Drug elevates lipid particles that are thought to be protective, leaves proatherogenic particles unchanged, and reduces markers of inflammation.
Treatment with tocilizumab in patients with rheumatoid arthritis (RA) appears to exert a favorable effect on lipid particle components, elevating particles that are thought to be protective, but leaving proatherogenic particles unchanged. Additionally, tocilizumab reduces markers of inflammation within the lipid particles studied. These were the results of a randomized, double-blind, placebo-controlled mechanistic study reported at the 2010 Annual Scientific Meeting of the American College of Rheumatology.
Tocilizumab is an IL-6 inhibitor used to treat patients with moderate to severe RA who have not responded to at least one first-line therapy. These findings of the MEASURE study are important, because tocilizumab elevates lipid levels, and doctors currently monitor lipid levels in patients taking this drug. Despite the positive findings, the study is too small to say with certainty that lipid monitoring is not necessary, said lead author Iain B. McInnes, MD, University of Glasgow, UK.
This mechanistic experimental trial used nuclear magnetic spectroscopy to evaluate lipid particle size and measured a large range of biomarkers in patients with active RA and an inadequate response to methotrexate. Patients were randomized to tocilizumab plus methotrexate (n=70) versus placebo plus methotrexate (62 patients). Of these, 65 patients and 58 patients, respectively completed a full 12 weeks of therapy and were then continued on open-label tocilizumab. At baseline, one third had previously taken an anti-TNF inhibitor and one-quarter were on steroids.
“Although this was not an efficacy study of tocilizumab plus methotrexate, the drug worked to reduce signs and symptoms of RA,” McInnes told the audience.
Large LDL particles do not cross the endothelial barrier, whereas small LDL particles (the ones that are atherogenic) do. The study showed a significant increase in large, more buoyant LDL particles in the tocilizumab-treated group (P=.0026) but no change in small, dense LDL compared to placebo plus methotrexate. VLDL was increased quickly in the tocilizumab group and this increase was sustained throughout the 12-week study.
Within HDL, a significant increase in small HDL particles was observed (P=.0001) compared to placebo, with no change in large HDL. Small HDL particles are thought to be protective against inflammation, he said. Within the HDL particles, sustained and significant reductions in SAA, D-dimer, and PLA2-IIA (P<.0001 for all these markers of inflammation versus placebo) were observed in the tocilizumab-treated group. High sensitivity C-reactive protein (hs-CRP) was also significantly reduced in the tocilizumab group compared to placebo (P<.0001). “The anticipated reductions in prothrombotic factors [ie, D-dimer, fibrinogen, and LPa] in the tocilizumab group are gratifying,” McInnes said.
In summary, McInnes said that “the study suggests that IL-6 has been reversed by tocilizumab and that the drug worked.” Moreover, “the changes in lipid parameters that occur with tocilizumab treatment, coupled with reductions in a wide range of inflammatory markers demonstrate the intrinsic linkage between inflammation and metabolic regulation in the context of RA. Furthermore, reductions in prothrombotic factors reflect qualitative changes in lipoproteins that may favor improvements in cardiovascular risk-benefit,” he stated.