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.

• Papers screened using: IL-17A Antagonist Intervention, Safety Outcomes Reported, Appropriate Study Design, Human Subjects, Approved Indications, Clinical Research, Adequate Sample Size, Safety Data Inclusion, Original Research Publication
• n = 200

Paper search

We performed a semantic search across over 138 million academic papers from the Elicit search engine, which includes Semantic Scholar and OpenAlex.

We ran this query: “Safety and immunologic consequences of IL-17A antagonism (infections, hypersensitivity)”

The search returned 200 total results from Elicit. We retrieved 200 papers most relevant to the query for screening.

Screening

We screened in sources based on their abstracts that met these criteria:

• IL-17A Antagonist Intervention: Does this study involve patients treated with IL-17A antagonists (secukinumab, ixekizumab, brodalumab, bimekizumab, or other IL-17A inhibitors)?
• Safety Outcomes Reported: Does this study report safety outcomes related to infections, hypersensitivity reactions, or other immunologic consequences?
• Appropriate Study Design: Is this study a randomized controlled trial, observational study (cohort, case-control), case series with ≥10 patients, systematic review, or meta-analysis?
• Human Subjects: Does this study involve human subjects of any age?
• Approved Indications: Does this study involve patients with any approved indication for IL-17A antagonists (such as psoriasis, psoriatic arthritis, ankylosing spondylitis, etc.)?
• Clinical Research: Is this study clinical research (not in vitro, animal, or preclinical research)?
• Adequate Sample Size: Is this study NOT a case report or case series with fewer than 10 patients?
• Safety Data Inclusion: Does this study report safety data (not focusing solely on efficacy outcomes without safety reporting)?
• Original Research Publication: Is this study a full research publication (not a conference abstract, letter, editorial, or commentary without original data)?

We considered all screening questions together and made a holistic judgement about whether to screen in each paper.

Data extraction

We asked a large language model to extract each data column below from each paper. We gave the model the extraction instructions shown below for each column.

• IL-17A Antagonist: Extract details about the IL-17A antagonist used, including:

  • Drug name (e.g., secukinumab, ixekizumab, brodalumab)
  • Dosage and frequency
  • Route of administration
  • Duration of treatment
  • Any comparator treatments included

• Patient Population: Extract patient population characteristics relevant to IL-17A antagonist safety, including:

  • Medical condition being treated (psoriasis, psoriatic arthritis, ankylosing spondylitis, etc.)
  • Sample size for safety analysis
  • Age range and mean age
  • Prior immunosuppressive therapy exposure
  • Baseline infection risk factors or immunocompromised status

• Study Design: Extract study design elements that affect safety data quality, including:

  • Study type (RCT, observational, post-marketing surveillance)
  • Safety follow-up duration
  • Total patient-years of exposure
  • Whether active safety monitoring was conducted
  • Loss to follow-up rates for safety outcomes

• Infection Outcomes: Extract all infection-related safety outcomes from IL-17A antagonist therapy, including:

  • Overall infection rates (per 100 patient-years or other measure)
  • Serious infection rates and types
  • Opportunistic infections (specify organisms/types)
  • Fungal infections, particularly Candida infections
  • Tuberculosis (active or reactivation)
  • Upper respiratory tract infections
  • Other specific infection types mentioned
  • Time to infection onset if reported

• Hypersensitivity Reactions: Extract all hypersensitivity and allergic reaction outcomes from IL-17A antagonist therapy, including:

  • Injection site reactions (rates and severity)
  • Systemic allergic reactions or anaphylaxis
  • Drug hypersensitivity reactions
  • Skin reactions (rash, urticaria, etc.)
  • Anti-drug antibody development and clinical consequences
  • Any immunogenicity-related adverse events

• Other Safety Outcomes: Extract other important safety outcomes beyond infections and hypersensitivity from IL-17A antagonist therapy, including:

  • Malignancy incidence
  • Major adverse cardiovascular events
  • Inflammatory bowel disease
  • Neutropenia or other hematologic effects
  • Serious adverse events overall
  • Treatment discontinuation due to adverse events
  • Deaths and causes

• Risk Factors: Extract any identified risk factors or predictors for safety outcomes with IL-17A antagonist therapy, including:

  • Patient characteristics associated with increased infection risk
  • Dose-related safety patterns
  • Time-dependent changes in safety outcomes
  • Concomitant medications affecting safety
  • Baseline disease severity impact on safety

• Safety Comparisons: Extract comparative safety data when available, including:

  • Safety outcomes compared to placebo
  • Safety outcomes compared to other biologics (TNF inhibitors, etc.)
  • Safety differences between different IL-17A antagonists
  • Safety differences between doses of the same drug
  • Long-term vs short-term safety patterns

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.

