I-CARE, a European Prospective Cohort Study Assessing Safety and Effectiveness of Biologics in Inflammatory Bowel Disease.

BACKGROUND AND AIMS: There is a need to evaluate the benefit-risk ratio of current therapies in inflammatory bowel disease (IBD) patients to provide the best quality of care. The primary objective of I-CARE (IBD Cancer and serious infections in Europe) was to assess prospectively safety concerns in IBD, with specific focus on the risk of cancer/lymphoma and serious infections in patients treated with anti-tumor necrosis factor and other biologic monotherapy as well as in combination with immunomodulators. METHODS: I-CARE was designed as a European prospective longitudinal observational multicenter cohort study to include patients with a diagnosis of Crohn's disease, ulcerative colitis, or IBD unclassified established at least 3 months prior to enrollment. RESULTS: A total of 10,206 patients were enrolled between March 2016 and April 2019, including 6169 (60.4%) patients with Crohn's disease, 3853 (37.8%) with ulcerative colitis, and 184 (1.8%) with a diagnosis of IBD unclassified. Thirty-two percent of patients were receiving azathioprine/thiopurines, 4.6% 6-mercaptopurine, and 3.2% methotrexate at study entry. At inclusion, 47.3% of patients were treated with an anti-tumor necrosis factor agent, 8.8% with vedolizumab, and 3.4% with ustekinumab. Roughly one-quarter of patients (26.8%) underwent prior IBD-related surgery. Sixty-six percent of patients had been previously treated with systemic steroids. Three percent of patients had a medical history of cancer prior to inclusion and 1.1% had a history of colonic, esophageal, or uterine cervix high-grade dysplasia. CONCLUSIONS: I-CARE is an ongoing investigator-initiated observational European prospective cohort study that will provide unique information on the long-term benefits and risks of biological therapies in IBD patients. (EudraCT, Number: 2014-004728-23; ClinicalTrials.gov, Number: NCT02377258).

Antibody decay, T cell immunity and breakthrough infections following two SARS-CoV-2 vaccine doses in infliximab- and vedolizumab-treated patients

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.

Infliximab is associated with attenuated immunogenicity to BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines

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 4{beta}7 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] 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-compared to vedolizumab-treated patients who received the BNT162b2 (fold change [FC] 0.29 [95% CI 0.21, 0.40], p<0.0001) and ChAdOx1 nCoV-19 (FC 0.39 [95% CI 0.30, 0.51], p<0.0001) vaccines. In both models, age [≥] 60 years, immunomodulator use, Crohns disease, and smoking were associated with lower, whilst 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. InterpretationInfliximab 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 contextO_ST_ABSEvidence before this studyC_ST_ABSFaced 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 4{beta}7 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, Crohns 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.