title: Ashkenazi Jewish origin protects against formation of antibodies to infliximab and therapy failure.
abstract: Infliximab is an anti-tumor necrosis factor (TNF) used for treatment of inflammatory bowel disease (IBD) as well as rheumatoid arthritis, psoriasis, and other inflammatory conditions. Antibodies to infliximab (ATI) develop in approximately 45% of infliximab-treated IBD patients and are correlated with loss of clinical response. Scarce data exist as to factors which predict infliximab immunogenicity.To investigate factors that may predict formation of antibodies to infliximab (ATI) and infliximab therapy failure an observational study of consecutive IBD patients treated with infliximab between 2009 and 2013 was performed. Trough levels of ATI were measured. Patients were monitored for disease activity using clinical activity indexes and were classified according to ATI formation and clinical response. All clinical and demographic parameters were analyzed for association with the designated outcomes.One hundred fifty-nine patients were included and 1505 sera were tested. On multivariate analysis, Jewish Ashkenazi ethnicity was protective against both development of ATI (odds ratio [OR] 0.35, 95% confidence interval [CI] 0.17-0.7, P = 0.005) and treatment failure (OR 0.29, 95% CI 0.13-0.66, P = 0.003). Concomitant immunomodulator therapy was also negatively associated with immunogenicity and infliximab therapy failure (OR 0.31, 95% CI 0.15-0.65, P = 0.002; OR 0.42 95% CI 0.18-0.99, p = 0.04, respectively), whereas episodic therapy was positively associated with both outcomes (OR 4.2 95% CI 1.07-16.1, p = 0.04, OR 4.45 95% CI 1.2-16.6, p = 0.026 respectively). All other variables, including IBD type, gender, weight, age, smoking status and disease duration, were not predictive of ATI formation or clinical failure. However, among Crohn's disease patients, a non-stricturing non-penetrating phenotype was protective against ATI formation (OR 0.4, 95% CI 0.14-0.96, p = 0.04). P = 0.04, respectively), whereas episodic/interrupted therapy was positively associated with both outcomes (OR 4.2, 95% CI 1.07-16.1, P = 0.04; OR 4.45, 95% CI 1.2-16.6, P = 0.026, respectively). All other variables, including IBD type, sex, weight, age, smoking status, and disease duration, were not predictive of ATI formation or clinical failure. However, among Crohn disease patients, a nonstricturing nonpenetrating phenotype was protective against ATI formation (OR 0.4, 95% CI 0.14-0.96, P = 0.04).Jewish Ashkenazi ethnicity is protective of ATI formation and infliximab therapy failure. These findings suggest a role for ethnicity, and implicitly for genetic predisposition, in modulating the risk of anti-TNF immunogenicity and treatment unresponsiveness.
authors.affiliation: From the Department of Gastroenterology, Sheba Medical Center Tel Hashomer (BU, OH-N, UK, MY, EF, OP, AL, YM, BA, AL, RE, SB-H); Institute of Clinical Pharmacology, Sheba Medical Center Tel Hashomer (RL); Pediatric Gastroenterology Unit, Edmond & Lily Safra Children's Hospital Tel Hashomer (BW); Sackler School of Medicine, Tel-Aviv University (BU, OH-N, UK, MY, EF, OP, RL, AL, YM, BA, AL, BW, RE, SB-H); and Rambam Health Care Campus & Bruce Rappaport School of Medicine, Technion Institute of Technology, Haifa, Israel (YC).
authors.forename: Bella
authors.initials: B
authors.lastname: Ungar
authors.forename: Ola
authors.initials: O
authors.lastname: Haj-Natour
authors.forename: Uri
authors.initials: U
authors.lastname: Kopylov
authors.forename: Miri
authors.initials: M
authors.lastname: Yavzori
authors.forename: Ella
authors.initials: E
authors.lastname: Fudim
authors.forename: Orit
authors.initials: O
authors.lastname: Picard
authors.forename: Ronen
authors.initials: R
authors.lastname: Loebstein
authors.forename: Adi
authors.initials: A
authors.lastname: Lahat
authors.forename: Yaakov
authors.initials: Y
authors.lastname: Maor
authors.forename: Benjamin
authors.initials: B
authors.lastname: Avidan
authors.forename: Alon
authors.initials: A
authors.lastname: Lang
authors.forename: Batia
authors.initials: B
authors.lastname: Weiss
authors.forename: Yehuda
authors.initials: Y
authors.lastname: Chowers
authors.forename: Rami
authors.initials: R
authors.lastname: Eliakim
authors.forename: Shomron
authors.initials: S
authors.lastname: Ben-Horin
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000276:immunology* / Q000627:therapeutic use; D000906:Antibodies / Q000097:blood*; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000208:ethnology / Q000276:immunology; D000069285:Infliximab; D007585:Jews / Q000208:ethnology*; D053208:Kaplan-Meier Estimate; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D012189:Retrospective Studies; D017211:Treatment Failure; D055815:Young Adult
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000906:Antibodies; D000911:Antibodies, Monoclonal; D015415:Biomarkers; D000069285:Infliximab