Anti-tumor necrosis factor alpha (anti-TNF-α) agents have been suggested as being favorable and a potential treatment for coronavirus disease of 2019 (COVID-19). High serum levels of TNF-α upon admission have been associated with a severe COVID-19 infection. From the literature studying sepsis, non-related to COVID-19, a previous meta-analysis had found an improved survival , in particular 28-day all-cause mortality, with monoclonal anti-TNF antibodies. In trials of acute inflammation, such as steroid-refractory and severe ulcerative colitis (UC), anti-TNF agents were shown to have a favorable adverse event profile, in addition to inducing higher remission rates and improving the percentage of colon-salvage[5-7].
The experience of IBD patients infected with COVID-19 has been reported through the SECURE-IBD database. As of July 13th, 2020, 15% of the patients on anti-TNF therapy required hospitalization with 2% requiring intensive care and 1% succumbing to the disease. Patients treated with steroids or sulfasalazine/mesalamine required intensive care in 15% and 8% of the cases respectively, and had a mortality of 9% and 6% . It appears that in the setting of maintenance therapy with anti-TNF antibodies, COVID-19 infections are associated with less serious complications as compared to other maintenance modalities. How an anti-TNF-α therapy could work for patients who had not been on treatment at the onset of their COVID-19 infection has yet to be defined.
Furthermore, important differences exist between the study populations of IBD trials and COVID-19 patients. IBD trials typically exclude patients with severe uncontrolled infections and those with heart failure. Severe COVID-19 infections would have likely been excluded from participation in these trials. Furthermore, the age group studied in these IBD trials tend to be in the 20 to 40 years old range, much younger than the critically ill patients with a severe COVID-19 infection. Although graded as severe, the disease burden of UC in such studies is usually confined to the intestine, without the outright systemic sepsis seen in severe COVID-19 cases.
The cumulative evidence in the literature has also been inconsistent regarding the safety profile for infectious adverse events with anti-TNF-α therapies in IBD. When compared to placebo, meta-analysis has found that UC patients treated with anti-TNF agents had increased long-term risks of opportunistic and of serious infections requiring intravenous antibiotics or hospitalization, or causing death . A higher risk of serious infectious complications has also been shown in patients with autoimmune arthritis receiving anti-TNF-α agents. In older patients with a severe COVID-19 infection, the safety profile leaves even less margin for error. Some reports have suggested a tolerable adverse event profile in elderly with inflammatory bowel and articular diseases[12-14], while others have found a higher rate of opportunistic infections and treatment failure with IBD cases[15,16].
The indication of anti-TNF-α treatment in the present pandemic would target pulmonary inflammation and mortality. The previous literature concerning both acute lung injury and acute respiratory distress syndrome feature higher local and systemic levels of TNF-α and have been associated with worse outcomes. Similar to the current COVID-19 pandemic, this suggests a possible role of TNF inhibitors in the treatment of acute pulmonary inflammation. However, previous reports have not shown favorable effects on survival of TNF blockade in patients with septic shock and ALI [17,18].
It is nonetheless worth noting that emerging data on the use of anti-TNF agents in patients with COVID-19 included the description of a case where infliximab was initiated in a 54 year-old female patient for a severe episode of ulcerative colitis. She specifically received two doses of infliximab 10 mg/kg, while being reported as having a concomitant infection with COVID-19 that was qualified as mild. The patient had an uneventful recovery. In their cohort of 40 patients with IBD, the authors reported 2 deaths (5%) due to acute respiratory distress syndrome in patients aged 77 and 86 years, and who were treated with mesalamine with or without methotrexate. A complementary element to note with the reported fatality rate is the fact that most patients were described to have interrupted their immunomodulator or biologic maintenance therapy upon the diagnosis of a COVID-19 infection. This adds an additional challenge to the proper interpretation of the safety of anti-TNF use during an active episode of COVID-19 and its potential effect on complications’ occurrence. Although the initiation of an anti-TNF agent in a patient with a mild case of COVID-19 seems safe, and potentially beneficial, it remains important to note that more cases are required to properly assess which patients might benefit from its use as a therapeutic agent for COVID-19.
With no experience with this novel virus, TNF blockade, although mechanistically promising, may harbor serious risks in fragile older patients. We endorse the hypothesis stipulating that this therapy might prevent severe complications of systemic inflammation in COVID-19 infections, but further investigation into the evolution of COVID-19 infections in IBD patients already treated with anti-TNF agents could provide valuable insight into the benefits of suppressing the TNF-α cascade. Caution should however be used in projecting any outcomes observed in patients on maintenance therapy to initiating antibody treatment in a naïve but COVID-19 afflicted patients.
Conflict of interest: The authors have no conflict of interest to disclose.
1 Tursi A, Vetrone LM, Papa A. Anti-tnf-alpha agents in inflammatory bowel disease and course of covid-19. Inflamm Bowel Dis 2020
2 Feldmann M, Maini RN, Woody JN, Holgate ST, Winter G, Rowland M, Richards D, Hussell T. Trials of anti-tumour necrosis factor therapy for covid-19 are urgently needed. The Lancet 2020;395:1407-1409.