Five studies had full text available, while five relied on abstract-only data. Studies included primary RCTs, systematic reviews and meta-analyses, and large pooled safety analyses incorporating post-marketing surveillance data. The included IL-17A antagonists were secukinumab, ixekizumab, brodalumab, bimekizumab, and netakimab, with secukinumab being the most extensively studied agent across all three major indications (psoriasis, psoriatic arthritis, and ankylosing spondylitis).

Infection Outcomes

Overall Infection Rates

Treatment-emergent adverse events were significantly more common with IL-17 inhibitors compared to placebo in ankylosing spondylitis patients (RR 1.11, 95% CI 1.01-1.22). Upper respiratory tract infections were consistently the most common infection type across all indications. Serious infection rates were low across all indications, ranging from 1.2 to 1.9 per 100 patient-years, with no increased risk compared to placebo in meta-analyses.

Fungal Infections

Candida infections emerged as a consistent safety signal across IL-17A antagonist therapy, with rates varying by agent and indication.

Candida infections were consistently more common with IL-17A antagonists compared to placebo across multiple studies. The infections were predominantly nonserious and mild-to-moderate in severity, with oral candidiasis being the most common presentation. A clear dose-response relationship was observed for secukinumab in psoriasis, with the 300 mg dose showing higher rates (3.55 per 100 SYs) compared to the 150 mg dose (1.85 per 100 SYs). Notably, Candida infection rates varied by indication, being highest in psoriasis (2.2-2.9 per 100 PY) and lowest in ankylosing spondylitis (0.7 per 100 PY).

Opportunistic and Other Specific Infections

Opportunistic infections were rare across all indications, with incidence rates below 0.2 per 100 patient-years. No cases of tuberculosis reactivation were reported in the large pooled analysis by Deodhar et al., though five active tuberculosis cases were identified in post-marketing surveillance. The specific opportunistic infections documented included esophageal and gastrointestinal candidiasis, herpes zoster, toxoplasmosis, and Mycobacterium avium complex infection. Viral infections showed no increased risk compared to placebo, with exposure-adjusted incidence rates ranging from 2.7 to 3.5 per 100 patient-years across indications.

Hypersensitivity and Immunogenicity Outcomes

Injection Site Reactions

Injection site reactions occurred at low rates with secukinumab across all indications, ranging from 0.6 to 1.6 per 100 patient-years. Rates were lowest in ankylosing spondylitis patients. Among different IL-17A antagonists, ixekizumab showed the highest rate of injection site reactions (RR 3.97), while secukinumab had the lowest (RR 0.49). These reactions were consistently reported as one of the most frequent adverse events across phase II trials.

Hypersensitivity Reactions and Anti-Drug Antibodies

Hypersensitivity reactions were uncommon with IL-17A antagonists. The reporting rate for hypersensitivity was 2.4 per 100 patient-years in the pooled analysis by Deodhar et al.. Development of treatment-emergent anti-drug antibodies (ADAs) occurred in less than 1% of patients, with no discernible impact on efficacy or pharmacokinetics. One case of immunogenicity was reported, but it did not result in clinically significant consequences.

Allergic reactions or hypersensitivities were actually less common with IL-17 inhibitors compared to control groups in psoriatic arthritis patients (RR 0.72). This finding contrasts with the expectation that immunologic therapies would increase allergic reactions, suggesting that IL-17A antagonism may not substantially increase systemic hypersensitivity risk.

Other Safety Outcomes

Cardiovascular Events

Major adverse cardiovascular events (MACE) remained low across all indications and studies, with rates below 0.7 per 100 patient-years. In the psoriatic arthritis trial by Mease et al., four patients receiving secukinumab experienced stroke (0.6 per 100 patient-years) and two had myocardial infarction (0.3 per 100 patient-years), compared to zero events in the placebo group. However, MACE rates were comparable between secukinumab and etanercept in psoriasis patients. Importantly, no apparent increase in MACE occurred over time in long-term follow-up studies.

