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Penicillamine-associated pemphigus: Is it really pemphigus?
Penicillamine-associated pemphigus: Is it really pemphigus? James L. Troy, M.D., David N. Silvers, M.D., Marc E. Grossman, M.D., and Israeli A. Jaffe, M.D. New York, NY Penicillamine-associated bullous eruptions share with spontaneously occurring pemphigus intraepidermal acantholysis, epidermal intercellular deposition of immunoglobulin, and circulating serum antibody against the intercellular regions of the epidermis. We report the case of a penicillamine-associated bullous eruption in which there were some of the histologic features of pemphigus, but none of the immunofluorescent features. Instead, the immunofluorescent findings of bullous pemphigoid were demonstrated. Review of the literature reveals that clinical and histologic features of penicillamine-associated bullous eruptions differ in important respects from those of spontaneously occurring pemphigus. Our report adds immunologic data to evidence that the penicillamine-associated bullous eruptions may not be the same disease as spontaneously occurring pemphigus. (J AM ACAD DERMATOL 4:547-555, 1981.)
In 1969, Degos et all described a bullous dermatosis resembling pemphigus in a patient with hepatolenticular degeneration (Wilson's disease) treated with penicillamine. Subsequently, thirty additional cases of so-called penicillamine-associated or penicillamine-induced pemphigus have been reported.v " the majority in patients with rheumatoid arthritis receiving n-penicillamine. The bullous dermatosis associated with penicillamine has been considered a form of pemphigus because of histologic and immunologic similarities. Cases of penicillamine-associated pemphigus have consistently demonstrated intraepidermal acantholysis on histologic examination of bullous lesions. Direct immunofluorescence has detected intercellular deposition of immunoglobulin in the From the Departments of Dermatology, Pathology. and Medicine, the College of Physicians and Surgeons of Columbia University. and the Presbyterian Hospital. Reprint requests to: Dr. James L. Troy, Dermatopathology Section. Suite 7 J, New York University Medical Center. 530 First Ave., New York. NY 10016/212-340-7250.
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skin in all cases in which the test has been performed. 3- 13 Indirect immunofluorescence used to detect circulating serum antibody directed against the intercellular region has been positive in 72% of those cases tested. I - 7, 9- 13 Immunofluorescent findings similar to bullous pemphigoid have not been reported previously. We are reporting the case of a woman with rapidly progressive, seropositive rheumatoid arthritis who developed a bullous eruption after 9 months of n-penicillamine therapy. The clinical features were similar to those reported in previous cases of penicillamine-associated bullous eruptions. Skin lesions showed intraepidermal bullae with acantholytic cells, but the dermal infiltrate, similar to cases described previously, was unusual for pemphigus. Immunofluorescent findings were those only of bullous pemphigoid, i.e., dermoepidermal junction deposition of immunoglobulin with circulating serum antibody directed at the basement zone. No immunofluorescent features of pemphigus were demonstrated.
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Fig. 1. Papules and vesicles are present in erythematous macular areas of the medial knee.
CASE REPORT The patient was a 50-year-old Caucasian woman who was admitted to the Columbia-Presbyterian Medical Center in February, 1980, for treatment of rapidly progressive and disabling rheumatoid arthritis. Four years prior to admission, the patient developed generalized polyarthritis. Despite various types of treatment, her disease progressed relentlessly with episodic flares. Initially, she was treated with aspirin and nonsteroidal medications, including indomethacin and ibuprofen. She then received weekly intramuscular injections of aurothioglucose suspension to a total dose of 1,500 mg of gold over a period of 9 months, with minimal control of her symptoms. Naproxen, choline salicylate, and sulindac were reinstituted but were unsuccessful, and she was begun on oral n-penicillamine in June, 1979, in gradually increasing doses to a level of I gm daily. On admission, she was bedridden with contracture deformities of the elbows and knees. She had severe ulnar deviation of the wrists and fingers bilaterally. All joints had limited range of motion, but no joints were erythematous or swollen. There was a rheumatoid nodule over the left elbow. A 5-cm oval, shallow, well-demarcated ulcer was present on the lower anterior portion of the left leg. There was no organomegaly. White blood cell count was 6,900 cells/rnrn", with 80% neutrophils, 5% eosinophils, 12% lymphocytes, and 3% monocytes. Hemoglobin was lOA gm/dl with a
mean corpuscular volume of 69. Erythrocyte sedimentation rate was 80 mm/hr (normal, less than 20 mm/hr). Urinalysis showed trace albumin, pyuria, and no hematuria or casts. Serum iron and total iron binding capacity were 51/207. The antinuclear antibody (ANA) test was negative. There were no antibodies to double-stranded deoxyribonucleic acid (DNA) by the FaIT technic. Serum total hemolytic complement was 348 U (normal, 160 to 210 U). Latex fixation was positive at a dilution of 1: 16,000. Serum contained trace cryoglobulins. Serum protein electrophoresis showed a mild diffuse elevation of 11 and 12 globulins. The chest x-ray showed old apical scarring. Shortly after admission, a maculopapular, erythematous, mildly pruritic eruption appeared in localized areas of the trunk, arms, and legs. Within 3 days, tense 2- to 10-mm blisters formed within the areas of erythema (Figs. 1 and 2). Penicillamine therapy was discontinued. Erythematous papules and crops of vesicles and bullae continued to appear during the next 4 weeks. Blisters became flaccid and spontaneously resolved within 5 to 7 days, leaving macular hyperpigmentation. There were no intraoral or conjunctival lesions. Tissue for biopsy was taken from four lesions at different times. A papular lesion showed a dermal infiltrate of eosinophils and some neutrophils, with eosinophils extending into the spongiotic epidermis in a pattern consistent with "eosinophilic spongiosis." A vesicle less than 18 hours old showed a similar dermal
