INTRODUCTION — Methotrexate (MTX) is commonly used for the treatment of patients with rheumatoid arthritis (RA) and in several other forms of inflammatory arthritis and autoimmune disease. It was first used for the treatment of RA and psoriasis in 1951, following its development in the late 1940s as a chemotherapeutic agent for malignancy . However, it received little attention in the therapy of rheumatic diseases until case series describing use in RA were published in the early 1980s [2,3].
Short-term randomized trials in the mid-1980s further documented its efficacy in RA, and subsequent long-term studies showed that the response was sustained and that toxicity was manageable. These and other findings led to the widespread use of "low-dose" MTX (relative to the much higher doses required for cancer therapy) as an initial therapy and anchor drug for RA and supported its use in other immune disorders. (See "Initial treatment of rheumatoid arthritis in adults".)
The pharmacology of low-dose MTX and its mechanism of action, dosing, and administration in the treatment of RA will be reviewed here. The role of MTX in treatment and its efficacy, safety, adverse effects, and influence on prognosis are discussed separately. (See "Major side effects of low-dose methotrexate" and "Hepatotoxicity associated with chronic low-dose methotrexate for nonmalignant disease" and "Methotrexate-induced lung injury" and "Initial treatment of rheumatoid arthritis in adults" and "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy".)
The clinical use and toxicity of high-dose MTX for treatment of malignancy are also discussed in detail separately. (See "Therapeutic use and toxicity of high-dose methotrexate".)
Absorption and route of administration — Methotrexate (MTX) can be given by oral, subcutaneous, and intramuscular routes. Oral MTX is variably absorbed in the dose range used to treat rheumatoid arthritis (RA). Food does not affect MTX absorption to a significant degree . Thus, the medication may be given with a meal or in the fasting state.
Serum levels of MTX consistently increase when the drug is administered parenterally, which is not the case for oral ingestion of doses of 15 mg or greater administered all at one time [5,6]. This difference in absorption may have therapeutic implications as some patients may respond better to parenteral therapy, presumably because more drug reaches the circulation (see 'Parenteral therapy' below). This difference in drug levels between parenteral and oral administration may be more pronounced at higher doses within the usual therapeutic range.
As an example, a 7.5 mg weekly dose is absorbed better than a 15 to 20 mg dose . Bioavailability (f) is defined as the ratio of oral drug absorption divided by intravenous drug absorption. Since f may drop off by a mean of 13.5 percent as the dose of MTX is increased from a starting dose of 7.5 mg to the typical maintenance weekly doses employed in RA, a patient may do better clinically when switched from oral (PO) to intramuscular (IM) or subcutaneous (SC) administration of the same dose of the drug (see 'Parenteral therapy' below). At a 17.5 to 20 mg weekly dose of MTX, for example, a 13.5 percent difference in f between the PO and IM routes of administration is equivalent to one full 2.5 mg MTX tablet. As the variation in the confidence intervals for the drop-off in f extends to 27 percent, selected patients may have an even greater difference in f between parenteral and oral dosing.
At higher doses, decreased bioavailability may be even more pronounced. This was illustrated in a pharmacokinetic analysis of 15 patients taking more than 25 mg/week of MTX (mean of 30 mg/week); the ratio of oral to subcutaneous absorption was decreased by approximately one-third .
Metabolism and elimination — MTX is a prodrug that becomes active only when polyglutamated within cells. The process of polyglutamation is slow and takes as long as 27.5 weeks to reach steady state . This delay in steady-state polyglutamation explains the time to achievement of the plateau effect of clinical response previously described with MTX .
MTX is primarily cleared via the kidneys, with 80 to 90 percent being excreted unchanged in the urine; thus, any impairment of glomerular filtration rate (GFR) will result in sustained serum levels of the drug that may induce bone marrow or other toxicities.
Nonsteroidal antiinflammatory drugs (NSAIDs) may decrease the excretion of MTX; however, NSAIDs can be safely given together with low-dose MTX (in the dose range used for RA), assuming that appropriate monitoring for drug toxicity is performed. The safety of such concurrent use was shown in a systematic review of randomized trials and large studies involving patients with RA . The use of antiinflammatory doses of salicylates with MTX should be avoided, although lower doses are easily tolerated and should not be a problem [10,11]. (See "General principles and overview of management of rheumatoid arthritis in adults".)
Drug interactions — MTX has minimal interaction with other drugs as only 50 percent is protein bound. However, there is a risk of increased toxicity when combined with other folate-depleting drugs such as trimethoprim, which is most often given as trimethoprim-sulfamethoxazole, and probenecid. Effects of sulfasalazine (SSZ) on MTX and folate uptake do not appear to preclude their use in combination. NSAID use together with low-dose MTX is also generally well tolerated. (See 'Metabolism and elimination' above.)
