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Background and Aims: Anti-tumour necrosis factor [TNF] treatment failure in patients with inflammatory bowel disease [IBD] is common and frequently related to low drug concentrations. In order to identify patients who may benefit from dose optimisation at the outset of anti-TNF therapy, we sought to define epigenetic biomarkers in whole blood at baseline associated with anti-TNF drug concentrations at week 14., Methods: DNA methylation from 1104 whole blood samples from 385 patients in the Personalised Anti-TNF Therapy in Crohn's disease [PANTS] study were assessed using the Illumina EPIC Beadchip [v1.0] at baseline and weeks 14, 30, and 54. We compared DNA methylation profiles in anti-TNF-treated patients who experienced primary non-response at week 14 if they were assessed at subsequent time points and were not in remission at week 30 or 54 [infliximab n = 99, adalimumab n = 94], with patients who responded at week 14 and when assessed at subsequent time points were in remission at week 30 or 54 [infliximab n = 99, adalimumab n = 93]., Results: Overall, between baseline and week 14, we observed 4999 differentially methylated positions [DMPs] annotated to 2376 genes following anti-TNF treatment. Pathway analysis identified 108 significant gene ontology terms enriched in biological processes related to immune system processes and responses. Epigenome-wide association [EWAS] analysis identified 323 DMPs annotated to 210 genes at baseline associated with higher anti-TNF drug concentrations at Week 14. Of these, 125 DMPs demonstrated shared associations with other common traits [proportion of shared CpGs compared with DMPs] including body mass index [23.2%], followed by C-reactive protein [CRP] [11.5%], smoking [7.4%], alcohol consumption per day [7.1%], and IBD type [6.8%]. EWAS of primary non-response to anti-TNF identified 20 DMPs that were associated with both anti-TNF drug concentration and primary non-response to anti-TNF with a strong correlation of the coefficients [Spearman's rho = -0.94, p <0.001]., Conclusion: Baseline DNA methylation profiles may be used as a predictor for anti-TNF drug concentration at week 14 to identify patients who may benefit from dose optimisation at the outset of anti-TNF therapy., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Background: We sought to report the effectiveness of infliximab and adalimumab over the first 3 years of treatment and to define the factors that predict anti-TNF treatment failure and the strategies that prevent or mitigate loss of response., Methods: Personalised Anti-TNF therapy in Crohn's disease (PANTS) is a UK-wide, multicentre, prospective observational cohort study reporting the rates of effectiveness of infliximab and adalimumab in anti-TNF-naive patients with active luminal Crohn's disease aged 6 years and older. At the end of the first year, sites were invited to enrol participants still receiving study drug into the 2-year PANTS-extension study. We estimated rates of remission across the whole cohort at the end of years 1, 2, and 3 of the study using a modified survival technique with permutation testing. Multivariable regression and survival analyses were used to identify factors associated with loss of response in patients who had initially responded to anti-TNF therapy and with immunogenicity. Loss of response was defined in patients who initially responded to anti-TNF therapy at the end of induction and who subsequently developed symptomatic activity that warranted an escalation of steroid, immunomodulatory, or anti-TNF therapy, resectional surgery, or exit from study due to treatment failure. This study was registered with ClinicalTrials.gov, NCT03088449, and is now complete., Findings: Between March 19, 2014, and Sept 21, 2017, 389 (41%) of 955 patients treated with infliximab and 209 (32%) of 655 treated with adalimumab in the PANTS study entered the PANTS-extension study (median age 32·5 years [IQR 22·1-46·8], 307 [51%] of 598 were female, and 291 [49%] were male). The estimated proportion of patients in remission at the end of years 1, 2, and 3 were, for infliximab 40·2% (95% CI 36·7-43·7), 34·4% (29·9-39·0), and 34·7% (29·8-39·5), and for adalimumab 35·9% (95% CI 31·2-40·5), 32·9% (26·8-39·2), and 28·9% (21·9-36·3), respectively. Optimal drug concentrations at week 14 to predict remission at any later timepoints were 6·1-10·0 mg/L for infliximab and 10·1-12·0 mg/L for adalimumab. After excluding patients who had primary non-response, the estimated proportions of patients who