levoleucovorin and Arthritis--Rheumatoid

To conduct a systematic literature review and meta-analysis to estimate the incidence of anaemia, leucopoenia, neutropenia and thrombocytopenia associated with MTX plus folic acid among patients with rheumatic diseases.. We searched MEDLINE, PubMed and EMBASE through August 2016 for all randomized controlled clinical trials with a MTX monotherapy arm. We excluded randomized controlled clinical trials for cancer and included only double-blind studies that reported on haematologic adverse events. Studies were excluded if patients did not receive folic acid or leucovorin supplementation. Full text articles were assessed by two independent reviewers. Incidence estimates were calculated using random-effects models.. Of 1601 studies identified, 30 (1.87%) were included, representing 3858 patients; all had RA. Seventeen trials reported on anaemia (n = 2032), 17 reported on leucopoenia (n = 2220), 16 reported on neutropenia (n = 2202) and 12 reported on thrombocytopenia (n = 1507). The incidence for any anaemia was 2.55% (95% CI 0.60-5.47%), any leucopoenia 1.17% (95% CI 0.16-2.80%), any neutropenia 1.77% (95% CI 0.33-4.00%), and any thrombocytopenia 0.19% (95% CI 0.00-0.86%). Four cases of severe anaemia were reported, as defined by authors, along with three cases of severe neutropenia. No cases of severe leucopoenia, severe thrombocytopenia or pancytopenia were reported.. Cytopenias are an uncommon side effect of low-dose MTX with folic acid supplementation among RA patients. Further research is needed to reach a more precise estimate.

Topics: Anemia; Antirheumatic Agents; Arthritis, Rheumatoid; Folic Acid; Humans; Leucovorin; Leukopenia; Methotrexate; Neutropenia; Pancytopenia; Randomized Controlled Trials as Topic; Rheumatic Diseases; Severity of Illness Index; Thrombocytopenia; Vitamin B Complex

To review the evidence for benefits and harms of folate (folic acid or folinic acid) supplementation on methotrexate (MTX) treatment for rheumatoid arthritis (RA), to assess whether or not folate supplementation would reduce MTX toxicity or reduce MTX benefits, and to decide whether a higher MTX dosage is essential.. We performed a sensitive search strategy and searched systematically the Medline, Embase, Web of Science and Cochrane Library databases from inception to 2 June 2016. Abstracts from major rheumatology meetings and major trial registers were also searched to retrieve all randomized controlled trials that interested us.. Seven studies with 709 patients were included. No significant heterogeneity was found between these trials. For RA patients treated with MTX, those supplied with folate were less likely to have elevated transaminase (odds ratio [OR] 0.15; 95% confidence interval [95% CI] 0.10, 0.23 [p < 0.00001]) and gastrointestinal side-effects such as nausea and vomiting (OR 0.71; 95% CI 0.51, 0.99 [p = 0.04]). Folate appeared to promote compliance to MTX as it reduced patient withdrawal compared to placebo (OR 0.29; 95% CI 0.21, 0.42 [p < 0.00001]). There was no statistical difference for mouth sores between folate and placebo (OR 0.83; 95% CI 0.57, 1.22 [p = 0.35]). As the markers of disease activity in those trials were not consistent, it was impossible to decide whether folate supplementation reduced MTX efficacy. Besides, we compared high-dose folate (≥25 mg per week) and low-dose folate (≤10 mg per week) on MTX efficacy, finding no statistical difference (OR 2.07; 95% CI 0.81, 5.30 [p = 0.13]), nor on MTX toxicity (OR 1.56; 95% CI 0.80,3.04 [p = 0.19]).. Folate supplementation can reduce the incidence of hepatotoxicity and gastrointestinal side-effects of MTX in patients with RA. It can also reduce patient withdrawal from MTX treatment. Although it tended to reduce mouth sores, it had no statistical significance. No significant difference was found between high-dose folate and low-dose folate on MTX efficacy or toxicity.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Folic Acid; Humans; Leucovorin; Methotrexate

To perform a systematic review of the benefits and harms of folic acid and folinic acid in reducing the mucosal, gastrointestinal, hepatic, and hematologic side effects of methotrexate (MTX); and to assess whether folic or folinic acid supplementation has any effect on MTX benefit.. We searched the Cochrane Library, MEDLINE, EMBASE, and US National Institutes of Health clinical trials registry from inception to March 2012. We selected all double-blind, randomized, placebo-controlled clinical trials in which adult patients with rheumatoid arthritis (RA) were treated with MTX (dose ≤ 25 mg/week) concurrently with folate supplementation. We included only trials using low-dose folic or folinic acid (a starting dose of ≤ 7 mg weekly) because the high dose is no longer recommended or used. Data were extracted from the trials, and the trials were independently assessed for risk of bias using a predetermined set of criteria.. Six trials with 624 patients were eligible for inclusion. Most studies had low or unclear risk of bias for key domains. The quality of the evidence was rated as "moderate" for each outcome as assessed by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) working group, with the exception of hematologic side effects, which were rated as "low." There was no significant heterogeneity between trials, including where folic acid and folinic acid studies were pooled. For patients supplemented with any form of exogenous folate (either folic or folinic acid) while receiving MTX therapy for RA, a 26% relative (9% absolute) risk reduction was seen for the incidence of gastrointestinal side effects such as nausea, vomiting, or abdominal pain (RR 0.74, 95% CI 0.59 to 0.92; p = 0.008). Folic and folinic acid also appear to be protective against abnormal serum transaminase elevation caused by MTX, with a 76.9% relative (16% absolute) risk reduction (RR 0.23, 95% CI 0.15 to 0.34; p < 0.00001), as well as reducing patient withdrawal from MTX for any reason [60.8% relative (15.2% absolute) risk reduction, RR 0.39, 95% CI 0.28 to 0.53; p < 0.00001].. The results support a protective effect of supplementation with either folic or folinic acid for patients with RA during treatment with MTX. There was a clinically important significant reduction shown in the incidence of GI side effects and hepatic dysfunction (as measured by elevated serum transaminase levels), as well as a clinically important significant reduction in discontinuation of MTX treatment for any reason.

Topics: Adult; Antirheumatic Agents; Arthritis, Rheumatoid; Female; Folic Acid; Humans; Leucovorin; Male; Methotrexate

