Treatment Patterns for Alopecia Areata in the US.

Importance: Alopecia areata (AA) is characterized by hair loss ranging from patches of hair loss to more extensive forms, including alopecia totalis (AT) and alopecia universalis (AU). There is a lack of consensus for treatment. Understanding current practice patterns could help the identification of treatment needs and development of standards of care. Objective: To review treatment patterns for adults with AA in the US between 2015 and 2020. Design, Setting, and Participants: This retrospective cohort study used medicine and pharmacy claims for commercially insured individuals from the IBM MarketScan Research Database to assess adults (≥18 years) newly treated for AA between October 15, 2015, and February 28, 2020. Alopecia areata was identified based on having at least 1 diagnosis of International Statistical Classification of Diseases and Related Health Problems, Tenth Revision code L63.x. Patients were required to have at least 365 days of continuous health plan enrollment before and after the cohort entry date. Patients were required to be free of AA diagnosis codes 365 days before the cohort entry date. Statistical analyses were conducted between 2019 and 2023. Main Outcomes and Measures: Main outcomes were treatment patterns for all patients with AA and subgroups of (1) patients with AT or AU and (2) those cared for by a dermatologist on the cohort entry date. Longitudinal therapy course during the first year after the diagnosis was also examined. Results: The study cohort consisted of 45 483 individuals (mean [SD] age, 43.8 [14.2] years; 29 903 [65.7%] female). During the year of follow-up, 30 217 patients (66.4%) received at least 1 AA treatment. The most common treatments were intralesional (19 014 [41.8%]), topical (18 604 [40.9%]), intramuscular (17 328 [38.1%]), and oral (9378 [20.6%]) corticosteroids. Compared with patients without AT or AU, patients with AT or AU a lower frequency of intralesional steroid (359 [11.1%] vs 18 655 [44.1%], P < .001) and higher frequency of topical corticosteroid (817 [25.4%] vs 17 787 [42.1%], P < .001) use. Almost half of patients (21 489 [47.2%]) received no treatment on the day of diagnosis. By 12 months, 32 659 (71.8%) were not receiving any treatment, making no treatment the largest study group. Conclusions and Relevance: In this large cohort study of commercially insured individuals, corticosteroids were the most commonly used treatment for adults with AA between 2015 and 2020. At 365 days after diagnosis, more than two-thirds of patients were no longer receiving any AA treatment. Further studies are needed to understand the reasons for the absence of treatment.

Trends in use of antipsychotics and psychoactive drugs in older patients after major surgery.

BACKGROUND: Professional society guidelines recommend limiting the use of antipsychotics in older patients with postoperative delirium. How these recommendations affected the use of antipsychotics and other psychoactive drugs in the postoperative period has not been studied. METHODS: This retrospective cohort study included patients 65 years or older without psychiatric diagnoses who underwent major surgery in community hospitals (CHs) and academic medical centers (AMCs) in the United States. The outcome was the rate of hospital days exposed to antipsychotics, antidepressants, antiepileptics, benzodiazepines, hypnotics, and selective alpha-2 receptor agonist dexmedetomidine in the postoperative period by hospital type. RESULTS: The study included 4,098,431 surgical admissions from CHs (mean age 75.0 [standard deviation, 7.1] years; 50.8% female) during 2008-2018 and 2,310,529 surgical admissions from AMCs (75.0 [7.4] years; 49.4% female) during 2009-2018. In the intensive care unit (ICU) setting, the number of exposed days per 1000 hospital-days declined for haloperidol (CHs: 33-21 days [p < 0.01]; AMCs: 24-15 days [p < 0.01]) and benzodiazepines (CHs: 261-136 days [p < 0.01]; AMCs: 150-77 days [p < 0.01]). The use of atypical antipsychotics, antidepressants, antiepileptics, and dexmedetomidine increased, while hypnotic use varied by the hospital type. In the non-ICU setting, the rate declined for haloperidol in CHs but not in AMCs (CHs: 10-6 days [p < 0.01]; AMCs: 4-3 days [p = 0.52]) and for benzodiazepines in both settings (CHs: 126-56 days [p < 0.01]; AMCs: 30-27 days [p < 0.01]). The use of antiepileptics and antidepressants increased, while the use of atypical antipsychotics and hypnotics varied by the hospital type. CONCLUSIONS: The use of haloperidol and benzodiazepines in the postoperative period declined at both CHs and AMCs. These trends coincided with the increasing use of other psychoactive drugs.

Emulation of Randomized Clinical Trials With Nonrandomized Database Analyses: Results of 32 Clinical Trials.

