The risk of respiratory tract infections and symptoms in psoriasis patients treated with interleukin 17 pathway–inhibiting biologics: A meta-estimate of pivotal trials relevant to decision making during the COVID-19 pandemic

Abstract

To the Editor: Biologic agents have revolutionized psoriasis treatment.1Menter A. Strober B.E. Kaplan D.H. et al.Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with biologics.J Am Acad Dermatol. 2019; 80: 1029-1072Abstract Full Text Full Text PDF PubMed Scopus (364) Google Scholar However, they are considered “immunosuppressive,” and thus, safety assessments focus on infection, particularly those that are serious or opportunistic, or both. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has focused attention on respiratory track infections (RTIs).2Lebwohl M. Rivera-Oyola R. Murrell D.F. Should biologics for psoriasis be interrupted in the era of COVID-19?.J Am Acad Dermatol. 2020; 82: 1217-1218Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar The conceptual model of COVID-19 is that immunosuppression early in disease may be harmful, yet may be helpful in “late” severe COVID-19 illness; which may be mediated by a dysregulated hyperimmune response characterized by proinflammatory cytokines including interleukin 17 (IL-17).3Schett G. Sticherling M. Neurath M.F. COVID-19: risk for cytokine targeting in chronic inflammatory diseases?.Nat Rev Immunol. 2020; 20: 271-272Crossref PubMed Scopus (233) Google Scholar The effect of IL-17 inhibitors on COVID-19 is unknown, neither the risk of initial infection nor the risk of progression to worse disease. Current understanding of viral immunology suggests that IL-17 is not a dominant cytokine in viral immunity; however, IL-17 is important to mucosal immunity, raising the hypothesis that biologics targeting IL-17 could potentially increase RTI risk.4Das S. Khader S. Yin and yang of interleukin-17 in host immunity to infection.F1000Res. 2017; 6: 741Crossref PubMed Scopus (53) Google Scholar To test this hypothesis, we calculated a meta-estimate from the placebo-controlled period of phase 3 pivotal IL-17 trials of terms consistent with RTI of secukinumab, ixekizumab, and brodalumab abstracted from United States Food and Drug Administration prescribing information. RTI is a broad term classified by clinical judgment. The Medical Dictionary for Regulatory Activities (MedDRA), used to classify adverse events (AEs), has multiple terms for RTIs. To assess for RTIs, we summed the number of AEs that are associated with RTIs, divided by the total number of subjects in each study, and then calculated a meta-estimate. We found an increased risk of RTIs in the groups receiving IL-17 inhibitors compared with placebo (odds ratio, 1.56; 95% confidence interval, 1.04-2.33; Fig 1). Because prescribing information is not inclusive of all respiratory AEs from the pivotal trials that supported approval of IL-17 inhibitors, we conducted a summary risk estimate using data from the placebo-controlled period of these studies obtained from clinicaltrials.gov. This more detailed analysis yielded similar findings to our meta-estimate of prescribing information data (odds ratio, 1.31; 95% confidence interval, 1.05-1.62; Fig 2). Sensitivity analyses varying the terms analyzed yielded similar findings but with loss of statistical significance. Evaluating the risk of RTI in clinical trials is difficult because the diagnosis is made clinically without objective testing, and therefore, the etiology of these symptoms, be they viral, bacterial, fungal, or allergic, is unknown. Furthermore, there is substantial variation in the rates of RTIs in the placebo groups across the trials, demonstrating a lack of precision in measuring this outcome. For example, rates of “upper RTI” ranged from 0.0% to 7.44% in the placebo groups evaluated. In addition, owing to variation in reporting of MedDRA terms, the events were unevenly pooled because terms are reported inconsistently. It is also possible that patients may have had more than one RTI event, which could impact our estimates. These findings highlight the need for more meticulous evaluation of the impact of IL-17 inhibitors on RTIs in the setting of the novel coronavirus pandemic. Nevertheless, our meta-estimate demonstrates a potential safety signal for RTI associated with IL-17 inhibition and supports guidance issued by American Academy of Dermatology that clinicians should use their clinical judgment to continue or discontinue patients on these drugs in patients who have not tested positive or exhibited symptoms of COVID-19 and to discontinue these agents in patients who test positive for COVID-19 symptoms.5American Academy of Dermatology AssociationGuidance on the use of immunosuppressive agents.https://www.aad.org/member/practice/coronavirus/clinical-guidance/biologicsDate accessed: April 24, 2020Google Scholar Reply to research letterJournal of the American Academy of DermatologyVol. 83Issue 6PreviewTo the Editor: In light of the current coronavirus disease 2019 (COVID-19) pandemic, scientists have debated the safety of immunosuppressive biologic therapies. We read with interest the letter by Wan et al,1 “The risk of respiratory tract infections and symptoms in psoriasis patients treated with interleukin 17-pathway inhibiting biologics: A meta-estimate of pivotal trials relevant to decision-making during the COVID-19 pandemic.” We agree that caution should be used when exposing patients to systemic biologic agents in the setting of not only COVID-19 but also any acute or chronic infection, as Kaushik and Lebwohl2 have previously emphasized. Full-Text PDF