Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Jun;11(3):737-753.
doi: 10.1007/s40744-024-00671-4. Epub 2024 Apr 29.

Safety Profile of Upadacitinib up to 5 Years in Psoriatic Arthritis, Ankylosing Spondylitis, and Non-radiographic Axial Spondyloarthritis: An Integrated Analysis of Clinical Trials

Gerd R Burmester  1 , Jayne Stigler  2 , Andrea Rubbert-Roth  3 , Yoshiya Tanaka  4 , Valderilio F Azevedo  5 , Derek Coombs  2 , Ivan Lagunes  2 , Ralph Lippe  2 , Peter Wung  2 , Lianne S Gensler  6
Affiliations

Safety Profile of Upadacitinib up to 5 Years in Psoriatic Arthritis, Ankylosing Spondylitis, and Non-radiographic Axial Spondyloarthritis: An Integrated Analysis of Clinical Trials

Gerd R Burmester et al. Rheumatol Ther. 2024 Jun.

Abstract

Introduction: This integrated analysis of the phase 2/3 and phase 3 SELECT trials describes the safety profile of upadacitinib, an oral Janus kinase inhibitor, for up to 5 years of exposure across psoriatic arthritis (PsA), ankylosing spondylitis (AS), and non-radiographic axial spondyloarthritis (nr-axSpA) (including pooled axial spondyloarthritis [axSpA]).

Methods: Safety data from five trials of upadacitinib in PsA (2 trials), AS (2 trials), and nr-axSpA (1 trial) were analyzed up to a data cut-off of August 15, 2022. One PsA study included adalimumab as an active comparator. Treatment-emergent adverse events (TEAEs) were summarized for PsA (pooled upadacitinib 15 mg once daily and adalimumab 40 mg biweekly), AS (pooled upadacitinib 15 mg), nr-axSpA (upadacitinib 15 mg), and pooled axSpA (pooled upadacitinib 15 mg from axSpA trials). TEAEs were reported as exposure-adjusted event rates per 100 patient-years (E/100 PY).

Results: A total of 1789 patients (PsA, n = 907; AS, n = 596; nr-axSpA, n = 286) received ≥ 1 dose of upadacitinib 15 mg for 3689 PY of exposure or adalimumab (n = 429) for 1147 PY of exposure. Overall TEAEs and serious TEAEs were highest in PsA and numerically higher with upadacitinib versus adalimumab; rates were similar between AS and nr-axSpA. In PsA, higher rates of serious infection, herpes zoster (HZ), lymphopenia, and nonmelanoma skin cancer (NMSC) were observed with upadacitinib versus adalimumab. Rates of malignancy excluding NMSC, adjudicated major adverse cardiovascular events, and adjudicated venous thromboembolic events were comparable between upadacitinib and adalimumab in PsA and were similar across diseases.

Conclusion: Higher rates of serious infection, HZ, lymphopenia, and NMSC were observed with upadacitinib versus adalimumab in PsA; slightly elevated rates for most of these TEAEs were seen with upadacitinib in PsA versus axSpA. Upadacitinib 15 mg demonstrated a generally consistent safety profile across disease states with no new safety signals identified.

Trial registration: SELECT-AXIS 1: NCT03178487; SELECT-AXIS 2: NCT04169373; SELECT-PsA 1: NCT03104400; SELECT-PsA 2: NCT03104374.

Keywords: Adalimumab; Ankylosing spondylitis; JAK inhibitor; Non-radiographic axial spondyloarthritis; Psoriatic arthritis; Safety; Upadacitinib.

Plain language summary

Psoriatic arthritis, ankylosing spondylitis, and non-radiographic axial spondyloarthritis are a group of diseases that cause pain and inflammation of the joints and/or spine. Safety data were combined from five studies: two in psoriatic arthritis, two in ankylosing spondylitis, and one in non-radiographic axial spondyloarthritis. Patients were treated with upadacitinib or adalimumab for up to 5 years. Adalimumab was only used for patients participating in one of the two psoriatic arthritis studies. Side effects from treatment were more common in patients with psoriatic arthritis than those with ankylosing spondylitis and non-radiographic axial spondyloarthritis; more patients with psoriatic arthritis had side effects with upadacitinib than adalimumab. A similar number of patients across treatment groups and diseases had side effects that made them stop treatment. The number of cancer cases (except cancer of the upper layer of the skin), cardiovascular issues, and blood clots were similar between the upadacitinib and adalimumab groups in psoriatic arthritis and across diseases. Serious infections, painful rashes that cause blisters (herpes zoster, also commonly referred to as shingles), low levels of white blood cells, and cancer of the upper layer of the skin were more common with upadacitinib than adalimumab in patients with psoriatic arthritis; overall, these events occurred more often with upadacitinib in patients with psoriatic arthritis than with ankylosing spondylitis and non-radiographic axial spondyloarthritis. Our results showed that the safety of upadacitinib was generally similar across diseases, and patients could tolerate it well for up to 5 years. No new safety risks were found with upadacitinib treatment.

