Health care utilization and cost associated with switching biologics within the first year of biologic treatment initiation among patients with ankylosing spondylitis

BACKGROUND: Costs associated with biologic switching and discontinuation can be high in chronic inflammatory diseases. Inappropriate use of medications may have cost implications for both payers and patients. Understanding of biologic utilization and switching rates is lacking among patients with ankylosing spondylitis (AS). OBJECTIVE: To compare direct costs of treatment switchers, nonswitchers, and discontinuers among patients with AS who newly initiated a biologic. METHODS: Patients aged ≥ 18 years with an AS diagnosis and ≥ 1 pharmacy claim for an FDA-approved subcutaneous biologic for AS between January 1, 2016, and December 31, 2016 (identification period) were identified from the Truven Health MarketScan Databases. At the time of biologic initiation (index date), eligible patients were continuously enrolled with medical and pharmacy claims for ≥ 1 year before (baseline period) and ≥ 1 year after the index date (follow-up period). Patients with AS were categorized into 3 mutually exclusive groups of nonswitchers (patients who remained on their index biologic), switchers (patients who had a prescription for a biologic therapy other than their index biologic), and discontinuers (patients who had gaps in prescription claims [> 120 days]) based on their biologic utilization pattern during the 1-year follow-up period. Health care costs (inflated to year 2017 costs) during follow-up were described across the 3 groups separately and by disease. Adjusted health care resource utilization and costs during 1-year follow-up were estimated, controlling for age, sex, fulltime work status, and Charlson Comorbidity Index (Deyo’s modification) during the baseline period. RESULTS: A total of 791 patients with AS who were newly initiating a biologic were categorized as switchers (15.4%), nonswitchers (53.1%), and discontinuers (31.5%). Switchers and discontinuers had higher all-cause health care utilization than nonswitchers during the 1-year follow-up period. Switchers had higher mean total health care costs than nonswitchers ($71,280 vs. $66,573) due to increased medical ($13,897 vs. $12,043) and pharmacy costs ($57,384 vs. $54,530). Discontinuers had the lowest total health care costs ($41,179) but had the highest medical costs ($19,079). Adjusted analyses for covariates confirmed similar trends as the unadjusted analysis, where discontinuers had significantly lower total health care and pharmacy costs but had higher medical costs (with increased emergency department and outpatient visits) than nonswitchers (all P < 0.001). Switchers had increased outpatient visits and costs versus nonswitchers in the adjusted analysis (P < 0.001); small sample sizes in the switcher group may have limited the ability to detect significant trends in the adjusted analysis. CONCLUSIONS: Biologic switching resulted in higher total health care costs than remaining on the same biologic in patients with AS. These findings highlight the clinical and economic impact of discontinuing or switching biologic therapies in patients with AS, which may inform treatment and/or formulary decision making.

Health care utilization and cost associated with switching biologics within the first year of biologic treatment initiation among patients with ankylosing spondylitis Esther Yi, PharmD; Dong Dai, PhD; Olivia W Piao, MS; Josh Z Zheng, MS; Yujin Park, PharmD ABSTRACT BACKGROUND: Costs associated with biologic switching and discontinuation can be high in chronic inflammatory diseases. Inappropriate use of medications may have cost implications for both payers and patients. Understanding of biologic utilization and switching rates is lacking among patients with ankylosing spondylitis (AS).

OBJECTIVE:
To compare direct costs of treatment switchers, nonswitchers, and discontinuers among patients with AS who newly initiated a biologic.

METHODS:
Patients aged ≥ 18 years with an AS diagnosis and ≥ 1 pharmacy claim for an FDA-approved subcutaneous biologic for AS between January 1, 2016, and December 31, 2016 (identification period) were identified from the Truven Health MarketScan Databases. At the time of biologic initiation (index date), eligible patients were continuously enrolled with medical and pharmacy claims for ≥ 1 year before (baseline period) and ≥ 1 year after the index date (follow-up period). Patients with AS were categorized into 3 mutually exclusive groups of nonswitchers (patients who remained on their index biologic), switchers (patients who had a prescription for a biologic therapy other than their index biologic), and discontinu- What is already known about this subject • Currently, the available biologics approved for the treatment of ankylosing spondylitis (AS) in the United States include tumor necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, and golimumab) and interleukin-17A inhibitors (ixekizumab and secukinumab).
• Patients may discontinue or switch biologic therapies in clinical practice due to adverse events, lack of efficacy, or formulary changes.
• A few studies have retrospectively identified treatment patterns in patients with AS, but there is limited real-world evidence comparing health care costs and resource utilization associated with switching or discontinuing between approved biologics.

