Incidence of checkpoint inhibitor-associated inflammatory arthritis, immunomodulation and mortality in cancer patients on immunotherapy: a retrospective cohort study.

OBJECTIVES: Immune checkpoint inhibitor (ICI) associated inflammatory arthritis (ICI-IA) occurs in 4-6% of ICI-treated patients based on one observational study. We identified cases of ICI-IA using administrative claims to study its incidence and characteristics at the population level. METHODS: We used the Medicare 5% sample to identify patients initiating ICIs. Cancer patients were identified by having ≥ 2 ICD-9/10-CM diagnosis codes from an oncologist for lung cancer, melanoma, or renal/urothelial cancer. ICI-IA was defined as having two Medicare claims ≥ 30 days apart with combinations of ICD-9/10-CM diagnosis codes that favored specificity. ICI-IA was identified in patients with a musculoskeletal diagnosis after ICI initiation, who had i.) no inflammatory arthritis or inflammatory rheumatic disease before ICI initiation ever, and ii) no musculoskeletal complaint in the one year prior to ICI. We examined DMARD utilization and visits to rheumatology in patients with ICI-IA. Landmark analysis and a time varying Cox proportional hazards model for overall survival was constructed. RESULTS: The incidence of ICI-IA was 7.2 (6.1-8.4) per 100 patient years. Patients with ICI-IA were mean (SD) age 73.5(7.0) years, 48% women, 91% white. Median(IQR) time from ICI initiation to first ICI-IA diagnosis was 124(56, 252) days. Only 24(16%) received care from a rheumatologist, and 24(16%) were prescribed a DMARD (46% by a rheumatologist). The HR for mortality in patients with ICI-IA was 0.86 (95% CI 0.59-1.26, p= 0.45). CONCLUSIONS: The incidence of ICI-IA identified in claims data is similar to that reported in observational studies, however, few patients are treated with a DMARD or see a rheumatologist. There was no difference in overall survival between ICI-treated patients with and without ICI-IA.

Identifying inpatient mortality in MarketScan claims data using machine learning.

PURPOSE: Inpatient mortality is an important variable in epidemiology studies using claims data. In 2016, MarketScan data began obscuring specific hospital discharge status types for patient privacy, including inpatient deaths, by setting the values to missing. We used a machine learning approach to correctly identify hospitalizations that resulted in inpatient death using data prior to 2016. METHODS: All hospitalizations from 2011 to 2015 with discharge status of missing, died, or one of the other subsequently obscured values were identified and divided into a training set and two test sets. Predictor variables included age, sex, elapsed time from hospital discharge until last observed claim and until healthcare plan disenrollment, and absence of any discharge diagnoses. Four machine learning methods were used to train statistical models and assess sensitivity and positive predictive value (PPV) for inpatient mortality. RESULTS: Overall 1 307 917 hospitalizations were included. All four machine learning approaches performed well in all datasets. Random forest performed best with 88% PPV and 93% sensitivity for the training set and both test sets. The two factors with the highest relative importance for identifying inpatient mortality were having no observed claims for the patient on days 2-91 following hospital discharge and patient disenrollment from the healthcare plan within 60 days following hospital discharge. CONCLUSION: We successfully developed machine learning algorithms to identify inpatient mortality. This approach can be applied to obscured data to accurately identify inpatient mortality among hospitalizations with missing discharge status.

Accuracy of administrative claims prescription fill data to estimate glucocorticoid use and dose in patients with rheumatoid arthritis.

PURPOSE: To assess accuracy of administrative claims prescription fill-based estimates of glucocorticoid use and dose, and approximate bias from glucocorticoid exposure misclassification. METHODS: We identified adults with rheumatoid arthritis with linked Medicare and CorEvitas registry data. An algorithm identifying glucocorticoid use and average dose over 90 days from Medicare prescription fills was compared to physician-reported measures from a CorEvitas visit during the same period, using weighted kappa to compare doses (none, ≤5 mg, 5-10 mg, >10 mg/day). A deterministic sensitivity analysis examined the effect of exposure misclassification on estimated glucocorticoid-associated infection risk from a prior study. RESULTS: We identified 621 observations among 494 patients. Prescription fills identified glucocorticoid use in 41.9% of observations versus 31.1% identified by CorEvitas physician-report. For glucocorticoid use (yes/no), prescription fills had sensitivity 88.1% (95% CI 82.7-92.3), specificity 79.0% (74.8-82.7), PPV 65.4% (59.3-71.2), NPV 93.6% (90.6-95.9), and 81.8% agreement with CorEvitas, with kappa 0.61 (moderate to substantial agreement). There was 89.5% agreement between prescription fills and physician-reported doses, with weighted kappa 0.56 (moderate agreement). Applying these results to a prior Medicare study evaluating glucocorticoid-associated infection risk [risk ratio 1.44 (95% CI 1.41-1.48)] led to an externally adjusted risk ratio of 1.74 when accounting for exposure misclassification, representing -17% bias in infection risk estimate. CONCLUSIONS: This study supports the use of claims data to estimate glucocorticoid use and dose, but investigators should account for exposure misclassification, which may lead to underestimates of glucocorticoid risks. Our results could be applied to adjust risk estimates in other studies that use prescription fills to estimate glucocorticoid use.

