Four-year real-world experience of secukinumab in a large Italian cohort of axial spondyloarthritis

Objectives This study aims to evaluate in a real-life Italian multicenter cohort of axial spondyloarthritis (axSpA) (1) the 4-year effectiveness and safety of secukinumab, (2) the drug retention rate (DRR), and (3) the impact of the line of bDMARDs treatment, subtype of axSpA, and sex on achieving low disease activity (LDA) and very low disease activity (VLDA). Methods Consecutive axSpA patients receiving secukinumab between 2016 and 2023 were prospectively evaluated. Data on disease characteristics, previous/ongoing treatments, comorbidities, and follow-up duration were collected. Treatment response was evaluated at 6 and 12 months after initiation and yearly up to 48 months (T48). DRR and effectiveness outcomes were evaluated according to bDMARDs treatment, axSpA subtype, and sex. Infections and adverse events (AEs) were recorded. Results We enrolled 272 patients (48.2% male; median age, 51; 39.7% HLA-B27+; 40.4% nr-axSpA), of whom 30.9% were naïve to secukinumab. Overall, secukinumab yielded improvement in effectiveness outcomes; the naïve patients maintained lower disease activity vs. the non-naïve ones. At T48, the LDA and VLDA rates were higher in naïve patients and in male individuals. Treatment was discontinued in 104 patients due to primary/secondary loss of effectiveness and in 34 patients due to AEs. The DRR at T48 was 67.4% in the whole population, regardless of treatment line, axSpA subtype, and sex. Conclusions Secukinumab was safe and effective in all axSpA patients irrespective of treatment line, disease subtype, and sex. The patients achieved sustained 4-year remission and DRR.


Introduction
Axial spondyloarthritis (axSpA) is a chronic inflammatory immune-mediated disease that belongs to the spectrum of spondyloarthritides (SpA).It predominantly affects the axial skeleton by causing inflammation and structural changes (1,2) and can be classified into radiographic axSpA (r-axSpA) or nonradiographic axSpA (nr-axSpA), according to the presence of sacroiliitis on conventional radiographs in the former or the presence of active sacroiliitis on magnetic resonance imaging (MRI) in the absence of structural damage of sacroiliac joints (SIJ) detectable on X-rays in the latter (2).Patients suffer from pain, stiffness, restricted mobility, and functional deficits.The most typical symptom-inflammatory back pain (IBP)-is mainly caused by inflammation in the SIJ and/or the spine.Extraspinal manifestations (peripheral arthritis, enthesitis, and dactylitis) and extra-musculoskeletal manifestations such as anterior uveitis, psoriasis, and inflammatory bowel disease (IBD) may occur as well (1,2).AxSpA is strongly associated with human leukocyte antigen (HLA)-B27 (3).The Assessment of SpondyloArthritis International Society (ASAS) classification criteria (4) are currently used for the classification of patients with axSpA.The European Alliance of Associations for Rheumatology (EULAR) and the American College of Rheumatology (ACR) guidelines recommend treating active axSpA patients with persistently high disease activity, despite undergoing non-steroidal antiinflammatory drugs (NSAIDs), with biological disease-modifying anti-rheumatic drugs (bDMARDs) or targeted synthetic diseasemodifying anti-rheumatic drugs (tsDMARDs) (5,6).Tumor necrosis factor alpha inhibitors (TNFi) or IL-17 inhibitors (IL-17i) are now recommended as first-line bDMARD (7).Given that up to 50% of patients treated with TNFi do not achieve a clinically significant response, IL-17i have acquired a key role in axSpA treatment (8)(9)(10)(11).
Data from RCTs may not fully mimic secukinumab treatment in a real-world setting because clinical trials are highly regulated and do not represent everyday practice.Despite some limitations associated with real-world evidence (RWE) studies, such as analysis design and incomplete or missing data, these observational studies (prospective or retrospective) complement the evidence generated by RCTs and depend on everyday therapeutic use in the realworld setting.
In the context of axSpA, other RWE studies have investigated the effectiveness and safety of secukinumab in a real-life setting both in Italian (27)(28)(29)(30) and international cohorts (31)(32)(33)(34)(35)(36), even in comparison with TNFi (9,10,31,32), but only for a limited observational period.In addition, the impact of different lines of bDMARDs treatment (LoBT), axSpA subtype, and sex on the achievement of clinical remission and on secukinumab drug survival has not yet been fully investigated (28,29).Establishing secukinumab's effectiveness, safety, and drug retention rate is key to improve treatment decision-making.

