Safety of Upadacitinib in Immune-Mediated Inflammatory Diseases: Systematic Literature Review of Indirect and Direct Treatment Comparisons of Randomized Controlled Trials

Adv Ther. 2024 Feb;41(2):567-597. doi: 10.1007/s12325-023-02732-6.Epub 2024 Jan 2.


Eduardo Mysler 1Gerd R Burmester 2Christopher D Saffore 3John Liu 4Lani Wegrzyn 4Chelsey Yang 5Keith A Betts 6Yan Wang 6Alan D Irvine 7 8Remo Panaccione 9


Author information

1Rheumatology, Organización Medica de Investigación, Buenos Aires, Argentina.

2Department of Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany.

3AbbVie Inc, North Chicago, IL, USA. christopher.saffore@abbvie.com.

4AbbVie Inc, North Chicago, IL, USA.

5Analysis Group Inc., Beijing, China.

6Analysis Group Inc., Los Angeles, CA, USA.

7Department of Clinical Medicine, Trinity College Dublin, Dublin, Ireland.

8Wellcome-HRB Clinical Research Facility, St. James' Hospital, Dublin, Ireland.

9Division of Gastroenterology and Hepatology, Inflammatory Bowel Disease Unit, Cumming School of Medicine, University of Calgary, Calgary, Canada.


Introduction: Immune-mediated inflammatory diseases including rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), non-radiographic axial spondylarthritis (nr-axSpA), atopic dermatitis (AD), ulcerative colitis (UC), and Crohn's disease (CD) pose a substantial burden on patients and their quality of life. Upadacitinib is an orally administered, selective, and reversible Janus kinase inhibitor indicated for seven conditions, but data on its safety versus other active treatments are limited. A systematic literature review of indirect and direct treatment comparisons of randomized controlled trials (RCTs) was conducted to assess the safety profile of upadacitinib.

Methods: MEDLINE, Embase, and Cochrane Library databases were searched for indirect and direct treatment comparisons of RCTs that (1) included licensed upadacitinib dosages; (2) studied any of the seven conditions; (3) reported any adverse events (AEs), serious AEs (SAEs), AEs leading to discontinuation, major adverse cardiovascular event, venous thromboembolism, malignancies, infections or serious infections, and death; and (4) were published between January 2018 and August 2022.

Results: A total of 25 studies were eligible for inclusion. SAEs, AEs leading to discontinuation, and any AEs were commonly studied. RA was the most studied condition, followed by AD and UC. Most studies (16/25, 64%) reported no statistically significant difference in the studied safety outcomes between upadacitinib and other active treatments (e.g., tumor necrosis factor blockers, interleukin receptor antagonists, integrin receptor antagonists, T cell co-stimulation modulator), or placebo (placebo ± methotrexate or topical corticosteroids). Other studies (9/25, 36%) reported mixed results of no statistically significant difference and either statistically higher (8/25, 32%) or lower rates (1/25, 4%) on upadacitinib.

Conclusion: Most studies suggested that upadacitinib has no statistically significant difference in the studied safety outcomes compared to active treatments or placebo in patients with RA, PsA, AS, AD, UC, and CD. A few studies reported higher rates, but findings were inconsistent with limited interpretation.

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