Introduction

Steatotic liver disease (SLD) is a common problem after liver transplantation (LT). Previous studies have confirmed the role of donor PNPLA3 rs738409 G allele as a risk factor for post-LT SLD, but the role of other recipient and donor genetic risk variants is largely unknown.

Aims & Methods

Aims: To study the prevalence of genetic risk variants for SLD in LT recipients and donors and their impact on development of post-LT SLD.
Methods: Of 807 adult patients undergoing LT in Finland between 2000–2019, 56 SLD-associated genetic risk variants were extracted from genotype data for 666 donor-recipient-pairs. Recipient genotypes were compared with ~10 000 Finnish population controls from gnomAD database. Incident post-LT SLD was assessed from protocol liver biopsies. The impact of donor and recipient genetic variants was studied in multivariate Cox regression analysis adjusted for phenotype factors.

Results

Of 56 risk variants, the minor allele frequencies (MAFs) of 17 variants were significantly different between LT recipients and population controls. The greatest MAF differences were observed for PNPLA3 rs738409-G (0.33 vs 0.22, p = 2.56 x 10^-20), TNF rs1800629-A (0.19 vs 0.12, p = 1.48 x 10^-12), IFNL4 rs12979860-T (0.29 vs 0.24, p = 7 x 10^-6 ), CD14 rs2569190-A (0.41 vs 0.37, p = 0.005) and MERTK rs4374383-A (0.36 vs 0.33, p = 0.014).
Patients transplanted for metabolic dysfunction-associated steatohepatitis (MASH) (n = 42) exhibited high prevalence of PNPLA3 rs738409-G (0.63 vs 0.22, p = 1.47 x 10^-19) and low prevalence of the protective HSD17B13 rs6834314-G (0.07 vs 0.21, p = 0.001) and MARC1 rs2642438-A (0.14 vs 0.29, p = 0.002)
Incidence of post-LT SLD was 29.1% in median follow-up time of 7.6 years. The lowest incidence (14.8%) was observed among patients transplanted for acute liver failure, and the highest (52.9%) in patients transplanted for MASH.
Final multivariate regression model to predict post-LT SLD included high SLD-risk indication (HR 2.03, p < 0.001), BMI (HR 1.10, p < 0.001), diabetes (HR 1.37, p = 0.016) and alcohol consumption (HR 2.01, p < 0.001). Table 1 shows the hazard ratios of the donor and recipient genetic variants most strongly predicting post-LT SLD after adjusting for recipient phenotype factors (high-SLD risk indication, BMI, diabetes, and alcohol consumption).

Conclusion

SLD-associated risk alleles were common in LT recipients, especially in MASH. Post-LT SLD incidence was high (29.1%), but with large variation across transplantation indications. Donor, but not recipient, PNPLA3 allele was most strongly associated with post-LT SLD. Several other donor and recipient genetic variants also contributed to post-LT SLD. Both LT recipient and donor genotypes provide novel insights into the genetic determinants of SLD after LT, providing help in future individual risk assessment.

Introduction

Subcutaneous infliximab (IFX-SC) is available in France since February 2021. Beyond pivotal studies enabling marketing authorization, real-world data are needed to assess usage, efficacy and safety of IFX-SC. The aim of RIPOSTE study is to evaluate the real-world use of IFX-SC in France. We present here results from data extracted between 2021 and 2023.

Aims & Methods

This study is based on data from the French administrative health databases (SNDS). All patients with at least one IFX-SC or intravenous (IV) delivery between February 1, 2021 and December 31, 2023, were included, regardless of indication. Diagnoses of Crohn's disease (CD) and ulcerative colitis (UC) were based on published algorithms¹. Four patient groups were defined: (1) IFX-IV incident user (no administration of IFX-IV during look-back period); (2) IFX-IV prevalent user (at least one administration of IV IFX during look-back period); (3) IFX-SC initiation group (patients who received less than 3 infusions of IFX-IV before initiating IFX-SC); (4) IFX-SC switch group (patients who had received at least 3 infusions of IFX-IV before initiating IFX-SC). Patients were followed from the 1^st IFX infusion until IFX discontinuation, initiation of another advanced therapy, death, or December 31, 2023. Discontinuation of infliximab was defined as no new delivery within 3 months of the end of estimated exposure. Persistence of IFX-SC was assessed by the Kaplan-Meier method. Concomitant exposure of immunosuppressant (IS) and the occurrence of serious adverse events were assessed.

