Baricitinib inhibits structural joint damage progression in patients with rheumatoid arthritis-a comprehensive review

Abstract

Baricitinib is an oral selective inhibitor of Janus kinase (JAK)1 and JAK2 that has proved effective and well tolerated in the treatment of rheumatoid arthritis (RA) in an extensive programme of clinical studies of patients with moderate-to-severe disease. In a phase 2b dose-ranging study of baricitinib in combination with traditional disease-modifying antirheumatic drugs (DMARDs) in RA patients, magnetic resonance imaging showed that baricitinib 2 mg or 4 mg once daily provided dose-dependent suppression of synovitis, osteitis, erosion and cartilage loss at weeks 12 and 24 versus placebo. These findings correlated with clinical outcomes and were confirmed in three phase 3 studies (RA-BEGIN, RA-BEAM and RA-BUILD) using X-rays to assess structural joint damage. In patients naïve to DMARDs (RA-BEGIN study), baricitinib 4 mg once daily as monotherapy or combined with methotrexate produced smaller mean changes in structural joint damage than methotrexate monotherapy at week 24. Differences versus methotrexate were statistically significant for combined therapy. In patients responding inadequately to methotrexate (RA-BEAM study), baricitinib 4 mg plus background methotrexate significantly inhibited structural joint damage at week 24 versus placebo, and the results were comparable to those observed with adalimumab plus background methotrexate. In patients responding inadequately to conventional synthetic DMARDs (csDMARDs; RA-BUILD study), baricitinib 4 mg again significantly inhibited radiographic progression compared with placebo at week 24. Benefits were also observed with baricitinib 2 mg once daily, but the effects of baricitinib 4 mg were more robust. The positive effects of baricitinib 4 mg on radiographic progression continued over 1 and 2 years in the long-term extension study RA-BEYOND, with similar effects to adalimumab and significantly greater effects than placebo. Findings from the phase 3 studies of patients with RA were supported by preclinical studies, which showed that baricitinib has an osteoprotective effect, increasing mineralisation in bone-forming cells. In conclusion, baricitinib 4 mg once daily inhibits radiographic joint damage progression in patients with moderate-to-severe RA who are naïve to DMARDs or respond inadequately to csDMARDs, including methotrexate, and the beneficial effects are similar to those observed with adalimumab.

Keywords: Baricitinib; Joint damage; Joint erosion; Radiographic progression; Rheumatoid arthritis.

Fig. 1

Inhibition of radiographic progression at week 24 with baricitinib, methotrexate and their combination in DMARD-naïve patients with early RA participating in RA-BEGIN [22]. a Least squares mean change from baseline in mTSS and its components, and b cumulative probability of distribution of change from baseline in mTSS (using linear extrapolation). The table shows the proportion of patients with no radiographic progression, measured as change in mTSS ≤ 0, ≤ 0.5 and ≤ SDC. p values for continuous and categorical data were obtained using analysis of covariance and logistic regression, respectively. *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001 versus methotrexate. Δ, change from baseline; JSN, joint space narrowing; LSM, least squares mean; MTX, methotrexate; SDC, smallest detectable change; mTSS, modified total Sharp score. Reproduced with permission from Fleischmann et al. [22]

Fig. 2

Inhibition of radiographic progression by baricitinib at 1 and 2 years in patients originally participating in RA-BEGIN, RA-BEAM and RA-BUILD, and then RA-BEYOND [12]. Graphs show least squares mean change from baseline (± SEM) in joint damage evaluated using a mTSS, b erosion score (ES) and c joint space narrowing (JSN) score. The tables show the number of patients with available data at each timepoint. Missing data were imputed using linear extrapolation. p values were obtained using a mixed model for repeated measures. *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001 for baricitinib 4 mg versus placebo (RA-BEAM, RA-BUILD) or methotrexate (RA-BEGIN); ⁺p ≤ 0.05, ⁺⁺p ≤ 0.01, ⁺⁺⁺p ≤ 0.001 for adalimumab versus placebo (RA-BEAM); ^‡p ≤ 0.05 for baricitinib 4 mg versus baricitinib 4 mg plus methotrexate (RA-BEGIN). ADA, adalimumab; Bari, baricitinib; LS, least squares; mTSS, van der Heijde modified Total Sharp Score; PBO, placebo; SEM, standard error of the mean. Reproduced with permission from van der Heijde et al. [12]

Fig. 3

Radiographic progression evaluated using cumulative percentile change in mTSS from baseline at 1 and 2 years by original randomisation for patients participating in a RA-BEGIN, b RA-BEAM and c RA-BUILD, and then RA-BEYOND [12]. Each point represents an individual patient. The table in each figure shows the proportion of patients with no radiographic progression (≤ SDC in mTSS). p values were obtained using a logistic regression model with treatment included as a factor. **p ≤ 0.01, ***p ≤ 0.001 for baricitinib 4 mg or adalimumab versus placebo or baricitinib 4 mg plus methotrexate versus methotrexate (RA-BEGIN). Δ, change from baseline; mTSS, van der Heijde modified Total Sharp Score; n, number of patients reaching threshold; N, number of patients with non-missing baseline and > 1 non-missing post-baseline mTSS values; N-obs, number of patients included in analysis; SDC, smallest detectable change. Reproduced with permission from van der Heijde et al. [12]

Fig. 4

a Observed and b adjusted proportions of patients with radiographic progression (CFB in mTSS > SDC) at week 52 in patients from RA-BEGIN with (group A) or without (group B) a sustained clinical response, defined as a DAS28-hsCRP score of ≤ 3.2 at weeks 16, 20 and 24. c Observed and d adjusted proportions of patients with radiographic progression at week 52 in patients with (group A) or without (group B) a sustained clinical response, defined as a SDAI score of ≤ 11 at weeks 16, 20 and 24 [11]. Adjusted proportions were estimated using a multivariable logistic regression model. Bari, baricitinib; CFB, change from baseline; DAS28-hsCRP, Disease Activity Score for 28-joint count based on high-sensitivity C-reactive protein; mTSS, van der Heijde-modified total Sharp score; MTX, methotrexate; SDAI, Simplified Disease Activity Index; SDC, smallest detectable change (1.4 in the RA-BEGIN modified intent-to-treat population). Reproduced with permission from van der Heijde et al. [11]

Fig. 5

Least squares mean change in radiographic progression from baseline to week 24 in 1234 patients with moderate-to-severe active RA participating in RA-BEAM [10]. Error bars indicate standard error. **p ≤ 0.01, ***p < 0.001 for baricitinib or adalimumab versus placebo. LSM, least squares mean; mTSS, van der Heijde modified Total Sharp Score; RA, rheumatoid arthritis. Reproduced with permission from Taylor et al. [10]

Fig. 6

Results of exploratory analyses from RA-BUILD: inhibition of radiographic progression at week 24 for baricitinib versus placebo in 684 patients with moderate-to-severe active RA [9]. a Least squares mean change from baseline in mTSS and its components and b proportion of patients with no radiographic progression. Error bars indicate standard error. *p ≤ 0.05, **p ≤ 0.01 versus placebo. LS, least squares; mTSS, van der Heijde modified Total Sharp Score; RA, rheumatoid arthritis. Figure 4a reproduced with permission from Dougados et al. [9]