Elicit: IL-17A Blockade in Psoriatic Arthritis and Axial Spondyloarthritis

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IL-17A Blockade in Psoriatic Arthritis and Axial Spondyloarthritis

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May 5, 2026

Clinical evidence for IL-17A blockade in psoriatic arthritis and axial spondyloarthritis

IL-17A blockade with ixekizumab or secukinumab demonstrates robust and sustained efficacy for both psoriatic arthritis and axial spondyloarthritis, with clinically meaningful improvements in joint symptoms, axial manifestations, and skin disease, accompanied by an acceptable safety profile characterized primarily by increased mucocutaneous candida infections.

Abstract

IL-17A blockade demonstrates consistent efficacy across the spectrum of psoriatic arthritis and axial spondyloarthritis in multiple randomized controlled trials. In radiographic axial spondyloarthritis, ixekizumab achieved ASAS40 response rates of 48-52% at week 16 versus 18% with placebo, while secukinumab showed approximately 60% ASAS20 responses across trials. In non-radiographic axial spondyloarthritis, ixekizumab demonstrated ASAS40 rates of 30-40% versus 13-19% with placebo at weeks 16 and 52. For psoriatic arthritis, meta-analytic evidence shows pooled ACR20 response relative risks of 2.04 (95% CI: 1.79-2.33), with individual trials reporting ACR20 rates of 50-62% versus 17-30% with placebo at week 24. Skin manifestations improved substantially, with PASI 75 response rates of 69-75% versus 7.5% placebo at week 12. TNF-naive patients showed greater absolute benefits than TNF-experienced populations, though both groups demonstrated significant improvements. The safety profile was generally favorable, with treatment-emergent adverse event rates of 57-77% and low serious adverse event rates (6% or less). Candida infections occurred more frequently with IL-17A inhibition (4.7% with secukinumab 300 mg), though most were mild to moderate. Discontinuation rates due to adverse events were low (2.4%), and treatment discontinuation rates were actually lower in IL-17A inhibitor groups versus placebo (RR 0.54). These data establish IL-17A blockade as an effective therapeutic option for both psoriatic arthritis and axial spondyloarthritis with an acceptable benefit-risk profile.

Methods

We analyzed 10 sources from an initial pool of 200, using 7 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: Population, Intervention, Study Design, Clinical Outcomes, Age Group, Sample Size, Publication Type

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: “Clinical evidence for IL-17A blockade in psoriatic arthritis and axial spondyloarthritis”

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 study design details including:

Extract details about the IL-17A blocking therapy including:

Extract patient characteristics relevant to psoriatic arthritis and axial spondyloarthritis including:

Extract details about control/comparator groups including:

Extract all efficacy outcomes related to joint/musculoskeletal manifestations including:

Extract efficacy outcomes specifically related to psoriatic skin manifestations including:

Extract comprehensive safety data for IL-17A blockade including:

Assess and extract study quality indicators including:

Results

Characteristics of Included Studies

The review included 10 sources comprising 7 primary randomized controlled trials (RCTs), 2 systematic reviews/meta-analyses, and 1 narrative review. Four studies evaluated ixekizumab, five evaluated secukinumab, and two meta-analyses evaluated multiple IL-17 inhibitors.

Study

Full text retrieved?

Study design

Duration

Sample size

Funding

Geographic scope

van der Heijde et al., 2018

Yes

Phase III RCT

52 weeks with optional 2-year extension

341 randomized

Eli Lilly and Company

84 sites in 12 countries across Europe, Asia, North America

Deodhar et al., 2019

No

Phase III RCT

52 weeks

303 randomized (105 placebo, 96 ixekizumab Q4W, 102 ixekizumab Q2W)

Eli Lilly and Company

107 sites in 15 countries

Baeten et al., 2013

No

Phase II proof-of-concept RCT

Week 6 efficacy, week 28 safety

30 randomized (24 secukinumab, 6 placebo), 29 completed

Novartis

8 sites in Europe (4 Germany, 2 Netherlands, 2 UK)

Baraliakos et al., 2020

Yes

Phase 3b RCT

52 weeks

498 randomized, 425 completed (85%)

Novartis

97 centers in Europe, Russia, Israel

Naik et al., 2017

Yes

Systematic review and meta-analysis of RCTs

12-24 weeks

1,718 in treatment arm, 840 in placebo arm

Industry-sponsored

Not reported

Mease et al., 2015

No

Phase III RCT

52 weeks

606 randomized

Novartis Pharma

Not reported

Mease & McInnes, 2016

Yes

Narrative review of phase III trials

At least 52 weeks

Not reported

Novartis Pharma

Not reported

González Alonso et al., 2022

Yes

Systematic review and meta-analysis of RCTs

Week 12 primary timepoint

23 studies included

AbbVie

Not reported

Aparicio et al., 2021

Yes

Narrative review of phase III trials and real-world studies

Up to 5 years

Not reported

Novartis

Not reported

Mease et al., 2016

Yes

Phase III RCT (SPIRIT-P1)

24 weeks double-blind, 3 years total

417 randomized, 382 completed 24 weeks

Eli Lilly and Company

Not reported

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The primary studies enrolled biologic-naive or biologic-experienced patients with active disease. Van der Heijde et al. included only biologic-naive patients with radiographic axial spondyloarthritis, while Deodhar et al. enrolled patients with non-radiographic axial spondyloarthritis. The PsA trials (Baraliakos, Mease 2015, Mease 2016) included patients meeting CASPAR criteria. Baseline disease activity was substantial across studies, with BASDAI scores ≥4 in axial SpA trials and active joint counts in PsA trials.

Treatment regimens varied by agent and indication. Ixekizumab was administered at 80 mg subcutaneously every 2 or 4 weeks following a 160 mg loading dose. Secukinumab dosing differed between studies: the early phase II trial used intravenous 2×10 mg/kg, while later trials used subcutaneous 150 mg or 300 mg with weekly loading for 4 weeks then monthly maintenance.

Joint and Axial Efficacy Outcomes

Axial Spondyloarthritis Studies

The ixekizumab COAST-V trial in radiographic axial SpA demonstrated superior efficacy over placebo at week 16, with ASAS40 response rates of 52% (ixekizumab Q2W), 48% (ixekizumab Q4W), 36% (adalimumab), and 18% (placebo). Both ixekizumab dosing regimens achieved statistical significance versus placebo (p<0.0001).

In non-radiographic axial SpA (COAST-X), ixekizumab showed sustained efficacy with ASAS40 responses at week 16 of 40% (Q2W) and 35% (Q4W) versus 19% placebo, and at week 52 of 31% (Q2W) and 30% (Q4W) versus 13% placebo. Both primary endpoints were statistically significant (p≤0.0037).

The early proof-of-concept secukinumab trial in ankylosing spondylitis achieved ASAS20 response rates of 59% versus 24% placebo at week 6, with 99.8% probability of superiority. The MAXIMISE trial in PsA with axial manifestations reported ASAS20 responses at week 12 of 63% (secukinumab 300 mg), 66% (150 mg), and 31% (placebo), with ASAS40 responses of 44% (300 mg), 40% (150 mg), and 12% (placebo). Responses were sustained through week 52, with ASAS20 rates of 80-81% across secukinumab groups.

The comprehensive review by Aparicio et al. synthesized data from multiple MEASURE trials, reporting ASAS20 response rates of approximately 60% across MEASURE 1, 2, and 3, and 58.4% in MEASURE 5. The PREVENT study in TNF-naive patients showed ASAS40 rates of 41.4% and 42.2%. Long-term data demonstrated sustained improvements over 2-3 years, with mean radiographic progression (mSASSS) of only 0.3 and 95.3% of patients without baseline syndesmophytes remaining free of new syndesmophytes at week 104.

