Background/Purpose: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Post-baseline (BL) increases in mean low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were observed in Phase 3 (Ph 3) studies of tofacitinib (mostly with background DMARDs). In the Ph 3, 24-month (mo) ORAL Start study (NCT01039688), methotrexate (MTX)-naïve patients (pts) treated with tofacitinib monotherapy had significant and clinically meaningful improvements in RA signs and symptoms, physical function, and inhibition of radiographic progression vs MTX‑treated pts. Here, the lipid profile during tofacitinib monotherapy treatment over 24 mos was investigated in these MTX-naïve pts with RA.

Methods: Pts were randomized 2:2:1 to receive tofacitinib 5 mg twice daily (BID), tofacitinib 10 mg BID, or MTX (mean dose by Mo 3, 18.5 mg/week). LDL-C, HDL-C, and triglyceride (TG) levels were measured at BL and Mos 3, 6, 9, 12, 18, and 24, and descriptive statistics provided. Categorical changes (defined by National Cholesterol Education Program Adult Treatment Panel III) in LDL-C, HDL-C, and TG levels from BL to maximum on-treatment values through Mo 6 were compared using shift analyses.

Results: 956 pts were treated: tofacitinib 5 mg BID, n=373; tofacitinib 10 mg BID, n=397; and MTX, n=186. With both tofacitinib doses, median increases in LDL-C, HDL-C, and TG levels were observed at Mo 3 (first time point for analysis) but generally stabilized thereafter (Fig 1). Median increases and decreases in LDL-C, HDL-C, and TG levels were observed with MTX treatment (Fig 1). The total cholesterol (TC)/HDL-C ratio remained unchanged from BL through Mo 24 in all treatment groups. Categorical increases in lipid profile (ie shifts from a lower to higher lipid category) from BL through Mo 6 in pts receiving tofacitinib 5 mg BID, tofacitinib 10 mg BID, or MTX, respectively, were reported in: 52.2%, 57.3%, and 27.7% of pts for LDL-C; 5.7%, 10.2%, and 1.1% of pts for HDL-C; and 24.0%, 21.6%, and 14.7% of pts for TG levels. A similar percent of pts in each treatment group had BL LDL-C <130 mg/dL (tofacitinib 5 mg BID: n=251/362 [69.3%]; tofacitinib 10 mg BID: n=277/391 [70.8%]; MTX: n=132/184 [71.7%]). A minority of these pts had maximum on‑treatment LDL-C ≥160 mg/dL by Mo 6 (tofacitinib 5 mg BID: n=32/251 [12.7%]; tofacitinib 10 mg BID: n=38/277 [13.7%]; MTX: n=4/132 [3.0%]).

Conclusion: Tofacitinib monotherapy was associated with increases in LDL-C, HDL-C, and TG levels by Mo 3 (first time point measured) which generally stabilized thereafter. TC/HDL‑C ratios were unchanged across all treatment groups. These changes were consistent with changes observed in the tofacitinib Ph 3 program. Most pts had LDL‑C <130 mg/dL at BL and a minority of these had maximum on‑treatment LDL-C ≥160 mg/dL by Mo 6.

Fig 1. Median change (mg/dL) from BL in LDL-C (A), HDL-C (B), TG (C) at Mos 3, 9, 18, and 24 by treatment group