Browsing by Author "Gerussi, Alessio"

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    An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs
    (Elsevier, 2021) Cordell, Heather J.; Fryett, James J.; Ueno, Kazuko; Darlay, Rebecca; Aiba, Yoshihiro; Hitomi, Yuki; Kawashima, Minae; Nishida, Nao; Khor, Seik-Soon; Gervais, Olivier; Kawai, Yosuke; Nagasaki, Masao; Tokunaga, Katsushi; Tang, Ruqi; Shi, Yongyong; Li, Zhiqiang; Juran, Brian D.; Atkinson, Elizabeth J.; Gerussi, Alessio; Carbone, Marco; Asselta, Rosanna; Cheung, Angela; de Andrade, Mariza; Baras, Aris; Horowitz, Julie; Ferreira, Manuel A. R.; Sun, Dylan; Jones, David E.; Flack, Steven; Spicer, Ann; Mulcahy, Victoria L.; Byan, Jinyoung; Han, Younghun; Sandford, Richard N.; Lazaridis, Konstantinos N.; Amos, Christopher I.; Hirschfield, Gideon M.; Seldin, Michael F.; Invernizzi, Pietro; Siminovitch, Katherine A.; Ma, Xiong; Nakamura, Minoru; Mells, George F.; PBC Consortia; Canadian PBC Consortium; Chinese PBC Consortium; Italian PBC Study Group; Japan-PBC-GWAS Consortium; US PBC Consortium; UK-PBC Consortium; Medicine, School of Medicine
    Backgrounds & aims: Primary biliary cholangitis (PBC) is a chronic liver disease in which autoimmune destruction of the small intrahepatic bile ducts eventually leads to cirrhosis. Many patients have inadequate response to licensed medications, motivating the search for novel therapies. Previous genome-wide association studies (GWAS) and meta-analyses (GWMA) of PBC have identified numerous risk loci for this condition, providing insight into its aetiology. We undertook the largest GWMA of PBC to date, aiming to identify additional risk loci and prioritise candidate genes for in silico drug efficacy screening. Methods: We combined new and existing genotype data for 10,516 cases and 20,772 controls from 5 European and 2 East Asian cohorts. Results: We identified 56 genome-wide significant loci (20 novel) including 46 in European, 13 in Asian, and 41 in combined cohorts; and a 57th genome-wide significant locus (also novel) in conditional analysis of the European cohorts. Candidate genes at newly identified loci include FCRL3, INAVA, PRDM1, IRF7, CCR6, CD226, and IL12RB1, which each play key roles in immunity. Pathway analysis reiterated the likely importance of pattern recognition receptor and TNF signalling, JAK-STAT signalling, and differentiation of T helper (TH)1 and TH17 cells in the pathogenesis of this disease. Drug efficacy screening identified several medications predicted to be therapeutic in PBC, some of which are well-established in the treatment of other autoimmune disorders. Conclusions: This study has identified additional risk loci for PBC, provided a hierarchy of agents that could be trialled in this condition, and emphasised the value of genetic and genomic approaches to drug discovery in complex disorders. Lay summary: Primary biliary cholangitis (PBC) is a chronic liver disease that eventually leads to cirrhosis. In this study, we analysed genetic information from 10,516 people with PBC and 20,772 healthy individuals recruited in Canada, China, Italy, Japan, the UK, or the USA. We identified several genetic regions associated with PBC. Each of these regions contains several genes. For each region, we used diverse sources of evidence to help us choose the gene most likely to be involved in causing PBC. We used these 'candidate genes' to help us identify medications that are currently used for treatment of other conditions, which might also be useful for treatment of PBC.
