# 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.

| 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 of RCTs | Ankylosing spondylitis | Secukinumab, ixekizumab | 1,733 patients | 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 | Up to 5 years |
| ... | ... | ... | ... | ... | ... | ... |

### Infection Outcomes

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 |
| 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 |
| A. Gottlieb et al., 2022 | Psoriasis | Not specified | 1.4 per 100 PY | 3.5 per 100 PY | Not specified |
| ... | ... | ... | ... | ... | ... |

### Fungal Infections

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

| Study | Indication | Treatment | Candida infection rate | Comparison group rate | Notes |
|-------|-----------|-----------|----------------------|----------------------|-------|
| D. Saunte et al., 2017 | Psoriasis/PsA | Brodalumab | 4.0% | 0.3% (placebo) | Slightly increased incidence |
| P. C. van de Kerkhof et al., 2016 | Psoriasis | Secukinumab 300 mg | 3.55 per 100 SYs | 1.37 per 100 SYs (etanercept) | Nonserious, mild/moderate skin/mucosal |
| ... | ... | ... | ... | ... | ... |

### 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 |
| ... | ... | ... | ... | ... |

#### Other Safety Outcomes

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

| Study | Indication | Treatment | MACE rate | Specific events |
|-------|-----------|-----------|-----------|----------------|
| P. Mease et al., 2015 | Psoriatic arthritis | Secukinumab | 0.6 per 100 PY (stroke) <br> 0.3 per 100 PY (MI) | 4 strokes, 2 myocardial infarctions |
| ... | ... | ... | ... | ... |

### 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.