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Pemphigus foliaceus and proteinuria induced by α-mercaptopropionylglycine
Volume 8 Number 5 May, 1983
Acquired progressive lymphangioma
REFERENCES 1. Wilson Jones E: Malignant vascular tumours. Clin Exp Dermatol 1:287-312, 1976. 2. Gold SC: Angioendothelioma (lymphatic type). Br J Dermatol 82:92-93, 1970. 3. Wilson Jones E: Malignant angioendothelioma of the skin. Br J Dermatol 76:21-39, 1964. 4. Sanderson KV, Mackie R: Turnouts of the skin, in Rook A, Wilkinson DS, Ebling FJG, editors: Textbook of dermatology, ed. 3. Oxford, 1979, Blackwell Scientific Publications, vol. 2, p. 2224. 5. Wilson Jones E, Feiwel M: Malignant angio-endothelioma. Proc R Soc Med 56:299-300, 1963. 6. Lewis R, Wallace HJ: Angioendothelioma. Br J Dermatol 79:361, 1967.
7. Wilson Jones E: The pathology of malignant angioendothelioma of the skin. XII[ Congressus Internationalis Dermatologiae, Munich, pp. 70-71, ! 9 6 7 , 8. Norman CF, Nancy BE: Successful treatment of juvenile hemangiomas with prednisone: J Ped!atr 72:351-357, 1968. .... 9. Gange RW, Wilson Jones E: Lymphangioma-like Kaposi's sarcoma. Br J Dermatol 100:327-334, 1979. 10. Ackerman AB: The patch stage of Kaposi's sarcoma. Am J Dermatopatbol h 165-172, 1979. 11. Schwartz RA, Burgess GH, Hoshaw RA: Patch stage Kaposi's sarcoma. J AM ACAD DERMATOL2:509-512, 1980.
I"r
Pemphigus foliaceus and proteinuria induced by o -merc aptopropionylglycine Paul A. L u c k y , M . D . , F l e m m i n g Skovby, M . D . , and Samuel O. Thier, M . D .
New Haven, CT Pemphigus foliaceus and proteinuria occurred in a patient with cystinuria treated with ~-mercaptopropionylglycine. This drug is similar to D-penicillamine in structure and function, and it is being used in patients who are unable to tolerate D-penicillamine. Although side effects of D-penicillamine are common, no major adverse reactions have been reported previously with a-mercaptopropionylglycine. Pemphigus foliaceus and proteinuria occurring during therapy with o~-mercaptopropionylglycine and D-penicillamine are discussed. (J AM ACAD DERMATOL 8: 667-672, 1983.)
P e m p h i g u s foliaceus and as complications of therapy Although this drug is useful several medical disorders,
proteinuria can occur with D-penicillamine. in the m a n a g e m e n t of there is a high inci-
From the Departments of Dermatology, HumanGenetics,and Internal Medicine, Yale UniversitySchool of Medicine. Reprint requeststo: Dr. PaulA. Lucky,Departmentof Dermatology, P.O. Box 3333, Yale UniversitySchoolof Medicine, New Haven, CT 06510.
dence of adverse effects, and alternative agents have therefore b e e n sought. One such drug, o~mercaptopropionylglycine (o~-MPG), is similar to D-penicillamine in structure a n d in m o d e o f action in the treatment o f cystinuria. B e c a u s e it has been reported to be as effective as D-penicillamine, but to h a v e fewer adverse effects, ce-MPG is n o w being tested in this country. This is the first report of p e m p h i g u s foliaceus and proteinuria following the use of c~-MPG.
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Fig. 1. Chest of patient with pemphigus foliaceus 1 week (A) and 2 weeks (B) after the onset of erythema and pruritus. The eruption began as erythematous macules and evolved into flaccid bullae and shallow erosions.
