Scand J Rheumatology 13: 93-95, 1984

Thiopronine-Induced Pemphigus Vulgaris in Rheumatoid Arthritis

FRANCESCO TROTTA, MASSIMO SCARAMELLI, GIOVANNA CERVI and ANNA ROSA VIRGILI' From the Department of Rheumatology and the 'Department of Dermatology, Arcispedale S. Anna and University of Ferrara, Ferrara, Ituly

Trotta, F., Scaramelli, M., Cervi, G. & Virgili, A. R. Thiopronine-induced pemphigus vulgaris in rheumatoid arthritis. (Submitted for publication December 8, 1982.) Scand J Rheumatology 13: 93-95, 1984.

Thiopronine, a D-penicillamine-like agent, is being prescribed increasingly for RA. Among side effects, only benign skin reactions have been mentioned to date. A single case of pemphigus erythematosus induced by this drug was recently reported. We describe here 3 other patients who developed pemphigus vulgaris during long-term thiopronine therapy and who improved after the drug was stopped.

F. Trotta, Department of Rheumatology, Arcispedale S. Anna and University of Ferrara, Ferraru , Italy.

Sulphydril compounds with penicillamine-like activity are being employed increasingly against rheumatoid arthritis (RA). Among these drugs, even thiopronine has recently been recognized in controlled trials (2, 10) as an effective agent. While the numbers of patients who have undergone this treatment are too small to permit of definitive conclusions, the spectrum of side effects observed hitherto seems to be quite similar to that of D-penicilla- mine.

With regard to skin lesions, pemphigus foliaceous, pemphigus vulgaris, pemphigus erythematosus and pemphigus resembling dermatitis herpetiformis are recognized as potential complications in RA patients treated with D-penicillamine (5, 7-9, 12). A case of pemphigus erythematosus was recently reported after prolonged treatment with thiopron- ine (1). Here, 3 patients with RA who developed pemphigus vulgaris during long-term thiopronine therapy are described.

CASE REPORTS Case 1 A 66-year-old woman with a 3-year history of seropositive RA bas previously treated with antimalar- ials and naproxen without much benefit. In July 1980 the antimalarials were discontinued and thiopronine was introduced at 500 mg daily, in association with naproxen. The patient was followed up regularly and no side effects were noted at first.

However, after 1 1 months of treatment several bullous elements appeared on the trunk, but without mucous membrane involvement. Upon biopsy, vesicles with acantholysis and adjacent spongiosis were revealed at the subgranular layer level. There were perivascular lymphocyte infiltrates in the dermis. Direct immunofluorescence study of perilesional skin proved negative. LE cell preparation, antinuclear antibodies and the antinative-DNA test were negative, as was the test for circulating epidermal intercellular antigen antibodies. Pemphigus vulgaris was diagnosed. Thiopronine was discontinued and a treatment with 6-methyl-prednisolone, 20 mg a day was initiated, subsequently reduced to 4 mg 6 weeks later. The skin lesions gradually resolved, but in spite of treatment, new bullae still continued to appear for 8 months.

Case 2 This 72-year-old man had had a classical seropositive RA for 9 years, irregularly treated with steroids, antimalarials and indomethacin. In June 1980 treatment with thiopronine (500 mg/day) was initiated.

Scan

d J

Rhe

umat

ol D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Tor

onto

on

11/2

0/14

For

pers

onal

use

onl

y.

94 F. Trotta et al. Scand J Rheumatology 13

In addition ketoprofen 100-150 mg per day was given. In April 1982 the patient developed an intensely itchy eruption which subsequently turned into small vesicles on the trunk and the upper part of the legs. The mucous membranes were unaffected. The histopathological examination showed intra- epidermal superficial clefts, with acantholytic cells. In the dermis there was a perivascular infiltrate with lymphocytes, histiocytes and eosinophils. Direct immunofluorescence studies of the skin biopsy proved negative. No epithelial intercellular material antibodies were detected in the patient’s serum. LE cell preparation, antinuclear antibodies and the antinative-DNA test proved negative. The lesions began to improve within 2 months of suspension of thiopronine. The treatment consisted of topical steroids and 6-methyl-prednisolone 8 to 4 mgtday for 6 weeks.

Case 3 This 53-year-old woman, who had had seropositive RA for 1 year, was started on thiopronine (500 mgtday) in May 1980 in addition to ibuprofen 600-900 mg/day. In January 1982 she developed some small pruritic patches on the upper trunk. In some places individual blisters could also be observed; however, the mucosa remained unaffected. The dermatologist considered the lesions consistent with a diagnosis of pemphigus. Thiopronine was discontinued and the lesions were improving with topical steroids alone. 4 months later the patient was re-examined and no new blisters were observed.

