Introduction

Upadacitinib (UPA) is an oral, reversible Janus kinase inhibitor (JAKi) approved for the treatment of moderately to severely active Crohn’s disease (CD) and ulcerative colitis (UC).^1-4 Abnormal levels of liver enzymes are frequently encountered in patients with inflammatory bowel disease. However, data on liver enzyme elevations in UC and CD patients treated with JAKi are limited.

Aims & Methods

This post hoc analysis evaluated changes in liver enzymes over time in phase 3 trials of UPA in CD (U-EXCEL, U-EXCEED, U-ENDURE) and UC (U-ACCOMPLISH, U-ACHIEVE). Patients were randomized 2:1 to receive once-daily (QD) UPA 45 mg (UPA45) or placebo (PBO) induction therapy for 12 weeks (wks) in the CD trials and 8 wks in the UC trials.^3,4 Patients who achieved clinical response to UPA induction therapy were rerandomized (1:1:1) to PBO, UPA 15 mg (UPA15), or UPA 30 mg (UPA30) QD for the 52-wk maintenance studies.^3,4 Data from the induction studies were pooled, as were data from the maintenance studies. Least-squared (LS) mean changes from baseline (BL) in alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin (TBili) were calculated using ANCOVA models with treatment as a main factor, and BL and indication as covariates for induction and maintenance periods. The proportions of UPA-treated patients with Grade 3-4 liver enzyme elevations (ALT, AST, and ALP: >5.0 x upper limit normal [ULN]; TBili: >3.0 x ULN) were assessed.

Results

This analysis included 2,118 patients. At induction, BL mean [SD] ALT (PBO 19.4 [15.7] U/L; UPA45 18.2 [15.4] U/L), AST (PBO 19.5 [26.4] U/L; UPA45 17.8 [13.4] U/L), ALP (PBO 74.5 [25.8] U/L; UPA45 74.7 [35.2] U/L), and TBili (PBO 6.9 [4.4] μmol/L; UPA45 6.8 [4.0] μmol/L) were similar across treatment arms and within normal ranges. LS mean changes [SE] from BL in ALT, AST, ALP, and TBili were 4.7 [0.4] U/L, 4.7 [0.5] U/L, -8.7 [0.5] U/L, and 1.8 [0.1] μmol/L, respectively, by wk 4 of UPA induction and remained relatively stable across all treatment groups through wk52 of maintenance (Table). Incidences of Grade 3 or 4 elevations in liver enzymes were low throughout induction and maintenance (ALT: UPA45 1.1%, UPA15 2.1%, UPA30 1.0%; AST: UPA45 1.4%, UPA15 1.3%, UPA30 1.5%; ALP: UPA45 <0.1%, UPA15 0%, UPA30 0.2%; TBili: UPA45 0.4%, UPA15 0.4%, UPA30 0.6%). There were no events of drug-induced liver injury (DILI) in CD; 1 event was reported in UPA45 in UC induction, 1 event each in UPA15 and UPA30 in UC maintenance, all were nonserious and possibly attributed to other underlying conditions (i.e., alcohol) and/or concomitant medications (i.e., isoniazid, estrogen-containing contraceptive) (see Table footnotes).

Conclusion

Patients with moderately to severely active CD or UC receiving UPA experienced early changes in liver enzymes, which remained stable thereafter. Grade 3-4 elevations were rare and nonserious. Further evaluations of these liver enzyme changes and association with UPA benefit/risk over long-term extension studies are warranted.

