Real‐world retention rates and effectiveness of secukinumab in psoriasis: Results from a multicenter cohort study (RAILWAY)

Psoriasis is a chronic, immune‐mediated inflammatory skin disease with a high negative impact on patient's quality of life. Secukinumab, the first interleukin 17A inhibitor, has been used for the systemic treatment of psoriasis, but its long‐term, real‐world retention rates in Japan have not been fully investigated. In this multicenter, noninterventional, retrospective chart review study, the retention rate of secukinumab and its effectiveness among patients with psoriasis in Japan was evaluated up to 5 years. Data of patients who received secukinumab after December 26, 2014, were collected from medical charts obtained from seven sites, all certified for biologics use by the Japanese Dermatological Association. Patient characteristics, secukinumab retention, factors affecting secukinumab retention, reason for drug discontinuation, and effectiveness data were collected. The primary end point was secukinumab retention rate at week 52. A total of 123 patients were included in the analysis. Of these, 27 patients discontinued secukinumab by week 52, yielding a 78.0% (95% confidence interval, 69.6–84.4) retention rate at week 52. For patients whose Psoriasis Area and Severity Index (PASI) score was available, mean ± standard deviation PASI at baseline and at week 52 were 9.21 ± 7.37 and 1.4 ± 2.6, respectively. During the entire study period, “insufficient response” was the most common reason for discontinuation, and “history of biologics use” was a factor significantly associated with secukinumab discontinuation (hazard ratio, 1.72; p = 0.018). This study demonstrates the real‐world retention rate and effectiveness of secukinumab in patients with psoriasis in Japan for up to 5 years and provides clinical insights into psoriasis treatment strategies.


| INTRODUC TI ON
Psoriasis is a chronic, immune-mediated inflammatory skin disease that can affect the skin or joints or both.It is characterized by hyperplasia of the epidermis and dysregulated keratinocyte proliferation. 1 With an increasing understanding of its immune pathophysiology, psoriasis is now recognized as a systemic disease with skin manifestations.Psoriasis is unequally distributed across geographical regions, with the highest prevalence of the disease in Australasia (1.58%) and western Europe (1.52%). 2 Although the overall prevalence is relatively lower at 0.34% in Japan, 3 the disease can be stigmatizing and have a large negative impact on patients' quality of life.
Several biologics targeting tumor necrosis factor α, interleukin (IL) 12/23p40, IL-17, or IL-23p19 have been used as systemic treatment for psoriasis.Secukinumab, a human monoclonal IgG1/kappa antibody, is the first IL-17A inhibitor approved for clinical use.It has demonstrated sustained and robust efficacy in moderate to severe plaque psoriasis, active psoriatic arthritis (PsA), and generalized pustular psoriasis in both adult and pediatric populations, [4][5][6][7][8][9] as well as in several rheumatic diseases, including ankylosing spondylitis, 10 nonradiographic axial spondyloarthritis, 11 and enthesitis-related arthritis. 12pan was the first country to approve secukinumab for the treatment of psoriasis vulgaris and PsA, on December 26, 2014.
Moreover, secukinumab was the most frequently used IL-17 inhibitor in the recently published survey by the Japanese Society for Psoriasis Research (JSPR; 2013-2018), 13 and secukinumab contributed to 32.6% of IL-17 inhibitor use in patients with psoriasis vulgaris undergoing systemic therapy in the Western Japan Psoriasis Registry (WJPR). 14ile the efficacy of secukinumab in treating psoriasis has been shown to sustain for up to 3 years in Japanese patients 15 and up to 5 years in other populations as described in the secukinumab retreatment-as-needed versus fixed-interval maintenance regimen for moderate to severe plaque psoriasis: A randomized, doubleblind, noninferiority trial (SCULPTURE) extension study 4 and the efficacy of response and safety of two fixed secukinumab regimens in psoriasis (ERASURE)/full year investigative examination of secukinumab vs. etanercept using two dosing regimens to determine efficacy in psoriasis (FIXTURE) studies, 16 previous research on secukinumab drug retention in the real world has yielded highly variable results, with some studies reporting lower drug retention rates than those observed in clinical trials. 17,18Currently, the majority of Japanese real-world studies on secukinumab drug retention among patients with psoriasis published earlier were single-center in design, [19][20][21]

| Study design
RAILWAY was a multicenter, noninterventional, retrospective chart review study of patients with psoriasis who had received secukinumab treatment at participating medical institutions in Japan.Data were extracted from medical charts obtained from seven Japanese sites during the period from November 2, 2020, to September 21,