Case report A 46-year-old man of Ashkenazi Jewish ancestry had a history of renal calculi since the age of 13. Analysis of a calculus removed at the age o f 18 revealed pure cystine, and a diagnosis of cystinuria was confirmed by the demonstration of increased amounts of cystine, omithine, arginine, and lysine in the patient's urine. Treatment with D-penicillamine was started at the age of 30 but was stopped 10 years later because of proteinuria in excess of 3 grn/24 hr. Conservative management, including alkalinization of the urine and a high fluid intake, was not effective in preventing growth of staghorn calculi. Therapy with a-MPG ( " T h i o l a " ; Santen Pharmaceutical Co., Ltd., Osaka, Japan) was initiated in February, 1981, following approval of the treatment protocol by the Human Investigation Committee of the Yale University School of Medicine and after informed consent was obtained from the patient. The patient's urinary excretion of protein prior to starting oe-MPG was 300 mg/24 hr. The dose o f a-MPG was increased in increments of
200 mg per 24 hr over 4 days to a total dose of 800 mg/24 hr (200 mg/6 hr). In March the patient complained of oropharyngeal pain, but mucous membrane lesions were absent. There was no pruritus, urticaria, blistering, or erythema. Routine laboratory evaluation showed a mild eosinophilia (white blood count, 7500; eosinophils, 10%), and the o~-MPG was discontinued. The oropharyngeal pain resolved and the eosinophilia cleared. In May, 1981, a-MPG was restarted at a dose of 200 mg four times daily. A 24-hour urine collection from July, 1981, contained 1.1 gm of protein. In early August, the patient noted pruritus and erythema, initially on the upper portion of the chest and then on his forearms. The pruritus increased and the erythema spread to involve his face, back, and abdomen. One week after the onset of symptoms, small flaccid bullae appeared within the erythematous patches (Fig. 1, A). The a-MPG was discontinued. Large numbers of erythematous patches and bullae continued to appear during the following week, and the patient was hospitalized. Examination at that time revealed patchy ery-
Volume 8 Number 5 May, 1983
Pemphigus fbliaceus and proteinuria
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Fig. 2. Small flaccid bullae on erythematous bases (A) are typical of pemphigus foliaceus. Histology (B) of bullae on perilesional skin demonstrates intraepidermal acantholysis. Edema and clefting of the epidermis with an infiltrate of predominantly eosinophils is present. (Hematoxylin-eosin stain; original magnification, x 120.) thema involving the scalp, face, and chest (Fig. 1, B), back, upper arms, abdomen, upper thighs, and the shaft of the penis. Within the erythematous lesions were bullae in various stages of evolution. Most were 2 to 5 mm in diameter, but a few larger intact flaccid blisters were seen (Fig. 2, A). Many of the erythematous patches demonstrated only shallow erosions where bullae had been located. Nikolsky's sign was present. Laboratory studies included a normal complete blood cell count and platelet count. Wintrobe sedimentation rate was 39 mm/hr. Serum creatinine was 1.8 mg/dl (0.6-1.5). During the prior 5 years it had ranged
from 1.2 to 2.5 mg/dl. Uric acid was 9.9 mg/dl (4.56.5), bicarbonate, 17.9 mg/dl (25.1-30.5), chloride, 109 mg/dl (100-106), and phosphate, 5.1 mg/dl (3.1-4.5). The remainder of the SMA 20 was within normal limits. Proteinuria had increased to 7.3 gm/24 hr. Antinuclear antibody and rheumatoid factor were negative, and serum immunoglobulins were within normal limits. Skin biopsies of lesional and perilesional skin showed subcorneal and intraepidermal bullae with acantholysis (Fig. 2, B). The epidermis was spongiotic, and a mixed cellular infiltrate with a predominance of eosinophils was noted. Collagen, adnexae, and blood
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vessels appeared normal, Direct immunofluorescence of the patient's skin was negative for IgG, IgA, IgM, and C3. Indirect immunofluorescence of the patient's serum was also negative. Treatment was begun with prednisone, 120 rag/daily in divided doses, open-wet dressings with a 1:8,000 solution of potassium permanganate, and triamcinolone cream, 0.1%, applied topically. Five days later no new bullae were seen, and the patient's skin lesions had begun to re-epithelialize. Prednisone was maintained at 120 mg/daily in a single dose for 2 weeks and then tapered slowly over 2 months. There was no residual scarring. Two months after prednisone had been stopped, the cutaneous examination was normal and the 24-hour urinary excretion of protein had decreased to 500 mg/24 hr. DISCUSSION This is the first report of pemphigus foliaceus and proteinuria occurring as complications of treatment with oz-MPG. Our patient's primary disease was cystinufia, an autosomal recessive disorder which affects the transport of cystine and dibasic amino acids in the kidney and the small intestine. The clinical manifestations of this disease result from the excessive urinary excretion of cystine, which causes the formation of cystine calculi. 1 The medical treatment of cystinuria consists of a high fluid intake to decrease the urinary concentration and alkalinization to increase the solubility of urinary cystine. Crawhall et al 2 introduced the use of D-penicillamine for treatment of patients with cystinuria, m-penicillamine is a sulfhydryl amino acid which was initially used to chelate copper in Wilson's diseasefl but is now also used in the treatment of lead poisoning, 4 rheumatoid arthritis, 5 sclerodermafl and primary biliary cirrhosis. 7 In cystinuria, D-penicillamine reacts with cystine in a thiol-disulfide exchange, thereby creating a mixed (penicillamine-cysteine) disulfide and cysteine, both of which are more soluble than cystine in the urine? Although the drug is effective in dissolving cystine calculi and preventing their formation, as many as 50% of patients treated develop serious adverse reactions.1 Proteinuria occurs in more than 30% of patients treated with D-penicillamine. s Biopsies have demonstrated an immune complex glomerulonephritis, with deposition of IgG and C3 in a granular pattern along the basement membrane. If the drug
