The clinical and economic burdens of metabolic dysfunction-associated steatohepatitis.

AIMS: This study aimed to assess and compare the health care resource utilization (HCRU) and medical cost of metabolic dysfunction-associated steatohepatitis (MASH) by disease severity based on Fibrosis-4 Index (FIB-4) score among US adults in a real-world setting. MATERIALS AND METHODS: This observational cohort study used claims data from the Healthcare Integrated Research Database (HIRD) to compare all-cause, cardiovascular (CV)-related, and liver-related HCRU, including hospitalization, and medical costs stratified by FIB-4 score among patients with MASH (identified by International Classification of Diseases, Tenth Revision, Clinical Modification [ICD-10-CM] code K75.81). Hospitalization and medical costs were compared by FIB-4 score using generalized linear regression with negative binomial and gamma distribution models, respectively, while controlling for confounders. RESULTS: The cohort included a total of 5,104 patients with MASH and comprised 3,162, 1,343, and 599 patients with low, indeterminate, and high FIB-4 scores, respectively. All-cause hospitalization was significantly higher in the high FIB-4 cohort when compared with the low FIB-4 reference after covariate adjustment (rate ratio, 1.63; 95% CI, 1.32-2.02; P<.0001). CV-related hospitalization was similar across all cohorts; however, CV-related costs were 1.26 times higher (95% CI, 1.11-1.45; P<.001) in the indeterminate cohort and 2.15 times higher (95% CI, 1.77-2.62; P<.0001) in the high FIB-4 cohort when compared with the low FIB-4 cohort. Patients with indeterminate and high FIB-4 scores had 2.97 (95% CI, 1.78-4.95) and 12.08 (95% CI, 7.35-19.88) times the rate of liver-related hospitalization and were 3.68 (95% CI, 3.11-4.34) and 33.73 (95% CI, 27.39-41.55) times more likely to incur liver-related costs, respectively (P<.0001 for all). LIMITATIONS: This claims-based analysis relied on diagnostic coding accuracy, which may not capture the presence of all diseases or all care received. CONCLUSIONS: High and indeterminate FIB-4 scores were associated with significantly higher liver-related clinical and economic burdens than low FIB-4 scores among patients with MASH.

MASH is a serious liver disease that can lead to fibrosis, cirrhosis, and other complications. There is a need to understand the impact of disease severity on the burden of MASH. Health care claims data were used to assess the use of medical resources, including hospitalization, and medical costs among patients with 3 different levels of severity of MASH, as assessed via FIB-4 score. FIB-4 is a widely available non-invasive marker of severity. Rates of all-cause, cardiovascular-related and liver-related hospitalization and medical costs were several-fold higher in patients with high disease severity of MASH than those with low disease severity of MASH.

Assessing the Burden and Cost of COVID-19 Across Variants in Commercially Insured Immunocompromised Populations in the United States: Updated Results and Trends from the Ongoing EPOCH-US Study.

INTRODUCTION/METHODS: EPOCH-US is an ongoing, retrospective, observational cohort study among individuals identified in the Healthcare Integrated Research Database (HIRD®) with ≥ 12 months of continuous health plan enrollment. Data were collected for the HIRD population (containing immunocompetent and immunocompromised [IC] individuals), individual IC cohorts (non-mutually exclusive cohorts based on immunocompromising condition and/or immunosuppressive [IS] treatment), and the composite IC population (all unique IC individuals). This study updates previous results with addition of the general population cohort and data specifically for the year of 2022 (i.e., Omicron wave period). To provide healthcare decision-makers the most recent trends, this study reports incidence rates (IR) and severity of first SARS-CoV-2 infection; and relative risk, healthcare utilization, and costs related to first COVID-19 hospitalizations in the full year of 2022 and overall between April 2020 and December 2022. RESULTS: These updated results showed a 2.9% prevalence of immune compromise in the population. From April 2020 through December 2022, the overall IR of COVID-19 was 115.7 per 1000 patient-years in the composite IC cohort and 77.8 per 1000 patient-years in the HIRD cohort. The composite IC cohort had a 15.4% hospitalization rate with an average cost of $42,719 for first COVID-19 hospitalization. Comparatively, the HIRD cohort had a 3.7% hospitalization rate with an average cost of $28,848 for first COVID-19 hospitalization. Compared to the general population, IC individuals had 4.3 to 23 times greater risk of hospitalization with first diagnosis of COVID-19. Between January and December 2022, hospitalizations associated with first COVID-19 diagnosis cost over $1 billion, with IC individuals (~ 3% of the population) generating $310 million (31%) of these costs. CONCLUSION: While only 2.9% of the population, IC individuals had a higher risk of COVID-19 hospitalization and incurred higher healthcare costs across variants. They also disproportionately accounted for over 30% of total costs for first COVID-19 hospitalization in 2022, amounting to ~ $310 million. These data highlight the need for additional preventive measures to decrease the risk of developing severe COVID-19 outcomes in vulnerable IC populations.

