Association between Tumor Necrosis Factor Inhibitors and the Risk of Hospitalization or Death among Patients with Immune-Mediated Inflammatory Disease and COVID-19

Zara Izadi*, Erica J. Brenner, Satveer K. Mahil, Nick Dand, Zenas Z.N. Yiu, Mark Yates, Ryan C. Ungaro, Xian Zhang, Manasi Agrawal, Jean Frederic Colombel, Milena A. Gianfrancesco, Kimme L. Hyrich, Anja Strangfeld, Loreto Carmona, Elsa F. Mateus, Saskia Lawson-Tovey, Eva Klingberg, Giovanna Cuomo, Marta Caprioli, Ana Rita Cruz-MachadoAna Carolina Mazeda Pereira, Rebecca Hasseli, Alexander Pfeil, Hanns Martin Lorenz, Bimba Franziska Hoyer, Laura Trupin, Stephanie Rush, Patricia Katz, Gabriela Schmajuk, Lindsay Jacobsohn, Andrea M. Seet, Samar Al Emadi, Leanna Wise, Emily L. Gilbert, Alí Duarte-García, Maria O. Valenzuela-Almada, Carolina A. Isnardi, Rosana Quintana, Enrique R. Soriano, Tiffany Y.T. Hsu, Kristin M. D'Silva, Jeffrey A. Sparks, Naomi J. Patel, Ricardo Machado Xavier, Claudia Diniz Lopes Marques, Adriana Maria Kakehasi, René Marc Flipo, Pascal Claudepierre, Alain Cantagrel, Philippe Goupille, Zachary S. Wallace, Suleman Bhana, Wendy Costello, Rebecca Grainger, Jonathan S. Hausmann, Jean W. Liew, Emily Sirotich, Paul Sufka, Philip C. Robinson, Pedro M. Machado, Christopher E.M. Griffiths, Jonathan N. Barker, Catherine H. Smith, Jinoos Yazdany, Michael D. Kappelman

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

75 Citations (Scopus)


Importance: Although tumor necrosis factor (TNF) inhibitors are widely prescribed globally because of their ability to ameliorate shared immune pathways across immune-mediated inflammatory diseases (IMIDs), the impact of COVID-19 among individuals with IMIDs who are receiving TNF inhibitors remains insufficiently understood. Objective: To examine the association between the receipt of TNF inhibitor monotherapy and the risk of COVID-19-associated hospitalization or death compared with other commonly prescribed immunomodulatory treatment regimens among adult patients with IMIDs. Design, Setting, and Participants: This cohort study was a pooled analysis of data from 3 international COVID-19 registries comprising individuals with rheumatic diseases, inflammatory bowel disease, and psoriasis from March 12, 2020, to February 1, 2021. Clinicians directly reported COVID-19 outcomes as well as demographic and clinical characteristics of individuals with IMIDs and confirmed or suspected COVID-19 using online data entry portals. Adults (age ≥18 years) with a diagnosis of inflammatory arthritis, inflammatory bowel disease, or psoriasis were included. Exposures: Treatment exposure categories included TNF inhibitor monotherapy (reference treatment), TNF inhibitors in combination with methotrexate therapy, TNF inhibitors in combination with azathioprine/6-mercaptopurine therapy, methotrexate monotherapy, azathioprine/6-mercaptopurine monotherapy, and Janus kinase (Jak) inhibitor monotherapy. Main Outcomes and Measures: The main outcome was COVID-19-associated hospitalization or death. Registry-level analyses and a pooled analysis of data across the 3 registries were conducted using multilevel multivariable logistic regression models, adjusting for demographic and clinical characteristics and accounting for country, calendar month, and registry-level correlations. Results: A total of 6077 patients from 74 countries were included in the analyses; of those, 3215 individuals (52.9%) were from Europe, 3563 individuals (58.6%) were female, and the mean (SD) age was 48.8 (16.5) years. The most common IMID diagnoses were rheumatoid arthritis (2146 patients [35.3%]) and Crohn disease (1537 patients [25.3%]). A total of 1297 patients (21.3%) were hospitalized, and 189 patients (3.1%) died. In the pooled analysis, compared with patients who received TNF inhibitor monotherapy, higher odds of hospitalization or death were observed among those who received a TNF inhibitor in combination with azathioprine/6-mercaptopurine therapy (odds ratio [OR], 1.74; 95% CI, 1.17-2.58; P =.006), azathioprine/6-mercaptopurine monotherapy (OR, 1.84; 95% CI, 1.30-2.61; P =.001), methotrexate monotherapy (OR, 2.00; 95% CI, 1.57-2.56; P <.001), and Jak inhibitor monotherapy (OR, 1.82; 95% CI, 1.21-2.73; P =.004) but not among those who received a TNF inhibitor in combination with methotrexate therapy (OR, 1.18; 95% CI, 0.85-1.63; P =.33). Similar findings were obtained in analyses that accounted for potential reporting bias and sensitivity analyses that excluded patients with a COVID-19 diagnosis based on symptoms alone. Conclusions and Relevance: In this cohort study, TNF inhibitor monotherapy was associated with a lower risk of adverse COVID-19 outcomes compared with other commonly prescribed immunomodulatory treatment regimens among individuals with IMIDs.

Original languageEnglish
Pages (from-to)e2129639
JournalJAMA Network open
Issue number10
Early online date1 Oct 2021
Publication statusPublished - 1 Oct 2021


  • Adult
  • Arthritis, Rheumatoid/drug therapy
  • COVID-19/mortality
  • Comorbidity
  • Drug Therapy, Combination/adverse effects
  • Female
  • Hospitalization/statistics & numerical data
  • Humans
  • Inflammatory Bowel Diseases/drug therapy
  • Male
  • Middle Aged
  • Pandemics
  • Psoriasis/drug therapy
  • Registries
  • Retrospective Studies
  • SARS-CoV-2
  • Tumor Necrosis Factor Inhibitors/therapeutic use


Dive into the research topics of 'Association between Tumor Necrosis Factor Inhibitors and the Risk of Hospitalization or Death among Patients with Immune-Mediated Inflammatory Disease and COVID-19'. Together they form a unique fingerprint.

Cite this