Methods

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Participants

Patients in our open-label trial of low-dose oral pulse methotrexate who had biopsy-proven granulomatous hepatitis had either 1) had complications of glucocorticoid therapy [three patients]; 2) failed to respond to glucocorticoid therapy (persistent fever and symptoms when receiving high doses of glucocorticoids) or required continuous daily high-dose therapy [three patients]; or 3) refused glucocorticoid therapy (one patient). These patients had received previous ineffective treatments, including antituberculous therapy (four patients), indomethacin (two patients), and colchicine (one patient). Other causes of hepatic granulomas were excluded on the basis of history, serologic test results, cultures of liver and other organ biopsy specimens, imaging studies, and, in some, exploratory laparotomy. Patients were excluded if they had leukopenia (< 2.5 x 10⁹/L), thrombocytopenia (< 70 x 10⁹/L), creatinine level of 176.8 µmol/L or more or active alcoholism or if they were pregnant. The study was approved by the Human Investigation Review Committee of the Tufts-New England Medical Center.

Treatment Regimen

Methotrexate was administered as weekly oral pulse therapy in three doses of 5 mg over 24 hours (total dose, 15 mg/wk). Initially, three patients received lower weekly doses of methotrexate (5 to 12.5 mg/wk), which were increased to 15 mg/wk when symptoms were not completely controlled. One patient weighing 86 kg required a dose of 20 mg/wk to achieve a therapeutic range ( 0.2 mg/kg per week). Prednisone was tapered once fever and symptoms subsided.

Patients were seen after 2 weeks of therapy and then every 1 to 3 months, at which times weight, temperature, a complete blood count, creatinine level, and biochemical tests of hepatic function were obtained. Because of possible toxic side effects, patients were warned to report symptoms of cough or shortness of breath promptly, to practice contraception, and to not drink alcohol. Liver biopsy specimens were obtained before methotrexate was started and annually while patients were receiving methotrexate.

Results

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Seven patients (five men and two women), ranging in age from 31 to 70 years, participated in the study. Granulomatous hepatitis had been present for 1.5 to 25 years (mean, 9.4 years). All patients had documented recurrent fevers. Common associated symptoms included fatigue or malaise (four patients), weight loss or anorexia (four patients), and abdominal pain (two patients). Hepatomegaly was detected in three patients, and three patients had had a splenectomy. Patients whose biopsy specimens were taken from other tissues had granuloma detected in bone marrow (four of five patients), in spleen (two of five patients), and in lymph nodes (one of five patients). At entry, all but one patient had abnormal results of biochemical tests of liver function despite prednisone therapy. Six patients had increased serum aminotransferase levels, and four patients had increased serum alkaline phosphatase levels. One patient had jaundice.

The methotrexate dose ranged from 0.097 to 0.285 mg/kg body weight per week. All patients with fever at entry became afebrile within 3 months of starting methotrexate, and all but one became afebrile within 1 month. Prednisone therapy was tapered and discontinued within 6 months (mean, 4.5 months) in the four patients who were receiving prednisone when methotrexate was started. Fatigue and anorexia were ameliorated in all patients and resolved in all but one patient. All patients who had had anorexia or weight loss before methotrexate therapy gained weight during the first 6 months of methotrexate therapy. In general, increases in liver enzyme levels were less than three times the control values before methotrexate administration, and paired Student t-tests did not show a significant change with methotrexate therapy. However, the only patient who had jaundice at entry showed the most striking improvement in biochemical test results, with all variables returning to normal. Methotrexate was well tolerated in all but two patients, who had nausea and anorexia on the day of methotrexate administration. No bone marrow suppression, opportunistic infection, or interstitial pneumonitis was noted.

Liver biopsy specimens were obtained from all patients before methotrexate treatment; examination of the specimens showed multiple noncaseating granulomas in portal and lobular regions. Three patients had fibrosis before methotrexate therapy. After methotrexate therapy, liver biopsy specimens were obtained again from four patients (patients 1 to 4); assessment of these specimens showed no granulomas. Three patients (patients 2 to 4) had stable or decreased fibrosis and inflammation (Figure 1). A liver biopsy specimen was obtained from one patient (patient 1) 3 years after the discontinuation of methotrexate therapy; examination of the specimen showed chronic hepatitis with bridging fibrosis.

View larger version (178K): [in this window] [in a new window]   Figure 1. Liver biopsy specimen from patient 3 before and after methotrexate therapy. Top. Biopsy specimen before methotrexate therapy. Multiple, noncaseating granulomas are shown. (Hematoxylin and eosin; original magnification, x 175.) Bottom. Biopsy specimen after 1 year of methotrexate therapy. No granuloma, fibrosis, or increase in inflammation is present. (Hematoxylin and eosin; original magnification, x 175.).

