Spondyloarthritis (SpA) comprises a heterogeneous group of immune-mediated diseases characterized by inflammation affecting the axial skeleton and/or peripheral joints, enthesis and extra-musculoskeletal manifestations, such as skin/nail psoriasis, uveitis, and inflammatory bowel disease (IBD).1 The most prevalent subtypes of SpA are represented by psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA), which share both genetic and clinical characteristics and are usually placed under the umbrella of SpA.2 These diseases represent a public health burden due to the significant morbidity associated which may result in permanent mobility limitations and poorer quality of life.

A wide array of therapeutic options is now available for treating patients with PsA and axSpA after demonstrating safety and efficacy in randomized controlled trials. Available drugs target different signaling pathways, such as inhibitors of tumor necrosis factor (TNF), interleukin (IL)-17 and JAK-STAT pathways. In addition, patients with PsA can be treated with inhibitors of IL-12/23, IL-23, and phosphodiesterase type 4 (PDE4). The European Alliance of Associations for Rheumatology (EULAR), the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA), and the Pan American League of Associations for Rheumatology (PANLAR) have developed updated recommendations for the management of PsA, encompassing all currently available treatment options to support physicians in decision-making.3–5

Ixekizumab (IXE) is an IgG4 monoclonal antibody that specifically binds to interleukin 17A approved for both PsA and axSpA, among other conditions. IXE has been shown to be effective in several phase III clinical trials in patients with PsA (SPIRIT-P1 and SPIRIT-P2),6,7 as well as in patients with radiographic axSpA (COAST-V and COAST-W)8,9 and non-radiographic axSpA (COAST-X).10 However, there are limited real-world data on drug survival in routine clinical practice, making the Spanish registry BIOBADASER 3.0 a key resource to evaluate real-world data in an observational cohort of patients treated with IXE.11 Accordingly, the objective of this study was to evaluate the 12-months retention rate to IXE and to identify potential predictive factors for drug withdraw in patients with axSpA and PsA.

A total of 335 patients who received at least one dose of IXE were included in this analysis. Among these, 85 (25.4%) and 250 (74.6%) had a diagnosis of axSpA and PsA, respectively. Baseline demographic and clinical characteristics in the overall population and stratified by disease are represented in Table 1. The mean age at treatment initiation was 52.1 (SD=10.9) years. Males represented 46.6% of the total population, with a higher proportion in axSpA (60%) compared to PsA (42%). Mean disease duration was 10.9 (SD=8.9) years. IXE was prescribed as initial biologic DMARD in 5.3% of patients only and as second or subsequent line in 94.7%.

Retention rate after 12-months and reasons of discontinuation

A total of 341 treatments for 335 patients were included in this analysis. In the overall population, the probability of IXE retention after 12 months of follow-up was 69.5% (95% CI: 64.0–74.3) (Table 2). Drug retention was higher in patients treated in first line (81.7% (95% CI: 53.1–93.8)) in comparison with those treated in second or later lines (68.8% (95% CI: 63.1–73.8)).

Table 2.

Probability of retention after 12-months of treatment with IXE and reasons of discontinuation.

	Overall treatmentsN=341	axSpAN=86	PsAN=255
Probability of retention (95% CI) 1 year
Total	69.5 (64.0–74.3)	63.8 (51.5–73.7)	71.3 (65.0–76.6)
First line	81.7 (53.1–93.8)	–	92.3 (56.6–98.9)
Second or later lines	68.8 (63.1–73.8)	65.2 (52.7–75.1)	70.0 (63.4–75.6)
Discontinuation, n (%)	135 (40.3)	29 (34.1)	106 (42.4)
Discontinuation due to inefficacy, n (%)
Among patients who discontinued	94/135 (69.6)	22/29 (75.9)	72/106 (67.9)
Among the total population	94/335 (28.1)	22/85 (25.9)	72/250 (28.8)
Discontinuation due to adverse event, n (%)
Among patients who discontinued	30/135 (22.2)	7/29 (24.1)	23/106 (21.7)
Among total population	30/335 (9.0)	7/85 (8.2)	23/250 (9.2)

axSpA: axial spondyloarthritis; PsA: psoriatic arthritis.

When stratifying patients by diagnosis, we found that the probability of retention after one year was slightly higher in PsA patients in comparison with axSpA (71.3% (95% CI: 65.0–76.6) versus 63.8% (95% CI: 51.5–73.7), respectively), but with no significant differences (p=0.23) (Table 2 and Fig. 1). The number of discontinued treatments in the overall population after 12-months follow-up was 135 (40.3%), mainly due to inefficacy (69.6%), with no differences between axSpA and PsA, and 22.2% of withdrawals were due to adverse events. The description of adverse events is provided in Supplementary Table 1.

Fig. 1.

Retention rate of IXE in axSpA and PsA patients over 12-months follow-up (p=0.23).

In this multicentre real-world study, IXE exhibited an acceptable retention rate of 69.5% in patients with PsA and axSpA after one-year of follow-up, with a higher rate in those treated in the first line (81.7%). When stratifying by disease, the probability of retention was 71.3% for PsA and 63.8% for axSpA after one year. Overall, 40.3% of patients discontinued the treatment after one year, most of them due to inefficacy.