had loss of response by years 1, 2, and 3 were, for infliximab 34·4% (95% CI 30·4-38·2), 54·5% (49·4-59·0), and 60·0% (54·1-65·2), and for adalimumab 32·1% (26·7-37·1), 47·2% (40·2-53·4), and 68·4% (50·9-79·7), respectively. In multivariable analysis, loss of response at year 2 and 3 for patients treated with infliximab and adalimumab was predicted by low anti-TNF drug concentrations at week 14 (infliximab: hazard ratio [HR] for each ten-fold increase in drug concentration 0·45 [95% CI 0·30-0·67], adalimumab: 0·39 [0·22-0·70]). For patients treated with infliximab, loss of response was also associated with female sex (vs male sex; HR 1·47 [95% CI 1·11-1·95]), obesity (vs not obese 1·62 [1·08-2·42]), baseline white cell count (1·06 [1·02-1·11) per 1 × 10 9 increase in cells per L), and thiopurine dose quartile. Among patients treated with adalimumab, carriage of the HLA-DQA1*05 risk variant was associated with loss of response (HR 1·95 [95% CI 1·17-3·25]). By the end of year 3, the estimated proportion of patients who developed anti-drug antibodies associated with undetectable drug concentrations was 44·0% (95% CI 38·1-49·4) among patients treated with infliximab and 20·3% (13·8-26·2) among those treated with adalimumab. The development of anti-drug antibodies associated with undetectable drug concentrations was significantly associated with treatment without concomitant immunomodulator use for both groups (HR for immunomodulator use: infliximab 0·40 [95% CI 0·31-0·52], adalimumab 0·42 [95% CI 0·24-0·75]), and with carriage of HLA-DQA1*05 risk variant for infliximab (HR for carriage of risk variant: infliximab 1·46 [1·13-1·88]) but not for adalimumab (HR 1·60 [0·92-2·77]). Concomitant use of an immunomodulator before or on the day of starting infliximab was associated with increased time without the development of anti-drug antibodies associated with undetectable drug concentrations compared with use of infliximab alone (HR 2·87 [95% CI 2·20-3·74]) or introduction of an immunomodulator after anti-TNF initiation (1·70 [1·11-2·59]). In years 2 and 3, 16 (4%) of 389 patients treated with infliximab and 11 (5%) of 209 treated with adalimumab had adverse events leading to treatment withdrawal. Nine (2%) patients treated with infliximab and two (1%) of those treated with adalimumab had serious infections in years 2 and 3., Interpretation: Only around a third of patients with active luminal Crohn's disease treated with an anti-TNF drug were in remission at the end of 3 years of treatment. Low drug concentrations at the end of the induction period predict loss of response by year 3 of treatment, suggesting higher drug concentrations during the first year of treatment, particularly during induction, might lead to better long-term outcomes. Anti-drug antibodies associated with undetectable drug concentrations of infliximab, but not adalimumab, can be predicted by carriage of HLA-DQA1*05 and mitigated by concomitant immunomodulator use for both drugs., Funding: Guts UK, Crohn's and Colitis UK, Cure Crohn's Colitis, AbbVie, Merck Sharp and Dohme, Napp Pharmaceuticals, Pfizer, and Celltrion Healthcare., Competing Interests: Declaration of interests CR reports receiving salary from the National Institute of Health Research outside the submitted work. RN reports receiving non-financial support from Immunodiagnostik. CWL has received consulting fees from AbbVie, Galapagos, Takeda, Janssen, Novartis, Pfizer, GSK, BMS, Boehringer Ingelheim, Celltrion, Amgen, and Iterative Health and payment or honoraria from AbbVie, Galapagos, Takeda, Janssen, Novartis, Pfizer, GSK, BMS, Boehringer Ingelheim, Celltrion Healthcare, Amgen, and Fresnius Kabi. SS has received consulting fees from Takeda, AbbVie, Merck, Ferring, Pharmacosmos, Warner Chilcott, Janssen, Falk Pharma, Biohit, TriGenix, Celgene, and Tillots Pharma; payment or honoraria from AbbVie, Takeda, Celltrion Healthcare, Pfizer, Biogen, AbbVie, Janssen, Merck, Warner Chilcott, Falk Pharma, and Janssen; is chair of the Research Committee of the British Society of Gastroenterology; is chair of the Clinical Research Committee of the European Colitis and Crohns Organisation; and is co-director of research for the South Asian IBD Alliance. PMI reports research grants from Celltrion Healthcare, Takeda, Pfizer, and Galapagos; personal payments from AbbVie, Arena, Boehringer Ingelheim, BMS, Celltrion Healthcare, Elasmogen, Endpoint Health, Gilead, Janssen, Lilly, Pfizer, Sandoz, and Takeda; and travel support from Takeda, AbbVie, and Tillotts Pharma, outside the submitted work. RKR has