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Background: Single nucleotide polymorphisms (SNPs) in TNF receptor superfamily (TNFRSF) 1A and 1B, and Fas ligand (FASLG) genes, have been associated with responsiveness to infliximab (IFX) in Crohn's disease., Aim: To investigate if SNPs in TNFRSF1A and 1B, and FAS (TNFRSF6) and FASLG (TNFSF6), associated with short- or long-term clinical and biological efficacy and with acute severe infusion reactions., Methods: Observational, retrospective and explorative cohort study of IFX-treated Caucasian patients with Crohn's disease classified as primary nonresponders (n = 21), response failures on maintenance therapy (n = 37), maintained remission (n = 47) and occurrence of acute severe infusion reactions (n = 20)., Results: During IFX maintenance therapy, minor allele carriage of TNFRSF1B, rs976881 is associated with loss of response [OR 3.3 (1.2-9.1), P = 0.014]. Minor allele homozygosity increased the risk substantially (OR estimated 19, P = 0.006), and furthermore associated with a mean CRP increase of 17 mg/L as compared to a mean decrease of 17 mg/L in all others (P = 0.036). In contrast, minor allele carriage of TNFRSF1B, rs1061622 is associated with beneficial response to IFX induction [OR 4.2 (1.2-18.2), P = 0.014], and with persistence of remission during maintenance therapy [OR 5.5 (1.5-25.5), P = 0.007]. Carriage of the minor allele of FASLG, rs76110 increased risk of severe infusion reactions [OR 4.0 (1.1-22.4), P = 0.041]; minor allele carriage of TNFRSF1B, rs652625 decreased the risk (OR estimated 0.2, P = 0.043 )., Conclusions: The TNFRSF1B polymorphisms may contribute to predict efficacy of infliximab. Moreover, FASLG and TNFRSF1B polymorphisms may confer genetic susceptibility to severe infusion reactions. These findings could potentially aid clinical decisions if confirmed in larger studies., (© 2012 Blackwell Publishing Ltd.)

Background: Infliximab (IFX) elicits acute severe infusion reactions in about 5% of patients with inflammatory bowel disease (IBD)., Aim: To investigate the role of anti-IFX antibodies (Ab) and other risk factors., Methods: The study included all IBD patients treated with IFX at a Danish university hospital until 2010 either continuously (IFX every 4-12 weeks) or episodically (reinitiation after >12 weeks). Anti-IFX Ab were measured using radioimmunoassay., Results: Twenty-five (8%) of 315 patients experienced acute severe infusion reactions. Univariate analysis showed that patients who reacted were younger at the time of diagnosis (19 vs. 26 years, P=0.013) and at first IFX infusion (28 vs. 35 years, P=0.012). Furthermore, they more often received episodic therapy (72% vs. 31%, P<0.001) and logistic regression revealed this as the only significant predictor of reactions (OR 5 [2-13]; P<0.001). IFX reinitiation after 6 months intermission further increased the risk (OR 8 [3-20], P<0.001). Most reactions (n=14, 88%) occurred at 2nd infusion in the 2nd treatment series (P=0.006). Anti-IFX IgG Ab were highly positive in 19 of 20 patients (95%) shortly after the reactions (median 84 U/mL). Anti-IFX IgG Ab measured prior to the retreatment series were negative in 7 of 11 patients tested (64%). Anti-IFX IgE Ab were negative in all patients with reactions., Conclusions: Acute severe infusion reactions were strongly associated with development of anti-IFX IgG Ab, but not with anti-IFX IgE Ab. The risk was particularly high at the 2nd infusion in retreatment series. Negative anti-IFX Ab before reinitiation did not rule out reactions., (© 2011 Blackwell Publishing Ltd.)

Background: Treatment options for fistulizing Crohn's disease (CD) are limited., Aim: To examine whether fistula closure is maintained at week 26 following treatment with certolizumab pegol., Methods: Patients with draining fistulas at baseline from PRECiSE 2 (n = 108) received open-label induction with certolizumab pegol 400 mg at weeks 0 (baseline), 2 and 4. Response was defined as ≥100-point decrease from baseline in the Crohn's Disease Activity Index. Nonresponders (50/108) were excluded. At week 6, responders with draining fistulas (N = 58) were randomised to certolizumab pegol 400 mg (n = 28) or placebo (n = 30) every 4 weeks across weeks 8-24. Fistula closure was evaluated throughout the study, with a final assessment at week 26., Results: The majority of patients (55/58) had perianal fistula. At week 26, 36% of patients in the certolizumab pegol group had 100% fistula closure compared with 17% of patients receiving placebo (P = 0.038). Protocol-defined fistula closure (≥50% closure at two consecutive post-baseline visits ≥3 weeks apart) was not statistically significant (P = 0.069) with 54% and 43% of patients treated with certolizumab pegol and placebo achieving this end point, respectively., Conclusion: Continuous treatment with certolizumab pegol improves the likelihood of sustained perianal fistula closure compared with placebo., (© 2010 Blackwell Publishing Ltd.)