2021.
All seven institutions were certified by the Japanese Dermatological Association to provide biologic treatment for skin diseases, including psoriasis.The dermatology institutions were selected in principle of the feasibility of data collection required for this study and accepted to comply with study objective to assess the secukinumab retention rate and its contributing factors.

| Participants
Patients who were 20 years and older at enrollment and who were diagnosed with psoriasis vulgaris, with or without PsA, and were receiving or had received secukinumab treatment (prescribed according to package insert in Japan) were included in the study.To avoid selection bias of patients, recruitment from one institution was limited to ≤30% of total recruited patients, and patients with earlier secukinumab initiation in each institution were included regardless of actual treatment duration.Written or oral informed consent was obtained from the participating patients before data collection and recorded in the patient's medical record.Data were collected for patients who started secukinumab treatment at the participating institutions after December 26, 2014   (the date of regulatory approval of secukinumab by the Ministry of Health, Labour and Welfare) and whose first day of secukinumab treatment (index date) was >52 weeks before the informed consent collection date.Because the objectives of RAILWAY involved survival analysis at specific time points, patients with fewer than two follow-up visits at the participating centers after secukinumab initiation were excluded.
The study was approved by institutional review boards and/or independent ethics committees prior to data collection.

| Study assessments and variables
The primary end point was the secukinumab retention rate at week Quality Index were collected as baseline characteristics, together with the initial and last date of secukinumab treatment and the reasons for discontinuation.The date of secukinumab discontinuation was defined as "the day when the discontinuation decision for secukinumab treatment was made" according to the data in individual patients' medical charts.

| Statistical analysis
All efficacy end points were summarized using descriptive statistics.
The retention rate was estimated along with 95% confidence intervals (CIs) using the Kaplan-Meier method.Missing data were handled as missing values and no imputation was applied.As a post hoc analysis, the characteristics of patients treated with and remained taking secukinumab at different time points were also summarized using descriptive statistics.

| Patient characteristics
In total, 125 patients were enrolled in the current study.Of these, two of the patients had participated in the postmarketing clinical study CAIN457AJP01 (NCT02547714; a prospective phase 4 study assessing the direct switch from cyclosporine A to secukinumab) 22 and were excluded from the final analysis set.Among these 123 patients, 54, 47, 14, and three patients started secukinumab in 2015, 2016, 2017, 2018, and 2019, respectively.
The baseline characteristics of the 123 patients included are summarized in Table 1.The mean ± standard deviation (SD) age at secukinumab initiation was 54.9 ± 13.9 years (range, 17-85 years); a majority of the patients were men (67.5%) and the mean ± SD BMI (obtained in 54 of patients) was 24.55 ± 4.56 kg/m 2 .The mean ± SD duration of psoriasis was 12.26 ± 11.33 years, and 25.2% of the patients had concomitant PsA at baseline.The mean ± SD PASI score at the index date was 9.21 ± 7.37.Over half of the patients (52.8%) had received at least one biological treatment before, with infliximab being the most used biologic.

| Reason for drug discontinuation
Among 79 patients who discontinued secukinumab during the entire study period, "insufficient response" was the most common reason for discontinuation, followed by "others" and "adverse events" (Table 2).For those discontinuing due to insufficient response,

