Background/Purpose: Understanding interactions of inflammatory cytokines and lipid metabolism in RA is of considerable interest. Blocking IL-6 receptor elevates lipid levels in RA while lowering inflammatory disease activity¹. Sirukumab (SIR), a human monoclonal antibody that selectively binds to the IL-6 cytokine with high affinity, demonstrated efficacy in RA in the phase 3 SIRROUND studies. This study evaluated the relationships between lipid levels and the suppression of inflammation and disease activity by SIR compared to adalimumab (ADA) in patients with moderate to severe RA.

Methods: Plasma from the SIRROUND-H (monotherapy) study was evaluated: 99 patients in SIR 50mg q4w group, 95 patients in SIR 100mg q2w group, and 140 patients in ADA 40mg q2w group (subcutaneous). Fasting HDL, LDL, IDL, VLDL levels and concentrations of specific particles (large, medium, small, and, for LDL, very small) plus triglycerides were measured using NMR. Apolipoproteins (Apo) A1 and B, total cholesterol, and cholesterol/HDL ratio were measured at Covance, LLC. CRP and SAA were measured using ELISA. Disease activity was measured using CDAI and DAS(CRP). Analyses were performed at baseline (BL), Wk 4, Wk 8 and Wk 24 timepoints. We compared changes from BL using non-parametric Wilcoxon signed-rank and Mann-Whitney tests (comparisons between treatment groups).

Results: SIR treatment significantly increased cholesterol, triglycerides, ApoA1, ApoB, HDL, IDL, LDL, and VLDL levels (p<0.0001 both SIR groups Wk 24 vs BL) while minimal changes were observed with ADA treatment. Increases in lipid biomarkers by SIR were observed by Wk 4 and sustained through Wk 24. Total cholesterol, LDL and large LDL particles were inversely correlated with CRP, and large and medium HDL and medium and small VLDL particles were inversely correlated with both CRP and SAA levels at BL (p<0.0001, -0.42<r<-0.30). Post-treatment increases in lipids were associated with reduced inflammation with SIR treatment: increases in HDL correlated with decreased SAA while increased ApoA1, cholesterol, LDL, and large LDL particles correlated with strong suppression of CRP and SAA at Wk 4 (p<0.0001 and -0.43<r<-0.31). In contrast, these trends were not observed with ADA as lipid levels post treatment remained similar to BL. BL values and changes from BL in lipid parameters did not correlate with disease activity. Results were similar for both doses of SIR. These results were confirmed in the placebo-controlled SIRROUND-D study.

Conclusion: Patients with higher BL inflammation have lower starting lipid levels. IL-6 inhibition by SIR results in significant increases in lipid levels that correlate to suppression of acute phase reactants. These findings were not observed with ADA where lipid levels were generally unchanged. The results suggest that the increase in lipid levels with SIR may be at least in part associated with improvement of underlying inflammation in RA.

Reference:

1. Robertson J, et al. Nat Rev Rheumatol. 2013;9(9):513-23.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/increases-in-lipid-levels-following-sirukumab-treatment-are-associated-with-suppression-of-inflammation-in-rheumatoid-arthritis-results-from-two-phase-3-trials/