References

1. 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. May 26 2022;399:2113-2128.
2. Loftus EV, Jr., Panés J, Lacerda AP, et al. Upadacitinib Induction and Maintenance Therapy for Crohn's Disease. N Engl J Med. May 25 2023;388(21):1966-1980. doi:10.1056/NEJMoa2212728
3. AbbVie. Rinvoq (Upadacitinib): Highlights of Prescribing Information [Package Insert]. AbbVie. Accessed March 21, 2024, //efaidnbmnnnibpcajpcglclefindmkaj/https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/211675s015lbl.pdf
4. AbbVie. Rinvoq (Upacitinib): Summary of Product Characteristics [Package Insert]. AbbVie. Accessed March 21, 2024, efaidnbmnnnibpcajpcglclefindmkaj/https://www.ema.europa.eu/en/documents/product-information/rinvoq-epar-product-information_en.pdf

Disclosure

AbbVie Disclosure: AbbVie Inc. funded these studies (U-EXCEL, NCT03345849; U-EXCEED, NCT03345836; U-ENDURE, NCT03345823) and UC (U-ACCOMPLISH, NCT03653026; U-ACHIEVE, NCT02819635) and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, writing and approval of the publication. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship.
Acknowledgments: AbbVie and the authors thank all the trial investigators and the patients who participated in these clinical trials. Paulette Krishack, PhD, and Jeanie Meckes, PhD, of AbbVie, provided medical writing assistance for the development of this publication.
Declaration of Interests:
Marla Dubinsky is a consultant for AbbVie, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Corporation, Eli Lilly, Gilead Sciences, Janssen Pharmaceuticals, Pfizer, Prometheus Labs, Sanofi, Shire, Takeda, and receives research grants from AbbVie and Janssen Pharmaceuticals.
Miguel Regueiro has served as a consultant, speaker and advisory board member for AbbVie
Christina Ha has received financial support from advisory board fees from AbbVie, Bristol Myers Squibb, Bausch Health, Roivant, Janssen, Pfizer, and Takeda; consultant fees from AbbVie; educational grant funding from Bristol Myers Squibb, Pfizer, Janssen, AbbVie and the Helmsley Charitable trust.
Gil Y. Melmed is a consultant for AbbVie, Arena, Boehringer Ingelheim, Bristol Myers Squibb, Dieta, Ferring, Fresenius Kabi, Genentech, Gilead Sciences, Lilly, Janssen, Oshi Health, Pfizer, Prometheus Labs, Samsung Bioepis, Shionogi, Takeda, and Techlab, Viatris He has received research grants from Pfizer.
Alessandro Armuzzi has received consulting and/or advisory board fees from AbbVie, Allergan, Amgen, Arena, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Galapagos, Gilead, Janssen, Lionhealth, MSD, Mylan, Nestlé, Pfizer, Protagonist Therapeutics, Roche, Samsung Bioepis, Sandoz, and Takeda; lecture and/or speaker bureau fees from AbbVie, Amgen, Biogen, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Galapagos, Gilead, Janssen, Merck & Co, Mitsubishi Tanabe, Novartis, Pfizer, Roche, Samsung Bioepis, Sandoz, Takeda and Tigenix; and research grants from Biogen, Merck & Co, Pfizer, and Takeda.
Peter M. Irving has received lecture fees from AbbVie, BMS, Celgene, Celltrion, Falk Pharma, Ferring, Galapagos, Gilead, MSD, Janssen, Pfizer, Takeda, Tillotts, Sapphire Medical, Sandoz, Shire, Warner Chilcott; Financial support for research: Celltrion, MSD, Pfizer, Takeda; Advisory fees: AbbVie, Arena, Boehringer Ingelheim, BMS, Celgene, Celltrion, Genentech, Gilead, Hospira, Janssen, Lilly, MSD, Pfizer, Pharmacosmos, Prometheus, Roche, Sandoz, Samsung Bioepis, Takeda, Topivert, VH2, Vifor Pharma, and Warner Chilcott.
Samuel I. Anyanwu, Elena Dubcenco, Fernando Aponte, Isheeta Shah, Tao Wang, Smitha Suravaram,and Hannah Palac are AbbVie employees and may own AbbVie stock and/or stock options.
David T. Rubin has served as a consultant for AbbVie, Altrubio, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Dizal Pharmaceuticals, Galapagos, Ichnos Sciences S.A., InDex Pharmaceuticals, Iterative Health, Janssen, Lilly, Pfizer, Prometheus Biosciences, Reistone, Syneos, and Takeda. He has received grant support from Takeda.

