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1
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Huang Y, Gong K, Tao M, Zhu Y, Li Y, Wang Y, Wu H, Hao W, Sun X. Mechanism of berbamine-mediated DNA damage in synovial fibroblasts to alleviate rheumatoid arthritis. Eur J Pharmacol 2025; 997:177597. [PMID: 40185320 DOI: 10.1016/j.ejphar.2025.177597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2024] [Revised: 03/20/2025] [Accepted: 04/02/2025] [Indexed: 04/07/2025]
Abstract
Rheumatoid arthritis (RA) is a common chronic autoimmune disease characterised by the proliferation and infiltration of fibroblast-like synoviocytes (FLS). However, pharmaceutical approaches to inhibit FLS in the treatment of RA are limited. Berbamine (BBM), a natural compound extracted from Phellodendron chinense Schneider, has demonstrated anti-tumour and anti-inflammatory effects. This study aimed to investigate the inhibitory effect of BBM on FLS in RA and to delineate the specific mechanisms involved, thereby proposing a novel therapeutic strategy for RA. Using the cell counting kit 8 assay and flow cytometry, we found that BBM reduced the proliferative ability of MH7A rheumatoid arthritis fibroblast-like synoviocytes by blocking the cell cycle and inducing apoptosis. In addition, BBM led to a decrease in the mitochondrial membrane potential and an increase in reactive oxygen species (ROS) and DNA damage. To explore the explicit mechanism of BBM, we used the ROS inhibitor N-acetyl-L-cysteine and the anti-apoptotic drug Z-VAD-FMK to rescue the effects of BBM. BBM effectively inhibited joint inflammation in RA cells in vivo. Regarding the safety confirmation, BBM does not damage the liver, spleen, and kidneys of collagen-induced arthritis mice. In summary, we found that the traditional Chinese medicine extract BBM alleviated RA by promoting ROS production and DNA damage in rheumatoid arthritis fibroblast-like synoviocytes providing new ideas for the clinical treatment of RA with traditional Chinese medicine.
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Affiliation(s)
- Yinger Huang
- Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510315, China; School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China
| | - Kunxiang Gong
- Institute of Reproductive Health and Perinatology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China
| | - Mengyuan Tao
- Institute of Antibody Engineering, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, 510515, China
| | - Yinfu Zhu
- Institute of Antibody Engineering, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, 510515, China
| | - Yiran Li
- Institute of Antibody Engineering, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, 510515, China
| | - Yi Wang
- Institute of Antibody Engineering, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, 510515, China
| | - Heyong Wu
- Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510315, China
| | - Wenbo Hao
- Institute of Antibody Engineering, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, 510515, China.
| | - Xiaomin Sun
- Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510315, China; School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China.
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2
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Eldew H, Soldera J. Evaluation of biological therapies in autoimmune hepatitis: A case-based systematic review. World J Gastrointest Pathophysiol 2025; 16:101481. [PMID: 40123748 PMCID: PMC11923927 DOI: 10.4291/wjgp.v16.i1.101481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Revised: 02/17/2025] [Accepted: 02/25/2025] [Indexed: 03/18/2025] Open
Abstract
BACKGROUND Autoimmune hepatitis (AIH) is typically treated with immunomodulators and steroids. However, some patients are refractory to these treatments, necessitating alternative approaches. Biological therapies have recently been explored for these difficult cases. AIM To assess the efficacy and safety of biologics in AIH, focusing on patients unresponsive to standard treatments and evaluating outcomes such as serological markers and histological remission. METHODS A case-based systematic review was performed following the PRISMA protocol to evaluate the efficacy and safety of biological therapies in AIH. The primary focus was on serological improvement and histological remission. The secondary focus was on assessing therapy safety and additional outcomes. A standardized search command was applied to MEDLINE, EMBASE, and Cochrane Library databases to identify relevant studies. Inclusion criteria encompassed adult AIH patients treated with biologics. Data were analyzed based on demographics, prior treatments, and therapy-related outcomes. A narrative synthesis was employed to address biases and provide a comprehensive overview of the evidence. RESULTS A total of 352 studies were reviewed, with 30 selected for detailed analysis. Key findings revealed that Belimumab led to a favourable response in five out of eight AIH patients across two studies. Rituximab demonstrated high efficacy, with 41 out of 45 patients showing significant improvement across six studies. Basiliximab was assessed in a single study, where the sole patient treated experienced a beneficial outcome. Additionally, a notable number of AIH cases were induced by anti-tumor necrosis factor (TNF) medications, including 16 cases associated with infliximab and four cases with adalimumab. All these cases showed improvement upon withdrawal of the biologic agent. CONCLUSION Belimumab and Rituximab show promise as effective alternatives for managing refractory AIH, demonstrating significant improvements in clinical outcomes and liver function. However, the variability in patient responses to different therapies highlights the need for personalized treatment strategies. The risk of AIH induced by anti-TNF therapies underscores the need for vigilant monitoring and prompt symptom recognition. These findings support the incorporation of biologic agents into AIH treatment protocols, particularly for patients who do not respond to conventional therapies.
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Affiliation(s)
- Haifa Eldew
- Consultant in Acute Internal Medicine with Specialist Interest in Hepatology, Princess Royal University Hospital, Kings College Hospital Foundation Trust, Orpington Kent BR6 8ND, United Kingdom
| | - Jonathan Soldera
- Acute Medicine and Gastroenterology, University of South Wales, Cardiff CF37 1DL, United Kingdom
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3
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Cheema PK, Iafolla MAJ, Abdel-Qadir H, Bellini AB, Chatur N, Chandok N, Comondore VR, Cunningham M, Halperin I, Hu AB, Jaskolka D, Darvish-Kazem S, Khandaker MH, Kitchlu A, Sachdeva JS, Shapera S, Woolnough NRJ, Nematollahi M. Managing Select Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitors. Curr Oncol 2024; 31:6356-6383. [PMID: 39451777 PMCID: PMC11506662 DOI: 10.3390/curroncol31100473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 10/12/2024] [Accepted: 10/16/2024] [Indexed: 10/26/2024] Open
Abstract
The increased use of immune checkpoint inhibitors (ICIs) across cancer programs has created the need for standardized monitoring and management of immune-related adverse events (irAEs). Delayed recognition without appropriate treatment can have serious and life-threatening consequences. The management of irAEs presents a unique set of challenges that must be addressed at a multidisciplinary level. Although various national and international guidelines and working groups provide high-level recommendations for the management of irAEs, practical guidance is lacking. Furthermore, timely collaboration between specialists requires institutional protocols that enable the early recognition, assessment, and treatment of irAEs. Such protocols should be developed by institution specialists and include algorithms for all healthcare providers involved in the care of patients treated with ICIs. At William Osler Health System in Brampton, Ontario, practical step-by-step multidisciplinary treatment approaches with recommendations for the management of irAEs were developed in collaboration with experts across Canada. Here, we provide an in-depth description of the approaches, outlining baseline investigations prior to the initiation of ICIs, as well as the monitoring and management of irAEs based on symptoms, severity, and involved organ systems. We encourage other centres to adapt and modify our approaches according to their specific needs and requirements.
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Affiliation(s)
- Parneet K. Cheema
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
| | - Marco A. J. Iafolla
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
| | - Husam Abdel-Qadir
- Women’s College Hospital Research Institute, Toronto, ON M5S 1B2, Canada;
- Division of Cardiology, Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, Toronto, ON M5G 2N2, Canada
| | - Andrew B. Bellini
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
| | - Nazira Chatur
- Division of Gastroenterology, Faculty of Medicine, Vancouver General Hospital (Sanders), University of British Columbia, Vancouver, BC V5Z 1M9, Canada;
| | - Natasha Chandok
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
| | - Vikram R. Comondore
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
| | - Morven Cunningham
- Toronto Centre for Liver Disease, University Health Network, Toronto, ON M5G 2C4, Canada;
| | - Ilana Halperin
- Division of Endocrinology, Department of Medicine, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada;
| | - Anne B. Hu
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
| | - Diana Jaskolka
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
| | - Saeed Darvish-Kazem
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
| | - Masud H. Khandaker
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
| | - Abhijat Kitchlu
- Division of Nephrology, Department of Medicine, University Health Network, University of Toronto, Toronto, ON M5G 2C4, Canada;
| | - Jasdip S. Sachdeva
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
| | - Shane Shapera
- Department of Medicine, University of Toronto, Toronto, ON M5G 2N2, Canada;
| | - Nicholas R. J. Woolnough
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
| | - Massey Nematollahi
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
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Bensaghir I, Tahiri L, Farih S, Rkain H, Allali F. Certolizumab-Induced Liver Injury in Ankylosing Spondylitis: A Case Report and Causality Assessment. Cureus 2024; 16:e66569. [PMID: 39258044 PMCID: PMC11385431 DOI: 10.7759/cureus.66569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/10/2024] [Indexed: 09/12/2024] Open
Abstract
Certolizumab-induced liver injury is exceptionally rare, with only a few cases reported in the literature. We present the case of a 34-year-old man with axial ankylosing spondylitis (AS) who developed a drug-induced liver injury following treatment with certolizumab. Despite the initial ineffectiveness of non-steroidal anti-inflammatory drugs and an inadequate response to infliximab, the patient achieved remission of AS symptoms with certolizumab. However, he subsequently developed elevated liver enzymes indicative of hepatocellular injury. Investigations excluded viral hepatitis and autoimmune liver diseases, pointing to certolizumab as the likely cause. The updated Roussel Uclaf Causality Assessment Method confirmed a probable causal relationship between certolizumab and hepatotoxicity. Discontinuation of certolizumab led to normalization of liver enzymes without recurrence of liver injury. This case highlights the need for vigilant monitoring for hepatotoxicity in patients receiving tumor necrosis factor inhibitors.
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Affiliation(s)
- Imane Bensaghir
- Department of Rheumatology B, Ayachi Hospital, Ibn Sina Hospital Center, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, MAR
| | - Latifa Tahiri
- Department of Rheumatology B, Ayachi Hospital, Ibn Sina Hospital Center, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, MAR
| | - Sara Farih
- Department of Rheumatology B, Ayachi Hospital, Ibn Sina Hospital Center, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, MAR
| | - Hanan Rkain
- Department of Rheumatology B, Ayachi Hospital, Ibn Sina Hospital Center, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, MAR
- Department of Exercise Physiology and Autonomous Nervous System, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, MAR
| | - Fadoua Allali
- Department of Rheumatology B, Ayachi Hospital, Ibn Sina Hospital Center, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, MAR
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5
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Gemmell A, Fraser A, Oien K, Seenan JP. Drug-induced liver injury with autoimmune features secondary to infliximab for ulcerative colitis. BMJ Case Rep 2023; 16:e254272. [PMID: 37879703 PMCID: PMC10603518 DOI: 10.1136/bcr-2022-254272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2023] Open
Abstract
We present a patient with a drug-induced liver injury with autoimmune features as a result of infliximab therapy for ulcerative colitis. This is a rare but serious side effect in patients receiving this treatment which clinicians should consider in the event of liver function test derangement.
