Cytokine Storm in IBD: Balancing the Risks of IBD Medical Therapy

We thank our colleagues for their interest in our report on the treatment strategies and outcomes of patients with inflammatory bowel disease (IBD) during the first months of the coronavirus disease 2019 (COVID-19) pandemic.1Rodriguez-Lago I. et al.Gastroenterology. 2020; 159: 781-783Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar This series described the outcomes of 40 patients (23 ulcerative colitis, 13 Crohn’s disease, and 4 IBD unclassified) diagnosed between February 27 and April 8, 2020. Approximately 20%–30% of patients were under biologic or immunosuppressive therapy, respectively, but we did not observe a relationship between any of these therapies and major adverse outcomes, including the development of systemic inflammatory response syndrome or acute respiratory distress syndrome, need for hospital or intensive care unit admission, or death. Age was the only predictive factor associated with a worse prognosis; patients >65 years of age showed a higher probability of being admitted (90% vs 40%; P = .009), or developing acute respiratory distress syndrome (30% vs 0%; P = .013), which is in line with findings across different cohorts irrespective of the presence of a previous diagnosis of IBD. Our personal, social, and working conditions have changed dramatically since then, and >77 million people have been infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) according to the Center for Systems Science and Engineering at Johns Hopkins University (https://coronavirus.jhu.edu/map.html; accessed December 21, 2020). Many researchers worldwide have evaluated the impact of this infection on IBD patient care. A recent systematic review of 21 studies found that around one-third of patients with IBD needed hospital admission and only a small proportion of them were admitted to the intensive care unit.2D'Amico F. et al.Clin Gastroenterol Hepatol. 2020; 18: 2689-2700Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar Some patient and treatment-related factors have shown a relationship with worse outcomes, including older age, active disease, or the presence of multiple comorbidities. Additionally, the use of systemic corticosteroids or mesalamine have been also associated with a poor prognosis.3Bezzio C. et al.Gut. 2020; 69: 1213-1217Crossref PubMed Scopus (168) Google Scholar, 4Brenner E.J. et al.Gastroenterology. 2020; 159: 481-491 e3Abstract Full Text Full Text PDF PubMed Scopus (321) Google Scholar, 5Singh S. et al.Gastroenterology. 2020; 159: 1575-1578 e4Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar The outcomes among those patients receiving immunosuppressive or biological therapies are still uncertain, as Macaluso and Orlando indicate, but some authors have already suggested that they could even protect against severe COVID-19. A systematic review and meta-analysis demonstrated that the relative risk of hospitalization, intensive care unit admission, and mortality are not affected by immunosuppressive therapy, whereas the same outcomes may be similar or even reduced with the use of biologic agents.6Singh A.K. et al.United European Gastroenterol J. 2020 Nov; 192050640620972602Crossref Scopus (31) Google Scholar SARS-CoV-2 infection leads to a fast activation of the innate immune system and an increase in circulating levels of effector cytokines, such as tumor necrosis factor (TNF)α, IL-1β, IL-6, IL-8, G-CSF, and GM-CSF, with higher levels in those more critically ill. Many of these disturbances are similar to those observed in secondary hemophagocytic lymphohistiocytosis, which is usually triggered by infections. The hyperinflammatory state induced by COVID-19 is mainly driven by endothelial damage and capillary leak, as a consequence of the secretion of the aforementioned cytokines, among others. Because higher baseline TNFα levels have been associated with an increased risk of death due to COVID-19, the administration of anti-TNFα agents have been suggested to be potentially beneficial in this setting. Notably, the SECURE-IBD registry has recently observed that patients under combination therapy or thiopurine monotherapy showed a 4-fold increase in the risk of severe COVID-19, compared with TNFα antagonist monotherapy.7Ungaro R.C. et al.Gut. 2020 Oct 20; (gutjnl-2020-322539)PubMed Google Scholar In patients with COVID-19 pneumonia, tocilizumab—an IL-6 inhibitor—decreased the probability of the composite outcome of mechanical ventilation or death, but it did not improve survival rates. Similar results have been observed with sarilumab, another IL-6 blocker. Thus, it seems that more selective inhibition of inflammatory mediators does not clearly improve outcomes of this disease. Meanwhile, TNFα blockade induces an early down-regulation of multiple cytokines, including IL-1, IL-6, and GM-CSF. Data from the SECURE-IBD registry support the hypothesis that less selective inhibition of the inflammatory cascade seems beneficial in terms of hospital admission and death.7Ungaro R.C. et al.Gut. 2020 Oct 20; (gutjnl-2020-322539)PubMed Google Scholar These findings are similar to those observed in the COVID-19 Global Rheumatology Alliance registry, where the use of TNFα antagonists was associated with a lower rate of hospital admission, compared with the subgroup of patients with no disease-modifying antirheumatic drugs. Therefore, data regarding the outcomes of the infection during anti-TNFα therapy is reassuring, while the outcomes with ustekinumab or vedolizumab would need further evaluations. Still, no prospective and robust data have clearly elucidated the best risk stratification and management strategies for patients with IBD complicated with COVID-19 during this overwhelming situation. We agree with our colleagues that a careful approach to each concept and recommendation should be applied here. Additional data will be soon available from the ENEIDA registry of the Spanish IBD Working group on Crohn’s disease and ulcerative colitis, from a cohort of >66,000 patients.8Zabana Y. et al.Gastroenterol Hepatol. 2020; 43: 551-558Crossref PubMed Scopus (10) Google Scholar This case-control prospective study will help us to define more exactly both the risks of contracting the infection and developing more severe outcomes. Meanwhile, almost 1 year after the onset of the pandemic, many questions remain open; thus, careful and individualized risk stratification needs to be implemented. We are sure that the hard work of all gastroenterologists involved and the close collaboration inside multidisciplinary teams will give us the best information to improve IBD patient care in the near future. Could Patients With Inflammatory Bowel Disease Treated With Immunomodulators or Biologics Be at Lower Risk for Severe Forms of COVID-19?GastroenterologyVol. 160Issue 5PreviewThe Coronavirus Disease 2019 (COVID-19) pandemic is undoubtedly the global health crisis of our time. In this regard, we read with interest the paper by Iago Rodríguez-Lago and colleagues1 on the outcome of patients with inflammatory bowel disease (IBD) during the severe acute respiratory syndrome coronavirus 2 pandemic in the Basque Country, Spain. Interestingly, patients with IBD and COVID-19 had a good overall prognosis, despite that approximately one-third of them were under immunomodulator therapy, and 18% were on biologics. Full-Text PDF