Importance: Nonrandomized studies using insurance claims databases can be analyzed to produce real-world evidence on the effectiveness of medical products. Given the lack of baseline randomization and measurement issues, concerns exist about whether such studies produce unbiased treatment effect estimates. Objective: To emulate the design of 30 completed and 2 ongoing randomized clinical trials (RCTs) of medications with database studies using observational analogues of the RCT design parameters (population, intervention, comparator, outcome, time [PICOT]) and to quantify agreement in RCT-database study pairs. Design, Setting, and Participants: New-user cohort studies with propensity score matching using 3 US claims databases (Optum Clinformatics, MarketScan, and Medicare). Inclusion-exclusion criteria for each database study were prespecified to emulate the corresponding RCT. RCTs were explicitly selected based on feasibility, including power, key confounders, and end points more likely to be emulated with real-world data. All 32 protocols were registered on ClinicalTrials.gov before conducting analyses. Emulations were conducted from 2017 through 2022. Exposures: Therapies for multiple clinical conditions were included. Main Outcomes and Measures: Database study emulations focused on the primary outcome of the corresponding RCT. Findings of database studies were compared with RCTs using predefined metrics, including Pearson correlation coefficients and binary metrics based on statistical significance agreement, estimate agreement, and standardized difference. Results: In these highly selected RCTs, the overall observed agreement between the RCT and the database emulation results was a Pearson correlation of 0.82 (95% CI, 0.64-0.91), with 75% meeting statistical significance, 66% estimate agreement, and 75% standardized difference agreement. In a post hoc analysis limited to 16 RCTs with closer emulation of trial design and measurements, concordance was higher (Pearson r, 0.93; 95% CI, 0.79-0.97; 94% meeting statistical significance, 88% estimate agreement, 88% standardized difference agreement). Weaker concordance occurred among 16 RCTs for which close emulation of certain design elements that define the research question (PICOT) with data from insurance claims was not possible (Pearson r, 0.53; 95% CI, 0.00-0.83; 56% meeting statistical significance, 50% estimate agreement, 69% standardized difference agreement). Conclusions and Relevance: Real-world evidence studies can reach similar conclusions as RCTs when design and measurements can be closely emulated, but this may be difficult to achieve. Concordance in results varied depending on the agreement metric. Emulation differences, chance, and residual confounding can contribute to divergence in results and are difficult to disentangle.

Head and neck dermatitis is exacerbated by Malassezia furfur colonization, skin barrier disruption, and immune dysregulation.

Introduction & objectives: Head and neck dermatitis (HND) is a refractory phenotype of atopic dermatitis (AD) and can be a therapeutic challenge due to lack of responsiveness to conventional treatments. Previous studies have suggested that the microbiome and fungiome may play a role in inducing HND, but the underlying pathogenic mechanisms remain unknown. This study aimed to determine the link between HND and fungiome and to examine the contribution of Malassezia furfur. Materials and methods: To identify the effect of the sensitization status of M. furfur on HND, 312 patients diagnosed with AD were enrolled. To elucidate the mechanism underlying the effects of M. furfur, human keratinocytes and dermal endothelial cells were cultured with M. furfur and treated with Th2 cytokines. The downstream effects of various cytokines, including inflammation and angiogenesis, were investigated by real-time quantitative PCR. To identify the association between changes in lipid composition and M. furfur sensitization status, D-squame tape stripping was performed. Lipid composition was evaluated by focusing on ceramide species using liquid chromatography coupled with tandem mass spectrometry. Results: Increased sensitization to M. furfur was observed in patients with HND. Additionally, sensitization to M. furfur was associated with increased disease severity in these patients. IL-4 treated human keratinocytes cultured with M. furfur produced significantly more VEGF, VEGFR, IL-31, and IL-33. IL-4/M. furfur co-cultured dermal endothelial cells exhibited significantly elevated VEGFR, TGF-ß, TNF-α, and IL-1ß levels. Stratum corneum lipid analysis revealed decreased levels of esterified omega-hydroxyacyl-sphingosine, indicating skin barrier dysfunction in HND. Finally, M. furfur growth was inhibited by the addition of these ceramides to culture media, while the growth of other microbiota, including Cutibacterium acnes, were not inhibited. Conclusions: Under decreased levels of ceramide in AD patients with HND, M. furfur would proliferate, which may enhance pro-inflammatory cytokine levels, angiogenesis, and tissue remodeling. Thus, it plays a central role in the pathogenesis of HND in AD.

Alopecia areata in underrepresented groups: preliminary analysis of the all of us research program.

Alopecia areata (AA) is an autoimmune condition characterized by patchy, nonscarring hair loss. Few studies of AA have adequately included participants from underrepresented groups when evaluating the burden of AA in the United States. We conducted a cross-sectional study of personal/demographic factors and AA using the ongoing All of Us (AoU) Research Program. AoU enrolls adults over 18 years either as direct volunteers or through participating Health Care Provider Organizations by prioritizing recruiting underrepresented groups. We linked data from surveys and electronic health records (EHRs) to estimate the prevalence of AA by race/ethnicity, physical disability, sexual orientation/gender identity (LGBTQIA +), income, and education. The latest AoU release (version 5) includes 329,038 participants. Average age was 51.8 years (standard deviation, SD 16.7), and 60.2% of participants were female. Of these, 251,597 (76.5%) had EHR data and 752 were diagnosed with AA (prevalence, 0.30%; 95% CI 0.28-0.32). We used multivariate logistic regression adjusted for age and other factors to estimate the odds ratio (OR) and 95% confidence intervals (CIs) for prevalence of AA. Compared to Whites, Blacks and Hispanics had higher odds of AA (OR, 1.72; 95% CI 1.39-2.11 and OR, 2.13; 95% CI 1.74-2.59, respectively). Lower odds of AA were observed in participants with less than a high school degree (OR, 0.80; 95% CI 0.59-1.08), household income ≤ $35,000 (OR, 0.67; 95% CI 0.54-0.83), and no health insurance (OR 0.35; 95% CI 0.20-0.56). In this diverse population of US adults, participants with skin of color had higher prevalence of AA. Lower prevalence of AA among individuals with lower education and income levels and those lacking health insurance may reflect limited access to dermatologic care and potentially higher levels of undiagnosed AA in these groups.