Methotrexate (MTX) is a disease modifying antirheumatic drug (DMARD) used as a first line agent for treating rheumatoid arthritis (RA). Pharmacologically, it is classified as an antimetabolite due to its antagonistic effect on folic acid metabolism. Many patients treated with MTX experience mucosal, gastrointestinal, hepatic or haematologic side effects. Supplementation with folic or folinic acid during treatment with MTX may ameliorate these side effects.. To identify trials of supplementation with folic acid or folinic acid during MTX therapy for rheumatoid arthritis and to assess the benefits and harms of folic acid and folinic acid (a) in reducing the mucosal, gastrointestinal (GI), hepatic and haematologic side effects of MTX, and (b) whether or not folic or folinic acid supplementation has any effect on MTX benefit.. We originally performed MEDLINE searches, from January 1966 to June 1999. During the update of this review, we searched additional databases and used a sensitive search strategy designed to retrieve all trials on folic acid or folinic acid for rheumatoid arthritis from 1999 up to 2 March 2012.. We selected all double-blind, randomised, placebo-controlled clinical trials (RCTs) in which adult patients with rheumatoid arthritis were treated with MTX (at a dose equal to or less than 25 mg/week) concurrently with folate supplementation. In this update of the review we only included trials using 'low dose' folic or folinic acid (a starting dose of ≤ 7 mg weekly).. Data were extracted from the trials, and the trials were independently assessed for risk of bias using a predetermined set of criteria.. Six trials with 624 patients were eligible for inclusion. Most studies had low or unclear risk of bias for key domains. The quality of the evidence was rated as 'moderate' for each outcome as assessed by GRADE, with the exception of haematologic side effects which were rated as 'low'. There was no significant heterogeneity between trials, including where folic acid and folinic acid studies were pooled.For patients supplemented with any form of exogenous folate (either folic or folinic acid) whilst on MTX therapy for rheumatoid arthritis, a 26% relative (9% absolute) risk reduction was seen for the incidence of GI side effects such as nausea, vomiting or abdominal pain (RR 0.74, 95% CI 0.59 to 0.92; P = 0.008). Folic and folinic acid also appear to be protective against abnormal serum transaminase elevation caused by MTX, with a 76.9% relative (16% absolute) risk reduction (RR 0.23, 95% CI 0.15 to 0.34; P < 0.00001), as well as reducing patient withdrawal from MTX for any reason (60.8% relative (15.2% absolute) risk reduction, RR 0.39, 95% CI 0.28 to 0.53; P < 0.00001).We analysed the effect of folic or folinic acid on the incidence of stomatitis / mouth sores, and whilst showing a trend towards reduction in risk, the results were not statistically significant (RR 0.72, 95% CI 0.49 to 1.06)It was not possible to draw meaningful conclusions on the effect of folic or folinic acid on haematologic side effects of methotrexate due to small numbers of events and poor reporting of this outcome in included trials.It does not appear that supplementation with either folic or folinic acid has a statistically significant effect on the efficacy of MTX in treating RA (as measured by RA disease activity parameters such as tender and swollen joint counts, or physician's global assessment scores).. The results support a protective effect of supplementation with either folic or folinic acid for patients with rheumatoid arthritis during treatment with MTX.There was a significant reduction shown in the incidence of GI side effects, hepatic dysfunction (asmeasured by elevated serum transaminase levels) as well as a significant reduction in discontinuation of MTX treatment for any reason. A trend towards a reduction in stomatitis was demonstrated however this did not reach statistical significance.This updated review with its focus on lower doses of folic acid and folinic acid and updated assessment of risk of bias aimed to give a more precise and more clinically relevant estimate of the benefit of folate supplementation for patients with rheumatoid arthritis receiving methotrexate.

Topics: Abdominal Pain; Adult; Antirheumatic Agents; Arthritis, Rheumatoid; Folic Acid; Folic Acid Antagonists; Gastrointestinal Diseases; Hematologic Diseases; Humans; Leucovorin; Methotrexate; Nausea; Vomiting

Topics: Arthritis, Rheumatoid; Evidence-Based Medicine; Folic Acid; Humans; Immunosuppressive Agents; Leucovorin; Methotrexate; Review Literature as Topic

Methotrexate is a folic acid antagonist widely used for the treatment of inflammatory disorders for more than 50 years. Methotrexate is a standard systemic therapy for severe psoriasis and rheumatoid arthritis. Folic acid supplementation has been advocated to limit the toxicity of methotrexate on blood cells, gastrointestinal tract and liver. However, there is still controversy regarding the usefulness of folic acid supplementation.. We sought to assess the evidence for the efficacy of folic acid supplementation in patients treated with methotrexate for inflammatory diseases. We also investigated whether folic acid supplementation may decrease the efficacy of methotrexate.. Cochrane and MEDLINE databases were systematically searched. Randomized controlled trials in patients treated with methotrexate for rheumatoid arthritis or psoriasis with or without arthritis were included. Study selection, assessment of methodological quality, data extraction and analysis were carried out by two independent researchers. We selected double-blind randomized placebo-controlled trials. Analysis was performed for each subgroup of side-effects: gastrointestinal, mucocutaneous, haematological and hepatic.. Six randomized controlled trials met the inclusion criteria, with a total sample of 648 patients. There were 257 patients in the placebo group, 198 patients treated with folic acid, and 193 patients treated with folinic acid. The statistical analysis showed a significant reduction of 35.8% of hepatic side-effects induced by methotrexate for patients with supplementation with folic or folinic acid (95% confidence interval -0.467 to -0.248). There was no statistical difference for mucocutaneous and gastrointestinal side-effects although there was a trend in favour of supplementation. The effect of supplementation on haematological side-effects could not be assessed accurately due to a low incidence of these events in the population studied. We were unable to analyse the effect of supplementation on the effectiveness of methotrexate, as markers of activity used in each study were not comparable.. Supplementation with folic acid is an effective measure to reduce hepatic adverse effects associated with methotrexate treatment. There is no difference between folinic acid and folic acid, but the lower cost of the latter promotes its use.

Topics: Arthritis, Rheumatoid; Chemical and Drug Induced Liver Injury; Drug Eruptions; Folic Acid; Gastrointestinal Diseases; Hematologic Diseases; Humans; Immunosuppressive Agents; Leucovorin; Liver Diseases; Methotrexate; Psoriasis; Randomized Controlled Trials as Topic

To assess the effects of folic acid and folinic acid in reducing the mucosal and gastrointestinal (GI) and haematologic side effects of low-dose of Methotrexate (MTX) in patients with Rheumatoid Arthritis (RA) and to determine whether or not folate supplementation alters MTX efficacy.. We searched the Cochrane Controlled Clinical Trial's Register (CCTR), the Cochrane Musculoskeletal Group Specialized Register and Medline up to and including June 1999, using the search strategy developed by the Cochrane Collaboration (Dickersin 1994). We also handsearched the following: (i) bibliographic references; (ii) current contents of the last 6 months; (iii) abstracts of the rheumatology meetings; and (iv) all issues of four journals; Journal of Rheumatology, Arthritis & Rheumatism, Clinical and Experimental Rheumatology, and British Journal of Rheumatology. All languages were included. Principal investigators were also contacted in order to look for unpublished literature.. We selected all double-blind, randomized, placebo-controlled, clinical trials (RCTs), in which adult RA patients were treated with a low dose of MTX (<20 mg / week) concurrently with folate supplementation.. Two observers extracted the data and assessed the quality of the trials. (BS, Z0) The overall treatment effect across trials was calculated using a fixed effect model. Disease activity was evaluated using standardized mean differences to ensure comparability across outcome measures. Results are presented with 95% Confidence Inervals (95% CI). Subgroup analyses were conducted evaluating different doses and sensitivity analysis looking at the quality of the trials. Publication bias was assessed with an inverted funnel plot technique. Heterogeneity of the trials was measured using a standard chi square test. Costs per month in different countries were compared.. Of the 12 trials retrieved, 7 met the inclusion criteria. The total sample included 307 patients, of which 147 were treated with folate supplementation, 80 patients with folinic acid and 67 patients with folic acid. A 79% reduction in mucosal and GI side effects was observed for folic acid [OR = 0.21 (95% CI 0.10 to 0.44)]. For folinic acid, a clinically but non-statistically significant reduction of 43% was found [OR = 0. 57 (95% CI 0.28 to 1.15)]. No major differences were observed between low and high doses of folic or folinic acid. Haematologic side effects could not be analyzed, since details of each haematologic side effect by patients were not provided. No consistent differences in disease activity parameters were observed when comparing placebo and folic or folinic acid at low or high doses, although patients on high dose folinic acid had an increase in the number of tender joints, but not swollen joints. Large differences in costs across countries were found, but folinic acid was more expensive in all.. The results support the protective effect of folate supplementation in reducing MTX side effects related to the oral and GI systems. We could not determine if folic was different from folinic acid. Therefore, for folinic acid to be considered cost-effective it must be found more effective than folic acid at reducing MTX side effects.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Folic Acid; Folic Acid Antagonists; Gastrointestinal Diseases; Hematologic Diseases; Humans; Leucovorin; Methotrexate

