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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.

Background and Aims Vitamin D has a regulatory role in innate and adaptive immune processes. Previous studies have reported that low pretreatment vitamin D concentrations are associated with primary non-response (PNR) and non-remission to anti-TNF therapy. This study aimed to assess whether pretreatment 25-hydroxyvitamin D concentrations predicted PNR and non-remission to infliximab and adalimumab in patients with active luminal Crohn’s disease. Methods 25-Hydroxyvitamin D concentrations were measured in stored baseline samples from 659 infliximab- and 448 adalimumab-treated patients in the Personalised Anti-TNF Therapy in Crohn’s disease (PANTS) study. Cut-offs for vitamin D were deficiency 50 nmol/L. Results About 17.1% (189/1107; 95% CI, 15.0–19.4) and 47.7% (528/1107; 95% CI, 44.8–50.6) of patients had vitamin D deficiency and insufficiency, respectively. 22.2% (246/1107) of patients were receiving vitamin D supplementation. Multivariable analysis confirmed that sampling during non-summer months, South Asian ethnicity, lower serum albumin concentrations, and non-treatment with vitamin D supplementation were independently associated with lower vitamin D concentrations. Pretreatment vitamin D status did not predict response or remission to anti-TNF therapy at week 14 (infliximab Ppnr = .89, adalimumab Ppnr = .18) or non-remission at week 54 (infliximab P = .13, adalimumab P = .58). Vitamin D deficiency was, however, associated with a longer time to immunogenicity in patients treated with infliximab, but not adalimumab. Conclusions Vitamin D deficiency is common in patients with active Crohn’s disease. Unlike previous studies, pretreatment vitamin D concentration did not predict PNR to anti-TNF treatment at week 14 or nonremission at week 54.

Contains fulltext : 288037.pdf (Publisher’s version ) (Closed access) BACKGROUND: The effects that therapies for inflammatory bowel disease (IBD) have on immune responses to SARS-CoV-2 vaccination are not yet fully known. Therefore, we sought to determine whether COVID-19 vaccine-induced antibody responses were altered in patients with IBD on commonly used immunosuppressive drugs. METHODS: In this multicentre, prospective, case-control study (VIP), we recruited adults with IBD treated with one of six different immunosuppressive treatment regimens (thiopurines, infliximab, a thiopurine plus infliximab, ustekinumab, vedolizumab, or tofacitinib) and healthy control participants from nine centres in the UK. Eligible participants were aged 18 years or older and had received two doses of COVID-19 vaccines (either ChAdOx1 nCoV-19 [Oxford-AstraZeneca], BNT162b2 [Pfizer-BioNTech], or mRNA1273 [Moderna]) 6-12 weeks apart (according to scheduling adopted in the UK). We measured antibody responses 53-92 days after a second vaccine dose using the Roche Elecsys Anti-SARS-CoV-2 spike electrochemiluminescence immunoassay. The primary outcome was anti-SARS-CoV-2 spike protein antibody concentrations in participants without previous SARS-CoV-2 infection, adjusted by age and vaccine type, and was analysed by use of multivariable linear regression models. This study is registered in the ISRCTN Registry, ISRCTN13495664, and is ongoing. FINDINGS: Between May 31 and Nov 24, 2021, we recruited 483 participants, including patients with IBD being treated with thiopurines (n=78), infliximab (n=63), a thiopurine plus infliximab (n=72), ustekinumab (n=57), vedolizumab (n=62), or tofacitinib (n=30), and 121 healthy controls. We included 370 participants without evidence of previous infection in our primary analysis. Geometric mean anti-SARS-CoV-2 spike protein antibody concentrations were significantly lower in patients treated with infliximab (156·8 U/mL [geometric SD 5·7]; p

Contains fulltext : 288038.pdf (Publisher’s version ) (Open Access) BACKGROUND: COVID-19 vaccine-induced antibody responses are reduced in patients with inflammatory bowel disease (IBD) taking anti-TNF or tofacitinib after two vaccine doses. We sought to assess whether immunosuppressive treatments were associated with reduced antibody and T-cell responses in patients with IBD after a third vaccine dose. METHODS: VIP was a multicentre, prospective, case-control study done in nine centres in the UK. We recruited immunosuppressed patients with IBD and non-immunosuppressed healthy individuals. All participants were aged 18 years or older. The healthy control group had no diagnosis of IBD and no current treatment with systemic immunosuppressive therapy for any other indication. The immunosuppressed patients with IBD had an established diagnosis of Crohn's disease, ulcerative colitis, or unclassified IBD using standard definitions of IBD, and were receiving established treatment with one of six immunosuppressive regimens for at least 12 weeks at the time of first dose of SARS-CoV-2 vaccination. All participants had to have received three doses of an approved COVID-19 vaccine. SARS-CoV-2 spike antibody binding and T-cell responses were measured in all participant groups. The primary outcome was anti-SARS-CoV-2 spike (S1 receptor binding domain [RBD]) antibody concentration 28-49 days after the third vaccine dose, adjusted by age, homologous versus heterologous vaccine schedule, and previous SARS-CoV-2 infection. The primary outcome was assessed in all participants with available data. FINDINGS: Between Oct 18, 2021, and March 29, 2022, 352 participants were included in the study (thiopurine n=65, infliximab n=46, thiopurine plus infliximab combination therapy n=49, ustekinumab n=44, vedolizumab n=50, tofacitinib n=26, and healthy controls n=72). Geometric mean anti-SARS-CoV-2 S1 RBD antibody concentrations increased in all groups following a third vaccine dose, but were significantly lower in patients treated with infliximab (2736·8 U/mL [geometric SD 4·3]; p

Contains fulltext : 291657.pdf (Publisher’s version ) (Open Access) BACKGROUND: Anti-TNF drugs, such as infliximab, are associated with attenuated antibody responses after SARS-CoV-2 vaccination. We aimed to determine how the anti-TNF drug infliximab and the anti-integrin drug vedolizumab affect vaccine-induced neutralising antibodies against highly transmissible omicron (B.1.1.529) BA.1, and BA.4 and BA.5 (hereafter BA.4/5) SARS-CoV-2 variants, which possess the ability to evade host immunity and, together with emerging sublineages, are now the dominating variants causing current waves of infection. METHODS: CLARITY IBD is a prospective, multicentre, observational cohort study investigating the effect of infliximab and vedolizumab on SARS-CoV-2 infection and vaccination in patients with inflammatory bowel disease (IBD). Patients aged 5 years and older with a diagnosis of IBD and being treated with infliximab or vedolizumab for 6 weeks or longer were recruited from infusion units at 92 hospitals in the UK. In this analysis, we included participants who had received uninterrupted biological therapy since recruitment and without a previous SARS-CoV-2 infection. The primary outcome was neutralising antibody responses against SARS-CoV-2 wild-type and omicron subvariants BA.1 and BA.4/5 after three doses of SARS-CoV-2 vaccine. We constructed Cox proportional hazards models to investigate the risk of breakthrough infection in relation to neutralising antibody titres. The study is registered with the ISRCTN registry, ISRCTN45176516, and is closed to accrual. FINDINGS: Between Sept 22 and Dec 23, 2020, 7224 patients with IBD were recruited to the CLARITY IBD study, of whom 1288 had no previous SARS-CoV-2 infection after three doses of SARS-CoV-2 vaccine and were established on either infliximab (n=871) or vedolizumab (n=417) and included in this study (median age was 46·1 years [IQR 33·6-58·2], 610 [47·4%] were female, 671 [52·1%] were male, 1209 [93·9%] were White, and 46 [3·6%] were Asian). After three doses of SARS-CoV-2 vaccine, 50% neutralising titres (NT50s) were significantly lower in patients treated with infliximab than in those treated with vedolizumab, against wild-type (geometric mean 2062 [95% CI 1720-2473] vs 3440 [2939-4026]; p

