Drug survival of biologic agents in patients with psoriatic arthritis from a medical center in southern Taiwan
Sebastian Yu1, Yu-Hsiang Tsao2, Hung-Pin Tu3, Cheng-Che E Lan4
1 Department of Dermatology, Kaohsiung Medical University Hospital; Department of Dermatology, College of Medicine; Neuroscience Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
2 Department of Medical Research, Division of Medical Statistics and Bioinformatics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
3 Department of Public Health and Environmental Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
4 Department of Dermatology, Kaohsiung Medical University Hospital; Department of Dermatology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
Correspondence Address:
Dr. Cheng-Che E Lan
Department of Dermatology, College of Medicine, Kaohsiung Medical University, 100 Shih-Chuan 1st Rd, Kaohsiung 807378
Taiwan
Dr. Hung-Pin Tu
Department of Public Health and Environmental Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, 100 Shih-Chuan 1st Rd, Kaohsiung 807378
Taiwan
Source of Support: None, Conflict of Interest: None
DOI: 10.4103/ds.ds_8_22
Background: Psoriasis is a chronic inflammatory disease involving the skin and/or joints. Till 2016, there were five biologic agents for psoriatic arthritis treatment in Taiwan: etanercept, adalimumab, golimumab, ustekinumab, and secukinumab. Although European guidelines recommend tumor necrosis factor-α (TNF-α) inhibitors as the first-line biologic agents for axial disease of psoriatic arthritis, the drug survival of biologic agents in Asian populations remains unclear. Objectives: We investigated 5-year drug survival of biologic agents in patients with psoriatic arthritis. Methods: We used Kaohsiung Medical University Hospital Research Database to evaluate real-world 5-year drug survival of biologic agents for psoriatic arthritis in a medical center from southern Taiwan. Results: The 5-year drug survival rates of ustekinumab, etanercept, and adalimumab were significantly different. Ustekinumab and etanercept showed higher 5-year survival rates for psoriatic disease than adalimumab. Golimumab and secukinumab had a short follow-up time to obtain a conclusive 5-year survival rate. Conclusion: Considering that TNF-α inhibitors are often the first-line biologic agents for psoriatic arthritis in guidelines in western countries, the finding that ustekinumab is superior to TNF-α inhibitor adalimumab in terms of 5-year survival for psoriatic disease may imply that the therapeutic response of biologic agents may differ between different ethnic groups.
Keywords: Biologic agent, interleukin-17, psoriasis, psoriatic arthritis, tumor necrosis factor-α, interleukin-12/23
Biologic agents are a novel class of drugs blocking specific immune mediators that are involved in the pathogenesis of the disease.[1] For example, ustekinumab is an anti-IL-12/23 p40 monoclonal antibody and is indicated for the treatment of psoriasis and psoriatic arthritis.[2],[3] Other biologic agents used for the treatment of psoriasis include antitumor necrosis factor-α (TNF-α) agents such as etanercept,[4] adalimumab,[5] and golimumab[6] as well as anti-IL-17 agent secukinumab.[7] The introduction of biologic agents in the recent two decades has led to a tremendous advancement in the treatment of psoriasis and psoriatic arthritis. Long-term use of biologic agents for maintenance treatment of psoriatic arthritis marks the need to analyze drug survival of the available biologic agents. Several factors can result in discontinuation of biologic agents, including but not limited to safety concerns (e.g. infection, malignancy), adverse effects, cost, availability, drug resistance due to immunogenicity, and lack of effectiveness. Data obtained from clinical trials document the effectiveness of biologic agents through certain follow-up periods. However, the recruited populations in clinical trials are often selected with certain inclusion and exclusion criteria and are different from real-world patients.
To date, only a few studies have evaluated the drug survival of biologics among psoriatic arthritis patients in real-world settings, and the sample sizes in these studies are rather small.[8],[9],[10] A pharmaceutical company-sponsored post-market surveillance study that investigated the drug survival of etanercept, adalimumab, ustekinumab, and infliximab in a registry (PSOriasis Longitudinal Assessment and Registry, PSOLAR) found that drug survival was superior for ustekinumab compared with infliximab, adalimumab, and etanercept in patients with psoriasis.[11] A systematic review and meta-analysis also showed that ustekinumab has longer drug survival than TNF-α inhibitors, including etanercept, adalimumab, and infliximab, in the treatment of psoriasis. However, the study populations of these studies are mainly limited to North America and Europe.[12] More recently, a medical center in Taiwan investigated the skin response of different biologic agents in 75 patients and showed that PASI-75, 90, and 100 were highest in secukinumab, followed by ustekinumab, adalimumab, and etanercept.[13] Nevertheless, data regarding real-world drug survival of biologic agents for psoriatic arthritis in Asian populations are still relatively lacking.
