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PubMed2000

A comparison of methotrexate with placebo for the maintenance of remission in Crohn's disease. North American Crohn's Study Group Investigators.

BACKGROUND: Patients with Crohn's disease often have relapses. Better treatments are needed for the maintenance of remission. Although methotrexate is an effective short-term treatment for Crohn's disease, its role in maintaining remissions is not known. METHODS: We conducted a double-blind, placebo-controlled, multicenter study of patients with chronically active Crohn's disease who had entered remission after 16 to 24 weeks of treatment with 25 mg of methotrexate given intramuscularly once weekly. Patients were randomly assigned to receive either methotrexate at a dose of 15 mg intramuscularly once weekly or placebo for 40 weeks. No other treatments for Crohn's disease were permitted. We compared the efficacy of treatment by analyzing the proportion of patients who remained in remission at week 40. Remission was defined as a score of 150 or less on the Crohn's Disease Activity Index. RESULTS: Forty patients received methotrexate, and 36 received placebo. At week 40, 26 patients (65 percent) were in remission in the methotrexate group, as compared with 14 (39 percent) in the placebo group (P=0.04; absolute reduction in the risk of relapse, 26.1 percent; 95 percent confidence interval, 4.4 percent to 47.8 percent). Fewer patients in the methotrexate group than in the placebo group required prednisone for relapse (11 of 40 [28 percent] vs. 21 of 36 [58 percent], P=0.01). None of the patients who received methotrexate had a severe adverse event; one patient in this group withdrew because of nausea. CONCLUSIONS: In patients with Crohn's disease who enter remission after treatment with methotrexate, a low dose of methotrexate maintains remission.

Adult↗

PubMed2002

Significant impairment of high-dose methotrexate clearance following vancomycin administration in the absence of overt renal impairment.

BACKGROUND: Methotrexate is an antimetabolite cytotoxic drug which is predominantly renally excreted. Vancomycin, a glycopeptide antibiotic that is used in the febrile neutropaenic patient, can be nephrotoxic. There are no previous reports of any interactions between these two drugs. PATIENTS AND METHODS: We describe two patients with osteosarcoma treated with high-dose methotrexate-containing chemotherapy who had significantly delayed methotrexate clearance several weeks following exposure to vancomycin. RESULTS: These patients were treated with alternating chemotherapy consisting of 12 g/m2 methotrexate, 60 mg/m2 cisplatin, 75 mg/m2 adriamycin and 15 g/m2 ifosfamide. In both patients, serum methotrexate levels fell to below 0.2 micromol/l within 48-96 h during initial treatment cycles. However, following recent exposure to therapeutic vancomycin in the preceding 10 days and in the absence of overt renal impairment, both patients manifested markedly prolonged methotrexate clearance, requiring 170-231 h to reach serum levels of less than 0.2 microM. Subclinical renal impairment was documented by impaired glomerular filtration rates in both cases by technetium 99 m diethylene triamine penta-acetic acid scanning. Subsequent methotrexate cycles using an unmodified schedule were cleared within 72 h. Both cases had their glomerular filtration rate re-assessed, which showed marked improvement. CONCLUSIONS: Recent exposure to vancomycin, even in the absence of overt renal impairment, may adversely affect methotrexate excretion, which can subsequently lead to increased toxicity of the antimetabolite. The glomerular filtration rate should be measured in such cases so that appropriate dose modification of methotrexate can be made.

Adult↗

PubMed2004

Treatment of accidental intrathecal methotrexate overdose with intrathecal carboxypeptidase G2.

The bacterial enzyme carboxypeptidase G2 (CPDG2) rapidly hydrolyzes methotrexate to inactive metabolites. We administered recombinant CPDG2 (2000 U) intrathecally to seven cancer patients 3 to 9 hours after they had received an accidental overdose of intrathecal methotrexate (median dose = 364 mg; range = 155-600 mg). Four of the seven patients had cerebrospinal fluid (CSF) exchange to remove methotrexate before CPDG2 administration. Immediate symptoms of the methotrexate overdoses included seizures (n = 5), coma (n = 2), and cardiopulmonary compromise (n = 2). Before CPDG2 administration, the median concentrations of methotrexate in CSF were 264 microM (range = 97-510 microM) among patients who had CSF exchange and 8050 microM (range = 2439-16 500 microM) among patients who did not. After intrathecal CPDG2 administration, methotrexate concentrations in CSF declined by more than 98%. All patients recovered completely from the intrathecal methotrexate overdose except for two patients who had memory impairments. Antibodies to CPDG2 were not detected in plasma after treatment with intrathecal CPDG2. Intrathecal CPDG2 is well tolerated, rapidly decreases CSF methotrexate concentrations, and appears to be efficacious for treating accidental intrathecal methotrexate overdoses.

Adult↗

PubMed1996

A phase I investigation of the sequential use of methotrexate and paclitaxel with and without G-CSF for the treatment of solid tumors.

BACKGROUND: Paclitaxel is a novel agent with significant activity in several solid tumors. Preclinical data suggested that methotrexate prior to paclitaxel would be synergistic. To determine the qualitative and quantitative toxicity of this regimen we performed a phase I study in patients with solid tumors. PATIENTS AND METHODS: Patients with solid tumors previously treated with no more than two prior chemotherapy regimens were given methotrexate intravenously on day 1, followed by paclitaxel, as a 24-hour infusion on day 2. The starting dose (level '0') was 40 mg/m2 for methotrexate and 135 mg/m2 for paclitaxel. RESULTS: After achieving a maximum tolerated dose, additional patients were enrolled with the addition of G-CSF 5 mu g/kg/d on days 4-13. At the starting dose level, dose-limiting toxicity consisting of neutropenic fever occurred in 3 of 4 patients. At dose level -1, methotrexate 30 mg/m2 and paclitaxel 110 mg/m2, neutropenic fever occurred in 7 of 10 patients during the first course. At dose level -2, methotrexate 23 mg/m2 and paclitaxel 85 mg/m2, neutropenic fever occurred in 1 of 7 patients. To abrogate the neutropenia we explored the same combination with the addition of G-CSF. Neutropenic fever remained the only dose-limiting toxicity. At dose level '0' with G-CSF, 1 of 7 patients developed dose-limiting toxicity. At dose level 1 plus G-CSF, methotrexate 40 mg/m2 and paclitaxel 170 mg/m2, dose-limiting neutropenic fever occurred in 4 of 6 patients. Partial responses occurred in 4 of 41 patients entered on this study. Pharmacokinetic data suggested that methotrexate did not increase paclitaxel levels. CONCLUSION: The combination of methotrexate and paclitaxel is feasible, but neutropenic fever, even with the addition of G-CSF prevents further escalations of paclitaxel beyond 135 mg/m2 following methotrexate.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2000

Do patients with rheumatoid arthritis established on methotrexate and folic acid 5 mg daily need to continue folic acid supplements long term?

BACKGROUND: It is postulated that some aspects of methotrexate toxicity may be related to its action as an anti-folate. Folic acid (FA) is often given as an adjunct to methotrexate therapy, but there is no conclusive proof that it decreases the toxicity of methotrexate and there is a theoretical risk that it may decrease the efficacy of methotrexate. OBJECTIVES: To look at the effect of stopping FA supplementation in UK rheumatoid arthritis (RA) patients established on methotrexate <20 mg weekly and FA 5 mg daily, to report all toxicity (including absolute changes in haematological and liver enzyme indices) and to report changes in the efficacy of methotrexate. METHODS: In a prospective, randomized, double-blind, placebo-controlled study, 75 patients who were established on methotrexate <20 mg weekly and FA 5 mg daily were asked to stop their FA and were randomized to one of two groups: placebo or FA 5 mg daily. Patients were evaluated for treatment toxicity and efficacy before entry and then at intervals of 3 months for 1 yr. RESULTS: Overall, 25 (33%) patients concluded the study early, eight (21%) in the group remaining on FA and 17 (46%) in the placebo group (P = 0.02). Two patients in the placebo group discontinued because of neutropenia. At 9 months there was an increased incidence of nausea in the placebo group (45 vs. 7%, P = 0.001). The placebo group had significantly lower disease activity on a few of the variables measured, but these were probably not of clinical significance. CONCLUSIONS: It is important to continue FA supplementation over the long term in patients on methotrexate and FA in order to prevent them discontinuing treatment because of mouth ulcers or nausea and vomiting. Our data suggest that FA supplementation is also helpful in preventing neutropenia, with very little loss of efficacy of methotrexate.

Aged↗

PubMed2000

A comparison of the efficacy and safety of leflunomide and methotrexate for the treatment of rheumatoid arthritis.

OBJECTIVE: To compare the clinical efficacy and safety of leflunomide and methotrexate for the treatment of rheumatoid arthritis (RA). METHODS: In this multicentre, double-blind trial, 999 subjects with active RA were randomized to leflunomide (n = 501; loading dose 100 mg/day for 3 days, maintenance dose 20 mg/day) or methotrexate (n = 498; 10-15 mg/week) for 52 weeks. After 1 yr the subjects could choose to stay for a second year of double-blind treatment. The primary end-points were tender and swollen joint counts and overall physician and patient assessments. Analyses were of the intent-to-treat group. RESULTS: After 1 yr, the mean changes in the leflunomide and methotrexate groups, respectively, were -8.3 and -9.7 for tender joint count; -6.8 and -9.0 for swollen joint count; -0.9 and -1.2 for physician global assessment; -0.9 and -1.2 for patient global assessment; -14.4 and -28.2 for erythrocyte sedimentation rate. Improvements seen with methotrexate were significantly greater than those with leflunomide. No further improvement occurred after the second year of treatment and the distinction between the two treatments in terms of tender joint count and patient global assessment was lost. During the first year of treatment, a small and equivalent degree of radiographically assessed disease progression was seen with both drugs. After 2 yr, disease progression was significantly less with methotrexate. The most common treatment-related adverse events in both groups were diarrhoea, nausea, alopecia, rash, headache, and elevated plasma liver enzyme levels. Over 2 yr, 21 subjects receiving methotrexate were withdrawn due to elevated plasma liver enzymes vs eight subjects taking leflunomide. Two drug-related deaths from pulmonary causes were recorded with methotrexate vs no drug-related deaths among the subjects receiving leflunomide. CONCLUSIONS: Both leflunomide and methotrexate are efficacious for prolonged treatment of RA. At the doses used, some clinical benefit of methotrexate over leflunomide was observed in the first year of treatment. This benefit must be weighed against the potential toxicity of this drug when used without folate supplementation.

Adolescent↗

PubMed2003

Systemic methotrexate exposure is greater after intrathecal than after oral administration.

PURPOSE: To compare systemic exposure after intrathecal and oral methotrexate administration. PATIENTS AND METHODS: We analyzed red cell methotrexate polyglutamate concentrations with a sensitive radioligand-binding assay in 80 patients enrolled in the Children's Cancer Group (CCG) trial 1922 for acute lymphoblastic leukemia. Methotrexate concentrations were measured 7 days after the last doses of intrathecal and oral routes, using patients as their own controls. Intrathecal methotrexate was given on an age-adjusted schedule. Data was normalized to the actual dose received per body surface area. RESULTS: The mean red cell methotrexate concentration 7 days after the last of four weekly intrathecal doses of methotrexate was 178 pmol/mL red blood cells, which was significantly greater than the result 7 days after subsequent weekly oral methotrexate of 122 pmol/mL (P = 0.00001). Intrathecal dosing resulted in an average systemic exposure ratio of 1.7 to 1 compared with oral administration. CONCLUSION: Intrathecal methotrexate administration results in significantly greater systemic exposure than oral administration. Our data support the hypothesis that the systemic effect of intrathecal methotrexate affects ALL therapy.

Administration, Oral↗

PubMed2005

Oral methotrexate in ulcerative colitis.

BACKGROUND: We performed an audit of methotrexate for ulcerative colitis, because efficacy is unclear. Aim : To investigate the role of methotrexate in the management of ulcerative colitis. METHODS: Patients with ulcerative colitis treated with oral methotrexate at the inflammatory bowel disease clinics of Oxford and Wycombe General Hospital, UK, were evaluated. Efficacy was defined by remission (complete steroid withdrawal for >3 months) and response (good, partial or nil, proportionate reduction of steroids). RESULTS: There were 50 patients (42 ulcerative colitis alone; eight had rheumatoid arthritis associated with ulcerative colitis and were analysed separately). Indications for methotrexate in ulcerative colitis alone were azathioprine intolerance (31 of 42) and lack of benefit from azathioprine (11 of 42). The mean dose of methotrexate in ulcerative colitis alone was 19.9 mg/week for a median of 30 weeks (range: 7-395). Remission occurred in 42%. The response was good in 54% and partial in 18%. Side-effects occurred in 23%; 10% stopped treatment because of side-effects. Of those treated with methotrexate because of treatment failure with azathioprine, three of 11 achieved remission, but four came to colectomy within 90 days of starting methotrexate. The colitis remained in remission in seven of eight of those with RA treated with methotrexate and ulcerative colitis (mean dose 15.0 mg/week). CONCLUSION: Oral methotrexate (approximately 20 mg/week) is well-tolerated and moderately effective in steroid-dependent or steroid-refractory patients with ulcerative colitis.

Adolescent↗

PubMed1994

PUVA and methotrexate therapy of psoriasis: how closely do dermatology departments follow treatment guidelines? Psoriasis Audit Workgroup of the British Association of Dermatologists.

Following publication of treatment guidelines for patients with psoriasis, a six-centre audit was undertaken to assess current therapeutic practice for two second-line treatments, PUVA and methotrexate. The audit consisted of random sampling of casenotes by external auditors from a paired dermatology department, and assessment by questionnaire. One hundred and eight PUVA and 118 methotrexate casenotes were audited. The commonest indications for treatment were: (a) failure of tropical therapy--PUVA (mean 81% of casenotes), methotrexate (84%); (b) repeated hospital admissions--PUVA (16%), methotrexate (25%). For both PUVA and methotrexate, some aspects of treatment were well documented: PUVA--psoralen dosage (91%), response to PUVA (89%), cumulative lifetime UVA dosage (81%); methotrexate--pretreatment assessment of full blood count (91%), urea and electrolytes (85%), liver function tests (84%). For other aspects documentation was less complete: PUVA--no documentation of presence/absence of skin cancer history (66%), note of photoactive drugs (32%); methotrexate--concurrent medication (69%), history of presence/absence of liver disease (36%). Another aspect which was poorly documented in both PUVA and methotrexate notes was whether advice on contraception/fertility had been given. There was no indication in 29 of 32 casenotes of females of child-bearing age receiving PUVA, and 52 of 63 case notes of relevant patients on methotrexate. This project has demonstrated that formal, multicentre audit based on published guidelines is a practical proposition.

Clinical Protocols↗

PubMed1987

Studies on the mechanism by which indomethacin increases the anticancer effect of methotrexate.

The effect of indomethacin on the response of the NC carcinoma to methotrexate has been examined in vivo and in vitro. Survival was prolonged in mice treated with indomethacin 1.25 mg kg-1 twice daily plus methotrexate 4 mg kg-1 daily, compared to mice given either drug alone or controls. Indomethacin 1 microgram ml-1 increased the killing of cultured NC cells by methotrexate. This was not due to displacement of methotrexate from binding sites on the serum proteins. Nor was it due (entirely) to inhibition of prostaglandin synthesis, since flurbiprofen did not mimic the effect. Inhibition of cyclic AMP phosphodiesterase seems unlikely to explain the effect of indomethacin since theophylline had little or no effect on NC cell killing by methotrexate. Indomethacin 1 microgram ml-1 increased the accumulation of tritium in NC cells incubated with [3H]-methotrexate. In contrast, with normal epithelial cells from human embryonic intestine, indomethacin 1 microgram ml-1 did not alter the cytotoxicity of methotrexate or the accumulation of tritium during incubation with [3H]-methotrexate. The beneficial interaction between indomethacin and methotrexate may have therapeutic potential in man.

Animals↗

PubMed1993

Treatment of antigen-induced arthritis in rabbits with liposome-entrapped methotrexate injected intra-articularly.

Rabbits with a bilateral antigen-induced arthritis were injected intra-articularly in one joint with methotrexate as the free drug or entrapped in liposomes. Free methotrexate (1 mg) injected as a single dose at the time of antigen challenge, suppressed the development of joint swelling and the rise in skin surface temperature of treated joints by 20-30% compared with contralateral control arthritic joints. The beneficial effect of methotrexate occurred within 24 h of injection and was maintained for at least 56 days. However, methotrexate was ineffective in suppressing arthritis when injected 7 days after antigen challenge. Liposomal methotrexate suppressed the development of arthritis at a dose one-tenth that of the free drug and it was also effective in suppressing arthritis of 7 days duration, although significant beneficial effects of liposomal methotrexate were delayed for 10 to 14 days after injection. Neither free nor liposomal methotrexate was effective in suppressing an established arthritis, having no significant effect on joint swelling or skin surface temperature when injected 21 and 35 days after antigen challenge. At the end of the study, 8 or 9 weeks after induction of arthritis, the joints were examined morphologically and histologically. Free methotrexate generally had no significant effect on joint pathology. However, liposomal methotrexate suppressed the development of synovial hyperplasia, cellular infiltration and the erosion of cartilage and bone when injected at the time of antigen challenge or 7 days later, but affected none of these parameters in an established arthritis of 3 weeks duration.

Animals↗

PubMed2002

Characterization of methotrexate transport and its drug interactions with human organic anion transporters.

Life-threatening drug interactions are known to occur between methotrexate and nonsteroidal anti-inflammatory drugs (NSAIDs), probenecid, and penicillin G. The purpose of this study was to characterize methotrexate transport, as well as to determine the site and the mechanism of drug interactions in the proximal tubule. Mouse proximal tubule cells stably expressing basolateral human organic anion transporters (hOAT1 and hOAT3) and apical hOAT (hOAT4) were established. The K(m) values for hOAT1-, hOAT3-, and hOAT4-mediated methotrexate uptake were 553.8 microM, 21.1 microM, and 17.8 microM, respectively. NSAIDs (salicylate, ibuprofen, ketoprofen, phenylbutazone, piroxicam, and indomethacin), probenecid, and penicillin G dose dependently inhibited methotrexate uptake mediated by hOAT1, hOAT3, and hOAT4. Kinetic analysis of inhibitory effects of these drugs on hOAT3-mediated methotrexate uptake revealed that these inhibitions were competitive. The K(i) values for the effects of salicylate, phenylbutazone, indomethacin, and probenecid on hOAT3-mediated methotrexate uptake were comparable with therapeutically relevant plasma concentrations of unbound drugs. In addition, in the presence of human serum albumin, the K(i) values were comparable with therapeutically relevant total plasma concentrations of drugs. In conclusion, these results suggest that methotrexate is taken up via hOAT3 and hOAT1 at the basolateral side of the proximal tubule and effluxed or taken up at the apical side via hOAT4. In addition, hOAT1, hOAT3, and hOAT4 are the sites of drug interactions between methotrexate and NSAIDs, probenecid, and penicillin G. Furthermore, it was predicted that hOAT3 is the site of drug interactions between methotrexate and salicylate, phenylbutazone, indomethacin, and probenecid in vivo.

Animals↗

PubMed1978

Refractory acute leukaemia in adults treated with sequential colaspase and high-dose methotrexate.

Thirty-nine adults with acute leukaemia who had relapsed when receiving extensive chemotherapy were treated with a combination of methotrexate and colaspase (L-asparaginase) given sequentially. Patients initially received 50-80 mg/m(2) methotrexate, followed three hours later by intravenous colaspase, 40 000 IU/m(2). Seven days later intravenous methotrexate, 120 mg/m(2) was given. Each dose of methotrexate was followed 24 hours later by colaspase, and the two-day course of treatment was repeated every 7-14 days. The methotrexate dose was increased to tolerance by increments of 40 mg/m(2) with each course, while the colaspase dose remained constant unless abnormal liver function developed, when it was reduced by half.Overall, 18 out of 39 patients achieved complete remission (46%). Of these, 13 out of 21 (62%) had acute lymphoblastic leukaemia, three out of seven (43%) acute undifferentiated leukaemia, and two out of 11 (18%) acute myeloblastic leukaemia. The median duration of complete remission was 20 weeks and the median duration of survival in complete responders was 45 weeks. The median number of courses needed to achieve complete remission was three. The maximum tolerated dose of methotrexate was 400 mg/m(2) (median 200 mg/m(2)). Major side effects were due to colaspase. Methotrexate in doses of up to 400 mg/m(2) caused minimal myelosuppression and stomatitis, which suggested that colaspase given sequentially provides relative protection from methotrexate toxicity without the need for folinic acid (citrovorum factor) rescue.The combination of sequential colaspase and methotrexate is highly effective in reinducing remission in patients with acute lymphoblastic leukaemia or acute undifferentiated leukaemia. The regimen is easy to administer and relatively non-toxic, so it is suitable for use in outpatients, either alone or combined with other agents.

