Better COVID Outcomes Confirmed in TNF Inhibitor Users

Tara Haelle

October 21, 2021

UPDATED November 8, 2021 // Editor's note: This article has been updated with comments from an expert in the field.

Among patients with immune-mediated inflammatory diseases (IMIDs) who get COVID-19, the risk for hospitalization and death is lower if they are receiving tumor necrosis factor (TNF) inhibitor monotherapy, compared with receiving most other common drugs for these conditions, with or without TNF inhibitors, according to a study published October 18 in JAMA Network Open. The only combination not associated with an increased risk for hospitalization or death was TNF inhibitor therapy with methotrexate.

"These findings support the continued use of TNF inhibitor monotherapy during the pandemic and warrant further research investigating the association of other biologic therapies with COVID-19 outcomes," write Zara Izadi, MPharm, of the University of California, San Francisco, and her colleagues. "Treatment with TNF inhibitor combination therapy was associated with a more favorable safety profile when methotrexate rather than azathioprine/6-mercaptopurine was used, suggesting that clinicians would benefit from weighing the risks versus benefits of deescalating treatment or changing medications when a patient is receiving concomitant TNF inhibitors and azathioprine/6-mercaptopurine," they write.

Findings Mirror Those Seen in Other Settings

These findings are in line with what has been found in other settings, according to Joel M. Gelfand, MD, director of the psoriasis and phototherapy treatment center, vice chair of clinical research, and medical director of the dermatology clinical studies unit at the University of Pennsylvania, Philadelphia, Pennsylvania.

Dr Joel M. Gelfand

"In the beginning of the pandemic, there was concern about use of immune-modulating treatments, and many patients self-discontinued treatments like TNF inhibitors," Gelfand, who was not involved in the study, told Medscape Medical News. "This has ultimately proved unnecessary and unfortunately resulted in harm to many patients due to flaring of their underlying disease."

Benjamin Cohen, MD, clinical director for inflammatory bowel diseases at the Cleveland Clinic, in Ohio, similarly found the results "reassuring" in that they reaffirm what early evidence showed. They also point to an option for patients in whom TNF inhibitor therapy is insufficient.

"If patients require combination therapy when using an anti-TNF, these data suggest methotrexate may be a better combination agent than thiopurine immunosuppressants," Cohen, who was not involved in the study, told Medscape Medical News. He added that "it's important to advise patients with immune-mediated inflammatory diseases to get vaccinated against COVID-19 to reduce their overall risk of poor outcomes."

Gelfand also emphasized the importance of vaccinating patients against COVID-19 as soon as possible and of getting a third dose for those who are already fully vaccinated with the Pfizer or Moderna shots, as recommended by the Centers for Disease Control and Prevention.

"I typically recommend this third dose be taken 6 months after the second dose," Gelfand said. "The good news is that TNF inhibitors do not seem to meaningfully impact response to mRNA vaccines."

Study Details

The researchers analyzed data from three international registries of adults with rheumatic diseases, inflammatory bowel disease, and psoriasis who had COVID-19 between March 12, 2020, and February 1, 2021. The registries included the Secure Epidemiology of Coronavirus Under Research Exclusion for Inflammatory Bowel Disease (SECURE-IBD) registry, the Psoriasis Patient Registry for Outcomes, Therapy and Epidemiology of COVID-19 Infection (PsoProtect), and the physician-reported registry from the Global Rheumatology Alliance (GRA).

The population included 6077 patients from 74 countries. About half of the cohort (52.9%) were from Europe; more than half were women (58.6%). The average age was 48 years. A little over one third of the patients (35.3%) had rheumatoid arthritis, 25.3% had Crohn's disease, 12.5% had ulcerative colitis, 10.3% had spondyloarthritis, and 9.3% had psoriatic arthritis. Smaller percentages had psoriasis (4.9%), another type of arthritis or multiple types (1.7%), or another inflammatory bowel disease (0.6%).

One in five patients (21.3%) were hospitalized, and 3.1% died. The researchers compared outcomes for those who were receiving TNF inhibitor therapy alone to outcomes for those who were taking azathioprine/6-mercaptopurine therapy (alone or with a TNF inhibitor), methotrexate (alone or with a TNF inhibitor), and Janus kinase (JAK) inhibitors. They adjusted their analysis to account for active disease and common comorbidities, as well as geography and the period during the pandemic in which the person was admitted, because treatment regimens and hospitalization indications have varied over time.

All of the therapies except the combination of TNF inhibitors and methotrexate were associated with higher odds of hospitalization and death than TNF inhibitor monotherapy.

