Rheumatoid arthritis patients treated with medications targeting the tumor necrosis factor (TNF) pathway or with standard disease-modifying anti-rheumatic drugs (DMARDs) showed substantial reductions in arterial inflammation, a key predictor of future cardiovascular disease, a randomized trial indicated.
After 24 weeks of treatment with a TNF inhibitor or with a three-DMARD combination regimen, patients had significantly lower values for the target-to-background ratio (TBR) in the carotid arteries and aorta relative to baseline, with little difference between the two study arms, reported Daniel Solomon, MD, of Brigham and Women's Hospital in Boston, and colleagues.
The reductions in this inflammation marker were "clinically important" but also somewhat puzzling, the researchers noted in Annals of the Rheumatic Diseases, because they expected the TNF inhibitors to outperform the DMARD combination.
"This theory was based on the fact that vascular endothelium is a select target for TNF where it induces pro-inflammatory, pro-coagulant and pro-apoptotic genes known to damage the endothelium," they wrote. "In addition, TNF induces endothelial adhesion molecules which mediate inflammatory cell trafficking to the arterial walls where oxidised low density lipoprotein (LDL) accumulates in an early stage of atherosclerosis."
Patients in the trial had active rheumatoid arthritis despite methotrexate treatment, suggesting they were experiencing "a high degree of systemic inflammation" that would diminish with any clinically effective step-up treatment, Solomon and colleagues speculated.
They conceived the study to evaluate the impact of different treatment strategies for rheumatoid arthritis on cardiovascular risk. Previous studies had indicated that biologic therapies do affect this risk, but they were largely observational or post-hoc analyses rather than randomized trials.
A total of 115 patients were assigned 1:1 to a TNF inhibitor (either adalimumab [Humira] or etanercept [Enbrel]) or to the addition of the DMARDs sulfasalazine and hydroxychloroquine to low-dose methotrexate for so-called triple therapy.
Mean patient age was just under 60, with disease duration averaging about 16 months. Some 70% were women and 80% were white. Arthritis severity ratings on the 28-joint Disease Activity Score (DAS28) system averaged 4.8 at enrollment.
TBR was assessed with 18F-fluorodeoxyglucose-PET and CT scans.
Mean baseline TBR values stood at 2.72 in the TNF inhibitor arm and 2.62 for those assigned to the triple DMARD regimen. After 24 weeks, these fell by 0.24 and 0.19 points, respectively. The difference between them did not approach statistical significance. The largest changes from baseline were seen in the aorta's most diseased segments.
Solomon and colleagues also looked for associations between the changes in TBR and DAS28 scores, finding only a very weak positive correlation.
Limitations to the study included the relatively small number of patients, short follow-up, and reliance on a biomarker of vascular inflammation instead of hard clinical outcomes. Solomon and colleagues explained that evaluating cardiovascular events would require "thousands of patients," far larger than any previous trial in rheumatoid arthritis patients.
Future studies could try other types of therapies such as inhibitors of the interleukin-6 and Janus kinase pathways and B-cell depletion, the researchers noted.
Disclosures
The study was funded by the National Institutes of Health; Amgen and AbbVie supplied the study drugs.
Solomon and other authors reported extensive relationships with pharmaceutical companies and other commercial entities.
Primary Source
Annals of the Rheumatic Diseases
https://www.medpagetoday.com/rheumatology/generalrheumatology/102023
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