Validation of serostatus of rheumatoid arthritis using ICD-10 codes in administrative claims data.

PURPOSE: To determine the accuracy of International Classification of Diseases- Tenth Revision (ICD-10) diagnosis codes for rheumatoid arthritis (RA) serostatus using a U.S. claims database (Optum Clinformatics Data Mart, Optum) and to compare the results to a previous validation study performed in IBM Marketscan Research Database (sensitivity 73%, positive predictive value, PPV, 84%). METHODS: In Optum (01/01/2016-03/31/2020) linked with laboratory results, we selected RA patients based on ≥2 ICD-10 diagnosis codes for RA (M05 or M06) and at least one dispensing of RA treatments. We included individuals with at least one laboratory result for rheumatoid factor (RF) or anti-cyclic citrullinated peptide (CCP) performed 365 days prior to and including the cohort entry date. An individual was "seropositive" if at least one of the 2 diagnosis codes used to define RA status was M05. "Seronegative" patients were required to have only M06. Secondary analyses were performed using subsets of M05 and M06 diagnosis codes. We calculated the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and kappa of M05 and M06 against the prespecified reference standard laboratory data. RESULTS: We identified 14 490 adult RA patients who had at least 1 RF or anti-CCP result. The number of patients identified for each reference standard definition ranged from 3315 (reference standard definition: high + anti-CCP) to 13 636 (any + RF). PPV for seropositive RA, M05, was 77.1%. The PPV of M06 for seronegative RA was 61.6%. When we applied more restricted definitions of M05 and M06, the PPV for seropositive RA increased to 79.2%. The PPV for seronegative RA also notably increased to 89.5%. CONCLUSION: ICD-10 codes (M05 and M06) can help identify RA serostatus in claims data, but their limitations should be acknowledged. The PPVs for seropositive and seronegative RA found in the Optum database were lower than those found in MarketScan, perhaps related to database variability or differing patient characteristics and clinical practice. When more restricted definitions of M05 and M06 were used, the PPVs for seropositive and seronegative RA improved to 79.2% and 89.5%, respectively.

Risk of malignant melanoma and non-melanoma skin cancer in rheumatoid arthritis patients initiating methotrexate versus hydroxychloroquine: a cohort study.

OBJECTIVES: To characterise the incidence rate of skin cancer associated with methotrexate and hydroxychloroquine in older adults with rheumatoid arthritis (RA). METHODS: RA patients aged ≥65 years who initiated methotrexate or hydroxychloroquine as their first disease modifying antirheumatic drugs (DMARDs). The primary outcome was new occurrence of any skin cancer (i.e. malignant melanoma or non-melanoma skin cancer; NMSC) based on validated algorithms (positive predictive value >83%). Secondary outcomes were malignant melanoma, NMSC, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC). We estimated the incidence rates (IRs) and hazard ratios (HRs) for each outcome in the 1:1 propensity score (PS)-matched methotrexate and hydroxychloroquine groups. RESULTS: We included 24,577 PS-matched pairs of methotrexate and hydroxychloroquine initiators. Compared with hydroxychloroquine (IR 25.20/1,000 person-years), methotrexate initiators (IR 26.21/1,000 person-years) had a similar risk of any skin cancer [HR 1.03 -(95%CI 0.92, 1.14)] over a mean follow-up of 388 days. The HR (95%CI) associated with methotrexate was 1.39 (0.87, 2.21) for malignant melanoma, 1.01(0.90, 1.12) for NMSC, 1.37 (1.13, 1.66) for BCC, and 0.79 (0.63, 0.99) for SCC compared with hydroxychloroquine. CONCLUSIONS: In this large cohort of older RA patients initiating methotrexate or hydroxychloroquine as their first DMARD, we found no difference in the risk of skin cancer including malignant melanoma and NMSC. However, for specific components of NMSC, methotrexate initiators had higher risk of BCC but lower risk of SCC compared with hydroxychloroquine initiators.

Tofacitinib and Risk of Malignancy: Results From the Safety of Tofacitinib in Routine Care Patients With Rheumatoid Arthritis (STAR-RA) Study.

