The TTTT BLyS promoter haplotype associates with good response to rituximab therapy in seropositive rheumatoid arthritis resistant to TNF blockers.

OBJECTIVE.: To investigate the polymorphisms in the promoter region of B-Lymphocyte Stimulator (BLyS) gene as markers of response to rituximab (RTX) in rheumatoid arthritis (RA). METHODS.: The study was first conducted in 152 Italian RA patients and then replicated in 117 patients (73 Italian, 44 British). Response to therapy (DAS28; EULAR criteria) was evaluated at months +4 and +6 after RTX and patients were classified according to the best response they showed during this period. BLyS promoter polymorphisms were analyzed by RFLP-PCR, BLyS promoter haplotypes by Expectation-Maximization algorithm and BLyS serum levels by ELISA. RESULTS.: The TTTT BLyS promoter haplotype appeared significantly associated with response to RTX only in the subset of seropositive (rheumatoid factor and/or anti-CCP positive) patients. The replication series confirmed that this association was limited to seropositive RA patients who previously failed anti-tumor necrosis factor (TNF) agents. In the whole series of anti-TNF-failure seropositive patients, TTTT-carrying patients were more prevalent in good responders (18/43; 41.9\%) than in moderate (20/83; 24.1\%) and in non responders (1/21; 4.8\%), (good vs. non responders: OR 14.4, 95\%CI:1.77-117.39, p=0.0028). Furthermore, the TTTT BLyS haplotype was selected as an independent marker of good response to RTX by multivariate analysis (good vs. non responders: OR 16.2, 95\% CI 1.7-152.5; p=0.01; good vs. moderate plus non responders: OR 3.05, 95\%CI:1.19-7.82, p=0.02). The relationship between BLyS polymorphims and BLyS serum levels remained unclear. CONCLUSION.: BLyS promoter genotyping may be suitable to identify seropositive RA patients who may show good response to RTX after anti-TNF agents failure.