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PubMed1996

Correlation of altered tyrosine phosphorylation with methotrexate resistance in a cisplatin-resistant subline of L1210 cells.

Collateral resistance to cisplatin and methotrexate has been reported in several cell lines. A murine leukemia cell line (L1210/DDP) selected for cisplatin resistance also has been shown to be highly resistant to methotrexate. Of the mechanisms proposed for methotrexate resistance, only changes in methotrexate transport into the cells were found in an earlier report. Methotrexate enters mammalian cells via an active transport system. In the present study, we demonstrated that the transport into the cell may be impaired in the resistant cells due to altered tyrosine phosphorylation of a membrane protein with a molecular mass of 66 kDa. This alteration was manifested by altered tyrosine phosphorylation of the 66 kDa protein and may be an underlying modification that renders the cells resistant to methotrexate. These results suggest involvement of tyrosine phosphorylation in folate transport and methotrexate resistant in L1210/DDP cells.

Affinity Labels↗

PubMed1994

Synergistic action of taxol with tiazofurin and methotrexate in human breast cancer cells: schedule-dependence.

Taxol (paclitaxel, (NSC 125973)) is an active agent in the treatment of metastatic carcinoma of the breast; however, positive responses were observed in only about 60% of cases. Therefore, drug combinations which might improve the effectiveness are required. Since tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide, NSC 286193), methotrexate (MTX) and taxol exert their anticancer action in different phases of the cell cycle and have different biochemical targets, we tested the hypothesis that tiazofurin and methotrexate might by synergistic with taxol. MDA-MB-435 human breast cancer cells were grown in monolayer in flasks. In the growth inhibition assay for tiazofurin, methotrexate and taxol the IC50s were 12.5, 0.5 and 0.016 microM, respectively, and in the clonogenic assay 4.5, 0.065 and 0.004 microM. When taxol was given 6 hr before tiazofurin, antagonism was observed and summation was seen when drugs were given simultaneously. Synergism was obtained in both growth inhibitory and clonogenic assays when tiazofurin was followed 12 hr later by taxol. Methotrexate and taxol had an antagonistic effect when they were added simultaneously or when taxol was given 6 hr before methotrexate; summation was observed when taxol was followed 12 hr later by methotrexate. Synergistic action was obtained in the clonogenic assay when methotrexate was followed 12 hr later by taxol. The protocols yielding synergism should be of value in the design of taxol-based clinical trials for breast cancer.

Cell Division↗

PubMed1996

Life-threatening neutropenia following methotrexate treatment of ectopic pregnancy: a report of two cases.

BACKGROUND: Medical treatment of ectopic pregnancy with methotrexate is an increasingly common alternative to surgical management. Initial reports of methotrexate therapy described a very low incidence of complications. We report our experience with two patients who developed profound toxicity following methotrexate treatment of ectopic pregnancy. CASE: The first patient received a single dose of methotrexate (50 mg/m2 intramuscularly) for a confirmed ectopic pregnancy. The second patient received three doses of methotrexate (1 mg/kg). Both patients developed life-threatening neutropenia and febrile morbidity requiring hospitalization and supportive care. CONCLUSION: To our knowledge, this is the first description of significant morbidity secondary to bone marrow suppression following methotrexate treatment of ectopic pregnancy. Most patients with ectopic pregnancy who are treated with methotrexate can expect resolution of their symptoms and a low risk of mild complications. However, serious complications after this therapy are possible and may occur even with the single-dose regimen.

Adult↗

PubMed1982

Factors controlling the concentrations of methotrexate in cultured hepatic cells.

The polyglutamate metabolites of methotrexate are as inhibitory to the target enzyme dihydrofolate reductase as is methotrexate. Because of their greater retention they have a longer half-life within the cells and thus a greater potential for cytotoxicity. These metabolites have been found in numerous cells and tissues and are extensively synthesized in cultured hepatic cells. Uptake of methotrexate by primary cultures of rat hepatocytes occurs by a pathway which is independent of the folate coenzymes but appears to be related in some way to cholic acid and organic anion uptake. The evidence for the commonality of these pathways is (a) an instability of both uptake systems in the absence of hormones in the culture medium, (b) nearly equal inhibition of uptake by PCMS and NEM, and (c) cross competition of cholic acid and methotrexate for entry into the cells. Cholic acid and BSP can also selectively inhibit methotrexate polyglutamate formation in hepatocytes. Methotrexate entry into H35 hepatoma cells is mediated by the transport system which is shared by folate coenzymes and is not inhibited by cholic acid, BSP or sulfhydryl reagents. At concentrations of cholic acid or BSP which inhibit methotrexate polyglutamate formation in hepatocytes there is little or no loss of polyglutamate formation in H35 cells, possibly because BSP and cholic acid are taken up less by H35 cells than by hepatocytes.