Psoriatic Arthritis Studies

The ACR response rates demonstrated consistent efficacy of IL-17A inhibition in PsA. In the Mease et al. 2015 trial, secukinumab achieved ACR20 response rates at week 24 of 50.0% (150 mg) and 50.5% (75 mg) versus 17.3% placebo (p<0.001), with ACR50 responses significantly better than placebo and sustained improvements through 52 weeks.

The SPIRIT-P1 trial of ixekizumab showed ACR20 responses at week 24 of 62.1% (Q2W) and 57.9% (Q4W) versus 30.2% placebo (p≤0.001), with ACR50 and ACR70 improvements evident as early as weeks 4 and 8. Disease activity measured by DAS28-CRP decreased by -2.04 (Q2W) and -1.96 (Q4W) versus baseline, and physical function improved with HAQ-DI changes of -0.50 (Q2W) and -0.44 (Q4W). Radiographic progression measured by mTSS was minimal: 0.08 (Q2W) and 0.17 (Q4W) compared to placebo.

Meta-analytic evidence from Naik et al. demonstrated pooled relative risks for achieving ACR20 of 2.04 (95% CI: 1.79-2.33; p<0.001) at week 12 and 2.01 (95% CI: 1.72-2.34; p<0.001) at week 24. ACR50 responses showed relative risks of 3.94 (95% CI: 2.83-5.49) at week 12 and 3.37 (95% CI: 2.83-4.32) at week 24. ACR70 responses demonstrated relative risks of 6.03 (95% CI: 2.12-17.18) at week 12 and 5.65 (95% CI: 3.57-8.95) at week 24.

The González Alonso et al. meta-analysis confirmed these findings with odds ratios at week 12 of 3.60 (95% CI: 2.85-4.55) for ACR20, 10.85 (95% CI: 6.20-18.94) for ACR50, and 7.94 (95% CI: 4.23-14.91) for ACR70.

Skin Efficacy Outcomes

Skin outcomes were primarily reported in PsA trials. The SPIRIT-P1 trial showed robust PASI 75 response rates at week 12 of 75.3% (ixekizumab Q4W) and 69.5% (Q2W) versus 7.5% placebo, with responses observed as early as week 4. Nearly half of patients with ≥3% affected body surface area achieved complete psoriasis clearance.

Nail psoriasis improved substantially with ixekizumab, with mean NAPSI score changes at week 24 of -14.0 (Q4W) and -15.5 (Q2W) versus -2.4 placebo. Complete nail psoriasis resolution occurred in 36.5% of ixekizumab Q2W patients.

The González Alonso meta-analysis reported a pooled odds ratio for PASI75 at week 12 of 21.26 (95% CI: 13.72-32.95), demonstrating substantial skin efficacy across IL-17 inhibitor trials in PsA.

Safety Profile

Overall Adverse Events and Infections

Treatment-emergent adverse event rates varied across studies. In COAST-X, overall adverse events occurred in 57% (placebo), 66% (ixekizumab Q4W), and 77% (ixekizumab Q2W). The MAXIMISE trial reported non-serious adverse events in 47% (placebo) versus 36-39% in secukinumab groups. The SPIRIT-P1 trial showed adverse event rates of 47.2% (placebo), 64.4% (adalimumab), and 65.7-66.4% (ixekizumab).

The most common adverse events across trials were nasopharyngitis, upper respiratory tract infections, and injection site reactions. Infections showed similar frequencies across treatment groups in most studies, though the Naik meta-analysis found no significant increase in infection risk (RR: 1.06, 95% CI: 0.91-1.23).

Serious infections occurred at low rates. COAST-V reported one serious infection each in the ixekizumab Q2W (1%), Q4W (1%), and adalimumab (1%) groups, with none in placebo. COAST-X documented one serious infection in the ixekizumab Q4W group. The MAXIMISE trial reported 7 serious infections across treatment groups. Aparicio et al.’s review noted low exposure-adjusted incidence rates for serious infections, with no active tuberculosis reactivation cases and rare new latent TB infection (EAIR 0.08 per 100 patient-years).

Candida and Opportunistic Infections

Candida infections emerged as a recognized adverse event with IL-17A blockade. COAST-V reported one Candida infection (1%) in the adalimumab group. The MAXIMISE trial documented 8 non-serious Candida infections. Mild-to-moderate candidiasis occurred in 4.7% of patients receiving secukinumab 300 mg in the studies reviewed by Mease & McInnes. The Naik meta-analysis found Candida infections trended higher but not statistically significant (RR: 3.35, 95% CI: 0.75-14.95).

No treatment-emergent opportunistic infections were reported in COAST-V, and the Naik meta-analysis found no tuberculosis cases.

Serious Adverse Events and Cardiovascular Events

Serious adverse event rates were generally low. The MAXIMISE trial reported serious adverse events in 6% of secukinumab-treated patients, with no single event occurring more than once. The Naik meta-analysis found no significant difference in serious adverse events between IL-17 inhibitors and placebo (RR: 0.82, 95% CI: 0.42-1.59).

Cardiovascular events were rare but notable. The MAXIMISE trial documented ischaemic cardiomyopathy, cardiogenic shock, myocardial infarction, and ischaemic stroke, with one fatal event from ischaemic cardiomyopathy not considered study drug-related. The Mease et al. 2015 study reported 4 strokes (0.6 per 100 patient-years) and 2 myocardial infarctions (0.3 per 100 patient-years) in secukinumab groups versus none in placebo, though the study was not large or long enough to definitively evaluate these uncommon events. SPIRIT-P1 reported no major cerebrocardiovascular events.

Malignancies, Laboratory Abnormalities, and Other Safety Outcomes

Malignancy rates were low. COAST-V reported no malignancies, while COAST-X found none through 52 weeks. The MAXIMISE trial documented 3 malignancies: small cell lung cancer, metastases to the spine, and an adrenal neoplasm. Aparicio et al. reported a malignancy EAIR of 0.85 per 100 patient-years. SPIRIT-P1 found no malignancies during the study period.

Laboratory abnormalities were infrequent. COAST-V showed no increased risk of Grade 3 or 4 neutropenia. SPIRIT-P1 reported Grade 1 and 2 neutropenia but no Grade 3 or higher.

Treatment discontinuation rates due to adverse events were low, ranging from 2.4% in SPIRIT-P1 to rates consistent with previous IL-17A inhibitor data in MAXIMISE. The Naik meta-analysis found lower discontinuation rates in treated versus placebo groups (RR: 0.54, 95% CI: 0.31-0.93), suggesting better tolerability.

No deaths occurred in COAST-V, COAST-X, or SPIRIT-P1. The MAXIMISE trial reported one death from ischaemic cardiomyopathy not considered related to study drug.

Immunogenicity was low. COAST-V found low frequencies of anti-drug antibodies with no association with immune reactions or reduced efficacy. SPIRIT-P1 reported 11 patients developing anti-ixekizumab antibodies, with none having detectable neutralizing antibodies. Aparicio et al. noted anti-drug antibodies in only 0.68% of AS patients and 0.35% of PsA patients.

Synthesis

The evidence demonstrates consistent efficacy of IL-17A blockade across the spectrum of psoriatic arthritis and axial spondyloarthritis, with some important distinctions based on disease phenotype and prior treatment exposure.