Contains fulltext : 291656.pdf (Publisher’s version ) (Open Access)

ObjectiveAntitumour necrosis factor (TNF) drugs impair serological responses following SARS-CoV-2 vaccination. We sought to assess if a third dose of a messenger RNA (mRNA)-based vaccine substantially boosted anti-SARS-CoV-2 antibody responses and protective immunity in infliximab-treated patients with IBD.DesignThird dose vaccine induced anti-SARS-CoV-2 spike (anti-S) receptor-binding domain (RBD) antibody responses, breakthrough SARS-CoV-2 infection, reinfection and persistent oropharyngeal carriage in patients with IBD treated with infliximab were compared with a reference cohort treated with vedolizumab from the impaCt of bioLogic therApy on saRs-cov-2 Infection and immuniTY (CLARITY) IBD study.ResultsGeometric mean (SD) anti-S RBD antibody concentrations increased in both groups following a third dose of an mRNA-based vaccine. However, concentrations were lower in patients treated with infliximab than vedolizumab, irrespective of whether their first two primary vaccine doses were ChAdOx1 nCoV-19 (1856 U/mL (5.2) vs 10 728 U/mL (3.1), pCompared with vedolizumab-treated, infliximab-treated patients were more likely to experience SARS-CoV-2 breakthrough infection (HR 2.23 (95% CI 1.46 to 3.38), p=0.00018) and reinfection (HR 2.10 (95% CI 1.31 to 3.35), p=0.0019), but this effect was uncoupled from third vaccine dose anti-S RBD antibody concentrations. Reinfection occurred predominantly during the Omicron wave and was predicted by SARS-CoV-2 antinucleocapsid concentrations after the initial infection. We did not observe persistent oropharyngeal carriage of SARS-CoV-2. Hospitalisations and deaths were uncommon in both groups.ConclusionsFollowing a third dose of an mRNA-based vaccine, infliximab was associated with attenuated serological responses and more SARS-CoV-2 breakthrough infection and reinfection which were not predicted by the magnitude of anti-S RBD responses, indicative of vaccine escape by the Omicron variant.Trial registration numberISRCTN45176516.

During illness, adaptations of the hypothalamic-pituitary-thyroid axis reduce energy expenditure, protein catabolism and modulate immune responses to promote survival. Lower serum free triiodothyronine-to-thyroxine (fT3/fT4) ratio has been linked to non-response to treatment in a range of diseases, including in biologic-treated patients with inflammatory bowel disease.To assess whether baseline serum fT3/fT4 ratio predicted primary non-response (PNR) and non-remission to infliximab and adalimumab in patients with Crohn's disease METHODS: Thyroid function tests were undertaken in stored serum from biologic-naïve adult patients with active luminal Crohn's disease immediately prior to treatment with infliximab (427 originator; 122 biosimilar) or adalimumab (448) in the Personalised Anti-TNF Therapy in Crohn's Disease study (PANTS).Baseline median [IQR] fT3/fT4 ratios were lower in women than men (0.30 [0.27-0.34] vs 0.32 [0.28-0.36], p 0.001), in patients with more severe inflammatory disease, and in patients receiving corticosteroids (0.28 [0.25-0.33] vs. 0.32 [0.29-0.36], p 0.001). Multivariable logistic regression analysis demonstrated that fT3/fT4 ratio was independently associated with PNR at week 14 (odds ratio [OR] 0.51, 95% confidence interval [CI] 0.31-0.85, p = 0.009), but not non-remission or changes in faecal calprotectin concentrations at week 54. The optimal threshold to determine PNR was 0.31 (area under the curve 0.57 [95% CI 0.54-0.61], sensitivity 0.62 [95% CI 0.41-0.74], and specificity 0.53 [95% CI 0.42-0.73]).Lower baseline serum fT3/fT4 ratio was associated with female sex, corticosteroid use and disease activity. It predicted PNR to anti-TNF treatment at week 14, but not non-remission at week 54.

Background and Aims Infliximab attenuates serological responses to SARS-CoV-2 infection. Whether this is a class effect, or if anti-tumour necrosis factor [anti-TNF] level influences serological responses, remains unknown. Methods Seroprevalence and the magnitude of SARS-CoV-2 nucleocapsid antibody responses were measured in surplus serum from 11 422 (53.3% [6084] male; median age 36.8 years) patients with immune-mediated inflammatory diseases, stored at six therapeutic drug monitoring laboratories between January 29 and September 30, 2020. Data were linked to nationally held SARS-CoV-2 PCR results to July 11, 2021. Results Rates of PCR-confirmed SARS-CoV-2 infection were similar across treatment groups. Seroprevalence rates were lower in infliximab- and adalimumab- than vedolizumab-treated patients (infliximab: 3.0% [178/5893], adalimumab: 3.0% [152/5074], vedolizumab: 6.7% [25/375], p = 0.003). The magnitude of SARS-CoV-2 reactivity was similar in infliximab- vs adalimumab-treated patients (median 4.30 cut-off index [COI] [1.94–9.96] vs 5.02 [2.18–18.70], p = 0.164), but higher in vedolizumab-treated patients (median 21.60 COI [4.39–68.10, p Conclusion Anti-TNF treatment is associated with lower SARS-CoV-2 nucleocapsid seroprevalence and antibody reactivity when compared to vedolizumab-treated patients. Higher seropositivity rates in patients with undetectable anti-TNF levels support a causal relationship, although confounding factors, such as combination therapy with a immunomodulator, may have influenced the results.

