mycophenolic-acid and Hepatitis--Autoimmune

The goal of autoimmune hepatitis treatment is to achieve clinical and biochemical remission, which is associated with significantly improved outcomes. Induction treatment with corticosteroids and the subsequent addition of steroid-sparing therapy with gradual tapering of corticosteroids remains the standard of care. Several alternatives to azathioprine and second-line agents, such as mycophenolate mofetil, tacrolimus, cyclosporine, sirolimus, or rituximab, have been evaluated in those with intolerance or inadequate response to standard-of-care therapy. Treatment withdrawal is achievable in less than 20% of patients after 2 years of sustained remission. Liver transplantation should be considered in those with progressive liver disease or those with complications such as hepatocellular carcinoma.

Topics: Adrenal Cortex Hormones; Azathioprine; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Mycophenolic Acid; Treatment Outcome

Autoimmune hepatitis (AIH) is a chronic liver disease, characterized by elevated levels of transaminases, immunoglobulin G, and positive autoantibodies. The disease course is dynamic and presents heterogeneous disease manifestations at diagnosis. This review summarizes the issues regarding the treatment and monitoring of AIH in adult patients. Glucocorticoids and azathioprine are the first line of treatment. Alternative first-line treatments include budesonide or mycophenolate mofetil (MMF). Although no randomized controlled trials have been performed, MMF, cyclosporine, tacrolimus, 6-mercaptopurine, 6-thioguanine, allopurinol, sirolimus, everolimus, infliximab, or rituximab have been attempted in patients not responding to or intolerant to first-line treatments. Most patients require life-long special monitoring, with or without maintenance treatment.

Topics: Adult; Azathioprine; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Mycophenolic Acid; Tacrolimus

Autoimmune hepatitis (AIH) in pregnancy has many unique considerations. Evidence provided from single center studies with patient level data and nationwide population studies provide valuable insight into this complex situation. Because a planned pregnancy is a safer pregnancy, preconception counseling is a crucial opportunity to optimize care and risk stratify women with AIH. Women with chronic liver disease who receive preconception advice and counseling are more likely to achieve stable liver disease at conception and undergo appropriate variceal surveillance. Loss of biochemical response in pregnancy is associated with adverse outcomes in unstable disease. New onset AIH in pregnancy should be managed with classical treatment regimens. The continued use of immunosuppression in pregnancy, with the exception of mycophenolate mofetil, has not shown to adversely affect the rates of stillbirth or congenital malformation. Previously adopted immunosuppression withdrawal paradigms in pregnancy should no longer be considered advantageous, because remission loss postdelivery is likely (12%-86%). Population studies, report improved outcomes with preterm birth rates falling from 20% to 9%-13% in AIH pregnancies over a 20-year period. Newer data have also demonstrated an increased risk of gestational diabetes and hypertensive complications in AIH pregnancy, which has implications for management and preeclampsia prevention with aspirin use. This review aims to provide the framework to guide and manage pregnancy in AIH outlining pearls and pitfalls to ensure optimal outcomes for mother, baby and to reduce variation in practice.

Topics: Female; Hepatitis, Autoimmune; Humans; Immunosuppression Therapy; Infant, Newborn; Mycophenolic Acid; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Premature Birth; Stillbirth

Autoimmune hepatitis (AIH) is an acute or chronic inflammatory disease of the liver caused by an immune response of unknown origin. It affects people from all ethnic groups irrespective of age or sex. AIH is characterized by hyperglobulinemia, presence of circulating autoantibodies, and liver inflammation. The clinical picture of the disease varies from asymptomatic or mild to severe acute hepatitis or liver failure. A timely and prompt diagnosis is of utmost importance to prevent progression to advanced liver disease by immediate initiation of immunosuppressive treatment. So far, several diagnostic scoring systems have been proposed, which incorporated demographic data as well as biochemical, clinical, and histological characteristics of the disease. However, due to the high heterogeneity of the disease presentation, diagnosis of AIH remains challenging. Most patients initially respond to first‑ line treatment, which consists of corticosteroids combined with azathioprine or mycophenolate mofetil. However, insufficient response to the treatment and intolerance due to side effects are common, so a significant proportion of patients require second- and / or third‑ line therapies. Herein, we review the challenges and recent advances in AIH diagnosis and management.

Topics: Autoantibodies; Azathioprine; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Mycophenolic Acid

Autoimmune hepatitis (AIH) is an immunoinflammatory chronic liver disease with dynamic and rather heterogeneous disease manifestations. A trend of increasing prevalence of AIH has been observed worldwide, along with a relative increase in the percentage of male patients. AIH is characterized and diagnosed based on serum biochemistry and liver histology: elevated aminotransferases and serum immunoglobulin G (IgG), the presence of serum anti-nuclear antibody or anti-smooth muscle antibody, and interface lympho-plasmacytic hepatitis. Clinical manifestations differ among disease subtypes with distinct time-frames, i.e., AIH with a chronic insidious onset, and acute-onset AIH (the diagnosis of which is often challenging due to the lack of typical serum findings). The absence of disease-specific biomarkers or histological findings may expand the disease phenotype into drug-induced AIH-like liver injury. Corticosteroids and azathioprine are recommended first-line treatments for AIH. The complete normalization of aminotransferases and serum IgG is an essential treatment response to ensure long-term overall survival. An incomplete response or intolerance to these drugs is considered an indication for second-line treatment, especially with mycophenolate mofetil. Life-long maintenance treatment is required for the majority of patients, but the few who achieve prolonged and stringent biochemical remission with lower alanine aminotransferase and IgG within the normal range may be able to discontinue the medications. In the future, the quality of life of AIH patients should be managed by personalized medicine, including the appropriate selection and dosing of first-line therapy and perhaps alternating with potential therapeutics, and the prediction of the success of treatment withdrawal.

Topics: Autoantibodies; Azathioprine; Hepatitis, Autoimmune; Humans; Mycophenolic Acid; Quality of Life

Autoimmune liver disease (ALD) is a chronic liver disease caused by immune dysfunction in the body. However, no causative or curative medical treatment with proven efficacy exists to cure ALDs, and liver transplantation (LT) remains the only effective treatment available. However, the problem of recurrence of ALDs (rALDs) still remains after LT, which seriously affects the survival rate of the patients. Therefore, clinicians need to be aware of the risk factors affecting rALDs after LT. Therefore, this meta-analysis aims to define the risk factors for rALDs, which include the recurrence of primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune hepatitis.. A systematic search in Pubmed, Embase, Cochrane library and Web of Science databases was performed from 1980 to 2019. The inclusion criteria were risk factors for developing rALDs after LT. However, case series, case reports, reviews, meta-analysis and studies only including human immunodeficiency virus cases, children, and pregnant patients were excluded.. The electronic database search yielded 1728 results. Sixty-three retrospective cohort studies met the inclusion criteria and 13 were included in the meta-analysis. The final cohort included 5077 patients, and among them, 21.96% developed rALDs. Colectomy before LT, HR 0.59 (95% confidence interval [CI]: 0.37-0.96), cholangiocarcinoma, HR 3.42 (95% CI: 1.88-6.21), multiple episodes of acute cellular rejection, HR 2.07 (95% CI: 1.27-3.37), model for end-stage liver disease score, HR 1.05 (95% CI: 1.02-1.08), use of mycophenolate mofetil, HR 1.46 (95% CI: 1.00-2.12) and the use of cyclosporin A, HR 0.69 (95% CI: 0.49-0.97) were associated with the risk of rprimary sclerosing cholangitis. In addition, the use of tacrolimus, HR 1.73 (95% CI: 1.00-2.99) and cyclosporin A, HR 0.59 (95% CI: 0.39-0.88) were associated with the risk of rALD.. Multiple risk factors for rALDs were identified, such as colectomy before LT, cholangiocacinoma, multiple episodes of acute cellular rejection, model for end-stage liver disease score, and especially the use of mycophenolate mofetil, cyclosporin A and tacrolimus.

Topics: Adult; Calcineurin Inhibitors; Cholangiocarcinoma; Cholangitis, Sclerosing; Colectomy; Cyclosporine; End Stage Liver Disease; Enzyme Inhibitors; Female; Graft Rejection; Hepatitis, Autoimmune; Humans; Liver Cirrhosis, Biliary; Liver Diseases; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Recurrence; Retrospective Studies; Risk Factors; Survival Rate; Tacrolimus

The standard management of autoimmune hepatitis (AIH) is based on corticosteroids, alone or in combination with azathioprine. Second-line treatments are needed for patients who have refractory disease. However, high-quality data on the alternative management of AIH are scarce.. To evaluate the efficacy and safety of tacrolimus and mycophenolate mofetil (MMF) and the quality of evidence by using the Grading of Recommendations Assessment, Development and Evaluation approach (GRADE).. A systematic review and meta-analysis of the available data were performed. We calculated pooled event rates for three outcome measures: Biochemical remission, adverse events, and mortality, with their corresponding 95% confidence intervals (CI).. The pooled biochemical remission rate was 68.9% (95%CI: 60.4-76.2) for tacrolimus, and 59.6% (95%CI: 54.8-64.2) for MMF, and rates of adverse events were 25.5% (95%CI: 12.4-45.3) for tacrolimus and 24.1% (95%CI: 15.4-35.7) for MMF. The pooled mortality rate was estimated at 11.5% (95%CI: 7.1-18.1) for tacrolimus and 9.01% (95%CI: 6.2-12.8) for MMF. Pooled biochemical remission rates for tacrolimus and MMF in patients with intolerance to standard therapy were 56.6% (CI: 43.4-56.6). Tacrolimus and MMF are in practice considered effective for patients with AIH who are non-responders or intolerant to first-line treatment, but we found no high-quality evidence to support this statement.

Topics: Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Mycophenolic Acid; Tacrolimus; Treatment Outcome

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.

Topics: Alanine Transaminase; Aspartate Aminotransferases; Autoantibodies; Azathioprine; Disease Progression; Glucocorticoids; Hepatitis, Autoimmune; Humans; Immunoglobulin G; Immunosuppressive Agents; Induction Chemotherapy; Maintenance Chemotherapy; Mercaptopurine; Mycophenolic Acid; Prednisolone

Autoimmune hepatitis (AIH) is a rare immune-mediated liver disease with few major advances in treatment options over the last several decades. Available options are effective in most patients albeit are imprecise in their mechanisms. Novel and more tolerable induction regimens and alternative options for management of patients intolerant or with suboptimal response to traditional therapies including in the post-transplant setting remain an important unmet need. This review aims to summarize recent data on pharmacological options and investigational drugs in development for patients with AIH. Standard therapy using prednisone with or without azathioprine remains the mainstay of therapy and is effective in most patients. Budesonide may be considered for induction in early disease and in those with mild fibrosis, but has not been approved for maintenance therapy. Mycophenolate mofetil (MMF) in combination with steroids might be an alternative first-line therapy, but results from a randomized trial are awaited. MMF as a second-line maintenance agent has moderate efficacy though more frequent adverse events in patients with cirrhosis may be seen. Tacrolimus may be an equally effective second-line option particularly in non-responders, but data remain limited. Management of recurrent AIH post-liver transplantation remains controversial with insufficient data to support long-term steroid use. Moving forward, expanding the scope of therapeutic options to include biologics including B-cell depleting agents may be a promising step. Recent insights in understanding the pathogenesis of AIH could serve as a basis for future therapies, including the elucidation of different immunoregulatory pathways and the potential role of the intestinal microbiome.

Topics: Animals; Azathioprine; Disease Management; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Liver; Mycophenolic Acid; Prednisone; Randomized Controlled Trials as Topic; Remission Induction; Tacrolimus

First-line treatment for autoimmune hepatitis (AIH) typically includes corticosteroids in combination with azathioprine. Mycophenolate mofetil (MMF) is often used as a rescue therapy in patients who are intolerant of, or nonresponsive to, standard therapy.. To systematically review studies and perform a meta-analysis on the efficacy and safety of MMF as a second-line therapy for AIH patients.. MEDLINE, EMBASE and Cochrane Central were searched for studies that reported data on efficacy and safety of MMF as a second-line therapy in AIH. We calculated the pooled response rate, adverse events rate and discontinuation rate due to side effects, with their corresponding 95% confidence intervals.. Twelve studies comprising 397 patients, followed for a median of 34 months (range, 12-47 months), were included. MMF doses ranged from 0.5-4.0 g/d. Pooled response rate was 0.58 (95% CI 0.54-0.63). Pooled adverse events rate was 0.14 (95% CI 0.11-0.17), and pooled discontinuation rate due to side effects was 0.08 (95% CI 0.06-0.11). Five studies (n = 309) specified response rates according to reason for using MMF. Pooled response rate in the subgroup with intolerance to standard therapy was 0.82 (95% CI 0.77-0.87) and pooled response rate among nonresponders was 0.32 (95% CI 0.24-0.39).. The overall efficacy of MMF as second-line therapy in AIH was high. Response rate was greater in patients who started the medication due to intolerance to standard therapy as opposed to nonresponse. Overall, MMF was well tolerated, with a low discontinuation rate due to side effects.

Topics: Antibiotics, Antineoplastic; Azathioprine; Drug-Related Side Effects and Adverse Reactions; Female; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Male; Mycophenolic Acid; Treatment Outcome

To systematically evaluate the efficacy of mycophenolate mofetil (MMF) compared with the standard treatment for autoimmune hepatitis.. Medline (PubMed), Embase, and Cochrane Library databases were searched between 1966 and June 2018 for studies on prednisone and/or azathioprine/mycophenolate mofetil in autoimmune hepatitis. The keywords and descriptor terms used were 'hepatitis', 'autoimmunity', 'prednisone', 'prednisolone', 'azathioprine', and 'mycophenolate mofetil'. The Z test and Cochrane Q test were used in the statistical analysis.. Seven hundred and eighty-eight related articles were found; 779 studies were excluded after further review. Ultimately, seven studies (583 participants) were included. The remission rate of aminotransferase and immunoglobulin (Ig)-G levels with standard treatment was 33.33-86.67%, and the nonresponse rate was 15.15-66.67%. Although the remission rate of the aminotransferase level with prednisone and MMF was 55.17-88.89% and that of the IgG level was 61.16-88.89%, the nonresponse rate was 6.42-33.33%. Remission rates of the aminotransferase level (P<0.05, I=49%) and IgG level (P<0.01, I=0) with MMF were superior to those of standard treatment, and the nonresponse rate was lower (P<0.01, I=0). For those with no response to the standard treatment who were switched to MMF, the remission rates were 0, 13.33, 22.22, 25, and 34.04%. Sequential treatment with MMF was effective (P<0.01, I=90%).. Compared with the standard treatment, the combination of prednisone and MMF as a first-line treatment enables patients with autoimmune hepatitis to obtain higher remission rates of aminotransferase and IgG levels and a lower nonresponse rate. The validity and safety of long-term MMF use needs investigated further.

