Elicit: IL-17A Antagonism: Safety and Immunologic Impacts

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IL-17A Antagonism: Safety and Immunologic Impacts

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May 5, 2026

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. More on methods

Records from Elicit search

n = 200

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

Papers screened out

n = 190

Papers included for extraction

n = 10

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Paper search

We performed a semantic search across over 138 million academic papers from the Elicit search engine, which includes all of 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:

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.

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

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

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

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

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

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

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

Extract comparative safety data when available, including:

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 (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

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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

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

P. C. van de Kerkhof et al., 2016

Psoriasis (etanercept)

93.7 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

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

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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.

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

D. Saunte et al., 2017

Psoriasis/PsA

Secukinumab

1.7%

2.3% (ustekinumab)

Slightly increased vs placebo

D. Saunte et al., 2017

Psoriasis/PsA

Ixekizumab

3.3%

0.8% (etanercept)

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

P. C. van de Kerkhof et al., 2016

Psoriasis

Secukinumab 150 mg

1.85 per 100 SYs

1.37 per 100 SYs (etanercept)

Nonserious, mild/moderate skin/mucosal

A. Deodhar et al., 2019

Psoriasis

Secukinumab

2.2 per 100 PY

Not applicable

Pooled clinical trials

A. Deodhar et al., 2019

Psoriatic arthritis

Secukinumab

1.5 per 100 PY

Not applicable

Pooled clinical trials

A. Deodhar et al., 2019

Ankylosing spondylitis

Secukinumab

0.7 per 100 PY

Not applicable

Pooled clinical trials

A. Gottlieb et al., 2022

Psoriasis

Secukinumab

2.9 per 100 PY

Not applicable

Oral candidiasis most common

A. Gottlieb et al., 2022

Psoriatic arthritis

Secukinumab

1.5 per 100 PY

Not applicable

Oral candidiasis most common

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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

Study

Indication

Opportunistic infections

Tuberculosis

Other notable infections

A. Deodhar et al., 2019

Psoriasis/PsA/AS

<0.2 per 100 PY

No reactivation cases; 5 active TB in post-marketing

Esophageal candidiasis, gastrointestinal candidiasis, herpes zoster, toxoplasmosis, M. avium complex

A. Gottlieb et al., 2022

Psoriasis/PsA/AS

<0.2 per 100 PY

Rare

Viral infections: PsO 3.5/100 PY, PsA 2.7/100 PY, AS 3.3/100 PY

Yufeng Yin et al., 2020

Ankylosing spondylitis

No significant difference vs placebo

No significant difference vs placebo

Ear infections, urinary tract infections

H. Azadeh et al., 2022

Ankylosing spondylitis

RD 0.01 vs placebo (P=0.04)

Not mentioned

Urinary tract infections, diarrhea

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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

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

G. Brown et al., 2015

Psoriasis

Anti-IL-17 agents

Frequently reported

Not specified

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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

Study

Indication

Treatment

MACE rate

Specific events

P. Mease et al., 2015

Psoriatic arthritis

Secukinumab

0.6 per 100 PY (stroke)
0.3 per 100 PY (MI)

4 strokes, 2 myocardial infarctions

P. C. van de Kerkhof et al., 2016

Psoriasis

Secukinumab 300 mg

0.42 per 100 SYs

Comparable to etanercept (0.34)

P. C. van de Kerkhof et al., 2016

Psoriasis

Secukinumab 150 mg

0.35 per 100 SYs

Comparable to etanercept (0.34)

A. Deodhar et al., 2019

Psoriasis

Secukinumab

0.3 per 100 PY

No increase over time

A. Deodhar et al., 2019

Psoriatic arthritis

Secukinumab

0.4 per 100 PY

No increase over time

A. Deodhar et al., 2019

Ankylosing spondylitis

Secukinumab

0.6 per 100 PY

No increase over time

A. Gottlieb et al., 2022

All indications

Secukinumab

<0.7 per 100 PY

No apparent increase over time

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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

Study

Indication

Treatment

Serious AEs

Discontinuation due to AEs

Deaths

P. C. van de Kerkhof et al., 2016

Psoriasis

Secukinumab 300 mg

7.4 per 100 SYs

Not mentioned

Not mentioned

P. C. van de Kerkhof et al., 2016

Psoriasis

Secukinumab 150 mg

6.8 per 100 SYs

Not mentioned

Not mentioned

A. Deodhar et al., 2019

Psoriasis

Secukinumab

6.9 per 100 PY

6.4%

9 deaths (0.2%)

A. Deodhar et al., 2019

Psoriatic arthritis

Secukinumab

7.9 per 100 PY

7.5%

11 deaths (0.4%)

A. Deodhar et al., 2019

Ankylosing spondylitis

Secukinumab

6.3 per 100 PY

7.3%

5 deaths (0.8%)

Yufeng Yin et al., 2020

Ankylosing spondylitis

IL-17 inhibitors

No significant difference vs placebo

No significant difference vs placebo

2 deaths (MI, suicide)

