Relapse after withdrawal from anti-TNF therapy for inflammatory bowel disease: an observational study, plus systematic review and meta-analysis.

BACKGROUND: Infliximab and adalimumab have established roles in inflammatory bowel disease (IBD) therapy. UK regulators mandate reassessment after 12 months' anti-TNF therapy for IBD, with consideration of treatment withdrawal. There is a need for more data to establish the relapse rates following treatment cessation. AIM: To establish outcomes following anti-TNF withdrawal for sustained remission using new data from a large UK cohort, and assimilation of all available literature for systematic review and meta-analysis. METHODS: A retrospective observational study was performed on 166 patients with IBD (146 with Crohn's disease (CD) and 20 with ulcerative colitis [UC) and IBD unclassified (IBDU)] withdrawn from anti-TNF for sustained remission. Meta-analysis was undertaken of all published studies incorporating 11 further cohorts totalling 746 patients (624 CD, 122 UC). RESULTS: Relapse rates in the UK cohort were 36% by 1 year and 56% by 2 years for CD, and 42% by 1 year and 47% by 2 years for UC/IBDU. Increased relapse risk in CD was associated with age at diagnosis [hazard ratio (HR) 2.78 for age <22 years], white cell count (HR 3.22 for >5.25 × 109 /L) and faecal calprotectin (HR 2.95 for >50 µg/g) at drug withdrawal. Neither continued immunomodulators nor endoscopic remission were predictors. In the meta-analysis, estimated 1-year relapse rates were 39% and 35% for CD and UC/IBDU respectively. Retreatment with anti-TNF was successful in 88% for CD and 76% UC/IBDU. CONCLUSIONS: Assimilation of all available data reveals remarkable homogeneity. Approximately one-third of patients with IBD flare within 12 months of withdrawal of anti-TNF therapy for sustained remission.

The long duration, in vivo, inhibition of prostaglandin synthetase by 2-methyl-8-cis-12-trans-14-cis-eicosatrienoic acid.

Competitive inhibition of prostaglandin synthetase by 8-cis-12-trans-14-cis-eicosatrienoic acid has been reported to occur in vitro. No in vivo effects were observed, possibly due to rapid metabolic degradation of this fatty acid by beta-oxidation. The present study involved the evaluation of this compound in vivo, and the preparation and evaluation in vivo of its alpha and beta methyl-substituted analogs which retain the carbon skeleton of the parent compound, and which might be expected to be resistant to beta-oxidation. Using a newly developed radioimmunoassay for the total urinary metabolites of prostaglandin E, data were obtained that indicates that both the parent compound and its 2-methyl analog are prostaglandin synthetase inhibitors in vivo. The 2-methyl analog exhibited an unusually long duration of activity as compared to both indomethacin and the parent compound. The lengthened duration of action of the 2-methyl analog may be explained both by its possible resistance to beta-oxidation, and to possible alteration in rates of either fatty acid transport, or incorporation/release from triglycerides (acylation/deacylation of triglycerides).