As for psoriatic arthritis, the European guidelines recommend TNF-α inhibitors as the first-line biologic agents for an axial disease of psoriatic arthritis.[14] The experience with IL-17 inhibition in terms of long-term efficacy and safety is still limited, and IL-17 inhibitors may be considered when there is relevant skin involvement. Currently, IL-12/23 inhibitor ustekinumab is not the treatment of choice for axial disease of psoriatic arthritis according to the European guidelines. Considering that the genetic and environmental factors differ between the Asian and western countries, it is crucial to investigate if the European guidelines are relevant for Asian populations. Indeed, the prevalence of psoriasis and psoriatic arthritis differs between the Asian and Caucasian populations.[15] The difference in prevalence may be attributed to various factors including the high-sugar western diet[16],[17],[18] and genetic variations.[19],[20] For example, it has been demonstrated that Asian atopic dermatitis has more prominent T-helper 17-skewing psoriasiform features as compared to its American/European counterparts.[21],[22],[23],[24] It might be possible that immune mediators of psoriasis and psoriatic arthritis have variations among different ethnic groups, contributing to the different response profiles of biologic agents among different ethnic groups. Since drug survival is a marker for treatment sustainability, a better understanding of drug survival in the Taiwanese and Asian patients with psoriatic arthritis in real-world settings is indicated.
Materials and MethodsData source
Kaohsiung Medical University Hospital (KMUH) is a medical center located in southern Taiwan with around 6000 patient visits per day and 1600 beds. In this retrospective study, we used the KMUH Research Database (KMUHRD), which is a database with coverage of ambulatory care, hospitalization, drug dispensation records, and biochemical data in KMUH and the other three Kaohsiung Medical University-affiliated hospitals, including Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Municipal Siaogang Hospital, and Kaohsiung Municipal Cijin Hospital.[25],[26] The drug dispensation records in the KMUHRD include the type of prescriber, name, date, amount, and prescribed dosage of the dispensed drug, and the length of the prescription (drug survival).[26] The KMUHRD includes the data for patients who attended the aforementioned hospitals from 2009 to 2018. The International Classification of Diseases, 9th revision, Clinical Modification (ICD-9-CM) is adopted to document the diagnoses in medical records before 2016 and the International Classification of Diseases, 10th revision (ICD-10), is used thereafter. The database is managed by the Division of Medical Statistics and Bioinformatics, Department of Medical Research, KMUH. The accuracy of ICD-9-CM and ICD-10 coding is verified by random medical claims review executed by the Bureau of National Health Insurance of Taiwan that enforces penalties for false claims.[27],[28],[29],[30] The KMUHRD ensures patients' confidentiality by assigning an anonymous code to each patient.[25] This study was approved by the Institutional Review Board of the KMUH (KMUHIRB-E (II)-20200037). The patient consent is waived by IRB.
Study population
The study cohort (patients with psoriatic arthritis) consisted of patients diagnosed with psoriatic arthritis from January 1, 2009, to December 31, 2018. Taiwan Food and Drug Administration approved etanercept, adalimumab, golimumab, ustekinumab, and secukinumab for psoriatic arthritis treatment on August 13, 2003; August 21, 2006; May 28, 2012; October 1, 2014; and June 27, 2016, respectively. Etanercept, adalimumab, golimumab, ustekinumab, and secukinumab have been reimbursed by National Health Insurance of Taiwan since November 1, 2009; August 1, 2009; February 1, 2013; October 1, 2016; and January 1, 2018, respectively. Among them, golimumab and secukinumab were not routinely available in the Kaohsiung Medical University-affiliated hospitals during the study period. Therefore, follow-up time for golimumab and secukinumab was relatively short. People younger than 12 years or older than 100 years were excluded. Confirmation of psoriatic arthritis was based on the ICD-9-CM code 696.0 and/or ICD-10 code L405. Only subjects who had three or more times of the corresponding diagnostic codes were included. The study cohort was further divided into two groups based on the use of biologic agents. The patients who have received biologic agents once or more than once were defined as biologic group, while those who never received any biologic agents were defined as the non-biologic group. The biologic agents analyzed during the study period include etanercept, adalimumab, golimumab, ustekinumab, and secukinumab. A biologic agent was regarded as discontinued on the last date the biologic agent was prescribed. Patients with psoriatic arthritis in this study got biologic agents either because of their psoriatic arthritis or skin psoriasis. If the patient applied biologic agents through psoriatic arthritis route, the biologic agent use would be continuously reimbursed as the patient needed. If the patient applied biologic agents through the skin psoriasis route, the biologic agent use would be reimbursed for only 2 years but could be applied again depending on the disease activity. If a biologic agent was held for a period of time and then restarted without introduction of other biologic agents, the biologic agent is regarded as continuously used. First-line biologic is defined as the first biologic a patient experienced, and second-line biologic is the second biologic a patient experienced. The flowchart of the study design is shown in [Figure 1].