Animals↗

PubMed1989

Methotrexate in rheumatoid arthritis: studies with animal models.

The present studies have shown that low doses of methotrexate can suppress the inflammation and joint destruction associated with animal models of arthritis. The antiinflammatory effects of methotrexate are probably related to its inhibitory effect on chemotaxis. At the low doses used, methotrexate does not induce systemic immunosuppression. In methotrexate-treated rats, an improvement in IL-2 synthesis is observed and increases in IL-2 levels are expected to improve cell mediated immunity. Suppressor cells appear to be very sensitive to methotrexate. Macrophage function is modulated by methotrexate. All of these effects including the effects on joint destruction are probably due to inhibition of DHFR activity of critical cells that are involved in the pathogenesis of rat arthritis induced either by adjuvant or by streptococcal cell walls. Some of these effects have been extended to human arthritis but additional studies are required to understand how low dose methotrexate exerts its beneficial effects in humans.

Animals↗

PubMed1994

Comparison of oral pulse methotrexate with placebo in the treatment of severe glucocorticosteroid-dependent asthma.

BACKGROUND: This study compared the efficacy of weekly oral administration of methotrexate and placebo in treatment of 24 subjects with chronic glucocorticosteroid-dependent asthma. METHODS: The 33-week randomized, double-blind, placebo-controlled crossover trial compared once weekly 15 mg doses of methotrexate with placebo. At the time of entry, the subjects' mean dosage of prednisone was 23.8 mg/day (range, 12.5 to 85 mg) and glucocorticosteroid therapy had been used continuously for a mean duration of 78 months (range, 5 to 360 months). RESULTS: Of the 21 subjects who completed the study, 13 tolerated lower daily prednisone doses during methotrexate treatment compared with placebo. When treated with methotrexate, subjects required 14.2% less prednisone than when treated with placebo (p = 0.0447), their subjective symptom scores improved 21.4% (p < 0.05), and mean forced expiratory volume in 1 second values tended to improve. Mean serum theophylline levels did not change significantly between the methotrexate and placebo arms of the study. Adverse effects were minimal, with nausea and headache occurring twice as often during methotrexate therapy compared with placebo. CONCLUSION: Short-term, low-dose, pulse therapy with orally administered methotrexate results in a decrease in the daily glucocorticosteroid requirement in a majority of subjects with severe asthma and is accompanied by improvement in subjective symptom scores without unacceptable side effects or deterioration of pulmonary function.

Administration, Oral↗

PubMed1989

The effect of methionine on methotrexate metabolism in rat hepatocytes in monolayer culture.

The effect of methyl donors on the metabolism of methotrexate has been investigated in rat hepatocytes in monolayer culture. Pulse exposure to low concentrations of methotrexate (1 microM, 3h) in the absence of methionine results in the facile formation of the di- to pentaglutamates with the di- and triglutamate predominating. Further incubation after the removal of methotrexate (MTX) results in a shift to the tetra- and pentaglutamate at the expense of the shorter chain length derivatives. The same measurement in the presence of 1 mM methionine causes approx. an 80% inhibition in the formation of polyglutamates. This effect can be partially achieved when methionine is replaced by choline or betaine. No alteration in the formation of 7-hydroxymethotrexate could be detected by similar changes in methionine concentrations in the medium. The activity of the enzymes which synthesize and degrade methotrexate polyglutamates, folylpolyglutamate synthetase and gamma-glutamyl hydrolase, respectively, were the same in extracts of cells grown in the absence and in the presence of 1 mM methionine. Incubation of the hepatocytes with methionine causes a significant increase in 5,6,7,8-tetrahydrofolate (H4folate), 5,10-methylenehydrofolate and 10-formyltetrahydrofolate and a decrease in 5-methyltetrahydrofolate. These results suggest that the inhibition of glutamylation of methotrexate could be due in part to an elevation in reduced folates which can more effectively compete with methotrexate as a substrate for folylpolyglutamate synthetase. Inhibition in methotrexate glutamylation by methionine, betaine and choline in hepatocytes may contribute to the alleviation of hepatic toxicity by methyl donors.

