Major adverse effects of low-dose methotrexate

INTRODUCTION — Methotrexate (MTX) use can be associated with a variety of adverse effects over a wide range of severity (table 1); the risk of most adverse effects is influenced by the MTX dose and treatment regimen. In rheumatoid arthritis (RA) and other disorders, MTX is administered as long-term, low-dose therapy, usually 7.5 to 25 mg weekly, unlike its use for treatment of malignant disease, where it may be administered in a cyclic fashion in doses of 1 gram or more.

The most commonly observed adverse effects of MTX at doses typically used for the treatment of RA are rarely life-threatening, in contrast with the high doses used in the treatment of malignancies. Nevertheless, they may become clinically significant if they result in premature discontinuation or dose alteration of a drug that is the best therapeutic alternative for a given individual.

Potentially life-threatening hepatotoxicity, pulmonary damage, and myelosuppression may be seen with use of MTX as either high- or low-dose therapy, while nephrotoxicity is a manifestation of high-dose therapy that occurs rarely, if ever, with low-dose MTX treatment.

The major adverse effects of low-dose MTX are reviewed here. Hepatotoxicity associated with chronic, low-dose MTX and MTX-induced lung injury are described in more detail separately. (See "Hepatotoxicity associated with chronic low-dose methotrexate for nonmalignant disease" and "Methotrexate-induced lung injury".)

The use of low-dose MTX in patients with RA and other rheumatic diseases and the clinical use and adverse effects of high-dose MTX and related adverse effects are described separately. (See "Use of methotrexate in the treatment of rheumatoid arthritis" and "Therapeutic use and toxicity of high-dose methotrexate".)

COMMON TOXICITIES

Symptoms and findings — One or more of the following common toxicities associated with methotrexate (MTX) are seen in some form, at some time, in most patients:

●Gastrointestinal problems, such as nausea, stomach upset, and loose stools

●Stomatitis or soreness of the mouth

●Abnormal liver chemistries, which are typically mild elevations in hepatic transaminases (see 'Hepatotoxicity' below)

●A macular punctate cutaneous eruption, which usually occurs on the extremities, often affecting the elbows and knees, but sparing the trunk

●Central nervous system symptoms, including headache, fatigue, malaise, or impaired ability to concentrate

●Alopecia

●Fever, which is drug-related, although fever can also occur due to infection

●Hematologic abnormalities, particularly macrocytosis, in addition to infrequent but severe myelosuppression (see 'Myelosuppression' below)

Central nervous system and gastrointestinal complaints commonly occur within 24 to 48 hours after the weekly MTX dose. However, alopecia can develop within weeks and is not generally dose related. Macrocytosis may take many months to develop; it should not always be assumed to be due to folate deficiency, as patients on MTX are typically receiving daily folate supplementation; it may instead be from an unrelated cause (eg, due to vitamin B12 deficiency) or can occur on MTX with normal serum levels of both folate and vitamin B12. Rash may appear within days of each weekly MTX dose and fade by the time of the next week's dose. On the other hand, stomatitis may persist for days or weeks; it can be mild or, on occasion, painful enough to make eating difficult and result in a desire to discontinue therapy.

Management — Most of the common toxicities of MTX can be managed symptomatically, but patients with persistent symptoms sometimes require MTX dose reduction.

●Nausea – Patients who continue to have nausea associated with MTX administration may get some relief with a histamine H2 blocker (eg, famotidine 10 to 20 mg orally) or a proton pump inhibitor (eg, omeprazole 20 to 40 mg orally). These drugs are usually cycled in a weekly manner with MTX, being used the evening before, the day of, and the morning after the weekly MTX dose. Patients with nausea and other gastrointestinal symptoms also benefit from daily folic acid supplementation. Nausea may also be improved by increasing the dose of daily folic acid up to 3 to 5 mg or adding leucovorin (folinic acid) 8 to 10 hours after the weekly MTX dose. (See 'Prevention of adverse effects with folate' below.)

