Infliximab, a powerful biologic that is used to treat inflammatory bowel disease (IBD), blunts the body's immune response to COVID-19 infection, indicates research. This impaired response may boost susceptibility to recurrent COVID-19 and help drive the evolution of new variants of SARS-CoV-2, the virus responsible for the infection, warn the researchers led by Dr Tariq Ahmad at the Royal Devon and Exeter NHS Foundation Trust.
Careful monitoring of IBD patients treated with infliximab will be needed after vaccination against COVD-19 to ensure they mount a strong enough antibody response to ward off the infection, they advise.
Infliximab belongs to a class of medicines called anti-tumour necrosis factor (anti-TNF) drugs. These drugs suppress the production of an inflammatory protein involved in the development of several conditions, including ulcerative colitis and Crohn's disease which are types of inflammatory bowel disease.
Around 2m people worldwide are treated with anti-TNF drugs, which are known to impair protective immunity following vaccination against pneumonia, flu, and viral hepatitis, as well as increasing the risk of serious infection, particularly respiratory infections.
Because of these risks, patients taking these drugs have been advised to shield during the coronavirus pandemic and/or take extra precautions to minimise their risk of catching COVID-19.
With these issues in mind, the researchers wanted to find out if anti-TNF drugs might blunt the body's immune response to SARS-CoV-2 as well. They therefore compared the antibody responses to SARS-CoV-2 in IBD patients treated with infliximab or another biologic called vedolizumab.
Vedolizumab is a gut monoclonal antibody that has a dosing schedule similar to that of infliximab. But it isn't associated with increased susceptibility to systemic infection or blunted immune responses to vaccination.
In all, 6935 IBD patients (average age 39) were recruited from 92 UK hospitals between September and December 2020 for the CLARITY IBD study: around two thirds (4685) of them were being treated with infliximab and around a third (2250) with vedolizumab. Nearly 40% (2589 out of 6935) had been swab (PRC) tested for SARS-CoV-2. And rates of symptomatic and confirmed SARS CoV-2 infection were similar in both treatment groups.
Some 389 (8%) of the infliximab group and 201(9%) of the vedolizumab group had symptoms indicative of COVID-19 infection; 89 out of 1712 of those taking infliximab tested positive for the virus (just over 5%) as did 38 out of 877 (just over 4%) of those taking vedolizumab.
But fewer patients treated with infliximab had detectable antibodies to the virus in their blood than those treated with vedolizumab: 3.4% (161/4685) vs 6% (134/2250).
And only around half (48%; 39/81) of the patients treated with infliximab whose COVID-19 infection was confirmed by a swab test subsequently developed antibodies compared to 83% (30/36) of those treated with vedolizumab.
And the addition of other commonly used drugs to dampen down the inflammatory response, such as thiopurine or methotrexate, further blunted the antibody response to SARS-CoV-2 in patients treated with infliximab, only a third of whom had detectable antibodies to SARS-CoV-2.
An increase in antibodies to SARS-CoV-2 was observed 4 weeks after a positive swab test in patients taking vedolizumab, but not in those treated with infliximab.
"Similar rates of symptomatic and proven SARS-CoV-2 infection and hospitalisations between infliximab-treated and vedolizumab-treated patients suggest that our findings cannot be explained by differences in acquisition or severity of infection alone. Rather, infliximab seems to be directly influencing the serological response to infection," explain the researchers.
"Infliximab may directly impede the immune mechanisms responsible for generating antibody responses," they suggest.
This is an observational study, and so can't establish cause. And the researchers acknowledge certain limitations to their study, including that weakened immune responses in patients treated with infliximab don't automatically translate into a heightened risk of infection. Protective immunity after vaccination involves more than just antibodies. And the only anti-TNF drug studied was infliximab.
Nevertheless, they suggest that a weakened antibody response has potentially far-reaching implications.
It may increase susceptibility to recurrent COVID-19 in patients treated with infliximab, which might then lead to chronic colonisation of the virus in the nose and throat. This "may act as a reservoir to drive persistent transmission and the evolution of new SARS-CoV-2 variants," they warn.
And they conclude: "Serological testing and virus surveillance should be considered to detect suboptimal vaccine responses, persistent infection, and viral evolution to inform public health policy.
"If attenuated serological responses following vaccination are also observed, then modified immunisation strategies will need to be designed for millions of patients worldwide."
Study details
Anti-SARS-CoV-2 antibody responses are attenuated in patients with IBD treated with infliximab
Nicholas A Kennedy, James R Goodhand, Claire Bewshea, Rachel Nice, Desmond Chee, Simeng Lin, Neil Chanchlani, Jeffrey Butterworth, Rachel Cooney, Nicholas M Croft, Ailsa L Hart, Peter M Irving, Klaartje B Kok, Christopher A Lamb, Jimmy K Limdi, Jonathan Macdonald, Dermot PB McGovern, Shameer J Mehta, Charles D Murray, Kamal V Patel, Richard CG Pollok, Timothy Raine, Richard K Russell, Christian P Selinger, Philip J Smith, Jack Bowden, Timothy J McDonald, Charlie W Lees, Shaji Sebastian, Nicholas Powell, Tariq Ahmad
Published in Gut on 22 March 2021
Abstract
Objective
Antitumour necrosis factor (anti-TNF) drugs impair protective immunity following pneumococcal, influenza and viral hepatitis vaccination and increase the risk of serious respiratory infections. We sought to determine whether infliximab-treated patients with IBD have attenuated serological responses to SARS-CoV-2 infections.
Design
Antibody responses in participants treated with infliximab were compared with a reference cohort treated with vedolizumab, a gut-selective anti-integrin α4β7 monoclonal antibody that is not associated with impaired vaccine responses or increased susceptibility to systemic infections. 6935 patients were recruited from 92 UK hospitals between 22 September and 23 December 2020.
Results
Rates of symptomatic and proven SARS-CoV-2 infection were similar between groups. Seroprevalence was lower in infliximab-treated than vedolizumab-treated patients (3.4% (161/4685) vs 6.0% (134/2250), p<0.0001). Multivariable logistic regression analyses confirmed that infliximab (vs vedolizumab; OR 0.66 (95% CI 0.51 to 0.87), p=0.0027) and immunomodulator use (OR 0.70 (95% CI 0.53 to 0.92), p=0.012) were independently associated with lower seropositivity. In patients with confirmed SARS-CoV-2 infection, seroconversion was observed in fewer infliximab-treated than vedolizumab-treated patients (48% (39/81) vs 83% (30/36), p=0.00044) and the magnitude of anti-SARS-CoV-2 reactivity was lower (median 0.8 cut-off index (0.2–5.6) vs 37.0 (15.2–76.1), p<0.0001).
Conclusions
Infliximab is associated with attenuated serological responses to SARS-CoV-2 that were further blunted by immunomodulators used as concomitant therapy. Impaired serological responses to SARS-CoV-2 infection might have important implications for global public health policy and individual anti-TNF-treated patients. Serological testing and virus surveillance should be considered to detect suboptimal vaccine responses, persistent infection and viral evolution to inform public health policy.