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Fig. 2. Erythematous papules, some surmounted by vesicles, are present on the flexor forearm. infiltrate with adjacent midepidermal acantholysis. Another lesion of approximately 12 to 18 hours' duration showed an intraepidermal vesicle containing neutrophils , eosinophils, fibrin, and acantholytic keratinocytes (Figs. 3 and 4). In the dermis, there was a diffuse infiltrate ofneutrophils and eosinophils (Fig. 5). A vesicle of unknown age showed an intraepidermal blister containing neutrophils and eosinophils with few acantholytic cells. The dermal infiltrate was dense and contained neutrophils and eosinophils, with neutrophils extending into the walls of blood vessels in a pattern suggestive of a leukocytoc1astic angiitis. None of the biopsy specimens showed supepidermal bulla formation. An aspirate of one of the vesicles showed no bacterial growth. Direct immunofluorescence of a blister of unknown duration demonstrated IgO deposition in a linear pattern at the dermoepidermal junction; another blister of 12 to 18 hours' duration showed sparse scattered deposits of IgM at the dermoepidermal junction. Circulating serum antibody to the basement zone was detected at a titer of 1; 320 in one specimen. A second serum sample obtained at plasmapheresis had no antibody directed at skin. There was no circulating antibody to the intercellular region detected in the two separate serum samples. Two weeks after the appearance of the eruption, the patient developed digital gangrene which was attributed
to rheumatoid vasculitis. No biopsy of gangrenous areas was performed. She was treated with cyclophosphamide, 1.5 gm intravenously, and two plasmaphereses were performed. Decubitis ulcers formed over the lumbar spinous processes and at the site of a rheumatoid nodule. Cellulitis developed and was successfully treated with parenteral oxacillin, 3 gm intravenously daily in divided doses for 7 days. Two weeks later, after the rash had stopped appearing, progressive digital gangrene and probable bowel ischemia prompted treatment with a repeated dose of cyclophosphamide, 1.5 gm intravenously, methylprednisolone, 1 gm intravenously daily, and repeated plasmapheresis. An oculomotor gaze palsy (Brown's syndrome) and episc1eritis appeared in the left eye. Progressive ischemia of the limbs developed, and the patient died 9 weeks after admission. At autopsy, changes of acute and chronic vasculitis of small muscular arteries of skin, pericardium, epicardium, pleura, spleen, pancreas, nerves, esophagus, small and large intestines, and urinary bladder were seen. No deposits of immunoglobulin or complement were detected in clinically normal appearing skin from the anterior thigh. DISCUSSION Penicillamine ({3,f3-dimethyl cysteine) is the sulfur amino acid hydrolysate of penicillin. 14 This
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Fig. 3. This intraepidermal vesicle contains inflammatory and acantholytic cells. There is a
dense, diffuse inflammatory infiltrate in the superficial dermis. (x69.)
heavy metal chelator has been used in the treatment of Wilson's disease since 1956. 15 It has been tried in the treatment of a variety of other diseases, including Waldenstrom 's macroglobulinemia, cystinuria, heavy metal intoxication, Sjogren's syndrome, psoriatic arthritis, morphea, and progressive systemic sclerosis.v'"-" Since the mid-1970s, the isomer n-penicillamine has been used extensively in the treatment of rheumatoid arthritis. 17 Many side effects associated with use of this drug have been reported. Major problems have included altered taste sensation, gastrointestinal upset, stomati tis, proteinuria, thrombocytopenia, and leukopenia. Isolated cases of nephrotic syndrome .I'<" dermatomyositis ,"? myasthenia gravis,!? systemic lupus erythematosus-like syndrome ;!" and Goodpasture's syndrome" have been reported in association with penicillamine therapy.
Dermatologic side effects have been common, occurring in 44% of penicillamine-treated patients.!" Pruritic maculopapular eruptions as well as urticaria have been seen in the first few days of therapy. IS Within the first few months of use, facial and generalized dryness and scaling, hair loss, cheilitis, and stomatitis have occurred. IS Less commonly observed and appearing later in the course of therapy have been epidermoid cysts, 20 fragile skin over pressure points which forms hemorrhagic blisters when traumatized and heals with milia formation ,21 elastosis perforans serpiginosa," and epidermolysis bullosa.F The bullous eruption associated with penicillamine has been termed pemphigus on histologic and immunologic grounds. Critical review of the reports in the English literature of penicillamineinduced or penicillamine-associated pemphigus
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Fig. 4. Higher magnification of the edge of the blister pictured in Fig. 3 shows an
intraepidermal vesicle with acantholytic cells. (x240. ) reveals that important distinctions exist between the phenomenon described and spontaneously occurring pemphigus vulgaris. Clinical and histologic features differentiating the two disease processe s can be identified . Immunologic similarities may not be consistent, as demonstrated by our case . The appearance and disappearance of the eruption closely related in time to the use of penicillamine , the usual limited and localized cutaneous involvement, and the rarity of oral involvement are all clinical features which differentiate the penicillamine-associated bullous eruption from that seen in spontaneously occurring pemphigus. The penicillamine-associated bullous eruptions appeared after an average of 13 months of treatment (range, 2 to 48 months). 1- J3 In most cases, the eruption resolved within several weeks after
withdrawal of penicillamine therapy. In only six cases was the eruption pre sent at 4 months after discontinuing therapy , 5,8, 12, 13 and in only one case was it recurrent at 2 years . 5 The persistent eruptions lasted despite vigorous therapy wit h systemic corticosteroids and/or immunosuppressives . Five cases were characterized by crusted plaques without clinically apparent blisters. 5.9. 10 Vesicles and bullae were of variable size and most appeared in limited areas of the trunk and upper extremities , although generalized eruptions have been reported . Only 13% of reports mention the presence of oral blisters or ero sions in association with the cutaneous eruption 1. 9 ; one case of the eruption limited to the oral mucosa has been seen . 13 The uncommon oral inv olvement in penicillam ineassociated eruption s is distinctly different from pemph igus vulgaris, in which nearly all cases have
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Fig. 5. Higher magnification of Fig. 3 shows spongiosis with neutrophils extending from the superficial dermis into the epidermis. The dermal infiltrate is composed primarily of neutrophils. ( X 240 .)
oral mucosal lesions . 24 The relatively rare form of pemphigus called "pemphigus foliaceus" can have limited cutaneous involvement during some of the indolent course of the disease, and it almost never has oral involvement. " However, the lengthy clinical course of pemphigus foliaceus and the peculiar "seborrheic distribution " of the lesions are different from the patterns of the penici llamine-associated eruptions. No case report has described in detail both the typical epidermal and dermal histologic findings of pemphigus in association with penicillamine therapy . Most reports have relied solely on epidermal acantholysis as the only histologic correlation. Those reports describing dermal infiltrates have not emphasized that the characteristics which were described are very unusual for the diagnosis of pemphigus.