MTX is usually well tolerated in patients taking trimethoprim-sulfamethoxazole prophylaxis (usually as one double-strength tablet three times weekly, such as on a Monday-Wednesday-Friday regimen), but this combination should be avoided when the antibiotic is used in a twice-daily regimen for treatment of an active infection. Significant bone marrow and other toxicities have been observed with use of a daily sulfa antibiotic regimen.
In vitro data suggest that SSZ can interfere with cellular uptake of MTX by blocking the action of the reduced folate carrier protein that transports the major circulating form of folate, 5-methyltetrahydrofolate, as well as 5-formyltetrahydrofolate, and folic acid . The clinical significance of this finding is uncertain, but the possibilities that coadministration of SSZ could attenuate the effectiveness of MTX and cause or exacerbate intracellular folate deficiency have both been raised as potentially important interactions that need further investigation. Despite this interaction, the combination of SSZ with MTX and hydroxychloroquine ("triple therapy") can be an effective treatment for RA . (See "Sulfasalazine: Pharmacology, administration, and adverse effects in the treatment of rheumatoid arthritis" and "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy", section on 'DMARD triple therapy'.)
MECHANISM OF ACTION — Methotrexate (MTX) has several biologic effects that are thought to be important in exerting its immunomodulatory and immunosuppressive effects, including inhibition of folate metabolism and adenosine-receptor-mediated effects that diminish inflammation, as well as several other actions of uncertain relative importance. The precise mechanisms by which MTX works clinically are not entirely clear. The following have been described:
●Inhibition of folic acid metabolism – MTX is a structural analogue of folic acid that can competitively inhibit the binding of dihydrofolic acid (FH2) to the enzyme dihydrofolate reductase (DHFR). DHFR is responsible for reducing FH2 to folinic acid (5-formyl tetrahydrofolate [FH4]; also termed leucovorin), the active intracellular metabolite. Thus, MTX decreases the amount of intracellular FH4 available and affects the metabolic pathways within the cell that are FH4 dependent. These pathways include purine and pyrimidine metabolism, as well as amino acid and polyamine synthesis. MTX may also bind directly to other folate-dependent enzymes, including those which are integral to purine biosynthesis.
●Adenosine-receptor-mediated effects – MTX also results in increased extracellular concentrations of adenosine, an autacoid with robust antiinflammatory activity, which may be important in how it acts [14,15]. The increased levels of adenosine appear to result from extracellular dephosphorylation of adenine nucleotides, which is mediated by ecto-5'-nucleotidase. Supporting evidence of a role for adenosine includes:
•The demonstration in animals that the nonspecific adenosine receptor antagonists, theophylline and caffeine, reduce the beneficial effects of MTX . There is no evidence of an antagonistic effect of caffeine or theophylline in humans treated with MTX, although the possibility of an interaction has not been well studied.
•Findings that rodents that lack adenosine receptors do not experience the same antiinflammatory effect from MTX as animals with these adenosine receptors .
•The observation of an association between certain allelic variants of enzymes involved in the metabolism of adenosine and clinical response of patients with early rheumatoid arthritis (RA) to MTX therapy .
●Other mechanisms – MTX has a variety of other effects that may be important, but their relative roles in its mechanism of action as an antirheumatic agent are uncertain. These effects include the inhibition of methylation reactions vital for cellular activities and replication, clonal deletion via apoptosis of activated peripheral T cells, decreased production of proinflammatory cytokines by activated T cells, suppression of interleukin (IL)-1 beta production by mononuclear cells, suppression of the clonal growth of peripheral and synovial T and B cells, increased production of IL-10, and suppression of intracellular adhesion by activated T cells [19-24]. MTX has also been shown to significantly decrease circulating IL-6 in patients treated for RA and to affect other cytokines as well .
MTX may also have other biologic effects relevant to its use in patients with RA. It is possible that MTX may achieve an antiatherogenic effect by improving the efficiency of reverse cholesterol transport from foam cells , although both total cholesterol and low-density lipoprotein (LDL) do increase slightly in patients starting MTX . MTX has been reported to increase LDL cholesterol when used as monotherapy or combined with etanercept or hydroxychloroquine and sulfasalazine (SSZ) [27,28]. These effects are speculated to be the result of lipid changes associated with decreased inflammation. A large multicenter randomized trial has examined the effects of MTX for the prevention of cardiovascular disease in nonrheumatic disease patients with a history of a cardiovascular event ; the study was discontinued as there was no apparent beneficial effect of MTX. However, a meta-analysis of 10 observational studies of the effects of MTX on cardiovascular outcomes in patients with RA, psoriasis, and polyarthritis showed a beneficial effect .
PRECAUTIONS AND PREVENTION OF ADVERSE EFFECTS — Methotrexate (MTX) use can increase the risk of a number of adverse effects (see "Major side effects of low-dose methotrexate"); key steps to help prevent MTX-related adverse effects include strict avoidance of use during conception and pregnancy, performance of needed immunizations prior to treatment, daily supplementation with folic acid during therapy with MTX, and limiting intake of alcoholic beverages. (See 'Pregnancy' below and 'Immunizations' below and 'Folic acid supplementation' below and 'Alcohol use' below and 'Pulmonary disease' below.)