PubMed Disclaimer

Conflict of interest statement

Gerd R. Burmester has received honoraria for consulting and lecture from AbbVie, Janssen, Novartis, and Pfizer. Andrea Rubbert-Roth has received honoraria for lectures and consulting fees from AbbVie, Amgen, BMS, Chugai, Eli Lilly, Gilead, Janssen, Novartis, Roche, and Sanofi. Yoshiya Tanaka has received speaker fees and/or honoraria from Eli Lilly, AstraZeneca, Abbvie, Asahi Kasei, Gilead, Chugai, Boehringer-Ingelheim, GlaxoSmithKline, Eisai, Taisho, BMS, Pfizer and, Taiho; received research grants from Asahi Kasei, Mitsubishi-Tanabe, Eisai, Chugai, and Taisho. Yoshiya Tanaka is also an Editorial Board member of Rheumatology and Therapy, however was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Valderilio F. Azevedo has received funding for clinical trials, research grants, and/or honoraria for lectures and advice from AbbVie, Amgen, Bristol-Myers Squibb, Celltrion, Eli Lilly, Fresenius Kabi, GSK, Janssen, Novartis, Organon, Pfizer, and UCB. Jayne Stigler, Derek Coombs, Ivan Lagunes, Ralph Lippe, and Peter Wung are employees of AbbVie Inc. and may hold stock or options. Lianne S. Gensler has received grants from Novartis and UCB Pharma paid to her institution and consulting fees from AbbVie, Fresenius Kabi, Gilead, Janssen, Eli Lilly, MoonLake, Novartis, Pfizer, and UCB Pharma.