Journal of the American Academyof Dermatology
is continued, nephrotic syndrome may result) Other immune diseases have occurred in patients taking D-penicillamine, including lupus erythematosus, 1° polymyositis, 11 myasthenia gravis, 12 and a Goodpasture-like syndrome, la Leukopenia, thrombocytopenia, aplastic anemia, hematuria, and transient loss of taste and smell have been reported.i4 The most common complications of therapy with D-penicillamine are dermatologic. TM Temporally, two different types of adverse reactions have been identified. Early reactions, occurring during the first weeks of therapy, usually consist of mild or localized erythema, pruritus, urticaria, dryness, and scaling. In general, these resolve spontaneously without discontinuing the drug, and antihistamines, emollients, or topical steroids are adequate for symptomatic relief. If the D-penicillamine is stopped until after the symptoms resolve, it can usually be restarted without recurrent problems. Late cutaneous reactions occurring after several months of therapy are often of a more serious nature and require discontinuation of the drag. Approximately thirty cases of pemphigus foliaceus in patients receiving D-penicillamine have been reported. Pemphigus foliaceus '~.16 is an autoimmune blistering disease in which small, flaccid bullae occur on either erythematous or apparently normal skin. It usually presents spontaneously in previously healthy individuals, and, although cases have been reported in infants, the disease generally occurs in middle-aged men and elderly women. The incidence may be increased in Jews. The clinical diagnosis of pemphigus foliaceus may be difficult to make because of the multiple patterns of presentation. Most commonly, delicate bullae appear symmetrically on the trunk, face, or scalp. Nikolsky's sign is present, and minimal manipulation or contact with clothing will shear off the tops of the blisters, leaving shallow, crusted ulcers. Another presentation consists of very transient early bullae followed by an eczematous eruption similar to seborrheic dermatitis. Less commonly, pemphigus foliaceus can resemble dermatitis herpetiformis, presenting with erythematous patches and grouped papules and vesicles. Although pemphigus foliaceus may present acutely, involving a large percentage of the cutaneous surface, more often localized disease is
Volume 8 Number 5 May, 1983
present initially and extension in a symmetric fashion takes place gradually. Histologically, the bullae in pemphigus foliaceus occur high within the epidermis. There is loss of cohesion between epidermal cells, resulting in the formation of clefts near to or within the granular layer. Although the etiology of pemphigus foliaceus is not known, its pathophysiology is thought to involve the formation of autoantibodies against the intercellular cement substance. In some cases direct immunofluorescence has been positive for IgG and C3 in lesional and perilesional skin. t6 Positive as well as negative indirect immunofluorescence has been reported. Marsden et aW investigated seven cases of pemphigus foliaceus among 104 patients with rheumatoid arthritis who had taken D-penicillamine for 6 to 12 months. Bullae were seen initially in only two patients, whereas scaly plaques were noted in the others. In two of the cases, the rash persisted for 12 to 23 months following the discontinuation of penicillamine, despite therapy with prednisolone alone or in combination with azathioprine. Kristensen and Wadskov is reported a 61-year-old man with scleroderma who developed pemphigus foliaceus after 9 months of Dpenicillamine therapy. Immunofluorescence studies demonstrated intercellular deposits of IgG and C3 in the epidermis. Although therapy was not discussed, the patient still had active pemphigus foliaceus 1 year later. While most cases of D-penicillamine-induced pemphigus foliaceus either resolved after treatment or were controlled with steroids and immunosuppressives, two fatal cases have been documented.19,2° o~-Mercaptopropionylglycine (c~-MPG) is a thiol compound which has been used as a substitute for D-penicillamine. The two drugs have structural similarities. In clinical trials in Japan, over 1,000 patients experienced no major adverse reactions from o~-MPG. Minor side effects were noted in five patients and included itching, temporary nausea, and facial hyperemia. 2~,22 c~-MPG functions similarly to D-penicillamine in cystinuria and has been reported to be as effective as D-penicillamine in preventing the formation and even in dissolving cystine renal calculi.22 Seven groups of investigators have treated forty-eight cystinuric patients with c~-MPG from 45 days to 5 years without sig-
Pemphigus foliaceus and proteinuria 671
