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.

Medical treatments in the short term management of reflux oesophagitis.

BACKGROUND: Oesophagitis arises when reflux of acid from the stomach into the oesophagus causes mucosal inflammation. It is a common problem and a systematic review on the optimum treatment would be useful. OBJECTIVES: To assess the effectiveness of proton pump inhibitors (PPIs), H2 receptor antagonists (H2RAs), prokinetic therapy, sucralfate and placebo in healing oesophagitis or curing reflux symptoms or both. To compare adverse effects with the different treatments. SEARCH STRATEGY: We searched MEDLINE, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials and the National Research Register until December 2004 and reference lists of articles. We also contacted manufacturers and researchers in the field. SELECTION CRITERIA: Randomised controlled trials assessing the healing of oesophagitis or reflux symptoms or both. Treatment involving PPIs, H2RAs, prokinetics, sucralfate and combinations either in comparison to another treatment regimen or to placebo for 2 and 12 weeks. DATA COLLECTION AND ANALYSIS: Two reviews independently assessed trial quality and extracted data. MAIN RESULTS: We included 134 trials involving 35,978 oesophagitis participants. Five RCTs evaluated standard dose of PPI versus placebo in 965 participants. There was a statistically significant benefit of taking standard dose PPI therapy compared to placebo in healing of oesophagitis (RR = 0.22; 95% CI 0.15 to 0.31). Ten RCTs reported on the outcome for H2RA versus placebo evaluating 1241 participants. There was statistically significant benefit of taking H2RA compared to placebo in healing of oesophagitis (RR 0.74,95% CI = 0.66 to 0.84). Three RCTs evaluated prokinetic therapy versus placebo in 198 participants. There was no statistically significant benefit of taking prokinetic therapy compared to placebo in healing of oesophagitis (RR 0.71, 95% CI 0.46 to 1.10). Twenty six RCTs reported the outcome for PPI versus H2RA or H2RA plus prokinetics, evaluating 4032 participants. There was statistically significant benefit of taking PPI therapy compared to H2RA or H2RA plus prokinetics in healing of oesophagitis (RR 0.51, 95% CI 0.44 to 0.59). AUTHORS' CONCLUSIONS: PPI therapy is the most effective therapy in oesophagitis but H2RA therapy is also superior to placebo. There is a paucity of evidence on prokinetic therapy but no evidence that it is superior to placebo.