Malignancy

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. In the comprehensive analysis by Deodhar et al., psoriasis patients showed an exposure-adjusted incidence rate of 0.8 per 100 patient-years, with 76 non-hematological malignant tumors, 2 hematological malignant tumors, and 1 hematological tumor of unspecified malignancy documented. The updated pooled analysis by Gottlieb et al. confirmed malignancy incidence remained at or below 1 per 100 patient-years, with no increase observed over time.

Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) events were uncommon across all indications. Deodhar et al. reported exposure-adjusted incidence rates ranging from 0.01 to 0.1 per 100 patient-years in psoriasis, 0.05 to 0.08 in psoriatic arthritis, and 0.1 to 0.4 in ankylosing spondylitis. The higher rate in ankylosing spondylitis patients likely reflects the known association between this condition and IBD rather than a treatment effect. Gottlieb et al. confirmed low IBD incidence of 0.01 to 0.4 per 100 patient-years across indications. Meta-analyses found no significant difference in IBD incidence between IL-17 inhibitors and control groups.

Hematologic Effects

Neutropenia was consistently identified as a safety signal, though events were generally mild and transient. Deodhar et al. reported exposure-adjusted incidence rates of 0.3 per 100 patient-years in psoriasis, 0.2 in psoriatic arthritis, and 0.5 in ankylosing spondylitis. In ankylosing spondylitis patients, neutropenia showed a significant increase with IL-17 inhibitors compared to placebo (risk difference 0.04, P=0.03). Phase II trials noted that a small percentage of patients experienced low-grade neutropenia that was predominantly transient and asymptomatic.

Serious Adverse Events and Treatment Discontinuation

Serious adverse event rates were consistently low, ranging from 6.3 to 7.9 per 100 patient-years across indications, with no significant difference compared to placebo in meta-analyses. Treatment discontinuation due to adverse events occurred in 5.3-7.7% of patients across indications. Deaths were rare, occurring in 0.2-0.8% of patients. Causes of death in psoriasis patients included pulmonary embolism, arrhythmia, and alcohol poisoning; in psoriatic arthritis patients, acute myocardial infarction and septic shock; and in ankylosing spondylitis patients, acute respiratory failure and cerebrovascular accident.

Synthesis

Context and Population Distinctions

Safety outcomes with IL-17A antagonists showed clear patterns that varied by indication and patient population. Candida infection rates were highest in psoriasis patients (2.2-2.9 per 100 patient-years), intermediate in psoriatic arthritis (1.5 per 100 patient-years), and lowest in ankylosing spondylitis (0.7 per 100 patient-years). This gradient likely reflects differences in baseline mucocutaneous immune function and the extent of IL-17-dependent defense mechanisms at different anatomic sites. Psoriasis patients with disrupted skin barrier function and pre-existing cutaneous inflammation may have greater vulnerability to mucocutaneous candidiasis when IL-17A is inhibited.

Serious infection rates showed the inverse pattern, being highest in psoriatic arthritis patients (1.8-1.9 per 100 patient-years) and lowest in ankylosing spondylitis (1.2 per 100 patient-years). This may reflect the higher prevalence of metabolic comorbidities in the psoriatic arthritis population, including hypertension (39.9%), hyperlipidemia (23.0%), and diabetes (12.4%), as well as higher body mass index. These baseline characteristics likely contributed to infection susceptibility independent of IL-17A antagonism. Additionally, 23-35% of psoriatic arthritis patients had inadequate response to or intolerance of TNF inhibitors, suggesting a more treatment-refractory population with potentially greater disease burden.

Dose-Response Relationships

A clear dose-response relationship emerged for Candida infections with secukinumab in psoriasis patients. Van de Kerkhof et al. demonstrated that the 300 mg dose resulted in skin/mucosal candidiasis at 3.55 per 100 subject-years compared to 1.85 per 100 subject-years with the 150 mg dose. Gottlieb et al. confirmed this pattern, noting Candida infections were more common with the 300 mg dose compared to 150 mg in psoriasis patients. Importantly, this dose-response was specific to Candida infections and was not observed for other adverse events, suggesting it reflects the biological importance of IL-17A in antifungal immunity rather than a general toxicity effect. No dose-response relationship was observed for serious adverse events, serious infections, cardiovascular events, or malignancy.