Construction of variables
Variables included age, sex, and comorbidities. Age was stratified into five groups that included <30 years, 30–39 years, 40–49 years, 50–59 years, and ≧60 years. Comorbidities were confirmed by enhanced ICD-9-CM and ICD-10 coding method, which is commonly used in observational studies based on claim data.[31] Diagnoses of comorbidities were based on having ≥3 outpatient claims during the study period. Comorbidities and their corresponding codes (ICD-9-CM; ICD-10) included congestive heart failure (398.91, 402.01, 402.11, 402.91, 404.01, 404.03, 404.11, 404.13, 404.91, 404.93, 425.4–425.9, 428.x; I50.x), peripheral vascular disease (093.0, 437.3, 440.x, 441.x, 443.1–443.9, 47.1, 557.1, 557.9, V43.4; I71.x, I96.x, 790, I739, Z958, and H738), diabetes mellitus (without chronic complication 250.0–250.3, 250.8, 250.9; E109, E119, E139, E08.x, E09.x, E10.x, E11.x, and E13.x; and with chronic complication 250.4–250.7; E08.x, E09.x, E10.x, E11.x, and E13.x), cerebrovascular disease (362.34, 430.x–438.x; and I60–I69), hypertension (401–405; I10–I13, and I15), hyperlipidemia (272; E75, E77, E78, and E88), myocardial infarction (410.x, 412.x; I21.x, and I25.x), chronic kidney disease (403.01, 403.11, 403.91, 404.02, 404.03, 404.12, 404.13, 404.92, 404.93, 582.x, 583.0–583.7, 585.x, 586.x, 588.0, V42.0, V45.1, V56.x; N03, N05, N06, N07, N14, N15, N16, N18, N19, and N25), cancer (140–208; C00, Z51, C15, C30, C40, C41, C53, C69, C81–C85, C88, C90–C96, and D45), dementia (290.x; F05, F039, and F015), chronic obstructive pulmonary disease (416.8, 416.9, 490.x–505.x, 506.4, 508.1, 508.8; J449, J40, J41, J42, J46, J47, J67, J60, J61, J62, J63, J64, and J65), rheumatologic disease (446.5, 710.0–710.4, 714.0–714.2, 714.8, 725.x; M32, M34, M353, M057, M050, and M052), peptic ulcer (531.4–531.7, 532.1–532.7, 533.4–533.7, 534.4–534.7, 531.0–531.3, 532.0–532.3, 533.0–533.3, 534.0–534.3, 531.9, 532.9, 533.9, and 534.9; K25-K27 and K56), hepatitis (573.3; K71.x, K75.2, K75.3, K75.8, K75.9, and K76.4), and acquired immunodeficiency syndrome (042–044; B24, Z97, Z46, Z20, Z96, and O98).
Statistical analysis
Characteristics of the study participants for the continuous and categorical variables were analyzed by t-test/Wilcoxon rank-sum test and the Chi-squared test/Fisher exact test, as appropriate, for comparisons between psoriatic arthritis with biologic therapy and without biologic therapy. The Kaplan–Meier method was used to estimate survival curves for each group, and the log-rank test was used to test the homogeneity between the survival curves. SAS statistical software, version 9.4 (SAS Institute, Cary, NC, USA), was used for all statistical analyses. All statistical tests were two sided, and a two-tailed P < 0.05 was considered significant.
ResultsDemographic characteristics of patients with psoriatic arthritis
[Table 1] shows demographic characteristics of the study population. There were 894 patients with psoriatic arthritis identified. Among them, 163 patients received biologic agents, while 731 patients never received any biologic agents. The age was significantly different between patients with biologic agents and patients without biologic agents, while the sex was not significantly different between the two groups. The uses of acitretin, methotrexate, cyclosporine, non-steroidal anti-inflammatory drugs (NSAIDs), leflunomide, sulfasalazine, and phototherapy were also significantly different between patients with biologic agents and patients without biologic agents. The distribution of comorbidities (Charlson index categories) was not significantly different between the two groups.