3 Li X, Xu S, Yu M, Wang K, Tao Y, Zhou Y, Shi J, Zhou M, Wu B, Yang Z, Zhang C, Yue J, Zhang Z, Renz H, Liu X, Xie J, Xie M, Zhao J. Risk factors for severity and mortality in adult covid-19 inpatients in wuhan. J Allergy Clin Immunol 2020
4 Lv S, Han M, Yi R, Kwon S, Dai C, Wang R. Anti-tnf-alpha therapy for patients with sepsis: A systematic meta-analysis. Int J Clin Pract 2014;68:520-528.
5 Samaan MA, Bagi P, Vande Casteele N, D'Haens GR, Levesque BG. An update on anti-tnf agents in ulcerative colitis. Gastroenterol Clin North Am 2014;43:479-494.
6 Fausel R, Afzali A. Biologics in the management of ulcerative colitis - comparative safety and efficacy of tnf-alpha antagonists. Ther Clin Risk Manag 2015;11:63-73.
7 Croft A, Walsh A, Doecke J, Cooley R, Howlett M, Radford-Smith G. Outcomes of salvage therapy for steroid-refractory acute severe ulcerative colitis: Ciclosporin vs. Infliximab. Aliment Pharmacol Ther 2013;38:294-302.
8 Brenner ej, ungaro rc, colombel jf, kappelman md. Secure-ibd database public data update. Covidibd.Org. Accessed on 07/13/20.
9 Bhatraju PK, Ghassemieh BJ, Nichols M, Kim R, Jerome KR, Nalla AK, Greninger AL, P ipavath S, Wurfel MM, Evans L, Kritek PA, West TE, Luks A, Gerbino A, Dale CR, Goldman JD, O'Mahony S, Mikacenic C. Covid-19 in critically ill patients in the seattle region - case series. N Engl J Med 2020;382:2012-2022.
10 Shah ED, Farida JP, Siegel CA, Chong K, Melmed GY. Risk for overall infection with anti-tnf and anti-integrin agents used in ibd: A systematic review and meta-analysis. Inflamm Bowel Dis 2017;23:570-577.
11 Minozzi S, Bonovas S, Lytras T, Pecoraro V, Gonzalez-Lorenzo M, Bastiampillai AJ, Gabrielli EM, Lonati AC, Moja L, Cinquini M, Marino V, Matucci A, Milano GM, Tocci G, Scarpa R, Goletti D, Cantini F. Risk of infections using anti-tnf agents in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis: A systematic review and meta-analysis. Expert Opin Drug Saf 2016;15:11-34.
12 Ali M, McClean C, Zou Y, Goh J. Pth-076 inflammatory bowel disease: The consequences of anti-tnf therapy in the elderly. Gut 2016;65:A256.252-A257.
13 Migliore A, Bizzi E, Lagana B, Altomonte L, Zaccari G, Granata M, Canzoni M, Marasini B, Massarotti M, Massafra U, Ranieri M, Pilla R, Martin LS, Pezza M, Vacca F, Galluccio A. The safety of anti-tnf agents in the elderly. Int J Immunopathol Pharmacol 2009;22:415-426.
14 Cheng D, Cushing KC, Cai T, Ananthakrishnan AN. Safety and efficacy of tumor necrosis factor antagonists in older patients with ulcerative colitis: Patient-level pooled analysis of data from randomized trials. Clin Gastroenterol Hepatol 2020
15 de Jong ME, Smits LJT, van Ruijven B, den Broeder N, Russel M, Romkens TEH, West RL, Jansen JM, Hoentjen F. Increased discontinuation rates of anti-tnf therapy in elderly inflammatory bowel disease patients. J Crohns Colitis 2020
16 Lobaton T, Ferrante M, Rutgeerts P, Ballet V, Van Assche G, Vermeire S. Efficacy and safety of anti-tnf therapy in elderly patients with inflammatory bowel disease. Aliment Pharmacol Ther 2015;42:441-451.
17 Malaviya R, Laskin JD, Laskin DL. Anti-tnfalpha therapy in inflammatory lung diseases. Pharmacol Ther 2017;180:90-98.
18 Abraham E, Anzueto A, Gutierrez G, Tessler S, Pedro GS, Wunderink R, Nogare AD, Nasraway S, Berman S, Cooney R, Levy H, Baughman R, Rumbak M, Light RB, Poole L, Allred R, Constant J, Pennington J, Porter S. Double-blind randomised controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock. The Lancet 1998;351:929-933.
19 Rodriguez-Lago I, Ramirez de la Piscina P, Elorza A, Merino O, Ortiz de Zarate J, Cabriada JL. Characteristics and prognosis of patients with inflammatory bowel disease during the sars-cov-2 pandemic in the basque country (spain). Gastroenterology 2020
1. Department of Surgery, Hôpital Maisonneuve-Rosemont, Montréal, Québec, Canada. 5415, boulevard de l'Assomption, Montréal, Québec, Canada, H1T 2M4
2. Division of General Surgery, Université de Montréal, Montréal, Québec, Canada'
Hôpital Maisonneuve-Rosemont, 5415, boulevard de l'Assomption, Montréal, Québec, Canada, H1T 2M4
Tel: +1 514 252 3400
Department of Pharmaceutics, Utrecht University, the Netherlands
Department of Pharmaceutics, Jiaxing University Medical College, Zhejiang, China