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Conway R, Carey JJ. Risk of liver disease in methotrexate treated patients. World J Hepatol 2017; 9:1092-1100. [PMID: 28989565 PMCID: PMC5612840 DOI: 10.4254/wjh.v9.i26.1092] [Citation(s) in RCA: 97] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Revised: 04/20/2017] [Accepted: 07/10/2017] [Indexed: 02/06/2023] Open
Abstract
Methotrexate is the first line drug treatment for a number of rheumatic and non-rheumatic diseases. It is effective in controlling disease activity and preventing disease-related damage, and significantly cheaper than many alternatives. Use in rheumatoid arthritis infers a significant morbidity and mortality benefit. Methotrexate is generally well tolerated but can cause symptomatic adverse events. Multiple serious adverse events have been attributed to methotrexate, based largely on older reports using high or daily doses, and subsequent case reports and circumstantial evidence. The risk with modern dosing regimens: Lower doses, weekly schedules, and concomitant folic acid is less clear. Clarification and dissemination of the actual risk is crucial so appropriate judgements can be made for patients who may benefit from this treatment. Methotrexate has been associated with a range of liver related adverse events ranging from asymptomatic transaminase elevations to fibrosis and fatal hepatic necrosis. Concern over potential liver toxicity has resulted in treatment avoidance, cessation, or recommendations for investigations which may be costly, invasive and unwarranted. Modern laboratory monitoring of liver blood tests may also influence the risk of more serious complications. The majority of present day studies report an approximate doubling of the relative risk of elevated transaminases in methotrexate treated patients but no increased risk of symptomatic or severe liver related adverse events. In this article we will review the evidence around methotrexate and liver related adverse events.
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Affiliation(s)
- Richard Conway
- Centre for Arthritis and Rheumatic Diseases, St. Vincent’s University Hospital, Dublin 4, Ireland
- CARD Newman Research Fellow, University College Dublin, Belfield, Dublin 4, Ireland
| | - John J Carey
- Department of Rheumatology, Galway University Hospitals, Merlin Park, Galway H91 YR71, Ireland
- Clinical Sciences Institute, National University of Ireland Galway, Galway H91 TK33, Ireland
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Paul S, Sepehr GJ, Weinstein B, Roper J. Co-occurrence of idiopathic granulomatous hepatitis and primary biliary cirrhosis. Dig Dis Sci 2014; 59:2831-5. [PMID: 25108519 DOI: 10.1007/s10620-014-3216-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2013] [Accepted: 05/12/2014] [Indexed: 01/30/2023]
Abstract
BACKGROUND PBC is an autoimmune disease affecting the bile ducts. Granulomas can be found in portal triads in 45 % of patients with PBC. Idiopathic granulomatous hepatitis is a rare disease of unknown cause which is characterized by recurrent fevers, sweats, elevated levels of liver enzyme tests, particularly the serum alkaline phosphatase, and granulomas in the portal and lobular regions of the liver. Previous literature suggests that a diagnosis of idiopathic granulomatous hepatitis can be made only if PBC has been excluded. STUDY We reviewed instances in which PBC and idiopathic granulomatous hepatitis occurred in the same patient. RESULTS We report three patients in whom both diseases occurred: 1) A patient with PBC who was diagnosed 15 years later with idiopathic granulomatous hepatitis; 2) A patient with idiopathic granulomatous hepatitis who developed PBC 12 years later; and 3) A patient who had features of both idiopathic granulomatous hepatitis and PBC at the time of initial diagnosis. CONCLUSIONS Our experience with these patients suggests that idiopathic granulomatous hepatitis and PBC can occur in the same individual. Knowing this association is important, as clinical deterioration in a patient with either disease could suggest the presence of the other and should be treated accordingly.
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Affiliation(s)
- Sonali Paul
- Division of Gastroenterology and Hepatology, Tufts Medical Center, 800 Washington Street, Box #233, Boston, MA, 02111, USA,
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Analysis of the clinical relevance of antimitochondrial antibodies to the β- and γ-subunits of the F1F0-ATPase in patients with primary biliary cirrhosis. BMC Gastroenterol 2012; 12:152. [PMID: 23095491 PMCID: PMC3523002 DOI: 10.1186/1471-230x-12-152] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2012] [Accepted: 09/21/2012] [Indexed: 01/12/2023] Open
Abstract
Background In a recent study we showed that in patients with primary biliary cirrhosis (PBC) being positive or negative for anti-M2 antibodies reacting with the 2-oxoacid-dehydrogenase complex (ODC) also antibodies to the beta- and gamma-subunits of F1F0-ATPase (anti-β, anti-γ) occur. This is a mitochondrial enzyme but parts are also expressed on plasma membranes of endothelial cells. Here we wanted to analyse in more detail their clinical relevance. Methods Fifty-nine untreated and histologically defined PBC patients who had been followed for at least five years were included into the study (51 anti-M2 positive, 8 anti-M2 negative). Twenty-three of them were treated in the follow up with ursodeoxycholic acid (UDCA), eight received during a trial methotrexate (MTX). In 13 patients orthotopic liver transplantation (OLT) had to be performed. Serum samples before and during therapy were available. Patients were analysed with respect to laboratory parameters, disease activity and histological stages. Patients’ sera were tested by ELISA for IgG- and IgM-antibodies against the beta- and gamma-subunits which had been recombinant expressed in E.coli and highly purified by electro-elution from SDS-gels after electrophoresis. Results Fifty-nine percent of the anti-M2 positive and 50% of the anti-M2 negative PBC patients had anti-β- and/or anti-γ-antibodies. There were no differences between anti-β- and/or anti-γ-antibody positive or negative patients with respect to biochemical parameters, immunoglobulins, histological stages or disease activity. Antibody reactivity significantly decreased during UDCA and MTX-treatment and also after OLT. Conclusions Antibodies to the β- and γ-subunits of F1F0-ATPase occur in anti-M2 positive and –negative PBC but do not have any relevance with respect to clinical activity or prognosis. However, in contrast to the anti-M2 antibodies they decrease during UDCA and immunosuppressive therapy.
