CD6 and syntaxin binding protein 6 variants and response to tumor necrosis factor alpha inhibitors in Danish patients with rheumatoid arthritis.
BACKGROUND
TNFα inhibitor therapy has greatly improved the treatment of patients with rheumatoid arthritis, however at least 30% do not respond. We aimed to investigate insertions and deletions (INDELS) associated with response to TNFα inhibitors in patients with rheumatoid arthritis (RA).


RESULTS
In the DANBIO Registry we identified 237 TNFα inhibitor naïve patients with RA (81% women; median age 56 years; disease duration 6 years) who initiated treatment with infliximab (n=160), adalimumab (n=56) or etanercept (n=21) between 1999 and 2008 according to national treatment guidelines. Clinical response was assessed at week 26 using EULAR response criteria. Based on literature, we selected 213 INDELS potentially related to RA and treatment response using the GeneVa® (Compugen) in silico database of 350,000 genetic variations in the human genome. Genomic segments were amplified by polymerase chain reaction (PCR), and genotyped by 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. At baseline the median DAS28 was 5.1. At week 26, 68 (29%) patients were EULAR good responders, while 81 (34%) and 88 (37%) patients were moderate and non-responders, respectively. A 19 base pair insertion within the CD6 gene was associated with EULAR good response vs. no response (OR=4.43, 95% CI: 1.99-10.09, p=7.211×10(-5)) and with EULAR good response vs. moderate/no response (OR=4.54, 95% CI: 2.29-8.99, p=3.336×10(-6)). A microsatellite within the syntaxin binding protein 6 (STXBP6) was associated with EULAR good response vs. no response (OR=4.01, 95% CI: 1.92-8.49, p=5.067×10(-5)).


CONCLUSIONS
Genetic variations within CD6 and STXBP6 may influence response to TNFα inhibitors in patients with RA.
DANBIO Registry and Department of Rheumatology, Copenhagen University Hospital at Glostrup, Copenhagen, Denmark. krintel@sophine.dk
Sophine B
SB
Krintel
Laurent
L
Essioux
Assaf
A
Wool
Julia S
JS
Johansen
Ehud
E
Schreiber
Tomer
T
Zekharya
Pinchas
P
Akiva
Mikkel
M
Ostergaard
Merete L
ML
Hetland
D000068879:Adalimumab; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D015703:Antigens, CD / Q000235:genetics*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics*; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D003718:Denmark; D000068800:Etanercept; D005260:Female; D005838:Genotype; D006801:Humans; D054643:INDEL Mutation; D007074:Immunoglobulin G / Q000627:therapeutic use; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D055815:Young Adult
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D018501:Antirheumatic Agents; C062279:CD6 antigen; D002352:Carrier Proteins; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; C465215:STXBP6 protein, human; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068879:Adalimumab; D000068800:Etanercept