Methotrexate


Methotrexate (MTX) is the most commonly used rheumatology drug and is the starter drug for nearly all patients with rheumatoid arthritis. It was originally a cancer drug but used in lower doses in rheumatology. It is oral, injectable or injectable solution can be taken orally. 


Dose range is 10-25 mg. 

Adverse effects


  • Nausea
  • Oral ulcers
  • Hair loss
  • Diarrhea
  • "the blahs"
  • headache
  • Liver enzyme elevation/liver disease
  • Lung disease

Lung/Interstitial pneumonitis

7x more likely on MTX. Low-dose MTX may induce pulmonary AEs, such as cough and dyspnea. Hypersensitivity pneumonitis due to LD-MTX is believed to be relatively rare and is characterized by fever, shortness of breath, eosinophilia, and interstitial lung abnormalities on chest imaging; some cases progress to permanent lung damage. Prior studies suggest that pneumonitis occurs in 0.1% to 1% of patients using LD-MTX. However, systemic rheumatic diseases may have pulmonary manifestations, such as interstitial lung disease, that are unrelated to LD-MTX and pose a challenge for determining causality. In addition, LD-MTX may increase risk for infection because of its immunosuppressive effects. [1]
In a study of nearly 5000 patients by Solomon et al ,6 patients (0.3%) in the LD-MTX group and 1 (0.04%) in the placebo group had possible pneumonitis (HR, 6.94 [CI, 0.85 to 56.0]; exact test P = 0.044); no cases could be considered probable or definite because too little information was provided. The cases in the LD-MTX group occurred between 2 and 27 months after randomization. All participants were men, none reported any history of tobacco use, and 2 died. In addition, when considering any pulmonary AE, there was an increased risk with LD-MTX (HR, 1.42 [CI, 1.14 to 1.77]). Finally, the risk for any infectious AE, pulmonary or otherwise, was elevated (HR, 1.15 [CI, 1.01 to 1.30]). [1]


Methotrexate and lymphomas

A rare side effect of MTX is lymphoma. Some are treatable just by stopping MTX but most are treated by chemotherapy. The type of lymphoma associated with MTX are also associated with EBV. So, if an RA patient gets NHL, the question arises, can they continue MTX or ever take MTX again. 

[1] D Solomon. Adverse Effects of Low-Dose Methotrexate. Ann Int Med. 17 Mar 2020

[2] VuMedi - Weinblatt on MTX