of hypersensitivity, the most likely mechanism.' The first reports of fever caused by azathioprine were in patients treated for connective tissuediseases" and kidney transplantation.' Sincethen azathioprinehas been usedin a wider spectrum of diseases, with a corresponding increasein reports of hypersensitivity reactions.v? Monitoring patients for drug reactionsis especially important in the elderly, who may be taking multiple medications. Infection and azathioprine hypersensitivity may mimic each other." 8

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REFERENCES 1. Greaves MW, Burton Jl., Marks 1M, et al. Azathioprine in treatment of bullous pemphigoid. Br Med J 1971;1:144. 2. Lipsky BA, Hirschmann rv. Drug fever. lAMA 1981;245: 851-4. 3. Wolff K, Shreiner E. Immunosuppressive Therapic bei Pemphigus vulgaris: vorlaufige Erfahrungen mit Azathioprin. Arch Klin Exp DermatoI1969;235:63-77. 4. Michot F. Erfahrungen in der Langzeitbehandlung von Kollagenkrankheiten mit Azathioprin. Med Klin 1968;63: 1262-6. 5. King JO, Laver MC, Fairley KF, et al. Sensitivity to azathioprine. Med 1 Aust 1972;2:939-41. 6. Assini JF, Hamilton R, Strosberg JM. Adverse reactions to azathioprine mimicking gastroenteritis. J Rheumatol1986; 13:1117-1118. 7. Mosbech H, Andersen CWo Azatioprin-induceret idiosynkrasi. Ugeskr Laeg 1982;144:2424. 8. Rosenthal E. Azathioprine shock. Postgrad Med 1 1986;62: 677-8. 9. Cocco AE, Pavlides GP. Fever due to azathioprine in the treatment of patients with an inflammatory bowel disease. Md State Med J 1977;26:61-2.

Dermatomyositis presenting as panniculitis Warren J. Winkelman, MD,a Robin C. Billick, MD, FRCPC,b and Herbert Srolovitz, MD, FRCPCc

Montreal, Quebec, Canada Dermatomyositis is a systemic illness characterized by classic cutaneous findings in association with muscular weakness. 1 A patient with dermatomyositis presenting initially as a nonspecific panniculitis, a rare event, is discussed. Case report. A 24-year-old Filipino woman was seen in November 1987 with tender red plaques of the left arm with diffuse subcutaneous induration (Fig. 1), infraorbital erythema and edema, and a low-grade fever of 3 months' duration after summer sun exposure. Results of the remainder of the examination were normal. Findings of biochemical, hematologic, and immunologic screens were normal. Histopathologic examination of the arm lesion demonstrated focalliquefaction degeneration in the dermoepidermaljunction, parakeratosis, rare follicular plugging, and a mild superficial and deep perivascular lymphocytic infiltrate. The subcutaneous tissue (Fig. 2) manifested a predominately lobular panniculitis with spotty adipocyte necrosis, aggregates of lymphocytes and plasma cells with rare germinal center formation (Fig. 3), and a lymphocytic vasculitis. Direct immunofluorescence was negative for immunoglobulin deposition in tissue. From the Division of Dermatology, Royal Victoria Hospital, McGill University," and the Division of Derrnatology'' and the Department of Pathology," Sir Mortimer B. Davis-Jewish General Hospital, McGill University. Reprint requests: Warren J. Winkelman, MD, Division of Dermatology, MeGill University, Royal Victoria Hospital, Room LS.OI, 687 Pine Ave. West, Montreal, Quebec, Canada H3A IAI.

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Fig. 1. Plaque on left arm with superficial scaling and subcutaneous induration.

Hydroxychloroquine, for a suspected lupus panniculitis, was instituted at an initial dosage of 200 mg orally twice weekly, increasing to daily doses, with subsequent improvement. In February 1988 an exacerbation of symptoms was noted with concomitant development of a periorbital discoloration, Gottron's papules, muscle weakness, tenderness ofthe shoulders and thighs, diffuse arthralgias, and elevation of muscle enzyme levels. Immunologic findings were unchanged. Electromyography and muscle biopsy were consistent with dermatomyositis. Evaluation was negative for underlying malignancy. Hydroxychloroquine was discontinued and prednisone, 60 mg/day, together with methotrexate, 2.5 mg orally three times weekly, were instituted. Improvement of the cutaneous and myositis symptoms and the panniculitis, as well as a concurrent drop in muscle enzyme levels were noted. A gradual tapering of prednisone was met with an exacerbation of all symptoms in September 1988. At the time of writing (June 1989), the patient was lost to follow-up but her condition was well controlled on low-dose methotrexate and prednisone.

Discussion. Panniculitis in dermatomyositis is infrequently reported, although its existence was recognized in the earlier part of this century. In 1924 Weber and Gray? described a 22-year-old WOman with painful inflammatory nodules of the arms and thighs that resembled erythema nodosum and that appeared concurrently with