Assessing the risk and costs of COVID-19 in immunocompromised populations in a large United States commercial insurance health plan: the EPOCH-US Study.

OBJECTIVE: To estimate the prevalence of patients with an immunocompromising condition at risk for COVID-19, estimate COVID-19 prevalence rate (PR) and incidence rate (IR) by immunocompromising condition, and describe COVID-19-related healthcare resource utilization (HCRU) and costs. METHODS: Using the Healthcare Integrated Research Database (HIRD), patients with ≥1 claim for an immunocompromising condition of interest or ≥2 claims for an immunosuppressive (IS) treatment and COVID-19 diagnosis during the infection period (1 April 2020-31 March 2022) and had ≥12 months baseline data were included. Cohorts (other than the composite cohort) were not mutually exclusive and were defined by each immunocompromising condition. Analyses were descriptive in nature. RESULTS: Of the 16,873,161 patients in the source population, 2.7% (n = 458,049) were immunocompromised (IC). The COVID-19 IR for the composite IC cohort during the study period was 101.3 per 1000 person-years and the PR was 13.5%. The highest IR (195.0 per 1000 person-years) and PR (20.1%) were seen in the end-stage renal disease (ESRD) cohort; the lowest IR (68.3 per 1000 person-years) and PR (9.4%) were seen in the hematologic or solid tumor malignancy cohort. Mean costs for hospitalizations associated with the first COVID-19 diagnosis were estimated at nearly $1 billion (2021 United States dollars [USD]) for 14,516 IC patients, with a mean cost of $64,029 per patient. CONCLUSIONS: Immunocompromised populations appear to be at substantial risk of severe COVID-19 outcomes, leading to increased costs and HCRU. Effective prophylactic options are still needed for these high-risk populations as the COVID-19 landscape evolves.

People who have a medical condition or take a medicine that can suppress their immune system (immunocompromised) have a high risk of getting COVID-19. Our study looked at how many immunocompromised people got COVID-19. We also looked at the costs and lengths of hospital stays for people with COVID-19. We found that 2.7% of the people in this large US population with health insurance were immunocompromised. People who were immunocompromised were more likely to get COVID-19 than people who were not immunocompromised. About 14% of the immunocompromised people in this study got COVID-19 and, of those, 24% were hospitalized. Immunocompromised patients in this study had long hospital stays and high costs associated with COVID-19. The risk of getting COVID-19 and having a severe case seemed to be highest for people with advanced kidney disease. The study results showed that COVID-19 can cause severe health issues in immunocompromised people and the use of vaccinations, medications, and other measures to prevent COVID-19 are especially important for immunocompromised people.

Holistic View of Autografting Patients by Percentage of Total Body Surface Area Burned: Medical Record Abstraction Integrated with Administrative Claims.

Aim: This retrospective observational study provides a holistic view of the clinical and economic characteristics of inpatient treatment of patients with thermal burns undergoing autografting, by integrating real-world data (RWD) from medical records from healthcare providers (HCPs) and administrative claims. Methods: We identified eligible patients between July 1, 2010, and November 30, 2019, from the HealthCore Integrated Research Database® (HIRD®) and obtained their medical records from HCPs. We abstracted data from medical records to describe patient demographics and clinical characteristics and obtained costs of treatment from claims. Results: Two hundred patients were stratified into cohorts based on the percentage of total body surface area (%TBSA) burned: minor (< 10%), moderate (10%-24%), and major (≥ 25%). Data obtained from medical records and administrative claims were comparable to previous findings from administrative claims data. This privately insured study cohort predominantly consisted of White men. Diabetes mellitus and hypertension were frequently reported in a relatively young population. Key clinical characteristics that could influence burn treatment decisions and long-term outcomes, such as body mass index, size of autograft donor site, and mesh ratio, were frequently underdocumented in patients' medical records. Conclusion: Evidence generated from 2 orthogonal RWD sources confirmed that patients with larger %TBSA burned required more intensive care, thereby incurring higher costs. This study highlights considerable incompleteness in many critical fields in medical records, which limits the ability to generate broader insights. More comprehensive documentation of clinical characteristics and outcomes of autografts and donor sites in the operative and medical notes is critical to appropriately evaluate their impact on outcomes of burn treatments in future research using RWD.

Identification of inadequate responders to advanced therapy among commercially-insured adult patients with Crohn's disease and ulcerative colitis in the United States.

