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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) 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.ConclusionInfliximab 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.

IntroductionThe longest component of the time-to-diagnosis is the interval between symptom onset and an individual seeking help. Recent reports in patients with sexually transmitted infections, who also suffer delays in diagnosis, suggest that this barrier may be overcome by the anonymity of direct-to-public testing. We sought to characterise the availability of online direct-to-public calprotectin testing in 2023 in the UK.MethodsWe undertook an online search using the Google search engine on May 25th, 2023, with the terms ‘buy’ or ‘purchase’ AND ‘calprotectin’ AND ‘inflammatory bowel disease’. Collection kits were procured and stool samples tested to receive follow-up advice for known positive and negative stool samples. We recorded data regarding the assay, consumer information and the clinical advice offered on return of a positive and negative test.ResultsOverall, 54.5% (6/11) of available tests were home lateral flow tests, the remainder were home collection laboratory-based tests. Of the laboratory-based tests, three were conventional enzyme-linked immunosorbent assay (ELISA) assays and two were OC sensor tests. The lateral flow tests were considerably cheaper than the laboratory-based tests (median [range] cost £14.20 [£7.85–21.00] vs £75.85 [£59–151], p<0.0001). The median turnaround time for the laboratory tests was 14 (range 1–23) days. All but one provider used a positivity threshold of 50ug/g. Six of the eleven platforms explicitly stipulated testing in the setting of gastrointestinal symptoms or suggested exclusion criteria. The median (IQR) Flesch Kincaid readability score for the instructions and result reporting were 54.3 (46.2–63.1) and 62.9 (51.9–72): equivalent to a school reading grade of 9.2 (7.3–10.4) and 7.6 (6.7–11.1), respectively. Only two of the lateral flow tests provided written recommendations about follow up of positive results, whereas all but one laboratory-based providers recommended onward discussion with a medical practitioner. Two providers offered private referrals or consultations and six provided safety netting advice with regards to negative results.ConclusionsIn the UK online direct-to-public calprotectin testing is already readily available from multiple providers. Consumers can choose between home-based lateral flow tests or conventional laboratory testing. Further work is needed to redefine the diagnostic accuracy of calprotectin used in this way, however, the rapid turnaround times and anonymity suggest that direct-to-public calprotectin testing could be used to reduce the time to IBD diagnosis.

IntroductionPANTS (Personalised Anti-TNF Therapy in Crohn’s disease) is a prospective observational UK-wide study investigating the effectiveness of infliximab (IFX) and adalimumab (ADL) in active luminal Crohn’s disease. Here we report remission rates through three years of follow up; rates of and the factors that predicted loss of response (LOR); and the effect of dose intensification on drug persistence.MethodsRemission was defined as CRP of ≤3 mg/L and HBI of ≤4 points (sPCDAI ≤15 in children), without corticosteroid therapy or exit for treatment failure.LOR was defined in patients who initially responded to anti-TNF therapy at week 14 and continued in the PANTS extension, by symptomatic IBD activity that warranted an escalation of corticosteroids, immunomodulatory or anti-TNF therapy, resectional surgery, or exit due to adverse events.The effect of dose intensification at the time of LOR on drug persistence was stratified by optimal anti-TNF drug level (IFX 7, ADL 12) (mg/L) and presence of antibodies (anti-IFX 9, anti-ADL 6) (AU/mL), measured using IDKmonitor® ELISA assays.ResultsJuly 2016, 1610 patients were included in PANTS: 358/955 (37%) treated with IFX (221/358 [62%] originator and 137/358 [38%] with biosimilar) and 187/655 (29%) treated with ADL, who had not exited for treatment failure at the end of year 1, opted to enrol in the extension.Overall, 41.8%, 39.4%, and 41.3% of IFX- and 38.2%, 39.7%, and 39.2% of ADL-treated patients were in remission at year 1, 2 and 3, respectively. For both drugs, a dose- response association was seen for week 14 drug concentration and remission, up to 8 mg/L for infliximab and 14 mg/L for adalimumab.34.3%, 54.0%, and 60.3% of IFX-, and 31.9%, 47.3%, and 69.0% of ADL-treated patients lost response at year 1, 2 and 3, respectively. Multivariable regression analyses showed that low drug concentration was the major independent risk factor associated with LOR for both drugs (figure 1).In patients who developed immunogenicity, factors associated with subsequent drug clearance were lower week 14 drug level (p<0.01), non-immunomodulator use (p=0.04), and obesity (<0.01), but not carriage of HLA-DQA1*05 (p<0.34).In the setting of LOR (n = 686 episodes), 42% patients had their anti-TNF dose intensified and 29% exited the study without further action. Compared to patients who experienced LOR with optimal drug levels, dose intensification was associated with lower rates of drug persistence in patients with immunogenic-pharmacokinetic and non-immunogenic pharmacokinetic treatment failure in patients treated with IFX, but not ADL.ConclusionsLong term remission was observed in about 40% of patients treated with IFX and ADL. Loss of response and non-remission was predicted by low drug levels.Abstract O59 Figure 1Cox-proportional hazards model across the three years, demonstrating the factors associated with loss of response to infliximab and adalimumab

