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 in patients with moderate-to-severe plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis: integrated pooled clinical trial and post-marketing surveillance data

A. Deodhar, P. Mease, I. McInnes, X. Baraliakos, K. Reich, A. Blauvelt, C. Leonardi, B. Porter, A. D. Gupta, A. Widmer, L. Pricop, T. Fox

Arthritis Research & Therapy·

2019·

243 citations

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IL-17A Antagonist

- Drug name: Secukinumab - Dosage and frequency: 75 mg, 150 mg, 300 mg; intravenous (up to 10 mg/kg) or subcutaneous (s.c.) - Route of administration: Intravenous or subcutaneous - Duration of treatment: Up to 5 years for PsO and PsA, up to 4 years for AS - Comparator treatments: Not mentioned

Patient Population

- Medical condition being treated: Psoriasis (PsO), Psoriatic Arthritis (PsA), Ankylosing Spondylitis (AS) - Sample size for safety analysis: PsO - 5181, PsA - 1380, AS - 794 - Age range: ≥ 18 years - Prior immunosuppressive therapy exposure: Continued use of sulfasalazine, methotrexate, corticosteroids, and non-steroidal anti-inflammatory drugs; some patients had inadequate response or intolerance to TNF inhibitors - Baseline infection risk factors or immunocompromised status: Hypertension (39.9% in PsA), hyperlipidemia (23.0% in PsA), diabetes (12.4% in PsA), history of IBD (0.3% in PsO, 0.6% in PsA, 3.1% in AS), uveitis (17% in AS)

Study Design

- Study type: Randomized controlled trials (RCTs) and post-marketing surveillance - Safety follow-up duration: Up to 5 years for PsO and PsA; up to 4 years for AS - Total patient-years of exposure: 10,416.9 (PsO), 3866.9 (PsA), 1943.1 (AS); cumulative post-marketing exposure ~96,054 patient-years - Active safety monitoring: Implied by detailed AE and SAE reporting and use of EAIRs - Loss to follow-up rates for safety outcomes: Not specifically mentioned

Infection Outcomes

- Overall infection rates: Not explicitly mentioned - Serious infection rates: PsO: 1.4, PsA: 1.9, AS: 1.2 per 100 patient-years - Opportunistic infections: Esophageal candidiasis, gastrointestinal candidiasis, herpes zoster, toxoplasmosis, Mycobacterium avium complex infection - Fungal infections (Candida): PsO: 2.2, PsA: 1.5, AS: 0.7 per 100 patient-years - Tuberculosis: No reactivation cases; 5 active TB cases in post-marketing data - Upper respiratory tract infections: Most common type of infection - Time to infection onset: Not mentioned

Hypersensitivity Reactions

- Injection site reactions: EAIRs were 1.2, 1.3, and 0.8 per 100 patient-years in PsO, PsA, and AS, respectively. - Hypersensitivity reactions: Reporting rate was 2.4 per 100 patient-years. - Anti-drug antibody development: Less than 1% of patients developed treatment-emergent ADAs, with no impact on efficacy or pharmacokinetics. - Immunogenicity-related adverse events: One case reported, but no further details provided. - Systemic allergic reactions or anaphylaxis: Not mentioned. - Skin reactions (rash, urticaria, etc.): Not mentioned.

Other Safety Outcomes

- Malignancy incidence: EAIR of 0.8 per 100 patient-years in PsO, with 76 non-hematological malignant tumors, 2 hematological malignant tumors, and 1 hematological tumor of unspecified malignancy. - Major adverse cardiovascular events: EAIRs of 0.3, 0.4, and 0.6 per 100 patient-years in PsO, PsA, and AS, respectively. - Inflammatory bowel disease: EAIRs ranged from 0.01 to 0.1 in PsO, 0.05 to 0.08 in PsA, and 0.1 to 0.4 in AS. - Neutropenia or other hematologic effects: EAIRs of 0.3, 0.2, and 0.5 per 100 patient-years in PsO, PsA, and AS, respectively. - Serious adverse events overall: EAIRs of 6.9, 7.9, and 6.3 per 100 patient-years in PsO, PsA, and AS, respectively. - Treatment discontinuation due to adverse events: 331 (6.4%) in PsO, 104 (7.5%) in PsA, and 58 (7.3%) in AS. - Deaths and causes: 9 deaths in PsO (pulmonary embolism, arrhythmia, alcohol poisoning, etc.), 11 deaths in PsA (acute myocardial infarction, septic shock, etc.), and 5 deaths in AS (acute respiratory failure, cerebrovascular accident, etc.).