| Factors affecting secukinumab retention
From the univariate Cox regression analysis (Table 3), "history of biologics use" showed a significant negative association with | 1419 combination product of vitamin D 3 and steroids at the start of secukinumab treatment was also identified as a factor associated with secukinumab retention (HR, 2.77; p = 0.018).However, when comparing the subgroups of patients with or without concomitant use of topical agents, no statistically significant difference was observed.
BMI, body weight, concomitant PsA, duration of psoriasis, and comorbidities were not significantly associated with secukinumab retention during the entire study period; however, noticeable numerical differences in median time to secukinumab discontinuation as well as retention rates at up to 3 years between the subgroups of BMI <25.0 kg/m 2 and ≥25.0 kg/m 2 (Figure 3c) and body weight <60 kg versus ≥60 kg were observed (Figure 3d).The results of other subgroup analyses of secukinumab retention are presented in Figure S1.
Further descriptive analysis was performed to assess the characteristics of patients treated with and remaining on secukinumab for up to 5 years (Table S1).In addition to the factors highlighted in Figure 3, the proportion of patients with concomitant PsA was numerically lower in the patients who continued secukinumab over 1 year than those who discontinued, which was not distinct at later time points.The proportion of current smokers was lower in the patients who remained on the treatment for ≥3 or ≥5 years than those who discontinued.Patients with concomitant systemic treatment at baseline were numerically lower in patients who remained on secukinumab for ≥1, ≥3, or ≥5 years.

| Effectiveness
A total of 59 patients had a PASI score available at the start of secukinumab treatment.The mean ± SD PASI score at baseline was 9.21 ± 7.37.Although PASI score data were available only for a limited number of patients, the absolute PASI scores showed an early decrease and maintenance of low PASI score over time (Figure 4a).
At the same time, the proportion of patients with PASI scores ≤3 exceeded 80% at all time points from week 24 to year 5.The ratio (number) of patients with a PASI score of 0 at each time point was   5b).Because the primary reason for secukinumab use was not collected, it is unknown whether the main treatment was for psoriatic skin lesions or arthritis.However, four of these seven patients did not present with concomitant PsA at baseline.

| DISCUSS ION
RAILWAY is one of the few multicenter studies investigating the real-world drug retention rate of secukinumab in Japan and, importantly, at time points extending up to 5 years.There were no major differences in patient characteristics in RAILWAY from other published cohorts in Japan on secukinumab retention [19][20][21]23 and from those in nationwide/regional surveys by the JSPR 13 or the WJPR. 14 T52-week or 1-year retention rates of secukinumab reported from single-center studies in Japan ranged from 69.9% 21 to 78.3%.19 The 52-week retention rate of 78.0% in the present study was at the high end of the results from Japan and matched the results of the retention rate of 80% from the meta-analysis of 16 studies at 12 months by Augustin et al (N = 4691; 95% CI, 0.75-0.85).24 The multicenter nature of this study can help generalize how secukinumab is used among patients with psoriasis in Japan.

TA B L E 2
Reasons for discontinuation of secukinumab, n (%).

Full analysis set (n = 123)
Patients who discontinued secukinumab (n = 79 a )   study reported that secukinumab exhibited stable and sustained efficacy, 4 whereas patients who achieved ≥75% improvement from baseline PASI/PASI90 within week 16 were less likely to experience reduction or loss of efficacy than those with insufficient response. 36,37Although a few reports have previously implied that the early response may affect the drug retention rate, it is worthwhile to examine this potential association.In addition to finding factors potentially contributing to treatment retention, a post hoc analysis was performed where clinical characteristics of patients who were on/ off secukinumab at year 1, 3, and 5 were described and compared.
The results suggested that the presence of PsA, smoking history, and concomitant systemic treatment might have influence the treatment retention on earlier, later, and overall time points, respectively.
Several studies have examined PsA as a predictor of secukinumab retention and showed discrepancy in results. 19,38[41] Moreover, the authors speculate that patients with concomitant systemic treatment at baseline might have more refractory disease than patients without, resulting in a higher likelihood of treatment Common factors that can contribute to drug retention in the treatment of psoriasis.
discontinuation. 42Although the findings obtained from this study should be examined further, these data may provide new insights about the long-term, real-world use of secukinumab in Japan.

| Limitation
Selection bias and/or missing or incomplete data are inherent limitations of noninterventional studies.Although being a nationwide investigation in Japan, the study included only seven institutions; however, the institutions routinely prescribed secukinumab to a large number of patients, and patient characteristics followed a similar pattern as in the survey by the JSPR 13 and that by the WJPR.

| CON CLUS ION
This multicenter study demonstrated the real-world retention rate and effectiveness of secukinumab in patients with psoriasis in Japan for up to 5 years and provides important clinical insights into the treatment of psoriasis with secukinumab.History of biologics use may be an important factor in predicting secukinumab retention.
More large-scale studies are warranted to further understand the factors influencing drug retention and effectiveness.