In addition, patients with reduced renal function may require a lower dose or avoidance of MTX altogether. (See 'Dosing and limits to use with reduced renal function' below.)
There is no universally accepted method to determine which of several folate enzymes might predict toxicity to MTX prior to initial dosing, although several publications have pointed to an association of methylene tetrahydrofolate reductase (MTHFR) polymorphisms with toxicity . MTHFR regenerates reduced folate species intracellularly; the MTX effect on this enzyme system results in decreased production of methyl-tetrahydrofolate and is associated with increased cellular toxicity and the potential for hyperhomocysteinemia. (See "Overview of homocysteine".)
Pregnancy — Use of MTX should be avoided in women who are contemplating becoming pregnant and those who are pregnant because of its documented embryotoxicity and teratogenicity. Women of childbearing potential should use effective contraception before and during MTX treatment. If there is any uncertainty about the possibility of pregnancy, blood testing is appropriate prior to initiating MTX. These issues and recommendations regarding discontinuation of MTX in anticipation of pregnancy are discussed in more detail elsewhere. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Methotrexate'.)
Immunizations — MTX in the dose range used to treat rheumatoid arthritis (RA; eg, 12.5 to 25 mg once weekly) appears to slightly decrease responses to immunizations; thus, patients with RA who are about to be treated with MTX should, if not previously given, be immunized with diphtheria, pertussis, tetanus (DPT) vaccine, killed polio vaccine, pneumococcal vaccine, inactivated influenza vaccine, and hepatitis B, but not measles, mumps, and rubella (MMR) vaccine, oral (live) polio vaccine, live attenuated influenza vaccine, or yellow fever vaccine. Furthermore, nonimmunized patients should avoid close interaction with household contacts who are receiving live polio vaccine. Immunization in patients with autoimmune and inflammatory rheumatic diseases is discussed in more detail separately. (See "Immunizations in autoimmune inflammatory rheumatic disease in adults".)
Holding MTX for two weeks following seasonal influenza vaccination is a reasonable option in patients with stable, well-controlled RA, given evidence that this may improve the frequency of satisfactory vaccine responses in such patients with little risk of sustained flares of RA disease activity. The immunogenicity of seasonal influenza vaccine was shown to be improved without an increase in RA disease activity in a randomized trial involving 316 patients that compared patients on MTX in whom the drug was held for a period of two weeks immediately after immunization with patients in whom it was not held (satisfactory vaccine response in 76 versus 55 percent) . Although mean disease activity was similar in the two groups, RA disease flares were experienced by 11 percent of the patients in whom MTX was held and in five percent of those in whom it was not; patients returned to their baseline level of disease activity following resumption of weekly MTX. (See "Immunizations in autoimmune inflammatory rheumatic disease in adults".)
Folic acid supplementation — In all patients taking chronic low-dose MTX, we recommend treatment with folic acid (1 mg daily) to reduce risk of several common MTX toxicities and the likelihood of treatment discontinuation. The dose may be increased to 5 mg/day as needed, based upon reporting of residual symptoms. Leucovorin (folinic acid) is an alternative to folic acid. Use of daily folic acid or weekly leucovorin supplementation also prevents the increase in the plasma concentration of homocysteine that otherwise occurs as a result of MTX administration . (See "Major side effects of low-dose methotrexate" and "Overview of homocysteine".)
Folic acid can be taken daily, including the day on which MTX is administered, because it is passively taken up by the cell and does not compete with MTX for uptake by the reduced folate carrier. There is no evidence of toxicity of folic acid in this dose range. Moreover, there is no evidence that giving MTX and folic acid on the same day in any way affects the efficacy of MTX.
Symptoms and findings most likely to be decreased by folic acid treatment include gastrointestinal symptoms and hepatic transaminase elevations; stomatitis and mouth sores may also be reduced, and fewer patients on folic acid supplementation discontinue MTX therapy [33-37]. These toxicities can be predicted by the baseline folate status at the time of initiation of MTX therapy. MTX interferes with the cellular utilization of folic acid, and folate depletion is considered to be the cause of most of these complaints. Most trials of folic acid for this purpose have supported this approach and have noted that many of these reactions can be alleviated or prevented by the addition of supplemental folic acid, without reducing the efficacy of MTX [33-37]. As rapidly dividing cells take up folate, and therefore MTX, more readily, it is these populations that are more susceptible to the effects of the drug. Thus, oral and gut mucosa and bone marrow are the most common sites of side effects, reflecting the increased need for folate in these rapidly dividing cells.
