Introduction

Upadacitinib (UPA), an oral, reversible JAK inhibitor approved for the treatment of moderately to severely active ulcerative colitis (UC),^1,2 has shown sustained efficacy and an acceptable safety profile in long-term studies of multiple autoimmune conditions.^3–5

Aims & Methods

We report efficacy and safety of UPA after almost 3 years (yrs) of therapy in patients (pts) with moderately to severely active UC from the U-ACTIVATE (NCT03006068) study, consisting of 1 yr maintenance and around 2 yrs long-term extension (LTE). Pts aged 16–75 yrs with UC for ≥90 days prior to study entry, an Adapted Mayo score (AMS) of 5–9 and an endoscopic subscore of 2 or 3, were eligible for induction studies (U-ACCOMPLISH [NCT03653026]; U-ACHIEVE Induction [NCT02819635]) and randomised to placebo (PBO) or UPA 45 mg once daily (QD) for 8 weeks (wks). Clinical responders were re-randomised to PBO, UPA 15 mg QD (UPA15) or UPA 30 mg QD (UPA30) for 52 wks (U-ACHIEVE Maintenance). Pts who completed 52-wks of maintenance were eligible to enter this LTE on their maintenance dose. Efficacy was evaluated by clinical remission (per AMS and Partial Mayo score), maintenance of clinical remission (per AMS), clinical response, endoscopic remission, endoscopic improvement and maintenance of endoscopic remission during the LTE at Wk 96 (endpoints are defined in the Table). Safety was assessed by treatment-emergent adverse events (TEAEs), presented as exposure-adjusted event rates (EAERs; events per 100 pt yrs [E/100 PY]). Efficacy and safety analyses were based on data up to June 30, 2023 and analysed as observed without imputation for missing values.

Results

At Wk 96, approximately three-quarters of pts with UC treated with either UPA15 or UPA30 achieved clinical remission (per AMS) (Table). Of pts in clinical remission at Wk 0 of the LTE (per AMS), a similar proportion maintained this response with UPA15 and a slightly higher response rate was observed with UPA30 at Wk 96 of the LTE. Clinical outcomes and endoscopic improvement were observed in the majority of patients in both UPA groups. Endoscopic remission was achieved by almost half of pts treated with UPA. Of endoscopic remitters at Wk 0 of the LTE study, more than half maintained remission status at Wk 96 of the LTE, with a slightly higher response rate observed with UPA30. For safety, 369 pts (UPA15, n=142; UPA30, n=227) with 789.4 PY (UPA15, 302.5 PY; UPA30, 486.9 PY) of exposure were analysed. Rates of serious TEAEs and TEAEs leading to treatment discontinuation were similar across treatment groups. No deaths were reported in the UPA15 group; there was 1 TEAE leading to death (EAER: 0.2 E/100 PY) in a pt requiring prolonged hospitalisation for worsening COVID-19 infection in the UPA30 group (Table).

Table. Summary of efficacy and safety^a (as observed)

Conclusion

Achievement of clinical and endoscopic endpoints at LTE Wk 96 demonstrates the continued benefit of almost 3 yrs of therapy with UPA. The long-term safety profile for UPA in pts with UC was consistent with previous analyses,^1,2 with no new safety concerns identified in this ongoing LTE study.

References

1. Danese S, et al. Lancet 2022;399:2113–28
2. Vermeire S, et al. Lancet Gastroenterol Hepatol 2023;8:976–89
3. Baraliakos X, et al. Arthritis Res & Ther 2023;25:172
4. Fleischmann R, et al. RMD Open 2022;8:e002012
5. Simpson EL, et al. JAMA Dermatol 2022;158:404–13