BACKGROUND: The purpose of this analysis was to assess the frequency of inadequate response over 1 year from advanced therapy initiation among patients with Crohn's disease (CD) or ulcerative colitis (UC) in the United States using a claims-based algorithm. Factors associated with inadequate response were also analyzed. METHODS: This study utilized claims data of adult patients from the HealthCore Integrated Research Database (HIRD®) from January 01, 2016 to August 31, 2019. Advanced therapies used in this study were tumor necrosis factor inhibitors (TNFi) and non-TNFi biologics. Inadequate response to an advanced therapy was identified using a claims-based algorithm. The inadequate response criteria included adherence, switching to/added a new treatment, addition of a new conventional synthetic immunomodulator or conventional disease-modifying drugs, increase in dose/frequency of advanced therapy initiation, and use of a new pain medication, or surgery. Factors influencing inadequate responders were assessed using multivariable logistic regression. RESULTS: A total of 2437 patients with CD and 1692 patients with UC were included in this analysis. In patients with CD (mean age: 41 years; female: 53%), 81% had initiated TNFi, and 62% had inadequate response. In patients with UC (mean age: 42 years; female: 48%), 78% had initiated a TNFi, and 63% had an inadequate response. In both patients with CD and UC, inadequate response was associated with low adherence (CD: 41%; UC: 42%). Inadequate responders were more likely to be prescribed a TNFi (for CD: odds ratio [OR] = 1.94; p < 0.001; for UC: OR = 2.76; p < 0.0001). CONCLUSION: More than 60% of patients with CD or UC had an inadequate response to their index advanced therapy within 1 year after initiation, mostly driven by low adherence. This modified claims-based algorithm for CD and UC appears useful to classify inadequate responders in health plan claims data.

Costs and Healthcare Resource Utilization for Obstructive Hypertrophic Cardiomyopathy With Septal Reduction Therapy.

BACKGROUND: Patients with obstructive hypertrophic cardiomyopathy (oHCM) and severe refractory symptoms may require invasive septal reduction therapies (SRTs), either surgical septal myectomy (SM) or transcatheter alcohol septal ablation (ASA). The main objective of this study was to quantify all-cause and oHCM-related healthcare resource utilization (HCRU) and costs for patients receiving SM or ASA. METHODS: This retrospective study utilized medical and pharmacy claims submitted during 2012-2020. HCRU and costs for 119 adults with oHCM who had at least 1 SM (n = 95) or ASA (n = 24) were compared for baseline and follow-up periods. RESULTS: The mean inpatient hospitalization stay was longer for SM (8.3 days) than ASA (6.0 days). Postprocedure HCM-related medication usage was greater following SM (98%) than ASA (88%). The mean number of HCM-related outpatient visits increased from pre- to post procedure (12.2 vs 15.9 in the SM group; 7.2 vs 9.5 in the ASA group), with most patients having at least 1 cardiology visit post procedure (86% of the SM group; 83% of the ASA group). Total mean HCM-related costs (reported in United States currency) increased with both procedures ($27,045 vs $119,772 in the SM group; $11,278 vs $54,351 in the ASA group), driven by increased inpatient hospitalization ($10,325 vs $112,923 in the SM group; $5509 vs $47,450 in the ASA group) and surgical costs ($6665 vs $92,031 in the SM group; $52 vs $44,815 in the ASA group). CONCLUSIONS: Our results indicate increasing costs for patients undergoing SRT, driven by inpatient hospitalizations and surgical costs. Commercially insured and Medicare Advantage patients with oHCM experience high healthcare costs and economic burden attributable to SRT.

Identifying inadequate response among patients with ankylosing spondylitis and psoriatic arthritis prescribed advanced therapy in a real-world, commercially insured adult population in the USA.

OBJECTIVE: This study aimed to assess treatment patterns and frequency of inadequate response associated with advanced therapy initiation among patients with ankylosing spondylitis (AS) and psoriatic arthritis (PsA) in the USA. METHODS: Adult patients with AS or PsA who initiated advanced therapy were identified from the HealthCore Integrated Research Database®. Inadequate response to advanced therapies (tumour necrosis factor inhibitors [TNFi] and non-TNFi biologics) was identified using a claims-based algorithm. Factors influencing inadequate response were assessed using multivariable logistic regression. RESULTS: In total, 646 patients with AS, and 1433 patients with PsA were evaluated. Among patients with AS (mean age, 43 years; male, 58%), 93% patients initiated TNFi, and 69% of patients had inadequate response. In patients with PsA (mean age, 49 years; male, 47%), 67% initiated TNFi, and 77% had inadequate response. Low adherence was the main predictor of inadequate response in patients with AS (56%) and PsA (63%). Inadequate responders were more likely to be female (odds ratio [OR] 2.05 for AS and 1.37 for PsA). Prior exposure to TNFi was associated with 3.89- and 2.14-fold greater odds of inadequate response in both AS and PsA patients, respectively, while patients using methotrexate were less likely to have inadequate response (OR 0.48 for AS and 0.72 for PsA; all p < 0.05). CONCLUSIONS: Over 69% of patients with AS and 77% of patients with PsA had inadequate response to their index advanced therapy during 1 year after initiation. Health plan claims data appear useful to classify inadequate responders in AS and PsA. Key Points • Estimating inadequate response to advanced therapies and identifying factors associated with this outcome using claims data could improve treatment outcomes in AS and PsA. • In a sample of commercially insured US patients, over 69% of patients with AS and 77% of patients with PsA had inadequate response to their index advanced therapy during 1 year after initiation. Patient characteristics such as sex and prior therapy use were predictive of inadequate response to advanced therapies. • Health plan claims data appear useful to classify inadequate responders in AS and PsA and identify factors associated with this outcome.