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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

D. Saunte, U. Mrowietz, L. Puig, C. Zachariae\ (2017).Candida infections in patients with psoriasis and psoriatic arthritis treated with interleukin‐17 inhibitors and their practical management. British Journal of Dermatology

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

G. Brown, M. Malakouti, E. Wang, J. Koo, E. Levin\ (2015).Anti-IL-17 phase II data for psoriasis: A review. Journal of dermatological treatment (Print)

Yufeng Yin, Ming-jun Wang, Meng-ru Liu, E. Zhou, Tianqi Ren, and 5 more\ (2020).Efficacy and safety of IL-17 inhibitors for the treatment of ankylosing spondylitis: a systematic review and meta-analysis. Arthritis Research & Therapy

A. Deodhar, P. Mease, I. McInnes, X. Baraliakos, K. Reich, and 7 more\ (2019).Long-term safety of secukinumab in patients with moderate-to-severe plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis: integrated pooled clinical trial and post-marketing surveillance data. Arthritis Research & Therapy

P. Mease, I. McInnes, B. Kirkham, A. Kavanaugh, P. Rahman, and 7 more\ (2015).Secukinumab Inhibition of Interleukin-17A in Patients with Psoriatic Arthritis. New England Journal of Medicine

P. C. van de Kerkhof, C. Griffiths, K. Reich, C. Leonardi, A. Blauvelt, and 5 more\ (2016).Secukinumab long-term safety experience: A pooled analysis of 10 phase II and III clinical studies in patients with moderate to severe plaque psoriasis. Journal of American Academy of Dermatology

A. Gottlieb, A. Deodhar, I. McInnes, X. Baraliakos, K. Reich, and 13 more\ (2022).Long-term Safety of Secukinumab Over Five Years in Patients with Moderate-to-severe Plaque Psoriasis, Psoriatic Arthritis and Ankylosing Spondylitis: Update on Integrated Pooled Clinical Trial and Post-marketing Surveillance Data. Acta Dermato-Venereologica

Kexin Jiang, Yuheng Jia, Li Chen, Fangyang Huang, Mao Chen\ (2024).Association of Interleukin-17 Inhibitors With Hypertension in Patients With Autoimmune Diseases: A Systematic Review and Meta-analysis on Randomized Controlled Trials. Journal of Cardiovascular Pharmacology

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Long-term Safety of Secukinumab Over Five Years in Patients with Moderate-to-severe Plaque Psoriasis, Psoriatic Arthritis and Ankylosing Spondylitis: Update on Integrated Pooled Clinical Trial and Post-marketing Surveillance Data

A. Gottlieb, A. Deodhar, I. McInnes, X. Baraliakos, K. Reich, S. Schreiber, W. Bao, K. Marfo, H. Richards, L. Pricop, A. Shete, V. Trivedi, Deborah Keefe, C. Papavassilis, P. Jagiello, P. Papanastasiou, P. Mease, M. Lebwohl

Acta Dermato-Venereologica·

2022·

78 citations

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IL-17A Antagonist

- Drug name: Secukinumab - Dosage and frequency: Intravenous up to 10 mg/kg, subcutaneous at 75, 150, or 300 mg - Route of administration: Intravenous and subcutaneous - Duration of treatment: Up to 5 years - Comparator treatments: Not mentioned

Patient Population

- Medical condition being treated: Psoriasis, Psoriatic Arthritis, Ankylosing Spondylitis - Sample size for safety analysis: 12,637 patients - Age range and mean age: Patients aged ≥ 18 years; no mean age provided - Prior immunosuppressive therapy exposure: Inadequate response or intolerance to TNF-α inhibitors; prior history of biologics other than TNFi - Baseline infection risk factors or immunocompromised status: Active/ongoing CVD, history of IBD, latent tuberculosis

Study Design

- Study type: Pooled data from 28 clinical trials (including Phase III and Phase IV trials) and post-marketing surveillance - Safety follow-up duration: Up to 5 years - Total patient-years of exposure: 15,063 (psoriasis), 5,985 (psoriatic arthritis), 3,527 (ankylosing spondylitis) - Active safety monitoring: Implied by use of exposure-adjusted incidence rates and AESIs - Loss to follow-up rates for safety outcomes: Not mentioned

Infection Outcomes

- Overall infection rates: Serious infections - PsO: 1.4/100 PY, PsA: 1.8/100 PY, AS: 1.2/100 PY - Opportunistic infections: < 0.2/100 PY across all indications - Candida infections: PsO: 2.9/100 PY, PsA: 1.5/100 PY, AS: 0.7/100 PY; Most common type: Oral candidiasis - Tuberculosis: Rare - Upper respiratory tract infections: No increased risk; EAIRs - PsO: 3.5/100 PY, PsA: 2.7/100 PY, AS: 3.3/100 PY - Time to infection onset: Not mentioned

Hypersensitivity Reactions

- Injection site reactions: 1.6, 1.3, and 0.6 per 100 PY in PsO, PsA, and AS patients, respectively. - Systemic allergic reactions or anaphylaxis: Not mentioned. - Drug hypersensitivity reactions: Not mentioned. - Skin reactions (rash, urticaria, etc.): Not mentioned. - Anti-drug antibody development and clinical consequences: Not mentioned. - Immunogenicity-related adverse events: Not mentioned.

