Risk of Adverse Outcomes Due to COVID-19 May Be Lower with TNF Inhibitor Monotherapy

Patients with immune-mediated inflammatory diseases (IMIDs) receiving tumor necrosis factor (TNF) inhibitor monotherapy have a lower risk of COVID-19-associated hospitalization or death than those on other commonly prescribed immunomodulatory treatment regimens. This finding is according to a cohort study that included data from three international registries.¹

“Our findings are in favor of the continued use of TNF inhibitor monotherapy for patients with IMIDs,” says co-first author Zara Izadi, MPharm, MAS, a doctoral candidate and a graduate student researcher at the University of California, San Francisco. “In addition, clinicians would benefit from weighing the risks vs. benefits of de-escalating treatment or changing medications when a patient is receiving concomitant TNF inhibitors and azathioprine/mercaptopurine.”

Preliminary Data

TNF inhibitors are widely prescribed for rheumatoid arthritis (RA), Crohn’s disease, ulcerative colitis and psoriasis. However, the effect of COVID-19 on patients with IMIDs who are receiving TNF inhibitors remains poorly understood. Biologic and disease-modifying anti-rheumatic drugs (DMARDs) are risk factors for infection, and they could predispose a patient to severe COVID-19 and increase COVID-19-related mortality. Conversely, because the cytokine storm led by interleukin (IL) 6 and TNF-α is believed to play an important role in the development of many of COVID-19’s serious complications, it has been proposed that biologic inhibitors of these cytokines may decrease the severity of COVID-19.²

In 2020, a study by Brenner et al. found TNF inhibitor use at the time of COVID-19 diagnosis was not associated with severe COVID-19. The researchers analyzed data from the SECURE-IBD registry, which included 525 patients with inflammatory bowel disease (IBD) from 33 countries. Risk factors for severe COVID-19 included increasing age, other comorbidities, systemic corticosteroids and sulfasalazine/5-aminosalicylate use, but not TNF inhibitor use.³ Gianfrancesco et al. studied data from the COVID-19 Global Rheumatology Alliance’s (GRA; a section of the ACR) physician-reported registry of COVID-19 outcomes among people with rheumatic diseases. In 600 patients from 40 countries, prevalent use compared with no use of TNF inhibitors at COVID-19 diagnosis was associated with a lower risk of COVID-19-associated hospitalization, whereas glucocorticoid exposure of 10 mg or more per day was associated with higher odds of hospitalization.⁴

Meanwhile, an analysis of data from the PsoProtect registry by Mahil et al., which included 374 patients with moderate to severe psoriasis from 25 countries, found higher odds of hospitalization among patients treated with non-biologic systemic therapies compared with biologic therapies, including TNF inhibitors.⁵

TNF Inhibitor Safety

Although these studies of international registries have provided preliminary information regarding COVID-19 outcomes among patients who received TNF inhibitor therapies during the pandemic, they were often underpowered to perform detailed analyses of commonly used medications, such as monotherapy vs. combination therapy, or medications that are used less often.¹ To shed light on the safety of TNF inhibitor and DMARD use in patients with IMIDs and COVID-19, Izadi et al. completed a pooled analysis of data from three international COVID-19 registries comprising individuals with rheumatic diseases, IBD and psoriasis from March 12, 2020, to Feb. 1, 2021. The study’s primary outcome was COVID-19-associated hospitalization or death.

“Our dataset represented patients from 74 countries and multiple immune-mediated disease diagnoses,” says Ms. Izadi. “The findings can guide healthcare professionals on therapeutic approaches in patients with IMIDs during the pandemic.”

A total of 6,077 patients were included in the analyses, 3,441 from GRA, 2,336 from SECURE-IBD and 300 from PsoProtect. Patients had a mean age of 49. Fifty-nine percent were women, and 59% were from Europe. The most common IMID diagnosis was RA, followed by Crohn’s disease. Treatment exposure categories included TNF inhibitor monotherapy, TNF inhibitors combined with methotrexate, TNF inhibitors combined with azathioprine/6-mercaptopurine, methotrexate monotherapy, azathioprine/6-mercaptopurine monotherapy and Janus kinase (JAK) inhibitor monotherapy.

