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.

Using high-frequency phosphorus monitoring for water quality management: a case study of the upper River Itchen, UK.

Increased concentrations of phosphorus (P) in riverine systems lead to eutrophication and can contribute to other environmental effects. Chalk rivers are known to be particularly sensitive to elevated P levels. We used high-frequency (daily) automatic water sampling at five distinct locations in the upper River Itchen (Hampshire, UK) between May 2016 and June 2017 to identify the main P species (including filterable reactive phosphorus, total filterable phosphorus, total phosphorus and total particulate phosphorus) present and how these varied temporally. Our filterable reactive phosphorus (considered the biologically available fraction) data were compared with the available Environment Agency total reactive phosphorus (TRP) values over the same sampling period. Over the trial, the profiles of the P fractions were complex; the major fraction was total particulate phosphorus with the mean percentage value ranging between 69 and 82% of the total P present. Sources were likely to be attributable to wash off from agricultural activities. At all sites, the FRP and Environment Agency TRP mean concentrations over the study were comparable. However, there were a number of extended time periods (1 to 2 weeks) where the mean FRP concentration (e.g. 0.62 mg L-1) exceeded the existing regulatory values (giving a poor ecological status) for this type of river. Often, these exceedances were missed by the limited regulatory monitoring procedures undertaken by the Environment Agency. There is evidence that these spikes of elevated concentrations of P may have a biological impact on benthic invertebrate (e.g. blue-winged olive mayfly) communities that exist in these ecologically sensitive chalk streams. Further research is required to assess the ecological impact of P and how this might have implications for the development of future environmental regulations.