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. 2021 Oct 1;4(10):e2129639.
doi: 10.1001/jamanetworkopen.2021.29639.

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  1   2 , Erica J Brenner  3 , Satveer K Mahil  4   5 , Nick Dand  6   7 , Zenas Z N Yiu  8   9 , Mark Yates  10 , Ryan C Ungaro  11 , Xian Zhang  12 , Manasi Agrawal  11 , Jean-Frederic Colombel  11 , Milena A Gianfrancesco  2 , Kimme L Hyrich  13   14   15 , Anja Strangfeld  16 , Loreto Carmona  17 , Elsa F Mateus  18   19 , Saskia Lawson-Tovey  14   15   20 , Eva Klingberg  21 , Giovanna Cuomo  22 , Marta Caprioli  23 , Ana Rita Cruz-Machado  24   25 , Ana Carolina Mazeda Pereira  26 , Rebecca Hasseli  27 , Alexander Pfeil  28 , Hanns-Martin Lorenz  29 , Bimba Franziska Hoyer  30   31 , Laura Trupin  2 , Stephanie Rush  2 , Patricia Katz  2 , Gabriela Schmajuk  2   32 , Lindsay Jacobsohn  2 , Andrea M Seet  2 , Samar Al Emadi  33 , Leanna Wise  34 , Emily L Gilbert  35 , Alí Duarte-García  36   37 , Maria O Valenzuela-Almada  36 , Carolina A Isnardi  38 , Rosana Quintana  38 , Enrique R Soriano  39 , Tiffany Y-T Hsu  40   41 , Kristin M D'Silva  41   42 , Jeffrey A Sparks  40   41 , Naomi J Patel  41   43 , Ricardo Machado Xavier  44 , Claudia Diniz Lopes Marques  45 , Adriana Maria Kakehasi  46 , René-Marc Flipo  47 , Pascal Claudepierre  48   49 , Alain Cantagrel  50 , Philippe Goupille  51   52 , Zachary S Wallace  41   42 , Suleman Bhana  53 , Wendy Costello  54 , Rebecca Grainger  55 , Jonathan S Hausmann  56   57 , Jean W Liew  58 , Emily Sirotich  59   60 , Paul Sufka  61 , Philip C Robinson  62   63 , Pedro M Machado  64   65   66 , Christopher E M Griffiths  8   9 , Jonathan N Barker  67 , Catherine H Smith  4   5 , Jinoos Yazdany  2 , Michael D Kappelman  3 ; Psoriasis Patient Registry for Outcomes, Therapy and Epidemiology of COVID-19 Infection (PsoProtect); the Secure Epidemiology of Coronavirus Under Research Exclusion for Inflammatory Bowel Disease (SECURE-IBD); and the COVID-19 Global Rheumatology Allianc; Psoriasis Patient Registry for Outcomes, Therapy and Epidemiology of COVID-19 Infection (PsoProtect); the Secure Epidemiology of Coronavirus Under Research Exclusion for Inflammatory Bowel Disease (SECURE-IBD); and the COVID-19 Global Rheumatology Alliance (GRA)
Collaborators, Affiliations

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 et al. JAMA Netw Open. .