Other Safety Outcomes

- Malignancy incidence: ≤ 1/100 patient-years - Major adverse cardiovascular events: < 0.7/100 patient-years - Inflammatory bowel disease: 0.01-0.4/100 patient-years - Neutropenia or other hematologic effects: Not mentioned - Serious adverse events overall: EAIRs of 7.0, 8.2, and 5.8 per 100 patient-years for PsO, PsA, and AS - Treatment discontinuation due to adverse events: 5.3%, 6.0%, and 7.7% for PsO, PsA, and AS - Deaths and causes: 0.2%, 0.4%, and 0.8% for PsO, PsA, and AS

Risk Factors

- Patient characteristics: Susceptibility to cardiovascular disease, metabolic comorbidities, and inflammatory bowel diseases due to inflammatory disease burden and genetic overlap. - Dose-related safety patterns: Candida infections more common in PsO patients treated with 300 mg dose compared to 150 mg dose. - Time-dependent changes: No significant increase in serious infections, IBD, malignancy, or MACE over time. - Concomitant medications: Sulfasalazine, methotrexate, corticosteroids, and NSAIDs may affect safety profile. - Baseline disease severity: Active or ongoing CVD, history of IBD, latent tuberculosis considered in patient selection and management.

Safety Comparisons

- Safety outcomes compared to placebo: Not mentioned - Safety outcomes compared to other biologics (TNF inhibitors, etc.): Not mentioned - Safety differences between different IL-17A antagonists: Not mentioned - Safety differences between doses of the same drug: Candida infections were more common with the 300 mg dose compared to the 150 mg dose in PsO patients - Long-term vs short-term safety patterns: No apparent increases in safety events over time; consistent safety profile

Secukinumab, a selective interleukin (IL)-17A inhibitor, is approved for use in adult and paediatric psoriasis, psoriatic arthritis, ankylosing spondylitis and non-radiographic axial spondyloarthritis. The aim of this study was to report the long-term safety of secukinumab in pooled data from 28 clinical trials and a post-marketing safety surveillance in psoriasis, psoriatic arthritis and ankylosing spondylitis patients. Analyses included 12,637 secukinumab-treated patients, corresponding to 15,063, 5,985 and 3,527 patient-years of exposure in psoriasis, psoriatic arthritis and ankylosing spondylitis patients, respectively. Incidences of serious adverse events were low, with no identifiable patterns across indications. Active tuberculosis or latent tuberculosis infections were rare. The incidence of opportunistic infections was < 0.2/100 patient-years, the incidence of malignancy was ≤ 1/100 patient-years, and the incidence of major adverse cardiovascular events was < 0.7/100 patient-years, with no apparent increases over time. Secukinumab demonstrated a favourable safety profile for up to 5 years of treatment across the 3 indications, and no new safety signals were identified.

Interleukin (IL)-17-mediated inflammation plays a pivotal role in the pathogenesis of chronic immunemediated inflammatory diseases (IMIDs) (1)(2)(3). Therapeutic blockade of the IL-17 pathway results in the inhibition of both pathological and physiological mechanisms. The IL-17 family members IL-17A and IL-17F have pleiotropic effects on multiple immune cell types and play an important role in host defence against infections (specifically fungal infections) (1,4). Therefore, it is important to address the effect of IL-17 blockade on opportunistic infections.

The pathogenesis of PsO, PsA and AS share common systemic inflammatory pathways and cytokines. Because of the inflammatory disease burden and genetic overlap, patients with IMIDs are more susceptible to cardiovascular disease (CVD), metabolic comorbidities and inflammatory bowel diseases (IBDs) vs the general population (5)(6)(7)(8)(9)(10)(11)(12)(13). These comorbidities, along with the concomitant medications used to treat these conditions, may affect the safety profile of treatments for PsO, PsA and AS.

Assessing the safety profile of a drug using data from multiple clinical trials and post-marketing experience across indications is best suited to identify risks that may

Long-term Safety of Secukinumab Over Five Years in Patients with Moderate-to-severe Plaque Psoriasis, Psoriatic Arthritis and Ankylosing Spondylitis: Update on Integrated Pooled Clinical Trial and Post-marketing Surveillance Data

become evident in a larger dataset. Secukinumab, a direct IL-17A inhibitor, has shown long-lasting efficacy and safety in treating the complete spectrum of psoriatic and spondyloarthritis (SpA) disease manifestations, including the nails, scalp, palms and soles, as well as PsA and axial SpA (axSpA) (14)(15)(16)(17)(18)(19)(20)(21).