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Affiliation(s)
- Ailsa Gemmell
- Queen Elizabeth University Hospital, NHSGGC, Glasgow, UK
| | - Andrew Fraser
- Gastroenterology, Queen Elizabeth University Hospital, Glasgow, UK
| | - Karin Oien
- Pathology, Queen Elizabeth University Hospital, Glasgow, UK
| | - John Paul Seenan
- Gastroenterology, Queen Elizabeth University Hospital, Glasgow, UK
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6
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Lopetuso LR, Cuomo C, Mignini I, Gasbarrini A, Papa A. Focus on Anti-Tumour Necrosis Factor (TNF)-α-Related Autoimmune Diseases. Int J Mol Sci 2023; 24:ijms24098187. [PMID: 37175894 PMCID: PMC10179362 DOI: 10.3390/ijms24098187] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 05/01/2023] [Accepted: 05/02/2023] [Indexed: 05/15/2023] Open
Abstract
Anti-tumour necrosis factor (TNF)-α agents have been increasingly used to treat patients affected by inflammatory bowel disease and dermatological and rheumatologic inflammatory disorders. However, the widening use of biologics is related to a new class of adverse events called paradoxical reactions. Its pathogenesis remains unclear, but it is suggested that cytokine remodulation in predisposed individuals can lead to the inflammatory process. Here, we dissect the clinical aspects and overall outcomes of autoimmune diseases caused by anti-TNF-α therapies.
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Affiliation(s)
- Loris Riccardo Lopetuso
- Center for Diagnosis and Treatment of Digestive Diseases, CEMAD, Gastroenterology Department, Fondazione Policlinico Gemelli, IRCCS, 00168 Rome, Italy
- Department of Medicine and Ageing Sciences, "G. d'Annunzio" University of Chieti-Pescara, 66100 Chieti, Italy
- Center for Advanced Studies and Technology (CAST), "G. d'Annunzio" University of Chieti-Pescara, 66100 Chieti, Italy
| | - Claudia Cuomo
- Center for Diagnosis and Treatment of Digestive Diseases, CEMAD, Gastroenterology Department, Fondazione Policlinico Gemelli, IRCCS, 00168 Rome, Italy
| | - Irene Mignini
- Center for Diagnosis and Treatment of Digestive Diseases, CEMAD, Gastroenterology Department, Fondazione Policlinico Gemelli, IRCCS, 00168 Rome, Italy
| | - Antonio Gasbarrini
- Center for Diagnosis and Treatment of Digestive Diseases, CEMAD, Gastroenterology Department, Fondazione Policlinico Gemelli, IRCCS, 00168 Rome, Italy
- Department of Translational Medicine and Surgery, School of Medicine, Catholic University, 00168 Rome, Italy
| | - Alfredo Papa
- Center for Diagnosis and Treatment of Digestive Diseases, CEMAD, Gastroenterology Department, Fondazione Policlinico Gemelli, IRCCS, 00168 Rome, Italy
- Department of Translational Medicine and Surgery, School of Medicine, Catholic University, 00168 Rome, Italy
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7
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Muacevic A, Adler JR, Panoutsakou M, Lalla E, Androutsakos T. Infliximab (IFX)-Biosimilar Induced Drug-Induced Liver Injury (DILI): A Case Report. Cureus 2022; 14:e32525. [PMID: 36654618 PMCID: PMC9839355 DOI: 10.7759/cureus.32525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/14/2022] [Indexed: 12/15/2022] Open
Abstract
Infliximab (IFX) is a chimeric human-murine monoclonal antibody that prevents tumor necrosis factor alpha (TNF-α) activation by binding to both soluble and transmembrane forms of TNF-α. Antagonists of TNF (anti-TNF agents) can cause drug-induced liver injury (DILI). We present a non-anti-TNF naïve patient suffering from severe Crohn's disease who developed DILI with a hepatocellular pattern, without jaundice, after two infusions of an IFX biosimilar.
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8
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Farshidpour M, Hutson W. Immune Checkpoint Inhibitors Induced Hepatotoxicity; Gastroenterologists' Perspectives. Middle East J Dig Dis 2022; 14:244-253. [PMID: 36619143 PMCID: PMC9489307 DOI: 10.34172/mejdd.2022.279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 01/10/2022] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND: Immune checkpoint inhibitors (ICIs) have promising clinical activity and are essential medications for patients with several malignancies. However, by deranging the immune system, these novel agents could lead to immune-related adverse events (IRAEs). Hepatotoxicity with checkpoint inhibitors usually results in acute hepatitis or drug-induced liver injury. METHODS: This review article discusses the recent clinical evidence available regarding checkpoint inhibitor-induced hepatitis and reviews an approach to their diagnosis and management. CONCLUSION: ICIs have improved patients' outcomes with different forms of malignancy; however, ICIs-related liver damage is a clinically significant entity in these patients. All patients should be monitored carefully for IRAEs while undergoing treatment with ICIs.
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Affiliation(s)
- Maham Farshidpour
- Loma Linda University Transplantation Institute,Corresponding Author: Maham Farshidpour, MD Loma Linda University Transplant Institute 197 E Caroline St, Suite 1400, San Bernardino, CA 92408 Tel: + 909 558 3636 Fax: + 909 337 2222
| | - William Hutson
- West Virginia University - Department of Medicine Section of Gastroenterology & Hepatology
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9
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Lee TL, Tsai TF. Non-immune functions of inflammatory cytokines targeted by anti-psoriatic biologics: a review. Inflamm Res 2022; 71:157-168. [PMID: 34981130 DOI: 10.1007/s00011-021-01528-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 11/25/2021] [Accepted: 11/25/2021] [Indexed: 12/01/2022] Open
Abstract
PURPOSE Psoriasis is an inflammatory disease characterized by skin thickening with silvery white desquamation due to dysregulated inflammatory pathways and elevated levels of inflammatory cytokines. Biologic agents targeting these inflammatory cytokines have brought about significant improvement in clearing psoriatic lesions in patients with moderate-to-severe psoriasis. Moreover, biologics exert both beneficial and detrimental effects on comorbidities in psoriasis, which include increased risk of cardiovascular events, metabolic syndrome, among other conditions. However, non-immune functions of cytokines targeted by biologics, and, hence, the potential risks and benefits of biologics for psoriasis to different organs/systems and comorbidities, have not been well elucidated. RESULTS This review summarizes current understanding of the pathogenesis of psoriasis-related comorbidities and emerging discoveries of roles of cytokines targeted in psoriasis treatment, including tumor necrosis factor α and interleukins 12, 23, and 17, aiming to complete the safety profile of each biologics and provide therapeutic implications on psoriasis-related comorbidities, and on diseases involving other organs or systems.
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Affiliation(s)
- Tung-Lin Lee
- Department of Medical Education, National Taiwan University Hospital, Taipei, Taiwan
| | - Tsen-Fang Tsai
- Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, 7 Chung-Shan S. Rd., Taipei, 100, Taiwan.
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10
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Araujo DV, Muniz TP, Yang A, Keshavarzi S, Sorotsky H, Butler MO, Saibil S, Spreafico A, Hogg D. Real World Outcomes and Hepatotoxicity of Infliximab in the Treatment of Steroid-Refractory Immune-Related Adverse Events. ACTA ACUST UNITED AC 2021; 28:2173-2179. [PMID: 34208089 PMCID: PMC8293058 DOI: 10.3390/curroncol28030201] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 05/25/2021] [Accepted: 06/01/2021] [Indexed: 02/08/2023]
Abstract
Background and aims: Current guidelines state that infliximab is contraindicated for the treatment of immune checkpoint inhibitor-related hepatitis (ir-hepatitis) due to the risk of inducing further liver damage. As this recommendation is largely based on the use of infliximab for rheumatologic diseases, we evaluated the efficacy and hepatotoxicity of infliximab in patients with steroid-refractory immune-related adverse events (irAEs). Methods: We retrospectively reviewed consecutive patients treated with infliximab for irAEs at Princess Margaret Cancer Centre. To assess hepatotoxicity, we compared the mean value of ALT, AST, and total bilirubin (BT) before and after infliximab treatment. We used logistic regression to assess factors associated with infliximab efficacy. Results: Between January 2010 and February 2019, 56 patients were identified. The median age of the patients was 63 (27–84) years. Colitis was the most frequent toxicity (66%), followed by pneumonitis (11%). Infliximab was used to treat ir-hepatitis in one patient. The median number of infliximab doses was 1 (1–3) and led to toxicity resolution in 43 (76%) patients. The mean ALT, AST, and BT levels before and after infliximab treatment were not statistically different. The patient treated for ir-hepatitis had a complete recovery, with no incremental liver toxicity. Conclusions: In this dose-limited setting, infliximab was effective in resolving irAEs and did not induce hepatotoxicity.
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Affiliation(s)
- Daniel V. Araujo
- Department of Medical Oncology and Hematology, Princess Margaret Cancer Center, Toronto, ON M5G 1X6, Canada; (T.P.M.); (H.S.); (M.O.B.); (S.S.); (A.S.); (D.H.)
- Department of Medical Oncology, Hospital de Base, Sao Jose do Rio Preto 15090 000, Brazil
- Correspondence: ; Tel.:+55-17-3201-5096
| | - Thiago Pimentel Muniz
- Department of Medical Oncology and Hematology, Princess Margaret Cancer Center, Toronto, ON M5G 1X6, Canada; (T.P.M.); (H.S.); (M.O.B.); (S.S.); (A.S.); (D.H.)
| | - Anjie Yang
- Department of Pharmacy, University Health Network, Toronto, ON M5G 2M9, Canada;
| | - Sareh Keshavarzi
- Department of Biostatistics, Princess Margaret Cancer Center, Toronto, ON M5G 2M9, Canada;
- Biostatistics Division, Dalla Lana School of Public Health, University of Toronto, Toronto, ON M5T 3M7, Canada
| | - Hadas Sorotsky
- Department of Medical Oncology and Hematology, Princess Margaret Cancer Center, Toronto, ON M5G 1X6, Canada; (T.P.M.); (H.S.); (M.O.B.); (S.S.); (A.S.); (D.H.)