Study design, patients, and data collection
A cohort of patients with axSpA treated with secukinumab were studied in an observational prospective study from September 2016 to May 2023 in 11 Italian rheumatology centers.The study was sustained by the Italian Society of Rheumatology (SIR) "Spondyloarthritis and Psoriatic Arthritis study group-A.Spadaro." Patients' written consents were acquired according to the Declaration of Helsinki, when their data were recorded in the database for treatment.The Ethics Committee's approval was obtained from all participating centers (approval no.23943), as well as the written informed consent for the anonymous use of personal data from every patient, in compliance with Italian Legislative Decree 196/2003.
All included patients had undergone structured medical and physical examinations by rheumatologists.Demographic data were collected, including age, sex, body mass index (BMI), disease characteristics, duration and onset of back pain, whether IBP was present, age at diagnosis, history and/or presence of arthritis, enthesitis, dactylitis, and extra-articular SpA manifestations (anterior uveitis, psoriasis, and IBD), response to NSAIDs, and family history of SpA.In addition, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) level, and HLA-B27 were determined, and X-rays and magnetic resonance imaging (MRI) of the SIJ was performed if clinically justified.Treatment data were collected about previous/ongoing treatments, concomitant medications, including conventional synthetic (cs) diseasemodifying antirheumatic drugs (DMARDs), NSAIDs, and glucocorticosteroids (GCs), or previous biologics at the time of the first administration of secukinumab.The presence of comorbidities and concomitant therapies was also investigated (yes/no) and registered.Baseline data were retrieved by reviewing the clinical charts, face-to-face interview, and patients' extensive medical record.

Patients' enrollment and follow-up
Axial SpA was diagnosed using ASAS criteria (4), and patients who initiated secukinumab treatment for moderate or severe disease according to EULAR and ACR guidelines were considered (5,6), and those who continued taking secukinumab for more than three months were included.All patients were screened before enrollment and starting treatment as suggested by the European guidelines (5,6).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, in accordance with the manufacturer's instructions (22).In subjects affected by active and severe psoriasis-according to the treating physician-a dosage up to 300 mg per administration could be employed.Follow-up started at the start date of secukinumab administration and ended at the stop date for the treatment, death, or the end of the study (May 31, 2023), whichever occurred first.Finally, the duration of secukinumab therapy (expressed in months), previous LoBT, reasons for discontinuation (e.g., ineffectiveness, side effects, adverse events-AEs), infections, concomitant GCs, csDMARDs, and NSAIDs were also registered in our cohort of patients.

Treatment response
Initially, the treatment response was assessed at 6 and 12 months, followed by annual assessment until 48 months.

Treatment retention
Drug survival of up to 4 years of secukinumab treatment was defined as the probability of long-term drug retention rate (DRR), as shown by Kaplan-Meier curves.It was calculated as the number of days of treatment (start and stop date from the first and last dose of treatment).

Statistical analysis
Statistics firstly provided a descriptive analysis of the collected data.Data were expressed as frequencies and percentages for categorical variables and as median and interquartile range (IQR) for continuous variables.Naïve and non-naïve patients' characteristics were compared using the chi-square test or the Fisher exact test for categorical variables and the t-test or the Wilcoxon rank test for continuous variables, based on data distribution.Effectiveness measures and outcomes data were compared from the beginning and after 48 months with the chisquare test or the Wilcoxon rank test as appropriate.The Kaplan-Meier curve was exploited to measure the cumulative DRR of secukinumab considering discontinuation due to ineffectiveness or AEs.Furthermore, Kaplan-Meier curves were also retained to assess the impact of previous LoBT, r-axSpA/nr-axSpA, sex, and patients' clinical characteristics on the DRR of secukinumab.Survival curves were completed by using the log rank test.All statistical analyses were carried out with the SPSS 13.0 software (SSPS Inc., IL, USA).Two-tailed p-values lower than 0.05 were considered statistically significant.