ACK N OWLED G M ENTS
The authors thank the patients and investigators of the study for data collection.The authors are grateful for Kazuko Matsumoto (a former employee of Novartis Pharma K.K.) for her essential contribution to the study design, data analysis, data interpretation, and article preparation.The authors also thank Yutaka Nakagawa (Novartis Malaysia Sdn Bhd) for providing medical editorial assistance with this article and members of Medical Affairs in Maruho Co., Ltd, Osaka, Japan for scientific discussion.

FU N D I N G I N FO R M ATI O N
The study was supported by Novartis Pharma K.K., Tokyo, Japan, and thus data and assessment of factors contributing to secukinumab drug retention from larger-scale, multicenter study may help identify patients who could benefit from secukinumab treatment.RAILWAY (Retention and Effectiveness of Secukinumab in Psoriasis Patients in a Real World Setting: A Multi-Center Cohort Study in Japan) was therefore conducted to investigate the retention rate of secukinumab and its effectiveness in patients with psoriasis in Japan.
52 in patients with psoriasis with or without PsA.The secondary end points included secukinumab retention rates at other time points up to year 5, factors affecting secukinumab retention rates, and treatment response to secukinumab.Patient demographics, psoriasis medical history, previous psoriasis therapies, comorbidities, C-reactive protein levels on the index date, Psoriasis Area and Severity Index (PASI), and Dermatology Life | 1417 TADA et al.
the median time to secukinumab discontinuation was 585.5 days (83 weeks) (95% CI, 372.0-742.0days).Of 10 patients whose reason for discontinuation was "others," six discontinued secukinumab at their own discretion, two patients reported "improvement in symptoms" as the reason of secukinumab discontinuation and one patient requested drug cessation because of the financial burden.Eight patients discontinued secukinumab due to an adverse event, with four of them suspected to be related to secukinumab (Krebs von den Lungen 6 increased [n = 2], platelet count decreased [n = 1], and bacterial arthritis [n = 1]).
secukinumab retention (hazard ratio [HR], 1.72; p = 0.018).Concomitant use of topical vitamin D 3 analog alone and/or fixed-dose F I G U R E 1 Kaplan-Meier estimate of secukinumab retention over 52 weeks.F I G U R E 2 Kaplan-Meier estimate of secukinumab retention over 5 years.CI, confidence interval; NR, no record.

Figure 5
Figure 5 illustrates the PASI score distribution at baseline, at week 16, and at the time of secukinumab discontinuation.When comparing the PASI score distribution at baseline and week 16, a decline in the proportion of PASI >10 and an increase in the proportion of PASI 0 to ≤3 is observed at week 16.Conversely, when comparing the PASI score distribution at week 16 and at secukinumab discontinuation, an increase in the proportion of PASI >10 and a decrease in the proportion of PASI 0 to ≤3 is observed at secukinumab discontinuation.Of note, among patients who discontinued secukinumab due to insufficient response, seven of 18 patients presented with a PASI 0 to ≤3 at secukinumab discontinuation (Figure 5b).Because