received grants from Nestle, consulting fees from AbbVie, payment or honoraria from Tillotts Pharma and Janssen, and support for attending meetings or travel from Celltrion Healthcare. JRG reports grants from F Hoffmann-La Roche, Biogen, Celltrion Healthcare, and Galapagos and non-financial support from Immundiagnostik outside the submitted work. TA reports grants or contracts from MSD, AbbVie, Hospira (Pfizer), Napp Pharmaceuticals, Celgene, Celltrion, F Hoffmann-La Roche, Biogen, Nova Pharmaceuticals, Galapagos, Takeda, and Pfizer; consulting fees from Amgen, Celltrion, Janssen, and Eli Lilly; payment or honoraria from F Hoffmann-La Roche, Pfizer, and Takeda; and support for attending meetings or travel from Tillotts Pharma and Celltrion Healthcare. NAK reports institutional grants or contracts from AbbVie, Biogen, Celgene, Celltrion Healthcare, Galapagos, MSD, Napp Pharmaceuticals, Pfizer, Pharmacosmos, Roche, and Takeda; personal consulting fees from Amgen, Bristol Myers Squibb, Celltrion Healthcare, Falk Pharma, Galapagos, Janssen, Pfizer, Pharmacosmos, Takeda, and Tillotts Pharma; personal payments or honoraria from Amgen, Celltrion Healthcare, Falk Pharma, Galapagos, Janssen, Pharmacosmos, Galapagos, Takeda, and Tillotts Pharma; support for attending meetings or travel from AbbVie, Falk Pharma, Janssen, and Pharmacosmos; participation in the Data Monitoring Committee for BEACON study; and is chair of the British Society of Gastroenterology IBD Clinical Research Group. NC, SL, CB, BH, AT, RS, MB, and TJM decare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background and Aims: We sought to determine whether six commonly used immunosuppressive regimens were associated with lower antibody responses after seasonal influenza vaccination in patients with inflammatory bowel disease [IBD]., Methods: We conducted a prospective study including 213 IBD patients and 53 healthy controls: 165 who had received seasonal influenza vaccine and 101 who had not. IBD medications included infliximab, thiopurines, infliximab and thiopurine combination therapy, ustekinumab, vedolizumab, or tofacitinib. The primary outcome was antibody responses against influenza/A H3N2 and A/H1N1, compared to controls, adjusting for age, prior vaccination, and interval between vaccination and sampling., Results: Lower antibody responses against influenza A/H3N2 were observed in patients on infliximab (geometric mean ratio 0.35 [95% confidence interval 0.20-0.60], p = 0.0002), combination of infliximab and thiopurine therapy (0.46 [0.27-0.79], p = 0.0050), and tofacitinib (0.28 [0.14-0.57], p = 0.0005) compared to controls. Lower antibody responses against A/H1N1 were observed in patients on infliximab (0.29 [0.15-0.56], p = 0.0003), combination of infliximab and thiopurine therapy (0.34 [0.17-0.66], p = 0.0016), thiopurine monotherapy (0.46 [0.24-0.87], p = 0.017), and tofacitinib (0.23 [0.10-0.56], p = 0.0013). Ustekinumab and vedolizumab were not associated with reduced antibody responses against A/H3N2 or A/H1N1. Vaccination in the previous year was associated with higher antibody responses to A/H3N2. Vaccine-induced anti-SARS-CoV-2 antibody concentration weakly correlated with antibodies against H3N2 [r = 0.27; p = 0.0004] and H1N1 [r = 0.33; p < 0.0001]., Conclusions: Vaccination in both the 2020-2021 and 2021-2022 seasons was associated with significantly higher antibody responses to influenza/A than no vaccination or vaccination in 2021-2022 alone. Infliximab and tofacitinib are associated with lower binding antibody responses to influenza/A, similar to COVID-19 vaccine-induced antibody responses., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Objective: Delayed second dose SARS-CoV-2 vaccination trades maximal effectiveness for a lower level of immunity across more of the population. We investigated whether patients with inflammatory bowel disease treated with infliximab have attenuated serological responses to a single dose of a SARS-CoV-2 vaccine., Design: Antibody responses and seroconversion rates in infliximab-treated patients (n=865) were compared with a cohort treated with vedolizumab (n=428), a gut-selective anti-integrin α4β7 monoclonal antibody. Our primary outcome was anti-SARS-CoV-2 spike (S) antibody concentrations, measured using the Elecsys anti-SARS-CoV-2 spike (S) antibody assay 3-10 weeks after vaccination, in patients without evidence of prior infection. Secondary outcomes were seroconversion rates (defined by a cut-off of 15 U/mL), and antibody responses following past infection or a second dose of the