OBJECTIVES: Results of the ORAL Surveillance safety trial have indicated that there is an increased risk for the development of malignancies with tofacitinib therapy when compared to treatment with tumor necrosis factor inhibitors (TNFi). This study was undertaken to further examine this safety concern in rheumatoid arthritis (RA) patients in a real-world setting. METHODS: Using US insurance claims data from Optum Clinformatics (2012-2020), IBM MarketScan Research Databases (2012-2018), and Medicare (parts A, B, and D, 2012-2017), we created 2 cohorts of RA patients who had initiated treatment with tofacitinib or TNFi. The first cohort, designated the real-world evidence (RWE) cohort, included RA patients from routine care. For the second cohort, designated the randomized controlled trial (RCT)-duplicate cohort, we emulated the inclusion and exclusion criteria that were applied in the ORAL Surveillance trial of tofacitinib, which allowed us to assess the comparability of our results with the results of that trial. Cox proportional hazards models with propensity score fine-stratification weighting were used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the risk of any malignancy (excluding nonmelanoma skin cancer). Database-specific estimates were meta-analyzed using fixed-effects models with inverse-variance weighting. RESULTS: The RWE cohort consisted of 83,295 patients, including 10,504 patients (12.6%) who received treatment with tofacitinib. The pooled weighted HR for the primary outcome of any malignancy associated with tofacitinib treatment compared to any malignancy associated with TNFi therapy was 1.01 (95% CI 0.83, 1.22) in the RWE cohort and 1.17 (95% CI 0.85, 1.62) in the RCT-duplicate cohort (compared to the ORAL Surveillance trial HR of 1.48 [95% CI 1.04, 2.09]). CONCLUSION: We did not find evidence of an increased risk of malignancy development with tofacitinib therapy, in comparison with TNFi therapy, in RA patients treated in a real-world setting. However, our results cannot rule out the possibility of an increase in risk that may accrue with a longer duration of treatment with tofacitinib.

Cardiovascular Risks of Hydroxychloroquine vs Methotrexate in Patients With Rheumatoid Arthritis.

BACKGROUND: Hydroxychloroquine is often used as a first-line treatment of rheumatoid arthritis despite limited evidence on its cardiovascular risk. OBJECTIVES: We conducted a cardiovascular safety evaluation comparing hydroxychloroquine to methotrexate among patients with rheumatoid arthritis. METHODS: Using Medicare data (2008-2016), we identified 54,462 propensity score-matched patients with rheumatoid arthritis, aged ≥65 years, who initiated hydroxychloroquine or methotrexate. Primary outcomes were sudden cardiac arrest or ventricular arrythmia (SCA/VA) and major adverse cardiovascular event (MACE). Secondary outcomes were cardiovascular mortality, all-cause mortality, myocardial infarction, stroke, and hospitalized heart failure (HF). We also examined treatment effect modification by history of HF. RESULTS: Hydroxychloroquine was not associated with risk of SCA/VA (HR: 1.03; 95% CI: 0.79-1.35) or MACE (HR: 1.07; 95% CI: 0.97-1.18) compared with methotrexate. In patients with history of HF, hydroxychloroquine initiators had a higher risk of MACE (HR: 1.30; 95% CI: 1.08-1.56), cardiovascular mortality (HR: 1.34; 95% CI: 1.06-1.70), all-cause mortality (HR: 1.22; 95% CI: 1.04-1.43), myocardial infarction (HR: 1.74; 95% CI: 1.25-2.42), and hospitalized HF (HR: 1.29; 95% CI: 1.07-1.54) compared to methotrexate initiators. Cardiovascular risks were not different in patients without history of HF except for an increased hospitalized HF risk (HR: 1.57; 95% CI: 1.30-1.90) among hydroxychloroquine initiators. CONCLUSIONS: In older patients with rheumatoid arthritis, hydroxychloroquine and methotrexate showed similar SCA/VA and MACE risks; however, hydroxychloroquine initiators with history of HF had higher risks of MACE, cardiovascular mortality, all-cause mortality, and myocardial infarction. An increased hospitalized HF risk was observed among hydroxychloroquine initiators regardless of an HF history.

Tofacitinib and risk of cardiovascular outcomes: results from the Safety of TofAcitinib in Routine care patients with Rheumatoid Arthritis (STAR-RA) study.

OBJECTIVES: Recent results from 'ORAL Surveillance' trial have raised concerns regarding the cardiovascular safety of tofacitinib in patients with rheumatoid arthritis (RA). We further examined this safety concern in the real-world setting. METHODS: We created two cohorts of patients with RA initiating treatment with tofacitinib or tumour necrosis factor inhibitors (TNFI) using deidentified data from Optum Clinformatics (2012-2020), IBM MarketScan (2012-2018) and Medicare (parts A, B and D, 2012-2017) claims databases: (1) A 'real-world evidence (RWE) cohort' consisting of routine care patients and (2) A 'randomised controlled trial (RCT)-duplicate cohort' mimicking inclusion and exclusion criteria of the ORAL surveillance trial to calibrate results against the trial findings. Cox proportional hazards models with propensity score fine stratification weighting were used to estimate HR and 95% CIs for composite outcome of myocardial infarction and stroke and accounting for 76 potential confounders. Database-specific effect estimates were pooled using fixed effects models with inverse-variance weighting. RESULTS: In the RWE cohort, 102 263 patients were identified of whom 12 852 (12.6%) initiated tofacitinib. The pooled weighted HR (95% CI) comparing tofacitinib with TNFI was 1.01 (0.83 to 1.23) in RWE cohort and 1.24 (0.90 to 1.69) in RCT-duplicate cohort which aligned closely with ORAL-surveillance results (HR: 1.33, 95% CI 0.91 to 1.94). CONCLUSIONS: We did not find evidence for an increased risk of cardiovascular outcomes with tofacitinib in patients with RA treated in the real-world setting; however, tofacitinib was associated with an increased risk of cardiovascular outcomes, although statistically non-significant, in patients with RA with cardiovascular risk factors. TRIAL REGISTRATION NUMBER: NCT04772248.

Risk of Hospitalization for Serious Infection After Initiation of Ustekinumab or Other Biologics in Patients With Psoriasis or Psoriatic Arthritis.