Table 1: Demographic characteristics of enrolls with psoriatic arthritisInitiation, duration, and switch among ustekinumab, adalimumab, etanercept, and secukinumab
Among the 163 patients who received biologic agents for psoriatic arthritis, the majority of patients used adalimumab (98, 60.12%) as the first-line biologic, followed by etanercept (28, 17.18%), ustekinumab (14, 8.59%), golimumab (14, 8.59%), and secukinumab (9, 5.52%). Mean years (standard deviation [SD]) on therapy as the first-line biologic for ustekinumab, adalimumab, etanercept, golimumab, and secukinumab were 4.44 (1.58), 2.68 (2.20), 5.19 (2.00), 1.85 (1.45), and 0.44 (0.23), respectively. Patients who used ustekinumab, adalimumab, etanercept, golimumab, or secukinumab as the second-line biologic were 8 (22.22%), 4 (11.11%), 5 (13.89%), 3 (8.33%), and 16 (44.44%), respectively, and mean years (SD) on therapy were 1.48 (1.04), 3.41 (0.27), 4.24 (2.89), 3.89 (1.11), and 0.63 (0.34), respectively. Only seven patients were administered the third biologic. Among them, four patients (57.14%) used secukinumab, two patients used golimumab (28.57%), and one patient used adalimumab (14.29%) [Table 2].
Table 2: Duration and switch among ustekinumab, adalimumab, etanercept, golimumab, and secukinumabDrug survival of ustekinumab, adalimumab, and etanercept as the first-line biologic agents for psoriatic arthritis
We further analyzed the drug survival of biologic agents. Since the follow-up time for golimumab and secukinumab as the first-line biologics was too short to obtain conclusive results, we only compared 5-year drug survival of ustekinumab, adalimumab, and etanercept as the first-line biologics for psoriatic arthritis [Figure 2]. The 5-year drug survival of the three biologic agents was significantly different (P = 0.031) [Figure 2]a. While 5-year drug survival of adalimumab, ustekinumab, and etanercept exhibited values above 50%, ustekinumab and etanercept had higher 5-year drug survival than adalimumab. As ustekinumab is commonly used in skin psoriasis and there is concern that patients with skin psoriasis may be miscoded with psoriatic arthritis ICD-9 or ICD-10 coding, we further examined drug survival of ustekinumab in patients who received NSAIDs once or more for their psoriatic arthritis treatment during the study period. There was no significant difference in 5-year drug survival of ustekinumab between these patients and patients with psoriatic arthritis receiving ustekinumab regardless of NSAIDs use (P = 0.900) [Figure 2]b. Furthermore, there was a significant difference between 5-year drug survival rate of ustekinumab in these patients and 5-year drug survival rates of adalimumab and etanercept in patients with psoriatic arthritis regardless of NSAIDs use (P = 0.036) [Figure 2]c. These results indicated that ustekinumab had high 5-year drug survival for patients with psoriatic disease who experienced NSAIDs for their psoriatic arthritis treatment.
Figure 2: Five-year drug survival of adalimumab, etanercept, and ustekinumab for psoriatic arthritis. (a) The 5-year survival rates for psoriatic arthritis are significantly different among adalimumab, etanercept, and ustekinumab (P = 0.031). Among the three biologic agents, adalimumab has a lower 5-year survival rate than ustekinumab and etanercept. (b) There is no significant difference in 5-year drug survival of ustekinumab between patients with psoriatic arthritis NSAIDs and patients with psoriatic arthritis regardless of non-steroidal anti-inflammatory drugs use. (c) 5-year drug survival of ustekinumab in patients with psoriatic patients using NSAIDs is higher than 5-year drug survival of adalimumab and etanercept in patients with psoriatic arthritis regardless of NSAIDs use (P = 0.036). NSAIDs, non-steroidal anti-inflammatory drugs. DiscussionThe present study analyzed the drug survival of ustekinumab, adalimumab, and etanercept for psoriatic arthritis in a medical center in southern Taiwan during 2009–2018. Based on these results, the 5-year drug survival of the three biologic agents as the first-line biologic for psoriatic arthritis was significantly different. The drug survival rates of ustekinumab, etanercept, and adalimumab were all greater than 50%, suggesting sustainable efficacy of these biologic agents for managing psoriatic arthritis. Adalimumab was the first choice for psoriatic arthritis in 99 out of 153 patients (64.7%), while the years on therapy was 2.71 and the 5-year drug survival was lower than ustekinumab and etanercept. It should be noted that it was not until January of 2018 that secukinumab was reimbursed by Taiwan National Health Insurance for psoriatic arthritis treatment, and therefore, the follow-up time for secukinumab was too short for analysis in the present study.