Efficacy Across Disease Subtypes

In radiographic axial spondyloarthritis, ixekizumab achieved ASAS40 responses of 48-52% at week 16, while secukinumab showed approximately 60% ASAS20 response rates across multiple MEASURE trials. In non-radiographic axial SpA, ixekizumab demonstrated lower but still significant ASAS40 rates of 30-40% at weeks 16 and 52. This pattern suggests greater absolute response rates in patients with established structural disease, which may reflect differences in disease duration (16 years mean symptom duration in COAST-V versus active disease without definite radiographic changes in COAST-X) or underlying disease biology. However, both phenotypes showed statistically significant improvements over placebo, establishing efficacy across the axial SpA spectrum.

For PsA with predominantly peripheral arthritis, ACR20 response rates ranged from 50-62%, comparable to radiographic axial SpA responses. In PsA with axial manifestations specifically (MAXIMISE trial), ASAS20 responses of 63-66% at week 12 exceeded those in pure axial SpA trials, potentially reflecting the selected population with both peripheral and axial disease or the higher baseline inflammatory burden.

Context-Dependent Efficacy: TNF-Naive Versus TNF-Experienced Populations

The Aparicio review noted greater benefits in TNF inhibitor-naive patients compared to those with prior TNF exposure. In the PREVENT study of non-radiographic axial SpA, TNF-naive patients achieved ASAS40 rates of 41-42%, while the broader population including TNF-experienced patients showed 30-40% ASAS40 responses in COAST-X. This finding aligns with the general principle that biologic-naive populations respond more robustly to targeted therapies, whether reflecting less refractory disease biology or the absence of treatment-induced immunological changes. Both populations benefit from IL-17A blockade, but effect sizes are larger in biologic-naive cohorts.

Dose-Response Relationships

Ixekizumab dosing at 80 mg every 2 weeks versus every 4 weeks showed minimal differences in efficacy across studies. In COAST-V, ASAS40 rates were 52% (Q2W) versus 48% (Q4W); in COAST-X, 40% (Q2W) versus 35% (Q4W) at week 16; and in SPIRIT-P1, ACR20 rates were 62.1% (Q2W) versus 57.9% (Q4W). These modest differences suggest both regimens operate near the plateau of the dose-response curve, with Q4W providing substantial efficacy at lower cumulative drug exposure.

For secukinumab, the MAXIMISE trial directly compared 300 mg versus 150 mg dosing and found nearly identical ASAS20 responses (63% versus 66%) at week 12 and sustained responses at week 52 (81% versus 80%). This equivalence contrasts with psoriasis dosing where 300 mg showed superiority, suggesting disease-specific dose requirements or ceiling effects in joint outcomes.

Safety Signal Interpretation

While overall infection rates were not significantly increased (RR 1.06), the pattern of Candida infections emerged consistently across studies. The non-significant pooled RR of 3.35 (95% CI: 0.75-14.95) reflects low absolute event rates but consistent directional effects, with 8 non-serious cases in MAXIMISE and 4.7% incidence at the 300 mg secukinumab dose. This mechanistic expectation based on IL-17’s role in mucocutaneous immunity appears clinically manageable, with most infections being mild to moderate.

The cardiovascular events reported in the Mease et al. 2015 study (4 strokes, 2 MIs in secukinumab groups versus none in placebo) must be interpreted cautiously given the study’s acknowledgment that it was insufficiently powered for rare events. The MAXIMISE trial’s cardiovascular events occurred in a population with baseline metabolic risk factors common in PsA. Without consistent signals across all trials and with no events in SPIRIT-P1, these findings may reflect background cardiovascular disease in inflammatory arthritis populations rather than drug-specific effects, though continued surveillance remains warranted.

The finding of lower discontinuation rates in treated versus placebo groups (RR 0.54) supports overall tolerability, with most discontinuations driven by insufficient efficacy rather than adverse events.

References

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. Mease, I. McInnes\ (2016).Secukinumab: A New Treatment Option for Psoriatic Arthritis. Rheumatology and Therapy

D. van der Heijde, James Cheng-Chung Wei, M. Dougados, P. Mease, A. Deodhar, and 10 more\ (2018).Ixekizumab, an interleukin-17A antagonist in the treatment of ankylosing spondylitis or radiographic axial spondyloarthritis in patients previously untreated with biological disease-modifying anti-rheumatic drugs (COAST-V): 16 week results of a phase 3 randomised, double-blind, active-controlled and. The Lancet

A. G. González Alonso, D. Fernández Fernández, R. Dos-Santos, I. González Fernández, P. Castro-Santamaria, and 6 more\ (2022).AB0902 Efficacy of IL-17 inhibitors in Psoriatic Arhtritis. Sistematic Review of Scientific Literature and Meta-Analysis. Annals of the Rheumatic Diseases

M. Aparicio, C. Guillén-Astete, C. López-Medina, C. Sastré, F. R. Rodríguez Martínez\ (2021).Evidence for the Use of Secukinumab in Patients with Radiographic and Non-radiographic Axial Spondyloarthritis in the Last 5 Years. Rheumatology and Therapy

P. Mease, D. M. van der Heijde, C. Ritchlin, M. Okada, R. Cuchacovich, and 5 more\ (2016).Ixekizumab, an interleukin-17A specific monoclonal antibody, for the treatment of biologic-naive patients with active psoriatic arthritis: results from the 24-week randomised, double-blind, placebo-controlled and active (adalimumab)-controlled period of the phase III trial SPIRIT-P1. Annals of the Rheumatic Diseases

D. Baeten, X. Baraliakos, J. Braun, J. Sieper, P. Emery, and 18 more\ (2013).Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial. The Lancet

X. Baraliakos, L. Gossec, E. Pournara, S. Jeka, A. Mera-Varela, and 6 more\ (2020).Secukinumab in patients with psoriatic arthritis and axial manifestations: results from the double-blind, randomised, phase 3 MAXIMISE trial. Annals of the Rheumatic Diseases

A. Deodhar, D. van der Heijde, L. Gensler, Tae-Hwan Kim, W. Maksymowych, and 12 more\ (2019).Ixekizumab for patients with non-radiographic axial spondyloarthritis (COAST-X): a randomised, placebo-controlled trial. The Lancet

G. S. Naik, W. Ming, Itai M. Magodoro, B. Akinwunmi, S. Dar, and 3 more\ (2017).Th17 Inhibitors in Active Psoriatic Arthritis: A Systematic Review and Meta-Analysis of Randomized Controlled Clinical Trials. Dermatology

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Evidence for the Use of Secukinumab in Patients with Radiographic and Non-radiographic Axial Spondyloarthritis in the Last 5 Years

M. Aparicio, C. Guillén-Astete, C. López-Medina, C. Sastré, F. R. Rodríguez Martínez

Rheumatology and Therapy·

2021·

9 citations

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Study Design

- Type of study: Randomized controlled phase III trials and real-world observational analyses - Duration of follow-up: Up to 5 years - Sample size: Not mentioned - Number of study sites and geographic locations: Not mentioned - Funding source: Novartis

IL-17A Agent

- Specific agent name: Secukinumab - Dosage and dosing regimen: 150 mg or 300 mg; Europe: 150 mg once weekly for the first five doses, then 150 mg per month; US: Optional loading dose, start with 150 mg every 4 weeks - Route of administration: Subcutaneous injection - Loading dose details: Required in Europe, optional in the US - Duration of treatment period: Up to 5 years

Patient Population

- Specific diagnosis: Radiographic and non-radiographic axial spondyloarthritis (axSpA), ankylosing spondylitis (AS), psoriatic arthritis (PsA) with spinal involvement - Disease duration: Not mentioned - Prior biologic exposure: Predominantly naïve to TNF inhibitors in PREVENT study; greater benefit in TNF inhibitor-naïve patients - Baseline disease activity scores: Not mentioned - Key inclusion/exclusion criteria: Not mentioned - Demographics: Younger age associated with faster attainment of ASAS20/40; no gender influence; effectiveness independent of HLA-B27 status

Comparator Groups

- Placebo control details: Placebo was used as a control group in several studies, including the MEASURE studies and the SKIPPAIN study. - Active comparator agents: Adalimumab (a TNF inhibitor) was used as an active comparator in the SURPASS study. - Randomization ratio: Not mentioned. - Crossover or rescue therapy provisions: Not mentioned. - Concomitant medications allowed: Not specified, but improvements in disease activity parameters suggest possible use of conventional treatments like NSAIDs.