Background Anti-TNF drugs increase the risk of serious respiratory infections and impair protective immunity following pneumococcal, influenza, and viral hepatitis vaccinations. Therefore, we sought to determine whether patients with inflammatory bowel disease treated with infliximab have attenuated serological responses following SARS-CoV-2 infection. Methods CLARITY IBD is a multicentre, prospective observational cohort study. Antibody responses in participants treated with infliximab were compared to 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 22nd September and 23rd December 2020. Nucleocapsid anti-SARS-CoV2 antibodies were measured using the Roche Elecsys assay. Clinical data and serum were collected every 8 weeks. Durability was defined as nonreduction in antibody level by at least 50% from baseline. Results At baseline, rates of symptomatic and proven SARS-CoV-2 infection were similar between groups. Seroprevalence was lower in infliximab- than vedolizumab-treated patients (3.4% [161/4685], vs 6.0% [134/2250], p Conclusion Seroprevalence, seroconversion in PCR-confirmed cases, and the magnitude and durability of anti-SARS-CoV2 antibodies were reduced in infliximab- compared with vedolizumab-treated patients. Serological testing and virus surveillance should be considered in patients treated with anti-TNF drugs to detect suboptimal vaccine responses, persistent infection, and viral evolution to inform public health policy.

We report SARS-CoV-2 vaccine-induced immunity and risk of breakthrough infections in patients with inflammatory bowel disease treated with infliximab, a commonly used anti-TNF drug and those treated with vedolizumab, a gut-specific antibody targeting integrin a4b7 that does not impact systemic immunity. In infliximab-treated patients, the magnitude of anti-SARS-CoV2 antibodies was reduced 4-6-fold. One fifth of both infliximab- and vedolizumab-treated patients did not mount a T cell response. Antibody half-life was shorter in infliximab-treated patients. Breakthrough SARS-CoV-2 infections occurred more frequently in infliximab-treated patients and the risk was predicted by the level of antibody response after second vaccine dose. Overall, recipients of two doses of the BNT162b2 vaccine had higher anti-SARS-CoV-2 antibody concentrations, higher seroconversion rates, shorter antibody half-life and less breakthrough infections compared to ChAdOx1 nCoV-19 vaccine recipients. Irrespective of biologic treatment, higher, more sustained antibody levels were observed in patients with a history of SARS-CoV-2 infection prior to vaccination. Patients treated with anti-TNF therapy should be offered third vaccine doses.

OFR-8 Figure 1ConclusionsInfliximab 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.

To inform healthcare policy for immunosuppressed patients there is a need to define SARS-CoV-2 vaccine responses. Here we report SARS-CoV-2 vaccine-induced antibody and T cell responses in patients treated with anti-tumour necrosis factor (anti-TNF), a commonly used biologic in inflammatory diseases, compared to patients treated with vedolizumab, a gut-specific antibody targeting integrin a4b7 that does not impair systemic immunity. In anti-TNF recipients, the magnitude of anti-SARS-CoV2 antibodies was reduced five-fold, and rapidly decayed towards the seroconversion threshold by 14 weeks after second dose of vaccine. In contrast, anti-SARS-CoV-2 antibodies were sustained up to 16 weeks in vedolizumab-treated patients. Anti-SARS-CoV2 antibody decay was not observed in vaccinated patients previously infected with SARS-CoV-2. T cell responses were absent in one-fifth of anti-TNF and vedolizumab-treated patients after a second dose of either vaccine. Our data have important implications for anti-TNF recipients, including the need for vaccine prioritization, booster doses, and social distancing strategies.

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

ObjectiveDelayed 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.DesignAntibody 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.ResultsGeometric 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) pConclusionInfliximab 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 numberISRCTN45176516.

BackgroundDelayed 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.MethodsAntibody responses and seroconversion rates in infliximab-treated patients (n=865) were compared to 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 3-10 weeks after vaccination in patients without evidence of prior infection. Secondary outcomes were seroconversion rates, and antibody responses following past infection or a second dose of the BNT162b2 vaccine.FindingsGeometric 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] PInterpretationInfliximab 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.FundingRoyal Devon and Exeter and Hull University Hospital Foundation NHS Trusts. Unrestricted educational grants: F. Hoffmann-La Roche AG (Switzerland), Biogen GmbH (Switzerland), Celltrion Healthcare (South Korea) and Galapagos NV (Belgium).Research in contextEvidence before this studyFaced with further surges of SARS-CoV-2 infection, a growing number of countries, including the UK, have opted to delay second vaccine doses for all people. This strategy trades maximal effectiveness against a lower level of protective immunity across more of the at-risk population.We have previously shown that seroprevalence, seroconversion in PCR-confirmed cases, and the magnitude of anti-SARS-CoV-2 antibodies following SARS-CoV-2 infection are reduced in infliximab-compared with vedolizumab-treated patients. Whether single-doses of vaccines are effective in patients treated with anti-TNF therapies is unknown.We searched PubMed from 25 November 2019 to 23 March 2021 with the terms “anti-tumour necrosis factor” or “anti-integrin” or “infliximab” or “adalimumab” or “vedolizumab” or “biological therapy” or “biologic therapy” AND “SARS-CoV-2” or “coronavirus” or “COVID-19” or AND “seroprevalence” or “seroconversion” or “antibody” or “antibody response” or “magnitude” or “immunogenicity” AND “vaccine” or “vaccination” or “immunisation” or “immunization” or “ChAdOx1 nCoV-19” or “BNT162b2” or “mRNA-1273”, without restriction on language.Serological responses to SARS-CoV-2 vaccines have been reported in registration trials and small observational cohorts of healthy volunteers. Two small studies, including one unpublished preprint, found that COVID-19 vaccine immunogenicity rates were lower in transplant recipients and patients with malignancy receiving immunosuppressive therapy, and fewer patients treated with potent immunosuppressants seroconverted than healthy controls. No studies have assessed the effect of anti-TNF therapy on immunogenicity following SARS-CoV-2 vaccination.Added value of this studyTo test if anti-TNF drugs attenuate serological responses to primary SARS-CoV-2 vaccines, we analysed anti-SARS-CoV-2 spike (S) antibody concentrations and seroconversion rates in 1293 patients with inflammatory bowel disease who received primary vaccinations with either the ChAdOx1 nCoV-19 or BNT162b2 vaccines. 865 were treated with the anti-TNF drug infliximab and outcomes were compared to a reference cohort of 428 patients treated with vedolizumab, a gut selective anti-integrin α4β7 monoclonal antibody that is not associated with impaired systemic immune responses.Anti-SARS-CoV-2 antibody levels and rates of seroconversion were lower following primary vaccination with both the BNT162b2 and ChAdOx1 nCoV-19 vaccines in patients with IBD treated with infliximab compared to vedolizumab. Older age, immunomodulator use, Crohn’s disease (versus ulcerative colitis or inflammatory bowel disease unclassified), and current smoking were associated with lower anti-SARS-CoV-2 antibody concentrations, irrespective of vaccine type. Non-white ethnicity was associated with higher anti-SARS-CoV-2 (S) antibody concentrations following primary vaccination with both vaccines. Antibody concentrations and seroconversion rates were higher in patients with past SARS-CoV-2 infection prior to a single-dose of either vaccine, and after 2 doses of the BNT162b2 vaccine.Implications of the available evidenceOur findings have important implications for patients treated with anti-TNF therapy, particularly for those also treated with an immunomodulator. Poor antibody responses to a single-dose of vaccine exposes these patients to a potential increased risk of SARS-CoV-2 infection. However, higher rates of seroconversion in patients with two exposures to SARS-CoV-2 antigen, even in the presence of TNF blockade, suggest that all patients receiving these drugs should be prioritized for optimally timed second doses. Until patients receive a second vaccine dose, they should consider that they are not protected from SARS-CoV-2 infection and continue to practice enhanced physical distancing and shielding if appropriate. Even after two antigen exposures, a small subset of patients failed to mount an antibody response. Antibody testing and adapted vaccine schedules should be considered to protect these at-risk patients.

