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PubMed2000

Radiation recall dermatitis induced by methotrexate in a patient with Hodgkin's disease.

Radiation recall dermatitis refers to an inflammatory skin reaction at a previously irradiated field subsequent to chemotherapy administration. A number of antineoplastic agents have been reported to cause this phenomenon. We observed radiation recall dermatitis in a patient with stage IV nodular sclerosing Hodgkin's disease after methotrexate therapy for acute graft-versus-host disease (GVHD) prophylaxis. The patient had previously undergone matched related bone marrow transplantation with busulfan and cyclophosphamide as a preparative regimen. Subsequently, she received cyclosporine and methotrexate for acute GVHD prophylaxis. Two areas of skin previously irradiated to 3,000 cGy developed radiation recall dermatitis after two doses of methotrexate given 2 days apart and exacerbated by the third and fourth doses. This reaction occurred 34 days after the last dose of radiation therapy (RT). We believe this is the first case of radiation recall dermatitis after methotrexate therapy. Given the increased use of methotrexate in several neoadjuvant and adjuvant protocols in association with RT, its potential to produce radiation recall reactions should be considered.

Adult↗
PubMed2001

Methotrexate osteopathy demonstrated by Technetium-99m HDP bone scintigraphy.

The authors report a case of methotrexate osteopathy as revealed by Tc-99m HDP bone scintigraphy in a patient with rheumatoid arthritis. Methotrexate is used widely in high doses as a chemotherapeutic agent. Lower doses are given in rheumatoid and psoriatric arthritis. Methotrexate affects bone metabolism, resulting in methotrexate osteopathy, characterized by osteoporosis, osseus pain, and even spontaneous (micro)fractures. Radiographic visualization of microfractures is difficult. Tc-99m HDP bone scans have been shown to be very sensitive in the visualization of changes in bone metabolism as a result of methotrexate osteopathy.

Antirheumatic Agents↗
PubMed1979

Methotrexate-induced diffuse interstitial pulmonary fibrosis.

Three patients received respectively 190 mg, 175 mg, and 196 mg of methotrexate and developed bilateral pulmonary infiltrates without evidence of peripheral blood eosinophilia. Sputum in the three cases failed to reveal acid-fast bacilli, pathogenic fungi, or opportunistic organisms by cultures and appropriate stains. Despite discontinuance of the drug and/or institution of corticosteroid therapy, progressive respiratory failure led to death. In all three cases, autopsy revealed gross and microscopic features indistinguishable from those seen in the Hamman-Rich syndrome, and methotrexate hepatotoxicity was present in one. Pulmonary eosinophilia or granulomas, classically seen in previously reported cases of methotrexate pneumonitis, were not observed. It is suggested therefore that methotrexate be added to the list of agents capable of inducing diffuse interstitial pulmonary fibrosis. Conversely, diffuse interstitial pulmonary fibrosis should be considered in the differential diagnosis of patients receiving methotrexate who develop bilateral pulmonary infiltrates seen on chest roentgenograms.

Aged↗
PubMed1983

Mechanisms of immunological eradication of a syngeneic guinea pig tumor. II. Effect of methotrexate treatment and T cell depletion of the recipient on adoptive immunity.

The influence of methotrexate on the development of immunity to the line 10 hepatoma was studied in guinea pigs. Chronic methotrexate treatment had no apparent effect on the ability of immune guinea pigs to suppress the growth of inoculated tumor cells. In contrast, the same methotrexate regimen inhibited the development of tumor immunity if started before the 8th day after immunization with a vaccine containing viable line 10 cells admixed with Bacillus Calmette-Guérin (BCG) cell walls. Thus, methotrexate selectively inhibited the afferent limb of the immune response. In adoptive transfer experiments, methotrexate-treated recipient guinea pigs were capable of being passively sensitized with immune spleen cells, indicating that the primary cell-mediated immune response of the recipient was not required for adoptive immunity. The contribution of recipient T cells in adoptive immunity was further investigated in guinea pigs deleted of T cells by thymectomy, irradiation, and bone marrow reconstitution. Despite demonstrable deficiency in T lymphocyte reactions, "B" animals were fully capable of rejecting tumors after transfer of immune cells. These results suggest that the expression of adoptive immunity was independent of recipient T cell participation. In addition, sublethal irradiation of immune spleen cells prior to adoptive transfer abolished their efficacy. Proliferation of transferred immune cells in the recipient may be essential for expression of adoptive immunity.

