1316 Mycophenolate for Autoimmune Hepatitis Treatment: Prospective Assessment of Its Efficacy and Safety for Induction and Maintenance of Remission in a Large Cohort of Treatment-Naive Patients
“…Antinuclear antibodies (ANA), smooth muscle antibodies (SMA), antibodies against liver kidney microsomal type‐1 (anti‐LKM1), and against liver cytosol type‐1 (anti‐LC1) were initially detected by indirect immunofluorescence on 5‐μm fresh frozen sections of in‐house rodent kidney, liver, and stomach tissue substrates as we described previously . Anti‐LKM1, anti‐LC1, and antibodies against soluble liver antigen/liver pancreas (anti‐SLA/LP) were also evaluated by immunoblotting using rat liver microsomal or cytosolic extracts .…”
Section: Methodsmentioning
confidence: 99%
“…All biopsies were assessed using the Knodell histologic/activity index score . According to previous publications of our group, patients were divided into two groups according to inflammation (minimal–mild [score, 0–8] and moderate–severe [score, 9–18]) and fibrosis (minimal/mild–moderate [score, 0–2] and severe fibrosis–cirrhosis [score, 3–4]. Detailed description of biopsies from original AS‐AIH patients was included in the analysis.…”
Aims: The definition of original acute severe autoimmune hepatitis (AS-AIH) is unclear. However, its rapid recognition and early treatment is potentially life-saving. Therefore, we present herein an open, real-world observational study for the assessment of the efficacy and safety of early high-dose i.v. corticosteroids in original AS-AIH patients.Methods: Prospectively collected data from 184 AIH patients were analyzed retrospectively. Original AS-AIH defined as an acute symptomatic presentation of newly diagnosed AIH (transaminases >10× upper limit of normal, bilirubin >4 mg/dL, and international normalized ratio [INR] ≥1.5) without histological lesions of chronic disease.Results: Thirty-four of 184 (18.5%) patients had original AS-AIH.These patients were promptly treated with i.v. corticosteroids (either 1 g methylprednisolone for 3 consecutive days followed by i.v. 1 mg/kg/day prednisolone or i.v. 1.5 mg/kg/day prednisolone from the beginning). Only 1/34 (2.9%) died due to sepsis; none required liver transplantation during follow-up (65 [1-175] months). No significant differences were detected in baseline characteristics between original AS-AIH patients and those with insidious presentation (not-AS-AIH; n = 117) apart from antinuclear antibodies negativity (P = 0.038), and higher immunoglobulin G, transaminases, INR, and bilirubin in original AS-AIH patients (P = 0.001 for all). Complete response and corticosteroids withdrawal (for patients treated >12 months) were significantly more frequent in original AS-AIH (n = 28) than in not-AS-AIH (n = 79; P = 0.026 and P = 0.016, respectively). Presence of original AS-AIH was the only independent predictor for achieving complete response.Conclusions: Prompt initiation of high-dose i.v. corticosteroids in original AS-AIH seems safe and efficient as it prevents disease deterioration and the need for liver transplantation. The long-term overall survival of these patients was high (97% for 5.3 years), and the long-term treatment response and corticosteroids withdrawal rates were higher compared to not-AS-AIH patients.
“…Antinuclear antibodies (ANA), smooth muscle antibodies (SMA), antibodies against liver kidney microsomal type‐1 (anti‐LKM1), and against liver cytosol type‐1 (anti‐LC1) were initially detected by indirect immunofluorescence on 5‐μm fresh frozen sections of in‐house rodent kidney, liver, and stomach tissue substrates as we described previously . Anti‐LKM1, anti‐LC1, and antibodies against soluble liver antigen/liver pancreas (anti‐SLA/LP) were also evaluated by immunoblotting using rat liver microsomal or cytosolic extracts .…”
Section: Methodsmentioning
confidence: 99%
“…All biopsies were assessed using the Knodell histologic/activity index score . According to previous publications of our group, patients were divided into two groups according to inflammation (minimal–mild [score, 0–8] and moderate–severe [score, 9–18]) and fibrosis (minimal/mild–moderate [score, 0–2] and severe fibrosis–cirrhosis [score, 3–4]. Detailed description of biopsies from original AS‐AIH patients was included in the analysis.…”
Aims: The definition of original acute severe autoimmune hepatitis (AS-AIH) is unclear. However, its rapid recognition and early treatment is potentially life-saving. Therefore, we present herein an open, real-world observational study for the assessment of the efficacy and safety of early high-dose i.v. corticosteroids in original AS-AIH patients.Methods: Prospectively collected data from 184 AIH patients were analyzed retrospectively. Original AS-AIH defined as an acute symptomatic presentation of newly diagnosed AIH (transaminases >10× upper limit of normal, bilirubin >4 mg/dL, and international normalized ratio [INR] ≥1.5) without histological lesions of chronic disease.Results: Thirty-four of 184 (18.5%) patients had original AS-AIH.These patients were promptly treated with i.v. corticosteroids (either 1 g methylprednisolone for 3 consecutive days followed by i.v. 1 mg/kg/day prednisolone or i.v. 1.5 mg/kg/day prednisolone from the beginning). Only 1/34 (2.9%) died due to sepsis; none required liver transplantation during follow-up (65 [1-175] months). No significant differences were detected in baseline characteristics between original AS-AIH patients and those with insidious presentation (not-AS-AIH; n = 117) apart from antinuclear antibodies negativity (P = 0.038), and higher immunoglobulin G, transaminases, INR, and bilirubin in original AS-AIH patients (P = 0.001 for all). Complete response and corticosteroids withdrawal (for patients treated >12 months) were significantly more frequent in original AS-AIH (n = 28) than in not-AS-AIH (n = 79; P = 0.026 and P = 0.016, respectively). Presence of original AS-AIH was the only independent predictor for achieving complete response.Conclusions: Prompt initiation of high-dose i.v. corticosteroids in original AS-AIH seems safe and efficient as it prevents disease deterioration and the need for liver transplantation. The long-term overall survival of these patients was high (97% for 5.3 years), and the long-term treatment response and corticosteroids withdrawal rates were higher compared to not-AS-AIH patients.