In patients who have not had a satisfactory response to folic acid, we use leucovorin (folinic acid), the reduced form of folate. Leucovorin is considerably more expensive than folic acid, and timing and dosing are critical both in preventing toxicity and in maintaining the efficacy of MTX. A typical dose is 2.5 to 5 mg given once weekly, 10 to 12 hours after MTX administration. The purpose of this timing is to avoid competition for uptake. The dose of the L-isomer (L-leucovorin) is one-half the dose of the racemic preparation (leucovorin calcium).
Leucovorin also reduces MTX toxicity [38-41], although at doses above 7 mg/week, it may diminish the efficacy of MTX [40,41]. Leucovorin is reduced folate (FH4), while folic acid is the form of the vitamin found prior to the metabolic reduction to FH4 by the enzyme dihydrofolate reductase (DHFR). Since DHFR is one of the target enzymes of MTX, leucovorin is more potent in overcoming the metabolic block in this pathway.
The benefit of folate supplementation is best illustrated by an updated systematic review and meta-analysis of six randomized trials involving 624 patients, which found a reduction in adverse effects without loss of MTX efficacy with the use of folic acid or of leucovorin supplementation compared with placebo [36,37,42]. Reductions were seen in the number of patients with abnormally elevated serum hepatic transaminases (relative risk [RR] 0.23, 95% CI 0.15-0.34); in gastrointestinal side effects, including nausea, vomiting, or abdominal pain (RR 0.74, 95% CI 0.59-0.92); and in withdrawal from using MTX for any reason (RR 0.39, 95% CI 0.28-0.53). The absolute risk reductions in transaminase elevations above normal, gastrointestinal side effects, and MTX discontinuation were 16, 9, and 15 percent, respectively. There was a statistically nonsignificant trend suggesting a possible decrease in stomatitis and in mouth sores as well.
However, some data have suggested that daily folate may reduce the efficacy of MTX for RA. This was illustrated in a post-hoc analysis of the outcomes of two control groups in two separate randomized controlled trials that compared leflunomide with MTX . A clinically modest, but statistically significant, decrease in efficacy was noted in those who received MTX and folate concomitantly (American College of Rheumatology [ACR] criteria for 20, 50, and 70 percent improvement [ACR20, ACR50, and ACR70] in patients not receiving folate were a mean of 17, 14, and 12 percent higher, respectively, compared with patients who did take folate) . Liver enzyme abnormalities were less frequently noted in those receiving folate. Adverse effects of MTX were not reduced by folate administration in this particular study, although they clearly have been in randomized trials designed to examine this question [36,37,42].
Despite the efficacy of folic acid in relieving the above symptoms, there is no compelling evidence that the hepatic or pulmonary toxicity is related to folate depletion. However, hepatic folate stores are depleted by MTX at the doses used in RA, and these stores can be repleted by short-term oral leucovorin . Nonetheless, a relationship between folate depletion and hepatic toxicity has not been definitively established. (See "Hepatotoxicity associated with chronic low-dose methotrexate for nonmalignant disease".)
Alcohol use — Drinking alcoholic beverages while using low-dose MTX is discouraged because of the risk of hepatotoxicity. Abstinence may be the best approach, but some intermittent alcohol intake may be tolerated. Patients who drink alcoholic beverages regularly and are unwilling to stop or to agree to only imbibe occasionally should be treated cautiously and followed for abnormalities of transaminase enzymes or serum albumin concentrations at six- to eight-week intervals. It is likely that the tolerance for alcohol while on MTX is highly variable, but there is no reliable mechanism to predict this with certainty. Alcohol intake of up to a few drinks per week is usually tolerated initially, as long as the transaminase enzymes and serum albumin are monitored at appropriate intervals. European guidelines are more liberal in the amount of alcohol allowed. However, there are no long-term studies of actual hepatic tissue showing that increased alcohol intake is safe in the majority of patients on MTX. (See "Hepatotoxicity associated with chronic low-dose methotrexate for nonmalignant disease", section on 'Approach to monitoring in rheumatoid arthritis'.)
Pulmonary disease — We avoid use of MTX in most patients with underlying lung disease. Pulmonary toxicity is a risk of MTX therapy; thus, a baseline chest radiograph should be obtained prior to initiating MTX treatment. Pulmonary toxicity of MTX, including its pathogenesis, manifestations, evaluation, and management, is discussed in detail separately. (See "Methotrexate-induced lung injury".)
DOSING AND ADMINISTRATION
Dose titration — For most patients, we initiate methotrexate (MTX) therapy at a dose between 7.5 and 15 mg once weekly, depending upon the degree of disease activity, size and age of the patient, the presence of comorbidities, and renal function.
As examples, the author would treat a 70-year-old patient weighing 55 kg with moderately active disease with an initial dose of 7.5 mg once weekly, while an otherwise healthy 30-year-old patient weighing 80 kg with highly active disease would be started on 15 mg once weekly. Starting doses below 15 mg are also indicated in patients with an estimated glomerular filtration rate (eGFR) of <60 mL/minute. (See 'Dosing and limits to use with reduced renal function' below.)
