Subcorneal pustular dermatosis-type IgA pemphigus induced by thiol drugs

ARTICLE

There is a new group of blistering diseases associated with neutrophilic infiltrates and intra epidermal IgA deposits. To date, more than 40 cases with vesiculopustular eruptions associated with a pemphigus-like pattern of IgA deposition have been reported under different names [1], including intercellular IgA dermatosis [2], intraepidermal neutrophilic IgA dermatosis [3], IgA pemphigus foliaceus [4], intercellular IgA vesiculopustular dermatosis [5], and intraepidermal IgA pustulosis [6]. This disease entity includes two distinct disorders with different histological features and IgA deposition patterns in the epidermis. A subcorneal pustular dermatosis (SPD) type and an intraepidermal neutrophilic (IEN) infiltration type [4]. Patients with the SPD type present with scaly erythematous plaques composed of vesiculopustules on the flexures of axillae, groins, and submammary areas, the features of which are indistinguishable from that of SPD of Sneddon-Wilkinson.

Patients with the IEN type present with vesiculopustular eruptions with central crusts or erosions. The eruptions occur on the trunk and extremities in a grouped or annular fashion. Herpetiform vesicles filled with pus may be present. Mucosal and esophageal involvement is usually absent. It is controversial which epidermal antigen is targeted by circulating IgA antibodies in such patients. Recent reports demonstrated that IgA antibodies are directed against desmoglein 3 [7] and desmocollin [8] in patients with the IEN type and the SPD type, respectively.

IgA pemphigus is often associated with other disorders including monoclonal IgA gammopathy, myeloma, B-cell lymphoma [6], Crohn's disease [9], ulcerative colitis [10], rheumatoid arthritis, Sjogren's syndrome [11], colitis [12] and HIV infection [13]. Pemphigus lesions are induced by various kinds of drugs although the vast majority of drug-induced pemphigus is due to thiol or masked thiol compounds including D-penicillamine, captoril, bucillamine, thiopronin, gold, and pyritinol. However, to our knowledge, no case of drug-induced IgA pemphigus has been reported. Here we report on a 49 year-old woman with SPD type IgA pemphigus which arose during a course of chrysotherapy for rheumatoid arthritis.

Case report

A 49-year-old woman was referred to our clinic in June 1998 because of vesiculopustular eruptions on her trunk. She had a 15 year-history of rheumatoid arthritis, and had been treated with prednisolone, 11 mg/day, and non-steroidal anti-inflammatory drugs. In addition, she had been given bucillamine, 300 mg/day (total; 143,100 mg) for the last 16 months, and gold sodium thiomalate (total; 140 mg) for 17 months. Her familial history was not contributory. In May 1998, vesiculopustular eruptions occurred on her chest, and developed on her trunk.

Physical examination showed flaccid vesiculopustular eruptions ranging from 5 to 10 mm in size, and erosive and scaly erythemic plaques on her chest and back (Fig. 1). The eruptions were particularly prominent on her anterior chest and submammary areas. Neither mucous lesions nor Nikolsky's sign was observed. There was no lymph node swelling or other systemic symptoms.

Laboratory examinations disclosed the following abnormalities: white blood cell count, 12,300/mul (normal, between 2,800 and 8,800), C-reactive protein, 10.1 mg/dl (normal, below 0.3), and rheumatoid factor, 83 U/ml (normal, below 5). Serum IgG, IgA and IgM levels, and complement were normal and no antinuclear antibodies were detected. No pathogenic organism was isolated from the pustules.

A skin from the eruption showed neutrophilic infiltration in the epidermis and a subcorneal pustule containing many neutrophils at the granular layers (Fig. 2). A few acantholytic cells were observed in the pustule. No Kogoj's spongiform pustules were observed.

Immunohistological and serological investigations

Direct immunofluorescence revealed pemphigus-like intercellular deposition of IgA in the upper 3-4 layers of the epidermis (Fig. 3a). No deposits of IgG, IgM or complement component C3 were observed. Indirect immunofluorescence failed to demonstrate the presence of circulating IgA directed against the intercellular spaces of the epidermis. When normal keratomed skin was incubated overnight under explant culture conditions in medium containing 20% patient's serum [14], intercellular IgA deposits were found (Fig. 3b). No deposits of IgA were observed in a control study in which the skin specimens were incubated with 20% normal sera.

