FormalPara Key Summary Points

Why carry out this study?

IXE, an anti-IL17 therapy, has recently shown efficacy and safety in the treatment of PsA in its clinical development. However, there is limited evidence in a real-life setting.

What did the study ask?/What was the hypothesis of the study?

The aim of this multicenter observational study was to describe patients’ characteristics, treatment patterns, persistence, and effectiveness of IXE in PsA patients in a real-world setting in Spain.

What was learned from the study?

The PsA population in this study showed long-standing disease, with more than 7 years since diagnosis and 95.5% of the patients being treated with at least one b/tsDMARD previous to IXE.

PsA patients who started IXE treatment presented a high persistence, reaching 84.3% at 48 weeks and a reduction in the DAPSA score from 23.7 (95% CI 19.5–27.9) to 14.8 (95% CI 10.5–19.2) and 14.3 (95% CI 11.1–17.4) at 12 and 24 weeks, respectively (p ≤ 0.005).

Introduction

Psoriatic arthritis (PsA) is a progressive chronic inflammatory arthropathy with an unknown etiology. PsA usually presents a wide variety of clinical manifestations including joints inflammation, dactylitis, entheses, and skin and nail lesions [1,2,3]. It affects men and women almost equally with a peak age of onset between 40 and 50 years [2]. Although the epidemiology of the disease is not yet clear, a recently published meta-analysis describes a worldwide-pooled PsA prevalence and incidence rates that are 133 per 100,000 subjects (95% confidence interval, CI 107–164 per 100,000 subjects) and 83 per 100,000 person-years (95% CI 41–167 per 100,000 person-years), respectively [4]. In Spain, results of the EPISER2016 study estimated a prevalence of PsA rate of 0.58% (95% CI 0.38–0.87) in adults aged ≥ 20 years [5].

The management of patients with PsA requires a multidisciplinary approach with the cooperation of rheumatologists and dermatologists [1, 6, 7]. The management goal of psoriatic arthritis (PsA) is to control inflammation and preserve the patient's functional capacity in order to maximize health-related quality of life. Non-musculoskeletal manifestations (psoriasis, nail involvement, uveitis, and inflammatory bowel disease) and comorbidities such as metabolic syndrome, cardiovascular disease, or depression should also be considered [6, 7]. Treatments for PsA include conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and biologic and targeted synthetic disease-modifying antirheumatic drug (b/tsDMARDs). Most recent bDMARDs include drugs that have been developed focusing on new therapeutic targets such as Janus kinases (JAK) or phosphodiesterase.

Ixekizumab (IXE) is an IgG4 monoclonal antibody that neutralizes with high affinity and specificity interleukin-17A (both IL-17A and IL-17A/F). IL-17A is implicated in the pathogenesis of PsA by driving inflammation, which in turn leads to erosive bone damage and pathological new bone formation. Neutralization of IL-17A by IXE inhibits these disease characteristics [8].

IXE has shown efficacy and safety in biologic-naïve PsA patients (SPIRIT P1) [9] and in those previously exposed to anti-TNF (SPIRIT P2) [10], and it has shown superiority to adalimumab in a combined outcome reaching a 100% improvement in Psoriasis Area and Severity Index score (PASI100) + a 50% improvement in the American Colleague Rheumatology criteria (ACR50) (SPIRIT H2H) in biologic-naïve PsA patients [11].

The recommended dosage is 160 mg, followed by 80 mg every 4 weeks. For PsA patients with coexistent PsO, the dosing regimen recommended is the one for PsO patients (160 mg, followed by 80 mg at weeks 2, 4, 6, 8, 10, and 12, then every 4 weeks) [8, 12].

IXE is indicated for the treatment of active PsA in adult patients who have responded inadequately to, or who are intolerant to, one or more DMARD therapies. Also, since 2019, has been reimbursed in Spain for PsA indication after a treatment with a biologic anti-TNF. Currently, the real-world evidence (RWE) available in the literature is still limited.

The aim of this study was to evaluate the persistence, treatment patterns, and effectiveness of IXE in PsA patients in a real-world setting in Spain.

