Rheumatoid arthritis (RA) treatments can reduce the risk for cardiovascular diseases (CVD) when restoration of normal HDL anti-oxidant functions is achieved, according to researchers at the University of California Los Angeles (UCLA).
The study, “Improvement in HDL Function in Early Rheumatoid Arthritis Patients Treated with Methotrexate Monotherapy or Combination Therapy in the TEAR Trial,” published in Arthritis and Rheumatology, may lead to the development of new targeted therapies for the prevention of CVD in RA patients.
Patients with RA have significant increased risk for CVD when compared to the general population. Though disease-modifying anti-rheumatic therapies for RA reduce CVD-related mortality, researchers have not fully understood how the drugs work toward the protective result.
The recent UCLA team study showed that high levels of RA inflammation, which is strongly linked with cardiovascular events, are also associated with abnormal function of HDL, the so-called good cholesterol.
HDL (complex particles composed of lipids, cholesterol, and several HDL-associated proteins) are known to have anti-oxidant and anti-atherogenic functions, which are important for lowering risk for cardiovascular events. But when systemic inflammation occurs, HDL becomes pro-inflammatory and non-protective, maybe because its proteins become altered.
The researchers hypothesized that drugs used for RA patients can improve the anti-oxidant function of HDL. The team examined data from 550 RA patients enrolled in the Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) 2-year trial (NCT00259610) who randomly received Rheumatrex (methotrexate) monotherapy, Rheumatrex plus Enbrel (etanercept), or triple therapy of Rheumatrex, Azulfidine (sulfasalazine), and Plaquenil (hydroxychloroquine).
Patients had minimal prior use of disease-modifying drugs, an average disease duration of less than 4.3 months; and more than 84 percent of the patients were positive for rheumatoid factor. Patients who did not achieve low disease activity after six months of Rheumatrex monotherapy were randomly assigned to the double or triple-therapy groups.
The researchers measured disease activity over a two-year follow-up through 28 joint count (DAS28), erythrocyte sedimentation rate (ESR), or C-reactive protein (CRP) levels. Disease activity was compared with HDL anti-oxidant function and with the levels of four HDL-associated proteins.
They found the decrease in disease activity in early RA patients in all three groups of the TEAR trial was associated with improvements in HDL function profile. Specifically, a 10-unit decrease in CRP was associated with a 2.34% decreased in the HDL inflammatory index, a 3.42% increase in paraoxonase (PON1) activity, a 8.74% increase in HDL-associated apolipoprotein AI, and a 3.53% reduction in HDL-associated haptoglobin.
Investigators also reported that higher BMI (indicating overweight or obese patients) was associated with higher HDL inflammatory index, but the use of statins (cholesterol lowering drugs) could lower HDL inflammation levels and promote better HDL anti-oxidant function.
For researchers, the findings indicate that the development of alternative targeted therapies could prevent high risk RA patients from cardiovascular events.