Risk Factors

- Patient characteristics associated with increased infection risk: Genetic overlap with other immune-mediated diseases, common immune dysregulation, co-morbidities (hypertension, hyperlipidemia, diabetes), higher body mass index in PsO and PsA. - Dose-related safety patterns: No dose-response relationship observed in terms of safety events. - Time-dependent changes in safety outcomes: No increase in AE rates over time. - Concomitant medications affecting safety: Sulfasalazine, methotrexate, corticosteroids, non-steroidal anti-inflammatory drugs. - Baseline disease severity impact on safety: Not explicitly mentioned.

Safety Comparisons

- Safety outcomes compared to placebo: Not mentioned due to lack of long-term placebo comparison. - Safety outcomes compared to other biologics: Not mentioned. - Safety differences between different IL-17A antagonists: Not mentioned. - Safety differences between doses of the same drug: No dose-response relationship observed in terms of safety events. - Long-term vs short-term safety patterns: No increase in safety events over time, indicating consistent long-term safety patterns.

BACKGROUND

Secukinumab, a fully human immunoglobulin G1-kappa monoclonal antibody that directly inhibits interleukin (IL)-17A, has been shown to have robust efficacy in the treatment of moderate-to-severe psoriasis (PsO), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) demonstrating a rapid onset of action and sustained long-term clinical responses with a consistently favorable safety profile in multiple Phase 2 and 3 trials. Here, we report longer-term pooled safety and tolerability data for secukinumab across three indications (up to 5 years of treatment in PsO and PsA; up to 4 years in AS).

METHODS

The integrated clinical trial safety dataset included data pooled from 21 randomized controlled clinical trials of secukinumab 300 or 150 or 75 mg in PsO (14 Phase 3 trials and 1 Phase 4 trial), PsA (3 Phase 3 trials), and AS (3 Phase 3 trials), along with post-marketing safety surveillance data with a cut-off date of June 25, 2017. Adverse events (AEs) were reported as exposure-adjusted incident rates (EAIRs) per 100 patient-years. Analyses included all patients who received ≥ 1 dose of secukinumab.

RESULTS

A total of 5181, 1380, and 794 patients from PsO, PsA, and AS clinical trials representing secukinumab exposures of 10,416.9, 3866.9, and 1943.1 patient-years, respectively, and post-marketing data from patients with a cumulative exposure to secukinumab of ~ 96,054 patient-years were included in the analysis. The most frequent AE was upper respiratory tract infection. EAIRs across PsO, PsA, and AS indications were generally low for serious infections (1.4, 1.9, and 1.2, respectively), Candida infections (2.2, 1.5, and 0.7, respectively), inflammatory bowel disease (0.01, 0.05, and 0.1, respectively), and major adverse cardiac events (0.3, 0.4, and 0.6, respectively). No cases of tuberculosis reactivation were reported. The incidence of treatment-emergent anti-drug antibodies was low with secukinumab across all studies, with no discernible loss of efficacy, unexpected alterations in pharmacokinetics, or association with immunogenicity-related AEs.

CONCLUSIONS

Secukinumab demonstrated a favorable safety profile over long-term treatment in patients with PsO, PsA, and AS. This comprehensive assessment demonstrated that the safety profile of secukinumab was consistent with previous reports in patients with PsO, PsA, and AS, supporting its long-term use in these chronic conditions.

Article summary

Strengths (S) and limitations (L) of this study (S) Integrates safety data from a large patient population pooled over 21 clinical trials across multiple indications complemented with large post-marketing surveillance safety data (S) Exposure-adjusted incidence rates for reporting safety data enhances the robustness of the results by adjusting for treatment duration (S) Provides valuable evidence on the comprehensive safety profile of secukinumab that should inform clinical decision-making (L) Conduct of clinical trials is protocol-specified and may not fully reflect real-world clinical experience and lack of a long-term placebo comparison, due to ethical considerations, limits comparisons (L) Inflammatory bowel disease events were not adjudicated and post-marketing safety surveillance results have not been separated by individual dose regimen or by indication Background Interleukin (IL)-17A is involved in mucocutaneous defense [1] and plays a critical role in the pathogenesis of a range of immune-mediated diseases, including psoriasis (PsO), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) [2][3][4]. The disease pathogenesis of PsO, PsA, and AS is complex and involves an interplay among environmental, genetic, and immune triggers. There is a considerable genetic overlap with other immune-mediated diseases, and there is often evidence of common immune dysregulation, making these patients more susceptible to infections and/or adverse events (AEs) compared with the general population [5][6][7][8]. Furthermore, introduction of a foreign protein product, such as a monoclonal antibody, into the human body carries the possibility of an immunologic response and formation of anti-drug antibodies (ADAs) that may impact treatment efficacy and safety [9]. The presence of co-morbidities and use of concomitant medications further impacts these safety risks.