Twenty-two of the case reports describe in varying detail the histopathology of the lesions .t" Nine reports specifically mention high epidermal or subcomeal acantholysis. Y ' P The other reports describe acantholysis at other levels of the epidermis. Epidermal acantholysis , however , is not diagnostic of pemphigus. A variety of other bullous and nonbullous conditions also demonstrate acantholysis, including Darier's disease, familial benign pemphigus (Hailey-Hailey disease) , transient acantholytic dermatosis, viral vesicles , including herpes and varicella , impetigo, solar keratoses, and squamous cell carcinomas. 26 Of the sixteen reports describing histopathologic findings, eight specifically discuss the appearance of the dermis. 5.fl - I l A dermal infiltrate of neutrophils was reported in one case," and a mixed infiltrate of neutrophils and lymphocytes was re-
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ported in three cases. 5 , B, I O Of these mixed infiltrates, two were in a perivascular distribution, and in one instance, the infiltrate extended into the epidermis. Two reports mention chronic inflammation with a mixed cell population in the dermis.P-'? Two reports describe perivascular lymphocytes II or perivascular infiltrate without description of cell type." All of these types of infiltrates would be quite atypical for spontaneously occurring pemphigus vulgaris or foliaceus, in which one would expect to see only a mild inflammatory infiltrate of eosinophils and lymphocytes.t" Immunofluorescent studies have served as the strongest basis for the diagnosis of pemphigus in patients with bullous eruptions associated with penicillamine therapy. Not every patient has been studied with all available technics, but very consistent findings have been seen. Immunoglobulin deposits in the epidermal intercellular regions of skin from which tissue was taken for biopsy (i.e., detection by direct immunofluorescence) have been demonstrated in every case in which the appropriate study was done. By indirect immunofluorescent technics (in which the patient's serum is tested for the presence of antibody directed against skin), penicillamine-associated bullous eruptions have had antibody directed against the intercellular region of the epidermis in 72% of samples examined. Direct immunofluorescent detection of intercellular immunoglobulin deposition is felt to be very specific for the diagnosis of pemphigus?"; indirect immunofluorescent detection of circulating serum antibody against the intercellular region is consistent with pemphigus, although other conditions have been associated with circulating intercellular antibodies. These include myasthenia gravis, systemic lupus erythematosus, bullous pemphigoid, cicatricial pemphigoid, burns, bullous drug eruptions, and maculopapular eruptions associated with penicillin.F The only unusual aspect of the immunofluorescence of penicillamine-associated bullous eruptions has been the occurrence of concomitant deposition of immunoglobulin at intercellular and dermoepidermal junction regions in 25% of the cases in which direct immunofluorescent studies were performed.t":" This pattern of immuno-
globulin deposition also occurs in the very uncommon spontaneously occurring variant of pemphigus termed "pemphigus erythematosus. "25,27 The penicillamine-associated bullous eruption described herein is distinctly unusual for two reasons. First, there are no immunofluorescent findings which would suggest the diagnosis of pemphigus. The absence of the typical pemphigus-like intercellular immunoglobulin or antibody has never been reported before in cases of penicillamine-associated bullous eruptions. Second, the findings in this case demonstrate for the first time the deposition of immunoglobulin at the dermoepidermal junction on direct immunofluorescent examination and the presence of circulating serum antibody directed at the basement zone detected by indirect immunofluorescent examination. These findings, which would be the typical immunofluorescent features of bullous pemphigoid, cannot easily be resolved with the histopathologic finding of intraepidermal bulla formation. Indeed, to our knowledge, these histologic and immunofluorescent findings have never been reported to occur together in a bullous eruption, penicillamine-associated or not. Bullous pemphigoid has been noted to occur in association with rheumatoid arthritis. 28,29 Only six cases of these two diseases occurring coincidentally have been reported, however. Bullous pemphigoid has not been reported in a patient receiving penicillamine. Neither the clinical nor the histologic features of this case suggest a diagnosis of bullous pemphigoid. Deposition of immunoglobulin could be secondary to rheumatoid arthritis. In patients with rheumatoid arthritis who do not have a rash and who are not receiving penicillamine, immunoglobulin deposition in clinically normal skin can be detected. Rapoport et apo found 23% of a group of seventy patients with rheumatoid arthritis to have immunoglobulin detectable by direct immunofluorescence at the derrnoepidermal junction of normal-appearing forearm skin. None of these patients was studied by indirect immunofluorescent technic for circulating serum antibody directed against skin. The patient reported here did not have immunoglobulin detected in uninvolved skin obtained at postmortem examination, a finding which might have been expected if the immuno-
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globulin deposition had been due to rheumatoid arthritis. The finding of a circulating serum antibody directed against the basement zone is a new finding in a penicillamine-associated bullous eruption. No studies have been reported which determine the incidence of circulating antibody against the skin in patients with rheumatoid arthritis undergoing different types of therapy. However, one group of forty patients receiving penicillamine for rheumatoid arthritis who did not have rash did not have antibody circulating in the serum directed against the skin." It is doubtfulthat the immunofluorescent findings reported here are artifactuaI. Standard procedures were followed in the transport of the specimens and the testing procedures. The two specimens submitted for direct examination showed deposition of immunoglobulin at the dermoepidermal junction. One of two serum samples sent for indirect examination showed antibody directed at the basement zone at a significant titer. The second specimen was obtained during a plasmapheresis and may have been diluted. The sample of clinically normal skin submitted for direct immunofluorescence was obtained at postmortem examination and was snap-frozen to -60 C for 1 week before the test was performed. At the time that the skin sample was obtained, the patient had been without rash for 5 weeks and had received various types of immunosuppressive therapy. The reliability of this negative finding, which indicates that the deposition of immunoglobulin in the skin was not random, can therefore be questioned, although detectable intercellular immunoglobulin deposition can persist in patients with spontaneous pemphigus for several years despite clinical evidence of remission and cessation of therapy. 