Methotrexate in Crohn's disease: results of a randomized, double-blind, placebo-controlled trial.

BACKGROUND/AIMS: Immunosuppression with methotrexate may be useful in the treatment of Crohn's disease. We tested the efficacy of methotrexate in refractory Crohn's disease in a randomized, controlled trial. METHODOLOGY: Randomized, double-blind placebo-controlled trial of methotrexate in 33 patients with steroid-dependent Crohn's disease, 33% of whom had previously failed therapy with 6-mercaptopurine. Patients were given placebo or oral methotrexate 15 mg/week, or adjusted up to 22.5 mg/week, for up to 1 year or until treatment failure. Outcome was assessed by reduction in prednisone dosage, Crohn's Disease Activity Index, hospital admission, and laboratory parameters. RESULTS: Four patients were dropped from the study for non-compliance and one because of intercurrent illness, and 28 patients could be evaluated. Fewer methotrexate-treated patients (6/13 or 46%) had flares of Crohn's disease as compared to placebo-treated patients (12/15 or 80%), but this did not achieve statistical significance (p<0.1). There was a non-significant trend toward an increased number of significant side effects in the methotrexate-treated patients (3/13 or 23%) as compared to the placebo-treated patients (0/15 or 0%) (p<0.2). Laboratory indices of inflammation did not differ between the two groups. CONCLUSIONS: The methotrexate-treated group showed a trend toward fewer Crohn's disease flares, balanced by an increased number of significant side effects.

Response to higher doses of interferon alfa-2b in patients with chronic hepatitis C: a randomized multicenter trial. Hepatitis Interventional Therapy Group.

To evaluate response rates to 3, 5, or 10 million units (MU) of interferon alfa-2b, given thrice weekly, and to determine whether higher doses of interferon increase the likelihood or durability of the response, a multicenter, randomized trial was performed at nine academic medical centers in the United States. Two hundred forty eight patients with chronic hepatitis C were randomized to receive 3, 5, or 10 MU of interferon alfa-2b thrice weekly for 12 weeks. Based on the alanine aminotransferase (ALT) response at treatment-week 12, the patients were rerandomized to additional therapy at the same or at increased doses for an additional 12 to 36 weeks; in the case of no response to the highest dose, the patients were discontinued from the study. Serum ALT concentrations and liver histology were measured. The overall complete response rates to 3, 5, or 10 MU were not different at treatment-week 12 (31% vs. 42% vs. 40%, not significant). The majority of week-12 responders continued to respond during additional treatment. When the treatment was discontinued, 15.4% to 19.0% of patients maintained their response. Of the nonresponders to 3 MU at week 12, who were continued on 3 MU for an additional 12 weeks, none responded. However, response to additional therapy occurred in 12% of week-12 nonresponders, whose dose was escalated from 3 or 5 MU to 10 MU. The only baseline features associated with the treatment response were the absence of fibrosis or cirrhosis on the pretreatment liver biopsy and viral genotype. We conclude that the initial response to interferon in patients with chronic hepatitis C is not increased by treatment with higher doses of the drug. Patients who do not respond to 3 MU by treatment-week 12 will not respond with continued therapy at that dose; however, a proportion of patients who do not respond to 12 weeks of treatment with 3 or 5 MU may respond to higher doses. Although the long-term sustained response rates are marginally increased with interferon doses above 3 MU three times per week, the side effects are difficult to tolerate. The analysis of baseline factors in relation to response identified no single baseline factor associated with a low-enough response rate to warrant withholding interferon therapy from patients with chronic hepatitis C.

Hepatitis vaccines.