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    Outcome of COVID-19 in Patients with Autoimmune Hepatitis: an International Multi-Centre Study
    (Wiley, 2021) Efe, Cumali; Dhanasekaran, Renumathy; Lammert, Craig; Ebi, Berat; Higuera‐de la Tijera, Fatima; Aloman, Costica; Rıza Calışkan, Ali; Peralta, Mirta; Gerussi, Alessio; Massoumi, Hatef; Catana, Andreea M.; Torgutalp, Murat; Purnak, Tugrul; Rigamonti, Cristina; Gomez Aldana, Andres Jose; Khakoo, Nidah; Kacmaz, Hüseyin; Nazal, Leyla; Frager, Shalom; Demir, Nurhan; Irak, Kader; Ellik, Zeynep Melekoğlu; Balaban, Yasemin; Atay, Kadri; Eren, Fatih; Cristoferi, Laura; Batıbay, Ersin; Urzua, Álvaro; Snijders, Romee; Kıyıcı, Murat; Akyıldız, Murat; Ekin, Nazım; Carr, Rotonya M; Harputoğlu, Murat; Hatemi, Ibrahim; Mendizabal, Manuel; Silva, Marcelo; Idilman, Ramazan; Silveira, Marina; Drenth, Joost P.H.; Assis, David N.; Björnsson, Einar; Boyer, James L.; Invernizzi, Pietro; Levy, Chyntia; Schiano, Thomas D.; Ridruejo, Ezequiel; Wahlin, Staffan; Medicine, School of Medicine
    Background Data regarding outcome of Coronavirus disease 2019 (COVID‐19) in patients with autoimmune hepatitis (AIH) are lacking. Patients and methods We performed a retrospective study on AIH patients with COVID‐19 from 34 centres in Europe and the Americas. We analyzed factors associated with severe COVID‐19 outcomes defined as the need for mechanical ventilation, intensive care admission, and/or death. The outcomes of patients with AIH were compared to a propensity‐score matched cohort of non‐AIH patients with chronic liver diseases (CLD) and COVID‐19. The frequency and clinical significance of new‐onset liver injury (alanine aminotransferase>2xupper limit of normal) during COVID‐19 was also evaluated. Results We included 110 AIH patients (80%,female) with a median age of 49 (range:18–85) years at COVID‐19 diagnosis. New‐onset liver injury was observed in 37.1% (33/89) of the patients. Use of antivirals was associated with liver injury (p=0.041; odds ratio (OR) 3.36[1.05‐10.78]) while continued immunosuppression during COVID‐19 was associated with a lower rate of liver injury (p=0.009; OR 0.26[0.09‐0.71]). The rates of severe COVID‐19 (15.5% vs 20.2% p=0.231) and all‐cause mortality (10% vs 11.5%; p=0.852) were not different between AIH and non‐AIH CLD. Cirrhosis was an independent predictor of severe COVID‐19 in patients with AIH (p<0.001; OR 17.46[4.22‐72.13]). Continuation of immunosuppression or presence of liver injury during COVID‐19 was not associated with severe COVID‐19. Conclusions This international, multi‐center study reveals that patients with AIH were not at risk for worse outcomes with COVID‐19 than other causes of CLD. Cirrhosis was the strongest predictor for severe COVID‐19 in AIH patients. Maintenance of immunosuppression during COVID‐19 was not associated with increased risk for severe COVID‐19, but did lower the risk for new‐onset liver injury during COVID‐19.
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    Role of ductular reaction and ductular-canalicular junctions in identifying severe primary biliary cholangitis
    (Elsevier, 2022-08-19) Overi, Diletta; Carpino, Guido; Cristoferi, Laura; Onori, Paolo; Kennedy, Lindsey; Francis, Heather; Zucchini, Nicola; Rigamonti, Cristina; Viganò, Mauro; Floreani, Annarosa; D’Amato, Daphne; Gerussi, Alessio; Venere, Rosanna; Alpini, Gianfranco; Glaser, Shannon; Alvaro, Domenico; Invernizzi, Pietro; Gaudio, Eugenio; Cardinale, Vincenzo; Carbone, Marco; Medicine, School of Medicine
    Background & aims: Primary biliary cholangitis (PBC) is a chronic cholangiopathy characterised by immuno-mediated injury of interlobular bile ducts leading to intrahepatic cholestasis and progressive liver fibrosis. PBC histology is characterised by portal inflammation, progressive fibrosis, ductopenia, and the appearance of the so-called ductular reaction. The aim of the present study was to investigate the pathogenetic relevance of ductular reaction in PBC. Methods: Liver biopsies were collected from naïve people with PBC (N = 87). Clinical-serological parameters were obtained at diagnosis and after 1 year of ursodeoxycholic acid (UDCA) treatment. Histological staging was performed on all slides according to multiple scoring systems and criteria for PBC. Liver samples were obtained from Mdr2 -/- mice treated with or without UDCA. Samples were processed for histology, immunohistochemistry, and immunofluorescence. Results: Ductular reaction in people with PBC correlated with the disease stage and liver fibrosis, but not with disease activity; an extensive ductular reaction correlated with serum alkaline phosphatase levels at diagnosis, response to UDCA, and individuals' estimated survival, independently from other histological parameters, including disease stage. In people with PBC, reactive ductules were associated with the establishment of junctions with bile canaliculi and with fibrogenetic cell activation. Consistently, in a mouse model of intrahepatic cholestasis, UDCA treatment was effective in reducing ductular reaction and fibrosis and increasing ductular-canalicular junctions. Conclusions: Extensive ductular reaction outlines a severe histologic phenotype in PBC and is associated with an inadequate therapy response and a worse estimated prognosis. Lay summary: In people affected by primary biliary cholangitis (PBC), the histological appearance of extensive ductular reaction identifies individuals at risk of progressive fibrosis. Ductular reaction at diagnosis correlates with the lack of response to first-line therapy with ursodeoxycholic acid and serves to restore ductular-canalicular junctions in people with PBC. Assessing ductular reaction extension at diagnosis may add valuable information for clinicians.