27 Unusual immunologic phenomena have been seen in at least one other penicillamine-associated disease. A myasthenia gravis-like illness has been described in association with penicillamine use which is clinically indistinguishable from spontaneously occurring myasthenia gravis. However, the characteristics of the antibodies formed in the penicillamine-associated disease are different from those found in spontaneously occurring 0
myasthenia. 32 In the spontaneously occurring disease, there is polymorphism to the antiacetylcholine receptor (AChR) antibodies, which react with both the human and animal AChR. In contrast, in the penicillamine-associated disease, the serum AChR antibodies that are formed react with human receptor in the expected fashion, but react only at very low titer, if at all, with receptor preparations from various animal species. We are not aware of any studies in which the serum antibodies of penicillamine-associated pemphigus have been studied as they might compare to the antibodies in spontaneously occurring pemphigus. The question as to whether the penicillamineassociated bullous eruption is a variant of pemphigus or is a unique phenomenon which shares only some clinical, histologic, and immunofluorescent findings with pemphigus remains to be answered. We have presented evidence that consistent clinical and histologic features of the penicillamine-associated bullous eruptions are not identical to those of any form of pemphigus. This report suggests that the eruption does not consistently share the immunofluorescent features of pemphigus. Dr. Vivette D'Agati performed the autopsy. The immunofluorescent studies were performed in t!le {aooratory of Dr. Jean-Claude Bystryn at New York University. Mr. Alfred Lamme obtained the clinical photographs. Ms. Ida Nathan took the photomicrographs. REFERENCES 1. Degos R, Touraine R, Belaich S, Revuz J: Pemphigus chez un malade traite par penicillamine pour maladie de Wilson. Bull Soc Fr Dermatol Syphiligr 76:751-753, 1969. 2. Hewitt J, Benveniste M, Lessana-Leibowitch M: Pemphigus induced by n-penicillamine. Br Med J 3:371, 1975. 3. Davies M, Holt P: Pemphigus in a patient treated with penicillamine for generalized morphea. Arch Dermatol 112:1308-1309, 1976. 4. From E, Frederiksen P: Pemphigus vulgaris following u-penicillamine. Dermatologica 152:358-362, 1976. 5. Marsden R, Ryan T, Vanhegan R, Walshe M, Hill H, Mowat A: Pemphigus foliaceus induced by penicillamine. Br Med J 2:1423-1424, 1976. 6. Tan SO, Rowell NR: Pemphigus-like syndrome induced by n-penicillamine. Br J Dermatol 95:99-100, 1976. 7. Scherak 0, Kolarz 0, Ho1ubar K: Pemphigus erythematosus-like rash in a patient on penicillamine. Br Med J 1:838, 1977.
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8. Kristensen J, Wadskov S: Penicillamine-induced pemphigus foliaceus. Acta Derm Venereol (Stockh) 57:6971 , 1977 . 9. Hay KD, Muller HK, Reade P: n-Penicillamine-induced mucocutaneous les ions with features of pemphigus . Oral Surg 45:385-395, 1978 . 10. Kennedy C, Hodge L , Sanderson K: Skin changes caused by D-penicillamine treatment of arthritis. Clin Exp Dermatol 3: 107-116, 1978. 11. Sparrow G: Penicillamine pemph igus and nephrot ic syndrome occurring simultaneously. Br J Dermatol 98:103-105, 1978. 12. Dejong M, Doeglas H, Dijkstra J: Immunohistochemical findings in a patient with penicillamine pemphigus . Br J Dermatol 102:333·337, 1980. 13. Trau H, Schewack-Millet M, Gold I, Feinstein A , Horowitz I, Kaplinsky N: Penicillam ine-induced pemphigus . Arch Derm atol 116:721-722, 1980. 14. Walshe J: Toxic reactions to penicillamine in patients with Wilson 's disease. Postgrad Med J 44(suppl) :6-8 , 1968. 15. Walshe J : Penicillamine: A new oral therapy for Wilson's disease. Am J Med 21:487-495,1956. 16. Greer K, Askew P , Richardson D: Skin lesions induced by penicillamine. Arch DermatoI112:1267-1269, 1976. 17. Editorial: n-Penicillamine in rheumatoid arthritis. Lancet 1:1123 -1124, 1975 . 18. Stein H, Patterson AC , Offer R , Atkins C, Teufel A, Robinson H: Adverse effects of D-penicillam ine in rheumato id arthritis. Ann Intern Med 92:24-29, 1980. 19 . Oliver I , Liberman U, DeVries A: Lupus-like syndrome induced by penicillamine in cystinuria. JAMA 220:588 , 1972.
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20. Kueppers F, Daniels F Jr: Penicillamine-induced skin lesions in patient with Wilson's disease . Cutis 5:35·39, 1969. 2] . Katz R : Penicillamine-induced skin lesions. Arch Dermatol 95:196-198 , 1967. 22. Pass F , Goldfischer S , Stemlieb 1, Scheinberg H: Elastosis perforans serpiginosa during penicillamine therapy forWilson disease . Arch Dermatol108:713-715, 1973. 23. Beer W, Cooke K: Epidermolysis bullosa induced by penicillamine. Br J Dermatol 79: 123-125, 1967. 24. Zegarelli D, Zegarelli E: Intraoral pemphigus VUlgaris. Oral Surg 44:384 -393 , 1977. 25. Perry H, Brunsting L: Pemphigus foliaceus. Arch Dermatol 91:10-23. 1965 . 26. Lever W, Schaumburg-Lever G: Histopathology of the skin, ed. 5. Philade lphia, 1975, J . B. Lipincott Co. , p. 107. 27. Lever W: Pemphigus and pemphigoid. J AM ACAD DERMATOL 1:2-31, 1979. 28 . Lillicrap D: Rheumatoid arthrit is and pemphigoid. Proc R Soc Med 56:921-922, 1963 . 29. Salo 0, Rasanen J: Pemphigoid and rheumatoid artluitis . Ann Clin Res 4:173-177,1972. 30. Rapoport R, Kozin F, Mackel S, Jordon R: Cutaneous vascular immunofluorescence in rheumatoid arthritis . Am J Med 68:325-331, 1980. 31. Crouzet C, Bach J, Homberg J: Autoantibodies in D-penicillamine treated rheumatoid arthritis. Agents and Actions 6:351-354 , 1976. 32. Garlepp M, Kay P, Dawkins R, Bucknall R, Kemp A: Polymorphism of the acetylcholine receptor autoantigen. Clin Exp Immuno!. (In press.)