Reduced risk of NSAID-Induced adverse events with concomitant use of misoprostol (MICRO study).

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most frequently used medications for pain, even though they increase the risk for adverse cardiovascular events. OBJECTIVES: The objective of this study was to determine cardiovascular, cerebrovascular, and renal event rates between NSAIDs versus NSAIDs plus misoprostol. METHODS: A population-based historical cohort of U.S. veterans receiving prescription NSAIDs (1,681,609) versus NSAIDs plus misoprostol (5972 misoprostol users) was followed for 5 years. In an intent-to-treat analysis, NSAID and NSAID plus misoprostol groups were compared using propensity score-weighted Poisson regression models to estimate incident rate ratio (IRR) and Cox regression to estimate hazard ratio (HR). RESULTS: The most prescribed NSAIDs were diclofenac and ibuprofen. The mean follow-up was 35.2 ± 14.5 months. There were 439 total cardio-renal events (5.62/1000 patient-months) in the NSAID group and 419 patients (5.01/1000 patient-months) in the NSAID plus misoprostol group (Hazard Ratio (HR): 0.89; 95% confidence interval [CI]: 0.78-1.019; p = 0.09). The risk of cardiovascular event was lower in the NSAID plus misoprostol group (HR: 0.56; 95% CI: 0.34-0.93; p < 0.0001). Cerebrovascular event rates were lower in the NSAID plus misoprostol group (HR: 0.74; 95% CI: 0.60-0.94, p < 0.0001) and for renal (HR: 0.67; 95% CI: 0.49-0.89, p < 0.0001) events. All-cause mortality rate was not different between the two groups (HR: 1.05; 95% CI: 0.88-1.25, p = 0.61). CONCLUSION: Compared with NSAID use alone, the concomitant use of NSAID plus misoprostol is associated with a reduced risk of NSAID-induced cardiovascular, cerebrovascular, and renal adverse events. These data support the development of a safer NSAID when combined with misoprostol.

Characteristics of Patients With Obstructive Hypertrophic Cardiomyopathy in Real-World Community-Based Cardiovascular Practices.

The clinical profile of patients with obstructive hypertrophic cardiomyopathy (oHC) is not well characterized, with little evidence outside selected referral populations. Using longitudinal medical claims data from a United States nationwide database, we retrospectively identified adults who were newly diagnosed with oHC. Clinical characteristics were compared from 1 year before diagnosis and at the 2-year follow-up. Patients (N = 1,841) with oHC (age 63 ± 15 years; 52% were male) with geographic representation across the United States were identified. Most patients received care within community-based cardiovascular practices and 7% at referral hypertrophic cardiomyopathy (HC) centers. Baseline diagnostic procedures included electrocardiogram (66%), echocardiogram (51%), magnetic resonance imaging (4%), and HC genetic testing (0.7%). Baseline co-morbidities were hypertension (59%), coronary artery disease (30%), diabetes (19%), and atrial fibrillation (19%). For all HC-related medications, use significantly increased after diagnosis. During follow-up, 144 patients (8%) received an implantable cardioverter-defibrillator for sudden death prevention, 99 underwent septal myectomy (5%), and 24 underwent alcohol septal ablation (1%). By the 1-year follow-up, 2% of patients had sudden cardiac arrest and 26% had atrial fibrillation, and heart failure increased from 16% to 27%. In conclusion, in a community-based population of patients with oHC, patients' age at diagnosis of oHC was older than reported for referral populations and patients had a significant co-morbidity burden. Cardiovascular medication use was appropriate, but the rate of guideline-supported surgical procedures was low.

Healthcare resource utilization and cost of obstructive hypertrophic cardiomyopathy in a US population.

