Research in context
Evidence before this study
We did a PubMed search using the terms “rheumatoid arthritis”, “Janus Kinase” and “clinical trial” (article type) on Nov 28, 2018, to identify reports of phase 3 efficacy and safety trials of Janus kinase (JAK) inhibitors in rheumatoid arthritis, and obtained 44 articles. Of these, one reported a phase 3 randomised controlled trial of a JAK inhibitor as monotherapy in patients with inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs; ORAL SOLO), and one, a phase 3 randomised controlled trial in patients with inadequate response to methotrexate (ORAL STRATEGY). ORAL SOLO compared 5 mg or 10 mg of tofacitinib twice daily with placebo, assessing 20% improvement in the American College of Rheumatology criteria (ACR20), health assessment questionnaire-disability index (HAQ-DI), and 28-joint disease activity score using erythrocyte sedimentation rate (DAS28[ESR]) at 3 months, showing significantly better responses on tofacitinib versus placebo for ACR20 and HAQ-DI, but not DAS28(ESR). ORAL STRATEGY assessed non-inferiority of 5 mg of tofacitinib twice-daily monotherapy to 5 mg of tofacitinib plus methotrexate or adalimumab plus methotrexate, for ACR50 at 6 months.
Added value of this study
ORAL SOLO and SELECT-MONOTHERAPY were done in similar patient populations with established disease (approximately 6–8 years of rheumatoid arthritis disease duration), and moderately-to-severely active disease as evidenced by mean DAS 28 using C-reactive protein, and swollen and tender joint counts. ORAL SOLO compared tofacitinib with placebo on discontinuation of methotrexate and other csDMARDs in all three study groups with a washout before receiving study drug or placebo, whereas in SELECT-MONOTHERAPY no washout was permitted; at baseline, patients who were assigned to receive upadacitinib monotherapy switched from their previous stable methotrexate to upadacitinib, while others continued with their previous dose of methotrexate as a blinded study drug.
The efficacy of once-daily 15 and 30 mg of upadacitinib in combination with background csDMARDs in patients with inadequate response to csDMARDs was assessed in the SELECT-NEXT study. This trial is the first study to assess upadacitinib as monotherapy. The responses with upadacitinib in both studies at 12–14 weeks were consistent, and upadacitinib monotherapy was superior to methotrexate continuation for clinical and functional improvements. In alignment with the goals of the treat-to-target strategy, the achievement of more stringent efficacy endpoints, such as remission and low disease activity by clinical disease activity index and simplified disease activity index, were assessed. Upadacitinib monotherapy resulted in 40–50% of patients with inadequate response to methotrexate achieving low disease activity, and almost 20% achieving stringent remission by week 14.
Implications of all the available evidence
The data from our trial are supportive of monotherapy with JAK inhibitors as a potential treatment option enabling disease control in patients with inadequate response to methotrexate, for whom combination treatment might be difficult for various reasons.