Predisposing factors in sulphasalazine-induced systemic lupus erythematosus

Abstract

The aim of this study was to define predisposing factors in patients with sulphasalazine-induced systemic lupus erythematosus (SLE). Eleven patients with onset of SLE or SLE-like syndromes during sulphasalazine treatment are reported. Before the onset of SLE, five of the patients suffered from rheumatoid arthritis (RA), one from psoriatic arthropathy (PsoA), two from juvenile chronic arthritis (JCA) and three from ulcerative colitis (UC). At the time of diagnosis of drug-induced SLE, analysis of antinuclear antibodies (ANA), anti-double-stranded DNA antibodies (anti-dsDNA), anti-histone antibodies (anti-histones), acetylator status of the enzyme N-acetyltransferase 2 (NAT2) and HLA classification were performed. All patients were anti-DNA positive at disease onset and were determined to be slow acetylators. HLA A1 occurred in 4/10 patients, B8 in 5/10. HLA DR 3 was represented in one patient and DR 3(17) in five patients. The DQA1* 0501 allele was observed in 7/10 patients and DQB1 0201* in 6/10. Persistent SLE and development of nephritis were noted in patients with long duration of treatment and high cumulative dose of sulphasalazine (> 1000 g). In sulphasalazine-induced SLE, slow acetylator genotype and HLA haplotypes associated with idiopathic SLE seem to predict disease induction. Further, as the risk of developing persistent SLE and nephritis increases with long-standing sulphasalazine medication, it is of importance to monitor the patients with regard to signs of SLE during the entire treatment period.

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

“…A study of high-dose sulfasalazine (4.5-6 g daily) showed that 18 (95%) of 19 individuals with hemolysis were slow acetylators compared with 6 (35%) of 17 patients without hemolysis (van Hees et al, 1978). All 11 patients with sulfasalazine-associated lupus were slow acetylators (ϳ50% expected) (Gunnarsson et al, 1997). These findings could suggest that knowledge of acetylator status would help identify individuals who were more susceptible to side effects.…”

“…One study supports this supposition (Kumagai et al, 2004), whereas others do not (Azad Khan et al, 1980;Pullar et al, 1985;Bax et al, 1986;Kitas et al, 1992;Ricart et al, 2002). Slow acetylator status does seem to PHARMACOGENETICS, DRUG METABOLISM, AND CLINICAL PRACTICE increase the risk of side effects (Schroder and Price Evans, 1972;Azad Khan et al, 1980;Pullar et al, 1985;Rahav et al, 1990;Laversuch et al, 1995;Gunnarsson et al, 1997;Tanaka et al, 2002;Ohtani et al, 2003), although this risk has not been observed in all studies (Chalmers et al, 1990;Kitas et al, 1992;Wadelius et al, 2000;Ricart et al, 2002;Kumagai et al, 2004). It is reasonable to expect that slow acetylators might experience more problems with sulfasalazine given that a number of the side effects (e.g., nausea and vomiting) are associated with elevated sulfapyridine concentrations (Das et al, 1973;Rahav et al, 1990).…”

Sequence analysis of theN-acetyltransferase 2 gene (NAT2) among Jordanian volunteers

“…The NAT2 191G>A, 341T>C, and 590G>A clinically decrease the metabolism of isoniazid, sulphasalazine, and hydralazine associated with drug toxicity, such as hepatic, neuro-toxicity, and systemic lupus erythmatosus [2,7,8,10]. As Jordanian populations have a high frequency of slow-encoding NAT2 haplotype, the risk of toxicity induced by drugs metabolized by the NAT2 enzyme may be high among Jordanians.…”

“…Many studies have reported the association of genetic variants on NAT2 gene and cancers [6]. In addition, NAT2 polymorphisms have been linked to developing autoimmune diseases and sulphasalazine-induced systemic lupus erythematosus [7]. …”

Drug-Induced Glomerular Disease

“…Although arthritis, serositis, and hepatosplenomegaly may occur, major organ involvement is rare (67,73). GN is uncommon but has been reported with hydralazine (74), sulfasalazine (75), PTU (76), penicillamine (77), and anti-TNF-a therapy (78).…”