Topics: Alanine Transaminase; Aspartate Aminotransferases; Azathioprine; Glucocorticoids; Hepatitis, Autoimmune; Humans; Immunoglobulin G; Immunosuppressive Agents; Mycophenolic Acid; Prednisolone; Prednisone; Treatment Outcome

The gold-standard treatment for autoimmune hepatitis (AIH) is a prednisone/azathioprine combination. However, subgroups of patients may be unresponsive to this treatment. The aim of this study is to evaluate the efficacy of second-line immunosuppressive therapies for AIH through a systematic review and meta-analysis in adult patients.. The systematic review was registered at the PROSPERO platform under number 42015019831. Databases MEDLINE (PubMed), Lilacs, Cochrane, and Scielo were searched. The keywords used were 'Hepatitis, Autoimmune' and descriptors terms (MeSH and DeCS). These terms were linked with each immunosuppressant of interest.. A total of 1532 studies were identified. Of these, 1492 were excluded on the basis of title and abstract reading. Among the 40 studies retrieved for detailed full-text analysis, a total of 15 fulfilled the inclusion criteria for the analysis. The most studied second-line immunosuppressive was mycophenolate mofetil (MM). The mean reduction of aminotransferases was observed in 94.3% with tacrolimus/prednisone, 91.3% for cyclosporine/prednisone, 85.5% for budesonide, and 78.7% MM/prednisone. For MM/prednisone, the mean rate of histological remission was 88.6%, liver transplantation was indicated in 11.4%, and the mortality rate was 7.2%. Limitations were also present, such as the lack of randomized-controlled trials and prospective studies, the small number of patients, and the heterogeneity between remission criteria.. This is the first systematic review and meta-analysis to compare the second-line imunossupressant therapy for AIH. The most studied second-line immunosuppressive is the MM, with a reasonable histological remission. The use of combined tacrolimus/prednisone was the most effective for the normalization of aminotransferases.

Topics: Anti-Inflammatory Agents; Budesonide; Cyclophosphamide; Drug Therapy, Combination; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Mycophenolic Acid; Prednisone; Retreatment; Tacrolimus

Ten percent to 20% of children with autoimmune hepatitis (AIH) require second-line therapy to achieve remission. Although current guidelines exist on first-line management, evidence for second-line therapy in treatment-refractory patients is lacking. Our aim was to perform a systematic review and meta-analysis of the efficacy and safety of second-line treatments used in this population.. Electronic and manual searches were used to identify potential studies for inclusion. Studies were selected based on reported response rates to second-line therapies in children who failed response to prednisone and azathioprine. Data extraction and risk of bias assessment were performed independently by 2 reviewers. Meta-analysis using weighted estimate of response rates at 6 months was performed for each treatment option. Heterogeneity was assessed.. Fifteen studies of 76 pediatric patients with AIH were included in the review. Overall response rates at 6 months were estimated as 36% for mycophenolate mofetil (MMF) (N = 34, 95% confidence interval [CI] (16-57)), and 50% for tacrolimus (N = 4, 95% CI (0-100%)) and 83% for cyclosporine (N = 15, 95% CI (66%-100%)). Adverse effects were most frequent with cyclosporine (64% experiencing at least 1 adverse effect) followed by tacrolimus (54%) and MMF (48%). Pooled estimates of adverse events were 78% for cyclosporine (95% CI (54%-100%)), 42% for tacrolimus (95% CI (0%-85%)) and 45% for MMF (95% CI (25%-68%)). Sensitivity analyses were not performed due to small sample size.. Cyclosporine had the highest response rate at 6 months in children with standard-treatment-refractory AIH; however, it also had the highest rate of adverse events. MMF was the second most efficacious option with a low adverse effect rate.

Topics: Azathioprine; Child; Cyclosporine; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Induction Chemotherapy; Models, Statistical; Mycophenolic Acid; Pediatrics; Prednisone; Tacrolimus; Treatment Outcome

Autoimmune hepatitis (AIH) is an organ specific autoimmune condition which can manifest at any age of life. The heterogeneous nature of this condition means that great variation can be seen in severity, progression of disease and response to treatment within this patient group. Since the 1980s prednisolone and azathioprine have been used for induction and remission of the disease and remain the mainstay of treatment. Other immunosuppressive agents have been employed in difficult to treat cases. While there is less published data regarding these agents compared with the conventional treatments of steroid and azathioprine, there is mounting evidence to support the use of mycophenolate mofetil as a second-line agent. The calcineurin inhibitors, though less studied, additionally show promise. More data is needed on the use of biological agents in refractory disease. This review focuses on our centre's approach to treatment of AIH in the context of a contemporary review of the literature.

Topics: Azathioprine; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Mycophenolic Acid; Prednisolone; Severity of Illness Index

Corticosteroids alone or in combination with azathioprine are the mainstay therapies of autoimmune hepatitis. Suboptimal responses (treatment failure, partial response, drug toxicity), frequent relapse after drug withdrawal, and the emergence of alternative immunosuppressive medications have fueled the pursuit of new treatments. The goals of this review are to present current management strategies and evolving interventions.. PubMed searches from 1970 - 2014 provide the bases for this review. Corticosteroid regimens should be administered until resolution of symptoms, laboratory tests, and liver tissue abnormalities. Treatment failure warrants high doses of the original regimen, and relapse warrants re-treatment followed by long-term maintenance with azathioprine. The calcineurin inhibitors, budesonide, and mycophenolate mofetil are evolving as frontline therapies, and they may be considered as salvage therapies with the exception of budesonide. Rapamycin, rituximab, and infliximab have also rescued refractory patients but experiences are limited. Anti-oxidants, recombinant molecules, mAbs, and modulators of critical cell populations are key prospects.. Autoimmune hepatitis must be managed by multiple medications that supplement or supplant current regimens depending on the clinical situation. Rescue therapies will emerge as adjunctive interventions to minimize tissue damage (prevent fibrosis and hepatocyte apoptosis) and improve immune tolerance (regulatory T cell manipulations).

Topics: Adrenal Cortex Hormones; Animals; Antibodies, Monoclonal, Murine-Derived; Azathioprine; Budesonide; Hepatitis, Autoimmune; Humans; Immunologic Factors; Immunosuppressive Agents; Liver; Mycophenolic Acid; Rituximab; Salvage Therapy; Sirolimus

Autoimmune hepatitis has diverse clinical phenotypes and outcomes that challenge current diagnostic criteria and management algorithms.. To highlight the major difficulties in diagnosis and management, describe the efforts to ease them and encourage further progress in problem solving.. The MEDLINE database was reviewed for published experiences from 1984 to 2013.. Acute or acute severe (fulminant) hepatitis, asymptomatic mild disease, and histological findings of centrilobular necrosis or bile duct injury can confound diagnosis and treatment. Continuation of conventional therapy until normal liver test results and liver tissue reduces the frequency of relapse, but does not prevent its occurrence. Problematic patients can be identified using mathematical models, clinical phenotype, serological markers and the speed of improvement after treatment; however, their recognition and treatment are inconsistent. Mycophenolate mofetil can rescue patients with azathioprine intolerance but is less effective for refractory disease. Budesonide in combination with azathioprine can be used frontline, but is effective primarily in noncirrhotic, uncomplicated disease. Molecular and cellular interventions are feasible but largely unevaluated.. Resolution of the current challenges requires revision of diagnostic criteria, characterization of biological markers that reflect pathogenic pathways, development of dynamic indexes based on changes in disease behaviour, and introduction of new pharmacological, molecular and cellular interventions that have undergone rigorous evaluation.. These challenges reflect important remediable deficiencies in current management.

Topics: Biomarkers; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Liver; Liver Function Tests; Mycophenolic Acid; Outcome Assessment, Health Care; Recurrence; Severity of Illness Index

Nonstandard drugs that target critical pathogenic pathways or immune regulatory mechanisms constitute the next generation of treatments for autoimmune hepatitis. Mycophenolate mofetil impairs the proliferation of lymphocytes, decreases autoantibody production, and induces apoptosis of activated immunocytes. Patients treated for azathioprine intolerance improve more frequently than patients treated for refractory liver disease (54% versus 10%), and mycophenolate mofetil is emerging as a rescue therapy for this population. Complete corticosteroid withdrawal is possible in 40% of patients treated with mycophenolate mofetil, and the frequency of side effects ranges from 3-34%. Budesonide in combination with azathioprine has normalized liver tests more frequently (47% versus 18%) and with fewer side effects (28% versus 53%) than standard therapy after 6 months. Budesonide is emerging as a frontline treatment in non-cirrhotic patients with uncomplicated disease or contraindications to conventional corticosteroids. Cyclosporine and tacrolimus are effective salvage agents for steroid-refractory disease, but side effects have been common and occasionally serious. The 6- thioguanine nucleotides and rapamycin are feasible treatments for autoimmune hepatitis, but 6-thioguanine has major obstacles to overcome, especially the risk of liver toxicity or nodular regenerative hyperplasia. The nonstandard drug therapies emerging for autoimmune hepatitis reflect the need to supplement or supplant current treatment regimens. None has been licensed for use in autoimmune hepatitis, and their applications have been based on results from small singlecenter experiences.

Topics: Animals; Budesonide; Cyclosporine; Drug Discovery; Hepatitis, Autoimmune; Humans; Immunosuppression Therapy; Mycophenolic Acid; Tacrolimus; Thioguanine

Autoimmune hepatitis is an immune-mediated disease targeting hepatocytes. It is more common in middleaged Caucasian females, although may affect other patient populations and age groups. The diagnosis is made according to criteria based on the alkaline phosphatase: ALT ratio, IgG, the presence of autoantibodies, liver histology, response to therapy, and the absence of a viral, alcohol or drug etiology. More recently a simplified scoring system has been proposed. In the absence of treatment, the prognosis is very poor with a 60% three year mortality. There are guidelines on the indications for treatment and some groups of patients may not require treatment. The main element of treatment is prednisolone which decreases the 3 year mortality to 10%. Prednisolone is tapered down to 5-10 mg per day, as monotherapy or in combination with azathioprine. Approximately 80% of patients will respond to therapy with prednisolone with or without azathioprine and this should be given for at least 2 years. Remission is defined as an asymptomatic patient with serum aminotransferases that are normal or less than two-fold elevated, a normal level of IgG and inactive liver histology. Relapse occurs in up to 90% of patients following drug withdrawal. The sensitivity and specificity of liver histology to predict relapse off treatment is not high. Other treatments that have been proposed include mycophenolate mofetil, budesonide, cyclosporine A, tacrolimus, 6-MP, methotrexate, ursodeoxycholic acid, rapamycin and rituximab although experience with all these agents is limited.

Topics: Azathioprine; Budesonide; Cyclosporine; Hepatitis, Autoimmune; Humans; Mycophenolic Acid

Nonsteroidal medications, previously unfamiliar in the management of autoimmune hepatitis, can supplement or replace conventional corticosteroid regimens, especially in problematic patients. Mycophenolate mofetil is a next-generation purine antagonist that has been useful in treating patients with azathioprine intolerance. It has been less effective in salvaging patients with steroid-refractory disease. Azathioprine is the choice as a corticosteroid-sparing agent in treatment-naive patients and in individuals with corticosteroid intolerance, incomplete response and relapse after drug withdrawal. Tacrolimus is preferred over cyclosporine for recalcitrant disease because of its established preference in organ transplantation, but replacement with cyclosporine should be considered if the disease worsens on treatment. Rapamycin has antiproliferative and proapoptotic actions that warrant further study in autoimmune hepatitis. The nonstandard, nonsteroidal medications are mainly salvage therapies with off-label indications that must be used in highly individualized and well-monitored clinical situations.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Cyclosporine; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Mycophenolic Acid; Sirolimus

Autoimmune hepatitis (AIH) is a chronic, progressive hepatitis of uncertain cause which has fluctuating activity characterized by periods of flares and remissions. Initial placebo-controlled trials carried out in the 1970s demonstrated that immunosuppression with steroids was extremely effective in reducing flares and progression of disease. The late 1980s-1990s could be described as the 'Dark Ages' of AIH treatment research. Very few clinical studies were performed during this time, although it became increasingly apparent that not all patients tolerated or responded to traditional immunosuppression, and that not all patients were easy to diagnose because of overlapping features with other autoimmune conditions. Fortunately, clinical research in the treatment of AIH has experienced a renaissance in the 21st century.. This review highlights some of the more important recent discoveries, including the creation of the clinically useful short form of the autoimmune hepatitis diagnostic scoring system; accumulation of data supporting the use of mycophenolate and tacrolimus as second-line treatment; and the recent completion of the largest, double-blind, placebo-controlled trial of AIH treatment to date, comparing budesonide to prednisone.. These new findings are pertinent to the everyday clinical management of patients with AIH.

Topics: Azathioprine; Budesonide; Drug Hypersensitivity; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Mycophenolic Acid; Purine-Pyrimidine Metabolism, Inborn Errors; Tacrolimus

Autoimmune hepatitis (AIH) is a chronic liver disease of unknown etiology that is responsive to steroid and azathioprine treatment in more than 80% of patients after 3 years of treatment. There are few alternative treatment options for individuals with AIH who are unresponsive to steroids and azathioprine, and research on this is limited to open-label studies of a variety of immunosuppressive agents that involve only small numbers of patients. Mycophenolate mofetil is one of the most frequently used alternative agents for the treatment of AIH patients not responsive to standard therapy. In this article, we review and summarize currently available data regarding the use of mycophenolate mofetil as an alternative treatment option for patients with AIH.

