Introduction

Ulcerative colitis (UC) is characterized by chronically relapsing inflammation of the colonic mucosa. Tofacitinib (TOFA) is a paninhibitor of the JAK kinases, a family of intracellular kinases in volved in the signal transduction pathway of multiple inflammatory signals. Despite the efficacy shown by TOFA in inducing and maintaining remission in moderately-to-severely active UC, rates of primary non response remains high. We propose a new method to identify predictors of responsiveness to TOFA based on "ex-vivo" challenge of organ cultures from biopsies collected from candidate patients.

Aims & Methods

Baseline biopsies from inflamed areas of UC patients with active disease and candidate to receive TOFA 10mg b.i.d. for 8 weeks, were used for "ex-vivo" organ culture and stimulated with TOFA 20μM and 200nM or left untreated. After 24 hours, proteomic analysis was performed and quantitative expression of 92 inflammation-related human proteins (Olink® Human Inflammation panel) was correlated with week 8 clinical response defined by Modified Mayo Score (MMS). Intestinal biopsies were also collected at baseline and at 8 weeks for proteomic analysis. To decipher the nature of TOFA's effects, both unsupervised and supervised machine learning (ML) methods were employed (sklearn module, Python). The K-means method was used for unsupervised learning followed by a supervised ML approach to classify week 8 responders and non-responders. Data were transformed in into a second-order polynomial format and logistic regression was used for modelling.

Results

Between Jannuary 2022 and January 2023, 17 UC patients were enrolled. At week 8, 13/17 (76.5%) patients treated with TOFA showed clinical response. Unsupervised ML, utilizing proteomic data from organ cultures stimulated with TOFA 200nM, achieved a 90% success rate in predicting a positive clinical response. This prediction was based on forming two distinct clusters, with significant contributions from key variables such as CASP-8, CCL19, CCL20, CD5, CXCL9, EN-RAGE, GDNF, HGF, IL-18R1, MCP-1, MCP-2, MCP-4, MMP-10, OPG, PD-L1, STAMBP, TNFRSF9, TRANCE, TWEAK, and VEGFA. In our supervised ML approach, logistic regression was employed with 30 shuffle splits to refine the predictive model. The mean precision value for the best profile, logistic regression with Ridge regularization, was 0.73. We also discovered that transforming the dataset into second-order polynomial format significantly enhanced the model's performace. In this case, the most effective logistic regression model achived a mena precision score of 0.82.

Conclusion

Our predictive model demonstrates a high level of precision in identifying positive treatment responses, emphasizing the potential of further dataset expansion and the use of advanced machine-learning to predict response in TOFA-treated UC patients.

Disclosure

This study is supported by Pfizer

Clinical Case Summary

Although liver involvement is common in leukemia, acute hepatitis as its initial presentation is rare. This case highlights the diagnostic challenge of distinguishing reactive hematological changes from underlying malignancies in patients with unexplained hepatitis.
A 35-year-old woman presented in February 2024 with myalgias, fever with chills (38°C), jaundice, and right upper quadrant discomfort. Relevant history included recent intake of herbal supplements (vitamin C, zinc, echinacea, elderberry).
Initial laboratory findings showed leukocytosis, lymphocytosis (25%), monocytosis (12%), blasts (3%), thrombocytopenia (136×10⁹/L), and abnormal liver tests (AST 448 U/L, ALT 686 U/L, ALP 242 U/L, GGT 147 U/L, total bilirubin 4.14 mg/dL, direct bilirubin 2.9 mg/dL), with normal INR. Peripheral blood smear revealed mononuclear pleomorphism and lymphocytes with prominent nucleoli. Abdominal computed tomography showed moderate hepatomegaly without biliary or vascular abnormalities. Comprehensive testing for infeccious, autoimmune and metabolic causes was negative.
Liver tests improved and leukocytosis turned into leukopenia. Repeat blood smear was deemed reactive by Hematology. She was discharged and in early March re-evaluation, liver parameters normalized and leukopenia improved.
Later that month, she returned with fever, night sweats, and abdominal pain. Laboratory findings showed recurrent cytopenias and cytocholestasis. Blood smear revealed increasing blast count, and immunophenotyping suggested monoclonality. Bone marrow and liver biopsy confirmed B-cell acute lymphoblastic leukemia (ALL) with hepatic infiltration.
This case illustrates an unusual presentation of ALL as relapsing acute hepatitis. It reinforces the need to consider hematological malignancy in cryptogenic hepatitis, particularly when associated with evolving hematological changes. Serial blood smears, immunophenotyping, and timely bone marrow evaluation are essential to avoid diagnostic delay.

References

1. Hepatic biopsy: clusters of intermediate to large cells expressing TdT, CD20, PAX5, CD10, BCL6, CD43.
2. Bone marrow aspirate: 64% blasts, CD10+, CD20+ (strong homogeneous expression).
3. Bone marrow biopsy: increased cellularity due to diffuse interstitial infiltration by intermediate cells with blast-like morphology and lymphoid immunophenotype (TdT+, CD34+, MPO-, CD20+).

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