Of the patients, 21.3% were hospitalized and 3.1% died. Compared with TNF inhibitor monotherapy, a higher risk of COVID-19-related hospitalization and mortality was associated with a TNF inhibitor combined with azathioprine/6-mercaptopurine (odds ratio [OR]: 1.74; 95% confidence interval [CI], 1.17–2.58; P=0.006), azathioprine/6-mercaptopurine monotherapy (OR: 1.84; 95% CI, 1.30–2.61; P=0.001), methotrexate monotherapy (OR: 2.00; 95% CI, 1.57–2.56; P<0.001) and JAK inhibitor monotherapy (OR: 1.82; 95% CI, 1.21–2.73; P=0.004). However, patients who received a TNF inhibitor combined with methotrexate did not have a greater risk of COVID-19-related hospitalization or mortality (OR: 1.18; 95% CI, 0.85–1.63; P=0.33).

Clinician, Patient Reassurance

Dr. Yazdany

“Currently, people taking TNF inhibitors are concerned about getting severely ill should they get COVID-19. This study should provide some reassurance to the thousands of people taking anti-TNF medications during the pandemic,” says senior co-author Jinoos Yazdany, MD, MPH, professor of medicine at the University of California, San Francisco.

“For rheumatologists, although recommendations are to stop anti-TNF drugs if a patient gets COVID-19, practically, this [change] is quite difficult given the long half-life of these drugs. Although more data are needed to advise patients not to skip their next dose of anti-TNF medication in the setting of active COVID-19, hopefully these data provide some reassurance that even when the medications are not stopped, most patients do quite well.”

Dr. Velloso

In an invited commentary, Licio A. Velloso, MD, PhD, professor of medicine at University of Campinas in São Paulo, Brazil, writes that one of the greatest strengths of the study is the inclusion of a large number of patients with distinct ethnic backgrounds and IMIDs.⁶

“The numbers speak for themselves. We are talking about 6,000-plus patients with diverse genetic backgrounds. This [group] is the largest cohort evaluated so far. So indeed, this is very important and impactful data,” Dr. Velloso says. “Patients with COVID-19 present an early surge of inflammatory cytokines. TNF-α is one of the most important cytokines increased in this context. Thus, to be honest, I am not surprised that use of TNF-α inhibitors provides some benefit for this population.

“Of course, we are waiting for larger cohorts. In addition, considering the importance of IL-6 in the COVID-19 cytokine storm, I am looking forward to seeing the impact of the use of IL-6 inhibitors in the progression of COVID-19 in IMIDs,” Dr. Velloso says.

References

1. Izadi Z, Brenner EJ, Mahil SK, et al. Association between tumor necrosis factor inhibitors and the risk of hospitalization or death among patients with immune-mediated inflammatory disease and COVID-19. JAMA Netw Open. 2021 Oct 1;4(10):e2129639.
2. Hyrich KL, Machado PM. Rheumatic disease and COVID-19: Epidemiology and outcomes. Nat Rev Rheumatol. 2021 Feb;17(2):71–72.
3. Brenner EJ, Ungaro RC, Gearry RB, et al. Corticosteroids, but not TNF antagonists, are associated with adverse COVID-19 outcomes in patients with inflammatory bowel diseases: Results from an international registry. Gastroenterology. 2020 Aug;159(2):481–491.e3.
4. Gianfrancesco M, Hyrich KL, Al-Adely S, et al. Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: Data from the COVID-19 Global Rheumatology Alliance physician-reported registry. Ann Rheum Dis. 2020 Jul;79(7):859–866.
5. Mahil SK, Dand N, Mason KJ, et al. Factors associated with adverse COVID-19 outcomes in patients with psoriasis—insights from a global registry-based study. J Allergy Clin Immunol. 2021 Jan;147(1):60–71.
6. Velloso LA. Use of tumor necrosis factor inhibitors during the COVID-19 pandemic—evidence in favor of monotherapy. JAMA Netw Open. 2021 Oct 1;4(10):e2129707.