Browsing by Author "Madamba, Egbert"

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    Clinical Trial to Assess the Safety and Tolerability of Anti-IL 23 Monoclonal Antibody Guselkumab in Patients With Alcohol-Associated Liver Disease
    (2025) Díaz Piga, Luis Antonio; Morris, Sheldon; Dave, Shravan; Kim, Susy M.; Sarik, Wathnita; Richards, Lisa; Madamba, Egbert; Bettencourt, Ricki; Fulinara, Christian; Pham, Thuy; Miller, Grant; Carvalho-Gontijo Weber, Raquel; Momper, Jeremiah D.; He, Feng; Jain, Sonia; Jamieson, Catriona; Kisseleva, Tatiana; Brenner, David; Loomba, Rohit
    BackgroundThere are no FDA-approved therapies for alcohol-associated liver disease (ALD). Preclinical studies indicate that blocking IL-23/IL-17 signalling may reverse liver injury. Guselkumab, an IL-23-specific antibody approved for psoriasis, may be beneficial for ALD. AimsWe aimed to assess the safety and tolerability of guselkumab in patients with ALD. MethodsThis phase-1 dose-escalation study included patients with >= 2 DSM-5 criteria for alcohol use disorder, significant steatosis (MRI-PDFF >= 8%) and MRE < 3.63 kPa (to exclude advanced disease). Guselkumab was given subcutaneously on Days 1 and 29 in 30, 70 or 100 mg dose cohorts. Primary endpoints were adverse events (AEs) and dose-limiting toxicity. ResultsWe enrolled 13 patients (three 30 mg, three 70 mg, and seven 100 mg). Eleven completed the study and two early discontinued in the 100 mg group. Of them, 77% were men, and the median age was 53 [IQR 49-61] years. The median MRI-PDFF and MRE were 18.4% [IQR 8.4%-34.0%] and 2.5 [2.2-2.6] kPa, respectively. The most frequent AEs were hyperuricemia (13%, mild only) and elevated lipase (11%, mild and moderate). There were no serious adverse events or significant variations in liver enzymes. There was a suppression of peripheral interleukin (IL)-17, IL-23, IL-1b and TNF-alpha in the 70 and 100 mg groups, and a significant decrease in alcohol consumption over time (AUDIT-C: 6 [3-7] vs. 5 [1-6], p = 0.023). Conclusions Guselkumab is safe in doses up to 100 mg and may reduce inflammation markers in ALD. These findings support further phase 2 studies to evaluate the efficacy of guselkumab in ALD, particularly in patients with severe phenotypes.
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    High inherited risk predicts age-associated increases in fibrosis in patients with MASLD
    (2025) Díaz, Luis Antonio; Alazawi, William; Agrawal, Saaket; Arab, Juan Pablo; Arrese, Marco; Idalsoaga, Francisco; Barreyro, Fernando Javier; Gadano, Adrián; Marciano, Sebastián; Martínez Morales, Jorge; Villela Nogueira, Cristiane; Leite, Nathalie; Alves Couto, Claudia; Theodoro, Rafael; Dias Monteiro, Mísia Joyner de Sousa; Oliveira, Claudia P.; Pessoa, Mario G.; Reis Alvares-da-Silva, Mario; Madamba, Egbert; Bettencourt, Ricki; Richards, Lisa M.; Majithia, Amit R.; Khera, Amit V.; Loomba, Rohit; Ajmera, Veeral
    Background & AimsLimited data have prevented routine genetic testing from being integrated into clinical practice in metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to quantify the effect of genetic variants on changes in fibrosis severity per decade in MASLD.MethodsThis cross-sectional study included prospectively recruited adults with MASLD aged 18–70 who underwent magnetic resonance elastography (MRE) and genotyping for PNPLA3, TM6SF2, MBOAT7, GCKR, and HSD17B13. A genetic risk score (GRS) was calculated as the sum of established risk alleles in PNPLA3 minus protective variants in HSD17B13 (0=low risk, 1=high risk). We also estimated the polygenic risk score-hepatic fat content (PRS-HFC) and the adjusted version (PRS-5). The primary endpoint was the age-related change in liver stiffness measurement (LSM) on MRE by GRS. Findings were validated using an external cohort from Latin America.ResultsAmong 570 participants, the median age was 57 [49–64] years, 56.8% were women, and 34.2% were Hispanic. Median MRE was 2.4 [2.1–3.0] kPa, and 51% had high GRS. High GRS was independently associated with increased LSM (β=0.28 kPa, 95%CI:0.12–0.44, p=0.001) per 10-year age increase, while the low GRS group showed no significant difference. Similar findings were observed using PRS-HFC and PRS-5. PNPLA3 genotype alone also predicted higher LSM (C/G: β=0.32 kPa, 95%CI:0.02–0.61, p=0.034; G/G: β=0.87 kPa, 95%CI:0.52–1.22, p<0.0001) and G/G genotype was associated with significantly higher LSM by age 44, which was consistent in the validation population.ConclusionGRS, PRS-HFC, PRS-5, and PNPLA3 genotypes alone are associated with greater fibrosis per decade, resulting in divergent disease trajectories starting in midlife. Assessing genetic risk in MASLD will identify high-risk patients who require more frequent monitoring."