The MTX dose is increased as tolerated and as needed to control symptoms and signs of arthritis. The author's usual approach is to increase the dose after four weeks at a rate of 2.5 mg (one tablet)/week as indicated by disease activity and as tolerated. In patients with continued high disease activity, the author may increase by up to 5 mg/week if few comorbidities are present and the increase in the dose continues to be well tolerated. The optimal schedule for dose escalation is uncertain and will vary widely between individuals. By convention, the maximum dose in rheumatoid arthritis (RA) is usually 25 mg/week, as there is minimal evidence of safety and greater efficacy at higher weekly doses.
Other experts, including the section editor, typically initiate therapy at 15 mg once weekly in patients with normal renal function, increasing to 20 mg once weekly after 6 to 12 weeks, and to 25 mg weekly after 16 to 24 weeks in patients not in remission. Higher dose initiation is more likely to achieve steady-state intracellular concentrations of MTX polyglutamates and clinical benefit more rapidly, but there may be a tradeoff with an initial experience of more commonly experienced nuisance toxicities such as stomatitis, nausea, gastrointestinal intolerance, and fatigue.
Other alternative schedules for dose titration include the following:
●Among patients with severely active disease, some rheumatologists increase the oral MTX dose after the first four weeks by 5 mg weekly to a maximum dose of 25 mg/week.
●Historically, some advisory groups advocated a starting dose of between 10 to 15 mg/week and increasing the dose by 5 mg every two to four weeks, depending upon the clinical response and tolerability, up to a maximum dose of 20 to 30 mg/week [45,46]. However, doses >25 mg/week are typically avoided due to the availability of alternative agents and the lack of evidence for safety and greater efficacy of weekly doses in this range, as noted above. Moreover, as MTX is not polyglutamated at steady state for approximately 28 weeks, increasing the dose at frequent intervals should be done with the full recognition that it is not possible to judge the efficacy of any given dose over an interval of just a few weeks .
The dose at which MTX was initiated for the treatment of RA in all of the early randomized trials and which was used historically in clinical practice was usually 7.5 mg per week [47-49]. However, it has become common with greater experience with MTX to often use a higher starting dose, as noted, of 12.5 or 15 mg weekly in patients with normal renal function.
Alternatives to once-weekly oral therapy — For patients in whom doses of at least 15 mg once weekly are ineffective or poorly tolerated, there are two alternatives to switching to another disease-modifying antirheumatic drug (DMARD) or to adding a biologic agent. One is a trial of subcutaneous MTX administration (see 'Parenteral therapy' below); the other is splitting the oral dose, usually by giving it every 12 hours on the same day each week (see 'Split dosing' below). In this manner, a dose of oral MTX that would have decreased bioavailability could be split into two lesser doses, each with improved bioavailability. (See 'Pharmacology' above.)
Parenteral therapy — Most patients prefer oral over parenteral therapy, although gastrointestinal toxicities may be reduced and may be avoided by administering MTX parenterally. We prefer subcutaneous administration because of a high degree of bioavailability and the much lower level of discomfort compared with intramuscular use, which is no longer commonly employed. Anecdotal observations support this concept, although few trials have formally compared safety, tolerability, or efficacy when the drug is administered by these different routes. As examples:
●One randomized trial, involving 375 patients, found greater efficacy of MTX administered subcutaneously, compared with the drug given orally, with comparable tolerability . At week 16, a statistically significant greater proportion of patients receiving MTX by subcutaneous administration achieved American College of Rheumatology criteria for 20 percent improvement (ACR20) (85 versus 77 percent), and a switch from oral to subcutaneous administration in those oral MTX patients who had not achieved an ACR20 at week 16 resulted at week 24 in an ACR20 response in 30 percent of the previous ACR20 nonresponders (9 of 30 patients).
●Benefit from switching to parenteral administration was also seen in one arm of a trial evaluating treatment strategies for RA, in which a reduction in disease activity was observed in patients previously unable to achieve remission on maximally tolerated oral doses of MTX (of up to 30 mg/week) who were switched to subcutaneous administration of their dose. Similar improvement was seen in patients who were switched due to either insufficient efficacy or adverse effects, but no control group was available for comparison .
These findings are consistent with observations demonstrating increased levels of drug with parenteral rather than oral administration, especially at doses of 15 mg or greater weekly. (See 'Pharmacology' above.)
Some experts offer patients who are comfortable with subcutaneous administration the option to initiate therapy by this route, which has been shown in one study to be associated with a reduced likelihood of changing or discontinuing therapy compared with initial oral MTX monotherapy .
The liquid MTX formulation (prepared for parenteral use) may be consumed orally by mixing it with juice; this preparation is less expensive than tablets and may be used if expense is a serious issue and if the patient can be relied upon to measure the precise volume of drug. It is not recommended for patients with decreased finger dexterity, limited vision, or impaired cognition.
