Performance and predictors of minimal disease activity response in peripheral spondyloarthritis patients treated with adalimumab

Objectives: To examine concurrent validity and discrimination of modified minimal disease activity (mMDA) criteria in peripheral spondyloarthritis (pSpA) following OMERACT filter principles and determine predictors of mMDA response. Methods: Four mMDA versions were derived in the ABILITY‐2 study using the SPondyloArthritis Research Consortium of Canada (SPARCC) or Leeds Enthesitis Index (LEI) but excluding psoriasis. To assess concurrent validity, mMDA versions were correlated with Peripheral SpondyloArthritis Response Criteria (PSpARC) remission, Ankylosing Spondylitis Disease Activity Score for inactive disease (ASDAS ID), and physician global. Treatment discrimination was assessed between adalimumab and placebo at week 12. Multiple logistic regression was used to determine baseline predictors of long‐term mMDA responses and sustained mMDA. Results: The four mMDA versions showed a stronger positive correlation with PSpARC remission (rtet>0.95) versus ASDAS ID (rtet>0.75) at week 12 and years 1‐3 and were able to show discrimination (p<0.001). Responsiveness was shown at week 12; significantly more patients receiving adalimumab versus placebo achieved all four versions of mMDA. Approximately 40‐60% of adalimumab‐treated patients achieved mMDA‐LEI or SPARCC at years 1‐3. Achieving mMDA response after 12 weeks of adalimumab treatment was a robust positive predictor of attaining long‐term mMDA through 3 years (odds ratios: 11.38‐27.13 for mMDA‐LEI; 17.98‐37.85 for mMDA‐SPARCC). Conclusions: All four versions of mMDA showed concurrent validity and discriminated well between adalimumab and placebo treatment groups. Early mMDA response is a more consistent predictor of long‐term mMDA achievement than baseline characteristics. The 5 of 6 versions of mMDA could be an appropriate treatment target in pSpA patients.</p

A Phase 2b Study of ABT-494, a Selective JAK1 Inhibitor, in Patients With Rheumatoid Arthritis and an Inadequate Response to Anti–TNF Therapy

Objective: To compare the efficacy and safety of ABT-494, a novel selective Janus kinase 1 inhibitor, with placebo, in patients with moderate-to-severe rheumatoid arthritis (RA) and an inadequate response or intolerance to ≥1 anti–tumor necrosis factor (TNF) therapy. Methods: In this 12-week, double-blind, placebo-controlled, dose-ranging study, 276 patients with ≥1 prior anti-TNF therapy on a stable methotrexate dose were randomized equally to immediate-release ABT-494 3, 6, 12, or 18 mg twice daily or placebo. The primary endpoint was the proportion of patients achieving an ACR20 response at Week 12. Results: At Week 12, significantly more patients in the ABT-494 groups (53-71%) versus placebo (34%) achieved an ACR20 response (NRI, P<0.05), with a dose-response relationship among all ABT-494 doses (P<0.001). ACR50/70 response rates were significantly higher in the ABT-494 groups (35-42% and 22-26%) versus placebo (ACR50, 16% and ACR70, 4%). Changes in DAS28(CRP) [ΔDAS28(CRP)] were significantly greater for all doses of ABT-494 versus placebo (P≤0.001). Onset of action was rapid, with significant differences versus placebo at Week 2, in ACR20 and ΔDAS28(CRP) (P≤0.001 for 6-18 mg). The most frequent AEs were headache, nausea, upper respiratory and urinary tract infections. Infection rates were higher at higher doses of ABT-494, but none were serious. No deaths were reported on ABT-494. Conclusions: In patients with an inadequate response or intolerance to anti-TNF therapy, ABT-494 added onto methotrexate showed rapid, dose-dependent improvements in RA signs and symptoms, with similar safety and tolerability to drugs of this class. No new AEs were identified

Upadacitinib as monotherapy in patients with active rheumatoid arthritis and inadequate response to methotrexate (SELECT-MONOTHERAPY): a randomised, placebo-controlled, double-blind phase 3 study

Background: Upadacitinib, an oral Janus kinase (JAK)1-selective inhibitor, showed efficacy in combination with stable background conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in patients with rheumatoid arthritis who had an inadequate response to DMARDs. We aimed to evaluate the safety and efficacy of upadacitinib monotherapy after switching from methotrexate versus continuing methotrexate in patients with inadequate response to methotrexate. Methods: SELECT-MONOTHERAPY was conducted at 138 sites in 24 countries. The study enrolled adults (≥18 years) who fulfilled the 2010 American College of Rheumatology (ACR)–European League Against Rheumatism (EULAR) classification criteria for rheumatoid arthritis. Patients with active rheumatoid arthritis despite stable methotrexate were randomly assigned 2:2:1:1 to switch to once-daily monotherapy of upadacitinib 15 mg or 30 mg or to continue methotrexate at their existing dose as blinded study drug; starting from week 14, patients assigned to continue methotrexate were switched to 15 mg or 30 mg once-daily upadacitinib per prespecified random assignment at baseline. The primary endpoints in this report are proportion of patients achieving 20% improvement in the ACR criteria (ACR20) at week 14, and proportion achieving low disease activity defined as 28-joint Disease Activity Score using C-reactive protein (DAS28[CRP]) of 3·2 or lower, both with non-responder imputation at week 14. Outcomes were assessed in patients who received at least one dose of study drug. This study is active but not recruiting and is registered with ClinicalTrials.gov, number NCT02706951. Findings Patients were screened between Feb 23, 2016, and May 19, 2017 and 648 were randomly assigned to treatment. 598 (92%) completed week 14. At week 14, an ACR20 response was achieved by 89 (41%) of 216 patients (95% CI 35–48) in the continued methotrexate group, 147 (68%) of 217 patients (62–74) receiving upadacitinib 15 mg, and 153 (71%) of 215 patients (65–77) receiving upadacitinib 30 mg (p<0·0001 for both doses vs continued methotrexate). DAS28(CRP) 3·2 or lower was met by 42 (19%) of 216 (95% CI 14–25) in the continued methotrexate group, 97 (45%) of 217 (38–51) receiving upadacitinib 15 mg, and 114 (53%) of 215 (46–60) receiving upadacitinib 30 mg (p<0·0001 for both doses vs continued methotrexate). Adverse events were reported in 102 patients (47%) on continued methotrexate, 103 (47%) on upadacitinib 15 mg, and 105 (49%) on upadacitinib 30 mg. Herpes zoster was reported by one (<1%) patient on continued methotrexate, three (1%) on upadacitinib 15 mg, and six (3%) on upadacitinib 30 mg. Three malignancies (one [<1%] on continued methotrexate, two [1%] on upadacitinib 15 mg), three adjudicated major adverse cardiovascular events (one [<1%] on upadacitinib 15 mg, two [<1%] on upadacitinib 30 mg), one adjudicated pulmonary embolism (<1%; upadacitinib 15 mg), and one death (<1%; upadacitinib 15 mg, haemorrhagic stroke [ruptured aneurysm]) were reported in the study. Interpretation Upadacitinib monotherapy showed statistically significant improvements in clinical and functional outcomes versus continuing methotrexate in this methotrexate inadequate-responder population. Safety observations were similar to those in previous upadacitinib rheumatoid arthritis studies. Funding AbbVie Inc, USA