Successful Treatment of Autoimmune Hepatitis With Methotrexate

Abstract

Autoimmune hepatitis (AIH) is a chronic progressive condition of unknown etiology characterized by interface hepatitis, abnormal levels of serum globulins, and autoantibodies (1). AIH is a relatively common condition in the United States affecting 11% to 23% of patients with chronic liver disease (2). In children, AIH can have an aggressive course leading to cirrhosis and liver failure. Fortunately, AIH is usually responsive to immunosuppressive therapy with biochemical response expected in a minimum of 80% of patients and even higher response rates reported by Gregorio et al (3,4). Traditionally, steroids are the established therapy to induce remission in AIH; however, long-term use of steroids is limited by significant adverse effects including linear growth failure and osteoporosis. As a result, additional immunosuppressants or steroid-sparing agents (SSA) have been used to limit a patient's exposure to steroids. The most frequently used medication is 6-mercaptopurine (6-MP) or its derivative azathioprine (AZA). Although the majority of patients with respond to the above regimen of induction with steroids and 6-MP/AZA as maintenance therapy (5), there are few data on management of 6-MP/AZA therapeutic failures. Specifically, only a few reports have been published evaluating the efficacy of other immunomodulatory agents for those patients who fail 6-MP/AZA maintenance therapy. Other immunomodulating agents reported include cyclosporine (CSA), mycophenolate mofetil (MMF), and tacrolimus (3); however, to date there are no reports identifying the successful treatment of AIH in the pediatric population with methotrexate (MTX). Accordingly, we report 2 steroid-dependent pediatric patients with AIH, who had sustained remission on MTX. CLINICAL REPORTS Patient 1 is a 7-year-old girl who presented with jaundice, fatigue, and low-grade fever. Her medical history was significant for pauciarticular juvenile rheumatoid arthritis. On presentation, physical examination revealed an icteric girl with mildly enlarged liver but no splenomegaly, ascites, or peripheral edema. Laboratory investigations demonstrated an alanine aminotransferase (ALT) of 4390 U/L (normal <40), a γ-glutamyltransferase of 146 U/L, with a total protein of 8.3 (normal <80), an albumin of 3.9 g/dL (normal >3.5), a globulin of 4.4 g/dL (normal 2.3–3.5 g/dL), and an albumin/globulin ratio of 0.9. The international normalized ratio (INR) was 0.9, and the total bilirubin was 5.1 mg/dL (normal <1) with a direct fraction of 3.2 mg/dL. Viral hepatitis serologies, iron study, serum ceruloplasmin, urine copper, and α-1-antitrypsin were negative. She was diagnosed as having AIH type 1 based on positive serological markers including an anti-nuclear antibody titer of 1/1280 (normal <20), and an anti-smooth muscle antibody titer of 1/80 (normal <20). Liver biopsy was performed and demonstrated grade 2 inflammation with characteristic interface hepatitis and a mononuclear lobular infiltration, as well as stage 1 fibrosis. There was no evidence of bile duct damage to suggest an overlap syndrome of primary sclerosing cholangitis and autoimmune hepatitis. She was given prednisone 40 mg/day (2 mg · kg−1 · day−1) and AZA 25 mg/day (1.2 mg · kg−1 · day−1); however, due to persistently elevated transaminases her prednisone dose was increased to 60 mg/day (3 mg · kg−1 · day−1) and her AZA was gradually increased to 75 mg/day (2.9 mg · kg−1 · day−1). Despite these changes and documented high 6-methylmercaptopurine levels, her 6-thioguanine nucleotide levels remained <100 pmol/8 × 108 red blood cells (RBCs). In addition, multiple attempts were made to wean her steroids as the ALT approached normal (between 44 and 67 U/L), but these were unsuccessful due to recurrent flares as evidenced by increasing transaminases. Subsequently, the patient developed several steroid-induced adverse effects including arrest of linear growth, decreased bone density (BMD) with a z score of −2.6, and cushingoid appearance. Accordingly, due to the inability to wean the patient's steroids and increasing steroid adverse effects, her steroid-sparing therapy was revised. AZA was stopped, and once per week subcutaneous 10 mg/m2 MTX was given 9 months after initial diagnosis. After 6 weeks of MTX, the patient maintained normal ALT and AST levels and, within 12 months, was able to be weaned completely off steroids with improved linear growth and normalized BMD. One year after initiation of MTX therapy, liver biopsy showed improved inflammation to grade 1 without progression