- Cancer Center, Chaim Sheba Medical Center at Tel HaShomer, Ramat Gan 52621, Israel
| | - Marcus O. Butler
- Department of Medical Oncology and Hematology, Princess Margaret Cancer Center, Toronto, ON M5G 1X6, Canada; (T.P.M.); (H.S.); (M.O.B.); (S.S.); (A.S.); (D.H.)
| | - Samuel Saibil
- Department of Medical Oncology and Hematology, Princess Margaret Cancer Center, Toronto, ON M5G 1X6, Canada; (T.P.M.); (H.S.); (M.O.B.); (S.S.); (A.S.); (D.H.)
| | - Anna Spreafico
- Department of Medical Oncology and Hematology, Princess Margaret Cancer Center, Toronto, ON M5G 1X6, Canada; (T.P.M.); (H.S.); (M.O.B.); (S.S.); (A.S.); (D.H.)
| | - David Hogg
- Department of Medical Oncology and Hematology, Princess Margaret Cancer Center, Toronto, ON M5G 1X6, Canada; (T.P.M.); (H.S.); (M.O.B.); (S.S.); (A.S.); (D.H.)
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11
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Farkouh A, Baumgärtel C, Gottardi R, Hemetsberger M, Czejka M, Kautzky-Willer A. Sex-Related Differences in Drugs with Anti-Inflammatory Properties. J Clin Med 2021; 10:1441. [PMID: 33916167 PMCID: PMC8037587 DOI: 10.3390/jcm10071441] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 03/18/2021] [Accepted: 03/27/2021] [Indexed: 01/07/2023] Open
Abstract
There is increasing evidence of sex differences in the action of anti-inflammatory drugs, with women being at significantly higher risk of adverse effects. Nevertheless, clinicians' awareness of the implications of these sex differences on dosing and adverse event monitoring in routine practice is still in need of improvement. We reviewed the literature evaluating sex differences in terms of pharmacokinetics and pharmacodynamics of anti-inflammatory drugs. The anti-thrombotic activity of selective and non-selective COX-inhibitors tends to be stronger in men than women. Side effect profiles differ with regards to gastro-intestinal, renal and hepatic complications. Glucocorticosteroids were found to be more effective in men; women were more sensitive to corticosteroids when their oestradiol levels were high, a finding important for women taking hormonal contraception. TNF-alpha inhibitors have a longer half-life in men, leading to stronger immunosuppression and this a higher incidence of infections as side effects. Although research on sex differences in the effectiveness and safety of drugs is increasing, findings are often anecdotal and controversial. There is no systematic sex-differentiated reporting from clinical trials, and women are often under-represented. As personalized medicine is gaining in importance, sex, and gender aspects need to become integral parts of future research and policy making.
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Affiliation(s)
- André Farkouh
- Department of Pharmaceutical Sciences, University of Vienna, 1090 Vienna, Austria;
| | - Christoph Baumgärtel
- AGES Austrian Medicines and Medical Devices Agency and Austrian Federal Office for Safety in Health Care, 1200 Vienna, Austria;
| | - Roman Gottardi
- Vascular Surgery, MediClin Heart Institute Lahr/Baden, 77933 Lahr, Germany;
| | | | - Martin Czejka
- Department of Pharmaceutical Sciences, University of Vienna, 1090 Vienna, Austria;
| | - Alexandra Kautzky-Willer
- Gender Medicine Unit, Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, Austria;
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12
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Abstract
Given the liver's role in drug metabolism, it is uniquely sensitive to potential drug-induced liver injury (DILI) despite inherent protective mechanisms. In this article, we focus on the most common causes of DILI and their patterns of injury. Although not comprehensive, we attempt to cover several classes of commonly used drugs, and their associated patterns of injury and management.
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Affiliation(s)
- Jinyu Zhang
- Division of Gastroenterology and Hepatology, Department of Medicine, Henry Ford Hospital, 2799 West Grand Boulevard K-7, Detroit, MI 48202, USA
| | - Deepak Venkat
- Division of Gastroenterology and Hepatology, Department of Medicine, Henry Ford Hospital, 2799 West Grand Boulevard K-7, Detroit, MI 48202, USA.
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13
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Shah P, Sundaram V, Björnsson E. Biologic and Checkpoint Inhibitor-Induced Liver Injury: A Systematic Literature Review. Hepatol Commun 2020; 4:172-184. [PMID: 32025603 PMCID: PMC6996412 DOI: 10.1002/hep4.1465] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Accepted: 11/25/2019] [Indexed: 12/14/2022] Open
Abstract
Biologics are among the most commonly prescribed medications for several chronic inflammatory diseases. Tumor necrosis factor alpha inhibitors, more so than other agents, have been observed to cause drug‐induced liver injury. Additionally, because the approval and popularity of checkpoint inhibitors have grown, similar patterns of liver injury have been documented, with a majority of cases describing immune‐mediated hepatitis. Although the exact mechanism of injury is unknown, various host and medication characteristics play a role in the outcome of the molecular cascade invoked by biologics. Prognosis is usually favorable with cessation of the offending agent, but cases of acute liver failure requiring liver transplantation have also been observed. Therefore, algorithms have been created to assist clinicians in treating drug‐induced autoimmune hepatitis, mostly with corticosteroids. Additionally, case reports have documented successfully rechallenging patients with a different biologic without recurrence of liver injury, but data are limited. Further investigation is warranted regarding the potential for cross‐reactivity and mechanism of injury to develop guidelines to aid clinicians in further management of these patients.
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Affiliation(s)
- Parth Shah
- Division of Gastroenterology and Comprehensive Transplant Center Cedars-Sinai Medical Center Los Angeles CA
| | - Vinay Sundaram
- Division of Gastroenterology and Comprehensive Transplant Center Cedars-Sinai Medical Center Los Angeles CA
| | - Einar Björnsson
- Faculty of Medicine University of Iceland Reykjavik Iceland.,Division of Gastroenterology Department of Internal Medicine Landspitali University Hospital Reykjavik Iceland
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14
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Vozy A, De Martin E, Johnson DB, Lebrun-Vignes B, Moslehi JJ, Salem JE. Increased reporting of fatal hepatitis associated with immune checkpoint inhibitors. Eur J Cancer 2019; 123:112-115. [PMID: 31678768 DOI: 10.1016/j.ejca.2019.09.022] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Accepted: 09/24/2019] [Indexed: 02/08/2023]
Affiliation(s)
- Aurore Vozy
- Sorbonne Université, INSERM CIC-1421, AP-HP, Regional Pharmacovigilance Centre, Pitié-Salpêtrière Hospital, Department of Pharmacology, UNICO-GRECO APHP.Sorbonne Cardio-oncology program, F-75013 Paris, France; Sorbonne Université, IUC APHP.6, Pitié-Salpêtrière Hospital, Department of Medical Oncology, F-75013 Paris, France
| | - Eleonora De Martin
- AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, Unité Inserm-Paris Sud 1193, Univ Paris-Sud, Université Paris-Saclay, DHU Hépatinov, Villejuif, F-94800, France
| | - Douglas B Johnson
- Departments of Medicine and Oncology, Cardio-oncology Program, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Bénédicte Lebrun-Vignes
- Sorbonne Université, INSERM CIC-1421, AP-HP, Regional Pharmacovigilance Centre, Pitié-Salpêtrière Hospital, Department of Pharmacology, UNICO-GRECO APHP.Sorbonne Cardio-oncology program, F-75013 Paris, France
| | - Javid J Moslehi
- Departments of Medicine and Oncology, Cardio-oncology Program, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Joe-Elie Salem
- Sorbonne Université, INSERM CIC-1421, AP-HP, Regional Pharmacovigilance Centre, Pitié-Salpêtrière Hospital, Department of Pharmacology, UNICO-GRECO APHP.Sorbonne Cardio-oncology program, F-75013 Paris, France; Departments of Medicine and Oncology, Cardio-oncology Program, Vanderbilt University Medical Center, Nashville, TN, USA.
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15
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Wong F, Al Ibrahim B, Walsh J, Qumosani K. Infliximab-induced autoimmune hepatitis requiring liver transplantation. Clin Case Rep 2019; 7:2135-2139. [PMID: 31788265 PMCID: PMC6878066 DOI: 10.1002/ccr3.2456] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2019] [Revised: 08/07/2019] [Accepted: 08/18/2019] [Indexed: 12/20/2022] Open
Abstract
Autoimmune hepatitis is an infrequent but significant side effect of infliximab treatment. Diagnosis of autoimmune hepatitis is based on clinical, laboratory, and histological findings. Initial treatment involves cessation of infliximab and trial of prednisone. We present a rare case of infliximab-induced autoimmune hepatitis leading to liver failure requiring transplantation.
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Affiliation(s)
- Frederick Wong
- Division of GastroenterologyDepartment of Internal MedicineWestern UniversityLondonOntarioCanada
| | - Bashaar Al Ibrahim
- Division of GastroenterologyDepartment of Internal MedicineWestern UniversityLondonOntarioCanada
- Department of MedicineKing Faisal Special Hospital and Research CentreRiyadhSaudi Arabia
| | - Joanna Walsh
- Department of Pathology and Laboratory MedicineWestern UniversityLondonOntarioCanada
| | - Karim Qumosani
- Division of GastroenterologyDepartment of Internal MedicineWestern UniversityLondonOntarioCanada
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16
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Effect of sofosbuvir plus daclatasvir for treatment of chronic hepatitis C on patients with psoriasis. Eur J Gastroenterol Hepatol 2019; 31:1025-1029. [PMID: 30702448 DOI: 10.1097/meg.0000000000001370] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
AIM Until recently, clinicians caring for patients with psoriasis who were infected with hepatitis C virus (HCV) were concerned that treating one condition could exacerbate the other. We evaluated the outcome of treatment with direct-acting antiviral agents (DAAs) on patients with psoriasis having chronic hepatitis C (CHC) infection. PATIENTS AND METHODS This was an observational prospective cross-sectional study. It included CHC-naive patients with plaque psoriasis. All patients received sofosbuvir plus daclatasvir once daily for 12 weeks for treatment of CHC. Psoriasis area severity index (PASI) scores and the dermatology quality-of-life index were evaluated at the start of treatment with DAAs and then at 12 and 24 weeks after the end of HCV treatment. The primary end point was sustained virological response 12 weeks after treatment (SVR12). RESULTS A total of 34 CHC-naive patients were enrolled in this study. Most of them were of male sex (76.5%), and most of them had severe psoriasis, as the mean PASI score was 32. The primary and secondary end points (SVR12 and SVR24) for our patients were 100%. Regarding PASI and dermatology quality-of-life index scores, there was a highly significant difference before start of treatment and after treatment at 12 and 24 weeks. The most common adverse events are fatigue and headache. CONCLUSION Sofosbuvir plus daclatasvir is effective in the eradication of HCV and improvement of symptoms in patients with psoriasis having CHC infection. Future large series studies are needed to evaluate this promising effect of DAAs.
