Introduction
Extraintestinal manifestations (EIMs) in patients with Crohn’s disease (CD) are challenging to treat and can negatively impact quality of life, with an estimated prevalence of 6–47%.1 The efficacy and safety of upadacitinib (UPA), an oral reversible Janus kinase inhibitor, was demonstrated in three phase 3 randomized controlled double-blind clinical trials; UPA has been approved for the treatment of moderately to severely active CD.2–6 We evaluated the effect of UPA treatment on EIMs in patients in these trials.
Aims & Methods
In two phase 3 induction studies, U-EXCEL (NCT03345849) and U-EXCEED (NCT03345836), patients with moderately to severely active CD were randomized 2:1 to receive 12 weeks of once-daily UPA 45 mg or placebo. Clinical responders to 12 weeks of UPA 45 mg were re-randomized 1:1:1 to the phase 3 maintenance study U-ENDURE (NCT03345823) for 52 weeks of once-daily treatment with UPA 15 mg, UPA 30 mg, or placebo. This analysis utilized EIM data from a form where investigators recorded the presence (yes/no) of 16 pre-specified EIMs. Baseline EIMs were assessed, as well as EIM resolution at weeks 12 of induction and 52 of maintenance therapy for patients with EIMs at induction baseline. Arthropathy EIMs (peripheral and axial arthropathy including sacroiliitis and ankylosing spondylitis), classic EIMs (arthropathy EIMs, episcleritis, uveitis, iritis, erythema nodosum, pyoderma gangrenosum, Sweet’s syndrome, and oral aphthous ulcers), anemia, and all EIMs (arthropathy and classic EIMs, anemia, primary sclerosing cholangitis, autoimmune hepatitis, venous thromboembolism, chronic obstructive pulmonary disease, bronchiectasis, and nephrolithiasis) were evaluated. Differences in EIM resolution rates with UPA vs placebo in the pooled induction and the maintenance studies were evaluated. Data were reported using non-responder imputation incorporating multiple imputation for missing data due to COVID-19.
Results
At baseline, EIMs were observed in 41.1% (420/1021) of patients included in the pooled induction studies, and 39.8% (200/502) of patients included in the maintenance study efficacy analyses (Table). At week 12 of induction, resolution rates of all EIMs, classic EIMs, and arthropathy EIMs were greater in those receiving UPA 45 mg (30.5%, 44.4%, and 44.3%, respectively) than in those receiving placebo (21.1%, 19.7%, 20.6%; P ≤ .05); resolution rates for anemia were greater with placebo vs UPA 45 mg (Table). At week 52 of maintenance, the resolution rates of all EIMs, classic EIMs, arthropathy EIMs, and anemia were higher with UPA 30 mg (35.6%, 30.6%, 31.9%, 44.4%; P ≤.05) and numerically greater with UPA 15 mg (24.6%, 19.4%, 22.6%, 27.6%) vs placebo (15.2%, 12.8%, 13.6%, 15.4%; Table).
| Table. Summary of EIM Resolution During Induction and Maintenance |
| Characteristic | Induction (12 weeks) | Maintenance (52 weeks) |
| PBO | UPA 45 mg | PBO | UPA 15 mg | UPA 30 mg |
Baseline EIMs, % (na)
Any EIMsb
Classic EIMsc
Arthropathy EIMsd
Anemia |
39.8
(138)
29.7
(103)
26.8
(93)
14.1
(49) |
41.8
(282)
28.8
(194)
27.2
(183)
17.8
(120) |
40.0
(66)
28.5
(47)
26.7
(44)
15.8
(26) |
36.1
(61)
21.3
(36)
18.3
(31)
17.2
(29) |
43.5
(73)
29.2
(49)
28.0
(47)
21.4
(36) |
Resolution e, %
Any EIMsb
Classic EIMsc
Arthropathy EIMsd
Anemia |
21.1
19.7
20.6
30.6 |
30.5*
44.4***
44.3***
22.5 |
15.2
12.8
13.6
15.4 |
24.6
19.4
22.6
27.6 |
35.6***
30.6**
31.9**
44.4** |
EIM, extraintestinal manifestation; PBO, placebo; UPA, upadacitinib.
P values were nominal and not multiplicity adjusted
*P ≤ .05; **P ≤ .01; ***P ≤ .001.
†P value was multiplicity adjusted.
