Baricitinib, Methotrexate, or Combination in Patients With Rheumatoid Arthritis and No or Limited Prior Disease-Modifying Antirheumatic Drug Treatment

Abstract

Objective: We undertook this phase III study to evaluate baricitinib, an orally administered JAK-1/JAK-2 inhibitor, as monotherapy or combined with methotrexate (MTX) compared to MTX monotherapy in patients with active rheumatoid arthritis (RA) who had received no or minimal conventional synthetic disease-modifying antirheumatic drugs (DMARDs) and who were naive to biologic DMARDs.

Methods: A total of 588 patients were randomized 4:3:4 to receive MTX monotherapy (once weekly), baricitinib monotherapy (4 mg once daily), or the combination of baricitinib and MTX for 52 weeks. The primary end point assessment was a noninferiority comparison of baricitinib monotherapy to MTX monotherapy based on the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 24.

Results: The study met its primary objective. Moreover, baricitinib monotherapy was found to be superior to MTX monotherapy at week 24, with a higher ACR20 response rate (77% versus 62%; P ≤ 0.01). Similar results were observed for combination therapy. Compared to MTX monotherapy, significant improvements in disease activity and physical function were observed for both baricitinib groups as early as week 1. Radiographic progression was reduced in both baricitinib groups compared to MTX monotherapy; the difference was statistically significant for baricitinib plus MTX. The rates of serious adverse events (AEs) were similar across treatment groups, while rates of some treatment-emergent AEs, including infections, were increased with baricitinib plus MTX. Three deaths were reported, all occurring in the MTX monotherapy group. Malignancies, including nonmelanoma skin cancer, were reported in 1 patient receiving MTX monotherapy, 1 receiving baricitinib monotherapy, and 4 receiving baricitinib plus MTX.

Conclusion: Baricitinib alone or in combination with MTX demonstrated superior efficacy with acceptable safety compared to MTX monotherapy as initial therapy for patients with active RA.

Trial registration: ClinicalTrials.gov NCT01711359.

Figure 1

Patient disposition through 52 weeks. Enrollment: Central and South America 29%, US and Canada 21%, Japan 18%, Europe 14%, rest of world 19%. MTX = methotrexate; LTE = long‐term extension.

Figure 2

Primary and secondary efficacy analyses. A, Percentage of patients meeting the American College of Rheumatology 20% improvement criteria (ACR20) over time through week 52. The vertical line at week 24 indicates the primary efficacy time point. B, Percentage of patients with a Disease Activity Score in 28 joints using the C‐reactive protein level (DAS28‐CRP) or with a DAS28 using the erythrocyte sedimentation rate (DAS28‐ESR) of <2.6 or ≤3.2 at weeks 24 and 52. Solid parts of bars represent the percentage of patients with a DAS28 of ≤3.2; patterned parts of bars represent the percentage of patients with a DAS28 of <2.6. C, Percentage of patients with a Clinical Disease Activity Index (CDAI) score of ≤10 or ≤2.8 at weeks 24 and 52, and percentage of patients with a Simplified Disease Activity Index (SDAI) score of ≤11 or ≤3.3 at weeks 24 and 52. For the CDAI, solid parts of bars represent the percentage of patients with a score of ≤10, and patterned parts of bars represent the percentage of patients with a score of ≤2.8. For the SDAI, solid parts of bars represent the percentage of patients with a score of ≤11, and patterned parts of bars represent the percentage of patients with a score of ≤3.3. D, Percentage of patients achieving improvement of ≥0.22 or ≥0.3 in the Health Assessment Questionnaire disability index (HAQ DI) score at weeks 24 and 52. ∗ = P ≤ 0.05; ∗∗ = P ≤ 0.01; ∗∗∗ = P ≤ 0.001 versus methotrexate (MTX) monotherapy, by logistic regression. MCID = minimum clinically important difference.

Figure 3

Radiographic progression of structural joint damage. A and B, Mean change from baseline in modified Sharp/van der Heijde score (SHS), erosion, and joint space narrowing (JSN) through week 24 (A) and week 52 (B). C and D, Cumulative probability distribution of change from baseline in SHS (using linear extrapolation) at week 24 (C) and week 52 (D). Tables within C and D show the percentage of patients with no radiographic progression as defined by change in SHS ≤0, ≤0.5, and less than or equal to smallest detectable change (SDC). ∗ = P ≤ 0.05; ∗∗ = P ≤ 0.01; ∗∗∗ = P ≤ 0.001 versus methotrexate (MTX) monotherapy. LSM = least squares mean.