15,000 Patient-Years: Safety Data for Upadacitinib Treatment Across Multiple Rheumatic Conditions

EULAR 2024 (Vienna)—In a poster presentation at EULAR 2024, Gerd R. Burmester MD, professor of medicine, Department of Rheumatology and Clinical Immunology, the Charité University Hospital, Free University and Humboldt University of Berlin, described the long-term, integrated safety profile of upadacitinib for multiple rheumatology indications. The investigators used data from the SELECT clinical trials with active comparators.¹

The review characterized the safety of upadacitinib across the following indications: rheumatoid arthritis (RA), psoriatic arthritis (PsA), axial spondyloarthritis (axSpA), ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-axSpA), resulting in more than 15,000 patient-years of exposure.

Background

Upadacitinib is an orally administered Janus kinase (JAK) inhibitor. This agent is approved by the U.S. Food & Drug administration (FDA) as a 15 mg extended-release tablet for the treatment of:

• Adults with active, moderate to severe RA who have had an inadequate response to or cannot tolerate methotrexate;
• Adults with active PsA who have had an inadequate response to or cannot tolerate one or more tumor necrosis factor (TNF) inhibitors;
• Adults and children 12 years of age and older with refractory, moderate to severe atopic dermatitis whose disease is not adequately controlled with other systemic drugs, including biologics, or when the use of those therapies is inadvisable;
• Adults with moderate to severe active ulcerative colitis or Crohn’s disease who have had an inadequate response to or cannot tolerate one or more TNF inhibitors;
• Adults with active AS who have had an inadequate response to or cannot tolerate one or more TNF inhibitors;
• Adults with active nr-axSpA with objective signs of inflammation who have not had an adequate response to or cannot tolerate TNF inhibitor therapy; and
• Patients 2 years of age and older with active polyarticular juvenile idiopathic arthritis or active PsA who have had an inadequate response to or cannot tolerate one or more TNF inhibitors.²

Methods

Safety data were analyzed from 11 upadacitinib clinical trials, assembled with a cutoff date of Aug. 15, 2023. Of these trials, six were on RA, two were on PsA, two were on AS and one was on nr-axSpA.¹

Any treatment-emergent adverse event that occurred at the beginning of the study, after the first drug dose, 30 days or fewer after the last drug dose of upadacitinib and methotrexate use (doses not stated)—or 70 days or fewer for adalimumab, which was given as a 40 mg dose every other week—were coded using the most current version of the Medical Dictionary for Regulatory Activities (MedDRA), which uses standardized medical terminology to facilitate the sharing of regulatory information and is used internationally to monitor adverse events. Treatment-emergent adverse events were summarized and presented as exposure-adjusted event rates (events/100 patient-years with 95% confidence intervals).

Deaths, cardiovascular events, venous thromboembolic events and gastrointestinal perforations were adjudicated by independent, blinded committees following pre-specified definitions.

Results

Overall, 4,998 patients received at least one 15 mg dose of upadacitinib, totaling 15,895.8 patient-years of exposure. Most of this exposure was from studies in RA (RA: n=3,209; PsA: n=907; AS: n=596; nr-axSpA: n=286).¹

The rate of adverse events that led to study drug discontinuation was similar across all treatment groups and diseases. Adverse events that led to upadacitinib discontinuation widely varied and included:

• Pneumonia (RA: n=22 of 459);
• COVID-19 (PsA: n=7 of 121);
• Headache (AS: n=3 of 42); and
• Worsening axSpA and pulmonary embolism (nr-axSpA: both n=2 of 20).

The serious infection rate and opportunistic infection rate were similar across all treatment groups and diseases. However, the rate of serious infection was higher with exposure to upadacitinib than with exposure to adalimumab in patients with PsA. The most common serious infection and serious adverse event in patients who received 15 mg of upadacitinib for all diseases was COVID-19-related pneumonia.

In the RA and PsA studies, patients taking 15 mg of upadacitinib more often experienced elevated creatine phosphokinase (CPK) and herpes zoster infection then those on the active comparator treatments. Also, the elevated rates of herpes zoster infection in upadacitinib-treated patients were comparable across all diseases represented in the current study.

Higher rates of nonmelanoma skin cancer occurred in patients with RA and PsA treated with upadacitinib than those who received methotrexate or adalimumab. Rates of malignancy—excluding nonmelanoma skin cancer—were similar across treatment groups and diseases. Similar rates of major adverse cardiac events and venous thromboembolic events occurred across treatment groups and diseases.

Rates of extra-musculoskeletal manifestations, including uveitis and inflammatory bowel disease, were generally low across PsA, AS and nr-axSpA in upadacitinib-treated patients. The highest number of extra-musculoskeletal manifestations was reported for uveitis in patients with AS.

The most common cause of death across all diseases was COVID-19/COVID-19 pneumonia.

Conclusion

With the exception of serious infection in PsA, herpes zoster infection, elevated CPK and nonmelanoma skin cancer, the rates of treatment-emergent adverse events were generally similar for patients treated with 15 mg of upadacitinib and active comparators in RA and PsA. Across patients with RA, PsA, AS and nr-axSpA, upadacitinib demonstrated a generally consistent safety profile, with no new safety risks identified with long-term treatment, as shown in previous reports.

More real-world data—especially for diseases with fewer clinical trials (i.e., AS and nr-axSpA)—are needed to further contextualize and confirm these findings.

Michele B. Kaufman, PharmD, BCGP, is a freelance medical writer based in New York City and a pharmacist at New York Presbyterian Lower Manhattan Hospital.

References

1. Burmester GR, Cohen SB, Deodhar A, et al. Safety of upadacitinib across rheumatoid arthritis, psoriatic arthritis, and axial spondyloarthritis encompassing 15,000 patient-years of clinical trial data [POS0894]. Ann Rheum Dis. 024;83:1137–1138.
2. Highlights of prescribing information: Rinvoq (upadacitinib) extended-release tablets. U.S. Food & Drug Administration. 2023 Apr 26.