To assess the efficacy of folic acid and folinic acid in reducing the mucosal and gastrointestinal (GI) side effects of low dose methotrexate (MTX) in patients with rheumatoid arthritis (RA).. A systematic review was carried out using the methods recommended by the Cochrane Collaboration. We used MEDLINE and performed hand searches that included bibliographic references, Current Contents, abstracts of rheumatology meetings, and 4 rheumatology journals to select double blind randomized controlled trials (RCT) in which adult patients with RA were treated with low doses of MTX (< 20 mg/week), concurrently with folic or folinic acid. The quality of the RCT was assessed. The overall treatment effect across trials (reduction in toxicity) was estimated using a fixed effects model. Disease activity was evaluated using standardized mean differences to ensure comparability across outcome measures. Sensitivity analyses were conducted evaluating different doses and the quality of the trials. Costs per month in different countries were compared.. Of 11 trials retrieved, 7 met inclusion criteria. The total sample included 307 patients, of which 147 were treated with folate supplementation, 67 patients with folic, and 80 with folinic acid. A 79% reduction in mucosal and GI side effects was observed for folic acid [OR = 0.21 (95% CI 0.10 to 0.44)]. For folinic acid, a clinically but nonstatistically significant reduction of 42% was found [OR = 0.58 (95% CI 0.29 to 1.16)]. No major differences were observed between low and high doses of folic or folinic acid. Hematologic side effects could not be analyzed, since details by patients of each event were not provided. No consistent differences in disease activity variables were observed when comparing placebo and folic acid or folinic acid at low doses; patients receiving high dose folinic acid had increased tender and swollen joint counts. Substantial differences in costs across countries were found; folinic acid was more expensive.. Our results support the protective effect of folate supplementation in reducing MTX side effects related to the oral and GI systems.

Topics: Adult; Antidotes; Antimetabolites, Antineoplastic; Arthritis, Rheumatoid; Drug Interactions; Folic Acid; Hematinics; Humans; Leucovorin; Methotrexate; Randomized Controlled Trials as Topic

Toxicities related to low-dose weekly methotrexate are largely due to its antifolate properties. Preexisting folate deficiency is associated with methotrexate toxicity in some patients. At the onset of methotrexate therapy and throughout therapy, the physician should be vigilant regarding one or more nutrient deficiencies. A multivitamin and, where appropriate, specific daily folic acid supplements should be employed. The only regimen known presently (through controlled trials) to treat side effects is the low-dose folinic acid (leucovorin) protocol outlined herein. Folic acid may be helpful to treat mild gastrointestinal symptoms. Folinic acid supplementation should be considered prophylactically in those requiring methotrexate who are at increased risk of hepatic disease. Other possible factors besides methotrexate should always be considered with the onset of new patient complaints or laboratory abnormalities. Claims that folic acid therapy is safer and more convenient than folinic acid seem unwarranted when one reviews the literature carefully. Cost differences between folic acid supplementation and folinic acid supplementation have been exaggerated.

Topics: Antidotes; Antirheumatic Agents; Arthritis, Rheumatoid; Clinical Trials as Topic; Drug Therapy, Combination; Folic Acid Deficiency; Humans; Leucovorin; Methotrexate

Methotrexate (MTX) has become one of the most widely prescribed second-line agents world-wide for rheumatoid arthritis (RA). Studies have established efficacy in populations which have failed other second-line agents. Although MTX must be considered as a potential hepatotoxin, studies have shown that liver histologic changes can be predicted by monitoring of serum albumin and AST at four to eight week intervals. MTX pulmonary toxicity appears to be more common than liver disease. It most often presents with a subacute course with dry cough and dyspnea with or without fever. Clinicians must be aware of this presentation and withhold the drug when these symptoms appear. MTX may also cause mild renal impairment when used with NSAIDs. This effect has been observed with higher mean weekly doses in the 15 to 20 mg range, but not with a starting dose of 7.5 mg. Although MTX may exhibit a variety of effects in in vitro systems its mechanism of action in patients with RA has not yet been determined.

Topics: Antidotes; Antirheumatic Agents; Arthritis, Rheumatoid; Dermatologic Agents; Drug Therapy, Combination; Folic Acid; Hematinics; Humans; Kidney; Leucovorin; Liver; Lung; Methotrexate; Psoriasis

This review concentrates on the influence of folate supplementation on the toxicity and efficacy of methotrexate (MTX) in rheumatoid arthritis patients. The design, type of folate supplementation and timing of supplementation vary considerably between the six published controlled studies. Folate supplementation seems to have no effect on the efficacy of MTX but may influence toxicity in a favourable way. Further studies are needed to assess the type of supplementation (folic acid, folinic acid), the predisposing factors for toxicity and cost effectiveness.

Topics: Antidotes; Antirheumatic Agents; Arthritis, Rheumatoid; Folic Acid; Hematinics; Humans; Leucovorin; Methotrexate

Topics: Aging; Arthritis, Rheumatoid; Dose-Response Relationship, Drug; Geriatric Assessment; Humans; Leucovorin; Methotrexate

Topics: Arthritis, Rheumatoid; Drug Therapy, Combination; Folic Acid; Humans; Leucovorin; Methotrexate

To determine cost-effectiveness of folic or folinic acid supplementation in patients with rheumatoid arthritis (RA) who started methotrexate (MTX) treatment.. An economic evaluation, performed alongside a randomized, double blind, placebo controlled trial with followup of 48 weeks. Patients started MTX with placebo (n = 137), folic acid (n = 133), or folinic acid (n = 141). Outcome measures were drug survival and quality-adjusted life-years (QALY), measured with the EuroQol questionnaire. Both medical and nonmedical costs were analyzed.. Drug survival after 48 weeks was 60% for placebo, 81% for folic acid, and 87% for folinic acid. QALY during a 48 week period were 0.55 (95% CI 0.52-0.58) in the placebo group, 0.55 (95% CI 0.52-0.58) in the folic acid group, and 0.58 (95% CI 0.56-0.60) in the folinic acid group. Mean medical costs were 1398 US dollars (placebo), 1409 US dollars (folic acid), and 1776 US dollars (folinic acid). Mean total costs were 3339 US dollars, 3632 US dollars, and 3296 US dollars, respectively.. In terms of resource deployment, no statistically significant difference was found between the 3 strategies. The preferred strategy consists of folic acid supplementation because of improved drug survival.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Cost of Illness; Cost-Benefit Analysis; Double-Blind Method; Drug Therapy, Combination; Female; Folic Acid; Health Care Costs; Hematinics; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Patient Dropouts; Rheumatology; Time Factors

To determine if folinic acid supplementation during methotrexate (MTX) therapy for rheumatoid arthritis (RA) reduces both urinary 5-aminoimidazole-4-carboxamide (AICA) and urinary adenosine excretion more than does folic acid supplementation. AICA and adenosine are markers for MTX interference with purine metabolism.. Forty patients with RA who received MTX for 6 weeks were randomized to receive either daily folic acid or folinic acid supplements during an additional week of MTX therapy. Colorimetric and radioimmunocompetition assays were used to measure 24-hour urinary AICA and adenosine excretion levels, respectively.. At the end of 6 weeks, 24-hour urinary levels of AICA, but not adenosine, were elevated as compared with baseline levels (i.e., prior to MTX therapy). Folinic acid, but not folic acid, supplementation normalized urinary AICA levels during MTX therapy. Relatively high urinary levels of AICA were correlated with reduced disease activity. No similar correlations were seen with urinary adenosine levels.. The blockade of purine nucleotide biosynthesis by MTX at the AICA ribonucleotide transformylase-catalyzed step may be related to the efficacy of MTX, and this blockade is effectively relieved by folinic acid, but not by folic acid, supplementation.