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Kaplan MM, Bonder A, Ruthazer R, Bonis PAL. Methotrexate in patients with primary biliary cirrhosis who respond incompletely to treatment with ursodeoxycholic acid. Dig Dis Sci 2010; 55:3207-17. [PMID: 20559727 DOI: 10.1007/s10620-010-1291-5] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2010] [Accepted: 05/20/2010] [Indexed: 12/12/2022]
Abstract
BACKGROUND Approximately 35% of PBC patients have progressive disease despite treatment with UDCA. AIMS We offered treatment with methotrexate and colchicine to PBC patients who had not responded fully to UDCA, after at least 1 year of treatment. METHODS A total of 91 PBC patients failed to respond adequately to UDCA, defined as patients whose liver biopsies showed persistent interface hepatitis and whose serum alkaline phosphatase levels remained more than 50% above normal after at least 12 months on UDCA. We added colchicine (0.6 mg orally twice daily) for 6 months. If there was no decrease in alkaline phosphatase, methotrexate (0.25 mg/kg lean body weight orally per week) was added. Liver biopsies were performed at least three times: at diagnosis, after a patient had been on UDCA for at least 1 year (mean 3.4 years), and after a patient had been on methotrexate for at least 6 months (mean 2.2 years). A fourth liver biopsy was performed in 51 patients after they had been on methotrexate for at least another year (mean 3.5 years). RESULTS From the time that methotrexate was begun until the final visit, there were significant decreases in the mean levels of alkaline phosphatase, 323 to 151, ALT, 73 to 39, fibrosis, 2.5 to 2.0, and inflammation scores, 2.0 to 1.0, (p < 0.0001 for all). Based on pre-specified definitions, 73 patients (80%) responded to methotrexate while 18 (20%) did not. CONCLUSIONS In 91 PBC patients who responded incompletely to UDCA, colchicine and methotrexate significantly improved liver enzyme tests and liver histology.
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Affiliation(s)
- Marshall M Kaplan
- Division of Gastroenterology, Tufts Medical Center, 800 Washington Street, Boston, MA 02111, USA.
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Abstract
BACKGROUND Methotrexate has been used to treat patients with primary biliary cirrhosis as it possesses immunosuppressive properties. The previously prepared version of this review from 2005 showed that methotrexate seemed to significantly increase mortality in patients with primary biliary cirrhosis. Since that last review version, follow-up data of the included trials have been published. OBJECTIVES To assess the beneficial and harmful effects of methotrexate for patients with primary biliary cirrhosis. SEARCH STRATEGY Randomised clinical trials were identified by searching The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, and EMBASE (from their inception until September 2009). Reference lists were also read through. Authors of trials were contacted. SELECTION CRITERIA We searched to include randomised clinical trials comparing methotrexate with placebo, no intervention, or another drug irrespective of blinding, language, year of publication, or publication status. DATA COLLECTION AND ANALYSIS Our primary outcomes were mortality, and mortality or liver transplantation combined. Dichotomous outcomes were reported as relative risks (RR) and hazard ratios (HR) if applicable. Continuous outcomes were reported as mean differences (MD). MAIN RESULTS Five trials were included. Four trials with 370 patients compared methotrexate with placebo or no intervention (three trials added an equal dose of ursodeoxycholic acid to the intervention groups). The bias risk of these trials was high. We did not find statistically significant effects of methotrexate on mortality (RR 1.32, 95% CI 0.66 to 2.64), mortality or liver transplantation combined, pruritus, fatigue, liver complications, liver biochemistry, liver histology, or adverse events. The pruritus score (MD - 0.17, 95% CI - 0.25 to - 0.09) was significantly lower in patients receiving methotrexate. The prothrombin time was significantly worsened in patients receiving methotrexate (MD 1.60 s, 95% CI 1.18 to 2.02). One trial with 85 patients compared methotrexate with colchicine. The trial had low risk of bias. Methotrexate, when compared to colchicine, did not significantly effect mortality, fatigue, liver biopsy, or adverse events. Methotrexate significantly benefited pruritus score (MD - 0.68, 95% CI - 1.11 to - 0.25), serum alkaline phosphatases (MD - 0.41 U/l, 95% CI - 0.70 to - 0.12), and plasma immunoglobulin M (MD - 0.47 mg/dl, 95% CI - 0.74 to - 0.20) compared with colchicine. Other outcomes showed no statistical difference. AUTHORS' CONCLUSIONS Methotrexate had no statistically significant effect on mortality in patients with primary biliary cirrhosis nor the need for liver transplantation. Although methotrexate may benefit other outcomes (pruritus score, serum alkaline phosphatase, immunoglobulin M levels), there is no sufficient evidence to support methotrexate for patients with primary biliary cirrhosis.
