Upadacitinib Demonstrates Higher Rates of Adverse Events Compared with Adalimumab in PsA


Both overall TEAEs and serious TEAEs were numerically higher in those receiving upadacitinib compared with adalimumab.

Upadacitinib Demonstrates Higher Rates of Adverse Events in PsA Compared with Adalimumab

Gerd R. Burmester, MD

Credit: ResearchGate

Compared with adalimumab, patients with psoriatic arthritis (PsA) treated with upadacitinib, an oral Janus kinase (JAK) inhibitor, reported higher rates of serious infection, lymphopenia, nonmelanoma skin cancer (NMSC), and herpes zoster, according to findings from an integrated analysis of the phase 2/3 and phase 3 SELECT trials published in Rheumatology and Therapy.1

These treatment-emergent adverse events (TEAEs) were also slightly elevated among patients with PsA receiving upadacitinib compared with patients with axial spondyloarthritis (axSpA) treated with the drug. Despite these results, upadacitinib 15 mg was well tolerated and showed a generally consistent safety profile with no new safety signals were reported.

“Advances in understanding the pathogenesis of SpA have led to a new therapeutic option with targeted, small-molecule JAK inhibitors, which have also been assessed for treating different immune-mediated inflammatory diseases (IMIDs),” wrote a group of investigators led by Gerd R. Burmester, MD, professor of medicine in the Department of Rheumatology and Clinical Immunology at the Charité University Hospital in Berlin, Germany.

Patients with IMIDs are more likely to develop infections and other adverse events due to both their health conditions and the use of immunomodulatory therapies, including JAKs. For example, the ORAL Surveillance study revealed treatment with tofacitinib, another JAK inhibitor, was linked to increased cardiovascular risks in patients with rheumatoid arthritis (RA), leading to questions about the safety of this class of drug for patients with rheumatic diseases.2

Investigators evaluated the safety profile of upadacitinib 15 mg for up to 5 years of exposure among patients with PsA, non-radiographic axSpA (nr-axSpA), and ankylosing spondylitis (AS) using safety data from 5 trials (2 in PsA [SELECT-PsA 1 and SELECT-PsA 2]; 2 in AS [SELECT-AXIS 1 and SELECT-AXIS 2]; and 1 in nr-axSpA [SELECT-AXIS2]). One of the PsA studies used adalimumab as an active comparator.

TEAEs, adverse events of special interest (AESI), and laboratory values were evaluated. TEAEs were collected and summarized for all studies and reported as exposure-adjusted event rates per 100 patient-years (E/100 PY).

In total, the studies included 1789 patients who received ≥ 1 dose of upadacitinib for 3689 PY of exposure or adalimumab (n = 429) for 1147 PY of exposure. Of these patients, 907 had a PsA diagnosis, 596 had AS, and 286 had nr-axSpA. Patients in the PsA group reported the highest maximum duration of treatment (5.0 years, median 2.9 years), while the nr-axSpA cohort had the shortest duration (2.2 years, median 1.0 years).

The rates of TEAEs raged from 183.9 E/100 PY in the AS cohort to 232.9 E/100 PY in the PsA group. Both overall TEAEs and serious TEAEs were higher in patients with PsA and were numerically higher in those receiving upadacitinib compared with adalimumab. However, rates were similar among the AS and nr-axSpA populations.

TEAEs that led to discontinuation were comparable across groups, although there was a numerically lower rate among the AS cohort. The most common adverse events were respiratory tract infection, COVID-19 infection, and nasopharyngitis.

Patients with PsA treated with upadacitinib had higher rates of herpes zoster, serious infection, lymphopenia, and NMSC compared with the adalimumab cohort. However, the rates of malignancy (besides NMSC), adjudicated venous thromboembolic events, and adjudicated major adverse cardiovascular events were comparable across treatment groups in PsA and similar across diseases.

Investigators mentioned the lack of placebo control arms, as well as having no active comparator in the AS and nr-axSpA groups, as limitations of the study. Further, as these were long-term extension trials, only the patients who met the previous eligibility criteria were included in the analysis.

“The safety of upadacitinib will continue to be monitored in the ongoing clinical trial program and post-marketing reports,” investigators concluded.


  1. Burmester GR, Stigler J, Rubbert-Roth A, et al. Safety Profile of Upadacitinib up to 5 Years in Psoriatic Arthritis, Ankylosing Spondylitis, and Non-radiographic Axial Spondyloarthritis: An Integrated Analysis of Clinical Trials. Rheumatol Ther. Published online April 29, 2024. doi:10.1007/s40744-024-00671-4
  2. Ramiro S, Nikiphorou E, Sepriano A, Ortolan A, Webers C, Baraliakos X, Landewe RBM, Van den Bosch FE, Boteva B, Bremander A, et al. ASAS-EULAR recommendations for the management of axial spondyloarthritis: 2022 update. Ann Rheum Dis. 2023;82:19–34.
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