TA B L E 3
Abbreviations: BMI, body mass index; CI, confidence interval; CRP, C-reactive protein; NAFLD, nonalcoholic fatty liver disease; PASI, psoriasis area and severity index; PASI90, 90% or better improvement in PASI score with respect to baseline; PsA, psoriasis arthritis; TCS, topical corticosteroid.a Reference is <2 years.bReference is <10 years.cReference is <20 years.dThe reference was patients with "no/unknown use of topical agents" at baseline.
data on 2-year or longer retention of secukinumab are scarce.In a Japanese single-center study, the secukinumab retention rate was 56.6% at 2 years and 25.2% at 3 years,21 and a Japanese claims database study showed a rate of 74.2% at 2 years.25Some studies in Europe demonstrated a 2-year secukinumab survival rate of 74.3% in Spain26 and a 5-year survival rate of 69.8% in Greece.27RAILWAY provided insights into the real-world secukinumab retention rate for up to 5 years.Drug retention is not static data and cannot serve as a pure indicator of drug efficacy or safety as there are multiple contributing factors (Figure6).For instance, more biologic treatment options may support treatment selections that are more suitable for individual patient characteristics.In RAILWAY, not all but the majority (n = 101) of the patients started secukinumab in 2015 or 2016, when only a few biologics were available for psoriasis treatment.Of note, in the F I G U R E 3 Kaplan-Meier plot of secukinumab retention by (a) by history of biologic use before secukinumab; (b) achievement of ≥90% improvement in baseline Psoriasis Area and Severity Index (PASI90) at week 16; (c) body mass index (BMI); and (d) body weight.CI, confidence interval; HR, hazard ratio; NR, no record.present study, two patients discontinued secukinumab due to positive efficacy outcomes, whereas some patients discontinued due to insufficient response despite low PASI scores.History of biologics use and concomitant use of vitamin D 3 analog alone and/or fixed-dose combination product of vitamin D 3 and steroids at the start of secukinumab were factors significantly associated with secukinumab discontinuation.Similarly, the results from British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR) reported that a history of biologic use was negatively associated with drug retention. 34The negative association between the concomitant use of topical vitamin D 3 analog and/or combination therapy with topical corticosteroid and secukinumab retention warrants caution when interpreting the clinical relevance; no statistical significance was shown in the comparison of patients with or without concomitant topical treatment at baseline.In addition, the number of patients was limited in the corresponding subgroup, and one patient in this group discontinued secukinumab due to improvement in symptoms.Furthermore, in the present study, subgroup analyses were performed according to the presence or absence of concomitant topical drugs at the start of F I G U R E 4 Effectiveness results.(a) Mean PASI score of patients taking secukinumab over the 5-year time points.(b) Proportion of patients achieving different Psoriasis Area and Severity Index (PASI) scores over the 5-year time points.SD, standard deviation.F I G U R E 5 Psoriasis Area and Severity Index (PASI) score distribution at baseline, at week 16, and at the time of secukinumab discontinuation for (a) all patients who discontinued secukinumab and (b) all patients who discontinued secukinumab due to insufficient response.| 1423 TADA et al. secukinumab treatment and not during secukinumab treatment, and patient adherence to topical agents was not assessed.Therefore, the association between topical vitamin D 3 therapy and long-term drug retention requires further investigation.Kaplan-Meier curves showed numerical differences when comparing BMI <25.0 kg/m 2 versus ≥25.0 kg/m 2 and body weight <60 kg versus ≥60 kg at earlier time points such as years 1, 2, and 3, indicating BMI and weight as factors potentially affecting the retention rate.These results align with the efficacy data in a recent clinical trial showing that patients with high body weight (≥90 kg) displayed superior response to higher secukinumab dosing of every 2 weeks as compared with that of every 4 weeks. 35A long-term observational study is essential to confirm whether the impact of body weight and BMI on drug retention differs at 1 to 3 years versus at 4 to 5 years after treatment initiation.Patients who achieved PASI90 at week 16 also showed a trend towards higher drug retention rate, indicating that patients exhibiting an early response may have favorable prognosis for long-term treatment with secukinumab.A previous

14
PASI score was used to evaluate the effectiveness of secukinumab in this study, but its records were missing at many time points, possibly due to the use of other assessment methods in clinical practice.Multivariate regression was not used to analyze factors associatedwith secukinumab survival owing to the small number of patients or lack of data availability in some subgroups.Some patients discontinued secukinumab due to insufficient response despite low PASI score, but the detailed reason (eg, due to symptoms of PsA or nail psoriasis) was not collected in the study thus could not be investigated.Effectiveness results from this study should only be considered with caution, given the small number of patients over different time points.Nonetheless, RAILWAY indicated a rapid onset of action with secukinumab, and patients treated with secukinumab may be able to maintain a low absolute PASI score over time.