Safety and discontinuation
Reasons for discontinuation: Safety and tolerability were notable in patients treated with secukinumab (Table 3).
A total of 104 (38.2%) discontinued treatment with secukinumab throughout the follow-up, mostly owing to primary and secondary loss of effectiveness (17 and 45, respectively).Eight patients dropped out of the observational study spontaneously.Only 34 patients discontinued secukinumab due to AEs: skin rash at the injection site (13) and severe recurrent infections (seven); only one patient presented an IBD flare-up and five patients a new cancer diagnosis [breast cancer (one), follicular thyroid carcinoma (one), colo-rectal adenocarcinoma (two), and prostate cancer (one)].Blood count and liver and kidney function were monitored, and only two patients exhibited abnormal values.
Infections: A total of 57 mild infections were documented during the study period and were resolved after oral antimicrobial treatment, without hospitalization or drug discontinuation.Only seven patients developed severe infections, prompting the discontinuation of secukinumab (two bronchopneumonia, one urosepsis due to E. coli, two erysipelas or skin/soft tissue infections with sepsis due to S. aureus with hospitalization, and two recurrent candidiasis).
There were no discernible differences in safety between naïve and non-naïve patients.However, a slightly elevated frequency of primary/secondary loss of effectiveness was observed in non-naïve patients (Table 3).
In this study, we conducted an assessment of the effectiveness, safety, and DRR of secukinumab in 272 patients with axSpA in a real-world multicenter cohort followed for up to 4 years.To the best of our knowledge, no other studies have thus far been conducted for such an extended observation period and in such a large national cohort of patients.Furthermore, we examined the impact of previous LoBT, axSpA subtype, and sex on achieving good clinical control of disease activity and on drug survival.This study demonstrates that secukinumab provides rapid and sustained effectiveness for up to 48 months of treatment as evidenced by improvements in various outcomes (e.g., ASDAS and BASDAI) across all the study populations.These findings corroborated and built upon data obtained from other RTCs (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26) as well as observational and registry RWE studies on secukinumab (27)(28)(29)(30)(31)(32)(33)(34)(35)(36).Similarly, secukinumab showed sustained increments in the number of patients who achieved ASAS20 and ASAS40 responses in the MEASURE 2 (14,15), MEASURE 3 (16), and MEASURE 4 studies (17).Data from the extension phase of the MEASURE 1 study indicate that the proportion of patients meeting ASAS20 and ASAS40 criteria remained consistent over 3, 4, and 5 years of treatment among those continuing to take secukinumab (14,19,22,23).Furthermore, the European Spondyloarthritis Research Network Collaboration (EuroSpA) study demonstrates that patients with axSpA receiving secukinumab experience statistically significant improvements across various disease activity parameters (e.g., BASDAI and ASDAS-CRP), functional status, pain, and fatigue (32).An analysis of the BIOBADASER Spanish Registry reveals that patients with SpA, including AS and nr-axSpA patients, treated with secukinumab exhibit improvement after 1 year of treatment, which is sustained or enhanced after 2 and 3 years, with a slight, albeit not markedly better, response observed in biological-naïve patients, suggesting effectiveness in both naïve and non-responder patients.Similarly, the SERENA study, investigating the real-world effectiveness of secukinumab treatment in patients with active AS and SpA, reports significant improvements in disease activity and physical and mental wellbeing for up to 2 years in all patients (34,35).These benefits are more pronounced in biological-naïve patients compared to those with prior TNFi treatment (27-29, 31, 32).Additionally, a significantly reduced NSAID intake was observed in our axSpA population receiving secukinumab.A pooled analysis of a large dataset of patients from the MEASURE 2-4 studies had previously provided evidence of the sustained and long-term NSAID-sparing effect of secukinumab over 4 years of treatment (24).
Another aim of this study was to evaluate the impact of LoBT, axSpA subtype, and sex on achieving remission or LDA in our axSpA population.Regarding the first point, we observed that treatment-naïve patients benefited the most from secukinumab.Disease activity remained low throughout the 4-year study period, with a numerically higher benefit observed in the treatment-naïve group, underscoring an early and sustained response.It is well established that the effectiveness of secukinumab is highest when used as the first biological agent in axSpA patients compared to when used as a second-or third-line treatment as evidenced by various studies (27)(28)(29)(30)(38)(39)(40).Better PROs and higher rates of VLDA)/LDA, as per ASAS and BASDAI criteria, were observed in treatment-naïve patients compared to non-naïve patients in this study, consistent with findings from other real-life studies (27)(28)(29)(30)(38)(39)(40).However, LoBT did not appear to influence secukinumab discontinuation at the 4-year mark in our axSpA population, which was consistent with findings from other real-life studies, indicating that LoBT does not significantly affect secukinumab retention rates at 12 or 24 months in axSpA patients (27)(28)(29)(30)32).Therefore, secukinumab can be considered effective both as first-line therapy and in patients in whom multiple treatments have failed.