There are several explanations for the difference in drug survival among adalimumab, ustekinumab, and etanercept. First, etanercept was the only available biologic agent for psoriatic arthritis at the beginning of the study period. Patients with only fair response to etanercept may continue to use it because of the unavailability of alternative biologic agents, making the drug survival of etanercept longer. Second, most of the patients with psoriatic arthritis also have skin psoriasis lesions that could cause psychiatric comorbidities and impair patients' quality of life.[32],[33],[34] In view of holistic medicine, shifting from one biologic agent to another for a patient with psoriatic arthritis does not necessarily indicate ineffectiveness for the treatment of psoriatic arthritis but may be due to other reasons such as pursuing better skin response. Literature reviews show that better psoriasis skin response was achieved in ustekinumab-treated patients than adalimumab-treated patients.[35] Furthermore, psoriatic arthritis could be alleviated by certain disease-modifying antirheumatic drugs (DMARDs), including methotrexate, sulfasalazine, and leflunomide, while complete remission of skin psoriatic lesions mainly relies on biologic agents. In other words, it is conceivable that the patients with both severe skin psoriasis and psoriatic arthritis may have a higher preference to receive biologics that have a better effect on their skin lesions with concomitant DMARDs to control arthritis than receiving biologics to reach remission of psoriatic arthritis with limited adjunct therapies to clear the psoriatic skin lesions. Finally, the results may indicate that different ethnic groups may show different treatment responses to biologic agents. There have been reports showing that adalimumab and etanercept, both are TNF-α inhibitors, have equally effective treatments as biologic agents for patients with psoriatic arthritis; however, these studies were mainly conducted in the USA, Canada, UK, and Europe.[36],[37] The results of the present study show incomparable drug survival between adalimumab and etanercept in Taiwanese populations, suggesting that ethnic genetic background may have a significant impact on the response to biologic agents in patients with psoriatic arthritis.[19],[38],[39],[40] More solid evidence is needed to verify this hypothesis.
There are certain limitations present in the current study. First, the sample size was limited. More subjects with psoriatic arthritis would have helped to achieve more solid results. Second, the diagnosis of psoriatic arthritis depended on ICD coding on three occasions and there might be miscoding. Therefore, we examined medications for psoriatic arthritis but not skin psoriasis, including NSAIDs, leflunomide, and sulfasalazine. Almost 97.39% of patients with biologic use received NSAIDs treatment, indicating that these patients experienced treatments for psoriatic arthritis. In addition, the 5-year drug survival for secukinumab was not available. Further direct comparison studies between the Asian and Caucasian populations with psoriatic arthritis may provide more insights into this intriguing issue.
ConclusionIn this pilot study using KMUHRD, we demonstrate real-world drug survival regarding biologic agents for psoriatic arthritis in a patient cohort from southern Taiwan. The superiority of ustekinumab over TNF-α inhibitor adalimumab in terms of 5-year drug survival may reflect different immune milieus in Taiwanese or Asian populations as compared to populations in western countries. Further investigations in Taiwan and other Asian countries will provide a guidance for the prescription of biologic agents for psoriatic arthritis.
Acknowledgments
This study was supported by a grant from the Kaohsiung Medical University Research Foundation (KMU-Q108012) to SY, and grants from the Taiwan Ministry of Science and Technology (MOST-108-2314-B-037-081, MOST-108-2628-B-037-004, MOST-109-2628-B-037-013, and MOST-110-2628-B-037-007) to SY. This study is supported partially by Kaohsiung Medical University Research Center Grant (KMU-TC109B03 and KMU-TC110B03). The authors thank the help from the Division of Medical Statistics and Bioinformatics, Department of Medical Research, KMUH, and Center for Big Data Research (KMU-TC109B08), Kaohsiung Medical University, for providing administrative support, including the KMUHRD.
Authors' contributions
SY designed the study, analyzed data, interpreted data, and drafted the manuscript. YHT analyzed data and drafted the manuscript. HPT designed the study, analyzed data, interpreted data, and revised the manuscript. CCEL designed the study, interpreted data, and revised the manuscript. The finalized manuscript has been read and approved by all the authors.
Financial support and sponsorship
Nil.
Conflicts of interest
Dr. Sebastian Yu received speaker fees from AbbVie, Johnson & Johnson, and Novartis. Dr. Sebastian Yu holds shares of AbbVie and shares of Johnson & Johnson.Prof. Cheng-Che E. Lan, an editorial board member at Dermatologica Sinica, had no role in the peer review process of or decision to publish this article. The other authors declared no conflicts of interest in writing this paper.References
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