Genetic variation in proteins of the cryopyrin inflammasome influences susceptibility and severity of rheumatoid arthritis (the Swedish TIRA project).
OBJECTIVE
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.


METHODS
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.


RESULTS
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)].


CONCLUSIONS
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.
Kastbom
A
A
Division of Rheumatology/AIR, Department of Clinical and Experimental Medicine, SE-581 85 Linköping, Sweden. alfka@imk.liu.se
Verma
D
D
Eriksson
P
P
Skogh
T
T
Wingren
G
G
Söderkvist
P
P
D018501:Antirheumatic Agents / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D012720:Severity of Illness Index; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
D018501:Antirheumatic Agents; D002352:Carrier Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D014409:Tumor Necrosis Factor-alpha