nificant complications3 ~-28 The reported adverse effects of ol-MPG included: nausea (1 patient), fever (2 patients), urticaria (3 patients), soft feces (4 patients), and skin rash (6 patients). None of these symptoms required that any p a t i e n t be withdrawn from the study. One patient refused further treatment when a generalized rash appeared after 1 week of therapy. ~s All of the cutaneous eruptions occurred early, were transient, and did not recur when the o~-MPG was restarted. No skin biopsies were reported. Acantholysis in D-penicillamine-induced pemphigus foliaceus may result from modification of intercellular cement substance by the drug, making it antigenic. In some patients the immune response diminishes after withdrawal o f D-penicillamine, while in others the process is self-perpetuating. o~-MPG may cause pemphigus foliaceus in a manner similar to D-penicillamine, since the drugs have both structural and functional similarities. It is possible that previous treatment with D-penicillamine predisposed our patient to the development of pemphigus foliaceus. In the few cases of D-penicillamine-induced pemphigus foliaceus in which immunofluorescence studies have b e e n done, direct immunofluorescence has been positive. Despite the absence of this finding in the present case, however, the clinical and histologic features strongly support the diagnosis of pemphigus foliaceus. The development of severe proteinuria has not been reported in patients receiving o~-MPG. Its temporal relationship in our patient to the a-MPG therapy and concurrent skin toxicity, as well as its resolution when the o~-MPG was stopped, implicate the drug as the cause of his nephropathy. Physicians treating patients with oL-MPG should be aware of pemphigus foliaceus and proteinuria as potential complications. Identification of additional cases will provide the opportunity to determine the incidence of o~-MPG-induced pemphigus foliaceus and proteinuria and to compare the findings with those resulting from D-penicillamine. REFERENCES 1. Thier SO, Segal S: Cystinura, in Stanbury JB, Wyngaarden JB, Frederickson D, editors: The metabolic basis of inherited disease. New York, 1978, McGraw-Hill Book Co., pp. 1578-1592,
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2. Crawhall JC, Scowen EF, Watts RWE: Effect of penicillamine on cystinuria. Br Med I 1:588-590, 1963. 3. Walshe JM: Penicillamine: A new oral therapy for Wilson's disease. Am J Med 21:487-495, 1956. 4. Vitale LF, et al: Oral penicillamine therapy for lead poisoning in children. J Pediatr 83:1041-1045, 1973. 5. Multicenter Trial Group: Control trial of D-penicillamine in severe rheumatoid arthritis. Lancet 1:278-280, 1973. 6. Bluestone R, Grahame R, Holloway V, Holt PJL: Treatment of systemic sclerosis with penicillamine, and a new method of observing the effects of treatment. Ann Rheum Dis 29: 153-158, 1970. 7. Matloff DS, Alpert E, Resnick RH, Kaplan MM: A prospective trial of D-penieiIlamine in primary biliary cirrhosis. N Engl J Med 306:319-326, 1982. 8. Halperin EC, Thier SO, Rosenberg LE: The use of D=penicillamine in cystinuria: Efficacy and untoward reactions. Yale J Biol Med $4:439-446, 198l. 9. Jaffe IA, Treser G, Suzuki Y, Ehrenreich T: Nephropathy induced by D-penicillamine. Ann Intern Meal 69: 549-556, 1968. 10. Crouzet J, et al: Lupus induced by D-penicillamine during the treatment of rheumatoid arthritis. Ann Med Interne (Paris) 125:71-79, 1974. 11. Sehrader PL, Peters HA, Dahl DS: Polymyositis and penicillamine. Arch Neurol 27:456-457, 1972. 12. Bucknall RC, Dixon AStJ, Glieb EN: Myasthenia gravis associated with penicillamine treatment for rheumatoid arthritis. Br Med J 1:600-602, 1975. 13. Stemleib I, Bennett B, Scheinberg IH: D-Penicillamine induced Goodpasture's syndrome in Wilson's disease. Ann Intern Med 82:673-676, 1975. 14. Jaffe IA: D-Penicillamine, lit Kelley WN, Harris ED Jr, Ruddy S, Sledge CB: Textbook of rheumatology. Philadelphia, 1981, W. B. Saunders Co., pp. 815-821. 15. Perry HO, Brunsting LA: Pemphigus foliaceus. Arch Dermatol 91: 10-23, 1965. 16. Lever WF: Pemphigus and pempbigoid. J AM ACAD DERMATOL 1:2-31, 1979.
Journal of the American Academy of Dermatology
17. Marsden RA, et al: Pemphigus foliaceus induced by penicillamine. Br Med J 2:1423-1424, 1976. 18. Kristensen JK, Wadskov S: Penicillamine induced pemphigus foliaceus. Acta Derm Venereol (Stockh) $7:6971, 1977. 19. Sparrow GP: Penicillamine pemphigus and the nephrotic syndrome occurring simultaneously. Br J Dermatol 98:103-105, 1978. 20. Matkalak RM, Bailin PL: Penicillamine-induced pempbigus foliaceus. Arch Dermatol 117: 156-157, 1981, 21. Santen Pharmaceutical Co., Ltd., Osaka, Japan: Brochure on "Thiola," 1967. 22. King JS: Treatment of cystinuria with a-mercaptopropionylglycine: A preliminary report. Proc Soc Exp Biol Med 129: 927-932, 1968. 23. Sonoda T, et al: Effect of Thiola on cystinuria, in Proceedings of the International Symposium on Thiola. Osaka, 1980, Santen Pharmaceutical Co., Ltd., p. 231. 24. Nishimura R, Ishido T, Takai S: Studies on cystinuria. Proceedings of the 2nd International Symposium on Thiola. Osaka, 1942, Santen Pharmaceutical Co., Ltd., p. 47. 25. Kinoshita K, Yachiku S, Kotake T, Takenchi M, Sonoda T: Treatment of cystinuria with oz-mercaptopropionylglycine (MPG). Proceedings of the 2nd International Symposium on Thiola. Osaka, 1972, Santen Pharmaceutical Co., Ltd., p. 50. 26. Remien A, Kallistratos G, Burchardt P: Treatment of cystinuria with Thiola (a-mercaptopropionylglycine). Eur Urol 1:227-228, 1975. 27. Hautmann R, Terhorst B, Stuhlsatz HW, Lutzeyer W: Mercaptopropionylglycine: A progress report on cystine stone therapy. J UrN 117:628-630, 1977. 28. Johansen K, Gammelgard PA, Schonau-Jorgensen F: Treatment of cystinuria with alpha-mercaptopropionylglycine. Scand J Urol Nephrol 14:189-192, 1980.
