re: methotrexate

[Guest guest]

Hello

quick word of advice. I have a pt with fibrosing scleroderma with leg pain due

to fibrotic skin. He is on methotrexate and has a history of longterm antibiotic

use. My approach would usually be to do a lot of gut cleansing and look at heavy

metal load etc as initial trt. I don't think we can really get anywhere if he's

on methotrexate. What do you think. Otherwise he is well with no symptoms other

than the pain which is controlled with drugs. So, its not like i can really help

with symptomatic treatment. We tried pain relieving herbs but no difference was

made.

thoughts welcome !

hilary

[Guest guest]

Dear ,

you probably know this anyway - folic acid supplementation is important as

longterm treatment with MTX may lead to deficiency, and many of the side

effects can be avoided by taking 5mg folic acid per week.

I've only had 2 Pts " threatened " with MTX so far, but my plan had been to

support liver and any systems that seemed especially under attack/out of

balance. Sorry, no ideas re treatment strategy.. I saved some info on MTX

(from ibismedical.com) - pasted below. My sister in law is on it for

ulcerative colitis, which surprised me as one of the side effects is

indigestion...

Hope you're keeping well

Sabine xxx

Methotrexate

Brand Names: Amethopterin, Folex, Methotrate, Mexate, Rheumatrex

Clinical Names: Methotrexate

Summary

generic name: Methotrexate

trade names: Amethopterin®, Folex®, Methotrate®, Mexate®, Rheumatrex®

type of drug: Cytotoxic chemotherapy.

mechanism: Methotrexate works by interfering with the activation of folate,

specifically by inhibiting dihydrofolatereductase, thereby disrupting DNA

replication for all cells, but especially rapidly growing cancer cells.

used to treat: Cancer, psoriasis and rheumatoid arthritis.

overview of interactions:

.. nutrient affected by drug: Folic Acid

.. nutrient interactions affecting drug performance and toxicity: Folic Acid

.. nutrient affecting drug performance: Vitamin A

.. nutrient affecting drug performance: Vitamin B12 (Cobalamin)

Interactions

nutrient affected by drug: Folic Acid

.. mechanism: The primary mechanism of methotrexate relies upon interfering

with the activation of folic acid and the degree of folate depletion during

methotrexate therapy depends primarily upon the weekly administered dose.

nutrient interactions affecting drug performance and toxicity: Folic Acid

Methotrexate has varying patterns of use for different conditions and the

relationship of folic acid to the drug mechanism changes accordingly. This

difference is especially important in individuals using methotrexate as a

chemotherapeutic agent and those taking it for rheumatoid arthritis.

.. nutritional concerns with chemotherapy: Since methotrexate's interference

with folic acid metabolism is intentional, individuals prescribed this drug

for cancer treatment should limit their supplementation of folic acid to a

maximum of 400 mcg per day. Consultation with your prescribing physician or

other qualified healthcare provider is important because use of folic acid

at higher levels might work contrary to the drug's therapeutic intention.

However, this caution against folate supplementation does not extend to

individuals taking chemotherapeutic agents other than methotrexate.

.. research: As the use of methotrexate for the treatment of rheumatoid

arthritis has evolved so has the understanding of the use of folic acid by

individuals undergoing therapy. While use of methotrexate for treatment of

rheumatoid arthritis has grown in recent years, over 30% of patients abandon

treatment because of drug-related side effects. Initially researchers

assumed that methotrexate's effects on folic acid were the source of its

presumed benefits in cases of rheumatoid arthritis, as in chemotherapeutic

uses. However, with time and further research, practice has shifted to

support the supplemental use of folic acid to counter the adverse effects of

methotrexate in these cases for several reasons. First, its well-proven

ability to reduce toxic effects of methotrexate. Second, methotrexate causes

folate deficiency and the folate nutriture of patients taking even low dose

methotrexate declines precipitously without folic acid supplementation.

Third, plasma homocysteine levels can increase significantly in those taking

methotrexate but not folate; thereby significantly increasing risk of

cardiovascular disease. These and other benefits are gained with no apparent

loss of antirheumatic effect. Most researchers have found that folic acid

levels were not related to parameters of disease activity and concluded that

methotrexate does not exert its action in RA primarily by inhibiting

dihydrofolatereductase.

(Alarcon GS, SL. Arthritis Rheum 1997 Feb;40(2):391; van Ede AE, et

al. Semin Arthritis Rheum 1998 Apr;27(5):277-292; Hunt PG, et al. J

Rheumatol 1997 Nov;24(11):2230-2232; Leeb BF, et al. Clin Exp Rheumatol 1995

Jul-Aug;13(4):459-463; SL, et al. J Rheumatol 1998 Mar;25(3):441-446;

Shiroky JB. Rheum Dis Clin North Am 1997 Nov;23(4):969-680.)