BackgroundWe have successfully used whole-genome sequencing to provide additional information for transmission pathways in infectious spread. We report and interpret genomic sequencing results in clinical context from a large outbreak of COVID-19 with 46 cases across staff and patients in a community hospital in the UK.MethodsFollowing multiple symptomatic cases within a two-week period, all staff and patients were screened by RT-PCR and staff subsequently had serology tests.ResultsThirty staff (25%) and 16 patients (62%) tested positive for COVID-19. Genomic sequencing data showed significant overlap of viral haplotypes in staff who had overlapping shift patterns. Patient haplotypes were more distinct from each other but had overlap with staff haplotypes.ConclusionsThis study includes clinical and genomic epidemiological detail that demonstrates the value of a combined approach. Viral genetic sequencing has identified that staff transmission of COVID-19 was important in this community hospital outbreak.Key pointsDetailed analysis of a large community hospital outbreak in older adults and staff with concurrent clinical and genomic data, including working patterns.Staff transmission was important in this community hospital outbreak.We found plausible associations between staff and patient cases.

When used proactively, drug-tolerant anti-tumour necrosis factor (TNF) antibody assays provide early opportunity to suppress immunogenicity.To validate positivity thresholds of IDKmonitor drug-tolerant anti-infliximab and -adalimumab antibody assays.We applied positivity thresholds, defined by testing sera from 498 anti-TNF naive healthy adults, from the Exeter Ten Thousand study to data from our therapeutic drug monitoring (TDM) service and Personalised Anti-TNF Therapy in Crohn's disease (PANTS) cohort to explore associations with drug level and treatment outcomes.The 80% one-sided lower confidence interval of the 99th centile concentration for anti-infliximab and -adalimumab antibodies were lower than the manufacturers threshold of 10 arbitrary units (AU)/mL; 9 and 6 AU/mL, respectively. Using these new thresholds in the TDM cohort, more adalimumab- than infliximab- (11.2% [814/7272] vs 3.1% [390/12 683] P 0.0001) treated patients were reclassified as antibody-positive. Adalimumab drug concentrations in this reclassified group (median 8.1, interquartile range [IQR] 5.5-11.0 mg/L) were lower than those below the new threshold (5AU/mL) (median 9.9, IQR 7.1-13.0 mg/L; P 0.0001), but higher than at the manufacturer's threshold (10-29 AU/mL) (median 5.9 mg/L, IQR 3.5-8.7; P 0.0001). No difference in infliximab drug concentration was observed using the new or manufacturer's positivity threshold (P = 0.11). In the PANTS cohort, patients with anti-adalimumab antibody concentrations at or above the new threshold were more likely to be in primary non-response (25/68 [37%] vs. 64/332 [19%], P = 0.0035), and non-remission at week 54 (51/62 [82%] vs. 168/279 [60%], P = 0.0011), than patients with anti-drug antibody concentrations in the group below the new threshold (0-5 AU/mL); this was not seen for anti-infliximab antibodies.Laboratories should derive antibody positivity thresholds for assays they use. For adalimumab, low-concentration anti-drug antibodies were associated with lower drug levels and treatment failure.

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

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.

Ethical guidance for genomic research is increasingly sought and perceived to be necessary. Although there are pressing ethical issues in genomic research – concerning for example the recruitment of patients/participants; the process of taking consent; data sharing; and returning results to patients/participants – there is still limited useful guidance available for researchers/clinicians or for the research ethics committees who review such projects. This report outlines the ethical principles and guidance for genomic research co-produced with stakeholders during two workshops which took place in the UK between November 2016 and May 2017. The stakeholders involved in these workshops included: healthcare professionals, genomic research teams, academics, patients, biobank managers, and representatives from the Health Research Authority (HRA), NHS Research Ethics Committees, patient support groups, pharmaceutical industry, and health policy think tanks. The co-produced principles and guidance are specifically aimed at researchers/clinicians and members of NHS Research Ethics Committees, and are formulated with the intention to be clear and accessible, both in terms of content and language, to these groups.

Background Given the existential threat from COVID-19 and the consequent restrictive public health measures it is perhaps unsurprising that SARS-CoV-2 infection has been linked to increases in rates of depression in the general population. Few studies, however have addressed anxiety and depression in patients with inflammatory bowel disease (IBD) during the COVID19 pandemic. We aimed to define, in patients with IBD treated with infliximab or vedolizumab and/or an immunomodulator, the prevalence, demographic and disease-related factors associated with depression and the effect of restrictive public health measures on rates of depression. Methods CLARITY IBD is a United Kingdom (UK) wide, multicentre, prospective observational cohort study investigating the impact of infliximab and vedolizumab and/or concomitant immunomodulators (thiopurines or methotrexate) on SARS-CoV-2 acquisition, illness, and immunity in patients with IBD. Patients were recruited between 22nd September and 23rd December 2020 and then assessed every 8 weeks. We measured depression using the 8-item Patient Health Questionnaire (PHQ-8). Secondary outcomes were anxiety and IBD-related quality of life assessed using the General Anxiety Disorder Assessment (GAD-7) and IBD-Control questionnaires, respectively. Multivariable logistic regression models were used to identify factors independently associated with depression at entry to the study. Baseline and paired responses during the third UK government’s stay-at-home lockdown order which commenced on the 4th January 2021 were compared using the Wilcoxon signed-rank test. Results The prevalence of depression at entry to the CLARITY study was 26% (1794/6933): 14% patients satisfied criteria for mild, 6% moderate and 5% severe depression. Depression scores were associated with anxiety (Spearman’s rho= 0.78, p Conclusion Depression was negatively associated with infliximab therapy and was unchanged during the third UK stay-at-home lockdown. Longitudinal follow up in this cohort will allow us to determine whether COVID-19 vaccination influences depression and whether depression is linked to vaccine hesitancy or impaired serological responses to SARS-CoV-2 vaccination.