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Affiliation(s)
- Vanja Giljaca
- Department of Gastroenterology, Clinical Hospital Centre Rijeka, Kresimirova 42, Rijeka, Croatia, 51000
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Combes B, Emerson SS, Flye NL, Munoz SJ, Luketic VA, Mayo MJ, McCashland TM, Zetterman RK, Peters MG, Di Bisceglie AM, Benner KG, Kowdley KV, Carithers RL, Rosoff L, Garcia-Tsao G, Boyer JL, Boyer TD, Martinez EJ, Bass NM, Lake JR, Barnes DS, Bonacini M, Lindsay KL, Mills AS, Markin RS, Rubin R, West AB, Wheeler DE, Contos MJ, Hofmann AF. Methotrexate (MTX) plus ursodeoxycholic acid (UDCA) in the treatment of primary biliary cirrhosis. Hepatology 2005; 42:1184-1193. [PMID: 16250039 DOI: 10.1002/hep.20897] [Citation(s) in RCA: 98] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
This placebo-controlled, randomized, multicenter trial compared the effects of MTX plus UDCA to UDCA alone on the course of primary biliary cirrhosis (PBC). Two hundred and sixty five AMA positive patients without ascites, variceal bleeding, or encephalopathy; a serum bilirubin less than 3 mg/dL; serum albumin 3 g/dL or greater, who had taken UDCA 15 mg/kg daily for at least 6 months, were stratified by Ludwig's histological staging and then randomized to MTX 15 mg/m2 body surface area (maximum dose 20 mg) once a week while continuing on UDCA. The median time from randomization to closure of the study was 7.6 years (range: 4.6-8.8 years). Treatment failure was defined as death without liver transplantation; transplantation; variceal bleeding; development of ascites, encephalopathy, or varices; a doubling of serum bilirubin to 2.5 mg/dL or greater; a fall in serum albumin to 2.5 g/dL or less; histological progression by at least two stages or to cirrhosis. Patients were continued on treatment despite failure of treatment, unless transplantation ensued, drug toxicity necessitated withdrawal, or the patient developed a cancer. There were no significant differences in these parameters nor to the time of development of treatment failures observed for patients taking UDCA plus MTX, or UDCA plus placebo. The trial was conducted with a stopping rule, and was stopped early by the National Institutes of Health at the advice of our Data Safety Monitoring Board for reasons of futility. In conclusion, methotrexate when added to UDCA for a median period of 7.6 years had no effect on the course of PBC treated with UDCA alone.
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Affiliation(s)
- Burton Combes
- The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9151, USA.
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Abstract
BACKGROUND Methotrexate, a folic acid antagonist with immunosuppressive properties, has been used to treat patients with primary biliary cirrhosis. The therapeutic responses to methotrexate in randomised clinical trials have been heterogeneous. OBJECTIVES To assess the beneficial and harmful effects of methotrexate for patients with primary biliary cirrhosis. SEARCH STRATEGY Relevant randomised clinical trials were identified by searching The Cochrane Hepato-Biliary Group Controlled Trials Register (June 2004), The Cochrane Central Register of Controlled Trials on The Cochrane Library (Issue 2, 2004), MEDLINE (January 1966 to August 2004), EMBASE (January 1980 to August 2004), and manual searches of bibliographies. We contacted authors of trials and pharmaceutical companies. SELECTION CRITERIA Randomised clinical trials comparing methotrexate with placebo, no intervention, or another drug were included irrespective of blinding, language, year of publication, and publication status. DATA COLLECTION AND ANALYSIS Our primary outcomes were mortality and mortality or liver transplantation. Dichotomous outcomes were reported as relative risk (RR) and hazard ratio (HR) if applicable. Continuous outcomes were reported as weighted mean difference (WMD). We examined intervention effects by using both a random-effects model and a fixed-effect model. Heterogeneity was investigated by subgroup analyses and sensitivity analyses. MAIN RESULTS We identified four trials (370 patients) that compared methotrexate with placebo with or without ursodeoxycholic acid as co-intervention. One additional trial (87 patients) compared methotrexate with colchicine without and later with ursodeoxycholic acid as co-intervention. The methodological quality of the trials was low. We did not find significant effects of methotrexate on pruritus, fatigue, liver complications, liver biochemistry, liver histology, or adverse events. The pruritus score (WMD - 0.68, 95% CI - 1.11 to - 0.25), the levels of serum alkaline phosphatases (WMD - 0.41, 95% CI - 0.70 to - 0.12) and plasma immunoglobulin M (WMD - 0.47, 95% CI - 0.74 to - 0.20) were significantly lower in the patients receiving methotrexate. AUTHORS' CONCLUSIONS Methotrexate increased mortality in patients with primary biliary cirrhosis. We do not recommend methotrexate for patients with primary biliary cirrhosis outside randomised trials.
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Affiliation(s)
- Y Gong
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen University Hospital, Dept. 7102, Blegdamsvej 9, H:S Rigshospitalet, Copenhagen, Denmark, DK-2100.