Using pooled electronic health records data to conduct pharmacoepidemiology safety studies: Challenges and lessons learned.

PURPOSE: We assessed the suitability of pooled electronic health record (EHR) data from clinical research networks (CRNs) of the patient-centered outcomes research network to conduct studies of the association between tumor necrosis factor inhibitors (TNFi) and infections. METHODS: EHR data from patients with one of seven autoimmune diseases were obtained from three CRNs and pooled. Person-level linkage of CRN data and Centers for Medicare and Medicaid Services (CMS) fee-for-service claims data was performed where possible. Using filled prescriptions from CMS claims data as the gold standard, we assessed the misclassification of EHR-based new (incident) user definitions. Among new users of TNFi, we assessed subsequent rates of hospitalized infection in EHR and CMS data. RESULTS: The study included 45 483 new users of TNFi, of whom 1416 were successfully linked to their CMS claims. Overall, 44% of new EHR TNFi prescriptions were not associated with medication claims. Our most specific new user definition had a misclassification rate of 3.5%-16.4% for prevalent use, depending on the medication. Greater than 80% of CRN prescriptions had either zero refills or missing refill data. Compared to using EHR data alone, there was a 2- to 8-fold increase in hospitalized infection rates when CMS claims data were added to the analysis. CONCLUSIONS: EHR data substantially misclassified TNFi exposure and underestimated the incidence of hospitalized infections compared to claims data. EHR-based new user definitions were reasonably accurate. Overall, using CRN data for pharmacoepidemiology studies is challenging, especially for biologics, and would benefit from supplementation by other sources.

Risk of Serious Infection With Low-dose Glucocorticoids in Patients With Rheumatoid Arthritis: An Instrumental Variable Analysis.

BACKGROUND: Low-dose glucocorticoids are commonly used in the treatment of rheumatoid arthritis (RA). Observational studies have found an increased risk of serious infection associated with low-dose glucocorticoids, but concerns about residual confounding remain. METHODS: We identified adults with RA on stable immunomodulatory therapy for >6 months receiving no glucocorticoids or ≤5 mg/day using Medicare data from 2006 to 2015. We used provider preference for glucocorticoids as an instrumental variable (IV) to assess associations between low-dose glucocorticoid use and the risk of infection requiring hospitalization using a cause-specific proportional hazards model. RESULTS: We identified 163,603 qualifying treatment episodes among 120,656 patients. Glucocorticoids ≤5 mg/day were used by 25,373/81,802 (31.0%) of patients seen by a rheumatologist with low provider preference for glucocorticoids and by 36,087/81,801 (44.1%) of patients seen by a rheumatologist with high provider preference for glucocorticoids (adjusted odds ratio 1.81, 95% confidence interval 1.77, 1.84 for association between provider preference and glucocorticoids). Chronic obstructive pulmonary disease, opioids, antibiotics, previous emergency department visits, hospitalizations, and infections requiring hospitalization infections were unbalanced with regard to exposure but not to the IV. The incidence of infection requiring hospitalization was 8.0/100 person-years among patients unexposed to glucocorticoids versus 11.7/100 person-years among those exposed. The association between glucocorticoids and infection requiring hospitalization from IV analysis (hazard ratio 1.26 [1.02-1.56]) was similar to results from a standard multivariable model (hazard ratio 1.24 [1.21-1.28]). CONCLUSIONS: Among patients with RA on stable immunomodulatory therapy, IV analysis based on provider preference demonstrated an increased risk of infection requiring hospitalization associated with low-dose glucocorticoids, similar to a traditional analysis.

Oral Glucocorticoids and Incident Treatment of Diabetes Mellitus, Hypertension, and Venous Thromboembolism in Children.

