Lipoprotein Changes Associated With RA Treatment Regimens

Decreases in RA disease activity were consistently associated with increases in levels of total cholesterol over time.

Researchers have found that in patients with early rheumatoid arthritis (RA), levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) increased as disease activity decreased, according to a study published in Arthritis & Rheumatology.1

While findings from previous studies have suggested that cholesterol levels may increase after RA treatment2, the cholesterol changes have varied widely depending on the study, and few studies had long-term follow up of large groups of patients with early RA prospectively randomized to receive biologic or nonbiologic therapies.

In order to evaluate changes in cholesterol levels in patients with early RA, Christina Charles-Schoeman, MD, and colleagues from the University of California, Los Angeles, analyzed data from 755 patients enrolled in the Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) study. This study examined changes in serum cholesterol levels after patients with early RA were randomized to 3 different treatment regimens:  methotrexate (MTX) monotherapy, MTX and etanercept combination therapy, or triple therapy with MTX and sulfasalazine (SSZ) plus hydroxycloroquine (HCQ).

After 6 months, patients receiving MTX monotherapy who had not achieved low disease activity (as defined by 28-joint Disease Activity Score-Erythrocyte Sedimentation Rate [DAS28-ESR] < 3.2) were “stepped up” to either MTX plus etanercept combination therapy or triple therapy, as determined by a baseline randomization algorithm. No further changes in treatment assignment were allowed after 24 weeks of the study.

The researchers found that RA disease activity, measured by DAS28, ESR, or CRP, was inversely related to levels of TC, LDL-C, and HDL-C.  However, the authors note, “despite the increase in TC, LDL-C and HDL-C, the TC/HDL-C ratio (the atherogenic index) decreased slightly in all treatment arms. Results from the Framingham Study have shown that the TC/HDL-C ratio was a better predictor of CHD risk than was LDL or TC”.

The researchers also found that among the 3 treatment regimens studied, triple therapy was associated with higher levels of HDL-C and lower LDL-C and LDL: HDL ratios when compared to patients who received either MTX monotherapy or MTX plus etanercept combination therapy. This persisted over the study’s 2-year follow up period, even after controlling for variations in disease activity and inflammation.

“It remains unclear whether increases in serum cholesterol levels over time are related solely to specific drug mechanisms, suppression of inflammation, or a combination of these and other patient factors,” the researchers wrote.

The researchers also noted that the marked increases in cholesterol levels at 6 months were not maintained for the duration of the 2-year study; lipid levels decreased after 6 months, particularly by 48 weeks, with smaller changes afterwards through 102 weeks.

Summary and Clinical Applicability

In patients with early RA, cholesterol levels rose as disease activity decreased after treatment with either biologic or nonbiologic therapies. Of the treatment regimens studied, triple therapy (MTX + SSZ + HCQ) was associated with higher levels of HDL-C and lower levels of LDL-C when compared to patients who received either MTX monotherapy or MTX plus etanercept combination therapy.

The authors conclude that, “Changes in lipids associated with initiation of effective RA treatments (including MTX monotherapy) appear to be less related to the specific type of RA therapy and more related to a decrease in inflammation”.

These findings are limited by the study population consisting only of patients with early (mean disease duration <6 months at baseline) and predominantly seropositive RA, thus limiting the extent to which this data may be generalized to all RA patients.

Clinicians should be aware of possible changes in cholesterol profiles in their patients with early RA initiating treatment in order to address modifiable risk factors of cardiovascular disease.


1.     Charles-Schoeman C, Wang X, Lee YY, et al. Association of Triple Therapy With Improvement in Cholesteral Profiles Over Two-Year Followup in the Treatment of Early Aggressive Rheumatoid Arthritis Trial. Arthritis Rheum. 2016; doi:10.1002/art.39502.

2.     Navarro-millán I, Charles-schoeman C, Yang S, et al. Changes in lipoproteins associated with methotrexate or combination therapy in early rheumatoid arthritis: results from the treatment of early rheumatoid arthritis trial. Arthritis Rheum. 2013;65(6):1430-8.