Abstract

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Brenner reported receiving grants from the National Institutes of Health during the conduct of the study. Dr Mahil reported receiving grants from AbbVie, Celgene, Eli Lilly and Company, Janssen-Cilag, Novartis, Sanofi, and UCB outside the submitted work. Dr Yates reported receiving personal fees from AbbVie and UCB. Dr Ungaro reported receiving personal fees from AbbVie, Bristol Myers Squibb, Janssen Pharmaceuticals, and Pfizer and nonfinancial support from Takeda Pharmaceutical during the conduct of the study. Dr Agrawal reported receiving grants from the Dickler Family Fund, the Helmsley Charitable Trust, and the New York Community Trust during the conduct of the study. Dr Colombel reported receiving grants from AbbVie, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion Pharm, Eli Lilly and Company, Genentech, the Helmsley Charitable Trust, Janssen Pharmaceuticals, Pfizer, and Takeda Pharmaceutical during the conduct of the study; grants from AbbVie, Janssen Pharmaceuticals, and Takeda Pharmaceutical; and personal fees from AbbVie, Allergan, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Ferring Pharmaceuticals, Galmed Pharmaceuticals, GlaxoSmithKline, Iterative Scopes, Janssen Pharmaceuticals, Kaleido Biosciences, Landos Biopharma, Otsuka Pharmaceutical, Pfizer, Prometheus Biosciences, Sanofi, Takeda Pharmaceutical, and TiGenix outside the submitted work. Dr Gianfrancesco reported receiving grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases outside the submitted work. Dr Hyrich reported receiving grants from the European Alliance of Associations for Rheumatology during the conduct of the study; grants from Bristol Myers Squibb and Pfizer; and personal fees from AbbVie outside the submitted work. Dr Strangfeld reported receiving grants from AbbVie, Amgen, Bristol Myers Squibb, Celltrion Pharm, Eli Lilly and Company, Fresenius Kabi, Gilead Sciences, Hexal, Merck Sharp & Dohme, Mylan/Viatris, Pfizer, Roche, Samsung Bioepis, Sanofi-Aventis, and UCB and personal fees from AbbVie, Bristol Myers Squibb, Celltrion Pharm, Eli Lilly and Company, Pfizer, Roche, and UCB outside the submitted work. Dr Carmona reported receiving grants from AbbVie, Gebro Pharma, Grünenthal, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi Aventis, and UCB outside the submitted work. Dr Mateus reported receiving grants from AbbVie, A. Menarini Diagnostics, Amgen, Eli Lilly and Company, Grünenthal, Medac Pharma, Merck Sharp & Dohme, Novartis, and Pfizer and personal fees from Boehringer Ingelheim outside the submitted work. Dr Cruz-Machado reported receiving grants from Merck Sharp & Dohme outside the submitted work. Dr Hasseli reported receiving grants from Justus Liebig University during the conduct of the study. Dr Wise reported receiving personal fees from Aurinia Pharmaceuticals outside the submitted work. Dr Duarte-García reported receiving grants from the Centers for Disease Control and Prevention and the Rheumatology Research Foundation outside the submitted work. Dr Isnardi reported receiving grants from AbbVie, Laboratorio Elea Phoenix, and Pfizer during the conduct of the study and personal fees from Bristol Myers Squibb outside the submitted work. Dr Soriano reported receiving grants from Novartis, Pfizer, Roche, and UCB and personal fees from AbbVie, Amgen, Eli Lilly and Company, Janssen Pharmaceuticals, Novartis, Pfizer, and Sandoz outside the submitted work. Dr Sparks reported receiving grants from the National Institutes of Health and the Rheumatology Research Foundation and personal fees from Bristol Myers Squibb, Gilead Sciences, Inova Diagnostics, Optum, and Pfizer outside the submitted work. Dr Patel reported receiving grants from the National Institutes of Health during the conduct of the study. Dr Xavier reported receiving personal fees from AbbVie, Eli Lilly and Company, Novartis, Pfizer, and UCB outside the submitted work. Dr Kakehasi reported receiving grants from the National Council for Scientific and Technological Development during the conduct of the study; personal fees from AbbVie, Amgen, Boehringer Ingelheim, Eli Lilly and Company, Janssen Pharmaceuticals, Novartis, Pfizer, Sandoz, and UCB outside the submitted work. Dr Flipo reported receiving personal fees from AbbVie, Janssen Pharmaceuticals, Merck Sharp & Dohme, and Pfizer outside the submitted work. Dr Claudepierre reported receiving personal fees from AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly and Company, Galapagos, Janssen Pharmaceuticals, Merck & Co, Novartis, Pfizer, Roche Chugai, and UCB outside the submitted work. Dr Goupille reported receiving personal fees from AbbVie, Biogen, Bristol Myers Squibb, Eli Lilly and Company, Janssen Pharmaceuticals, Novartis, Pfizer, and UCB outside the submitted work. Dr Wallace reported receiving grants from Bristol Myers Squibb and Sanofi and personal fees from Medpace Holdings and Viela Bio outside the submitted work. Dr Bhana reported receiving personal fees from AbbVie, Amgen, Horizon Therapeutics, Novartis, and Pfizer outside the submitted work. Dr Grainger reported receiving personal fees from AbbVie, Cornerstone Pharmaceuticals, Janssen Pharmaceuticals, Novartis, and Pfizer and nonfinancial support from Pfizer outside the submitted work. Dr Hausmann reported receiving grants from the Childhood Arthritis and Rheumatology Research Alliance and the Rheumatology Research Foundation and personal fees from Biogen, Novartis, and Pfizer outside the submitted work. Dr Liew reported receiving grants from Pfizer outside the submitted work. Ms Sirotich reported receiving grants from the COVID-19 Global Rheumatology Alliance and serving as a board member of the Canadian Arthritis Patient Alliance outside the submitted work. Dr Robinson reported receiving grants from Janssen Pharmaceuticals and Novartis and personal fees from AbbVie, Atom Bioscience, BMC Pharma, Eli Lilly and Company, Gilead Sciences, Pfizer, Roche, and UCB outside the submitted work. Dr Machado reported receiving grants from Orphazyme and personal fees from AbbVie, Eli Lilly and Company, Galapagos, Novartis, Orphazyme, and UCB outside the submitted work. Dr Griffiths reported receiving grants from the National Institute for Health Research during the conduct of the study; grants from Boehringer Ingelheim, Eli Lilly and Company, Janssen Pharmaceuticals, and LEO Pharma; and personal fees from AbbVie, Almirall, Bristol Myers Squibb, Novartis, and UCB outside the submitted work. Dr Barker reported receiving personal fees from AbbVie, Almirall, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Janssen Pharmaceuticals, LEO Pharma, Novartis, Pfizer, Samsung Pharmaceutical, Sienna Biopharmaceuticals, Sun Pharmaceutical Industries, and UCB outside the submitted work. Dr Smith reported receiving grants from Guy’s and St Thomas’ Biomedical Research Centre and the Psoriasis Association during the conduct of the study and grants from the Horizon 2020 Initiative and the Medical Research Council outside the submitted work. Dr Yazdany reported receiving grants from the American College of Rheumatology, Gilead Sciences, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases during the conduct of the study; grants from AstraZeneca and Bristol Myers Squibb; and personal fees from Aurinia Pharmaceuticals, Eli Lilly and Company, and Pfizer outside the submitted work. Dr Kappelman reported receiving grants from AbbVie, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion Pharm, Eli Lilly and Company, Genentech, Janssen Pharmaceuticals, Pfizer, and Takeda Pharmaceutical during the conduct of the study; personal fees from AbbVie, Eli Lilly and Company, Johnson & Johnson, Pfizer, and Takeda Pharmaceutical; and owning shares in Johnson & Johnson outside the submitted work. No other disclosures were reported.