The presence of circulating IgA-class autoantibodies was examined by Western blotting using the epidermal extract. No positive band suggestive of desmogleins or desmocollins was detected.

Circulating IgG and IgA antibodies to pemphigus antigens, or desmoglein (Dsg) 1 and 3, were measured using commercially-available enzyme-linked immunosorbent assay (Elisa) kits designed for detecting IgG pemphigus antibodies. For detecting IgA-class autoantibodies, we modified the manufacturer's protocol, and used horse radish peroxidase-labelled monoclonal anti-human IgA instead of the provided second antibody. For positive controls we used serum samples from two patients with pemphigus vulgaris which contained both IgG- and IgA-class anti Dsg3 antibodies. The results indicated that the patient's serum did not contain IgG- or IgA-class antibodies directed against Dsg 1 or 3.

Clinical course

We diagnosed this case as the SPD type IgA pemphigus on the basis of clinicopathological features and the immunofluorescence findings of intercellular IgA deposition localized in the upper epidermis. Because of the possibility of thiol compound-induced SPD type IgA pemphigus, we discontinued the administration of both bucillamine and gold sodium thiomalate. Prednisolone, 30 mg/day resulted in a partial clearance of the eruptions, but new vesiculopustules continued to occur. When dapsone, 50 mg/day was administered, the eruptions promptly disappeared, leaving brownish pigmentation. Dapsone was tapered, and was stopped in 2 months. There has been no recurrence for 12 months with only a maintenance dose of prednisolone of 12 mg/day. Challenge tests with bucillamine or gold sodium thiomalate were not done.

Discussion

The present case was diagnosed as SPD type IgA pemphigus from the typical subcorneal pustule formation containing many neutrophils and deposition of intercellular IgA alone in the lesional epidermis. Our diagnosis is supported by the facts that circulating IgA antibodies to the intercellular spaces of normal human epidermis were detected by explant culture and that there was a good response to dapsone. The negative result using standard indirect immunofluorescence might have been due to by a low titer of circulating IgA antibody to epidermis, since IgA autoantibody was detected in only one half of such patients, and when it was detected, the titers were usually low [1]. The skin explant culture is more sensitive than the standard immunofluorescence to detect circulating IgA antibodies [14].

The most interesting point about our patient is that the eruptions occurred during a course of treatment with the thiol compounds, bucillamine and gold sodium thiomalate. To our knowledge, no case of drug-induced IgA pemphigus has been reported previously, whereas many cases of drug-induced (IgG) pemphigus caused by thiol compounds including D-penicillamine, captoril, bucillamine, and gold have been described. D-penicillamine-induced pemphigus usually occurs after an average of 13 months of treatment, and other thiol compounds also require several months of administration to induce pemphigus-like lesions [15]. Our patient had received bucillamine for 16 months (total; 143,100 mg) and gold sodium thiomalate for 17 months (total; 140 mg). Thus, similarly to the previous cases of drug-induced pemphigus, the present case required a long therapeutic period until the eruptions appeared. In addition to the thiol compounds, the coexistent rheumatoid arthritis might be another factor leading to IgA pemphigus because IgA pemphigus has been associated with systemic disorders including rheumatoid arthritis in a few patients [11].

In patients with drug-induced pemphigus, the reaction usually regresses within weeks after cessation of therapy, but it may persist for many years. In the present case, dapsone at 50 mg/day was necessary to control the disease, and no recurrence was noted for at least 12 months with a maintenance dose of the RA, prednisolone of 12 mg.

Another question is the nature of the target molecule recognized by circulating IgA antibody [7, 8, 16, 17]. Since the clinicopathological features of SPD type IgA pemphigus mimic those of pemphigus foliaceus, it is important to know whether IgA autoantibodies in our case recognize a pemphigus foliaceus antigen, Dsg1 or different molecules. Western blotting did not answer this question, probably because of the low antibody titer. However Elisa demonstrated clearly that the patient's serum did not contain IgA-class antibodies to Dsg1 or 3. Although desmocollin 1 might be a candidate molecule [8], no reactive band suggestive of desmocollin 1 was detected by our Western blotting system.