Split dosing — For patients who prefer to avoid an injection but require an alternative to once-weekly oral therapy due to insufficient efficacy or poor tolerance of MTX, we split the oral dose into two or three doses spaced evenly, every 12 hours, over a single 24-hour period.
Split dosing of oral MTX has the advantage of improved bioavailability and is thus more likely to result in a commensurate clinical improvement in clinical effects (see 'Absorption and route of administration' above). However, this hypothesis has not been formally studied in prospective investigations. Furthermore, no trials have directly compared toxicity in patients taking the drug all at once versus split dosing, and neither approach is clearly wrong. There are patients who seem to tolerate the drug better when given in divided-dose regimens. The reasons for this are unclear but may be related to the maximal serum concentration obtained with single- versus split-dose administration.
Daily MTX or dosing schedules that provide for administration of the MTX dose on two to four days over the course of a week should never be used because these schedules are significantly more toxic, especially to rapidly dividing cells in the bone marrow and mucosa tissues . (See 'Management of overdose' below.)
When MTX was first used, many practitioners adopted a regimen of dividing the dose into three equivalent amounts given every 12 hours for three doses. However, this schedule was developed by dermatologists to suppress rapidly dividing cells in psoriatic skin and has questionable rationale in the treatment of rheumatic diseases. Nevertheless, this approach may improve bioavailability.
Dosing and limits to use with reduced renal function — MTX is contraindicated in patients with RA if the eGFR is less than 30 mL/minute ; among patients with an eGFR of 30 to 59 mL/minute, a lower initial dose is warranted, and a more gradual dose increase, close monitoring, and a lower maximum weekly dose should be considered, depending upon the overall clinical status. Although low-dose MTX is not nephrotoxic, excretion is almost exclusively via the kidneys. Thus, it is prudent to monitor renal function and to reduce the dose, or discontinue the drug, if renal insufficiency develops.
There are no data to support a particular dose adjustment regimen, and caution is warranted when starting MTX in patients with moderate compromise in renal function. In such patients, we usually do not administer doses greater than 7.5 to 10 mg once weekly. The maximum dose used depends upon the patient's clinical response and their age, size, comorbidities, and degree of disease activity. (See 'Dose titration' above.)
The formulas used to calculate the eGFR (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equation (calculator 1) and Cockcroft-Gault (calculator 2)) contain the serum creatinine, which must be stable, and factors that affect muscle mass (lean body weight, age, and sex) and, therefore, affect the serum creatinine independent of GFR . (See "Assessment of kidney function".)
Monitoring and additional testing
Monitoring — Patients should be monitored for efficacy and side effects of therapy at regular intervals, and it is advisable to see patients or obtain laboratory tests every four weeks for the first three months of treatment. Once a steady-state dose of MTX has been established without clinical or laboratory toxicity, we and most clinicians monitor MTX with visits that occur at three-month intervals. The approach to monitoring is described in more detail separately. (See "Initial treatment of rheumatoid arthritis in adults", section on 'Monitoring and reevaluation' and "General principles and overview of management of rheumatoid arthritis in adults", section on 'Assessment and monitoring' and "General principles and overview of management of rheumatoid arthritis in adults", section on 'Tight control'.)
Briefly, patients on MTX should be queried regarding, and monitored for, stomatitis, alopecia, diarrhea, nausea/vomiting, flu-like symptoms, shortness of breath, symptoms of myelosuppression, hepatotoxicity, infection, lymph node swelling, pregnancy planning, and pregnancy. (See "Major side effects of low-dose methotrexate".)
The author obtains a complete blood count, aminotransferases, albumin, and creatinine every 4 weeks for the first 3 months or after increasing the dose, then every 8 to 12 weeks for months 4 through 6, then every 12 weeks. Drug monitoring for patients with RA is described separately. (See "General principles and overview of management of rheumatoid arthritis in adults", section on 'Drug monitoring and prevention of drug toxicity'.)
MTX polyglutamate levels — In selected patients suspected of inadequate adherence to therapy (eg, those who are receiving a high dose of MTX but have not had an adequate clinical response after six months of therapy despite efforts to improve drug delivery), it is reasonable to perform measurement of MTX polyglutamates in those patients in whom this information would change our treatment strategy. Such testing is available through several commercial laboratories. (See 'Split dosing' above and 'Parenteral therapy' above.)
Higher MTX red blood cell (RBC) levels are associated with good responses, while lower levels might indicate the need for either more MTX or the possibility of either poor adherence to the treatment regimen or poor absorption of the dose .
A level associated with clinical benefit is typically >60 nmol/L of total RBC polyglutamates .