The mean duration of methotrexate treatment has been 1.3 years (range, 5 months to 2.8 years). Four patients continue to receive methotrexate, whereas methotrexate therapy was successfully tapered and discontinued in three other patients (patients 1, 2, and 7). Patients 2 and 7 remain free of symptoms 1 year after receiving methotrexate.

Discussion

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In our study of seven patients with idiopathic granulomatous hepatitis, low-dose oral pulse methotrexate was effective in resolving fever, fatigue, and weight loss associated with the disease. All patients became afebrile within 3 months of starting methotrexate, and five of seven patients became afebrile within 1 month. Prednisone therapy was successfully discontinued in all patients within 6 months. Liver biopsy specimens taken before and after methotrexate therapy showed the disappearance of hepatic granulomas in the four patients who had a repeat liver biopsy after treatment. In three patients, methotrexate therapy was successfully tapered without the reappearance of hepatic granulomas. The lowest effective dose of methotrexate was 15 mg/wk or 0.20 mg/kg body weight per week Table 1, which is similar to methotrexate doses that we previously used in patients with primary biliary cirrhosis and primary sclerosing cholangitis [3, 4].

Other immunosuppressive agents used in the treatment of idiopathic granulomatous hepatitis include cyclophosphamide, vinblastine, and chlorambucil [5, 6]. However, these other agents have more toxic side effects than methotrexate [7-9]. Methotrexate has been previously used by others to treat a patient with granulomatous hepatitis [6]. It has been associated with such adverse effects as cirrhosis, bone marrow suppression, interstitial pneumonitis, and mucosal ulceration [10]. The only adverse effect we observed was mild nausea on the day of administration in two patients. Transient two- to sixfold increases in aminotransferase levels were noted, but levels returned to normal within 6 months of the start of methotrexate therapy.

Four of our seven patients with idiopathic granulomatous hepatitis had noncaseating granulomas in extrahepatic sites. Granulomas in bone marrow, muscle, and lymph nodes have been noted in other series [11, 12]. Our patients did not meet the criteria for sarcoidosis because of the absence of pulmonary involvement or the absence of typical extrapulmonary manifestations, such as arthropathy, uveitis or rash, or hypercalcemia. The causes of sarcoidosis and granulomatous hepatitis are unknown, and some investigators consider any extrahepatic, idiopathic granulomatous process to be sarcoidosis [6, 13, 14]. However, we and others [1, 5] believe that idiopathic granulomatous hepatitis is a separate disease with a specific clinical presentation that is distinct from sarcoidosis. Methotrexate has also been used in the treatment of skin lesions of sarcoidosis and in refractory sarcoidosis, in which it improved pulmonary function and reduced extrapulmonary manifestations of disease [15].

The action of methotrexate in inflammatory diseases is not well understood, but it does not appear to act solely by inhibiting dihydrofolic acid reductase. Kobayashi and colleagues [16] showed high levels of interleukin-1 in experimental granulomas in mice. Methotrexate may inhibit lymphocyte proliferation induced by interleukin-1 ß [17]. Administration of interleukin-1 induces fever, and blockade of interleukin-1-binding sites decreases inflammation without immunosuppression [18]. Thus, methotrexate may act as a specific anti-inflammatory drug rather than as an immunosuppressant.

Patients with possible idiopathic granulomatous hepatitis should receive a trial of antituberculous therapy if they have a positive skin-test result for tuberculosis or unexplained anergy because tuberculosis remains a prominent cause of hepatic granulomas. If symptoms of idiopathic granulomatous hepatitis continue, prednisone should be used as first-line therapy, and isoniazid should be added if the patient has a positive skin-test result for tuberculosis. Treatment with oral pulse methotrexate should be considered in patients with idiopathic granulomatous hepatitis if the glucocorticoid dose required for suppression of fever is high, if the patient cannot be successfully tapered to an alternate-day dose of glucocorticoid, or if symptoms of disease are refractory to glucocorticoid therapy. We recommend beginning with oral methotrexate at a dose of 15 mg/wk. In cases of persisting symptoms, we have increased the dose of methotrexate to at least 0.20 mg/kg per week. We obtain another liver biopsy specimen at 1 year to document resolution of hepatic granulomas and absence of hepatic toxicity from methotrexate. We then try to gradually reduce the methotrexate dose and discontinue treatment over several months.

In our study, seven patients with idiopathic granulomatous hepatitis (including six patients who required high doses of glucocorticoids) had a positive response to open-label, low-dose oral pulse methotrexate, suggesting that methotrexate may be an effective glucocorticoid-sparing agent for this disease and may be effective in patients who are refractory to glucocorticoid therapy. Although patients receiving methotrexate treatment were free of toxicity, long-term follow-up in additional patients is needed to assess the efficacy and safety of methotrexate in idiopathic granulomatous hepatitis.