Regarding axSpA subtype, in this analysis, patients with nr-axSpA presented slightly worse clinical measures, physical functioning, and inflammatory activity, which were likely due to the complexity and heterogeneity of this disease, often associated with other SpA features such as peripheral arthritis and extraarticular manifestations.However, the non-radiographic subtype did not appear to influence the persistence of effectiveness.These findings were expected, as secukinumab has been approved for use in the treatment of nr-axSpA in Europe and the USA, based on results from the PREVENT phase III study demonstrating significant and sustained improvement in signs and symptoms of patients with nr-axSpA through 52 weeks (26).
In our study population, male patients achieved better disease control than female ones.The male patients had higher rates of VLDA and LDA achievement than female patients, though the drug retention rates did not vary significantly, indicating consistent secukinumab efficacy over time regardless of sex (29,(39)(40)(41)(42)(43).While sex differences in axSpA prevalence and phenotypes are observed in many studies (44), most RCTs were not designed or powered to investigate sex differences or demonstrate treatment responses by sex (13,26).Previous pooled efficacy analyses of TNFi treatment reported sex differences (10,31,45), with notably lower levels of therapeutic response and treatment adherence in female patients (29,(46)(47)(48), despite comparable or worse disease burden at baseline in female patients compared to male patients.An important observation is the increasing number of women diagnosed with axSpA over the last decades (44,47).Moreover, in axSpA, the male-to-female ratio tends to decrease with disease onset after age 40 and the identification of nr-axSpA.Women are known to exhibit poorer responses to TNFi compared to men in SpA, while the influence of sex in IL-17i responses appears more controversial (43).In AS, male patients more frequently achieved inactive disease (ASDAS-ID response) in a post-hoc pooled analysis of all MEASURE trials, although no other efficacy outcomes were substantially affected by sex (45).Furthermore, real-world evidence with secukinumab suggests that male patients show higher retention rates than female patients in AS and axSpA (27)(28)(29)(30)(31)(32)(33)(34)(35)(36).Our study confirms the lesser ability of female patients to achieve inactive disease or LDA with secukinumab after 4 years of follow-up, although drug survival did not substantially differ between the two sexes.
Regarding persistence, in our axSpA population, a 48-month cumulative secukinumab DRR of 67.4% was estimated, with a median duration of 40 months of drug administration.The overall secukinumab DRR was high both in the short term and the long term, as a similar value (75%) was found at 24 months in our previous study (29).Similarly, the 3-year data from the phase 3 MEASURE 2 trial reported high retention rates varying between 76% and 86% in patients with AS ( 17).In open-label extensions of clinical trials with secukinumab, involving both biologic-naïve patients and those in whom TNFi treatment had failed, 84% of axSpA patients (15) remained on the drug after 5 years of follow-up, a retention rate higher than those obtained in our real-world study (67.4%), which is an expected finding since retention rates tend to be higher in clinical trials than in real-life studies due to the strict inclusion/exclusion criteria and close patient follow-up in the former scenario.To our knowledge, no national multicenter studies with secukinumab that reached 4 years of follow-up under clinical practice conditions have been published, as our study now does.This result is within the range of what has been published in similar real-life studies, which reported overall retention rates of 76% and 66%, respectively (27)(28)(29)(30)(31)(32)(33)(34)(35)(36).Similarly, according to previous studies (27)(28)(29)(30)(31)(32)(33)(34)(35)(36), inefficacy (22.8%) was found to be the main cause of secukinumab discontinuation in our study.
The assessment of baseline patient and disease characteristics associated with higher biologic retention may aid in identifying the most appropriate patient profile to achieve better long-term efficacy and safety.Another objective of this work was to identify the patient profile associated with better secukinumab survival.Prior exposure to LoBT, sex, and axSpA subtype did not influence the DRR.Additional analyses conducted in different subgroups of patients regarding age, smoking habits, and the presence versus absence of HLA-B27 and sacroiliitis on MRI did not highlight differences in the DRR.
