Anti-Cytokine Therapy Normalizes ACE2 Expression In IBD, May Protect Against COVID-19

Anti-cytokine therapy curbs inflammatory bowel disease (IBD) symptoms by normalizing reduced or elevated angiotensin-converting enzyme 2 (ACE2) levels, and could play a protective role in COVID-19 as well, researchers suggest.

"ACE2, the enzyme that SARS-COV-2 virus uses to infect human cells, is highly expressed in the bowel (and) is increased with some of the demographic factors associated with worse outcomes in COVID-19, such as obesity and increasing age," Dr. Dermot P. B. McGovern of Cedars-Sinai Medical Center in Los Angeles told Reuters Health by email.

ACE2 expression is altered in IBD and is associated with response to the anti-cytokine drug, infliximab, he explained, raising the possibility that infliximab may have a role in treating COVID-19. This possibility is supported by a recent paper in Cell, he said, which "shows that people with COVID19 have high TNF levels and that mouse models were relatively protected from some of the COVID-19-like manifestations by treatment with neutralizing antibodies to TNF."

For the current study, published in Gastroenterology, Dr. McGovern and colleagues investigated factors influencing intestinal ACE2 levels in Crohn's disease (CD), ulcerative colitis (UC) and non-IBD controls. They analyzed tissue samples from four small bowel biopsies and two rectal biopsy cohorts, as well as outcomes of anti-TNF and anti-IL12/IL-23 treatment (infliximab, ustekinumab) on small bowel and colonic ACE2 expression in three clinical trials.

ACE2 levels were consistently reduced in small bowel CD and elevated in colonic UC, when compared to non-IBD controls.

In CD patients, small bowel ACE2 was reduced in those who subsequently developed complicated disease.

In UC patients, colonic ACE2 was elevated in active disease and in those who subsequently required anti-TNF rescue therapy.

Further, elevated small bowel ACE2 was associated with demographic features - age and higher BMI - associated with poor COVID-19 outcomes.

Both small bowel and colonic ACE2 expression in active CD and UC were restored by anti-cytokine therapy, particularly in responders.

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Summing up, the authors state, "Reduced small bowel, but elevated colonic ACE2 levels in IBD are associated with inflammation and severe disease but normalized following anti-cytokine therapy suggesting compartmentalization of ACE2-related biology in small bowel and colonic inflammation. The restoration of ACE2 expression with anti-cytokine therapy may be important in the context of SARS-CoV-2 infection and potentially explain reports of reduced morbidity from COVID-19 in IBD patients treated with anti-cytokines."

Dr. McGovern said, "We also observed that ACE2 and JAK1 co-occurred, and speculated that this fact supported the rationale for a trial of baricitinib (a JAK1/2 inhibitor) in COVID-19. It also was recently reported in Science Advances that baricitinib was associated with a 71% mortality benefit in 83 patients with moderate-severe SARS-CoV-2 pneumonia."

"Infliximab may have potential for treating the more severe forms of COVID-19 that have been associated with the 'cytokine storm' phase of the illness," he added. "The mortality benefit from baricitinib...further supports our rationale. The intersection of immune-mediated or autoimmune diseases and infectious diseases is a complex one, but studying this space may yield important insights for developing new treatments or repurposing existing treatments in the fight to treat both types of diseases."

Dr. Jordan Axelrad, assistant professor of medicine at NYU Langone's Inflammatory Bowel Disease Center in New York City, commented in an email to Reuters Health, "While the present study did not directly analyze the intestinal tissues of patients with COVID-19, the data demonstrate that restoration of mucosal ACE2 homeostasis may be an important mechanism by which anti-cytokine drugs promote recovery in IBD, and possibly mitigate the secondary cytokine storm seen in severe COVID-19."

"Multiple studies have demonstrated that patients with IBD are at similar risk of severe COVID-19 to age- and sex-matched patients in the general population, which may be independent of anti-cytokine use," he said. "As such, further data is needed to understand if IBD patients are in fact at a reduced risk of morbidity from COVID-19, and whether this is linked to anti-cytokine therapy and ACE2 homeostasis."

"At this point, as dysregulation in ACE2 is associated with active/complicated IBD, and severe COVID-19, it is critical to ensure patients with active IBD are treated with effective therapies, such as anti-cytokines, to reduce the adverse implications of altered mucosal ACE2 homeostasis in IBD and COVID-19," he concluded.

—Marilynn Larkin

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