BNT162b2 vaccine., Results: Geometric mean (SD) anti-SARS-CoV-2 antibody concentrations were lower in patients treated with infliximab than vedolizumab, following BNT162b2 (6.0 U/mL (5.9) vs 28.8 U/mL (5.4) p<0.0001) and ChAdOx1 nCoV-19 (4.7 U/mL (4.9)) vs 13.8 U/mL (5.9) p<0.0001) vaccines. In our multivariable models, antibody concentrations were lower in infliximab-treated compared with vedolizumab-treated patients who received the BNT162b2 (fold change (FC) 0.29 (95% CI 0.21 to 0.40), p<0.0001) and ChAdOx1 nCoV-19 (FC 0.39 (95% CI 0.30 to 0.51), p<0.0001) vaccines. In both models, age ≥60 years, immunomodulator use, Crohn's disease and smoking were associated with lower, while non-white ethnicity was associated with higher, anti-SARS-CoV-2 antibody concentrations. Seroconversion rates after a single dose of either vaccine were higher in patients with prior SARS-CoV-2 infection and after two doses of BNT162b2 vaccine., Conclusion: Infliximab is associated with attenuated immunogenicity to a single dose of the BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines. Vaccination after SARS-CoV-2 infection, or a second dose of vaccine, led to seroconversion in most patients. Delayed second dosing should be avoided in patients treated with infliximab., Trial Registration Number: ISRCTN45176516., Competing Interests: Competing interests: NAK reports grants from F. Hoffmann-La Roche AG, grants from Biogen Inc, grants from Celltrion Healthcare, grants from Galapagos NV, non-financial support from Immundiagnostik, during the conduct of the study; grants and non-financial support from AbbVie, grants and personal fees from Celltrion, personal fees and non-financial support from Janssen, personal fees from Takeda, personal fees and non-financial support from Dr Falk, outside the submitted work. SL reports non-financial support from Pfizer, non-financial support from Ferring, outside the submitted work. JRG reports grants from F. Hoffmann-La Roche AG, grants from Biogen, grants from Celltrion Healthcare, grants from Galapagos NV, non-financial support from Immundiagnostik, during the conduct of the study. DC reports non-financial support from Ferring, personal fees and non-financial support from Pfizer, outside the submitted work. JRFC reports grants and personal fees from Samsung, Pfizer & Biogen; personal fees and non-financial support from Janssen & Abbvie; grants, personal fees and non-financial support from Takeda; personal fees from MSD, Sandoz, Celltrion & NAPP, outside the submitted work. AF reports personal fees from Takeda UK Ltd, personal fees from Dr Falk Pharma, personal fees from Tillotts, personal fees from Abbvie Ltd, personal fees from Sheild, personal fees from Ferring, from Pharmacosmos, personal fees from Allergan, personal fees from Janssen, outside the submitted work. PMI reports grants and personal fees from Takeda, grants from MSD, grants and personal fees from Pfizer, personal fees from Galapagos, personal fees from Gilead, personal fees from Abbvie, personal fees from Janssen, personal fees from Boehringer Ingelheim, personal fees from Topivert, personal fees from VH2, personal fees from Celgene, personal fees from Arena, personal fees from Samsung Bioepis, personal fees from Sandoz, personal fees from Procise, personal fees from Prometheus, outside the submitted work. NK reports personal fees from Janssen, outside the submitted work. KBK reports personal fees from Janssen, personal fees from Takeda, personal fees from PredictImmune, personal fees from Amgen, outside the submitted work. CAL reports grants from Genentech, grants and personal fees from Janssen, grants and personal fees from Takeda, grants from AbbVie, personal fees from Ferring, grants from Eli Lilly, grants from Pfizer, grants from Roche, grants from UCB Biopharma, grants from Sanofi Aventis, grants from Biogen IDEC, grants from Orion OYJ, personal fees from Dr Falk Pharma, grants from AstraZeneca, outside the submitted work. JM reports grants and personal fees from Takeda Pharmaceuticals, grants and personal fees from Biogen, personal fees and non-financial support from AbbVie, personal fees from Grifols, personal fees from Sandoz, personal fees from Celltrion, personal fees and non-financial support from Janssen, personal fees from Vifor Pharmaceuticals, personal fees from Predictimmune, personal fees from Bristol Myers Squibb, non-financial support from Ferring Pharmaceuticals, outside the submitted work. RCGP reports acting as consultant, advisory board member, speaker or recipient of educational grant from Dr