Association of HLA‐Bw35 with mucocutaneous lesions in rheumatoid arthritis patients undergoing sodium aurothiomalate therapy

Abstract

In previous studies, it has been demonstrated that adverse reactions during aurothiomalate therapy for rheumatoid arthritis (RA) might have a genetic basis. Thus, Panayi et al (1) and Wooley et a1 (2) showed that patients who were positive for HLA-B8 and DR3 had a significantly increased risk of developing toxic kidney manifestations during sodium aurothiomalate or D-penicillamine therapy. These studies were confirmed (3) and extended by Bardin et a1 (4) who observed a correlation between gold salt intolerance and the HLA-A1 Cw7 B8 DR3 haplotype and a possible association between the renal side effects of D-penicillamine and the haplotype HLA-AI B8 DR3.Further possible correlations between gold salt induced adverse reactions and HLA antigens in two studies (5,6) suggest an association between HLA-DR3 and thrombocytopenia.In this study, we describe a characteristic dissociation of HLA correlations with mucocutaneous le- sions and nephropathy in RA patients being treated with sodium aurothiomalate. In addition, we confirm the previously published data on the association of nephropathy with the presence of the phenotypic combination HLA-A1 B8 DR3. PATIENTS AND METHODSPatients. Seventy-four patients with rheumatoid arthritis as defined by the criteria of the American Rheumatism Association (7) were retrospectively selected for the study. There were 61 women and 13 men with an age range from 29-75 years. All patients had received parenteral gold salt therapy with sodium aurothiomalate for various periods. Retrospectively, 16 patients manifested renal and 33 patients manifested mucocutaneous lesions, while both adverse reactions were observed in only 2 patients. Lichenoid, maculopapular, eczematous, or nonspecific skin reactions, and aphthous stomatitis were regarded as druginduced mucocutaneous adverse reactions which rapidly improved after the therapy was stopped. Twenty of the patients showed dermatitis solely, 6 of them had stomatitis, and 8 presented both types of mucocutaneous manifestations. Nephropathy was noted when persistent proteinuria was present, confirmed by a 24-hour urinalysis which showed a protein loss of more than 0.5 mg and normalized when drug treatment was abrogated. Twenty-five patients without toxic reactions, who had been treated for a minimum of 8 months with sodium aurothiomalate, served as controls. None of the patients with adverse reactions from gold therapy developed thrombocytopenia, toxic liver reactions, hyperthermia, or leukopenia.HLA typing. HLA typing was performed ac-

Association of different HLA antigens with various toxic effects of gold salts in rheumatoid arthritis.

“…26 The frequency of Dw3 in our patients with proteinuria, however, was markedly lower than that of DR3 reported from England'0 but agreed with the frequencies reported from Norway'2 and from the United States. The comparison of gold induced mucocutaneous lesions with HLA antigens showed a similar trend of increased HLA-B35 and Dwl frequencies as reported by Nuesslein et al,13 although the current differences were not statistically significant. In patients with gold induced interstitial pneumonitis there was also a high prevalence of HLA-Dwl and B35.…”

“…For gold induced proteinuria the relative risks were 14 7-fold and 28-2-fold for those with antigens B8 and Dw3 respectively. Nuesslein et al,13 although the current differences were not statistically significant. In patients with gold induced interstitial pneumonitis there was also a high prevalence of HLA-Dwl and B35.…”

Association of HLA-B35 with mucocutaneous lesions in Israeli patients with rheumatoid arthritis receiving gold treatment.

“…The frequency of DR4 was found to be increased in most RA populations studied,2 and it has been suggested that certain DR antigens, especially DR3, are related to drug toxicity.4 Recently it has also been observed in patients with RA treated with sodium aurothiomalate that class I antigens (B35 and Cw4) are associated with the development of nephritis and dermatitis.5 6 We have previously reported that HLA-DR1 and not DR4 is associated 7 with RA in Israeli patients, as opposed to other Caucasian populations. The type of gold used by us (sodium aurothioglucose) is also different from the preparations studied previously.…”

“…4 Recently it has also been observed in patients with RA treated with sodium aurothiomalate that class I antigens (B35 and Cw4) are associated with the development of nephritis and dermatitis.5 6 Table 1 summarises the demographic and clinical data of patients with (group A) and without (group B) gold salt toxicity. There were no significant differences between the groups with respect to age, sex, disease duration, and the presence of rheumatoid factor.…”

Human Leucocyte Antigen Phenotypes and Gold-Induced Remissions in Patients With Rheumatoid Arthritis

“…. k V ---* * * response to gold [10, 14, 15], However, gold-induced proteinuria [9-11, 13, 25-28], thrombocytopenia [8,25] and dermatitis [10,13,27,29] have also been reported to be associated with HLA-DR3. Moreover, sideeffects were reported to occur more frequently in responders compared with non-responders in several studies on gold-treated RA patients [10,14,30].…”