The present case indicates that like other drug-induced pemphigus, IgA pemphigus can also be induced by chrysotherapy.

REFERENCES

1. Ongenae KC, Temmerman LJ, Vermander F, Naeyaert JM. Intercellular IgA dermatosis. Eur J Dermatol 1999; 9: 85-94.

2. Hashimoto T, Inamoto N, Nakayama K, Nishikawa T. Intercellular IgA dermatosis with clinical features of subcorneal pustular dermatosis. Arch Dermatol 1987; 123: 1062-5.

3. Huff JC, Goliz LE, Kunke KS. Intraepidermal neutrophilic IgA dermatosis. N Engl J Med 1985; 313: 1643-5.

4. Beutner EH, Chorzelski TP, Wilson RM, Kumar V, Michel B, Helm F. IgA pemphigus foliaceus: report of two cases and a review of the literature. J Am Acad Dermatol 1989; 129: 113-9.

5. Nishikawa T, Hashimoto Y, Teraki T, Ebihara T. The clinical and histopathological spectrum of IgA-pemphigus. Clin Exp Dermatol 1991; 16: 401-2.

6. Wallach D. Intraepidermal IgA pustulosis. J Am Acad Dermatol 1992; 27: 993-1000.

7. Wang J, Kwon J, Ding X, Fairley JA, Woodley DT, Chan LS. Nonsecretory IgA1 autoantibodies targeting desmosomal component desmoglein 3 in intraepidermal neutrophilic IgA dermatosis. Am J Pathol 1997; 150: 1901-7.

8. Hashimoto T, Kiyokawa C, Mori O, Miyasato M, Chidgey MA, Garrod DR. Human desmocollin 1 (Dcs1) is an autoantigen for the subcorneal pustular dermatosis type of IgA pemphigus. J Invest Dermatol 1997; 109: 127-31.

9. Borradori L, Saada V, Rybojad M, Flageul B, Kuffer R, Lemann M. Intraepidermal neutrophilic IgA pustulosis and Crohn's disease. Br J Dermatol 1992; 126: 383-6.

10. Miyakawa K, Miyamoto R, Baba S, Suzuki H, Dmochowski M, Hashimoto T. Vesiculopustular dermatosis with ulcerative colitis. Concomitant occurrence of circulating IgA anti-tercellular and anti-bacement membrane zone antibodies. Eur J Dermatol 1995; 5: 122-4.

11. Yoshida Y, Okamoto H, Mizuno K, Kore-eda S, Ohta K, Tanaka T, et al. Subcorneal pustular type of intraepidermal neutrophilic IgA dermatosis: a combined treatment with low-dose dapsone and high-dose nicotinamide. Eur J Dermatol 1996; 6: 287-9.

12. Wright S, Phillips T, Ryan J, Leigh IM. Intra-epidermal neutrophilic IgA dermatosis with colitis. Br J Dermatol 1989; 120: 113-9.

13. Myers SA, Rico MJ. Intraepidermal neutrophilic IgA dermatosis in an HIV infected patient. J Am Acad Dermatol 1994; 31: 502-4.

14. Supapannachart N, Mutasim DF. The distribution of IgA pemphigus antigen in human skin and the role of IgA anti-cell surface antibodies in the induction of intraepidermal acantholysis. Arch Dermatol 1993; 129: 605-8.

15. Santa Cruz DJ, Prioleau PG, Marcus MD, Uitto J. Pemphigus-like lesions induced by D-penicillamine. Am J Dermatopathol 1981; 3: 85-92.

16. Ebihara T, Hashimoto T, Iwatsuki K, Takigawa M, Ando M, Ohkawara A, et al. Autoantigens for IgA anti-intercellular IgA vesiculopustular dermatosis. J Invest Dermatol 1991; 97: 742-5.

17. Iwatsuki K. IgA pemphigus. In: Kanitakis J, Vassileva S, Woodley J. Diagnostic immunohistochemistry of the skin. An illustrated text: Champman & Hall Medical, London, 1998: 95-104.