Acquired progressive lymphangioma
REFERENCES 1. Wilson Jones E: Malignant vascular tumours. Clin Exp Dermatol 1:287-312, 1976. 2. Gold SC: Angioendothelioma (lymphatic type). Br J Dermatol 82:92-93, 1970. 3. Wilson Jones E: Malignant angioendothelioma of the skin. Br J Dermatol 76:21-39, 1964. 4. Sanderson KV, Mackie R: Turnouts of the skin, in Rook A, Wilkinson DS, Ebling FJG, editors: Textbook of dermatology, ed. 3. Oxford, 1979, Blackwell Scientific Publications, vol. 2, p. 2224. 5. Wilson Jones E, Feiwel M: Malignant angio-endothelioma. Proc R Soc Med 56:299-300, 1963. 6. Lewis R, Wallace HJ: Angioendothelioma. Br J Dermatol 79:361, 1967.
7. Wilson Jones E: The pathology of malignant angioendothelioma of the skin. XII[ Congressus Internationalis Dermatologiae, Munich, pp. 70-71, ! 9 6 7 , 8. Norman CF, Nancy BE: Successful treatment of juvenile hemangiomas with prednisone: J Ped!atr 72:351-357, 1968. .... 9. Gange RW, Wilson Jones E: Lymphangioma-like Kaposi's sarcoma. Br J Dermatol 100:327-334, 1979. 10. Ackerman AB: The patch stage of Kaposi's sarcoma. Am J Dermatopatbol h 165-172, 1979. 11. Schwartz RA, Burgess GH, Hoshaw RA: Patch stage Kaposi's sarcoma. J AM ACAD DERMATOL2:509-512, 1980.
I"r
Pemphigus foliaceus and proteinuria induced by o -merc aptopropionylglycine Paul A. L u c k y , M . D . , F l e m m i n g Skovby, M . D . , and Samuel O. Thier, M . D .
New Haven, CT Pemphigus foliaceus and proteinuria occurred in a patient with cystinuria treated with ~-mercaptopropionylglycine. This drug is similar to D-penicillamine in structure and function, and it is being used in patients who are unable to tolerate D-penicillamine. Although side effects of D-penicillamine are common, no major adverse reactions have been reported previously with a-mercaptopropionylglycine. Pemphigus foliaceus and proteinuria occurring during therapy with o~-mercaptopropionylglycine and D-penicillamine are discussed. (J AM ACAD DERMATOL 8: 667-672, 1983.)
P e m p h i g u s foliaceus and as complications of therapy Although this drug is useful several medical disorders,
proteinuria can occur with D-penicillamine. in the m a n a g e m e n t of there is a high inci-
From the Departments of Dermatology, HumanGenetics,and Internal Medicine, Yale UniversitySchool of Medicine. Reprint requeststo: Dr. PaulA. Lucky,Departmentof Dermatology, P.O. Box 3333, Yale UniversitySchoolof Medicine, New Haven, CT 06510.
dence of adverse effects, and alternative agents have therefore b e e n sought. One such drug, o~mercaptopropionylglycine (o~-MPG), is similar to D-penicillamine in structure a n d in m o d e o f action in the treatment o f cystinuria. B e c a u s e it has been reported to be as effective as D-penicillamine, but to h a v e fewer adverse effects, ce-MPG is n o w being tested in this country. This is the first report of p e m p h i g u s foliaceus and proteinuria following the use of c~-MPG.
667
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Journal of the American Academy of Dermatology
Fig. 1. Chest of patient with pemphigus foliaceus 1 week (A) and 2 weeks (B) after the onset of erythema and pruritus. The eruption began as erythematous macules and evolved into flaccid bullae and shallow erosions.
