• Asthma (see Asthma, [[Asthma]])
  • Multiple Chemotherapeutic Regimens
  • Rheumatoid Arthritis (RA) (see Rheumatoid Arthritis, [[Rheumatoid Arthritis]])
  • Psoriasis (see Psoriasis, [[Psoriasis]])


  • Folate Antagonist


  • Dose: 7.5-25 mg qweek PO
  • Monitor: CBC, LFT’s

Adverse Effects

Pulmonary Adverse Effects

  • Alveolar or Interstitial Pneumonitis with Variable Peripheral Eosinophilia (see Pneumonia, [[Pneumonia]], Drug-Induced Pulmonary Eosinophilia, [[Drug-Induced Pulmonary Eosinophilia]], and Interstitial Lung Disease-Etiology, [[Interstitial Lung Disease-Etiology]])
    • Epidemiology
      • Several hundred cases of methotrexate pulmonary toxicity have been reported
      • 50% of cases are diagnosed within 4 months of starting methrotrexate
      • Prevalence: 0.3-7.5%
      • Pulmonary toxicity occurs in 3-18% of RA patients treated with methotrexate
      • Toxicity is not related to age, underlying disease, underlying lung disease, or methotrexate dose
      • Synergism
        • Few reported cases with Nitrofurantoin use
        • Methorexate pneumonitis can be precipitated by addition of infliximab
    • Physiology
      • Probable hypersensitivity-type reaction (due to presence of peripheral eosinophilia in 50% of cases)
    • Diagnosis
      • ABG: hypoxemia
      • CBC: eosinophilia is present in at least 50% of cases
      • CXR/Chest CT Patterns
        • Homogeneous Infiltrate: multi-lobar involvement
        • Interstitial Infiltrates: lower-lobe predominance
        • Hilar Adenopathy/Pleural Effusion (seen in 10-15% of cases)
      • PFT’s: distinct from many other chemo-related pulmonary toxicities, the DLCO does not decline prior to onset of symptoms
      • FOB: important to rule out PCP, as PCP incidence is increased in setting of methotrexate use (with or without concomitant steroid use)
        • Hypercellularity with lymphocytosis
      • OLB: weakly-formed, non-caseating granulomas (seen in 33% of cases on biopsy)
        • These are unusual in other forms of chemo-associated lung disease
        • No cellular atypia (as is seen in other cytotoxic drug toxicities)
        • Lymphocytic infiltration: increases the probability of methrotrexate toxicity being etiologic
    • Clinical
      • Dyspnea/dry cough/fever starting anywhere from a few days-several weeks after start of methotrexate
    • Treatment
      • Withdraw Drug + Corticosteroids: almost always reversible with or without steroids
      • Reinstitution of Methotrexate: interestingly, in cases with previously demonstrated methotrexate toxicity, drug may be restarted after resolution of pulmonary symptoms, without recurrent signs of further toxicity
    • Prognosis: 15-20% mortality
      • 5 deaths have been reported
  • Cryptogenic Organizing Pneumonia (see Cryptogenic Organizing Pneumonia, [[Cryptogenic Organizing Pneumonia]] and Lung Nodule or Mass, [[Lung Nodule or Mass]])
    • May appear as nodular infiltrates
  • Acute Lung Injury-ARDS (see Acute Lung Injury-ARDS, [[Acute Lung Injury-ARDS]])
    • Few case reports of fatal reactions in patients receiving intrathecal methotrexate or from PO methotrexate administration after prior intrathecal methotrexate dosing
  • Pleural Effusion (see Pleural Effusion-Exudate, [[Pleural Effusion-Exudate]]): occurs in 10-15% of cases
  • Diffuse Alveolar Hemorrhage (see Diffuse Alveolar Hemorrhage, [[Diffuse Alveolar Hemorrhage]])
    • Path: bland alveolar hemorrhage (no capillaritis)
  • Epstein-Barr Virus-Related Lymphomas (see Lymphoma, [[Lymphoma]]): may be related to an alteration in immune surveillance due to methotrexate
    • Diagnosis: appear radiographically similar to methotrexate lung
    • Treatment: interestingly, these may resolve after withdrawal of methotrexate
  • Increased Risk of Pneumocystis Jirovecii Pneumonia (see Pneumocystis Jirovecii, [[Pneumocystis Jirovecii]])
    • Epidemiology: observed in patients treate with methorexate (with or without corticosteroids)

Clinical Patterns

  • Acute Onset-Type (more common pattern): onset of pulmonary symptoms within days-several weeks of starting methotrexate therapy
    • Dry Cough (common):
    • Fever (common):
    • Crackles (common):
    • Dyspnea (common):
  • Subacute/Chronic Onset-Type (less common pattern): onset of pulmonary symptoms months-years after starting methotrexate therapy
    • Dry Cough (common):
    • Fever (common):
    • Crackles (common):
    • Dyspnea (common):

Renal Adverse Effects

  • Acute Kidney Injury (see Acute Kidney Injury, [[Acute Kidney Injury]]): due to intratubular deposition and obstruction

Other Adverse Effects

  • Myelosuppression
  • Megaloblastic Anemia (see Anemia, [[Anemia]])
  • Mucositis
  • Alopecia
  • Nausea/Vomiting (see Nausea and Vomiting, [[Nausea and Vomiting]])


  • Methotrexate pneumonitis after initiation of infliximab therapy for rheumatoid arthritis. Arthritis Rheum 2002; 47:670-671 [MEDLINE]
  • Interstitial pneumonitis associated with infliximab therapy. J Rheumatol 2006; 33:1189-1193 [MEDLINE]
  • Interstitial pneumonitis associated with infliximab therapy without methotrexate treatment.
    Rheumatol Int. 2009 Dec;30(2):275-6 [MEDLINE]
  • Interstitial lung disease induced or exacerbated by TNF-targeted therapies: analysis of 122 cases.
    Semin Arthritis Rheum. 2011 Oct;41(2):256-64 [MEDLINE]