Clinical Case Summary

A 72-year-old man with a 49-year history of ulcerative colitis (UC), characterized as pancolitis and steroid-dependent, underwent routine surveillance colonoscopy. A congested, ulcerated mass was found in the recto-anal region, with no signs of active colitis in the rest of the colon.
From 2000–2012, he was treated with infliximab, discontinued due to secondary failure, followed by azathioprine (2012–2017), which was stopped due to leukopenia. Since then, he has been on vedolizumab. His medical history also includes hypertension and previous tobacco use.
The patient had been in clinical and biochemical remission for the last two years. Given his long-standing UC and the resection of a lateral spreading tumor (LST) via mucosectomy in 2019 showing hyperplastic mucosa with a focus of low-grade dysplasia, he has been under annual endoscopic surveillance.
At the current exam, a large exophytic, ulcerated mass with superficial necrosis and fibrin (Kudo IV) was seen in the recto-anal region, occupying approximately 1/6 of the luminal circumference and bleeding spontaneously.
Histology revealed a poorly differentiated neuroendocrine carcinoma (NEC) with a high proliferative index (Ki-67: 60%). Staging workup, including CT, pelvic MRI, and endoscopic ultrasound, identified a suspicious regional lymph node, that was confirmed by FDG-PET to be metabolically active.
After multidisciplinary discussion, the decision was made to start systemic chemotherapy without delay. If the patient responds, a total proctocolectomy with permanent ileostomy will be considered.
This case is notable for the rarity of recto-anal NECs, especially in UC patients. Their poor prognosis and unclear association with long-term UC or immunosuppressive treatment complicate management and raise important clinical questions.

References

Images that will be uploaded are: endoscopic findings of the colonic mass, histological specimens of the NEC, radiologic findings (PET)

Introduction

Iron deficiency anaemia (IDA) is a common comorbidity in inflammatory bowel diseases (IBD). Previous studies have already showed the predictive value of anaemia on hospitalization and mortality rates, however, these studies did not focus on the effect of IDA on patients with clinical and biochemical remission, however, due to the ethiopathology, certain effects are hypothesized.

Aims & Methods

This was a multicenter retrospective real-life cohort study assessing the effect of IDA on clinically and biochemically inactive IBD patients. We included patients from the outpatient setting who has been followed-up for a year. Patients with need of blood transfusion at baseline were excluded. IDA was defined as no clinical and biochemical activity, ferritin <30 μg/mL and transferrin saturation <20% with the presence of anemia. Primary outcome was disease aggravation, defined as need of change in the current treatment/hospitalization/abdominal surgery. Secondary outcome was proportion of major complications, defined as need of hospitalization/abdominal surgery. Pearson’s chi squared sample size calculation (n=720) was performed on our pilot results based on 200 IBD patients.

Results

In total, 711 patients (median age: 43.1 years [IQR: 32.3 - 49.6]; male/female ratio: 332/379; CD: 397, UC: 311; IDA/non-IDA 85/623) were enrolled. Mean follow-up period was 1.1±0.28 years. The presence of IDA increased the risk of disease aggravation (OR: 1.7) and major complications (OR: 2.8). Furthermore, male sex (OR: 0.6) and older age (OR: 0.8) were protective, and ileocoecal resection (OR: 2.0) and higher C-reactive protein levels (OR: 1.5) increased the disease aggravation.

Conclusion

IDA predicts the risk of relapse at some degree in patients with clinical and biochemical remission in the outpatient setting. IDA may help to identify underlying disease activity in patients with clinical and biochemical remission in time, therefore, we recommend to be implemented in the treat-to-target approach.