Methotrexate (MTX) is currently the most frequently used drugs in the treatment 
of rheumatoid arthritis (RA). The drug had been synthesized in 1948 and first 
tests to treat patients with psoriasis and RA were published in 1951. However, 
until the 1980s there was only limited use of MTX in the treatment of RA. Since 
the 1990s MTX is the disease-modifying antirheumatic drug (DMARD) of first 
choice for the treatment of RA in most countries worldwide. By definition, 
DMARDs in RA are those compounds for which an inhibiting effect on radiographic 
progression has been demonstrated. Several combinations of DMARDs have been 
tested, most commonly with MTX as the anchor drug. Regarding the route of 
administration of MTX there is some evidence that the parenteral route, most 
often performed subcutaneously, has some additional benefits over the oral 
route. In MTX monotherapy, dosages up to 30 mg/week are now used. There are now 
three main combinations that are playing an important role: MTX + sulfasalazine 
(SSZ) + hydroxychloroquine, MTX + leflunomide (LEF), and MTX + biologics such as 
antitumour necrosis factor (anti-TNF) and other new compounds which block the 
interleukin 6 (IL6) receptor or T-cell activation and delete B cells. Regarding 
clinical efficacy, MTX monotherapy has performed almost similarly well in 
comparison with biologic mono-therapy, both usually combined with 
glucocorticoids. However, structural damage is usually inhibited to a 
significantly greater degree with the biologics. The combination of MTX with 
biologics has proven superior to either agent alone in all aspects. Current 
strategic regimens which concentrate on systematic ways to bring patients into 
remission all include MTX as first choice.