Background: There are limited data evaluating all-cause and disease-related healthcare resource utilization (HCRU) and cost of care for patients with obstructive hypertrophic cardiomyopathy (oHCM). Methods: This was a retrospective study using US longitudinal medical and pharmacy claims data during 2012-2020. Adults with ≥2 oHCM diagnoses were identified, with the first diagnosis date used as the index date. HCRU and costs of care were reported for the year preindex (baseline) and at 1- and 2-year follow-ups. Results: We identified 1841 patients with oHCM (63 ± 15 years; 52% male). The mean number of hypertrophic cardiomyopathy (HCM)-related outpatient and cardiology visits increased from baseline to 1-year follow-up (2.3 vs. 7.8 and 0.6 vs. 2.2, respectively). At baseline, 8% of patients had ≥1 HCM-related inpatient hospitalization (mean 0.11 visits, 5.4 days length of stay), increasing to 27% postdiagnosis (mean 0.42 visits, 5.9 days length of stay). Total HCM-related costs increased from $5968 to $20,290 at 1-year follow-up, largely driven by inpatient hospitalization costs ($3889 vs. $14,369) and surgical costs ($2259 vs. $7217). The proportion with ≥1 HCM-related prescription increased from baseline (69%; mean fills 5.3) to 1-year follow-up (82%; mean fills 7.8). Pharmacy costs were generally low but also increased ($449 vs. $752). Conclusions: This benchmark economic dataset for management and evaluation of patients with oHCM shows increased HCM-related costs over a 2-year period after oHCM diagnosis, driven by inpatient hospitalizations and surgical costs. Medication use was high, but costs were low, possibly reflecting use of generic multi-indication drugs for oHCM treatment.

Clinical Diagnosis of Hypertrophic Cardiomyopathy Over Time in the United States (A Population-Based Claims Analysis).

Hypertrophic cardiomyopathy (HC) is a common genetic heart disease. However, the number of gene mutation carriers who develop HC and manifest clinical symptoms is not well established. Our objective was to estimate annual prevalence and incidence rates of clinically diagnosed HC in the United States. Data from the HealthCore Integrated Research Database (HIRD) were interrogated for years 2013-2019 to identify patients with ≥1 claim of HC International Classification of Diseases, Clinical Modification Ninth and Tenth Revision diagnosis codes. In 2013, among 16,243,109 patients, 8,526 were identified with HC, yielding an estimated prevalence of clinically diagnosed HC of 0.052% (0.035% for obstructive [oHC], 0.017% for nonobstructive [nHC]). This prevalence yielded an estimated 164,403 patients with clinical diagnosis of HC. For the same year, the incidence of new HC diagnoses was 0.030% (0.020% for oHC, 0.010% for nHC). Over the following 6 years, prevalence and incidence of HC increased by 0.005%/year (p <0.01) and 0.001%/year (p <0.01), respectively, with an estimated 262,591 patients with a clinical diagnosis of HC in 2019. Over this period, incidence of nHC increased (0.012% vs 0.026%, p <0.01), whereas incidence of oHC decreased (0.020% versus 0.015%, p <0.01). In conclusion, over 6 years, the number of patients with clinically diagnosed HC in the United States increased 1.5-fold to ∼262,591, primarily because of a rise in nHC diagnoses. These prevalence data support further investigation to better understand factors accounting for increasing clinical recognition of HC.

Dulaglutide Shows Sustained Reduction in Glycosylated Hemoglobin Values: 2-Year US Real-world Study Results.

PURPOSE: Due to the chronic and progressive nature of type 2 diabetes mellitus (T2DM), it is important to understand the long-term outcomes associated with antihyperglycemic medications. There are currently few long-term studies evaluating the real-world effectiveness of dulaglutide, a glucagon-like peptide-1 receptor agonist. The primary objective of this retrospective observational study was to evaluate glycemic control over a 24-month follow-up period among dulaglutide initiators with continuous treatment. The study used US claims data from the HealthCore Integrated Research Database between May 2014 and May 2019. METHODS: Patients were included if they were ≥18 years old with T2DM and had ≥1 pharmacy claim for dulaglutide during the index period between November 2014 and May 2017 (with index date = set as the earliest dulaglutide fill during index period), continuous enrollment in the 6 months' preindex and 24 months' postindex, ≥1 claim for dulaglutide or ≥60 days' supply in every quarter during the 24-month follow-up period, and ≥1 glycosylated hemoglobin (HbA1c) result at both baseline and 24 months. FINDINGS: At baseline, 872 patients (47.5% female) had a mean (SD) age of 54.5 (8.2) years and an HbA1c value of 8.68% (1.8%) (71.36 [19.7] mmol/mol). More than two thirds were being treated for dyslipidemia, hypertension, or cardiovascular disease. A significant HbA1c reduction was observed from baseline to 24 months (-1.3% [-14.2 mmol/mol]; P < 0.0001) for dulaglutide initiators with continuous treatment. A significant reduction in HbA1c level was also observed for all prespecified subgroups (age, index dulaglutide dose [0.75 mg or 1.5 mg], insulin use, sodium-glucose co-transporter 2 inhibitor use, and dipeptidyl peptidase-4 inhibitor use; all, P < 0.0001). Forty-three percent of patients achieved an HbA1c value < 7% (53 mmol/mol), and 73% achieved an HbA1c value < 8% (64 mmol/mol) at 24 months. Most (520 [59.6%]) patients were initiated on dulaglutide 0.75 mg. Of these patients, 70% increased to dulaglutide 1.5 mg during follow-up. The mean time to first dose change was 242 (196) days for 0.75 mg-1.5 mg and 225 (160) days for 1.5 mg-0.75 mg. Antihyperglycemic medication use preindex/postindex included: insulin, 28%/35%; dipeptidyl peptidase-4 inhibitors, 37%/20%; and sodium-glucose co-transporter 2 inhibitors, 29%/44%. IMPLICATIONS: In this real-world study among dulaglutide initiators with continuous treatment, a clinically significant reduction in HbA1c value was seen at the 3-month assessment and persisted for up to 24 months. These data support the use of dulaglutide as an effective long-term treatment for T2DM in clinical practice.

