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PubMed2005

Low-dose oral methotrexate for maintaining Crohn's disease remission: where we stand.

Methotrexate has been considered a second-line immunomodulating therapy, behind azathioprine (AZA) or its metabolite 6-mercaptopurine (6-MP), for the treatment of Crohn's disease (CD). Approximately 27% to 50% of patients with refractory CD are intolerant or resistant to AZA or 6-MP. Two well-designed randomized double-blind placebo-controlled trials have demonstrated that low-dose methotrexate (<25 mg/wk), given intramuscularly (IM), is effective in inducing and maintaining remission in CD. In clinical practice, IM injection involves an inconvenience for patients and higher costs. Furthermore, frequent IM injections increase the risk of complications such as peripheral nerve injury, local irritation, pain, bleeding, fibrosis, abscess formation, gangrene, and contractures. Alternatively, subcutaneous (SQ) injection has been advocated because it has been shown to have similar pharmacokinetics to IM injection. However, because of a recent and ongoing national shortage of parenteral methotrexate, patients who were receiving IM methotrexate had to switch to the oral form until the parenteral formulation becomes available. Oral methotrexate has been used with great success in treatment of rheumatoid arthritis and psoriasis for the past 50 years. However, the data on the usage of low-dose oral methotrexate in maintaining CD remission are scanty and controversial. The purpose of this article is to review the mechanism of action, absorption, and the objective evidence in supporting the use of oral methotrexate in maintaining CD remission.

Administration, Oral↗

PubMed2005

A mutation in the drug transporter gene ABCC2 associated with impaired methotrexate elimination.

Human multidrug resistance protein 2 (MRP2, encoded by ABCC2) is involved in active efflux of anionic drugs such as methotrexate. MRP2 is expressed on the luminal side of hepatocytes and renal proximal tubular cells, indicating an important role in drug elimination. We postulated that loss-of-function mutations in ABCC2, which are involved in the Dubin-Johnson syndrome, may be associated with impaired methotrexate elimination and an increased risk of toxicity. We studied the biological phenotype and ABCC2 coding sequence in a patient receiving a high-dose methotrexate infusion for large B-cell lymphoma and who had an unusual pharmacokinetic profile, mainly characterized by a three-fold reduction in the methotrexate elimination rate. This resulted in severe methotrexate over-dosing and reversible nephrotoxicity. An inversion of the urinary coproporphyrin isomer I/III ratio (a specific biological marker of the Dubin-Johnson syndrome) was observed in this patient. Genetic analysis of ABCC2 identified a heterozygous mutation replacing a highly conserved arginine by glycine in the cytoplasmic part of the second membrane-spanning domain (position 412 of MRP2), a region associated with substrate affinity. This genetic variant was not found in a control population. Functional analysis in transiently transfected Chinese hamster ovary cells revealed a loss of transport activity of the G412 MRP2 mutant protein. An ABCC2 mutation altering MRP2-mediated methotrexate transport and resulting in impaired drug elimination and subsequent renal toxicity was identified. Candidates for methotrexate therapy should be considered for MRP2 functional testing.

Animals↗

PubMed2003

Efficacy and safety of cyclosporine versus methotrexate in severe psoriasis: a study from north India.

Treatment of patients with severe psoriasis is difficult. Among the number of systemic drugs that are available, methotrexate has long been used, but cyclosporine has been recently recommended for the management of severe psoriasis. The purpose of this study was to compare the efficacy and safety of daily cyclosporine with weekly methotrexate in the management of severe psoriasis. Thirty consecutive patients with severe psoriasis were randomly assigned to treatment with cyclosporine or methotrexate. The initial dose of cyclosporine was 3 mg/kg/day, which was increased to a maximum of 4 mg/kg after two weeks of therapy when the response was not adequate. Methotrexate was administered weekly at a dose of 0.5 mg/kg. Clinical response was assessed by calculating PASI score in all patients at biweekly intervals. Patients were followed up fortnightly up to a maximum of 12 weeks. The doses of both drugs were gradually tapered once >75% reduction in disease severity was attained. Marked improvement (>75%) reduction in PASI was noted in all patients except for one in the cyclosporine group. The median time for marked improvement was 5.3 weeks with methotrexate and 6.8 weeks with cyclosporine. Patients on methotrexate were found to have more rapid and complete clearance than those on cyclosporine. Both drugs were well tolerated. Side effects in both the treatment groups were minor, transient, and manageable. At doses with comparable safety profiles, methotrexate resulted in more rapid and cost effective clearance of patients with severe psoriasis. Cyclosporine can provide an effective and safe alternative.