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Korzenik J, Larsen MD, Nielsen J, Kjeldsen J, Nørgård BM. Increased risk of developing Crohn's disease or ulcerative colitis in 17 018 patients while under treatment with anti-TNFα agents, particularly etanercept, for autoimmune diseases other than inflammatory bowel disease. Aliment Pharmacol Ther 2019; 50:289-294. [PMID: 31267570 DOI: 10.1111/apt.15370] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 04/11/2019] [Accepted: 05/22/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Anti-TNFα agents have revolutionised management of chronic inflammatory diseases. Paradoxically, these agents might provoke development of de novo autoimmune diseases. AIM To examine whether there is an increased risk of developing Crohn's disease (CD) and ulcerative colitis (UC) while under treatment with anti-TNFα agents for diseases other than inflammatory bowel disease (IBD) METHODS: A nationwide cohort study, based on Danish health registries, of all patients who utilised anti-TNFα agents for non-IBD indications. Included were patients, who had diseases for which anti-TNFα agent is indicated (rheumatoid arthritis, psoriasis/psoriatic arthritis, ankylosing spondylitis, others). The observation period for development of de novo IBD started from 2004. Exposed patients had received at least one dose of anti-TNFα. RESULTS In total 17 018 individuals with autoimmune diseases were exposed to anti-TNFα (the vast majority had infliximab, etanercept and adalimumab), and 63 308 individuals were not. Patients treated with etanercept had an increased risk of being diagnosed with CD and UC while under treatment, adjusted hazard ratio 2.0 [95% CI: 1.4-2.8] and 2.0 [95% CI: 1.5-2.8], respectively. The corresponding hazards ratios for infliximab were 1.3 [95% CI: 0.8-2.2] and 1.0 [95% CI:0.6-1.6], and for adalimumab 1.2 [95% CI: 0.8-1.8] and 0.6 [95% CI: 0.3-1.0]. CONCLUSIONS Patients treated for autoimmune diseases with anti-TNFα had an increased risk of being diagnosed with CD or UC while under treatment with etanercept. The nature of this association is uncertain. This finding has relevance to clinical care and insights into common mechanisms of the pathophysiology of these diseases.
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Affiliation(s)
- Joshua Korzenik
- Division of Gastroenterology, Hepatology, and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.,Harvard Medical School, Boston, Massachusetts
| | - Michael Due Larsen
- Center for Clinical Epidemiology, Odense University Hospital, Odense, Denmark.,Department of Clinical Research, Research Unit of Clinical Epidemiology, University of Southern Denmark, Odense, Denmark
| | - Jan Nielsen
- Center for Clinical Epidemiology, Odense University Hospital, Odense, Denmark.,Department of Clinical Research, Research Unit of Clinical Epidemiology, University of Southern Denmark, Odense, Denmark
| | - Jens Kjeldsen
- Department of Medical Gastroenterology S, Odense University Hospital, Odense, Denmark.,Department of Clinical Research, Research Unit of Medical Gastroenterology, University of Southern Denmark, Odense C, Denmark
| | - Bente Mertz Nørgård
- Division of Gastroenterology, Hepatology, and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.,Harvard Medical School, Boston, Massachusetts.,Center for Clinical Epidemiology, Odense University Hospital, Odense, Denmark.,Department of Clinical Research, Research Unit of Clinical Epidemiology, University of Southern Denmark, Odense, Denmark
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18
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Zhang HC, Luo W, Wang Y. Acute liver injury in the context of immune checkpoint inhibitor-related colitis treated with infliximab. J Immunother Cancer 2019; 7:47. [PMID: 30777137 PMCID: PMC6380028 DOI: 10.1186/s40425-019-0532-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Accepted: 02/11/2019] [Indexed: 02/07/2023] Open
Abstract
Background Immune checkpoint inhibitors (ICPIs), used to treat different advanced malignancies, are associated with a wide range of immune-related adverse reactions (irAEs) that deserve close monitoring of patients. Gastrointestinal reactions and hepatotoxicity may occur, which warrant careful evaluation to confirm the etiology and attribution to ICPIs as these events could affect future management. Case presentation We describe a case of a patient with prostate adenocarcinoma, treated with dual ICPIs comprised of ipilimumab and nivolumab, who developed elevated liver enzymes in the context of infliximab therapy prescribed to treat gastrointestinal irAE from his ICPIs. The patient’s grade 3 colitis became steroid-refractory, requiring a one-time infusion of infliximab, a biologic agent used commonly in inflammatory bowel disease, as a rescue therapy, to which he responded. The patient subsequently developed liver injury. This presented a diagnostic dilemma involving differential diagnoses of hepatotoxicity due to ICPI or infliximab exposure. A careful review of the clinical history, evaluation of the chronology of events, and exclusion of other causes of acute hepatitis were employed to make the final diagnosis of this event as infliximab-associated hepatotoxicity. Conclusion ICPIs such as CTLA-4 and PD-1 inhibitors have the potential to cause both gastrointestinal reactions and hepatotoxicity. An additional confounding factor in our patient’s case was the exposure to infliximab used to manage an established irAE that developed after the last exposure to ICPIs. The clinical history and data supported infliximab-associated hepatotoxicity, rather than an irAE. With the increasing application of ICPIs for different cancers, in conjunction with potential risks for irAE, the liver profile should be closely monitored during treatment with ICPI as well as with anti-TNF-α agents in this patient population.
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Affiliation(s)
- Hao Chi Zhang
- Division of Gastroenterology, Hepatology and Nutrition, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Wenyi Luo
- Department of Pathology/Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Yinghong Wang
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1466, Houston, TX, 77030, USA.
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19
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Forker R, Escher M, Stange EF. [A 20-year-old woman with ulcerative colitis and acute liver failure]. Internist (Berl) 2018; 58:982-989. [PMID: 28271269 DOI: 10.1007/s00108-017-0205-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
A 20-year-old woman presented with acute exacerbation of ulcerative colitis. After treatment with infliximab, she developed a fulminant liver failure. Under supportive therapy and steroid medication, recovery of symptoms and transaminases occurred. A few case reports about hepatic side effects of anti-TNF-α antibodies in patients with inflammatory bowel disease have been published. These side effects ranged from asymptomatic increase of transaminases to fulminant liver failure necessitating transplantation. The pathomechanism is not fully understood; in some case reports autoimmune phenomena have been described.
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Affiliation(s)
- R Forker
- Gastroenterologie, Rems-Murr-Klinik-Schorndorf, Schlichtener Str. 105, 73614, Schorndorf, Deutschland.
| | - M Escher
- Gastroenterologische Schwerpunktpraxis, Leonberg, Deutschland
| | - E F Stange
- Abteilung für Gastroenterologie, Hepatologie und Endokrinologie, Robert-Bosch-Krankenhaus Stuttgart, Stuttgart, Deutschland
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20
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Reynolds K, Thomas M, Dougan M. Diagnosis and Management of Hepatitis in Patients on Checkpoint Blockade. Oncologist 2018; 23:991-997. [PMID: 29853659 PMCID: PMC6192661 DOI: 10.1634/theoncologist.2018-0174] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Accepted: 05/08/2018] [Indexed: 12/26/2022] Open
Abstract
Many human tumors are recognized by the adaptive immune system, but these spontaneous antitumor responses are typically inadequate to mediate regression. Blockade of immune regulatory "checkpoint" receptors such as cytotoxic T-lymphocyte-associated antigen 4 and programmed cell death 1 can unleash antitumor immunity, resulting in tumor responses that can be durable. Alongside the enormous promise of immunotherapy for cancer, the immune dysregulation of checkpoint blockade has led to a plethora of new autoimmune adverse events. Hepatic toxicity occurs in 1%-17% of patients on immune checkpoint inhibitors, with the precise incidence dependent on both the drug used and the underlying malignancy. Hepatitis is most commonly a low-grade toxicity, but grade 3 and 4 hepatotoxicity does occur. Here we will answer frequently asked questions regarding immune-related hepatitis to assist in the recognition and management of this important condition. KEY POINTS Immune related hepatitis is a potentially serious complication of checkpoint blockade.The differential for elevated liver function tests in patients on checkpoint blockade is broad.Diagnostic testing such as viral serologies, liver ultrasound, cross sectional imaging, and liver biopsy may help in the diagnosis of immune related hepatitis in select patients.Patients with underlying cirrhosis are an at risk population for whom current grading criteria may underestimate the severity of liver inflammation.Severe immune related hepatitis is best managed by a multi-disciplinary team that includes a hepatologist.Most patients with immune related hepatitis respond to corticosteroids, but a substantial fraction require treatment with a secondary immunosuppressive agent.
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Affiliation(s)
- Kerry Reynolds
- Division of Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Molly Thomas
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Michael Dougan
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
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21
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Rizvi S, Gawrieh S. Autoimmune Hepatitis in the Elderly: Diagnosis and Pharmacologic Management. Drugs Aging 2018; 35:589-602. [PMID: 29971609 DOI: 10.1007/s40266-018-0556-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Autoimmune hepatitis (AIH) may present as acute or chronic hepatitis in the elderly. Advanced hepatic fibrosis and cirrhosis are common on first presentation in this population. In this review, we discuss the presentation, approach to diagnosis and management of AIH in the elderly. As polypharmacy is common in the elderly, careful medication use history is essential for detecting drug-induced AIH-like hepatitis. Steroid-sparing or minimizing therapeutic regimens are preferred to treat AIH in the elderly. For the purpose of induction, budesonide or lower dose prednisone in combination with azathioprine (AZA) regimens are preferred over high-dose prednisone monotherapy due to the higher risk of side effects of the later in the elderly. The goal of maintenance therapy should be to achieve full biochemical and histologic remission. Bone density monitoring and interventions to prevent steroid-related bone disease should be implemented throughout the course of the disease. Liver transplantation should be considered in the elderly patient with liver failure or early hepatocellular carcinoma if there are no significant comorbidities or compromise in functional status.
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Affiliation(s)
- Syed Rizvi
- Gastroenterology and Hepatology Division, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, WI, 53226, USA.
| | - Samer Gawrieh
- Gastroenterology and Hepatology Division, Indiana University School of Medicine, 702 Rotary Cir, Indianapolis, IN, 46202-5175, USA.
