Neutralizing autoantibodies against interleukin-10 can result in a phenocopy of monogenic defects of interleukin-10 signaling in children and may be associated with inflammatory bowel disease (IBD). The allele HLA-DRB1*01:03 is the strongest genetic risk factor for ulcerative colitis. We used a cellular interleukin-10 reporter assay and a confirmatory competitive enzyme-linked immunosorbent assay to assess neutralizing interleukin-10 autoantibodies in serum samples obtained from patients with IBD in the Oxford and U.K. IBD BioResource cohorts and from persons without IBD (controls). An in vitro cytokine-release bioassay was performed in a subgroup of patients to assess interleukin-10, interleukin-23, interleukin-1β, tumor necrosis factor, and interleukin-6. We performed HLA association analysis using imputation and high-resolution sequencing. Interleukin-10-neutralizing autoantibodies were detected in 173 of 4909 patients with IBD (3.5%; 95% confidence interval [CI], 3.0 to 4.1) and in none of 1006 controls (P<0.001). High anti-interleukin-10 activity in serum was associated with a reduction in detectable interleukin-10 and with an exaggerated proinflammatory cytokine response, consistent with functional neutralization of interleukin-10 signaling. Anti-interleukin-10 seropositivity was strongly associated with HLA-DRB1*01:03 on the basis of imputed data from the Oxford cohort (odds ratio, 50.0; 95% CI, 16.4 to 152.3; P = 6.14×10^-12) and the U.K. IBD BioResource cohort (odds ratio, 24.7; 95% CI, 14.5 to 42.1; P = 6.20×10^-32) and in a high-resolution sequencing analysis of data from the Oxford cohort (odds ratio, 29.5; 95% CI, 12.2 to 71.1; P = 4.85×10^-14). Neutralizing interleukin-10 autoantibodies were present in a subgroup of patients with IBD and were strongly associated with HLA-DRB1*01:03. (Funded by the National Institute for Health and Care Research and others.).

Background: Anti-tumour necrosis factor (TNF) agents are effective in Crohn’s disease (CD), but some patients lose responsiveness and require alternative biologic therapy. Until recently, ustekinumab and vedolizumab were the only other biological agents approved for use in CD. There are no randomised trials which compare the efficacy of these two agents in patients with anti-TNF refractory disease, but several retrospective cohort studies have compared their effectiveness in this setting. Aim: To review the effectiveness of ustekinumab and vedolizumab in anti-TNF refractory patients with CD. Methods: We included studies that compared the effectiveness of ustekinumab and vedolizumab in treating patients with anti-TNF refractory CD. We recorded the sample size, primary and secondary outcome measures and whether the studies employed adjustments for appropriate confounders. Results: Fourteen studies were included with a total sample size of 5651, of whom 2181 (38.6%) were treated with vedolizumab and the rest were treated with ustekinumab (61.4%). Of the fourteen studies included, eight found ustekinumab to be more effective in achieving clinical remission/steroid-free remission in the induction phase or during maintenance therapy (at least 1-year post-treatment) or that treatment persistence rates with ustekinumab were higher than with vedolizumab. Only one study reported vedolizumab to be superior during the maintenance phase in terms of clinical remission or treatment persistence rates. Biochemical outcomes were reported in five studies, two of which showed superiority for ustekinumab at 14 weeks and the other at 52 weeks. Only two studies reported endoscopic and/or radiologic outcomes; of these, one study showed ustekinumab to be significantly better at achieving endoscopic and radiologic responses. Adverse outcomes were broadly comparable, barring a single study which reported a lower hospitalisation rate for severe infection with ustekinumab. Conclusions: Most studies found ustekinumab to be more effective or non-inferior to vedolizumab in treating patients with anti-TNF refractory CD. Although many studies adjusted appropriately for confounders, the possibility of residual confounding remains and further data from prospective studies are warranted to confirm these findings. Further studies are required to compare these two therapies to other emerging therapies, such as Janus-kinase inhibitors.

Background: The clinical utility and cost‐effectiveness of pre‐thiopurine NUDT15 pharmacogenetic testing in European and admixed populations are unknown.Aims: To report the prevalence, penetrance, expressivity, and pathogenicity of NUDT15 variant allele carriage and the diagnostic accuracy and cost‐effectiveness of an inexpensive loop‐mediated isothermal amplification (LAMP) test.Methods: Retrospective case‐matched cohort study of rates of severe myelosuppression in patients with and without loss‐of‐function NUDT15 variant allele(s) treated with a thiopurine.Results: Overall, 1.3% of Europeans and 11.7% of South Asians carried a variant allele. Severe myelosuppression was associated with NUDT15 variant allele carriage (11.3% vs 0.95%; p < 0.001). Carriage of a single *3, *6 or *9 variant allele was associated with a shorter time to severe myelosuppression. Numbers needed to genotype to prevent myelosuppression in Europeans and South Asians were 786 and 23. Variant calling using the LAMP assay was fully concordant with Sanger sequencing (n = 154). It improved the safety of thiopurine dosing and was cost‐effective when used to reduce the frequency and cost of thiopurine blood monitoring for patients without risk variants.Conclusion: We recommend TPMT and NUDT15 genetic testing in patients of Asian and admixed ancestry. In Europeans, reflex NUDT15 testing should be considered in patients with reduced TPMT activity or loss‐of‐function genotype. Thiopurines should be avoided in patients with > 1 NUDT15 variant allele and in patients with both NUDT15 and TPMT variant alleles. In patients with a single NUDT15 variant allele, we recommend thiopurine dose reduction (< 1 mg/kg/day) and intensified blood test monitoring.

