Background Anti-TNF drugs are effective treatments for the management of Crohn's disease but treatment failure is common. We aimed to identify clinical and pharmacokinetic factors that predict primary non-response at week 14 after starting treatment, non-remission at week 54, and adverse events leading to drug withdrawal.Methods The personalised anti-TNF therapy in Crohn's disease study (PANTS) is a prospective observational UK-wide study. We enrolled anti-TNF-naive patients (aged ≥6 years) with active luminal Crohn's disease at the time of first exposure to infliximab or adalimumab between March 7, 2013, and July 15, 2016. Patients were evaluated for 12 months or until drug withdrawal. Demographic data, smoking status, age at diagnosis, disease duration, location, and behaviour, previous medical and drug history, and previous Crohn's disease-related surgeries were recorded at baseline. At every visit, disease activity score, weight, therapy, and adverse events were recorded; drug and total anti-drug antibody concentrations were also measured. Treatment failure endpoints were primary non-response at week 14 ,non-remission at week 54, and adverse events leading to drug withdrawal. We used regression analyses to identify which factors were associated with treatment failure. Findings We enrolled 955 patients treated with infliximab (753 with originator; 202 with biosimilar) and 655 treated with adalimumab. Primary non-response occurred in 295 (23•8%, 95% CI 21•4-26•2) of 1241 patients who were assessable at week 14. Non-remission at week 54 occurred in 764 (63•1%, 60•3-65•8) of 1211 patients who were assessable, and adverse events curtailed treatment in 126 (7•8%, 6•6-9•2) of 1610 patients. In multivariable analysis, the only factor independently associated with primary non-response was low drug concentration at week 14 (infliximab: odds ratio 0•35 [95% CI 0•20-0•62], p=0•00038; adalimumab: 0•13 [0•06-0•28], p<0•0001); the optimal week 14 drug concentrations associated with remission at both week 14 and week 54 were 7 mg/L for infliximab and 12 mg/L for adalimumab. Continuing standard dosing regimens after primary non-response was rarely helpful; only 14 (12•4% [95% CI 6•9-19•9]) of 113 patients entered remission by week 54. Similarly, week 14 drug concentration was also independently associated with non-remission at week 54 (0•29 [0•16-0•52] for infliximab; 0•03 [0•01-0•12] for adalimumab; p<0•0001 for both). The proportion of patients who developed anti-drug antibodies (immunogenicity) was 62•8% (95% CI 59•0-66•3) for infliximab and 28•5% (24•0-32•7) for adalimumab. For both drugs, suboptimal week 14 drug concentrations predicted immunogenicity, and the development of anti-drug antibodies predicted subsequent low drug concentrations. Combination immuno-modulator (thiopurine or methotrexate) therapy mitigated the risk of developing anti-drug antibodies (hazard ratio 0•39 [95% CI 0•32-0•46] for infliximab; 0•44 [0•31-0•64] for adalimumab; p<0•0001 for both). For infliximab, multivariable analysis of immunododulator ...

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The addition of an ear health team increased access to appropriate primary care management and the time to contact with ENT was reduced by using an electronic template and telehealth sessions.

Background and AimsThe causes of microscopic colitis are currently poorly understood. Previous reports have found clinical associations with coeliac disease and genetic associations at the human leukocyte antigen [HLA] locus on the ancestral 8.1 haplotype. We investigated pharmacological and genetic factors associated with microscopic colitis in the UK Biobank.MethodsIn total, 483 European UK Biobank participants were identified by ICD10 coding, and a genome-wide association study was performed using BOLT-LMM, with a sensitivity analysis performed excluding potential confounders. The HLA*IMP:02 algorithm was used to estimate allele frequency at 11 classical HLA genes, and downstream analysis was performed using FUMA. Genetic overlap with inflammatory bowel disease [Crohn’s disease and ulcerative colitis] was investigated using genetic risk scores.ResultsWe found significant phenotypic associations with smoking status, coeliac disease and the use of proton-pump inhibitors but not with other commonly reported pharmacological risk factors. Using the largest sample size to date, we confirmed a recently reported association with the MHC Ancestral 8.1 Haplotype. Downstream analysis suggests association with digestive tract morphogenesis. By calculating genetic risk scores, we also report suggestive evidence of shared genetic risk with Crohn’s disease, but not with ulcerative colitis.ConclusionsThis report confirms the role of genetic determinants in the HLA in the pathogenesis of microscopic colitis. The genetic overlap with Crohn’s disease suggests a common underlying mechanism of disease.

Background: Delay in the diagnosis of inflammatory bowel disease (IBD) is common and contemporary UK studies are lacking. Aim: To determine factors associated with, and the consequences of, a prolonged time to diagnosis in IBD. Methods: This quality improvement study included 304 adults with a new IBD diagnosis made between January 2014 and December 2017 across 49 general practices (GP) and gastroenterology secondary care services. Outcome measures were demographic, clinical and laboratory factors associated with a delayed time, defined as greater than upper quartile, to: (a) patient presentation (b) GP referral (c) secondary care diagnosis, and factors associated with a complicated disease course (hospitalisation and/or surgery and/or biologic treatment) in the year after diagnosis. Results: The median [IQR] diagnosis sub-intervals were: (a) patient = 2.1 months [0.9-5.1]; (b) GP = 0.3 months [0.0-0.9]; (c) secondary care = 1.1 months [0.5-2.1]. 50% of patients were diagnosed within 4 months and 92% were diagnosed within 2 years of symptom onset. Diagnostic delay was more common in Crohn's disease (7.6 months [3.1-15.0]) than ulcerative colitis (3.3 months [1.9-7.3]) (P < 0.001). Patients who presented as an emergency (P < 0.001) but not those with a delayed overall time to diagnosis (P = 0.35) were more likely to have a complicated disease course. Conclusion: Time to patient presentation is the largest component of time to IBD diagnosis. Emergency presentation is common and, unlike a delayed time to diagnosis, is associated with a complicated disease course.