.. nutritional support with rheumatoid conditions: Though its use is not

universally accepted, the ability of folic acid (or folinic acid) to reduce

methotrexate toxicity in individuals being treated for rheumatoid arthritis

has made its use an important adjunct in enabling patients to tolerate

methotrexate. At this time, research supports several rationales for

substantial folate supplementation by individuals taking methotrexate for

rheumatoid arthritis. Beyond the prevention of methotrexate toxicity, the

prevention or treatment of folate deficiency and the prevention of

hyperhomocysteinemia further contribute to the therapeutic value of

supplementation with high doses of folic acid. According to the several

studies cited, a daily dose of 1000-5000 mcg of folic acid or 2.5-5 mg of

folinic acid (an activated form of folic acid) can substantially reduce the

adverse effects of methotrexate without compromising its therapeutic effect

in rheumatoid patients.

( SL, et al. J Rheumatol 1998 Mar;25(3):441-446; Shiroky JB. Rheum Dis

Clin North Am 1997 Nov;23(4):969-980; Kamen B. Semin Oncol 1997 Oct;24(5

Suppl 18):S18-30-S18-39; , SL, et al. Ann Intern Med 1994;121:833-841;

Ortiz Z, et al. J Rheumatol 1998 Jan;25(1):36-43; Shiroky JB, et al. Arthrit

Rheum 1993;36:795.)

nutrient affecting drug performance: Vitamin A

.. mechanism: Researchers have found that vitamin A enhances antitumor

activity in animals taking methotrexate.

(Nakagawa, M, et al. Jpn J Cancer Res 1985;76:887-894.)

.. nutritional support: Individuals using methotrexate for the treatment of

tumors should consult their prescribing physician and/or a

nutritionally-oriented healthcare professional before initiating or

increasing supplementation of vitamin A.

nutrient affecting drug performance: Vitamin B12 (Cobalamin)

.. mechanism: Given methotrexate's intentional interference with normal

functioning of folic acid metabolism, problems with vitamin B12 deficiency

can be expected. Further, vitamin B12 and folic acid work together to

control homocysteine levels. Investigators have found that patients taking

methotrexate have lower B12/RBC levels than in controls, but that serum

levels of B12 were not different. They concluded that folate depletion may

be related to B12 deficiency in red blood cells.

(Leeb BF, et als. Clin Exp Rheumatol 1995 Jul-Aug;13(4):459-463.)

.. nutritional support: In no circumstances is methotrexate-induced Vitamin

B12 deficiency considered important to the drug's therapeutic efficacy.

However, since folate deficiency inherently results from methotrexate use,

some support to counterbalance the unintentional adverse effects on Vitamin

B12 levels would appear valuable. While supplementation with vitamin B12 is

harmless and indicated, individuals receiving treatment with methotrexate

should consult their prescribing physician and/or a nutritionally-oriented

healthcare professional before initiating or increasing supplementation of

Vitamin B12. In such cases, supplementation is often up to or greater than

1,000 mcg of vitamin B12 per day or be provided by a physician via vitamin

B12 injections.

References

Alarcon GS, SL. Guidelines for folate supplementation in rheumatoid

arthritis patients treated with methotrexate: comment on the guidelines for

monitoring drug therapy. Arthritis Rheum 1997 Feb;40(2):391; discussion

391-392. (Letter)

Duell PB, Malinow MR. Homocyst(e)ine: an important risk factor for

atherosclerotic vascular disease. Curr Opin Lipidol 1997 Feb;8(1):28-34.

(Review)

Abstract: Homocysteine is an intermediate compound formed duringmetabolism

of methionine. The results of many recent studies have indicated that

elevated plasma levels of homocyst(e)ine are associated with increased risk

of coronary atherosclerosis, cerebrovascular disease, peripheral vascular

disease, and thrombosis. The plasma level of homocyst(e)ine is dependent on

genetically regulated levels of essential enzymes and the intake of folic

acid, vitamin B6 (pyridoxine), and vitamin B12 (cobalamin). Impaired renal

function, increased age, and pharmacologic agents (e.g. nitrous oxide,

methotrexate) can contribute to increased levels of homocyst(e)ine.

Plausible mechanisms by which homocyst(e)ine might contribute to

atherogenesis include promotion of platelet activation and enhanced

coagulability, increased smooth muscle cell proliferation, cytotoxicity,

induction of endothelial dysfunction, and stimulation of LDL oxidation.