Topics: Adenosine; Aminoimidazole Carboxamide; Arthritis, Rheumatoid; Erythrocytes; Female; Folic Acid; Homocysteine; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Purines; Pyridoxine; Ribonucleotides; Treatment Outcome; Vitamin B 12

Topics: Arthritis, Rheumatoid; Drug Therapy, Combination; Female; Fluorouracil; Humans; Immunosuppressive Agents; Leucovorin; Male; Middle Aged

To study (i) the influence of methotrexate (MTX) therapy on homocysteine and folate metabolism in patients with rheumatoid arthritis (RA), (ii) the influence of the C677T mutation in the methylenetetrahydrofolate reductase gene (MTHFR) on the change in plasma homocysteine levels during MTX treatment, and (iii) the interference of folate and homocysteine metabolism with the efficacy and toxicity of treatment with MTX.. The 113 patients enrolled in this study were participating in a 48-week, multicentre, double-blind, placebo-controlled study comparing the efficacy and toxicity of MTX treatment with and without folic or folinic acid supplementation. The MTX dose was 7.5 mg/week initially and increased to a maximum of 25 mg/week if necessary. Concentrations of total folate, 5-methyl tetrahydrofolate (in serum and in erythrocytes) and of homocysteine, cysteine and cysteine-glycine and the MTHFR genotype were determined before the start of the study, after 6 weeks, and after 48 weeks or on withdrawal from the study. Blood was drawn from fasting patients at a standardized time in the morning, 16 h after intake of MTX. The laboratory results were related to parameters of efficacy and toxicity of MTX treatment.. Baseline values were distributed equally in the three treatment groups. The mean plasma homocysteine level (normal range 6-15 micromol/l) before the start of MTX was relatively high in all groups: 15.4 micromol/l [95% confidence interval (CI) 13.5 to 17.2] in the MTX plus placebo group (n=39), 14.3 micromol/l (95% CI 12.2 to 16.4) in the MTX plus folic acid group (n=35) and 15.9 micromol/l (95% CI 13.7 to 18.1) in the MTX plus folinic acid group (n=39). After 48 weeks of MTX therapy, the mean homocysteine level showed an increase in the placebo group (+3.6 micromol/l, 95% CI 1.7 to 5.6). In contrast, a decrease was observed in the groups supplemented with folic or folinic acid (folic acid, -2.7 micromol/l, 95% CI -1.4 to -4.0; folinic acid, -1.6 micromol/l, 95% CI -0.1 to -3.0). The differences in the change in plasma homocysteine level between the placebo group and each of the two folate-supplemented groups were statistically significant (P<0.0001), contrary to the difference between the folic and folinic acid groups (P=0.26). Linear regression analysis showed that the change in plasma homocysteine level was statistically significantly associated with folic or folinic acid supplementation (P=0.0001) but not with the presence or absence of the C677T mutation in the MTHFR gene. Homozygous mutants had a higher plasma homocysteine concentration at baseline. No relationship was found between the change in disease activity and the change in homocysteine concentration or the mean homocysteine concentration after 48 weeks of MTX therapy. Toxicity-related discontinuation of MTX treatment was not associated with the change in homocysteine concentration.. Low-dose MTX treatment in RA patients leads to an increased plasma homocysteine level. Concomitant folate supplementation with either folic or folinic acid decreases the plasma homocysteine level and consequently protects against potential cardiovascular risks. No relationship was found between the change in homocysteine concentration and the presence or absence of the C677T mutation in the MTHFR gene. Homocysteine metabolism was not associated with efficacy or toxicity of MTX treatment.

Topics: Adult; Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Daunorubicin; Female; Folic Acid; Genotype; Homocysteine; Humans; Leucovorin; Linear Models; Male; Methotrexate; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Oxidoreductases Acting on CH-NH Group Donors; Point Mutation

To study the effect of folates on discontinuation of methotrexate (MTX) as single-drug antirheumatic treatment due to toxicity, to determine which type of adverse events are reduced, to study the effects on the efficacy of MTX, and to compare folic with folinic acid supplementation in a 48-week, randomized, double-blind, placebo-controlled trial.. Patients with active RA (n = 434) were randomly assigned to receive MTX plus either placebo, folic acid (1 mg/day), or folinic acid (2.5 mg/week). The initial MTX dosage was 7.5 mg/week; dosage increases were allowed up to a maximum of 25 mg/week for insufficient responses. Folate dosages were doubled once the dosage of MTX reached 15 mg/week. The primary end point was MTX withdrawal because of adverse events. Secondary end points were the MTX dosage and parameters of efficacy and toxicity of MTX.. Toxicity-related discontinuation of MTX occurred in 38% of the placebo group, 17% of the folic acid group, and 12% of the folinic acid group. These between-group differences were explained by a decreased incidence of elevated liver enzyme levels in the folate supplementation groups. No between-group differences were found in the frequency of other adverse events or in the duration of adverse events. Parameters of disease activity improved equally in all groups. Mean dosages of MTX at the end of the study were lower in the placebo group (14.5 mg/week) than in the folic and folinic acid groups (18.0 and 16.4 mg/week, respectively).. Both folate supplementation regimens reduced the incidence of elevated liver enzyme levels during MTX therapy, and as a consequence, MTX was discontinued less frequently in these patients. Folates seem to have no effect on the incidence, severity, and duration of other adverse events, including gastrointestinal and mucosal side effects. Slightly higher dosages of MTX were prescribed to obtain similar improvement in disease activity in the folate supplementation groups.

Topics: Adult; Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Double-Blind Method; Female; Folic Acid; Hematinics; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Placebos; Prospective Studies; Treatment Outcome

To determine if simultaneously administered low dose leucovorin interferes with the efficacy of methotrexate (MTX).. An 8-week double blind placebo controlled study of leucovorin (1 mg) in 16 patients with rheumatoid arthritis receiving chronic MTX was performed at a single academic center.. A flare of disease activity was not observed. Clinical variables of arthritis activity did not change in the leucovorin treated population.. Low dose leucovorin when taken simultaneously with MTX did not interfere with the efficacy of MTX in a short term 8 week trial.

Topics: Aged; Arthritis, Rheumatoid; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Leucovorin; Male; Methotrexate; Middle Aged

To determine whether the side effects of methotrexate can be decreased by the concurrent use of leucovorin, without affecting the efficacy of the methotrexate.. We conducted a multicenter randomized, double-blind, placebo-controlled trial of leucovorin administration, 2.5-5.0 mg orally, to be given 24 hours after the single, weekly, oral dose of methotrexate. Every 3 weeks for 52 weeks, patients were evaluated for rheumatic disease activity and side effects. Dosage adjustments for both methotrexate and leucovorin were made as needed, according to a defined protocol. The primary outcome evaluated was the frequency of study withdrawals because of side effects and/or inefficacy. Secondary outcomes evaluated included the frequency of side effects and the relative efficacy of methotrexate in the leucovorin and placebo treatment groups.. Ninety-two evaluable patients were analyzed (44 took leucovorin and 48 placebo). Twenty-two patients withdrew early because of side effects unresponsive to our protocol, and 1 because of inefficacy; 17 had been taking placebo and 6 had been taking leucovorin (35% versus 14%, P < 0.02). The number of visits during which side effects were reported was reduced by almost 50% in the leucovorin treatment group (P < 0.001). There were significant reductions in the frequencies of all common side effects. At 52 weeks, disease activity was similar in both patient groups.. The methotrexate-leucovorin protocol used significantly reduces common side effects of methotrexate therapy without significantly altering efficacy.

Topics: Adolescent; Adult; Aged; Arthritis, Rheumatoid; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Placebos

Eight patients with active rheumatoid arthritis were given high dose intravenous methotrexate (MTX) (500 mg/m2) followed by oral leucovorin every 2 weeks for up to 6 months. All patients enrolled had previously failed conventional MTX therapy. Five patients completed 6 months of therapy. Three withdrew early, one due to inefficacy, one due to gastrointestinal intolerance and one due to sciatica requiring hospital admission. Fifty percent or greater improvements were seen in 5 of 8 clinical variables in those patients who completed 6 months of therapy. Six of 8 improvements achieved statistical significance at 24 weeks. Upon discontinuing therapy, patients flared within 8 to 12 weeks. Those who were maintained by low dose MTX after the high dose protocol were able to sustain their improvement throughout the subsequent 6 months of followup.

Topics: Administration, Oral; Adult; Arthritis, Rheumatoid; Dose-Response Relationship, Drug; Double-Blind Method; Humans; Infusions, Intravenous; Leucovorin; Methotrexate; Middle Aged; Time Factors

A double blind, placebo controlled trial examined the effects of folinic acid on the efficacy and toxicity of methotrexate in 27 patients with rheumatoid arthritis. Clinical and laboratory indices of disease activity worsened significantly in the 13 patients treated with folinic acid after four weeks of treatment, but not in the 14 patients treated with placebo. Exacerbation of rheumatoid arthritis led to withdrawal of the test drug in seven of the patients treated with folinic acid but in none of those treated with placebo. It is concluded that excerbation of rheumatoid arthritis is likely when folinic acid is given shortly after the weekly dose of methotrexate.