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22
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Lopetuso LR, Mocci G, Marzo M, D'Aversa F, Rapaccini GL, Guidi L, Armuzzi A, Gasbarrini A, Papa A. Harmful Effects and Potential Benefits of Anti-Tumor Necrosis Factor (TNF)-α on the Liver. Int J Mol Sci 2018; 19:E2199. [PMID: 30060508 PMCID: PMC6121684 DOI: 10.3390/ijms19082199] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 07/19/2018] [Accepted: 07/24/2018] [Indexed: 02/08/2023] Open
Abstract
Anti-tumor necrosis factor (TNF)-α agents represent an effective treatment for chronic inflammatory diseases. However, some concerns about their potentially undesirable effects on liver function have been reported. On the other hand, evidence of their therapeutic effects on certain liver diseases is accumulating. Many data showed the safety of anti-TNF-α in patients with chronic hepatitis B and C and in liver transplanted patients even if a strict follow-up and prophylaxis are recommended in well-defined subgroups. On the other side, anti-TNF-α-induced liver injury is not a rare event. However, it is often reversible after anti-TNF-α withdrawal. Anti-TNF-α agents have been tested in advanced stages of severe alcoholic hepatitis and non-alcoholic fatty liver disease. Limited data on the efficacy of anti-TNF-α in patients with autoimmune hepatitis and primary biliary cholangitis are also available. In this review, we explored the hepatic safety concerns in patients receiving anti-TNF-α agents with and without pre-existent hepatic diseases. In addition, the available evidence on their potential benefits in the treatment of specific hepatic diseases is discussed.
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Affiliation(s)
- Loris Riccardo Lopetuso
- Internal Medicine and Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli IRCCS-Università Cattolica del Sacro Cuore, 00168 Roma, Italy.
| | - Giammarco Mocci
- Gastroenterology Unit, Brotzu Hospital, 09121 Cagliari, Italy.
| | - Manuela Marzo
- Internal Medicine and Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli IRCCS-Università Cattolica del Sacro Cuore, 00168 Roma, Italy.
| | - Francesca D'Aversa
- Internal Medicine and Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli IRCCS-Università Cattolica del Sacro Cuore, 00168 Roma, Italy.
| | - Gian Lodovico Rapaccini
- Internal Medicine and Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli IRCCS-Università Cattolica del Sacro Cuore, 00168 Roma, Italy.
| | - Luisa Guidi
- Internal Medicine and Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli IRCCS-Università Cattolica del Sacro Cuore, 00168 Roma, Italy.
| | - Alessandro Armuzzi
- Internal Medicine and Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli IRCCS-Università Cattolica del Sacro Cuore, 00168 Roma, Italy.
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli IRCCS-Università Cattolica del Sacro Cuore, 00168 Roma, Italy.
| | - Alfredo Papa
- Internal Medicine and Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli IRCCS-Università Cattolica del Sacro Cuore, 00168 Roma, Italy.
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23
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Fiore M, Leone S, Maraolo AE, Berti E, Damiani G. Liver Illness and Psoriatic Patients. BIOMED RESEARCH INTERNATIONAL 2018; 2018:3140983. [PMID: 29546055 PMCID: PMC5818942 DOI: 10.1155/2018/3140983] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Revised: 10/30/2017] [Accepted: 01/04/2018] [Indexed: 12/12/2022]
Abstract
Psoriasis is a chronic inflammatory disease of the skin affecting approximately 2% of the world's population. Systemic treatments, including methotrexate and cyclosporin, are associated with potential hepatotoxicity, due to either direct liver damage or immunosuppression or both immunomediated and a direct liver injury; therefore, treatment of patients with psoriasis poses a therapeutic challenge. The aim of this minireview is to help clinicians in the management of psoriatic patients who develop signs of liver dysfunction. To find relevant articles, a comprehensive search was performed on PubMed, EMBASE, and Cochrane with appropriate combinations of the following keywords being considered: viral hepatitis, nonalcoholic fatty liver disease, psoriasis, hepatotoxicity, drug toxicity, cholestasis, and autoimmune liver diseases.
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Affiliation(s)
- Marco Fiore
- Department of Anaesthesiological, Surgical and Emergency Sciences, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Sebastiano Leone
- Department of Medicine, Division of Infectious Diseases, “San Giuseppe Moscati” Hospital, Avellino, Italy
| | - Alberto Enrico Maraolo
- Department of Clinical Medicine and Surgery, Section of Infectious Diseases, University of Naples Federico II, Naples, Italy
| | - Emilio Berti
- Department of Pathophysiology and Transplantation, Dermatology Unit, IRCCS Ca' Granda, University of Milan, Milan, Italy
| | - Giovanni Damiani
- Department of Pathophysiology and Transplantation, Dermatology Unit, IRCCS Ca' Granda, University of Milan, Milan, Italy
- Study Center of Young Dermatologists Italian Network (YDIN), Bergamo, Italy
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24
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Immunotherapy in metastatic urothelial carcinoma: focus on immune checkpoint inhibition. Nat Rev Urol 2017; 15:112-124. [PMID: 29205200 DOI: 10.1038/nrurol.2017.190] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Immunotherapy has been used in localized urothelial carcinoma for decades, especially in the treatment of superficial disease, in which instillation of BCG is a commonly used treatment option. Clinical investigations based on new insights into the immunogenic potential of metastatic urothelial carcinoma have led to the accelerated FDA approval of the immune checkpoint inhibitors atezolizumab, nivolumab, durvalumab, avelumab, and pembrolizumab. Preliminary findings suggest additional benefits of combinations of immunotherapeutic agents as a future treatment approach in metastatic urothelial carcinoma. Treatment experience with immunotherapy suggests that these drugs are associated with a unique spectrum of immune-related adverse events and specific immune-related patterns of response, including cases of pseudoprogression, which could impede the optimal use of immune checkpoint inhibitors in the clinic. Appropriate management of immune-related adverse events and a greater awareness of immune-mediated response patterns will help to inform treatment decisions and improve patient outcomes; predictive biomarkers of response might facilitate selection of patients who are most likely to respond to and benefit from these exciting new treatments.
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25
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Chiu YM, Lai MS, Chan KA. Assessing risk of liver enzyme elevation in patients with immune-mediated diseases and different hepatitis B virus serostatus receiving anti-TNF agents: a nested case-control study. Arthritis Res Ther 2017; 19:214. [PMID: 29089055 PMCID: PMC5664916 DOI: 10.1186/s13075-017-1413-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Accepted: 08/29/2017] [Indexed: 02/08/2023] Open
Abstract
Background Liver enzyme elevation is an important and common adverse effect among patients with immune-mediated diseases who receive tumour necrosis factor inhibitors (anti-TNF), and has various causes. Hence, we evaluated the relative risks of developing liver enzyme elevation in anti-TNF users with differing hepatitis B virus (HBV) infection status. Methods At a hospital in central Taiwan, 407 patients with rheumatoid arthritis, ankylosing spondylitis, or psoriasis/psoriatic arthritis received anti-TNF therapy between 1 January 2004 and 30 June 2012. We performed a nested case-control study (n = 368) of cases with serum alanine aminotransferase (ALT) > 40 international units/L ≤ 12 months after starting anti-TNF therapy, and corresponding controls without liver enzyme elevation. Conditional logistic regression was used to evaluate associations between liver enzyme elevation and HBV serostatus, as well as other risk factors. Results Thirty cases were compared to 338 controls. After adjustment for potential confounders, HBV surface antigen-positive (HBsAg+) serostatus was associated with substantially higher likelihood of developing elevated ALT (adjusted odds ratio 7.91, 95% confidence interval (CI) 2.16–31.31) relative to those with an uninfected HBV status; no such association was observed among HBsAg-negative/HBV core antibody-positive (HBsAg–/HBcAb+) patients (adjusted odds ratio 1.00, 95% CI 0.33–3.25). Increased risk of ALT elevation was associated with methotrexate used alone, without folic acid (adjusted odds ratio 11.60, 95% CI 2.52–56.46), and history of ALT elevation (adjusted odds ratio 13.71, 95% CI 4.32–45.75). Conclusions HBsAg+ patients with immune-mediated diseases who received anti-TNF therapy had an approximately eight-fold higher likelihood of liver enzyme elevation than those without HBV infection, whereas patients with HBsAg–/HBcAb+ serostatus had a risk similar to that of uninfected patients. Electronic supplementary material The online version of this article (doi:10.1186/s13075-017-1413-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Ying-Ming Chiu
- Division of Allergy, Immunology and Rheumatology, Changhua Christian Hospital, 135 Nanxiao St, Changhua, 500-06, Taiwan. .,Department of Nursing, College of Medicine and Nursing, Hungkuang University, Taichung, Taiwan.
| | - Mei-Shu Lai
- Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - K Arnold Chan
- Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.,Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.,Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan
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Diverse patterns of anti-TNF-α-induced lupus: case series and review of the literature. Clin Rheumatol 2017; 37:563-568. [DOI: 10.1007/s10067-017-3884-2] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2017] [Accepted: 10/17/2017] [Indexed: 02/08/2023]
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Tran-Minh ML, Sousa P, Maillet M, Allez M, Gornet JM. Hepatic complications induced by immunosuppressants and biologics in inflammatory bowel disease. World J Hepatol 2017; 9:613-626. [PMID: 28539989 PMCID: PMC5424291 DOI: 10.4254/wjh.v9.i13.613] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Revised: 04/01/2017] [Accepted: 04/24/2017] [Indexed: 02/06/2023] Open
Abstract
The incidence of inflammatory bowel diseases (IBD) is rising worldwide. The therapeutic options for IBD are expanding, and the number of drugs with new targets will rapidly increase in coming years. A rapid step-up approach with close monitoring of intestinal inflammation is extensively used. The fear of side effects represents one the most limiting factor of their use. Despite a widespread use for years, drug induced liver injury (DILI) management remains a challenging situation with Azathioprine and Methotrexate. DILI seems less frequent with anti-tumor necrosis factor agents and new biologic therapies. The aim of this review is to report incidence, physiopathology and practical guidelines in case of DILI occurrence with the armamentarium of old and new drugs in the field of IBD.
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Hepatic Issues and Complications Associated With Inflammatory Bowel Disease: A Clinical Report From the NASPGHAN Inflammatory Bowel Disease and Hepatology Committees. J Pediatr Gastroenterol Nutr 2017; 64:639-652. [PMID: 27984347 DOI: 10.1097/mpg.0000000000001492] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepatobiliary disorders are common in patients with inflammatory bowel disease (IBD), and persistent abnormal liver function tests are found in approximately 20% to 30% of individuals with IBD. In most cases, the cause of these elevations will fall into 1 of 3 main categories. They can be as a result of extraintestinal manifestations of the disease process, related to medication toxicity, or the result of an underlying primary hepatic disorder unrelated to IBD. This latter possibility is beyond the scope of this review article, but does need to be considered in anyone with elevated liver function tests. This review is provided as a clinical summary of some of the major hepatic issues that may occur in patients with IBD.