The past two decades have seen a series of breakthroughs in the understanding, prevention, and treatment of viral hepatitis. Developed countries have an increasing number of adults who are susceptible to hepatitis A virus (HAV) infection. The licensing of an effective hepatitis A vaccine presents new opportunities for prevention in persons at risk for HAV infection. Hepatitis B virus infection is an important cause of chronic liver disease throughout the world. Although a hepatitis B vaccine has been available in the United States for 15 years, recommendations for its use have undergone changes. Report of the discovery of hepatitis C virus (HCV) in 1989 has led to marked decrease in the risk of transfusion-transmitted viral hepatitis. HCV infection, however, remains a common cause of chronic liver disease, and a hepatitis C vaccine is needed to prevent the consequences of the disease. Basic research into the hepatitis C viral genome has elucidated some of the obstacles in the way of hepatitis C vaccine development.

Hepatitis vaccines.

The 1980s represented a decade of breakthroughs for the development of hepatitis vaccines. Plasma-derived and then recombinant hepatitis B vaccines were developed and introduced, killed hepatitis A vaccine was developed, and the virologic tools were discovered with which to lay the groundwork for a vaccine against hepatitis C. Even as the focus of the 1990s shifts toward antiviral therapy of chronic viral hepatitis, we cannot afford to neglect the importance of prevention by vaccination. Better vaccines and improved vaccination strategies for preventing hepatitis A and B will continue to demand research investment, and the most meager toehold will have to be exploited and pursued aggressively if a practical, effective hepatitis C vaccine is to be developed.

Acute hepatitis associated with the Chinese herbal product jin bu huan.

OBJECTIVE: To describe the hepatotoxicity associated with ingestion of the Chinese herbal product Jin Bu Huan Anodyne Tablets (Lycopodium, serratum) and to propose possible mechanisms of injury. DESIGN: Retrospective analysis. SETTING: Academic hepatology units and private practice facilities. PATIENTS: Seven previously healthy patients. MEASUREMENTS: Clinical, laboratory, radiologic, and histologic studies. RESULTS: Acute hepatitis occurred after a mean of 20 weeks (range, 7 to 52 weeks) of Jin Bu Huan ingestion and resolved in six patients within a mean of 8 weeks (range, 2 to 30 weeks); another patient is currently improving. Hepatitis was associated with symptoms of fever, fatigue, nausea, pruritus, and abdominal pain and with signs of jaundice and hepatomegaly. Biopsy specimens showed that one patient had hepatitis with eosinophils (consistent with a drug reaction) and the other had mild hepatitis, moderate fibrosis, and microvesicular steatosis. Decreasing the Jin Bu Huan dose in one patient improved liver test results. Reusing Jin Bu Huan in two other patients caused abrupt recrudescence of hepatitis. CONCLUSION: Jin Bu Huan can cause liver injury. Although the hepatotoxic mechanisms are not defined, they may include hypersensitive or idiosyncratic reactions or direct toxicity to active metabolites. Hepatotoxicity caused by herbal products underscores the toxicity caused by herbal products underscores the importance of national surveillance programs and quality control of the manufacture of these products.

Immunogenicity of a 'pre-S2 plus S' hepatitis B vaccine in healthy adults.

The product of the pre-S plus S gene of hepatitis B virus appears to be more immunogenic in mice than the S-gene product (HBsAg) alone. Therefore, we tested the immunogenicity in healthy adults of a hepatitis B vaccine containing the 'middle protein' gene product of pre-S2 plus S (pre-S vaccine). We compared the immunogenicity of three doses of the pre-S vaccine with that of a commercially available recombinant hepatitis B vaccine (Recombivax-HB); 87 seronegative adults were randomized to receive 12 micrograms (group 1), 24 micrograms (group 2), or 48 micrograms (group 3) of the pre-S vaccine or 10 micrograms of Recombivax-HB (group 4) by deltoid injection at 0, 1 and 6 months. Antibody to HBsAg (anti-HBs) appeared after booster vaccination in > or = 94% of vaccinees. Immunogenicity was best in recipients of 48 micrograms of the pre-S vaccine and Recombivax-HB, and geometric mean titres (GMT) for the pre-S vaccine were higher than those for Recombivax-HB only at the pre-S vaccine dose of 48 micrograms (group 3). Antibody to pre-S2 developed in 75% of the pre-S2 vaccine recipients (not in Recombivax-HB recipients) within 7 months. These findings indicate that the pre-S vaccine is immunogenic in healthy adults but that a dose of 48 micrograms of the current formulation is required to equal or exceed the immunogenicity of currently available, recombinant S-only vaccine. Studies in non-responders to S-only vaccines will be necessary to define an immunological advantage of the pre-S vaccines, and additional assessments will be necessary to determine whether anti-pre-S2 enhances protective efficacy.