Topics: Azathioprine; Drug Therapy, Combination; Female; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Male; Mycophenolic Acid; Prednisolone; Treatment Outcome

Autoimmune hepatitis is a chronic liver disease of unknown aetiology characterized by interface hepatitis, hypergammaglobulinaemia and circulating autoantibodies. In the last decade a number of advancements have been made in the field of clinical and basic research: the simplified diagnostic criteria, the complete response defined as normalization of transaminase levels, the molecular identification of the antigenic targets of anti-liver cytosol antibody type 1 and anti-soluble liver antigen, the detection of anti-actin antibodies, the description of de novo autoimmune hepatitis after liver transplantation for non-autoimmune liver diseases, the characterization of autoimmune hepatitis with overlapping features of primary biliary cirrhosis or primary sclerosing cholangitis, the preliminary experience with novel treatment strategies based on cyclosporine, mycophenolate mofetil and budesonide, the role played by "impaired" regulatory T cells and the development of novel animal models of autoimmune hepatitis.

Topics: Animals; Autoantibodies; Autoantigens; Biomarkers; Budesonide; Cholangitis, Sclerosing; Cyclosporine; Glucocorticoids; Hepatitis, Autoimmune; Humans; Hypergammaglobulinemia; Immunity, Cellular; Immunoglobulin G; Immunosuppressive Agents; Liver Cirrhosis, Biliary; Liver Transplantation; Mice; Mycophenolic Acid; Rats; Transaminases

Autoimmune Hepatitis (AIH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and overlap syndromes of these three disease entities are regarded as autoimmune liver diseases. These conditions are important differential diagnoses of elevated liver function tests as about 10 % of liver transplantations in Europe and North America are for these indications. The diagnosis is often difficult but can be facilitated by sequential measurement of relevant autoantibodies, exclusion of other liver disease, ultrasound, ERCP and liver histology. In AIH immunosuppressive therapy has been shown to prevent or stop the development of cirrhosis and improve the prognosis of the patients decisively. In other autoimmune liver diseases this evidence is missing making individual therapeutic decisions necessary. Ursodesoxycholic acid (UDCA) seems to slow disease progression in particular in early stages of PBC.

Topics: Adult; Autoantibodies; Autoimmune Diseases; Azathioprine; Biopsy; Child; Cholagogues and Choleretics; Cholangiopancreatography, Endoscopic Retrograde; Cholangitis, Sclerosing; Diagnosis, Differential; Enzyme-Linked Immunosorbent Assay; Female; Hepatitis, Autoimmune; Humans; Immunoassay; Immunosuppression Therapy; Immunosuppressive Agents; Liver; Liver Cirrhosis, Biliary; Liver Diseases; Liver Function Tests; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Prognosis; Ultrasonography; Ursodeoxycholic Acid

Autoimmune hepatitis (AIH) is characterised histologically by interface hepatitis, and serologically by the presence of non-organ and liver specific autoantibodies and increased levels of immunoglobulin G. Its onset is often ill-defined, frequently mimicing acute hepatitis. AIH usually responds to immunosuppressive treatment, which should be instituted as soon as diagnosis is made. Two types of AIH are recognized according to seropositivity for smooth muscle and/or antinuclear antibody (SMA/ANA, type 1 AIH) or liver kidney microsomal type 1 antibody (LKM1, type 2 AIH). There is a female predominance in both. LKM1 positive patients tend to present more acutely, at a younger age and commonly have immunoglobulin A deficiency, while duration of symptoms before diagnosis, clinical signs, family history of autoimmunity, presence of associated autoimmune disorders, response to treatment and long-term prognosis are similar in the 2 groups. Susceptibility to AIH type 1 is conferred by possession of HLA DR3 and DR4, while to AIH type 2 by possession of HLA DR7. Liver damage is likely to derive from an immune reaction to liver cell antigens, possibly triggered by a mechanism of molecular mimicry, where immune responses to external pathogens, e.g. viruses, become directed towards structurally similar self-components. In AIH this process would be perpetuated by impairment in immune regulation.

Topics: Age Factors; Anti-Inflammatory Agents; Autoantibodies; Biopsy; Child; Cyclosporine; Female; Fluorescent Antibody Technique; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Liver; Liver Function Tests; Male; Mycophenolic Acid; Prednisolone; Prognosis; Time Factors

Topics: Anti-Inflammatory Agents; Antimetabolites; Azathioprine; Calcineurin Inhibitors; Cyclophosphamide; Cyclosporine; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Mercaptopurine; Methotrexate; Mycophenolic Acid; Recurrence; Remission Induction; Risk Factors; Steroids; Tacrolimus; Treatment Outcome

Topics: Azathioprine; Folic Acid Antagonists; Hepatitis, Autoimmune; Humans; Immunity, Cellular; Immunosuppressive Agents; Interferon-gamma; Liver Transplantation; Methotrexate; Mycophenolic Acid; Tacrolimus; Tumor Necrosis Factor-alpha

Prednisone alone or a lower dose in combination with azathioprine is effective in improving symptoms, resolving laboratory and histologic features, and prolonging survival in patients with autoimmune hepatitis. The combination regimen of prednisone and azathioprine is preferred because of its lower frequency of corticosteroid-related side effects. Only patients with severe inflammatory activity have absolute indications for therapy. Treatment must be individualized in patients with mild-to-moderate disease. Medication should be continued at fixed daily maintenance levels until a remission, treatment failure, drug intolerance, or incomplete response has been established. Histologic examination before drug withdrawal ensures remission when symptoms and laboratory tests are normal or near normal. Treatment failure warrants high-dose therapy, whereas drug toxicity and incomplete response compel regimens that are modified individually according to response. Low-dose prednisone or indefinite azathioprine therapy are indicated in patients who have relapsed multiply. Empiric nonsteroidal treatments include ursodeoxycholic acid, cyclosporine, mycophenolate mofetil, and tacrolimus, and they have been used in limited studies to treat recalcitrant disease or corticosteroid intolerance. Investigational therapies promise to target critical pathogenic mechanisms affecting immunocyte activation, autoantigen recognition, cytokine interactions, and regenerative activity.

Topics: Azathioprine; Budesonide; Clinical Trials as Topic; Cyclosporine; Disease Progression; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Mycophenolic Acid; Prednisolone; Tacrolimus; Treatment Outcome; Ursodeoxycholic Acid

Refinements in the understanding of the mechanisms of immunocyte activation and the emergence of new immunosuppressive agents with highly selective actions has created opportunities for improving the treatment of autoimmune hepatitis. Drugs, such as budesonide and deflazacort, may inhibit immunocyte activation and limit corticosteroid-related side effects. Agents, such as cyclosporine and tacrolimus, can impair calcineurin activity and restrict the generation of transcription factors necessary for T cell responses. Intravenous immunoglobulin can bind anti-idiotype antibodies and reduce interleukin-2 secretion, and monoclonal antibodies directed against critical components of the T cell activation cascade can dampen the immune reaction. Drugs, such as mycophenolate mofetil, cyclophosphamide, methotrexate, and KF20444, can inhibit T cell proliferation, and other interventions promise to deplete activated T cells, impair effector mechanisms, and induce self-tolerance.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Autoantibodies; Budesonide; Cyclophosphamide; Cyclosporine; Hepatitis, Autoimmune; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Methotrexate; Mycophenolic Acid; Signal Transduction; Tacrolimus

Topics: Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Mycophenolic Acid

Currently, the standard therapy for autoimmune hepatitis (AIH) consists of a combination of prednisolone and azathioprine. However, 15% of patients are intolerant to azathioprine which necessitates cessation of azathioprine or changes in therapy. In addition, not all patients achieve complete biochemical response (CR). Uncontrolled data indicate that mycophenolate mofetil (MMF) can induce CR in a majority of patients. Better understanding of first-line treatment and robust evidence from randomised clinical trials are needed. The aim of this study was to explore the potential benefits of MMF as compared to azathioprine, both combined with prednisolone, as induction therapy in a randomised controlled trial in patients with treatment-naive AIH.. CAMARO is a randomised (1:1), open-label, parallel-group, multicentre superiority trial. All patients with AIH are screened for eligibility. Seventy adult patients with AIH from fourteen centres in the Netherlands and Belgium will be randomised to receive MMF or azathioprine. Both treatment arms will start with prednisolone as induction therapy. The primary outcome is biochemical remission, defined as serum levels of alanine aminotransferase and immunoglobulin G below the upper limit of normal. Secondary outcomes include safety and tolerability of MMF and azathioprine, time to remission, changes in Model For End-Stage Liver Disease (MELD)-score, adverse events, and aspects of quality of life. The study period will last for 24 weeks.. The CAMARO trial investigates whether treatment with MMF and prednisolone increases the proportion of patients in remission compared with azathioprine and prednisolone as the current standard treatment strategy. In addition, we reflect on the challenges of conducting a randomized trial in rare diseases.. EudraCT 2016-001038-91 . Prospectively registered on 18 April 2016.

Topics: Adult; Azathioprine; End Stage Liver Disease; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Multicenter Studies as Topic; Mycophenolic Acid; Prednisolone; Quality of Life; Randomized Controlled Trials as Topic; Severity of Illness Index; Treatment Outcome

As previous real-world studies and meta-analyses have shown that mycophenolate mofetil (MMF) might have better efficacy than azathioprine (AZA) in autoimmune hepatitis (AIH), we conducted a propensity matching study to assess the efficacy and safety of MMF vs. AZA.. All 126 consecutive treatment-naive adult AIH patients, diagnosed and followed in our department since 2016, were included. Patients received prednisolone 0.5-1 mg/kg/day plus either AZA 1-2 mg/kg/day or 1.5-2 g/day MMF. The tapering of prednisolone was identical between groups.. After propensity matching score and adjustment for known factors affecting response to treatment and outcome, 64 patients were included in the study (MMF = 32 and AZA = 32). Rates of non-response, complete biochemical response (CBR) at 6 and 12 months, and prednisolone withdrawal (6 months, 12 months, and end of follow-up) were identical between groups. However, MMF treatment was significantly associated with CBR at the end of follow-up [odds ratio (OR) 11.259; 95% CI: 1.3-97.4, p = 0.028]. AZA patients were more prone to stop treatment due to AZA intolerance/insufficient response (p = 0.0001). At the end of follow-up, the overall efficacy of each schedule was also significantly higher in the MMF group compared to the AZA group (p = 0.0001).. We showed for the first time in a propensity matching study that MMF can be used as first-line therapy in AIH as attested by the significantly higher CBR at end of follow-up compared to AZA. Whether this better efficacy is also associated with higher histological remission rates and sustained CBR off immunosuppression needs further evaluation.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Azathioprine; Drug Therapy, Combination; Female; Hepatitis, Autoimmune; Humans; Logistic Models; Male; Middle Aged; Mycophenolic Acid; Prednisolone; Propensity Score; Prospective Studies; Treatment Outcome; Young Adult

Standard therapy for autoimmune hepatitis (AIH) is corticosteroids with or without azathioprine. However, 20% of patients do not respond or are intolerant to conventional treatment. Therefore, we evaluated prospectively the efficacy and safety of mycophenolate mofetil (MMF) in inducing and/or maintaining remission in treatment-naïve AIH patients.. Fifty-nine treatment-naïve patients with well defined AIH were treated with prednisolone plus 1.5-2g/d of MMF. Patients were candidates for MMF withdrawal after at least 4 years. Treatment outcomes were defined according to the International Autoimmune Hepatitis Group report.. Treatment duration with MMF was 26months (range 3-92). Eighty-eight percent (52/59) of patients responded initially clinically and biochemically (normalization of transaminases and γ-globulins) most of them within 3months. The remaining 7 patients (12%) had partial response. In total, 59.3% (35/59) of patients had complete response (CR) with 37% (22/59) of them having achieved CR off prednisolone, while 28.8% (17/59) had initial CR with relapses. No patient was non-responder. Prednisolone withdrew in 57.6% (34/59) of patients in 8months. The only independent predictor of treatment outcome, was γ-GT (baseline γ-GT, p=0.008 and γ-GT on month 24, p<0.05). Severe side effects leading to MMF discontinuation occurred in only 3.4% (2/59) of patients. Six patients (2 according to protocol and 4 for personal reasons), stopped treatment with MMF, but 3 relapsed.. MMF seems safe and effective as first-line therapy in inducing and maintaining remission in treatment-naive patients with AIH, having a significant and rapid steroid sparing effect as attested by the fact that so far, 37% (22/59) of AIH patients achieved CR off prednisolone.

Topics: Adult; Aged; Anti-Inflammatory Agents; Drug Therapy, Combination; Female; gamma-Glutamyltransferase; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Prednisolone; Prospective Studies; Recurrence; Remission Induction; Time Factors; Treatment Outcome

The aim of this study was to evaluate the success of steroid (PRED) withdrawal due to replacement by mycophenolate mofetil (MMF) in orthotopic liver transplant (OLT) recipients with autoimmune hepatitis (AIH). Thirty patients with AIH > 12 months after OLT randomized to receive either PRED and tacrolimus (TAC) or MMF and TAC were followed for 24 months. Withdrawal of steroids showed no difference regarding graft and patient survival. Also we demonstrated significantly lower glucose levels with lower HbA1c and a reduced need for insulin as well as a significantly lower serum cholesterol in the MMF group. Patients without steroids showed a lower incidence of osteopenia. Maintenance therapy in OLT patients with AIH may be performed safely using MMF instead of prednisone.