Background Anti-drug antibodies can affect biopharmaceutical pharmacokinetics by increasing or decreasing drug clearance. Drug-tolerant (total), unlike drug-sensitive (free), antibody assays permit antibodies to be measured in the presence of a drug. We sought to confirm the positivity threshold of our total anti-tumour necrosis factor (TNF) antibody ELISA assays in a sample of healthy volunteers and to use this threshold to report the prevalence of clearing and transient antibodies in patients treated with infliximab and adalimumab. Methods Serum was obtained from a random sample of 498 anti-TNF-naïve healthy adults recruited to the Exeter Ten Thousand study and tested for total anti-drug antibodies to infliximab and adalimumab. Using recommendations for confirmatory anti-drug antibody validation, we used bootstrapping to calculate the 80% one-sided lower confidence interval [CI] of the 99th centile to define assay thresholds. We used paired drug and anti-drug antibody levels derived from our national therapeutic drug monitoring service to report the distribution of clearing (antibody positive, drug negative) vs. non-clearing (antibody positive, drug positive) antibodies. In patients with at least two test results, antibodies were classified as transient (single positive test with subsequent negative test) or persistent (at least two positive tests). Results The 80% one-sided lower CI of the 99th centile titre for total anti-drug antibody to infliximab and adalimumab were 8.7 AU/ml and 5.9 AU/ml, respectively. Using the manufacturer’s recommended threshold of 10 AU/ml for both total anti-TNF antibody assays, in healthy individuals, the prevalence of positive antibodies to infliximab and adalimumab was 1% (5/498) and 0.2% (1/498), respectively. Using the manufacturer’s threshold, at the time of last testing, of 7447 and 4054 patients treated with infliximab and adalimumab; 20.9% (n = 1,554) and 8.0% (n = 326) had clearing antibodies and 26.5% (n = 1973) and 12.1% (n = 490) had non-clearing antibodies, respectively (Figure 1). Using our newly defined threshold in the same cohorts; 21.1% (n = 1573) and 8.4% (n = 339) had clearing antibodies and 28.0% (n = 2083) and 20.0% (n = 812) had non-clearing antibodies, to infliximab and adalimumab, respectively. Amongst patients with at least two tests, most developed persistent antibodies (Figure 2). Irrespective of anti-TNF drug, or threshold used, less than 10% patients developed transient antibodies. Conclusion We report lower positivity thresholds for the IDKmonitor® total anti-TNF antibody ELISA assays than the manufacturer, in particular, for adalimumab. Transient antibody formation is uncommon: most patients develop persistent anti-drug antibodies that lead to drug clearance.

Background and aimsWe sought to define temporal changes in prevalence of inflammatory bowel disease (IBD) in East Devon, UK, in order to facilitate service planning over the next 5 years.MethodsMultiple primary and secondary care databases were used to identify and verify cases. Point prevalence and incidence of IBD were reported in April 2017 and from 2008 to 2016, respectively. Future prevalence and healthcare activity requirements were estimated by linear regression.ResultsPrevalence of ulcerative colitis (UC), Crohn’s disease (CD) and inflammatory bowel disease unclassified (IBDU) were 479.72, 265.94 and 35.34 per 100 000 persons, respectively. In 2016, the incidence rates of UC, CD and IBDU were 15.4, 10.7 and 1.4 per 100 000 persons per year, respectively. There were no significant changes in the incidence of CD (p=0.49, R=0.26) or UC (p=0.80, R=0.10). IBD prevalence has increased by 39.9% (95% CI 28.2 to 53.7) in the last 10 years without differences in the rate of change between UC and CD. Overall, 27% of patients were managed in primary care, a quarter of whom were eligible but not receiving endoscopic surveillance. Outpatient clinics, MRI and biologic use, but not helpline calls, admissions, or surgeries increased over and above the change in IBD prevalence.ConclusionsWe report one of the highest prevalence and incidence rates of IBD from Northern Europe. Overall, IBD incidence is static, but prevalence is increasing. We estimate that 1% of our population will live with IBD between 2025 and 2030.

ObjectiveTo determine the diagnostic accuracy of calprotectin to diagnose inflammatory bowel disease (IBD) in children in whom general practitioners (GPs) suspected IBD.DesignProspective observational cohort study of a new calprotectin-based primary care referral pathway.Setting48 GP practices and gastroenterology secondary care services at the Royal Devon and Exeter NHS Foundation Trust in the South-West of England, UK.Patients195 children aged between 4 and 18 years referred on the pathway between January 2014 and August 2017 for investigation of gastrointestinal symptoms were included.InterventionsPrimary-care-driven faecal calprotectin testing. Primary and secondary care records over 12 months from the point of calprotectin testing were used as the reference standard.Main outcome measuresDiagnostic accuracy of calprotectin testing to detect IBD.Results7% (13/195) tested patients were diagnosed with IBD. Using our prespecified cut-off of 100 µg/g, calprotectin had a diagnostic accuracy of 91% (95% CI 86% to 95%) with a sensitivity for distinguishing IBD from non-IBD of 100% (95% CI 75% to 100%), a specificity of 91% (95% CI 85% to 94%), a positive predictive value of 43% (95% CI 25% to 63%) and a negative predictive value of 100% (95% CI 98% to 100%). Calprotectin testing had no effect on the time to diagnosis, but a negative test contributed to saved referrals and was associated with fewer diagnostic tests in secondary care.ConclusionsCalprotectin testing of children with suspected IBD in primary care accurately distinguishes IBD from a functional gut disorder, reduces secondary care referrals and associated diagnostic healthcare utilisation.

Background International cohort studies have previously identified Crohn’s disease (CD), ileal disease, smoking, and age ( Methods In total, 163 patients between the age of 18 and 46 years who first presented to their general practitioner (GP) with gastrointestinal symptoms from January 2014 were included in this study. Patients above the age of 46 were excluded due to the increased risk of colorectal cancer with increasing age. This was also the upper age limit recommended for faecal calprotectin use in the investigation of suspected IBD. In addition to baseline demographic data, our main outcome measure was time to overall diagnosis including time from onset of symptoms to GP presentation (patient delay), time of GP presentation to referral (primary care delay), and time of referral to diagnosis (secondary care delay). Results The median time to diagnosis was 6.7 months [IQR 3.3–14.1], with no significant difference in time to diagnosis for IBD sub-types [CD, 9.8 months [IQR 5.5–18.5]; IBD-Unclassified, 7.0 months [IQR 4.5–8.5] and ulcerative colitis (UC), 5.2 months [IQR 2.9 −12.3] (p = 0.56 )]. The median time it took patients to present to their GP was 3.0 months [IQR 1.4–6.0]; median time for GP to refer to a gastroenterologist was 0.6 months [IQR 0.2–1.7]; and the median time from GP referral to diagnosis was 1.5 months [IQR 0.8–2.5]. On multivariable analysis, rectal bleeding (OR 0.33, 95% CI 0.15–0.71, p = 0.005) and abdominal pain (OR 2.49; 95% CI 1.13–5.89, p = 0.029) was negatively and positively associated with being in the upper quartile of patient delay. Urgent GP referrals (OR 0.14; 95% CI 0.05–0.36, p Conclusion Referrals triaged urgently and by a gastroenterologist were associated with a reduction in secondary care diagnostic delay. Adopting a combination of primary care faecal calprotectin testing and secondary care straight-to-test may impact diagnostic delays.