Results

A total of 55,230 patients received at least one IFX delivery between February 1, 2021, and December 31, 2023, including 36,778 treated only with IFX-IV and 18,452 with IFX-SC. Among patients treated by IFX-SC, 10,566 (57.3%) had CD, including 2,356 (22.3%) in initiation , and 4,393 (23.8%) had UC, including 1086 (24.7%) in initiation . Switch population involved 8210 CD patients (61.5%) and 33017 UC patients (24.8%). Mean age at cohort entry was 39.82 years (SD, 14.63) in CD and 43.36 years (SD, 15.80) in UC, with 51.14% and 55.03% of women, respectively. IS was combined with initiated IFX-SC in 65.75 % of CD and 59.48% of UC patients. More than 25% of IFX-SC initiated patients did not receive any IFX-IV while 68.2% received 2 IFX-IV infusions. In IFX-SC population, 10.22% of CD and 29.5% of UC patients were concomitantly diagnosed with ankylosing spondylitis (AS). In CD, the 23-month persistence rate was 55% for IFX-IV incident users, while rates were higher in patients treated with IFX-SC, 64% (initiation) and 73% (switch group) (p<0.001). In UC, the 23-month persistence rates were higher in both IFX-SC groups (initiator: 58%; switch: 74%) compared to IFX-IV incident users (44%) (p<0.001) (Table1). Regarding safety, cumulative incidence rate of severe infections at 12 months was numerically higher in IFX-IV group compared to IFX-SC (6% vs 2% in UC; 5% vs 3% in CD).

Table 1: Persistence rate (%) between IFX-SC and IFX-IV for IBD patients

Conclusion

Based on data from the entire French population, IBD patients who switched from IFX-IV to IFX-SC may benefit from a better persistence. Further analyses including propensity score matching to control for residual confounding are ongoing.

References

1. Kirchgesner J, Lemaitre M, Rudnichi A, et al. Therapeutic management of inflammatory bowel disease in real-life practice in the current era of anti-TNF agents: analysis of the French administrative health databases 2009-2014. Aliment Pharmacol Ther 2017;45:37–49.

Disclosure

Funding : Celltrion Healthcare France

Introduction

There is a global increase in the metabolic syndrome and inflammatory bowel diseases (IBD) prevalence, with a rise in patients who are being treated for both syndromes[1]. The growing use of GLP-1 analogs for both diabetes mellitus type 2 (DM2) and weight loss and the fact that these are originally gut-derived hormones with many gastrointestinal (GI) functions have raised concerns related to GLP-1 treatment in patients with IBD. We aimed to examine the efficacy of these agents in an Israeli nationwide cohort of IBD patients and matched controls (epi-IIRN).

Aims & Methods

IBD patients were identified using a previously validated algorithm and non-IBD matched controls (1:2-3 ratio) by year of birth, sex and jurisdiction. DM2 patients were identified if they had at least two occurrences of either any of the DM2 international classification of diseases 9 diagnoses, or a purchase of a non-insulin anti-diabetic medication. We included patients with GLP-1 dispensation for more than 6 months. The outcomes were changes in glycated hemoglobin (HbA1c) and body mass index (BMI), compared using Mann-Whitney test. Linear mixed effects models were constructed, with patients as random effects and change in either HbA1c or BMI (in each model) as outcomes. The models [HB1] were adjusted for sex, age, baseline HbA1c value, insulin and SGLT-2i treatment. Missing numeric values were carried forward from a previously recorded value for the same patient.

Results

Out of 1426 patients with diabetes who initiated GLP-1 agonists, 861 were treated for at least 6 months, 437 with IBD and 424 controls. IBD patients were significantly older, had lower BMI (<1 point difference), and were more likely to use glucocorticoids (Table 1). The change in HbA1c was not significantly different between IBD patients and controls (-0.3 [-1.1, 0.1] and -0.4 [-1.1, 0.1], respectively, p=0.74), neither was the change in BMI (-0.4 [-1.9, 0.5] and -0.5 [-2.3, 0.1], respectively, p=0.14). In the multivariate mixed effects models, IBD status in GLP-1 agonist users were not associated to change in HbA1c or change in BMI during treatment.

Conclusion

GLP-1 analogs show similar efficacy in patients with DM2 and IBD compared with patients without IBD. Further evidence is needed for their efficacy and tolerability in patients with IBD and overweight.

References

[1] Jess T, Jensen BW, Andersson M, et al. Inflammatory Bowel Diseases Increase Risk of Type 2 Diabetes in a Nationwide Cohort Study. Clin Gastroenterol Hepatol 2020; 18: 881-888.e1. doi:10.1016/j.cgh.2019.07.052

Disclosure

The authors report no conflict of interests