●Stomatitis – In patients with mild to moderate stomatitis, we gradually increase the folic acid dose from 1 mg daily up to 2 mg or higher (to a maximum of 5 mg daily) by 1 mg increments until the toxicity is controlled (see 'Prevention of adverse effects with folate' below). In patients without an adequate response and continued bothersome symptoms despite taking 5 mg daily, we add leucovorin. In patients in whom the combination of folate and leucovorin is inadequate, we gradually reduce the MTX dose to determine if a lower dose will be tolerated. Patients presenting with severe oral ulcers may require both a lowering of the MTX dose and an increase of folic acid. Once the acute toxicity has resolved, the patient may be able to increase the weekly dose of MTX back to the level being used prior to the onset of the oral ulcers. A recent decrement in kidney function should also be excluded as a contributing factor.

Stomatitis (oral mucositis) can occur at any dose of MTX but is more likely to be seen at higher doses. Data regarding the usefulness of supplements of folic acid or leucovorin are mixed. A systematic review in 1998 of folic acid or leucovorin supplementation concluded that these agents reduced the risk of stomatitis and other disorders of the digestive tract [1]. However, no difference in the proportion of patients developing mucositis (15 to 18 percent) or diarrhea (8 to 14 percent) were noted in a subsequent randomized trial in 434 patients that compared folic acid, leucovorin, and placebo [2]. Nevertheless, if a patient is not receiving folate supplementation, addition of folic acid or leucovorin may speed healing. (See "Oral toxicity associated with systemic anticancer therapy", section on 'Mucositis'.)

●Abnormal liver chemistries – The monitoring of liver chemistries and the management of patients with abnormalities in these tests are described in detail separately. (See "Hepatotoxicity associated with chronic low-dose methotrexate for nonmalignant disease", section on 'Approach to monitoring in rheumatoid arthritis'.)

●Rash – We reduce the MTX dose in patients with the infrequent manifestation of a cutaneous eruption from MTX, but discontinue the medication in patients who do not respond to dose reduction, as the rash may represent a hypersensitivity reaction.

●Neurotoxicity – Symptoms such as severe headaches, fatigue, and problems concentrating may require dose reduction, and in some patients will require drug discontinuation. The mechanism by which these occur is uncertain; it has been suggested that the neurotoxicity of MTX may be related to the accumulation of adenosine due to the inhibition of purine synthesis [3-5].

●Fever – Fever can be induced by MTX, but it is important to exclude infection as the cause before attributing this finding to MTX alone. Infections with Pneumocystis jirovecii (formerly termed Pneumocystis carinii) and fungi can occur; herpes zoster is rare, in contrast to its more frequent occurrence with glucocorticoids, tumor necrosis factor (TNF) inhibitors, azathioprine, Janus kinase inhibitors, or cyclophosphamide.

●Hematologic abnormalities – We withhold MTX in patients in whom the mean corpuscular volume (MCV) increases to about 110 microm³, based upon our clinical experience. This approach is supported by observations in a case series that sustained elevation in the MCV may be a predictor of hematologic toxicity due to folate depletion [6]. However, these observations have not been routinely confirmed in clinical practice. Thrombocytopenia and leukopenia or anemia are managed by dose reduction, but may require discontinuation of therapy depending upon their severity.

POTENTIAL SEVERE ADVERSE EFFECTS

Hepatotoxicity — Hepatotoxicity due to methotrexate (MTX) may result from direct damage to hepatocytes; or, in patients with concomitant viral hepatitis, MTX may enhance viral damage. Minor elevations in aminotransferases are common, but hepatic steatosis, fibrosis, and cirrhosis may infrequently occur. Hepatotoxicity associated with chronic low-dose MTX is discussed in detail separately. (See "Hepatotoxicity associated with chronic low-dose methotrexate for nonmalignant disease" and "Hepatitis B virus reactivation associated with immunosuppressive therapy".)

Severe hepatotoxicity is very uncommon in patients managed using appropriate prevention strategies (see "Hepatotoxicity associated with chronic low-dose methotrexate for nonmalignant disease"). These include:

●Screening before initiating long-term MTX therapy for hepatitis B and hepatitis C virus infection. In patients with infection, this should inform a decision whether to avoid the use of MTX, to try to eradicate the viral infection before initiating therapy, or to suppress viral replication during immunosuppressive therapy.

●Periodic monitoring of aminotransaminases and albumin. (See "General principles and overview of management of rheumatoid arthritis in adults", section on 'Drug monitoring and prevention of drug toxicity' and "Hepatotoxicity associated with chronic low-dose methotrexate for nonmalignant disease", section on 'Approach to monitoring in rheumatoid arthritis'.)