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Restellini S, Chazouillères O, Frossard JL. Hepatic manifestations of inflammatory bowel diseases. Liver Int 2017; 37:475-489. [PMID: 27712010 DOI: 10.1111/liv.13265] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Accepted: 09/27/2016] [Indexed: 12/18/2022]
Abstract
Inflammatory bowel diseases are associated with various hepatobiliary disorders, reported both in Crohn's disease and ulcerative colitis. They may occur at any moment in the natural course of the disease. The prevalence of liver dysfunction rises from 3% to 50% accordingly to definitions used in different studies. Fatty liver is considered as the most common hepatobiliary complication in inflammatory bowel diseases while primary sclerosing cholangitis is the most specific one. Less frequently, inflammatory bowel diseases-associated hepatobiliary disorders include: autoimmune hepatitis/ primary sclerosing cholangitis overlap syndrome, IgG4-associated cholangiopathy, primary biliary cholangitis, hepatic amyloidosis, granulomatous hepatitis, cholelithiasis, portal vein thrombosis and liver abscess. The spectrum of these manifestations varies according to the type of inflammatory bowel diseases. Treatments of inflammatory bowel diseases may cause liver toxicity, although incidence of serious complications remains low. However, early diagnosis of drug-induced liver injury is of major importance as it affects future clinical management. When facing abnormal liver tests, clinicians should undertake a full diagnostic work-up in order to determine whether the hepatic abnormalities are related to the inflammatory bowel diseases or not. Management of hepatic manifestations in inflammatory bowel diseases usually involves both hepatologists and gastroenterologists because of the complexity of some situations.
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Affiliation(s)
- Sophie Restellini
- Service de Gastroentérologie et Hépatologie, Hôpitaux Universitaires de Genève, Genève, Suisse
| | - Olivier Chazouillères
- Division d'Hépatologie, Centre de Référence des Maladies Inflammatoires des Voies Biliaires, et Université de Sorbonne, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, AP-HP, Hôpital Saint-Antoine, Paris, France
| | - Jean-Louis Frossard
- Service de Gastroentérologie et Hépatologie, Hôpitaux Universitaires de Genève, Genève, Suisse
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Chiu YM, Tang CH, Hung ST, Yang YW, Fang CH, Lin HY. A real-world risk analysis of biological treatment (adalimumab and etanercept) in a country with a high prevalence of tuberculosis and chronic liver disease: a nationwide population-based study. Scand J Rheumatol 2016; 46:236-240. [PMID: 27766916 DOI: 10.1080/03009742.2016.1202318] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
OBJECTIVES Few studies on tumour necrosis factor (TNF) inhibitor-associated tuberculosis (TB) and hepatic events have been performed in regions where these risks are elevated. This study aimed to provide a direct comparison between adalimumab and etanercept in a high-risk population and to address the implications for physicians working with patients in such an environment. METHOD Data collected from the National Health Insurance Research Database (NHIRD) in Taiwan between 2007 and 2011 were analysed retrospectively for incidences of eight adverse events associated with TNF-α inhibitors. Hazard ratios (HRs) of adalimumab vs. etanercept were calculated using a Cox proportional hazards model. RESULTS During this 5-year period, 86 events of TB were reported after 5317 person-years of exposure to adalimumab (1.62 events per 100 person-years), compared to 44 events after 7690 person-years of exposure to etanercept (0.57 events per 100 person-years). For serious hepatic events that led to hospitalization, 0.75 events were reported per 100 person-years of exposure to adalimumab compared to 0.39 events per 100 person-years of exposure to etanercept. Adjusted HRs for TB [aHR 3.06, 95% confidence interval (CI) 2.09-4.49, p < 0.0001], hospitalization due to a hepatic event (aHR 2.05, 95% CI 1.27-3.30, p = 0.0035), and serious infection (aHR 1.48, 95% CI 1.19-1.84, p = 0.0005) attained significance. CONCLUSIONS TNF-α-targeting therapies with the monoclonal antibody adalimumab confers significant added risk of TB and serious hepatic events compared to therapies with the soluble fusion protein etanercept. Tailored strategies to attenuate these risks are warranted in high-risk regions such as Taiwan.
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Affiliation(s)
- Y-M Chiu
- a Division of Allergy, Immunology and Rheumatology , Changhua Christian Hospital , Changhua , Taiwan.,b Department of Nursing , College of Medicine and Nursing, HungKuang University , Taichung , Taiwan
| | - C-H Tang
- c School of Health Care Administration , Taipei Medical University , Taipei , Taiwan
| | - S-T Hung
- d Formosa Biomedical Technology Corporation , Taipei , Taiwan
| | - Y-W Yang
- e Pfizer Limited , Taipei , Taiwan
| | - C-H Fang
- e Pfizer Limited , Taipei , Taiwan
| | - H-Y Lin
- f Division of Allergy, Immunology and Rheumatology, Department of Medicine , Taipei Veterans General Hospital , Taipei , Taiwan.,g Faculty of Medicine , National Yang-Ming University , Taipei , Taiwan
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Stine JG, Northup PG. Autoimmune-like drug-induced liver injury: a review and update for the clinician. Expert Opin Drug Metab Toxicol 2016; 12:1291-1301. [DOI: 10.1080/17425255.2016.1211110] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Jonathan G. Stine
- Division of Gastroenterology & Hepatology, Department of Medicine, University of Virginia, Charlottesville, VA, USA
| | - Patrick G. Northup
- Division of Gastroenterology & Hepatology, Department of Medicine, University of Virginia, Charlottesville, VA, USA
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Abstract
Infliximab (IFX) is commonly used to induce and maintain remission in inflammatory bowel disease (IBD). We report the first 2 cases of children with ulcerative colitis who had normal liver transaminases before IFX and were diagnosed with immunomediated hepatitis after IFX induction. Both the cases had negative antibodies for antinuclear, smooth muscle, and liver kidney microsome, with 1 patient having positive autoimmune serology (dsDNA) and overlap primary sclerosing cholangitis. IFX was discontinued and transaminases normalized without steroid administration. Clinicians treating pediatric patients with IBD with IFX should be aware of IFX immunomediated hepatitis. This phenomenon is previously reported in adult patients with IBD. To our knowledge, these are the first cases reported in pediatric patients with IBD.
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French JB, Bonacini M, Ghabril M, Foureau D, Bonkovsky HL. Hepatotoxicity Associated with the Use of Anti-TNF-α Agents. Drug Saf 2016; 39:199-208. [PMID: 26692395 PMCID: PMC4752395 DOI: 10.1007/s40264-015-0366-9] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Medications to inhibit the actions of tumour necrosis factor alpha have revolutionized the treatment of several pro-inflammatory autoimmune conditions. Despite their many benefits, several serious side effects exist and adverse reactions do occur from these medications. While many of the medications' potential adverse effects were anticipated and recognized in clinical trials prior to drug approval, several more rare adverse reactions were recorded in the literature as the popularity, availability and distribution of these medications grew. Of these potential adverse reactions, liver injury, although uncommon, has been observed in some patients. As case reports accrued over time and ultimately case series developed, the link became better established between this family of medicines and various patterns of liver injury. Interestingly, it appears that the majority of cases exhibit an autoimmune hepatitis profile both in serological markers of autoimmune liver disease and in classic autoimmune features seen on hepatic histopathology. Despite the growing evidence of this relationship, the pathogenesis of this reaction remains incompletely understood, but it appears to depend on characteristics of the medications and the genetic composition of the patients; it is likely more complicated than a simple medication class effect. Because of this still incomplete understanding and the infrequency of the occurrence, treatments have also been limited, although it is clear that most patients improve with cessation of the offending agent and, in certain cases, glucocorticoid use. However, more needs to be done in the future to unveil the underlying mechanisms of this adverse reaction.
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Affiliation(s)
- Joshua B French
- Section on Gastroenterology and Hepatology, Department of Internal Medicine, Wake Forest Health Sciences, Winston-Salem, NC, USA
| | | | - Marwan Ghabril
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Suite 225, 702 Rotary Circle, Indianapolis, IN, USA.
| | - David Foureau
- Department of Research, Carolinas HealthCare System, Charlotte, NC, USA
| | - Herbert L Bonkovsky
- Section on Gastroenterology and Hepatology, Department of Internal Medicine, Wake Forest Health Sciences, Winston-Salem, NC, USA
- Department of Medicine, University of Connecticut Health Science Center, Farmington, CT, USA
- Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA
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Salvi M, Macaluso L, Luci C, Mattozzi C, Paolino G, Aprea Y, Calvieri S, Richetta AG. Safety and efficacy of anti-tumor necrosis factors α in patients with psoriasis and chronic hepatitis C. World J Clin Cases 2016; 4:49-55. [PMID: 26881191 PMCID: PMC4733476 DOI: 10.12998/wjcc.v4.i2.49] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Revised: 09/10/2015] [Accepted: 11/11/2015] [Indexed: 02/05/2023] Open
Abstract
Up to date, in literature, it is still debated the role of anti-tumor necrosis factors (TNF)-α treatments in hepatitis C virus (HCV) patients. TNF-α performs a lot of functions, it is an important pro-inflammatory cytokine and it is involved in the host’s immunity. Since TNF-α is implicated in the apoptotic signaling pathway of hepatocytes infected by HCV, anti TNF-α therapy may increase the risk of viral replication or their reactivation. However the treatment of anti TNF-α could have a healthful role because TNF-α appears to be engaged in the pathogenesis of liver fibrosis, inducing apoptotic pathways. We describe the case of a patient with plaque-type psoriasis and concomitant chronic HCV, who was treated successfully with anti-TNF agents simultaneously to cyclosporine without sign of reactivation of HCV and increase of liver enzymes. Our personal experience shows that anti-TNF-α agents are not only effective but also safe. Furthermore the combination therapy of cyclosporine and anti-TNF-α appears to be well-tolerated and able to reduce the amount of liver enzymes as well as HCV-viral-load. However systematic, large-scale studies with long follow-ups will be needed to confirm our results, in association with close liver function monitoring.