Levels of homocysteine can be reduced with pharmacologic doses of folic

acid, pyridoxine, vitamin B12, or betaine, but further research is required

to determine the efficacy of this intervention in reducing morbidity and

mortality associated with atherosclerotic vascular disease.

Fiskerstrand T, Ueland PM, Refsum H. Folate depletion induced by

methotrexate affects methionine synthase activity and its susceptibility to

inactivation by nitrous oxide. J Pharmacol Exp Ther 1997

Sep;282(3):1305-1311.

Abstract: We compared the effects of methotrexate (MTX) and nitrous oxide on

the methionine (Met) synthase system in two variants of a human glioma cell

line. The cells were protected from cytotoxic effect of MTX by adding

thymidine and hypoxanthine to the cell culture medium. MTX (0-1 microM) was

associated with a dose- and time-dependent reduction in

5-methyltetrahydrofolate (5-methyl-THF) in both cell lines. Already after 3

hr of exposure, 5-methyl-THF was reduced by 50% and after additional 48 hr,

the level was undetectable. In addition to reduction in folate level,

homocysteine (Hcy) remethylation in intact cells was markedly inhibited as

judged by an increased export of Hcy from the cells, and Met synthase

activity in cell extracts and level of cellular methylcobalamin (CH3Cbl)

declined. MTX reduced Hcy remethylation and CH3Cbl level more efficiently

than nitrous oxide. In both cell variants, the inactivation of Met synthase

by nitrous oxide was almost completely prevented in cells pre-exposed to

MTX. This indicates that there is no catalytic turnover in cells exposed to

MTX, and emphasizes the importance of the sequence of administration for

synergistic effect of this drug combination. In conclusion, our data show

that MTX through depletion of 5-methyl-THF reduces both the Met synthase

activity and the cellular CH3Cbl level. Moreover, the effect of MTX on the

Hcy remethylation is more pronounced than the inhibition caused by nitrous

oxide. These observations should be taken into account in studies on MTX

pharmacodynamics.

Hunt PG, Rose CD, McIlvain-Simpson G, Tejani S. The effects of daily intake

of folic acid on the efficacy of methotrexate therapy in children with

juvenile rheumatoid arthritis. A controlled study. J Rheumatol 1997

Nov;24(11):2230-2232.

Abstract: OBJECTIVE: To determine the effect of 1 mg/day of folic acid on

the efficacy of methotrexate (MTX) to control disease activity in children

with juvenile rheumatoid arthritis (JRA). METHODS: Randomized, double blind,

placebo controlled, crossover trial of 13 weeks' duration. Nineteen children

with the diagnosis of JRA, fulfilling the American College of Rheumatology

diagnostic criteria, who had been receiving MTX for at least 6 months and

whose disease status had remained stable for at least one month before entry

were enrolled in the study. Subjects were randomly assigned to receive 1

mg/day of liquid folic acid or a liquid placebo for 6 weeks, followed by a

one week washout period, and subsequent crossover to the alternate form for

another 6 weeks. Disease activity indicators, including swollen joint count,

duration of morning stiffness, physician and patient global assessment, and

C-reactive protein, were assessed at study entry and at 6 and 13 weeks.

RESULTS: One patient flared during the first 2 weeks while taking placebo,

requiring study withdrawal and exclusion from outcome analysis. For the

remaining 18 patients, there was no statistical difference in disease

activity indicators with folic acid treatment compared to placebo.

CONCLUSION: Supplementation with 1 mg/day of folic acid may not affect the

clinical efficacy of oral weekly MTX in children with JRA.

Kamen B. Folate and antifolate pharmacology. Semin Oncol 1997 Oct;24(5 Suppl

18):S18-30-S18-39. (Review)

Abstract: Folic acid is a water-soluble vitamin associated with the other B

vitamins. In its fully reduced form (tetrahydrofolate), folate serves as a

1-carbon donor for synthesis of purines and thymidine as well as in the

remethylation cycle of homocysteine to methionine. Folate is essential for

normal cell growth and replication. It therefore is not surprising that

folate analogues have served and continue to serve well as antibiotics and

cytotoxic drugs in the treatment of cancer, autoimmune diseases, psoriasis,

and bacterial and protozoal infections. During the past 50 years, many of

the enzymes requiring folate as a co-factor (ie, thymidylate synthase), and

molecules critical in folate homeostasis (ie, the reduced folate carrier,

folylpolyglutamate synthase), have been purified and even crystallized. The

genes have been cloned, sequenced, and mapped, providing detailed knowledge

of their regulation and three-dimensional structure. This has, in part, led

to the rational synthesis of a large number of folate analogues that differ

from methotrexate, the " classical antifolate, " in transport, metabolism, and

intracellular targets. Currently, several new folate analogues with unique

biochemical properties and clinical applications are being tested. The goals

of this brief review are to review folate homeostasis, to highlight the

similarities and differences between natural folate and antifolates with

respect to biochemistry and metabolism, and to present the pharmacology of

methotrexate and several next-generation folate analogues, such as

trimetrexate and raltritrexed, with an emphasis on mechanisms of drug

resistance.