Biologic agents used in the management of PsO or PsA or AS have immunomodulatory potential via their effects on Type 17 (T helper [Th] and T Cell17) cell cytokines and other pathways, emphasizing the need to understand the unique safety profile of individual agents [10]. IL-17A also plays a role in the defense against extracellular pathogens [10] and other immune mechanisms. Therapy for these chronic diseases is typically intended for long-term use and, hence, understanding the long-term efficacy and safety of therapeutic compounds is particularly relevant for clinical decision-making.

Fully human monoclonal antibodies are derived from human gene sequences alone and are generally considered to have the least immunogenic potential among biologic agents [11]. Secukinumab, a fully human immunoglobulin G1-kappa monoclonal antibody that directly inhibits IL-17A, has been shown to have robust efficacy in the treatment of moderate-to-severe PsO [12][13][14][15], PsA [16][17][18], and AS [19,20] demonstrating a rapid onset of action and sustained long-term clinical responses with a consistently favorable safety profile observed in the context of multiple Phase 2 and 3 trials [17,20,21]. Secukinumab is currently approved in > 80 countries for use in PsO/PsA/ AS with over 150,000 patients treated [22].

Here, we present integrated pooled clinical trial safety data for secukinumab following long-term exposure of up to 5 years in PsO and PsA and up to 4 years in AS. Year-by-year AE rates in this cohort and the post-marketing data available from the secukinumab periodic safety update report (PSUR) submitted to global health authorities with a reporting cut-off date of June 25, 2017, are also reported and reviewed.

Studies and patients

The integrated clinical trial safety dataset included data pooled from 21 randomized controlled clinical trials of secukinumab in PsO (14 Phase 3 trials and 1 Phase 4 trial; N = 5181), PsA (3 Phase 3 trials; N = 1380), and AS (3 Phase 3 trials; N = 794) indications (see Fig. 1 for details), along with post-marketing surveillance data for secukinumab across the PsO, PsA, and AS indications from December 26, 2014 to June 25, 2017. Multiple secukinumab dose regimens were used in these studies and included intravenous (up to 10 mg/kg) or subcutaneous (s.c.; 75, 150, or 300 mg) loading followed by s.c. maintenance dosing (75, 150, or 300 mg). Placebo-treated patients were re-randomized to secukinumab between 12 and 24 weeks' post-baseline in the various studies. Eligible patients aged ≥ 18 years with moderate-to-severe plaque PsO or active PsA or AS were enrolled based on pre-specified eligibility criteria, which, along with the design of each study, have been reported in detail elsewhere [12,15,16,18,20,[23][24][25][26]. Of note, patients enrolled in these trials could have active/ongoing cardiovascular disease (unless severe or uncontrolled), previous history of inflammatory bowel disease (IBD), including Crohn's disease (CD) or uveitis (but not if active and ongoing), 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 (TB; prophylactic treatment started prior to enrollment). Patients could continue the following medications at stable doses: sulfasalazine, methotrexate, corticosteroids, and non-steroidal anti-inflammatory drugs. Patients with an inadequate response (if taken ≥ 3 months) or intolerance to tumor necrosis factor (TNF) inhibitors (not more than one in AS studies and not more than 3 in PsO and PsA studies) could also be included. Two studies (ERASURE and FIX-TURE) in the PsO pool also allowed patients with a prior history of usage of biologics other than TNF inhibitors (alefacept, briakinumab, efalizumab, and ustekinumab) after an appropriate washout period.

Safety assessments

Safety analyses included all patients who had received ≥ 1 dose of study medication, with data pooled at the individual patient level for all secukinumab treatment groups (any secukinumab) separately for the studies by indication. Analysis of the entire secukinumab treatment period was performed on safety data pooled at the patient level from the date of treatment initiation up to June 25, 2017. Analysis of the safety data was also performed by the approved secukinumab 300 and 150 mg doses separately for the studies by indication. Risks for AEs, serious AEs (SAEs), and selected AEs were expressed as exposure-adjusted incidence rates (EAIRs) per 100 patient-years for the entire treatment period. The EAIR was defined as the number of subjects exposed to the drug and experiencing a certain event divided by the total exposure time of all subjects who were at risk for the event.

AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 20.0 preferred terms (PTs) (https://www.meddra.org/). ADAs were measured using a Meso-scale Discovery bridging assay [27]. ADA-positive samples were analyzed to week 52 for drug-neutralizing potential, immunogenicity-related AEs, and impact on pharmacokinetics (PK) and efficacy of secukinumab. All clinical studies were conducted in compliance with the Declaration of Helsinki [28], International Council for Harmonization Guidelines for Good Clinical Practice, and local country regulations.

Results

The results are presented here in two sections: pooled clinical trial safety results and results from the post-marketing safety surveillance. Unless specified otherwise, the results predominantly reflect the pooled clinical trial data.

Baseline characteristics

Pooled safety analyses included 7355 secukinumabtreated patients with an overall exposure of 16,226.9 patient-years. A total of 5181 patients (representing 10,416.9 patient-years of exposure) were included in the PsO pooled analyses, 1380 patients (representing 3866.9 patient-years of exposure) in the PsA pooled analyses, and 794 patients (representing 1943.1 patient-years of exposure) in the AS pooled analyses. Demographics and baseline disease characteristics of the pooled secukinumab groups are provided in Table 1 . The baseline rates of hypertension (39.9%), hyperlipidemia (23.0%), and diabetes (12.4%) were comparatively higher in the PsA pool than in the other two indications. The mean body mass index was higher in the PsO (29.1) and PsA (29.8) pools compared with the AS pool (27.2) . The baseline rate of uveitis was higher in the AS pool (17%), which was expected given the propensity of this patient population to uveitis. A history of IBD (unspecified IBD, CD, and/or ulcerative colitis [UC]) was reported in 15 (0.3%) PsO, 8 (0.6%) PsA, and 25 (3.1%) AS patients, respectively.

Safety summary

The EAIRs of any AE with secukinumab treatment across the entire safety period were 204.4, 147.0, and 140.1 per 100 patient-years in the PsO, PsA, and AS pools, respectively. The EAIRs of any SAE with secukinumab treatment across the entire safety period were 6.9, 7.9, and 6.3 per 100 patient-years in the PsO, PsA, and AS pools, respectively, showing no discernible pattern across the treatment groups. A total of 9 (0.2%) deaths were reported in the secukinumab-treated PsO cohort (the primary reasons for death being pulmonary embolism, arrhythmia, alcohol poisoning, ruptured aneurysm, and myocardial infarction [2 patients] in the secukinumab 300 mg group and cerebral hemorrhage, cardiorespiratory arrest, and completed suicide in the secukinumab 150 mg group). There were 11 (0.8%) deaths in the PsA pool (150 mg group: acute myocardial infarction, septic shock, sepsis, pneumonia, metastatic small cell lung cancer, pancreatic carcinoma, and cardiac failure [2 patients]; 75 mg group: squamous cell carcinoma of the pharynx, myocardial infarction, and cerebrovascular event) and 5 (0.6%) in the AS pool (150 mg group: 1 unknown; 75 mg group: acute respiratory failure, cerebrovascular accident, acute myocardial infarction, and respiratory arrest). Discontinuations due to AEs numbered 331 (6.4%), 104 (7.5%), and 58 (7.3%) in the PsO, PsA, and AS pools, respectively (Table 2 ). The EAIRs of selected AEs with secukinumab were comparable across the PsO, PsA, and AS studies (Table 3 ). The rates were comparable with those reported previously [15,16,18,20], and no new safety signals were identified from those reported previously.

Infections

Over the entire safety period, upper respiratory tract infection (URTI) was the most common type of infection across all indications. In an overall dataset of 7355 patients, the EAIRs for serious infections were 1.4, 1.9, and 1.2 per 100 patient-years in the PsO, PsA, and AS pools, respectively (Table 3 ). A total of 14 cases (EAIR of 0.13 per 100 patient-years) of opportunistic infections were reported in the PsO pool, which included 10 cases of esophageal candidiasis, 3 cases of gastrointestinal candidiasis, and 1 case of herpes zoster infection. Eight cases (EAIR of 0.21 per 100 patient-years) of opportunistic infections were reported in the PsA pool, which included 4 cases of esophageal candidiasis and 1 case each of herpes zoster infection, toxoplasmosis, Mycobacterium avium complex infection, and pneumonia. The 2 cases (EAIR of 0.1 per 100 patient-years) of opportunistic infections reported in the AS pool were herpes zoster infection and esophageal candidiasis. A total of 5 cases (EAIR of 0.05 per 100 patient-years) of sepsis (PT) were reported in the PsO pool, 3 (EAIR of 0.08 per 100 patient-years) in the PsA pool, and none in the AS pool. Most infections were mild to moderate.

