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 of upadacitinib 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.