Rates of incident treatment were quantified in this study for diabetes mellitus, hypertension, and venous thromboembolism (VTE) associated with oral glucocorticoid exposure in children aged 1-18 years. The retrospective cohort included more than 930,000 children diagnosed with autoimmune diseases (namely, inflammatory bowel disease, juvenile idiopathic arthritis, or psoriasis) or a nonimmune comparator condition (attention-deficit/hyperactivity disorder) identified using US Medicaid claims (2000-2010). Associations of glucocorticoid dose per age- and sex-imputed weight with incident treated diabetes, hypertension, and VTE were estimated using Cox regression models. Crude rates were lowest for VTE (unexposed: 0.5/million person-days (95% confidence interval (CI): 0.4, 0.6); currently exposed: 15.6/million person-days (95% CI: 11.8, 20.1)) and highest for hypertension (unexposed: 6.7/million person-days (95% CI: 6.5, 7.0); currently exposed: 74.4/million person-days (95% CI: 65.7, 83.9)). Absolute rates for all outcomes were higher in unexposed and exposed children with autoimmune diseases compared with those with attention-deficit/hyperactivity disorder. Strong dose-dependent relationships were found between current glucocorticoid exposure and all outcomes (adjusted hazard ratios for high-dose glucocorticoids: for diabetes mellitus, 5.93 (95% CI: 3.94, 8.91); for hypertension, 19.13 (95% CI: 15.43, 23.73); for VTE, 16.16 (95% CI: 8.94, 29.22)). These results suggest strong relative risks, but low absolute risks, of newly treated VTE, diabetes, and especially hypertension in children taking high-dose oral glucocorticoids.

Burden and trajectory of multimorbidity in rheumatoid arthritis: a matched cohort study from 2006 to 2015.

OBJECTIVES: To compare the onset and trajectory of multimorbidity between individuals with and without rheumatoid arthritis (RA). METHODS: A matched, retrospective cohort study was completed in a large, US commercial insurance database (MarketScan) from 2006 to 2015. Using validated algorithms, patients with RA (overall and incident) were age-matched and sex-matched to patients without RA. Diagnostic codes for 44 preidentified chronic conditions were selected to determine the presence (≥2 conditions) and burden (count) of multimorbidity. Cross-sectional comparisons were completed using the overall RA cohort and conditional logistic and negative binomial regression models. Trajectories of multimorbidity were assessed within the incident RA subcohort using generalised estimating equations. RESULTS: The overall cohort (n=277 782) and incident subcohort (n=61 124) were female predominant (76.5%, 74.1%) with a mean age of 55.6 years and 54.5 years, respectively. The cross-sectional prevalence (OR 2.29, 95% CI 2.25 to 2.34) and burden (ratio of conditions 1.68, 95% CI 1.66 to 1.70) of multimorbidity were significantly higher in RA than non-RA in the overall cohort. Within the incident RA cohort, patients with RA had more chronic conditions than non-RA (ß 1.13, 95% CI 1.10 to 1.17), and the rate of accruing chronic conditions was significantly higher in RA compared with non-RA (RA × follow-up year, ß 0.21, 95% CI 0.20 to 0.21, p<0.001). Results were similar when including the pre-RA period and in several sensitivity analyses. CONCLUSIONS: Multimorbidity is highly prevalent in RA and progresses more rapidly in patients with RA than in patients without RA during and immediately following RA onset. Therefore, multimorbidity should be aggressively identified and targeted early in the RA disease course.

Risk for Serious Infection With Low-Dose Glucocorticoids in Patients With Rheumatoid Arthritis : A Cohort Study.

BACKGROUND: Low-dose glucocorticoids are frequently used for the management of rheumatoid arthritis (RA) and other chronic conditions, but the safety of long-term use remains uncertain. OBJECTIVE: To quantify the risk for hospitalized infection with long-term use of low-dose glucocorticoids in patients with RA receiving stable disease-modifying antirheumatic drug (DMARD) therapy. DESIGN: Retrospective cohort study. SETTING: Medicare claims data and Optum's deidentified Clinformatics Data Mart database from 2006 to 2015. PATIENTS: Adults with RA receiving a stable DMARD regimen for more than 6 months. MEASUREMENTS: Associations between glucocorticoid dose (none, ≤5 mg/d, >5 to 10 mg/d, and >10 mg/d) and hospitalized infection were evaluated using inverse probability-weighted analyses, with 1-year cumulative incidence predicted from weighted models. RESULTS: 247 297 observations were identified among 172 041 patients in Medicare and 58 279 observations among 44 118 patients in Optum. After 6 months of stable DMARD use, 47.1% of Medicare patients and 39.5% of Optum patients were receiving glucocorticoids. The 1-year cumulative incidence of hospitalized infection in Medicare patients not receiving glucocorticoids was 8.6% versus 11.0% (95% CI, 10.6% to 11.5%) for glucocorticoid dose of 5 mg or less per day, 14.4% (CI, 13.8% to 15.1%) for greater than 5 to 10 mg/d, and 17.7% (CI, 16.5% to 19.1%) for greater than 10 mg/d (all P < 0.001 vs. no glucocorticoids). The 1-year cumulative incidence of hospitalized infection in Optum patients not receiving glucocorticoids was 4.0% versus 5.2% (CI, 4.7% to 5.8%) for glucocorticoid dose of 5 mg or less per day, 8.1% (CI, 7.0% to 9.3%) for greater than 5 to 10 mg/d, and 10.6% (CI, 8.5% to 13.2%) for greater than 10 mg/d (all P < 0.001 vs. no glucocorticoids). LIMITATION: Potential for residual confounding and misclassification of glucocorticoid dose. CONCLUSION: In patients with RA receiving stable DMARD therapy, glucocorticoids were associated with a dose-dependent increase in the risk for serious infection, with small but significant risks even at doses of 5 mg or less per day. Clinicians should balance the benefits of low-dose glucocorticoids with this potential risk. PRIMARY FUNDING SOURCE: National Institute of Arthritis and Musculoskeletal and Skin Diseases.