Acute Disease↗

PubMed1997

Bronchoalveolar lavage cell profile in methotrexate induced pneumonitis.

BACKGROUND: Pneumonitis is a rare but potentially life threatening side effect of methotrexate treatment for rheumatoid arthritis which needs to be distinguished from interstitial lung disease due to rheumatoid arthritis. METHODS: To examine the value of bronchoalveolar lavage (BAL) in diagnosing methotrexate pneumonitis, the BAL cell profile of four patients with methotrexate pneumonitis was compared with findings in 16 patients with rheumatoid arthritis treated with methotrexate without clinical or radiological evidence of lung disease and eight patients with interstitial lung disease secondary to rheumatoid arthritis treated with methotrexate. RESULTS: Methotrexate pneumonitis was associated with an increase in the lymphocytes in the BAL fluid to 33-68% of total BAL cells. BAL lymphocytosis was also found in five patients in each of the two control groups. The four patients with methotrexate pneumonitis had a disproportionate increase in CD4+ cells to 72-84% of total lymphocytes and in the CD4/CD8 ratio to 17.0, 6.6, 8.7, and 4.0, respectively, figures which exceeded those of the two control groups. CONCLUSIONS: Methotrexate pneumonitis was associated with lymphocytic alveolitis with a preferential increase in CD4+ cells. This pattern differs from that in interstitial lung disease due to rheumatoid arthritis and may therefore assist in making an early diagnosis of methotrexate pneumonitis.

Aged↗

PubMed2005

Coadministration of lansoprazole and naproxen does not affect the pharmacokinetic profile of methotrexate in adult patients with rheumatoid arthritis.

Drugs prescribed for rheumatoid arthritis are often associated with gastrointestinal toxicity, and proton pump inhibitors may be coadministered for gastroprotection. In this open-label study, the effect of lansoprazole 30 mg qd and naproxen 500 mg bid on the pharmacokinetic profile of methotrexate was investigated. Twenty-seven adult rheumatoid arthritis patients on stable oral methotrexate doses (7.5-15 mg/week) for a minimum of 3 months were enrolled. Methotrexate pharmacokinetics were assessed on days -1 (methotrexate alone) and 7 (methotrexate with lansoprazole and naproxen). Pharmacokinetics of methotrexate and 7-hydroxymethotrexate were not altered by coadministration of methotrexate with lansoprazole and naproxen; point estimates and 90% confidence intervals for the peak plasma concentration and area under the plasma concentration-time curve of methotrexate and 7-hydroxymethotrexate were within the 0.80 to 1.25 boundaries. Therefore, coadministration of naproxen and lansoprazole for 7 days does not affect the pharmacokinetic profile of low doses of methotrexate.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed1993

Reversal of methotrexate-induced folate pool depletion by thymidine in a human leukemia cell line in vitro.

In an in vitro study using a human monocytic leukemia cell line, U-937, the effects of interferon-gamma (IFN-gamma) in combination with the antifolate methotrexate and the role of thymidine introduced as a biochemical modulator were investigated. Methotrexate alone or in combination with INF-gamma was found to enhance the induction of morphologic and functional monocytic differentiation in the U-937 cell line. Various cellular effects with the addition of thymidine to the medium with methotrexate and IFN-gamma were studied. Enhanced inhibition of cell growth and perturbation of the cell cycle were noted when methotrexate and IFN-gamma were used in combination, but not when methotrexate was used alone. The reduction of cellular folate by methotrexate was also enhanced in combination with IFN-gamma. Cell cycle delay, resulting in cell growth inhibition of folate depletion, caused the induction of differentiation in U-937 cells, which was found to be greater with methotrexate + IFN-gamma than with methotrexate alone. Cellular differentiation, as assessed by nitroblue tetrazolium reduction assay, indirect immunofluorescence and morphology, showed better effects towards the differentiation of U-937 cells when the agents were used in combination. However, addition of thymidine to the medium was found to cancel all the aforementioned effects. The addition of thymidine to the medium also caused reversal of the inhibitory effect of methotrexate and IFN-gamma on cell growth and repletion of the endogenous folate level. Repletion of the folate level by exogenous thymidine is a new possibility for the role of the thymidine in cellular growth.

