The genetic background to RA is incompletely understood. As new cytokine-targeted therapies emerge, early predictors of disease severity are becoming increasingly important. The inflammasomes are essential regulators of cytokine production. We investigated whether two polymorphisms in the genes encoding cryopyrin (CIAS1) and TUCAN (CARD8) influence susceptibility and disease course in RA.Genotype frequencies were assessed in 174 Swedish patients with early RA and 360 population-based controls without rheumatic disease. Genotypes were categorized according to the presence (+) or absence (-) of two wild-type alleles and compared between patients and controls. In the RA patients, antibodies towards cyclic citrullinated peptides (anti-CCP) and the 'shared epitope' (SE) were assessed, and medication and measures of disease activity were monitored regularly during 3 yrs.The combination of CIAS1/TUCAN -/-, as compared with CIAS1/TUCAN +/+, was significantly more common among patients than in controls [odds ratio (OR) 2.2, 95% CI 1.03-4.6]. This association was strengthened when patients were divided into anti-CCP+ [OR 2.8 (1.1-6.7)] or presence of > or = 1 SE copy [OR 2.8 (1.3-6.2)]. At most time-points during the 3-yr follow-up, patients with CIAS1/TUCAN -/- showed significantly higher disease activity. Furthermore, CIAS1/TUCAN -/- patients proved to be much more likely to receive TNF-blocking therapy [relative risk 20 (2.6-149)].Compound polymorphisms in CIAS1 and TUCAN associate with RA susceptibility and severity. The cryopyrin inflammasome needs further attention regarding a possible aetiopathogenetic connection with RA.