Immunosuppression and the risk of readmission and mortality in patients with rheumatoid arthritis undergoing hip fracture, abdominopelvic and cardiac surgery.

OBJECTIVES: The impact of immunosuppression on postoperative outcomes has primarily been studied in patients undergoing joint replacement surgery. We aimed to evaluate the impact of biologics and glucocorticoids on outcomes after other major surgeries. METHODS: This retrospective cohort study used Medicare data 2006-2015 to identified adults with rheumatoid arthritis undergoing hip fracture repair, abdominopelvic surgery (cholecystectomy, hysterectomy, hernia, appendectomy, colectomy) or cardiac surgery (coronary artery bypass graft, mitral/aortic valve). Logistic regression with propensity-score-based inverse probability weighting compared 90-day mortality and 30-day readmission in patients receiving methotrexate (without a biologic or targeted synthetic disease-modifying antirheumatic drug (tsDMARD)), a tumour necrosis factor inhibitor (TNFi) or a non-TNFi biologic/tsDMARD <8 weeks before surgery. Similar analyses evaluated associations between glucocorticoids and outcomes. RESULTS: We identified 10 777 eligible surgeries: 3585 hip fracture, 5025 abdominopelvic and 2167 cardiac surgeries. Compared with patients receiving methotrexate, there was no increase in the risk of 90-day mortality or 30-day readmission among patients receiving a TNFi (mortality adjusted OR (aOR) 0.83 (0.67 to 1.02), readmission aOR 0.86 (0.75 to 0.993)) or non-TNFi biologic/tsDMARD (mortality aOR 0.78 (0.49 to 1.22), readmission aOR 1.02 (0.78 to 1.33)). Analyses stratified by surgery category were similar. Risk of mortality and readmission was higher with 5-10 mg/day of glucocorticoids (mortality aOR 1.41 (1.08 to 1.82), readmission aOR 1.26 (1.05 to 1.52)) or >10 mg/day (mortality aOR 1.64 (1.02 to 2.64), readmission aOR 1.60 (1.15 to 2.24)) versus no glucocorticoids, although results varied when stratifying by surgery category. CONCLUSIONS: Recent biologic or tsDMARD use was not associated with a greater risk of mortality or readmission after hip fracture, abdominopelvic or cardiac surgery compared with methotrexate. Higher dose glucocorticoids were associated with greater risk.

Risk of Biologics and Glucocorticoids in Patients With Rheumatoid Arthritis Undergoing Arthroplasty: A Cohort Study.