OBJECTIVE: To compare the risk of serious infections requiring hospitalization in patients with psoriasis (PsO) or psoriatic arthritis (PsA) initiating ustekinumab versus other biologics or apremilast. METHODS: In this multi-database cohort study, we identified patients with PsO/PsA who initiated therapy with adalimumab, apremilast, certolizumab, etanercept, golimumab, ixekizumab, secukinumab, or ustekinumab between 2009 and 2018. The primary outcome measure was hospitalizations due to serious infections, which included bacterial, viral, or opportunistic infections. We estimated hazard ratios (HRs) comparing each study drug to ustekinumab after applying propensity score fine stratification weights for confounding control in each database. Database-specific weighted HRs were combined by meta-analysis. RESULTS: We identified 123,383 patients with PsO/PsA who initiated one of the study drugs. During a total of 117,744 person-years of follow-up, 1,514 serious infections occurred with a crude incidence of 1.29 per 100 person-years. After propensity score fine stratification and weighting, the incidence rates of serious infection among ustekinumab initiators ranged from 0.59 to 0.95 per 100 person-years. Compared with ustekinumab, the combined weighted HRs (95% confidence interval [95% CI]) for serious infections were 1.66 (95% CI 1.34-2.06) for adalimumab, 1.42 (95% CI 1.02-1.96) for apremilast, 1.09 (95% CI 0.68-1.75) for certolizumab, 1.39 (95% CI 1.01-1.90) for etanercept, 1.74 (95% CI 1.00-3.03) for golimumab, 2.92 (95% CI 1.80-4.72) for infliximab, 2.98 (95% CI 1.20-7.41) for ixekizumab, and 1.84 (95% CI 1.24-2.72) for secukinumab. CONCLUSION: Other biologics and apremilast were associated with a 1.4- to 3-times higher risk of hospitalization for serious infections in PsO/PsA patients when compared to ustekinumab; this finding should be considered in the safety profile of these therapies when selecting appropriate treatment regimens in patients with PsO/PsA.

Prevalence of Avoidable and Bias-Inflicting Methodological Pitfalls in Real-World Studies of Medication Safety and Effectiveness.

Many real-word evidence (RWE) studies that utilize existing healthcare data to evaluate treatment effects incur substantial but avoidable bias from methodologically flawed study design; however, the extent of preventable methodological pitfalls in current RWE is unknown. To characterize the prevalence of avoidable methodological pitfalls with potential for bias in published claims-based studies of medication safety or effectiveness, we conducted an English-language search of PubMed for articles published from January 1, 2010 to May 20, 2019 and randomly selected 75 studies (10 case-control and 65 cohort studies) that evaluated safety or effectiveness of cardiovascular, diabetes, or osteoporosis medications using US health insurance claims. General and methodological study characteristics were extracted independently by two reviewers, and potential for bias was assessed across nine bias domains. Nearly all studies (95%) had at least one avoidable methodological issue known to incur bias, and 81% had potentially at least one of the four issues considered major due to their potential to undermine study validity: time-related bias (57%), potential for depletion of outcome-susceptible individuals (44%), inappropriate adjustment for postbaseline variables (41%), or potential for reverse causation (39%). The median number of major issues per study was 2 (interquartile range (IQR), 1-3) and was lower in cohort studies with a new-user, active-comparator design (median 1, IQR 0-1) than in cohort studies of prevalent users with a nonuser comparator (median 3, IQR 3-4). Recognizing and avoiding known methodological study design pitfalls could substantially improve the utility of RWE and confidence in its validity.

Giant cell arteritis treatment patterns and rates of serious infections.

OBJECTIVES: Giant cell arteritis (GCA) afflicts older adults who may have age- and comorbidity-related risks for infection and is treated with immunosuppressants that increase risk of infection. We examined GCA treatment patterns and rates of serious infections in two real-world cohorts in the U.S. METHODS: We identified two GCA cohorts using two U.S. health insurance databases, Medicare (public, 2007-2017) and MarketScan (commercial, 2015-2019), by applying a validated claims-based algorithm with positive predictive value 79.0% for GCA. We required age ≥50 years and assessed baseline comorbidities, dispensing of immunosuppressants and prophylactic antibiotics, and vaccine administration. We calculated incidence rates (IR) of serious infections, defined as bacterial or viral infections requiring hospitalisation based on primary inpatient diagnosis code. Multivariable Cox proportional hazards models estimated hazard ratios for risk of serious infection for prespecified covariates. RESULTS: The Medicare cohort included 734 patients, 28% male, mean age 77.1; the MarketScan cohort included 1022 patients, 30% male, mean age 68.4. More than 85% used prednisone ≥60mg daily at index date and <10% used tocilizumab. Serious infections developed in 27.9% of Medicare and 7.2% of MarketScan patients: IR per 100 person-years = 10.7 (95% CI 9.3, 12.2) in Medicare and 6.3 (95% CI 5.0, 7.9) in MarketScan. Older age and higher frailty score were significantly associated with increased risk for serious infection. CONCLUSIONS: In these two U.S. GCA cohorts, high-dose glucocorticoids were the most common initial treatment, and over 25% of Medicare and 7% of MarketScan patients developed serious infection during follow-up. Older age and higher frailty score were associated with higher risk of serious infections, though maximum daily prednisone dose was not. Pneumocystis jiroveci pneumonia was rare in two GCA cohorts despite infrequent use of prophylactic antibiotics.