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Kaplan MM, Cheng S, Price LL, Bonis PAL. A randomized controlled trial of colchicine plus ursodiol versus methotrexate plus ursodiol in primary biliary cirrhosis: ten-year results. Hepatology 2004; 39:915-23. [PMID: 15057894 DOI: 10.1002/hep.20103] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Primary biliary cirrhosis frequently progresses despite treatment with ursodeoxycholic acid (UDCA), the only approved therapy. Previous studies suggested that colchicine and methotrexate may improve biochemical tests of liver function, symptoms, and liver histology. The aim of the present study was to determine if the addition of colchicine or methotrexate to UDCA would improve survival free of liver transplantation. Eighty-five patients with histologically confirmed primary biliary cirrhosis whose serum alkaline phosphatase levels were at least twice the normal level and who were not yet candidates for liver transplantation were randomly assigned to receive colchicine or methotrexate in a double-blind study. UDCA was administered to all patients after 2 years. The primary end point was survival free of liver transplantation. Patients were followed up for a total of up to 10 years or until treatment failure. Data were analyzed on an intention-to-treat basis. Transplant-free survival was similar in both groups: 0.57 for colchicine plus UDCA and 0.44 for methotrexate plus UDCA, results that are similar to those predicted by the Mayo prognostic model. Significant improvement in liver biochemical tests and liver histology was observed in a subset of patients in both treatment groups who remained in the study for all 10 years. In conclusion, neither colchcine plus UDCA nor methotrexate plus UDCA improved survival beyond that predicted by the Mayo prognostic model. However, clinical, histologic, and biochemical improvement observed among those who remained in the study for 10 years suggests a possible benefit of these drugs in a subset of patients.
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Affiliation(s)
- Marshall M Kaplan
- Division of Gastroenterology, Department of Medicine and the Tupper Research Institute, New England Medical Center and Tufts University School of Medicine, Boston, Massachusetts, USA.
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Bach N, Bodian C, Bodenheimer H, Croen E, Berk PD, Thung SN, Lindor KD, Therneau T, Schaffner F. Methotrexate therapy for primary biliary cirrhosis. Am J Gastroenterol 2003; 98:187-93. [PMID: 12526956 DOI: 10.1111/j.1572-0241.2003.07173.x] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Preliminary data suggested possible benefits of methotrexate in primary biliary cirrhosis. We assessed the effectiveness of methotrexate use in primary biliary cirrhosis and its tolerance in patients with this disease. METHODS A total of 110 primary biliary cirrhosis patients began methotrexate 15 mg/wk; for most, ursodeoxycholic acid was added during the study. We analyzed data from patients completing 5 yr of treatment with methotrexate to assess its effect on biochemical and histologic parameters after 5 yr of therapy. Based on an intent to treat analysis, we also compared survival of our patients (n = 110) with that of patients in a previously published, placebo-controlled trial of ursodeoxycholic acid (n = 180). RESULTS Only half of the study group completed 5 yr of methotrexate therapy. Therapy did not prevent progression of disease, as indicated by a rising Mayo risk score. Portal fibrosis tended to remain the same. Methotrexate did not diminish the risk of death or liver transplantation when compared with ursodeoxycholic acid or placebo; however, ursodeoxycholic acid use decreased the risk of death or transplant (p = 0.006). CONCLUSIONS Methotrexate is not well tolerated in primary biliary cirrhosis. The toxicity of methotrexate and its inability to prevent complications of progressive liver disease or improve survival and the need for liver transplantation limits its utility. The benefits of ursodeoxycholic acid were again confirmed.
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Affiliation(s)
- Nancy Bach
- Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA
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Abstract
Although primary biliary cirrhosis (PBC) is generally a progressive disease, the rate of progression varies greatly from one patient to another. The terminal phase is characterized by hyperbilirubinaemia (>100 micromol/l), a major decrease in the number of intrahepatic bile ducts, and extensive fibrosis or cirrhosis. It is now well established that orthotopic liver transplantation is the treatment of choice for patients entering the terminal phase of the disease.A variety of therapeutic agents have been proposed for treatment of patients with PBC. However, most have been found ineffective or too toxic to be widely used. In contrast, there is accumulating evidence from large therapeutic trials that long-term administration of ursodeoxycholic acid (UDCA) is safe and prolongs survival free of liver transplantation. Treatment with UDCA slows the histological progression and delays the onset of cirrhosis. In patients who have a sub-optimal response to UDCA therapy alone, the combination of colchicine or methotrexate with UDCA has minimal or no additional benefit, whereas that with corticosteroids is more promising but not yet demonstrated. Among causes of non-response to UDCA therapy, the most common is the PBC-autoimmune hepatitis overlap syndrome. The benefit from the combination of corticosteroids and UDCA in this setting is obvious.Further studies are needed to define the patients who are most likely to respond to UDCA therapy and to assess the benefit of combined medical treatments.
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Affiliation(s)
- R Poupon
- Service d'Hépato-gastroentérologie, Hôpital Saint-Antoine, Paris, France
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Kaplan MM, Schmid C, Provenzale D, Sharma A, Dickstein G, McKusick A. A prospective trial of colchicine and methotrexate in the treatment of primary biliary cirrhosis. Gastroenterology 1999; 117:1173-80. [PMID: 10535881 DOI: 10.1016/s0016-5085(99)70403-8] [Citation(s) in RCA: 45] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
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.
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Affiliation(s)
- M M Kaplan
- Division of Gastroenterology, Department of Medicine, New England Medical Center and Tufts University School of Medicine, Boston, Massachusetts, USA.
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Abstract
Methotrexate has proven to be a safe, effective, long-term therapy for rheumatoid arthritis. Its property as a corticosteroid-sparing drug in rheumatoid arthritis has been recognized and its potential has been explored in other inflammatory and autoimmune diseases. This article describes and analyzes the use of methotrexate for a wide variety of diseases, some of which are not the usual province of rheumatologists, to provide some guidance concerning its role for treatment. Methotrexate therapy seems promising for systemic lupus erythematosus, inflammatory myopathy, inflammatory eye disease, inflammatory bowel disease, and some manifestations of sarcoidosis. Its role in other diseases is not as well defined.
