Methotrexate: optimizing the efficacy in rheumatoid arthritis.

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.