Topics: Adult; Anti-Inflammatory Agents; Bone Density; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Glycated Hemoglobin; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Mycophenolic Acid; Prednisone; Tacrolimus; Time Factors

Conventional treatment of autoimmune hepatitis consists of either prednisone alone or in combination with azathioprine. Ten to 20% of patients do not respond to or are intolerant of this treatment. Novel drug treatments include immunosuppressive drugs such as tacrolimus (TAC), mycophenolate mofetil (MMF), methotrexate and cyclosporine. We describe a multi-centre Canadian experience with MMF and TAC.. To study a multi-centre patient population who had failed conventional therapy and were treated with non-conventional medical therapy for autoimmune hepatitis and document response.. Members of the Canadian Association for the Study of Liver (CASL) obtained MMF from Hoffmann-La Roche Ltd, as part of a compassionate release program, were contacted for standardized data on patients with AIH who received MMF or TAC. Response definitions based on aminotransferase changes were: Complete response (CR)-sustained normalization, partial response (PR)-improvement by greater than 50%, non-response (NR)-less than 50% improvement and relapse (RP)-initial CR or PR followed by an increase in aminotransferases.. A total of 16 patients were identified: six in Ontario, one in Quebec, five in Alberta and four in British Columbia. Three were treated with TAC, eleven with MMF and two with combination MMF and TAC. CR was observed in 50%, PR in 12.5%, RP in 25% and NR occurred in 12.5%. The CR for MMF without TAC was approximately 64%.. MMF is effective and well tolerated by patients with autoimmune hepatitis who do not respond to, or are intolerant of, conventional immunosuppressive agents.

Topics: Adult; Aged; Canada; Drug Therapy, Combination; Female; Glucocorticoids; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Prednisone; Retrospective Studies; Secondary Prevention; Tacrolimus; Transaminases; Treatment Outcome

The Swiss Autoimmune Hepatitis Cohort Study is a nationwide registry, initiated in 2017, that collects retrospective and prospective clinical data and biological samples from patients of all ages with autoimmune hepatitis treated at Swiss hepatology centres. Here, we report the analysis of the first 5 years of registry data.. A total of 291 patients with autoimmune hepatitis have been enrolled, 30 of whom were diagnosed before 18 years of age and composed the paediatric cohort. Paediatric cohort: median age at diagnosis 12.5 years (range 1-17, interquartile range (IQR) 8-15), 16 (53%) girls, 6 (32%) with type 2 autoimmune hepatitis, 8 (27%) with autoimmune sclerosing cholangitis, 1 with primary biliary cholangitis variant syndrome, 4 (15%) with inflammatory bowel disease and 10 (41%) with advanced liver fibrosis at diagnosis. Adult cohort: median age at diagnosis 54 years (range 42-64, IQR 18-81), 185 (71%) women, 51 (20%) with primary biliary cholangitis variant syndrome, 22 (8%) with primary sclerosing cholangitis variant syndrome, 9 (4%) with inflammatory bowel disease and 66 (32%) with advanced liver fibrosis at diagnosis. The median follow-up time for the entire cohort was 5.2 years (IQR 3-9.3 years). Treatment in children: 29 (97%) children were initially treated with corticosteroids, 28 of whom received combination treatment with azathioprine. Budesonide was used in four children, all in combination with azathioprine. Mycophenolate mofetil was used in five children, all of whom had previously received corticosteroids and thiopurine. Treatment in adults (data available for 228 patients): 219 (96%) were treated with corticosteroids, mostly in combination with azathioprine. Predniso(lo)ne was the corticosteroid used in three-quarters of patients; the other patients received budesonide. A total of 78 (33%) patients received mycophenolate mofetil, 62 of whom had previously been treated with azathioprine. Complete biochemical response was achieved in 13 of 19 (68%) children and 137 of 182 (75%) adults with available follow-up data. All children were alive at the last follow-up, and none had undergone liver transplantation. Five (2%) adults underwent liver transplantation, two of whom had a fulminant presentation. Four (2%) adults with autoimmune hepatitis died (two from liver-associated causes).. Patients with autoimmune hepatitis in Switzerland had clinical features similar to those in other cohorts. The proportion of patients diagnosed with primary biliary cholangitis variant syndrome was higher than expected. Autoimmune hepatitis was managed according to guidelines, except for the use of budesonide in a small proportion of paediatric patients. The outcomes were excellent, but the findings must be confirmed over a longer follow-up period.

Topics: Adolescent; Adult; Azathioprine; Budesonide; Child; Child, Preschool; Cohort Studies; Female; Hepatitis, Autoimmune; Humans; Infant; Inflammatory Bowel Diseases; Liver Cirrhosis; Liver Cirrhosis, Biliary; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Retrospective Studies; Switzerland

Autoimmune hepatitis can recur after liver transplantation (LT), though the impact of recurrence on patient and graft survival has not been well characterized. We evaluated a large, international, multicenter cohort to identify the probability and risk factors associated with recurrent AIH and the association between recurrent disease and patient and graft survival.. We included 736 patients (77% female, mean age 42±1 years) with AIH who underwent LT from January 1987 through June 2020, among 33 centers in North America, South America, Europe and Asia. Clinical data before and after LT, biochemical data within the first 12 months after LT, and immunosuppression after LT were analyzed to identify patients at higher risk of AIH recurrence based on histological diagnosis.. AIH recurred in 20% of patients after 5 years and 31% after 10 years. Age at LT ≤42 years (hazard ratio [HR] 3.15; 95% CI 1.22-8.16; p = 0.02), use of mycophenolate mofetil post-LT (HR 3.06; 95% CI 1.39-6.73; p = 0.005), donor and recipient sex mismatch (HR 2.57; 95% CI 1.39-4.76; p = 0.003) and high IgG pre-LT (HR 1.04; 95% CI 1.01-1.06; p = 0.004) were associated with higher risk of AIH recurrence after adjusting for other confounders. In multivariate Cox regression, recurrent AIH (as a time-dependent covariate) was significantly associated with graft loss (HR 10.79, 95% CI 5.37-21.66, p <0.001) and death (HR 2.53, 95% CI 1.48-4.33, p = 0.001).. Recurrence of AIH following transplant is frequent and is associated with younger age at LT, use of mycophenolate mofetil post-LT, sex mismatch and high IgG pre-LT. We demonstrate an association between disease recurrence and impaired graft and overall survival in patients with AIH, highlighting the importance of ongoing efforts to better characterize, prevent and treat recurrent AIH.. Recurrent autoimmune hepatitis following liver transplant is frequent and is associated with some recipient features and the type of immunosuppressive medications use. Recurrent autoimmune hepatitis negatively affects outcomes after liver transplantation. Thus, improved measures are required to prevent and treat this condition.

Topics: Adult; Female; Hepatitis, Autoimmune; Humans; Immunoglobulin G; Immunosuppressive Agents; Liver Transplantation; Male; Mycophenolic Acid; Recurrence; Risk Factors

Mycophenolate mofetil (MMF) is the most widely used second-line agent in autoimmune hepatitis (AIH). Individual dose adjustment of MMF may avoid adverse outcomes while maximizing efficacy. The aim of the present study was to develop population pharmacokinetic (popPK) models and maximum a posteriori Bayesian estimators (MAP-BEs) to estimate mycophenolic acid interdose area under the curve in AIH patients administered MMF using nonlinear mixed effect modelling.. We analysed 50 mycophenolic acid PK profiles from 34 different patients, together with some demographic, clinical, and laboratory test data. The median number of plasma samples per profile, immediately preceding and following the morning MMF dose, was 7. PopPK modelling was performed using parametric, top-down, nonlinear mixed effect modelling with NONMEM 7.3. MAP-BEs were developed based on the best popPK model and the best limited sampling strategy selected among several.. The pharmacokinetic data were best described by a 2-compartment model, Erlang distribution to describe the absorption phase, and a proportional error. The mean (relative standard error) of popPK parameter estimates of clearance, intercompartmental clearance, central volume and absorption rate with the final model were: 21.6 L h. The precise and accurate Bayesian estimator developed in this study for AIH patients on MMF can be used to improve the therapeutic management of these patients.

Topics: Alkanesulfonic Acids; Area Under Curve; Bayes Theorem; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Models, Biological; Mycophenolic Acid

Most patients with autoimmune hepatitis (AIH) respond to a combination of prednisolone and azathioprine. For patients who are intolerant or refractory to azathioprine, proposed alternative therapies are based on scarce data, limited to transplant centres and with short-term follow-up periods.. To evaluate the long-term efficacy and safety of MMF as a second-line therapy in patients with AIH managed at a tertiary non-transplant centre.. Retrospective analysis of a prospectively collated database identified AIH patients who received MMF from 2006 to 2015. Clinical, biochemical and immunological parameters were assessed at 3-, 6- and 12-months, and at last follow-up. Biochemical response (BR) was defined as improvement of transaminases, complete remission (CR) as normalisation of transaminases and IgG, while others were considered non-responders (NR).. Eighteen out of 151 (12%) AIH patients received MMF. Nine received MMF due to azathioprine-intolerance (group 1), while nine due to refractory disease (group 2). In group 1, CR and BR was achieved in six (67%) and two (22%) patients respectively. In group 2, CR and BR was achieved in one (11%) and five (56%) patients respectively. Adverse events occurred in eight patients (44%), with one patient requiring drug discontinuation. After a medium follow-up of 78 (31-116) months, there was a significant decrease in transaminase levels, mirrored by decrease in prednisolone dose from 25 to 6.25 mg/day (P<0.05).. Long-term therapy with MMF is safe and effective in AIH patients requiring second-line therapies, and these patients can be effectively managed at tertiary non-liver transplant centres.

Topics: Azathioprine; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Mycophenolic Acid; Prednisolone; Retrospective Studies; Transaminases; Treatment Outcome

Topics: Calcineurin Inhibitors; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Mycophenolic Acid; Salvage Therapy; Tacrolimus

Although standard treatment for autoimmune hepatitis (AIH) comprises prednisolone (PSL) and azathioprine (AZA), some patients are intolerant to or do not respond to PSL and/or AZA. The clinical practice guidelines of AIH in Europe and North America recommend mycophenolate mofetil (MMF) as second-line treatment in these patients. We administered MMF as second-line therapy to 7 patients with AIH (male/female 1/6, age range 27-79 years) who were intolerant to or failed to respond to standard treatment. At the commencement of MMF, the median ALT value was 84U/L (28-254U/L), and the PSL dose was 15.0mg/day (0-45mg/day). In terms of adverse effects of PSL, diabetes mellitus was observed in 4 patients (insulin injection in 2) and femoral head necrolysis in 2. Adverse effects of AZA were present in 2, and 5 patients were not treated with AZA. At 24 weeks of MMF treatment, the median ALT and daily PSL dose were decreased to 16U/L (6-41U/L) and 7.0mg, respectively. Blood sugar control improved, and insulin injection was discontinued in both the patients. While intractable diarrhea developed in 1 patient with cirrhosis, no adverse effect was observed in other 6 patients. In conclusion, MMF appeared effective and safe in at least non-cirrhotic patients with AIH who were intolerant or failed to respond to standard treatment with PSL and AZA in Japanese clinical practice.

Topics: Adult; Aged; Azathioprine; Europe; Female; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Reference Standards; Treatment Outcome

Non-alcoholic fatty liver disease (NAFLD) is nowadays the most common liver disease worldwide. Autoimmune hepatitis (AIH) is a relatively rare disease of the liver characterised by female predominance, circulating autoantibodies, polyclonal hypergammaglobulinaemia, interface hepatitis on histology and favourable response to immunosuppression. The possibility of an additional AIH diagnosis in patients with NAFLD (NAFLD/AIH concurrence) or the presence of AIH alone instead of a supposed NAFLD diagnosis represents a challenge for clinicians. We report herein two adult patients (a 33-year-old woman and a 59-year-old man) with a previous NAFLD diagnosis who proved finally to suffer from AIH alone. These two representative cases indicate how difficult and complicated could be sometimes the diagnosis of patients with AIH highlighting the range of disease manifestations and severity while they also underline that although NAFLD is by far the most frequent chronic liver disease this could not be always the case.

Topics: Adult; Antibodies, Antinuclear; Biopsy; Diagnosis, Differential; Diagnostic Errors; Elasticity Imaging Techniques; Female; Hepatitis, Autoimmune; Humans; Immunoglobulin G; Immunosuppressive Agents; Liver; Liver Function Tests; Male; Metabolic Syndrome; Middle Aged; Mycophenolic Acid; Non-alcoholic Fatty Liver Disease; Obesity, Morbid; Prednisolone

Topics: Aged; Hepatitis, Autoimmune; Humans; Immunoglobulin G; International Normalized Ratio; Mycophenolic Acid

Topics: Aged; Hepatitis, Autoimmune; Humans; Immunoglobulin G; International Normalized Ratio; Mycophenolic Acid

Data on rescue treatment of autoimmune hepatitis in patients that fail standard treatment are sparse.. To report our long-term experience with mycophenolate mofetil.. Retrospective study in 22 patients with autoimmune hepatitis who failed azathioprine and prednisolone due to adverse events (n = 14, 64%), lack of remission (n = 5, 23%) or a combination (n = 3, 13%).. Mycophenolate mofetil was started at a dose of 20 mg/kg/day and increased to a maximum of 3 g/day. Follow-up was 0-6 months in 7 patients; more than 12 months in 15 (68%) and more than 24 months in 10. Normal aminotransferase levels were obtained (n = 3) or maintained (n = 7) in 10 patients (45%) after three to 30 weeks. 12 patients (55%) were withdrawn during the first 6 months, due to adverse events. Three patients were switched to cyclosporine and one underwent liver transplantation. Successful treatment with mycophenolate mofetil continued in 10 patients (45%) for a median of 71 months (range 20-124). Of these, one stopped prednisolone, five have a prednisolone dose <5 mg daily and four patients 5-10 mg.. Approximately one of two patients with autoimmune hepatitis that fail standard treatment benefit from long-term maintenance with mycophenolate mofetil, especially those with previous intolerance to thiopurines, where mycophenolate mofetil is effective in two thirds.

