HDL Cholesterol Improves in RA with Anti-inflammatory Treatment

Anti-inflammatory treatment in rheumatoid arthritis patients, especially with infliximab added to methotrexate, improves HDL function and may potentially reduce cardiovascular risk, a study shows.

Cardiovascular disease is the foremost cause of mortality and morbidity in rheumatoid arthritis patients, and risk of cardiovascular disease is increased threefold in rheumatoid arthritis patients as compared to those without rheumatoid arthritis, according to a study published in a November issue of the journal Heart.

Increases in traditional risk factors, however, do not underlie the increased cardiovascular risk in rheumatoid arthritis. Rather, evidence suggests that the increased levels of inflammation associated with rheumatoid arthritis impair the reverse cholesterol transport and endothelial protective benefits usually conferred by HDL. On the contrary, research has shown HDL to become pro-inflammatory and pro-thrombotic in conditions like rheumatoid arthritis. This study shows that HDL benefits are restored by resolving the acute inflammatory stimulus, potentially reducing cardiovascular risk.

This was a 12-month randomized study that looked at the influence of methotrexate and the novel anti-inflammatory agent infliximab on HDL function and on cardiovascular risk factors in rheumatoid arthritis patients. It compared HDL function in 18 rheumatoid arthritis patients with 18 healthy controls, randomizing them to 54 week infusions of either methotrexate and infliximab (5 mg/kg) or methotrexate + placebo. All patients received infliximab thereafter until the trial’s completion at 110 weeks. HDL function was evaluated through measures of endothelial nitric oxide bioavailability, superoxide production, paraoxonase activity and cholesterol efflux at baseline, 54 weeks and 110 weeks.

Researchers reported that all HDL vascular assays were impaired at baseline in rheumatoid arthritis patients as compared with controls, with nitric oxide bioavailability reduced (p<0.01), superoxide production, increased (p<0.01) and paraoxonase activity reduced, also (p=0.03). After 54 weeks, while there were no significant changes in the methotrexate and placebo group, in the methotrexate and infliximab group total cholesterol increased from 5.01 mmol/L (1.5) to 6.23 mmol/L (1.63), p=0.04), and HDL increased from 2.90 mmol/L (1.34) to 3.65 mmol/L (1.22).

Responses to nitric oxide were greater in those patients who received methotrexate and infliximab as compared with methotrexate and placebo. In both groups, endothelial superoxide production responses to HDL were reduced, and paraoxonase activity and cholesterol efflux remained the same. In the 110-week analysis, all vascular measures improved relative to baseline in patients who had received ≥1 infliximab treatment. No significant trends were observed for cholesterol efflux.

The authors suggest that the superiority for methotrexate and infliximab over methotrexate and placebo with respect to HDL function indicates that the tumor necrosis factor (TNF)-α pathway may have a role in HDL vascular properties. TNF-α is a proximal cytokine, and its blockade’s anti-inflammatory effects on lipid metabolism are well-established.

The capacity of anti-inflammatory treatments to modify cardiovascular risk is under intensive study, with phase III studies of methotrexate, darapladib, and canakinumab ongoing. To date, darapladib, in the STABILITY and SOLID-TMI trials, has failed to reduce cardiovascular death. Methotrexate alone, the authors suggest, may not be sufficient, and inhibiting TNF-α, which is a broad immune effector, may better suppress inflammation and reduce cardiovascular risk.

Measuring and coming to better understanding of HDL function are both important, O’Neill et al. conclude. Their study “provides evidence for the use of anti-inflammatory treatments, particularly those modulating the tumor necrosis factor-α pathway, to restore the beneficial effects of HDL on the vasculature.”

References:

Francis O'Neill, Marietta Charakida, Eric Topham, et al. “Anti-inflammatory treatment improves high-density lipoprotein function in rheumatoid arthritis,” Heart. Nov. 16, 2016. DOI:  10.1136/heartjnl-2015-308953