Safety profile of upadacitinib in patients at risk of cardiovascular disease: integrated post hoc analysis of the SELECT phase III rheumatoid arthritis clinical programme

Ann Rheum Dis. 2023 Sep;82(9):1130-1141. doi: 10.1136/ard-2023-223916. Epub 2023 Jun 12.


Objective: Increased risk of serious adverse events (AEs) was reported for tofacitinib relative to tumour necrosis factor inhibitor therapy in patients with rheumatoid arthritis (RA) aged ≥50 years enriched for cardiovascular (CV) risk (ORAL Surveillance). We assessed post hoc the potential risk of upadacitinib in a similar RA population.

Methods: Pooled safety data from six phase III trials were evaluated post hoc for AEs in patients receiving upadacitinib 15 mg once a day (with or without conventional synthetic disease-modifying antirheumatic drugs), adalimumab 40 mg every other week with concomitant methotrexate (MTX), or MTX monotherapy in the overall trial population and in a subset of patients with higher CV risk (aged ≥50 years, ≥1 CV risk factor). Higher-risk patients from a head-to-head study of upadacitinib 15 mg versus adalimumab (SELECT-COMPARE) were assessed in parallel. Exposure-adjusted incidence rates for treatment-emergent AEs were summarised based on exposure to upadacitinib or comparators.

Results: A total of 3209 patients received upadacitinib 15 mg, 579 received adalimumab and 314 received MTX monotherapy; ~54% of the patients were included in the overall and SELECT-COMPARE higher-risk populations. Major adverse cardiovascular events (MACE), malignancy (excluding non-melanoma skin cancer (NMSC)) and venous thromboembolism (VTE) were more frequent in the higher-risk cohorts versus the overall population but were generally similar across treatment groups. Rates of serious infections in higher-risk populations and herpes zoster (HZ) and NMSC in all populations were higher with upadacitinib 15 mg than comparators.

Conclusions: An increased risk of MACE, malignancy (excluding NMSC) and VTE was observed in higher-risk populations with RA, yet risk was comparable between upadacitinib-treated and adalimumab-treated patients. Higher rates of NMSC and HZ were observed with upadacitinib versus comparators across all populations, and increased rates of serious infections were detected in upadacitinib-treated patients at higher CV risk.

Trial registration numbers: NCT02706873, NCT02675426, NCT02629159, NCT02706951, NCT02706847 and NCT03086343.

Keywords: antirheumatic agents; arthritis; cardiovascular diseases; methotrexate; tumor necrosis factor inhibitors.

Publication types

  • Clinical Trial, Phase III
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adalimumab / adverse effects
  • Antirheumatic Agents* / adverse effects
  • Arthritis, Rheumatoid* / chemically induced
  • Arthritis, Rheumatoid* / drug therapy
  • Cardiovascular Diseases* / chemically induced
  • Cardiovascular Diseases* / drug therapy
  • Cardiovascular Diseases* / epidemiology
  • Herpes Zoster* / chemically induced
  • Herpes Zoster* / epidemiology
  • Heterocyclic Compounds, 3-Ring / adverse effects
  • Humans
  • Methotrexate / adverse effects
  • Treatment Outcome
  • Venous Thromboembolism* / chemically induced


  • Adalimumab
  • Antirheumatic Agents
  • Heterocyclic Compounds, 3-Ring
  • Methotrexate
  • upadacitinib

Associated data