Background/Purpose: Baricitinib (formerly, LY3009104/ INCB028050 ) is a novel, oral inhibitor of JAK1 and JAK2 in the JAK-STAT pathway. Primary results of this phase 2b study have already been reported and show that baricitinib reduces signs and symptoms of rheumatoid arthritis (RA) with no unexpected safety signals¹. MRI was used in this study to examine dose dependency of baricitinib on joint changes in a subgroup of patients (pts) with erosive RA and inadequate response to methotrexate (MTX).

Methods: In this phase 2b randomized, double-blind, placebo-controlled trial, 301 pts with active, established RA (≥ 8 swollen and 8 tender joints) on stable MTX were randomized 2:1:1:1:1 to placebo or 1 of 4 once-daily LY doses (1, 2, 4 or 8 mg) for up to 24 weeks. 208 pts (placebo [n=68], 1 mg [n=34], 2 mg [n=40], 4 mg [n=33], 8 mg [n=33]) with definitive radiographic erosion had MRI of the dominant hand/wrist at baseline, week 12 and week 24. Pts assigned to placebo or 1 mg were reassigned to an exploratory 4 mg or 2 mg twice daily group at week 12 and excluded from the 24-week analysis. Fat-suppressed, T1-weighted 3D gradient-echo and STIR images were obtained with and without gadolinium contrast using 1.5T MRI and a hand frame to ensure reproducible positioning. MR images were read independently by 2 expert radiologists blinded to treatment and visit order. Images were scored using RAMRIS and a validated 9-point cartilage loss scale. Total inflammation (osteitis + 3x synovitis) and total joint damage (erosion + 2.5x cartilage loss) scores were calculated. ANCOVA adjusting for baseline score and dose group was used for analysis. Due to the exploratory nature of the substudy, 1-sided p-values less than 0.1 were considered indicative of possible MRI difference (trends) vs placebo.

Results: There was a significant (≥ smallest detectable change ) decrease in osteitis over 12 weeks in 15% of pts on placebo vs 29% and 29% on baricitinib 4 and 8 mg, respectively. Similarly, synovitis decreased in 18% of pts on placebo vs 33% and 29% of pts on 4 or 8 mg baricitinib. Bone erosion did not progress in 80% of placebo vs 96% and 88% of pts on 4 or 8 mg baricitinib. Significant decreases in adjusted mean synovitis, osteitis and total inflammation scores were observed in the 4 mg and 8 mg groups compared to placebo at week 12 that persisted to week 24 (table 1). A trend in improvement in total joint damage was also observed for the 4 mg group. These MRI improvements correlated with significant improvements in tender and swollen joints in the 4 mg and 8 mg groups and with numeric decreases in median CRP.

Conclusion: MRI findings in this subgroup of pts with active erosive RA suggest dose-dependent suppression of synovitis, osteitis and total inflammation by baricitinib for the 4-mg and 8-mg groups at 12 and 24 weeks. These findings corroborate previously demonstrated clinical efficacy of bariticinib.

¹Keystone et al. Ann Rheum Dis 2012;71(Suppl3):152

Table 1:  MRI and Clinical Changes Over 12 and 24 weeks
		Baricitinib Treatment Groups
MRI and Clinical Parameters	Placebo	1-mg	2-mg	4-mg	8-mg
Synovitis
12-week LS Mean change p-value a 24-week mean change	-0.6 – –	-1.2 NS –	-0.6 NS -0.8	-1.6 .036 -1.7	-1.5 .047 -2.1
Osteitis
12-week LS Mean change p-value a 24-week mean change	-0.4 – –	-1.3 NS –	-0.8 NS -1.0	-3.6 <.001 -3.7	-2.2 .037 -2.1
Total Inflammation
12-week LS Mean change p-value a 24-week mean change	-2.1 – –	-4.9 NS –	-2.7 NS -3.5	-8.6 .003 -8.7	-6.6 .027 -8.3
Bone Erosion
12-week LS Mean change p-value a 24-week mean change	0.8 – –	0.1 .071 –	0.1 .051 0.5	0.3 NS -0.5	0.5 NS 0.2
Cartilage Loss
12-week LS Mean change p-value a 24-week mean change	-0.2 – –	-0.0 NS –	-0.2 NS 0.2	-0.4 NS -0.3	-0.2 NS -0.1
Total Joint Damage
12-week LS Mean change p-value a 24-week mean change	0.4 – –	0.1 NS –	-0.3 NS 0.9	-0.8 .068 -1.3	-0.1 NS -0.0
CRP (mg/L)
12-week median 24-week median	4.6 —	3.1 —	2.4 3.4	2.3 2.5	2.6 2.5
Tender joints (of 68)
12-week LS Mean change p-value b 24-week mean change	-7.5 —	-8.8 NS —	-10.8 .064 -12.4	-13.7 <.001 -14.0	-13.4 .001 -17.5
Swollen joints (of 66)
12-week LS Mean change p-value b 24-week mean change	-6.7 — —	-8.4 NS —	-8.0 NS -10.0	-10.5 <.001 -10.5	-10.1 .002 -12.2
a 1-sided comparison vs Placebo; b 2-sided comparison vs Placebo; NS=non-significant

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