Adult↗

PubMed2006

Methotrexate therapy for the symptomatic treatment of primary biliary cirrhosis patients, who are biochemical incomplete responders to ursodeoxycholic acid therapy.

BACKGROUND: Ursodeoxycholic acid is widely used as the standard therapy for the treatment of primary biliary cirrhosis and other cholestatic liver diseases. Although it has been shown to improve biochemical markers and delay disease progression, its effect upon fatigue and pruritus, is at best uncertain. AIM: To assess the safety and efficacy of methotrexate for treating symptomatic primary biliary cirrhosis patients who were biochemical partial responders or non-responders to ursodeoxycholic acid therapy. METHODS: We treated eight consecutive primary biliary cirrhosis patients with methotrexate who were followed in a single hepatology clinical practice, who were symptomatic, and who had had an incomplete biochemical response to ursodeoxycholic acid therapy. Pruritus and fatigue were assessed at each clinic visit and graded from 0 (asymptomatic) to 4 (incapacitating). RESULTS: The median dose of methotrexate was 13.75 mg/week (range 7.5-15) and the mean duration of methotrexate therapy was 49 months (range 11-126). At the end of follow-up pruritus in six of seven patients had improved, and fatigue in all patients had improved with the addition of methotrexate therapy (pruritus: baseline 2.9 +/- 1.1 vs. end of treatment 0.6 +/- 1.5, P < or = 0.0175, and fatigue: baseline 3.0 +/- 0.8, vs. end of treatment 1.0 +/- 0.8, P < or = 0.0023). Improvement in symptoms was associated with a significant improvement in biochemical markers of cholestasis. No significant adverse effects of methotrexate were documented. CONCLUSIONS: Methotrexate should be considered as a potential additive treatment for symptomatic primary biliary cirrhosis patients who are incomplete biochemical responders to ursodeoxycholic acid therapy.

Adult↗

PubMed1979

Serum, tear and salivary concentrations of methotrexate in man.

1. Methotrexate handling has been studied in four patients with psoriasis and eleven patients with neoplastic disease. 2. Methotrexate levels in serum, tears and saliva were measured by radioimmunoassay while protein binding studies were performed by continuous ultrafiltration. 3. There was a close correlation between methotrexate concentrations in tears and serum (P less than 0.001, r = 0.714). Parotid salivary and serum methotrexate levels were similarly correlated (P less than 0.001, r = 0.557) but not mixed salivary and serum levels (P greater than 0.1, r = 0.232). 4. The mean protein binding was 95.11% +/- 2.26 (s.d.) while the ratio of methotrexate levels in tears to the free serum methotrexate level was 1:1.04. The corresponding parotid salivary level: free serum level ratio was 1:18.11. 5. No relationship could be determined between the methotrexate levels in tears and conjunctivitis observed in some of the patients under study.

Humans↗

PubMed1996

Lack of interaction between flucloxacillin and methotrexate in patients with rheumatoid arthritis.

1. The aim of the study was to examine the potential pharmacokinetic interaction between methotrexate and flucloxacillin. 2. Ten rheumatoid arthritis patients participated in the interaction study. Subjects were allocated to either methotrexate alone (5-15 mg per week) or methotrexate plus flucloxacillin (500 mg four times a day 48 h prior to sampling) in a random order. 3. There was a statistically, but not clinically, significant decrease in methotrexate AUC (1307 +/- 389 vs 1212 +/- 394 micrograms l-1 h) in the presence of flucloxacillin. Cmax and tmax parameters for methotrexate were not significantly altered in the presence of flucloxacillin. 4. Data from an additional 10 rheumatoid arthritis patients, starting on methotrexate, were added to the data from the placebo arm of the interaction study and a model dependent pharmacokinetic analysis was performed. The plasma concentration profiles were best described by a two-compartment model with a mean clearance of 11.9 (+/- 1.7) l h-1 and an initial volume of distribution of 31.2 (+/- 2.6) l. The pronounced intersubject variability in the pharmacokinetic parameters was not related to any of the available covariate information. 5. Our findings suggest that no important clinical interaction occurs between flucloxacillin and methotrexate in patients with rheumatoid arthritis.