Methods

Study Design

PRO-STIP is a single-cohort, multi-center, descriptive, and retrospective chart review observational study conducted at the rheumatology departments of eight Spanish hospitals. The study includes a cohort of adult patients with PsA who started treatment with IXE as per clinical practice from January 1, 2019 (date of IXE launch for PsA indication) up to 6 months before the start of the data extraction per each site. For each patient, medical information was reviewed from the start of treatment with IXE to permanent interruption or treatment switching. If the patient had not interrupted treatment, the information was reviewed up to the date of data extraction and inclusion in the study (Fig. 1).

Fig. 1
figure 1

Study design

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Due to the retrospective nature of the study, no treatment decision was affected during clinical practice. The study met the Spanish legislation about observational studies with human medicines (RDL 957/2020), Good Clinical Practice (GCP) guidelines and was conducted in accordance with the Declaration of Helsinki. The study protocol was evaluated by the Clinical Research Ethics Committee (CREC) at University Hospital 12 de Octubre, Madrid, which granted its approval. This approval was notified to all the CREC of the participant centers which agreed with the conduction of the study before starting the study in each hospital. Written informed consent was obtained from participants based on the hospitals that required it.

Patient Selection Criteria

All adult patients, PsA diagnosed according to the ClASsification for Psoriatic ARthritis (CASPAR) classification criteria, who started treatment with IXE between January 1, 2019, and December 21, 2020, and with a minimum follow-up period of 24 weeks (regardless of whether the patient continued treatment or not) were selected for the study. Patients were excluded if they were in joint remission at the time of recruitment and started treatment with IXE due to skin involvement. Also, patients were excluded if they had participated in a clinical trial of any pathology during the observation period of the study.

Study Objectives

The primary objective of the study was to evaluate IXE persistence during a minimum follow-up period of 24 weeks in all eligible patients with PsA. The secondary objectives included describing demographic and clinical characteristics, prescription patterns, and effectiveness while on IXE treatment. Additionally, the impact of the patient characteristics such as age, sex, body mass index (BMI), and number of previous DMARDs in the persistence on treatment was explored.

Study Variables and Statistical Analysis

A descriptive statistical analysis of the patient’s demographic and clinical characteristics was performed. Shapiro–Wilk tests were performed to assess the normality of continuous variables; if variable showed a normal distribution, results were presented as mean (standard deviation (SD)) and as median and interquartile range (IQR) if normality was not reached. Categorical variables were expressed as count and percentage.

Baseline Patient Demographics and Clinical Characteristics

Patients’ characteristics at baseline included age, gender, BMI, level of education, labor status, smoking status, alcohol use, disease duration, disease presentation form (according to physician’s criteria), PsA family history, number of flares in the 12 previous months to the study (considering the presence of a flare according to physician’s criteria), dactylitis, enthesitis, Health Assessment Questionnaire (HAQ) and Disease Activity in PSoriatic Arthritis (DAPSA) scores, active PsO presence, age of PsO diagnosis, time from PsO to PsA diagnosis, PsO presentation forms and comorbidities in the year prior to the start of the study (hypertension, metabolic syndrome, dyslipidemia, obesity, thyroid disease, emotional disorders, osteoporosis, and severe infections).

Ixekizumab Persistence Assessment

Persistence was summarized by treatment duration on IXE until permanent discontinuation or end of follow-up, and by the percentage of patients who maintained IXE at 24, 48, and 104 weeks of follow-up, estimated by Kaplan–Meier method. We considered a gap of < 60 days without any dose of IXE could be due to a temporal discontinuation while a gap ≥ 60 days meant a permanent discontinuation in line with a previous observational study about persistence [10]. Reasons for discontinuation were also collected: loss of effectiveness, adverse event, pregnancy, physician’s decision, patient’s preference or other.

Additionally, persistence analyses were conducted among different groups of patients according to age (≤ 65 vs. > 65 years), gender, BMI, previous b/tsDMARDs (0–1 b/tsDMARD vs. ≥ 2 b/tsDMARDs) and concomitant use of csDMARDs (monotherapy vs. concomitant csDMARD). A Cox model was generated to establish which of these factors could affect persistence and hazard ratios (HR) and significance level were calculated.

Ixekizumab Prescription Patterns

Treatment pattern outcomes, including IXE posology and changes in dosing and reasons for definitive treatment discontinuation (if applicable) were assessed. History of previous csDMARDs or b/tsDMARDs for PsA management was recorded to assess previous treatment exposure as well as concomitant therapies (non-steroid anti-inflammatory drugs-NSAIDs, csDMARDs, and corticosteroids).

