TNF Inhibitors Tied to Lower Risk for Serious, Fatal Covid-19 Outcomes

For patients with inflammatory diseases, tumor necrosis factor inhibitor (TNFi) monotherapy was linked with a lower risk of adverse Covid-19 outcomes versus other commonly prescribed immunomodulatory treatments, researchers reported.

In the pooled analysis of data from three international Covid-19 registries of patients with immune-mediated inflammatory diseases (IMIDs), those who received TNFi in combination with other agents, or other agents alone, had higher odds of hospitalization or death versus those who got only TNFi:

• TNFi plus azathioprine/6-mercaptopurine: odds ratio 1.74 (95% CI 1.17 to 2.58, P=0.006).
• Azathioprine/6-mercaptopurine monotherapy: OR 1.84 (95% CI 1.30 to 2.61, P=0.001).
• Methotrexate monotherapy: OR 2.00 (95% CI 1.57 to 2.56, P<0.001).
• Janus kinase (JAK) inhibitor monotherapy: OR 1.82 (95% CI 1.21 to 2.73, P=0.004).

The most common IMID diagnoses were rheumatoid arthritis (35.3%) and Crohn’s disease (25.3%), explained Zara Izadi, MPharm, MAS, University of California San Francisco, and co-authors in JAMA Network Open.

They suggested one possible reason for their finding was “the consequences of non-TNF inhibitor immunosuppressive medications for Covid-19 outcomes.” Previous studies have shown that thiopurine medications are linked with a higher risk of opportunistic viral infections, while JAK inhibitors have been known to curtail the innate immune response and lead to impaired viral clearance.

While other research has supported the idea of methotrexate therapy as decreasing the cytokine storm associated with Covid-19, Izadi’s group suggested that their result of worse outcomes with methotrexate versus TNFi monotherapy could mean that the latter is “exerting a protective benefit or that methotrexate therapy is exerting a harmful consequence.”

In an invited commentary accompanying the study, Licio A. Velloso, MD, PhD, of the University of Campinas in São Paulo, Brazil, noted that 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.”

He pointed out that the “inclusion of a large number of patients with distinct ethnic backgrounds and IMIDs” was a study strength, particularly because previous registry-based studies were done in a small number of patients from fairly homogeneous backgrounds.

The majority of current study patients came from Europe (>50%), and around a third were from North America, followed by patients from South America, Eastern Mediterranean, and Africa. Participants came from 74 different countries, although race/ethnicity were not recorded in the registries, Izadi’s group noted.

Data for this analysis came from the GRA, SECURE-IBD, and PsoProtect registries. Adults (mean age 48.8; 58.6% female) with an IMID diagnosis were included. Data were taken from mid-March 2020 to early February 2021. Out of 6,077 individuals, 21.3% were hospitalized, and 3.1% died.

“To limit confounding from other immunomodulatory medications, we excluded patients who received an exposure treatment regimen as well as concomitant immunomodulatory drugs, except when sulfasalazine, mesalamine, hydroxychloroquine or chloroquine, leflunomide, oral budesonide, or glucocorticoids were used as concomitant medications,” Izadi and co-authors said.

TNFi monotherapy ranged from 34.4% of patients to 72% in the three registries. Methotrexate monotherapy was the most prevalent regimen at Covid-19 diagnosis for GRA registry patients (41.8%). Jak inhibitor monotherapy was at a low of zero patients in PsoProtect and a high of 6.4% in the GRA registry. Very few patients received thiopurines, alone or paired with TNFi, in all of the registries, the authors reported.

As for other medication and factors associated with higher odds of hospitalization or death, the authors reported the following:

• Concomitant sulfasalazine or leflunomide in GRA: OR 1.55 (95% CI 1.03 to 2.35, P=0.04); OR 1.97 (95% CI 1.22 to 3.18, P=0.005), respectively.
• Concomitant oral budesonide in SECURE-IBD: OR, 2.71 (95% CI 1.11 to 6.60, P=0.03).
• Older age in pooled analysis: OR 1.04/1-year increase in age (95% CI 1.04 to 1.05, P<0.001).
• Active IMID at Covid-19 diagnosis: OR 1.27 (95% CI 1.04 to 1.55, P=0.02).
• Obesity: OR 1.39 (95% CI 1.10 to 1.75, P=0.005).
• Interstitial lung disease: OR 1.81 (95% CI 1.12 to 2.95, P=0.02).
• Obstructive lung disease: OR 2.34 (95% CI 1.69 to 3.24, P<0.001).
• Cardiovascular disease: OR 1.58 (95% CI 1.13 to 2.21, P=0.007).
• Diabetes: OR 1.54 (95% CI 1.16 to 2.05, P=0.003).
• Chronic kidney disease: OR 3.10 (95% CI 1.70 to 5.66, P<0.001).

Study limitations included the risk of reporting bias due to convenience sampling, differences in hospitalization thresholds and Covid-19 treatment across global regions, and lack of data on previous exposure and duration of IMID therapy.

The current findings check off another “good news” box for patients with IMIDs. A 2021 multi-center research-network study by Zachary Zinn, MD, of West Virginia University in Morgantown, and co-authors, included >53 million patient records, ultimately analyzing 214 patients with Covid-19 who also had recent TNFi or methotrexate exposure and >31,000 with Covid-19 without exposure to either of those agents. They reported that the likelihood of hospitalization and mortality were not significantly different between the two groups (risk ratio 0.91, 95% CI 0.68 to 1.22, P=0.5260 and RR 0.87, 95% CI 0.42 to 1.78, P=0.6958).

Then there’s the tantalizing prospect of a prophylactic effect of TNFi. A group in Iran reported in Rheumatology & Therapy that a “direct and positive correlation between the use of TNF-alpha blockers and a reduction in the incidence of Covid-19 could suggest the prophylactic role of these drugs in preventing Covid-19 in patients with RA and SpA,” while a separate industry-led group hypothesized that selinexor (XPovio) could be a viable anti-viral treatment option as the agent “inhibited viral infection prophylactically as well as therapeutically in vitro” in an animal model.

And researchers from Africa and South Asia reported that “the magnitude of the release of pro-inflammatory cytokines such as interleukin (IL)-1, (IL-6), and… TNF-α significantly differentiate between mild and severe cases of Covid-19,” so the “prophylaxis and the rapid treatment of cytokine storm by clinicians will significantly enhance the fight against the dreaded Covid-19 disease.”

A related concern has been whether patients on TNFi should get the Covid-19 vaccination. The American College of Rheumatology (ACR) set to quell those concerns with an August 2021 clinical guidance summary, noting that “[n]o evidence was found to support concern regarding the use or timing of immunomodulatory therapies in relation to vaccine safety, and guidance regarding medication timing.” However, ACR emphasized that the guidance was a “living document” that would be continuously updated.

1. Tumor necrosis factor inhibitor (TNFi) monotherapy was linked with a lower risk of adverse Covid-19 outcomes versus other commonly prescribed immunomodulatory treatment regimens among patients with immune-mediated inflammatory diseases (IMIDs).

2. The findings support the continued use of TNFi monotherapy among individuals with IMIDs during the pandemic.

Shalmali Pal, Contributing Writer, BreakingMED™

Cat ID: 190

Topic ID: 79,190,730,933,190,926,192,927,151,928,241,925,934