Adult↗

PubMed1981

Methotrexate accumulation and folate depletion in cells as a possible mechanism of chronic toxicity to the drug.

Methotrexate has been associated with chronic toxicities such as cirrhosis and neurological impairments ranging from mild learning disorders to a fatal leucoencephalopathy. The mechanism(s) for this toxicity is not completely understood. Certain tissues can convert methotrexate to polyglutamates. This results in a more persistent intracellular form of the drug. In this study the intracellular levels of folate and methotrexate were measured in the erythrocytes and liver of patients treated chronically with methotrexate. These tissues showed an accumulation of methotrexate as polyglutamates and a concomitant loss of folate. Folate concentrations were below normal in nine of 12 red cell and three of five liver samples. It is proposed that persistent methotrexate concentrations and/or the associated folate deficiency may be related to the toxicity of methotrexate, especially in time of cellular stress.

Erythrocytes↗

PubMed1975

DNA replication in methotrexate-treated human lymphoblasts.

The rate of DNA synthesis in cultures of human lymphoblasts decreased more than 80% within 30 min after the cells were exposed to methotrexate, a potent inhibitor of dihydrofolate reductase. Despite this rapid initial inhibition, DNA continued to be synthesized for at least an additional 6 h. The mode of this subsequent replication appeared to be semiconservative, as indicated by the buoyant density of 5-bromodeoxyuridine-substituted DNA in alkaline CsCl gradients. The growth rates of DNA chains in cells exposed to methotrexate were determined by sedimentation rate analysis in alkaline sucrose gradients. DNA synthesized during 2-min or 10-min pulses with labeled deoxycitidine in the presence of methotrexate had about the same sedimentation coefficient, 35 S, as controls. When methotrexate-treated cultures were pulse-labeled for 10 min and then chased for various times, DNA fragments of about 80 S accumulated. DNA synthesized in the presence of methotrexate was stable and elongated to bulk-size DNA after methotrexate inhibition of growth was removed by addition of thymidine and deoxycytidine. The data suggest that methotrexate reduces the rate of DNA replication by inhibiting chain initiation independently of chain elongation.

Cell Line↗

PubMed2001

An economic evaluation of single dose systemic methotrexate and laparoscopic surgery for the treatment of unruptured ectopic pregnancy.

OBJECTIVE: To compare the direct and indirect costs of single dose systemic methotrexate with laparoscopic surgery for the treatment of unruptured ectopic pregnancy. DESIGN: A cost minimisation study undertaken alongside a randomised trial. SETTING: Departments of Obstetrics and Gynaecology in three hospitals in Auckland, New Zealand. PARTICIPANTS: Sixty-two women with an ectopic pregnancy randomised to treatment with either a single dose of methotrexate (50 mg/m2) or laparoscopic surgery. MAIN OUTCOME MEASURES: Direct and indirect costs based on the results of the randomised trial. RESULTS: Direct costs per case were significantly lower in the methotrexate group (mean $NZ 1,470) than in the laparoscopy group (mean $NZ 3,083) with a mean difference of $NZ 1,613 (95% CI $NZ 1,166 - $NZ 2,061). These significant differences existed under a wide range of alternative assumptions about unit costs. The difference in direct costs in favour of methotrexate was greatest for women presenting with low pretreatment serum beta-hCG concentrations. Mean indirect costs were also significantly lower in the methotrexate group (mean $NZ 1,141) than in the laparoscopy group (mean $NZ 1899) with a mean difference of $NZ 758 (95% CI $NZ 277 - $NZ 1,240). For women presenting with pretreatment serum beta-hCG concentrations of over 1,500 IU/ L this difference in indirect costs is lost due to the prolonged follow up required and a higher rate of surgical intervention in women receiving methotrexate. CONCLUSION: This economic evaluation shows that treating suitable women with an ectopic pregnancy using systemic methotrexate therapy results in a significant reduction in direct costs. The indirect costs borne by the woman and her carers are only likely to be reduced in women with pretreatment serum beta-hCG concentrations under 1,500 IU/L.

Abortifacient Agents, Nonsteroidal↗

PubMed1984

Effects of methotrexate on biopterin levels and synthesis in rat cultured pineal glands.

Culture of rat pineal glands in methotrexate (0.5, 5, or 10 microM) for 6 or 24 h did not alter pineal tetrahydrobiopterin (85-90% of total biopterin in cultured glands), except for a decrease of 30% after 24 h culture in 10 microM methotrexate. However, pineal dihydrobiopterin and/or biopterin (10-15% of total biopterin) was increased by methotrexate up to 2.5-fold. Biopterin detected in the culture medium following pineal culture was also increased to a similar extent after methotrexate treatment and appeared to represent leakage of pineal dihydrobiopterin and/or biopterin. Culture of glands in 5 microM methotrexate did not alter the conversion of [U-14C]-guanosine to [14C]biopterin, suggesting that pineal tetrahydrobiopterin synthesis was not altered by methotrexate. Complete inhibition of dihydrofolate reductase activity measured in pineal homogenates was obtained following culture of glands in all concentrations of methotrexate studied. Therefore, dihydrofolate reductase and dihydrobiopterin do not appear to be involved in a major biosynthetic pathway for pineal tetrahydrobiopterin from GTP, although they may have a minor role in tetrahydrobiopterin synthesis.

Animals↗

PubMed2003

Efficacy of colchicine in patients with primary biliary cirrhosis poorly responsive to ursodiol and methotrexate.

OBJECTIVE: Approximately 20-30% of patients with primary biliary cirrhosis (PBC) respond fully to treatment with ursodeoxycholic acid (UDCA). The rest have progressive disease and eventually develop cirrhosis and liver failure. More effective treatment is needed. Methotrexate improved biochemical tests of liver function and liver histology in patients with PBC who had failed to respond to UDCA in one report and induced sustained biochemical and histological remission in another. The role of colchicine in PBC is unclear. We describe three patients with symptomatic PBC who responded very well to the addition of colchicine after they had failed to respond to UDCA alone and in combination with methotrexate. We suggest that colchicine should be tried in PBC patients who clearly fail to respond to UDCA. METHODS: Three patients with symptomatic biopsy-proven, antimitochondrial antibody-positive PBC failed to respond to UDCA and then to the addition of methotrexate. Colchicine was eventually added to the regimen. Symptoms, biochemical tests of liver function, and percutaneous liver biopsies were done at baseline, after treatment with UDCA, UDCA plus methotrexate, and UDCA plus methotrexate plus colchicine. RESULTS: All three patients responded after colchicine was added to UDCA and methotrexate. Symptoms, biochemical tests of liver function, and liver histology improved in all, and blood tests normalized in two. CONCLUSIONS: Colchicine may be effective treatment in some symptomatic patients with PBC who respond incompletely to UDCA alone or in combination with methotrexate. Colchicine may be tried in such patients.

Adult↗

PubMed1993

Vitamin A, a useful biochemical modulator capable of preventing intestinal damage during methotrexate treatment.

The effects of vitamin A on methotrexate treatment of mice inoculated with L1210 leukaemia cells or sarcoma 180 cells were studied. The small intestine of tumour transplanted mice was severely damaged after methotrexate treatment. Coadministration of vitamin A with methotrexate protected the small intestine from methotrexate-induced damage. The protective effect of vitamin A was histologically and biochemically demonstrated. Further, coadministration of vitamin A did not inhibit in vivo antitumour activity of methotrexate. Thus, biochemical modulation used to prevent methotrexate-induced malabsorption by vitamin A coadministration will be of great use in methotrexate cancer chemotherapy.

Animals↗

PubMed2004

Better efficacy of methotrexate given by intramuscular injection than orally in patients with rheumatoid arthritis.