Joint Efficacy Outcomes

- ASAS20 response rates: Approximately 60% in MEASURE 1, 2, and 3; 58.4% in MEASURE 5; 66% and 63% in MAXIMISE for secukinumab 150 mg and 300 mg, respectively. - ASAS40 response rates: 41.4% and 42.2% in PREVENT for TNF-naïve patients. - Disease Activity Score changes: Not explicitly mentioned, but improvements in disease activity are noted. - Physical function measures: Not explicitly mentioned. - Radiographic progression/structural damage measures: Mean change in mSASSS was 0.3; 95.3% of patients without baseline syndesmophytes remained free of them at week 104. - Time to response and sustained response data: Improvements sustained over 2-3 years in MEASURE 1 and 2. - Primary endpoint achievement and statistical significance: Significant improvements in ASAS20/40 response rates compared to placebo in most studies.

Skin Efficacy Outcomes

Not mentioned (the paper does not provide specific skin efficacy outcomes for psoriatic skin manifestations)

Safety Profile

- Overall adverse event rates: 46-70% - Serious adverse events: 0-6% - Infections: Low risk; no active TB cases; new latent TB infection EAIR 0.08 per 100 patient-years - Cardiovascular events: Not mentioned - Malignancies: EAIR 0.85 per 100 patient-years - Laboratory abnormalities: Not mentioned - Discontinuation rates due to adverse events: Insufficient efficacy was the most common reason for discontinuation - Deaths and causes: Not mentioned - Immunogenicity/anti-drug antibodies: Low incidence; 0.68% in AS, 0.35% in PsA

Risk of Bias

- Randomization method and adequacy: Not explicitly mentioned - Allocation concealment: Not mentioned - Blinding of participants, investigators, and outcome assessors: Not mentioned - Completeness of follow-up and handling of missing data: Not mentioned - Selective outcome reporting concerns: Not mentioned - Industry sponsorship and author conflicts of interest: Funded by Novartis; authors have conflicts of interest with pharmaceutical companies - Use of intention-to-treat vs. per-protocol analysis: Not mentioned

Axial spondyloarthritis (axSpA) is an inflammatory rheumatic disorder that causes chronic pain, primarily in the spine and sacroiliac joints. It is characterized by the presence of type 1 major histocompatibility complex HLA-B27 genetic marker, arthritis in peripheral joints, enthesitis and/or dactylitis and extra-articular manifestations. Current guidelines recommend biological therapy when first-line therapy is not sufficiently effective. The finding that the interleukin (IL)-17 axis is vital for the pathogenesis of axSpA propelled the development of secukinumab, a fully human monoclonal antibody directed against IL-17A. The present review provides evidence on the efficacy and safety of secukinumab in the treatment of radiographic and non-radiographic axSpA from nine randomized controlled phase III trials, as well as evidence from real-world observational analyses. The primary endpoint in six clinical trials was the proportion of patients meeting the Assessment of SpondyloArthritis international Society criteria for either 20% or 40% improvement (ASAS20, ASAS40) at week 16. Significantly more patients achieved the primary endpoint with secukinumab compared with placebo in all the studies except MEASURE 4. Both clinical trials and real-world studies showed significant improvements in the secondary endpoints of disease activity, quality of life, and pain and fatigue relative to placebo. The benefits of secukinumab were generally sustained during longer-term (up to 5 years) treatment. Overall, secukinumab was well tolerated with a low frequency of adverse events and treatment persistence was high in the real-world setting. Although indirect comparisons suggest that secukinumab and adalimumab have comparable efficacy and safety, they are being directly compared in the ongoing SURPASS study. During the current coronavirus disease 2019 (COVID-19) pandemic, it is advisable to continue biological therapy in patients who do not have severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection, but interrupt treatment during an infection, reinitiating once the patient has recovered from the infection. In conclusion, secukinumab is a largely safe and effective treatment for radiographic and non-radiographic axSpA.

INTRODUCTION

The term 'spondyloarthritis' is used to define a group of rheumatic disorders, characterized by a genetic association with type 1 major histocompatibility complex HLA-B27, extra-articular manifestations, and common clinical characteristics [1]. The group of spondyloarthropathies include axial spondyloarthritis (axSpA), psoriatic arthritis (PsA), reactive arthritis, and arthritis related to inflammatory bowel disease (IBD) [2].

When the conditions primarily affect the sacroiliac joints, with or without the involvement of the spine, they are termed axSpA [1,3]. The predominant clinical feature of axSpA is chronic back pain, which may be accompanied by arthritis in peripheral joints, enthesitis and/ or dactylitis, as well as extra-articular manifestations, such as uveitis or psoriasis [1]. Ankylosing spondylitis (AS) is the classical form of axSpA characterized by structural damage to the spine and sacroiliac joints that is visible on radiographic imaging [2]. Patients may or may not show sacroiliitis on X-ray; depending on the presence or absence of significant (grade C 2) sacroiliitis, axSpA can be classified either as radiographic axSpA (r-axSpA) or non-radiographic axSpA (nr-axSpA) [4]. For the most part, the severity of signs and symptoms and the degree of daily life impairment are similar in both the forms of axSpA. However, patients with nr-axSpA tend to be younger and have a shorter disease duration, and are more likely to have enthesitis or tender joints, compared with r-axSpA patients, whereas patients with r-axSpA tend to have worse spinal mobility [5].

In the current European and United States (US) guidelines, which were last updated in 2016 and 2019, respectively, recommendations for the treatment of radiographic and non-radiographic forms of axSpA are similar [4,6]. Both sets of guidelines recommend the use of biological therapy in patients with persistently active disease despite treatment with conventional first-line therapy [non-steroidal anti-inflammatory drugs (NSAIDs)] [4,6]. During the formulation of the guidelines, tumor necrosis factor (TNF) inhibitor therapy was preferred over secukinumab because considerable evidence on the safety and long-term efficacy of TNF inhibitor in axSpA was available, whereas there were limited clinical data for secukinumab in AS and none available in nr-axSpA. Taking this into account, the task force recommended TNF inhibitor as the first biological diseasemodifying antirheumatic drug (bDMARD) for current practice [4].

Secukinumab is the first-in-class interleukin (IL)-17A inhibitor, and is approved for the treatment of r-axSpA and nr-axSpA, as well as psoriasis and PsA in the US and Europe [7,8]. Secukinumab has been used to treat more than 500,000 patients across its four approved therapeutic indications worldwide since its launch (Novartis, Data on File). The aim of the current article is to review the evidence, from both randomized clinical trials and real-world observational analyses, supporting the efficacy and safety of secukinumab in the treatment of musculoskeletal manifestations of r-axSpA and nr-axSpA, focusing on the last 5 years of data.