Candida infection

Cutaneous or mucosal Candida infection (MedDRA high-level term) was reported in 221 (EAIR of 2.2 per 100 patient-years) patients across the PsO studies, 57 (EAIR of 1.5 per 100 patient-years) patients across the PsA studies, and 13 (EAIR of 0.7 per 100 patient-years) patients across the AS studies (Table 3 and Additional file 1: Table S1 ). All cases of Candida infection were localized, most were mild or moderate in severity (except for 4 cases in the PsO pool that were considered severe), were self-limited or responsive to standard treatment, and did not lead to discontinuation of study treatment. No cases of systemic candidiasis were reported in patients treated with secukinumab across all studies.

Neutropenia

Over the entire treatment period, the EAIRs per 100 patient-years for neutropenia with secukinumab treatment were 0.3, 0.2, and 0.5 in the PsO, PsA, and AS studies, respectively (Table 3 ). In the PsO pool, grade 3 neutropenia (defined as an absolute neutrophil count between 1.0 and 0.5 × 10 9 /L) was reported in 33 (0.6%) patients and grade 4 neutropenia (defined as an absolute neutrophil count of less than 0.5 × 10 9 /L) was reported in 2 (0.04%) patients. Of the cases of neutropenia, 7 were reported as severe, while the remaining were mild or moderate in severity (viral URTI was the most frequently co-reported AE [17 cases]); there

Inflammatory bowel disease

The EAIRs per 100 patient-year exposure for CD, UC, or unspecified IBD combined ranged from 0.01 to 0.1 in PsO, 0.05 to 0.08 in PsA, and 0.1 to 0.4 in the AS pools (Table 3 ). There were 41 (0.6%) reported cases of IBD (including CD and UC). Of these, 30 (0.4%) were new-onset cases. Across indications, 14 (0.2%) patients who reported IBD discontinued the study.

Major adverse cardiovascular events

The EAIR per 100 patient-years for major adverse cardiovascular events (MACE) with secukinumab treatment over the entire treatment period was 0.3, 0.4, and 0.6 in the PsO, PsA, and AS pools, respectively (Table 3 ).

Uveitis

In the PsO pool, the EAIR for uveitis was 0.02 per 100 patient-years over the entire treatment period; all cases of uveitis (n = 2) were de novo. In the PsA pool, the EAIR for uveitis was 0.1 per 100 patient-years over the entire treatment period; all cases of uveitis (n = 3) were de novo. The EAIR for uveitis in the AS pool was 1.4 per 100 patient-years over the entire treatment period; a total of 12 (46%) cases were de novo (Table 3 ). Among all cases of uveitis (n = 26) in the AS pool, one was reported as severe and the remainder were reported as mild or moderate. A total of 135 (17%) patients in the AS pool reported pre-existing (but not active or ongoing) uveitis at baseline, and 589 (74.2%) were HLA-B27 positive, which has a known association with the development of uveitis.

Malignancy

Malignant or unspecified tumors (Standardized MedDRA Queries [SMQ]) were reported in 81 patients (EAIR of 0.8 per 100 patient-years) in the PsO pool, which included 76 patients with non-hematological malignant tumors, 2 patients each with a hematological malignant tumor or a non-hematological tumor of unspecified malignancy, and 1 patient with a hematological tumor of unspecified malignancy. In the PsA pool, malignant or unspecified tumors were reported in 43 patients (EAIR of 1.1 per 100 patient-years), which included 37 patients with non-hematological malignant tumors, 5 patients with a non-hematological tumor of unspecified malignancy, and 1 patient with a hematological malignant tumor. In the AS pool, malignant or unspecified tumors were reported in 9 patients (EAIR of 0.5 per 100 patient-years), which included 6 patients with non-hematological malignant tumors, 2 patients with a non-hematological tumor of unspecified malignancy, and 1 patient with a hematological malignant tumor.

Suicidality

Over the entire treatment period, in the PsO studies, 8 patients (0.2%) reported some form of suicidality-related AEs, including 4 attempted suicides, 1 completed suicide, 2 cases of suicidal ideation, and 1 case of suicidal depression. Three cases (0.2%) of suicidal ideation were reported in the PsA studies. All suicidality cases presented at least one of the following: depression, anxiety, insomnia, bipolar disorder, co-medication with psychoactive drugs, alcoholism, and/or ongoing psychological or socio-economic issues. No cases of suicidality-related AEs were reported in the AS studies on secukinumab treatment. These suicidality safety results with secukinumab were consistent with an earlier report from a pooled analysis of data from 10 clinical studies in moderate-to-severe plaque PsO [29].