OBJECTIVE: To compare the clinical efficacy of methotrexate and tolerance to the drug in patients with rheumatoid arthritis who were switched from intramuscular to oral administration because of a shortage of the intramuscular preparation. METHODS: 143 patients were switched from intramuscular to oral methotrexate. Of these, 47 were switched back to the intramuscular form. A multiple choice questionnaire was sent by mail to evaluate clinical and biological criteria of efficacy and tolerance. RESULTS: When methotrexate was first switched from intramuscular to oral administration, increased disease activity, exacerbation of morning pain and hand stiffness, duration of morning stiffness, increased joint pain, and increased joint swelling were observed. There was a greater frequency of gastrointestinal symptoms, but without a significant increase in liver abnormalities. When intramuscular methotrexate became available again, 47 of the 143 patients were switched back and were followed for at least three months. On average, disease manifestations were improved and side effects reduced by the switch. CONCLUSIONS: Methotrexate given intramuscularly had improved clinical efficacy with fewer side effects than given orally. Intramuscular methotrexate administration should be considered when rheumatoid arthritis remains active in spite of high dose oral methotrexate.

Administration, Oral↗

PubMed2004

Expression of resistance markers to methotrexate predicts clinical improvement in patients with rheumatoid arthritis.

BACKGROUND: Methotrexate is transported into the cell by the reduced folate carrier (RFC) and out of the cell by members of the multidrug resistance protein family (MRP). Transport proteins may affect the therapeutic efficacy of this drug in patients with rheumatoid arthritis. OBJECTIVE: To investigate the potential benefit of the presence of RFC and the absence of functional MRP for the efficacy of methotrexate treatment. METHODS: The study involved 163 patients (116 female, 47 male; mean age 59.5 years) on methotrexate (mean weekly dose 12.2 mg). RFC was determined using reverse transcriptase polymerase chain reaction, and MRP function by flow cytometry, using a calcein acetoxymethylesther/probenecid assay. Clinical response to methotrexate was evaluated by the EULAR response criteria and the ACR 20% improvement criteria. The clinical data were obtained at the beginning of methotrexate treatment and at the time of blood sampling during ongoing therapy. Patients were divided into four groups according to the presence (+) or absence (-) of RFC and functional (f) MRP. RESULTS: fMRP+/RFC+ and fMRP-/RFC- patients more often had good EULAR response rates (60%, p = 0.014, and 53%, p = 0.035, respectively) in comparison with the fMRP-/RFC+ group (29%); fMRP+/RFC- patients had a low frequency of good disease activity responses. CONCLUSIONS: Absence of fMRP plus presence of RFC did not prove to be related to beneficial effects of methotrexate, but the lack or the presence of both fMRP and RFC led to a significantly better therapeutic outcome. Determination of these markers may predict responsiveness to methotrexate.

Antirheumatic Agents↗

PubMed2004

Long term safety of methotrexate in routine clinical care: discontinuation is unusual and rarely the result of laboratory abnormalities.

OBJECTIVE: To analyse patients with rheumatoid arthritis, treated with methotrexate in a weekly academic rheumatology clinic over 13 years, for continuation of courses and reasons for discontinuation. METHODS: All 248 patients with an analysable longitudinal course who took methotrexate in standard care between 1990 and 2003 were studied. Continuation of courses was analysed using life tables. All abnormal and severely abnormal values for aspartate aminotransferase (AST) >40 U/l, >80 U/l, albumin <35 g/l, <30 g/l, white blood cell (WBC) count <4.0 x 10(9)/l, <3.0 x 10(9)/l, and platelet count <150 x 10(9)/l, <100 x 10(9)/l, were identified. Responses of the clinician and subsequent laboratory values were reviewed. RESULTS: Over 1007 person-years, the probability of continuing methotrexate over five years was 79% (95% confidence interval, 72% to 84%). Severe laboratory abnormalities occurred in 2.9 per 100 person-years, specifically 0.9 for AST >80 U/l, 1.1 for albumin <30 g/l, 0.7 for WBC <3.0 x 10(9)/l, and 0.3 for platelets <100 x 10(9)/l. No severe laboratory abnormality progressed to further severity or clinical disease. Permanent discontinuations of methotrexate occurred in 46 patients (19%), 26 (10% of all patients) for adverse effects, 15 (32.6%) for inefficacy; only two discontinuations resulted from laboratory abnormalities, both of WBC, possibly from other sources. CONCLUSIONS: Methotrexate was associated with a high rate of continuation, and few clinically significant laboratory abnormalities. Discontinuation primarily reflected clinical rather than laboratory findings. Vigilance for methotrexate toxicity is required but methotrexate appears among the safest treatments for rheumatoid arthritis.

Antirheumatic Agents↗

PubMed1993

Methotrexate osteopathy in rheumatic disease.

OBJECTIVE: To determine whether two adults with stress fractures receiving low weekly doses of methotrexate had methotrexate osteopathy. CASE REPORTS: Two adult patients developed features consistent with methotrexate osteopathy while receiving low weekly doses of methotrexate. METHODS: Iliac crest biopsy samples were taken and bone histomorphometry carried out. RESULTS: Symptoms resolved when the methotrexate was discontinued. Bone histology showed changes consistent with osteoblast inhibition by methotrexate. CONCLUSIONS: When given in low doses for prolonged periods, methotrexate may have adverse effects on bone, particularly in post-menopausal women.

Aged↗

PubMed1995

Survival and drug discontinuation analyses in a large cohort of methotrexate treated rheumatoid arthritis patients.

OBJECTIVES: To determine the probability of drug continuation in a large cohort of methotrexate treated rheumatoid arthritis (RA) patients, the reasons for discontinuation of methotrexate, the overall survival of the members of this cohort, and the causes of death in these patients. METHODS: Yearly follow up was conducted in methotrexate treated RA patients who formed a cohort between 1981 and 1986 at a tertiary care centre. The probability of drug continuation and the patients' survival were calculated using standard statistical procedures; standardised mortality ratios were calculated using death certificate data and USA general population and mortality tables. RESULTS: The probability of methotrexate continuation at 10 years from the time the first members entered the cohort was 30%. Toxicity (and its severity) was the most frequent cause of discontinuing methotrexate. The cumulative probability of survival was 85% for women and 45% for men. A greater than expected number of deaths from infections was observed, but the number of deaths from cancer and cardiovascular diseases were within the range expected. CONCLUSIONS: Toxicity remains the most common cause for methotrexate discontinuation. Survival was comparable to that of other RA cohorts. Methotrexate may be implicated as an associated factor in the deaths from infections.

Arthritis, Rheumatoid↗

PubMed2003

Sodium-dependent methotrexate carrier-1 is expressed in rat kidney: cloning and functional characterization.

Previous Northern blot studies suggested strong expression of a homolog to the sodium-dependent hepatocellular methotrexate transporter in the kidneys. Here, we report on the cloning of the cDNA for the renal methotrexate carrier isoform-1 (RK-MTX-1) and its functional characterization. Sequencing revealed 97% homology to the rat liver methotrexate carrier with an identical open reading frame. Differences were located in the 5'-untranslated region and resulted in the absence of putative regulatory elements (Barbie box, Ah/ARNT receptor) identified in the cDNA for the hepatocellular carrier. For functional characterization, MTX-1 cDNA was stably expressed in Madin-Darby canine kidney (MDCK) cells. A sodium-dependent transport of methotrexate with a K(m) of 41 microM and a V(max) of 337 pmol.mg protein(-1).min(-1) was observed. This uptake was blocked by the reduced folates dihydro- and tetrahydrofolate as well as by methotrexate itself. Folate was inhibiting only weakly, whereas 5-methyltetrahydrofolate was a strong inhibitor. Further inhibitors of the methotrexate transport included the bile acids cholate and taurocholate and xenobiotics like bumetanide and BSP. PAH, ouabain, bumetanide, cholate, taurocholate, and acetyl salicylic acid were tested as potential substrates. However, none of these substances was transported by MTX-1. Furthermore, expression of RK-MTX-1 in MDCK cells enhanced methotrexate toxicity in these cells fivefold. Analysis of a fusion protein of RK-MTX-1 and the influenza virus hemagglutinin epitope by immunoblotting revealed a major band at 72 kDa within the cell membrane but not in the soluble fraction of transfected MDCK. Indirect immunofluorescence staining revealed an exclusive localization of the carrier in the plasma membrane, and by confocal laser-scanning microscopy we were able to demonstrate that the protein is expressed in the serosal region of MDCK tubules grown in a morphogenic collagen gel model.

Animals↗