1. Tumor necrosis factor antagonist use and associated risk reduction of cardiovascular events among patients with rheumatoid arthritis The Annals of the Rheumatic Diseases 2011;70:576–582. Prof. Lee Yeon Ah / R2 Hwang Jin Kyung Kyung Hee University Medical Center

2. Introduction In recent epidemiological studies, RA is associated with an increased risk of premature cardiovascular disease. Inflammation plays a key role in atherosclerosis among patients without an underlying inflammatory disease. Tumor necrosis factor-α antagonists –Have major advance of pain reduction and function improvement. –Reduce levels of CRP and pro-inflammatory cytokines. –Modify cardiovascular risk factors. (ex. insulin resistance and lipid metabolism) RA : Rheumatoid Arthritis

3. Introduction Published studies examining the association of anti-TNF with the risk of CV events have predominantly failed to demonstrate a reduced risk. However, promising results for improving CV outcomes with anti-TNF use have been reported by two European studies. The objective of this study Investigate the incidence of CV events among RA patients treated with anti- TNF, MTX, other non-biological DMARDs and prednisone in a large US- based cohort. CV : CardioVascular MTX : Methotrexate DMARDs : Disease-Modifying Antirheumatic Drugs

4. Methods Study design Population : RA patients, data from the Consortium of Rheumatology Researchers of North America (CORRONA) registry. Drug utilization : non-biological and biological DMARDs, established physician and patient-derived RA disease activity outcomes. Co-morbidities : CV risk factors and incident adverse events. Study approval : institutional review boards of participating academic sites, central institutional review board for community based private sites. CV : CardioVascular DMARDs : Disease-Modifying Antirheumatic Drugs

5. Methods Study population The CORRONA registry –Network of 268 participating academic and community rheumatologists at 103 sites in 35 states, USA. –Disease-based enrollment. Anti-TNF were prescribed to 43% of the study population. Current drug utilization and new drug starts are captured. Patients with and without a previous history of CV disease were included. CORRONA : Consortium of Rheumatology Researchers of North America CV : CardioVascular

6. Methods Endpoints The primary outcome –A composite CV endpoint (non-fatal MI, stroke/TIA) and CV-related death. The secondary outcomes –A composite of non-fatal CV events (non-fatal MI and stroke/TIA), as well as individual outcomes. All events were classified into one of four possible categories. –Definite/probable/possible/unlikely CV events –Events adjudicated as definite/probable  considered as true events. (positive predictive value : 95% for CV events) Death certificates were not collected as part of the study protocol, and thus case validation was limited to non-fatal CV events. CV : CardioVascular MI : Myocardiac Infarction TIA : Transient Ischemic Attack

7. Methods RA treatment exposure The index date for calculating drug exposure : the day of physician first reported prescribing the drug, ongoing non-biological or biological DMARD use at baseline was included. If the drug was started or stopped between study visits, the midpoint of the time interval was utilized. DMARD use category 1)TNF antagonist use : mono or combination therapy with non-biological DMARDs including MTX. 2)MTX use : mono or combination therapy with other non- biological DMARDs but not TNF antagonists. 3)Other non-biological DMARDs : excluding MTX and anti-TNF. Other biological agents (anakinra, abatacept and rituximab) were excluded.

8. Methods Covariates Demographics –Age, gender, race, BMI, education. RA-specific factors –RA factor, disease duration, nodules, disease activity level (DAS28) and physical function (modified HAQ score). CV risk factors –HTN, DM, previous MI, stroke or CAD, dyslipidemia, current smoking. Prednisone –Stratified into three dose categories : nonuse, 1–7 mg/day, ≥7.5 mg/day. NSAID –Naproxen, other non-selective NSAID and COX-2 selective inhibitors, aspirin. BMI : Body Mass Index CAD : Coronary Artery Disease DAS28 : Disease Activity Score in 28 joints HAQ : Health Assessment Questionnaire COX-2 : CycloOXygenase-2

9. Results Baseline characteristics according to medication exposure period TNF antagonist* : Mono or combination with any other DMARD, including MTX. Methotrexate† : Mono or combination with any other non-biological DMARD. No of unique patients‡ : Excludes patients without any DMARD therapy (N=373). BMI : Body Mass Index CAD : Coronary Artery Disease CDAI : Clinical Disease Activity Index COX-2 : CycloOXygenase 2 DAS28 : Disease Activity Score in 28 joints HAQ : Health Assessment Questionnaire MI : Myocardial Infarction NSAID : Non-Steroidal Anti-Inflammatory Drug RA : Rheumatoid Arthritis TIA : Transient Ischemic Attack TNF : Tumour Necrosis Factor.

10. Results Incidence rates of cardiovascular events by medication exposure Incidence rates expressed per 1000 patient years of exposure. Composite cardiovascular events* : includes MI, TIA/stroke and cardiovascular-related deaths. Adjusted risk of composite* cardiovascular events by DMARD and steroid exposure Adjusted for age, gender, smoking status, DM, HTN, dyslipidemia, Previous MI or stroke and HAQ score, aspirin use, naproxen use, NSAID use and COX-2 inhibitor use. Composite cardiovascular events* : includes MI, TIA/stroke and cardiovascular-related deaths. 26451788 + + =

11. Results Sensitivity analyses of risk of composite cardiovascular endpoint associated with TNF antagonist use The composite cardiovascular endpoint : includes MI, TIA/stroke and cardiovascular-related deaths. All HR reflect fully adjusted models for each endpoint, adjusting for age, gender, smoking status, DM, HTN, dyslipidemia, previous MI/stroke, modified HAQ score, aspirin use, naproxen use, NSAID use and COX-2 inhibitor use. *Shorter follow-up interval (<90 days) after last study visit for CV death ascertainment. †Longer follow-up interval (no limit) after last study visit for CV death ascertainment. CDAI : Clinical Disease Activity Index RF : Rheumatoid Factor Comparison of results for association of TNF antagonists with individual and composite cardiovascular endpoints All HR reflect fully adjusted models for each endpoint, adjusting for age, gender, smoking status, DM, HTN, dyslipidemia, previous MI/stroke, modified HAQ score, naproxen use, NSAID use and COX-2 inhibitor use.

12. Conclusion TNF antagonist use was associated with a reduced risk of cardiovascular events in patients with Rheumatoid arthritis.