Ixekizumab Retention Rate and Predictors of Treatment Persistence in Psoriatic Arthritis: Results of an Italian Multicenter Study

Introduction

Psoriatic arthritis (PsA) is a spondyloarthritis (SpA) associated with cutaneous and/or nail psoriasis (PsO) involving peripheral joints, axial joints and entheses. ¹ The disease affects men and women equally occurring most frequently between 40 and 50 years of age, and has a prevalence of 2-4% among adults in Western countries. ² PsA is often accompanied by comorbidities, including cardiovascular disease, metabolic and mental health disorders ³ and presents with different clinical pictures that often pose a challenging differential diagnosis with other inflammatory rheumatic diseases, including rheumatoid arthritis (RA) ⁴ and ankylosing spondylitis (AS). ⁵

PsA carries a considerable burden, as almost half of untreated patients go on to irreversible joint deformities and functional impairment within 2 years of onset. ⁶ This underscores the often-aggressive nature of PsA and the need for early intervention. Research has demonstrated that timely diagnosis and initiation of therapy can significantly slow disease progression, enhance quality of life, and reduce the risk of long-term disability. ⁷ Consequently, a multidisciplinary approach involving rheumatologists, dermatologists, and other specialists has become a standard of care, enabling comprehensive management of PsA’s various manifestations. ⁸

Therapeutic advances have significantly expanded the treatment options for PsA from conventional synthetic anti-rheumatic drugs (csDMARDs) to biological DMARDs (bDMARDs) and synthetic targeted DMARDs (tsDMARDs). ⁹ Among innovative therapies, ixekizumab (IXE) has emerged as a highly effective bDMARDs in the treatment of PsA.^10,11 IXE is a humanized IgG4 monoclonal antibody that specifically targets interleukin-17A (IL-17A), a key pro-inflammatory cytokine in PsA pathogenesis. By neutralizing IL-17A, IXE inhibits inflammatory pathways that drive joint damage, including erosive bone destruction and pathological bone formation. ¹² Since its initial approval by the European Medicines Agency (EMA) in April 2016 for plaque psoriasis (PsO), IXE’s indications have expanded to include active PsA, radiographic axial spondyloarthritis (r-axSpA), and non-radiographic axial spondyloarthritis (nr-axSpA).^13,14

Randomized controlled trials (RCTs) have robustly demonstrated IXE’s efficacy. The SPIRIT-P1 trial demonstrated a significant reduction in disease activity and radiographic progression in patients with biologically naïve PsA,^15,16 while the SPIRIT-P2 trial confirmed its value in treating patients after failure of anti-tumor necrosis factor (TNF) agents.^17,18

In addition, the SPIRIT-H2H trial demonstrated the superiority of IXE over adalimumab, a widely used anti-TNF therapy, in achieving optimal joint and skin responses in patients with biologically naïve PsA.^19,20 These results reinforced the role of IXE as a versatile therapeutic option, benefiting both treatment-naïve patients and those with previous exposure to biologics.

Although data from RCTs have validated the efficacy of IXE, real-world evidence is critical to understanding its performance in routine clinical practice. Real-world studies provide insights into the use of IXE in diverse patient populations and complex treatment scenarios that have not been fully considered in RCTs. ²¹ Although existing real-world studies support the efficacy of IXE, there remains a significant gap in assessing long-term outcomes, particularly drug retention rates (DRR). DRR is a critical parameter, depending not only on drug effectiveness but also on patient adherence, tolerability, and sustained therapeutic response.^22,23 This study aimed to fill these gaps by analyzing the long-term efficacy of IXE in a large multicenter cohort of PsA patients. Specifically, it focused on DRR at various time points and examined demographic and clinical predictors of treatment discontinuation. The results could improve our understanding of the role of IXE in the management of PsA and inform future treatment strategies.

Methods

This observational, retrospective, multicenter, nonprofit study was conducted in 26 tertiary rheumatology centers and recruited patients between 2018 and 2024. The research complied with the ethical principles outlined in the Declaration of Helsinki, 2008 revision, and received approval from the ethics committees of the participating centers (the main is the Comitato Etico dell’Area Vasta Emilia Nord, protocol code 34 713, approved on 28 August 2019). All patients provided written informed consent before analysis of their clinical data.

Patients eligible for inclusion met the classification criteria for the diagnosis of Psoriatic ARthritis (CASPAR) ²⁴ and being treated with IXE for PsA. Exclusion criteria were the presence of concomitant uveitis, inflammatory bowel disease (IBD), or changes from the standard dosing protocol of IXE, which consists of an initial dose of 160 mg followed by administration of 80 mg every 4 weeks. None had moderate-to-severe plaque psoriasis requiring induction dosing every 2 weeks.

