Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.
Genetic Variations within the CD6 and Syntaxin Binding Protein 6 Genes Associated with Response to Tumor Necrosis Factor Alpha Inhibitors in Danish Patients with Rheumatoid Arthritis Treated in Routine Care.
Hetland5, Merete L., Ostergaard1, Mikkel, Akiva3, Pinchas, Zekharya3, Tomer, Schreiber3, Ehud, Essioux2, Laurent, Johansen4, Julia S.
Copenhagen University Hospital at Glostrup, Copenhagen, Denmark
F. Hoffmann-La Roche Ltd, Basel, Switzerland
Compugen Ltd., Tel Aviv, Israel
Copenhagen University Hospital at Herlev, Copenhagen, Denmark
Copenhagen University Hospital at Glostrup, on behalf of DANBIO, Copenhagen, Denmark
Tumor necrosis factor alpha (TNFa) inhibitors have greatly improved treatment of patients with rheumatoid arthritis (RA). However, at least 30% of the patients do not respond and no validated predictive biomarker has been identified. Lack of response and risk of adverse drug reactions emphasize the need for predictive biomarkers. We aimed to investigate genetic variations associated with response to TNFa inhibitors in Danish patients with moderate to severe RA treated in routine care.
In the nationwide DANBIO registry we identified 237 TNFa inhibitor naive patients with RA (81% women, median age 56 years (interquartile range 4464), disease duration 6 years (214.3)) 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.
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: 1.9910.09, p=7.211 × 10-5, minor allele frequency (MAF) =0.15) and with EULAR good response versus moderate/no response (OR=4.54, 95% CI 2.298.99, p= 3.336 × 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 1.928.49, p=5.067 × 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 2.5014.24; p=3.623 × 10-6).
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 TNFa inhibitors in routine care. This suggests that genetic variations within these genes may influence response to TNFa inhibitors and therefore may be useful as predictive biomarkers in patients with moderate or severe RA treated with TNFa inhibitors.
To cite this abstract, please use the following information:
Hetland, Merete L., Ostergaard, Mikkel, Akiva, Pinchas, Zekharya, Tomer, Schreiber, Ehud, Essioux, Laurent, et al; Genetic Variations within the CD6 and Syntaxin Binding Protein 6 Genes Associated with Response to Tumor Necrosis Factor Alpha Inhibitors in Danish Patients with Rheumatoid Arthritis Treated in Routine Care. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :399