Table 2 Multinational recommendations for the use of methotrexate in RA (1–7, 9–10) and other rheumatic disorders (8)
RecommendationLevel of evidenceGrade of recommendationAgreement mean (SD)
1The work-up for patients starting methotrexate should include clinical assessment of risk factors for methotrexate toxicity (including alcohol intake), patient education, AST, ALT, albumin, CBC, creatinine, chest x ray (obtained within the previous year); consider serology for HIV, hepatitis B/C, blood fasting glucose, lipid profile and pregnancy test.4C8.2 (1.9)
2Oral methotrexate should be started at 10–15 mg/week, with escalation of 5 mg every 2–4 weeks up to 20–30 mg/week, depending on clinical response and tolerability; parenteral administration should be considered in the case of inadequate clinical response or intolerance.2bB7.8 (2.6)
3Prescription of at least 5 mg folic acid per week with methotrexate therapy is strongly recommended.1a–A7.5 (2.7)
4When starting methotrexate or increasing the dose, ALT with or without AST, creatinine and CBC should be performed every 1–1.5 months until a stable dose is reached and every 1–3 months thereafter; clinical assessment for side effects and risk factors should be performed at each visit.4C8.1 (2.1)
5Methotrexate should be stopped if there is a confirmed increase in ALT/AST greater than three times the ULN, but may be reinstituted at a lower dose following normalisation. If the ALT/AST levels are persistently elevated up to three times the ULN, the dose of methotrexate should be adjusted; diagnostic procedures should be considered in the case of persistently elevated ALT/AST more than three times the ULN after discontinuation.2bC7.4 (2.3)
6Based on its acceptable safety profile, methotrexate is appropriate for long-term use.2bB8.7 (1.9)
7In DMARD-naive patients the balance of the efficacy/toxicity favours methotrexate monotherapy over combination with other conventional DMARD; methotrexate should be considered as the anchor for combination therapy when methotrexate monotherapy does not achieve disease control.1a–A8.3 (2.1)
8Methotrexate, as a steroid-sparing agent, is recommended in giant-cell arteritis and polymyalgia rheumatica and can be considered in patients with systemic lupus erythematosus or (juvenile) dermatomyositis.1bB7.7 (2.1)
9Methotrexate can be safely continued in the perioperative period in RA patients undergoing elective orthopaedic surgery.1bB8.8 (1.9)
10Methotrexate should not be used for at least 3 months before planned pregnancy for men and women and should not be used during pregnancy or breast feeding.4C8.2 (2.7)
  • ALT, alanine aminotransferase; AST, aspartate aminotransferase; CBC, complete blood count; DMARD, disease-modifying antirheumatic drug; RA, rheumatoid arthritis; ULN, upper limit of normal.