Topics: Arthritis, Rheumatoid; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Leucovorin; Male; Methotrexate; Middle Aged

Folinic acid (leucovorin) supplementation has been suggested as a possible means of treating the short term side effects that occur with low dose methotrexate (MTX). However, it has not been established whether leucovorin will abrogate the antiarthritic effect of MTX. We entered 20 patients with rheumatoid arthritis treated with MTX into a 48 week randomized, double blind, crossover trial of folinic acid vs placebo. The dose of folinic acid was equal to the dose of MTX and it was given orally 4 h following the single, weekly MTX administration. Under these conditions, leucovorin did not decrease the therapeutic effect of MTX. While the incidence of stomatitis and gastrointestinal toxicity were lower during leucovorin treatment, our study lacked sufficient power to establish a statistically significant difference.

Topics: Administration, Oral; Arthritis, Rheumatoid; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Leucovorin; Male; Methotrexate; Middle Aged

In a double blind placebo controlled crossover study, each arm of 4 weeks' duration, 20 mg of folinic acid/week or placebo were administered to 13 patients with rheumatoid arthritis. These individuals were receiving weekly intramuscular methotrexate (MTX) but were about to discontinue because of side effects. While there was considerable improvement in nausea during the study, the effect of folinic acid could not be differentiated from that of placebo. There was no adverse effect on control of disease activity. It therefore seems likely that polyglutamated tissue stores of MTX do not contribute to drug efficacy and in this format folinic acid could not be shown to be more useful than placebo in reducing drug induced nausea.

Topics: Adult; Aged; Arthritis, Rheumatoid; Clinical Trials as Topic; Drug Therapy, Combination; Erythrocyte Volume; Female; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Severity of Illness Index

We reported a patient with rheumatoid arthritis who received chronic methotrexate (MTX) therapy and experienced several adverse reactions like hemocytopenia and renal impairment. Under the monitoring of the therapeutic drug concentration, calcium folate and other measures were used to accelerate methotrexate excretion and eliminate adverse reactions.. A 66-year-old man with rheumatoid arthritis received MTX and developed adverse effects of bone marrow suppression, like pancytopenia. He had a black stool, and he tested positive for occult blood, which was considered gastrointestinal bleeding. The blood MTX concentration reached 4.07 μmol/L, and leucovorin was administered to rescue the patient's life. Besides, hydration and alkaline urine were applied to quickly clear methotrexate inside the body.. Low-dose MTX has fewer adverse reactions but may cause bone marrow suppression- related side effects. Blood concentration monitoring can be used to guide the rescue of MTX poisoning.

Topics: Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Calcium; Folic Acid; Humans; Leucovorin; Male; Methotrexate

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Folic Acid; Humans; Leucovorin; Methotrexate

Methotrexate (MTX)is a folate antagonist that is administered in several conditions such as rheumatoid arthritis. Its use may associate with adverse effects presumably originating from folate deficiency. Although MTX side effects could be decreased by folate supplementation, the current guideline on folate administration is not precisely established, which could result in irreversible damage especially in high-risk groups like women in childbearing-age. Thus, this study aimed to investigate the in vitro rescuing effect of different folates including folic acid (FA), 5-methyltetrahydrofolate (MTHF) and folinic acid (5-Formyltetrahydrofolic acid, FTHF) on MTX-treated trophoblast cells.. HTR-8/SVneo cells were stressed with a minimum effective dose of MTX and simultaneously treated with different concentrations of FA, MTHF or FTHF. The rescuing effect was assessed by MTT viability assay. The evaluation was completed by microscopic monitoring, apoptosis assessment and measuring LINE-1 DNA methylation.. The MTT viability assay showed no MTX-rescuing effect of FA, but a significant effect of FTHF or MTHF. Microscopic observations supported the results of the viability assay. Accordingly, apoptosis was reduced in MTHF or FTHF treatments, while FA has no effect on the apoptosis induced by MTX. The LINE-1 methylation was not affected by MTX treatment, and not significantly modified in folate supplemented cultures.. Despite the general acceptance of administering FA to prevent adverse events of MTX therapy, our findings suggest that FA may not be optimal, and indicate FTHF or MTHF as a better choice. This study on trophoblast cells suggests that FTHF may be the optimal folate, particularly for women in childbearing-age.

Topics: Arthritis, Rheumatoid; Female; Folic Acid; Humans; Leucovorin; Methotrexate; Trophoblasts

Topics: Animals; Antirheumatic Agents; Arthritis, Rheumatoid; Dietary Supplements; Female; Formates; Humans; Leucovorin; Metabolic Networks and Pathways; Methotrexate; Mice, Inbred C57BL; Mitochondria; Vitamin B Complex

A 94-year-old woman with rheumatoid arthritis who had been treated with low-dose methotrexate was referred to our hospital because of a 3-day history of a fever and pancytopenia. With a diagnosis of febrile neutropenia of unknown origin, empirical antibiotic treatment and folinic acid therapy were initiated. Despite a recovery from pancytopenia, the high fever remained, and dyspnea developed. She was clinically diagnosed with Pneumocystis jirovecii pneumonia (PCP) and successfully treated with trimethoprim/sulfamethoxazole and adjunctive corticosteroid therapy. Folinic acid treatment effectively brought about rapid immune recovery but might have led to a clinical manifestation of PCP resembling immune reconstruction inflammatory syndrome.

Topics: Aged, 80 and over; Arthritis, Rheumatoid; Female; Humans; Immune Reconstitution Inflammatory Syndrome; Leucovorin; Methotrexate; Pneumocystis carinii; Pneumonia, Pneumocystis

We validated an algorithm to detect frequency errors in computerized healthcare data and estimated the incidence of these errors in an integrated healthcare system.. We applied Sentinel System analytic tools on the electronic health records of Kaiser Permanente, Northern California, January 1, 2010, through May 30, 2015,to identify rheumatoid arthritis (RA) patients with new use of methotrexate (365-day baseline period). We identified potential methotrexate frequency errors using ICD-9 code 995.20 (adverse drug event), Current Procedural Terminology (CPT) code 96409 for injection of leucovorin and prescription refill patterns. We performed chart review to confirm the frequency errors, assessed performance for detecting frequency errors, and estimated the incidence of chart-confirmed errors.. The study included 24,529 methotrexate dispensings among 3,668 RA patients. Among these, 722 (3%) had one dispensing and 23,807 (97.1%) had ≥2 dispensings during 1-year follow-up period. We flagged 653 (2.7%) with a potential medication error (46 with one dispensing and 607 with ≥2 dispensings). We sampled 94 for chart review, and confirmed three methotrexate errors. All three confirmed frequency errors involved a first methotrexate dispensing followed by injected rescue therapy, leucovorin, (positive predictive value, 60%; 95% confidence interval [CI], 15-95%). No potential errors were found among patients with ≥2 dispensings. We estimated the frequency error incidence among one methotrexate dispensing to be 0.4% (95%CI, 0.1% to 1.2%).. Rescue therapy is a specific indicator of methotrexate overdose among first methotrexate dispensings. This method is generalizable to other medications with serious adverse events treated with antidotes.