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35
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Stine JG, Lewis JH. Current and future directions in the treatment and prevention of drug-induced liver injury: a systematic review. Expert Rev Gastroenterol Hepatol 2015; 10:517-36. [PMID: 26633044 PMCID: PMC5074808 DOI: 10.1586/17474124.2016.1127756] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
While the pace of discovery of new agents, mechanisms and risk factors involved in drug-induced liver injury (DILI) remains brisk, advances in the treatment of acute DILI seems slow by comparison. In general, the key to treating suspected DILI is to stop using the drug prior to developing irreversible liver failure. However, predicting when to stop is an inexact science, and commonly used ALT monitoring is an ineffective strategy outside of clinical trials. The only specific antidote for acute DILI remains N-acetylcysteine (NAC) for acetaminophen poisoning, although NAC is proving to be beneficial in some cases of non-acetaminophen DILI in adults. Corticosteroids can be effective for DILI associated with autoimmune or systemic hypersensitivity features. Ursodeoxycholic acid, silymarin and glycyrrhizin have been used to treat DILI for decades, but success remains anecdotal. Bile acid washout regimens using cholestyramine appear to be more evidenced based, in particular for leflunomide toxicity. For drug-induced acute liver failure, the use of liver support systems is still investigational in the United States and emergency liver transplant remains limited by its availability. Primary prevention appears to be the key to avoiding DILI and the need for acute treatment. Pharmacogenomics, including human leukocyte antigen genotyping and the discovery of specific DILI biomarkers offers significant promise for the future. This article describes and summarizes the numerous and diverse treatment and prevention modalities that are currently available to manage DILI.
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Affiliation(s)
- Jonathan G. Stine
- University of Virginia Health System, Department of Medicine, Division of Gastroenterology and Hepatology, JPA and Lee Street, MSB 2145, PO Box 800708, Charlottesville VA 22908
| | - James H. Lewis
- Georgetown University Medical Center, Department of Medicine, Division of Gastroenterology and Hepatology, 3800 Reservoir Rd NW, Washington, DC 20007
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Vierling JM. Autoimmune Hepatitis and Overlap Syndromes: Diagnosis and Management. Clin Gastroenterol Hepatol 2015; 13:2088-108. [PMID: 26284592 DOI: 10.1016/j.cgh.2015.08.012] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Revised: 08/11/2015] [Accepted: 08/11/2015] [Indexed: 12/14/2022]
Affiliation(s)
- John M Vierling
- Departments of Medicine and Surgery, Baylor College of Medicine, Baylor-St Luke's Medical Center, Houston, Texas.
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Parra RS, Feitosa MR, Machado VF, Ramalho LNZ, da Rocha JJR, Feres O. Infliximab-associated fulminant hepatic failure in ulcerative colitis: a case report. J Med Case Rep 2015; 9:249. [PMID: 26518665 PMCID: PMC4627392 DOI: 10.1186/s13256-015-0730-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Accepted: 10/08/2015] [Indexed: 02/08/2023] Open
Abstract
INTRODUCTION Infliximab, an antibody against tumor necrosis factor alpha, is used to treat inflammatory bowel disease and has well-established efficacy and proven safety. Complications of this treatment are related to immunosuppression and include higher risk of serious infections and malignant neoplasia. Although extremely rare, fulminant liver damage related to infliximab therapy has been reported. CASE PRESENTATION We present the case of a 38-year-old Afro-Brazilian woman with refractory ulcerative colitis who was started on infliximab. She had no previous history of liver disease, alcohol abuse, or infection. After the fifth dose of the medication, drug-induced liver injury was diagnosed. Treatment was discontinued but our patient's condition was aggravated by severe cholestasis and grade III/IV encephalopathy, requiring liver transplantation. CONCLUSION Drug-induced liver injury is an uncommon complication of infliximab. Current consensus recommends screening for liver dysfunction prior to and during therapy. This case emphasizes the need for vigilance and highlights a rare and potentially lethal complication.
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Affiliation(s)
- Rogerio Serafim Parra
- Division of Coloproctology, Department of Surgery and Anatomy, Medical School of Ribeirão Preto, University of São Paulo, Avenida dos Bandeirantes, 3900, Ribeirão Preto, SP, Zip: 14048-900, Brazil.
| | - Marley Ribeiro Feitosa
- Division of Coloproctology, Department of Surgery and Anatomy, Medical School of Ribeirão Preto, University of São Paulo, Avenida dos Bandeirantes, 3900, Ribeirão Preto, SP, Zip: 14048-900, Brazil.
| | - Vanessa Foresto Machado
- Division of Coloproctology, Department of Surgery and Anatomy, Medical School of Ribeirão Preto, University of São Paulo, Avenida dos Bandeirantes, 3900, Ribeirão Preto, SP, Zip: 14048-900, Brazil.
| | - Leandra Naira Zambelli Ramalho
- Department of Pathology, Medical School of Ribeirão Preto, University of São Paulo, Avenida dos Bandeirantes, 3900, Ribeirão Preto, SP, Zip: 14048-900, Brazil.
| | - Jose Joaquim Ribeiro da Rocha
- Division of Coloproctology, Department of Surgery and Anatomy, Medical School of Ribeirão Preto, University of São Paulo, Avenida dos Bandeirantes, 3900, Ribeirão Preto, SP, Zip: 14048-900, Brazil.
| | - Omar Feres
- Division of Coloproctology, Department of Surgery and Anatomy, Medical School of Ribeirão Preto, University of São Paulo, Avenida dos Bandeirantes, 3900, Ribeirão Preto, SP, Zip: 14048-900, Brazil.
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Tennant E, Post JJ. Production of False-Positive Immunoglobulin M Antibodies to Hepatitis A Virus in Autoimmune Events. J Infect Dis 2015; 213:324-5. [DOI: 10.1093/infdis/jiv417] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2015] [Accepted: 07/31/2015] [Indexed: 12/17/2022] Open
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Abstract
PEGylation is the covalent conjugation of PEG to therapeutic molecules. Protein PEGylation is a clinically proven approach for extending the circulation half-life and reducing the immunogenicity of protein therapeutics. Most clinically used PEGylated proteins are heterogeneous mixtures of PEG positional isomers conjugated to different residues on the protein main chain. Current research is focused to reduce product heterogeneity and to preserve bioactivity. Recent advances and possible future directions in PEGylation are described in this review. So far protein PEGylation has yielded more than 10 marketed products and in view of the lack of equally successful alternatives to extend the circulation half-life of proteins, PEGylation will still play a major role in drug delivery for many years to come.
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Rodrigues S, Lopes S, Magro F, Cardoso H, Horta e Vale AM, Marques M, Mariz E, Bernardes M, Lopes J, Carneiro F, Macedo G. Autoimmune hepatitis and anti-tumor necrosis factor alpha therapy: A single center report of 8 cases. World J Gastroenterol 2015; 21:7584-7588. [PMID: 26140007 PMCID: PMC4481456 DOI: 10.3748/wjg.v21.i24.7584] [Citation(s) in RCA: 75] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2014] [Revised: 11/24/2014] [Accepted: 01/30/2015] [Indexed: 02/07/2023] Open
Abstract
This article describes cases of anti-tumor necrosis factor (TNF)-α-induced autoimmune hepatitis and evaluates the outcome of these patients in relation to their immunosuppressive strategy. A retrospective analysis of medical records was performed in our center, in order to detect cases of autoimmune hepatitis (AIH) associated with anti-TNF biologic agents. We describe and analyze eight cases of AIH following anti-TNF therapy, 7 with infliximab and 1 with adalimumab. A distinction should be made between induction of autoimmunity and clinically evident autoimmune disease. Liver biopsy is useful in detecting the role of the TNF-α antagonist in the development of AIH. The lack of relapse after discontinuing immunosuppressive therapy favors, as in this case series, an immune-mediated drug reaction as most patients with AIH have a relapse after treatment is suspended. Although AIH related to anti-TNF therapy is rare, a baseline immunological panel along with liver function tests should be performed in all patients with autoimmune disease before starting biologics.
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Rossi RE, Parisi I, Despott EJ, Burroughs AK, O'Beirne J, Conte D, Hamilton MI, Murray CD. Anti-tumour necrosis factor agent and liver injury: Literature review, recommendations for management. World J Gastroenterol 2014; 20:17352-17359. [PMID: 25516646 PMCID: PMC4265593 DOI: 10.3748/wjg.v20.i46.17352] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2014] [Revised: 04/24/2014] [Accepted: 07/25/2014] [Indexed: 02/06/2023] Open
Abstract
Abnormalities in liver function tests, including transient and self-limiting hypertransaminasemia, cholestatic disease and hepatitis, can develop during treatment with anti-tumour-necrosis-factor (TNF) therapy. The optimal management of liver injury related to anti-TNF therapy is still a matter of debate. Although some authors recommend discontinuing treatment in case of both a rise of alanine aminotransferase more than 5 times the upper limit of normal, or the occurrence of jaundice, there are no standard guidelines for the management of anti-TNF-related liver injury. Bibliographical searches were performed in PubMed, using the following key words: inflammatory bowel disease (IBD); TNF inhibitors; hypertransaminasemia; drug-related liver injury; infliximab. According to published data, elevation of transaminases in patients with IBD treated with anti-TNF is a common finding, but resolution appears to be the usual outcome. Anti-TNF agents seem to be safe with a low risk of causing severe drug-related liver injury. According to our centre experience, we found that hypertransaminasemia was a common, mainly self-limiting finding in our IBD cohort and was not correlated to infliximab treatment on both univariate and multivariate analyses. An algorithm for the management of liver impairment occurring during anti-TNF treatment is also proposed and this highlights the need of a multidisciplinary approach and suggests liver biopsy as a key-point in the management decision in case of severe rise of transaminases. However, hepatic injury is generally self-limiting and drug withdrawal seems to be an exception.
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Colombo D, Cassano N, Bellia G, Vena GA. Gender medicine and psoriasis. World J Dermatol 2014; 3:36-44. [DOI: 10.5314/wjd.v3.i3.36] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2013] [Revised: 02/24/2014] [Accepted: 04/29/2014] [Indexed: 02/06/2023] Open
Abstract
The study of specific differences between women and men is arousing huge interests in various fields of medicine, including dermatology. The available data on gender medicine applied to common skin diseases are unfortunately still scanty. Psoriasis is a chronic immune-mediated skin disease which affects 1%-3% of most populations worldwide and can involve also the joints and entheses. The pathogenesis of the disease is very complex, resulting from the interaction between genetic predisposition and several environmental triggers. The pathogenic role of sex hormones has also been hypothesized. The analysis of gender-specific differences in psoriasis seems to suggest some interesting findings, such as an earlier age of disease onset in females, a higher probability of severe disease in men, or different tendencies in care utilization, adherence to treatment, development of psychological distress, and coping strategies. Moreover, sex-related differences have been recently described in some epidemiological and clinical features among patients with psoriatic arthritis. The objective of this article is to review briefly the available evidence regarding gender differences in various aspects of psoriasis, such as epidemiology, genetics, risk factors, associated conditions, quality of life, clinical and therapeutic aspects.