‡P values were nominal and not multiplicity adjusted.
a The number of patients with the indicated EIMs at induction baseline.b Includes peripheral arthropathy, axial arthropathy (including sacroiliitis or ankylosing spondylitis), episcleritis, uveitis, iritis, erythema nodosum, pyoderma gangrenosum, Sweet’s syndrome, oral aphthous ulcers, anemia, primary sclerosing cholangitis, autoimmune hepatitis, venous thromboembolism, chronic obstructive pulmonary disease, bronchiectasis, and nephrolithiasis.
c Includes arthropathy EIMs (peripheral arthropathy and axial arthropathy [including sacroiliitis or ankylosing spondylitis]), episcleritis, uveitis, iritis, erythema nodosum, pyoderma gangrenosum, Sweet’s syndrome, and oral aphthous ulcers.
d Includes peripheral arthropathy and axial arthropathy (including sacroiliitis and ankylosing spondylitis).
e Among patients with the indicated EIM at baseline.
|
Conclusion
Patients with CD who received UPA generally had greater EIM resolution than did patients who received placebo. Over one-third of patients had early resolution of classic and arthropathy EIMs within 12 weeks of UPA treatment. In the maintenance study, UPA 30-mg treatment resulted in a significantly greater proportion of patients achieving EIM resolution than placebo treatment.
References
- Rogler G, et al. Gastroenterology. 2021;161:1118–1132.
- Colombel JF, et al. Gastroenterology. 2022;162(Suppl):1394.
- Loftus EV Jr. United European Gastroenterol J. 2022;10(Suppl 8):103-104.
- Panés J, et al. Am J Gastroenterol. 2022;117(Suppl):10.
- RINVOQ. Summary of Product Characteristics. AbbVie Deutschland GmbH & Co. KG; 2023. Accessed 24 April 2023. https://www.ema.europa.eu/en/documents/product-information/rinvoq-epar-product-information_en.pdf.
- RINVOQ. Summary of Product Characteristics. AbbVie Inc.; 2023. Accessed March 27, 2023. https://www.medicines.org.uk/emc/product/12830/smpc.
Disclosure
JFC has been a consultant or advisory board member for AbbVie, Amgen, Boehringer Ingelheim, Arena Pharmaceuticals, Celgene, Celltrion, Enterome, Ferring, Genentech, Johnson & Johnson, Lilly, Medimmune, Merck, Nextbiotix, Novartis, Otsuka, Pfizer, Protagonist, Second Genome, Gilead, Seres Therapeutics, Shire, Takeda, and Theradiag; a speaker for AbbVie, Celgene, Ferring, and Takeda; holds stock options for Intestinal Biotech Development and GENFIT; and has received research grants from AbbVie, Takeda, and Johnson & Johnson.
DPH has served as a consultant for AbbVie, Bristol-Myers Squibb, Fresenius Kabi, Janssen, Takeda, Pfizer, Prometheus, and UCB; and received research grants from Janssen and Pfizer.
QC has no disclosures to report.
SG has received consulting fees from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Gilead, Janssen, Pfizer, and Receptos; and speaker fees from AbbVie, Falk Pharma, Ferring, Janssen, Shield, and Takeda.
WR has served as a speaker for AbbVie, Celltrion, Falk Pharma GmbH, Ferring, Janssen, Galapagos Medice, MSD, Roche, Pfizer, Pharmacosmos, Shire, Takeda, Therakos, as a consultant for AbbVie, Amgen, AOP Orphan, Arena Pharmaceuticals, Astellas, Astra Zeneca, Bioclinica, Boehringer Ingelheim, Bristol Myers Squibb, Calyx, Celgene, Celltrion, Eli Lilly, Falk Pharma GmbH, Ferring, Galapagos, Gatehouse Bio Inc., Genentech, Gilead, Grünenthal, ICON, Index Pharma, Inova, Janssen, Landos Biopharma, Medahead, MedImmune, Microbiotica, Mitsubishi Tanabe Pharma Corporation, MSD, Novartis, OMass, Otsuka, Parexel, Periconsulting, Pharmacosmos, Pfizer, Protagonist, Provention, Quell Therapeutics, Sandoz, Seres Therapeutics, Setpointmedical, Sigmoid, Sublimity, Takeda, Teva Pharma, Therakos, Theravance, and Zealand; as an advisory board member for AbbVie, Amgen, Astra Zeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Galapagos, Janssen, Mitsubishi Tanabe Pharma Corporation, MSD, Pharmacosmos, Pfizer, Sandoz, and Takeda; and has received research funding from AbbVie, Janssen, MSD, Sandoz, Sanofi, and Takeda.
APL, ED, CD, SA, and TF are employees of AbbVie, and may own AbbVie stock and/or stock options.
DTR has served as a consultant for AbbVie, Altrubio, Arena Pharmaceuticals, Bristol-Myers Squibb, Genentech/Roche, Gilead, Iterative Scopes, Janssen, Lilly, Pfizer, Prometheus Biosciences, Takeda, and Techlab Inc.; and has received grants from Takeda.
Funding
AbbVie Inc. funded this study and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the abstract. All authors had access to relevant data and participated in the drafting, review, and approval of this abstract. No honoraria or payments were made for authorship. AbbVie and authors thank all the trial investigators and the patients who participated in this clinical trial. Medical writing support was provided by Morgan A Gingerich, PhD, of JB Ashtin, and funded by AbbVie.
