Introduction
The Janus kinase inhibitor (JAKi) upadacitinib (UPA) is approved for the treatment of moderate-to-severe ulcerative colitis (UC). However, safety warnings from the US Food and Drug Administration and the European Medicines Agency recommend caution when using JAKis in certain at-risk patients. These drug-class warnings are based on data from the ORAL Surveillance (OS) study, a safety outcomes trial comparing risk of cardiovascular (CV) events with the JAKi tofacitinib plus methotrexate vs a tumor necrosis factor inhibitor (TNFi) plus methotrexate in patients with rheumatoid arthritis (RA) who were ≥50 years of age with ≥1 CV risk factor.1 An OS study post hoc analysis observed higher major adverse CV event risk with tofacitinib vs TNFi in patients with RA plus a history of atherosclerotic CV disease (ASCVD).2 CV risk profiles may be different for patients with UC vs RA.
Aims & Methods
This analysis aimed to describe the CV risk profile for patients with UC relative to the CV risk profile for patients with RA included in the OS study. Patients with UC enrolled in the placebo-controlled UPA U-ACHIEVE and U-ACCOMPLISH induction trials3 were evaluated for the OS study inclusion criteria (age ≥50 years, ≥1 CV risk factor [CV event history, hypertension, diabetes mellitus, smoking/tobacco use, and high-density lipoprotein cholesterol <1.034 mmol/L]). In addition, history of coronary artery disease or ASCVD and 10-year CV disease risk for patients with UC with no prior CV disease were estimated using the American College of Cardiology ASCVD risk score calculation.
Results
Overall, 268/1097 (24.4%) patients with UC met the OS criteria and 624 (56.9%) had ≥1 CV risk factor, regardless of age. Few patients with UC (30; 2.7%) had a history of ASCVD, in contrast to the RA population (640/4362; 14.7%). The distribution of 10-year ASCVD risk scores for patients with UC was similar between the placebo and UPA treatment arms, but markedly different from patients with RA (Table). Most patients with UC were categorized as low risk (938; 85.5%), with another 52 (4.7%) categorized as borderline risk, 51 (4.6%) as intermediate risk, and 26 (2.4%) as high risk.
| Patient Populationa
|
Ulcerative Colitis
|
| Rheumatoid Arthritis2
|
ASCVD riskb, n (%)
| Placebo
N = 378
| UPA 45 mg
N = 719
| TOFA 5 mg
N = 1455
| TOFA 10 mg
N = 1456
| TNFi
N = 1451
|
HxASCVD
| 10 (2.6)
| 20 (2.8)
| 204 (14)
| 222 (15)
| 214 (15)
|
High (≥20%)
| 6 (1.6)
| 20 (2.8)
| 258 (18)
| 289 (20)
| 278 (19)
|
Intermediate (≥7.5% to <20%)
| 19 (5.0)
| 32 (4.5)
| 472 (32)
| 490 (34)
| 483 (33)
|
Borderline (≥5% to <7.5%)
| 13 (3.4)
| 39 (5.4)
| 198 (14)
| 169 (12)
| 153 (11)
|
Low (<5%)
| 330 (87.3)
| 608 (84.6)
| 306 (21)
| 268 (18)
| 308 (21)
|
aIn the rheumatoid arthritis population, the 10-year risk scores were multiplied by 1.5 prior to the derivation of risk categories; in ulcerative colitis, no multiplier was used. bASCVD risk score was calculated based on the following factors: patient age, sex, race, systolic blood pressure, total cholesterol, HDL, history of diabetes [Y/N] or smoking [Y/N], and hypertension treatment [Y/N]). ASCVD, atherosclerotic cardiovascular disease; HxASCVD, history of ASCVD; TNFi, tumor necrosis factor inhibitors, TOFA, tofacitinib; UPA, upadacitinib
|
Conclusion
The majority of patients in the UC trials had low estimated CV risk, while the majority of patients with RA included in the OS study were at intermediate or high CV risk. Caution should be used when extrapolating adverse events data from patients with RA to risk discussions for patients with UC.
References
1. Ytterberg SR, Bhatt DL, Mikuls TR, et al. Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis. N Engl J Med 2022;386:316-326.
2. Charles-Schoeman C, Buch MH, Dougados M, et al. Risk of major adverse cardiovascular events with tofacitinib versus tumour necrosis factor inhibitors in patients with rheumatoid arthritis with or without a history of atherosclerotic cardiovascular disease: a post hoc analysis from ORAL Surveillance. Ann Rheum Dis 2023;82:119-129.
3. Danese S, Vermeire S, Zhou W, et al. Upadacitinib as induction and maintenance therapy for moderately to severely active ulcerative colitis: results from three phase 3, multicentre, double-blind, randomised trials. Lancet 2022;399:2113-2128.
Disclosure
L Peyrin-Biroulet has received personal fees from Galapagos, AbbVie, Janssen, Genentech, Alimentiv, Ferring Pharmaceuticals, Tillotts Pharma, Celltrion, Takeda, Pfizer, InDex Pharmaceuticals, Sandoz, Celgene, Biogen, Samsung Bioepis, Inotrem, Allergan, MSD, Roche, Arena Pharmaceuticals, Gilead, Amgen, Bristol Myers Squibb, CSL Vifor, Norgine, Mylan, Lilly, Fresenius Kabi, OSE Immunotherapeutics, Enthera, Theravance Biopharma, Pandion Therapeutics, Gossamer Bio, Viatris, and Thermo Fisher Scientific; grants from AbbVie, MSD, Takeda, and Fresenius Kabi; and stock options from CTMA.
RK Cross is an advisory board member and consultant for AbbVie, Adiso, BMS, Fresenius Kabi, Fzata, Janssen, Magellan Health, Pfizer, Samsung Bioepis, Sebela, and Takeda; and a member of the Executive Committee for the IBD Education Group and Scientific Co-Director of CorEvitas.
KM De Felice is an advisory board member and honorary speaker for AbbVie and BMS.
D Ilo, B Duncan, J Liu, and CTJ Holweg are employees of AbbVie Inc. and may hold AbbVie stock and/or stock options.
R Chowdhury has no conflicts of interest to declare.
This study was funded by AbbVie. Medical writing and editorial assistance were provided by Jeffrey Kohn, PhD, and Lauren Smith, BA (Hons), from Complete HealthVizion, an IPG Health Company, funded by AbbVie.