Animals↗
PubMed1984

Immunologic recovery in human marrow graft recipients given cyclosporine or methotrexate for the prevention of graft-versus-host disease.

Immunologic recovery was studied in ten patients with aplastic anemia and 23 patients with hematologic malignancy who received HLA-identical marrow grafts and cyclosporine postgrafting as prophylaxis against graft-versus-host disease. Cyclosporine , 12.5 mg/kg/day, was administered beginning on the day before marrow infusion and continued for 50 days, when it was tapered and discontinued by 6 months postgrafting . Results were compared with data from concurrent and previously described patients receiving methotrexate as prophylaxis for graft-versus-host disease. Patients treated with cyclosporine or methotrexate had lower-than-normal immunologic parameters and were not different from one another 3-5 months postgrafting . By 11 to 18 months after grafting lymphocyte counts had normalized in both groups. Serum IgA levels were low and IgG levels had normalized in methotrexate-treated patients, and IgM was normal in cyclosporine -treated patients. In vivo antibody production to T-dependent antigens and skin test responses to recall antigens continued to be impaired. The response to the neoantigen dinitrochlorobenzene was still impaired in patients treated with cyclosporine and normal in patients given methotrexate. These data suggest that immunologic recovery after marrow transplantation is similar in cyclosporine -treated and methotrexate-treated patients.

Antibodies, Viral↗
PubMedDate not supplied

Intermediate-dose methotrexate and intravenous 6-mercaptopurine chemotherapy for children with acute lymphoblastic leukemia who did not respond to initial induction therapy.

PURPOSE: To determine the complete remission rate of children with acute lymphoblastic leukemia (ALL) who were not induced into remission by initial therapy, when subsequently treated with intermediate-dose methotrexate and intravenous 6-mercaptopurine. PATIENTS AND METHODS: Children with B-precursor ALL who did not achieve initial remission after 4 or 6 weeks of standard three- or four-drug induction chemotherapy were entered on study. Therapy consisted of three doses at weekly intervals of methotrexate 1,000 mg/m2 over 24 hours followed by 6-mercaptopurine 1,000 mg/m2 over 8 hours 20 minutes. Patients achieving a partial remission could receive two additional weekly courses of methotrexate and 6-mercaptopurine. Initially, patients received weekly intrathecal chemotherapy, but the study was amended to include intrathecal therapy only at week 1. RESULTS: Nineteen patients were entered on study. All were evaluable for toxicity and response. There were seven complete remissions, four partial remissions, six patients with no response, and two children with progressive disease, for an overall complete remission rate of 37%. One patient was removed from the study after the second course of methotrexate and 6-mercaptopurine because of renal failure. Two patients had neurologic toxicity resulting in a study amendment. No patients subsequently experienced neurologic toxicity. CONCLUSIONS: Intermediate-dose intravenous methotrexate and intravenous 6-mercaptopurine can induce remission in some patients with ALL who experience initial induction failure. Features predicting complete remission, however, could not be identified.

Adolescent↗
PubMed2005

Anomalies associated with failed methotrexate and misoprostol termination.

BACKGROUND: Methotrexate and misoprostol are frequently used in combination for medical termination of pregnancy. Despite their frequent use, published information about low-dose exposures to these known teratogens is sparse and neonatal follow-up data are limited. We present neonatal outcomes in three infants from two different women who had failed medical terminations with methotrexate and misoprostol. CASES: A young gravida 1, para 0, presented with intrauterine pregnancy complicated by first-trimester exposure to oral methotrexate and vaginal misoprostol. Ultrasonography determined that the fetus had intrauterine growth restriction and ventriculomegaly. The infant had growth and developmental delays. A young gravida 4, para 3-0-0-3, also presented after first trimester exposure to methotrexate and misoprostol, and was found to have a twin gestation. The infants were noted to have multiple congenital anomalies, growth restriction, and developmental delay. CONCLUSION: Even single doses of methotrexate and misoprostol used in medical termination of pregnancy can be associated with multiple congenital anomalies.

