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    3 Comments for this article
    Does Interleukin Inhibitors Increase the Infection Risk?
    Serdal Ugurlu, MD | University of Istanbul-Cerrahpasa
    I have certain points to understand the conclusion that can be made related to increased infectious risk.
    To begin with the methods, obtained data at the longest follow-up duration might hinder a placebo control comparison. The relative difference in exposure times with the treatment arm and placebo arm can cause a false-positive result.
    Referring to the odds ratios for serious infections stratified by individual drugs, we have specific concerns regarding Anakinra treatment. First, the inclusion of rheumatoid arthritis (RA) in this group of patients causes confusion. According to the American College of Rheumatology (ACR) treatment guidelines, Anakinra is
    indeed excluded from RA treatment (1). Since probable low Anakinra treatment response in RA brings along increased steroid use, this high steroid dose can give rise to a false impression of Anakinra being the cause of these infections. For instance, there are no such studies on RA patients with Rilonacept as an IL-1 inhibitor. A presumable inclusion of a Rilonacept study would have also incorrectly increased the infection odds ratio as well whereas in this review the odds ratio of Rilonacept is not increased. Second, autoinflammatory diseases, such as Familial Mediterranean Fever (FMF), have a different nature when compared to autoimmune conditions. Referring to the Figure 3 (Odds ratios for serious infections stratified by individual drug), the inclusion of Anakinra treatment in FMF can improve our understanding of the infection risk of this treatment method (2). Furthermore, evaluating FMF and RA patients in the same group might not be applicable in interpreting the infection risk.
    In addition, patients who have gout, often complicate with many comorbid conditions such as diabetes mellitus (3). These comorbidities can potentially be confounding factors in this study, resulting in infections.
    It would be of interest to hear the opinion of the authors on these points to understand the infection risk with interleukin inhibitor treatments.
    1. Singh JA, Saag KG, Bridges SL Jr, et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Rheumatol. 2016 Jan;68(1):1-26.
    2. Ben-Zvi I, Kukuy O, Giat E, et al. Anakinra for Colchicine-Resistant Familial Mediterranean Fever: A Randomized, Double-Blind, Placebo-Controlled Trial. Arthritis Rheumatol. 2017 Apr;69(4):854-862.
    3. Pillinger MH, Goldfarb DS, Keenan RT. Gout and its comorbidities. Bull NYU Hosp Jt Dis. 2010;68(3):199-203.
    Serdal Ugurlu, Professor: Division of Rheumatology, Department of Internal Medicine, Cerrahpasa Medical Faculty, University of Istanbul-Cerrahpasa, Istanbul, Turkey
    Bugra Han Egeli, Medical Doctor; Cerrahpasa Medical Faculty, University of Istanbul-Cerrahpasa, Istanbul, Turkey
    Doubts on increased cancer risk
    Martin Aringer, MD, Hendrik Schulze-Koops, MD | Division of Rheumatology, Rheumatology, University Medical Center & Faculty of Medicine TU Dresden; Rheumatology & Clinical Immunology, Ludwig Maximilian University, Munich
    We have with interest, but also with increasing concern, read and discussed this metaanalysis on the risk of infections and cancer in patients with rheumatologic diseases receiving interleukin inhibitors. The article has led to non-justified insecurity in patients with rheumatic diseases treated with biological disease modifying anti-rheumatic drugs (bDMARDs). In particular, the data on an increased rate of malignancy within six to twelve months of starting a bDMARD have made patients anxious and worried. While we find the approach of a metaanalysis of all available studies interesting, we have sincere issues with the factual way this analysis was performed and interpreted.
    First, for a rheumatologist, combining cytokines like interleukin-1 (IL-1), IL-6, IL-17 and IL-23 into one group is the equivalent of treating chicken, pork and beef the same. There are robust immunological and, importantly, functional differences between these cytokines. Second, not distinguishing between non-melanoma skin cancer, a disease that can be easily detected and healed, and solid organ tumors is troublesome in that it may exaggerate the risks patients face under such therapies.
    Third, and most relevant, we believe that data have been included that should not be in this metaanalysis. For example, the publication that has the most relevant difference in IL-6/IL-6 receptor blockade versus placebo, namely 40/1149 vs 1/392 patients in the placebo arm, apparently is the 5 year long-term extension of the LITHE trial, with the primary results published in 2011 (Kremer et al., Arthritis Rheum 2011;63:609ff). In the randomized part of this trial, only 12/797 patients treated with tocilizumab were reported to have developed a malignancy, vs 4/393 in the placebo arm, according to the combined information of both the relevant manuscripts. Similarly, in the sirukumab SIRROUND-T trial, only 5 of the 9 referenced malignancies occurred in the placebo-controlled phase (Aletaha et al., Lancet 2017;389:1206ff). To include events in long-term extension phases, which are not placebo-controlled, into such an analysis as performed by Dr. Bilal and colleagues is incorrect.
    The same concern extends to IL-17 blockade, where the study with highest number of malignancies (10/387 vs 0/98 in the placebo arm) apparently is the extension phase of the FUTURE2 trial. Moreover, the actual data of the primary manuscript are already shown in the line directly above (3/299 vs 0/98) in the table of the Bilal et al. manuscript, and thus apparently were counted twice. These issues shed sincere doubt on the authors’ findings of increased malignancy risks.
    Finally, the authors’ data actually show that the targeted interleukins are not equal. Under IL-1-targeting therapies, a smaller percentage than in the placebo arm were afflicted by some kind of malignancy, namely 7/1,663 patients (0.4%) vs 7/478 (1.5%) under placebo. Under IL-6 (receptor) blockade, the 58/7,639 patients (0.8%) with a newly diagnoses malignancy represent a similar frequency as the 24/3,231 (0.7%) in the placebo arm, when inclusion was corrected as explained above. Beyond the immunological background, these facts strongly argue against lumping bDMARDs targeting completely different cytokines.

