SLE : pathogenetic mechanisms in nephritis and sulphasalazine-induced lupus reactions

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease with a multifactorial and largely unknown etiology, in which genetic and environmental factors are known to influence disease susceptibility and expression. Nephritis is a common and severe disease manifestation in which immune complexes and complement deposits in the renal tissue are invariably seen. Anti-C1q antibodies are known to associate with proliferative forms of lupus nephritis.

One aim of these studies has been to investigate pathogenetic mechanisms of lupus nephritis, in particular the role of C1q, the first subcomponent of the classical complement cascade, and autoantibodies directed against this molecule. We also aimed to define predisposing factors and underlying pathogenetic mechanisms in sulphasalazine-induced SLE, and to determine the possibility of pathogenetic similarities between idiopathic and sulphasalazine-induced SLE.

In studies of ongoing IgG anti-C1q antibody production in peripheral blood mononuclear cells, high levels of IgG anti-C1q producing cells were recorded exclusively in patients with biopsy-proven proliferative lupus nephritis, thus indicating a pathogenetic role. Active production of anti-C1q antibodies was found to be superior in the prediction of proliferative nephritis as compared to analysis of antibodies in the serum. IgA anti-C1q antibodies were detected in patients with the immune complex-associated IgA nephropathy, indicating pathogenetic similarities with SLE nephritis.

In a follow-up study of patients with proliferative lupus nephritis, a high proportion of patients still had histological evidence of active renal disease at repeated biopsy after six months of therapy, despite intensive immunosuppressive treatment and apparent clinical improvement. Low serum C1q levels at both first and repeated biopsy predicted and associated with an unfavourable histological outcome. Beneficial prognostic factors at repeated biopsy were determined as low-grade proteinuria, normal C1q, levels and the absence of anti-C1q antibodies.

As for the role of predisposing factors in the development of sulphasalazine-induced SLE, slow acetylator genotype of N-acetyltransferase 2, HLA haplotypes in accordance with idiopathic SLE and enhanced IL-10 levels in serum were identified as factors associated with an increased susceptibility to development of lupus-like disease. In contrast to drug-induced SLE in general, anti-dsDNA was a common feature of sulphasalazine-induced SLE. Development of nephritis and persistent SLE occurred after high cumulative dose and long-term treatment with sulphasalazine. Similar pathogenetic mechanisms may be operative in both idiopathic and sulphasalazine-induced SLE, suggesting that sulphasalazine may act as an immunomodulator in genetically predisposed individuals.