Immunologic Research

, Volume 60, Issue 2–3, pp 289–310 | Cite as

Three decades of low-dose methotrexate in rheumatoid arthritis: Can we predict toxicity?

  • Vasco C. Romão
  • Aurea Lima
  • Miguel Bernardes
  • Helena Canhão
  • João Eurico Fonseca


Methotrexate (MTX) is the anchor disease-modifying antirheumatic drug (DMARD) in rheumatoid arthritis (RA) treatment. It is used in monotherapy and/or in combination with other synthetic or biological DMARDs, and is known to have the best cost-effectiveness and efficacy/toxicity ratios. However, toxicity is still a concern, with a significant proportion of patients interrupting long-term treatment due to the occurrence of MTX-related adverse drug reactions (ADRs), which are the main cause of drug withdrawal. Despite the extensive accumulated experience in the last three decades, it is still impossible in routine clinical practice to identify patients prone to develop MTX toxicity. While clinical and biological variables, including folate supplementation, partially help to minimize MTX-related ADRs, the advent of pharmacogenomics could provide further insight into risk stratification and help to optimize drug monitoring and long-term retention. In this paper, we aimed to review and summarize current data on low-dose MTX-associated toxicity, its prevention and predictors, keeping in mind practical RA clinical care.


Adverse drug reactions Methotrexate Predictors Rheumatoid arthritis Toxicity 


Conflict of interest

The authors declare that they have no conflict of interest.


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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Vasco C. Romão
    • 1
    • 2
  • Aurea Lima
    • 3
    • 4
    • 5
  • Miguel Bernardes
    • 6
    • 7
  • Helena Canhão
    • 1
    • 2
  • João Eurico Fonseca
    • 1
    • 2
  1. 1.Rheumatology Research UnitInstituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon Academic Medical CentreLisbonPortugal
  2. 2.Rheumatology Department, Hospital de Santa MariaLisbon Academic Medical CentreLisbonPortugal
  3. 3.Department of Pharmaceutical Sciences, CESPU Institute of Research and Advanced Training in Health Sciences and TechnologiesHigher Institute of Health Sciences (ISCS-N)Gandra PRDPortugal
  4. 4.Molecular Oncology Group CIPortuguese Institute of Oncology of Porto (IPO-Porto)PortoPortugal
  5. 5.Abel Salazar Institute for the Biomedical Sciences (ICBAS)University of PortoPortoPortugal
  6. 6.Faculty of Medicine of University of Porto (FMUP)PortoPortugal
  7. 7.Rheumatology DepartmentSão João Hospital CentrePortoPortugal

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