Secukinumab is currently approved in more than 100 countries for use in PsO, PsA and axSpA. Over 20,000 patients have been treated with secukinumab in a clinical trial setting, and approximately 500,000 patients have been treated worldwide since launch (22). A longerterm report (17) of pooled safety and tolerability data for secukinumab across the 3 indications (up to 5 years of treatment in PsO and PsA; up to 4 years in AS) was consistent with the safety profile observed in individual clinical trials (14)(15)(16)(18)(19)(20)(21).

This integrated safety assessment (ISA) in PsO, PsA and AS patients who received secukinumab treatment for up to 5 years included pooled clinical trial data and post-marketing safety surveillance data. The current report enhances the previously published pooled safety report (17) with a larger dataset and longer exposure to secukinumab.

Analysis design

The ISA included data from 28 clinical trials (19 PsO trials (11 Phase III, 8 Phase IV); 5 PsA trials (Phase III); 4 AS trials (Phase III)) and post-marketing safety surveillance data of secukinumab in the PsO, PsA and AS indications, along with the periodic safety update report (PSUR) from the time of initial secukinumab treatment to a cut-off date of 25 December 2018 (Fig. 1 ). Patients who received at least 1 dose of secukinumab, including those who were initially randomised to placebo and re-randomised to secukinumab per study protocol, were included in this analysis. Dosing regimens included intravenous (up to 10 mg/kg) and subcutaneous (75, 150 or 300 mg) secukinumab. All cumulative data for up to 5 years of secukinumab treatment in PsO, PsA and AS patients are reported.

Clinical trial analyses

Patients aged ≥ 18 years with moderate-to-severe plaque PsO, active PsA or AS were included in individual clinical trials per specific study protocols. The inclusion and exclusion criteria of the patients, along with the individual study designs, have been reported previously (14-16, 19, 20, 23-27) . All analyses were performed at descriptive level using SAS version 9.4.

At the time of enrolment, patients may have had active/ongoing CVD (unless severe or uncontrolled); a previous history of IBD, including Crohn's disease (CD) or uveitis (but not if active or ongoing); a history of basal cell carcinoma or actinic keratosis (successfully treated with no evidence of recurrence in the past 3 months); carcinoma in situ of the cervix or non-invasive malignant colon polyps (successfully removed); or latent tuberculosis (provided prophylactic treatment had started before enrolment). Per specific study protocols, patients may also have continued taking sulfasalazine, methotrexate, corticosteroids and/or nonsteroidal anti-inflammatory drugs (NSAIDs) at stable doses in the respective studies.

Patients with an inadequate response (therapy ≥ 3 months) or intolerance to tumour necrosis factor-α inhibitors (TNFi: not more than 1 in AS studies and not more than 3 in PsO and PsA studies) were included in these trials. Two PsO clinical trials (19) included patients with a prior history of biologics other than TNFi (alefacept, briakinumab, efalizumab and ustekinumab) after an appropriate washout period.

Safety assessments

Adverse events (AEs) and serious adverse events (SAEs) were retrieved using the clinical trial database. The AE preferred terms (PTs) and adverse events of special interest (AESIs) were coded using the Medical Dictionary for Regulatory Activities (MedDRA; version 21.1). In the clinical trial database, AEs, SAEs and AESIs were analysed using exposure-adjusted incidence rates (EAIRs; patient incidence rate/100 patient-years (PY)) calculated as the number of events/total exposure time. Data are summarized overall and by indication.

Post-marketing safety surveillance data

Post-marketing safety surveillance includes all non-clinical trial exposure to secukinumab and is based on worldwide sales. The AEs, SAEs and AESIs from post-marketing data were retrieved using the Novartis Safety Database and reported as crude incidence/PY.

Ethics

All clinical studies were conducted in compliance with the Declara tion of Helsinki (28), International Council for Harmonisation Guide lines for Good Clinical Practice, and local country regulations.

Study population

Safety analyses of the pooled clinical trials included At baseline, the rates of hypertension (37.6%), hyperlipidaemia (21.5%) and diabetes mellitus (10.2%) were numerically higher in patients with PsA vs patients with PsO (21.4%, 13.5% and 6.8%) and AS (23.2%, 9.6% and 3.2%). The rate of uveitis at baseline was higher in the AS dataset (18.0%), which was expected given the predisposition of these patients to uveitis (29). In the pooled PsO, PsA and AS datasets, a baseline medical history of IBD was reported by 1 (0.01%), 6 (0.22%) and 22 (1.9%) patients, respectively. A medical history of CD or ulcerative colitis (UC) at baseline was reported in 5 (0.06%) and 13 (0.15%) patients in the PsO cohort, 6 (0.22%) and 4 (0.15%) patients in the PsA cohort and 5 (0.4%) and 4 (0.4%) patients in the AS cohort (Table I ).

Safety summary

Over the entire observation period, the EAIR of any AE with secukinumab treatment was 224.9, 159.2 and 125.5 per 100 PY in PsO, PsA and AS patients, respectively. The EAIR/100 PY of any SAE was 7.0, 8.2 and 5.8 in PsO, PsA and AS patients, respectively, showing no noticeable patterns across indications (Table II ). Overall, 14 (0.2%), 11 (0.4%) and 9 (0.8%) deaths were reported among PsO, PsA and AS patients, respectively. Discontinuation from the clinical trial due to AEs was reported in 466 (5.3%), 162 (6.0%) and 88 (7.7%) PsO, PsA and AS patients, respectively (Table II ).