What this study adds
• This retrospective analysis of U.S. administrative claims data shows that within 1 year of initiating a biologic (adalimumab, certolizumab pegol, etanercept, golimumab, or secukinumab), 53.1% of patients with AS remained on their index biologic; 15.4% switched from their index biologic to a new therapy; and 31.5% discontinued their index biologic.
• Switchers and discontinuers had higher health care resource utilization (emergency and outpatient visits) than nonswitchers.
• Switchers had the highest total health care costs, which were driven by increased pharmacy and medical costs, while discontinuers had the lowest total health care costs due to decreased pharmacy costs from early discontinuation of medications but also had the highest medical costs.
Ankylosing spondylitis (AS) is a chronic, immune-mediated rheumatic disease that primarily affects the spine and manifests as progressive spinal stiffness and fusion. 1 The main clinical feature of AS is inflammatory back pain, which is caused by inflammation of the vertebrae and joints of the spine and entheses. 1,2 The prevalence of AS is estimated at 0.35% to 0.67% in the United States. 1,3-6 However, given that AS is often underdiagnosed or diagnosed late, 7 some believe it may actually affect approximately 1% in the United States. 3 The usual age of symptom onset is 15-35 years, with a delay in diagnosis of up to 14 years. 8,9 Factors that likely contribute to delayed diagnosis of AS include the broad prevalence of chronic lower back pain in the population (including mechanical back pain), gradual onset of the disease, and lack of specific symptoms or biomarkers unique to AS. 9 Several lines of evidence suggest that severe deformities, disabilities, and functional limitations often develop within the first 10 years of AS. 10,11 Along with severely affecting physical function, AS poses a substantial economic burden to patients, payers, and society due not only to health care utilization and costs related to delayed diagnosis but also to lifelong, continuous treatment. 12,13 In a study of U.S. administrative claims data, patients with AS had approximately 4-fold higher mean total all-cause health care costs than a matched control population without AS ($33,285 vs. $8,310 per patient per year), driven by increased use of medical outpatient services (i.e., emergency department [ED] visits, nonhospital-based outpatient visits, hospital-based outpatient visits, and other outpatient services) and pharmacy costs (all P < 0.05). 12 The majority of AS-specific total health care costs were related to AS medication costs. In a systematic review of the indirect costs relating to work absenteeism and presenteeism associated with AS, the mean annual indirect cost was $6,455 per patient per year, with a range of $661 to $45,954 depending on the components of indirect costs and their definitions. 14 Other studies, mostly from outside the United States, have found that indirect health care costs associated with AS were higher than direct costs. 15 The Assessment of SpondyloArthritis international Society (ASAS), the European League Against Rheumatism (EULAR), the American College of Rheumatology (ACR)/ Spondylitis Association of America (SAA), and the Spondyloarthritis Research and Treatment Network (SPARTAN) all recommend nonsteroidal anti-inflammatory drugs (NSAIDs) as first-line therapy in patients with active disease who have pain and stiffness; in patients with active disease despite NSAID treatment, use of biologic therapy is recommended. 16,17 Biologic therapies approved for the treatment of AS include the tumor necrosis factor inhibitors (TNFis) adalimumab, etanercept, certolizumab pegol, and golimumab and the interleukin (IL)-17A inhibitors secukinumab and ixekizumab. [18][19][20][21][22][23][24][25][26] Current practice suggests the use of a TNFi as first-line biologic therapy. 16 The 2019 update of the ACR/SAA/SPARTAN guidelines for the treatment of AS and nonradiographic axial spondyloarthritis conditionally recommends IL-17 inhibitors over treatment with a different TNFi among primary nonresponders to TNFis and treatment with a second TNFi over a non-TNFi biologic if the initial TNFi loses efficacy over time. 17 Lack of primary response or loss of effectiveness over time is a common reason for biologic switching. 27 Previous studies have also shown that switching biologics may be effective if the initial biologic fails 28,29 ; however, switching biologics may lead to increased health care utilization. Adherence to and persistence with biologic therapy in patients with AS is vital to achieve optimal outcomes of pain relief, improved physical function, and minimal joint damage. 30 Therefore, appropriate selection of medications is important for optimizing patient outcomes and minimizing costs.
Because of the array of biologic treatment options, it is important to assess the cost of switching or discontinuing biologics among patients with AS. Previous retrospective studies have predominantly focused on treatment patterns and costs of TNFis. 31,32 Therefore, there is a need for more studies evaluating the real-world health care costs and utilization associated with newer biologic treatments for RESULTS: A total of 791 patients with AS who were newly initiating a biologic were categorized as switchers (15.4%), nonswitchers (53.1%), and discontinuers (31.5%). Switchers and discontinuers had higher all-cause health care utilization than nonswitchers during the 1-year follow-up period. Switchers had higher mean total health care costs than nonswitchers ($71,280 vs. $66,573) due to increased medical ($13,897 vs. $12,043) and pharmacy costs ($57,384 vs. $54,530). Discontinuers had the lowest total health care costs ($41,179) but had the highest medical costs ($19,079). Adjusted analyses for covariates confirmed similar trends as the unadjusted analysis, where discontinuers had significantly lower total health care and pharmacy costs but had higher medical costs (with increased emergency department and outpatient visits) than nonswitchers (all P < 0.001). Switchers had increased outpatient visits and costs versus nonswitchers in the adjusted analysis (P < 0.001); small sample sizes in the switcher group may have limited the ability to detect significant trends in the adjusted analysis.
CONCLUSIONS: Biologic switching resulted in higher total health care costs than remaining on the same biologic in patients with AS. These findings highlight the clinical and economic impact of discontinuing or switching biologic therapies in patients with AS, which may inform treatment and/or formulary decision making. and Accountability Act (HIPAA) and federal guidance on Public Welfare and the Protection of Human Subjects.