Tumour necrosis factor inhibitor exposure and radiographic outcomes in Veterans with rheumatoid arthritis: a longitudinal cohort study.

OBJECTIVES: The aim was to estimate the impact of TNF inhibitor (TNFi) exposure on radiographic disease progression in US Veterans with RA during the first year after initiating therapy. METHODS: This historical longitudinal cohort design used clinical and claims data to evaluate radiographic progression after initiation of TNFi. US Veterans with RA initiating TNFi treatment (index date), ≥ 6 months pre-index and ≥ 12 months post-index VA enrolment/activity, and initial (6 months pre-index to 30 days post-index) and follow-up (10-18 months post-index) bilateral hand radiographs were eligible. The cumulative TNFi exposure and change in modified Sharp score (MSS) between initial and follow-up radiographs were calculated. The percentage of patients with clinically meaningful change in MSS (≥ 5) for each month of exposure was assessed using a longitudinal marginal structural model with inverse probability of treatment weights. Mean values and CIs were generated using 1000 bootstrapped samples. RESULTS: For 246 eligible patients, the mean (s.d.) age was 58 (11) years; 81% were male. The mean (s.d.) initial MSS was 19.6 (33.4) (range 0-214). The mean change (s.d.) in MSS was 0.3 (3.6) (median 0, range -19 to 22). Patients with the greatest exposure had the least radiographic progression for both crude and adjusted model analyses. Adjusted rates of MSS change ≥ 5 points (95% CI) were 10.6% (9.8%, 11.4%) for patients with 3 months of exposure compared with 5.4% (5.1%, 5.7%) for patients with 12 months of exposure. CONCLUSION: One-year changes in radiographic progression were small. Patients with the greatest cumulative TNFi exposure experienced the least progression.

Biologic and Glucocorticoid Use after Methotrexate Initiation in Patients with Rheumatoid Arthritis.

OBJECTIVE: Biologic therapies can improve disease control for patients with rheumatoid arthritis (RA) but may be both overused and underused. We aimed to identify predictors of greater use of biologic therapies and to identify factors associated with persistent glucocorticoid use. METHODS: Using national US Veteran's Affairs databases 2005-2016, we identified patients with RA receiving a first-ever prescription of methotrexate (MTX), requiring ≥ 6 months of baseline data. We evaluated predictors of biologic therapy initiation within 2 years of starting MTX and factors associated with baseline and persistent glucocorticoid use at 6-12 months using multivariable models. RESULTS: Among 17,415 patients starting MTX, 3263 patients received biologic therapy within 2 years (20.6% 2-yr incidence). In adjusted analyses, biologic use was substantially lower in older patients [e.g., aHR 0.20 (95% CI 0.16, 0.26) for patients ≥ 80 vs < 50] and patients with more comorbidities [aHR 0.79 (95% CI 0.72, 0.87) for Charlson score ≥ 3 vs < 3]. Patients with heart failure [aHR 0.68 (95% CI 0.54, 0.84)], cancer [aHR 0.78 (95% CI 0.66, 0.92)], or who were nonwhite [aHR 0.79 (95% CI 0.72, 0.87)] were also less likely to receive a biologic. In contrast, baseline and persistent glucocorticoid use was similar across age groups and more common in patients with greater comorbidity. CONCLUSION: Biologic therapy is initiated less frequently in patients with RA who are older, have more comorbidities, and who are nonwhite. While biologics may be avoided in older and sicker patients because of safety concerns, glucocorticoid use is similar regardless of age and is more frequent in patients with comorbidities, with implications for patient outcomes.

Low Persistence Rates in Patients With Rheumatoid Arthritis Treated With Triple Therapy and Adverse Drug Events Associated With Sulfasalazine.

