IL-17A Antagonism: Safety and Immunologic Impacts

Safety and immunologic consequences of IL-17A antagonism (infections, hypersensitivity)

IL-17A antagonists demonstrate a favorable safety profile with the primary immunologic consequence being an increased risk of mild-to-moderate mucocutaneous Candida infections, while serious infections, opportunistic infections, and hypersensitivity reactions remain uncommon and other safety outcomes stable over long-term follow-up.

Abstract

IL-17A antagonists demonstrate a favorable safety profile across psoriasis, psoriatic arthritis, and ankylosing spondylitis, with the most consistent safety signal being an increased risk of Candida infections. Candida infection rates varied by indication (2.2-2.9 per 100 patient-years in psoriasis, 1.5 in psoriatic arthritis, 0.7 in ankylosing spondylitis), were predominantly mild-to-moderate and mucocutaneous, and showed a dose-response relationship with secukinumab (3.55 per 100 subject-years at 300 mg versus 1.85 at 150 mg). In contrast, serious infection rates remained low (1.2-1.9 per 100 patient-years) with no significant increase compared to placebo, opportunistic infections were rare (<0.2 per 100 patient-years), and no tuberculosis reactivation cases occurred in pooled clinical trials. Hypersensitivity reactions were uncommon, with injection site reactions occurring at low rates (0.6-1.6 per 100 patient-years with secukinumab), though rates varied substantially between different IL-17A antagonists. Anti-drug antibody development occurred in less than 1% of patients without clinical consequences.

Other safety outcomes remained low and stable in long-term follow-up. Major adverse cardiovascular events occurred at rates below 0.7 per 100 patient-years without temporal increase, malignancy incidence remained at or below 1 per 100 patient-years, inflammatory bowel disease was uncommon (0.01-0.4 per 100 patient-years), and neutropenia was generally mild and transient. Comprehensive pooled analyses including over 12,000 patients with up to 5 years of exposure and post-marketing surveillance data exceeding 96,000 patient-years demonstrated no increase in serious adverse events, infections, or other safety outcomes over time, supporting the long-term safety of IL-17A antagonism across inflammatory conditions.

Methods

We analyzed 10 sources from an initial pool of 200, using 9 screening criteria. Each paper was reviewed for 8 key aspects that mattered most to the research question.

Paper search

We performed a semantic search across over 138 million academic papers from the Elicit search engine. We retrieved 200 papers most relevant to the query for screening.

Screening

We screened in sources based on their abstracts that met several safety outcome related criteria, including study design, approved indications, human subjects, and clinical research.

Data extraction

We extracted various data columns related to IL-17A antagonist, patient population, study design, infection outcomes, hypersensitivity reactions, other safety outcomes, risk factors, and safety comparisons.

Results

Characteristics of Included Studies

This review included 10 sources comprising primary randomized controlled trials, systematic reviews and meta-analyses, and pooled analyses with post-marketing surveillance data examining IL-17A antagonists across multiple indications.

Infection Outcomes

Infection rates varied across studies and indications, with most reporting exposure-adjusted incidence rates per 100 patient-years.

Fungal Infections

Candida infections emerged as a consistent safety signal across IL-17A antagonist therapy.

Hypersensitivity and Immunogenicity Outcomes

Injection Site Reactions

Other Safety Outcomes

Major adverse cardiovascular events (MACE) remained low across all indications, with rates below 0.7 per 100 patient-years.

Conclusion

Safety outcomes with IL-17A antagonists showed clear patterns that varied by indication and patient population. Candida infection rates were highest in psoriasis patients. Serious infection rates showed the inverse pattern. No dose-response relationship was observed for serious adverse events, serious infections, cardiovascular events, or malignancy. The absence of tuberculosis reactivation cases contrasts with the tuberculosis risk observed with TNF inhibitors.