of fibrosis. Repeated liver biopsies at 2 and 5 years after initiating MTX treatment demonstrated resolution of inflammation and fibrosis. Furthermore, aside from mild nausea following MTX injections, the patient denies any adverse effects of the medication and has remained off steroids for the past 7 years. Patient 2 is an 11-year-old girl who presented with jaundice, fatigue, and sore throat. Her medical history was negative for any hospitalization, surgeries, or chronic medical illnesses. Physical examination demonstrated a mildly icteric preadolescent girl without hepatosplenomegaly, ascites, or stigmata of chronic liver disease. Laboratory investigations demonstrated an ALT of 821 U/L, γ-glutamyltransferase of 192 U/L, and total protein of 8.7 with an albumin of 3.7 g/dL, globulin of 5 g/dL, and an albumin-to-globulin ratio of 0.8. Her INR was 1.2, with a total bilirubin of 3.4 mg/dL with a direct fraction of 1.1 mg/dL. Viral hepatitis serologies, iron study, ceruloplasmin, and α-1-antitrypsin were negative. She was diagnosed as having AIH type 1 based on an anti-smooth muscle antibodies titer of 1:132 (normal <20). Liver biopsy was performed and showed grade 3 inflammation characterized by interface hepatitis with mixed mononuclear lobular infiltrate and stage 3 fibrosis. There was no evidence of bile duct damage to suggest an overlap syndrome of primary sclerosing cholangitis and autoimmune hepatitis. She was subsequently given prednisone 60 mg/day (1 mg · kg−1 · day−1) and AZA 125 mg/day (2.1 mg · kg−1 · day−1). However, despite high 6-methylmercaptopurine levels, her 6-thioguanine nucleotide levels remained <120 pmol/8 × 108 RBCs. In addition, multiple attempts were made to wean her steroids as the ALT normalized, but were unsuccessful resulting in frequent flares as evidenced by an increase in transaminases. The patient also had significant adverse effects from chronic steroids including arrest of linear growth and decreased BMD with a z score of −2.1. One year after initial diagnosis, AZA was replaced by subcutaneous 10 mg/m2 MTX. Within 4 months of therapy, her transaminases decreased to twice the normal values and normalized after 10 months. Twelve months after initiation of MTX, her prednisone was tapered to 2.5 mg once per day and stopped after 14 months of MTX treatment. Follow-up bone densitometry after 8 months of MTX showed improvement of BMD z score to −1.66 and normalized after 2 years. Liver biopsy performed 1 year after initiation of MTX demonstrated improvement in the degree of inflammation to grade 2 and fibrosis to stage 2. Repeated liver biopsies at 2 and 5 years showed more improvement to grade 1 inflammation and stage 2 fibrosis. The patient denies any adverse effects of the medication and has not required any additional steroid boluses. DISCUSSION The majority of patients with AIH respond well to the standard immunosuppressive therapy of steroid induction with maintenance therapy of 6-MP/AZA. For patients who fail standard therapy, alternative therapeutic options are needed because insufficient suppression of inflammatory activity may lead to development of liver cirrhosis or chronic steroid. MTX is a structural analog of folic acid (6). MTX irreversibly binds dihydrofolate reductase resulting in the inhibition of DNA, RNA, thymidylate, and protein synthesis. MTX has also been shown to have a number of anti-inflammatory effects, including modulation of cytokine production important in the development and propagation of inflammation. Subsequently, given its targeted inhibition of lymphocytes, immunomodulatory roles, and anti-inflammatory effect, MTX has been extensively used in the treatment of a number of autoimmune diseases, including rheumatoid arthritis (7), psoriasis (8), and inflammatory bowel disease (9). Given its action as an antimetabolite, MTX was first used as a chemotherapeutic agent more than 50 years ago. Consequently, it has an extensive and well-described track record. Comparing MTX with other disease-modifying antirheumatic drugs, MTX has a relatively good safety profile with typical toxicities, including anemia, neutropenia, stomatitis, and oral ulcers, which can frequently be prevented or alleviated by folate supplementation. Despite these relatively minor adverse effects, there are reports of hepatic fibrosis, pulmonary fibrosis, and renal insufficiency developing in association with the long-term use of MTX (10). Long-term low-dose MTX is the most widely used traditional disease-modifying antirheumatic drug agent for rheumatoid arthritis, psoriatic arthritis, and skin psoriasis. Although hepatic