Treatment of immune-mediated inflammatory diseases with tumor necrosis factor inhibitors is associated with lower COVID-19 hospitalization and death rates compared to other treatments

1. Immune-mediated inflammatory disease patients treated with tumor necrosis factor (TNF) inhibitor were associated with fewer hospitalizations or deaths due to COVID-19 than those treated with only methotrexate, with only azathioprine/6-mercaptopurine, with TNF inhibitor and azathioprine/6-mercaptopurine, or with only a Jak inhibitor.

Evidence Rating Level: 3 (Average)

Study Rundown: Treatment of an immune-mediated inflammatory disease (IMID) impairs the immune system and so may compromise one’s ability to fight off infections such COVID-19. Alternatively, treatment of IMIDs may be beneficial as COVID infection causes a hyperinflammatory response. Tumor necrosis factor (TNF) inhibitors treat IMIDs by decreasing the pro-inflammatory TNF cytokine. This study sought to clarify if the use of TNF inhibitors in IMID patients is beneficial or detrimental in COVID infection. This study pools data from registries on IMID patients including rheumatic disease (inflammatory arthritis), IBD, and psoriasis to identify if there is an association between TNF inhibitor therapy and hospitalization or death due to COVID infection. The data was taken from the COVID-19 Global Rheumatology Alliance (GRA), Secure Epidemiology of Coronavirus Under Research Exclusion for IBD (SECURE-IDB), and Psoriasis Patient Registry for Outcomes, Therapy and Epidemiology of COVID-19 Infection (PsoProtect) registries, respectively. TNF inhibitors investigated during this study include adalimumab, certolizumab pegol, etanercept, golimumab, and infliximab; additionally, TNF inhibitors combined with methotrexate or azathioprine/6-mercaptopurine were investigated. Methotrexate and azathioprine/6-mercaptopurine were also investigated as monotherapies, as was Janus kinase (Jak) inhibitors like tofacitinib, baricitinib, and upadacitinib. 6077 IMID patients were treated with a TNF inhibitor when they were infected with COVID-19 (TNF monotherapy: 34.4% GRA patients, 61.9% SECURE-IBD patients, and 72.0% of PsoProtect patients; methotrexate monotherapy: 41.8% GRA patients). 21.3% of patients were hospitalized and 3.1% died. More GRA patients were hospitalized and died compared to SECURE-IBD or PsoProtect patients. IMID patients treated with methotrexate, with only azathioprine/6-mercaptopurine, with TNF inhibitor and azathioprine/6-mercaptopurine, or with only a Jak inhibitor more frequently were hospitalized and died than patients treated with only a TNF inhibitor. A strength of this study is that the databases used are international and created by trained staff, making them diverse and accurate. Additionally, these databases report if the disease is active, unlike electronic health records. Pooling data increased the power of this study to detect differences in hospitalization and death outcomes by treatment, though in the heterogeneous sample of IMIDs and COVID hospitalization protocols. Reporting bias may exist in this study as the registries used convenience sampling but is unlikely as this study used a sensitivity analysis to estimate bias. A limitation of this study is it could not perform an analysis based on the duration or severity of the IMID, nor did it control for previous IMID therapies.

Click to read the study in JAMA Network Open

Click to read an accompanying editorial in JAMA Network Open

Relevant Reading: Antecedent immunosuppressive therapy for immune-mediated inflammatory diseases in the setting of a COVID-19 outbreak

In-Depth [retrospective cohort]: Patients with inflammatory arthritis, IBD, or psoriasis (IMID patients) with confirmed or suspected COVID-19 pooled from three registries were compared on COVID hospitalization and death rates. This comparison was made based on the group’s TNF inhibitor medication use. Patients taking most other immunomodulatory drugs (any except sulfasalazine, mesalamine, hydroxychloroquine or chloroquine, leflunomide, oral budesonide, or glucocorticoids) were excluded. 6077 eligible patients with an IMID (35.3% rheumatoid arthritis, 25.3% Crohn disease, 12.5% ulcerative colitis, and 10.3% spondyloarthritis) received a TNF inhibitor treatment during their infection with COVID-19 (56.6% from GRA, 38.4% from SECURE-IBD, and 4.9% from PsoProtect; 52.9% European, 33.2% North America, age = 48.8±16.5 years, 58.6% female and 40.6% male). 34.4% of the GRA patients, 61.9% of the SECURE-IBD patients, and 72.0% of the PsoProtect patients were on TNF monotherapy; other eligible patients were commonly on methotrexate (41.8% of GRA patients). 21.3% of IMID patients were hospitalized and 3.1% of IMID patients died from COVID-19 infection. GRA patients, compared to SECURE-IBD and PsoProtect patients, were more commonly hospitalized (27.3% vs 13.5% and 14.0%) and died (4.8% vs 0.9% and 1.0%). TNF inhibitor with azathioprine/6-mercaptopurine therapy, compared to TNF inhibitor alone, was associated with greater odds of hospitalization or death (OR = 1.74, 95% CI = 1.17-2.58; P = 0.006) in all the registries. Compared to TNF inhibitor monotherapy, there was a higher risk of hospitalization or death for patients on methotrexate monotherapy (OR = 2.00, 95% CI = 1.57-2.56, P < 0.001), azathioprine/6-mercaptopurine monotherapy (OR = 1.84, 95% CI = 1.30-2.61, P = 0.001), and Jak inhibitor monotherapy (OR = 1.82, 95% CI = 1.21-2.73, P = 0.004). There was an association between hospitalization or death with older age (OR = 1.04, 95% CI = 1.04-1.05, P < 0.001), active IMID at the time of COVID-19 diagnosis (OR = 1.27, 95% CI = 1.04-1.55, P = 0.02), obesity (OR = 1.39, 95% CI = 1.10-1.75, P = 0.005), interstitial lung disease (OR = 1.81, 95%CI = 1.12-2.95, P = 0.02), obstructive lung disease (OR = 2.34, 95% CI = 1.69-3.24, P < 0.001), cardiovascular disease (OR = 1.58, 95% CI = 1.13-2.21, P = 0.007), diabetes (OR = 1.54, 95% CI = 1.16-2.05, P = 0.003), chronic kidney disease (OR = 3.10, 95% CI = 1.70-5.66, P < 0.001), concomitant use of sulfasalazine (OR = 1.62, 95% CI = 1.13-2.34, P = 0.009), leflunomide (OR = 1.89, 95% CI = 1.20-2.99, P = 0.006), or oral budesonide (OR = 2.86, 95% CI = 1.20-6.84, P = 0.02), and higher daily prednisone-equivalent glucocorticoid dose (OR = 1.07, 95% CI = 1.05-1.08, P < 0.001). By contrast, being of the female sex was associated with a decrease in odds of hospitalization (OR = 0.79, 95% CI = 0.66-0.96, P = 0.02).

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