Role of hepatitis C virus in non-B chronic liver disease.

To assess the contribution of the recently identified hepatitis C virus to chronic liver diseases of unknown cause and chronic hepatitis attributed by exclusion to non-A, non-B hepatitis, we tested for antibody to hepatitis C in hepatitis B surface antigen-negative patients with a spectrum of chronic liver diseases. Antibody to hepatitis C virus, a marker of hepatitis C infection, was detected with a first-generation radioimmunoassay at the following frequencies in the following patient groups: 69% of transfusion-associated non-A, non-B hepatitis; 53% of non-transfusion-associated non-A, non-B hepatitis; 26% of hepatitis B surface antigen-negative hepatocellular carcinoma; 8% of cryptogenic cirrhosis; 5% to 7% of autoimmune chronic liver diseases; 19% of patients with miscellaneous types of chronic liver disease; and 0.67% of healthy controls. Among non-transfusion-associated cases, 81% with a history of intravenous drug use but only 18% with occupational exposure as health workers had antibody to hepatitis C virus. Among cases of hepatocellular carcinoma, 63% of Japanese patients but only 11% of American patients had evidence of hepatitis C infection. Comparison in a subgroup of 79 serum samples of a second-generation radioimmunoassay with the first-generation assay demonstrated a 12% increase in antibody frequency from 30% to 42%. We conclude that hepatitis C plays a substantial role in transfusion-associated and non-transfusion-associated non-A, non-B hepatitis as well as in hepatocellular carcinoma, especially in Japan, a limited role in cryptogenic cirrhosis, and essentially no role in autoimmune chronic liver diseases. Application of more sensitive immunoassays will increase the frequency of antibody seropositivity in all subgroups, but relative distinctions among risk groups are likely to remain.

Absence of hepatitis B surface antigenemia after vaccination.

Vaccination against hepatitis B is readily available and provides safe and effective immunization for individuals at increased risk for this disease. However, since the available vaccines employ a protein consisting of hepatitis B surface antigen, the question has arisen whether a detectable surface antigenemia might occur in recently vaccinated individuals. Employing two current immunoassays for hepatitis B surface antigen, we could not detect this marker in individuals either 1 hour or 24 hours after vaccination. We therefore conclude that the presence of surface antigen in the blood cannot be attributed to recent vaccination.

Sulindac and indomethacin suppress the diuretic action of furosemide in patients with cirrhosis and ascites: evidence that sulindac affects renal prostaglandins.

Nonsteroidal anti-inflammatory drugs (NSAID) suppress prostaglandin-dependent renal blood flow and furosemide-induced diuresis in patients with cirrhosis and ascites. Since sulindac may selectively spare inhibition of renal prostaglandins, we evaluated the interactions of acute administration of sulindac or indomethacin with furosemide in 15 patients with cirrhosis and ascites. Prior to furosemide, indomethacin reduced creatinine clearance (by 55%), urinary volume (by 82%), sodium (by 93%), and prostaglandin E2 (by 87%) (all P less than 0.05), whereas sulindac had no effect. However, both drugs reduced furosemide-induced diuresis. Indomethacin appeared slightly more potent in reducing the diuresis (55% v 38%), natriuresis (67% v 52%), and prostaglandin E2 (PGE2) release (81% v 74%). In a similar protocol in healthy subjects, furosemide-induced diuresis and natriuresis were also blunted by both drugs. Thus, under conditions of enhanced prostaglandin activity from furosemide, sulindac does affect renal function. These data suggest that renal function should be monitored in patients with cirrhosis and ascites who receive sulindac as well as other NSAID.