Falk, Ferring, Janssen, Pharmacosmos and Takeda. TR reports grants and personal fees from Abbvie, personal fees from BMS, personal fees from Celgene, personal fees from Ferring, personal fees from Gilead, personal fees from GSK, personal fees from LabGenius, personal fees from Janssen, personal fees from Mylan, personal fees from MSD, personal fees from Novartis, personal fees from Pfizer, personal fees from Sandoz, personal fees from Takeda, personal fees from Galapagos, personal fees from Arena, outside the submitted work. PJS reports speaker fees and advisory board sponsorship from Janssen, Celltrion and Takeda outside the submitted work. AMV reports personal fees and non-financial support from Takeda, personal fees and non-financial support from Celltrion, personal fees and non-financial support from Merck Sharp & Dohme, outside the submitted work. SJ is an employee of Roche Diagnostics and holds Roche shares. SS reports grants from Takeda, Abbvie, AMGEN, Tillots Pharma, personal fees from Jaansen, Takeda, Galapagos, Celltrion, Falk Pharma, Tillots pharma, Cellgene, Pfizer, Pharmacocosmos, outside the submitted work. CWL reports personal fees from Abbvie, personal fees from Janssen, personal fees from Pfizer, personal fees from Takeda, grants from Gilead, personal fees from Gilead, personal fees from Galapagos, personal fees from Iterative Scopes, personal fees from Trellus Health, personal fees from Celltion, personal fees from Ferring, personal fees from BMS, during the conduct of the study. NP reports personal fees from Takeda, personal fees from Janssen, personal fees from Pfizer, personal fees from Bristol-Myers Squibb, personal fees from Abbvie, personal fees from Roche, personal fees from Lilly, personal fees from Allergan, personal fees from Celgene, outside the submitted work; and NP has served as a speaker/advisory board member for Abbvie, Allergan, Bristol Myers Squibb, Celgene, Falk, Ferring, Janssen, Pfizer, Tillotts, Takeda and Vifor Pharma. TA reports grants and non-financial support from F. Hoffmann-La Roche AG, grants from Biogen Inc, grants from Celltrion Healthcare, grants from Galapagos NV, non-financial support from Immundiagnostik, during the conduct of the study; personal fees from Biogen, grants and personal fees from Celltrion Healthcare, personal fees and non-financial support from Immundiagnostik, personal fees from Takeda, personal fees from ARENA, personal fees from Gilead, personal fees from Adcock Ingram Healthcare, personal fees from Pfizer, personal fees from Genentech, non-financial support from Tillotts, outside the submitted work., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Antitumour necrosis factor (anti-TNF) drugs impair protective immunity following pneumococcal, influenza and viral hepatitis vaccination and increase the risk of serious respiratory infections. We sought to determine whether infliximab-treated patients with IBD have attenuated serological responses to SARS-CoV-2 infections., Design: Antibody responses in participants treated with infliximab were compared with a reference cohort treated with vedolizumab, a gut-selective anti-integrin α4β7 monoclonal antibody that is not associated with impaired vaccine responses or increased susceptibility to systemic infections. 6935 patients were recruited from 92 UK hospitals between 22 September and 23 December 2020., Results: Rates of symptomatic and proven SARS-CoV-2 infection were similar between groups. Seroprevalence was lower in infliximab-treated than vedolizumab-treated patients (3.4% (161/4685) vs 6.0% (134/2250), p<0.0001). Multivariable logistic regression analyses confirmed that infliximab (vs vedolizumab; OR 0.66 (95% CI 0.51 to 0.87), p=0.0027) and immunomodulator use (OR 0.70 (95% CI 0.53 to 0.92), p=0.012) were independently associated with lower seropositivity. In patients with confirmed SARS-CoV-2 infection, seroconversion was observed in fewer infliximab-treated than vedolizumab-treated patients (48% (39/81) vs 83% (30/36), p=0.00044) and the magnitude of anti-SARS-CoV-2 reactivity was lower (median 0.8 cut-off index (0.2-5.6) vs 37.0 (15.2-76.1), p<0.0001)., Conclusions: Infliximab is associated with attenuated serological responses to SARS-CoV-2 that were further blunted by immunomodulators used as concomitant therapy. Impaired serological responses to SARS-CoV-2 infection might have important implications for global public health policy and individual anti-TNF-treated patients. Serological testing and virus surveillance should be considered to detect suboptimal vaccine responses, persistent