SummaryBackgroundAnti-tumour necrosis factor (anti-TNF) therapies are the most widely used biologic therapies for treating immune-mediated diseases. Their efficacy is significantly reduced by the development of anti-drug antibodies which can lead to treatment failure and adverse reactions. The biological mechanisms underlying antibody development are unknown but the ability to identify subjects at higher risk would have significant clinical benefits.MethodsThe PANTS cohort consists of Crohn’s disease patients recruited prior to first administration of anti-TNF, with serial measurements of anti-drug antibody titres. We performed a genome-wide association study across 1240 individuals from this cohort to identify genetic variants associated with anti-drug antibody development.FindingsThe Human Leukocyte Antigen allele, HLA-DQA1*05, carried by approximately 40% of Europeans, significantly increased the rate of anti-drug antibody development (hazard ratio [HR], 1.90; 95% confidence interval [CI], 1.60 to 2.25; P=5.88×10-13). This association was consistent for patients treated with adalimumab (HR, 1.89; 95% CI, 1.32 to 2.70) and infliximab (HR, 1.92; 95% CI, 1.57 to 2.33), and for patients treated with mono-(HR, 1.75; 95% CI, 1.37 to 2.22) or combination therapy with immunomodulators (HR, 2.0; 95% CI, 1.57 to 2.58).InterpretationHLA-DQA1*05 is significantly associated with an increased rate of anti-drug antibody formation in patients with Crohn’s disease treated with infliximab and adalimumab. Pre-treatment HLA-DQA1*05 genetic testing may help personalise the choice of anti-TNF therapy and allow the targeted use of immunomodulator therapy to minimise risk and maximise response.

Introduction Patients diagnosed with colonic IBD have increased risk of colorectal cancer (CRC). Colonoscopic surveillance reduces the risk of CRC-associated death through early detection; national/international guidelines recommend chromoendoscopy. We aimed to assess the burden of IBD in primary care unknown to our service and to identify patients eligible for surveillance. Methods We conducted a population-based observational study across primary and secondary care to evaluate the incidence/prevalence of IBD in our catchment. We identified cases from primary care using searches of practice databases and in secondary care using searches of hospital records. Case inclusion required a specialist diagnosis of ulcerative colitis (UC), Crohn’s disease (CD) or IBD unclassified. IBD was phenotyped according to the Montreal Classification and patients under the age of 75 years, who had been diagnosed with IBD with colonic disease involvement for more than 10 years, were deemed eligible for colonoscopic surveillance. Results Patients from 48/49 GP practices within our catchment were included. We identified 3690 patients with IBD living within our catchment of which 12% (875/3,690) were unknown to any local secondary care service. Overall, UC prevalence was 453/100 000 people (95% confidence interval 433–474), Crohn’s disease prevalence was 311/100 000 (95% CI 293–327), and IBD unclassified prevalence was 44/100 000 (95% CI 38–51). Patients managed solely in primary care, compared with those in secondary care, were older (mean age 60.9 vs 56.2 years, p Conclusions We report one of the highest prevalence rates of IBD in Western Europe (1 in 124 patients). 12% of patients living in our immediate catchment area were unknown to our service; a third of these were eligible for colonoscopic colorectal cancer surveillance. Effective colorectal cancer surveillance programmes in IBD must target primary-care populations and not just known secondary care populations.

Background Immunogenicity to anti-TNF therapy is a major cause of loss of response, treatment discontinuation and hypersensitivity reactions and currently cannot be predicted prior to treatment. A number of factors have been associated with the risk of immunogenicity, but knowledge of the cellular and molecular mechanisms remain limited. Our aim was to investigate genetic susceptibility to immunogenicity. Methods The PANTS (Personalised Anti-TNF Therapy in Crohn’s disease) study is a 3 year prospective observational UK-wide study investigating primary non-response, loss of response and adverse drug reactions to the anti-TNF drugs infliximab and adalimumab. Anti-drug antibodies (ADAs) were measured serially at trough using the IDKmonitor total ADAb ELISA assay. Immunogenicity was defined as (a) ADA titre ≥10 AU/ml and (b) ADA titre ≥10 AU/ml with no detectable drug. A genome-wide association study (GWAS) was carried out on imputed genotype data using a Cox proportional hazards model incorporating the anti-TNF used and presence of concomitant immunomodulator as covariates (SurvivalGWAS_SV v1.3.1). Results After quality control, we had genotype data for 1284 patients followed prospectively for a minimum of 12 months since starting anti-TNF therapy. Using a Cox proportional hazards model and an immunogenicity definition of ADAs titre ≥10 AU/ml we identified a genome-wide association on chromosome 6 (top SNP rs74291249 with p=5.6 × 10−13). We imputed the HLA alleles at 2- and 4-digit resolution using the HIBAG package and demonstrated that this signal was driven by HLA-DQA1*05 for both infliximab and adalimumab. No additive effect of having two DQA1*05 was seen. Figures 1 and 2 show immunogenicity-free survival stratified by HLA-DQA1*05 genotype and concomitant immunomodulators at baseline. Conclusion We have demonstrated that immunogenicity to anti-TNF is determined by HLA variants. Pre-treatment genetic testing might allow the use of individual risk profiles and targeted use of immunomodulatory therapies to deliver more durable, safe and cost-effective anti-TNF therapy.

Introduction PANTS (Personalised Anti-TNF Therapy in Crohn’s disease [CD]) is a 3 year prospective observational UK-wide study investigating primary non-response (PNR), loss of response and adverse drug reactions to infliximab (IFX: Remicade [REM], CT-P13) and adalimumab (ADL: Humira). We now report the wk 54 clinical effectiveness and safety outcomes, and immunogenicity data to date. Methods Inclusion criteria included: CD patients aged ≥6 years, active inflammatory disease (raised CRP [>3 mg/L] or calprotectin [≥50 µg/g]) and no prior anti-TNF therapy. PNR was defined at wk 12–14 as a requirement for ongoing steroids, or both HBI failed to fall by ≥3 points or to ≤4 and CRP failed to fall by ≥50% or to ≤3 mg/L. Remission was defined at wks 14 and 54 as HBI ≤3 points and CRP ≤3 mg/L and no concomitant steroids. Patients who stopped drug other than for elective withdrawal, pregnancy or loss to follow-up were regarded as treatment failures for subsequent endpoints. Drug (DL) and anti-drug antibody (ADA) levels were measured using the IDKmonitor drug tolerant assays. Immunogenicity was defined as ADA titre ≥10 AU/ml+undetectable DL. Results 1601 (49% male, median age 33 years [IQR 23–47]) eligible patients were recruited from 118 sites. Patients were treated with IFX (751 [47%]: REM, 200 [12%] CT-P13) or ADL (650 [41%]). Baseline characteristics included: median disease duration 3 years (IQR 1–10); steroids 27%, azathioprine 44%, mercaptopurine 8%, methotrexate 5%; median CRP in IFX 9 mg/L (IQR CI 3–24) and 6 mg/L (IQR 2–14) in ADL. PNR at week 12–14 was 21%, 21% and 26% in the REM, CT-P13 and ADL treated patients respectively. PNR was associated with older age (p=0.0004), higher BMI (p=0.03) and low DL (p Conclusions This is the largest prospective real-life study of anti-TNF therapy in IBD. We report the clinical effectiveness, safety and immunogenicity of REM, CT-P13, and ADL. This cohort provides a unique bioresource for multi-omic studies investigating personalised approaches to anti-TNF therapy.