STUDY VARIABLES
Patients were categorized into 3 mutually exclusive groups based on their biologic treatment pattern groups during the 1-year follow-up period.
• Nonswitchers: Patients who remained on the index biologic with no gaps in treatment (> 120 days) and no other claims for biologic therapies during the 1-year follow-up period • Switchers: Patients who had a prescription claim for a different biologic therapy (adalimumab, certolizumab pegol, etanercept, golimumab, secukinumab) than the index biologic and who switched therapies before permissible treatment gaps (> 120 days) were reached during the 1-year follow-up period • Discontinuers: Patients who had prescription claim gaps (time from exhaustion of previous days supply) during the 1-year follow-up period (gap > 120 days) Patient demographics (age, sex, employment status, insurance plan type, and geographic location) were assessed at the index date; all-cause health care resource utilization (hospitalizations, ED visits, and outpatient visits) and all-cause health care costs (including medical [inpatient, outpatient, and ED costs] and pharmacy costs) were measured both during the 1-year baseline period and the 1-year follow-up period. All-cause health care resource utilization and health care costs were calculated per patient per year; health care costs were inflated to year 2017 costs.

DATA ANALYSIS
Descriptive statistics were tabulated for patient characteristics and outcome variables (health care resource utilization and costs) comparing nonswitchers versus switchers and nonswitchers versus discontinuers. Continuous variables were summarized as means and standard deviations, while categorical variables were presented as counts and percentages, with missing data considered a separate category. Comparisons between treatment pattern groups were made using χ 2 tests for categorical variables and Wilcoxon rank-sum tests or unequal variance 2-sample t-tests for continuous variables.
Multivariable models were fitted to compare all-cause health care resource utilization and costs between switchers versus nonswitchers and discontinuers versus nonswitchers using a negative binomial distribution with log link function for all outcomes. Adjusted health care utilization and costs were estimated for nonswitchers, switchers, and AS. This study aimed to compare health care utilization and costs of switching and discontinuing biologics versus remaining on index biologic during 1 year of follow-up among patients with AS.

STUDY DESIGN AND PATIENT POPULATION
A retrospective, observational cohort study was conducted using the Truven Analytics MarketScan Commercial Claims and Encounters Database (CCAE) and the Medicare Supplemental and Coordination of Benefits Database (MDCR) from January 1, 2015, to December 31, 2017. The Truven Analytics MarketScan data source is widely used for analyzing epidemiologic and economic outcomes in the U.S. health care system. CCAE contains administrative claims data from a privately insured population, while the MDCR contains administrative claims data from retirees with Medicare supplemental insurance paid by employers, employer-paid portion, services provided under Medicare-covered payment, and any out-of-pocket expenses. The CCAE and MDCR include fully adjudicated deidentified medical claims, outpatient prescription drug claims, and person-level enrollment data that are linked with unique patient identifiers. Demographic variables (age, gender, employment status, insurance plan type, and geographic location) and detailed health care costs and utilization for health care services performed in both inpatient and outpatient settings are captured.
Patients aged ≥ 18 years with ≥ 1 pharmacy claim for a subcutaneously administered biologic that was approved by the U.S.

STUDY POPULATION AND PATIENT DEMOGRAPHICS
This study included 87,748 patients with ≥ 1 claim for adalimumab, certolizumab pegol, etanercept, golimumab, or secukinumab during the identification period between January 1, 2016, discontinuers based on the models. All models were adjusted to control for baseline covariates, including age, sex, full-time work status (yes or no), and baseline Charlson Comorbidity Index (Deyo's modification). All analyses were done using SAS software version 9.4 (SAS Institute, Cary, NC) in the EVICO platform.
Adjusted analyses of health care costs showed similar trends as the unadjusted analysis (Table 4).