Topics: Adolescent; Adult; Aged; Alanine Transaminase; Azathioprine; Drug Monitoring; Drug Resistance; Drug Substitution; Female; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Liver Function Tests; Maintenance Chemotherapy; Male; Mycophenolic Acid; Prednisolone; Retrospective Studies; Sweden; Treatment Outcome

Cyclosporine (CSA) is an alternative treatment for autoimmune hepatitis (AIH), however, its unknown long-term safety and efficacy have limited its use.. Examine the long-term outcome of children and young adults with AIH treated with CSA for at least 4 years.. Twenty patients were included in this retrospective study: 15 with classical AIH and 5 with autoimmune hepatitis/autoimmune sclerosing cholangitis overlap syndrome (ASC). CSA was administered as first (12 patients) or second-line (8 patients) treatment, alone or in combination with azathioprine or mycophenolate mofetil and/or prednisone.. CSA determined initial clinical and biochemical remission in all patients. At the end of follow-up (median 8.6; range 4-20.4 years), all patients are alive with their native liver; 15 in complete remission (75%), 2 with incomplete response to treatment and 3 listed for liver transplant. Side effects were mild and transitory after dose tapering or, in 1 case, after CSA withdrawal. Hypertrichosis and moderate gingival hyperplasia were the most frequent. Two patients presented mild transient glomerular filtration rate (GFR) reduction. Median GFR at the beginning and end of treatment was not statistically different for all patients.. CSA was effective and safe in the long-term treatment of our cohort of patients with AIH, tailoring the treatment remains key-points during CSA administration.

Topics: Adolescent; Azathioprine; Child; Child, Preschool; Cholangitis, Sclerosing; Cyclosporine; Drug Therapy, Combination; Female; Follow-Up Studies; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Mycophenolic Acid; Prednisone; Remission Induction; Retrospective Studies; Syndrome; Time Factors; Treatment Outcome

Development of autoimmune hepatitis (AIH) has been sporadically reported in patients with multiple sclerosis (MS) either concurrently or after treatment with immunomodulatory drugs, including interferon-beta (IFN-β) and steroids.. To report a large cohort of 14 patients with MS diagnosed with AIH during an assessment of deranged liver function tests (LFTs).. From 2005 to 2017, we prospectively identified 14 (13 women) patients with MS who suffered also from AIH after investigation in our department for the presence of deranged LFTs. Age at diagnosis of MS was 36.7 ± 9.3 years while at diagnosis of AIH 43.1 ± 12 years.. AIH diagnosis was based on elevation of aminotransferases in all patients [alanine aminotransferase: 520 IU/L (range: 115-1219)], elevation of IgG in 6, compatible autoantibody profile in all, including 5 patients with liver-specific autoantibodies and typical or compatible histological features in 11 patients. 5 patients were under treatment with IFN-β plus methylprednisolone pulses, 3 with IFN-β plus oral steroids, 1 with IFN-β, 4 with methylprednisolone pulses whereas 1 patient was free of treatment. The median time from IFN-β initiation to the development of hepatitis was 12 months (range:1-120). Treatment for AIH was initiated in 13 patients with prednisolone (0.5-1 mg/kg/day) plus mycophenolate myfetil (2 g/day) in 10 and prednisolone plus azathioprine in 3 with complete and partial response in 11 and 2 patients, respectively.. The differential diagnosis of hepatitis in MS patients should include AIH and in particular when immunomodulatory treatment has been preceded. Autoantibody testing and liver histology play fundamental role in establishing a prompt diagnosis of AIH in these patients. Treatment of AIH in patients with MS seems safe and efficient as complete or partial response was recorded in all of our patients.

Topics: Adult; Autoantibodies; Azathioprine; Female; Glucocorticoids; Hepatitis, Autoimmune; Humans; Immunologic Factors; Immunosuppressive Agents; Interferon-beta; Liver Function Tests; Male; Methylprednisolone; Multiple Sclerosis; Mycophenolic Acid; Prednisolone

Mycophenolate mofetil is a commonly used salvage therapy for patients with autoimmune hepatitis (AIH).. To evaluate the predictors of response to mycophenolate rescue therapy to facilitate clinical decision making.. We performed a retrospective observational cohort study of AIH patients managed in 17 major Australian liver centres who received mycophenolate after an inadequate response or intolerance to corticosteroids with/without thiopurine(s). Baseline demographic, clinical and laboratory variables were compared between responders and nonresponders. A multivariable logistic regression model was developed using forward selection to identify independent predictors of treatment response.. A total of 105 patients received mycophenolate rescue therapy of whom 63 (60%) achieved biochemical remission. On univariable analysis, older age (P = 0.003), INR < 1.1 (P = 0.02), and lower immunoglobulin gamma (IgG; P < 0.002) levels were associated with treatment response, while no association was found with cirrhosis status (P = 0.07) or treatment indication (P = 0.63). On multivariable analysis, lower pre-treatment serum IgG level (P = 0.01), higher age at commencing mycophenolate (P = 0.01) and higher INR (P = 0.03) were the only significant independent predictors. An IgG level <17 g/L had a positive and negative predictive value for response of 71% and 60% respectively, while age ≥54 years when commencing mycophenolate had a positive and negative predictive value for response of 80% and 59% respectively.. Mycophenolate remains an excellent treatment option for patients with AIH refractory to or intolerant of standard therapy with those most likely to benefit being older and/or having lower pre-treatment IgG levels.

Topics: Adrenal Cortex Hormones; Adult; Age Factors; Female; Hepatitis, Autoimmune; Humans; Immunoglobulin G; International Normalized Ratio; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Salvage Therapy; Treatment Outcome

Topics: Aged; Hepatitis, Autoimmune; Humans; Immunoglobulin G; Immunosuppressive Agents; International Normalized Ratio; Mycophenolic Acid

Topics: Aged; Hepatitis, Autoimmune; Humans; Immunoglobulin G; Immunosuppressive Agents; International Normalized Ratio; Mycophenolic Acid

Topics: Azathioprine; Child; Hepatitis, Autoimmune; Humans; Mycophenolic Acid

Little is known about outcomes of patients with autoimmune hepatitis (AIH) who have a suboptimal outcome to standard therapy and are then given mycophenolate mofetil as rescue therapy. We evaluated the efficacy and safety of mycophenolate mofetil in patients failed by or intolerant to corticosteroids, with or without azathioprine.. We performed a retrospective study of 105 patients with AIH who received mycophenolate mofetil therapy after an inadequate response or intolerance to standard therapy (98% received combination therapy with corticosteroids plus thiopurines). Patients were recruited from 17 liver clinics via the Australian Liver Association Clinical Research Network. We reviewed records for baseline demographic features and characteristics of liver disease, initial therapy, mycophenolate mofetil indications, treatment outcome, and side effects. The primary outcome was biochemical remission, defined as levels of alanine and aspartate transferase and IgG level within the normal reference range, with or without normal liver histology within the first 2 years of treatment.. The indication for mycophenolate mofetil therapy was non-response to treatment for 40% of cases and intolerance to therapy for 60%. Overall, 63 patients (60%) achieved biochemical remission following a median 12 weeks treatment with mycophenolate mofetil. The proportion of patients who achieved biochemical remission was similar between patients receiving mycophenolate mofetil for non-response to standard therapy (57%) and patients with intolerance to standard therapy (62%). However, a lower proportion of patients with cirrhosis achieved biochemical remission (47%) than patients without cirrhosis (6%) (P = .07). Serious adverse events occurred in 3 patients (2.7%) including 1 death, and 10 patients (9.2%) discontinued mycophenolate mofetil because of adverse events.. In this retrospective study of patients with AIH who received mycophenolate mofetil as a rescue therapy, we found the drug to be well tolerated and moderately effective, inducing biochemical remission in 60% of subjects. Rates of response are lower and rates of infection are higher in patients with AIH and cirrhosis. Prospective studies of mycophenolate mofetil are warranted for this population.

Topics: Adult; Alanine Transaminase; Aspartate Aminotransferases; Australia; Autoantibodies; Drug-Related Side Effects and Adverse Reactions; Female; Hepatitis, Autoimmune; Humans; Immunoglobulin G; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Salvage Therapy; Treatment Outcome

We studied the efficacy and safety of mycophenolate mofetil (MMF) and tacrolimus as second-line therapy in pediatric patients with autoimmune hepatitis (AIH) who were intolerant or non-responders to standard therapy (corticosteroid and azathioprine).. We performed a retrospective study of data from 13 centers in Europe, USA, and Canada. Thirty-eight patients (< 18 years old) who received second-line therapy (18 MMF and 20 tacrolimus), for a median of 72 months (range 8-182) were evaluated. Patients were categorized into two groups: Group 1 (n = 17) were intolerant to corticosteroid or azathioprine, and group 2 (n = 21) were non-responders to standard therapy.. Overall complete response rates were similar in patients treated with MMF and tacrolimus (55.6 vs. 65%, p = 0.552). In group 1, MMF and tacrolimus maintained a biochemical remission in 88.9 and 87.5% of patients, respectively (p = 0.929). More patients in group 2 given tacrolimus compared to MMF had a complete response, but the difference was not statistically significant (50.0 vs. 22.2%, p = 0.195). Biochemical remission was achieved in 71.1% (27/38) of patients by tacrolimus and/or MMF. Decompensated cirrhosis was more commonly seen in MMF and/or tacrolimus non-responders than in responders (45.5 vs. 7.4%, p = 0.006). Five patients who received second-line therapy (2 MMF and 3 tacrolimus) developed side effects that led to therapy withdrawal.. Long-term therapy with MMF or tacrolimus was generally well tolerated by pediatric patients with AIH. Both MMF and tacrolimus had excellent efficacy in patients intolerant to corticosteroid or azathioprine. Tacrolimus might be more effective than MMF in patients failing previous therapy.

Topics: Adolescent; Child; Drug Administration Schedule; Female; Follow-Up Studies; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Male; Mycophenolic Acid; Retrospective Studies; Tacrolimus; Treatment Outcome

Autoimmune diseases are sometimes associated with immune-mediated renal diseases and cryoglobulinemia is one of the causes. Cryoglobulinemia and cryoglobulinemic glomerulonephritis associated with primary Sjögren's syndrome are most frequent condition among non-hepatitis C virus-related condition. Its typical renal manifestation shows high amount of proteinuria with microscopic hematuria and renal insufficiency. We describe a case of 72-year-old woman with Hashimoto disease, autoimmune hepatitis, Sjögren's syndrome, and immune-related pancytopenia complicated by cryoglobulinemic glomerulonephritis. Before kidney biopsy, tubulointerstitial nephritis probably due to Sjögren's syndrome was suspected because of persistent hematuria without significant proteinuria and developing mild renal dysfunction over 6 months. The developing renal dysfunction associated with isolated hematuria is uncommon in glomerular diseases. Kidney biopsy, however, revealed established membranoproliferative glomerulonephritis with subendothelial deposits consisting of tubular structures with IgM, IgG, and C3 staining. Corticosteroids plus mycophenolate mofetil therapy successfully normalized renal function. Physician should not overlook cryoglobulinemic glomerulonephritis, which is potentially poor prognosis, even if urinalysis shows only persistent isolated hematuria in patients with autoimmune diseases.

Topics: Adrenal Cortex Hormones; Aged; Antibiotics, Antineoplastic; Autoimmune Diseases; Cryoglobulinemia; Female; Glomerulonephritis; Glomerulonephritis, Membranoproliferative; Hashimoto Disease; Hematuria; Hepatitis, Autoimmune; Humans; Kidney; Methylprednisolone; Mycophenolic Acid; Nephritis, Interstitial; Pancytopenia; Renal Insufficiency; Sjogren's Syndrome; Treatment Outcome

Predniso(lo)ne, alone or in combination with azathioprine, is the standard-of-care (SOC) therapy for autoimmune hepatitis (AIH). However, the SOC therapy is poorly tolerated or does not control disease activity in up to 20% of patients. We assessed the efficacy of mycophenolate mofetil (MMF) and tacrolimus as second-line therapy for patients with AIH.. We performed a retrospective study of data (from 19 centers in Europe, the United States, Canada, and China) from 201 patients with AIH who received second-line therapy (121 received MMF and 80 received tacrolimus), for a median of 62 months (range, 6-190 mo). Patients were categorized according to their response to SOC. Patients in group 1 (n = 108) had a complete response to the SOC, but were switched to second-line therapy as a result of side effects of predniso(lo)ne or azathioprine, whereas patients in group 2 (n = 93) had not responded to SOC.. There was no significant difference in the proportion of patients with a complete response to MMF (69.4%) vs tacrolimus (72.5%) (P = .639). In group 1, MMF and tacrolimus maintained a biochemical remission in 91.9% and 94.1% of patients, respectively (P = .682). Significantly more group 2 patients given tacrolimus compared with MMF had a complete response (56.5% vs 34%, respectively; P = .029) There were similar proportions of liver-related deaths or liver transplantation among patients given MMF (13.2%) vs tacrolimus (10.3%) (log-rank, P = .472). Ten patients receiving MMF (8.3%) and 10 patients receiving tacrolimus (12.5%) developed side effects that required therapy withdrawal.. Long-term therapy with MMF or tacrolimus generally was well tolerated by patients with AIH. The agents were equally effective in previous complete responders who did not tolerate SOC therapy. Tacrolimus led to a complete response in a greater proportion of previous nonresponder patients compared with MMF.

Topics: Adolescent; Adult; Aged; Canada; Child; China; Drug-Related Side Effects and Adverse Reactions; Europe; Female; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Tacrolimus; Treatment Outcome; United States; Young Adult

High-quality data on the management of autoimmune hepatitis (AIH) are scarce. Despite published guidelines, management of AIH is still expert based rather than evidence based.. To survey expert hepatologists, asking each to describe their practices in the management of patients with AIH.. A survey questionnaire was distributed to members of the International AIH Group. The questionnaire consisted of four clinical scenarios on different presentations of AIH.. Sixty surveys were sent, out of which 37 were returned. None reported budesonide as a first line induction agent for the acute presentation of AIH. Five (14%) participants reported using thiopurine S-methyltransferase measurements before commencement of thiopurine maintenance therapy. Thirteen (35%) routinely perform liver biopsy at 2 years of biochemical remission. If histological inflammatory activity is absent, four (11%) participants reduced azathioprine, whereas 10 (27%) attempted withdrawal altogether. Regarding the management of difficult-to-treat patients, mycophenolate mofetil is the most widely used second-line agent (n = ~450 in 28 centres), whereas tacrolimus (n = ~115 in 21 centres) and ciclosporin (n = ~112 in 18 centres) are less often reported. One centre reported considerable experience with infliximab, while rescue therapy with rituximab has been tried in seven centres.. There is a wide variation in the management of patients with autoimmune hepatitis even among the most expert in the field. Although good quality evidence is lacking, there is considerable experience with second-line therapies. Future prospective studies should address these issues, so that we move from an expert- to an evidence- and personalised-based care in autoimmune hepatitis.

