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

Abstract

ObjectivesThe 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.MethodsRandomised, 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.ResultsMedian 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)).ConclusionsThese 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.

Pathogenetic insights from the treatment of rheumatoid arthritis

“…Larger epidemiologic registers have also revealed a protective effect of TNF inhibitors on cardiovascular events in RA [83,84]. The MEASURE study definitively linked IL-6R signalling to these lipid particle assembly changes in RA [85].…”

According to the Materials of the 2015/2016 New European League Against Rheumatism (Eular) Guidelines for Reducing Cardiovascular Risk in Patients With Inflammatory Arthritis: General Characterization and Discussion Problems

“…Применение ингибиторов ФНОα и БПВП (в основном MT) ассоциируется с увеличением концентрации ОХС, ХС ЛПНП и, в большей степени, ХС ЛПВП, что улучшает от-ношение ОХС/ХС ЛПВП [57][58][59][60][61][62][63][64][65]. В исследованиях сооб-щалось о положительном эффекте РТМ, тоцилизумаба и тофацитиниба на показатели липидного спектра крови [47,[66][67][68][69][70][71][72]. Однако общий эффект лечения этими препа-ратами проявляется в увеличении уровней липидов крови без изменений отношения ОХС/ХС ЛПВП [57,[68][69][70][71][72].…”

“…ГИБП способствуют более выраженному увеличению со-держания липидов и липопротеидов крови по сравнению с БПВП. Тем не менее показано улучшение антиатероген-ных свойств ХС ЛПВП на фоне терапии ГИБП [66,67].…”

Biological treatments

“…Sonuç olarak, TCZ tedavisi alt›ndayken lipid parametrelerinde gözlenen de¤i-flikliklerin, kardiyovasküler hastal›k için herhangi bir ek risk getirmedi¤i, aksine klinik parametrelerdeki düzel-me sayesinde riski azaltabilece¤i düflünülmektedir. [51] • ‹nfüzyon reaksiyonlar›: Bu tip reaksiyonlar›n s›kl›¤› 4 mg/kg dozu için %8, 8 mg/kg dozu için %7 olarak bildirilmifltir. ‹nfüzyon s›ras›nda kan bas›nc›nda düfl-me veya yükselme, ilk 24 saat içinde bafl a¤r›s› ve deri reaksiyonlar› görülebilir.…”