    Martin Aringer, MD, Rheumatology, University Medical Center and Faculty of Medicine TU Dresden, Dresden, Germany

    Hendrik Schulze-Koops, MD, Rheumatology and Clinical Immunology, Ludwig Maximilian University, Munich, Gernamy
    CONFLICT OF INTEREST: Advisory boards Advisory Boards AbbVie, Astra Zeneca, BMS, Boehringer Ingelheim, Chugai, HEXAL, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi, UCB.
    Response to comments regarding infection and cancer risk
    Jawad Bilal, MD | Division of Rheumatology, Department of Medicine, University of Arizona, Tucson
    We have the read the comments of our colleagues with interest and appreciate an opportunity to respond to these comments.

    We acknowledge the possible heterogeneity between individual drugs and that variations between drugs may occur in any drug class. In the published manuscript, we had presented the risks for each individual drug, where possible, and reported heterogeneity statistics with each analysis.

    While it is true that majority of cancers were non-melanoma skin cancers in individuals using IL inhibitors, it should be noted that there were 98 cases of cancers in treatment group compared to 22 in placebo group
    after exclusion of non-melanoma skin cancers. Thus, an increased risk of clinically important malignancies remains a concern.

    We included the longest available event data for treatment groups to capture the longest term effects. Long term follow up can potentially introduce certain biases. In the published manuscript, we had acknowledged this trade off in significant detail in the limitations section of the manuscript.

    Finally, we want to offer sincere thanks in pointing out a duplicate inclusion of a study. We have removed the study, repeated the analysis, and found no changes in the results. The online erratum with regards to Figure 3 is published.
    Original Investigation
    October 18, 2019

    Risk of Infections and Cancer in Patients With Rheumatologic Diseases Receiving Interleukin Inhibitors: A Systematic Review and Meta-analysis

    Author Affiliations
    • 1Division of Rheumatology, Department of Medicine, University of Arizona, Tucson
    • 2Division of Rheumatology, Department of Medicine, University of Colorado, Denver
    • 3Division of Hematology/Oncology, Department of Medicine, Mayo Clinic Rochester, Rochester, Minnesota
    • 4Division of Hematology/Oncology, Department of Medicine, University of Arizona, Tucson
    • 5College of Pharmacy, Department of Pharmacy Practice and Science, University of Arizona, Tucson
    • 6Department of Medicine, University of Arizona, Tucson
    • 7Evidence-Based Practice Center, Mayo Clinic Rochester, Rochester, Minnesota
    • 8Mayo Clinic Libraries, Mayo Clinic Rochester, Rochester, Minnesota
    • 9College of Pharmacy, Department of Clinical Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
    • 10University of Arizona Arthritis Center, University of Arizona, Tucson
    JAMA Netw Open. 2019;2(10):e1913102. doi:10.1001/jamanetworkopen.2019.13102
    Key Points español 中文 (chinese)

    Question  What is the risk of serious infections, opportunistic infections, and cancer in patients with rheumatologic diseases treated with interleukin inhibitors?

    Findings  In this systematic review and meta-analysis of 74 randomized clinical trials comprising 29 214 patients, pooled results suggest that risk of serious infections, opportunistic infections, and cancer is increased in patients with rheumatologic diseases who are treated with interleukin inhibitors compared with placebo.

    Meaning  This analysis suggests estimates of risk for infections and cancer associated with the use of interleukin inhibitors that can inform shared decision-making when patients and clinicians are contemplating the use of interleukin inhibitors for rheumatologic diseases.


    Importance  The safety profile of interleukin (IL) inhibitors is not well established.

    Objective  To assess the risk of serious infections, opportunistic infections, and cancer in patients with rheumatologic diseases treated with IL inhibitors.

    Data Sources  Ovid MEDLINE and Epub Ahead of Print, In-Process & Other Non-Indexed Citations; Ovid MEDLINE Daily; Ovid Embase; Ovid Cochrane Central Register of Controlled Trials; Ovid Cochrane Database of Systematic Reviews; and Scopus were searched (inception to November 30, 2018).

    Study Selection  Randomized, placebo-controlled trials that evaluated IL inhibitor therapies in rheumatic diseases and reported safety data were included in the analyses.

    Data Extraction and Synthesis  This systematic review is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. Two investigators independently extracted study data and assessed risk of bias and certainty in the evidence. Fixed-effects meta-analysis was conducted to pool odds ratios (ORs) for serious infections, opportunistic infections, and cancers for IL inhibitors vs placebo.

    Main Outcomes and Measures  The outcomes of interest were the number of serious infections, opportunistic infections, and cancers in individuals receiving IL inhibitor therapies compared with placebo.

    Results  In this meta-analysis, 74 studies comprising 29 214 patients (24 236 patients for serious infections, 9998 for opportunistic infections, and 21 065 for cancer [number of patients overlaps for each outcome]) were included. Patients receiving IL inhibitors had a higher risk of serious infections (OR, 1.97; 95% CI, 1.58-2.44; P < .001, I2 = 0%; high certainty), opportunistic infections (OR, 2.35; 95% CI, 1.09-5.05; P = .03, I2 = 0%; moderate certainty), and cancer (OR, 1.49; 95% CI, 1.04-2.16; P = .03, I2 = 11%; moderate certainty).

    Conclusions and Relevance  The risk of serious infections, opportunistic infections, and cancer appears to be increased in patients with rheumatologic diseases who are treated with IL inhibitors compared with placebo.