title: Methotrexate in rheumatoid arthritis: optimizing therapy among different formulations. Current and emerging paradigms.
abstract: BACKGROUND
  Methotrexate (MTX) is currently considered the drug of choice, among the disease-modifying antirheumatic drugs, for the treatment of rheumatoid arthritis (RA) because of its favorable risk/benefit ratio, good safety profile, and low costs. Despite MTX's widespread use and large experience accumulated over the many years since its introduction into clinical practice, specific guidelines have not been published.
  
  
  OBJECTIVE
  We report here the available research regarding the optimal dosage and route of MTX administration.
  
  
  METHODS
  MEDLINE and the Cochrane Library were systematically searched for articles published between 1990 and 2013, using terms related to RA and MTX. The search was conducted by using both MeSH terms and free text. The references of the retrieved studies were also screened manually for additional articles.
  
  
  RESULTS
  For the treatment of rheumatic diseases, the antimetabolite drug MTX can be administered weekly by different routes: oral, subcutaneous, or intramuscular. One of the goals of treatment is to minimize acute and chronic toxicity. A starting dose of 15 mg/week orally, escalating to 25 to 30 mg/week or the highest tolerable dose (with a subsequent switch to parenteral administration in cases of insufficient response), seems to be the optimal evidence-based strategy for MTX treatment of RA. Oral MTX is widely preferred because of its low costs and patient preferences; the bioavailability of parenteral MTX is higher, however. This is supported by data from observational studies, in which patients switching from parenteral to oral MTX at an equal dose had disease exacerbations. In several trials, the subcutaneous formulation of MTX was considered, by both physicians and patients, to be more advantageous in terms of discomfort and compliance. In addition, a significant proportion of patients reported that this formulation led to greater independence, with a resulting improvement in quality of life.
  
  
  CONCLUSIONS
  Although MTX treatment can be initiated by using the oral administration route, parenteral administration of MTX is indicated in those patients with poor compliance toward the oral form. The subcutaneous route seems to be more effective than the oral route for MTX administration based on the results of several studies, and this route may be preferred because of better usability and absence of pain at the infusion site.
authors.affiliation: Department of Biotechnological and Applied Clinical Science, Rheumatology Unit, School of Medicine, University of L'Aquila, L'Aquila, Italy. Electronic address: paola.cipriani@cc.univaq.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Cipriani
authors.affiliation: Department of Biotechnological and Applied Clinical Science, Rheumatology Unit, School of Medicine, University of L'Aquila, L'Aquila, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Ruscitti
authors.affiliation: Department of Biotechnological and Applied Clinical Science, Rheumatology Unit, School of Medicine, University of L'Aquila, L'Aquila, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Carubbi
authors.affiliation: Department of Biotechnological and Applied Clinical Science, Rheumatology Unit, School of Medicine, University of L'Aquila, L'Aquila, Italy.
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Liakouli
authors.affiliation: Department of Biotechnological and Applied Clinical Science, Rheumatology Unit, School of Medicine, University of L'Aquila, L'Aquila, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Giacomelli
mesh_terms: D000284:Administration, Oral; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D001682:Biological Availability; D004333:Drug Administration Routes; D006801:Humans; D007263:Infusions, Parenteral; D007273:Injections, Intramuscular; D007279:Injections, Subcutaneous; D008727:Methotrexate / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D011788:Quality of Life
chemical_list: D018501:Antirheumatic Agents; D008727:Methotrexate
keywords: Methotrexate; disease-modifying anti-rheumatic drugs; rheumatoid arthritis; therapeutic strategy