Comparison of Healthcare Utilization and Costs Between RA Patients Receiving Biological and Conventional Synthetic DMARDs: A Nationwide Population-Based Cohort Study in Taiwan.

Background: The therapy with biological disease-modifying anti-rheumatic drugs (bDMARDs) has proven to rapidly reduce articular symptoms/signs, decrease morbidities, and improve health outcome in patients with rheumatoid arthritis (RA) and be cost-effective in Western countries. However, the difference in healthcare utilization and costs between conventional synthetic DMARDs (csDMARDs) and bDMARDs in the treatment of RA patients in Taiwan remains largely unexplored. Methods: Two cohorts of RA patients and their matched controls were identified from the National Health Insurance Research database (NHIRD). The csDMARD cohort comprised of patients who submitted claims during 1997-2003 for cyclosporine≥50 mg/day with concomitant use of ≥2 csDMARDs for ≥28 days (n=1,569), whilst the bDMARD cohort comprised of patients who had ≥1 claim during 2003-2011 for bDMARD (n = 1,530). The per-patient per-year healthcare utilization and costs were estimated by bootstrapping method, with a comparison being undertaken between csDMARD and bDMARD. Results: The incremental number of hospitalization days was reduced from 2.3 days for csDMARD to 0.58 day for bDMARD. When compared to csDMARD-treated patients, the incremental total costs and RA-related medication costs were significantly higher in bDMARD-treated patients (US$9,081 vs. US$2,481; US$8,992 vs. US$1,883). However, the combined incremental healthcare utilization costs and non-RA medication costs were significantly lower in bDMARDs-treated patients compared to csDMARD-treated patients (US$374.7 vs. US$1,156.2). Conclusion: Although total costs increased as a result of introducing biologics in RA treatment, biologics have undoubtedly given rise to the benefits of reduced healthcare utilization. The increase in medication costs from biologics was offset by the lower costs of healthcare utilization. Our findings suggest that the medication costs of biologics may be alleviated by an improvement in clinical outcomes.

Potential benefits of biologics on stroke and mortality in patients with rheumatoid arthritis: A nationwide population-based cohort study in Taiwan.

AIM: To examine the changes in the risks of death and cardiovascular diseases (CVD) in rheumatoid arthritis (RA) patients treated with conventional synthetic or biologic disease-modifying antirheumatic drugs (csDMARD or bDMARD) during 1997-2013. METHODS: Two cohorts of RA patients and their matched controls were identified from the National Health Insurance Research database. There were 1569 patients in the csDMARD cohort who received cyclosporine ≥50 mg/d with concomitant usage of ≥2 csDMARDs during 1997-2003. There were 1530 patients in the bDMARD cohort if patients had ≥1 claim for bDMARD during 2003-2011. Adjusted hazard ratios (aHRs) for the risk of death, myocardial infarction, and stroke, were assessed using the Kaplan-Meier survival curves and the Cox proportional hazards models. RESULTS: Compared with matched cohorts, the incidence of death was higher with csDMARD with a more than 6-fold increase (csDMARD vs controls: 33% vs 5%); while it only increased with a much smaller magnitude with bDMARD (bDMARD vs controls: 15% vs 11%). In addition, an increase in the reduction of incidence rate of stroke with bDMARD (bDMARD vs controls: 2% vs 5%) than that with csDMARD (csDMARD vs controls: 3% vs 4%) was found. Results from multivariate analysis showed that RA patients receiving bDMARD had a significantly lower increase in the risk of deaths (aHR 1.05; 95% CI 0.84-1.33) compared with those receiving csDMARD (aHR 8.75; 95% CI 7.43-10.31). In addition, bDMARD was associated with a higher reduction in the risk of stroke compared with csDMARD (bDMARD: aHR 0.37; 95% CI 0.22-0.62; csDMARD: aHR 0.73; 95% CI 0.51-1.05). CONCLUSION: Biologics used in RA patients have been shown to have a beneficial impact on improving clinical outcomes, including decreased risks of death and stroke. The economic burden from costs of biologics may be alleviated by improving outcomes.

TNF-alpha suppressed TGF-beta-induced CTGF expression by switching the binding preference of p300 from Smad4 to p65.

TGF-beta regulates diverse biologic effects including cell growth, cell death or apoptosis, cell differentiation, and extracellular matrix (ECM) synthesis. Connective tissue growth factor (CTGF), induced by TGF-beta has been reported to mediate stimulatory action of TGF-beta-induced ECM. Although TNF-alpha was reported to suppress theTGF-beta-induced CTGF gene expression, the molecular mechanism is not well clarified. In this study, we found the inhibitory effect of TNF-alpha on TGF-beta-induced CTGF expression in WT but not p65-/-MEF cells. TNF-alpha neither induced Smad7 expression nor affected TGF-beta-induced Smad2 phosphorylation and nuclear translocation. We demonstrated that p300 physically associated with p65 rather than Smad4 in the presence of both TNF-alpha and TGF-beta. Moreover, the TGF-beta-induced binding of p300 and acetylated H4, but not Smad4 to the CTGF promoter was disturbed by TNF-alpha treatment. Overall, our data showed that suppression of TNF-alpha on TGF-beta-induced CTGF expression is due to the competition of p300 by p65 and Smad4.