Disclosure

RP has received consulting fees, speaker fees and research support from Abbott, AbbVie, Alimentiv, Amgen, Arena Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Élan, Ferring, Galapagos, Genentech, Gilead, GlaxoSmithKline, Janssen, Lilly, Merck, Mylan, Oppilan Pharma, Pandion Pharma, Pfizer, Progenity, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Schering-Plough, Shire, Sublimity Therapeutics, Takeda, Theravance and UCB.
PDRH has received grants from AbbVie, Connectome Coordination Facility, National Institute of Health and Takeda; and has served as a consultant for GI Health Foundation, Imedex, Lilly, Pfizer, Takeda and Vindico Medical Education.
HN has received research support from AbbVie, Celgene, Daiichi Sankyo Company, EA Pharma, Janssen, JIMRO, Kissei Pharmaceutical, Kyorin Pharmaceutical, Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical, Nippon Kayaku, Pfizer, Takeda and Zeria; and has received grants from Boehringer Ingelheim, Bristol Myers Squibb and Hoya Group Pentax Medical.
SG has no conflicts of interest to disclose.
SD has received consultancy fees from AbbVie, Allergan, Amgen, AstraZeneca, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Enthera, Ferring, Gilead, Hospira, Janssen, Johnson & Johnson, Lilly, Merck Sharp and Dohme, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, TiGenix, UCB and Vifor.
J-FC reports personal fees from AbbVie, Amgen, Boehringer Ingelheim, Celgene, Celltrion, Enterome, Ferring, Genentech, Janssen/Johnson & Johnson, MedImmune, Merck, Pfizer, PPM Services, Protagonist, Second Genome, Seres, Shire, Takeda and Theradiag; has received grant support from AbbVie, Janssen, Johnson & Johnson and Takeda; and holds stock options in Genfit and Intestinal Biotech Development.
JE, MK, VR, XY and SSuravam are employees of AbbVie and may own stock and/or options.
SSchreiber has received speaker/consultancy fees from AbbVie, Advanced Molecular Transport, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Falk, Ferring, Galapagos/Gilead, Genentech/Roche, Janssen, Merck/Merck Sharp and Dohme, Pfizer, Prometheus and Takeda.

Acknowledgments:
AbbVie and the authors thank the participants, study sites and investigators who participated in this study. AbbVie funded this study and contributed to its design, research, analysis, data collection, interpretation of data, and the review and approval of this 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. Medical writing support was provided by Helena Patsos, PhD, of 2 the Nth (Cheshire, UK) and was funded by AbbVie.

Introduction

Updated nomenclature for steatotic liver disease (SLD) uses moderate-to-heavy alcohol drinking to classify metabolic dysfunction-associated steatotic liver disease (MASLD) and with increased alcohol intake (MetALD). However, the association between light-to-moderate alcohol drinking (≤14 g/d for females and ≤28 g/d for males) and the risk of SLD, particularly MASLD, remains unclear, with this knowledge gap being especially pronounced in Chinese populations where prospective cohort evidence remains scarce. In this study, we conducted a cohort study of 2942 Chinese adult participants using data from the Anhui Liver Disease Study (ALDS), where SLD and its subtypes were defined based on vibration-controlled transient elastography (VCTE).We examined the relationship between light-to-moderate alcohol drinking and the risk of SLD and MASLD.We further investigated gut microbiome changes linked to light-to-moderate drinking, and assessed the association between light-to-moderate alcohol-associated microbiota and SLD in a subset of the ALDS.

Aims & Methods

We aimed to investigate the association between light-to-moderate drinking and the risk of incident SLD/MASLD, assess the 1-year gut microbiome changes linked to light-to-moderate drinking, and examine the association between light-to-moderate alcohol-associated microbiota and SLD.In a cohort of 2942 Chinese adults from the Anhui Liver Disease Study (ALDS), alcohol intake was measured via a validated food frequency questionnaire, while SLD were diagnosed by vibration-controlled transient elastography. In a subset of ALDS (n=330), dietary information and fecal samples for 16S rRNA sequencing were collected twice, 1 year apart. Cox regression and logistic regression were used to calculate multivariable-adjusted hazard ratios (aHRs) and odds ratios (aORs) with 95%CIs, respectively.

Results

Upon 4 years of follow-up, 513 SLD (473 MASLD) were newly identified among participants without pre-existing SLD. Light-to-moderate alcohol drinkers exhibited higher risks of SLD (aHR=1.27, 95%CI: 1.03-1.58) and MASLD (aHR=1.27, 95%CI: 1.01-1.59) versus abstainers. Such positive association persisted in subgroups by age, sex, the number of cardiometabolic risk factors, physical activity, and diet quality. Beverage-specific analysis revealed positive associations with SLD risk for liquor (aHR=1.29, 95%CI:1.01-1.65) and beer (aHR=1.38, 95%CI: 0.96-1.99), but not wine. Longitudinal microbiome analysis identified 16 genera with altered abundance in light-to-moderate alcohol drinkers: 8 increased (including Actinomyces) and 8 decreased (all P_FDR<0.05). Among these genera, Actinomyces abundance correlated with SLD risk (aOR=1.19, 95%CI: 1.03-1.41).

Conclusion

Our findings support that light-to-moderate alcohol drinking was associated with higher risks of SLD and MASLD, which might be partly via modulation of gut microbial composition.