DISCUSSION

Over the past 3 years, 180 patients suffering from RA have been treated with thiopronine in the rheumatology department of S. Anna Hospital, Ferrara. 3 patients developed skin lesions resembling pemphigus, which improved upon discontinuing the drug. This time sequence strongly suggests that thiopronine caused the development of the dermatitis.

In these cases the skin disorder had the appearance of pemphigus vulgaris. The lesions developed after 11, 20 and 22 months respectively of continuous thiopronine therapy. The evolution followed a benign course and did not require high doses of steroids to control it. In case 1, however, deimatitis tended to have a prolonged course in spite of steroid treatment. To our knowledge pemphigus vulgaris, a well known adverse effect of D- penicillamine and other thiol compounds (3,5,6) has not previously been described among thiopronine therapy side effects. Under this treatment only one case of pemphigus erythematosus has recently been reported (1).

The exact cause of skin damage in thiopronine-treated patients is as yet unknown. In D- penicillamine-induced pemphigus, immune reactions may play a relevant role (9). In the cases reported here, antibodies against epidermal substance were not detected, as has been reported in some D-penicillamine-induced pemphigus cases (4, 12). A non-immunolo- gical biochemical mediated mechanism due to acantholytic properties of the sulphydril groups has also been suggested (1 l ) , and this may be the mechanism by which thiopronine induces pemphigus. Whatever further investigations may be necessary, these cases and the one reported (1) suggest that thiopronine toxicity is similar to that of D-penicillamine and imply that adverse reactions should be carefully avoided.

REFERENCES 1 . Alinovi, A., Benoldi, D. & Manganelli, P.: Pemphigus erythematosus induced by thiopronine.

Acta Dermatovener 62: 452, 1982. 2. Amor, B., Mery, C. Br de Gery, A.: Tiopronin (N-[2-mercaptopropionyl] glycin) in rheumatoid

arthritis. Arthritis Rheum 25: 698, 1982. 3. Civatte, J., Duterque, M., Blanchet, P., Belaich, S., Lazarovici, C., Morel, P., Foix, C. t

Fischesser, D.: Deux cas de pemphigus superficiel induit par le pyritinol. Ann Derm VCnCr 105: 573, 1978.

4. From, E. & Fredriksen, P.: Pemphigus vulgaris following ~-penicillamine. Dermatologica 152: 358, 1976.

5. Hewitt, J., Benveniste, M. & Lessana-Leibowitch, M.: Pemphigus induced by D-penicillamine. Br Med J iii: 371, 1975.

Scan

d J

Rhe

umat

ol D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Tor

onto

on

11/2

0/14

For

pers

onal

use

onl

y.

Scand J Rheumatology 13 Thiopronine-induced pernphigus in RA 95

6 . Huskisson, E. C., Jaffe, I. A., Scott, J. & Dieppe, P. A.: 5-thiopyridoxine in rheumatoid arthritis: clinical and experimental studies. Arthritis Rheum 23: 106, 1980.

7. Livden, J . K . , Naevdal, A. & Milde, E. J.: Pemphigus in rheumatoid arthritis treated with penicillamine. Scand J Rheumatology 10: 95, 1981.

8. Marsden, R. A., Dawber, R. P. R., Millard, P. R. & Mowat, A. G.: Herpetiform pemphigus induced by penicillamine. Br J Derm 97:451, 1977.

9. Marsden, R. A., Ryan, T. J., Vanhegan, R. I., Walshe, M., Hill, H. & Mowat, A. G.: Pemphigus foliaceus induced by penicillamine. Br Med J iv: 1423, 1976.

10. Pasero, G., Pellegrini, P., Ambanelli, U., Ciompi, M. L., Colamussi, V., Ferraccioli, G., Barbieri, P., Mazzoni, M. R., Menegale, G. & Trippi, D.: Controlled multicenter trial of tiopronin and D-penicillamine for rheumatoid arthritis. Arthritis Rheum 25: 923, 1982.

1 1 . Ruocco, V., de Luca, M., Pisani, M., de Angelis, E., Vitale, 0. & Astarita, C.: Pemphigus provoked by D (-) penicillamine. An experimental approach using in vitro tissue cultures. Dermatologica 164: 236, 1982.

12. Thorvaldsen, J.: Two cases of penicillamine-induced pemphigus erythematosus. Dermatologica 159: 167, 1979.

Scan

d J

Rhe

umat

ol D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Tor

onto

on

11/2

0/14

For

pers

onal

use

onl

y.