METHODS

We conducted a PubMed search on April 30, 2021 using the search terms ''secukinumab'' and ''axial'' and ''spondyl*''. Potentially relevant articles were chosen based on the title and abstract. Additionally, we searched for relevant abstracts presented at the annual congresses of the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR) held between 2016 and 2021. This review is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors therefore ethical approval was not required.

Mechanism of Action

Secukinumab is a fully human monoclonal antibody directed against IL-17A [9], the best characterized member of the superfamily of IL-17 ligands [10]. Once bound to its receptor, IL-17A upregulates inflammatory genes, leading to the release of pro-inflammatory cytokines (including TNF-a, IL-6 and IL-1b), chemokines (e.g., CXCL-1, -2 and -8), antimicrobial peptides, matrix metalloproteinases, and other inflammatory effector molecules, such as acutephase proteins and complement proteins [11]. Together, these molecules potentiate a positive feedback loop that accelerates and augments the inflammatory response [11]. The IL-17 axis has been shown to play a major role in the pathogenesis of axSpA, and may in fact be more prominent in its pathogenesis than TNF-a [10,11]. This led to the clinical development and eventual approval of secukinumab in axSpA (Fig. 1 ).

Recommended Dosage

Secukinumab is available in two dosage forms (150 or 300 mg), which provides physicians with some flexibility to titrate the dose according to the response. In Europe, the recommended starting dose in r-axSpA and nr-axSpA is 150 mg once weekly for the first five doses and then 150 mg per month thereafter [7]. The approved secukinumab dosage is similar in the US, except that the loading dose is optional, and patients can begin treatment with 150 mg every 4 weeks [8]. In both Europe and the US, patients with r-axSpA who have a suboptimal clinical response can be treated with 300 mg/month [7,8]; the higher dose is not currently approved for use in patients with nr-axSpA, but is being investigated for this group in the PREVENT extension trial (NCT02696031). Based on data from patients with PsA, patients with enthesitis at baseline and those who have not previously received TNF inhibitor therapy are most likely to achieve an additional benefit from increasing the dose of secukinumab to 300 mg [15].

Secukinumab Clinical Trial Program

The efficacy and safety of secukinumab for the treatment of axSpA were investigated in at least nine randomized controlled phase III trials (Table 1 ) [16][17][18][19][20][21][22][23]. The MEASURE studies (1 to 5) included patients with active AS [16,[19][20][21]24], the MAXIMISE study was in patients with PsA and spinal involvement [17], the PREVENT study was in patients with nr-axSpA [18], the SKIPPAIN study included patients with axSpA (AS and nr-axSpA) [23], and finally, SURPASS (NCT03259074), which is a study in patients with active AS, is the first head-to-head study comparing the effects of secukinumab versus adalimumab (a TNF inhibitor) [22].

The primary endpoint in the five MEASURE studies and the MAXIMISE study was the proportion of patients meeting the Assessment of SpondyloArthritis international Society criteria for 20% improvement (ASAS20) at week 16, i.e., an improvement of C 20% and absolute improvement of C 1 unit (on a ten-unit scale) in C 3 of the four main ASAS domains, with B 20% worsening in the remaining domain [16,17,[19][20][21]24], while it was ASAS40 at week 16 in the PREVENT study [18]. However, SKIP-PAIN and SURPASS studies had different primary endpoints; SKIPPAIN is the first study with secukinumab to determine the proportion of patients with a spinal pain numerical rating scale (NRS) score \ 4 at week 8 that was determined using an 11-point NRS [23], and SUR-PASS measured the proportion of patients with no radiographic progression, i.e., a B 0.5 change from baseline in the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) at week 104 [22].

Short-Term Efficacy

In MEASURE 1, 2, and 3, approximately 60% of patients receiving secukinumab at a maintenance dose of 150 mg achieved the ASAS20 endpoint at week 16, which was significant compared with placebo (P \ 0.001 vs. placebo in MEASURE 1 and 2 and P \ 0.05 vs. placebo in MEASURE 3) [21,25].

As in MEASURE 1, 2, and 3, the proportion of patients receiving secukinumab 150 mg (with or without loading doses) who achieved the ASAS20 endpoint at week 16 in MEASURE 4 was * 60% (59.5% in the group with loading dose and 61.5% in group without loading dose), but the proportion of patients who achieved this endpoint in the placebo group was 47% (i.e., higher than in MEASURE 1, 2, and 3). As a result, the difference in the primary endpoint between the secukinumab and placebo groups in MEASURE 4 did not reach statistical significance (P = 0.057 and P = 0.054, respectively) [21]. In MEASURE 5, 58.4% of patients receiving secukinumab 150 mg achieved the ASAS20 endpoint at week 16 compared with 36.6% receiving placebo (P \ 0.0001) [19].

The magnitude and direction of the primary endpoint results from the MEASURE studies have been confirmed in meta-analyses [26,27]. Similarly, these studies showed significant improvements in the secondary endpoints of disease activity, such as C-reactive protein (CRP) levels, Ankylosing Spondylitis Disease Activity Score (ASDAS), and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), relative to placebo [16,[19][20][21].

The other three studies (PREVENT, MAX-IMISE, and SKIPPAIN [17,18,23]) provide more Fig. 1 Timeline for the development and FDA approval of secukinumab [12][13] [14] The PREVENT study was conducted in patients with nr-axSpA and the population was predominantly naı ¨ve to TNF inhibitor therapy [18]; in this study, the primary endpoint of ASAS40 at week 16 was achieved by 41.4% of TNF-naı ¨ve patients who received secukinumab 150 mg with loading doses and 42.2% of those who received secukinumab 150 mg without loading doses, compared with 29.2% in the placebo group (P \ 0.05 for each secukinumab group) [18]. The MAXIMISE study was undertaken in patients with axial manifestations of PsA (i.e., BASDAI score C 4 and spinal pain score C 40 on a 0-100 mm visual analogue scale with an inadequate response to at least two NSAIDs), and reported results very similar to those in patients with AS. In MAXIMISE, 66% of patients receiving secukinumab 150 mg and 63% of those receiving secukinumab 300 mg achieved ASAS20 response at week 12, compared with 31% of patients receiving placebo (P \ 0.0001 for each comparison) [17].

The SKIPPAIN study was specifically conducted to investigate the effect of a bDMARD on pain reduction in axSpA patients. The preliminary (unpublished) data showed that significantly more patients on secukinumab 150 mg had improvements in spinal pain after 8 weeks of treatment than patients on placebo [32 vs. 20%; odds ratio 1.9 (95% confidence interval: 1.1-3.3); P \ 0.05] [23]. In the second half of Of C 4.0 cm on a 0-10-cm visual analogue scale b IV infusion of secukinumab 10 mg/kg at baseline, week 2 and week 4 c SC injection of secukinumab at baseline, and weeks 1, 2, 3, and 4, at the same dose as given for maintenance therapy the study, when all the patients were re-randomized to receive either secukinumab 150 or 300 mg, reduction in spinal pain at week 24 was more prominent in patients who were initially randomized to placebo and then switched to secukinumab at week 8 compared with patients who received secukinumab 150 mg at the baseline and were then randomized to secukinumab 150 mg or 300 mg at week 8 [23]. The reduction in spinal pain seen in SKIPPAIN can be considered clinically relevant, as well as statistically significant.

Disease activity scores in the SKIPPAIN study showed a marked improvement in ASDAS-CRP scores from baseline to week 8. A further improvement was noticed at week 24; more patients in the active treatment group achieved ASDAS low disease activity after secukinumab dose escalation compared with those who remained on the same dose [23].