Abortion, Incomplete↗
PubMed2005

Treatment of metastatic gestational choriocarcinoma with oral methotrexate in a combat environment.

BACKGROUND: Gestational trophoblastic neoplasia (GTN) is a rare neoplastic complication of pregnancy. This disease can be successfully treated with parenteral intravenous or intramuscular chemotherapy. We present a case of metastatic gestational choriocarcinoma following a term pregnancy that was treated successfully with oral methotrexate therapy. CASE: A 25-year-old, G4 P4, native Afghani with a history of irregular menses since the birth of her son 6 months ago received a physical examination that was within normal limits. Pelvic examination revealed minimal blood in the vault and slight bleeding from a closed cervical os. The uterus was slightly enlarged, 5 weeks in size, and without any adnexal masses. Laboratory evaluation was significant for a positive urine and serum beta-HCG. Pelvic ultrasound examination revealed a 5-cm uterus with a 2-cm endometrial stripe. Chest radiograph revealed multiple bilateral ill-defined pulmonary nodules confirmed by computerized tomography. The patient underwent dilation and curettage productive of a moderate amount of tissue. The patient continued to have positive serum beta-HCGs and was given the presumptive diagnosis of FIGO stage III gestational choriocarcinoma. Because of the lack of intravenous chemotherapeutic agents, the patient was begun on methotrexate 0.40 mg/kg orally on days 1-5, with 9 days off. The patient completed one course of chemotherapy, followed by an interval total abdominal hysterectomy with bilateral salpingo-oophorectomy. The patient had a complete response to therapy and was treated with oral methotrexate for 2 courses after a negative serum beta-HCG. The patient tolerated the chemotherapy without any complication. CONCLUSION: Methotrexate is routinely used in a parenteral intramuscular fashion for the treatment of gestational choriocarcinoma. Physicians should be aware that, in very limited situations, oral methotrexate in combination with hysterectomy still could offer a patient successful treatment for stage III GTN.

Administration, Oral↗
PubMed2006

Methotrexate, bleomycin, and Etoposide in the treatment of gestational trophoblastic neoplasia.

OBJECTIVE: The combination of methotrexate (1 g/m(2) day 1), bleomycin (10 mg day 3), and etoposide (100 mg/m(2) days 1-5) (MBE) has been used for disease relapse or as a second-line chemotherapy in the treatment of gestational trophoblastic neoplasia (GTN) resistant to multiple-agent chemotherapy. With the identification of ultra-high-risk GTN, MBE has also been used as first-line chemotherapy. The current study is to review the use of MBE in the treatment of GTN. METHODS: Patients who received MBE for GTN between 1985 and 2003 in Queen Mary Hospital were included in this study. Records were reviewed and data were analyzed. Outcomes including response rate, treatment complications, and survival were assessed. RESULTS: Methotrexate, bleomycin, and etoposide therapy was given as first line to 4 patients with ultra-high-risk GTN. Three responded to the treatment and remained disease free. Methotrexate, bleomycin, and etoposide were given as a second-line therapy to 8 patients who had drug resistance to the initial therapy. Seven responded, and 6 remained disease free at 5 years. Methotrexate, bleomycin, and etoposide were given as a second-line therapy to 8 patients who relapsed 2-18 months after their initial therapy. Seven patients responded, and 4 remained disease-free at 5 years, 2 defaulted, and one died of carcinoma of the colon. Of the 20 patients who received MBE, 12 developed grade 3/4 neutropenia, and 4 developed grade 3/4 thrombocytopenia. The overall response rate for MBE was 85%. CONCLUSION: Methotrexate, bleomycin, and etoposide should be considered as a second-line therapy in patients who have drug-resistant or recurrent GTN.

Adult↗
PubMed1989

Differences in the biochemical activity in hairless mouse skin and other organs after systemic and topical methotrexate treatment.