Case report A 46-year-old man of Ashkenazi Jewish ancestry had a history of renal calculi since the age of 13. Analysis of a calculus removed at the age o f 18 revealed pure cystine, and a diagnosis of cystinuria was confirmed by the demonstration of increased amounts of cystine, omithine, arginine, and lysine in the patient's urine. Treatment with D-penicillamine was started at the age of 30 but was stopped 10 years later because of proteinuria in excess of 3 grn/24 hr. Conservative management, including alkalinization of the urine and a high fluid intake, was not effective in preventing growth of staghorn calculi. Therapy with a-MPG ( " T h i o l a " ; Santen Pharmaceutical Co., Ltd., Osaka, Japan) was initiated in February, 1981, following approval of the treatment protocol by the Human Investigation Committee of the Yale University School of Medicine and after informed consent was obtained from the patient. The patient's urinary excretion of protein prior to starting oe-MPG was 300 mg/24 hr. The dose o f a-MPG was increased in increments of
200 mg per 24 hr over 4 days to a total dose of 800 mg/24 hr (200 mg/6 hr). In March the patient complained of oropharyngeal pain, but mucous membrane lesions were absent. There was no pruritus, urticaria, blistering, or erythema. Routine laboratory evaluation showed a mild eosinophilia (white blood count, 7500; eosinophils, 10%), and the o~-MPG was discontinued. The oropharyngeal pain resolved and the eosinophilia cleared. In May, 1981, a-MPG was restarted at a dose of 200 mg four times daily. A 24-hour urine collection from July, 1981, contained 1.1 gm of protein. In early August, the patient noted pruritus and erythema, initially on the upper portion of the chest and then on his forearms. The pruritus increased and the erythema spread to involve his face, back, and abdomen. One week after the onset of symptoms, small flaccid bullae appeared within the erythematous patches (Fig. 1, A). The a-MPG was discontinued. Large numbers of erythematous patches and bullae continued to appear during the following week, and the patient was hospitalized. Examination at that time revealed patchy ery-
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Fig. 2. Small flaccid bullae on erythematous bases (A) are typical of pemphigus foliaceus. Histology (B) of bullae on perilesional skin demonstrates intraepidermal acantholysis. Edema and clefting of the epidermis with an infiltrate of predominantly eosinophils is present. (Hematoxylin-eosin stain; original magnification, x 120.) thema involving the scalp, face, and chest (Fig. 1, B), back, upper arms, abdomen, upper thighs, and the shaft of the penis. Within the erythematous lesions were bullae in various stages of evolution. Most were 2 to 5 mm in diameter, but a few larger intact flaccid blisters were seen (Fig. 2, A). Many of the erythematous patches demonstrated only shallow erosions where bullae had been located. Nikolsky's sign was present. Laboratory studies included a normal complete blood cell count and platelet count. Wintrobe sedimentation rate was 39 mm/hr. Serum creatinine was 1.8 mg/dl (0.6-1.5). During the prior 5 years it had ranged
from 1.2 to 2.5 mg/dl. Uric acid was 9.9 mg/dl (4.56.5), bicarbonate, 17.9 mg/dl (25.1-30.5), chloride, 109 mg/dl (100-106), and phosphate, 5.1 mg/dl (3.1-4.5). The remainder of the SMA 20 was within normal limits. Proteinuria had increased to 7.3 gm/24 hr. Antinuclear antibody and rheumatoid factor were negative, and serum immunoglobulins were within normal limits. Skin biopsies of lesional and perilesional skin showed subcorneal and intraepidermal bullae with acantholysis (Fig. 2, B). The epidermis was spongiotic, and a mixed cellular infiltrate with a predominance of eosinophils was noted. Collagen, adnexae, and blood
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vessels appeared normal, Direct immunofluorescence of the patient's skin was negative for IgG, IgA, IgM, and C3. Indirect immunofluorescence of the patient's serum was also negative. Treatment was begun with prednisone, 120 rag/daily in divided doses, open-wet dressings with a 1:8,000 solution of potassium permanganate, and triamcinolone cream, 0.1%, applied topically. Five days later no new bullae were seen, and the patient's skin lesions had begun to re-epithelialize. Prednisone was maintained at 120 mg/daily in a single dose for 2 weeks and then tapered slowly over 2 months. There was no residual scarring. Two months after prednisone had been stopped, the cutaneous examination was normal and the 24-hour urinary excretion of protein had decreased to 500 mg/24 hr. DISCUSSION This is the first report of pemphigus foliaceus and proteinuria occurring as complications of treatment with oz-MPG. Our patient's primary disease was cystinufia, an autosomal recessive disorder which affects the transport of cystine and dibasic amino acids in the kidney and the small intestine. The clinical manifestations of this disease result from the excessive urinary excretion of cystine, which causes the formation of cystine calculi. 1 The medical treatment of cystinuria consists of a high fluid intake to decrease the urinary concentration and alkalinization to increase the solubility of urinary cystine. Crawhall et al 2 introduced the use of D-penicillamine for treatment of patients with cystinuria, m-penicillamine is a sulfhydryl amino acid which was initially used to chelate copper in Wilson's diseasefl but is now also used in the treatment of lead poisoning, 4 rheumatoid arthritis, 5 sclerodermafl and primary biliary cirrhosis. 7 In cystinuria, D-penicillamine reacts with cystine in a thiol-disulfide exchange, thereby creating a mixed (penicillamine-cysteine) disulfide and cysteine, both of which are more soluble than cystine in the urine? Although the drug is effective in dissolving cystine calculi and preventing their formation, as many as 50% of patients treated develop serious adverse reactions.1 Proteinuria occurs in more than 30% of patients treated with D-penicillamine. s Biopsies have demonstrated an immune complex glomerulonephritis, with deposition of IgG and C3 in a granular pattern along the basement membrane. If the drug