Data were extracted from medical records to ensure a comprehensive and standardized overview of patients’ clinical and treatment characteristics. Information collected included demographic data (e.g., age and sex), clinical features (e.g., type of joint involvement: axial, peripheral, or both), human leukocyte antigen B27 (HLA-B27) status, duration of disease, and year of diagnosis. Treatment data included line of therapy with (bDMARDs) (first-line or subsequent), concomitant use of conventional synthetic DMARDs (csDMARDs) or corticosteroids, and whether IXE therapy was discontinued. Disease activity at the time of initiation of IXE therapy was assessed using validated tools: the Disease Activity in Psoriatic Arthritis (DAPSA) ²⁵ for peripheral involvement and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) or the Ankylosing Spondylitis Disease Activity Score (ASDAS) ²⁶ for axial involvement. Disease activity was categorized as high, moderate, low, or in remission based on these scores to allow comparison between patients with different patterns of joint involvement.

Categorical variables were expressed as percentages and continuous variables were presented as medians with interquartile ranges (IQRs). The primary outcome was drug retention rate (DRR) at 360, 720 and 1080 days, which served as an indicator of the long-term efficacy of IXE in treating PsA. Patients who discontinued IXE during therapy were censored in the statistical analysis, and DRR data were illustrated by Kaplan-Meier survival curves.

A Cox proportional hazards model was used to identify independent predictors of treatment persistence. This statistical approach assessed the relationship between treatment persistence and variables such as age, sex, line of therapy (first-line or subsequent), monotherapy vs combination therapy with csDMARDs or corticosteroids, type of joint involvement (axial, peripheral, or both), year of treatment initiation, disease activity at baseline, and PsA duration. Results were expressed as hazard ratios (HRs) with 95% confidence intervals (CIs), and statistical Significance was defined as a P-value less than 0.05. Statistical analysis was performed with GraphPad Prism version 6.04 for Windows, GraphPad Software, Boston, MA, U.S.A.

Results

The study included 195 patients with a total follow-up period of 83 331 days. The median observation duration was 322 days (IQR: 108-648 days). Baseline clinical characteristics, summarized in Table 1, provide details on age, sex, disease duration, and comorbidities, as well as PsA-specific features such as axial, peripheral, or both joint involvements.

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Table 1.

Demographic and Clinical Characteristics of Patients Included in the Study.

Characteristics of the study population
Age, median (range)	56 (48-62)
Sex, n (%)
Female	117 (60%)
Male	78 (40%)
HLAB27, n (%)
Present	5 (2.6%)
Absent	82 (42%)
Unknown	108 (55%)
Clinical disease involvement, n (%)
Peripheral	105 (54%)
Axial	25 (13%)
Both	65 (33%)
Disease activity at baseline, n (%)
High	65 (33%)
Medium	60 (31%)
Low	29 (15%)
Remission	4 (2 %)
Unknown	37 (19%)
Disease score activity, median (range)
DAPSA	22.98 (14-30)
ASDAS	3 (1.89-3.63)
BASDAI	5 (2.85-7)
Median disease duration in months, median (range)	62.5 (30.75-117)
Line therapy, median (range)	2 (2-4)
csDMARD, n (%)
Concomitant theraphy at baseline	85 (46.4%)
Not used at baseline	98 (53.6%)
Use of steroid at baseline, n (%)
Yes	47 (24%)
No	148 (75.9%)

Drug retention rate for IXE were 66% (95% CI: 59-74%) at 12 months, 49% (95% CI: 41-59%) at 24 months, and 39% (95% CI: 30-51%) at 36 months (Figure 1). These findings revealed a gradual decline in treatment persistence over time, consistent with patterns typically observed for biologic therapies in chronic conditions like PsA. However, the relatively high DRR at 12 months (66%) and 36 months (39%) demonstrates IXE’s long-term efficacy in real-world settings.

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Figure 1.

Kaplan-Meier Curve for Ixekizumab Drug Survival.

Predictors of IXE discontinuation were identified through the analysis. Patients with concomitant axial and peripheral joint involvement had a significantly higher risk of discontinuation (HR 1.78, 95% CI: 1.04-3.06, P = 0.036). Similarly, those receiving IXE as a third-line or subsequent therapy were more likely to discontinue treatment (HR 1.17, 95% CI: 1.02-1.33, P = 0.021). These findings suggest that PsA patients with complex disease manifestations or previous biologic failures face greater challenges in achieving sustained benefits with IXE (Figure 2).

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Figure 2.

Cox Regression Analysis of Hazard Ratios (HR).

In contrast, low baseline disease activity strongly predicted better treatment persistence (HR 0.24, 95% CI: 0.09-0.62, P = 0.003), emphasizing the importance of initiating IXE when disease activity is relatively controlled. Younger age also emerged as a favorable factor, with older patients less likely to maintain treatment, although the difference was small (HR 0.98, 95% CI: 0.96-1.00, P = 0.045). These findings highlight the critical role of patient selection and optimal treatment timing in maximizing long-term outcomes with IXE.

Among patients who discontinued IXE, efficacy-related reasons were predominant. Lack of initial efficacy accounted for 49% of discontinuations, while loss of efficacy over time contributed to 43%. Adverse events were cited as the reason for discontinuation in 8% of cases. Importantly, no serious adverse events (SAEs) were reported. The most commonly observed adverse events included localized skin reactions, allergic responses, and general malaise.