DNA synthesis in epidermis, spleen, small intestine, and muscle of the hairless mouse was measured after systemic and topical methotrexate dosing. Mice intraperitoneally injected with methotrexate (5 mg/Kg) incorporated 3H-UdR in epidermis at 90% of baseline at 3 hrs, and the incorporation was not suppressed at 24 hrs. Muscle DNA synthesis was not suppressed. In the spleen and small intestine, incorporation was greatly suppressed to 10% at 3 hrs. On the other hand, after topically applied methotrexate (25 mg/Kg) treatment, epidermis and muscle were 60-90% of baseline at 3-24 hrs and spleen and small intestine were 5-10% at 3-6 hrs. In a prolonged time schedule study (4 days), epidermal incorporation after intraperitoneally applied methotrexate (5 mg/Kg) showed no suppression, but was instead stimulated to 180% at 2 days. 5-Fluorouracil, a thymidine kinase inhibitor in antitumor agents, was topically applied (25 mg/Kg) and compared for DNA synthesis. The incorporation of 3H-UdR was drastically suppressed at 3 hrs. The results suggest that methotrexate is percutaneously absorbed, but does not extensively suppress epidermal DNA synthesis in hairless mice, although it does suppress spleen and intestinal DNA synthesis.

Administration, Topical↗
PubMed2006

Liver injury in long-term methotrexate treatment in psoriasis is relatively infrequent.

BACKGROUND: Methotrexate-induced liver damage in psoriasis has led to dermatologic guidelines that stipulate monitoring of liver injury by means of serial liver biopsies. Recent literature data suggest that methotrexate may be considerably less hepatotoxic than previously assumed. AIM: To evaluate prevalence and development of liver injury in methotrexate treated psoriasis. METHODS: Retrospective chart review (1976-2005). RESULTS: Hundred and twenty-five patients (F58/M67; mean age 45.0, SD 12.7 years) received a median cumulative methotrexate dose of 2,113 mg (range 180-20 235) over a median period of 228 weeks (range 16-1763). Two hundred and seventy eight liver biopsies were analysed and 71% were classified as Roenigk grade I, 14% as Roenigk II, 14% grade IIIa, 2% grade IIIB and 2% grade IV. Liver injury was not associated with cumulative dose, weekly prescribed dose, age or duration of treatment. Obesity and diabetes were significant risk factors for liver injury. A total of 68 patients had multiple biopsies, 3% improved, 72% did not change and in 25% liver histology deteriorated. The majority of cases (84%) that progressed to Roenigk 2 had a cumulative dose of 1,500-6,000 mg. CONCLUSIONS: Methotrexate-related liver injury is less frequent than previously thought and mostly occurred at cumulative dose of <6,000 mg. Diabetes and being overweight are significantly correlated with liver injury.

Chemical and Drug Induced Liver Injury↗
PubMed1994

Methotrexate disposition following concomitant administration of ketoprofen, piroxicam and flurbiprofen in patients with rheumatoid arthritis.

The effects of three non-steroidal anti-inflammatory drugs (NSAIDs) on the pharmacokinetics of methotrexate were studied in 10 patients with rheumatoid arthritis. Ketoprofen (3 mg kg-1 day-1), flurbiprofen (3 mg kg-1 day-1), piroxicam (20 mg day-1), or a non-NSAID control (paracetamol/acetaminophen) were administered to patients for at least 6 days (13 days in the case of piroxicam to establish steady state) in a randomized crossover design prior to receiving a weekly oral dose of methotrexate. In the non-NSAID control portion of the study, MTX oral clearance (CLo) was 11.0 +/- 3.9 l h-1, renal clearance (CLR) was 7.9 +/- 2.8 l h-1, percent excreted unchanged was 72 +2- 19% and fraction unbound (fu) was 0.54 +/- 0.11. Values of oral clearance, renal clearance, fraction unbound and percentage excreted unchanged of methotrexate varied no more than 12.2% from non-NSAID control during concomitant administration of ketoprofen, flurbiprofen or piroxicam and were not statistically different from non-NSAID control. In contrast to other NSAIDs such as ibuprofen and salicylates, ketoprofen, flurbiprofen or piroxicam in clinically relevant doses do not appear to affect methotrexate disposition and may be used safely in combination with methotrexate.

Administration, Oral↗
PubMed1983

Effects of methotrexate in vitro on epidermal cell proliferation.