Efficacy in the Long Term

Long-term data from MEASURE 1 indicate that the improvements in the proportion of patients with ASAS20 are maintained during 2 years of continued secukinumab treatment [28]. After the completion of the 2-year MEASURE 1 study, patients were invited to continue open-label secukinumab treatment; data from this extension phase show that the proportion of patients meeting ASAS20 and ASAS40 criteria was maintained through 3, 4, and 5 years of treatment in patients who continued to take secukinumab [29][30][31]. Similarly, secukinumab provided sustained increases in the proportion of patients with ASAS20 and ASAS40 over 2-3 years in the MEASURE 2 study [32,33], over 3 years in MEASURE 3 [34], and over 2 years in MEASURE 4 [20]. The long-term clinical response in MEASURE 4 was similar in the groups who had and had not received a loading dose [20].

A pooled analysis of long-term data from MEASURE 1 and 2 confirmed the long-term clinical benefit of secukinumab; it showed that 24.5% of patients receiving secukinumab met ASAS criteria for partial remission at 3 years (an increase from 15.4% at 16 weeks), and 24.5% met the criteria for inactive disease (an increase from 17.6% at week 16) [35].

The long-term data from the PREVENT studies have been promising because patients with nr-axSpA receiving open-label secukinumab 150 mg after the first year of treatment [18] showed significant and sustained improvement in the manifestations of nr-axSpA (ASAS40) through 2 years of follow-up (data currently available as an abstract) [36]. A comparison between the long-term data (52 weeks and 104 weeks) for PREVENT and MEASURE studies is shown in Fig. 2 .

Efficacy in Improving Symptoms and Patient-Reported Outcomes

Back pain is a key symptom of axSpA, and has a significant impact on the physical and mental components of a patient's quality of life (QoL) and work productivity [37] . In MEASURE 2, patients reported rapid improvement in spinal pain and nocturnal pain scores after only 1 week of starting secukinumab 150 mg; an early improvement in both pain and fatigue occurred in patients with normal or elevated high-sensitivity CRP levels, and in those who had been previously treated with TNF inhibitors and those naı ¨ve to TNF inhibitor treatment [38]. These improvements were maintained over 2 years of treatment; for example, 77.6% of patients receiving secukinumab 150 mg had C 20% improvement in pain at 16 weeks, and 78.0% had this level of improvement at 2 years [38].

As described earlier, an improvement in spinal pain and nocturnal pain scores (average spinal pain score \ 4 on a 0-10 NRS) was observed in the SKIPPAIN study at 8 weeks and further reduction in spinal pain was observed at 24 weeks [23]. Figure 3 illustrates pain reduction outcomes from the MEASURE 2 and SKIPPAIN studies. Such reductions in pain can be considered clinically significant, and are likely to be impactful for patients.

Indeed, in addition to pain assessment, the MEASURE 1 study included a range of patientreported outcome (PRO) measures, including QoL (measured by the Short Form 36 [SF-36], EuroQoL 5-domain [EQ-5D] and Ankylosing Spondylitis Quality of life [ASQoL] questionnaire), fatigue (measured by the Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-F] scale) and work and activity impairment (measured by the Work Productivity and Activity Impairment-General Health [WPAI-GH] tool) [39]. In all QoL assessments, secukinumab 75 mg (in initial studies, a 75-mg dose was explored) and 150 mg were associated with improvements from baseline to week 16, which were significant versus placebo, and these improvements were maintained at week 52 [31,39]. Fatigue also decreased significantly with both doses of secukinumab versus placebo at week 16 [39]. Time missed from work due to health decreased in the secukinumab groups between baseline and week 16, but increased among patients in the placebo group [39].

Long-term data from MEASURE 1 and 2 showed that early improvements in fatigue were maintained over 2 years of treatment with secukinumab [40], and a pooled analysis of long-term data from these studies showed that QoL and WPAI-GH scores at 3 years correlated with clinical remission [35].

Fig. 2 Long-term efficacy of secukinumab 150 mg in TNF inhibitor-naı ¨ve patients in MEASURE and PREVENT trials [20,29,33,34,36]. Patients who continued with secukinumab therapy throughout the study period were known as responders. TNF tumor necrosis factor Fig. 3 Pain reduction outcomes in patients with axSpA in a the MEASURE 2 study (assessed using a 0-100 mm visual analogue scale ranging from no pain to unbearable pain) and b the SKIPPAIN study (assessed using a 11-point spinal pain numerical rating scale ranging from no pain to most intense pain imaginable) [23,38] Efficacy in Improving Enthesitis and Dactylitis axSpA patients with enthesitis have worse disease severity, spinal mobility, and QoL than those who do not have enthesitis [41], making effective relief of enthesitis symptoms an important clinical goal. A pooled analysis of data from MEASURE 1, 2, 3, and 4 assessed the effect of secukinumab on enthesitis using the Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) on the 693 patients who had this condition at baseline [42]. The mean change from baseline at week 16 in the overall MASES was -2.4 among patients receiving secukinumab 150 mg compared with -1.9 in the placebo group (P \ 0.05), and the change in axial MASES was -2.3 compared with -1.8, respectively (P \ 0.05). At week 16, 40.8% of patients receiving secukinumab 150 mg had complete resolution of enthesitis (overall MASES of 0) compared with 28.9% in the placebo group (P \ 0.01), and 42.7% had complete resolution of axial enthesitis compared with 30.1% in the placebo (P \ 0.001; Fig. 4 ) [42]. All improvements in MASES were maintained at week 52 [42].

In a pooled analysis of data from studies in patients with PsA, just over half of the patients with dactylitis at baseline achieved complete resolution during treatment with secukinumab 150 mg (52.1% in those who had received a loading dose and 52.5% in those who had not) and in 61.5% of patients who received secukinumab 300 mg [43].

Impact on Radiographic Progression or Structural Damage

New bone formation in the axial skeleton, entheses, and peripheral sites are distinctive features of axSpA. A previous inflammation or osteitis in the subchondral bone marrow triggers new bone formation, the progression of which can be radiographically determined [3,44]. In AS, the development of new syndesmophytes occurs gradually, with the rate of progression being faster in patients with existing syndesmophytes compared with those without syndesmophytes [45]. New bone formation is stimulated by the complex systems affected by inflammation that includes the wingless proteins/Dikkopf-1 pathway along with secreted frizzled-related proteins and growth factors like bone morphogenetic proteins [44]. The IL-23/IL-17 axis strongly drives this pathogenic process; IL-17A potentially affects osteoblastogenesis depending upon the exposed cell type, differentiation stage, and cytokine exposure (both timing and duration) [46]. As the formation of new bone is a slow process, and it is difficult to visualize the ongoing process radiographically, early suppression of the bony inflammation would be the most effective way to prevent bone formation [3].

A follow-up investigation of the original proof-of-concept phase II study with secukinumab (Fig. 5 ) [25] found that 87% of inflammatory changes and 30% of non-inflammatory (fatty) changes at vertebral edges on magnetic resonance imaging (MRI) resolved during longterm (94 weeks) treatment with intravenous (IV) secukinumab [47]. In addition, encouraging data on the impact of secukinumab on radiographic progression were reported from the MEASURE 1 study [28]. In patients who had matched X-rays at baseline and week 104, the mean change in the mSASSS was 0.3 [28]. Of the 64 secukinumab recipients who had no syndesmophytes on their baseline X-ray, 61 (95.3%) remained free of syndesmophytes at week 104; among the 104 who did have syndesmophytes at baseline, only 30% developed additional new syndesmophytes by week 104 [28]. Moreover, patients who continued to take open-label secukinumab after the completion of the MEASURE 1 study maintained a stable mSASSS through 4 years of treatment, as no radiographic progression was seen in [ 80% of the patients at 2 years [28] and in 79% patients at 4 years [28,31].