Animals↗

PubMed1996

[Individual dose adjustment of high-dose methotrexate in clinical practice].

Since its discovery in 1948 the clinical applications of methotrexate have widened; and in order to overcome resistances to methotrexate, the concept of high-dose methotrexate has been proposed. The use of rescue by folinic acid, as well as rapid dosage of MTX coupled with pharmacokinetic studies, have permitted us to administer an optimum dose of drug, with maximum therapeutic effects, but with reduced toxicity. Individual adaptation of posology, calculated using the test dose or according to population pharmacokinetic with a Bayesian method of parameter estimation (which allows us to adjust the dose of high-dose methotrexate during its infusion) permits control of inter and intra-individual variations of this drug. After analysis of the different methods proposed, we now present the results of 778 courses of treatment by high-dose methotrexate (while separating 238 courses for osteosarcoma as these formed a homogeneous group of patients). Theoretical maximum concentration and length of infusion were decided by physicians, followed by individual adaptation of posology by pharmacologists at the sixth hour of infusion of methotrexate. This treatment unites maximum security for the patient with no serious side effects (no grade 4 toxicity according to WHO classification), while receiving an optimum dose of methotrexate. In courses of MTX for osteosarcoma, the dose of MTX can be further intensified without risk, by administering on average 65% more than the usual dose in adults (8 g/m2) and 10% more than the usual dose in children (12 g/m2).

Antimetabolites, Antineoplastic↗

PubMed1991

Mechanisms of acquired resistance to methotrexate in a human squamous carcinoma cell line of the head and neck, exposed to different treatment schedules.

Mechanisms of acquired resistance to methotrexate (MTX) were evaluated in HNSCC-11B cells which were made resistant to methotrexate either by continuous (11B-MTX-C) or by pulse exposure (11B-MTX-P) to the drug. 11B-MTX-C cells were 91-fold resistant to methotrexate and 30-fold or 49-fold crossresistant to trimetrexate and 10-EdAM, respectively. Dihydrofolate reductase (DHFR) activity was increased 63-fold in 11B-MTX-C cells together with a decrease in [3H]-methotrexate transport and folylpolyglutamate synthase (FPGS) activity (2.5-fold and 3.8-fold, respectively). Against two novel antifolates targetting enzymes other than DHFR, minor crossresistance was observed for ICI-198, 583, but full sensitivity was retained for DDATHF. 11B-MTX-P cells were 46-fold resistant to methotrexate and 47-fold crossresistant to ICI-198,583 in short-term drug exposure, but showed only minor changes in methotrexate sensitivity following prolonged drug exposure. The resistant phenotype in 11B-MTX-P cells were characterised by a 5.6-fold decrease in FPGS activity. These results suggest that different mechanisms of methotrexate resistance in HNSCC cells in vitro can be obtained dependent on the schedule of exposure to the drug.

Antineoplastic Agents↗

PubMed1992

Methotrexate alters the fatty acid composition of NC adenocarcinoma cells in culture.

The effects of methotrexate and indomethacin alone and in combination have been examined on the fatty acid (FA) composition of total cellular lipids in cultured NC adenocarcinoma cells. These studies show that methotrexate can alter the lipid content of cancer cells. Methotrexate 16 ng/ml incubated with NC cells for 2 days increased the content of various FAs. When used alone, indomethacin 1 microgram/ml or methotrexate 8 ng/ml had no significant effect, but in combination caused FA increases, usually to about the same extent as with the higher concentration of methotrexate alone. No FA changes were seen up to 3 h with these drug concentrations or with methotrexate up to 10 micrograms/ml alone or with INDO 1 microgram/ml. These effects may explain previous findings that indomethacin potentiates methotrexate, an interaction which may be important in cancer therapy.