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    Inherited Genetic Risk of Liver Fibrosis in Lean Versus Nonlean Metabolic Dysfunction–Associated Steatotic Liver Disease (MASLD)
    (John Wiley & Sons Ltd., 2025) Tesfai, Kaleb; Díaz Piga, Luis Antonio; Arab, Juan Pablo; Arrese, Marco; Idalsoaga, Francisco; Ayares, Gustavo; Agrawal, Saaket; Barreyro, Fernando Javier; Gadano, Adrian; Marciano, Sebastián; Martínez Morales, Jorge; Villela‐Nogueira, Cristiane; Leite, Nathalie; Salles, Gil; Regina Cardoso, Claudia; Alves Couto, Claudia; Theodoro, Rafael; Monteiro. Mísia Joyner de Sousa Dias; Oliveira, Claudia P.; Pessoa, Mario G.; Alvares‐da‐Silva, Mario Reis; Huang, Daniel Q.; Madamba, Egbert; Singh, Seema; Lokanadham, Snigdha; Bettencourt, Ricki; Richards, Lisa M.; Khera, Amit V.; Loomba, Rohit; Ajmera, Veeral
    Introduction Previous studies have revealed conflicting results regarding liver fibrosis risk in lean metabolic dysfunction–associated steatotic liver disease (MASLD). We aimed to compare the risk of significant fibrosis in lean versus nonlean MASLD and identify fibrosis-associated factors in lean MASLD. Methods The study was a cross-sectional analysis of prospectively enrolled adults with MASLD. Individuals with lean MASLD were age- and sex-matched with nonlean MASLD. Fibrosis assessment included vibration-controlled transient elastography, magnetic resonance elastography and liver biopsy. A genetic risk score (GRS), summating the effect alleles of PNPLA3 and TM6SF2 minus the protective HSD17B13 genotype, was estimated to consider inherited genetic risk across BMI categories. Results were validated in an external Latin American cohort.ResultsThe mean ( SD) age of 312 included participants with MASLD was 58.3  11.6 years and 69.2% were female. 44 (14.1%) individuals were lean, 90 (28.9%) were overweight, 90 (28.9%) had class I obesity and 88 (28.1%) had class II or greater obesity. The prevalence of significant fibrosis was 27.3% in lean and 31.1% in nonlean (p = 0.653). Individuals with a high GRS had a higher prevalence of significant fibrosis compared to patients with low GRS (36.5% vs. 25.2%, p = 0.043) and the prevalence of significant fibrosis was similar in lean and nonlean patients with high GRS (31.3% vs. 37.1%, p = 0.645). The Latin American cohort exhibited similar results. Conclusions The prevalence of significant fibrosis and the effect of GRS were similar in lean and nonlean MASLD, highlighting that lean MASLD patients may have a comparable risk to overweight and obese MASLD.
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    Noninvasive pathway for stratifying fibrosis in suspected metabolic dysfunction and alcohol-associated liver disease (MetALD)
    (2025) Diaz Piga, Luis Antonio; Tavaglione, Federica; Mittal, Nikita; Bettencourt, Ricki; Amangurbanova, Maral; Johnson, Amy; Marti-Aguado, David; Tincopa, Monica; Loomba, Ria; Khan-Riches, Asma; Madamba, Egbert; Siddiqi, Harris; Richards, Lisa; Sirlin, Claude B.; Ajmera, Veeral; Loomba, Rohit
    Background: Metabolic dysfunction and alcohol-associated liver disease (MetALD) may increase liver fibrosis progression, but data on screening are scarce. We aimed to assess the performance of noninvasive tests (NITs) for detecting significant fibrosis in individuals with suspected MetALD.Methods: This is a cross-sectional study of prospectively enrolled adults identified as overweight or obese. We included adults with suspected MetALD defined by ≥1 of 5 cardiometabolic criteria and self-reported alcohol use within MetALD ranges or lower self-reported alcohol use but with phosphatidylethanol (PEth) levels ≥25 ng/mL. Clinical assessment included contemporaneous magnetic resonance elastography (MRE) and vibration-controlled transient elastography (VCTE). Significant fibrosis was defined as MRE ≥3.14 kPa (or VCTE ≥7.6 kPa if MRE was missing). Analyses included AUROCs.Results: Among 617 individuals screened, we identified 97 (15.7%) with suspected MetALD. The mean age was 50.6±12.8 years, 67% were men, the mean body mass index was 31.4±6.5 kg/m2, 12.4% had diabetes, and 8% had significant fibrosis. Fibrosis-4 ≥1.3 demonstrated good performance for significant fibrosis (AUROC: 0.78, 95% CI: 0.58–0.98, sensitivity 80%, specificity 76%, positive predictive value 17%, and negative predictive value 98%). VCTE ≥8 kPa also had good performance (AUROC: 0.85, 95% CI: 0.66–1.00, sensitivity 80%, specificity 91%, positive predictive value 36%, and negative predictive value 99%). A stepwise approach using fibrosis-4 followed by VCTE yielded a low false negative rate (2% misclassified as low risk).Conclusions: A clinical care algorithm utilizing a stepwise approach with fibrosis-4 and VCTE shows adequate performance in detecting significant fibrosis in individuals with suspected MetALD.