In 1969, Degos et all described a bullous dermatosis resembling pemphigus in a patient with hepatolenticular degeneration (Wilson's disease) treated with penicillamine. Subsequently, thirty additional cases of so-called penicillamine-associated or penicillamine-induced pemphigus have been reported.v " the majority in patients with rheumatoid arthritis receiving n-penicillamine. The bullous dermatosis associated with penicillamine has been considered a form of pemphigus because of histologic and immunologic similarities. Cases of penicillamine-associated pemphigus have consistently demonstrated intraepidermal acantholysis on histologic examination of bullous lesions. Direct immunofluorescence has detected intercellular deposition of immunoglobulin in the From the Departments of Dermatology, Pathology. and Medicine, the College of Physicians and Surgeons of Columbia University. and the Presbyterian Hospital. Reprint requests to: Dr. James L. Troy, Dermatopathology Section. Suite 7 J, New York University Medical Center. 530 First Ave., New York. NY 10016/212-340-7250.
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skin in all cases in which the test has been performed. 3- 13 Indirect immunofluorescence used to detect circulating serum antibody directed against the intercellular region has been positive in 72% of those cases tested. I - 7, 9- 13 Immunofluorescent findings similar to bullous pemphigoid have not been reported previously. We are reporting the case of a woman with rapidly progressive, seropositive rheumatoid arthritis who developed a bullous eruption after 9 months of n-penicillamine therapy. The clinical features were similar to those reported in previous cases of penicillamine-associated bullous eruptions. Skin lesions showed intraepidermal bullae with acantholytic cells, but the dermal infiltrate, similar to cases described previously, was unusual for pemphigus. Immunofluorescent findings were those only of bullous pemphigoid, i.e., dermoepidermal junction deposition of immunoglobulin with circulating serum antibody directed at the basement zone. No immunofluorescent features of pemphigus were demonstrated.
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Fig. 1. Papules and vesicles are present in erythematous macular areas of the medial knee.
CASE REPORT The patient was a 50-year-old Caucasian woman who was admitted to the Columbia-Presbyterian Medical Center in February, 1980, for treatment of rapidly progressive and disabling rheumatoid arthritis. Four years prior to admission, the patient developed generalized polyarthritis. Despite various types of treatment, her disease progressed relentlessly with episodic flares. Initially, she was treated with aspirin and nonsteroidal medications, including indomethacin and ibuprofen. She then received weekly intramuscular injections of aurothioglucose suspension to a total dose of 1,500 mg of gold over a period of 9 months, with minimal control of her symptoms. Naproxen, choline salicylate, and sulindac were reinstituted but were unsuccessful, and she was begun on oral n-penicillamine in June, 1979, in gradually increasing doses to a level of I gm daily. On admission, she was bedridden with contracture deformities of the elbows and knees. She had severe ulnar deviation of the wrists and fingers bilaterally. All joints had limited range of motion, but no joints were erythematous or swollen. There was a rheumatoid nodule over the left elbow. A 5-cm oval, shallow, well-demarcated ulcer was present on the lower anterior portion of the left leg. There was no organomegaly. White blood cell count was 6,900 cells/rnrn", with 80% neutrophils, 5% eosinophils, 12% lymphocytes, and 3% monocytes. Hemoglobin was lOA gm/dl with a
mean corpuscular volume of 69. Erythrocyte sedimentation rate was 80 mm/hr (normal, less than 20 mm/hr). Urinalysis showed trace albumin, pyuria, and no hematuria or casts. Serum iron and total iron binding capacity were 51/207. The antinuclear antibody (ANA) test was negative. There were no antibodies to double-stranded deoxyribonucleic acid (DNA) by the FaIT technic. Serum total hemolytic complement was 348 U (normal, 160 to 210 U). Latex fixation was positive at a dilution of 1: 16,000. Serum contained trace cryoglobulins. Serum protein electrophoresis showed a mild diffuse elevation of 11 and 12 globulins. The chest x-ray showed old apical scarring. Shortly after admission, a maculopapular, erythematous, mildly pruritic eruption appeared in localized areas of the trunk, arms, and legs. Within 3 days, tense 2- to 10-mm blisters formed within the areas of erythema (Figs. 1 and 2). Penicillamine therapy was discontinued. Erythematous papules and crops of vesicles and bullae continued to appear during the next 4 weeks. Blisters became flaccid and spontaneously resolved within 5 to 7 days, leaving macular hyperpigmentation. There were no intraoral or conjunctival lesions. Tissue for biopsy was taken from four lesions at different times. A papular lesion showed a dermal infiltrate of eosinophils and some neutrophils, with eosinophils extending into the spongiotic epidermis in a pattern consistent with "eosinophilic spongiosis." A vesicle less than 18 hours old showed a similar dermal
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Fig. 2. Erythematous papules, some surmounted by vesicles, are present on the flexor forearm. infiltrate with adjacent midepidermal acantholysis. Another lesion of approximately 12 to 18 hours' duration showed an intraepidermal vesicle containing neutrophils , eosinophils, fibrin, and acantholytic keratinocytes (Figs. 3 and 4). In the dermis, there was a diffuse infiltrate ofneutrophils and eosinophils (Fig. 5). A vesicle of unknown age showed an intraepidermal blister containing neutrophils and eosinophils with few acantholytic cells. The dermal infiltrate was dense and contained neutrophils and eosinophils, with neutrophils extending into the walls of blood vessels in a pattern suggestive of a leukocytoc1astic angiitis. None of the biopsy specimens showed supepidermal bulla formation. An aspirate of one of the vesicles showed no bacterial growth. Direct immunofluorescence of a blister of unknown duration demonstrated IgO deposition in a linear pattern at the dermoepidermal junction; another blister of 12 to 18 hours' duration showed sparse scattered deposits of IgM at the dermoepidermal junction. Circulating serum antibody to the basement zone was detected at a titer of 1; 320 in one specimen. A second serum sample obtained at plasmapheresis had no antibody directed at skin. There was no circulating antibody to the intercellular region detected in the two separate serum samples. Two weeks after the appearance of the eruption, the patient developed digital gangrene which was attributed
