Reply to: “Do IL-17 inhibitors increase risk of respiratory tract infections?”
Authors: Marilyn T. Wan, Daniel B. Shin, Kevin L. Winthrop, Joel M. Gelfand
Journal: Journal of the American Academy of Dermatology (2020)

To the Editor: We thank Drs Blauvelt and Ehst1Blauvelt A.E. Ehst B.D. Do IL-17 inhibitors increase risk of respiratory tract infections?.J Am Acad Dermatol. 2020; 83: e303-e304Abstract Full Text Full Text PDF Scopus (2) Google Scholar for their comments about the meta-estimate we reported, in which there was a higher risk of developing respiratory tract infections in patients with psoriasis treated with interleukin (IL) 17–targeting biologics compared with placebo.2Wan M.T. Shin D.B. Winthrop K.L. Gelfand J.M. 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.J Am Acad Dermatol. 2020; 83: 677-679Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar Respiratory tract infections, which are usually innocuous, have become of special interest since the pandemic caused by severe acute respiratory syndrome coronavirus 2. Therefore, we conducted a meta-estimate to rigorously determine whether there is a safety signal for respiratory tract infection with biologics that target IL-17. First, Blauvelt and Ehst1Blauvelt A.E. Ehst B.D. Do IL-17 inhibitors increase risk of respiratory tract infections?.J Am Acad Dermatol. 2020; 83: e303-e304Abstract Full Text Full Text PDF Scopus (2) Google Scholar suggest that grouping secukinumab and ixekizumab (which block IL-17A) with brodalumab (which blocks IL-17RA) may be inappropriate because brodalumab has a broader mechanism of action, which could lead to differential infectious consequences. Brodalumab (odds ratio [OR] 2.14; 95% confidence interval [CI] 1.17-3.89) had the highest respiratory tract infection risk. Inconsistent with this hypothesis, however, is that rates of respiratory tract infection in secukinumab (OR 1.84; 95% CI 1.33-2.5) appeared more similar to those of brodalumab, with ixekizumab (OR 1.11; 95% CI 0.85-1.45) being the outlier. We agree further study is warranted. Second, Blauvelt and Ehst1Blauvelt A.E. Ehst B.D. Do IL-17 inhibitors increase risk of respiratory tract infections?.J Am Acad Dermatol. 2020; 83: e303-e304Abstract Full Text Full Text PDF Scopus (2) Google Scholar suggest that mucocutaneous candidiasis infections could explain the results and that loss of statistical significance in sensitivity analyses that eliminate terms that could be related to monilial infections (eg, oropharyngeal pain) suggests that IL-17 inhibitors are unlikely to be associated with increased respiratory tract infections. When oropharyngeal pain is excluded, the measure of association remains identical (OR 1.56), but the P value increases from 0.03 to 0.06. We emphasize that it is widely accepted scientifically that the focus is on the point estimate with 95% CIs, not arbitrary thresholds of statistical significance. Therefore, readers should not be reassured by a loss of statistical significance because, in fact, the results are essentially the same.3Ogdie A. Troxel A.B. Mehta N.N. Gelfand J.M. Psoriasis and cardiovascular risk: strength in numbers part 3.J Invest Dermatol. 2015; 135: 2148-2150Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar Third, Blauvelt and Ehst1Blauvelt A.E. Ehst B.D. Do IL-17 inhibitors increase risk of respiratory tract infections?.J Am Acad Dermatol. 2020; 83: e303-e304Abstract Full Text Full Text PDF Scopus (2) Google Scholar speculate that investigators and patients are unblinded, given that the treatment effects of IL-17 inhibitors are large and occur early. They then hypothesize that there may be both patient and investigator bias to report more adverse events on active drug. Alternatively, one might hypothesize the opposite, that patients responding well to treatment might not want to divulge symptoms that may result in drug discontinuation. Fourth, Blauvelt and Ehst1Blauvelt A.E. Ehst B.D. Do IL-17 inhibitors increase risk of respiratory tract infections?.J Am Acad Dermatol. 2020; 83: e303-e304Abstract Full Text Full Text PDF Scopus (2) Google Scholar raise concerns about labeling biologics used for psoriasis as "immunosuppressives" and state this terminology can lead to misplaced "fear of biologics." Although we appreciate the authors' concern, we are merely using the terminology applied by the Food and Drug Administration.4Center for Drug Evaluation and Research. Application number: 125521Orig1s000.https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/125521Orig1s000OtherRedt.pdfDate accessed: May 5, 2020Google Scholar Fifth, we appreciate that Blauvelt and Ehst1Blauvelt A.E. Ehst B.D. Do IL-17 inhibitors increase risk of respiratory tract infections?.J Am Acad Dermatol. 2020; 83: e303-e304Abstract Full Text Full Text PDF Scopus (2) Google Scholar share their opinion that IL-17 inhibitors do not increase the risk of developing respiratory tract infections, according to their clinical experience. We, too, have treated hundreds of patients with IL-17 inhibitors. We are humbled to know that clinical experience alone is insufficient to determine these risks,5Sackett D.L. Rosenberg W.M.C. Gray J.A.M. Haynes R.B. Richardson W.S. Evidence based medicine: what it is and what it isn't.BMJ. 1996; 312: 71-72Crossref PubMed Google Scholar and therefore our laboratory is committed to providing our colleagues and patients with the best, most rigorous assessments of available data combined with a measured interpretation of the results. We certainly agree with Blauvelt and Ehst1Blauvelt A.E. Ehst B.D. Do IL-17 inhibitors increase risk of respiratory tract infections?.J Am Acad Dermatol. 2020; 83: e303-e304Abstract Full Text Full Text PDF Scopus (2) Google Scholar that more meticulous evaluation of the risk of respiratory tract infections associated with various classes of biologics used to treat psoriasis is needed. Reply to: Do interleukin 17 inhibitors increase risk of respiratory tract infections?Journal of the American Academy of DermatologyVol. 83Issue 4PreviewTo the Editor: In a recent meta-estimate, Wan et al1 conclude that patients with psoriasis on interleukin (IL) 17 blockers are possibly at increased risk of respiratory tract infections (RTIs). We agree with the need and wisdom to better understand the infectious risk that these medications pose; however, we take issue with the manner in which the data were derived and how the discussion was framed, especially during the coronavirus disease 2019 (COVID-19) pandemic. Full-Text PDF