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Affiliation(s)
- W S Wilke
- Department of Rheumatic and Immunologic Diseases, Cleveland Clinic Foundation, Ohio, USA
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González-Koch A, Brahm J, Antezana C, Smok G, Cumsille MA. The combination of ursodeoxycholic acid and methotrexate for primary biliary cirrhosis is not better than ursodeoxycholic acid alone. J Hepatol 1997; 27:143-9. [PMID: 9252088 DOI: 10.1016/s0168-8278(97)80294-2] [Citation(s) in RCA: 45] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND/AIMS Many therapies have been tried in primary biliary cirrhosis. It has been suggested that a combination of ursodeoxycholic acid and methotrexate may offer advantages. Because the benefit and safety of this combination is uncertain, we conducted this prospective, randomized, double-blind, controlled trial. METHODS Twenty-five patients with well-defined primary biliary cirrhosis were randomly assigned to receive either ursodeoxycholic acid (500 mg/day) plus methotrexate (10 mg/week) or ursodeoxycholic acid plus placebo for a period of 48 weeks. Clinical, biochemical and histologic evolution were assessed. RESULTS In both groups the clinical response was similar and heterogeneous. In patients of ursodeoxycholic acid alone group, biochemical and histologic changes were comparable to those of patients of ursodeoxycholic acid plus methotrexate at 48 weeks. The addition of methotrexate was not associated with substantial adverse affects. CONCLUSIONS The use of methotrexate in combination with ursodeoxycholic acid was not followed by an additive benefit over ursodeoxycholic acid alone, nor was substantial toxicity added. Unless larger and longer controlled trials with clinical, biochemical and histologic controls show it to be a safe and effective therapy for primary biliary cirrhosis, ursodeoxycholic acid+methotrexate should not be used as a proven and accepted treatment.
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Affiliation(s)
- A González-Koch
- Gastroenterology Center, University of Chile Clinical Hospital, Santiago
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Hunter J, Hirst BH. Intestinal secretion of drugs. The role of P-glycoprotein and related drug efflux systems in limiting oral drug absorption. Adv Drug Deliv Rev 1997. [DOI: 10.1016/s0169-409x(97)00497-3] [Citation(s) in RCA: 175] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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Abstract
Refractory inflammatory bowel disease can be treated by surgery or using nutritional supplementation or replacement. Immunosuppressive agents may also play a role for refractory disease; they have gained widespread acceptance, due not only to trials that demonstrate efficacy but also to the realization that these side-effects are minor compared to those associated with long-term, high-dose corticosteroids. To date, 6-mercaptopurine and azathioprine remain the drugs of choice based upon extensive clinical experience, but both methotrexate and cyclosporin are promising immunosuppressants for otherwise refractory disease.
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Affiliation(s)
- R A Kozarek
- Virginia Mason Clinic, Seattle, Washington 98101
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16
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Buscher HP, Zietzschmann Y, Gerok W. Positive responses to methotrexate and ursodeoxycholic acid in patients with primary biliary cirrhosis responding insufficiently to ursodeoxycholic acid alone. J Hepatol 1993; 18:9-14. [PMID: 8101853 DOI: 10.1016/s0168-8278(05)80004-2] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Methotrexate (2.5 mg/day) was used in addition to ursodeoxycholic acid (10-15 mg/kg per day) in 8 female patients with primary biliary cirrhosis. All patients had undergone ursodeoxycholic acid treatment for more than 6 months preceding this study and their serum alkaline phosphatase remained constant at more than 300 U/l for more than 2 months. One patient showed histologic stage I, three stage II, two stage III and two stage IV disease. Within 6 months, fatigue and itching disappeared in all symptomatic patients. Serum alkaline phosphatase activities improved dramatically (621 +/- 299 to 378 +/- 258, mean +/- S.D.) in all but one patient and normalized in four. Serum gamma-glutamyltransferase activities (180 +/- 99 U/l vs. 150 +/- 125 U/l) and immunoglobulin M concentrations (616 +/- 424 vs. 362 +/- 195 mg/dl) also improved. Adverse effects of methotrexate therapy were only regularly observed within the first 2-6 weeks, such as fatigue and transient enhancement of transaminases and serum bile acid concentrations. We conclude that methotrexate may be a highly effective drug for the treatment of primary biliary cirrhosis in patients whose symptoms and/or laboratory liver function tests are not improved enough by ursodeoxycholic acid alone. However, its influence on histology and the natural history of the disease needs to be established.
