SELECT-COMPARE – Upadacitinib for Rheumatoid Arthritis

Upadacitinib Versus Placebo or Adalimumab in Patients With Rheumatoid Arthritis and an Inadequate Response to Methotrexate: Results of a Phase III, Double-Blind, Randomized Controlled Trial

Fleischmann R, Pangan AL, Song IH, et al.

Arthritis Rheumatol. 2019 Nov;71(11):1788-1800. [Full text]

Summary by Alyssa Bosso

Treat-to-target guidelines for Rheumatoid Arthritis (RA) recommend adjusting therapy when disease activity persists to prevent joint damage, disability and other long-term sequelae including cardiovascular disease and osteoporosis. Biologic disease modifying antirheumatic drugs (bDMARDs) such as TNF inhibitors and IL-6 inhibitors have enabled disease control in many patients with an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (DMARDs) like first-line methotrexate. More recently, Janus Kinase (JAK) inhibitors, a class of targeted synthetic drugs (tsDMARDs) have emerged as an alternative treatment option for refractory RA with the advantage of oral administration.

SELECT-COMPARE is the largest of 6 global, phase III, double-blind, randomized-controlled trials of upadacitinib, a JAK1 selective inhibitor, in RA. It was powered to assess the superiority of upadacitinib over adalimumab, a TNF inhibitor, when added to stable background methotrexate in patients not at target with methotrexate alone [1].

Patient population and Design

RA patients that with >18 years of age and had an inadequate response to methotrexate were eligible. Included patients had received MTX for at least 3 months and met criteria for persistent active disease, defined as ≥ 6 swollen joints, ≥ 6 tender joints, and hsCRP ≥ 5mg/L. Additionally, either ≥ 3 erosions on hand/feet x-rays or ≥ 1 erosion plus RF or anti-CCP antibody positivity was required. Patients with prior exposure to adalimumab, prior exposure to a JAK inhibitor, inadequate response to a prior bDMARD or exposure to more than 1 bDMARD were excluded. Patients exposed to just 1 bDMARD could be included if they had < 3 months exposure or had discontinued the bDMARD due to intolerance, but these patients could only make up 20% of the study population.


Patients were randomized in a 2:2:1 ratio to receive upadacitinib 15mg daily, placebo, or adalimumab 40mg every other week, all while continuing methotrexate. The primary end points were achievement of an American College of Rheumatology 20% (ACR20) improvement response and a Disease Activity Score in 28 joints using C-reactive protein level (DAS28-CRP) of < 2.6 in the upadacitinib group compared to the placebo group at week 12.

Key ranked secondary end points included ACR50, DAS28-CRP ≤ 3.2, change in pain severity score, and change in Health Assessment Questionnaire disability index (HAQ-DI) in the upadacitinib group compared to the adalimumab group at week 12. Radiographic progression, measured by the Modified total Sharp score (mTSS), in the upadacitinib group compared to the placebo group was evaluated at week 26. Additionally, investigator-reported adverse events were collected and summarized up to week 26.


A total of 1629 patients were randomized and received at least 1 dose of study drug; n=651 for placebo group, n=651 for upadacitinib group and n=327 for adalimumab group. Baseline demographics and disease characteristics were balanced across the treatment arms. The trial met both of its primary endpoints for the comparison of upadacitinib versus placebo at week 12 (71% vs. 36% for ACR20 and 29% vs. 6% for DAS28-CRP<2.6; P ≤ 0.001 for both). Upadacitinib demonstrated superiority to adalimumab in all key ranked secondary endpoints: achievement of an ACR50 improvement response (45% vs. 29%; P ≤ 0.001), achievement of a DAS28-CRP score of ≤3.2 (45% vs. 29%; P ≤ 0.001), mean reduction in pain severity score (32.1mm vs. 25.6mm, P ≤ 0.001) and mean reduction in HAQ-DI (0.60 vs. 0.49; P ≤ 0.01).

The upadacitinib group showed less radiographic progression compared with the placebo group at week 26 (mean ΔmTSS: 0.24 vs 0.92; P ≤ 0.001) and had a greater proportion of patients with no radiographic progression (ΔmTSS ≤0: 86% vs. 76%; P≤0.01).

Total adverse events and rates of serious infection were higher in the upadacitinib and adalimumab groups compared to placebo group (Total AEs 64.2% UPA and 60.2% ADA vs. 53.2% PBO; serious infections: 1.8% UPA and 1.5% ADA vs. 0.8% PBO). More patients developed herpes zoster with upadacitinib than adalimumab (0.8% vs. 0.3%). Greater increases  in levels of LDL and HDL cholesterol, CPK and ALT/AST occurred in the patients receiving upadacitinib.


In SELECT-COMPARE, upadacitinib in combination with MTX demonstrated superiority for achievement of remission outcomes to the combination of adalimumab and MTX, the gold standard at the time for difficult-to-treat RA. These differences were observed as early as week 8 and persisted through week 26 of treatment. Based on the positive results from the SELECT program of multinational phase III trials, Upadacitinib received U.S. FDA approval for adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate in August 2019 [2].

Adverse events observed through week 26 of SELECT-COMPARE were summarized in Table 2. Later, the safety profile of in RA patients was assessed with an integrated analysis of 5 SELECT trials [3]. Upadacitinib at the approved dose of 15mg daily was associated with an increased risk of herpes zoster and CPK elevation versus placebo, adalimumab and MTX. This is consistent with other Rates of opportunistic infection, malignancy, major adverse cardiac events, and venous thromboembolism were comparable across the treatment groups.  

The 2021 American College of Rheumatology guidelines conditionally recommend addition of a bMARD or tsDMARD when patients taking maximally tolerated doses of methotrexate are not at target; no preference is given to either [4]. The guidelines also conditionally recommend switching to a bDMARD or tsDMARD of a different class over switching to a bDMARD or tsDMARD belonging to the same class, which demonstrates why it is useful to have multiple classes of DMARDs available.

F: Follow up12 weeks, additional end points at 26 weeks
R: Randomization2:2:1 to receive upadacitinib 15mg daily, placebo, or adalimumab 40mg every other week, in conjunction with a stable background dose of methotrexate. Stratified by prior exposure to biologic DMARD and geographic region
I: Intention to treatYes
S: Similar at baselinedemographic and disease characteristics were balanced across treatment groups. Age, sex, RA duration, MTX dose, oral glucocorticoid use/dose, disease activity scales, hsCRP levels, radiographic scores.
B: BlindingYes
E: Equal treatmentYes
S: Source (funding)AbbVie, Inc

  1. Tanaka Y. A review of upadacitinib in rheumatoid arthritis. Mod Rheumatol. 2020 Sep;30(5):779-787. doi: 10.1080/14397595.2020.1782049. Epub 2020 Jul 13. PMID: 32530345.
  2. Duggan S, Keam SJ. Upadacitinib: First Approval. Drugs. 2019 Nov;79(16):1819-1828. Doi: 10.1007/s40265-019-01211-z. PMID: 31642025.
  3. Cohen SB, van Vollenhoven RF, Winthrop KL, et al. Safety profile of upadacitinib in rheumatoid arthritis: integrated analysis from the SELECT phase III clinical programme. Ann Rheum Dis. 2020 Oct 28;80(3):304–11. doi: 10.1136/annrheumdis-2020-218510.
  4. Fraenkel, L, Bathon, JM, England, BR, et al.  (2021), 2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Care Res, 73: 924-939.