In Rheumatoid Arthritis, Tailoring Treatments to Modify CV Risk is a Tricky Business
—Investigators conducted a secondary analysis of the TARGET trial to determine differences in cardiovascular risk between rheumatoid arthritis patients treated with triple therapy or tumor necrosis factor inhibitor.
In patients with rheumatoid arthritis (RA) who do not adequately respond to methotrexate, the addition of sulfasalazine and hydroxychloroquine (triple therapy) or tumor necrosis factor alpha inhibitor (TNFi) did not improve cardiovascular risk measured by vascular inflammation. Both treatment strategies did improve lipid profiles, however.
Katherine P. Liao, MD, MPH, of Harvard Medical School and the Division of Rheumatology, Inflammation, and Immunity at Brigham and Women’s Hospital, Boston, MA, and colleagues published their report in Arthritis Research & Therapy.1
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How was the study designed?
The investigators conducted a secondary analysis of the TARGET study which had 138 RA patients, with moderate disease activity and treated with Methotrexate (MTX) ≥15 mg. The current study had 122 patients where the median age was 57 years; 76% were female, RA disease duration was 1.5 years and the median MTX dose was 20 mg weekly. Those on statin therapy at baseline were excluded in this analysis. The participants were randomized to receive either triple therapy (methotrexate, sulfasalazine, and hydroxychloroquine; n=61) or a Tumor Necrosis Factor inhibitor (TNFi) in combination with methotrexate (n=61).
The primary outcome was the change in arterial inflammation as measured by fluorodeoxyglucose positron emission/computed tomography (FDG-PET/CT) scans of the carotid arteries and aorta, between the two treatment groups from baseline to 24 weeks. This change was measured using the mean of the maximum target-to-background ratio in the most diseased segment (MDS TBR) of arterial F-FDG uptake. The study also assessed if differential changes in lipid and lipoprotein parameters were associated with different changes in CV risk as measured by arterial FDG PET/CT.
Blood samples were also collected at the start and end of the study to measure routine lipids values and advanced lipoprotein parameters using nuclear magnetic resonance technology. In this secondary analysis, the authors compared the lipid profiles of the participants in each group to their FDG-PET/CT scans. Clinical disease activity data by using the Disease Activity Score 28 (DAS28)-CRP at the baseline and at the end of the study were collected.
Changes in routine lipid profile
Participants receiving triple therapy showed a modest increase of 3.1 mg/dl (P=.03) in high-density lipoprotein cholesterol (HDL-C) on average. A similar increase in HDL-C was seen in the TNFi group with an average increase of 2.9 mg/dl (P=.03). In terms of total cholesterol (TC), no change was seen in the triple therapy group while TC increased on an average by 11 mg/dl (P=.002) in the TNFi group. Similarly, no significant change in LDL-C was observed in the triple therapy arm but a 5.8 mg/dL increase on average (P=.02) was seen in the TNFi group. It is important to note that when comparing across treatment arms, no significant difference in change was observed. Participants on triple therapy had a larger reduction in TG to the TNFi arm after adjusting for multiple factors including disease activity. Also patients on triple therapy had a larger reduction of TC/HDL-C (average 0.28) after adjusting for disease activity.
Changes in advanced lipoproteins
For participants in the triple-therapy arm, there was a significant reduction in apolipoprotein B (5.4 mg/dL; P=.02) and LDL-P (75.3 nmol/L; P=.048), which are associated with lower cardiovascular risk. A small increase in LDL particle size (0.1 nm; P=.004) was also observed. HDL particle number demonstrated a decrease of 0.02 umol/L (P=.01).
For participants in the TNFi arm, there was an increase in apolipoprotein A1 (6.3 mg/dL; P=.01) and HDL particle number (1.2 umol/L; P=.004) levels, suggesting a beneficial effect on anti-atherogenic particles. The apolipoprotein B/apolipoprotein A1 ratio decreased, suggesting improved lipid metabolism.
Despite these changes in lipid profiles, there were no significant differences in arterial inflammation between the two treatment groups, as measured by FDG-PET/CT scans. “We expected lipid changes before and after treatment but were not sure exactly where the difference in change across treatments would lie,” Dr. Liao told 鶹ý. “With regards to the relationship between lipids and vascular inflammation, we were somewhat surprised that there was no association at all.”
What are the clinical implications?
The effects of RA treatments on lipid profiles highlight the need for tailored therapeutic approaches in certain situation. “…based on the findings of this study, if a patient with active RA is on a maximal dose of methotrexate, but has elevated triglycerides, one might consider favoring triple therapy over adding a TNFi to escalate therapy,” said Dr. Liao.
“However, since the difference in triglyceride change is modest, we would also need to take into account other important factors such as patient preference. Triple therapy involves taking 2 oral medications twice a day and 1 oral medication weekly, compared to methotrexate (taken weekly) and TNFi which is an injection or infusion where the shortest interval is weekly,” she added.
Moreover, the study suggests that monitoring advanced lipoprotein parameters could provide a more comprehensive understanding of CV risk in RA patients. Routine lipid measurements alone might not suffice, as advanced lipoproteins offer additional insights into atherogenicity and CV risk. “The biggest challenge was determining which lipid measurements to focus on after routine lipids,” said Dr. Liao. “There are myriad lipid biomarkers out there. We eventually focused on lipid and lipoprotein measurements that are available to order in clinical care, some more commonly ordered than others. In doing so, it is possible that we simply did not measure the biomarkers that differed greatly between the two treatment arms.”
This study had limitations, including 33% of subjects using low-dose steroids, which can affect total cholesterol and HDL-C levels. However, strict limits on steroid dosage changes were implemented, and baseline steroid use was similar between groups, with steroid use accounted for in the analysis.
Another limitation is the study's reliance on FDG-PET/CT scans to measure arterial inflammation. While this method is effective, it may not fully capture the CV risk changes associated with lipid modifications. The absence of significant correlations between lipid changes and arterial inflammation suggests that other factors might influence CV risk in RA patients.
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