Background/Purpose: Treatment with baricitinib (bari), an oral inhibitor of JAK1/JAK2, demonstrated improvements in signs and symptoms of RA through 52 wks in a Phase 2b study¹. Bari treatment also resulted in dose- and time-dependent changes in serum lipids detectable by Wk 2 and persisting through Wk 24 and was associated with increases in LDL particle size and HDL and VLDL particle numbers². Increases in HDL, but not LDL cholesterol, correlated with decreases in CRP at Wk 12. Changes from baseline in serum cholesterol through 52 wks of bari treatment as well as changes in the apolipoprotein content of LDL, VLDL, and HDL particles with bari treatment at Wks 4 and 12 were evaluated. The relationship between cholesterol changes and measures of clinical efficacy was also explored.

Methods: Patients (pts) with RA were randomized to QD doses of placebo (PBO) (n=98) or bari 1 mg (n=49), 2 mg (n=52), 4 mg (n=52), or 8 mg (n=50) for 12 wks. Pts assigned to 2-, 4-, or 8-mg bari continued blinded treatment for an additional 12 wks. Pts who completed the 24-wk study could enter a 2-yr, open-label extension. Serum samples were collected through 52 wks for conventional lipid determinations (total cholesterol, LDL, HDL, and triglycerides). Apolipoprotein content was assessed at Wks 4 and 12 for PBO, 4-, and 8-mg bari groups. Pearson correlations and partial correlations, adjusted for assigned treatments, between changes in cholesterol and efficacy measures were evaluated at 12 wks.

Results: Pts treated with bari through 52 wks maintained a stable cholesterol and triglyceride profile with no further changes beyond Wks 12 and 24. Increases in apolipoprotein A-I, apolipoprotein B, and total apolipoprotein CIII were observed with 4- and 8-mg bari with no increase in LDL-associated apolipoprotein CIII. Bari treatment also demonstrated a significant reduction in HDL-associated SAA at the 4- and 8-mg doses compared to PBO while a significant reduction in Lp(a) was observed only in the 8-mg bari group (all p<0.05). These changes in apolipoproteins coincided with the increases in serum lipids apparent by Wk 4. In pts treated across all doses of bari, a significant correlation was observed between change in HDL cholesterol and absolute DAS28-CRP score at Wk 12 (r=-0.33, p<0.001) as well as the change from baseline to Wk 12 in the DAS28-CRP (r=-0.29, p<0.001). Specifically, pts achieving DAS28-CRP <2.6 and larger decreases in DAS28-CRP demonstrated larger increases in HDL cholesterol. No significant correlations were observed in the PBO arm between HDL and disease activity measures and no significant correlations were observed between disease activity and total cholesterol or LDL levels in the bari arms.

Conclusion: In addition to increases in serum cholesterol and lipoprotein particle number (HDL and VLDL) and size (LDL), there were changes in apolipoprotein content of these particles in pts treated with bari. The increase in HDL cholesterol with bari treatment correlated with an improvement in DAS28-CRP. Further studies are necessary to determine if these changes influence long-term cardiovascular outcomes.

¹ Taylor P, et al. Ann Rheum Dis 2013;72:A65-A66

² Kremer J, et al. Ann Rheum Dis 2013;72(Suppl 3):241

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/increases-in-serum-cholesterol-with-baricitinib-treatment-are-associated-with-favorable-changes-in-apolipoprotein-content-and-with-improvement-in-das28-crp-in-patients-with-rheumatoid-arthritis/