Background: Patients with rheumatoid arthritis (RA) are at increased risk for infection after arthroplasty, yet risks of specific biologic medications are unknown. Objective: To compare risk for postoperative infection among biologics and to evaluate the risk associated with glucocorticoids. Design: Retrospective cohort study. Setting: Medicare and Truven MarketScan administrative data from January 2006 through September 2015. Patients: Adults with RA who were having elective inpatient total knee or hip arthroplasty, either primary or revision, and had a recent infusion of or prescription for abatacept, adalimumab, etanercept, infliximab, rituximab, or tocilizumab before surgery. Measurements: Propensity-adjusted analyses using inverse probability weights evaluated comparative risks for hospitalized infection within 30 days and prosthetic joint infection (PJI) within 1 year after surgery between biologics or with different dosages of glucocorticoids. Secondary analyses evaluated non-urinary tract hospitalized infections and 30-day readmissions. Results: Among 9911 patients treated with biologics, 10 923 surgical procedures were identified. Outcomes were similar in patients who received different biologics. Compared with an 8.16% risk for hospitalized infection with abatacept, predicted risk from propensity-weighted models ranged from 6.87% (95% CI, 5.30% to 8.90%) with adalimumab to 8.90% (CI, 5.70% to 13.52%) with rituximab. Compared with a 2.14% 1-year cumulative incidence of PJI with abatacept, predicted incidence ranged from 0.35% (CI, 0.11% to 1.12%) with rituximab to 3.67% (CI, 1.69% to 7.88%) with tocilizumab. Glucocorticoids were associated with a dose-dependent increase in postoperative risk for all outcomes. Propensity-weighted models showed that use of more than 10 mg of glucocorticoids per day (vs. no glucocorticoid use) resulted in a predicted risk for hospitalized infection of 13.25% (CI, 9.72% to 17.81%) (vs. 6.78%) and a predicted 1-year cumulative incidence of PJI of 3.83% (CI, 2.13% to 6.87%) (vs. 2.09%). Limitation: Residual confounding is possible, and sample sizes for rituximab and tocilizumab were small. Conclusion: Risks for hospitalized infection, PJI, and readmission after arthroplasty were similar across biologics. In contrast, glucocorticoid use, especially with dosages above 10 mg/d, was associated with greater risk for adverse outcomes. Primary Funding Source: Rheumatology Research Foundation, National Institutes of Health, and Bristol-Myers Squibb.

Increased Mortality Rates With Prolonged Corticosteroid Therapy When Compared With Antitumor Necrosis Factor-α-Directed Therapy for Inflammatory Bowel Disease.

OBJECTIVES: Crohn's disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) that compromise quality of life and may increase mortality. This study compared the mortality risk with prolonged corticosteroid use vs. antitumor necrosis factor-α (anti-TNF) drugs in IBD. METHODS: A retrospective cohort study was conducted among Medicaid and Medicare beneficiaries from 2001 to 2013 with IBD prescribed either >3,000 mg of prednisone or equivalent within a 12-month period or new initiation of anti-TNF therapy, each treated as time-updating exposures. The primary outcome was all-cause mortality. Secondary outcomes included common causes of death. Marginal structural models were used to determine odds ratios (ORs) and 95% confidence intervals (CIs) for anti-TNF use relative to corticosteroids. RESULTS: Among patients with CD, 7,694 entered the cohort as prolonged corticosteroid users and 1,879 as new anti-TNF users. Among patients with UC, 3,224 and 459 entered the cohort as prolonged CS users and new anti-TNF users, respectively. The risk of death was statistically significantly lower in patients treated with anti-TNF therapy for CD (21.4 vs. 30.1 per 1,000 person-years, OR 0.78, 0.65-0.93) but not for UC (23.0 vs. 30.9 per 1,000 person-years, OR 0.87, 0.63-1.22). Among the CD cohort, anti-TNF therapy was also associated with lower rates of major adverse cardiovascular events (OR 0.68, 0.55-0.85) and hip fracture (OR 0.54, 0.34-0.83). CONCLUSIONS: Compared with prolonged corticosteroid exposure, anti-TNF drug use was associated with reduced mortality in patients with CD that may be explained by lower rates of major adverse cardiovascular events and hip fracture.

Biomarker-related risk for myocardial infarction and serious infections in patients with rheumatoid arthritis: a population-based study.

BACKGROUND: Rheumatoid arthritis (RA) disease activity and associated systemic inflammation has been associated with serious infection (SIEs), myocardial infarction (MI) and coronary heart disease (CHD) events based on a few registry studies or clinical trials. There are few data from large-scale population-based studies given feasibility challenges in conducting such investigations. METHODS: Multibiomarker disease activity (MBDA) test scores (n=77 641) were linked to Medicare for US patients with RA. Outcomes of interest were hospitalised pneumonia/sepsis (SIE), MI and a composite CHD outcome. The MBDA score ranges from 1 to 100 and was analysed as time-varying. Cox proportional hazards models evaluated the association between MBDA score and SIEs, MI and CHD events, controlling for potential confounders. A sensitivity analysis excluded C reactive protein (CRP) from the MBDA score. RESULTS: There were 17 433 and 16 796 patients eligible for the SIE and MI/CHD analyses, respectively. Mean (SD) age was 69 (11) years, 79% were women, 81% were white and 38% were disabled. Over 16 424 person-years of follow-up, there were 452 SIE events, 132 MIs and 181 CHD events. Higher MBDA scores were associated with SIEs (HR=1.32, 95% CI 1.23 to 1.41 per 10 unit MBDA score change). For MI/CHD events, a threshold effect was present; higher disease activity by MBDA score was associated with increased MI (HR=1.52, 95% CI 0.92 to 2.49) and CHD rates (HR=1.54, 95% CI 1.01 to 2.34, comparing scores ≥30 vs <30). Analyses of the MBDA score without CRP yielded similar results. CONCLUSION: Higher MBDA scores were associated with hospitalised infection, MI and CHD events in a large, predominantly older, US RA population.

