Therapies for Inflammatory Bowel Disease Do Not Pose Additional Risks for Adverse Outcomes of SARS-CoV-2 Infection

An IG-IBD Study

Cristina Bezzio; Alessandro Armuzzi; Federica Furfaro; Sandro Ardizzone; Monica Milla; Sonia Carparelli; Ambrogio Orlando; Flavio Andrea Caprioli; Fabiana Castiglione; Chiara Viganò; Davide Giuseppe Ribaldone; Fabiana Zingone; Rita Monterubbianesi; Nicola Imperatore; Stefano Festa; Marco Daperno; Ludovica Scucchi; Antonio Ferronato; Luca Pastorelli; Paola Balestrieri; Chiara Ricci; Maria Cappello; Carla Felice; Gionata Fiorino; Simone Saibeni


Aliment Pharmacol Ther. 2021;54(11_12):1432-1441. 

In This Article


In this study, the majority of IBD patients had an asymptomatic (13.7%) or favourable course (70.8%) of SARS-CoV-2 infection. However, UC patients were more likely than CD patients to have symptoms and to develop moderate or severe COVID-19. Among the 145 patients who had moderate or severe COVID-19, age ≥60 years, male sex, obesity, arterial hypertension and another concomitant IMID were risk factors for an adverse outcome. Considering variables related to IBD, disease activity of any severity was an additional risk factor, but no single IBD medication was found at multivariable analysis to be associated with adverse COVID-19 outcomes. On the contrary, anti-TNF agents were associated with a lower risk of pneumonia in UC patients and with lower risks of hospitalisation and severe COVID-19 in CD patients.

Overall, our findings confirm that the course of COVID-19 in IBD patients is similar to that observed in the general population.[3–7] Moreover, they confirm that the general risk factors for worse outcomes of COVID-19 (age, male sex and comorbidities) in IBD patients are similar to those in the general population, as already observed in other studies of IBD patients.[3–14] Among IBD-related risk factors, the finding of a negative role of disease activity agrees with previously reported studies.[9,12]

Understanding if IBD therapies affect the evolution of SARS-CoV-2 infection is crucial because of the possible consequences on the management of these patients. Indeed, stopping, postponing or avoiding therapies due to the fear of a negative impact on the infection could lead to IBD flares with detrimental consequences. This study found that patients taking anti-TNF agents had lower risks of pneumonia (UC patients), hospitalisation and severe COVID-19 (CD patients); this protective role against severe COVID-19 confirms findings of previous studies.[8,11,13] Due to the small subgroup of patients in combination therapy with anti-TNF agents and immunosuppressants, we are not able to draw conclusions about its reported potential negative impact.[13] The potential protective role of anti-TNF agents could be due to their downregulation of ACE2 expression in the intestine,[22] their known effects on cytokine storms,[23] or to a general dampening of the inflammatory response during the hyperimmune phase of the infection.[2]

Our study did not find an association between salicylates and COVID-19 outcomes, once confounders were eliminated through multivariable analysis. This finding is in apparent contrast to reports of an association between salicylate use and a negative course of SARS-CoV-2 infection from the SECURE-IBD international registry.[11,13] This potential negative role of salicylates is a matter of debate: besides the theoretical plausibility,[24] it is possible that several biases led to this finding, including the fact that anti-TNF agents were used as a comparator.[25] Our study also did not find any impact of corticosteroids, in contrast to earlier studies where these drugs were negative factors for a worse outcome of COVID-19 with a possible dose-dependent effect.[8,11,14] However, the close association with disease activity and the lack of complete information about doses, reasons for taking these drugs and duration of therapy do not allow us to draw firm conclusions.

Using the risk factors identified in multivariable analysis for moderate-to-severe COVID-19, we developed two indices of the risk for adverse outcomes in UC and CD patients. In our models, scores ≥0.9 for UC patients and ≥2.20 for CD patients were the best cut-offs to identify those at higher risk. These indices could be useful in identifying IBD patients who could be prioritised for vaccination, especially in contexts where vaccines are scarce and when boosters will become necessary. However, due to the relatively low absolute number of IBD patients at higher risk of adverse outcomes, these indices could have a relatively poor diagnostic accuracy. Moreover, they need to be validated before they are used in clinical practice.

This study reports the findings from a large cohort of consecutive IBD patients with COVID-19 from a single country, where the management of IBD is relatively homogeneous. The participation of many IG-IBD centres across Italy makes our study a reliable portrait of the Italian situation of IBD patients infected by SARS-CoV-2. Importantly, we evaluated UC and CD patients separately since UC and CD are different diseases, with different therapies and different indices to assess disease activity. Indeed, in our study, the UC and CD populations differed significantly in terms of baseline characteristics, including therapies, and symptoms of SARS-CoV-2 infection, so we analysed them separately for COVID-19 risk factors. Instead, none of the prior studies on COVID-19 outcomes in IBD patients distinguished between UC and CD patients. Finally, the fact that we adjusted our risk factor analyses for several confounders should clarify some of the conflicting results reported so far.

Our study has some limitations. First, we cannot exclude the under-reporting of cases: some participating centres may not have included all their patients due to the voluntary referral, and asymptomatic and mild forms of SARS-CoV-2 infection may have been missed (mainly patients in remission or not under strict monitoring). On the contrary, we also cannot exclude the over-reporting of asymptomatic and mild forms of SARS-CoV-2 infection in patients under close follow-up (ie, patients in biological therapy). Our findings can be extended only to other settings similar in social, cultural, political and economic backgrounds. Finally, the proposed indices to identify IBD patients at higher risk of adverse COVID-19 outcomes should be validated before clinical implementation.

In conclusion, this study confirms that SARS-CoV-2 generally has a mild course in IBD patients, and that the risk factors for moderate-to-severe COVID 19 are the same as observed in the general population. On the basis of these results, we feel that no additional or different precautions should be adopted for IBD patients. In particular, because we did not find any evidence for a negative effect of IBD therapies on the outcome of SARS-CoV-2 infection, our study provides support for the recommendations of the European Crohn's and Colitis Organisation,[26] which state to not stop in advance medications needed to maintain IBD in remission and to avoid flares due to discontinuation. The indices created here to identify UC and CD patients with a higher risk of adverse COVID-19 outcomes may boost the effectiveness of ongoing and future vaccination programs and of future specific therapies for SARS-CoV-2 by identifying a subset of IBD patients who merit prioritisation.