Table. Likelihood of COVID-19 Hospitalization or Death in Relation to Treatment Regimen

Treatment Odds ratio P value
Azathioprine/6-mercaptopurine monotherapy 1.84 .001
Azathioprine/6-mercaptopurine with TNF inhibitor 1.74 .006
Methotrexate monotherapy 2 <.001
JAK inhibitor monotherapy 1.82 .004
Methotrexate with TNF inhibitor 1.18 .33


The researchers explored several possible explanations for the findings, including the possibility that high serum TNF concentrations may have been associated with more organ damage at the time of COVID-19 admission, owing to interaction with SARS-CoV-2–associated hyperinflammation.

"Therefore, blocking TNF could inhibit this detrimental immune response," the authors write. "Multiple case series reporting favorable outcomes among patients receiving TNF inhibitor therapy support this assertion."

Another possibility relates to the effects of taking non-TNF inhibitor medications for immunosuppression. The authors note that thiopurine medications are linked to a greater risk for opportunistic viral infections and that JAK inhibitors may reduce the body's ability to clear the virus because of its suppression of innate immune response.

The authors also postulate that methotrexate may lower the likelihood of cytokine storm linked to COVID-19, even though methotrexate monotherapy was associated with poorer outcomes. "This association could mean that TNF inhibitor therapy is exerting a protective benefit or that methotrexate therapy is exerting a harmful consequence," the authors write.

Caution Needed in Interpreting Uncontrolled, Registry-Based Data

The findings were not surprising to Stephen B. Hanauer, MD, medical director of the Digestive Health Center at Northwestern University Feinberg School of Medicine, Chicago, Illinois, who was not involved in the research.

Dr Stephen B. Hanauer

"We've been monitoring IBD [inflammatory bowel disease] patients through the Secure registry similar to the rheumatologic and dermatologic societies and have not identified a signal of harm from any international groups," Hanauer told Medscape Medical News. He noted that these registries also have not shown an increased risk for COVID-19 complications among patients receiving TNF inhibitors, anti-adhesion therapies, or anti-IL12/23 inhibitors, compared with the general population not taking these therapies.

The study's size and the diversity of patients strengthens its findings.

"The benefit of registry data is that it allows the investigators to capture details about disease activity that can influence results, and by pooling all the registries to get a large number of patients, the authors were able to control for other potential confounding factors associated with severe COVID-19 outcomes," Cohen said.

However, the registries' use of convenience sampling increases the potential for reporting bias, such as the possibility that practitioners may be more likely to report cases with bad outcomes, Cohen said, although the results remained similar after a sensitivity analysis. The study also lacked a control group, and the registries did not collect data uniformly.

Gelfand similarly advised caution in interpreting these findings, inasmuch as the study is a "collection of spontaneous reports" that should be viewed as hypothesis generating rather than testing.

"Fortunately, more rigorous studies have been conducted, typically in large medical record systems, and have confirmed the hypothesis that TNF inhibitors are associated with a lower risk of poor COVID-19 outcomes, compared to other treatments," Gelfand said.

Previous smaller studies similarly found better outcomes among patients taking TNF inhibitors, compared with other therapies, but their participants were predominantly from North America and Europe, noted Licio A. Velloso, MD, PhD, of the University of Campinas, in São Paulo, Brazil, in an accompanying commentary.

On the basis of the findings of this study, "which included a much larger sample comprising distinct diseases and patients with a multitude of genetic backgrounds, the evidence in favor of the continued use of TNF inhibitor monotherapy for patients with IMIDs during the COVID-19 pandemic has become more substantial," Velloso writes. "The finding that maintenance of TNF inhibitor monotherapy is associated with reductions in the risk of severe COVID-19 among patients with IMIDs offers new perspective that may guide health care professionals in the difficult decisions regarding therapeutic approaches among this specific group of patients."

The research was funded by the American College of Rheumatology, the European Alliance of Associations for Rheumatology, the UK's National Institute for Health Research Biomedical Research Center, and the Psoriasis Association. Many authors reported receiving grants and/or personal fees from a variety of pharmaceutical companies. Velloso has disclosed no relevant financial relationships. Hanauer has served as a consultant to companies that market TNF inhibitors. Gelfand has consulted for and received research grants from companies that market TNF inhibitors. Cohen has received an educational grant from Pfizer and advisory board, consulting, or speaking fees from AbbVie, Celgene-Bristol Myers Squibb, Rafael Pharmaceuticals, Pfizer, Sublimity Therapeutics, Takeda, TARGET RWE, and Vindico Medical Education.

JAMA Netw Open. Published online October 18, 2021. Full text, Commentary

Tara Haelle is a Dallas-based science and medical journalist.

For more news, follow Medscape on Facebook, Twitter, Instagram, and YouTube.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.