A prospective trial of colchicine and methotrexate in the treatment of primary biliary cirrhosis.

BACKGROUND & AIMS: The aim of this study was to determine if colchicine or methotrexate improves blood test results, symptoms, and/or liver histology in patients with primary biliary cirrhosis. METHODS: Patients with histologically confirmed primary biliary cirrhosis whose serum alkaline phosphatase (ALP) levels were at least 2 times above normal and who were not yet candidates for liver transplantation received colchicine or methotrexate and were followed up for 2 years. RESULTS: In patients receiving colchicine (n = 43), mean pruritus score decreased from 1.63 to 1.12 (P = 0.04), ALP level from 494 to 355 U/L (P < 0.0001), and alanine aminotransferase (ALT) level from 79 to 61 U/L (P < 0.0001). In patients receiving methotrexate (n = 42), pruritus score decreased from 1.25 to 0.44 (P = 0.0001), ALP from 478 to 235 U/L (P < 0.0001), and ALT from 96 to 61 U/L (P = 0.0001). Methotrexate but not colchicine significantly improved liver histology (P = 0.005) and serum immunoglobulin G levels (P = 0.0002). Methotrexate improved most blood test results more than colchicine. Serum bilirubin levels increased slightly with each drug, and albumin levels decreased slightly. CONCLUSIONS: Both colchicine and methotrexate improved biochemical test results and symptoms in primary biliary cirrhosis, but the response to methotrexate was greater.

Synthesis of interleukin-1 beta in primary biliary cirrhosis: relationship to treatment with methotrexate or colchicine and disease progression.

Primary biliary cirrhosis (PBC) is a chronic, progressive, cholestatic liver disease. Interleukin-1 beta (IL-1 beta) may play a role in the pathogenesis of PBC by contributing to altered immune function and fibrosis. Colchicine or methotrexate has some beneficial effects in the treatment of PBC, and also affects interleukin-1 (IL-1). Therefore, we prospectively studied the synthesis of IL-1 beta by peripheral blood mononuclear cells (PBMC) from 42 patients with PBC entered into a randomized, double-blind, double-dummy controlled trial of colchicine and methotrexate. PBMC obtained at entry, 6, 12, 18, and 24 months were stimulated to produce IL-1 beta with phytohemagglutinin (PHA), lipopolysaccharide (LPS), Staphylococcus epidermidis, recombinant IL-2, or mitochondrial antigen. Patients in the two treatment groups did not differ at entry in biochemical measures or liver histological stage. Over 24 months in both groups, serum bilirubin and histologic stage remained stable and alkaline phosphatase decreased significantly. For all patients, synthesis of IL-1 beta increased constitutively and in response to immune-mediated stimulants (PHA, IL-2, and mitochondrial antigen) but not the bacterial stimulants LPS or S epidermidis. Compared with levels of IL-1 beta at entry, PHA induced increases for patients treated with methotrexate (12, 18, and 24 months) or colchicine (18 and 24 months). At 24 months, IL-2-induced IL-1 beta synthesis was increased in patients treated with methotrexate, whereas S epidermidis-induced IL-1 beta was enhanced in colchicine-treated patients. Before treatment, IL-1 beta production did not relate to severity of disease except in response to S epidermidis.(ABSTRACT TRUNCATED AT 250 WORDS)

Interstitial pneumonitis after low-dose methotrexate therapy in primary biliary cirrhosis.

Interstitial pneumonitis is an uncommon complication of low-dose methotrexate therapy in patients with psoriasis but occurs in 3%-5% of patients with rheumatoid arthritis. We found a higher incidence of interstitial pneumonitis in patients with primary biliary cirrhosis (14%) and describe its clinical manifestations, treatment, and possible etiology. Blood tests, arterial blood gas determinations, chest radiographs, bronchoscopy, tear production, autoantibody tests, and serum immunoglobulin levels were obtained in six women who developed interstitial pneumonitis while receiving methotrexate in a double-blind prospective trial of methotrexate vs. colchicine in 87 patients with primary biliary cirrhosis. Six of 43 patients (14%) who received methotrexate compared with no patients receiving colchicine developed interstitial pneumonitis 19-61 weeks after starting treatment. The pneumonitis was characterized by dyspnea, hypoxemia, and bilateral lung infiltrates, all of which responded within 24 hours to the administration of intravenous glucocorticoids. There was no correlation between the pneumonitis and pre-existing lung disease, the severity of the primary biliary cirrhosis, the titer of antimitochondrial antibody, or other diseases associated with primary biliary cirrhosis. Patients with primary biliary cirrhosis receiving low-dose methotrexate (15 mg/wk) are more susceptible to interstitial pneumonitis than patients with psoriasis or rheumatoid arthritis. The pneumonitis appears to be a hypersensitivity reaction and responds rapidly to intravenous glucocorticoid therapy.

Impact of a mandatory second-opinion program on medicaid surgery rates.

The effect of the Massachusetts second-opinion program on the volume of elective surgery in the Medicaid population was assessed using two approaches: a study of the program experience and surgery decisions of 2,501 program referrals, and an analysis of Medicaid surgery rates before and after program implementation. Nonconfirmation rates, which averaged 14.5 per cent, varied by procedure from 4 per cent for cholecystectomy to 26 per cent for disc surgery. The patient's surgery decision was related to the outcome of the second-opinion consultation: 85.5 per cent of the confirmed patients had the originally proposed operation, as compared with 31 per cent of the nonconfirmed patients. In the year after program implementation, the program was associated with a 20 per cent reduction in the volume of those procedures covered by the program. The greatest percentage declines were for hysterectomies, meniscectomies, hemorrhoidectomies and tonsillectomies/adenoidectomies. The decline in surgery rates was attributed both to a direct effect on patients referred to the program and to a sentinel effect whereby fewer operations were proposed. We conclude that the mandatory second-opinion program in Massachusetts saved Medicaid $3 to $4 for every dollar spent.