Most common adverse events

The EAIRs of AE PTs in secukinumab-treated patients were comparable across PsO, PsA and AS studies (Table II ), with no new safety signals identified from those previously reported. The most common AEs during the entire safety period in PsO, PsA and AS patients were nasopharyngitis (EAIR/100 PY: 22.6, 11.6 and 10.7, respectively), headache (EAIR/100 PY: 7.3, 3.8 and 3.8, respectively), diarrhoea (EAIR/100 PY: 4.2, 3.9 and 4.0, respectively) and upper respiratory tract infection (URTI; EAIR/100 PY: 5.3, 8.8 and 4.5, respectively) (Table II ).

Adverse events of special interest

Infections. Over the entire observation period, the EAIRs/100 PY for serious infections were 1.4, 1.8 and 1.2 in PsO, PsA and AS patients, respectively (Table II ). The incidence of opportunistic infections was less than 0.2/100 PY across the 3 indications (PsO 0.19/100 PY; PsA 0.18/100 PY; AS 0.14/100 PY) (Table II ). Candida infections. Over the entire observation period, AEs related to Candida infection were reported in 426 (4.8%), 90 (3.4%) and 25 (2.2%) PsO, PsA and AS patients, respectively. This corresponded to an incidence of 2.9, 1.5 and 0.7 per 100 PY in PsO, PsA and AS patients, respectively (Table II ). The most common type of Candida infection was oral candidiasis (EAIR/100 PY: PsO 1.54; PsA 0.83; AS 0.31). Across indications, Candida infections were responsive to standard treatment and did not necessitate study drug discontinuation. Viral infections. No increased risk of viral infections was observed in patients treated with secukinumab vs placebo in the short term, and EAIRs were generally comparable over the long term. No dose-response relationship was observed for safety events with secukinumab treatment within each indication (Table III ). Across indications and doses (300 and 150 mg), the most common viral infection was viral influenza (MedDRA term) (Table III ). The EAIR/100 PY for any viral infection in PsO, PsA and AS patients was 3.5, 2.7 and 3.3, respectively. Inflammatory bowel disease. The incidence of IBD (standardized MedDRA query (SMQ); includes preferred terms (PTs) of IBD, CD or UC) ranged from 0.01-0.1/100 PY in PsO, 0.03-0.1/100 PY in PsA and 0.03-0.4/100 PY in AS patients (Table II ). Among PsO patients, 20 (16 new onset), 14 (12 new onset) and 2 (both new onset) patients reported UC, CD and IBD, respectively. Among PsA patients, 6 (5 new onset), 6 (4 new onset) and 2 (both new onset) patients reported UC, CD and IBD, respectively. Among AS patients, 8 (5 new onset), 15 (11 new onset), and 1 (new onset) patients reported UC, CD and IBD, respectively. Uveitis. In PsO patients, the EAIR of uveitis was 0.01/100 PY (2 patients) over the entire treatment period; both cases were mild-to-moderate and new onset. In PsA patients, the EAIR of uveitis was 0.1/100 PY (6 patients); all cases reported were mild-to-moderate in patients with no previous history of uveitis. In AS patients, the EAIR of uveitis was 1.2/100 PY (42 cases) (Table II ). Major adverse cardiovascular events. Over the entire treatment period, the incidence of major adverse cardio- vascular events (MACE) was 0.4/100 PY in both PsO and PsA patients and 0.7/100 PY in AS patients (Table II ). Malignancy. Among PsO patients, malignant or unspecified tumours (SMQ) were reported in 127 patients (EAIR 0.9/100 PY) over the entire observation period (Table II ). The most common type of malignancy reported was basal cell carcinoma (41 patients: EAIR 0.3/100 PY). Two PsO patients reported PTs related to haematological malignancy, namely, acute leukaemia, B cell lymphoma, lymphoproliferative disorder and plasma cell myeloma. Overall, 60 PsA patients reported a malignant or unspecified tumour (EAIR 1.0/100 PY) (Table II ). Basal cell carcinoma was the most common malignancy reported (19 patients: EAIR 0.32/100 PY). PTs related to haematological malignancies in PsA patients were chronic lymphocytic leukaemia (2 patients) and B cell lymphoma (1 patient). Malignant or unspecified tumours were reported in 19 AS patients (EAIR 0.5/100 PY) (Table II ). One AS patient reported B cell lymphoma.

Year-by-year incidence of adverse events of special interest

Serious infections, Candida infection, IBD, UC and CD showed no increase on a year-by-year basis with secukinumab treatment across PsO, PsA and AS studies (Fig. 2 ).