Topics: Azathioprine; Biopsy; Budesonide; Cyclosporine; Health Care Surveys; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Methyltransferases; Mycophenolic Acid; Rituximab; Tacrolimus

Autoimmune hepatitis (AIH) is an immune-mediated liver disease, which requires long-term immunosuppression. Ten to fifteen percent of patients experience insufficient/intolerance response to standard therapy. Although alternate immunosuppression has been applied, there is little long-term data reported on safety, efficacy, steroid-dose reduction and disease evolution in patients with difficult AIH who were on Tacrolimus therapy.. Clinical, biochemical, immunological profiles, treatment response and side effects of 17 AIH patients treated with Tacrolimus between 2003 and 2014 were analyzed from two tertiary referral liver centers.. Tacrolimus was started on 16/17 (94%) patients due to insufficient response to standard therapy. The median duration of treatment was 24 months and patients were followed up for median of 60 months. Tacrolimus dosage was 2 mg/day (median). During first year of therapy, there was a significant improvement in immunoglobulin G and Aspartate transaminase level. 9/17 (52%) compliant and definite AIH patients remained on Tacrolimus at end of follow-up and prednisolone dose reduction was achieved from 10 to 5 mg. All patients are alive and one patient underwent liver transplantation. 4/17 (24%) patients developed overlap with primary sclerosing cholangitis over follow-up period. No significant side effects were observed with Tacrolimus therapy.. Tacrolimus could be used in compliant patients with difficult to treat AIH in experienced centers. Its use is safe and can improve liver biochemistry, IgG and reduce steroid requirement. However, due to the lack of immunomodulatory effect, unmet need for effective immune-regulatory therapies still remain for AIH patients.

Topics: Adolescent; Adult; Aged; Anti-Inflammatory Agents; Aspartate Aminotransferases; Azathioprine; Cholangitis, Sclerosing; Cyclosporine; Female; Follow-Up Studies; Hepatitis, Autoimmune; Humans; Immunoglobulin G; Immunosuppressive Agents; Male; Mercaptopurine; Middle Aged; Mycophenolic Acid; Prednisolone; Retreatment; Tacrolimus; Time Factors; Treatment Outcome; Young Adult

Systemic lupus erythematosus-related hepatitis, known as lupus hepatitis, is a rare manifestation of systemic lupus erythematosus, and is usually subclinical with mild abnormalities of serum liver enzymes. While cases with clinically significant and refractory lupus hepatitis are uncommon, treatment options for lupus hepatitis are to be established. Here, we report the case of a 45-year-old man with progressive lupus hepatitis accompanied by autoimmune haemolytic anaemia. Lupus hepatitis of this patient was refractory to tacrolimus, azathioprine and cyclophosphamide, but was successfully treated by mycophenolate mofetil. Mycophenolate mofetil might be an effective therapeutic option for refractory lupus hepatitis.

Topics: Anemia, Hemolytic, Autoimmune; Biopsy; Diagnosis, Differential; Drug Resistance; Drug Substitution; Hepatitis; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Liver Function Tests; Lupus Erythematosus, Systemic; Male; Middle Aged; Mycophenolic Acid; Predictive Value of Tests; Remission Induction; Treatment Outcome

Front-line therapy with mycophenolate mofetil (MMF) in autoimmune hepatitis (AIH) has shown high on-treatment remission rates.. To study prospectively in a real-world fashion the long-term outcome of a large group of consecutive treatment-naïve AIH patients.. Between 2000 and 2014, 158 patients were recruited but only 131 were eligible for treatment (109 MMF/prednisolone; 22 prednisolone ± azathioprine). Long-term data on outcome after drug withdrawal were evaluated. Patients stopped treatment after having achieved complete response (normal transaminases and IgG) for at least the last 2 years.. At diagnosis, 31.6% of patients had cirrhosis and 72.8% insidious presentation. A total of 102 of 109 (93.6%) responded initially to MMF within 2 (1-18) months. A total of 78 of 109 (71.6%) had complete response on treatment and 61 of 78 (78.2%) maintained remission off prednisolone. MMF-treated patients had increased probability of complete response compared to those receiving azathioprine (P = 0.03). Independent predictors of complete response were lower ALT at 6 months (P = 0.001) and acute presentation (P = 0.03). So far, treatment withdrawal was feasible in 40/109 patients and 30 (75%) are still in remission after 24 (2-129) months. Remission maintenance was associated with longer MMF treatment (P = 0.005), higher baseline ALT (P < 0.02), lower IgG on 6 months (P = 0.004) and histological improvement.. Mycophenolate mofetil proved to be an efficient first-line treatment for AIH, achieving so far the highest rates of remission maintenance off treatment (75%) ever published for at least a median of 2 years, although the remission criteria used were strict. However, the risk of potential bias and overestimation of intervention benefits from MMF cannot be completely excluded as this is a real world and not a randomised controlled trial.

Topics: Adult; Azathioprine; Drug Therapy, Combination; Female; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Liver Cirrhosis; Male; Middle Aged; Mycophenolic Acid; Prednisolone; Prospective Studies; Remission Induction; Treatment Outcome

Autoimmune hepatitis (AIH) is an immune-mediated chronic liver disease characterized by hepatocellular inflammation, necrosis, and fibrosis, which can progress to cirrhosis and fulminant hepatic failure. The standard treatment for AIH includes corticosteroids alone or in combination with azathioprine. Although most patients achieve remission using the standard regimen, some patients do not respond due to either drug intolerance or refractory disease; in such cases alternative immunosuppressive agents should be explored. The second-line therapies are cyclophilin inhibitors such as cyclosporine A or tacrolimus, and nowadays mycophenolate mofetil (MMF) is widely used if azathioprine-based therapies are not tolerated. Although these are recommended as an alternative to the first-line regimen, there is insufficient evidence for the efficacy of second-line therapies, with the evidence based mainly on expert opinion. Therefore, we report an AIH patient receiving the standard regimen in whom remission did not occur due to side effects to azathioprine, but was successfully treated with MMF in combination with corticosteroids as an alternative to the standard regimen.

Topics: Alanine Transaminase; Alopecia; Antibiotics, Antineoplastic; Aspartate Aminotransferases; Azathioprine; Female; Hepatitis, Autoimmune; Humans; Liver; Middle Aged; Mycophenolic Acid; Pancytopenia; Prednisolone

Antibodies (Abs) to soluble liver antigen/liver pancreas (anti-SLA/LP) are considered markers of worse prognosis and outcome in patients with autoimmune hepatitis (AIH) although this assumption has recently been attributed to their frequent co-expression with Abs against Ro52 (anti-Ro52). To assess the clinical significance of anti-SLA/LP Abs alone or in combination with anti-Ro52 in AIH patients and determine the immunodominant Ro52 epitopes according to the anti-SLA/LP status.. Twenty-three anti-SLA/LP-positive and 106 anti-SLA/LP-negative AIH patients were included. Anti-SLA/LP were determined by ELISA using recombinant antigen, and confirmed by immunoblot using cytosolic rat liver fraction or HuH-7 extract. Anti-Ro52 Abs were determined by ELISA using recombinant antigen. Epitope mapping was assessed by ELISA using overlapping peptides covering the whole Ro52 protein in 26 AIH patients and 12 patients with Sjögren's syndrome.. Anti-SLA/LP positivity was not associated with the clinical, laboratory or histological characteristics of AIH patients. Treatment response, corticosteroid withdrawal, relapse after stopping treatment and outcome, were not associated with the presence of anti-SLA/LP, anti-Ro52 or double reactivity. Moreover, Ro52 epitope mapping revealed new epitopes unique for AIH and independent from anti-SLA/LP positivity.. Neither anti-SLA/LP nor anti-Ro52 Abs or their combination could specify a distinct group of AIH patients in terms of clinical characteristics, treatment response and outcome. Further studies are needed to clarify whether the newly discovered immunodominant epitopes of Ro52 antigen which were associated specifically with AIH have any clinical or pathogenetic significance in AIH.

Topics: Autoantibodies; Autoantigens; Biomarkers; Enzyme-Linked Immunosorbent Assay; Epitope Mapping; Greece; Hepatitis, Autoimmune; Humans; Kaplan-Meier Estimate; Mycophenolic Acid; Oligonucleotides; Polymerase Chain Reaction; Ribonucleoproteins

Not all patients with autoimmune hepatitis (AIH) respond to standard medical therapy with corticosteroids and azathioprine. Such patients may develop end-stage liver disease with poor prognosis unless transplantation is considered. Alternatively, the introduction of new therapeutic strategies could potentially ameliorate deterioration of liver function. Patients in our tertiary center were selected for everolimus therapy when exhibiting nonresponse or intolerance to combinations of the standard and empirical drugs in use (e.g., mycophenolate mofetil, calcineurin inhibitors [CNIs]). We here report the efficacy of everolimus treatment of patients with AIH.. Seven patients (six female, mean age 47 years, range 22-62 years) in whom disease control could not be achieved with standard therapy or the alternative drugs in use were included.. Treatment with everolimus induced a clear reduction of transaminases within 2 weeks. After 3-5 months three patients had normal alanine aminotransferase (ALT) levels (10-45 IU) and four patients had ALT levels below 55 IU compared to a three- to fivefold elevated level prior to everolimus treatment. Sustained remission after 1 year of treatment was observed in three patients; in another two patients ALT was 45-68 U/L. Four patients in remission after 3 years were rebiopsied. Two showed no histological progression, and in two the fibrosis had decreased. Side effects noted were myalgias and minor bacterial infections not leading to discontinuation of the drug.. Our experience indicates that everolimus may be of value in selected patients with therapy-resistant AIH and comorbidity/side effects that excludes the use of CNIs.

Topics: Adrenal Cortex Hormones; Adult; Alanine Transaminase; Azathioprine; Drug Resistance, Multiple; Everolimus; Female; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Liver Function Tests; Male; Middle Aged; Mycophenolic Acid; Remission Induction; Tertiary Care Centers; Treatment Outcome; Young Adult

Biochemical remission is widely considered a satisfactory treatment end point in autoimmune hepatitis (AIH). The significance of persisting histological activity despite biochemical remission is unknown. We aimed to assess the frequency and prognostic significance of persisting histological inflammation in patients with AIH who had achieved biochemical remission with treatment.. We studied 120 patients (median age at diagnosis 57 years; 81% female) with AIH by International Criteria (59% definite), who received immunosuppressive treatment and underwent a follow-up liver biopsy after at least 6 months of sustained biochemical remission (defined as normal serum ALT and globulin).. Fifty-five patients (46%) had persisting histological activity (Ishak histological activity index (HAI) ≥4). These patients had higher serum ALT (24 vs. 18 IU/l, P=0.003) and AST (27 vs. 23 IU/l, P=0.03) at the time of follow-up biopsy, compared with patients who achieved histological remission (HAI ≤3). They had less frequent regression of fibrosis on follow-up biopsy compared with those achieving histological remission (32 vs. 60%, P=0.004) and had excess mortality (standardized mortality ratio 1.4 vs. 0.7, P<0.05). The excess mortality was due to liver disease. On multivariate analysis, persisting histological activity was independently associated with all-cause death/transplantation (HR 3.1 (95% CI 1.2-8.1); P=0.02); an association with liver-related death/transplantation fell short of significance (HR 9.7 (95% CI 0.84-111.6; P=0.07).. Persisting histological activity, despite biochemical remission, is frequent in patients with treated AIH and is associated with lower rates of fibrosis regression and reduced long-term survival.

Topics: Adult; Aged; Anti-Inflammatory Agents; Azathioprine; Biomarkers; Biopsy; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Inflammation; Kaplan-Meier Estimate; Liver Cirrhosis; Male; Middle Aged; Mycophenolic Acid; Predictive Value of Tests; Prednisolone; Prognosis; Proportional Hazards Models; Retrospective Studies; Time Factors

Topics: Adult; Aged; Antibodies, Monoclonal; Antibody Specificity; Basiliximab; Blood Donors; Blood Grouping and Crossmatching; Female; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Isoantibodies; Isoantigens; Kidd Blood-Group System; Liver Transplantation; Mycophenolic Acid; Operative Blood Salvage; Platelet Transfusion; Prednisolone; Recombinant Fusion Proteins; Rh-Hr Blood-Group System; Tacrolimus; Tissue Donors; Transplantation Immunology

(1) Standard treatment of autoimmune hepatitis in adults should be steroid based. In early trials, prednisolone +/- azathioprine was superior to the azathioprine mono-therapy (which was not significantly better than placebo). Prednisolone plus azathioprine has similar efficacy to, but is better tolerated than a higher-dose of prednisolone alone and therefore has become standard therapy. (2) In most treated patients, serum transaminases and globulin/IgG fall, but percentage attaining normal values within 6 months varies between 10 and 90%. Patients failing to do so have a worse longer-term outcome. (3) A higher initial prednisolone dose (1 mg/kg/day) plus azathioprine achieved 76% serum transaminase normalisation after 6 months but needs longer-term evaluation. (4) Histological remission (minimal hepatitis on re-biopsy) lags behind transaminase normalisation by 6-12 months and is achieved in 55-70% of patients after 24-36 months prednisolone. This lag and the inefficacy of azathioprine mono-therapy justifies continuing prednisolone (5-10 mg/day), even after transaminase normalisation, for a total of >2 years. (5) Repeat biopsy should be considered because 40-60% of patients still have (usually mild) persisting inflammation, despite normal serum transaminases and IgG. In such patients, fibrosis is less likely to regress and long-term mortality is higher. (6) In a large trial, non-cirrhotic treatment-naïve patients given budesonide (9 mg/day) plus azathioprine were more likely to achieve normal serum ALT after 6 months than those receiving prednisolone plus azathioprine and had less side effects. This trial was short term in nature and lacked follow-up histology. Budesonide is recommended in non-cirrhotic patients who develop prednisolone-related side effects. In an open study of mycophenolate plus prednisolone, 88% of treatment-naïve patients achieved normal serum transaminases. However, half relapsed during or after steroid withdrawal and only one of eight re-biopsied patients achieved histological remission. Mycophenolate is teratogenic, limiting its use in younger women.. Despite its limitations, no regime has yet been shown clearly to be better than prednisolone and azathioprine-based therapy.