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    SARS-CoV-2 vaccination and risk of severe COVID-19 outcomes in patients with autoimmune hepatitis
    (Elsevier, 2022-10) Efe, Cumali; Taşçılar, Koray; Gerussi, Alessio; Bolis, Francesca; Lammert, Craig; Ebik, Berat; Stättermayer, Albert Friedrich; Cengiz, Mustafa; Gökçe, Dilara Turan; Cristoferi, Laura; Peralta, Mirta; Massoumi, Hatef; Montes, Pedro; Cerda, Eira; Rigamonti, Cristina; Yapalı, Suna; Adali, Gupse; Çalışkan, Ali Rıza; Balaban, Yasemin; Eren, Fatih; Eşkazan, Tuğçe; Barutçu, Sezgin; Lytvyak, Ellina; Zazueta, Godolfino Miranda; Kayhan, Meral Akdogan; Heurgue-Berlot, Alexandra; De Martin, Eleonora; Yavuz, Ahmet; Bıyık, Murat; Narro, Graciela Castro; Duman, Serkan; Hernandez, Nelia; Gatselis, Nikolaos K.; Aguirre, Jonathan; Idilman, Ramazan; Silva, Marcelo; Mendizabal, Manuel; Atay, Kadri; Güzelbulut, Fatih; Dhanasekaran, Renumathy; Montano-Loza, Aldo J.; Dalekos, George N.; Ridruejo, Ezequiel; Invernizzi, Pietro; Wahlin, Staffan; Medicine, School of Medicine
    Background Data regarding outcome of Coronavirus disease 2019 (COVID-19) in vaccinated patients with autoimmune hepatitis (AIH) are lacking. We evaluated the outcome of COVID-19 in AIH patients who received at least one dose of Pfizer- BioNTech (BNT162b2), Moderna (mRNA-1273) or AstraZeneca (ChAdOx1-S) vaccine. Patients and methods We performed a retrospective study on AIH patients with COVID-19. The outcomes of AIH patients who had acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection after at least one dose of COVID-19 vaccine were compared to unvaccinated patients with AIH. COVID-19 outcome was classified according to clinical state during the disease course as: (i) no hospitalization, (ii) hospitalization without oxygen supplementation, (iii) hospitalization with oxygen supplementation by nasal cannula or mask, (iv) intensive care unit (ICU) admission with non-invasive mechanical ventilation, (v) ICU admission with invasive mechanical ventilation or (vi) death, and data was analyzed using ordinal logistic regression. Results We included 413 (258 unvaccinated and 155 vaccinated) patients (81%, female) with a median age of 52 (range: 17–85) years at COVID-19 diagnosis. The rates of hospitalization were (36.4% vs. 14.2%), need for any supplemental oxygen (29.5% vs. 9%) and mortality (7% vs. 0.6%) in unvaccinated and vaccinated AIH patients with COVID-19. Having received at least one dose of SARS-CoV-2 vaccine was associated with a significantly lower risk of worse COVID-19 severity, after adjusting for age, sex, comorbidities and presence of cirrhosis (adjusted odds ratio [aOR] 0.18, 95% confidence interval [CI], 0.10–0.31). Overall, vaccination against SARS-CoV-2 was associated with a significantly lower risk of mortality from COVID-19 (aOR 0.20, 95% CI 0.11–0.35). Conclusions SARS-CoV-2 vaccination significantly reduced the risk of COVID-19 severity and mortality in patients with AIH.