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.

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

Overall Infection Rates

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, with rates varying by agent and indication.

Other Safety Outcomes

• Malignancy incidence remained low and stable across indications. Van de Kerkhof et al. reported rates of 0.77 per 100 subject-years for secukinumab 300 mg and 0.97 for secukinumab 150 mg, comparable to etanercept at 0.68.

• Inflammatory bowel disease (IBD) events were uncommon across all indications.

• Neutropenia was consistently identified as a safety signal, though events were generally mild and transient.

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, intermediate in psoriatic arthritis, and lowest in ankylosing spondylitis. Serious infection rates showed the inverse pattern.

The therapeutic inhibition of IL-17A increases susceptibility to Candida infections, though the infections observed were predominantly mild-to-moderate and nonserious.

The increased risk of non-severe infections coupled with no increase in serious infections or opportunistic infections suggests IL-17A inhibition modestly reduces resistance to common pathogens without fundamentally compromising immune surveillance.