Risk of malignancy associated with paediatric use of tumour necrosis factor inhibitors.

OBJECTIVE: To determine whether tumour necrosis factor inhibitor (TNFi) use is associated with an increased rate of incident malignancy compared with no TNFi use in the treatment of juvenile idiopathic arthritis (JIA), paediatric inflammatory bowel disease (pIBD) and paediatric plaque psoriasis (pPsO). METHODS: We performed a retrospective cohort study of administrative claims data from the USA from 2000 to 2014. Exposure to TNFi was considered permanent from the first observed exposure onward. The malignancy outcome was defined by diagnosis codes with evidence of cancer treatment. We calculated standardised incidence ratios (SIRs) comparing the observed number of malignancies to the expected numbers according to cancer surveillance data. We used multivariable Cox proportional hazards models to estimate adjusted HRs (aHRs) for incident malignancy. RESULTS: We identified 15 598 children with TNFi use and 73 839 children with no TNFi use (30 703 and 121 801 person-years of follow-up, respectively). We identified 15 malignancies among children with TNFi use (SIR 2.9 (1.6 to 4.9)) and 42 malignancies among children without TNFi use (SIR 2.1 (1.5 to 2.9)). The aHR was 1.58 (0.88 to 2.85) for TNFi use versus no TNFi use. In pIBD, TNFi use with thiopurine use was associated with a higher SIR (6.0 (1.2 to 17.5)) compared with TNFi use without thiopurine use (2.5 (0.7 to 6.4)). CONCLUSION: Children diagnosed with JIA, pIBD and pPsO had an increased rate of malignancy compared with the general population, but treatment with TNFi did not appear to significantly further increase the risk compared with no TNFi use. More data are needed about the long-term risks of TNFi use.

Development of algorithms for identifying fatal cardiovascular disease in Medicare claims.

BACKGROUND: Cause of death is often not available in administrative claims data. OBJECTIVE: To develop claims-based algorithms to identify deaths due to fatal cardiovascular disease (CVD; ie, fatal coronary heart disease [CHD] or stroke), CHD, and stroke. METHODS: Reasons for Geographic and Racial Differences in Stroke (REGARDS) study data were linked with Medicare claims to develop the algorithms. Events adjudicated by REGARDS study investigators were used as the gold standard. Stepwise selection was used to choose predictors from Medicare data for inclusion in the algorithms. C-index, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were used to assess algorithm performance. Net reclassification index (NRI) was used to compare the algorithms with an approach of classifying all deaths within 28 days following hospitalization for myocardial infarction and stroke to be fatal CVD. RESULTS: Data from 2,685 REGARDS participants with linkage to Medicare, who died between 2003 and 2013, were analyzed. The C-index for discriminating fatal CVD from other causes of death was 0.87. Using a cut-point that provided the closest observed-to-predicted number of fatal CVD events, the sensitivity was 0.64, specificity 0.90, PPV 0.65, and NPV 0.90. The algorithms resulted in positive NRIs compared with using deaths within 28 days following hospitalization for myocardial infarction and stroke. Claims-based algorithms for discriminating fatal CHD and fatal stroke performed similarly to fatal CVD. CONCLUSION: The claims-based algorithms developed to discriminate fatal CVD events from other causes of death performed better than the method of using hospital discharge diagnosis codes.

Linkage of a Population-Based Cohort With Primary Data Collection to Medicare Claims: The Reasons for Geographic and Racial Differences in Stroke Study.

We described the linkage of primary data with administrative claims using the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study and Medicare. REGARDS study data were linked with Medicare claims by use of Social Security numbers. We compared REGARDS participants by Medicare linkage status, having fee-for-service (FFS) coverage or not, and with a 5% sample of Medicare beneficiaries who had FFS coverage in 2005, overall, by age (45-64 and ≥65 years), and by race. Among REGARDS participants who were ≥65 years of age, 80% had data linked to Medicare on their study-visit date (64% with FFS coverage). No differences except race and sex were present between REGARDS participants without Medicare linkage and those with data linked to Medicare with and without FFS coverage. After the age-sex-race adjustment, comorbid conditions and health-care utilization were similar for those with FFS coverage in the REGARDS study and the 5% sample of Medicare beneficiaries. Among REGARDS participants aged 45-64 years, 11% had FFS coverage on their study-visit date. In this age group, differences were present between participants with and without FFS coverage and the Medicare 5% sample with FFS coverage. In conclusion, REGARDS participants aged ≥65 years with FFS coverage are representative of the study cohort and the US population aged ≥65 years with FFS coverage.