Topics: Administration, Oral; Algorithms; Antidotes; Antirheumatic Agents; Arthritis, Rheumatoid; California; Clinical Coding; Delivery of Health Care, Integrated; Drug Administration Schedule; Drug Overdose; Electronic Health Records; Female; Humans; Incidence; International Classification of Diseases; Leucovorin; Male; Medication Errors; Methotrexate; Middle Aged; Product Surveillance, Postmarketing

Methotrexate (MTX), an antifolate, is the anchor drug for the treatment of rheumatoid arthritis (RA). It is inexpensive, effective, and generally safe. When clinical response is inadequate, biological therapies are commonly used in combination with MTX. However, biological agents have safety concerns (i.e. infections, malignancy) and the addition of a biologic agent is expensive, making strategies to improve MTX efficacy important. Inhibition of pathways of folate metabolism involving purine metabolism by MTX, have been traditionally emphasized as important in MTX efficacy. However, inhibition MTX catabolism may also be important. MTX is irreversibly hydroxylated to form 7-hydroxy methotrexate (7-OH-MTX) by aldehyde oxidase (EC 1.2.3.1) (AOX). Catabolism of MTX to 7-OH-MTX is the first metabolic process imposed on an oral dose of MTX and will alter subsequent interactions of MTX with other enzymes. 7-OH-MTX is less potent than MTX in the treatment of rat adjuvant arthritis. RA patients with a low capacity to catabolize MTX to 7-OH-MTX do better clinically than individuals who are rapid formers of 7-OH-MTX. Therefore, altering the catabolism of MTX may be an innovative way to improve MTX efficacy. Raloxifene is a FDA-approved therapy for postmenopausal osteoporosis and for the reduction of invasive breast cancers but has no known activity in RA. Raloxifene is a potent inhibitor of human liver AOX. Postmenopausal women with RA frequently have low bone mineral density and would be candidates for raloxifene and MTX combination therapy. The effect of raloxifene on MTX metabolism has never been studied. Our hypothesis is that in postmenopausal women with RA and osteoporosis treated with MTX and raloxifene, the inhibition of AOX with resultant decreased formation of 7-OH MTX; will increase MTX levels and improve MTX efficacy. This hypothesis could be studied in an open-label, proof of concept clinical study in individuals before and after the addition of raloxifene. Red blood cell MTX and 7-OH-MTX levels and RA disease activity (DAS28) would be measured. In possible future studies, there are dietary substances, as supplements, (e.g. epigallocatechin gallate in green tea and resveratrol) which inhibit human liver AOX which could be evaluated.

Topics: Animals; Antirheumatic Agents; Arthritis, Rheumatoid; Biological Products; Drug Therapy, Combination; Female; Folic Acid; Folic Acid Antagonists; Humans; Leucovorin; Male; Methotrexate; Osteoporosis; Purines; Raloxifene Hydrochloride; Rats; Rats, Inbred Lew; Treatment Outcome

Low-dose methotrexate (ld-MTX) that is administered during rheumatoid arthritis (RA) treatment has hematological adverse effects such as pancytopenia, although rare. Although well-established and widely used for hematological adverse effects caused by high-dose MTX, leucovorin (folinic acid) treatment does not have an agreed-upon administration for ld-MTX-induced pancytopenia. Here, we aimed to figure out whether there was any difference in response time between the regimens with and without folinic acid prescribed to our patients who developed pancytopenia while on MTX therapy, and to identify risk factors for its development. Our cases were collectively assessed together with other rare cases available in the literature that were reported in a similar manner with an explicitly indicated response time, in days. Thereupon, we looked for any difference in response time between the regimens with and without folinic acid. In total, ten of our patients experienced pancytopenia while on ld-MTX treatment. Mean day on which hematological response was achieved was as follows: 7 days in one patient on folic acid monotherapy, 6 days in three patients on granulocyte-colony stimulating factor (G-CSF) monotherapy, 4.5 days in two patients on leucovorin monotherapy, and 4 days in the remaining three patients who were treated with G-CSF + folinic acid/leucovorin. When we collectively evaluated our patients and the patients with an explicitly stated response duration in the literature (15 patients) and compared regimens including folinic acid to those without folinic acid, duration until response/recovery from pancytopenia was significantly shorter in folinic acid group than that in the group without folinic acid (5.47 ± 2.9 days vs 10 ± 3.77 days, p = 0.002). Treatment modalities including folinic acid (leucovorin) either with or without G-CSF result in a shorter recovery/response time compared to other agents. Leucovorin should definitely be considered and applied in rescue therapy for ld-MTX-associated side effects.

Topics: Aged; Aged, 80 and over; Antirheumatic Agents; Arthritis, Rheumatoid; Disease Management; Female; Folic Acid; Granulocyte Colony-Stimulating Factor; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Pancytopenia; Retrospective Studies; Rheumatology

A woman aged 77 years with a history of rheumatoid arthritis (RA) presented with inflammatory colitis confined to her rectum, which was incidentally found by a screening colonoscopy. Histopathological examination of colonic biopsies showed non-specific inflammatory infiltrates of lymphocytes, the cause of which was unknown. She had been diagnosed with RA 5 years before, and she was receiving methotrexate 6 mg weekly, to which tocilizumab had been added 4 years earlier, which achieved stable control of her disease. She had no gastrointestinal symptoms or other health problems. Tocilizumab-induced colitis was considered likely, and the drug was discontinued. Metronidazole was also prescribed because of possible Clostridium difficile-associated colitis. 3 months later, a repeat colonoscopy showed no improvement of the colitis. The methotrexate was also discontinued, and folinic acid was prescribed daily for 2 weeks, leading to complete resolution of the colitis observed at repeat colonoscopy.

Topics: Aged; Anti-Infective Agents; Antibodies, Monoclonal, Humanized; Antidotes; Antirheumatic Agents; Arthritis, Rheumatoid; Colitis; Colonoscopy; Drug Therapy, Combination; Female; Humans; Incidental Findings; Leucovorin; Methotrexate; Metronidazole

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Folic Acid; Folic Acid Antagonists; Humans; Leucovorin; Methotrexate

A 70-year-old woman underwent emergent clipping surgery for subarachnoid hemorrhage under general anesthesia. Her laboratory data showed thrombocytopenia (4.0 x 10(4) microl(-1)). She had taken prednisolone (3 mg x day(-1)) and methotrexate (MTX) (10 mg x week(-1)) for rheumatoid arthritis for the last 10 years. Anesthesia was induced with remifentanil as well as propofol, maintained with remifentanil and sevoflurane in oxygen. The operation was performed uneventfully without platelet transfusion. Since the cause of thrombocytopenia was suspected to be MTX, we started rescue therapy by calcium folinate postoperatively. Platelet count was normalized two days later (11.6 x 10(4) microl(-1)). One month after the operation, she was discharged uneventfully.

Topics: Aged; Anesthesia, General; Arthritis, Rheumatoid; Emergencies; Female; Humans; Immunosuppressive Agents; Intracranial Aneurysm; Leucovorin; Methotrexate; Piperidines; Platelet Transfusion; Postoperative Care; Propofol; Remifentanil; Subarachnoid Hemorrhage; Thrombocytopenia; Treatment Outcome; Vascular Surgical Procedures

Morbidity and mortality from pneumonia is increased in patients with rheumatoid arthritis. Factors contributing to this have been recently identified and a number of recommendations have been implemented in an attempt to reverse this trend. The present paper shows that these measures have combined to produce a fourfold reduction in both admissions and case fatality rates. In the study population, immunisation rates against influenza and pneumococcus have improved to 86% and 65%, oral steroid consumption has halved and disease modifying drugs were usually appropriately suspended during acute infection. These measures may now merit more widespread adoption.