Ixekizumab Effectiveness

Effectiveness was evaluated by DAPSA changes from baseline until 12 and 24 weeks in patients while on treatment with all three measurements using general linear model with repeated measures ANOVA and Greenhouse–Geisser correction; Tukey post hoc test was used in case of significance. A 95% confidence level was fixed. It was considered remission (≤ 4), low activity (> 4 – ≤ 14), moderate activity (> 14 – ≤ 28) and high activity (> 28) by DAPSA score [13]. R software was used to perform the statistical analyses [14].

Results

Demographic and Clinical Characteristics

A total of 89 patients met the inclusion criteria and were included in the analysis. Sociodemographic and clinical characteristics at baseline are shown in Tables 1 and 2. Participants’ mean age at the initiation of IXE treatment was 51.5 years (SD 11.6), 55.1% were women and the median BMI was 23.6 kg/m2 (IQR 20.9–27.0) (Table 1). The median time from symptom onset to disease diagnosis was 1.0 years (IQR 0.2–2.2), and the median time from PsA diagnosis to the initiation of IXE was 7.7 years (IQR 3.4–14.6). The enrolled patients had the next presentation forms of the disease: 55.1% peripheral, 13.6% axial, and 30.3% mixed PsA (peripheral and axial). The median of flares was 1.0 (IQR 1.0–1.2) flares in the 12 previous months of the study, with a mean baseline HAQ score of 1.2 (SD 0.7) and median baseline DAPSA score 22.0 (IQR 17.7–25.0); 85.4% of patients had co-existence of PsA with PsO at baseline. The mean age at PsO diagnosis was 31.9 (SD 13.9). In 40.8% of cases, PsO was mild (Table 2). Dactylitis and enthesis were presented in 14.6 and 23.6% of patients, respectively. Almost three out of four patients (72.2%) had at least one comorbidity, with a median of 2.0 (IQR 0–3.0). The most frequent comorbidities were obesity, dyslipidemia, and hypertension, which were present in 34.8, 33.7, and 29.2% of patients, respectively (Table 3).

Table 1 Baseline sociodemographic characteristics
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Table 2 Baseline clinical characteristics of patients
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Table 3 Comorbid conditions
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Ixekizumab Persistence

A total of 28 patients (31.5%) discontinued treatment with IXE during the study follow-up. As less than 50% of patients discontinued treatment at the end of the follow-up, the median persistence was not reached. The mean time of persistence was 86.9 weeks (95% CI 80.6–93.2); 75% of patients were persistent at 71.9 weeks (95% CI 68.0–75.8) (Table 4).

Table 4 IXE persistence according to Kaplan–Meier curves
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Persistence rates at 24, 48, and 104 weeks were of 95.5%, 84.3%, and 68.5%, respectively (Fig. 2A). Figure 2B–F shows the persistence analysis by subgroups (age, sex and BMI, number of previous DMARDs, and monotherapy or concomitant treatment). All the HR CI 95% contains the value 1, which indicates that there were no statistically significant differences in persistence between the subgroups analyzed.

Fig. 2
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Cumulative persistence in all patients and by subgroups

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The main reasons for treatment discontinuation were loss of effectiveness (21.3%), adverse reactions (2.2%), patient preference (2.2%), medical choice (2.2%), contraindication (1.1%), and other reasons (2.2%). Of the 28 patients who definitively discontinued IXE, 18 (64.3%) started a new treatment for PsA; ustekinumab was the most widely used drug after discontinuation (22.2%).

Prescription Patterns

Most patients started IXE with doses of 160 mg in two 80 mg injections at week 0. All of them received 80 mg doses afterwards, except for one patient who discontinued after the starting dose. The mean time between the initial doses of IXE to 80 mg doses was of 3.9 weeks (SD 1.4) (Fig. 3).