Immunogenicity

Treatment-emergent ADAs were reported with secukinumab in < 1% of patients across all studies at week 52. All treatment-emergent ADAs were associated with normal PK [30], and none were associated with loss of secukinumab efficacy or immunogenicity-related AEs.

Injection site reactions

The EAIR of injection site reactions (high-level term) was 1.2, 1.3, and 0.8 in the PsO, PsA, and AS pools, respectively.

Incidence of AEs by secukinumab dose

Safety data for any AE, any SAE, serious infections, Candida infection, IBD, and MACE for the approved 300 and 150 mg secukinumab dose are shown in Additional file 1: Table S2 . The EAIRs were generally comparable, and there was no dose-response relationship observed in terms of safety events with secukinumab treatment within each indication.

Incidence of AEs year-by-year

Data on a year-by-year basis for any AE, any SAE, serious infections, Candida infection, IBD, and MACE showed no increase with secukinumab treatment over time across studies within each indication (Fig. 2 ). The EAIR per 100 patient-years for uveitis on a year-by-year basis was as follows: 0.02 (N = 5181; year 1), 0.0 (N = 3268; year 2), 0.0 (N = 2246; year 3), 0.07 (N = 1627; year 4), and 0.0 (N = 1210; year 5) in PsO clinical trials; 0.2 (N = 1380; year 1), 0.0 (N = 1183; year 2), 0.0 (N = 948; year 3), 0.2 (N = 587; year 4), and 0.0 (N = 290; year 5) in PsA clinical trials; and 1.1 (N = 794; year 1), 1.9 (N = 700; year 2), 2.2 (N = 557; year 3), and 2.5 (N = 332; year 4) in AS clinical trials.

Post-marketing safety surveillance results

The cumulative post-marketing exposure to secukinumab was estimated to be 96,054 patient-years across the approved indications (Table 4 ). The exposure-adjusted reporting rates (EARRs) for infections and serious infections were 4.7 and 1.8 per 100 patient-years, respectively.

Neutropenia was reported at a rate of 0.07 per 100 patient-years. The reporting rate of hypersensitivity was 2.4 per 100 patient-years. The EARRs for malignancies and MACE were both 0.2 per 100 patient-years, with most assessable cases having multiple confounders, risk factors, or alternative explanations for the events. IBD was reported at a rate of 0.2 per 100 patient-years. The reporting rate for suicidal ideation and behavior was 0.04 per 100 patient-years. Twenty-nine cases of opportunistic infections were reported in the post-marketing data, including 5 cases of TB infection (no reactivation cases), 2 cases of herpes infection, and 17 cases of esophageal candidiasis. There was 1 case of immunogenicity, and no cases of either hepatitis B reactivation or interactions with live vaccines were reported. The safety profile from the PSUR was consistent to that reported in randomized clinical trials (RCTs) with secukinumab.

Discussion

In [1] any MI, any CVA, and [2] all other CV events that are fatal, out of a listing of 2200+ terms. AE adverse event, AS ankylosing spondylitis, CV cardiovascular, CVA CV accident, EAIR exposure-adjusted incidence rate per 100 patient-years, IBD inflammatory bowel disease, MedDRA Medical Dictionary for Regulatory Activities, MACE major adverse cardiovascular event, MI myocardial infarction, N number of patients in the analysis, PsO psoriasis, PsA psoriatic arthritis, PT preferred term, SAE serious AE of Th17 cells intact (e.g., the release of IL-22 and TNF) thus limiting the scope for off-target-related effects with secukinumab compared with other biologics. It does not directly influence the Th1 pathway and, thus, is expected to leave Th1-based host immunity largely intact, which may improve the overall safety profile [3,4,10]. An increased risk of infections is potentially associated with any immunomodulatory biologic agent [31]. Furthermore, the immune dysregulations underlying severe PsO and spondyloarthritis are also recognized risk factors for an increased potential of developing infections [32]. The use of systemic therapies for PsO seems to further increase this risk of infections [33]. In this analysis, serious infections ranged between an EAIR of 1.2 and 1.9 per 100 patient-years in clinical trials with no clinically meaningful differences in EAIRs across the indications. This incidence of treatment-emergent infections is particularly reassuring and is an important clinical consideration in the management of patients with immune-mediated diseases such as PsO, PsA, and AS.

Neutrophils are important mediators and regulators of innate and adaptive immune responses, and a reduction in peripheral neutrophil counts is a potential effect of immune-modulating agents [34][35][36], including tofacitinib, brodalumab, and ixekizumab [37,38]. Over the entire treatment period in this clinical trial safety pool, the EAIRs per 100 patient-years for neutropenia with secukinumab were 0.3, 0.2, and 0.5 in the PsO, PsA, and AS studies, respectively. Also, in the post-marketing safety surveillance, neutropenia was reported as uncommon (EARR of ≥ 1/1000 to < 1/100).