●Routine use of daily folic acid supplementation, which is associated with a reduced risk of hepatic transaminase elevations. (See 'Prevention of adverse effects with folate' below.)

●Counseling of patients to avoid or minimize alcohol intake while on MTX, although the amount of alcohol intake which might be safe while using MTX has not been formally evaluated. Some patients will tolerate daily alcohol, and some will not. (See "Hepatotoxicity associated with chronic low-dose methotrexate for nonmalignant disease".)

●Particular caution regarding the use of MTX is also warranted in the setting of metabolic dysfunction-associated steatotic liver disease (MASLD) or metabolic dysfunction-associated steatohepatitis (MASH). (See "Hepatotoxicity associated with chronic low-dose methotrexate for nonmalignant disease", section on 'Pretreatment evaluation'.)

Pulmonary toxicity — Pulmonary toxicity of MTX is seen with both high- and low-dose treatment and may present with acute or chronic symptoms. It is more common during the first year of treatment [7]. Either symptomatic or asymptomatic radiographic lung damage may be due to inflammation, infection, or MTX-related neoplasia. We and most other experts usually obtain a baseline chest radiograph prior to initiating MTX treatment, if one has not been recently obtained [8] (see "Methotrexate-induced lung injury", section on 'Prevention'), although some experts do not do so in individuals perceived clinically to be at low risk of established pulmonary disease. Pulmonary toxicity, including its pathogenesis, prevention, manifestations, evaluation, and management, is discussed in detail separately. (See "Methotrexate-induced lung injury".)

Risk of infection — MTX is an immunomodulatory but not significantly immunosuppressive agent in the doses used for rheumatoid arthritis (RA) [9]; it is not associated with opportunistic infections in the overwhelming majority of those treated with MTX unless the patients are also being treated with high-dose glucocorticoids, other immunosuppressive disease-modifying antirheumatic drugs (DMARDs), or biologic agents. MTX can affect T cell activity in the weekly doses used in the treatment of rheumatic diseases [10,11], and cases of Pneumocystis pneumonia have been reported [12,13].

In patients with severe infections (eg, pneumonia requiring hospitalization), we hold the MTX dose until the patient has recovered from the illness. We do not withhold therapy in patients with minor infections (eg, pharyngitis or a urinary tract infection treated with a short course of oral antibiotics).

MTX may also decrease the immunogenicity of multiple types of preventive vaccinations (table 2); strategies to mitigate this risk are discussed in detail separately. (See "Immunizations in autoimmune inflammatory rheumatic disease in adults", section on 'Timing of vaccination'.)

Myelosuppression — Myelosuppression is the major dose-limiting adverse effect of high-dose MTX, but is infrequent in patients receiving low-dose therapy. With low-dose weekly therapy, as used in RA, hematologic toxicity in association with macrocytic red blood cells may be seen [6], but a more serious abnormality is the development of pancytopenia [14]. Occasionally, anemia, leukopenia, or thrombocytopenia may occur without significant reductions in other cell lines. To prevent these complications, guidelines from the American College of Rheumatology (ACR) recommend that a routine peripheral complete blood count should be performed every four weeks during the first three months of therapy, every 8 to 12 weeks from three to six months, and every 8 to 12 weeks thereafter, depending upon the nature and/or severity of abnormalities noted during monitoring [15].

Myelosuppression with low-dose MTX is more likely if kidney function is impaired (eg, in the setting of an acute illness or addition or change of a nonsteroidal antiinflammatory drug [NSAID]) or if MTX is taken daily instead of weekly. (See "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Pharmacology'.)

Risk of lymphoproliferative disorders — Lymphoproliferative disorders occur with increased frequency in RA, independent of specific therapies, but MTX therapy may increase such risk. Data from a large observational cohort (the National Data Bank for Rheumatic Diseases) found a small increase, based upon patient reports, which was not statistically significant (standardized incidence ratio of 1.7, 95% CI 0.9-3.2) [16]. Rarely, lymphoproliferative “malignancies” may develop after long-term therapy but regress spontaneously after MTX is withdrawn. They are usually of B-cell origin and some are associated with latent Epstein Barr virus infection [17]. Lymphoproliferative disorders in RA are discussed in more detail separately. (See "Disease outcome and functional capacity in rheumatoid arthritis", section on 'Lymphoproliferative disorders'.)

