Background/Purpose: Rheumatoid arthritis (RA) increases patients’ risk of developing cardiovascular diseases (CVD). Hyperlipidemia is an important CVD risk factor in the general population. The objective of this study was to compare the risk of incident hyperlipidemia in early RA patients after initiation of disease modifying anti-rheumatic drugs (DMARDs).

Methods: We conducted a cohort study in patients receiving their first RA diagnosis after at least 12 months without evidence of RA or DMARD prescription, using insurance claims data (2001-2012). Four mutually exclusive groups were defined based on DMARD initiation, TNF-α inhibitors ± non-biologic (nb) DMARDs, methotrexate ± non-hydroxycholorquine nbDMARDs, hydroxychloroquine ± non-methotrexate nbDMARDs, and other nbDMARDs only. The primary outcome was incident hyperlipidemia as defined by a diagnosis and a prescription for a lipid-lowering agent. For the subgroup of patients with laboratory results available, we analyzed change in lipid levels as the secondary outcome. Multivariable Cox proportional hazard models estimated the relationship between DMARD use and incident hyperlipidemia. Propensity scores (PS) were calculated to improve confounding control. PS decile-stratified analyses were performed for each pairwise comparison after asymmetrically trimming at 2.5^th and 97.5^th percentile of the PS distribution to address confounding by indication.

Results: Of the 17,145 RA patients included in the study, 364 developed hyperlipidemia. The incidence rates (95% confidence interval (CI)) for hyperlipidemia per 1,000 person-years were 30.7 (21.9-41.8) for TNF-α inhibitors, 28.9 (24.9-33.4) for methotrexate, 20.1 (16.3-24.6) for hydroxychloroquine, and 36.4 (26.5-48.7) for other nbDMARDs.  The adjusted hazard ratios(HR) (95% CI) for hyperlipidemia were 1.41 (0.99-2.00) for TNF-α inhibitors, 0.81 (0.63-1.04) for hydroxychloroquine, and 1.33 (0.95-1.84) for other nbDMARDs compared with methotrexate in the full cohort, while 1.18 (0.80-1.73), 0.75 (0.58-0.98) and 1.41 (1.01-1.98), respectively in the PS trimmed cohort. In the subgroup analysis, hydroxychloroquine use showed significant reduction in low density lipoprotein (-8.9 mg/dl, 95% CI -15.8, -2.0), total cholesterol (-12.3 mg/dl, 95% CI -19.8, -4.8) and triglyceride (-19.5 mg/dl, 95% CI -38.7, -0.3) from baseline compared with methotrexate. 

Conclusion: Based on both a reduced adjusted HR for incident hyperlipidemia and a reduction in lipid levels, use of hydroxychloroquine may be associated with a lower risk of hyperlipidemia among early RA patients. A possible increase in the risk of hyperlipidemia in TNF-α inhibitor initiators was noted in our primary analysis, but not in the PS stratified analysis.  These findings suggest a complex relationship between DMARDs, inflammation and lipids.

Table: Relative risk of hyperlipidemia in patients with early rheumatoid arthritis based on DMARD use