Journal of the American Academyof Dermatology
is continued, nephrotic syndrome may result) Other immune diseases have occurred in patients taking D-penicillamine, including lupus erythematosus, 1° polymyositis, 11 myasthenia gravis, 12 and a Goodpasture-like syndrome, la Leukopenia, thrombocytopenia, aplastic anemia, hematuria, and transient loss of taste and smell have been reported.i4 The most common complications of therapy with D-penicillamine are dermatologic. TM Temporally, two different types of adverse reactions have been identified. Early reactions, occurring during the first weeks of therapy, usually consist of mild or localized erythema, pruritus, urticaria, dryness, and scaling. In general, these resolve spontaneously without discontinuing the drug, and antihistamines, emollients, or topical steroids are adequate for symptomatic relief. If the D-penicillamine is stopped until after the symptoms resolve, it can usually be restarted without recurrent problems. Late cutaneous reactions occurring after several months of therapy are often of a more serious nature and require discontinuation of the drag. Approximately thirty cases of pemphigus foliaceus in patients receiving D-penicillamine have been reported. Pemphigus foliaceus '~.16 is an autoimmune blistering disease in which small, flaccid bullae occur on either erythematous or apparently normal skin. It usually presents spontaneously in previously healthy individuals, and, although cases have been reported in infants, the disease generally occurs in middle-aged men and elderly women. The incidence may be increased in Jews. The clinical diagnosis of pemphigus foliaceus may be difficult to make because of the multiple patterns of presentation. Most commonly, delicate bullae appear symmetrically on the trunk, face, or scalp. Nikolsky's sign is present, and minimal manipulation or contact with clothing will shear off the tops of the blisters, leaving shallow, crusted ulcers. Another presentation consists of very transient early bullae followed by an eczematous eruption similar to seborrheic dermatitis. Less commonly, pemphigus foliaceus can resemble dermatitis herpetiformis, presenting with erythematous patches and grouped papules and vesicles. Although pemphigus foliaceus may present acutely, involving a large percentage of the cutaneous surface, more often localized disease is
Volume 8 Number 5 May, 1983
present initially and extension in a symmetric fashion takes place gradually. Histologically, the bullae in pemphigus foliaceus occur high within the epidermis. There is loss of cohesion between epidermal cells, resulting in the formation of clefts near to or within the granular layer. Although the etiology of pemphigus foliaceus is not known, its pathophysiology is thought to involve the formation of autoantibodies against the intercellular cement substance. In some cases direct immunofluorescence has been positive for IgG and C3 in lesional and perilesional skin. t6 Positive as well as negative indirect immunofluorescence has been reported. Marsden et aW investigated seven cases of pemphigus foliaceus among 104 patients with rheumatoid arthritis who had taken D-penicillamine for 6 to 12 months. Bullae were seen initially in only two patients, whereas scaly plaques were noted in the others. In two of the cases, the rash persisted for 12 to 23 months following the discontinuation of penicillamine, despite therapy with prednisolone alone or in combination with azathioprine. Kristensen and Wadskov is reported a 61-year-old man with scleroderma who developed pemphigus foliaceus after 9 months of Dpenicillamine therapy. Immunofluorescence studies demonstrated intercellular deposits of IgG and C3 in the epidermis. Although therapy was not discussed, the patient still had active pemphigus foliaceus 1 year later. While most cases of D-penicillamine-induced pemphigus foliaceus either resolved after treatment or were controlled with steroids and immunosuppressives, two fatal cases have been documented.19,2° o~-Mercaptopropionylglycine (c~-MPG) is a thiol compound which has been used as a substitute for D-penicillamine. The two drugs have structural similarities. In clinical trials in Japan, over 1,000 patients experienced no major adverse reactions from o~-MPG. Minor side effects were noted in five patients and included itching, temporary nausea, and facial hyperemia. 2~,22 c~-MPG functions similarly to D-penicillamine in cystinuria and has been reported to be as effective as D-penicillamine in preventing the formation and even in dissolving cystine renal calculi.22 Seven groups of investigators have treated forty-eight cystinuric patients with c~-MPG from 45 days to 5 years without sig-
Pemphigus foliaceus and proteinuria 671
