麻豆传媒

The tumor necrosis factor (TNF) inhibitor infliximab (Remicade) was associated with attenuated serological responses to SARS-CoV-2 infection in patients with inflammatory bowel disease (IBD), a multicenter study from the U.K. found.

These responses were further attenuated in those who also received immunomodulators, said Tariq Ahmad, MD, of the Royal Devon and Exeter NHS Foundation Trust in England, and colleagues.

Compared with vedolizumab (Entyvio), infliximab was independently tied to lower seropositivity (OR 0.66, 95% CI 0.51-0.87, P=0.0027), as was concomitant immunomodulator use (OR 0.70, 95% CI 0.53-0.92, P=0.012), they reported online in .

Furthermore, in patients with confirmed SARS-CoV-2 infection, seroconversion was observed in fewer infliximab-treated patients (39 of 81) compared with vedolizumab-treated patients (30 of 36; P=0.00044). Additionally, the magnitude of anti-SARS-CoV-2 reactivity was also lower, with a median 0.8 cutoff index (0.2-5.6) versus 37.0 (15.2-76.1), respectively (P<0.0001).

Since impaired serological responses to SARS-CoV-2 might have important implications for public health and TNF inhibitor-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," wrote Ahmad and team.

The gut-selective anti-integrin α4β7 monoclonal antibody vedolizumab has not been linked to or increased susceptibility to systemic infection or attenuated serological responses after pneumococcal, influenza, and viral hepatitis vaccination or to an increased risk of serious respiratory infections.

The CLARITY IBD study analyzed antibody responses in 6,935 consecutive IBD patients ages 5 and older recruited from 92 U.K. hospitals from Sept. 22 to Dec. 23, 2020; 4,685 were treated with infliximab and 2,250 were treated with vedolizumab.

Men made up about half of both groups. Mean age was 37 in the infliximab group and about 44 in the vedolizumab group. Overall, 56.9% of patients had Crohn's disease, 40.5% had ulcerative colitis, and 2.5% were unclassified.

At recruitment, 56.3% of infliximab and 18.8% of vedolizumab patients were on concomitant immunomodulators such as thiopurines and methotrexate.

A sandwich electrochemiluminescence immunoassay targeted a recombinant protein of the nucleocapsid antigen for identifying antibodies against SARS-CoV-2.

Rates of symptomatic and proven SARS-CoV-2 infection were similar between groups, but seroprevalence was lower in infliximab-treated patients, at 3.4%, compared with vedolizumab-treated patients at 6.0% (P<0.0001).

In other study findings, the overall seroprevalence of anti-SARS-CoV-2 antibodies was 4.3%, adding to evidence that IBD patients are at similar risk of SARS-CoV-2 infection as the general population, the study authors said.

Furthermore, only a third of patients on concurrent immunomodulators had detectable anti-SARS-CoV-2 antibodies. In patients treated with infliximab alone, the seroconversion rate was 60%, and in patients treated with infliximab and an immunomodulator, the rate fell to 37% (P=0.046). There was also a significant difference in the magnitude of anti-SARS-CoV-2 reactivity (P=0.035).

Infliximab may directly impede the immune mechanisms responsible for generating antibody responses, the authors explained: "This is biologically plausible, since the proinflammatory actions of TNF include stimulation of B cell immunoglobulin synthesis, induction of germinal center formation, costimulation of antigen-activated T cells and maturation of antigen presenting cells."

Asked for her perspective, Serre-Yu Wong, MD, PhD, of Icahn School of Medicine at Mount Sinai in New York City, pointed to the large numbers in the study and said the findings suggest that IBD patients on TNF inhibitors will need close watching.

Her group recently conducted a single-center serological study in U.S. patients that found no difference between IBD patients on infliximab versus those on vedolizumab. "But we didn't look at titers, and ours was different in that while the U.K. researchers tested for the nucleocapsid antigen, we tested for the receptor-binding domain of the spike protein," Wong told 麻豆传媒. "This could make a huge difference since there are differences in neutralizing capacity and longevity with spike versus nucleocapsid. The data suggest greater neutralizing capacity and longevity with targeting the spike protein, and the vaccines we have currently in the United States target spike."

As for the interaction between infliximab and the new SARS-CoV-2 variants, Wong said that, as with other diseases, there could be a worrisome lower recognition of variant strains.

Her group is currently planning to test for antibodies to both nucleocapsid and spike "because that's the only way to differentiate between a natural infection and a vaccination," she said.

Among several study limitations, the authors cited the fact that it is not known whether attenuated immune responses in infliximab-treated patients translates into an increased risk of infection. Moreover, the study only assessed humoral responses to infection, and it is likely that protective immunity additionally requires induction of memory T-cell responses.

In addition, the study's patient-reported data were subject to recall bias that may have underestimated the prevalence of possible COVID-19 symptoms.

Finally, the only TNF inhibitor investigated was infliximab, but the authors expect that the key findings would apply to other anti-TNF monoclonal antibodies, including adalimumab, certolizumab, and golimumab, as well.

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