A number of studies show the efficacy of methotrexate (MTX) for rheumatoid 
arthritis (RA) in general. However, is there any reason to single this drug out 
for early RA? Mechanistically, it probably works differently in RA than in 
cancer, at least in part. Thus, in addition to dihydrofolate reductase-related 
effects, MTX inhibits aminoimidazocarboxamide transformylase, decreases 
leukotriene B4 production, and increases adenosine release at concentrations 
achieved with low-dose MTX regimens. Clinically, it is well tolerated over 
relatively long periods. Further, a recent meta-analysis of radiology studies 
shows that MTX compares favorably with intramuscular gold and is better than 
azathioprine. Toxicity remains a concern in treating early RA, particularly as 
pulmonary "hypersensitivity reactions" continue (1% to 7.6%), infections (both 
fungal and perioperative) are documented, and more cirrhosis is found. With all 
of the above in mind, the use of MTX seems reasonable but not necessarily 
uniformly appropriate and not yet proved for early RA. Studies of MTX in early 
RA, particularly in combination with other drugs, are only beginning.