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.