Real-world comparative risks of herpes virus infections in tofacitinib and biologic-treated patients with rheumatoid arthritis.

OBJECTIVE: To evaluate the risks of herpes zoster (HZ) and herpes simplex virus (HSV) infection associated with tofacitinib compared with biologic agents among patients with rheumatoid arthritis (RA). METHODS: Using health plan data from 2010 to 2014, patients with RA initiating tofacitinib or biologics with no history of HZ or HSV were identified, as were incident cases of HZ or HSV. Crude incidence rates were calculated by drug exposure. Cox proportional hazards models evaluated the adjusted association between tofacitinib and HZ, and a composite outcome of HZ or HSV. RESULTS: A total of 2526 patients initiating tofacitinib were compared with initiations of other biologics: anti-tumour necrosis factor (TNF) (n=42 850), abatacept (n=12 305), rituximab (n=5078) and tocilizumab (n=6967). Patients receiving tofacitinib were somewhat younger (mean age 55 years) versus those on other biologics, and somewhat less likely to use concomitant methotrexate (MTX) (39% vs 43%-56%, depending on drug). Crude incidence of HZ associated with tofacitinib was 3.87/100 patient-years (py). After multivariable adjustment, HZ risk was significantly elevated, HR 2.01 (95% CI 1.40 to 2.88) compared with abatacept. Rates and adjusted HRs for all other RA biologics were comparable with each other and abatacept. Older age, female sex, prednisone >7.5 mg/day, prior outpatient infection and greater number of hospitalisations were also associated with increased HZ risk. Incidence rates for the combined outcome were greatest for tofacitinib (7.61/100 py) and also significantly elevated after adjustment (HR=1.40, 95% CI 1.09 to 1.81). CONCLUSIONS: The rate of zoster associated with tofacitinib was approximately double that observed in patients using biologics.

Comparative effects of biologics on cardiovascular risk among older patients with rheumatoid arthritis.

OBJECTIVES: To compare the coronary heart disease risk among patients with rheumatoid arthritis (RA) initiating common biologic disease-modifying antirheumatic drugs of different mechanisms. METHODS: We conducted a retrospective cohort study of patients with RA enrolled in Medicare, a public health plan covering >90% of US residents 65 years or older, from 2006 to 2012 who (1) initiated a biologic, (2) had complete medical and pharmacy coverage for at least 12 months before biologic initiation and (3) were free of coronary heart disease at the time of initiation. We compared the incidence rates (IRs) of (1) acute myocardial infarction (AMI) and (2) a composite outcome of AMI or coronary revascularisation and used multivariable adjusted Cox regression models to examine the associations between the type of biologic and the two outcomes. RESULTS: We identified 47 193 eligible patients with RA with mean age 64 (SD 13) years; 85% were women. Crude IRs for AMI ranged from 5.7 to 8.8 cases per 1000 person-years (PYs). AMI risk was significantly elevated among antitumour necrosis factor (anti-TNF) initiators overall (adjusted HR (aHR) 1.3; 95% CI 1.0 to 1.6) and individually among etanercept (aHR 1.3; 95% CI 1.0 to 1.8) and infliximab (aHR 1.3; 95% CI 1.0 to 1.6) compared with abatacept initiators. Crude IRs for the composite outcome ranged from 7.6 to 14.5 per 1000 PYs. Tocilizumab initiators were at reduced risk of the composite outcome compared with abatacept initiators (aHR 0.64, 95% CI 0.41 to 0.99). DISCUSSION: Findings from this observational study of patients with RA suggested that anti-TNF biologics may be associated with higher AMI risk compared with abatacept.

Mortality associated with medical therapy versus elective colectomy in ulcerative colitis: a cohort study.