Epidermal cell migration activity and epidermal cell proliferation are clearly dissociable in explant culture. Epidermal cell migration requires a non-dialysable, 65,000 mol. wt factor which is destroyed at 100 degrees C but is stable at 80 degrees C for at least 30 min. In the presence of dialysed serum or heated (80 degrees C for 30 min) or DNA synthesis inhibitors (methotrexate or hydroxyurea), cells will migrate from the explant but will not proliferate. At least two factors are required for normal proliferation under these restricted conditions--an adequate supply of DNA precursers, i.e. nucleosides, and a heat liable (80 degrees C) non-dialysable serum component. Methotrexate in concentrations of 1.0 microgram/ml or greater added to cultures in normal fetal calf serum significantly inhibited mitoses; however, when added to serum dialysed to remove thymidine, mitotic inhibition occurred at a concentration of 0.1 microgram/ml of methotrexate and when added to dialysed serum and kept in dialysed serum, inhibition occurred with 0.01 microgram/ml of methotrexate. Methotrexate did not inhibit outgrowth. Hydroxyurea also inhibited mitoses but did not effect outgrowth.

Animals↗
PubMed2005

Monitoring patients on methotrexate: hepatic fibrosis not seen in patients with normal serum assays of aminoterminal peptide of type III procollagen.

BACKGROUND: The aminoterminal peptide of type III procollagen (PIIINP) is formed during the synthesis of type III collagen and can be measured in the serum. It has been used as a marker for hepatic fibrosis in patients on long-term methotrexate and it has been suggested that serial assay of PIIINP could reduce or eliminate the need for liver biopsies in these patients. OBJECTIVES: To determine whether routine use of the PIIINP assay in a cohort of patients on methotrexate would reliably identify those who were developing hepatic fibrosis and exclude those who were not, thereby reducing or eliminating the need for liver biopsies in this latter group. METHODS: Data were available from a clinical series of 38 patients on methotrexate, who had undergone a total of 70 liver biopsies and 306 PIIINP assays. Liver biopsies were graded using the Roenigk classification. RESULTS: In 34 patients, the findings on 46 liver biopsies could be compared with the results of contemporaneous PIIINP assays. Apart from two biopsies from two patients where fibrosis was no longer detected on a subsequent biopsy, all four biopsies showing fibrosis had abnormal results on over half of the associated PIIINP assays. There were no biopsies showing fibrosis where all associated PIIINP assays were normal. However, 50% of biopsies without fibrosis had at least one abnormal associated assay. In 23 patients, the results of serial PIIINP assays performed between two sequential liver biopsies were correlated with changes in the biopsy in terms of fibrosis. Data were available for 32 pairs of liver biopsies. Apart from a biopsy pair in one patient where fibrosis on the second biopsy was not detected on a third biopsy, all four biopsy pairs defined as showing deterioration had abnormal results on over half of the intervening PIIINP assays. There were no biopsy pairs showing deterioration where all intervening assay results were normal. However, 63% of stable biopsy pairs had at least one abnormal intervening assay. Two patients with nonalcoholic steatohepatitis, which manifests a pattern of fibrosis not scored under the Roenigk classification, had persistently and substantially elevated PIIINP levels. CONCLUSIONS: The data presented support the view that follow-up liver biopsies, as recommended by published guidelines, for patients on long-term low-dose methotrexate can be avoided if PIIINP levels are consistently normal. This approach would have reduced the number of patients requiring biopsy in our series by 45%. The PIIINP assay will also be helpful in the management of patients on methotrexate in whom liver biopsy is contraindicated, and in patients with nonalcoholic steatohepatitis.

Adult↗
PubMed2006

Methotrexate and ciclosporin combination for the treatment of severe psoriasis.

BACKGROUND: Psoriasis is a chronic skin disease that often requires long-term therapy to control the symptoms. Combination therapies for severe psoriasis have advantages for disease control and are thought to reduce long-term side-effects. OBJECTIVE: To assess the efficacy and side-effects of methotrexate plus ciclosporin used in combination for the treatment of severe psoriasis. METHODS: In this prospective study, 20 patients were treated with the combination of methotrexate and ciclosporin. Methotrexate was given intramuscularly as a single weekly dose of 10 mg and ciclosporin at a dose of 3.5 mg/kg/day in two equally divided doses. Clinical response was assessed according to clinical outcome and the Psoriasis Area and Severity Index which were evaluated at the beginning of therapy (PASI1), after cessation of one agent (PASI2), and at the end of therapy (PASI3). RESULTS: All the patients had previously received one or more systemic treatment. There were 10 women and 10 men (mean age 44 years). The median (minimum to maximum) duration of methotrexate and ciclosporin treatments were 12.5 (4-55) and 14.0 (4-80) weeks, respectively. Median duration of combination therapy was 9.5 weeks (range 4-50). The median of previously used and end-of-study cumulative doses of methotrexate were 181.8 mg (range 0-785) and 330.8 mg (range 50-845), respectively. The median PASI scores were decreased by 77.4% (range 51.2-90.2) and 75.9% (range 10.1-100) at PASI2 and PASI3, respectively. CONCLUSION: Patients with severe psoriasis had clinically significant improvement after the initiation of combination therapy. Healing rate was decreased upon cessation of one of the medications. Short-term side-effects were minor, transient and manageable. Long-term follow-up of patients treated with this combination is needed.