Risk of venous thromboembolism associated with methotrexate versus hydroxychloroquine for rheumatoid arthritis: A propensity score-matched cohort study.

AIMS: Patients with rheumatoid arthritis (RA) have an increased risk of venous thromboembolism (VTE), likely related to underlying inflammation. We examined VTE risk associated with two commonly used immunomodulators in RA patients, methotrexate and hydroxychloroquine. METHODS AND RESULTS: Using U.S. Medicare claims data (2008-2017), we identified RA patients (≥65 years) who initiated methotrexate or hydroxychloroquine without prior use of any immunomodulators. The primary outcome was VTE, a composite of pulmonary embolism (PE) or deep vein thrombosis (DVT). Secondary outcomes included PE, DVT, and all-cause mortality. After 1:1 propensity score matching for confounding control, we identified 26,534 pairs of methotrexate and hydroxychloroquine initiators (mean (SD) age 74 (7) years; 79% female). During a total of 56,686 person-years of follow-up, 208 methotrexate and 83 hydroxychloroquine initiators developed VTE. The incidence rate of VTE was higher among methotrexate initiators (6.94/1,000 person-years) than hydroxychloroquine initiators (3.11/1,000 person-years) with a hazard ratio (HR) of 2.26 (95% CI 1.75, 2.91). Methotrexate initiators had a greater risk of PE (HR 3.30, 95% CI 2.28, 4.77) and DVT (HR 1.53, 95% CI 1.07, 2.19) than hydroxychloroquine initiators. All-cause mortality was similar between the two groups (HR 0.91, 95% CI 0.83, 1.00). CONCLUSION: In this large real-world cohort of older RA patients, treatment with methotrexate was associated with a 2-fold increased risk of VTE relative to hydroxychloroquine, although all-cause mortality was similar. Future experimental studies with non-user control groups are needed to determine the causal relationships between the study drugs and VTE and whether methotrexate elevates or hydroxychloroquine reduces the risk of VTE.

Patient characteristics associated with use of TNF vs interleukin inhibitors as first-line biologic treatment for psoriatic arthritis.

BACKGROUND: Previous studies have examined treatment patterns among patients who use tumor necrosis factor (TNF) inhibitors for psoriatic arthritis (PsA). However, little data exist for a comparison between the TNF inhibitor treatment pattern and that of newly available biologics such as interleukin (IL)-12/23 or 17 inhibitors in the United States. OBJECTIVES: To (a) examine patient characteristics and their association with initiation of TNF inhibitors vs IL-12/23 or 17 inhibitors among PsA patients and (2) compare treatment persistence of PsA patients who initiated TNF inhibitors vs IL-12/23 or 17 inhibitors as first-line biologic treatment in a real-world setting in the United States. METHODS: Using claims data from MarketScan (2013-2017), we identified a cohort of PsA patients who initiated TNF inhibitors or IL-12/23 or 17 inhibitors. The primary outcome was treatment persistence, defined as continuous use of the index drug at 1 year, regardless of refill gaps. The secondary outcome was treatment persistence with high adherence at 1 year (ie, refill gaps ≤ 30 days). Multivariable logistic regression was used to assess the association between patient characteristics and treatment initiation and persistent use of TNF inhibitors vs IL-12/23 or 17 inhibitors. RESULTS: We identified 3,180 TNF inhibitor initiators and 214 IL-12/23 or 17 inhibitor initiators. Initiators of IL-12/23 or 17 inhibitors had more comorbidities than TNF inhibitor initiators. The proportion of patients with treatment persistence was 53.0% in TNF inhibitor initiators and 53.7% in IL-12/23 or 17 inhibitor initiators; 37.1% of TNF inhibitor users and 24.8% of IL-12/23 or 17 inhibitor users were treatment persistent with high adherence. There was no difference in 1-year treatment persistence between the 2 groups after adjusting for baseline characteristics (adjusted odds ratio [aOR] for TNF inhibitors vs IL-12/23 or 17 inhibitors: 0.86, 95% CI = 0.63-1.15). However, use of TNF inhibitors was associated with a greater treatment persistence with high adherence compared with use of IL-12/23 or 17 inhibitors (aOR = 1.61, 95% CI = 1.15-2.26). CONCLUSIONS: PsA patients who initiated an IL 12/23 or 17 inhibitor had a greater comorbidity burden compared with those who initiated TNF inhibitors. Treatment persistence was similar between the 2 groups, whereas medication adherence was higher with TNF inhibitors than with IL 12/23 or 17 inhibitors during the first year of treatment. DISCLOSURES: This study was funded by an investigator-initiated research grant from Pfizer, Inc (grant number: WI235988). The content is solely the responsibility of the authors. The sponsor was given the opportunity to make nonbinding comments on a draft of the manuscript. Publication of the manuscript was not contingent on approval by the sponsor. Kim has received research grants to the Brigham and Women's Hospital from Roche, AbbVie, and Bristol-Myers Squibb for unrelated topics. Merola is a consultant and/or investigator for BMS, AbbVie, Dermavant, Lilly, Novartis, Janssen, UCB, Sun Pharma, and Pfizer. Jin, Chen, Lee, and Landon have nothing to disclose.

