ABSTRACT
The development of methotrexate (MTX) as a therapy for rheumatoid arthritis (RA) evolved initially from positive case reports, uncontrolled case series and then several decades later placebo controlled studies followed by active comparator studies. These studies established MTX as a major therapy for RA. The importance of MTX in the treatment paradigm has only been enhanced over the past decade by the increased efficacy observed when small molecules and biologics are added to MTX. Since the first randomised studies were performed in the 1980s, MTX has now become the most well-studied disease modifying therapy to date and the most popular drug worldwide in the treatment of RA. This chapter will review the history of the development of MTX in RA.