Adult↗
PubMed1994

High-dose methotrexate treatment and liver function in patients with osteosarcoma.

OBJECTIVES: To study the effects of short-term high-dose methotrexate therapy on liver function in patients with osteosarcoma. DESIGN: Open prospective study. SETTING: Department of Internal Medicine and Oncology, Istituto Ortopedico Rizzoli, Bologna, Italy. SUBJECTS: Fourteen patients with osteosarcoma, with no evidence of previous or actual liver disease at the time of diagnosis. INTERVENTIONS: All patients received a cumulative dose of 30-57 gm-2 of methotrexate within 6 months as neo-adjuvant chemotherapy (pre- and post-surgery). Each course of chemotherapy included methotrexate at a dose of 8-12 gm-2 and, in addition, adriamycin and cisplatinum. MAIN OUTCOME MEASURES: Galactose elimination capacity and antipyrine clearance were measured at baseline, after the first course of chemotherapy, at the end of the pre-operative period and at the end of chemotherapy. In each case they were carried out after transaminase levels had returned to normal. RESULTS: Galactose elimination capacity decreased from 2.45 (+/- 0.48) mM min-1 to 2.04 (+/- 0.60) mM min-1 after the five planned courses of chemotherapy (P = 0.013, Wilcoxon signed-rank test), without any change in routine liver function tests. No differences in antipyrine clearance and half-life were demonstrated (n = 8). CONCLUSIONS: The data are consistent with a decreased reserve capacity of the liver after short-term, high-dose methotrexate. Long-term survivors deserve monitoring of liver function for safer methotrexate use, in the light of progressive dosage increments to improve prognosis in neoplastic diseases.

Adolescent↗
PubMed1988

Pancytopenia induced by low-dose methotrexate for rheumatoid arthritis.

Four cases of pancytopenia related to low-dose weekly pulse methotrexate therapy for rheumatoid arthritis are described. All patients were aged above 60 years and had renal impairment. In every case marrow recovery followed withdrawal of methotrexate. However, one patient developed pneumonitis and died. Cholangitis, respiratory infection and increase in methotrexate dose were precipitating factors. Pharmacokinetic data indicated prolonged tissue drug exposure in two cases studied; dose-related toxicity was further supported by successful resumption of methotrexate in reduced dosage in two cases. It is possible that methotrexate dose should be modified during intercurrent illness in patients older than 60 years who have renal impairment.

Aged↗
PubMed2000

Fertility outcome following combined methotrexate treatment of unruptured extrauterine pregnancy.

OBJECTIVE: To assess the effectiveness of systemic treatment with methotrexate in combination with local injection for unruptured tubal pregnancy, and to evaluate reproductive function following treatment. DESIGN: Prospective, open clinical study. SETTING: University clinic. POPULATION: Sixty-seven women with unruptured tubal pregnancy. METHODS: Systemic methotrexate (intramuscular methotrexate 0.5 mg/kg for up to five days) in combination with local application of 12.5 mg methotrexate via laparoscopy. MAIN OUTCOME MEASURES: The subsequent surgical intervention required and future fertility. RESULTS: In 89.6% of women no further surgical intervention was required and 47 women (81%) experienced subsequently an intrauterine pregnancy. In 39 of 40 women who underwent hysterosalpingography following treatment, patency of the affected tube was observed. CONCLUSIONS: Combined local and systemic methotrexate treatment for unruptured tubal pregnancy seems to be more effective than each therapeutic modality alone.

Abortifacient Agents, Nonsteroidal↗