Risk of candidiasis associated with interleukin-17 inhibitors: A real-world observational study of multiple independent sources

Abstract

Summary Background Biologics directed against the T-helper (Th)-17 pathway have been approved for several inflammatory diseases. Interleukin (IL)-17 is involved in anti- Candida host defense, and clinical trials suggested increased candidiasis incidence during IL-17 inhibitor therapy. We describe the worldwide epidemiology of candidiasis during Th17 inhibitor therapy, and immunological mechanisms involved in candidiasis susceptibility. Methods A comprehensive analysis of multiple independent sources reporting Candida adverse events during biologics inhibiting the Th17 pathway was performed. Association between Th17 inhibitors and candidiasis was assessed using safety reports of (1) WHO and (2) EMA, (3) a population-based prescriptions registry, and (4) a psoriasis cohort. In a cohort of psoriasis patients experiencing candidiasis during Th17 inhibitors, Candida killing by immune cells and serum inflammatory proteome were analyzed. Findings A strong association between IL-17 inhibitors and candidiasis (ROR 10·20) was found in the WHO database, particularly for cutaneous (ROR 12·28), oropharyngeal (ROR 19·18), and esophageal candidiasis (ROR 21·20). Risk was higher relative to TNF-α inhibitors (4–10-fold, depending on candidiasis type), confirmed by EMA reports (16–33-fold), prescriptions registry (2–42-fold), and a psoriasis cohort (3–25-fold). After start of IL-17 inhibitors, patients’ risk of candidiasis requiring antifungals increased 2–16 fold. In the psoriasis cohort, 58% of IL-17 treatment episodes were associated with candidiasis. In Th17 inhibitor recipients, proteins involved in anti- Candida immunity and Candida killing by mononuclear leukocytes were impaired. Interpretation IL-17 inhibitors are associated with an increased risk of oropharyngeal, esophageal, and cutaneous candidiasis, posing a significant disease burden for IL-17 inhibitor recipients. Funding RadboudUMC.

Radiation Exposure Perturbs IL-17RA-Mediated Immunity Leading to Changes in Neutrophil Responses That Increase Susceptibility to Oropharyngeal Candidiasis

“…In one example of experimental vulvovaginal candidiasis (VVC), IL-17 was dispensable for protection against infection [ 23 ]. This aligns with data from humans where IL-17 deficiency does not lead to increased susceptibility to VVC [ 24 ]. Yet, others have shown that IL-17 is beneficial against Candida in the vaginal tract [ 25 ].…”

“…These findings could also be relevant to individuals receiving therapies targeting the Th17/IL-17 axis for autoimmune conditions, including psoriasis. Patients receiving these IL-17-related inhibitors have an increased risk of developing Candida infections, especially oropharyngeal and esophageal candidiasis [ 24 ]. In the HNI-induced OM model, when WT mice were administered α-IL-17A antibodies, more severe damage to the oral cavity developed [ 28 ].…”

Arid5a mediates an IL-17-dependent pathway that drives autoimmunity but not antifungal host defense

“…Anti-IL-17 therapy is not associated with risks to systemic candidiasis, likely because the major mechanisms of antifungal control at cutaneous/mucosal surfaces is through neutrophil recruitment and β-defensin production whereas circulating neutrophils are less IL-17-dependent (4, 41, 53, 54). In contrast, during systemic candidiasis IFN-γ, IL-12 as well as IL-17 signaling contribute to effective immunity against C. albicans (55–57).…”

“…Conversely, IL-17 and Type 17 cells have been implicated in the pathogenesis of many autoimmune and inflammatory diseases (3), highlighted in the success of anti-cytokine drugs targeting IL-17 or the IL-17 receptor. Though unquestionably these drugs have improved patients' disease activity and quality of life, their use is associated with adverse side effects including worsening bowel inflammation in patients with inflammatory bowel disease (IBD) and the frequent development of opportunistic fungal infections, especially oral and espophageal candidiasis (4)(5)(6).…”

Comorbidity in Adult Psoriasis: Considerations for the Clinician

“…Biologics are associated with slightly increased risk of infections, and anti-IL17 agents are associated with an increased risk of mucocutaneous candidiasis. 171 Risks of serious infections are generally slightly higher for patients on anti-TNF than on anti-IL17 and anti-IL23 agents. 158 Increased awareness of infections and candidiasis and prescription of relevant treatment are warranted in patients on biologics and other immunomodulators.…”