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Cansu DÜ, Güncan S, Bilge NŞY, Kaşifoğlu T, Korkmaz C. Does isoniazid chemoprophylaxis increase the frequency of hepatotoxicity in patients receiving anti-TNF-α agent with a disease-modifying antirheumatic drug? Eur J Rheumatol 2014; 1:62-66. [PMID: 27708877 DOI: 10.5152/eurjrheumatol.2014.019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2014] [Accepted: 04/23/2014] [Indexed: 01/05/2023] Open
Abstract
OBJECTIVE The aim of this study is to determine the incidence of isoniazid (INH)-related hepatotoxicity in patients with rheumatologic diseases receiving tumor necrosis factor-α (TNF-α) antagonists along with a disease-modifying antirheumatic drug (DMARD). MATERIAL AND METHODS We have retrospectively evaluated 87 patients receiving anti-TNFα agents who were followed up between June 2005 and February 2010 at our rheumatology department. Sixty-one of 87 patients have received INH prophylaxis for 9 months for latent tuberculosis infection. RESULTS A total of 61 (70.1%) of 87 patients used INH prophylaxis (Group I), while the remaining 26 (29.9%) (Group II) had not; 53 patients had used any DMARD in Group I, while 21 patients had used in Group II. No significant differences were found among Group I and II with respect to clinical features. When two groups were compared, in Group I, elevations of liver enzymes were detected in five patients (8.1%) who had normal baseline values. Among these patients, hepatotoxicity developed in two patients. Hepatotoxicity developed one patient in Group II (p=0.85). CONCLUSION INH chemoprophylaxis was well tolerated in patients using anti-TNF-α agent and a DMARD. It seems not to be a strong risk factor for hepatotoxicity. However, comorbidities and other drugs used may be additional factors in the elevation of transaminases.
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Affiliation(s)
- Döndü Üsküdar Cansu
- Division of Rheumatology, Department of Internal Medicine, Eskişehir Osmangazi University Faculty of Medicine, Eskişehir, Turkey
| | - Sabri Güncan
- Division of Rheumatology, Department of Internal Medicine, Eskişehir Osmangazi University Faculty of Medicine, Eskişehir, Turkey
| | - N Şule Yaşar Bilge
- Division of Rheumatology, Department of Internal Medicine, Eskişehir Osmangazi University Faculty of Medicine, Eskişehir, Turkey
| | - Timuçin Kaşifoğlu
- Division of Rheumatology, Department of Internal Medicine, Eskişehir Osmangazi University Faculty of Medicine, Eskişehir, Turkey
| | - Cengiz Korkmaz
- Division of Rheumatology, Department of Internal Medicine, Eskişehir Osmangazi University Faculty of Medicine, Eskişehir, Turkey
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Castiella A, Zapata E, Lucena MI, Andrade RJ. Drug-induced autoimmune liver disease: A diagnostic dilemma of an increasingly reported disease. World J Hepatol 2014; 6:160-168. [PMID: 24799984 PMCID: PMC4009471 DOI: 10.4254/wjh.v6.i4.160] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2013] [Revised: 01/09/2014] [Accepted: 04/03/2014] [Indexed: 02/06/2023] Open
Abstract
The aetiology of autoimmune hepatitis (AIH) is uncertain but the disease can be triggered in susceptible patients by external factors such as viruses or drugs. AIH usually develops in individuals with a genetic background mainly consisting of some risk alleles of the major histocompatibility complex (HLA). Many drugs have been linked to AIH phenotypes, which sometimes persist after drug discontinuation, suggesting that they awaken latent autoimmunity. At least three clinical scenarios have been proposed that refers to drug- induced autoimmune liver disease (DIAILD): AIH with drug-induced liver injury (DILI); drug induced-AIH (DI-AIH); and immune mediated DILI (IM-DILI). In addition, there are instances showing mixed features of DI-AIH and IM-DILI, as well as DILI cases with positive autoantibodies. Histologically distinguishing DILI from AIH remains a challenge. Even more challenging is the differentiation of AIH from DI-AIH mainly relying in histological features; however, a detailed standardised histologic evaluation of large cohorts of AIH and DI-AIH patients would probably render more subtle features that could be of help in the differential diagnosis between both entities. Growing information on the relationship of drugs and AIH is being available, being drugs like statins and biologic agents more frequently involved in cases of DIAILD. In addition, there is some evidence on the fact that patients diagnosed with DIAILD may have had a previous episode of hepatotoxicity. Further collaborative studies in DIAILD will strengthen the knowledge and understanding of this intriguing and complex disorder which might represent different phenotypes across the spectrum of disease.
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Affiliation(s)
- Agustin Castiella
- Agustin Castiella, Eva Zapata, Gastroenterology Service, Mendaro Hospital, Mendaro, 20850 Guipuzcoa, Spain
| | - Eva Zapata
- Agustin Castiella, Eva Zapata, Gastroenterology Service, Mendaro Hospital, Mendaro, 20850 Guipuzcoa, Spain
| | - M Isabel Lucena
- Agustin Castiella, Eva Zapata, Gastroenterology Service, Mendaro Hospital, Mendaro, 20850 Guipuzcoa, Spain
| | - Raúl J Andrade
- Agustin Castiella, Eva Zapata, Gastroenterology Service, Mendaro Hospital, Mendaro, 20850 Guipuzcoa, Spain
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Liver Injury Secondary to Anti-TNF-Alpha Therapy in Inflammatory Bowel Disease: A Case Series and Review of the Literature. Case Rep Gastrointest Med 2014; 2014:956463. [PMID: 24707412 PMCID: PMC3966260 DOI: 10.1155/2014/956463] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2013] [Accepted: 12/10/2013] [Indexed: 02/08/2023] Open
Abstract
Background. Biologic therapy to inhibit tumor necrosis factor-alpha (TNF-α) is an effective, safe treatment for patients with inflammatory bowel disease (IBD). All TNF-α inhibitors have been associated with liver toxicity, but many of these cases have been reported in patients receiving therapy for rheumatologic disease. Herein we report the first single-center case series of TNF-α antagonist related liver injury in patients with IBD. Methods. A retrospective case series was performed at the Henry Ford Inflammatory Bowel Diseases Center. IRB approval was obtained. Results. 2 patients were treated with infliximab, whereas the 3rd patient was treated with adalimumab for IBD. All 3 patients had negative viral markers, normal autoimmune serologies, and normal biliary imaging studies. Liver biopsy was performed in all 3 patients, and evidence of portal inflammation was seen. Liver enzymes normalized after discontinuation of therapy in all patients, and no long term effects have been observed. One patient was successfully transitioned from infliximab to adalimumab without relapse of either IBD or liver injury. Conclusion. Liver injury secondary to TNF-α antagonist is an underrecognized, important clinical entity with potentially serious consequences. The mechanism of drug-induced injury is idiosyncratic. Larger cohort studies are needed to establish risk factors and injury patterns related to hepatotoxicity in these patients.
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Pompili M, Biolato M, Miele L, Grieco A. Tumor necrosis factor-α inhibitors and chronic hepatitis C: a comprehensive literature review. World J Gastroenterol 2013; 19:7867-7873. [PMID: 24307780 PMCID: PMC3848134 DOI: 10.3748/wjg.v19.i44.7867] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Revised: 10/31/2013] [Accepted: 11/12/2013] [Indexed: 02/06/2023] Open
Abstract
Tumor necrosis factor-α (TNF-α) inhibitors are known to increase reactivation of concurrent chronic hepatitis B, but their impact on the hepatitis C virus (HCV) is controversial. Some conditions of immunosuppression, such as liver transplantation, typically cause an increase in the rate of HCV evolution. Inhibition of TNF-α, a cytokine involved in the apoptotic signaling pathway of hepatocytes infected by HCV, could potentially increase viral replication. Currently available clinical data appear to contradict this hypothesis. A review of medical literature revealed that a total of 216 patients with HCV were exposed to one or more treatments with TNF-α inhibitors, with a median observation time of 1.2 years and 260 cumulative patient-years of exposure. Only three cases of drug withdrawal due to suspected HCV liver disease recrudescence were reported. Treatment with TNF-α inhibitors in patients with HCV infection appears to be safe in the short term, but there are insufficient data to assess their long-term safety. Universal screening for HCV before beginning treatment with TNF-α inhibitors is currently controversial. The presence of HCV is not a contraindication to therapy with TNF-α inhibitors, with the exception of cirrhotic patients. In cases of cirrhosis, the benefit/risk ratio should be evaluated at the individual level. Prior to treatment with TNF-α inhibitors, patients with HCV should be referred to a hepatologist to determine the necessity of hepatic disease assessment, using liver biopsy or non-invasive methods, and the potential indication for antiviral therapy. In patients with HCV infection who are treated with TNF-α inhibitors, liver function monitoring every three months is advised.
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Colina F, Molero A, Casís B, Martínez-Montiel P. Infliximab-related hepatitis: a case study and literature review. Dig Dis Sci 2013; 58:3362-7. [PMID: 23645381 DOI: 10.1007/s10620-013-2698-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2013] [Accepted: 04/18/2013] [Indexed: 02/08/2023]
Affiliation(s)
- Francisco Colina
- Department of Pathology, Hospital Universitario 12 de Octubre, Avenida de Córdoba s/n, 28041, Madrid, Spain,
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Rowe BW, Gala-Lopez B, Tomlinson C, Girgis S, Shapiro JAM. Fulminant hepatic failure necessitating transplantation following the initiation of infliximab therapy: a cautionary tale times two. Transpl Int 2013; 26:e110-2. [PMID: 24047326 DOI: 10.1111/tri.12185] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Affiliation(s)
- Bradley W Rowe
- Department of Surgery, University of Alberta, Edmonton, AB, Canada
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Dang LJ, Lubel JS, Gunatheesan S, Hosking P, Su J. Drug-induced lupus and autoimmune hepatitis secondary to infliximab for psoriasis. Australas J Dermatol 2013; 55:75-9. [PMID: 23651182 DOI: 10.1111/ajd.12054] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2012] [Accepted: 02/18/2013] [Indexed: 12/16/2022]
Abstract
We describe a case of previously unreported autoimmune hepatitis and lupus-like syndrome induced by infliximab treatment for chronic plaque psoriasis. The condition resolved after withdrawal of infliximab, with the liver injury having been reversed and minimal periportal fibrosis. In a two-part discussion we review the current literature on the pharmacology of infliximab and provide recommendations for management of infliximab side effects.
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Affiliation(s)
- Lucy J Dang
- Dermatology Department, Monash University, Australia; Eastern Health Clinical School, Monash University, Australia
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