In this large clinical trial safety analysis, the EAIR per 100 patient-years exposures for CD or UC or unspecified IBD was low and ranged between 0.01 and 0.1 in the three cohorts. Discontinuations due to IBD were low with secukinumab (14 [0.19%]). Also, in the post-marketing safety surveillance analysis, the cumulative reporting rate of IBD remained stable at approximately 0.2 reported events per 100 patient-years. Incidence rates per 100 patient-years of CD and UC have been reported in the literature ranging from ~0.3 in PsO, 0.1 in PsA, and 0.7 in AS patients [39][40][41]. Previous exposure to anti-TNF agents and smoking are identified risk factors for IBD exacerbation [42,43]. In this safety pool, almost one third of all PsA and AS patients were previously exposed to anti-TNF treatments (with an inadequate response or intolerance); previous biologic exposure was also apparent in the PsO cohort, but the rates were lower (15.1%). Each cohort also included a sizeable patient population of current smokers at baseline (30% in PsO and AS, and 19% in PsA). Nevertheless, the overall observed incidence of IBD, including new-onset cases, and discontinuations of secukinumab treatment due to IBD, was uncommon (< 1%). It is important to emphasize that while patients with a previous history of IBD, including CD or UC, could enroll in these trials, the risk of IBD in this cohort could be different from that observed in the real-world, as patients with active IBD were excluded from all clinical trials [40,44]. Incidences of suicidality-related AEs were low in the PsO and PsA studies, and none were reported in the AS studies. There was no evidence to suggest that treatment with secukinumab increases the risk of suicidality-related AEs beyond background risk in patients with these systemic inflammatory diseases [45,46].

The incidence of treatment-emergent ADAs was low with secukinumab across all studies evaluated, with no discernible loss of efficacy, unexpected alterations in PK, or association with immunogenicity-related AEs. Considering the reported potential for immunogenicity with secukinumab as compared with other biologic agents [47,48], this is particularly reassuring and relevant for clinical decision-making.

AE rates calculated on a year-by-year interval basis did not show an increased rate over time for most selected AEs with secukinumab treatment and revealed no new safety signals. EAIR for uveitis was generally low across the three indications. In the AS clinical trials, considering the background rate of uveitis medical history of 17% in the patient population, the decreasing sample size for each subsequent yearly interval may be skewing the EAIRs, given the relative low absolute number of uveitis events reported each year (skewing would be less evident for higher EAIRs). The year-by-year rates should be followed closely as additional long-term exposure data are accumulated. The observed rates of flares and even new-onset uveitis with secukinumab was low and reassuring given the background rate of uveitis in the medical history of this pool (especially in AS patients).

Post-marketing safety data are considered complementary to data from RCTs. Secukinumab was associated with a consistent safety profile in the post-marketing setting across five successive PSUR periods (Dec 26, 2014, to June 25, 2017), with a cumulative post-marketing exposure estimated to be ~96,054 patient-years in the approved indications of PsO, PsA, and AS.

Additionally, a recent analysis assessed the outcomes of pregnancies from this safety cohort, which did not find any evidence for increased rates of adverse pregnancy outcomes with secukinumab. However, the analysis was limited by a sizeable amount of missing outcome data and relatively short exposure to secukinumab [49,50].

Despite reassuring findings, there are limitations to this safety analysis. The conduct of clinical trials is protocol-specified, which may not fully reflect real-world clinical experience. Some studies included in the analysis differ in terms of baseline selection criteria, patient characteristics, and treatment regimens, which is a methodological limitation. However, pooling of data from large clinical trials and post-authorization safety surveillance has enabled a more comprehensive overview of the safety profile of secukinumab. It should be noted that IBD events were not adjudicated in this analysis. The lack of a long-term placebo comparison, due to ethical considerations, limits comparisons. Furthermore, the post-marketing safety surveillance results have not been separated by individual dose regimen or by indication. Rather than using only crude incidence rates, this report included the more robust safety assessment rate by using EAIRs which adjust for potential differences in duration of drug exposure. We believe that factors such as underlying disease activity, co-morbid conditions, and concomitant medications in the patient population are unlikely to have confounded these reported events, but this was not assessed, as it was beyond the scope of the current analyses. The strength of this report is the fact that this integrates safety data from a large patient population pooled over 21 clinical trials across multiple indications, and is complemented with large post-marketing surveillance safety data. The use of EAIRs also enhances the robustness of the results by adjusting for treatment duration. Thus, this report provides valuable evidence on the comprehensive safety profile of secukinumab that should inform clinical decision-making.