UNADJUSTED ALL-CAUSE HEALTH CARE RESOURCE UTILIZATION AND COSTS DURING THE 1-YEAR FOLLOW-UP PERIOD
In the 1-year follow-up period, discontinuers and switchers had higher all-cause health care utilization than nonswitchers (   31 Notably, approximately two thirds of discontinuers or switchers in our study were women compared with < 50% of nonswitchers. This female predominance was also previously reported among TNFi discontinuers, which may be a sign of lower response or higher rate of adverse events with all biologic treatments in women than in men. 33,34 During the 1-year follow-up period, all-cause health care utilization and cost subcategories demonstrated similar trends regarding switching or discontinuing treatment pattern groups. Patients who switched or discontinued biologics had higher health care resource utilization and medical costs than those who remained on their index biologic. Different trends were observed with switchers and discontinuers with regard to total health care costs. Patients who switched biologics had the highest total health care costs, driven by an increase in pharmacy and medical costs. The mean health care cost for discontinuers was the lowest among the treatment groups due to low pharmacy costs from early discontinuation of therapy. However, discontinuers had the highest mean medical costs, indicating that these patients may still have unstable disease states. Furthermore, discontinuing biologics results in medication wastage from a payer perspective, as initiating a costly drug and not completing treatment causes an excess in medication and imposes an unnecessary economic burden.
Adjusted all-cause health care utilization and costs during the 1-year follow-up period demonstrated similar trends as the unadjusted analysis. Of note, only increases in outpatient costs and outpatient visits were significantly

Discussion
In this retrospective analysis of a U.S. administrative claims database, patients with AS who switched or discontinued biologics were found to have endured a greater economic burden than patients who remained on their index biologic. Overall, 53.1% of patients remained on their index biologic, 15.4% switched their biologic, and 31.5% discontinued their biologic therapy within the 1-year follow-up period. The proportion of switching patterns was similar to what was observed in a previously published retrospective claims analysis using the U.S. Humana database, which was used to evaluate biologic switching patterns across rheumatic indications, including rheumatoid arthritis, psoriasis, psoriatic  Given that patients' reasons for switching among TNFis were primarily due to a lack of efficacy or adverse events, 35-37 more than 40% of patients with AS treated with TNFis may initiate add-on therapy with NSAIDs, opioids, corticosteroids, conventional synthetic disease-modifying antirheumatic drugs, antidepressants, anxiolytics, sleeping aids, and topical analgesics. 30 This results in an increase in medication burden and treatment costs; thus, shared decision making between physicians and patients is important to optimize treatment and outcomes. Future studies exploring reasons for switching or discontinuing are warranted, as these may provide a better perspective on selecting more durable treatments.

LIMITATIONS
Despite having several strengths, due to its nature, this study has a few limitations. There is potential for misclassification of clinical characteristics or events, as all data were dependent on claims information. The validity of the analysis related to switching is only sensitive to the accuracy of the data recorded from the claims database. The measurement error around claims for expensive medication is likely low; however, uncertainty around the cost Activity Index and Health Assessment Questionnaire scores, respectively.
In our study, at baseline, switchers had significantly higher health care resource utilization and medical costs compared with nonswitchers, which may suggest that these patients had more complicated disease conditions at baseline. A previous study using a claims database in China reported that patients with AS receiving biologics have the highest direct medical costs compared with those on other conventional therapies. 32 To account for potential confounding of baseline health status, we adjusted for baseline covariates that may represent a patient's need for health care services as a proxy for health status or predictors of future health care utilization (e.g., age, sex, and comorbidities).
Few studies in the United States have reported on health care utilization and costs of switching or discontinuing biologics among patients with AS; therefore, this study provides valuable insight into the financial implications of switching treatments, which is different in switchers versus nonswitchers in the adjusted analysis. Small sample sizes in the switchers group may have precluded the ability to detect significant trends across other health care utilization and costs outcomes in the adjusted analysis. However, adjusting for covariates that may have contributed to a worse clinical state (e.g., age and comorbidities) revealed that discontinuers did have higher medical costs than nonswitchers due to higher outpatient costs from early discontinuation, further supporting that these patients may still have active disease.
Although the reasons for discontinuation or switch were not evaluated in this study, prior studies in patients who discontinued or switched biologics found that the most common reasons were adverse events, lack of treatment effect, or disease progression. [35][36][37][38] Of note, higher disease activity is a predictor of discontinuation 35    Based on the definition of a permissible treatment gap of > 120 days, patients may be misclassified as discontinuers, and this may bias differences in cost estimates toward null.
Our study did not capture data for patients who restarted therapy or their reasons for switch or discontinuation.
Additional long-term analyses of real-world data, as well as analyses linking claims to electronic medical records data, are warranted to corroborate these findings, with the goal of identifying treatments with sustained safety and efficacy to alleviate the clinical and economic burden of switching or discontinuing biologic therapies.