Duration of therapy and dose reduction — We generally continue MTX treatment indefinitely in patients with RA who require this medication. This approach is both effective and safe [45,57-59]. Selection of patients for dose reduction and the optimal approach have not been adequately addressed in clinical trials. Based upon our clinical experience, we take the following approaches:
●In patients in remission for at least six months, eg, with stable, well-controlled disease on 20 to 25 mg/week, the author tries to reduce the dose by 2.5 mg every one to two months to 15 mg/week, unless there is a resultant increase in disease activity. The section editor prefers to reduce the dose by 5 mg increments every three months, rather than changing the dose during the interval between visits, while the smaller decrement is preferred by the author because of the unpredictable effect of the reduced dose on intracellular MTX polyglutamates.
●In patients already on 15 mg/week or less who desire a trial of a reduced dose or who have bothersome side effects but well-controlled, stable disease, we perform a trial of every-other-week dosing, while carefully monitoring for a possible flare in disease activity. The original weekly dose schedule should be resumed if the patient experiences a disease flare.
We do not completely withdraw MTX, unless indicated for toxicity, because such discontinuation usually leads to a flare of RA within three to six weeks .
The outcome of every-other-week dosing varies in part with whether or not the patient is in remission at the time that the regimen is changed. One randomized trial included 51 patients who had been on MTX for at least nine months and who were in remission for at least six months . The patients were assigned to weekly or every-other-week MTX, which reduced the monthly dose by one-half. The frequency of maintenance of remission at 24 weeks was the same in the two groups (95 versus 91 percent). All the patients whose synovitis recurred during every-other-week therapy were controlled after resumption of weekly MTX.
The outcomes were not as good in another trial of patients who were clinically stable but not in remission . Among the 23 patients who were switched to every-other-week MTX, 12 had no change in their clinical status for the six-month duration of the study . The remaining 11 patients experienced a worsening in disease activity and had to be placed back on a weekly dosing regimen. Regression analysis of clinical and demographic features failed to reveal any predictive variables that would help in the decision to try every-other-week therapy.
MANAGEMENT OF OVERDOSE — Patients may sometime take an excessive dose of methotrexate (MTX), which is usually unintended and is most often due to mistaken or accidental daily (rather than the intended weekly) ingestion of the medication . Such unintended overdoses can also occur due to drug interactions or comorbidities and are occasionally fatal. Both patient education and pharmacy vigilance are important preventive strategies.
Management depends upon whether there is clinical or laboratory evidence of toxicity. We take the following steps in patients who have taken an overdose of MTX:
●Patients should temporarily discontinue any MTX usage.
●The following laboratory tests should be obtained:
•Complete blood count and platelet count
•Alanine and aspartate aminotransferases and serum albumin
Laboratory testing in patients who overdose should be performed daily to every other day for at least two weeks, depending upon the level and the rate and direction of change, because the development of laboratory abnormalities can be delayed for several days and up to 7 to 10 days following the overdose.
MTX serum drug levels are generally not useful in this setting as the drug only remains in the system for about 24 hours after a dose in patients with normal renal function.
●In patients with progressively worsening laboratory findings (from one day to the next) or results of testing that are markedly abnormal, we hospitalize the patient and treat with intravenous leucovorin (5 to 10 mg every 12 hours) until the patient has recovered. Recovery is characterized by resolution of pancytopenia with increased cell counts to a safe and acceptable range; reduction of hepatic aminotransferases to less than twice the upper limit of normal; and resolution of severe stomatitis, gastrointestinal symptoms, and impaired cognition (cognitive "fog"). As examples, patients requiring such treatment include those with the following:
•Hepatic aminotransferases elevated to >3 times the upper limit of normal or >4 times the baseline and increasing.
•Thrombocytopenia or anemia that is worsening.
•Leukopenia that is worsening, in which case the patient may also need to be in isolation if neutrophil or lymphocyte counts are <500 cells/microL and will need antibiotics if febrile. (See "Prophylaxis of infection during chemotherapy-induced neutropenia in high-risk adults".)
•Patients should also be supported symptomatically (eg, for diarrhea) and with appropriate management of fluid and electrolyte status as indicated clinically.
●For aminotransferases in patients whose laboratory testing is abnormal but less than three times the upper limit of normal, and in whom such tests do not worsen over 7 to 10 days, we manage in the same fashion as in patients who have mildly abnormal laboratory studies on MTX (ie, by dose reduction, observation, and regular testing until the aminotransferases and serum albumin return to the normal ranges).
Prior studies with annual liver biopsies and monthly measurement of transaminase enzymes have shown that any elevation of transaminase enzymes into the abnormal range (>upper limit of normal), if repeated in 6 of 12 monthly measures, is associated with deterioration in the liver histopathology seen at the time of an annual biopsy . (See "Hepatotoxicity associated with chronic low-dose methotrexate for nonmalignant disease", section on 'Approach to monitoring in rheumatoid arthritis'.)
●We resume MTX once the patient's laboratory testing, including the tests noted above and the red blood cell (RBC) folate level (not the serum folate), has returned to normal and stomatitis and gastrointestinal toxicity has resolved (which typically occurs at about the same time as the labs normalize).