Animals↗

PubMed2004

Sirolimus and tacrolimus without methotrexate as graft-versus-host disease prophylaxis after matched related donor peripheral blood stem cell transplantation.

Methotrexate in combination with a calcineurin inhibitor is a standard graft-versus-host disease (GVHD) prophylactic regimen in allogeneic stem cell transplantation. However, methotrexate is associated with delayed engraftment, mucositis, idiopathic pneumonia syndrome, and other transplant-related complications. Sirolimus, a novel immunosuppressant without methotrexate's toxicities, has been used successfully in solid organ transplantation. We hypothesized that replacing methotrexate with sirolimus would preserve effective prophylaxis of GVHD while minimizing transplant-related toxicity after allogeneic peripheral blood stem cell transplantation. We enrolled 30 patients in a phase II study to test the efficacy of tacrolimus in combination with sirolimus in lieu of methotrexate in preventing GVHD after allogeneic peripheral blood stem cell transplantation from HLA-matched related donors. Grade II GVHD occurred in 3 patients (10%), and no patient developed grade III or IV GVHD. Neutrophil and platelet engraftment were prompt, occurring on days 14 and 13, respectively. All patients survived to hospital discharge (median, 18 days), and peritransplantation toxicity was mild. Four patients developed thrombotic microangiopathy, and 3 patients developed hepatic veno-occlusive disease. Chronic GVHD occurred in 11 patients. Relapse-free and overall survival at 100 days were 93% and 97%, respectively, and were 71% and 67% at 1 year. Causes of death included relapse (n = 6), veno-occlusive disease (n = 1), and late pulmonary toxicity (n = 1). Sirolimus in combination with tacrolimus is a promising alternative to methotrexate-based regimens for GVHD prophylaxis after matched related donor peripheral blood stem cell transplantation. Mucositis was modest, engraftment was prompt, and transplant-related toxicity was modest. Methotrexate-free, sirolimus-based GVHD prophylactic regimens should be tested in randomized trials against the current standard of care.

Adult↗

PubMed2006

High-dose methotrexate in pediatric acute lymphoblastic leukemia: impact of ABCC2 polymorphisms on plasma concentrations.

OBJECTIVE: The adenosine triphosphate-binding cassette (ABC) class transporter ABCC2 (MRP2 [multidrug resistance related protein 2] or cMOAT [canalicular multispecific organic anion transporter]) is involved in the cellular outward transport and elimination of methotrexate. We hypothesized that common genetic variations may contribute to the variability of high-dose methotrexate pharmacokinetics. METHODS: Polymorphisms in all 32 exons of the ABCC2 gene were analyzed in a reference group of 59 healthy white subjects by polymerase chain reaction, single-strand conformation polymorphism, and sequencing. Subsequently, we assessed the association of polymorphisms with the methotrexate plasma concentrations in 44 pediatric patients with acute lymphoblastic leukemia (ALL) (29 male and 15 female patients; mean age, 6.8+/-4.8 years). Patients received 4 cycles of 5000 mg/m2 body surface area according to the ALL-Berlin-Frankfurt-Muenster (BFM) 95 or ALL-BFM 2000 protocol. RESULTS: In the reference group we detected 8 frequent single-nucleotide polymorphisms. Five of these were in complete linkage disequilibrium. Overall, 5 new polymorphisms are described. The genotype distribution of the patient cohort was not significantly different from the reference collective. The mean plasma methotrexate area under the curve from 36 to 48 hours after the start of the infusion was significantly 2-fold higher in female patients carrying at least 1 -24T allele as compared with all other patients (14.2+/-12.8 h.micromol/L versus 6.9+/-4.2 h.micromol/L, P<.001). The risk to have 2 or more cycles necessitating an intensification of folinate rescue was 9-fold (95% confidence interval, 1.8- to 44-fold) in female patients carrying at least 1 T allele (P=.0067). CONCLUSION: The data suggest a hitherto unknown gender-specific impact of the -24C>T ABCC2 gene polymorphism on high-dose methotrexate pharmacokinetics. Whereas a nonfunctional MRP2 variant has been described in a patient with severe impairment of methotrexate excretion, our study is the first to suggest that a frequent ABCC2 polymorphism contributes to variability of methotrexate kinetics.