Fig. 3
figure 3

IXE utilization patterns throughout the observation period. From the eight patients who maintained the initial dose of 80 mg every 4 weeks, five patients persisted. From 81 patients with an initial dose of 160 mg, ten patients changed IXE posology, and 56 patients persisted

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Most patients (79.8%) had received a treatment with csDMARDs before the initiation of IXE, with methotrexate (MTX) being the most frequently prescribed (74.2% of patients). There were 95.5% (85) of patients that were treated with one or more b/tsDMARDs prior to IXE (mean 2.7; SD 1.6), with adalimumab in 68.5% of patients as the most frequent, followed by etanercept (44.9%) and secukinumab (36.0%) (Fig. 4).

Fig. 4
figure 4

Number of DMARDs before starting IXE

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Of the total number of patients, 37.1% received IXE in combination with csDMARD, in most cases (78.8%) with MTX, while 62.9% received it as monotherapy.

Moreover, 44.9% of the patients received other drugs concomitant with IXE as part of the PsA treatment, being the most frequent systemic corticosteroids (65.0%) and non-steroidal anti-inflammatory drugs (NSAIDs) (55.0%).

Effectiveness

A total of 24 patients had baseline values and at 12 and 24 weeks. Of them, the estimated marginal mean DAPSA score significantly decreased from 23.7 (95% CI 19.5–27.9) at baseline to 14.8 (95% CI 10.5–19.2) at 12 weeks (p = 0.005) and 14.3 (95% CI 11.1–17.4) at 24 weeks (p = 0.004). No statistically significant differences were observed between weeks 12 and 24 (p = 0.902) (Fig. 5A). From the start of the IXE, at 12 weeks and 24 weeks, the proportion of patients with high disease activity was reduced from 16.7% to 8.3%, and with moderate activity from 70.8% to 33.3% (Fig. 5B).

Fig. 5
figure 5

IXE effectiveness evaluation by DAPSA. *Number of patients with available information. A Repeated measures ANOVA; Paired comparisons with Tukey post hoc: baseline-12 weeks, p = 0.005; baseline-24 weeks, p = 0.004. B Disease Activity index for Psoriatic Arthritis (DAPSA) in categories: remission (≤ 4), low activity (> 4 to ≤ 14], moderate activity (> 14 to ≤ 28], high activity (> 28)

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Discussion

PRO-STIP is the first multicenter study that has evaluated IXE treatment effectiveness, persistence, and treatment patterns in PsA patients in routine clinical practice in Spain, with the RWE study involving a higher number of patients at European level assessing these three objectives. Almost 96% of the patients in the PRO-STIP study presented experience with at least one b/tsDMARD, having received two or more in 72% of the cases, suggesting that our population presented a longer standing disease. The main results have shown that PsA patients who started IXE treatment presented a high persistence rate, which ranged from 95.5% to 68.5% at 24 to 104 weeks, not reaching the median time of persistence during the follow-up period. An improvement in the disease activity at 12 and 24 weeks, assessed with the DAPSA score, was also observed in those patients who continued treatment.

There is limited RWE assessing IXE in PsA patients available in the literature to put our results in context. Two studies conducted in the United States assessed the sociodemographic characteristics, treatment patterns, and IXE persistence in PsA patients included in two claims databases (MarketScan administrative claims and Truven Databases) [15, 16]. At the European level, the main evidence comes from two Italian and one Spanish study. The Italian studies comprised a retrospective study using administrative databases of Italian Entities [17] and a single-center, observational study which included 26 patients affected by both moderate-to-severe plaque-type PsO and moderate-to-severe PsA [18]. A third study was conducted in Italy, including 70 PsA patients treated with anti-IL-12/23 and anti-IL-17 biologic agents, but only eight patients were treated with IXE and specific outcomes by drug were not reported [19]. In Spain, the retrospective, single-center study conducted by Braña et al. focused on IXE persistence and safety data in PsA patients in routine clinical practice [20]. Finally, an Israeli study evaluated the sociodemographic characteristics, persistence, and effectiveness of IXE treatment in PsA patients, specifically after secukinumab failure [21].

In general, the main patients’ characteristics found in our study in terms of age, gender, years of disease, and coexistence of active PsO were similar to those reported in the available RWE studies with slight variations [15, 16, 18, 20, 21]. In the PRO-STIP study, a high proportion of patients presented comorbidities (72.2%), which may have implications in the treatment response rates found. This was highlighted in the Perrotta study, where the presence of comorbidities was associated with a lower probability of achieving minimal disease activity in PsA patients treated with IL-12/23 and IL-17 inhibitors [19].

