Aminosalicylates and COVID-19: Facts or Coincidences?

Dear Editors:

It was with great interest that we read the paper of Brenner et al¹ published recently in Gastroenterology. In the setting of Coronavirus Disease 2019 (COVID-19), the authors defined severity as the need for intensive care unit admission and ventilator use, and/or death. The paper reports that tumor necrosis factor (TNF) antagonists do not appear to be associated with severe COVID-19, but sulfasalazine or 5-aminosalicylate (5-ASA) use adjusted for age, comorbidities, inflammatory bowel disease (IBD) disease characteristics, and corticosteroids were positively associated with the outcome of hospitalization or death (adjusted odds ratio 3.1; 95% CI, 1.3–7.7).¹ These findings are surprising and unexpected, because neither immunomodulators nor TNF antagonists have been associated positively with the composite outcome. Oral delayed-release mesalamine is a pH-dependent drug; the formulation allows delayed release from the terminal ileum to the colon, resulting in local topical activity on the mucosa and low systemic concentration.² Depending on the dose and type of formulation, only 15% to 67% of the drug is absorbed and excreted in the urine (mostly in the acetylated form), whereas 24% to 67% passes to the stool (approximately 50% in acetylated form). Colonic epithelial cells acetylate 5-ASA rapidly, however N-acetyl 5-ASA is poorly absorbed by epithelial cells.³ Therefore, how can we explain that aminosalicylates with low bioavailability are associated with poor outcomes in patients with IBD with COVID-19? Two explanations occur: one relates to methodological aspects, and the other with mechanistic pathways of 5-ASA. To guarantee that we are following the right path, we suggest a complementary analysis to the work of Brenner et al.¹:

• 1.In the multivariate regression, the group of 5-ASA should analyze patients on monotherapy with aminosalicylates (without other concomitant drugs to treat IBD).
• 2.Comorbidities like hypertension, diabetes, and cardiovascular conditions were reported to be associated with worst prognosis in patients with COVID-19, and to have different weight from that of history of stroke, asthma, NAFLD, or cirrhosis. In this work, the authors considered all comorbidities as having similar influence. From our point of view, this can be a potential source of bias, particularly because 10% of the comorbidities were classified as “Others.”
• 3.Including more than 1 covariate per 10 events, in the regression model, may lead to bias.⁴

After setting these aspects, the other hypothesis may be related to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor, on a mechanistic perspective. A less explored mechanism of action of 5-ASA is its capacity to bind the peroxisome proliferator-activated receptor gamma (PPAR-γ).⁵ PPAR-γ is highly expressed in adipocytes but also in the colon.⁶ The binding of 5-ASA to PPARγ has clinical relevance because it occurs for concentrations that are effective in maintenance therapy in patients with IBD.⁵ Besides, 5-ASA induces the expression of PPAR-γ.^{5 , 7} The expression of PPAR-γ is lower in the intestinal epithelium of patients with ulcerative colitis when compared to controls or patients with Crohn’s disease, and correlates with ulcerative colitis activity.⁷ In adipocytes and in the vascular tissue, PPAR-γ also increases the expression of the angiotensin-converting enzyme 2 (ACE2),^{5 , 7} the binding receptor for SARS-CoV-2. However, COVID-19 severity is partly influenced by the mechanism responsible for viral entry in the host cell. It is important to note that ACE2 might be internalized with the virus, or be kept in the host cell membrane, or shed to the circulation. Only shed or membrane-bound ACE2 can act as a protective enzyme of the renin-angiotensin system, with favorable outcomes. Also, PPAR-γ activation inhibits the expression of TMPRSS2, a transmembrane serine protease relevant for both viral entry with ACE2 internalization.⁸

In conclusion, studies that explore the nature of the puzzle among 5-ASA, PPARγ, and ACE2 are imperative to ascertain whether 5-ASA determines more severe outcomes in patients with IBD with COVID-19: fact or coincidence?