The management of high-dose (eg, chemotherapy for malignancy) MTX overdose is described in detail separately. (See "Therapeutic use and toxicity of high-dose methotrexate", section on 'Prevention and management of high-dose methotrexate toxicity'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Rheumatoid arthritis".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Beyond the Basics topics (see "Patient education: Rheumatoid arthritis symptoms and diagnosis (Beyond the Basics)" and "Patient education: Rheumatoid arthritis treatment (Beyond the Basics)" and "Patient education: Disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis (Beyond the Basics)" and "Patient education: Rheumatoid arthritis and pregnancy (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Methotrexate (MTX) can be administered orally or subcutaneously. In rheumatic disease, it is always only given weekly. Oral MTX is variably absorbed in the dose range used to treat rheumatoid arthritis (RA), particularly at the higher part of this range. However, food does not affect MTX absorption to a significant degree. MTX is primarily cleared via the kidneys, with most being excreted unchanged in the urine. Coadministration with other folate-depleting drugs such as trimethoprim-sulfamethoxazole or probenecid may increase the risk of toxicity. (See 'Pharmacology' above.)
●MTX is a structural analogue of folic acid that can competitively inhibit the binding of dihydrofolic acid (FH2) to the enzyme dihydrofolate reductase (DHFR), which is responsible for reducing FH2 to folinic acid (FH4; leucovorin), the active intracellular metabolite. Thus, MTX decreases the amount of intracellular FH4 available and affects the metabolic pathways within the cell that are FH4 dependent. However, the mechanism by which it improves the signs and symptoms of RA is likely to be complex. Potential mechanisms of action also include enhancement of extracellular concentrations of adenosine. (See 'Mechanism of action' above.)
●MTX is contraindicated in patients with RA if the estimated glomerular filtration rate (eGFR) is less than 30 mL/minute; among patients with an eGFR of 30 to 59 mL/minute, a lower initial dose is warranted, and a more gradual dose increase, close monitoring, and a lower maximum weekly dose should be considered, depending upon the overall clinical status. (See 'Dosing and limits to use with reduced renal function' above.)
●MTX should not be used in women who are contemplating becoming pregnant or who are pregnant, in patients with liver disease or excessive alcohol intake, and in patients with underlying lung disease. We prefer that patients agree to limit their alcohol consumption while receiving MTX, although patients' tolerance for alcohol while on MTX will vary. Appropriate immunizations should be performed prior to starting MTX. (See 'Precautions and prevention of adverse effects' above and 'Folic acid supplementation' above and 'Pregnancy' above and 'Alcohol use' above and 'Pulmonary disease' above and 'Immunizations' above.)
●We generally initiate therapy with a dose between 7.5 and 15 mg weekly, depending upon the patient's age, size, comorbidities, renal function, and degree of disease activity. Higher dose initiation, preferred by some experts, is more likely to achieve steady-state intracellular concentrations of MTX polyglutamates more rapidly, but there may be a tradeoff with an initial experience of more commonly experienced nuisance toxicities such as stomatitis and nausea. We usually increase the dose after the first month of therapy, depending upon the clinical response, tolerability, and the factors noted above, by 2.5 to 5 mg/week. The maximum dose we generally employ is approximately 25 mg/week. (See 'Dosing and administration' above.)
●For patients in whom MTX 15 to 25 mg orally once weekly is ineffective or poorly tolerated, a trial of subcutaneous MTX administration is an alternative, along with splitting the oral dose into two or three doses spaced evenly, every 12 hours, over a single 24-hour period. Daily MTX or dosing schedules that require administration of the drug on two to four days over the course of a week are significantly more toxic and should never be used. (See 'Dose titration' above and 'Split dosing' above and 'Parenteral therapy' above.)
●In all patients taking low-dose MTX on a chronic basis, we recommend treatment with folic acid (1 mg daily) (Grade 1A). The dose may be increased up to 5 mg/day as needed, based upon reporting of residual symptoms. Leucovorin (folinic acid; weekly oral racemic leucovorin 2.5 to 5 mg or L-isomer of leucovorin 1 to 2 mg) should only be used in patients who have not had a satisfactory response to folic acid (ie, toxicities remain). (See 'Folic acid supplementation' above.)
●Patients with RA who require treatment with MTX should generally be treated indefinitely, since complete withdrawal of MTX usually leads to a flare of RA within three to six weeks and since this approach is generally effective and safe. In patients with well-controlled disease on 20 to 25 mg/week, we reduce the dose by 2.5 mg/week every one to two months to a dose of 15 mg/week, as tolerated, while carefully monitoring for a possible flare in disease activity. (See 'Duration of therapy and dose reduction' above.)
●Management of MTX overdose depends upon whether there is clinical or laboratory evidence of toxicity. It requires temporary drug discontinuation and clinical and laboratory assessment and monitoring. Some patients require hospitalization, intravenous leucovorin therapy, and other interventions until the abnormalities resolve. (See 'Management of overdose' above.)
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