One prospective study described 25 cases of lymphoma in patients with RA who were being treated with MTX throughout France over a three-year period. Among these were seven cases of Hodgkin disease (27.8 and 2.8 cases per 100,000 per year for males and females respectively), an incidence that was more than expected for an age- and sex-matched population (adjusted standardized incidence ratio [SIR] of 7.4) [18]. The incidence of non-Hodgkin lymphoma was not increased by MTX therapy. Chemotherapy should be withheld until MTX has been stopped, since some of these tumors regress within four weeks after MTX has been discontinued [19-22]. Continued vigilance is necessary in those who regress, since relapse has occurred [18]. (See "Disease outcome and functional capacity in rheumatoid arthritis", section on 'Lymphoproliferative disorders'.)

Nephrotoxicity — Significant nephrotoxicity due to MTX may occur with use of high doses, but occurs very rarely, if at all, in patients on low-dose regimens. However, even at the low weekly doses used in rheumatic diseases, MTX use may be associated with slight decreases in creatinine clearance [23]. MTX is primarily cleared via the kidneys, with 80 to 90 percent being excreted unchanged in the urine. Thus, impaired renal excretion of the administered MTX and consequent prolonged exposure to the drug increase the risk of myelosuppression and other toxicities. Glucarpidase (carboxypeptidase G2), a recombinant bacterial enzyme that cleaves MTX into inactive metabolites, speeds clearance, and may be used when impaired kidney function causes delayed elimination of MTX in patients receiving high-dose MTX. Its role in patients who develop kidney toxicity while receiving chronic low-dose therapy is unclear. MTX-induced kidney failure and the use of glucarpidase in the management of this complication are discussed in more detail elsewhere. (See "Crystal-induced acute kidney injury", section on 'Methotrexate' and "Therapeutic use and toxicity of high-dose methotrexate", section on 'Glucarpidase (carboxypeptidase G2)'.)

Kidney damage due to precipitation of MTX crystals and tubular injury may occur with high-dose MTX; it is very rare with chronic low-dose therapy. (See "Therapeutic use and toxicity of high-dose methotrexate", section on 'Renal toxicity'.)

Pregnancy risk — MTX is an abortifacient that can also induce congenital anomalies if taken during pregnancy. It is therefore contraindicated in pregnant individuals. We advise contraceptive use in females taking MTX as well as discontinuation of therapy in both females and males at least three months prior to conception. Oligospermia and chromatid breaks have been described in males on MTX. However, many male patients taking weekly MTX have successfully had healthy children. (See "Safety of rheumatic disease medication use during pregnancy and lactation" and "Effects of antiinflammatory and immunosuppressive drugs on gonadal function and teratogenicity in males with rheumatic diseases".)

OTHER ADVERSE EFFECTS

Nodulosis — Methotrexate (MTX) has been demonstrated to exacerbate rheumatoid nodule formation (accelerated nodulosis) in some patients with rheumatoid arthritis (RA), despite the effective suppression of synovial inflammation [24]. This activity may be mediated via the agonist stimulation of adenosine A1 receptors by MTX, thereby leading to enhanced giant cell formation [25]. Rheumatoid nodules and the management of accelerated nodulosis associated with MTX are discussed in more detail separately. (See "Rheumatoid nodules" and "Rheumatoid nodules", section on 'Methotrexate-induced accelerated nodulosis'.)

Others — Additional potential adverse effects of MTX include:

●Skin cancer risk – A limited amount of evidence has suggested that MTX use in patients with RA or psoriatic arthritis may be associated with an increased risk of melanoma and non-melanoma skin cancers, but the number of cases in most studies have been small [26-29]. Additional data that further support an association of MTX with skin cancer come from a randomized trial comparing MTX (15 to 20 mg weekly) with placebo, designed to examine MTX for the prevention of cardiovascular events in patients with established coronary artery disease, in which an incidental finding was the greater incidence of non-basal-cell skin cancers in patients receiving MTX (31 versus 10 cases, rate ratio 3.08, p = 0.002) [30]. Strengths of the trial included its relatively large size, involving 4786 patients, and median follow-up of 2.3 years, longer than most randomized trials involving MTX. Further study of this association is warranted to confirm these findings.