Background: Anti-tumour necrosis factor (TNF) drugs have revolutionised Crohn's disease management but treatment failure is common. We sought clinical and pharmacokinetic factors that predict and mitigate primary non-response at week 14, non-remission at week 54, and adverse events leading to drug withdrawal. Methods: We conducted a prospective observational UK-wide study in 1610 biologic naive patients with active luminal Crohn's disease (955 infliximab [753 Remicade; 202 biosimilar CT-P13] and 655 adalimumab). Findings: Primary non-response (PNR) occurred in 23·8% (95% CI 21·4%-26·2%), non-remission in 63·1% (95% CI 60·3%-65·8%), and adverse events curtailed treatment in 7·8% (95% CI 6·6%-9·2%) patients. The only independent risk factor for PNR was low drug level. The optimal week 14 drug levels associated with remission at weeks 14 and 54 were 7 mg/L and 12 mg/L for infliximab and adalimumab, respectively. Continuing standard dosing regimens after PNR was rarely helpful: only 12·4% (14/113; 95% CI 6·9%-19·9%) entered remission by week 54. Obesity, smoking, low albumin levels, higher baseline markers of disease activity, and development of anti-drug antibodies were associated with low drug levels, which mediated week 54 non-remission. Immunogenicity rates at week 54 were 62·8% (95% CI 59·0-66·3%) for infliximab and 28·5% (95% CI 24·0-32·7%) for adalimumab. For both drugs, sub-optimal week 14 drug levels were the main determinant of immunogenicity; whilst subsequent anti-drug antibody formation was the principle factor accounting for low drug levels. Combination thiopurine or methotrexate therapy mitigated this risk with similar effect sizes for both anti-TNF drugs and for infliximab led to lower week 54 non-remission rates. Interpretation: Anti-TNF treatment failure is common and associated with low drug levels, partly mediated by immunogenicity Clinical trials are required to investigate whether personalised induction regimens and treatment-to-target dose intensification improve outcomes. Funding: Charities: CORE, CCUK, C3. Unrestricted grants: Abbvie, Merck Sharp & Dohme, NAPP, Pfizer and Celltrion. Declaration of Interest: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and declare: N.A.K has consulted for Falk and received honoraria from Falk, Allergan, Pharmacosmos and Takeda for unrelated topics and is a deputy editor of Alimentary Pharmacology & Therapeutics Journal; G.A.H reports non-financial support from AbbVie, outside the submitted work; and that he is now an employee of AbbVie and owns stock in the company; M.R. is an employee of AbbVie and owns stock in the company; D.G. reports honoraria from AbbVie; G.J.W has consulted for AbbVie and received honoraria from Falk and AbbVie for unrelated topics and a fellowship from NIHR; A.H has served as consultant, advisory board member or speaker for AbbVie, Atlantic, Bristol-Myers Squibb, Celltrion, Falk, Ferring, Janssen, MSD, Napp Pharmaceuticals, Pfizer, Pharmacosmos, Shire and Takeda and also serves on the Global Steering Committee for Genentech outside the submitted work;. S.S reports personal fees from AbbVie, Merck, Takeda, grants from Takeda, Tillotts, AbbVie, Merck, outside the submitted work; P.M.I reports personal fees from Abbvie, Janssen, Pfizer, Sandoz, VH squared, Samsung Bioepis, and Ferring , grants from MSD, grants and personal fees from Takeda, non-financial support from Falk, outside the submitted work; D.McG reports grants from NIH and Helmsley Charitable Trust, during the conduct of the study; grants and personal fees from Janssen, Precision IBD Inc, Second Genome, Qu Biologics, Pfizer, Gilead and Takeda, outside the submitted work; C.W.L reports grants and personal fees from Abbvie and Gilead personal fees from GSK, Janssen, Takeda, Amgen, Pfizer, Samsung Bioepis, Celgene, grants outside the submitted work; J.R.F.C reports personal fees from Abbvie, grants and personal fees from Takeda, Hospira and Biogen, personal fees from Janssen, MSD, Celltrion, NAPP, and Sandoz, outside the submitted work; J.L has served as consultant, advisory board member or speaker for Shire (International/UK) AbbVie, Atlantic, BMS, Celltrion, Falk, Ferring (International/UK), Janssen, MSD, Napp Pharmaceuticals, Pfizer, GSK, Allergan, Cornerstone US, and Takeda and has received travel support from AbbVie, Warner Chilcot, Takeda and Pfizer outside the submitted work; R.K.R reports honoraria from Abbvie, Ferring , Therakos and Celltrion, grants from Nestec, outside the submitted work; J.R.G received honoraria from Falk, Abbvie and Shield therapeutics for unrelated topics. T.A has received unrestricted research grants, advisory board fees, speaker honorariums and support to attend international meetings from AbbVie, Merck, Janssen, Takeda, Ferring, Tillotts, Ferring, Pfizer, NAPP, Celltrion, Hospira for unrelated topics, no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work. H.G, B.H, C.B, M.H.P, T.M, A.T, R.N, 473 S.B, N.C, N.M.H, P.H, S.L, M.P, J.C.M have no conflicts of interest to declare. Ethical Approval: The South West Research Ethics committee approved the study (REC Reference: 12/SW/0323) in January 2013.

