Using Interpretable Machine Learning to Identify Baseline Predictive Factors of Remission and Drug Durability in Crohn’s Disease Patients on Ustekinumab

Ustekinumab has shown efficacy in Crohn's Disease (CD) patients. To identify patient profiles of those who benefit the most from this treatment would help to position this drug in the therapeutic paradigm of CD and generate hypotheses for future trials. The objective of this analysis was to determine whether baseline patient characteristics are predictive of remission and the drug durability of ustekinumab, and whether its positioning with respect to prior use of biologics has a significant effect after correcting for disease severity and phenotype at baseline using interpretable machine learning. Patients' data from SUSTAIN, a retrospective multicenter single-arm cohort study, were used. Disease phenotype, baseline laboratory data, and prior treatment characteristics were documented. Clinical remission was defined as the Harvey Bradshaw Index <= 4 and was tracked longitudinally. Drug durability was defined as the time until a patient discontinued treatment. A total of 439 participants from 60 centers were included and a total of 20 baseline covariates considered. Less exposure to previous biologics had a positive effect on remission, even after controlling for baseline disease severity using a non-linear, additive, multivariable model. Additionally, age, body mass index, and fecal calprotectin at baseline were found to be statistically significant as independent negative risk factors for both remission and drug survival, with further risk factors identified for remission

Epigenetic biomarkers for clinical outcomes and mechanisms driving emergence of drug resistance in ovarian cancer

Epithelial ovarian cancer (EOC) has a poor prognosis, with a 5 year survival rate of ~40%. A major therapeutic barrier is disease chemoresistant to the standard therapeutic regimen of taxol and platinum. Efficacious therapies in chemoresistant disease, a fuller understanding of the molecular mechanisms driving tumour evolution, and drugs to prevent emergence of chemoresistance are required. Bevacizumab, a VEGF inhibitor approved for second line treatment of recurrent, chemoresistant EOC, requires stratification biomarkers to identify patients who will benefit. We investigated VEGF gene promoter methylation in EOC from ICON7 clinical trial patients. Patients with low VEGF-B methylation showed better overall survival (OS) when treated with standard chemotherapy (HR=2.07(1.23, 3.49), P=0.006) but not bevacizumab (HR=1.77(0.99, 3.15), P=0.05), potentially identifying a patient sub-group which should not be treated with bevacizumab. An association between VEGF-C methylation and progression-free survival (PFS) in ICON7 patients (HR=0.66(0.52, 0.84), P=0.0006) was confounded by stage. ICGC patient samples collected at relapse showed elevated VEGF-C compared to primary presentation. In a CRISPR-generated VEGF-C null EOC model we demonstrated an autocrine mechanism by which VEGF-C deregulation and over-expression may drive EOC stage and metastasis by suppressing anoikis-induced apoptosis and promoting growth in non-adherent conditions. Further, we investigated the role of epigenetics and heterogeneity in acquisition of resistance to platinum-based therapies. Epigenetically defined sub-populations which show a reversibly resistant "drug tolerant" phenotype have been demonstrated to exist in chemosensitive tumour populations of many cancers. We isolated reversibly cisplatin tolerant populations (CTPs) from a cisplatin sensitive EOC cell line A2780, which were re-sensitised by EZH2 and HDAC inhibitors. Epigenomic profiling of these populations revealed heavily H3K27me3-modified chromatin in CTPs, preferentially in non-coding regions of the genome, which we hypothesise as a novel mechanism of tolerance for cisplatin as an initial stage for acquisition of stable resistance.Open Acces

Impact of psoriatic arthritis and comorbidities on ustekinumab outcomes in psoriasis: a retrospective, observational BADBIR cohort study

Objectives Psoriasis and psoriatic arthritis (PsA) are independently associated with comorbidities, including obesity and metabolic syndrome, which may impact treatment outcomes. This study aimed to assess baseline differences between patients with plaque psoriasis alone and those with concomitant PsA, and to investigate the impact of these characteristics on ustekinumab (UST) persistence and outcomes.Methods 9057 patients receiving UST or conventional systemic disease-modifying antirheumatic drugs were selected from the British Association of Dermatologists Biologic and Immunomodulators Register. The psoriasis and PsA cohorts were compared at baseline. Time to discontinuation during 10-year follow-up was assessed using multivariable Cox regression and Kaplan–Meier analyses, stratifying for interacting covariates and PsA status. Generalised linear mixed models assessed the impact of baseline characteristics on Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index over time.Results Greater comorbidity burden, including hypertension, diabetes, obesity and depression, and greater inability to work were observed in the PsA cohort than in the psoriasis cohort. PsA (HR 1.98), female sex (HR for male sex 0.72) and depression (HR 1.21) were associated with shorter UST persistence. PsA showed a differential association with UST persistence by PASI strata and prior biologic exposure. Quality of life was negatively impacted by depression and PsA.Conclusions The negative impact of comorbidities on treatment persistence identified in this study emphasises the need for patient-centric, multidisciplinary care in screening for and managing comorbidities in psoriasis and PsA treatment. Psychological support and lifestyle management of modifiable risk factors, including obesity, should be considered

Supplemental Material - Characteristics of Patients With Psoriasis Treated With Various Biologics – A Danish Cohort Study

Supplemental Material for Characteristics of Patients With Psoriasis Treated With Various Biologics – A Danish Cohort Study by Christopher Willy Schwarz, Lone Skov, Alexander Egeberg, Alun Passey, Jennifer Lee, Patricia Gorecki, and Nikolai Loft in Journal of Psoriasis and Psoriatic Arthritis®</p