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Affiliation(s)
- H P Buscher
- Medizinische Universitätsklinik, Freiburg, Germany
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Affiliation(s)
- H C Mitchison
- Department of Medicine, University of Newcastle upon Tyne, UK
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The results of a randomized double blind controlled trial evaluating malotilate in primary biliary cirrhosis. A European multicentre study group. J Hepatol 1993; 17:227-35. [PMID: 8445237 DOI: 10.1016/s0168-8278(05)80043-1] [Citation(s) in RCA: 30] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
One hundred and one patients were included in a double-blind controlled trial to determine whether malotilate (diisopropyl 1,3-dithiol-2-ylidene malonate) is therapeutically effective in primary biliary cirrhosis. Fifty-two patients received malotilate (500 mg three times a day) and 49 patients placebo. The mean follow-up time was 28 months (range 6-46 months). The large majority of patients did not have advanced liver disease since only ten patients were in Child-Pugh class B and none in class C, and the median bilirubin and albumin at entry were normal. Malotilate had no clear effect on pruritus. In malotilate recipients the following statistically significant biochemical changes occurred: alkaline phosphatase decreased 21%, AST 20%, ALT 40%, IgA 12% and IgM 26%. In the placebo group no significant changes occurred. Evaluation of entry and 2-year liver biopsies indicated that malotilate diminished plasma cell and lymphocytic infiltrate and piece-meal necrosis, but had no effect on liver fibrosis. There was no difference in survival or in disease progression according to Child-Pugh criteria. In six patients receiving malotilate, but in none on placebo, treatment was discontinued due to suspected side effects. All patients recovered completely. We conclude that malotilate has an immune-modulating, anti-inflammatory but not anti-fibrotic effect in primary biliary cirrhosis. The clinical relevance of the observed benefits, however, appears too slight to recommend malotilate as single drug therapy in primary biliary cirrhosis.
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19
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Bissuel F, Bizollon T, Dijoud F, Bouletreau P, Cordier JF, Chazot C, Gouillat C, Trepo C. Pulmonary hemorrhage and glomerulonephritis in primary biliary cirrhosis. Hepatology 1992; 16:1357-61. [PMID: 1446892 DOI: 10.1002/hep.1840160609] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
We observed life-threatening intrapulmonary hemorrhages and focal proliferative glomerulonephritis in a 41-yr-old woman with primary biliary cirrhosis. The severity of the symptoms necessitated blood transfusions and mechanical ventilation; the patient improved with the help of corticosteroid therapy. No formal evidence of either Goodpasture's syndrome or any other well-defined systemic vasculitis could be found. Neutrophil cytoplasmic antibodies were initially positive and became undetectable after 3 mo of immunosuppressive treatment without relapse. This association has not been described previously and may be added to the list of extrahepatic immune-mediated conditions associated with primary biliary cirrhosis.
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Affiliation(s)
- F Bissuel
- Services d'Hépato-gastroentérologie, Hôpital de l'Hôtel-Dieu, Lyon, France
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20
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Mevorach D, Leibowitz G, Brezis M, Raz E. Induction of remission in a patient with Takayasu's arteritis by low dose pulses of methotrexate. Ann Rheum Dis 1992; 51:904-5. [PMID: 1352962 PMCID: PMC1004779 DOI: 10.1136/ard.51.7.904] [Citation(s) in RCA: 26] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
A 42 year old woman with Takayasu's arteritis responded to treatment with prednisone (60 mg daily) but developed severe side effects. Cyclophosphamide treatment did not produce a clinical improvement or steroid sparing effect. A treatment trial with a weekly pulse of low dose methotrexate improved her symptoms and the patency of her occluded left subclavian artery.
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Affiliation(s)
- D Mevorach
- Department of Medicine, Hadassah University Hospital, Mount Scopus, Jerusalem, Israel
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21
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Abstract
The transport of methotrexate (MTX) was investigated in organ-cultured endoscopic biopsy specimens of intestinal mucosa from normal subjects. In biopsy specimens from the proximal small intestine incubated with [3H]MTX (0.1 microM) for 2 hr at pH 5.5, [3H]MTX accumulated in the intracellular fluid to a concentration 3.5-fold higher than that of the medium, but at pH 6.5 and 7.5, the concentration was the same as that of the medium. In biopsy specimens from the cecum incubated under similar conditions, no accumulation against a concentration gradient was found. However, the accumulation of MTX was significantly higher at pH 5.5 than at 7.5. At [MTX] = 0.1 microM, the initial rate of MTX transport in the small intestine was significantly affected by medium pH and was optimal at pH 5.5. The relationship between the initial rate of uptake and medium [H+] was hyperbolic, suggestive of saturability with respect to [H+] with a Km of 132.2 nm [H+], corresponding to a medium pH of 6.88. At medium [MTX] = 10 microM, this effect was abolished. At pH 5.5, the relationship between the initial rate of uptake and medium [MTX] was sigmoidal, suggestive of a positive cooperativity, with napp of 1.8. [MTX] at 0.5 Vmax was 20.37 microM. Folic acid inhibited 37% of MTX flux. At pH 7.5, the relationship between the initial rate of uptake of MTX and medium [MTX] was linear. These data indicate the presence of a proton-dependent active transport of MTX in the human proximal small intestine, which is partially shared with folic acid.
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Affiliation(s)
- J Zimmerman
- Department of Gastroenterology, Hadassah University Hospital, Jerusalem, Israel
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22
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23
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Abstract
Since autoimmune processes are probably involved in the early stages of primary biliary cirrhosis (PBC), immunomodulatory drugs have been investigated with the aim of prolonging survival, delaying transplantation, slowing histological progression and relieving symptoms. Corticosteroids, azathioprine, chlorambucil and, more recently, cyclosporin A and methotrexate have all be subjected to clinical investigation. In the latest of these, a European multicentre trial, cyclosporin A has been shown to delay death or transplantation with a reduction in liver related deaths and slowing of the rise of serum bilirubin. The incidence of nephrotoxicity and hypertension are low at the doses used.
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Affiliation(s)
- G P Bray
- Institute of Liver Studies, King's College Hospital School of Medicine and Dentistry, Denmark Hill, London, UK
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24
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Abstract
A 48-year-old woman with primary biliary cirrhosis (PBC) and multiple sclerosis (MS) is reported. She presented with a visual deficit in 1975. In the course of a diagnostic evaluation, she was found to have PBC. In 1986, the diagnosis of MS was made. The patient's liver function deteriorated and liver transplantation was performed in May 1988. This is the third known case of this association.