Incidence of adverse events of special interest by secukinumab dose

Overall, the reported EAIRs for any AE, any SAE, serious infections, IBD and MACE for the approved 300 mg and 150 mg secukinumab doses were comparable and no noticeable trends were observed in the doseresponse relationship with secukinumab treatment in terms of safety events within each indication. However, Candida infections were more common in PsO patients treated with the 300 mg dose compared with the 150 mg dose. The imbalance between doses was limited to non-serious, localised mucosal or cutaneous candidiasis, with no reports of chronic or systemic disease in any treatment group.

Suicidality

Over the entire observation period, among PsO patients, 6 patients attempted suicide, 2 committed suicide, 5 reported suicidal ideation, and 1 reported suicidal depression (EAIR 0.09/100 PY). A total of 4 PsA patients reported suicidal ideation (EAIR 0.07/100 PY). Among AS patients, 1 patient reported suicidal depression (EAIR 0.03/100 PY). No new safety signals in relation to suicidality were identified.

Advances in dermatology and venereology

Acta Dermato-Venereologica

Injection-site reactions

The incidence of injection-site reactions (high-level term) in PsO, PsA and AS patients was 1.6, 1.3 and 0.6 per 100 PY, respectively.

Post-marketing safety surveillance data

As of 25 December 2018, across the approved indications, the cumulative post-marketing exposure to secukinumab was estimated to be 285,811 PY.

The cumulative crude exposure-adjusted reporting rates (EARRs) for infections and infestations and for serious infections were 5.2 and 1.4 per 100 PY, respectively. The cumulative EARRs of malignancy and MACE were 0.3 and 0.2 per 100 PY, respectively. Most assessable cases were confounded by multiple risk factors or alternative explanations for events related to malignancies or MACE. The cumulative EARR reported for IBD was 0.2/100 PY. The reporting rate for suicidal ideation and behaviour was 0.04/100 PY.

The risk of IBD, serious infections, malignancy and MACE determined in the 6 PSUR periods was consistent with the previously reported safety profile of secukinumab (Fig. 3 ).

DISCUSSION

This large safety analysis included 12,637 patients (cumulative secukinumab exposure in PsO, PsA and AS patients: 15,063, 5,985 and 3,527 per 100 PY, respectively) pooled from 28 clinical trials with up to 5 years of data, in addition to post-marketing surveillance data (total exposure 285,811 PY). This analysis demonstrated that secukinumab was associated with generally low frequencies of AEs with no discernible patterns regarding SAEs across indications. The most frequently reported AE across indications was URTI.

Pooled analyses typically have a large dataset and are a reliable source for assessing less-frequent treatmentemergent AEs. Furthermore, long-term follow-up may indicate an increase in the frequency of safety events over time. The present analysis was conducted to answer 2 primary questions: (1) whether the overall safety profile of secukinumab was consistent with that reported in previous clinical trials (14)(15)(16)(18)(19)(20)(21) and pooled safety findings (17), and (2) whether there were any new safety findings in a larger dataset with long-term exposure to secukinumab.

We analysed a larger dataset (12,637 vs 7,355 patients ( 17)) with a longer exposure to secukinumab across the PsO (15,063 PY vs 10,417 PY ( 17)), PsA (5,985 PY vs 3,867 PY ( 17)) and AS (3,527 PY vs 1,943 PY ( 17)) indications compared with a previous safety publication. In the present analysis, the cumulative post-marketing exposure to secukinumab was approximately 285,811 PY (cut-off date 25 December 2018) compared with 96,054 PY in the previous report (17).

Secukinumab was associated with a low frequency of AEs, with no pattern among SAEs across the Fig. 3 . Crude incidence (reporting rate) of adverse events with secukinumab across 6 periodic safety update reporting periods. Graphs demonstrating crude incidence reporting rate/100 patient-years (PY) for malignancy, serious infections, major adverse cardiovascular event (MACE) and inflammatory bowel disease (IBD) across the 3 indications, based on periodic safety update report (PSUR) data from 2014 to 2018. a Rates for total IBD (unspecified IBD, Crohn's disease and/or ulcerative colitis). AS: ankylosing spondylitis; EARR: exposure-adjusted reporting rate; N: number of patients in the analysis; PsA: psoriatic arthritis; PsO: psoriasis; PTYRR: patient-treatment years reporting rate. treatment groups in PsO, PsA and AS. The incidence rates of AESIs, such as serious infections, IBD, malignancy and MACE and suicidality-related AEs were consistent with findings from previous reports (14)(15)(16)(17)(18)(19)(20)(21)30), with no new safety signals across any indication. Consistent with previous data (17), in this pool, Candida infections were more common in PsO patients receiving secukinumab 300 mg vs secukinumab 150 mg. Overall, the rates of occurrence of injection-site reactions reported in this analysis were low and consistent with event rates reported previously (17)(18)(19)(20). Any modulation of the host immune response in chronic inflammatory conditions using a biologic agent may increase the risk for infections, including fungal infections (31). Furthermore, immune dysregulation in conditions such as PsO and spondyloarthritis have the potential to predispose patients to severe infections (32). It is noteworthy that secukinumab selectively targets IL-17A and does not affect the T helper type 1 (Th1) pathway. The host immunity regulated via the Th1 pathway is expected to remain largely intact in patients receiving secukinumab treatment. In this large pooled dataset comprising patients who received secukinumab for a period of up to 5 years, the incidence of serious infections ranged from 1.2/100 to 1.8/100 PY, with no clinically meaningful differences in EAIRs across the 3 indications. The reported EAIRs for any viral respiratory infections with secukinumab treatment in the PsO, PsA and AS datasets were 3.5/100 PY, 2.7/100 PY and 3.3/100 PY, respectively. Overall, the risk of viral respiratory infections did not appear to increase with secukinumab treatment. These results are consistent with those from an independent review, which concluded that IL-17A inhibition was not associated with an increased risk of viral infections (33). The incidence of infections during secukinumab treatment indicated a favourable benefitrisk profile, which is essential in clinical decision-making to manage patients with IMIDs, such as PsO, PsA and AS.