When these data were compared with a historical cohort of biological-naı ¨ve patients receiving NSAIDs, patients treated with secukinumab in MEASURE 1 showed less marked radiographic progression over 2 years, although the between-group difference did not reach statistical significance [48].

In the MAXIMISE study, assessment of inflammation/bone marrow lesions in the spine and sacroiliac joints (Berlin MRI score C 1) at the baseline and at week 12 showed that patients receiving secukinumab 150 mg or 300 mg had a statistically significant improvement in inflammation at week 12 compared with placebo [49] and this reduction in inflammatory MRI lesions was sustained at week 52 [17]. Similarly, in the PREVENT study, secukinumab 150 mg, with and without the loading dose, significantly improved the Berlin MRI score in patients with inflammation in their sacroiliac joints versus placebo (-1.68 and -1.03, respectively, vs. -0.39; both P \ 0.0001) at week 16, and this improvement was maintained through 1 year [18]. The comparative effects of secukinumab and a TNF inhibitor (adalimumab biosimilar) on radiographic progression are currently being assessed in the phase IIIb SURPASS study [22]; planned completion of this study is in December 2021.

Subgroup Analyses

Estimating the prognosis of patients with axSpA is challenging because the type and severity of symptoms are heterogeneous, and treatment outcome measures are either patient-reported or are assessed by measuring radiographic progression, which may not be feasible in all cases. Miceli-Richard and colleagues investigated the predictive potential of baseline demographic (age, gender, body mass index) and disease characteristics (CRP levels, TNF status, MASES, occiput-to-wall distance, BASMI, and Physician's Global Assessment scores) using logistic regression analysis and machine learning, and their preliminary findings were presented at the ACR conference in 2020 [50]. They found that factors like younger age, lower body mass index, higher levels of high-sensitive CRP, TNF inhibitor-naı ¨ve status, lower occiput-to-wall distance score, and lower MASES score were found to be associated with a better response to secukinumab therapy in patients with AS [50].

In prespecified subgroup analyses of the randomized controlled trials, the magnitude of the benefit with secukinumab 150 mg was greater in TNF inhibitor-naı ¨ve than -experienced patients [9,27]. While elevated CRP levels are predictive of a better response to TNF inhibitors, there was a consistent benefit in the clinical efficacy of secukinumab, irrespective of baseline CRP levels. Nevertheless, a non-significant improvement in response to secukinumab was observed in patients with elevated baseline CRP levels versus normal baseline levels [51]. The efficacy of secukinumab in improving axial symptoms regardless of peripheral joint involvement is well founded. Findings of a post hoc, hypothesis-generating analysis also found that treatment with secukinumab significantly improved the symptoms of peripheral arthritis, such as swollen and tender joints, in patients with AS (findings presented at the EULAR conference in 2020) [52].

Preliminary data from a large pooled population of patients with AS suggest that the effectiveness of secukinumab was found to be independent of HLA-B27 status. However, patients positive for HLA-B27 experienced a non-significant increase in the therapeutic benefit compared with HLA-B27-negative patients [53].

Similarly, recent conference presentations reported that young age resulted in faster attainment of ASAS20/40 and a greater reduction in disease activity measures than older age [54], and that gender had no influence on secukinumab treatment outcomes [55].

Moreover, data from the MEASURE-2J study (in Japanese patients), MEASURE 5 study (70% Chinese patients) and subgroups of Asian patients participating in MEASURE 1 and 2 demonstrated that the effects of secukinumab were similar in Asian and non-Asian individuals [19,24,56,57].

Real-World Efficacy and Retention

Randomized clinical trials have excellent internal validity, but careful patient selection means that the results are not always generalizable to a more heterogeneous real-world population. Observational and registry studies, including the European Spondyloarthritis Research Network Collaboration (EuroSpA), have shown that patients with axSpA receiving secukinumab in clinical practice experience statistically significant improvements in a range of disease activity parameters (e.g., BASDAI, ADAS-CRP, CRP and affected joint counts), QoL, pain, and fatigue [58][59][60]. The ongoing non-interventional AQUILA study is investigating the real-world effectiveness of secukinumab treatment in patients with active AS and PsA. Preliminary reported described improvements in disease activity (e.g., PGA, BASDAI, and CRP) and in physical and mental well-being [Assessment of Spondyloarthritis Health Index (ASAS-HI), Beck's Depression Inventory Version II (BDI-II)] up to 1 year in all patients [61,62]. These benefits were seen in more patients with no prior TNF inhibitor treatment than those with prior TNF inhibitor treatment [62].

Persistence with secukinumab treatment is high in the real-world setting. Data from observational and registry studies, including EuroSpA, showed that the 12-month retention rates with secukinumab at any line of treatment were between 68 and 80% in patients with AS or PsA (Fig. 6 ) [58,59,63,64]. Retention was highest when secukinumab was used as the first biological agent (76-84% at 12 months), but decreased with subsequent lines of treatment (67-75% as second-line biological and 56-66% as third-line) [58,65,66]. The most common reason for treatment discontinuation in these real-world studies was insufficient efficacy [58,59,63,66], and data from EuroSpA showed that this was also the most common reason for discontinuing TNF inhibitor therapy [58].

Another preliminary report from the AQUILA study showed that the 12-month adherence rate for secukinumab was 64.5% for AS and 56.0% for PsA. Comparatively, the persistence rate was higher in biological/biosimilarnaı ¨ve patients than -experienced patients, with insufficient response/efficacy and adverse events (AEs) being the most common reasons for treatment discontinuation in both patient groups [67].

Safety

The safety/tolerability profile of secukinumab in patients with axSpA is consistent with that in patients with plaque psoriasis [9]; the incidence of immunogenicity was low, as evidenced by detection of anti-drug antibodies in only 0.68% of patients with AS and 0.35% with PsA [68]. During the placebo-controlled periods of the Fig. 6 Twelve-month retention rates with secukinumab in real-world studies [58,59,[63][64][65][66]. Horizontal line indicates median randomized controlled trials (i.e., the first 12-16 weeks), between 46 and 70% of patients receiving secukinumab and from 44 to 64% of patients receiving placebo reported AEs; serious AEs (SAEs) were seen in 0-6% of patients randomized to secukinumab and 1-4% of patients randomized to placebo [9]. The most common AE was nasopharyngitis [9].

An integrated safety analysis was undertaken on data from 21 randomized controlled trials with secukinumab, including MEASURE 1, 2, and 3 (n = 794), and post-marketing surveillance data [69]. In patients with AS, the exposure-adjusted incidence rate (EAIR) of any AE was 140.1 per 100 patient-years, and of any SAE was 6.3 per 100 patient-years (Table 2 ) [69]. The most common AEs were viral upper respiratory tract infection, headache, diarrhea, and upper respiratory tract infection [69]. The EAIR for uveitis was 1.4 per 100 patient-years in randomised trials, and 0.03 per 100 patient-years in post-marketing surveillance data, indicating no increase in the risk of uveitis during secukinumab treatment in patients with axSpA [70].

Similarly, 5-year data across a range of indications show a low rate of malignancy in patients receiving secukinumab; the EAIR was 0.85 per 100 patient-years, and the observed number of malignancies was comparable to the expected number [71].