●Impaired response to vaccination – Use of MTX may interfere with the response to pneumococcal vaccine when used alone or in combination with the anti-tumor necrosis factor (TNF)-alpha agent etanercept, as well as the response to other vaccines [31-34]. It may be best to withhold two weekly doses of MTX when vaccines are administered. To the best of our knowledge, the effects of MTX on coronavirus disease 2019 (COVID-19) vaccines have not been formally studied. Immunization in patients receiving low-dose MTX is discussed in detail separately. (See "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Immunizations' and "Immunizations in autoimmune inflammatory rheumatic disease in adults".)

●Ocular changes – MTX only rarely affects the eye; reported adverse effects include periorbital edema, pain, blurred vision, photophobia, blepharitis, conjunctivitis, and optic neuropathy related to folate deficiency [35].

●Bone abnormalities with high-dose MTX – High-dose MTX regimens (such as those used for osteosarcoma or acute lymphoblastic leukemia) are associated with an increase in bone resorption and inhibition of bone formation, possibly resulting in both osteoporosis and fractures [36,37]. However, this has only rarely been observed with MTX in the dose range used for rheumatic disease [38-41].

PREVENTION OF ADVERSE EFFECTS WITH FOLATE — We administer folic acid supplementation on a daily basis in patients taking chronic low-dose methotrexate (MTX) to reduce risk of several common MTX toxicities and the likelihood of treatment discontinuation. The use of folic acid and of leucovorin in this setting is discussed in detail separately. (See "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Folic acid supplementation'.)

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" and "Society guideline links: Side effects of anti-inflammatory and anti-rheumatic drugs".)

SUMMARY AND RECOMMENDATIONS

●Common toxicities – One or more of the common toxicities associated with methotrexate (MTX) may be seen at some time in most patients. These include gastrointestinal problems such as nausea, stomach upset, and loose stools; stomatitis or soreness of the mouth; a macular punctate rash that usually occurs on the extremities and that spares the trunk; central nervous system problems including headache, fatigue, or impaired ability to concentrate; alopecia; fever; and hematologic abnormalities, particularly macrocytosis. (See 'Common toxicities' above.)

●Hepatotoxicity – Hepatotoxicity due to MTX may result from direct damage to hepatocytes; or, in patients with concomitant viral hepatitis, MTX may enhance viral damage. Patients should be screened for hepatitis before beginning therapy and should be monitored for toxicity regularly while receiving the drug. (See 'Hepatotoxicity' above and "Hepatotoxicity associated with chronic low-dose methotrexate for nonmalignant disease".)

●Pulmonary toxicity – Pulmonary toxicity of MTX may present with acute or chronic symptoms and is more common in the first year of treatment. Either symptomatic or asymptomatic radiographic lung damage may be due to inflammation, infection, or MTX-related pneumonitis. We usually obtain a baseline chest radiograph before initiating MTX treatment. (See 'Pulmonary toxicity' above and "Methotrexate-induced lung injury".)

●Myelosuppression and risk of lymphoproliferative disorders – Hematologic toxicity of low-dose weekly therapy includes red blood cell macrocytosis and, less often, anemia, thrombocytopenia, or leukopenia. Pancytopenia is very uncommon. Patients receiving MTX should be monitored periodically with a complete blood count and platelet count. Myelosuppression with low-dose MTX is more likely if kidney function is impaired in the setting of an acute illness or addition or change of a nonsteroidal antiinflammatory drug (NSAID). MTX may also increase the risk of lymphoproliferative malignancy in patients with rheumatoid arthritis (RA). (See 'Myelosuppression' above and 'Risk of lymphoproliferative disorders' above.)

●Nephrotoxicity – Impairment of glomerular filtration rate will result in sustained serum levels of the drug that may induce bone marrow or other toxicities, because it is primarily cleared unchanged through the kidneys. Kidney damage due to precipitation of MTX crystals and tubular injury may occur with high-dose MTX, but it is very rare with chronic low-dose therapy. (See 'Nephrotoxicity' above.)

●Other adverse effects – Additional adverse effects include exacerbation of rheumatoid nodulosis; marked adverse effects upon the fetus during pregnancy, which should be avoided while on MTX; diminished vaccine responses; and rare ocular abnormalities. (See 'Nodulosis' above and 'Pregnancy risk' above and 'Others' above.)

●Prevention of adverse effects with folate – 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 should only be used in patients who have not had a satisfactory response to folic acid (ie, toxicities remain). (See 'Prevention of adverse effects with folate' above.)