fibrosis after long-term exposure has been documented, the actual epidemiological data demonstrate a low frequency. Specifically, a systematic literature search on MTX monotherapy for juvenile rheumatoid arthritis demonstrated a favorable long-term safety profile with an incidence of fibrosis of 2.7% after 4 years of MTX exposure (11). The prevalence of elevated liver enzymes (greater than twice the upper limit of normal) occurred in 13% of patients (11). More recently, a prospective study (12) of 54 patients with psoriatic disease had a liver biopsy according to dermatology guidelines on long-term MTX treatment with full assessment of risk factors with a mean duration of 6.9 years, and a mean cumulative dose of 4396 mg. Results demonstrated no cases of advanced fibrosis or cirrhosis with only mild fibrosis occurring in 11 (22%) patients (12). The presence of early mild changes was related to a number of risk factors including pretreatment hepatic abnormalities, diabetes, obesity, and current and/or previous heavy alcohol use. Review of the literature identified only 2 adult cases of MTX used for maintenance of remission in AIH. Burak et al (13) treated a 52-year-old woman with refractory AIH type 1, who presented with jaundice, marked elevation in liver enzymes, positive anti-nuclear antibodies, and a liver biopsy consistent with autoimmune hepatitis. Liver enzymes did not normalize with prednisone alone. When AZA was added, the disease flared. Subsequently, weekly low-dose (7.5 mg) oral MTX resulted in normalization of liver enzymes and improved liver histology with maintenance of remission. Repeat liver biopsy after 2 years of MTX demonstrated only mild inflammation without increase in the overall degree of fibrosis (13). Venkataramani et al (14) reported a 59-year-old man with chronic auto-antibody–negative AIH with multiple relapses on steroid therapy and a confirmed allergic response to AZA. Consequently, he was given prednisone (40 mg daily) and MTX (15 mg once weekly). Four months after initiation of treatment his transaminases normalized. Repeat liver biopsy 7 months after initiation of MTX therapy showed minimally active hepatitis with no progression of fibrosis (14). In our series, both patients were given prednisone and AZA with initial response but developed significant exacerbations when attempts to wean the steroids were made. In addition, our patients developed significant adverse effects necessitating an alternative treatment regimen. There is no established second-line therapy for patients with AIH failing standard therapy. Several alternative drugs have been used in patients with AIH including CSA, tacrolimus, and MMF. However, each of these treatment regimens is not without risks. For instance, major drawbacks of CSA are its potential adverse effects (eg, renal insufficiency, hypertension) (15). In another study (16), 36 adult patients who failed standard therapy were treated with MMF; only 14 patients (39%) experienced remission, with >30% developing significant gastrointestinal adverse effects. Tacrolimus has also been used in an open-label trial in 21 patients with AIH. Although results of the trial demonstrated significant improvement in liver enzymes, numerous patients demonstrated significant renal impairment associated with the medication (17). Subsequently, the decision to use MTX in our patients was made based on the favorable known long-term safety profile of MTX, as well as the potential negative adverse effects of other newer immunosuppressive medications. This decision, however, is not perfect considering that 1 of the known adverse effects of MTX is an increase in liver transaminases as well as the concerns of developing liver fibrosis with long-term use of MTX. Consequently, because of these concerns, our policy was to perform periodic liver biopsies. In both of our patients, these biopsies demonstrated histological improvement with regard to inflammatory activity without evidence of progression in fibrosis even after 5 years of MTX therapy. CONCLUSIONS MTX can be used as a second-line therapy in pediatric patients with AIH type I with whom traditional therapy with steroids and AZA/6-MP has failed or if the patient was to become intolerant to this regimen. Recent data on the risk of liver fibrosis/cirrhosis with the use of relatively low-dose long-term MTX therapy, in both the dermatology and rheumatology literature, demonstrated a favorable safety profile. A multicenter prospective double-blind study is needed to more accurately assess the long-term safety for the use of MTX in patients with autoimmune hepatitis.