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

Abstract

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. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-023-02732-6.

Biologics Versus JAK Inhibitors. Part I: Cancer Risk. A Narrative Review

“…In the three studies with abrocitinib, including 787 patients with AD, no cases of cancer were reported [ 77 , 99 , 100 ]. Regarding upadacitinib, a recent SR including 25 RCTs (> 10,000 patients) reported that most of the RCTs did not find a significant increase in the rate of malignancies with upadacitinib therapy when compared to placebo or to anti-TNFs [ 101 , 103 , 105 ]. However, an extended study of a phase 3 RCT (493 patients with RA) showed a higher rate of neoplasia in the 12 mg/day group, mainly at the expense of NMSC [ 102 ].…”

“…We found nine studies on the risk of neoplasms with selective JAK 1 (JAK-1) inhibitors: three focusing on abrocitinib [77,99,100] and six on upadacitinib [55,[101][102][103][104][105]. In the three studies with abrocitinib, including 787 patients with AD, no cases of cancer were reported [77,99,100].…”