“…There is not sufficient data to recommend an alternative to azathioprine as first‐line therapy. Mycophenolate mofetil (MMF) has proven to be effective and safe as first‐line treatment in uncontrolled studies, with remission rates up to 88% and dosages from 1000–2000 mg/day 20 , 21 . A simple algorithm for AIH treatment is presented in Figure 1.…”
Section: How Should We Treat An Aih Patient?mentioning
confidence: 99%
“…Mycophenolate mofetil (MMF) has proven to be effective and safe as first-line treatment in uncontrolled studies, with remission rates up to 88% and dosages from 1000–2000 mg/day. 20,21 A simple algorithm for AIH treatment is presented in Figure 1. Figure 1.Treatment algorithm for an adult patient with a first presentation of autoimmune hepatitis (AIH).…”
Section: How Should We Treat An Aih Patient?mentioning
Autoimmune hepatitis is a rare and chronic liver disease that is characterised by increased serum transaminases and immunoglobulin G, inflammatory liver histology and presence of circulating autoantibodies. An autoimmune hepatitis diagnosis justifies life-long treatment in most patients in order to prevent development of cirrhosis and end-stage liver disease. The cornerstone of treatment is steroid induction therapy followed by maintenance therapy with azathioprine, which is effective in most cases. For patients who do not respond to standard treatment, second-line treatment with other immunosuppressants can be effective. Treatment should be aimed at biochemical remission of the disease, which is defined as normalization of transaminases and immunoglobulin G. Patients should be monitored intensively during the first months of treatment in order to monitor side-effects, assess symptoms and individualise treatment. Specialist consultation should be sought in difficult-to-treat patients. Future studies and networking initiatives should result in optimization of current treatment strategies in autoimmune hepatitis.
“…Intolerance, inadequate response or contraindication to corticosteroid and azathioprine treatment, including a requirement for high‐dose corticosteroids (>10 mg prednisolone per day) to maintain remission, should prompt consideration of second‐line therapies. Mycophenolate mofetil is typically offered as a second‐line agent for those patients intolerant to azathioprine (Table 1) 28 and although there is no high‐quality trial evidence to support this approach, there are extensive case series data suggesting efficacy 29‐42 . The efficacy of mycophenolate mofetil as a second‐line drug for those patients with insufficient response to standard therapy is questionable, and optimising first‐line therapy by checking adherence and drug levels needs to be considered.…”
Summary
Background
Current therapeutic options for autoimmune hepatitis (AIH) are limited by adverse events associated with corticosteroids and thiopurines and the limited evidence base for second‐ and third‐line treatment options. Furthermore, current treatment approaches require long‐term exposure of patients to pharmacological agents. There have been significant advances in the understanding of the mechanisms underpinning autoimmunity and an expansion in the available therapeutic agents for suppressing autoimmune responses or potentially restoring self‐tolerance.
Aim
To review the mechanisms and evidence for experimental therapies that are being actively explored in the management of AIH.
Methods
We have reviewed the literature relating to a range of novel therapeutic immunomodulatory treatment strategies and drugs.
Results
Drugs which block B cell‐activating factor of the tumour necrosis factor family (BAFF) and tumour necrosis factor α are currently in clinical trials for the treatment of AIH. Experimental therapies and technologies to increase immune tolerance, such as pre‐implantation factor and regulatory T cell therapies, are undergoing development for application in autoimmune disorders. There is also evidence for targeting inflammatory pathways to control other autoimmune conditions, such as blockade of IL1 and IL6 and Janus‐associated kinase (JAK) inhibitors.
Conclusions
With the range of tools available to clinicians and patients increasing, it is likely that the therapeutic landscape of AIH will change over the coming years and treatment approaches offering lower corticosteroid use and aiming to restore immune self‐tolerance should be sought.
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