Topics: Adult; Azathioprine; Glucocorticoids; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Mycophenolic Acid; Prednisolone; Treatment Outcome

Corticosteroids and azathioprine are widely accepted as the initial therapy for autoimmune hepatitis. However, the disease is refractory to steroids in about 10%-20% of patients, for whom currently there is no standardized treatment. Here we describe our experience with sirolimus in treatment of steroid refractory autoimmune hepatitis.. This is a longitudinal follow-up study. Between November 2007 and January 2014, 5 subjects with steroid refractory autoimmune hepatitis were treated with sirolimus at our institution.. A response, defined as a sustained >50% fall in alanine aminotransferase (ALT) levels, was achieved in 4/5 patients. A complete response, sustained normalization of ALT levels, was achieved in 2/5 patients. The need for steroids was significantly reduced in all patients (P < .05).. In this small series, sirolimus appears to be useful in the treatment of patients with steroid refractory autoimmune hepatitis.

Topics: Adult; Alanine Transaminase; Aspartate Aminotransferases; Azathioprine; Bilirubin; Drug Resistance; Female; Glucocorticoids; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Longitudinal Studies; Male; Middle Aged; Mycophenolic Acid; Prednisone; Sirolimus; Young Adult

We reported that combined presence of autoantibodies (Abs) against filamentous-actin (AFA) and α-actinin are specific for autoimmune hepatitis type 1 (AIH-1) diagnosis.. To explore our data and assess whether anti-α-actinin and AFA Abs could be used as indicators of response to treatment and predictors of AIH-1 flares in a large cohort of AIH-1 patients.. Seven hundred and sixty-four serial serum samples of 86 consecutive AIH-1 patients, 509 pathological and 110 normal controls were tested for the presence of anti-α-actinin and AFA Abs by an in-house IgG-specific ELISA and a standardised commercially available ELISA respectively. Patients sera were divided into baseline group (active disease before treatment initiation, n = 86) and then according to treatment response into group A-responders (n = 40 patients), group B-relapsers/incomplete responders (n = 37 patients) and group C-not-treated (n = 9 patients).. Anti-α-actinin and AFA levels were significantly higher at baseline. Double reactivity against α-actinin and AFA was associated with disease activity (OR 4.9; 95% CI: 2.7-9). Anti-α-actinin optical densities (ODs) before treatment decreased significantly at first remission (P < 0.05). Treatment response was associated with anti-α-actinin Abs negativity before treatment (OR 3.4; 95% CI: 1.3-8.9) and absence of double positivity for anti-α-actinin and AFA Abs before treatment (OR 3.8; 95% CI: 1.4-10.4). Responders had lower baseline levels of anti-α-actinin than relapsers and/or incomplete responders (P = 0.002). Binary logistic regression revealed lower levels of anti-α-actinin as the only independent predictors of response (P = 0.05).. Anti-α-actinin Abs at baseline appear to predict treatment response and therefore they might be used for monitoring treatment outcome in AIH-1.

Topics: Actinin; Actins; Adolescent; Adult; Aged; Autoantibodies; Biomarkers; Cohort Studies; Drug Monitoring; Enzyme-Linked Immunosorbent Assay; Female; Hepatitis, Autoimmune; Humans; Immunoglobulin G; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Predictive Value of Tests; Young Adult

Autoimmune hepatitis in children is of type 1, with antinuclear or anti-smooth muscle antibodies, more frequent in teenage girls, or of type 2, with anti-liver-kidney microsomes 1 and/or anti-liver cytosol 1 antibodies, in younger children. Other autoimmune diseases may be present in the patient or his relatives. The diagnosis relies on autoantibodies testing and histology. The treatment with steroids and azathioprine is efficient in most cases. Cyclosporine A is also successfully used. Relapses under treatment are frequent. A long-term treatment may be necessary. Liver transplantation is rarely indicated.

Topics: Antibodies, Antinuclear; Autoantibodies; Autoantigens; Azathioprine; Child; Cyclosporine; Genetic Predisposition to Disease; Glucocorticoids; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Liver Transplantation; Muscle, Smooth; Mycophenolic Acid; Prednisone

De novo autoimmune hepatitis (AIH) describes the development of hepatitis with autoimmune features in liver transplant (LT) patients without prior diagnosis of AIH. We aimed to evaluate the incidence and risk factors for de novo AIH.. A cohort of 576 patients with LT for aetiologies other than AIH was evaluated.. De novo AIH was diagnosed in 17 patients (3%) with an overall incidence of 4.0 cases per 1000 patient-years. By univariate Cox analysis, patients who received cyclosporine A had lower risk (HR 0.24, 95% CI 0.07-0.80, P = 0.02), whereas patients who had female donors (HR 3.03, 95% CI 1.11-8.25, P = 0.03), donors ≥40-years (HR 6.95, 95% CI 1.93-25.03, P = 0.003), and those who received tacrolimus (HR 4.39, 95% CI 1.47-13.13, P = 0.008) and mycophenolate mofetil (HR 6.37, 95% CI 1.62-25.13, P = 0.008) had higher risk. Survival was similar in patients with de novo AIH compared with the LT population (mean survival time, 17 ± 1.5 vs. 16 ± 0.5 years, Log-rank test; P = 0.4).. The incidence of de novo AIH is low and does not impact on long-term survival. Recipients of female or older donor grafts, or recipients using tacrolimus, or mycophenolate mofetil as part of their immunosuppressive regimen have a higher risk of de novo AIH, whereas LT recipients maintained on cyclosporine A have a lower risk.

Topics: Adolescent; Adult; Age Factors; Aged; Canada; Child; Child, Preschool; Cohort Studies; Cyclosporine; Female; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Incidence; Infant; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Risk Factors; Sex Factors; Survival Rate; Tacrolimus; Tissue Donors; Young Adult

Topics: Female; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Male; Mycophenolic Acid

Treatment failure occurs in 20% of autoimmune hepatitis patients on prednisolone and azathioprine (AZA). There is no established second line treatment.. To assess the efficacy of mycophenolate mofetil as second line treatment after AZA-intolerance or AZA-nonresponse in autoimmune hepatitis and overlap syndromes.. Consecutive patients from the Dutch Autoimmune Hepatitis Group cohort, consisting of 661 patients, with autoimmune hepatitis or overlap syndromes, AZA-intolerance or AZA-nonresponse and past or present use of mycophenolate mofetil were included. Primary endpoint of mycophenolate mofetil treatment was biochemical remission. Secondary endpoints were biochemical response (without remission), treatment failure and prevention of disease progression.. Forty-five patients treated with mycophenolate mofetil were included. In autoimmune hepatitis remission or response was achieved in 13% and 27% in the AZA-nonresponse group compared to 67% and 0% in the AZA-intolerance group (P = 0.008). In overlap-syndromes remission or response was reached in 57% and 14% in the AZA-nonresponse group and 63% and 25% of the AZA-intolerance group (N.S.); 33% had side effects and 13% discontinued mycophenolate mofetil. Overall 38% had treatment failure; this was 60% in the autoimmune hepatitis AZA-nonresponse group. Decompensated liver cirrhosis, liver transplantations and death were only seen in the autoimmune hepatitis AZA-nonresponse group (P < 0.001).. Mycophenolate mofetil induced response or remission in a majority of patients with autoimmune hepatitis and azathioprine-intolerance and with overlap syndromes, irrespective of intolerance or nonresponse for azathioprine. In autoimmune hepatitis with azathioprine nonresponse mycophenolate mofetil is less often effective.

Topics: Adolescent; Adult; Aged; Child; Cohort Studies; Female; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Netherlands; Retrospective Studies; Severity of Illness Index; Syndrome; Treatment Outcome; Young Adult

Topics: Hepatitis, Autoimmune; Humans; Mycophenolic Acid

Topics: Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Azathioprine; Diagnosis, Differential; Drug Therapy, Combination; Epstein-Barr Virus Infections; Female; Gingival Diseases; Hepatitis, Autoimmune; Herpesvirus 4, Human; Hodgkin Disease; Humans; Iatrogenic Disease; Immunocompromised Host; Immunosuppressive Agents; Lymphoproliferative Disorders; Mandibular Diseases; Mycophenolic Acid; Oral Ulcer; Prednisone; Remission Induction; Rituximab; Virus Activation

Autoimmune hepatitis is characterized by hepatocellular inflammation often progressing to cirrhosis. Standard treatment consists of corticosteroids and azathioprine. For the 20% of patients with refractory disease or those who are intolerant to medication, there is no standardized treatment.. To evaluate mycophenolate mofetil (MMF) as an alternative therapy for autoimmune hepatitis. . The present retrospective study identified all patients with autoimmune hepatitis who were treated with MMF over a 10-year period at the Henry Ford Hospital (Michigan, USA). These patients were evaluated for tolerance and response.. Of the 90 patients participating in the study, 48% had a complete response, 32% experienced relapses and 21% were refractory. MMF was initiated in 21 patients - 12 (57%) for refractory disease and nine (43%) for medication intolerance. Of the 12 patients converted for refractory disease, all showed biochemical improvement but none had a complete response. Of the patients converted due to intolerance, 88% maintained complete remission. For all patients converted to MMF, there was a mean decrease in steroid dose from 18.9 mg⁄day to 7.8 mg⁄day (P=0.01).. In patients with autoimmune hepatitis who were intolerant to conventional therapy, MMF was well tolerated, with 88% of patients maintained in remission. MMF did not induce remission in those refractory to conventional therapy; however, it resulted in a significant decrease in steroid use. Prospective studies are needed to better assess the role of MMF as an alternative therapy.

Topics: Adult; Aged; Aged, 80 and over; Cohort Studies; Drug Resistance; Drug Tolerance; Female; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Treatment Outcome

Autoimmune hepatitis (AIH) is refractory to standard therapy with prednisone and azathioprine in 20% of patients. Investigators are exploring alternative immunosuppressant treatments, including mycophenolate mofetil (MMF). We assessed the outcome of MMF therapy in patients with AIH and related disorders. A retrospective analysis was performed in 16 patients with AIH, immune cholangitis, and overlap syndromes between AIH, primary biliary cirrhosis, and primary sclerosing cholangitis. MMF was used in lieu of azathioprine on account of patients' intolerance to azathioprine, disease that was refractory to prednisone plus azathioprine, or the perceived potency of MMF. With initiation of MMF, median ALT decreased from 81.5 U/l to 42.5 U/l (P = 0.03). Median prednisone dose decreased from 10 mg to 2.5 mg (P = 0.01). Prednisone was completely withdrawn in three patients. Five of 16 patients (31%) achieved biochemical remission, defined as a reduction in ALT from greater than to less than twice normal. Seven additional patients (44%) were maintained in biochemical remission. Two patients had an incomplete response to MMF and two patients experienced treatment failure. MMF was tolerated well in all but one patient, who discontinued the drug on account of paresthesias. MMF may be a safe and effective alternative to azathioprine in patients with AIH and related disorders.

Topics: Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Mycophenolic Acid; Retrospective Studies; Treatment Outcome

The relationship between liver dysfunction and coeliac disease is well established, ranging from transaminitis to chronic liver disease. In this report, we describe for the first time the development of a 'seronegative' autoimmune hepatitis in a teenager previously diagnosed with coeliac disease. He had normal liver function tests (LFTs) at diagnosis and was strictly compliant with a gluten-free diet. On screening blood tests at 1 year post diagnosis, he presented with raised LFTs leading to a diagnosis of autoimmune hepatitis on liver biopsy, successfully treated with mycophenolate mofetil. By using screening LFTs, we may well have prevented this patient from developing disease complications.

Topics: Adolescent; Celiac Disease; Follow-Up Studies; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Male; Mycophenolic Acid

Topics: Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Mycophenolic Acid

The aim of this study was to evaluate the outcome of mycophenolate mofetil (MMF) therapy in children with autoimmune liver disease who are resistant to or intolerant of standard immunosuppression.. (a) failure to achieve/maintain remission with prednisolone/azathioprine therapy or (b) significant treatment side-effects. Initial MMF dose was 20mg/kg/day, gradually increased to a maximum of 40 mg/kg/day. Azathioprine was stopped when MMF was commenced.. Twenty-six children (17 female) were recruited. Median (range) age at diagnosis was 9.9 (1.2-14.4) years. Sixteen had Type 1 autoimmune hepatitis (AIH), two Type 2 AIH, and eight had autoimmune sclerosing cholangitis (ASC). Median (range) time from diagnosis to addition of MMF was 14.9 (0.2-108.6) months. Eighteen children responded to MMF, aspartate aminotransferase (AST) normalising in 14. At median (range) follow-up of 61.5 (19.5-96.3) months, AST remained normal in 12. All 18 children were well, but two had clinical signs of portal hypertension. Eight (6 ASC) did not respond: AST remained elevated in seven, one was listed for transplant for decompensated liver disease and one had clinical signs of portal hypertension. MMF was well tolerated. Leukopenia (n=7) was the most common side-effect.. MMF is an effective rescue therapy for children with AIH, but not for those with ASC.