IntroductionVitamin D has a regulatory role in innate and adaptive immune processes. Previous small studies have reported that low pre-treatment vitamin D concentrations are associated with primary non-response (PNR) to anti-TNF therapy. We investigated whether pre-treatment vitamin D predicted PNR and non-remission to infliximab and adalimumab in patients with Crohn’s disease in the PANTS (Personalised Anti-TNF Therapy in Crohn’s disease) study.MethodsPNR was defined using composite endpoints using the Harvey Bradshaw Index (HBI) in adults and the short paediatric Crohn’s disease activity index (sPCDAI) in children, corticosteroid use, and C-reactive protein (CRP). Remission was defined as CRP of ≤3 mg/L and HBI of ≤4 points (sPCDAI index ≤15 in children), without corticosteroid therapy or exit for treatment failure. 25-hydroxyvitamin D concentrations were measured in stored baseline serum samples and cut-offs for vitamin D status were: deficiency<25nmol/L, insufficiency 25–50nmol/L and adequacy>50nmol/L.ResultsSamples from 659/898 infliximab and 448/605 adalimumab treated patients included in the PANTS study were included.17.1% (189/1107; 95% confidence interval [CI] 15.0 - 19.4%) and 47.7% (528/1107; 95% CI 44.8 - 50.6%) patients had vitamin D deficiency and insufficiency respectively. 22.2% (246/1107) patients were receiving vitamin D supplementation at baseline.Multivariable analysis confirmed that baseline sampling during non-summer months, South Asian ethnicity, lower serum albumin concentrations, higher HBI and nontreatment with vitamin D supplements were independently associated with lower vitamin D concentrations (figure 1).PNR at week 14 and non-remission at week 54 occurred in 19.3% (116/600; 95%CI 16.4 - 22.7%) and 58.8% (351/597; 95%CI 54.8- 62.7%) patients treated with infliximab and 25.3% (100/396; 95%CI 21.2- 29.8%) and 65.3% (246/377; 95%CI 60.3- 69.9%) of patients treated with adalimumab respectively.Pre-treatment vitamin D status did not predict response or remission status to anti-TNF therapy at week 14 (infliximab Ppnr =0.87, adalimumab Ppnr =0.18) or non-remission at week 54 (infliximab P =0.13, adalimumab P =0.59).ConclusionsVitamin D deficiency is common in patients with active Crohn’s disease. Unlike previous studies, pre-treatment vitamin D concentration did not predict PNR to anti-TNF treatment at week 14 or non-remission at week 54.Abstract P82 Figure 1

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), p<0.0001) or BNT162b2 vaccines (2164 U/mL (4.1) vs 15 116 U/mL (3.4), p<0.0001). However, no differences in anti-S RBD antibody concentrations were seen following third and fourth doses of an mRNA-based vaccine, irrespective of the combination of primary vaccinations received. Post-third dose, anti-S RBD antibody half-life estimates were shorter in infliximab-treated than vedolizumab-treated patients (37.0 days (95% CI 35.6 to 38.6) vs 52.0 days (95% CI 49.0 to 55.4), p<0.0001).Compared 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 number ISRCTN45176516.

