Posttraumatic Stress Disorder and Risk of Systemic Lupus Erythematosus Among Medicaid Recipients.

OBJECTIVE: We studied posttraumatic stress disorder (PTSD), a severe trauma-related mental disorder, and systemic lupus erythematosus (SLE) risk in a large, diverse population enrolled in Medicaid, a US government-sponsored health insurance program for low-income individuals. METHODS: We identified SLE cases and controls among patients ages 18-65 years enrolled in Medicaid for ≥12 months in the 29 most populated US states from 2007 to 2010. SLE and PTSD case statuses were defined based on validated patterns of International Classification of Diseases, Ninth Revision codes. Index date was the date of the first SLE code. Controls had no SLE codes but had another inpatient or outpatient code on the index date and were matched 1:10 to cases by age, sex, and race. Conditional logistic regressions calculated odds ratios (ORs) and 95% confidence intervals (95% CIs) for the association of PTSD with incident SLE, adjusting for smoking, obesity, oral contraceptive use, and other covariates. RESULTS: A total of 10,942 incident SLE cases were matched to 109,420 controls. The prevalence of PTSD was higher in SLE cases, at 10.74 cases of PTSD per 1,000 person-years (95% CI 9.37-12.31) versus 7.83 cases (95% CI 7.42-8.27) in controls. The multivariable-adjusted OR for SLE among those with PTSD was 2.00 (95% CI 1.64-2.46). CONCLUSION: In this large, racially and sociodemographically diverse US population, we found patients with a prior PTSD diagnosis had twice the odds of a subsequent diagnosis of SLE. Studies are necessary to clarify the mechanisms driving the observed association and to inform possible interventions.

Examining the potential direct cardiovascular benefit of tumor-necrosis factor inhibitor in rheumatoid arthritis: Natural and controlled direct effect analyses.

BACKGROUND/PURPOSE: Tumor necrosis factor inhibitors (TNFi) may have a direct benefit on cardiovascular (CV) disease beyond reducing rheumatoid arthritis (RA) disease activity measured by the Clinical Disease Activity Index (CDAI). METHODS: We compared TNFi initiators and methotrexate (MTX) monotherapy initiators from the CorEvitas RA registry. Two approaches to the "direct effect" of TNFi beyond CDAI were used. In the natural direct effect (NDE) analysis, the potential CV benefit of TNFi was partitioned into NDE and the natural indirect effect (NIE) mediated by CDAI during the first 6 months. We also estimated the controlled direct effects (CDE), corresponding to the direct benefit of TNFi when CDAI trajectories were hypothetically equalized between the initiators of TNFi and MTX monotherapy at a constant value. Estimates were given on the hazard ratio scale. RESULTS: We identified 5764 initiators of TNFi and 3588 initiators of MTX monotherapy. TNFi initiators were younger (58 vs. 64 years) with a shorter disease duration. Our total effect estimates (TNFi vs. MTX [reference]) were protective in direction (0.76-0.91). The NDE estimate was 0.76 [95% confidence interval (CI) 0.59, 0.98], whereas the NIE estimate was 1.00 [95%CI 1.00, 1.00]. In the CDE analyses accounting for longitudinal CDAI, the CDE estimates was 1.27 [95%CI 0.60, 2.69]. CONCLUSIONS: We could not convincingly demonstrate a direct benefit of TNFi outside its impact on CDAI. At present, the emphasis should be on the stringent control of RA disease activity, a known important CV risk factor, regardless of medication choice.

Comparative risks of cardiovascular disease events among SLE patients receiving immunosuppressive medications.

OBJECTIVES: SLE patients have elevated cardiovascular disease (CVD) risk, but it is unclear whether this risk is affected by choice of immunosuppressive drug. We compared CVD risks among SLE patients starting MMF, CYC or AZA. METHODS: Using Medicaid Analytic eXtract (2000-2012), adult SLE patients starting MMF, CYC or AZA were identified and propensity scores (PS) were estimated for receipt of MMF vs CYC and MMF vs AZA. We examined rates of first CVD event (primary outcome), all-cause mortality, and a composite of first CVD event and all-cause mortality (secondary outcomes). After 1:1 PS-matching, Fine-Gray regression models estimated subdistribution hazard ratios (HRs.d.) for risk of CVD events. Cox regression models estimated HRs for all-cause mortality. The primary analysis was as-treated; 6- and 12-month intention-to-treat (ITT) analyses were secondary. RESULTS: We studied 680 PS-matched pairs of patients with SLE initiating MMF vs CYC and 1871 pairs initiating MMF vs AZA. Risk of first CVD event was non-significantly reduced for MMF vs CYC [HRs.d 0.72 (95% CI: 0.37, 1.39)] and for MMF vs AZA [HRs.d 0.88 (95% CI: 0.59, 1.32)] groups. In the 12-month ITT, first CVD event risk was lower among MMF than AZA new users [HRs.d 0.68 (95% CI: 0.47, 0.98)]. CONCLUSION: In this head-to-head PS-matched analysis, CVD event risks among SLE patients starting MMF vs CYC or AZA were not statistically reduced except in one 12-month ITT analysis of MMF vs AZA, suggesting longer-term use may convey benefit. Further studies of potential cardioprotective benefit of MMF are necessary.

Interactions Between Genome-Wide Genetic Factors and Smoking Influencing Risk of Systemic Lupus Erythematosus.