Summary

Secukinumab demonstrated a favorable safety profile over long-term treatment in patients with PsO, PsA, and AS. The safety profile of secukinumab was consistent in these pooled patient populations and with what has been reported earlier for individual studies of secukinumab [12, 13, 15-21, 23, 24, 26, 49] . This long-term (up to 5 years) safety assessment provides a broader understanding of the safety of secukinumab and supports its long-term use in these chronic systemic inflammatory conditions.

Additional file

Additional file 1: Table S1 . EAIR for Candida infection related preferred terms. Table S2 . Summary of secukinumab safety by dose. Table S3 . Summary of studies included in the pooled safety analysis of the entire secukinumab treatment period (from commencement date up to the cut-off date of June 25, 2017) . (DOCX 33 kb)

Availability of data and materials

The datasets generated and/or analyzed during the current study are not publicly available. 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 based on scientific merit. All data provided are anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. The data may be requested from the corresponding author of the manuscript.

Authors' contributions

All authors were involved in the drafting and critical review of the manuscript and approved the final version for submission. AD, PJM, IBM, XB, KR, AB, and CL were involved in the acquisition of clinical data and participated as investigators in multiple clinical studies from which data were pooled and reported in the manuscript. BP, ADG, AW, LP, and TF were involved with the conception or design of the work and the development of the statistical analysis plan. AD, PJM, IBM, XB, BP, ADG, AW, LP, and TF were involved with the interpretation of data in the manuscript. ADG and AW were involved with the analysis of the data in the manuscript. All authors agreed to be accountable for all aspects of the work and attested to the accuracy and integrity of the work.

Ethics approval and consent to participate

All clinical studies were conducted in compliance with the Declaration of Helsinki, International Council for Harmonization Guidelines for Good Clinical Practice and local country regulations. All patients provided written informed consent to participate in the respective studies.

Consent for publication Not applicable.

Competing interests A Deodhar: Received honoraria for consulting or speaking for, or has received research grants from AbbVie, Amgen, Boehringer Ingelheim, Bristol Myer Squibb (BMS), Eli Lilly, Glaxo Smith & Kline (GSK), Janssen, Novartis, Pfizer, and UCB. PJ Mease: Grant/research support from: AbbVie, Amgen, BMS, Celgene, Crescendo Bioscience, Genentech, Janssen, Lilly, Merck, Novartis, Pfizer and UCB; Consultant for: AbbVie, Amgen, BMS, Celgene, Crescendo Bioscience, Genentech, Janssen, Lilly, Merck, Novartis, Pfizer and UCB; Speakers bureau: AbbVie, Amgen, BMS, Celgene, Crescendo Bioscience, Genentech, Janssen, Lilly, Merck, Novartis, Pfizer and UCB. IB McInnes: Research grants, consultation fees, or speaker honoraria: AbbVie, Amgen, BMS, Celgene, Janssen, Lilly, Novartis, Pfizer and UCB. X Baraliakos: Grant/research support from: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB, Werfen, Consultant for: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB, Werfen, Speakers bureau: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB, Werfen.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. University of Glasgow, Glasgow, UK. 4 Rheumazentrum Ruhrgebiet Herne, Ruhr-University Bochum, Bochum, Germany. 5 Translational Research in Inflammatory Skin Diseases, Institute for Health Services Research in Dermatology and Nursing, University Medical Center Hamburg-Eppendorf, Skinflammation® Center, Hamburg, Germany. 6 Oregon Medical Research Center, Portland, USA. 7 Saint Louis University Health Science Center, St. Louis, USA. 8 Novartis Pharmaceuticals Corporation, East Hanover, USA. 9 Novartis Healthcare Private Limited, Hyderabad, India. 10 Novartis Pharma AG, Basel, Switzerland.

Acknowledgements

AcknowledgementsThe authors thank the patients who participated in these studies, the study investigators and Abhijit Shete (Novartis Pharma AG, Basel, Switzerland) and Jorge Safi (Novartis Pharmaceuticals Corporation, East Hanover, USA) for valuable medical review.Medical writing and editorial support for this manuscript were provided by M K Vivek Sanker, Novartis Healthcare Private Limited, India, which was funded by Novartis Pharma in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3).\
Funding

FundingThe clinical studies providing data and these analyses were funded by Novartis Pharma AG, Basel, Switzerland.

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Abstract screening pilot

Abstract screening results

Extraction pilot

Extraction results

Research report
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