to rheumatoid vasculitis. No biopsy of gangrenous areas was performed. She was treated with cyclophosphamide, 1.5 gm intravenously, and two plasmaphereses were performed. Decubitis ulcers formed over the lumbar spinous processes and at the site of a rheumatoid nodule. Cellulitis developed and was successfully treated with parenteral oxacillin, 3 gm intravenously daily in divided doses for 7 days. Two weeks later, after the rash had stopped appearing, progressive digital gangrene and probable bowel ischemia prompted treatment with a repeated dose of cyclophosphamide, 1.5 gm intravenously, methylprednisolone, 1 gm intravenously daily, and repeated plasmapheresis. An oculomotor gaze palsy (Brown's syndrome) and episc1eritis appeared in the left eye. Progressive ischemia of the limbs developed, and the patient died 9 weeks after admission. At autopsy, changes of acute and chronic vasculitis of small muscular arteries of skin, pericardium, epicardium, pleura, spleen, pancreas, nerves, esophagus, small and large intestines, and urinary bladder were seen. No deposits of immunoglobulin or complement were detected in clinically normal appearing skin from the anterior thigh. DISCUSSION Penicillamine ({3,f3-dimethyl cysteine) is the sulfur amino acid hydrolysate of penicillin. 14 This
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Fig. 3. This intraepidermal vesicle contains inflammatory and acantholytic cells. There is a
dense, diffuse inflammatory infiltrate in the superficial dermis. (x69.)
heavy metal chelator has been used in the treatment of Wilson's disease since 1956. 15 It has been tried in the treatment of a variety of other diseases, including Waldenstrom 's macroglobulinemia, cystinuria, heavy metal intoxication, Sjogren's syndrome, psoriatic arthritis, morphea, and progressive systemic sclerosis.v'"-" Since the mid-1970s, the isomer n-penicillamine has been used extensively in the treatment of rheumatoid arthritis. 17 Many side effects associated with use of this drug have been reported. Major problems have included altered taste sensation, gastrointestinal upset, stomati tis, proteinuria, thrombocytopenia, and leukopenia. Isolated cases of nephrotic syndrome .I'<" dermatomyositis ,"? myasthenia gravis,!? systemic lupus erythematosus-like syndrome ;!" and Goodpasture's syndrome" have been reported in association with penicillamine therapy.
Dermatologic side effects have been common, occurring in 44% of penicillamine-treated patients.!" Pruritic maculopapular eruptions as well as urticaria have been seen in the first few days of therapy. IS Within the first few months of use, facial and generalized dryness and scaling, hair loss, cheilitis, and stomatitis have occurred. IS Less commonly observed and appearing later in the course of therapy have been epidermoid cysts, 20 fragile skin over pressure points which forms hemorrhagic blisters when traumatized and heals with milia formation ,21 elastosis perforans serpiginosa," and epidermolysis bullosa.F The bullous eruption associated with penicillamine has been termed pemphigus on histologic and immunologic grounds. Critical review of the reports in the English literature of penicillamineinduced or penicillamine-associated pemphigus
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Fig. 4. Higher magnification of the edge of the blister pictured in Fig. 3 shows an
intraepidermal vesicle with acantholytic cells. (x240. ) reveals that important distinctions exist between the phenomenon described and spontaneously occurring pemphigus vulgaris. Clinical and histologic features differentiating the two disease processe s can be identified . Immunologic similarities may not be consistent, as demonstrated by our case . The appearance and disappearance of the eruption closely related in time to the use of penicillamine , the usual limited and localized cutaneous involvement, and the rarity of oral involvement are all clinical features which differentiate the penicillamine-associated bullous eruption from that seen in spontaneously occurring pemphigus. The penicillamine-associated bullous eruptions appeared after an average of 13 months of treatment (range, 2 to 48 months). 1- J3 In most cases, the eruption resolved within several weeks after
withdrawal of penicillamine therapy. In only six cases was the eruption pre sent at 4 months after discontinuing therapy , 5,8, 12, 13 and in only one case was it recurrent at 2 years . 5 The persistent eruptions lasted despite vigorous therapy wit h systemic corticosteroids and/or immunosuppressives . Five cases were characterized by crusted plaques without clinically apparent blisters. 5.9. 10 Vesicles and bullae were of variable size and most appeared in limited areas of the trunk and upper extremities , although generalized eruptions have been reported . Only 13% of reports mention the presence of oral blisters or ero sions in association with the cutaneous eruption 1. 9 ; one case of the eruption limited to the oral mucosa has been seen . 13 The uncommon oral inv olvement in penicillam ineassociated eruption s is distinctly different from pemph igus vulgaris, in which nearly all cases have
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Fig. 5. Higher magnification of Fig. 3 shows spongiosis with neutrophils extending from the superficial dermis into the epidermis. The dermal infiltrate is composed primarily of neutrophils. ( X 240 .)
oral mucosal lesions . 24 The relatively rare form of pemphigus called "pemphigus foliaceus" can have limited cutaneous involvement during some of the indolent course of the disease, and it almost never has oral involvement. " However, the lengthy clinical course of pemphigus foliaceus and the peculiar "seborrheic distribution " of the lesions are different from the patterns of the penici llamine-associated eruptions. No case report has described in detail both the typical epidermal and dermal histologic findings of pemphigus in association with penicillamine therapy . Most reports have relied solely on epidermal acantholysis as the only histologic correlation. Those reports describing dermal infiltrates have not emphasized that the characteristics which were described are very unusual for the diagnosis of pemphigus.