Leeb BF, Witzmann G, Ogris E, Studnicka-Benke A, Andel I, Schweitzer H,

Smolen JS. Folic acid and cyanocobalamin levels in serum and erythrocytes

during low-dose methotrexate therapy of rheumatoid arthritis and psoriatic

arthritis patients. Clin Exp Rheumatol 1995 Jul-Aug;13(4):459-463.

Abstract: OBJECTIVE. To compare folic acid (FA) levels in patients being

treated with methotrexate (MTX) with those of untreated patients in order to

investigate potential folate depletion by MTX and its possible relationship

to the drug's efficacy. METHODS. In 33 patients on low-dose MTX therapy and

in 24 controls, FA and cyanocobalamin (B12) levels were determined in serum

and red blood cells (RBC). In addition, MTX levels in the RBC and serum were

measured, and clinical and laboratory measures of disease activity were

evaluated. RESULTS. MTX treated patients had lower FA levels than controls

(median 4.36 vs 7.37 ng/ml, p < 0.001). A significant correlation between

serum FA and MTX/RBC (p < 0.01) and between the weekly dose and MTX/RBC (p <

0.01) was seen. There was apparently no correlation between FA and the

cumulative total MTX. MTX patients had lower B12/RBC levels than the

controls (p < 0.001); the serum levels of B12 were not different. Clinical

features, ESR and CRP did not correlate with FA, B12 or MTX levels.

CONCLUSIONS. The degree of folate depletion during MTX therapy depends

primarily upon the weekly administered dose. Folate depletion may be related

to B12 deficiency in RBC. Since FA levels were not related to parameters of

disease activity it is conceivable that MTX does not exert its action in RA

primarily by inhibiting dihydrofolatereductase. Therefore, additional folate

compounds, if necessary, should not lead to a reduction in the efficacy of

MTX.

SL, Baggott JE, Lee JY, Alarcon GS. Folic acid supplementation

prevents deficient blood folate levels and hyperhomocysteinemia during

longterm, low dose methotrexate therapy for rheumatoid arthritis:

implications for cardiovascular disease prevention. J Rheumatol 1998

Mar;25(3):441-446. Abstract: OBJECTIVE: To determine the effect of longterm

methotrexate (MTX) therapy and folic acid supplementation on folate

nutriture and homocysteine levels in patients with rheumatoid arthritis.

METHODS: A double blind, placebo controlled trial lasting one year was

conducted at one academic medical center. A total of 79 patients taking low

dose MTX were followed up to one year. The patients were randomized to

receive placebo or 5 or 27.5 mg folic acid supplementation per week.

RESULTS: Plasma and erythrocyte folate levels and plasma homocysteine levels

were determined. The folate nutriture of patients taking low dose MTX

declined without folic acid supplementation. Plasma homocysteine levels

increased significantly over a one year period in the placebo group. Low

folate nutriture and hyperhomocysteinemia occurred with greater frequency in

the placebo group than in the folic acid supplemented groups. CONCLUSION:

For longterm, low dose MTX therapy, there are now at least 3 reasons to

consider supplementation with folic acid (a low cost prescription): (1) to

prevent MTX toxicity, (2) to prevent or treat folate deficiency, and (3) to

prevent hyperhomocysteinemia, considered by many investigators to be a risk

factor for cardiovascular disease.

, SL, Baggott, JE, Vaughn, WH, et al. Supplementation with folic acid

during methotrexate therapy for rheumatoid arthritis. Ann Intern Med

1994;121:833-841.

Nakagawa M, Yamaguchi T, Ueda H, Shiraishi N, Komiyama S, Akiyama S, Ogata

J, Kuwano M. Potentiation by vitamin A of the action of anticancer agents

against murine tumors. Jpn J Cancer Res (Gann) 1985;76:887-894.