Frailty and Clinical Outcomes of Direct Oral Anticoagulants Versus Warfarin in Older Adults With Atrial Fibrillation : A Cohort Study.

BACKGROUND: The role of differing levels of frailty in the choice of oral anticoagulants for older adults with atrial fibrillation (AF) is unclear. OBJECTIVE: To examine the outcomes of direct oral anticoagulants (DOACs) versus warfarin by frailty levels. DESIGN: 1:1 propensity score-matched analysis of Medicare data, 2010 to 2017. SETTING: Community. PATIENTS: Medicare beneficiaries with AF who initiated use of dabigatran, rivaroxaban, apixaban, or warfarin. MEASUREMENTS: Composite end point of death, ischemic stroke, or major bleeding by frailty levels, defined by a claims-based frailty index. RESULTS: In the dabigatran-warfarin cohort (n = 158 730; median follow-up, 72 days), the event rate per 1000 person-years was 63.5 for dabigatran initiators and 65.6 for warfarin initiators (hazard ratio [HR], 0.98 [95% CI, 0.92 to 1.05]; rate difference [RD], -2.2 [CI, -6.5 to 2.1]). For nonfrail, prefrail, and frail persons, HRs were 0.81 (CI, 0.68 to 0.97), 0.98 (CI, 0.90 to 1.08), and 1.09 (CI, 0.96 to 1.23), respectively. In the rivaroxaban-warfarin cohort (n = 275 944; median follow-up, 82 days), the event rate per 1000 person-years was 77.8 for rivaroxaban initiators and 83.7 for warfarin initiators (HR, 0.98 [CI, 0.94 to 1.02]; RD, -5.9 [CI, -9.4 to -2.4]). For nonfrail, prefrail, and frail persons, HRs were 0.88 (CI, 0.77 to 0.99), 1.04 (CI, 0.98 to 1.10), and 0.96 (CI, 0.89 to 1.04), respectively. In the apixaban-warfarin cohort (n = 218 738; median follow-up, 84 days), the event rate per 1000 person-years was 60.1 for apixaban initiators and 92.3 for warfarin initiators (HR, 0.68 [CI, 0.65 to 0.72]; RD, -32.2 [CI, -36.1 to -28.3]). For nonfrail, prefrail, and frail persons, HRs were 0.61 (CI, 0.52 to 0.71), 0.66 (CI, 0.61 to 0.70), and 0.73 (CI, 0.67 to 0.80), respectively. LIMITATIONS: Residual confounding and lack of clinical frailty assessment. CONCLUSION: For older adults with AF, apixaban was associated with lower rates of adverse events across all frailty levels. Dabigatran and rivaroxaban were associated with lower event rates only among nonfrail patients. PRIMARY FUNDING SOURCE: National Institute on Aging.

Validation of claims-based algorithms to identify patients with psoriasis.

PURPOSE: Accurately identifying patients with psoriasis (PsO) is crucial for generating real-world evidence on PsO disease course and treatment utilization. METHODS: We developed nine claims-based algorithms for PsO using a combination of the International Classification of Diseases (ICD)-9 codes, specialist visit, and medication dispensing using Medicare linked to electronic health records data (2013-2014) in two healthcare provider networks in Boston, Massachusetts. We calculated positive predictive value (PPV) and 95% confidence interval (CI) for each algorithm using the treating physician's diagnosis of PsO via chart review as the gold standard. Among the confirmed PsO cases, we assessed their PsO disease activity. RESULTS: The nine claims-based algorithms identified 990 unique patient records. Of those, 918 (92.7%) with adequate information were reviewed. The PPV of the algorithms ranged from 65.1 to 82.9%. An algorithm defined as ≥1 ICD-9 diagnosis code for PsO and ≥1 prescription claim for topical vitamin D agents showed the highest PPV (82.9%). The PPV of the algorithm requiring ≥2 ICD-9 diagnosis codes and ≥1 prescription claim for PsO treatment excluding topical steroids was 81.1% but higher (82.5%) when ≥1 diagnosis was from a dermatologist. Among 411 PsO patients with adequate information on PsO disease activity in EHRs, 1.5-5.8% had no disease activity, 31.3-36.8% mild, and 26.9-35.1% moderate-to-severe across the algorithms. CONCLUSIONS: Claims-based algorithms based on a combination of PsO diagnosis codes and dispensing for PsO-specific treatments had a moderate-to-high PPV. These algorithms can serve as a useful tool to identify patients with PsO in future real-world data pharmacoepidemiologic studies.

Identification of Acute Giant Cell Arteritis in Real-World Data Using Administrative Claims-Based Algorithms.

