SAN FRANCISCO, CA—Patients with rheumatoid arthritis (RA) treated with 4 weeks of the JAK1 selective inhibitor filgotinib had a preferential increase in high density lipoprotein-cholesterol (HDL-C), investigators reported at the 2015 ACR/ARHP Annual Meeting.
“As a consequence, the atherogenic index in RA patients improved with doses of 150mg and 300mg once daily,” noted René Galien, PhD, of Galapagos SASU in Romainville, France, and colleagues.
“This correlated with changes in HDL-C proteins and enzymes involved in HDL-C homeostasis such as ApoA-1, paraoxonase-1 (PON-1), LCAT, and CETP, but not in those linked to low density lipoprotein-cholesterol (ApoB, PCSK9),” he added.
Patients with active RA typically present with low lipid levels, including total cholesterol, LDL-C, HDL-C, and triglycerides, “and yet are at a higher risk of cardiovascular disease,” Dr. Galien stated. “RA therapies may modulate lipid levels, presumably because of their anti-inflammatory effects, but some treatments preferentially increase LDL-C, thereby worsening the atherogenic index.”
Previously, treatment with filgotinib for 4 weeks showed little effect on LDL-C and a dose-dependent increase in HDL-C. The goal of this double-blind Phase 2A study was to characterize further the lipid profile of patients with RA patients after filgotinib treatment.
A total of 91 patients with insufficient response to methotrexate were randomly assigned to receive placebo or filgotinib 30mg, 75mg, 150mg, or 300mg once-daily orally for 4 weeks as add-on to methotrexate.
Blood was sampled predose and on the last day of treatment. Plasma PCSK9, ApoC-II, ApoC-III, SAA, and CETP concentrations were measured, as were plasma cholesterol (total and non-HDL-C), HDL-C, triglycerides, ApoA-I, and ApoB.
Results showed that compared to baseline, HDL-C increased after treatment with filgotinib 75mg, 150mg and 300mg, whereas total cholesterol and non-HDL-C increased in plasma only with the 300mg dose. The total cholesterol/HDL-C ratio, or atherogenic index, decreased after 4 weeks of treatment.
“Plasma concentrations of ApoA-I, ApoB, ApoC-II, and ApoC-III also indicated a preferential increase in HDL-C over LDL-C, with an increase in ApoA-I, and no change in ApoB concentrations, resulting in a decrease in ApoB/ApoA-I ratio,” the investigators reported. Further, concentrations of ApoC-II and ApoC-III were “not impacted by filgotinib treatment.”
CETP gene expression in circulating white blood cells decreased following treatment, as did protein concentration and enzyme activity in plasma. LCAT activity and paraoxonase-1 (PON-1) levels increased with filgotinib treatment; however, plasma concentration of PCSK9 did not change.
“Further longer-term studies are needed to confirm these findings and their cardiovascular relevance,” Dr. Galien concluded.