OBJECTIVE: Combination treatments for patients with rheumatoid arthritis (RA) with an inadequate response to methotrexate (MTX) alone include the addition of a tumor necrosis factor inhibitor (TNFi) or the addition of sulfasalazine (SSZ) and hydroxychloroquine to MTX (triple therapy). We compared persistence and adherence rates between these 2 combination therapies in US veterans and report the reasons for discontinuation of combination treatment in these groups. METHODS: Using Veteran's Affairs clinical and administrative data from 2006 to 2012, veterans with RA escalating treatment from MTX to MTX-TNFi or triple therapy were examined for a 12-month period after combination initiation. Persistence was defined as treatment without a ≥90-day gap in therapy. Adherence was calculated using the proportion of days covered ≥80% at 12 months. Matching weights-adjusted models were applied to more closely mimic randomization in this study. The reasons that patients discontinued their combination regimens were identified by chart abstraction. RESULTS: Full persistence at 1 year was 45% in the MTX-TNFi patients (n = 2,125) and 18% in the triple therapy patients (n = 171) (P < 0.001). Adherence was higher for the MTX-TNFi group (26%) than the triple therapy group (11%) (P < 0.0001). The triple therapy group was associated with significantly more treatment discontinuation, which was most often due to adverse drug events from SSZ. CONCLUSION: Differences in persistence and adherence between the MTX-TNFi and triple therapy groups appear to be primarily related to adverse drug events that were most often attributed to SSZ.

Utility of administrative and clinical data to predict major change in medical treatment in US Veterans enrolled in the Veterans Affairs Rheumatoid Arthritis (VARA) registry.

OBJECTIVES: To examine factors associated with major therapeutic changes (MTC) among US Veterans with moderate/severe rheumatoid arthritis (RA) based on Disease Activity Score based on 28 joints (DAS28). METHODS: We used data from patients enrolled in the Veterans Affairs Rheumatoid Arthritis (VARA) registry from 1/1/2006 through 12/31/2014. The index date was a clinic visit with DAS28 >3.2 (moderate/severe disease) following an 18-month pre-index period that included ≥2 DAS28 measurements ≥60 days apart. The patients were followed for MTC from 7 days pre-index through 90 days post-index. Poisson multivariable regression models were used to identify associations with MTC. Chart review of a subset of randomly selected patients explored factors that impacted therapeutic decisions. RESULTS: Among 941 patients, 396 (42.1%) had MTC. Of these, 369 (39.2%) patients had worsening DAS28 at index, 118 (12.5%) had DAS28 improvements, and 454 (48.2%) patients had no change in DAS28 versus pre-index DAS28. Of the patients with worsening DAS28, no change in DAS28, and improved DAS28, respectively, 50.5%, 62.6%, and 70.3% had no MTC. Regression analyses showed index DAS28, oral steroid or non-biologic disease-modifying anti-rheumatic drug (nbDMARD) use in the previous year were associated with an increased likelihood of MTC; use of nbDMARDs in the previous 90 days was associated with a decreased likelihood of MTC. The most common reason for not modifying therapy despite DAS28 >3.2 was a judgement of mild disease. CONCLUSIONS: Clinicians frequently do not institute major therapeutic changes despite DAS28 indicating moderate/severe disease activity; multiple factors are involved in real-world treatment decisions.

Body mass index and persistence of conventional DMARDs and TNF inhibitors in rheumatoid arthritis.

OBJECTIVES: Obese patients with rheumatoid arthritis (RA) may be more likely to discontinue therapy than non-obese patients, possibly signifying a more refractory phenotype. The purpose of this study was to examine the association between body mass index (BMI) and discontinuation rates for different RA treatments accounting for confounding factors. METHODS: Veterans Affairs administrative databases were used to define initial courses of methotrexate (MTX), hydroxychloroquine, sulfasalazine, prednisone, and self-injectable tumour necrosis factor inhibitors (TNFi). Discontinuation was defined as a lapse in drug refill >90 days. Using overweight BMI (25-30 kg/m2) as the referent group, multivariable Cox proportional hazards models were used to evaluate associations between BMI category and time to treatment discontinuation. RESULTS: There were 46,970 initial RA treatment courses identified from 2005-2014 among 23,669 Veterans with RA. In multivariable models, severe obesity (BMI >35 kg/m2), compared to overweight BMI, was not associated with treatment discontinuation with the exception of prednisone [HR 1.10 (1.04, 1.17) p<0.001]. Patients with low (<20 kg/m2) and normal BMI (20-25 kg/m2) were more likely to discontinue MTX, TNFi, and HCQ compared to overweight patients. Other factors associated with earlier MTX and/or TNFi discontinuation included female sex, black race, greater comorbidity, depression, malignancy, congestive heart failure, current smoking, and more recent calendar year. CONCLUSIONS: Obesity was not associated with therapy discontinuation among veterans with RA after accounting for confounding factors, suggesting that obesity is not a biological mediator of more refractory disease. Conversely, low BMI, comorbidity, and depression were identified as important predictors of drug discontinuation.

Initiation of Disease-Modifying Therapies in Rheumatoid Arthritis Is Associated With Changes in Blood Pressure.