Topics: Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Clinical Protocols; Female; Glucocorticoids; Granulocyte Colony-Stimulating Factor; Humans; Influenza Vaccines; Leucovorin; Leukocyte Count; Male; Middle Aged; Neutropenia; Patient Admission; Pneumococcal Vaccines; Prednisone; Respiratory Tract Infections; Risk Factors; United Kingdom; Vaccination; Vitamin B Complex

To assess the catabolism of methotrexate (MTX) to 7-hydroxy-MTX (7-OH-MTX) in patients with rheumatoid arthritis as well as the effect of folic acid and folinic acid on this catabolism.. Urinary excretion of MTX and its catabolite, 7-OH-MTX, was measured in 2 24-hour urine specimens collected after MTX therapy. Urine samples were collected from patients after the sixth and seventh weekly doses of MTX. MTX and 7-OH-MTX concentrations were determined by high-performance liquid chromatography mass spectrometry. Swelling and pain/tenderness indices were used to measure symptoms before and at 6 and 7 weeks of therapy. Patients received either folic acid or folinic acid supplements (1 mg/day) from week 6 to week 7.. Folic acid inhibited aldehyde oxidase (AO), the enzyme that produces 7-OH-MTX, but folinic acid did not. Excretion of 7-OH-MTX (determined as a percentage of the dose of MTX or as mg 7-OH-MTX/gm creatinine) was not normally distributed (n=39). Patients with marked improvement in swelling and pain/tenderness indices had a lower mean 7-OH-MTX excretion level (P<0.05). Patients who received folic acid supplements had decreased 7-OH-MTX excretion (P=0.03). Relatively high 7-OH-MTX excretion was correlated with relatively high MTX excretion and with relatively low MTX retention in vivo (P<0.05) (n=35).. Our findings of a non-normal distribution of 7-OH-MTX excretion suggest that there are at least 2 phenotypes for this catabolism. Decreased 7-OH-MTX formation suggests folic acid inhibition of AO and a better clinical response, while increased 7-OH-MTX formation may interfere with MTX polyglutamylation and binding to enzymes and, therefore, may increase MTX excretion and decrease MTX retention and efficacy in vivo.

Topics: Aldehyde Oxidase; Arthritis, Rheumatoid; Chromatography, High Pressure Liquid; Folic Acid; Health Status; Humans; Joints; Leucovorin; Methotrexate; Pain; Tandem Mass Spectrometry; Treatment Outcome

Topics: Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Antirheumatic Agents; Arthritis, Rheumatoid; Bleomycin; Cyclophosphamide; Doxorubicin; Female; Humans; Leucovorin; Lymphoma, B-Cell; Maxillary Neoplasms; Methotrexate; Nose Neoplasms; Prednisone; Vincristine

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Dietary Supplements; Drug Antagonism; Folic Acid; Folic Acid Deficiency; Humans; Leucovorin; Methotrexate; Purines

To investigate whether interactions of sulfasalazine (SSZ) with reduced folate carrier (RFC), the dominant cell membrane transporter for natural folates and methotrexate (MTX), may limit the efficacy of combination therapy with MTX and SSZ in patients with rheumatoid arthritis.. Human RFC-(over)expressing CEM cells of T cell origin were used to analyze the effect of SSZ on the RFC-mediated cellular uptake of radiolabeled MTX and the natural folate leucovorin. Moreover, both cells with and those without acquired resistance to SSZ were used to assess the antiproliferative effects of MTX in combination with SSZ.. Transport kinetic analyses revealed that SSZ was a potent noncompetitive inhibitor of RFC-mediated cellular uptake of MTX and leucovorin, with mean +/- SD K(i) (50% inhibitory concentration) values of 36 +/- 6 microM and 74 +/- 7 microM, respectively. Consistent with the inhibitory interaction of SSZ with RFC, a marked loss of MTX efficacy was observed when MTX was coadministered with SSZ: up to 3.5-fold for CEM cells in the presence of 0.25 mM of SSZ, and >400-fold for SSZ-resistant cells in the presence of 2.5 mM of SSZ. Importantly, along with diminished efficacy of MTX, evidence for cellular folate depletion was obtained by the demonstration of an SSZ dose-dependent decrease in leucovorin accumulation.. At clinically relevant plasma concentrations, interactions of SSZ with RFC provide a biochemical rationale for 2 important clinical observations: 1) the onset of (sub)clinical folate deficiency during SSZ treatment, and 2) the lack of additivity/synergism of the combination of SSZ and MTX when these disease-modifying antirheumatic drugs are administered simultaneously. Thus, when considering use of these drugs in combination therapies, the present results provide a rationale both for the use of folate supplementation and for spacing administration of these drugs over time.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport; Cell Line; Dose-Response Relationship, Drug; Drug Interactions; Drug Resistance; Drug Therapy, Combination; Folic Acid; Humans; Leucovorin; Membrane Transport Modulators; Membrane Transport Proteins; Methotrexate; Reduced Folate Carrier Protein; Sulfasalazine

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Drug Therapy, Combination; Folic Acid; Hematinics; Humans; Leucovorin; Methotrexate

To study (a) purine metabolism during treatment with methotrexate (MTX) in patients with rheumatoid arthritis (RA) and (b) the relation of purine metabolism with efficacy and toxicity of MTX treatment.. One hundred and three patients with active RA who started treatment with MTX were included. The initial MTX dosage was 7.5 mg/week and raised to a maximum of 25 mg weekly if necessary. The purine enzymes 5'-nucleotidase (5'NT), purine-nucleoside-phosphorylase (PNP), hypoxanthine-guanine-phosphoribosyltransferase (HGPRT), and adenosine-deaminase (ADA) were measured before the start, after six weeks, and after 48 weeks or at study withdrawal. The laboratory results were related to measures of efficacy and toxicity of MTX treatment.. Baseline values of 5'NT and PNP (16.9 and 206.8 nmol/10(6) mononuclear cells/h, respectively) were similar to those in former studies. Activities of HGPRT and ADA were relatively low at the start (8.7 and 80.3 nmol/10(6) mononuclear cells/h, respectively). After six weeks purine enzyme activities showed no important changes from baseline. After 48 weeks of MTX treatment a decrease of the enzyme activities of ADA (-21.6 nmol/10(6) mononuclear cells/h; 95% CI -28.6 to -14.7), PNP (-78.9 nmol/10(6) mononuclear cells/h; 95% CI -109.0 to -48.7), and HGPRT (-2.0 nmol/10(6) mononuclear cells/h; 95% CI -3.1 to -0.9) was found. No association was shown between the enzyme activities of ADA, PNP, and HGPRT, and the efficacy or toxicity of MTX treatment. In contrast, enzyme activity of 5'NT showed a decrease in the subgroup of patients discontinuing MTX treatment because of hepatotoxicity.. MTX treatment in patients with RA leads to a significant decrease of the purine enzyme activities of ADA, PNP, and HGPRT that is not related to the anti-inflammatory efficacy or toxicity of MTX. Hepatotoxicity was related to a decrease in the enzyme activity of 5'NT. These changes may be explained by direct or indirect (via purine de novo and salvage metabolism and the homocysteine pathway) effects of MTX.

Topics: Adenosine Deaminase; Adult; Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Blood Sedimentation; Female; Folic Acid; Humans; Hypoxanthine Phosphoribosyltransferase; Leucovorin; Male; Methotrexate; Middle Aged; Nucleotidases; Purine-Nucleoside Phosphorylase; Purines; Regression Analysis

Topics: Alcohol Drinking; Antirheumatic Agents; Arthritis, Rheumatoid; Drug Therapy, Combination; Folic Acid; Humans; Leucovorin; Methotrexate

Methotrexate (MTX) is an antineoplastic agent widely used in low dose to treat patients with rheumatoid arthritis (RA). Its side effects can partly be explained by folate antagonism. Folinic acid (Leucovorin) is generally administered with MTX to decrease MTX-induced toxicity. However information regarding the inhibitory effect of folinic acid against cytogenetic damage caused by MTX is limited. The aim of this study was to assess the protective effect of folinic acid against MTX-genotoxicity.. This study was done on Wistar albino rats and in patients with RA. Forty rats of both sexes were randomized into four equal groups and dosed in the following way: Group-I, distilled water vehicle; Group-II, 0.5 mg/kg folinic acid; Group-III, 0.5 mg/kg MTX; Group-IV, 0.5 mg/kg folinic acid plus 0.5 mg/kg MTX. Doses were given i.p., once daily for 8 consecutive days. A bone marrow chromosomal study and a micronucleus test were performed for each rat. Twenty patients with RA (5 males and 15 females) on a 10 mg weekly dose of MTX, i.m., for one month, were administered the same dose of MTX in addition to 10 mg of folinic acid as a single dose 4 hours after MTX administration, i.m., every week for another 4 weeks. Chromosomal studies as well as a micronucleus test were evaluated for each patient.. MTX produced a significant genetic injury as proved by the increased incidence of chromosomal aberration and micronuclei formation in Group-III animals. Inversely, folinic acid (group IV) produced a significant protection against genetic damages induced by MTX. In RA patients, folinic acid provides satisfactory improvement of MTX-induced genetic damage.. Folinic acid has a protective affect against MTX genotoxicity in human as well as in animal models.