IntroductionAnti-TNF treatment failure in patients with IBD is common. International guidelines recommend switching out of class when anti-TNF drug levels are therapeutic and within class with an immunomodulator when anti-TNF drug levels are suboptimal and associated with antibody development.We sought to define the: 1) risk of immunogenicity to a second anti-TNF stratified by immunogenicity to first anti-TNF, 2) rates of drug persistence following failure to first anti-TNF drug and 3) strategies to mitigate development of immunogenicity.MethodsWe performed a retrospective cohort study across 38 UK hospitals. 1058 patients [532 (51%) male, 755 (71%) Crohn’s disease] had both infliximab and adalimumab therapeutic drug monitoring performed by our service from May 2013 to October 2020 were identified. Drug and antibody levels were measured using the IDKmonitor® drug-tolerant ELISA assays. Treatment failure included primary nonresponse, secondary loss of response, adverse drug reactions and IBD-related surgery, and patients were identified by case note review. Immunogenic failure was defined as treatment failure with suboptimal drug levels (infliximab level <2 mg/L, adalimumab level <6 mg/L) with an antibody concentration ≥10 AU/ml. Pharmacodynamic (PD) failure was defined as treatment failure despite adequate drug levels.ResultsPatients who developed immunogenicity to adalimumab (first) were more likely to develop immunogenicity to infliximab (second) (64% vs 40%, p < 0.001), and patients who developed immunogenicity to infliximab (first) were more likely to develop immunogenicity to adalimumab (second) (34% vs 20%, p = 0.002). Patients who developed: antibodies and undetectable drug, low drug levels, or low drug levels with immunogenicity to infliximab (first), were more likely to develop these outcomes to adalimumab (second) (all p<0.001).There was no difference in drug persistence to second anti-TNF in patients with pharmacodynamic and immunogenic treatment failure to first anti-TNF (p = 0.86). In patients with immunogenic (but not pharmacodynamic) failure, commencing an immunomodulator at the time of switching to second anti-TNF drug was associated with longer drug persistence than in patients treated with an immunomodulator throughout or not all (Figure 1).Abastract HMO-4 Figure 1Drug persistence to second anti-TNF in patients stratified by immunomodulator useConclusionsImmunogenicity to the first anti-TNF was associated with immunogenicity to the second anti-TNF, irrespective of drug sequence. Commencing an immunomodulator at the time of switching to second anti-TNF was associated with improved drug persistence in immunogenic, but not pharmacodynamic, failure. However, 50% of patients remained on second anti-TNF at 5 years in both groups, suggesting switching in-class may be appropriate, irrespective of the cause of treatment failure to first anti-TNF.

IntroductionAnti-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 drug.We aimed to confirm the positivity threshold of our total anti-tumour necrosis factor (TNF) antibody ELISA assays in healthy volunteers and to use this threshold to report the prevalence of clearing and transient antibodies in patients treated with infliximab and adalimumab.MethodsSerum was obtained from 498 anti-TNF-naïve healthy adults recruited to the Exeter 10,000 study and tested for total anti-drug antibodies to infliximab and adalimumab. We used bootstrapping to calculate the 80% one-sided lower confidence interval [CI] of the 99th centile recommended by the FDA 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).ResultsThe 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 these thresholds, at the time of last testing, of 7,428 and 4,043 patients treated with infliximab and adalimumab; 21.1% and 8.3% had clearing antibodies and 27.9% and 20.0% had non-clearing antibodies, to infliximab and adalimumab, respectively.Amongst patients with at least two tests, most developed persistent antibodies. Irrespective of anti-TNF drug, or threshold used, less than 10% patients developed transient antibodies.Across both our national TDM cohort and the PANTS study, there were significant associations between anti-drug antibody and drug levels (figure 1). In PANTS, higher anti-drug antibody levels were associated with poorer outcomes at weeks 14 and 54.Abstract P118 Figure 1Relationship between adalimumab drug and anti-drug antibody levels in national TDM cohortConclusionsWe 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.