Figures

Fig. 1
Fig. 1
Exposure-adjusted event rates for adverse events of special interesta. ADA adalimumab; AE adverse event; AESI adverse event of special interest; AS ankylosing spondylitis; axSpA axial spondyloarthritis; COVID-19 coronavirus disease 2019; CI confidence interval; CPK creatine phosphokinase; EMM extra-musculoskeletal manifestation; EOW every other week; IBD inflammatory bowel disease; MACE major adverse cardiovascular event; NMSC nonmelanoma skin cancer; nr-axSpA non-radiographic axial spondyloarthritis; PsA psoriatic arthritis; QD once daily; TB tuberculosis; UPA upadacitinib; VTE venous thromboembolism. aIncludes AS and nr-axSpA; UPA sample sizes include patients who switched from placebo. bOpportunistic infections excluding tuberculosis and herpes zoster. cPer the protocol, CPK elevation was not measured in the nr-axSpA study. dLymphoma AEs reported in patients with PsA treated with UPA 15 mg were transient abnormal lymphocyte morphology and were not confirmed to be true lymphomas. eMACE was defined as non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death. fVTE includes deep vein thrombosis and pulmonary embolism (fatal and non-fatal). gIBD includes inflammatory bowel disease, colitis ulcerative, ulcerative colitis, Crohn’s disease, ulcerative proctitis, and proctitis. hUveitis includes uveitis, iritis, and iridocyclitis. iPsoriasis includes psoriasis, nail psoriasis, guttate psoriasis, rebound psoriasis, pustular psoriasis, paradoxical psoriasis, erythrodermic psoriasis, psoriasis area severity index, psoriasis area severity index increased, psoriasis severity index decreased, psoriatic arthropathy, and juvenile psoriatic arthritis. AESIs are presented as exposure-adjusted incidence rates in Supplementary Materials Figure S2
Fig. 1
Fig. 1
Exposure-adjusted event rates for adverse events of special interesta. ADA adalimumab; AE adverse event; AESI adverse event of special interest; AS ankylosing spondylitis; axSpA axial spondyloarthritis; COVID-19 coronavirus disease 2019; CI confidence interval; CPK creatine phosphokinase; EMM extra-musculoskeletal manifestation; EOW every other week; IBD inflammatory bowel disease; MACE major adverse cardiovascular event; NMSC nonmelanoma skin cancer; nr-axSpA non-radiographic axial spondyloarthritis; PsA psoriatic arthritis; QD once daily; TB tuberculosis; UPA upadacitinib; VTE venous thromboembolism. aIncludes AS and nr-axSpA; UPA sample sizes include patients who switched from placebo. bOpportunistic infections excluding tuberculosis and herpes zoster. cPer the protocol, CPK elevation was not measured in the nr-axSpA study. dLymphoma AEs reported in patients with PsA treated with UPA 15 mg were transient abnormal lymphocyte morphology and were not confirmed to be true lymphomas. eMACE was defined as non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death. fVTE includes deep vein thrombosis and pulmonary embolism (fatal and non-fatal). gIBD includes inflammatory bowel disease, colitis ulcerative, ulcerative colitis, Crohn’s disease, ulcerative proctitis, and proctitis. hUveitis includes uveitis, iritis, and iridocyclitis. iPsoriasis includes psoriasis, nail psoriasis, guttate psoriasis, rebound psoriasis, pustular psoriasis, paradoxical psoriasis, erythrodermic psoriasis, psoriasis area severity index, psoriasis area severity index increased, psoriasis severity index decreased, psoriatic arthropathy, and juvenile psoriatic arthritis. AESIs are presented as exposure-adjusted incidence rates in Supplementary Materials Figure S2
Fig. 1
Fig. 1
Exposure-adjusted event rates for adverse events of special interesta. ADA adalimumab; AE adverse event; AESI adverse event of special interest; AS ankylosing spondylitis; axSpA axial spondyloarthritis; COVID-19 coronavirus disease 2019; CI confidence interval; CPK creatine phosphokinase; EMM extra-musculoskeletal manifestation; EOW every other week; IBD inflammatory bowel disease; MACE major adverse cardiovascular event; NMSC nonmelanoma skin cancer; nr-axSpA non-radiographic axial spondyloarthritis; PsA psoriatic arthritis; QD once daily; TB tuberculosis; UPA upadacitinib; VTE venous thromboembolism. aIncludes AS and nr-axSpA; UPA sample sizes include patients who switched from placebo. bOpportunistic infections excluding tuberculosis and herpes zoster. cPer the protocol, CPK elevation was not measured in the nr-axSpA study. dLymphoma AEs reported in patients with PsA treated with UPA 15 mg were transient abnormal lymphocyte morphology and were not confirmed to be true lymphomas. eMACE was defined as non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death. fVTE includes deep vein thrombosis and pulmonary embolism (fatal and non-fatal). gIBD includes inflammatory bowel disease, colitis ulcerative, ulcerative colitis, Crohn’s disease, ulcerative proctitis, and proctitis. hUveitis includes uveitis, iritis, and iridocyclitis. iPsoriasis includes psoriasis, nail psoriasis, guttate psoriasis, rebound psoriasis, pustular psoriasis, paradoxical psoriasis, erythrodermic psoriasis, psoriasis area severity index, psoriasis area severity index increased, psoriasis severity index decreased, psoriatic arthropathy, and juvenile psoriatic arthritis. AESIs are presented as exposure-adjusted incidence rates in Supplementary Materials Figure S2
Fig. 1
Fig. 1
Exposure-adjusted event rates for adverse events of special interesta. ADA adalimumab; AE adverse event; AESI adverse event of special interest; AS ankylosing spondylitis; axSpA axial spondyloarthritis; COVID-19 coronavirus disease 2019; CI confidence interval; CPK creatine phosphokinase; EMM extra-musculoskeletal manifestation; EOW every other week; IBD inflammatory bowel disease; MACE major adverse cardiovascular event; NMSC nonmelanoma skin cancer; nr-axSpA non-radiographic axial spondyloarthritis; PsA psoriatic arthritis; QD once daily; TB tuberculosis; UPA upadacitinib; VTE venous thromboembolism. aIncludes AS and nr-axSpA; UPA sample sizes include patients who switched from placebo. bOpportunistic infections excluding tuberculosis and herpes zoster. cPer the protocol, CPK elevation was not measured in the nr-axSpA study. dLymphoma AEs reported in patients with PsA treated with UPA 15 mg were transient abnormal lymphocyte morphology and were not confirmed to be true lymphomas. eMACE was defined as non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death. fVTE includes deep vein thrombosis and pulmonary embolism (fatal and non-fatal). gIBD includes inflammatory bowel disease, colitis ulcerative, ulcerative colitis, Crohn’s disease, ulcerative proctitis, and proctitis. hUveitis includes uveitis, iritis, and iridocyclitis. iPsoriasis includes psoriasis, nail psoriasis, guttate psoriasis, rebound psoriasis, pustular psoriasis, paradoxical psoriasis, erythrodermic psoriasis, psoriasis area severity index, psoriasis area severity index increased, psoriasis severity index decreased, psoriatic arthropathy, and juvenile psoriatic arthritis. AESIs are presented as exposure-adjusted incidence rates in Supplementary Materials Figure S2
See this image and copyright information in PMC

References

    1. Ehrenfeld M. Spondyloarthropathies. Best Pract Res Clin Rheumatol. 2012;26:135–145. doi: 10.1016/j.berh.2012.01.002. - DOI - PubMed
    1. Khan MA. Update on spondyloarthropathies. Ann Intern Med. 2002;136:896–907. doi: 10.7326/0003-4819-136-12-200206180-00011. - DOI - PubMed
    1. Fragoulis GE, McInnes IB, Siebert S. JAK-inhibitors. New players in the field of immune-mediated diseases, beyond rheumatoid arthritis. Rheumatology (Oxford) 2019;58:i43–i54. doi: 10.1093/rheumatology/key276. - DOI - PMC - PubMed
    1. Tanaka Y, Luo Y, O'Shea JJ, Nakayamada S. Janus kinase-targeting therapies in rheumatology: a mechanisms-based approach. Nat Rev Rheumatol. 2022;18:133–145. doi: 10.1038/s41584-021-00726-8. - DOI - PMC - PubMed
    1. Adas MA, Alveyn E, Cook E, Dey M, Galloway JB, Bechman K. The infection risks of JAK inhibition. Expert Rev Clin Immunol. 2022;18:253–261. doi: 10.1080/1744666X.2022.2014323. - DOI - PMC - PubMed

Associated data