Kennedy NA, Goodhand JR, Bewshea C, et al., Contributors to the CLARITY IBD study
© Jennifer Murray
Infection with the novel coronavirus SARS-CoV-2 leading to coronavirus disease-2019 (COVID-19) has a broad spectrum of clinical presentations and disease severity. A number of host and viral factors contribute to this heterogeneity in presentation and severity, including the host immune response . Given that immune-mediated inflammatory diseases (IMIDs) including Inflammatory Bowel Disease (IBD), are characterised by immune dysregulation and use of biologic or immunosuppressive therapies, COVID-19 presents a particular challenge.
It is recognised that anti-tumour necrosis factor (TNF) drugs, the most commonly prescribed biologic class, impair vaccine effectiveness in the case of other viral infections such as influenza  and viral hepatitis  and increase the risk of serious infections . As the COVID-19 pandemic evolves, understanding the host serological response to SARS-CoV-2, subsequent immunity and the impact that immune-related therapies have on this is essential. A critical research gap exists in the understanding of whether anti-TNF drugs diminish serological responses and resulting immunity to SARS-CoV-2 infection. The study by Kennedy et al. aimed to investigate this within the IBD population.
In this multicentre, prospective, observational cohort study, antibody responses in patients treated with infliximab, a commonly used and hospital-administered anti-TNF drug, were compared with those in a reference cohort of vedolizumab-treated patients. In contrast to infliximab, vedolizumab (a gut-selective anti-integrin α4β7 monoclonal antibody) is not associated with reduced serological response to vaccination or serious infection and is hospital administered on a similar dosing schedule to infliximab.
The study recruited 6935 consecutive IBD patients from 92 UK National Health Service infusion units over a 3-month period (4685 infliximab vs 2250 vedolizumab). Sera and data on variables including demographics, co-morbidities, IBD activity and history, COVID-19 history and shielding behaviour were collected. The infliximab-treated group had a higher proportion of Crohn’s Disease patients than the vedolizumab-treated group (66.6% vs 36.8%). There were no differences in the proportion of patients in each cohort who tested positive by PCR for SARS-CoV-2, reported symptoms of suspected or probable COVID-19 or were hospitalised with confirmed COVID-19.
The primary outcome demonstrated a statistically significant lower seroprevalence of anti-SARS-CoV-2 antibodies in the infliximab-treated group compared with vedolizumab-treated patients [3.4% (161/4685) vs 6.0% (134/2250), p<0.0001], confirmed on propensity matched analysis [3.9% (67/1704) vs 6.2% (105/1707), p<0.0037]. Interestingly, alongside infliximab [vs vedolizumab OR 0.66 (95% CI 0.51–0.87), p=0.002], immunomodulator use was identified as being independently associated with reduced seropositivity on multivariable regression analysis [OR 0.7 (95% CI 0.53–0.92), p=0.012].
Secondary outcomes were the proportion of participants with a positive anti-SARS-CoV-2 antibody following a positive PCR test to SARS-CoV-2 and the magnitude of the anti-SARS-CoV-2 antibody reactivity. A reduced number of infliximab-treated patients seroconverted compared with vedolizumab-treated patients [48% (39/81) vs 83% (30/37), p=0.00044] and the magnitude of anti-SARS-CoV-2 antibody reactivity was significantly lower in the infliximab PCR-positive group compared with the vedolizumab PCR-positive group.
This is the largest dataset published on serological response to SARS-CoV-2 in anti-TNF-treated patients. Data from other published European observational studies have pointed to a similar trend.
A German study  including 793 patients with IMIDs and 1256 healthy controls [controls cohorted into health care professional (HCP) and non-HCP cohorts] found a reduced seroprevalence in IMID patients treated with cytokine inhibitors [TNF/interleukin (IL)-6/IL-23/IL-17 and Janus kinase inhibitors] compared with those not on cytokine inhibitors [prevalence 0.75% (95%CI 0.20–1.92%) vs 3.09% (95%CI 1.33–6.09%)]. The IMID group not on cytokine inhibitors had similar seropositivity to the HCP control cohort. The study did not differentiate or compare biologic classes although many of those on cytokine inhibitor therapy were on anti-TNF drugs (42.5%). A cohort study of 354 IBD patients on biologic therapy recruited across Germany and Italy reported similar seropositivity to the general population in the areas in which the patients were enrolled . On univariate analysis, anti-TNF therapy was significantly associated with reduced seropositivity, but significance was not maintained on multivariate analysis. An early dataset published by McGregor et al.  comprising 640 UK patients recruited from London and Oxford during the first wave of the pandemic showed a trend towards lower seropositivity in infliximab-treated versus vedolizumab-treated patients in the Oxford cohort but numbers were small and not powered for this comparison.
Alongside the large multicentre dataset, this study has several strengths. Given the prospective recruitment of consecutive patients from infusion clinics, it avoids the reporting and confirmation bias seen in some of the disease-related COVID-19 registries. Patients were also recruited over a short 3-month time frame between September 2020 and December 2020; PCR testing was widely available at this point, minimising testing bias, and all PCR-positive cases were linked and confirmed with nationally held databases. With the rapidly evolving nature of the pandemic, the short recruitment window prevents time course within the pandemic becoming a significant co-variable.
The major finding of this study of reduced seropositivity in infliximab-treated patients is potentially impactful but it must be interpreted within the bigger picture. Importantly, it has not yet been shown that reduced seropositivity confers an increased risk of recurrent COVID-19 infection. The studies described are only measuring serological response and it is likely that protective immunity via T cell-mediated immunity also plays an important role.
Looking ahead, given that IMID patents were excluded from COVID-19 vaccine trials, the study results raise important questions. Data on vaccine efficacy, post-vaccination seroconversion rates and impact of immune-related therapies on vaccination are eagerly awaited. Initial serological studies following vaccination in a subset of this UK cohort  indicate significantly reduced antibody levels and seroconversion rates in infliximab-treated patients when compared with vedolizumab-treated patients following a single dose of COVID-19 vaccine. Higher seroconversion rates were seen in the subgroup of patients with two vaccine doses and we await the full results of this along with several other European and international prospective cohort studies.
Jennifer Murray - Short Biography
Jennifer Murray is a first-year gastroenterology registrar in London, UK. She has developed an interest in IBD, having worked as an IBD clinical research fellow at the Royal London Hospital prior to commencing registrar training.