Results

There was no significant difference between the groups with regard to patient details, with a median age of 55 years in the SSZ group and 57 years in the AUR group and median disease duration of 10 years and 9 years respectively. Seventy per cent of patients treated with SSZ were seropositive for rheumatoid factor compared with 75% of patients treated with AUR. Eighty two per cent of the SSZ treated group and 85% of the AUR treated group were women. At baseline, patients in the SSZ group had been treated with a mean of one previous DMARD and patients in the AUR group had received an average of 1.1 DMARDs previously. During treatment, only two patients in the SSZ group and one patient in the AUR group received prednisolone 5 mg or 7.5 mg per day. No patients were ever treated with hydralazine or procainamide, which are associated with drug induced lupus. Eighteen of the SSZ group and 24 of the AUR group had previously had penicillamine, but only two of the patients, both in the SSZ group developed a positive ANA.

Thirty four patients had stopped taking SSZ at five years because of lack or loss of effect; 26 patients treated with AUR had also stopped for this reason. There were three non-drug related deaths in the SSZ group and four non-drug deaths in the AUR group. Twenty four patients treated with SSZ and 48 treated with AUR withdrew because of side effects. SSZ was more likely to be continued and to result in a sustained response over the five year period than AUR (table 1). Clinical results have been published more fully by McEntegertet al.12

Discussion

Although the exact aetiology is unclear, SLE is a multifactorial disease in which both genetic and environmental factors, including drug treatment, are involved. Drug induced lupus is a well recognised but uncommon disease entity that occurs with treatment with any of a number of drugs. It differs from idiopathic disease in that malaise and musculoskeletal symptoms predominate, while renal and central nervous system involvement are rare or absent.10

The diagnosis of drug related SLE developing on a background of RA may be difficult, as many of the signs, symptoms and serological abnormalities reported in these patients may be a natural consequence of the underlying disease, rather than the drug. This may be particularly true in disease developing in the context of RA treated with SSZ.

SSZ is a commonly used DMARD in RA and other inflammatory joint diseases that has a relatively low risk of toxicity.13 RA results in polyarthritis and malaise, and extra-articular features such as pleurisy or pericarditis, or both, are not infrequent manifestations. RA and SLE may rarely coexist but it is more common for ANAs to be found in RA alone in 10–70% of patients.14 ,15 The development of ANAs or dsDNA antibodies should not necessitate withdrawal from treatment, although careful follow up will be required. These antibodies develop in 5–15% of patients taking SSZ for RA, without clinical symptoms of SLE.16 The most useful diagnostic criteria for drug induced SLE is the rapid improvement of the clinical features after withdrawal of the drug, thus providing evidence that the lupus syndrome is induced by SSZ rather than unmasked by it. Failure to recognise this complication may lead to delay in withdrawing the offending drug or inappropriate treatment.

In one review of SSZ induced SLE, 88% had arthralgia, 33% had fever and 25% had rashes.17 ,18 Leucopenia, anaemia, vasculitis and pneumonitis have also been reported although serious renal disease has not been reported.2 ,7 ANAs often develop, but dsDNA antibodies, which are highly specific for SLE, are rarely found in drug induced lupus.19

Serological abnormalities are often found, but the frequency of drug induced lupus is low. ANAs may be detected in as many as 50–90% of patients depending on the drug, dose and duration of treatment.9 The development of ANAs suggests a drug induced autoimmune phenomenon, resulting in other antibodies than the classic antihistones. The true incidence and prevalence has never been clearly elucidated, but it remains that more patients develop ANAs but remain asymptomatic than develop clinical symptoms.

SSZ is reduced in the colon to 5-aminosalicylic acid and sulphapyridine. 5-ASA is mostly unabsorbed and sulphapyridine is acetylated. Genetically determined variation in acetylation leads to variation in rates of metabolism. Sixty per cent of the British population are slow acetylators and are more likely than rapid acetylators to experience adverse reactions with drugs requiring acetylation for metabolism and are also more likely to develop drug induced SLE.20

Although of moderate size and duration, this study is still too small and follow up too short to provide answers about uncommon side effects from either SSZ or AUR. Baseline ANA status should be determined before treatment with any of the drugs known to be incriminated in the development of drug induced lupus and patients should be observed carefully for signs and symptoms of SLE. Indeed, as so many drugs have been implicated to date, all patients starting DMARD treatment for inflammatory arthritis should have baseline ANA checked.

In conclusion, ANAs are common in patients with RA. Side effects of commonly used DMARDs share features with signs and symptoms of SLE. In this study, 11–14% of patients became strongly ANF positive during follow up, but the presence or development of ANAs did not correlate with clinical disease or increase the likelihood of withdrawing from treatment. Larger cohorts followed up prospectively are being studied to elucidate the relevance of this effect in long term use of SSZ.