Topics: Adult; Animals; Antirheumatic Agents; Arthritis, Rheumatoid; Chromosome Aberrations; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Injections, Intramuscular; Injections, Intraperitoneal; Leucovorin; Male; Methotrexate; Micronucleus Tests; Middle Aged; Rats; Rats, Wistar

Topics: Arthritis, Rheumatoid; Drug Therapy, Combination; Folic Acid; Humans; Leucovorin; Methotrexate

Topics: Arthritis, Rheumatoid; Drug Therapy, Combination; Folic Acid Antagonists; Humans; Leucovorin; Methotrexate

Topics: Arthritis, Rheumatoid; Folic Acid; Humans; Leucovorin; Methotrexate

Topics: Adult; Arthritis, Rheumatoid; Bone Marrow Transplantation; Cyclosporine; Female; Graft vs Host Disease; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Leucovorin; Leukemia, Myeloid, Acute; Methotrexate; Neutropenia; Prednisolone

In a patient suffering from rheumatoid arthritis, we report the first simultaneous occurrence of two side effects of low-dose methotrexate: an acute megaloblastic anaemia and a pneumonitis. A combination of methotrexate suspension, folinic acid and corticosteroids led to recovery. The correlation between the haematologic and pneumologic toxicity is discussed.

Topics: Acute Disease; Anemia, Megaloblastic; Arthritis, Rheumatoid; Humans; Leucovorin; Lung Diseases, Interstitial; Male; Methotrexate; Middle Aged; Prednisolone

Topics: Arthritis, Rheumatoid; Drug Therapy, Combination; Folic Acid; Humans; Leucovorin; Methotrexate

To determine which risk factors are associated with serious pancytopenia associated with low dose methotrexate (MTX) therapy.. All Ottawa area rheumatologists, hematologists and dermatologists were surveyed to obtain cases of pancytopenia associated with low dose MTX therapy between 1981 and 1991. Pancytopenia was defined as white blood cells < 3.5 x 10(9)/l and platelets < 140 x 10(9)/l and hemoglobin < 100 g/l. A case control method was used to evaluate risk factors.. Fifteen cases of pancytopenia were identified from returned questionnaires (93% response rate) and from reviewing the medical records of 2 major teaching hospitals. All patients were hospitalized, had MTX therapy discontinued and were treated: 12 patients received transfusions, 8 leucovorin therapy, and 4 folic acid. Two patients died, only 1 directly due to MTX therapy. Identified risk factors were (1) elevated BUN or creatinine levels, (2) increasing mean corpuscular volume values, (3) increased age and (4) concomitant trimethoprim-sulfamethoxazole therapy.. Pancytopenia associated with low dose MTX therapy is a life threatening adverse effect often associated with known risk factors. A change in monitoring guidelines and patient education are suggested as means of risk reduction.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Arthritis, Psoriatic; Arthritis, Rheumatoid; Blood Urea Nitrogen; Canada; Creatinine; Dose-Response Relationship, Drug; Female; Folic Acid; Health Surveys; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Pancytopenia; Psoriasis; Risk Factors; Surveys and Questionnaires; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Arthritis, Rheumatoid; Humans; Leucovorin; Methotrexate

Five patients with severe, treatment refractory rheumatoid arthritis were treated with high dose intravenous methotrexate (500 mg/m2) followed by leucovorin (50 mg/m2). Four courses of chemotherapy were given over a 2-month interval. At the end of the final course, there was a 50% or greater improvement in joint swelling and pain indices and morning stiffness in all patients. Clinical responses persisted for 6-14 weeks posttherapy. High dose methotrexate-leucovorin was associated with a significant reduction in DR antigen expression on peripheral Leu 2, Leu 3 and Leu 4 lymphocytes.

Topics: Arthritis, Rheumatoid; Drug Therapy, Combination; HLA-DR Antigens; Humans; Injections, Intravenous; Leucovorin; Methotrexate; Pain; Pilot Projects; Recurrence; T-Lymphocytes

High-dose leucovorin (folinic acid) supplementation was tested in a prospective, unblinded manner for 4 weeks in 7 rheumatoid arthritis patients who were being treated successfully with low-dose methotrexate (MTX). Nausea caused by MTX disappeared; however, the underlying rheumatic disease worsened in all patients. Subjective clinical assessment, Ritchie articular index, grip strength, erythrocyte sedimentation rate, and levels of C-reactive protein showed statistically significant deterioration. All these parameters improved after the leucovorin was stopped. This is the first direct clinical evidence implying folate antagonism in the action of low-dose MTX therapy in rheumatoid arthritis patients.

Topics: Arthritis, Rheumatoid; Drug Synergism; Drug Therapy, Combination; Humans; Leucovorin; Methotrexate; Middle Aged

Topics: Arthritis, Rheumatoid; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Stomatitis

The folate status of 29 healthy control subjects, 16 rheumatoid arthritis (RA) patients taking methotrexate (MTX), and 20 RA patients who were not being treated with MTX was estimated by an assay of the folate-dependent enzymatic synthesis of serine from formate and glycine, which is termed the C1 index. Analysis of variance demonstrated that the specific activity of the enzyme system in lymphocytes was significantly lower in the MTX-treated group, with an activity approximately one-half that of the control and the non-MTX-treated groups. Since the C1 index is one of the first biochemical parameters found to be different between MTX-treated and non-MTX-treated groups, alterations in folate-mediated amino acid metabolism may be involved in the mechanism of response to MTX therapy. Use of the C1 index may assist in the development of protocols which preserve the efficacy of MTX therapy while minimizing toxicity.

Topics: Adult; Arthritis, Rheumatoid; Diet; Erythrocytes; Female; Folic Acid; Humans; In Vitro Techniques; Leucovorin; Lymphocytes; Male; Methotrexate; Middle Aged; Serine; Vitamins

Low dose pulse MTX was associated with the development of pancytopenia in six patients with RA. Two patients died. Factors implicated in the occurrence of this complication were renal impairment in five patients, medication errors by two patients, preexisting marrow injury from occult alcoholism in one patient, and an apparent idiosyncratic reaction to the drug in another. Medication errors were associated with the use of five or more medications, and the unusual schedule of administration of low dose MTX may also have been contributory. From a consideration of the clinical pharmacokinetics of MTX, we suggest other factors that may predispose to the occurrence of marrow toxicity: the presence of hypoalbuminemia, interactions between MTX and other protein bound or weakly acidic drugs, and the repetitive dosing schedule of low dose MTX. Based on our experience, patients with impaired renal function (creatinine greater than or equal to 2.0 mg/dL) should not receive MTX. Renal function should be monitored regularly during treatment with MTX, and blood counts should be observed carefully if a new drug is added or substituted. A 5 mg test dose of MTX before initiating weekly therapy may identify patients with severe hypersensitivity to the drug. The potential risks of using MTX in a patient unwilling to accept blood products should be acknowledged and discussed with the patient. Furthermore, we recommend the use of leucovorin if pancytopenia occurs, even if low or undetectable serum levels of MTX are present.

Topics: Adult; Aged; Arthritis, Rheumatoid; Bone Marrow; Female; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Pancytopenia; Risk

Topics: Arthritis, Rheumatoid; Bone Marrow; Deoxyuridine; Humans; Injections, Intra-Articular; Kinetics; Leucovorin; Methotrexate; Synovial Fluid

Topics: Arthritis, Rheumatoid; Epilepsy; Growth Substances; Humans; Leucovorin; Propylene Glycols; Pteridines; Schizophrenia; Structure-Activity Relationship