Topics: Adolescent; Aspartate Aminotransferases; Child; Child, Preschool; Female; Follow-Up Studies; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Infant; Male; Mycophenolic Acid; Retrospective Studies

Topics: Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Mycophenolic Acid

Standard treatment for autoimmune hepatitis (AIH) involves immune suppression by using prednisone alone or in combination with azathioprine (AZA). Although this regimen achieves remission in approximately 80%, some patients are intolerant or do not respond. Mycophenolate mofetil (MMF) is a potent immunosuppressant. However, its utility in AIH is not well-defined.. We performed a retrospective longitudinal analysis of patients with AIH.. We identified 128 patients with AIH: mean age, 42.8 years; 83% female; 69% white. At presentation, median AST and ALT were 227 and 261 U/L, respectively, and bridging fibrosis and cirrhosis were present in 38% and 22%, respectively. Overall, 29 patients received MMF; 12 were switched to MMF after intolerance or nonresponse to prednisone +/- AZA, whereas 17 received MMF +/- prednisone as initial therapy. The main reasons for switching to MMF were nausea/vomiting (n = 4) and failure to normalize liver enzymes (n = 3). Ten of the 29 patients who received MMF therapy (34%) discontinued MMF as a result of side effects. Sixteen (84%) of the remaining 19 patients on MMF achieved remission, which closely matched the remission rate of those who remained on prednisone +/- AZA (82%). The only independent clinical factor that predicted the eventual need for the use of MMF was absence of cirrhosis (P = .0067).. (1) MMF was associated with a high rate of intolerance (34%). (2) In those who could tolerate it, it was associated with a high rate of remission (84%). (3) Absence of cirrhosis on presentation was the only independent factor associated with eventual need for MMF.

Topics: Adult; Alanine Transaminase; Aspartate Aminotransferases; Drug Therapy, Combination; Female; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Liver Cirrhosis; Longitudinal Studies; Male; Middle Aged; Mycophenolic Acid; Prednisone; Retrospective Studies; Treatment Outcome

In patients with autoimmune hepatitis, efficient immunosuppressive therapy is essential to avoid progression to cirrhosis. There is no established second line therapy for patients failing standard therapy with steroids and azathioprine. The aim of this study was to examine the possible role of mycophenolate mofetil (MMF) as second line treatment of autoimmune hepatitis (AIH).. We were able to identify 37 patients (29 women, 8 men) with AIH proven according to International AIH Group criteria who failed standard therapy. One patient on MMF was excluded due to non-compliance. A total of 28 of 36 patients had experienced side effects necessitating stop of treatment. One patient stopped azathioprine due to pregnancy. A total of nine patients did not respond sufficiently to azathioprine. A total of four patients with a treatment duration of 3 months or less because of severe side effects were considered as intolerant to MMF. Remission was defined as aspartate transaminase (ASP) < twice upper normal limit (UNL).. Of 36 patients on MMF included in the analysis, 14 patients (39%) experienced remission. A total of 22 patients (61%) did not respond sufficiently to MMF. The response rate to MMF was dependent on the cause of treatment cessation of azathioprine. Of eight patients with prior nonresponse to azathioprine, six (75%) did not respond to MMF and only two (25%) reached biochemical remission. Of 28 patients with azathioprine intolerance in 16 (57%) patients, the response to MMF was insufficient and in 12 patients (43%) remission was reached. The difference did not reach statistical significance due to the relatively small numbers included.. In the light of its good tolerability, MMF seems to be an alternative for patients who could not tolerate azathioprine previously. However, our data suggest that a majority of patients fail MMF particularly if they are switched because of an insufficient response to azathioprine.

Topics: Adult; Female; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Male; Mycophenolic Acid; Treatment Outcome

Topics: Acute Disease; Adjuvants, Immunologic; Aged; Anti-Inflammatory Agents; Antibodies, Antinuclear; Budesonide; Drug Synergism; Glatiramer Acetate; Hepatitis, Autoimmune; Humans; Iatrogenic Disease; Interferon beta-1b; Interferon-beta; Liver; Male; Mannitol; Multiple Sclerosis; Mycophenolic Acid; Peptides; Treatment Outcome

Topics: Adult; Antibodies, Antinuclear; Female; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Liver Cirrhosis, Biliary; Mycophenolic Acid; Nuclear Pore Complex Proteins

The immunosuppressive treatment for autoimmune hepatitis (AIH) patients is prednisone and azathioprine. Ten percent to 20% of patients do not respond or are intolerant of standard treatment. The aim of this study was to assess the biochemical, histologic, and hematologic parameters during mycophenolate mofetil (MMF) treatment in AIH patients who did not respond to or were intolerant of prednisone and/or azathioprine.. A retrospective study was performed of 15 AIH patients who received MMF either as monotherapy or in combination with prednisone after failure or intolerance of the initial regimen. Records were reviewed as to initial therapy, reasons why MMF was initiated, liver enzyme levels, histology on MMF, and complications.. The mean age was 60 +/- 15 years. All patients were started on MMF at 1 gram twice a day, 3 on MMF monotherapy, and 12 on prednisone and MMF. The average MMF treatment duration was 41 months. Alanine aminotransferase levels decreased significantly from 91.73 +/- 88.69 to 60.87 +/- 71.2 (P = .03) on MMF treatment. Inflammatory scores (2.59 +/- 0.97 to 1.14 +/- 1.21, P = .02) and Ishak fibrosis scores (4.10 +/- 1.37 to 2.5 +/- 1.51, P = .02) also decreased. No significant hematologic complications were noted during MMF treatment.. Administration of MMF, either as monotherapy or in combination with prednisone, results in biochemical and histologic improvement in AIH patients who are prednisone and/or azathioprine intolerant or resistant without the development of significant complications. MMF should be studied prospectively as an alternative agent in the treatment of autoimmune liver disease.

Topics: Alanine Transaminase; Biopsy; Drug Therapy, Combination; Drug Tolerance; Female; Follow-Up Studies; Glucocorticoids; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Prednisolone; Prodrugs; Retrospective Studies; Treatment Outcome

Rapamycin (Rapa), one of the newer immunosuppressants has been found to control and prevent autoimmune features in animal models. This is the first report describing the successful control of post-transplant autoimmune hepatitis (AIH) with Rapa. Post-transplant AIH is diagnosed in the presence of raised transaminases, elevated immunoglobulin G, presence of autoantibodies and histologic changes consistent with AIH on liver biopsy. It may represent a recurrence of the original AIH that led to transplantation or present as a de novo AIH after liver transplant. Post-transplant AIH has conventionally been treated with Prednisolone (Pred) and Azathioprine (AZA). In this report, tailoring of immunosuppression after diagnosis of post-transplant AIH is described with special emphasis on those treated successfully with Rapa. Fifteen of 21 patients responded to treatment with an increase in dose of Pred and addition of AZA or Mycophenolate Mofetil (MMF) to calcineurin inhibitor. Five non-responders and one other patient with post-transplant AIH were treated with addition of Rapa. All six responded to treatment but drug was withdrawn in one patient. Adverse events were minimal. Rapa may prove to be an important addition in the control of autoimmune liver disease.

Topics: Autoantibodies; Azathioprine; Biopsy; Calcineurin Inhibitors; Child; Child, Preschool; Hepatitis, Autoimmune; Humans; Immunoglobulin G; Immunosuppressive Agents; Infant; Infant, Newborn; Liver; Liver Diseases; Male; Mycophenolic Acid; Postoperative Complications; Prednisolone; Sirolimus; Time Factors; Transaminases; Treatment Outcome

Mycophenolate mofetil is an immunosuppressive agent frequently used in regimens to prevent allograft rejection. In this review we focus on mycophenolate mofetil as a potential drug for chronic autoimmune diseases.. We searched PubMed for relevant literature and present two case histories.. Treatment with mycophenolate mofetil is best documented in lupus nephritis. In this context, some studies have documented an effect equal to cyclophosphamide for induction treatment, and equal to azathioprine, and better than cyclophosphamide for remission maintenance. Mycophenolate mofetil is today an alternative, although experimental, agent for the treatment of certain autoimmune diseases when conventional drugs have failed or are not tolerated; in the future it may become more widely used for immunosuppression. To establish the role for mycophenolate mofetil, more prospective controlled multicentre studies are warranted.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Chronic Disease; Crohn Disease; Dermatologic Agents; Female; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lupus Nephritis; Mycophenolic Acid; Vasculitis

Topics: Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Mycophenolic Acid; Treatment Outcome

To assess the outcomes of empiric therapy with mycophenolate mofetil in patients with autoimmune hepatitis.. Mycophenolate mofetil is a purine antagonist that selectively inhibits immunocyte proliferation, and its empiric use in autoimmune hepatitis has been stimulated by small clinical experiences.. Eight patients received mycophenolate mofetil (0.5-3 g daily) for 19 +/- 7 months as frontline therapy or after adverse responses to conventional corticosteroid treatment. Seventeen patients who had been treated with high-dose corticosteroid regimens after treatment failure constituted a historical comparison population.. Five of the 8 patients receiving mycophenolate mofetil and all 17 patients who had been treated with the conventional corticosteroid regimens for treatment failure responded to therapy. The frequency of response (62% vs. 100%, P = 0.02) was lower during longer intervals of treatment (19 +/- 7 months vs. 6 +/- 1 months, P = 0.02) in the patients receiving mycophenolate mofetil. None receiving mycophenolate mofetil resolved their laboratory abnormalities, whereas 6 patients in the comparison group improved to normal tests (0% vs. 35%, P = 0.1). Histologic resolution did not occur in 4 patients sampled during treatment, and successive specimens in 2 patients showed progressive fibrosis. Corticosteroids could not be withdrawn in the patients treated with mycophenolate mofetil, whereas discontinuation was possible in 7 patients in the comparison group (0% vs. 41%, P = 0.06).. Mycophenolate mofetil did not induce laboratory resolution, prevent progressive fibrosis, or allow corticosteroid withdrawal. Clinical trials are needed to evaluate its role and target population.

Topics: Adrenal Cortex Hormones; Adult; Aspartate Aminotransferases; Azathioprine; Bilirubin; Biomarkers; Dose-Response Relationship, Drug; Female; Follow-Up Studies; gamma-Globulins; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Prednisone; Retrospective Studies; Time Factors; Treatment Outcome

The development of de novo autoimmune liver disease after liver transplantation (LT) has been described in both children and adults. Reported herein is a case that is best characterized as post-LT de novo hepatitis with features of autoimmune hepatitis (AIH)-primary biliary cirrhosis (PBC) overlap. A 56-year-old man underwent LT for decompensated liver disease secondary to non-alcoholic steatohepatitis. His liver function tests became markedly abnormal 8 months after LT. Sequential liver transplant biopsy findings were confusing and shared findings seen with both AIH and PBC. Although standard autoimmune serological tests were negative, a dramatic biochemical response was observed to a regimen consisting of prednisone, mycophenolate mofetil, and ursodeoxycholic acid added to maintainance tacrolimus. The donor was histocompatibility leukocyte antigen, DR4, positive, a haplotype associated with the development of AIH-PBC overlap syndrome. In conclusion the authors believe that this may be a case of post-LT de novo overlap syndrome of AIH-PBC, a novel 'autoimmune-type' response.

Topics: Cholagogues and Choleretics; Drug Therapy, Combination; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Liver Cirrhosis, Biliary; Liver Function Tests; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prednisone; Treatment Outcome; Ursodeoxycholic Acid

Corticosteroids and azathioprine are considered standard treatment for autoimmune hepatitis. There are, however, well-known systemic side effects that may preclude continuation with these immunosuppressive therapies, and small trials of the anti-metabolite mycophenolate mofetil have been reported. We report liver biopsy findings in a follow-up biopsy of a patient who had been switched from azathioprine to mycophenolate mofetil for treatment of presumed, steroid-responsive autoimmune hepatitis. Both cytoplasmic features of adaptation and nuclear alterations were noted in hepatocytes. Possible mechanisms for these findings are discussed.

Topics: Azathioprine; Female; Hepatitis, Autoimmune; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunosuppressive Agents; Middle Aged; Mycophenolic Acid; Prednisone

There are limited therapeutic options available for patients with autoimmune hepatitis in whom conventional treatment fails. A case series of five patients unresponsive to or unable to take azathioprine, 6-mercaptopurine or corticosteroids who were treated with mycophenolate mofetil (MMF) is reported. While on MMF, alanine aminotransferase normalized or remained normal in all patients. MMF had a steroid-sparing effect and histological remission was demonstrated in one patient after seven months of MMF. One patient experienced an uncomplicated episode of pyelonephritis. In conclusion, MMF can effectively induce and maintain remission in refractory autoimmune hepatitis patients.

Topics: Adult; Aged; Alanine Transaminase; Biomarkers; Female; Glucocorticoids; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Prednisone

Topics: Drug Approval; Drug Labeling; Hepatitis, Autoimmune; Humans; Mycophenolic Acid; Patient Selection

Topics: Anti-Inflammatory Agents; Budesonide; Cyclophosphamide; Cyclosporine; Hepatitis, Autoimmune; Humans; Immunologic Factors; Immunosuppressive Agents; Interleukins; Methotrexate; Mycophenolic Acid; Prednisolone; Tacrolimus; Treatment Outcome

Azathioprine is standard therapy for maintenance of remission in patients with autoimmune hepatitis. However, approximately 15% of patients are intolerant of therapy and 10% do not respond to it. There is a need for alternative therapies. We describe here the results of mycophenolate mofetil therapy in patients with autoimmune hepatitis.. We studied seven patients with type 1 AIH (six female). Three were intolerant of azathioprine and had elevated transaminases and liver histology showing active disease despite prednisolone therapy. Four had been on a dose of 2 mg per kg of azathioprine without complete normalisation of ALT, and had liver biopsies showing active disease. All were treated with mycophenolate 1 g bd and were followed for a median of 46 months (21-59). End points were improvement in histological inflammation, ALT and prednisolone dose.. Five of the seven (71%) patients had normal transaminases after 3 months of treatment. The steroid dose fell from a median of 20 mg per day to 2 mg per day at 9 months (p=0.0001) and the hepatic activity index fell from median 11 to 3 (p=0.001) after 7 months of therapy. One patient required dose reduction because of a fall in white cell count. No other adverse effects were seen.. Mycophenolate mofetil is effective and well tolerated in patients with type 1 AIH who are intolerant of, or do not respond to, azathioprine.

Topics: Adolescent; Adult; Alanine Transaminase; Anti-Inflammatory Agents; Azathioprine; Dose-Response Relationship, Drug; Drug Resistance; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Leukocyte Count; Liver; Mycophenolic Acid; Prednisone