infection and viral evolution to inform public health policy., Trial Registration Number: ISRCTN45176516., Competing Interests: Competing interests: NAK reports grants from F. Hoffmann-La Roche AG, grants from Biogen Inc, grants from Celltrion Healthcare, grants from Galapagos NV, non-financial support from Immundiagnostik, during the conduct of the study; grants and non-financial support from AbbVie, grants and personal fees from Celltrion, personal fees and non-financial support from Janssen, personal fees from Takeda, personal fees and non-financial support from Dr Falk, outside the submitted work. JRG reports grants from F. Hoffmann-La Roche AG, grants from Biogen Inc, grants from Celltrion Healthcare, grants from Galapagos NV, non-financial support from Immundiagnostik, during the conduct of the study. DC reports non-financial support from Ferring, personal fees and non-financial support from Pfizer, outside the submitted work. SL reports non-financial support from Pfizer, non-financial support from Ferring, outside the submitted work. RC reports personal fees from Takeda, outside the submitted work. NMC reports trial funding, advisory board and speaker fees paid to his institution from AbbVie, Eli Lilly, Takeda, Shire, Pfizer and Janssen. ALH reports personal fees from Abbvie, personal fees from Allergan, personal fees from BMS, personal fees from Celltrion, personal fees from Falk, personal fees from GSK, personal fees from Takeda, personal fees from Pfizer, personal fees from Janssen, personal fees from Galapogos, personal fees from Astra Zeneca, outside the submitted work. PMI reports grants and personal fees from Takeda, grants from MSD, grants and personal fees from Pfizer, personal fees from Galapagos, personal fees from Gilead, personal fees from Abbvie, personal fees from Janssen, personal fees from Boehringer Ingelheim, personal fees from Topivert, personal fees from VH2, personal fees from Celgene, personal fees from Arena, personal fees from Samsung Bioepis, personal fees from Sandoz, personal fees from Procise, personal fees from Prometheus, outside the submitted work. KBK reports personal fees from Janssen, personal fees from Takeda, personal fees from PredictImmune, personal fees from Amgen, outside the submitted work. CAL reports grants from Genentech, grants and personal fees from Janssen, grants and personal fees from Takeda, grants from AbbVie, personal fees from Ferring, grants from Eli Lilly, grants from Pfizer, grants from Roche, grants from UCB Biopharma, grants from Sanofi Aventis, grants from Biogen IDEC, grants from Orion OYJ, personal fees from Dr Falk Pharma, grants from AstraZeneca, outside the submitted work. JKL reports personal fees from MSD, personal fees from Janssen, grants and personal fees from Takeda, grants and personal fees from Galapagos, personal fees from Tillotts, outside the submitted work. JM reports grants and personal fees from Takeda Pharmaceuticals, grants and personal fees from Biogen, personal fees and non-financial support from AbbVie, personal fees from Grifols, personal fees from Sandoz, personal fees from Celltrion, personal fees and non-financial support from Janssen, personal fees from Vifor Pharmaceuticals, personal fees from Predictimmune, personal fees from Bristol Myers Squibb, non-financial support from Ferring Pharmaceuticals, outside the submitted work. DPBM reports grants from the Leona M. and Harry B. Helmsley Charitable Trust, during the conduct of the study; personal fees from Takeda Pharmaceuticals, personal fees from Pfizer, personal fees from Bridge Biotherapeutics, personal fees from Palatin Technologies, personal fees from Boehringer-Ingelheim, personal fees and other from Prometheus Biosciences, personal fees from Gilead, outside the submitted work. KVP reports personal fees and non-financial support from Takeda, personal fees and non-financial support from Janssen, personal fees and non-financial support from Abbvie, personal fees from DrFalk, non-financial support from Ferring, outside the submitted work. RCGP reports acting as consultant, advisory board member, speaker or recipient of educational grant from Dr Falk, Ferring, Janssen, Pharmacosmos and Takeda. TR reports grants and personal fees from Abbvie, personal fees from BMS, personal fees from Celgene, personal fees from Ferring, personal fees from Gilead, personal fees from GSK, personal fees from LabGenius, personal fees from Janssen, personal fees from Mylan, personal fees from MSD, personal fees from Novartis, personal fees from Pfizer, personal fees from Sandoz, personal