Background Primary care faecal calprotectin testing distinguishes inflammatory bowel disease (IBD) from functional gut disorder in young patients presenting with abdominal symptoms; however, previous evaluations have excluded patients with alarm symptoms. Aims We sought to evaluate the diagnostic accuracy of calprotectin to distinguish IBD from functional gut disorder in young adults in whom general practitioners (GPs) suspected IBD; including patients reporting gastrointestinal alarm symptoms. We hypothesised that calprotectin would reduce secondary care referrals and healthcare costs. Methods We undertook a prospective cohort study of 789 young adults (18-46 years old) presenting with gastrointestinal symptoms to 49 local general practices that had undergone calprotectin testing (1053 tests: between Jan 2014 and May 2016) because of suspected IBD. We considered calprotectin levels of ≥100 μg/g positive. Primary and secondary care records over 12 months from the point of calprotectin testing were used as the reference standard. Results Overall, 39% (308/789) patients reported gastrointestinal alarm symptoms and 6% (50/789) tested patients were diagnosed with IBD. The positive and negative predictive values of calprotectin testing for distinguishing IBD from functional gut disorder in patients with gastrointestinal alarm symptoms were 50% (95% CI 36%-64%) and 98% (96%-100%): and in patients without gastrointestinal alarm symptoms were 27% (16%-41%) and 99% (98%-100%), respectively. We estimate savings of 279 referrals and £160 per patient. Conclusions Calprotectin testing of young adults with suspected IBD in primary care accurately distinguishes IBD from functional gut disorder, even in patients with gastrointestinal alarm symptoms and reduces secondary care referrals and diagnostic healthcare costs.

Introduction Anti-TNFα therapy has been associated with demyelination since early trials in Multiple Sclerosis (MS) demonstrated disease worsening.Subsequent small case series have reported plausible clinical associations although epidemiological studies have produced conflicting data.The specific clinical features of demyelination following anti-TNF therapy have not been described.This study uses a systematic independent assessment of causality to describe the clinical characteristics and outcomes of anti-TNFα associated demyelination. Method Patients were recruited from 28 hospitals.Inclusion criteria included i)no history of neurological symptoms prior to anti-TNFα exposure,ii)MRI brain and/or spinal cord or electrophysiological tests consistent with PNS or CNS demyelination,iii)demyelination illness confirmed by neurologist and drug withdrawn.An adjudication panel comprising at least 3 neurologists and a neuro-radiologist identified definite and probable cases from case report forms.Probable cases required a consistent history and signs and objective radiological±electrophysiological evidence of demyelination.Definite cases had a recurrence of demyelination on drug rechallenge. Results 54 cases were recruited, of whom 35 (24 female) were adjudicated as definite or probable cases. Adalimumab,Infliximab,Etanercept and Certolizumab were implicated in 17/35 (49%), 15/35 (43%), 5/35 (14%), and 1/35 (3%) of cases respectively.Average age of symptom onset was 40 (95%CI 37–44) years. The mean duration of anti-TNFα exposure was 27 (95%CI 18–36) months prior to symptom onset onset of demyelination. 22 cases (63%) presented with brain ± spinal lesions, 8 (23%) spine only demyelination, and 5 (14%) peripheral demyelination.On drug withdrawal patients were followed for a mean of 42 (95%CI 32–52) months.Of those with CNS lesions, 11/30 (37%) developed a relapsing demyelinating syndrome or MS and only 5/30 (17%) had complete resolution of their symptoms with a mean time to resolution of 419 days (95% CI 36–802). Conclusion This large case series adds comprehensive clinical information to the existing reports of demyelinating events associated with anti-TNFα therapy for inflammatory disorders.Consistent with known risk factors for MS, young females appear to be over represented.Over one third of patients appear to develop a relapsing illness/MS and complete neurological recovery is uncommon.We aim to build this cohort further so that we might explore clinically useful genetic markers that identify at-risk patients. Disclosure of Interest None Declared

Current guidelines on consenting individuals to participate in genomic research are diverse. This creates problems for participants and also for researchers, particularly for clinicians who provide both clinical care and research to their patients. A group of 14 stakeholders met on 7 October 2015 in Exeter to discuss the ethical issues and the best practice arising in clinically based genomic research, with particular emphasis on the issue of returning results to study participants/patients in light of research findings affecting research and clinical practices. The group was deliberately multidisciplinary to ensure that a diversity of views was represented. This report outlines the main ethical issues, areas of best practice and principles underlying ethical clinically based genomic research discussed during the meeting. The main point emerging from the discussion is that ethical principles, rather than being formulaic, should guide researchers/clinicians to identify who the main stakeholders are to consult with for a specific project and to incorporate their voices/views strategically throughout the lifecycle of each project. We believe that the mix of principles and practical guidelines outlined in this report can contribute to current debates on how to conduct ethical clinically based genomic research.

Introduction Thiopurines are commonly used in the maintenance treatment of inflammatory bowel disease (IBD) but this is limited by myelosuppression in 7% of patients.1 Thiopurine S-methyltransferase (TPMT) variants only explain 20% of thiopurine-induced myelosuppression (TIM) in Europeans suggesting the presence of other genetic determinants.2 We aimed to identify the clinical features of TIM and to identify novel variants associated with TIM through a genome wide association study and whole exome sequencing. Method We recruited 491 IBD patients with TIM from 82 hospitals. Inclusion criteria included drug exposure in the 7 days prior to TIM, white blood cell count ≤2.5 ×109/L, or neutrophil count ≤1.0 ×109/L and that TIM necessitated dose reduction/drug withdrawal. After expert adjudication, 329 cases assigned a high likelihood of causality were genotyped and exome sequenced with 635 thiopurine-tolerant IBD controls for use in the final analyses. Results We first confirmed an association of TIM with TPMT in an initial GWAS. We then, using exome sequencing, discovered a novel 6 bp in-frame deletion (rs746071566; AGGAGTC/A,p.Gly17_Val18del) at position 48611918 of chromosome 13 in exon 1 of NUDT15 (5.8% cases, 0.2% controls, OR=38.2,p=1.33×10-8). This deletion was replicated in an independent cohort (3/75 [4%] cases vs. 2/785 [0.3%] thiopurine-tolerant IBD controls; OR=16.2, p=0.006). All NUDT15 coding variants were confirmed with complete concordance by Sanger sequencing. Multivariable logistic regression demonstrated that adjusted dose (OR 2.2,p=9.4×10-11), NUDT15 genotype (OR 21.7,p=2.0×10-8) and TPMT genotype (OR 2.2,p=2.6×10-4 for MUT/WT and OR 51.2,p=1.8×10-4 for MUT/MUT) were independently associated with TIM. Conclusion These are the largest ever clinical and genetic analyses of thiopurine-induced myelosuppression. We identified NUDT15 coding variants, including a novel 6 bp deletion; carriage of any coding variant confers a 22-fold increase in the odds of TIM, independent of TMPT genotype and thiopurine dose. Although NUDT15 variants are less common than TPMT variants, their effect size for heterozygotes is greater. The number of patients needed to genotype to prevent TIM due to NUDT15 coding variant heterozygosity is 100. The estimated absolute risk of TIM in NUDT15 heterozygotes is 59%. A future clinical decision tool incorporating NUDT15 and TPMT genotypes will offer personalised thiopurine therapy and prevent the considerable morbidity and costs associated with severe bone marrow toxicity. Reference . Gisbert JP & Gomollon F.doi10.1111/j.1572-0241.2008.01848.x (2008) . Yang SK et al. doi10.1038/ng.3060 (2014) Disclosure of Interest None Declared