BACKGROUND: Ulcerative colitis (UC) can be treated with surgery or medications. Patients often must choose between long-term immunosuppressant therapy or total colectomy. Whether one of these treatment approaches has a mortality benefit is uncertain. OBJECTIVE: To determine whether patients with advanced UC treated with elective colectomy have improved survival compared with those treated with medical therapy. DESIGN: Retrospective matched cohort study. SETTING: Data from all 50 states for Medicaid beneficiaries (2000 to 2005), Medicare beneficiaries (2006 to 2011), and dual-eligible persons (2000 to 2011). PATIENTS: 830 patients with UC pursuing elective colectomy and 7541 matched patients with UC pursuing medical therapy. MEASUREMENTS: The primary outcome was time to death. Cox proportional hazards models were used to compare the survival of patients with advanced UC treated with elective colectomy or medical therapy. The models controlled for significant comorbid conditions through matched and adjusted analysis. RESULTS: The mortality rates associated with elective surgery and medical therapy were 34 and 54 deaths per 1000 person-years, respectively. Elective colectomy was associated with improved survival compared with long-term medical therapy (adjusted hazard ratio [HR], 0.67 [95% CI, 0.52 to 0.87]), although this result did not remain statistically significant in all sensitivity analyses. Post hoc analysis by age group showed improved survival with surgery in patients aged 50 years or older with advanced UC (HR, 0.60 [CI, 0.45 to 0.79]; P = 0.032 for age-by-treatment interaction). LIMITATIONS: Retrospective nonrandomized analysis is subject to residual confounding. The source cohort was derived from different databases throughout the study. Sensitivity and secondary analyses had reduced statistical power. CONCLUSION: Elective colectomy seemed to be associated with improved survival relative to medical therapy among patients aged 50 years or older with advanced UC. PRIMARY FUNDING SOURCE: National Institutes of Health and Agency for Healthcare Research and Quality.

Effectiveness and Safety of Immunomodulators With Anti-Tumor Necrosis Factor Therapy in Crohn's Disease.

BACKGROUND & AIMS: The benefit of continuing immunomodulators when "stepping up" to anti-tumor necrosis factor (anti-TNF) therapy for Crohn's disease (CD) is uncertain. This study assessed the effectiveness and safety of immunomodulators with anti-TNF therapy in CD. METHODS: We conducted a retrospective cohort study of new users of anti-TNF therapy for CD in Medicare. Users of anti-TNF combination therapy with immunomodulators were matched to up to 3 users of anti-TNF monotherapy via propensity score and compared by using 3 metrics of effectiveness-surgery, hospitalization, and discontinuation of anti-TNF therapy or surgery-and 2 metrics of safety-serious infection and non-Candida opportunistic infection. Cox regression was used for all analyses. RESULTS: Among new users of infliximab, we matched 381 users of combination therapy to 912 users of monotherapy; among new users of adalimumab, we matched 196 users of combination therapy to 505 users of monotherapy. Combination therapy occurred predominantly as "step up" after thiopurine therapy. The rates of surgery (hazard ratio [HR], 1.20; 95% confidence interval, 0.73-1.96), hospitalization (HR, 0.82; 0.57-1.19), discontinuation of anti-TNF therapy or surgery (HR, 1.09; 0.88-1.34), and serious infection (HR, 0.93; 0.88-1.34) did not differ between users of anti-TNF combination therapy and monotherapy. However, the risks of opportunistic infection (HR, 2.64; 1.21-5.73) and herpes zoster (HR, 3.16; 1.25-7.97) were increased with combination therapy. CONCLUSIONS: We found that continuation of immunomodulators after "stepping up" to anti-TNF therapy did not improve outcomes but was associated with an increased risk of opportunistic infection.

Risk of hospitalised infection in rheumatoid arthritis patients receiving biologics following a previous infection while on treatment with anti-TNF therapy.

BACKGROUND: The risk of subsequent infections in rheumatoid arthritis (RA) patients who receive biologic therapy after a serious infection is unclear. OBJECTIVE: To compare the subsequent risk of hospitalised infections associated with specific biologic agents among RA patients previously hospitalised for infection while receiving anti-tumour necrosis factor (anti-TNF) therapy. METHODS: Using 2006-2010 Medicare data for 100% of beneficiaries with RA enrolled in Medicare, we identified patients hospitalised with an infection while on anti-TNF agents. Follow-up began 61 days after hospital discharge and ended at the earliest of: next infection, loss of Medicare coverage or 18 months after start of follow-up. We calculated the incidence rate of subsequent hospitalised infection for each biologic and used Cox regression to control for potential confounders. RESULTS: 10 794 eligible hospitalised infections among 10183 unique RA patients who contributed at least 1 day of biologic exposure during follow-up. We identified 7807 person-years of exposure to selected biologics--333 abatacept, 133 rituximab and 7341 anti-TNFs (1797 etanercept, 1405 adalimumab, 4139 infliximab)--and 2666 associated infections. Mean age across biologic exposure cohorts was 64-69 years. The crude incidence rate of subsequent hospitalised infection ranged from 27.1 to 34.6 per 100 person-years. After multivariable adjustment, abatacept (HR: 0.80, 95% CI 0.64 to 0.99) and etanercept (HR: 0.83, 95% CI 0.72 to 0.96) users had significantly lower risks of subsequent infection compared to infliximab users. CONCLUSIONS: Among RA patients who experienced a hospitalised infection while on anti-TNF therapy, abatacept and etanercept were associated with the lowest risk of subsequent infection compared to other biologic therapies.