A recent retrospective study (C Efe et al. Clin Gastroenterol Hepatol 2017; 15: 1950-6) examined both mycophenolate mofetil (MMF, n=121) and tacrolimus (TAC, n=80) as second-line therapies for autoimmnue hepatitis with a median followup of 62 months. Patients were divided into two groups. The first group (n=108) had a complete response to steroids/azathioprine but had side effects. The second group (n=93) were nonresponders to steroids/azathioprine. Overall, the cohort examined patients as young as 7 years and as old as 76 years.
- No significant difference in complete response noted in 69.4% of MMF-treated compared with 72.4% in TAC-treated patients.
- In group 1 patients (responders to azathioprine), MMF and TAC maintained biochemical remission in 91.9% and 94.1% respectively.
- In group 2 (prior nonresponders), TAC-treated patients had a complete response rate of 56.5% compared with 34% for MMF-treated patients (P=.029).
- Liver-related deaths and transplantation occurred with similar rates: MMF 13.2% compared with TAC 10.3%. With each treatment, 10 patients withdrew from treatment due to side effects.
My take: In this study, both agents were effective in those who changed due to side effects. However, tacrolimus-treated patients had a higher response among prior nonresponders.
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A recent study (AN Zizzo et al. JPGN 2017; 65: 6-15) performed a systematic review and meta-analysis of pediatric autoimmune hepatitis (AIH) studies.
The most remarkable finding was that there were only 76 patients from 15 qualifying studies.
- Response to mycophenolate mofetil (MMF) with 34 patients was 36% (according to abstract) at 6 months (discrepancy in article –results state 38% response)
- Response to cyclosporine with 15 patients was 83% (discrepancy in article –results state 86% response)
- Response to tacrolimus with 4 patients was 50%
- Adverse effects were very common, particularly with cyclosporine (64% noted at least 1 adverse effect)
The article has an associated editorial (N Kerkar, pg 2-3). “The adverse event profile of cyclosporine with gingival hyperplasia, hypertrichosis, nephrotoxicity, and neurotoxicity made it challenging for long-term use in children.” Besides the small number of patients, “the studies that were included were largely “observational”‘ which limits their findings as well. The study authors recommend MMF as the preferred option for 2nd-line therapy.
My take: Fortunately, most patients with autoimmune hepatitis respond to first line therapy with azathioprine/steroids. It is unclear what is the optimal 2nd-line treatment for refractory patients.
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Between Journals and online resources, textbooks are increasingly less useful. Case in point -this past month, Clinical Gastroenterology and Hepatology published a special issue: The Art and Science of Managing Liver Disease. Some of the articles are excellent reviews.
With autoimmune hepatitis (AIH), the authors make a number of useful points and concisely summarized diagnosis and management. A few points:
- Anti-soluble liver antigen/liver-pancreas (SLA/LP) and Asialoglycoprotein receptor (ASGPR) useful in diagnosis of AIH type 1 or 2 and is prognostic for severe disease.
- In U.S. current guidelines suggest an azathioprine dose of 50 mg (for adults) whereas in Europe the dose is typically 1-2 mg/kg/day. The authors suggest that the U.S. guidelines could lead to undertreatment, particularly with increasing rates of obesity.
- The authors state that routine “testing for TPMT deficiency before AZA treatment of AIH is unnecessary, because severe TPMT deficiency occurs in 0.3%-0.5% of the general population and does not invariably cause AZA-induced bone marrow toxicity.” [I will probably continue to check TPMT activity.] They do recommend TPMT testing in cirrhotic patients and those with cytopenias.
- The authors note that successful long-term withdrawal can occur in 19-40% but recommend biochemical remission (>12-24 months) and histologic remission. They caution against withdrawal in patients after a relapse due to increased risks of progression to cirrhosis and/or death.
- When discussing alternative therapies, the authors note that mycophenolate mofetil (MMF) is typically effective for patients intolerant to AZA but not likely to work in AZA nonresponders.
- Alternative agents reviewed included tacrolimus, cyclosporine, sirolimus/everolimus, rituximab, and infliximab.
Other topics in this issue included NAFLD, HCC, Varices, Hepatic encephalpathy, HBV, HCV, Acute-on-Chronic Liver Failure, PSC and Malignancy, DILI, and noninvasive imaging for liver fibrosis.
Notes from NASPGHAN’s postgraduate course:
Refractory Autoimmune Hepatitis (AIH): — Vicky Ng
Dr. Ng’s talk started with an overview of AIH and referred to AASLD guidelines: Diagnosis and Management of Autoimmune Hepatitis – AASLD
Recommendations included the following:
- Cholangiography for all new cases of AIH
- Starting azathioprine after seeing some improvement in transaminases with steroids
- Monitoring for HCC
- Monitor bone density/bone protection strategies discussed
- Long term Rx needed in majority, though small number may be able to come off therapy if doing well for 2 years and normal liver biopsy
- This is applicable in 15-20% of patients
- Reasons for refractory disease: non response, drug intolerance, non-compliance, overlap syndrome, comorbidities
- If treatment failure, options could include increasing steroids and azathioprine. If concerns for decompensation, refer for liver transplant evaluation.
- NO standard Rx for refractory, but consider MMF (mycophenolate mofetil), cyclosporin (CYA), or tacrolimus (FK)
- MMF most promising agent for refractory disease. Small studies of MMF in adults/pediatrics indicates response in about 2/3rds of patients; best for those intolerant to azathioprine & helpful in dropping steroid dosing. In pediatrics, a starting dose of 20 mg/kg/day is typical and increasing up to 40 mg/kg/day. Pediatric study: 18/26 (69%) with response and 14/18 with normal AST w/in 2 months.
- Tacrolimus –small study showed about ~90% response. Dose was 0.1 mg/kg/day & target trough was 3 ng/mL
- Briefly discussed budesonide. More data in pediatrics needed.
Postgraduate Course Syllabus (posted with permission): PG Syllabus
Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) and specific medical management interventions should be confirmed by prescribing physician. Application of the information in a particular situation remains the professional responsibility of the practitioner.