PURPOSE: This study reports the effect of disease-modifying therapies for rheumatoid arthritis (RA) on systolic and diastolic blood pressure (SBP, DBP) over 6 months and incident hypertension over 3 years in a large administrative database. METHODS: We used administrative Veterans Affairs databases to define unique dispensing episodes of methotrexate, leflunomide, sulfasalazine, hydroxychloroquine, tumor necrosis factor inhibitors, and prednisone among patients with RA. Changes in SBP and DBP in the 6 months before disease-modifying antirheumatic drug initiation were compared with changes observed in the 6 months after initiation. The risk of incident hypertension within 3 years (new diagnosis code for hypertension and prescription for antihypertensive) was also assessed. Multivariable models and propensity analyses assessed the impact of confounding by indication. RESULTS: A total of 37,900 treatment courses in 21,216 unique patients contributed data. Overall, there were no changes in SBP or DBP in 6 months prior to disease-modifying antirheumatic drug initiation (all P > 0.62). In contrast, there was a decline in SBP (ß = -1.08 [-1.32 to -0.85]; P < 0.0001) and DBP (ß = -0.48 [-0.62 to -0.33]; P < 0.0001) over the 6 months following initiation. The greatest decline was observed among methotrexate and hydroxychloroquine users. Methotrexate users were 9% more likely to have optimal blood pressure (BP) after 6 months of treatment. Patients treated with leflunomide had increases in BP and a greater risk of incident hypertension compared with patients treated with methotrexate (hazard ratio, 1.53 [1.21-1.91]; P < 0.001). CONCLUSIONS: Blood pressure may improve with treatment of RA, particularly with methotrexate or hydroxychloroquine. Leflunomide use, in contrast, is associated with increases in BP and a greater risk of incident hypertension.

Evaluation of the Case-Crossover (CCO) Study Design for Adverse Drug Event Detection.

INTRODUCTION: The case-crossover (CCO) design was originally intended to study exposures characterized as intermittent with acute effects. The performance of the CCO design is not well characterized under alternative exposure and outcome relationships. OBJECTIVE: The purpose of this study was to evaluate the ability of the CCO to identify simulated treatment effects under different drug exposures and outcomes relationships while varying the duration of the 1:1 matched risk and control windows. METHODS: The simulated data were obtained from the Observational Medical Dataset Simulator, version 2 (OSIM2). The area under the receiver operator characteristic curve (AUC) was calculated to compare CCO performance across outcome types, simulated relative risk (RR), and duration of risk and control windows. RESULTS: The AUC for acute outcomes was higher for shorter risk and control windows and improved with higher simulated RR. For example, the AUC for the simulated RR of 4 was 0.95 for a 30-day window length and 0.78 for a 360-day window length. The AUC for the accumulative outcomes increased with longer risk and control windows and stronger simulated RR. For example, the AUC for the simulated RR of 4 was 0.85 for a 360-day window length and 0.23 for a 30-day window length. Risk and control window lengths did not appear to sufficiently alter the AUC for insidious onset outcomes. CONCLUSIONS: The CCO performed best for acute-onset outcomes, but may be useful for exploring adverse outcomes with accumulative effects. Careful consideration must be given to the hypothesized drug exposure and outcome distribution because specification of risk and control window duration affects CCO performance.

Models solely using claims-based administrative data are poor predictors of rheumatoid arthritis disease activity.

BACKGROUND: This study developed and validated a claims-based statistical model to predict rheumatoid arthritis (RA) disease activity, measured by the 28-joint count Disease Activity Score (DAS28). METHOD: Veterans enrolled in the Veterans Affairs Rheumatoid Arthritis (VARA) registry with one year of data available for review before being assessed by the DAS28, were studied. Three models were developed based on initial selection of variables for analyses. The first model was based on clinically defined variables, the second leveraged grouping systems for high dimensional data and the third approach prescreened all possible predictors based on a significant bivariate association with the DAS28. The least absolute shrinkage and selection operator (LASSO) with fivefold cross-validation was used for variable selection and model development. Models were also compared for patients with <5 years to those ≥5 years of RA disease. Classification accuracy was examined for remission (DAS28 < 2.6) and for low (2.6-3.1), moderate (3.2-5.1) and high (>5.1) activity. RESULTS: There were 1582 Veterans who fulfilled inclusion criteria. The adjusted r-square for the three models tested ranged from 0.221 to 0.223. The models performed slightly better for patients with <5 years of RA disease than for patients with ≥5 years of RA disease. Correct classification of DAS28 categories ranged from 39.9% to 40.5% for the three models. CONCLUSION: The multiple models tested showed weak overall predictive accuracy in measuring DAS28. The models performed poorly at predicting patients with remission and high disease activity. Future research should investigate components of disease activity measures directly from medical records and incorporate additional laboratory and other clinical data.