OBJECTIVE: To identify interactions between genetic factors and current or recent smoking in relation to risk of developing systemic lupus erythematosus (SLE). METHODS: For the study, 673 patients with SLE (diagnosed according to the American College of Rheumatology 1997 updated classification criteria) were matched by age, sex, and race (first 3 genetic principal components) to 3,272 control subjects without a history of connective tissue disease. Smoking status was classified as current smoking/having recently quit smoking within 4 years before diagnosis (or matched index date for controls) versus distant past/never smoking. In total, 86 single-nucleotide polymorphisms and 10 classic HLA alleles previously associated with SLE were included in a weighted genetic risk score (wGRS), with scores dichotomized as either low or high based on the median value in control subjects (low wGRS being defined as less than or equal to the control median; high wGRS being defined as greater than the control median). Conditional logistic regression models were used to estimate both the risk of SLE and risk of anti-double-stranded DNA autoantibody-positive (dsDNA+) SLE. Additive interactions were assessed using the attributable proportion (AP) due to interaction, and multiplicative interactions were assessed using a chi-square test (with 1 degree of freedom) for the wGRS and for individual risk alleles. Separate repeated analyses were carried out among subjects of European ancestry only. RESULTS: The mean ± SD age of the SLE patients at the time of diagnosis was 36.4 ± 15.3 years. Among the 673 SLE patients included, 92.3% were female and 59.3% were dsDNA+. Ethnic distributions were as follows: 75.6% of European ancestry, 4.5% of Asian ancestry, 11.7% of African ancestry, and 8.2% classified as other ancestry. A high wGRS (odds ratio [OR] 2.0, P = 1.0 × 10-51 versus low wGRS) and a status of current/recent smoking (OR 1.5, P = 0.0003 versus distant past/never smoking) were strongly associated with SLE risk, with significant additive interaction (AP 0.33, P = 0.0012), and associations with the risk of anti-dsDNA+ SLE were even stronger. No significant multiplicative interactions with the total wGRS (P = 0.58) or with the HLA-only wGRS (P = 0.06) were found. Findings were similar in analyses restricted to only subjects of European ancestry. CONCLUSION: The strong additive interaction between an updated SLE genetic risk score and current/recent smoking suggests that smoking may influence specific genes in the pathogenesis of SLE.

External Validation of a Risk Score for Major Toxicity Among Nonsteroidal Anti-Inflammatory Drug Users: Real-World Application.

OBJECTIVE: We previously derived and validated a risk score for major nonsteroidal anti-inflammatory drug (NSAID) toxicity over 1 year among NSAID users in a randomized controlled trial. This work was extended to examine the risk score's performance in an external population using real-world data. METHODS: Patients enrolled in the Corrona Rheumatoid Arthritis (RA) Registry were included if they initiated use of an NSAID. We defined the original risk factors previously identified in the risk score for major NSAID toxicity: age; male sex; history of cardiovascular disease, hypertension, and diabetes; tobacco use; statin use; elevated serum creatinine and hematocrit values; and RA. Additionally, we defined the occurrence of major toxicity, including major adverse cardiovascular events, acute kidney injury, significant gastrointestinal events, and mortality. The original risk factors were assessed in Cox regression examining discrimination and calibration. Low (less than 1%), intermediate (1%-4%), and high (more than 4%) risk categories for 1-year risk were applied to the population. RESULTS: A total of 5231 patients from Corrona who had a new NSAID exposure period were included. The original risk score model showed good discrimination (C-index 0.70). Not all of the original variables were statistically significant in real-world data. Using the original risk score weights, 1363 (26.1%) patients had predicted risk of less than 1%, 3571 (68.3%) had predicted risk of 1% to 4%, and 297 (5.7%) had predicted risk of more than 4%. CONCLUSION: The original NSAID major toxicity risk score demonstrated good model fit characteristics in this external real-world cohort. These results suggest that such a risk score is valid in typical practice and could be considered for clinical care.

Readmissions, revisions, and mortality after treatment for proximal humeral fractures in three large states.

BACKGROUND: Proximal humeral fractures can be treated non-operatively or operatively with open reduction and internal fixation (ORIF) and arthroplasty. Our objective was to assess practice patterns for operative and non-operative treatment of proximal humeral fractures. We also report on complications, readmissions, in-hospital mortality, and need for surgery after initial treatment of proximal humeral fractures in California, Florida, and New York. METHODS: The State Inpatient Databases and State Emergency Department Databases from the Healthcare Cost and Utilization Project, sponsored by the Agency for Healthcare Research and Quality, were used for the states of California (2005-2011), Florida (2005-2014), and New York (2008-2014). Data on patients with proximal humeral fractures was extracted. Patients underwent non-operative or operative (ORIF or arthroplasty) treatment at baseline and were followed for at least 4 years from the index presentation. If the patient needed subsequent surgery, time to event was calculated in days, and Kaplan-Meier survival curves were plotted. RESULTS: At the index visit, 90.3% of patients with proximal humeral fractures had non-operative treatment, 6.7% had ORIF, and 3.0% had arthroplasty. 7.6% of patients initially treated non-operatively, 6.6% initially treated with ORIF, and 7.2% initially treated with arthroplasty needed surgery during follow-up. Device complications were the primary reason for readmission in 5.3% of ORIF patients and 6.7% of arthroplasty patients (p < 0.0001). All-cause in-hospital mortality was 9.8% for patients managed non-operatively, 8.8% for ORIF, and 10.0% for arthroplasty (p = 0.003). CONCLUSIONS: A majority of patients with proximal humeral fractures underwent non-operative treatment. There was a relatively high all-cause in-hospital mortality irrespective of treatment. Given the recent debate on operative versus non-operative treatment for proximal humeral fractures, our study provides valuable information on the need for revision surgery after initial treatment. The differences in rates of revision surgery between patients treated non-operatively, with ORIF, and with arthroplasty were small in magnitude. At nine years of follow-up, ORIF had the lowest probability of needing follow-up surgery, and arthroplasty had the highest.