Twenty-two of the case reports describe in varying detail the histopathology of the lesions .t" Nine reports specifically mention high epidermal or subcomeal acantholysis. Y ' P The other reports describe acantholysis at other levels of the epidermis. Epidermal acantholysis , however , is not diagnostic of pemphigus. A variety of other bullous and nonbullous conditions also demonstrate acantholysis, including Darier's disease, familial benign pemphigus (Hailey-Hailey disease) , transient acantholytic dermatosis, viral vesicles , including herpes and varicella , impetigo, solar keratoses, and squamous cell carcinomas. 26 Of the sixteen reports describing histopathologic findings, eight specifically discuss the appearance of the dermis. 5.fl - I l A dermal infiltrate of neutrophils was reported in one case," and a mixed infiltrate of neutrophils and lymphocytes was re-
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ported in three cases. 5 , B, I O Of these mixed infiltrates, two were in a perivascular distribution, and in one instance, the infiltrate extended into the epidermis. Two reports mention chronic inflammation with a mixed cell population in the dermis.P-'? Two reports describe perivascular lymphocytes II or perivascular infiltrate without description of cell type." All of these types of infiltrates would be quite atypical for spontaneously occurring pemphigus vulgaris or foliaceus, in which one would expect to see only a mild inflammatory infiltrate of eosinophils and lymphocytes.t" Immunofluorescent studies have served as the strongest basis for the diagnosis of pemphigus in patients with bullous eruptions associated with penicillamine therapy. Not every patient has been studied with all available technics, but very consistent findings have been seen. Immunoglobulin deposits in the epidermal intercellular regions of skin from which tissue was taken for biopsy (i.e., detection by direct immunofluorescence) have been demonstrated in every case in which the appropriate study was done. By indirect immunofluorescent technics (in which the patient's serum is tested for the presence of antibody directed against skin), penicillamine-associated bullous eruptions have had antibody directed against the intercellular region of the epidermis in 72% of samples examined. Direct immunofluorescent detection of intercellular immunoglobulin deposition is felt to be very specific for the diagnosis of pemphigus?"; indirect immunofluorescent detection of circulating serum antibody against the intercellular region is consistent with pemphigus, although other conditions have been associated with circulating intercellular antibodies. These include myasthenia gravis, systemic lupus erythematosus, bullous pemphigoid, cicatricial pemphigoid, burns, bullous drug eruptions, and maculopapular eruptions associated with penicillin.F The only unusual aspect of the immunofluorescence of penicillamine-associated bullous eruptions has been the occurrence of concomitant deposition of immunoglobulin at intercellular and dermoepidermal junction regions in 25% of the cases in which direct immunofluorescent studies were performed.t":" This pattern of immuno-
globulin deposition also occurs in the very uncommon spontaneously occurring variant of pemphigus termed "pemphigus erythematosus. "25,27 The penicillamine-associated bullous eruption described herein is distinctly unusual for two reasons. First, there are no immunofluorescent findings which would suggest the diagnosis of pemphigus. The absence of the typical pemphigus-like intercellular immunoglobulin or antibody has never been reported before in cases of penicillamine-associated bullous eruptions. Second, the findings in this case demonstrate for the first time the deposition of immunoglobulin at the dermoepidermal junction on direct immunofluorescent examination and the presence of circulating serum antibody directed at the basement zone detected by indirect immunofluorescent examination. These findings, which would be the typical immunofluorescent features of bullous pemphigoid, cannot easily be resolved with the histopathologic finding of intraepidermal bulla formation. Indeed, to our knowledge, these histologic and immunofluorescent findings have never been reported to occur together in a bullous eruption, penicillamine-associated or not. Bullous pemphigoid has been noted to occur in association with rheumatoid arthritis. 28,29 Only six cases of these two diseases occurring coincidentally have been reported, however. Bullous pemphigoid has not been reported in a patient receiving penicillamine. Neither the clinical nor the histologic features of this case suggest a diagnosis of bullous pemphigoid. Deposition of immunoglobulin could be secondary to rheumatoid arthritis. In patients with rheumatoid arthritis who do not have a rash and who are not receiving penicillamine, immunoglobulin deposition in clinically normal skin can be detected. Rapoport et apo found 23% of a group of seventy patients with rheumatoid arthritis to have immunoglobulin detectable by direct immunofluorescence at the derrnoepidermal junction of normal-appearing forearm skin. None of these patients was studied by indirect immunofluorescent technic for circulating serum antibody directed against skin. The patient reported here did not have immunoglobulin detected in uninvolved skin obtained at postmortem examination, a finding which might have been expected if the immuno-
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globulin deposition had been due to rheumatoid arthritis. The finding of a circulating serum antibody directed against the basement zone is a new finding in a penicillamine-associated bullous eruption. No studies have been reported which determine the incidence of circulating antibody against the skin in patients with rheumatoid arthritis undergoing different types of therapy. However, one group of forty patients receiving penicillamine for rheumatoid arthritis who did not have rash did not have antibody circulating in the serum directed against the skin." It is doubtfulthat the immunofluorescent findings reported here are artifactuaI. Standard procedures were followed in the transport of the specimens and the testing procedures. The two specimens submitted for direct examination showed deposition of immunoglobulin at the dermoepidermal junction. One of two serum samples sent for indirect examination showed antibody directed at the basement zone at a significant titer. The second specimen was obtained during a plasmapheresis and may have been diluted. The sample of clinically normal skin submitted for direct immunofluorescence was obtained at postmortem examination and was snap-frozen to -60 C for 1 week before the test was performed. At the time that the skin sample was obtained, the patient had been without rash for 5 weeks and had received various types of immunosuppressive therapy. The reliability of this negative finding, which indicates that the deposition of immunoglobulin in the skin was not random, can therefore be questioned, although detectable intercellular immunoglobulin deposition can persist in patients with spontaneous pemphigus for several years despite clinical evidence of remission and cessation of therapy. 