fees from Takeda, personal fees from Galapagos, personal fees from Arena, outside the submitted work. RKR reports grants from NHS Research Scotland Senior Research Fellowship, personal fees from Nestlé, personal fees from AbbVie, personal fees from Dr Falk, personal fees from Takeda, personal fees from Napp, personal fees from Mead Johnson, personal fees from Nutricia, personal fees from 4D Pharma, outside the submitted work. CPS reports grants and personal fees from AbbVie, grants and personal fees from Janssen, grants and personal fees from Takeda, personal fees from Dr Falk, personal fees from Pfizer, personal fees from Galapagos, personal fees from Arena, personal fees from Fresenius Kabi, outside the submitted work. PJS reports speaker fees and advisory board sponsorship from Janssen, Celltrion and Takeda outside the submitted work. CWL reports personal fees from Abbvie, personal fees from Janssen, personal fees from Pfizer, personal fees from Takeda, grants from Gilead, personal fees from Gilead, personal fees from Galapagos, personal fees from Iterative Scopes, personal fees from Trellus Health, personal fees from Celltion, personal fees from Ferring, personal fees from BMS, during the conduct of the study. SS reports grants from Takeda, Abbvie, AMGEN, Tillots Pharma, personal fees from Jaansen, Takeda, Galapagos, Celltrion, Falk Pharma, Tillots pharma, Cellgene, Pfizer, Phamrmacocosmos, outside the submitted work. NP reports personal fees from Takeda, personal fees from Janssen, personal fees from Pfizer, personal fees from Bristol-Myers Squibb, personal fees from Abbvie, personal fees from Roche, personal fees from Lilly, personal fees from Allergan, personal fees from Celgene, outside the submitted work; and NP has served as a speaker/advisory board member for Abbvie, Allergan, Bristol Myers Squibb, Celgene, Falk, Ferring, Janssen, Pfizer, Tillotts, Takeda and Vifor Pharma. TA reports grants and non-financial support from F. Hoffmann-La Roche AG, grants from Biogen Inc, grants from Celltrion Healthcare, grants from Galapagos NV, non-financial support from Immundiagnostik, during the conduct of the study; personal fees from Biogen Inc, grants and personal fees from Celltrion Healthcare, personal fees and non-financial support from Immundiagnostik, personal fees from Takeda, personal fees from ARENA, personal fees from Gilead, personal fees from Adcock Ingram Healthcare, personal fees from Pfizer, personal fees from Genentech, non-financial support from Tillotts, outside the submitted work., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background & Aims: Anti-tumor necrosis factor (anti-TNF) therapies are the most widely used biologic drugs for treating immune-mediated diseases, but repeated administration can induce the formation of anti-drug antibodies. The ability to identify patients at increased risk for development of anti-drug antibodies would facilitate selection of therapy and use of preventative strategies., Methods: We performed a genome-wide association study to identify variants associated with time to development of anti-drug antibodies in a discovery cohort of 1240 biologic-naïve patients with Crohn's disease starting infliximab or adalimumab therapy. Immunogenicity was defined as an anti-drug antibody titer ≥10 AU/mL using a drug-tolerant enzyme-linked immunosorbent assay. Significant association signals were confirmed in a replication cohort of 178 patients with inflammatory bowel disease., Results: The HLA-DQA1*05 allele, carried by approximately 40% of Europeans, significantly increased the rate of immunogenicity (hazard ratio [HR], 1.90; 95% confidence interval [CI], 1.60-2.25; P = 5.88 × 10 -13 ). The highest rates of immunogenicity, 92% at 1 year, were observed in patients treated with infliximab monotherapy who carried HLA-DQA1*05; conversely the lowest rates of immunogenicity, 10% at 1 year, were observed in patients treated with adalimumab combination therapy who did not carry HLA-DQA1*05. We confirmed this finding in the replication cohort (HR, 2.00; 95% CI, 1.35-2.98; P = 6.60 × 10 -4 ). This association was consistent for patients treated with adalimumab (HR, 1.89; 95% CI, 1.32-2.70) or infliximab (HR, 1.92; 95% CI, 1.57-2.33), and for patients treated with anti-TNF therapy alone (HR, 1.75; 95% CI, 1.37-2.22) or in combination with an immunomodulator (HR, 2.01; 95% CI, 1.57-2.58)., Conclusions: In an observational study, we found a genome-wide significant association between HLA-DQA1*05 and the development of antibodies against anti-TNF agents. A randomized