Abstract: Combinations of retinol palmitate (RP) and six different

anticancer agents were examined to determine their effects on the life-span

of mice bearing ascites sarcoma 180 or P388 leukemia. With ascites sarcoma

180, administration of a fixed dose of RP (3.3 mg/kg) considerably enhanced

the antitumor effects of 5-fluorouracil (5-FU) (5 mg/kg, or 20 mg/kg),

methotrexate (MTX) (0.5 mg/kg, or 1 mg/kg) and

1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea

(ACNU) (12.5 mg/kg), when given by intraperitoneal injection. However RP

failed to potentiate the antitumor effects of adriamycin (ADM) and

6-mercaptopurine (6-MP) against sarcoma 180. With P388 leukemia, RP (167

mg/kg, or 333 mg/kg) enhanced the antitumor effects of 6-MP (25 mg/kg, or 50

mg/kg), MTX (1 mg/kg, or 2 mg/kg), ADM (0.2 mg/kg), ACNU (5 mg/kg) and

cis-dichlorodiammine-platinum (CDDP) (1 mg/kg) to a considerable extent, but

it did not potentiate the antitumor effect of 5-FU. The combination of RP

with ACNU or CDDP was particularly effective against P388 leukemia.

Ortiz Z, Shea B, Suarez-Almazor ME, Moher D, Wells GA, Tugwell P. The

efficacy of folic acid and folinic acid in reducing methotrexate

gastrointestinal toxicity in rheumatoid arthritis. A metaanalysis of

randomized controlled trials. J Rheumatol 1998 Jan;25(1):36-43.

Abstract: OBJECTIVE: 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). METHODS: 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. RESULTS: 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. CONCLUSION: Our results support the

protective effect of folate supplementation in reducing MTX side effects

related to the oral and GI systems.

Shiroky JB. Folic acid and methotrexate in rheumatoid arthritis. Ann Intern

Med 1996 Jan 1;124(1 Pt 1):73-74. (Letter)

Shiroky JB, Neville C, Esdaile JM, Choquette D, Zummer M, Hazeltine M,

Bykerk V, Kanji M, St-Pierre A, Robidoux L, et al. Low-dose methotrexate

with leucovorin (folinic acid) in the management of rheumatoid arthritis.

Arthrit Rheum 1993;36:795.

Abstract: OBJECTIVE. To determine whether the side effects of methotrexate

can be decreased by the concurrent use of leucovorin, without affecting the

efficacy of the methotrexate. METHODS. 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. RESULTS. 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.

CONCLUSION. The methotrexate-leucovorin protocol used significantly reduces

common side effects of methotrexate therapy without significantly altering

efficacy.

Shiroky JB. The use of folates concomitantly with low-dose pulse

methotrexate. Rheum Dis Clin North Am 1997 Nov;23(4):969-680. (Review)

Abstract: 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.

van Ede AE, Laan RF, Blom HJ, De Abreu RA, van de Putte LB. Methotrexate in

rheumatoid arthritis: an update with focus on mechanisms involved in

toxicity. Semin Arthritis Rheum 1998 Apr;27(5):277-292. (Review)

Abstract: OBJECTIVES: To provide an update of the current knowledge of the

mechanism of action of low-dose methotrexate (MTX) in the treatment of

patients with rheumatoid arthritis (RA), with an emphasis on the mechanisms

involved in toxicity. We also considered strategies currently used to

prevent or decrease toxicity of MTX. METHODS: We reviewed the literature

dealing with the subjects of MTX treatment of RA, the mechanisms of action

of low-dose MTX regarding efficacy and toxicity, and strategies used to

prevent or decrease MTX toxicity. RESULTS: MTX is a fast working and

effective second-line antirheumatic agent (SLA). Its use is limited mainly

because of side effects. The mechanisms of action regarding efficacy and

toxicity are probably determined by different metabolic pathways. Recent

data indicate that the antiinflammatory effect of MTX is mediated by

adenosine. However, MTX side effects can only partly be explained by folate

antagonism and may also depend on its action on other related metabolic

pathways. The latter include the homocysteine-methionine-polyamine pathway

and purine metabolism. Variants in these metabolic routes (ie, the C677T

mutation in the methylene-tetrahydrofolate reductase [MTHFR] gene), may

predispose to the development of side effects. Currently the most promising

strategy to decrease or prevent toxicity of MTX is concomitant prescription

of folic acid or folinic acid. Other strategies are currently under

investigation. CONCLUSIONS: MTX benefits a majority of RA patients.

Approximately 30% of patients, however, abandon treatment because of

drug-related side effects. Folic acid or folinic acid likely reduces MTX

toxicity. More data, however, are needed to evaluate a potential detrimental

effect on the antirheumatic efficacy of MTX.

re: methotrexate

> Hello

> quick word of advice. I have a pt with fibrosing scleroderma with leg pain

due to fibrotic skin.