Background and Aims: Loss of response (LoR) is a major limitation of anti-tumor necrosis factor (anti-TNF) therapy in inflammatory bowel disease (IBD). It can result from immunogenicity or other, less well-defined mechanisms. Specific HLA alleles have been linked to immunogenicity, but their association with LoR are not fully understood. In this study, we aimed to assess the relationship between HLA alleles and LoR, and investigate the impact of concomitant immunomodulator use. Methods: LoR and sustained response to infliximab or adalimumab were defined in 25 642 IBD patients from the IBD BioResource. We applied multivariable Cox proportional hazards models to assess the effect of HLA alleles on time to LoR. The effect of concomitant immunomodulator use was also evaluated. Significantly associated alleles were further tested in patients treated with ustekinumab and vedolizumab. Results: HLA-DQA1*05:01 was associated with reduced time to LoR in infliximab-treated patients (P = 5.34E-07), while HLA-DQA1*05:05 was associated with reduced time to LoR in adalimumab-treated patients (P = 3.20E-05). Neither allele was associated with LoR to ustekinumab or vedolizumab. Concomitant use of immunomodulators conferred a protective effect against LoR to infliximab and adalimumab in carriers of HLA-DQA1*05:01 and HLA-DQA1*05:05, respectively. However, this protective effect was not observed in adalimumab-treated patients who carried neither allele subtype (P = .11). Conclusions: Our findings highlight distinct associations between HLA-DQA1*05 allele subtypes and time to LoR of infliximab and adalimumab in IBD-treated patients. The protective effect of immunomodulator use is allele-specific for adalimumab. These results provide a rationale for incorporating HLA testing into personalized anti-TNF management to optimize treatment durability.

Background/Objectives: The management of inflammatory bowel disease (IBD) varies due to differences in healthcare systems, treatment costs, access to diagnostics, and diverse clinical practices between specialists. Despite the frequent advocacy of a treat-to-target (T2T) approach, there is insufficient clarity on how clinicians implement T2T in real-world settings. We aim to conduct a large, global survey among IBD experts to identify current practices in management. Methods: A prospective, cross-sectional study was conducted using a 16-item survey divided into two sections—for ulcerative colitis (UC) and Crohn’s disease (CD)—and distributed to practicing IBD clinicians. Results: A total of 261 respondents from 88 countries participated in the survey, with the majority (253/261) being physicians and eight being IBD nurse specialists. Despite global guidance, only a quarter of the respondents routinely perform an endoscopy to assess the response after starting an advanced therapy (28.4% in UC vs. 23.5% in CD). Moreover, despite an increasing academic focus on intestinal ultrasound (IUS), 171 (66%) of respondents in UC and 132 (51%) in CD reported that they do not routinely undertake IUS to guide treatment decisions. Faecal calprotectin for monitoring treatment response was routinely used by 87% (90% in UC and 84% in CD) of the respondents. Forty-five percent reported use of therapeutic drug monitoring (TDM) both proactively and reactively and 35% reported only using TDM reactively. Conclusions: Our study shows considerable variation in IBD management across different countries and interpretation of the T2T approach. This highlights the need for standardised and pragmatic guidelines to help improve outcomes for patients with IBD globally.

Background: Ileo-colonoscopy provides accurate assessment of mucosal inflammation in Crohn’s disease. Magnetic resonance imaging (MRI) offers a non-invasive alternative. MRI-based scores such as the simplified MaRIA (sMaRIA) have been proposed for measuring treatment response in clinical trials, but systematic comparisons with endoscopic scoring systems in prospective datasets are lacking. Methods: PROFILE trial participants underwent ileo-colonoscopy and small bowel MRI at baseline and week 48 (end-of-trial). Using this dataset our primary objective was to assess the correlation between Simple Endoscopic Score for Crohn’s Disease (SES-CD) and sMaRIA scores using contemporaneous ileo-colonoscopy and MRI studies. We also assessed the utility of sMaRIA as a clinical trial endpoint, and correlation between baseline sMaRIA and need for future surgery. Endoscopic and MRI remission were defined as SES-CD and sMaRIA scores of 0. Ulcer subscores were also examined. Results: In total, :285 patients had paired baseline ileo-colonoscopy and MRI studies and 220 had paired end-of-trial studies—undertaken a median of 35 and 22 days apart respectively. Correlation between total SES-CD and sMaRIA scores on end-of-trial studies was moderate (Spearman’s ρ = 0.428). MRI/sMaRIA identified only 18/143 ulcerated segments seen on ileo-colonoscopy. While remission rates between PROFILE treatment arms were significantly different on ileo-colonoscopy/SES-CD (P = .005), this difference was not seen on MRI/sMaRIA (P = .564). Patients requiring abdominal surgery had higher baseline sMaRIA scores than those who did not (P = .015), while SES-CD scores were not different between these groups (P = .830). Conclusions: MRI should be considered as complementary to ileo-colonoscopy for assessing ileal Crohn’s disease. sMaRIA should not replace SES-CD in clinical trials.