the utility of glycated haemoglobin (HbA1c) for the diagnosis and monitoring of diabetes in sub-Saharan Africa is uncertain due to limited data on the performance of the available HbA1c assay methods in this population, which has a high prevalence of haemoglobin variants. We aimed to compare the diagnostic accuracy of the major HbA1c methodologies (Boronate Affinity, Capillary Electrophoresis, High Performance Liquid Chromatography, Immunoassay) in an African population, and assess the impact of the common haemoglobin variant HbAS (sickle cell trait). whole blood samples were obtained from 182 individuals living with type 2 diabetes in Uganda. HbA1c values for each method were compared to average glucose measured over 14 days by continuous glucose monitoring (CGM). To determine concordance, the three HbA1c assay methods were compared to the capillary electrophoresis method. there was a strong correlation between CGM average glucose levels and all four HbA1c methodologies (r=0.81-0.89) which did not differ in those with and without HbAS (present in 37/182 participants). The presence of HbAS did not alter the relationship between HbA1c and CGM glucose for any assay (p for interaction >0.2 for all methods). Diagnostic accuracy for CGM average glucose thresholds of 7 and 10mmol/L was similar across methods (area under the receiver operating characteristic curve 0.80-0.84 and 0.76-0.84 respectively). The maximum bias between the HbA1c assay methodologies was 2 mmol/mol (2.07%). all major HbA1c technologies offer accurate and comparable HbA1c measurement even in this population with high prevalence of haemoglobin variants.

Objective  Why about a quarter of patients with inflammatory bowel disease (IBD) suffer symptoms for more than a year before their diagnosis made is unclear. Low public awareness, embarrassment and the apprehension of invasive tests are cited. The anonymity of direct-to-public calprotectin testing may overcome these barriers. We sought to characterise what calprotectin testing is available directly to the public in the UK.Design/method We conducted a cross-sectional evaluation of the calprotectin assays available online in the UK. Collection kits were procured from eligible providers, and surplus stool tested to receive follow-up advice for known positive (>50–100 μg/g) and negative (<50 μg/g) stool samples. Results Half (54.5% (6/11)) of the available tests were home lateral flow tests and the remainder were laboratory-based ELISAs. The lateral flow tests were considerably cheaper than the laboratory-based tests (median (range) cost £14.20 (£7.85–21.00) vs £75.85 (£59–151), p<0.0001). The median turnaround time for the laboratory tests was 14 (range: 1–23) days. All but one provider used a positivity threshold of 50 μg/g. All tests included written and pictorial instructions with the testing kit. Contact with a physician was recommended for similar proportions of positive and negative calprotectin results (54.5% (6/11) vs 54.5% (6/11), p=1).Conclusion In the UK, the public can choose between inexpensive home-based lateral flow tests or send stool samples for gold-standard laboratory testing of calprotectin. The low cost and rapid turnaround times suggest that direct-to-public calprotectin testing could be promoted to try to reduce the time to IBD diagnosis. 

Abstract Background We sought to determine the prevalence, clinical impact, neutralizing capacity, and cross-reactivity of pre-existing antibodies to infliximab and adalimumab in antitumor necrosis factor (TNF) treatment-naïve patients with active luminal crohn disease. Methods The prevalence of antibodies to infliximab and adalimumab at entry to the “Personalised Anti-TNF Therapy in Crohn's Disease Study” (PANTS) were measured using the drug-tolerant IDKmonitor Total antidrug antibody ELISAs. Neutralizing capacity in positive cases was determined using iLite™ cell-based assays. Results Pre-existing antibodies to infliximab were more common (6.3%, 96/1525 vs 2.4%, 36/1525, P < 0.01) and detectable at higher concentrations [median (IQR) 23.9 (14.2–55.2) AU/mL vs 7.2 (6.3–10.4) AU/mL, P < 0.0001] to infliximab than adalimumab. A few patients [1.3% (95% CI 0.6–1.8) 20/1525] had antidrug antibody reactivity to both drugs. None of the detected antidrug antibodies had demonstrable anti-TNF neutralizing capacity. No associations were seen between pre-existing antibody positivity, adverse drug reactions, drug levels, or response status at weeks 14 or 54 or subsequent immunogenicity. Cross-reactivity with rheumatoid factor and antimouse antibodies was detected (>10 IU/mL) in 6.6% (95% CI 3.2–13.0) (7/106) and 17.0% (95% CI 10.5–25.2) (19/112) of patients with pre-existing antibodies. Conclusions Pre-existing antidrug antibodies are common but do not neutralize anti-TNF drug activity in vitro, promote drug clearance, or influence clinical response to anti-TNF drugs. Further work is required to understand this cross-reactivity and to determine the exact nature of the antibodies detected in drug-naïve individuals.