Effect of interleukin-6 receptor blockade on surrogates of vascular risk in rheumatoid arthritis: MEASURE, a randomised, placebo-controlled study

Abstract

Objectives: The interleukin-6 receptor (IL-6R) blocker tocilizumab (TCZ) reduces inflammatory disease activity in rheumatoid arthritis (RA) but elevates lipid concentrations in some patients. We aimed to characterise the impact of IL-6R inhibition on established and novel risk factors in active RA.

Methods: Randomised, multicentre, two-part, phase III trial (24-week double-blind, 80-week open-label), MEASURE, evaluated lipid and lipoprotein levels, high-density lipoprotein (HDL) particle composition, markers of coagulation, thrombosis and vascular function by pulse wave velocity (PWV) in 132 patients with RA who received TCZ or placebo.

Results: Median total-cholesterol, low-density lipoprotein-cholesterol (LDL-C) and triglyceride levels increased in TCZ versus placebo recipients by week 12 (12.6% vs 1.7%, 28.1% vs 2.2%, 10.6% vs -1.9%, respectively; all p<0.01). There were no significant differences in mean small LDL, mean oxidised LDL or total HDL-C concentrations. However, HDL-associated serum amyloid A content decreased in TCZ recipients. TCZ also induced reductions (>30%) in secretory phospholipase A2-IIA, lipoprotein(a), fibrinogen and D-dimers and elevation of paraoxonase (all p<0.0001 vs placebo). The ApoB/ApoA1 ratio remained stable over time in both groups. PWV decreases were greater with placebo than TCZ at 12 weeks (adjusted mean difference 0.79 m/s (95% CI 0.22 to 1.35; p=0.0067)).

Conclusions: These data provide the first detailed evidence for the modulation of lipoprotein particles and other surrogates of vascular risk with IL-6R inhibition. When compared with placebo, TCZ induced elevations in LDL-C but altered HDL particles towards an anti-inflammatory composition and favourably modified most, but not all, measured vascular risk surrogates. The net effect of such changes for cardiovascular risk requires determination.

Keywords: Cardiovascular Disease; DMARDs (biologic); Inflammation; Lipids; Rheumatoid Arthritis.

Figure 1

Study design. MTX, methotrexate; TCZ, tocilizumab. (A) *Patients who did not achieve ≥20% improvement from baseline in swollen and tender joint counts at week 16 were offered escape therapy with open-label TCZ 8 mg/kg. ^†60 placebo+MTX and 65 TCZ+MTX patients completed 12 weeks. ^‡59 placebo+MTX and 65 TCZ+MTX patients completed 24 weeks. (B) *TCZ 8 mg/kg every 4 weeks+background MTX (7.5–25 mg weekly). ^†Escape therapy, open-label TCZ (8 mg/kg every 4 weeks+background MTX). ^‡Patients who received at least one dose of TCZ (double-blind or open-label).

Figure 2

(A–F) Effects on lipoproteins (TCZ vs placebo). HDL, high-density lipoprotein; LDL, low-density lipoprotein; MTX, methotrexate; SAA, serum amyloid A; sPLA2-IIA, secretory phospholipase A2-IIA; TCZ, tocilizumab. *p<0.0001 (TCZ vs placebo).

Figure 3

(A–D) Effects on inflammatory and thrombotic markers (TCZ vs placebo). hs-CRP, high-sensitivity C-reactive protein; MTX, methotrexate; TCZ, tocilizumab. *p<0.0001 (TCZ vs placebo).