Implications for sequencing of biologic therapy and choice of second anti-TNF in patients with inflammatory bowel disease: results from the IMmunogenicity to Second Anti-TNF therapy (IMSAT) therapeutic drug monitoring study.

BACKGROUND: Anti-drug antibodies are associated with treatment failure to anti-TNF agents in patients with inflammatory bowel disease (IBD). AIM: To assess whether immunogenicity to a patient's first anti-TNF agent would be associated with immunogenicity to the second, irrespective of drug sequence METHODS: We conducted a UK-wide, multicentre, retrospective cohort study to report rates of immunogenicity and treatment failure of second anti-TNF therapies in 1058 patients with IBD who underwent therapeutic drug monitoring for both infliximab and adalimumab. The primary outcome was immunogenicity to the second anti-TNF agent, defined at any timepoint as an anti-TNF antibody concentration ≥9 AU/ml for infliximab and ≥6 AU/ml for adalimumab. RESULTS: In patients treated with infliximab and then adalimumab, those who developed antibodies to infliximab were more likely to develop antibodies to adalimumab, than patients who did not develop antibodies to infliximab (OR 1.99, 95%CI 1.27-3.20, p = 0.002). Similarly, in patients treated with adalimumab and then infliximab, immunogenicity to adalimumab was associated with subsequent immunogenicity to infliximab (OR 2.63, 95%CI 1.46-4.80, p < 0.001). For each 10-fold increase in anti-infliximab and anti-adalimumab antibody concentration, the odds of subsequently developing antibodies to adalimumab and infliximab increased by 1.73 (95% CI 1.38-2.17, p < 0.001) and 1.99 (95%CI 1.34-2.99, p < 0.001), respectively. Patients who developed immunogenicity with undetectable drug levels to infliximab were more likely to develop immunogenicity with undetectable drug levels to adalimumab (OR 2.37, 95% CI 1.39-4.19, p < 0.001). Commencing an immunomodulator at the time of switching to the second anti-TNF was associated with improved drug persistence in patients with immunogenic, but not pharmacodynamic failure. CONCLUSION: Irrespective of drug sequence, immunogenicity to the first anti-TNF agent was associated with immunogenicity to the second, which was mitigated by the introduction of an immunomodulator in patients with immunogenic, but not pharmacodynamic treatment failure.

Efficacy, tolerability, and predictors of response to infliximab therapy for Crohn's disease: a large single centre experience.

BACKGROUND: Infliximab is licenced for use in Crohn's disease (CD). Trial data demonstrate that infliximab is effective for inducing remission of active CD, healing fistulising CD, and preventing relapse once in remission. However, long-term data regarding efficacy, safety, and predictors of response are still emerging. AIM: To examine these issues in a large cohort of patients who received infliximab for CD. METHODS: A retrospective analysis of prospectively collected data was performed for 210 patients receiving infliximab for luminal or fistulising CD. Response to infliximab induction therapy, and sustained clinical benefit, were assessed by a decrease in Harvey-Bradshaw Index (HBI) of ≥ 2 points. Remission was defined as an HBI ≤ 4. Physician's global assessment was used where HBI could not be obtained. Demographic and disease factors that may predict response to therapy were analysed by Kaplan-Meier plots and univariate and multivariate analyses. RESULTS: Overall, 173 (82.4%) patients responded to infliximab induction, with 114 (65.9%) achieving sustained clinical benefit. Almost 40% of the study cohort had an HBI ≤ 4, indicating remission, at last point of follow-up (median 24 months). Concomitant immunosuppression predicted sustained clinical benefit in the first 6 months of therapy (P=0.03). An inflammatory disease phenotype (P=0.04 univariate analysis, P=0.03 Kaplan Meier analysis) and male gender (P=0.03) also predicted sustained clinical benefit. Episodic therapy was associated with an increased likelihood of secondary non-response. Adverse events, including malignancies, were few. CONCLUSION: In this single centre study, infliximab was efficacious and well-tolerated in CD.

Adalimumab as second line anti-tumour necrosis factor alpha therapy for Crohn's disease: A single centre experience.

BACKGROUND AND AIMS: Non-response, loss of response, or intolerance to anti-tumour necrosis factor alpha (anti-TNFα) therapy is well recognised in Crohn's disease (CD) patients. Data concerning outcomes following the use of a second anti-TNFα therapy, particularly in patients who do not respond to a first anti-TNFα agent, are still emerging. The aim of this study was to assess response and tolerability to adalimumab following infliximab failure in a single centre cohort of CD patients. METHODS: Data were collected prospectively on 44 patients who received adalimumab therapy following infliximab failure. Initial response to adalimumab therapy at 6weeks following induction was defined using a two point decrease in the Harvey-Bradshaw Index, with remission at this point defined using a Harvey Bradshaw index≤4. Sustained clinical benefit at the last point of follow up was determined using a physician's global assessment. Corticosteroid-free sustained clinical benefit was also assessed at this point. RESULTS: Thirty-four (77%) patients had initial response to adalimumab therapy, with 28 (64%) having sustained clinical benefit. Corticosteroid-free sustained clinical benefit was achieved in nine (53%) of 17 patients requiring steroids at commencement of adalimumab. Four (44%) of the 9 patients who were primary non-responders to infliximab responded to adalimumab. The majority of CD patients who failed adalimumab therapy required surgery. CONCLUSIONS: Second-line anti-TNFα therapy with adalimumab is effective at both inducing remission and maintaining response in CD patients who have failed infliximab, regardless of the reason for infliximab failure.

NOD-like receptors and inflammation.

The nucleotide-binding and oligomerization domain, leucine-rich repeat (also known as NOD-like receptors, both abbreviated to NLR) family of intracellular pathogen recognition receptors are increasingly being recognized to play a pivotal role in the pathogenesis of a number of rare monogenic diseases, as well as some more common polygenic conditions. Bacterial wall constituents and other cellular stressor molecules are recognized by a range of NLRs, which leads to activation of the innate immune response and upregulation of key proinflammatory pathways, such as IL-1beta production and translocation of nuclear factor-kappaB to the nucleus. These signalling pathways are increasingly being targeted as potential sites for new therapies. This review discusses the role played by NLRs in a variety of inflammatory diseases and describes the remarkable success to date of these therapeutic agents in treating some of the disorders associated with aberrant NLR function.