Tofacitinib improves atherosclerosis despite up-regulating serum cholesterol in patients with active rheumatoid arthritis: a cohort study

Abstract

Patients with rheumatoid arthritis (RA) have an increased cardiovascular (CV) risk. This study aimed to analyze the effects of Tofacitinib treatment, a Janus kinase inhibitor, on atherosclerosis in patients with RA. Patients with an active RA (28-joint disease activity score-erythrocyte sedimentation rate > 3.2) despite methotrexate (MTX) treatment 12 mg/week were included in this open-label prospective study and started on Tofacitinib (10 mg/day, 5 mg twice/day). Japanese guideline does not allow high dose of MTX. All patients used a stable dosage of MTX, steroids, and statins or lipid-lowering drugs. The primary endpoint was the comparison of the carotid intima-media thickness (CIMT) at the baseline and 54 weeks after Tofa treatment. Clinical data were collected at regular visits. Forty-six patients completed this study. CIMT did not significantly change from baseline to 54 weeks (1.09 ± 0.69 and 1.08 ± 0.78 mm, p = 0.82). In 12 patients who had atherosclerosis at baseline (carotid intima-media thickness > 1.10 mm), there was a significant decrease in CIMT (0.05± 0.026 mm; p < 0.05). However, the decrease in CIMT was of limited clinical significance. Tofacitinib increased fasting total cholesterol levels from baseline to 54 weeks (216 ± 25.3 and 234 ± 28.8 mg/dL, p < 0.01). Tofacitinib affects atherosclerosis in patients with active RA The CIMT in RA patients was stable. Tofacitinib decreased the CIMT of patients who had increased CIMT at baseline. Tofacitinib reduced RA disease activity and limited vascular damage despite up-regulating cholesterol in patients with an active RA.

Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs

“…Whether these changes increase the risk of cardiovascular disease is also unclear . In fact, jakinibs may limit vascular damage in patients with autoimmune disease despite increasing cholesterol …”

“…151,152 In fact, jakinibs may limit vascular damage in patients with autoimmune disease despite increasing cholesterol. 153 In April 2017, the US FDA expressed concern about thromboembolic events (deep venous thrombosis and pulmonary embolism) observed in clinical trials of baricitinib in RA. The European and Japanese labels for baricitinib were recently updated to include a precaution related to potential thromboembolic events in patients at risk, but the extent to which this complication is a significant risk for jakinibs in general needs further assessment, 154 particularly as many cause thrombocytopenia through their ability to inhibit TPO.…”

Impact of Janus kinase inhibitors on risk of cardiovascular events in patients with rheumatoid arthritis: systematic review and meta-analysis of randomised controlled trials

“…However, the role of these agents in the modulation of cardiovascular risk remains undetermined 15 16. Limited evidence suggested that tofacitinib-based therapy positively modifies the risk of cardiovascular disease,17 18 while a growing body of literature indicated that Jakinibs adversely affect several cardiovascular risk factors (such as serum lipid profile and platelet count) and potentially increase thrombotic risk which directly leads the US Food and Drug Administration (FDA) to restrict approval to only 2 mg baricitinib 19–22. Additionally, in upadacitinib premarketing trials, major adverse cardiovascular events (MACEs) continuously reported in patients with RA receiving upadacitinib has further generated cardiovascular concerns 23…”

Vascular and cerebral benefits of Tofacitinib in rheumatoid arthritis: evidence in rat adjuvant-induced arthritis

“…Tofacitinib improved ED in AIA and to investigate whether the bene ts of Tofacitinib on ED translate into a reduction of CV events in RA patients. Supporting this hypothesis, Tofacitinib tended to reduce carotid intima-media thickness in a small cohort of RA patients (43).…”