Compared with the general population, patients with PsO, PsA and AS have an up to 4-fold increased risk of IBD (13). Smoking, infections and high doses of NSAIDs (used in PsA/AS) are risk factors associated with manifestation or relapse of existing IBD (12,13,(34)(35)(36). Furthermore, previous failure of a TNFi in patients with PsO, PsA or AS has been reported to be related to IBD-associated exacerbations and lesser disease control (13,37). An estimated one-third of patients with IBD experience exacerbation of symptoms within 12 months of withdrawal of the TNFi (38).

This analysis included patients with PsO, PsA and AS who were previously treated (with inadequate response) with a TNFi. The pooled datasets also included a considerable population of patients who were smokers at baseline (33.8% PsO, 20.0% PsA and 30.6% AS). However, the effects of current smoking and prior TNFi in contributing to IBD in secukinumab-treated patients are currently indeterminate. In this large pooled dataset, the incidence of CD, UC or unspecified IBD was low and ranged from 0.01/100 PY to 0.4/100 PY in patients with PsO, PsA or AS. Overall, these reported IBD event rates with secukinumab treatment are consistent with previously reported uncommon (EAIR <1%) event rates (13). The analysis confirmed no relevant interaction between the use of secukinumab and relapse/worsening of known or new-onset IBD.

Anterior uveitis is the most common extra-articular manifestation of AS occurring in approximately 20-30% of patients with AS (39). In our analysis, 18% of patients in the pooled AS safety clinical trial dataset had uveitis at baseline; over the course of 5 years, the incidence of uveitis was 1.2/100 PY in the AS population (compared with 0.01/100 PY in PsO and 0.1/100 PY in PsA patients).

A population-based longitudinal cohort study from 1994 to 2010 in 188,882 patients reported an increased incidence of MACE in PsA, AS and PsO patients (8), indicating immune-mediated conditions are probably independent risk factors for MACE. Furthermore, hypertension, dyslipidaemia, diabetes and smoking are regarded as traditional cardiovascular risk factors (6), and the elevated risk of CVD in patients with PsO, PsA and AS is partially attributable to the presence of these traditional risk factors (5,6). In our pooled dataset, at baseline, 21.4-37.6% of patients had hypertension, 9.6-21.5% had hyperlipidaemia, 3.3-10.2% had diabetes mellitus and 20.0-33.8% were smokers. Despite the presence of baseline risk factors for MACE in this analysis, the incidence of MACE did not appear to increase over time in patients with PsO, PsA or AS.

The risk of malignancy was consistent with the rates across indications in the previous report (17). The use of a larger dataset and the longer exposure to secukinumab did not appear to increase the risk of malignancy over time. An in-depth analysis of malignancy risk in secukinumab-treated PsO, PsA and AS patients compared with patients from the Surveillance, Epidemiology and End Results (SEER) Program in the US has been published recently (40).

Similar to previous findings (17), we did not observe an increased rate of reported AESIs over time with secukinumab treatment on a year-by-year interval basis.

Post-marketing safety data are considered complementary to data from randomised controlled trials. Secukinumab was associated with a consistent safety profile in a post-marketing setting across 6 successive PSUR periods (26 December 2014 to 25 December 2018), with 285,811 cumulative post-marketing PY in the approved indications of PsO, PsA and AS.

Limitations and strengths

Despite reassuring findings, there are certain limitations to this safety analysis. Individual study protocols have defined inclusion and exclusion criteria of clinical trials, which may not fully reflect routine clinical practice. Studies included in the analysis may differ in terms of baseline selection criteria, patient characteristics and treatment regimens. The lack of a long-term placebo comparison, due to ethical considerations, limits comparisons. Post-marketing safety surveillance results have not been separated by individual dose regimen or by indication. The mean exposure to study treatment should be considered when interpreting results of the current analysis. Furthermore, it should be noted that the mean exposure to study treatment reduced over time in the year-by-year analysis.