nificant complications3 ~-28 The reported adverse effects of ol-MPG included: nausea (1 patient), fever (2 patients), urticaria (3 patients), soft feces (4 patients), and skin rash (6 patients). None of these symptoms required that any p a t i e n t be withdrawn from the study. One patient refused further treatment when a generalized rash appeared after 1 week of therapy. ~s All of the cutaneous eruptions occurred early, were transient, and did not recur when the o~-MPG was restarted. No skin biopsies were reported. Acantholysis in D-penicillamine-induced pemphigus foliaceus may result from modification of intercellular cement substance by the drug, making it antigenic. In some patients the immune response diminishes after withdrawal o f D-penicillamine, while in others the process is self-perpetuating. o~-MPG may cause pemphigus foliaceus in a manner similar to D-penicillamine, since the drugs have both structural and functional similarities. It is possible that previous treatment with D-penicillamine predisposed our patient to the development of pemphigus foliaceus. In the few cases of D-penicillamine-induced pemphigus foliaceus in which immunofluorescence studies have b e e n done, direct immunofluorescence has been positive. Despite the absence of this finding in the present case, however, the clinical and histologic features strongly support the diagnosis of pemphigus foliaceus. The development of severe proteinuria has not been reported in patients receiving o~-MPG. Its temporal relationship in our patient to the a-MPG therapy and concurrent skin toxicity, as well as its resolution when the o~-MPG was stopped, implicate the drug as the cause of his nephropathy. Physicians treating patients with oL-MPG should be aware of pemphigus foliaceus and proteinuria as potential complications. Identification of additional cases will provide the opportunity to determine the incidence of o~-MPG-induced pemphigus foliaceus and proteinuria and to compare the findings with those resulting from D-penicillamine. REFERENCES 1. Thier SO, Segal S: Cystinura, in Stanbury JB, Wyngaarden JB, Frederickson D, editors: The metabolic basis of inherited disease. New York, 1978, McGraw-Hill Book Co., pp. 1578-1592,
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2. Crawhall JC, Scowen EF, Watts RWE: Effect of penicillamine on cystinuria. Br Med I 1:588-590, 1963. 3. Walshe JM: Penicillamine: A new oral therapy for Wilson's disease. Am J Med 21:487-495, 1956. 4. Vitale LF, et al: Oral penicillamine therapy for lead poisoning in children. J Pediatr 83:1041-1045, 1973. 5. Multicenter Trial Group: Control trial of D-penicillamine in severe rheumatoid arthritis. Lancet 1:278-280, 1973. 6. Bluestone R, Grahame R, Holloway V, Holt PJL: Treatment of systemic sclerosis with penicillamine, and a new method of observing the effects of treatment. Ann Rheum Dis 29: 153-158, 1970. 7. Matloff DS, Alpert E, Resnick RH, Kaplan MM: A prospective trial of D-penieiIlamine in primary biliary cirrhosis. N Engl J Med 306:319-326, 1982. 8. Halperin EC, Thier SO, Rosenberg LE: The use of D=penicillamine in cystinuria: Efficacy and untoward reactions. Yale J Biol Med $4:439-446, 198l. 9. Jaffe IA, Treser G, Suzuki Y, Ehrenreich T: Nephropathy induced by D-penicillamine. Ann Intern Meal 69: 549-556, 1968. 10. Crouzet J, et al: Lupus induced by D-penicillamine during the treatment of rheumatoid arthritis. Ann Med Interne (Paris) 125:71-79, 1974. 11. Sehrader PL, Peters HA, Dahl DS: Polymyositis and penicillamine. Arch Neurol 27:456-457, 1972. 12. Bucknall RC, Dixon AStJ, Glieb EN: Myasthenia gravis associated with penicillamine treatment for rheumatoid arthritis. Br Med J 1:600-602, 1975. 13. Stemleib I, Bennett B, Scheinberg IH: D-Penicillamine induced Goodpasture's syndrome in Wilson's disease. Ann Intern Med 82:673-676, 1975. 14. Jaffe IA: D-Penicillamine, lit Kelley WN, Harris ED Jr, Ruddy S, Sledge CB: Textbook of rheumatology. Philadelphia, 1981, W. B. Saunders Co., pp. 815-821. 15. Perry HO, Brunsting LA: Pemphigus foliaceus. Arch Dermatol 91: 10-23, 1965. 16. Lever WF: Pemphigus and pempbigoid. J AM ACAD DERMATOL 1:2-31, 1979.
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17. Marsden RA, et al: Pemphigus foliaceus induced by penicillamine. Br Med J 2:1423-1424, 1976. 18. Kristensen JK, Wadskov S: Penicillamine induced pemphigus foliaceus. Acta Derm Venereol (Stockh) $7:6971, 1977. 19. Sparrow GP: Penicillamine pemphigus and the nephrotic syndrome occurring simultaneously. Br J Dermatol 98:103-105, 1978. 20. Matkalak RM, Bailin PL: Penicillamine-induced pempbigus foliaceus. Arch Dermatol 117: 156-157, 1981, 21. Santen Pharmaceutical Co., Ltd., Osaka, Japan: Brochure on "Thiola," 1967. 22. King JS: Treatment of cystinuria with a-mercaptopropionylglycine: A preliminary report. Proc Soc Exp Biol Med 129: 927-932, 1968. 23. Sonoda T, et al: Effect of Thiola on cystinuria, in Proceedings of the International Symposium on Thiola. Osaka, 1980, Santen Pharmaceutical Co., Ltd., p. 231. 24. Nishimura R, Ishido T, Takai S: Studies on cystinuria. Proceedings of the 2nd International Symposium on Thiola. Osaka, 1942, Santen Pharmaceutical Co., Ltd., p. 47. 25. Kinoshita K, Yachiku S, Kotake T, Takenchi M, Sonoda T: Treatment of cystinuria with oz-mercaptopropionylglycine (MPG). Proceedings of the 2nd International Symposium on Thiola. Osaka, 1972, Santen Pharmaceutical Co., Ltd., p. 50. 26. Remien A, Kallistratos G, Burchardt P: Treatment of cystinuria with Thiola (a-mercaptopropionylglycine). Eur Urol 1:227-228, 1975. 27. Hautmann R, Terhorst B, Stuhlsatz HW, Lutzeyer W: Mercaptopropionylglycine: A progress report on cystine stone therapy. J UrN 117:628-630, 1977. 28. Johansen K, Gammelgard PA, Schonau-Jorgensen F: Treatment of cystinuria with alpha-mercaptopropionylglycine. Scand J Urol Nephrol 14:189-192, 1980.