References

[1] Israelsen M, Francque S, Tsochatzis EA, Krag A. Steatotic liver disease. Lancet. 2024;404(10464):1761-78. https://doi.org/10.1016/S0140-6736(24)01811-7.
[2] Younossi ZM, Stepanova M, Ong J, Trimble G, AlQahtani S, Younossi I, Ahmed A, Racila A, Henry L. Nonalcoholic Steatohepatitis Is the Most Rapidly Increasing Indication for Liver Transplantation in the United States. Clin Gastroenterol Hepatol. 2021;19(3):580-9 e5. https://doi.org/10.1016/j.cgh.2020.05.064.
[3] Wong VWS, Ratziu V, Bugianesi E, Francque S, Zelber-Sagi S, Valenti L, Roden M, Schick F, Yki-Järvinen H, Gastaldelli A, Vettor R, Frühbeck G, Dicker D, Easl, Easl, Easd, Easo. EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). J Hepatol. 2024;81(3):492-542. https://doi.org/10.1016/j.jhep.2024.04.031.
[4] Mak LY, Liu K, Chirapongsathorn S, Yew KC, Tamaki N, Rajaram RB, Panlilio MT, Lui R, Lee HW, Lai JC, Kulkarni AV, Premkumar M, Lesmana CRA, Hsu YC, Huang DQ. Liver diseases and hepatocellular carcinoma in the Asia-Pacific region: burden, trends, challenges and future directions. Nat Rev Gastroenterol Hepatol. 2024;21(12):834-51. https://doi.org/10.1038/s41575-024-00967-4.

Introduction

JAK inhibitors (JAKi) are small molecules capable of crossing the placenta via passive diffusion or active extracellular transport from early pregnancy.¹ Data on the risks of in utero JAKi exposure are limited,² particularly regarding pregnancy outcomes, infant infections, vaccine responses, and childhood development.

Aims & Methods

We conducted a multicenter retrospective JAKi and pregnancy observational study supported by the ECCO Collaborative Network for Exceptionally Rare Case Reports (CONFER). Pregnant women with inflammatory bowel disease (IBD) exposed to tofacitinib (TOFA), upadacitinib (UPA), or filgotinib (FILGO) during pregnancy were enrolled from 21 centers across 15 countries. Data collected included maternal demographics, IBD characteristics, disease activity, medication use - including timing and duration of JAKi exposure - along with maternal, pregnancy, and infant outcomes.

Results

Of 43 JAKi exposed pregnancies, 17 (39.5%) were unplanned. Disease activity was present in 22 (51.2%) of the pregnancies. One-in-five women initiated JAKi in pregnancy (n=8, 18.6%). Abortion occurred in 8 cases, at a median gestational age (GA) of 8.5 weeks (range 3-16). Of these, 3 (7.0%) were spontaneous and 5 (11.6%) induced, with two terminations due to concerns about potential adverse effects of JAKi treatment. Of the remaining 35 pregnancies 26 (74.3%) were exposed to TOFA (5 mg BID (n=9), 10 mg BID (n=17)), 8 (22.9%) to UPA (30 mg daily (n=2), 45 mg daily (n=6)) and one (2.9%) to FILGO (200 mg daily). The majority received JAKi treatment throughout pregnancy (n=24, 68.6%). Discontinuation of JAKi during the 1^st or 2^nd trimester was followed by disease activity in 7 of 11 cases (63.6%). Maternal complication risk was low: no cases of DVT or (pre)eclampsia; premature rupture of membranes (GA 34–37) occurred in 3 cases, and 4 women required hospitalization due to infection or other complications. Among 35 live births, one infant (2.9%) was preterm (GA 34), three (8.6%) were small for gestational age, one (2.9%) had an Apgar score <7 at 5 minutes, and no congenital abnormalities were reported. Follow-up infant data are shown in table 1. One-third of breastfeeding women continued JAKi treatment. A high adherence rate to the national immunization schedule was seen. Three (8.6%) skipped the live rotavirus vaccine due to in uteroJAKi exposure. No adverse effects were reported following live attenuated or inactivated vaccines, and no malignancies were observed.

Conclusion

In this global multicenter study of JAKi exposure during pregnancy in women with IBD, maternal complication rates were low, and no increased risk of adverse pregnancy outcome were observed among live births. While disease activity was common, particularly following early discontinuation of JAKi, infant outcomes - including development, infection risk, and vaccine response - were reassuring. These findings provide important preliminary safety data to guide decision-making regarding the use of JAKi in pregnancy, though further prospective studies are needed to confirm long-term safety.

References

1. Fein KC, Arral ML, Kim JS, et al. Placental drug transport and fetal exposure during pregnancy is determined by drug molecular size, chemistry, and conformation. J Control Release 2023;361:29-39.
2. Torres J, Chaparro M, Julsgaard M, et al. European Crohn's and Colitis Guidelines on Sexuality, Fertility, Pregnancy, and Lactation. J Crohns Colitis 2023;17:1-27.

Disclosure

M. Julsgaard: Advisory board for AbbVie. G. Santana: Speaker and advisory board for pfizer.