The strength of this report is that these analyses integrate safety data from a large patient population pooled (>12,000 patients) from over 28 clinical trials across multiple indications and are complemented with a large post-marketing surveillance safety dataset. Furthermore, the use of EAIRs that adjust for potential differences in the duration of drug exposure enhances the robustness of this analysis. This long-term (up to 5 years) safety assessment also provides a broader understanding of the safety of secukinumab and supports its long-term use in chronic systemic inflammatory conditions. The data cut-off timing of post-marketing surveillance did not include the COVID-19 pandemic.

Conclusion

In this updated safety analysis, secukinumab demonstrated a favourable safety profile over long-term treatment in patients with PsO, PsA and AS. The safety profile of secukinumab in these pooled populations was consistent with that reported previously in the individual studies of secukinumab (13)(14)(15)(16)(17)(18)(19)(20). No new safety signals were identified.

Acknowledgements

ACKNOWLEDGEMENTSThe authors thank the patients who participated in these studies and the study investigators.The authors thank Sandeep Subramaniam, Avinash Thakur and Vivek Sanker (Novartis Healthcare Private limited, Hyderabad, India), and Trudy Mcgarry (Novartis Ireland Limited, Dublin, Ireland) for editorial and medical writing support, which was funded by Novartis Pharma AG, Switzerland, in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3).This analysis was funded by Novartis Pharma AG.Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies.These requests are reviewed and approved by an independent review panel on the basis of scientific merit.All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.Conflicts of interest.ABG has received honoraria as an advisory board member and consultant for AnaptsysBio, Avotres Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb Co., Incyte, GSK, Janssen, Pharma, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical Industries, Inc., UCB, Dermavant, and Xbiotech, and has received research/educational grants from Boehringer Ingelheim, Incyte, Janssen, Novartis, UCB, Xbiotech, and Sun Pharma.AD has been a consultant & Advisory Board member for AbbVie, Amgen, Aurinia, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Glaxo Smith Kline, Janssen, MonnLake, Novartis, Pfizer, and UCB, and has received research grants from AbbVie, Eli Lilly, Glaxo Smith Kline, Novartis, Pfizer, UCB.IBM has received grant/research support from AbbVie, Janssen, Novartis, Lilly, Celgene, UCB Pharma, BMS, Boehringer Ingelheim, AstraZeneca, Pfizer and has acted as a consultant for AbbVie, Janssen, Novartis, Lilly, Celgene, Compugen, UCB Pharma, BMS, Boehringer Ingelheim, AstraZeneca and Pfizer.XB has received grant/research support and/or consultancy fees from AbbVie, Amgen, Bristol-Myers Squibb, Celltrion, Celgene, Chugai, Gilead, Janssen, Lilly, MSD, Novartis, Pfizer, Sandoz, UCB.KR has served as advisor and/or paid speaker for and/ or participated in clinical trials sponsored by Abbvie, Almirall, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Forward Pharma, Gilead, Galderma, Janssen-Cilag, Kyowa Kirin, Leo, Lilly, Medac, Novartis, Ocean Pharma, Pfizer, Sanofi, UCB; and is a co-founder of Moonlake Immunotherapeutics.SS received fees for Advisory Boards/Consulting Fees from Abbvie, Allergan, Amgen, AMT, Arena, Biogen, Bristol-Myers Squibb, Boehringer, Celgene, Celltrion, Falk, Janssen, Gilead, Lilly, Merck, Pfizer, Roche, Takeda; Tillotts.Funding (Grants): none.Research/Clinical Trials: all of the above.Speaker Fees: Abbvie, Amgen, Arena, Biogen, Bristol-Myers Squibb, Celgene, Celltrion, Falk, Ferring, Janssen, Gilead, Lilly, Merck, Pfizer, Roche, Takeda, Tillotts.WB, KM, HBR, LP, AS, VT, DK, CCP, PJ, and PP are employed by Novartis.PJM reports research grants, consulting, and/or speaker for Abbvie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Galapagos, GlaxoSmithKline, Janssen, Novartis, Pfizer, SUN Pharma, and UCB.ML is an employee of Mount Sinai and receives research funds from: Abbvie, Amgen, Arcutis, Avotres, Boehringer Ingelheim, Dermavant Sciences, Eli Lilly, Incyte, Janssen Research & Development, LLC, Ortho Dermatologics, Regeneron, and UCB, Inc., and is a consultant for Aditum Bio, Almirall, AltruBio Inc., AnaptysBio, Arcutis, Inc., Aristea Therapeutics, Arrive Technologies, Avotres Therapeutics, BiomX, Boehringer-Ingelheim, Bristol-Myers Squibb, Cara Therapeutics, Castle Biosciences, Corrona, Dermavant Sciences, Dr Reddy's Laboratories, Evelo Biosciences, Evommune, Inc., Facilitatation of International Dermatology Education, Forte Biosciences, Foundation for Research and Education in Dermatology, Helsinn Therapeutics, Hexima Ltd, LEO Pharma, Meiji Seika Pharma, Mindera, Pfizer, Seanergy, and Verrica.

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