Adolescent↗

PubMed1997

Medical abortion with methotrexate 75 mg intramuscularly and vaginal misoprostol.

Methotrexate (50 mg/m2 intramuscularly and 50 mg orally) followed by vaginal misoprostol have proven to be > 90% effective at causing abortion in women at less than 49 days' gestation. Although the effectiveness of the oral dose (which has a lower serum bioavailability) demonstrates that a methotrexate dose of 50 mg/m2 may be more than necessary, an intramuscular regimen is more advantageous because it is less costly. This trial was designed to investigate the potential effectiveness of a single dose of methotrexate, 75 mg intramuscularly, in a regimen for early abortion. One hundred subjects received 75 mg methotrexate intramuscularly followed 5 to 6 days later by 800 micrograms misoprostol vaginally. The misoprostol dose was repeated if the abortion did not occur. Outcome measures included successful abortion (complete abortion without requiring a surgical procedure), duration of vaginal bleeding, and side effects. One subject was lost to follow-up. Complete abortion occurred in 94 of 99 (94.9%, 95% CI 90.6, 99.3%) patients. The complete abortion rate was no different for earlier gestations: 38 of 40 (95.0%, 95% CI 88.2, 100%) at up to 42 days' gestation and 56 of 59 (94.9%, 95% CI 89.3, 100%) at more than 42 days' gestation (p = 0.99). Abortion occurred in the 24 h following the initial or repeat misoprostol dose (immediate success) in 70.7%; the remaining 24.2% of women who aborted did so after a delay of 22 +/- 10 days (mean + standard deviation). Vaginal bleeding lasted 17 +/- 8 days and 11 +/- 7 days in immediate success and delayed success patients, respectively. Overall, 77.8%, 86.9%, and 91.9% of patients had passed the pregnancy by 14, 28, and 35 days, respectively, after receiving methotrexate. This preliminary evaluation demonstrates that a medical abortion regimen using 75 mg methotrexate intramuscularly appears to have similar effectiveness to one with 50 mg/m2 methotrexate.

Abortifacient Agents, Nonsteroidal↗

PubMed1998

Oral methotrexate and vaginal misoprostol for early abortion.

A prospective trial including 300 pregnant women seeking elective abortion was conducted to evaluate the safety and efficacy of methotrexate and misoprostol for abortion at < or = 63 days' gestation. Subjects received methotrexate 50 mg orally and were randomly allocated to receive 800 micrograms of misoprostol vaginally 3, 4, or 5 days after administration of the methotrexate. The misoprostol dose was repeated 48 and 96 h later if abortion did not occur. Outcome measures included successful abortion (complete abortion without requiring a surgical procedure) and side effects. Complete abortion occurred in 273 of 300 patients (91%, 95%, CI 87, 94%) patients. No significant statistical differences were found in the success rates when misoprostol was given days 3, 4, or 5 after the administration of methotrexate (p = 0.69). Vaginal bleeding lasted 7.1 +/- 3.8 days, spotting 4.1 +/- 2.5 days, and total bleeding 11.2 +/- 4.1 days. Side effects for methotrexate were minimal, whereas, for misoprostol they were mild and transient except for pain. The use of methotrexate and misoprostol together could be an alternative to the intramuscular use of methotrexate or the use of antiprogestins and prostaglandin for medical abortion.

Abortifacient Agents, Nonsteroidal↗

PubMed2001

Prophylactic methotrexate after linear salpingostomy: a decision analysis.

OBJECTIVE: To compare two strategies for managing women after linear salpingostomy for treatment of tubal pregnancy: observation and prophylactic methotrexate. DESIGN: Decision analysis. SETTING: Outpatient tertiary-care center. PATIENT(S): One thousand hypothetical women treated with a linear salpingostomy for ectopic pregnancy. INTERVENTION(S): Observation after salpingostomy and treatment of persistent ectopic pregnancy with a single dose of methotrexate (current standard of care) versus treatment with prophylactic methotrexate at the time of salpingostomy. MAIN OUTCOME MEASURE(S): Number of ruptured ectopic pregnancies, surgical procedures, complications, and cost for each group (observation vs. prophylaxis). RESULT(S): Prophylactic methotrexate results in fewer cases of tubal rupture (0.4% vs. 3.7%) and fewer procedures (1.9% vs. 4.7%) at a lower cost ($67.55 less/patient) compared with observation alone. Methotrexate-associated complications occur more frequently with prophylaxis (5.5% vs. 0.8%). Certain conditions change which strategy is preferable. Observation is the best strategy when the persistent ectopic pregnancy rate is <9%, the success of prophylaxis is <95%, the complication rate associated with methotrexate is >18%, or the rupture rate of persistent ectopic pregnancies is <7.3%. CONCLUSION(S): Prophylactic methotrexate at the time of linear salpingostomy for the treatment of ectopic pregnancy is preferable to observation as long as certain conditions exist.