Figures

Figure.
Figure.. Adjusted Odd Ratios (ORs) of COVID-19–Associated Hospitalization or Death Among Patients Receiving Immunomodulatory Treatment Regimens vs Tumor Necrosis Factor Inhibitor (TNFi) Monotherapy
Registry-specific and pooled analyses, with TNFi monotherapy used as the reference category. Pooled estimates were obtained using hierarchical multivariable mixed-effects logistic regression analysis with registry and calendar month random effects nested within country. Pooled sensitivity analysis (n = 5213) excludes patients with a presumptive COVID-19 diagnosis (defined as a diagnosis based on symptoms alone). All ORs were adjusted for age, sex, current smoking, immune-mediated disease activity (remission vs active), important comorbidities (cardiovascular disease, diabetes, hypertension, obstructive lung disease, interstitial or other chronic lung disease, kidney disease, obesity [body mass index ≥30; calculated as weight in kilograms divided by height in meters squared], and cancer), and prednisone-equivalent glucocorticoid dose. The pooled sensitivity analysis was also adjusted for concomitant receipt of leflunomide and oral budesonide. The pooled analysis (N = 6077) was additionally adjusted for concomitant receipt of sulfasalazine. The COVID-19 Global Rheumatology Alliance (GRA) registry-level analysis included 3441 patients and was adjusted for immune-mediated disease diagnosis and concomitant receipt of sulfasalazine, hydroxychloroquine or chloroquine, and leflunomide medications. The Psoriasis Patient Registry for Outcomes, Therapy and Epidemiology of COVID-19 Infection (PsoProtect) registry-level analysis included 300 patients. The Secure Epidemiology of Coronavirus Under Research Exclusion for Inflammatory Bowel Disease (SECURE-IBD) registry-level analysis included 2336 patients and was adjusted for immune-mediated disease diagnosis and concomitant receipt of mesalamine, sulfasalazine, and oral budesonide medications. AZA/6MP indicates azathioprine/6-mercaptopurine; JAKi, Janus kinase inhibitor; and MTX, methotrexate.
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