OBJECTIVE: The objective of this study was to validate claims-based algorithms for identifying acute giant cell arteritis (GCA) that will help generate real-world evidence on comparative effectiveness research and epidemiologic studies. Among patients identified by the GCA algorithm, we further investigated whether GCA flares could be detected by using claims data. METHODS: We developed five claims-based algorithms based on a combination of International Classification of Diseases, Ninth Revision (ICD-9) diagnosis codes, specialist visits, and dispensed medications using Medicare Parts A, B, and D linked to electronic medical records (2006-2014). Acute cases of GCA were determined by chart review using the treating physician's diagnosis of GCA as the gold standard. Among the patients identified with acute GCA, we assessed if a GCA flare occurred during the year after initial diagnosis. RESULTS: The number of patients identified by each algorithm ranged from 220 to 896. Positive predictive values (PPVs) of the algorithms ranged from 60.7% to 84.8%. Requirement for disease-specific workups, multiple diagnosis codes, or specialist visits improved the PPVs. The highest PPV (84.8%) was noted in an algorithm that required two or more diagnosis codes of GCA from inpatient, emergency department, or outpatient rheumatology visits plus a prednisone-equivalent dose greater than or equal to 40 mg/day occurring 14 days before or after the second ICD-9 diagnosis date, with the cumulative days' supply greater than or equal to 14 days. Among patients identified as having GCA, 18.2% of patients had definite evidence of a flare and 25% had a potential flare. CONCLUSION: A claims-based algorithm requiring two or more ICD-9 diagnosis codes from inpatient, emergency department, or outpatient rheumatology visits and high-dose glucocorticoid dispensing can be a useful tool to identify acute GCA cases in large administrative claims databases.

Emulating Randomized Clinical Trials With Nonrandomized Real-World Evidence Studies: First Results From the RCT DUPLICATE Initiative.

BACKGROUND: Regulators are evaluating the use of noninterventional real-world evidence (RWE) studies to assess the effectiveness of medical products. The RCT DUPLICATE initiative (Randomized, Controlled Trials Duplicated Using Prospective Longitudinal Insurance Claims: Applying Techniques of Epidemiology) uses a structured process to design RWE studies emulating randomized, controlled trials (RCTs) and compare results. We report findings of the first 10 trial emulations, evaluating cardiovascular outcomes of antidiabetic or antiplatelet medications. METHODS: We selected 3 active-controlled and 7 placebo-controlled RCTs for replication. Using patient-level claims data from US commercial and Medicare payers, we implemented inclusion and exclusion criteria, selected primary end points, and comparator populations to emulate those of each corresponding RCT. Within the trial-mimicking populations, we conducted propensity score matching to control for >120 preexposure confounders. All study measures were prospectively defined and protocols registered before hazard ratios and 95% CIs were computed. Success criteria for the primary analysis were prespecified for each replication. RESULTS: Despite attempts to emulate RCT design as closely as possible, differences between the RCT and corresponding RWE study populations remained. The regulatory conclusions were equivalent in 6 of 10. The RWE emulations achieved a hazard ratio estimate that was within the 95% CI from the corresponding RCT in 8 of 10 studies. In 9 of 10, either the regulatory or estimate agreement success criteria were fulfilled. The largest differences in effect estimates were found for RCTs where second-generation sulfonylureas were used as a proxy for placebo regarding cardiovascular effects. Nine of 10 replications had a standardized difference between effect estimates of <2, which suggests differences within expected random variation. CONCLUSIONS: Agreement between RCT and RWE findings varies depending on which agreement metric is used. Interim findings indicate that selection of active comparator therapies with similar indications and use patterns enhances the validity of RWE. Even in the context of active comparators, concordance between RCT and RWE findings is not guaranteed, partially because trials are not emulated exactly. More trial emulations are needed to understand how often and in what contexts RWE findings match RCTs. Registration: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT03936049, NCT04215523, NCT04215536, NCT03936010, NCT03936036, NCT03936062, NCT03936023, NCT03648424, NCT04237935, NCT04237922.

Use of biologic or targeted-synthetic disease-modifying anti-rheumatic drugs and risk of diabetes treatment intensification in patients with rheumatoid arthritis and diabetes mellitus.

OBJECTIVES: Given that RA treatment might affect the severity of diabetes mellitus (DM), we compared the risk of DM treatment intensification in patients with both RA and DM newly initiating a biologic DMARD or tofacitinib. METHODS: Using claims data from the IBM MarketScan database (2005-2016), we identified patients aged ≥18 years with RA who initiated abatacept, a TNF inhibitor (TNFi), rituximab, tocilizumab or tofacitinib. Patients were required to have type 1 or type 2 DM and to use at least one antidiabetic drug at baseline. We assessed DM treatment intensification (i.e. addition of a new insulin or non-insulin antidiabetic medication). We also assessed non-insulin antidiabetic medication switching events. RESULTS: We included 10 019 patients with RA and DM initiating a biologic DMARD or tofacitinib. Baseline insulin use was the highest in rituximab initiators (44%) and lowest in tofacitinib initiators (35%). The incidence rate per 1000 person-years for DM treatment intensification ranged from 148.2 (tofacitinib) to 198.0 (rituximab). The risk of DM treatment intensification was similar between abatacept and TNFi [hazard ratio (HR) 0.97, 95% CI: 0.82, 1.15], rituximab (HR 0.99, 95% CI: 0.79, 1.23) and tocilizumab (HR 0.94, 95% CI: 0.74, 1.19), but lower for tofacitinib compared with abatacept (HR 0.67, 95% CI: 0.50, 0.90). The risk of non-insulin DM treatment switching was not different between abatacept and other biologic DMARDs. CONCLUSION: In patients with both RA and DM, we found no difference in the risk of DM treatment switching or intensification after initiating abatacept vs TNFi, rituximab and tocilizumab, whereas the risk appeared to be lower for tofacitinib.