Variation Between IL-17A Antagonists

Different IL-17A antagonists showed distinct safety profiles, particularly for injection site reactions. In psoriatic arthritis, ixekizumab had the highest rate of injection site reactions (RR 3.97), while secukinumab had the lowest (RR 0.49). For Candida infections in psoriasis/psoriatic arthritis populations, brodalumab showed the highest rate (4.0%), followed by ixekizumab (3.3%) and secukinumab (1.7%). These differences may reflect variations in dosing frequency, formulation characteristics, or the specific molecular targets (IL-17A alone versus IL-17RA receptor blockade with brodalumab, which affects both IL-17A and IL-17F signaling).

Hypertension risk also varied by agent. In the meta-analysis by Jiang et al., only secukinumab exhibited a notable association with hypertension among the four IL-17 inhibitors examined (secukinumab, ixekizumab, bimekizumab, and brodalumab). This finding was particularly pronounced in patients with psoriatic arthritis, and risk increased with prolonged treatment duration. The mechanism underlying this agent-specific effect remains unclear but may relate to secukinumab’s specific binding characteristics or patient selection factors.

Study Quality Hierarchy and Long-Term Safety

The strongest evidence for IL-17A antagonist safety comes from the large pooled analyses with post-marketing surveillance conducted by Deodhar et al. and Gottlieb et al., which included 7,355 and 12,637 patients respectively, with cumulative exposure exceeding 96,000 patient-years. These comprehensive analyses demonstrated no increase in serious infections, inflammatory bowel disease, malignancy, or major adverse cardiovascular events over time, providing reassurance about long-term safety.

However, the study by Mease et al., while smaller and shorter in duration, identified cardiovascular signals that warrant continued monitoring. Four strokes and two myocardial infarctions occurred in secukinumab-treated patients versus zero in placebo recipients, though the study acknowledged it was neither large enough nor long enough to definitively evaluate uncommon serious adverse events. The longer-term data showing stable MACE rates of less than 0.7 per 100 patient-years without temporal increase suggests these early signals may reflect the underlying cardiovascular risk in inflammatory disease populations rather than a treatment-specific effect.

The convergent findings from multiple meta-analyses of randomized controlled trials provide additional confidence in the safety profile. Yufeng Yin et al., Gao et al., and Azadeh et al. all found no significant increase in serious adverse events with IL-17 inhibitors compared to placebo, despite increased rates of non-severe infections. This consistency across independent systematic reviews, each including slightly different study populations, strengthens the conclusion that serious safety events are not elevated with short-to-intermediate term IL-17A antagonist therapy.

Mechanistic Explanations

The pattern of predominantly mucocutaneous Candida infections with IL-17A antagonists has a clear mechanistic basis. IL-17A plays a critical role in immunological protection against Candida species, as evidenced by findings in patients with genetic defects in IL-17-related immune responses. The therapeutic inhibition of this pathway predictably increases susceptibility to Candida infections, though the infections observed were predominantly mild-to-moderate and nonserious. The anatomic specificity (primarily oral and mucocutaneous sites) and fungal specificity of these infections support this mechanistic understanding.

The low rate of opportunistic infections other than Candida (<0.2 per 100 patient-years) indicates that IL-17A antagonism does not cause broad immunosuppression. The absence of tuberculosis reactivation cases in pooled clinical trials contrasts sharply with the tuberculosis risk observed with TNF inhibitors, suggesting IL-17A has a more limited role in mycobacterial immunity than TNF. This mechanistic distinction has important clinical implications for patient selection and monitoring.

The increased risk of non-severe infections (RR 1.82) 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. This pattern is consistent with IL-17A’s role in mucosal immunity and early pathogen responses while other immune pathways remain intact.

References

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• Q. Gao, Y.-X. Zhao, X. Wang, J. Shi, H-M Wang (2021). Efficacy and safety of IL-17 inhibitors for patients with psoriatic arthritis: a systematic review and meta-analysis. European Review for Medical and Pharmacological Sciences
• H. Azadeh, Reza Alizadeh-Navaei, Alireza Rezaiemanesh, M. Rajabinejad (2022). Immune-related adverse events (irAEs) in ankylosing spondylitis (AS) patients treated with interleukin (IL)-17 inhibitors: a systematic review and meta-analysis. InflammoPharmacology
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