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25
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Abstract
Nine women with symptomatic precirrhotic primary biliary cirrhosis have been treated with oral pulse methotrexate, 15 mg/wk, for 12-34 months. Three women had pruritus, two fatigue, and four pruritus and fatigue. Itching disappeared and fatigue lessened or disappeared in all within 4-11 months after starting methotrexate. All who itched were able to discontinue cholestyramine (five) or antihistamines (two). Biochemical tests of liver function improved in all patients and then worsened in three when methotrexate was discontinued or the dose lowered. Mean serum alkaline phosphatase decreased from 471 to 171 U/L (P less than 0.01), serum bilirubin from 0.99 to 0.59 mg/dL (P less than 0.05), and serum alanine aminotransferase from 132 to 61 U/L (P = 0.02), and serum cholesterol fell from 265 to 213 mg/dL (NS). The decrease in serum cholesterol was significant, P = 0.05, if data were used just from the six women whose baseline serum cholesterol levels were elevated. Serum albumin remained normal in all. The serum bilirubin levels became normal in three of four patients with elevated levels. The serum alkaline phosphatase levels became normal in four patients and the alanine aminotransferase levels in three. Liver histology improved in five patients and was stable in the remaining four based on a quantitative evaluation of coded liver biopsy specimens. The improvement in histology was primarily due to decreased portal inflammation and bile duct injury. The titer of antimitochondrial antibody decreased in seven patients. The data suggest that methotrexate may be effective treatment for precirrhotic primary biliary cirrhosis. Controlled trials are needed to evaluate long-term efficacy and toxicity.
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Affiliation(s)
- M M Kaplan
- Gastroenterology Division, New England Medical Center Hospitals, Boston, Massachusetts
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26
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27
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Lammert JK, Mullarkey MF. Promises and Problems with the Use of Methotrexate in the Asthmatic Patient. Immunol Allergy Clin North Am 1991. [DOI: 10.1016/s0889-8561(22)00306-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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28
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29
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Poupon RE, Eschwège E, Poupon R. Ursodeoxycholic acid for the treatment of primary biliary cirrhosis. Interim analysis of a double-blind multicentre randomized trial. The UDCA-PBC Study Group. J Hepatol 1990; 11:16-21. [PMID: 1975819 DOI: 10.1016/0168-8278(90)90265-s] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Based on uncontrolled observations, we have proposed ursodeoxycholic acid (UDCA) as a novel therapeutic approach in primary biliary cirrhosis (PBC). To confirm and extend our original findings, we have designed a double-blind multicentre randomized clinical trial. An interim analysis was planned at 6 months, involving all subjects included in the trial, with a final analysis at 2 years. The UDCA-PBC trial began in June 1987 and will be completed in March 1990. Seventy patients were randomized to receive UDCA and 68 a placebo. The two groups were well matched with respect to age, sex, duration and prevalence of symptoms and histologic severity (50% of the UDCA group had stage III-IV disease vs. 37% of the placebo group). During the first 6 months of follow-up, six patients withdrew from the trial. At 6 months, the proportion of patients with jaundice was significantly lower (p less than 0.01) in UDCA recipients than in the placebo group. There was a similar decrease in the proportion of patients with pruritus and fatigue in both groups. The following laboratory test values were significantly lower in UDCA recipients than in the placebo group after 6 months of therapy: serum bilirubin, alkaline phosphatase, alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), gamma-glutamyltranspeptidase activities (p less than 0.001), cholesterol (p less than 0.003) and IgM levels (p less than 0.03). The results of this interim analysis confirm and extend the biochemical data provided by our previous pilot study. However the final analysis of the trial is necessary for a definitive assessment of the safety and efficacy of UDCA therapy in PBC.
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30
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Wiesner RH, Ludwig J, Lindor KD, Jorgensen RA, Baldus WP, Homburger HA, Dickson ER. A controlled trial of cyclosporine in the treatment of primary biliary cirrhosis. N Engl J Med 1990; 322:1419-24. [PMID: 2184355 DOI: 10.1056/nejm199005173222003] [Citation(s) in RCA: 153] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Primary biliary cirrhosis is a progressive disease of the liver characterized by the immunologic destruction of bile ducts; effective therapy is lacking. We therefore evaluated the safety and efficacy of low-dose cyclosporine in 29 patients with primary biliary cirrhosis without evidence of damage to the lobular architecture (precirrhotic disease) or portal hypertension. The patients were randomly assigned to receive either cyclosporine (4 mg per kilogram of body weight per day) or placebo. After one year 17 of the 19 patients assigned to cyclosporine had improvement or stability in their degree of fatigue, and 18 in their degree of pruritus. In contrast, among the 10 patients assigned to placebo, fatigue increased in 4 (P less than 0.06) and pruritus worsened in 6 (P less than 0.001). Those assigned to cyclosporine also had significant decreases in serum levels of bilirubin, alanine aminotransferase, alkaline phosphatase, gamma globulin, and the titer of antimitochondrial antibodies. For the 20 patients who have completed two years in the study, liver biopsies (coded specimens) showed evidence of histologic progression in only 1 of 13 patients in the cyclosporine group, as compared with 5 of 7 in the placebo group (P less than 0.003). No patient has permanently discontinued cyclosporine because of side effects; however, signs of nephrotoxicity developed in 12 of 19, and 9 of 19 had increased blood pressure. We conclude that in patients with precirrhotic primary biliary cirrhosis, immunosuppressive therapy with cyclosporine is promising and deserves further evaluation.
