# 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.

# 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.

| Study                                     | Full text retrieved? | Study type                               | Indication(s)                                        | IL-17 inhibitor(s)                       | Sample size                   | Follow-up duration                 |
|-------------------------------------------|---------------------|-----------------------------------------|---------------------------------------------------|-----------------------------------------|-------------------------------|-------------------------------------|
| P. Mease et al., 2015                    | No                  | Phase 3 RCT                            | Psoriatic arthritis                                | Secukinumab 150 mg, 75 mg            | 606 patients                  | Mean 438.5 days                   |
| Yufeng Yin et al., 2020                  | Yes                 | Systematic review and meta-analysis    | Ankylosing spondylitis                             | Secukinumab, ixekizumab              | 1,733 patients (1,153 IL-17i, 580 placebo) | Week 16                          |
| A. Deodhar et al., 2019                  | Yes                 | Pooled clinical trials + post-marketing surveillance | Psoriasis, psoriatic arthritis, ankylosing spondylitis | Secukinumab 75, 150, 300 mg       | 7,355 patients (5,181 PsO, 1,380 PsA, 794 AS) | Up to 5 years (PsO, PsA), 4 years (AS) |
| P. C. van de Kerkhof et al., 2016         | No                  | Pooled phase II/III trials             | Moderate to severe plaque psoriasis                 | Secukinumab 300 mg, 150 mg            | 3,993 subjects (3,430 secukinumab) | 52 weeks                        |
| A. Gottlieb et al., 2022                  | Yes                 | Pooled clinical trials + post-marketing surveillance | Psoriasis, psoriatic arthritis, ankylosing spondylitis | Secukinumab 75, 150, 300 mg       | 12,637 patients                | Up to 5 years                     |
| Kexin Jiang et al., 2024                 | No                  | Meta-analysis of RCTs                  | Diverse autoimmune diseases                        | Secukinumab, ixekizumab, bimekizumab, brodalumab | 9,909 patients                | Not specified                    |
| D. Saunte et al., 2017                   | No                  | Systematic review of clinical trials   | Psoriasis or psoriatic arthritis                     | Brodalumab, secukinumab, ixekizumab  | Not specified                      | Not specified                    |
| Q. Gao et al., 2021                      | Yes                 | Systematic review and meta-analysis of RCTs | Psoriatic arthritis                                  | Secukinumab, ixekizumab, brodalumab, bimekizumab | 5,327 patients                 | 12-52 weeks                      |
| H. Azadeh et al., 2022                   | No                  | Systematic review and meta-analysis of RCTs and non-RCTs | Ankylosing spondylitis                             | Secukinumab, ixekizumab, bimekizumab, netakimab | 2,612 patients (1,848 IL-17i, 764 placebo) | Not specified                    |
| G. Brown et al., 2015                    | No                  | Review of phase II trials              | Psoriasis                                         | Secukinumab, ixekizumab, brodalumab  | Not specified                      | At least 12 weeks                 |

## Infection Outcomes

### Overall Infection Rates

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

| Study                                     | Indication                                 | Overall infections | Serious infections | Upper respiratory tract infections | Nasopharyngitis |
|-------------------------------------------|-------------------------------------------|--------------------|--------------------|----------------------------------|-----------------|
| A. Deodhar et al., 2019                  | Psoriasis                                  | Not specified       | 1.4 per 100 PY    | Most common infection type       | Not specified    |
| A. Deodhar et al., 2019                  | Psoriatic arthritis                         | Not specified       | 1.9 per 100 PY    | Most common infection type       | Not specified    |
| A. Deodhar et al., 2019                  | Ankylosing spondylitis                     | Not specified       | 1.2 per 100 PY    | Most common infection type       | Not specified    |
| P. C. van de Kerkhof et al., 2016         | Psoriasis (secukinumab 300 mg)            | 91.1 per 100 SYs   | 1.4 per 100 SYs   | Not specified                    | Not specified    |
| P. C. van de Kerkhof et al., 2016        | Psoriasis (secukinumab 150 mg)            | 85.3 per 100 SYs   | 1.1 per 100 SYs   | Not specified                    | Not specified    |
| A. Gottlieb et al., 2022                  | Psoriasis                                  | Not specified       | 1.4 per 100 PY    | 3.5 per 100 PY                  | Not specified    |
| A. Gottlieb et al., 2022                  | Psoriatic arthritis                         | Not specified       | 1.8 per 100 PY    | 2.7 per 100 PY                  | Not specified    |
| A. Gottlieb et al., 2022                  | Ankylosing spondylitis                     | Not specified       | 1.2 per 100 PY    | 3.3 per 100 PY                  | Not specified    |
| Yufeng Yin et al., 2020                  | Ankylosing spondylitis                     | RR 1.11 vs placebo  | No significant difference vs placebo | Most frequently reported | Frequently reported |

## Hypersensitivity and Immunogenicity Outcomes

### Injection Site Reactions

| Study                                     | Indication              | Treatment       | Injection site reaction rate | Comparison            |
|-------------------------------------------|------------------------|------------------|-----------------------------|-----------------------|
| A. Deodhar et al., 2019                  | Psoriasis               | Secukinumab     | 1.2 per 100 PY             | Not specified          |
| A. Deodhar et al., 2019                  | Psoriatic arthritis      | Secukinumab     | 1.3 per 100 PY             | Not specified          |
| A. Deodhar et al., 2019                  | Ankylosing spondylitis   | Secukinumab     | 0.8 per 100 PY             | Not specified          |
| A. Gottlieb et al., 2022                  | Psoriasis               | Secukinumab     | 1.6 per 100 PY             | Not specified          |
| A. Gottlieb et al., 2022                  | Psoriatic arthritis      | Secukinumab     | 1.3 per 100 PY             | Not specified          |
| A. Gottlieb et al., 2022                  | Ankylosing spondylitis   | Secukinumab     | 0.6 per 100 PY             | Not specified          |
| Q. Gao et al., 2021                      | Psoriatic arthritis      | Ixekizumab      | RR 3.97 vs control         | Highest rate among IL-17i |
| Q. Gao et al., 2021                      | Psoriatic arthritis      | Secukinumab     | RR 0.49 vs control         | Lowest rate among IL-17i  |

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.

### Other Safety Outcomes

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. Additionally, malignancy incidence remained low and stable across indications.

### Synthesis

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). Furthermore, 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). These patterns reflect differences in baseline mucocutaneous immune function and the extent of IL-17-dependent defense mechanisms at different anatomic sites.

The strongest evidence for IL-17A antagonist safety comes from large pooled analyses with post-marketing surveillance, showing no increase in serious infections, inflammatory bowel disease, malignancy, or MACE over time, providing reassurance about long-term safety.