Discussion

The multicenter study presented here evaluated the real-world efficacy of IXE in a heterogeneous cohort of PsA patients. Over a median follow-up of 322 days, IXE provided clinically significant benefits, with DRR values of 66% at 12 months and 39% at 36 months. These findings line up with previous research, such as the single-center study by Bellis et al, which reported a DRR of 43.8% at 38 months in a cohort of 80 PsA patients. Importantly, our study included a larger and more diverse population, reflecting real-world clinical practice. This diversity was evident in the higher proportions of older male patients and those with a longer disease duration.

Ixekizumab was first approved by the U.S. Food and Drug Administration (FDA) in December 2017 for the treatment of active PsA in children 6 years and older, following promising results from the SPIRIT-P1 and SPIRIT-P2 phase 2 clinical trials.^15,17 These studies demonstrated the efficacy of IXE in addressing both joint and skin manifestations in PsA patients, extending its indications beyond moderate to severe plaque psoriasis (PsO) in adults and children over 6 years old.^27,28 Additionally, IXE has been approved for treating r-axSpA and nr-axSpA, underscoring its versatility in managing chronic inflammatory musculoskeletal diseases.^14,29

Although IXE’s efficacy has been well-documented in randomized controlled trials (RCTs), relatively few studies have assessed the DRR. Drug retention rate is particularly relevant in PsA, a long-lasting chronic disease involving both axial and peripheral joints, as it informs treatment decisions and optimizes patient outcomes.

Our cohort also had a higher percentage of patients receiving IXE as third- or subsequent-line disease-modifying biologic antirheumatic drugs (bDMARDs), with 45% compared to 30% in the study by Bellis et al. ³⁰ This highlights the potential of IXE in the management of difficult-to-treat PsA, with robust DRR values even in refractory cases. These results are consistent with those of Brana et al. who reported a 12-month DRR of 65% in a smaller retrospective cohort of 72 patients with PsA. ³¹ In a Japanese study comparing DRR of various biologics in PsA, 10-years retention rate of IXE was approximately 50%. The sample size however was relatively small considering just 16 patients treated with IXE and therefore these data are not comparable with our data. ³²

A noteworthy finding from our analysis is the impact of clinical and demographic factors on IXE discontinuation. Patients with concomitant axial and peripheral joint involvement or a history of bDMARD failure were significantly more likely to discontinue therapy. In contrast, younger age and lower disease activity at baseline were associated with greater treatment persistence, consistent with previously published data from other studies. These observations underscore the importance of early initiation of treatment and careful patient selection to maximize therapeutic outcomes.

While concurrent csDMARD use at baseline did not significantly influence treatment efficacy in our cohort, we observed a non-significant trend toward. However, the absence of data on csDMARD adherence during follow-up limits our ability to draw definitive conclusions. Prospective studies with serial medication assessments are needed to clarify whether concomitant csDMARDs modulate treatment response.

Safety data from our study were encouraging. Treatment discontinuation due to SAEs occurred in only 8% of patients, compared to 13% in the Bellis et al study. Most adverse events were mild, including localized or diffuse skin reactions and systemic symptoms such as malaise and allergic responses. Only 1 patient discontinued therapy due to an infectious complication. These findings reinforce IXE’s favorable safety profile and suitability for long-term use.

Our study has some limitations. Since it is a retrospective analysis, it is subject to bias in data collection, as study operations, data entry, and data quality control were not planned in advance.

As a retrospective study, our findings may be influenced by selection/recall bias, missing data, and the absence of a comparator arm. Generalizability may also be limited by the predominantly Italian cohort.

Another limitation is the underrepresentation of HLA-B27-positive patients, with only 2.6% of our cohort testing positive compared with 12% typically reported among Italian patients with PsA.^33,34 Although this discrepancy may affect the generalizability of the results, it does not diminish the clinical utility of IXE, as HLA-B27 is not essential for the diagnosis or management of PsA.

An additional restriction is that PASI or BSA were not considered because they are not part of the usual rheumatological assessment.

The variability of disease activity indices, such as DAPSA and BASDAI, may also have introduced biases due to subjective evaluations in patient and physician assessment of symptoms. Although these scores are widely used in both clinical trials and daily practice, there is no consensus on the optimal measure for assessing severity and disease activity in PsA, highlighting the need for further standardization.

In conclusion, our study represents 1 of the largest real-world investigations of IXE in patients with PsA. This multicenter study confirmed the efficacy of IXE as a long-term treatment for PsA in clinical practice. Negative predictors of treatment persistence are advanced line and mixed involvement and positive predictors of treatment persistence are advanced age, and low disease activity. These results provide valuable insights for clinicians managing PsA, particularly in complex cases, and contribute to the growing body of evidence supporting IXE as a solid treatment option to optimize patient outcomes.