controlled biomarker trial is required to determine whether pretreatment testing for HLA-DQA1*05 improves patient outcomes by helping physicians select anti-TNF and combination therapies. ClinicalTrials.gov ID: NCT03088449., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Accelerated induction regimens of infliximab have been proposed to improve response rates in patients with steroid-refractory acute severe colitis., Aim: To determine the differences in outcome for acute severe ulcerative colitis between accelerated and standard-dose infliximab METHODS: We collected data on hospitalised patients receiving differing regimens of rescue therapy for steroid-refractory acute severe ulcerative colitis. Our primary outcome was 30-day colectomy rate. Secondary outcomes were colectomy within index admission, and at 90 days and 12 months. We used propensity score analysis with optimal calliper matching using high risk covariates defined a priori to reduce potential provider selection bias., Results: We included 131 patients receiving infliximab rescue therapy; 102 received standard induction and 29 received accelerated induction. In the unmatched cohort, there was no difference by type of induction in the 30-day colectomy rates (18% vs 20%, P = .45), colectomy during index admission (13% vs 20%, P = .26) or overall colectomy (20% vs 24%, P = .38). In the propensity score-matched cohort of 52 patients, 30-day colectomy (57% vs 27%, P = .048) and index admission colectomy (53% vs 23%, P = .045) rates were higher in those receiving standard induction compared to accelerated induction but there was no difference in overall colectomy rates (57% vs 31%, P = .09). There was no significant difference in length of stay or in complication and infection rates., Conclusion: In a propensity score-matched cohort, steroid-refractory acute severe ulcerative colitis patients, short-term, but not long-term, colectomy rates appear to be lower in those receiving an accelerated induction regimen., (© 2019 John Wiley & Sons Ltd.)

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 immunomodulator (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 use, and week 14 drug and anti-drug antibody concentrations showed an independent effect of immunomodulator use on week 54 non-remission (odds ratio 0·56 [95% CI 0·38-0·83], p=0·004)., Interpretation: Anti-TNF treatment failure is common and is predicted by low drug concentrations, mediated in part by immunogenicity. Clinical trials are required to investigate whether personalised induction regimens and treatment-to-target dose intensification improve outcomes., Funding: Guts UK, Crohn's and Colitis UK, Cure Crohn's Colitis, AbbVie, Merck Sharp and Dohme, Napp Pharmaceuticals, Pfizer, and Celltrion., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Crohn's disease (CD) is a chronic inflammation of the digestive tract that significantly impairs patients' quality of life and well-being. Anti-TNF biologicals revolutionised the treatment of CD, yet many patients do not adequately respond to such therapy. Previous studies have demonstrated a pro-inflammatory pattern in the composition of CD patients' immunoglobulin G (IgG) N-glycome compared to healthy individuals. Here, we utilised the high-throughput UHPLC method for N-glycan analysis to explore the longitudinal effect of the anti-TNF drugs infliximab and adalimumab on N-glycome composition of total serum IgG in 198 patients, as well as the predictive potential of IgG N-glycans at baseline to detect primary non-responders to anti-TNF therapy in 1315 patients. We discovered a significant decrease in IgG agalactosylation and an increase in monogalactosylation, digalactosylation and sialylation during the 14 weeks of anti-TNF treatment, regardless of therapy response, all of which suggested a diminished inflammatory environment in CD patients treated with anti-TNF therapy. Furthermore, we observed that IgG N-glycome might contain certain information regarding the anti-TNF therapy outcome before initiating the treatment. However, it is impossible to predict future primary non-responders to anti-TNF therapy based solely on IgG N-glycome composition at baseline. [ABSTRACT FROM AUTHOR]

The article presents a review of several studies pertaining to digestive disease researches. It provides overview of the study on the fecal loss of infliximab, the endoscopic recurrence after the curative resection of Crohn's disease, and the genetic risk factors of Clostridium difficile. It also mentions the findings and recommendations presented in such studies.