To date, real-world data on the use of IXE for PsA and, most importantly, in axSpA, is scarce. For this reason, this study provides new evidence on the use of this drug in clinical practice. The retention rate of IXE in Spain was quite similar to that observed in a single-centre study from the United Kingdom, with a 69% probability in both studies.17 This reflects a consistency in our findings, which can mirror the clinical practice in other regions. When stratifying by disease, we again found a similar retention rate in both studies, with a slightly higher probability in PsA patients. The retention rate in PsA was around 71.3% in our study, which is subtly higher compared to that reported by Braña et al.18 This can be explained by the lower number of patients included and by the single-centre design of that study.

Factors associated with a greater risk of IXE withdrawal in the overall population were female sex and longer disease duration, whereas concomitant methotrexate decreased the risk of withdrawal. Interestingly, neither the diagnosis nor the fact of initiating IXE as a first or second/later lines seemed to have an influence on the retention rate. Female sex has been previously reported as a risk factor for drug withdrawal among PsA patients. A previous analysis on secukinumab (another IL-17A inhibitor) reported that females had a higher risk of drug discontinuation in axSpA and PsA compared to male patients.19 Similarly, other studies reported that female sex represents a risk factor for treatment discontinuation in PsA, probably due to the higher prevalence of polyarticular patterns and the greater incidence of concomitant fibromyalgia in this population.20,21 Unfortunately, in this cohort, the presence of fibromyalgia was not collected to verify whether this factor explains the lower retention rate in the female population. While female sex was not associated with a lower retention rate in axSpA patients in our analysis, this has been reported in other studies with bDMARDs.22,23

Methotrexate was, conversely, associated with a decreased risk of IXE withdrawal in the overall population and in PsA. Concomitant use of methotrexate has previously demonstrated an improved retention rate of infliximab and golimumab in patients with PsA.24,25 However, clinical trials with IXE indicate that concomitant use of methotrexate does not impact the therapeutic response or retention rate of the drug.26–28 Our results showed the opposite, while these results need to be interpreted with caution since this is an observational study with a potential prescription bias.

In our study, the majority of patients were treated with IXE in second or later lines, as reported in previous real-world data from our country.29,30 However, this had no impact on the retention rate in the overall population, as shown in the Cox regression. Curiously, in our axSpA patients, being treated in second or later lines was found as a protective factor against IXE withdrawal. However, due to the small number of patients treated in the first line and the potential use of IXE as the last alternative for patients who did not respond to previous treatments, these results should be interpreted with caution. The high percentage of patients treated with IXE in second or later lines reflects the Spanish regulations regarding the prescription of biological drugs which generally position the use of biosimilar anti-TNFs as the first therapeutic option for these patients.

Among patients who discontinued treatment, the primary reason for withdrawal was inefficacy (70%), while 22% discontinued due to adverse events, which in line with data reported previously.17 These percentages were very similar when stratified by both diseases, although there was a slightly higher rate of discontinuation in PsA compared to axSpA. This slightly increased discontinuation in PsA may be explained by the greater heterogeneity of the disease, with multiple affected domains, and the challenge of achieving efficacy across all domains (e.g., joints, enthesis and skin).

This study has both limitations and strengths. One limitation is that we did not report the effectiveness of these drugs. The prospective nature of the study meant that some patients did not complete the follow-up visits, resulting in fewer patients with available data regarding disease activity. Therefore, we focused this analysis on the retention rate, which accounts for patient loss of follow-up. Another limitation is the absence of certain clinical information in this registry, such as the presence of concomitant IBD. One strength of this study is its prospective design, which reduces recall bias and missing data typically seen in retrospective analyses. Additionally, the observational nature of this study, using real-world data, enhances the external validity of the findings. Lastly, the quality of the collected data is significant, as BIOBADASER is a well-known registry that includes both online and on-site monitoring by a specialized Clinical Research Associate once a year, ensuring the reliability of the results.

In conclusion, this multicentre analysis provided new real-world data on the use of IXE in the BIOBADASER Spanish registry, showing an optimal retention rate in patients with PsA and axSpA after one year of follow-up. Overall, female sex and longer disease duration were associated with an increased risk of treatment withdrawal while the concomitant use of methotrexate with a reduced risk. The reasons for drug discontinuation were consistent with previous literature.

Data curation: VJ, SB, SM-D, YP-V, PP-R, JM, AM-V, LM, DR-M, LM, TP-P. Methodology: CL-M, LO-V, FS-A, I-C. Statistical analysis: LO-V, FS-A. Supervision: CL-M, IC. Interpretation of the data: CL-M, LO-V, FS-A, IC. Writing original manuscript: CL-M. Reviewing and manuscript approval: all.

The study was approved by the Ethics Review Committee of the Hospital Universitario Clinic Barcelona (approval code FER-ADA-2015-01), although the Hospital de Canarias Ethics Committee currently acts as the reference committee.

Informed consent was obtained from all the participants.

Not applicable.

BIOBADASER was supported by the Spanish Foundation of Rheumatology and Spanish Agency of Medicines and Medical Devices (AEMPS), as well as the following pharmaceutical companies: Abbvie, Biogen, Bristol-Myers and Squibb (BMS), Celltrion, Galapagos, Janssen, Lilly, Merck Sharp and Dohm (MSD), Novartis, Pfizer, Regeneron, and Samsung Bioepis. The abovementioned pharmaceutical companies had no role in data collection, analysis, interpretation, and presentation of the data.

Authors declare no competing interests regarding this manuscript.

The data supporting the findings of this study are available from the Spanish Foundation of Rheumatology, although restrictions apply to the availability of these data, which were used under the license for the current study and are therefore not publicly available. However, the data are available from the authors upon reasonable request and with permission from the Spanish Foundation of Rheumatology.