27 Unusual immunologic phenomena have been seen in at least one other penicillamine-associated disease. A myasthenia gravis-like illness has been described in association with penicillamine use which is clinically indistinguishable from spontaneously occurring myasthenia gravis. However, the characteristics of the antibodies formed in the penicillamine-associated disease are different from those found in spontaneously occurring 0
myasthenia. 32 In the spontaneously occurring disease, there is polymorphism to the antiacetylcholine receptor (AChR) antibodies, which react with both the human and animal AChR. In contrast, in the penicillamine-associated disease, the serum AChR antibodies that are formed react with human receptor in the expected fashion, but react only at very low titer, if at all, with receptor preparations from various animal species. We are not aware of any studies in which the serum antibodies of penicillamine-associated pemphigus have been studied as they might compare to the antibodies in spontaneously occurring pemphigus. The question as to whether the penicillamineassociated bullous eruption is a variant of pemphigus or is a unique phenomenon which shares only some clinical, histologic, and immunofluorescent findings with pemphigus remains to be answered. We have presented evidence that consistent clinical and histologic features of the penicillamine-associated bullous eruptions are not identical to those of any form of pemphigus. This report suggests that the eruption does not consistently share the immunofluorescent features of pemphigus. Dr. Vivette D'Agati performed the autopsy. The immunofluorescent studies were performed in t!le {aooratory of Dr. Jean-Claude Bystryn at New York University. Mr. Alfred Lamme obtained the clinical photographs. Ms. Ida Nathan took the photomicrographs. REFERENCES 1. Degos R, Touraine R, Belaich S, Revuz J: Pemphigus chez un malade traite par penicillamine pour maladie de Wilson. Bull Soc Fr Dermatol Syphiligr 76:751-753, 1969. 2. Hewitt J, Benveniste M, Lessana-Leibowitch M: Pemphigus induced by n-penicillamine. Br Med J 3:371, 1975. 3. Davies M, Holt P: Pemphigus in a patient treated with penicillamine for generalized morphea. Arch Dermatol 112:1308-1309, 1976. 4. From E, Frederiksen P: Pemphigus vulgaris following u-penicillamine. Dermatologica 152:358-362, 1976. 5. Marsden R, Ryan T, Vanhegan R, Walshe M, Hill H, Mowat A: Pemphigus foliaceus induced by penicillamine. Br Med J 2:1423-1424, 1976. 6. Tan SO, Rowell NR: Pemphigus-like syndrome induced by n-penicillamine. Br J Dermatol 95:99-100, 1976. 7. Scherak 0, Kolarz 0, Ho1ubar K: Pemphigus erythematosus-like rash in a patient on penicillamine. Br Med J 1:838, 1977.
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8. Kristensen J, Wadskov S: Penicillamine-induced pemphigus foliaceus. Acta Derm Venereol (Stockh) 57:6971 , 1977 . 9. Hay KD, Muller HK, Reade P: n-Penicillamine-induced mucocutaneous les ions with features of pemphigus . Oral Surg 45:385-395, 1978 . 10. Kennedy C, Hodge L , Sanderson K: Skin changes caused by D-penicillamine treatment of arthritis. Clin Exp Dermatol 3: 107-116, 1978. 11. Sparrow G: Penicillamine pemph igus and nephrot ic syndrome occurring simultaneously. Br J Dermatol 98:103-105, 1978. 12. Dejong M, Doeglas H, Dijkstra J: Immunohistochemical findings in a patient with penicillamine pemphigus . Br J Dermatol 102:333·337, 1980. 13. Trau H, Schewack-Millet M, Gold I, Feinstein A , Horowitz I, Kaplinsky N: Penicillam ine-induced pemphigus . Arch Derm atol 116:721-722, 1980. 14. Walshe J: Toxic reactions to penicillamine in patients with Wilson 's disease. Postgrad Med J 44(suppl) :6-8 , 1968. 15. Walshe J : Penicillamine: A new oral therapy for Wilson's disease. Am J Med 21:487-495,1956. 16. Greer K, Askew P , Richardson D: Skin lesions induced by penicillamine. Arch DermatoI112:1267-1269, 1976. 17. Editorial: n-Penicillamine in rheumatoid arthritis. Lancet 1:1123 -1124, 1975 . 18. Stein H, Patterson AC , Offer R , Atkins C, Teufel A, Robinson H: Adverse effects of D-penicillam ine in rheumato id arthritis. Ann Intern Med 92:24-29, 1980. 19 . Oliver I , Liberman U, DeVries A: Lupus-like syndrome induced by penicillamine in cystinuria. JAMA 220:588 , 1972.
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20. Kueppers F, Daniels F Jr: Penicillamine-induced skin lesions in patient with Wilson's disease . Cutis 5:35·39, 1969. 2] . Katz R : Penicillamine-induced skin lesions. Arch Dermatol 95:196-198 , 1967. 22. Pass F , Goldfischer S , Stemlieb 1, Scheinberg H: Elastosis perforans serpiginosa during penicillamine therapy forWilson disease . Arch Dermatol108:713-715, 1973. 23. Beer W, Cooke K: Epidermolysis bullosa induced by penicillamine. Br J Dermatol 79: 123-125, 1967. 24. Zegarelli D, Zegarelli E: Intraoral pemphigus VUlgaris. Oral Surg 44:384 -393 , 1977. 25. Perry H, Brunsting L: Pemphigus foliaceus. Arch Dermatol 91:10-23. 1965 . 26. Lever W, Schaumburg-Lever G: Histopathology of the skin, ed. 5. Philade lphia, 1975, J . B. Lipincott Co. , p. 107. 27. Lever W: Pemphigus and pemphigoid. J AM ACAD DERMATOL 1:2-31, 1979. 28 . Lillicrap D: Rheumatoid arthrit is and pemphigoid. Proc R Soc Med 56:921-922, 1963 . 29. Salo 0, Rasanen J: Pemphigoid and rheumatoid artluitis . Ann Clin Res 4:173-177,1972. 30. Rapoport R, Kozin F, Mackel S, Jordon R: Cutaneous vascular immunofluorescence in rheumatoid arthritis . Am J Med 68:325-331, 1980. 31. Crouzet C, Bach J, Homberg J: Autoantibodies in D-penicillamine treated rheumatoid arthritis. Agents and Actions 6:351-354 , 1976. 32. Garlepp M, Kay P, Dawkins R, Bucknall R, Kemp A: Polymorphism of the acetylcholine receptor autoantigen. Clin Exp Immuno!. (In press.)