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Affiliation(s)
- R H Wiesner
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905
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31
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Hanauer SB. Inflammatory bowel disease revisited: newer drugs. SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY. SUPPLEMENT 1990; 175:97-106. [PMID: 1978406 DOI: 10.3109/00365529009093133] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The development of new drug therapy is an evolutionary process progressing from clinical success with current treatments through an understanding of interactions in the immune and inflammatory events that culminate in the tissue injury of IBD. The basic immunoinflammatory response is reviewed, with identification of the recognized and potential sites of activity of current therapies. Potential sites and implications for future interventions by newer therapies are discussed as we anticipate the discovery of the etiology and eventual cure for ulcerative colitis and Crohn's disease.
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Affiliation(s)
- S B Hanauer
- University of Chicago Medical Center, Dept. of Medicine, Illinois 60637
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32
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Batta AK, Arora R, Salen G, Tint GS, Eskreis D, Katz S. Characterization of serum and urinary bile acids in patients with primary biliary cirrhosis by gas-liquid chromatography-mass spectrometry: effect of ursodeoxycholic acid treatment. J Lipid Res 1989. [DOI: 10.1016/s0022-2275(20)38207-9] [Citation(s) in RCA: 65] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
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Kaplan MM. Chronic liver diseases: current therapeutic options. HOSPITAL PRACTICE (OFFICE ED.) 1989; 24:111-6, 121-3, 126-30. [PMID: 2493463 DOI: 10.1080/21548331.1989.11703680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
MESH Headings
- Adrenal Cortex Hormones/therapeutic use
- Autoimmune Diseases/diagnosis
- Autoimmune Diseases/drug therapy
- Autoimmune Diseases/pathology
- Azathioprine/therapeutic use
- Cholangitis, Sclerosing/diagnosis
- Cholangitis, Sclerosing/drug therapy
- Cholangitis, Sclerosing/pathology
- Chronic Disease
- Colchicine/therapeutic use
- Diagnosis, Differential
- Drug Therapy, Combination
- Hepatitis B/diagnosis
- Hepatitis B/drug therapy
- Hepatitis B/pathology
- Hepatitis C/diagnosis
- Hepatitis C/drug therapy
- Hepatitis C/pathology
- Hepatitis, Chronic/diagnosis
- Hepatitis, Chronic/drug therapy
- Hepatitis, Chronic/therapy
- Humans
- Interferon Type I/therapeutic use
- Liver Cirrhosis, Biliary/diagnosis
- Liver Cirrhosis, Biliary/drug therapy
- Liver Cirrhosis, Biliary/pathology
- Liver Diseases/diagnosis
- Liver Diseases/drug therapy
- Liver Diseases/pathology
- Methotrexate/therapeutic use
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Affiliation(s)
- M M Kaplan
- Tufts University School of Medicine, Boston
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34
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Kozarek RA, Patterson DJ, Gelfand MD, Botoman VA, Ball TJ, Wilske KR. Methotrexate induces clinical and histologic remission in patients with refractory inflammatory bowel disease. Ann Intern Med 1989; 110:353-356. [PMID: 2492786 DOI: 10.7326/0003-4819-110-5-353] [Citation(s) in RCA: 351] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
STUDY OBJECTIVE To determine whether methotrexate has anti-inflammatory activity in refractory inflammatory bowel disease. DESIGN Nonrandomized, open-label, preliminary trial of methotrexate along with standard medications for 12 weeks. SETTING Referral-based gastroenterology practice. PATIENTS Twenty-one patients with refractory inflammatory bowel disease (14, Crohn disease; 7, chronic ulcerative colitis); 17 taking variable doses of corticosteroids and 14 on sulfasalazine or metronidazole. Of the 21 patients, 10 had previously failed azathioprine or 6-mercaptopurine trials. INTERVENTIONS Sulfasalazine and metronidazole were continued and prednisone dose was tapered according to clinical response. Methotrexate was given as a 25-mg intramuscular injection weekly for 12 weeks, then switched to a tapering oral dose if a clinical and objective improvement was noted. MEASUREMENTS AND MAIN RESULTS Sixteen of twenty-one patients (11 of 14 patients with Crohn disease, 5 of 7 patients with chronic ulcerative colitis) had an objective response as measured by disease activity indices (modified Crohn's Disease Activity Index, 13.3 to 5.4 [P = 0.0001], Ulcerative Colitis Activity Index, 13.3 to 6.3 [P = 0.007]). Prednisone dosage decreased from 21.4 mg +/- 5.6 (SEM) to 5.5 mg +/- 2.0; P = 0.006 and 38.6 mg +/- 6.35 to 12.9 mg +/- 3.4; P = 0.01, respectively. Five patients with Crohn colitis had colonoscopic healing and 4 had normal histology at 12 weeks. In contrast, none of the 7 patients with ulcerative colitis had normal flexible sigmoidoscopies, despite histologic improvement in 5. Side effects included mild rises in transaminase levels in 2 patients, transient leukopenia in 1, self-limited diarrhea and nausea in 2 patients, and 1 case each of brittle nails and atypical pneumonitis. CONCLUSIONS Although this pilot study is encouraging, further work is needed before methotrexate can be recommended for inflammatory bowel disease.
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