Method: In the nationwide DANBIO registry we identified 237 TNFα inhibitor naive patients with RA (81% women, median age 56 years (interquartile range 44-64), disease duration 6 years (2-14.3)) who initiated treatment with infliximab (n=160), adalimumab (n=56), and etanercept (n=21) according to national guidelines between 1999 and 2008. The patients were registered in DANBIO at onset of treatment and followed prospectively. Clinical response was assessed at week 26 using EULAR response criteria. Over 200 genetic variations were tested for association with response. Genomic segments were amplified by polymerase chain reaction, and genotyped by either Sanger sequencing or fragment analysis. We tested the association between genotypes and EULAR good response versus no response, and EULAR good response versus moderate/no response using Fisher’s exact test.
Result: Median disease activity score (DAS28) at baseline was 5.1 decreasing to 3.6 at week 26. Sixty-eight (29%) patients were EULAR good responders, while 81 (34%) patients were moderate responders and 88 (37%) patients were non responders. A 19 base pair insertion within the CD6 gene was associated with EULAR good response versus no response (OR=4.43, 95% CI: 1.99-10.09, p=7.211 x 10-5, minor allele frequency (MAF) =0.15) and with EULAR good response versus moderate/no response (OR=4.54, 95% CI 2.29-8.99, p= 3.336 x 10-6). A microsatellite within the syntaxin binding protein 6 (STXBP6) on chromosome 14 was associated with EULAR good response versus no response (OR=4.01, 95% CI 1.92-8.49, p=5.067 x 10-5, MAF=0.25). Patients with one of these variations were more likely to achieve a EULAR good response compared to patients without these variations (OR=5.8; 95% CI 2.50-14.24; p=3.623 x 10-6).
Conclusion: Genetic variations within the CD6 gene and the STXBP6 gene were significantly associated with EULAR good response in a cohort of Danish patients with RA treated with TNFα inhibitors in routine care. This suggests that genetic variations within these genes may influence response to TNFα inhibitors and therefore may be useful as predictive biomarkers in patients with moderate or severe RA treated with TNFα inhibitors.
Disclosure: S. B. Krintel, None; G. Palermo, Hoffmann-La Roche AG, 3 ; A. Wool, Compugen Ltd., 3 ; J. S. Johansen, None; L. Essioux, Hoffmann-La Roche , 3 ; E. Schreiber, Compugen Ltd., 3 ; T. Zekharya, Compugen Ltd., 3 ; P. Akiva, Compugen Ltd., 3 ; M. Østergaard, None; M. L. Hetland, Roche Diagnostics, 2 .