Methotrexate vs azathioprine in second-line therapy of sarcoidosis

Chest. 2013 Sep;144(3):805-812. doi: 10.1378/chest.12-1728.


Background: Steroids remain the first-choice therapeutic in sarcoidosis; however, long-term use is associated with toxicity. Evidence defining the best second-line therapeutic is currently lacking. The aim of this study was to compare the effect of methotrexate and azathioprine on prednisone tapering, pulmonary function, and side effects in the second-line treatment of sarcoidosis.

Methods: An international retrospective cohort study was performed, reviewing all patients with sarcoidosis who started methotrexate or azathioprine until 2 years after initiation or discontinuation. A linear mixed model with FEV1, vital capacity (VC), diffusing capacity of lung for carbon monoxide (DLCO), and prednisone dose changes over time as end points was used. Side effects were compared with χ2 tests.

Results: Two hundred patients were included, of whom 145 received methotrexate and 55 azathioprine. Prednisone daily dose decreased a mean of 6.32 mg/y (P < .0001) while on therapy, with a similar steroid-sparing capacity for methotrexate and azathioprine. Of all patients completing 1 year of therapy, 70% had a reduction in daily prednisone dose of at least 10 mg. FEV1 showed a mean increase of 52 mL/y (P = .006) and VC of 95 mL/y (P = .001) in both treatment groups. DLCO % predicted increased, with a mean of 1.23%/y (P = .018). There were more patients with infections in the azathioprine group (34.6% vs 18.1%, P = .01), but no differences regarding other side effects.

Conclusions: This retrospective study comparing the effect of second-line therapy in sarcoidosis shows that both methotrexate and azathioprine have significant steroid-sparing potency, a similar positive effect on lung function, and comparable side effects, except for a higher infection rate in the azathioprine group.

Publication types

  • Comparative Study
  • Multicenter Study

MeSH terms

  • Azathioprine / administration & dosage*
  • Dose-Response Relationship, Drug
  • Female
  • Follow-Up Studies
  • Forced Expiratory Volume
  • Humans
  • Immunosuppressive Agents / administration & dosage
  • Male
  • Methotrexate / administration & dosage*
  • Middle Aged
  • Respiratory Function Tests
  • Retrospective Studies
  • Sarcoidosis, Pulmonary / drug therapy*
  • Sarcoidosis, Pulmonary / physiopathology
  • Treatment Outcome
  • Vital Capacity


  • Immunosuppressive Agents
  • Azathioprine
  • Methotrexate