The risk of serious infections and opportunistic infections during treatment with secukinumab is also low (summarized in Table 2 ). There have also been concerns that prolonged biological therapy can increase the risk of tuberculosis (TB) reactivation in patients with latent TB, but a pooled analysis of data across studies in a variety of indications (including the MEASURE 1, 2, 3, and 4 studies) showed no active cases of TB [72]. New latent TB infection was identified as an AE in 2/977 of the AS patients in this analysis (0.2%; EAIR 0.08 per 100 patient-years) [72]. However, no cases of TB reactivation were reported in the integrated safety analysis described above [69].

Evidence with secukinumab has shown that the incidence of new-onset IBD is low in patients with axSpA, although these patients are more likely to develop IBD than the general population [73,74]. A pooled analysis of data from secukinumab randomized controlled trials showed that 13/794 patients with AS developed IBD, including ulcerative colitis in four patients (EAIR 0.2 per 100 patient-years), Crohn's disease in eight (EAIR 0.4) and IBD undefined in one (EAIR 0.1) [73]. Nine events were new-onset cases and four occurred in patients with preexisting IBD. Notably, the risk of IBD development during secukinumab treatment does not increase over time [73]. Real-world data suggest that the risk of IBD development during secukinumab is higher in AS patients with a history of IBD than in those without such a history [74].

Although data on the use of secukinumab in pregnancy are limited, the available evidence has not highlighted a strong signal for adverse pregnancy outcomes [75].

COVID-19

Data on the risk of coronavirus disease 2019 (COVID-19) in patients receiving secukinumab are currently limited, but case reports indicate that secukinumab treatment does not adversely affect the course of the disease and can be safely continued or reinitiated once the patient has recovered from COVID-19 illness [76][77][78][79]. A population-based cohort study of psoriasis patients in Israel indicated that IL-17A inhibitor treatment was not associated with an increased risk of developing COVID-19 infection, hospitalization or mortality compared with methotrexate or with non-systemic/non-immunomodulatory agents [80]. Current recommendations advise continuing biological therapy in patients who do not have severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection, and temporarily discontinuing treatment in those who test positive for the infection [81].

Anecdotal data suggest that some patients with psoriasis discontinued treatment with their biological therapy because they feared that it would increase their risk of developing COVID-19 infection [82]. This highlights the need for individualized treatment decisions and good communication between patients and physicians about the risks and benefits of treatment versus no treatment during the COVID-19 pandemic [81,82].

The authors are not aware of any contraindications to the use of COVID-19 vaccines in patients being treated with secukinumab. Indeed, vaccination is highly encouraged in such patients, with EULAR releasing a viewpoint that states ''there is no reason to withhold these vaccines from patients with RMDs [rheumatic and musculoskeletal diseases] and patients treated with drugs that influence the immune system'' [83].

How does Secukinumab Compare with TNF Inhibitors?

As mentioned, there is currently only one direct head-to-head clinical study comparing outcomes in axSpA patients taking secukinumab versus those treated with the TNF inhibitor adalimumab, which is currently ongoing [22]. In the absence of direct comparisons, an indirect comparison of secukinumab and adalimumab was made using matching-adjusted data from the MEASURE 1 and 2 studies and from the ATLAS study with adalimumab [84]. There was no difference in ASAS20 or ASAS40 outcomes between secukinumab and adalimumab in the placebo-anchored comparison, but the unanchored comparisons significantly favored secukinumab for ASAS20 at weeks 16 and 24, and for ASAS40 at weeks 24 and 52 [84].

The potential financial impact of treatment of AS with secukinumab and adalimumab in the Finnish healthcare system was compared using a model-based budget impact analysis [85], based on treatment response data from the indirect comparison of these biologicals [84]. Secukinumab was estimated to be more cost effective than adalimumab based on the higher response rate found in the indirect comparison, suggesting that secukinumab may be a more affordable and accessible option than adalimumab [85].

A study of 1-year outcomes in patients receiving secukinumab or TNF inhibitors for AS in five Nordic registries showed that secukinumab and TNF inhibitors were similarly effective when used as first-or second-line biological therapy, but secukinumab was less effective when used in the third-line setting [65]. However, the authors noted that their results could be subject to channeling bias, whereby the secukinumab cohort included more patients with severe (and potentially treatment-resistant) disease, since the secukinumab group included more patients who had received at least three prior biologicals.

The data on the effectiveness of secukinumab and TNF inhibitors as second-line biological therapy was supported by two other observational studies (the Swiss Clinical Quality Management cohort [86] and the KOBIO registry in Korea [66]), which compared secukinumab with a TNF-inhibitor in patients with axSpA or AS who had received at least one prior TNF inhibitor. However, unlike the Nordic registry data, the Swiss study showed that secukinumab and a TNF inhibitor were similarly effective whether used as second-or later-line biological treatment [86]. In that cohort (as in the Nordic registries), secukinumab was more likely to be used as the third-line than the second-line biological [86]. The retention rate was similar with secukinumab and TNF inhibitors [86].

Secukinumab can be used in patients with axSpA who also have demyelinating disease (e.g., multiple sclerosis) or heart failure, whereas most TNF inhibitors are contraindicated in patients with moderate or severe heart failure (New York Heart Association class III or IV) [87] and should be used with caution in patients with demyelinating diseases. Although physicians should be vigilant about the potential for tuberculosis and opportunistic infections in any patient taking biological agents, the incidence of these events with secukinumab is very low, and there is no black box warning about these events in the prescribing information for secukinumab as there is for the TNF inhibitors [8,87]. Similarly, there is no warning about an increased risk of malignancy with secukinumab, while there is such a warning for TNF inhibitors [8].

CONCLUSIONS

Data from both randomized trials and observational studies with secukinumab in a range of patients with axSpA continue to accumulate. Randomized trials have established the longterm (5-year) efficacy of secukinumab across multiple domains of axSpA with a favorable and consistent safety profile. While no direct comparative data are yet available, indirect comparisons indicate that secukinumab is as effective as TNF inhibitor therapy in patients with axSpA, and that its safety profile is at least as good as TNF inhibitors. On this basis but acknowledging the limitations of the available evidence (from indirect comparisons, not headto-head studies), the authors' opinion is that secukinumab and TNF inhibitors have comparable efficacy and safety and so both should be considered first-line therapies in patients with axSpA.

Compliance with Ethics Guidelines. This review is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors therefore ethical approval was not required.

Data Availability. Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

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annex

Author Contributions. Marı ´a Aparicio, Carlos A Guille ´n-Astete, Clementina Lo ´pez-Medina, Carlos Sastre and Fernando J. Rodrı ´guez Martı ´nez were responsible for the conceptualization and design of the review, critically reviewing and revising all drafts of the review, and approving the final version of the manuscript.

Disclosures. Fernando J. Rodrı ´guez has been a consultant for UCB, Janssen and Novartis. Clementina Lo ´pez-Medina reports speaker fees from UCB, Janssen, AbbVie and Novartis. Maria Aparicio reports speaker fees from UCB, MSD, Pfizer, Lilly, and Novartis. Carlos A Guille ´n-Astete reports speaker fees, commercial and scientific consultancies, and research projects by Novartis. Carlos Sastre is an employee of Novartis.

Acknowledgements

ACKNOWLEDGEMENTSFunding.Development of this manuscript and associated publication charges (Rapid Service Fee) were funded by Novartis.Medical writing and Editorial Assistance.We would like to thank Mitali Choudhury of Springer Healthcare Communications who wrote the first and second drafts of this manuscript.This medical writing assistance was funded by Novartis.Authorship.All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

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Abstract screening pilot

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