Abortifacient Agents, Nonsteroidal↗

PubMed1999

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

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

Alanine Transaminase↗

PubMed1997

Low-dose methotrexate therapy for childhood sarcoidosis.

OBJECTIVE: To evaluate the effectiveness of low oral doses of methotrexate as a steroid-sparing agent in children with sarcoidosis. STUDY DESIGN: An open-label, noncontrolled trial. Methotrexate was administered orally at a single weekly dose of 10 to 15 mg/m2. Duration of therapy was open ended, but patients received treatment for a minimum of 6 months to be considered as having completed the study. RESULTS: Seven children with biopsy-proven sarcoidosis completed the study. The mean dose of prednisone was successfully tapered from 49 mg/day (1.3 mg/kg) to 18 mg/day (0.5 mg/kg) after 3 months of methotrexate therapy and to 9.9 (0.2 mg/kg) and 7.3 mg/day (0.1 mg/kg) after 6 months and at the end of the follow-up period, respectively. Other clinical and laboratory parameters improved significantly after methotrexate therapy was started. There was significant clinical improvement, as confirmed by the reduction of the clinical severity score from 8 +/- 1.1 to 0.8 +/- 0.5 point after 3 months of methotrexate therapy, and to 0.7 and 0.5 +/- 0.3 point after 6 months and at the end of the follow-up, respectively. Laboratory measurements revealed marked improvement, as reflected by a significant reduction in the erythrocyte sedimentation rate and an increase of hemoglobin values. The mean serum angiotensin-converting enzyme activity dropped significantly. No adverse side effects were noted with methotrexate therapy. CONCLUSION: Our study demonstrated that low-dose oral methotrexate therapy was effective and safe and had steroid-sparing properties in seven children with sarcoidosis.

Administration, Oral↗

PubMed1998

Methotrexate in patients with Crohn's disease after 6-mercaptopurine.

OBJECTIVE: The objective of this study was to describe the clinical outcome of children with Crohn's disease treated with subcutaneous methotrexate. SUBJECTS/METHODS: Fourteen patients (10 boys) with extensive Crohn's disease diagnosed at a mean age of 10.6 +/- 3.6 years had previously received various medical therapies for 4.3 +/- 4.0 years. Because of the severity of their disease, 6-mercaptopurine had been introduced but discontinued because of the patients' failure to respond (n = 11) or the development of pancreatitis (n = 3). Subsequently, low-dose, weekly, subcutaneous methotrexate was initiated. Pediatric Crohn's Disease Activity Index scores and prednisone requirement were followed as outcome measures. RESULTS: Overall, 9 (64%) of the 14 patients showed improvement, including 6 (55%) of 11 patients who had previously received an adequate trial of 6-mercaptopurine and all three patients who were intolerant of 6-mercaptopurine. Improvement in clinical and laboratory measures occurred by 4 weeks and were similar whether (n = 8) or not (n = 6) the dose of corticosteroids was increased before the start of subcutaneous methotrexate. Three patients were tapered from their initial methotrexate dose after the minimization of corticosteroids and remain well. One patient receiving daily corticosteroids died suddenly after acute onset of illness. Among patients responding, methotrexate was discontinued because of side effects (n = 2) or electively (n = 2). Of the latter two patients, one has resumed methotrexate after disease relapse, whereas the other patient has had a sustained remission. CONCLUSIONS: Low-dose, weekly, subcutaneous methotrexate can induce remission in some pediatric patients with Crohn's disease who fail to adequately respond to other immunomodulator medications.

Adolescent↗