As we previously commented, our results suggest that our population presented a long-standing disease, although the population included in the study of Braña et al. was even more pre-treated (90% had received ≥ 2 b/tsDMARD) [20]. However, Perrone et al. found that only 55.6% of the patients had not been previously treated with biologics in the Italian population studied [17].

This is the first study that reports dosing of IXE in real practice in Europe. The majority of the patients used the approved dose for PsA of the SmPC. Most patients started IXE at the recommended starting dose and thereafter some degree of variability in the frequency of the 80 mg dosing. This variability may relate to differential PsO presence in this sample. The only studies which report dosing and changes are the American studies conducted by Murage in 2021 [15] and Pizzicato in 2023 [16] where most patients start IXE at the posology recommended in the SmPC (93.4% and 75%, respectively) [15, 16].

The persistence on IXE found in our study (84.3% at 48 weeks and 68.5% at 104 weeks) was higher than that the reported by Braña et al., in Spain (65% at 1 year and 57% at 2 years) [20]. These differences can be explained by the single-center nature of the study with a particular clinical practice and by the high percentage of patients with depression in comparison with our study, where the authors state that can be a risk factor to discontinue IXE.

Other studies have reported similar or lower persistence rates at week 52 (40% to 80%). The differences found in these cases may be explained by multiple factors, such as the characteristics of the population treated, the line of therapy in which IXE was prescribed, the differences in disease management by country or the time gaps without medication allowed to calculate the persistence with the treatment [15,16,17, 21].

In PRO-STIP, no differences in persistence were reported between the subgroups analyzed (gender, age, obesity); only a favorable trend for having a better persistence was observed in previous treatment with 0 and 1 previous b/tsDMARDs (vs. ≥ 2 b/tsDMARDs). Similarly, Braña et al. concluded that factors such as age, duration of disease, female gender, smoking status, obesity, metabolic comorbidities, or prior exposure to other biologics did not affect drug persistence [20].

The main reason for discontinuation found in our study was loss of effectiveness (21.3%) followed by other reasons such as adverse events, patient preference, and medical choice in lower percentages. This seems to be in line with the study conducted by Berman et al. where the main reasons of discontinuation reported were worsening of psoriasis, peripheral arthritis, or axial disease, or due to adverse events [20] and results of Braña et al., where the discontinuation due to loss of effectiveness response appeared in 14 of 72 patients (19.4%) where IXE was the third or subsequent line of treatment in the majority of the patients [20].

In terms of effectiveness, the 24 patients included in the PRO-STIP study with available DAPSA activity measurements showed a reduction in disease activity from baseline to 12 weeks and a maintenance thereof at 24 weeks of treatment; the proportion of patients with severe and moderate activity was also reduced. Despite the small number of patients with data (24/89), these findings in the improvement of disease activity with IXE are aligned with those of other studies carried out in a real clinical practice setting. The study conducted by Manfreda et al. [18] reported a reduction of the DAPSA score and other indexes at 24 and 48 weeks, and in the observational study published by Berman et al., the DAPSA index decreased at 6 months and 12 months of treatment even in patients treated with IXE after secukinumab failure [21].

The main limitations of the study are those inherent to its retrospective design, e.g., the presence of missing values that are not routinely collected in clinical practice and the presence of inconsistencies or errors in the medical records that could condition the collection of data and subsequent analysis. In our study, the information on sociodemographic and clinical characteristics, treatment patterns, and persistence was very complete for the entire sample, but that related to effectiveness was collected only in a small percentage of the sample, since it is not systematically collected in routine clinical practice, hence the results should be interpreted with caution. Linked to data collection, another limitation was that specific information on the most frequent adverse effects was not collected, although safety was explored as a possible cause for treatment discontinuation. Additionally, this study may not be fully generalizable to the clinical practice across Spain, but it represents the variability of eight different centers spread throughout the Spanish geography.

Conclusions

This Spanish real-world cohort of PsA patients treated with IXE had a long-standing disease but showed a high persistence on IXE during the follow-up period, with lack of effectiveness being the main cause of discontinuation. Nevertheless, improvements in disease activity measured with DAPSA at 12 and 24 weeks suggest that IXE could be an effective treatment.