Pharmacogenetic methods for determining a predicting responsiveness to antifolate therapy for subjects that present with recent-onset undifferentiated arthritis. The methods are based on the determination of a set of clinical parameter values and determining a predicted responsiveness to antifolate therapy by correlating the parameter values with predefined responsiveness values associated with ranges of parameter values. Parameters values that are decisive for responsiveness to antifolate therapy may include polymorphisms in the methylenetetrahydrofolate dehydrogenase (MTHFD1) gene as well as in three genes involved in the adenosine release pathway, the presence or absence of Rheumatoid factors, gender, pre- or postmenopausal status and/or smoking status.