In contrast to TNFi, in our study, secukinumab retention was not associated with patient age, sex, HLA-B27 positivity, or radiographic status, results that were similarly reported by other studies (32)(33)(34)(35)(36). Overall, secukinumab is effective regardless of previous experience with TNFi.The findings on sex were consistent with the MEASURE studies, where drug survival was comparable between male and female axSpA patients treated with secukinumab over 52 weeks (43).Similarly, in pooled analyses of the MEASURE studies, secukinumab was effective in patients with r-axSpA regardless of their HLA-B27 status (19, 25,43,49).Other than the aforementioned factors, baseline patient characteristics did not have a major impact on the overall secukinumab retention in this study, except for disease duration and concomitant peripheral involvement.The reasons that can be hypothesized are as follows: (1) subjects with higher disease duration are mostly multi-failure bDMARDs patients and (2) the presence of other extraspinal manifestations indicates a subtype of disease that is more complex and difficult to treat and to target.
Regarding safety, in general, secukinumab treatment was well tolerated in patients with axSpA.Throughout the treatment period, no new or unexpected safety signals were observed.The incidence of adverse events (AEs) of special interest was low, and no new cases of uveitis were reported; only one inflammatory bowel disease (IBD) flare-up was observed, suggesting a low risk of uveitis or IBD with secukinumab treatment.Additionally, no cases of hepatitis B or tuberculosis reactivations were observed in our cohort.Secukinumab appears to be safe in axSpA patients with latent tuberculosis infection (LTBI), even in those not receiving anti-TB prophylaxis, which was consistent with a pooled analysis of data across studies in various indications (including the MEASURE 1, 2, 3, and 4 studies), which showed no active cases of TB (50,51).
The safety profile was consistent with the established safety profile across approved indications and what has been previously reported in RCTs and their long-term extension studies (50)(51)(52)(53).An integrated safety analysis, based on data from 21 RCTs with secukinumab, including MEASURE 1, 2, and 3 (n = 794), along with post-marketing surveillance data (50)(51)(52), reported that the exposure-adjusted incidence rate (EAIR) of any AE was 140.1 per 100 patient-years and of any serious AE was 6.3 per 100 patientyears (50)(51)(52).The most common AEs were viral upper respiratory tract infection, headache, diarrhea, and urinary tract infection (50), consistent with our findings.Similarly, 5-year data across a range of indications show a low rate of malignancy in patients receiving secukinumab (54,55); the EAIR was 0.85 per 100 patient-years, and the observed number of malignancies in our study (n = 5) was comparable to the expected number (54).
The strength of this study lies in the fact that its findings complement those of clinical trials.Real-world evidence (RWE) studies offer valuable insights into predictive factors for the effectiveness, safety, and survival of secukinumab in a heterogeneous Italian patient population with various clinical SpA characteristics, a perspective not commonly addressed in RCTs.Moreover, the study enrolled a larger cohort of patients than previous studies and followed them for an extended duration.
However, this study has limitations.Firstly, due to the retrospective collection of patient data solely from available sources, inherent data gaps were unavoidable; retrospective data collection carries a risk of bias due to a lack of standardization.Secondly, a small proportion of patients received secukinumab as first-line treatment, while a larger number received it as second-line or later treatment.Thirdly, radiographic and imaging assessments during the 48-month follow-up were limited.Future studies assessing secukinumab use in axSpA across different regions and countries are warranted.
In conclusion, this real-world study showed a 67.4% retention rate of secukinumab at 4 years of treatment with an acceptable safety profile in axSpA patients, regardless of the length of treatment break, axSpA subtype, or sex.We demonstrated that secukinumab rapidly improves disease activity in axSpA patients, resulting in high persistence rates at 48 months of follow-up.Drug survival reflects treatment safety, effectiveness, and tolerability, serving as a marker of therapeutic success.Finally, our study indicates that secukinumab use in clinical practice aligns with the latest ASAS/EULAR recommendations for axSpA management, positioning IL-17 inhibitors as one of the primary biological disease-modifying antirheumatic drug (bDMARD) options in current practice.

TABLE 1
Baseline characteristics of 272 axSpA patients treated with secukinumab during 48 months of follow-up.