Antibodies, Monoclonal↗

PubMed2006

Methotrexate in rheumatoid arthritis is frequently effective, even if re-employed after a previous failure.

Effectiveness of therapy with individual disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis (RA) is limited, and the number of available DMARDs is finite. Therefore, at some stage during the lengthy course of RA, institution of traditional DMARDs that have previously been applied may have to be reconsidered. In the present study we investigated the effectiveness of re-employed methotrexate in patients with a history of previous methotrexate failure (original course). A total of 1,490 RA patients (80% female, 59% rheumatoid factor positive) were followed from their first presentation, yielding a total of 6,470 patient-years of observation. We identified patients in whom methotrexate was re-employed after at least one intermittent course of a different DMARD. We compared reasons for discontinuation, improvement in acute phase reactants, and cumulative retention rates of methotrexate therapy between the original course of methotrexate and its re-employment. Similar analyses were peformed for other DMARDs. Methotrexate was re-employed in 86 patients. Compared with the original courses, re-employment was associated with a reduced risk for treatment termination because of ineffectiveness (P = 0.02, by McNemar test), especially if the maximum methotrexate dose of the original course had been low (<12.5 mg/week; P = 0.02, by logistic regression). In a Cox regression model, re-employed MTX was associated with a significantly reduced hazard of treatment termination compared with the original course of methotrexate, adjusting for dose and year of employment (hazard ratio 0.64, 95% confidence interval 0.42-0.97; P = 0.04). These findings were not recapitulated in analyses of re-employment of other DMARDs. Re-employment of MTX despite prior inefficacy, but not re-employment of other DMARDs, is an effective therapeutic option, especially in those patients in whom the methotrexate dose of the original course was low.

Acute-Phase Reaction↗

PubMed2006

Suppression of inflammation by low-dose methotrexate is mediated by adenosine A2A receptor but not A3 receptor activation in thioglycollate-induced peritonitis.

Prior studies demonstrate that adenosine, acting at one or more of its receptors, mediates the anti-inflammatory effects of methotrexate in animal models of both acute and chronic inflammation. Both adenosine A2A and A3 receptors contribute to the anti-inflammatory effects of methotrexate treatment in the air pouch model of inflammation, and the regulation of inflammation by these two receptors differs at the cellular level. Because different factors may regulate inflammation at different sites we examined the effect of low-dose weekly methotrexate treatment (0.75 mg/kg/week) in a model of acute peritoneal inflammation in adenosine A2A receptor knockout mice and A3 receptor knockout mice and their wild-type littermates. Following intraperitoneal injection of thioglycollate there was no significant difference in the number or type of leukocytes, tumor necrosis factor alpha (TNF-alpha) and IL-10 levels that accumulated in the thioglycollate-induced peritoneal exudates in adenosine A2A knockout mice or wild-type control mice. In contrast, there were more leukocytes, TNF-alpha and IL-10 in the exudates of the adenosine A3 receptor-deficient mice. Low-dose, weekly methotrexate treatment increased the adenosine concentration in the peritoneal exudates of all mice studied, and reduced the leukocyte accumulation in the wild-type mice and A3 receptor knockout mice but not in the A2A receptor knockout mice. Methotrexate reduced exudate levels of TNF-alpha in the wild-type mice and A3 receptor knockout mice but not the A2A receptor knockout mice. More strikingly, IL-10, a critical regulator of peritoneal inflammation, was increased in the methotrexate-treated wild-type mice and A3 knockout mice but decreased in the A2A knockout mice. Dexamethasone, an agent that suppresses inflammation by a different mechanism, was similarly effective in wild-type mice, A2A mice and A3 knockout mice. These findings provide further evidence that adenosine is a potent regulator of inflammation that mediates the anti-inflammatory effects of methotrexate. Moreover, these data provide strong evidence that the anti-inflammatory effects of methotrexate and adenosine are mediated by different receptors in different inflammatory loci, an observation that may explain why inflammatory diseases of some organs but not of other organs respond to methotrexate therapy.

Adenosine↗