Can methotrexate (MTX) toxicity cause fever in the absence of infection?

From the Guidelines

Methotrexate toxicity can indeed cause fever in the absence of infection, as evidenced by the British Association of Dermatologists' guidelines which explicitly warn patients about fever/flu-like illness as a sign of methotrexate toxicity 1.

Key Points to Consider

• Methotrexate is known to produce a range of toxic effects, including myelosuppression, hepatotoxicity, and pulmonary fibrosis, as outlined in the guidelines for the management of psoriasis and psoriatic arthritis 1.
• The medication can induce fever as part of its toxic profile, which may be accompanied by other symptoms such as mouth ulceration, tiredness, and nausea 1.
• It is crucial to differentiate between methotrexate-induced fever and fever caused by infection, given the drug's immunosuppressive properties that increase the risk of infections 1.
• Regular monitoring for toxicity and patient education on recognizing signs of methotrexate toxicity, including fever, are essential components of safe prescribing practices 1.

Clinical Implications

• When a patient on methotrexate presents with fever, clinicians should consider methotrexate toxicity as a potential cause, particularly if other signs of toxicity are present or if the patient has risk factors for adverse effects 1.
• A thorough evaluation to rule out infection is also necessary, given the increased susceptibility to infections associated with methotrexate use 1.
• The British Association of Dermatologists' guidelines provide a comprehensive framework for the safe prescribing of methotrexate, including patient counseling on potential toxicities and the importance of regular monitoring 1.

From the FDA Drug Label

The most frequently reported adverse reactions include ... malaise, undue fatigue, chills and fever, Although clinically variable, the typical patient with methotrexate induced lung disease presents with fever, cough, dyspnea, hypoxemia, and an infiltrate on chest X-ray; infection (including pneumonia) needs to be excluded. acute chemical arachnoiditis manifested by such symptoms as headache, back pain, nuchal rigidity, and fever;

Methotrexate toxicity can cause fever. The drug label lists fever as a potential adverse reaction, and it can occur in the absence of infection, as seen in methotrexate-induced lung disease and acute chemical arachnoiditis 2, 2, 2.

From the Research

Methotrexate Toxicity and Fever

• Methotrexate (MTX) toxicity can cause a range of symptoms, including fever, even in the absence of infection 3, 4.
• High-dose methotrexate (HD-MTX) is defined as a dose higher than 500 mg/m2 and can produce toxicity and side effects such as bone marrow suppression, pulmonary toxicity, nephrotoxicity, hematologic toxicity, and an increased risk of infections 5, 6.
• Fever is a common symptom of MTX toxicity, with 71% of patients experiencing fever in one study 4.
• MTX neurotoxicity can present with a wide variety of symptoms, including high fever, status epilepticus, and encephalopathy 3.
• The clinical features of MTX toxicity are under-researched, but it is essential to recognize the signs and symptoms of MTX toxicity to provide prompt treatment and prevent further complications 7, 4.

Risk Factors for Methotrexate Toxicity

• Risk factors for methotrexate-associated toxicity include a history of renal dysfunction, volume depletion, acidic urine, and drug interactions 6.
• Patients with renal insufficiency are at higher risk of MTX toxicity, and dose adjustments should be made accordingly 5, 6.
• Wrong use and dosage of MTX can be harmful to patients, and patients should be informed about the proper use of MTX 4.

Treatment and Management of Methotrexate Toxicity

• Treatment of severe MTX toxicity has three main goals: clearance of MTX from the bloodstream, folinic acid therapy, and organ treatment 5.
• Leucovorin is highly beneficial in preventing myelosuppression, gastric toxicity, and neurotoxic effects after HD-MTX therapy 5, 6.
• Glucarpidase has been licensed for the treatment of high plasma MTX levels of >1 μmol/L in patients with compromised renal function who have delayed MTX elimination 5, 6.