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Table 2 Summary of recommendations for the use of methotrexate in juvenile idiopathic arthritis

From: Methotrexate in juvenile idiopathic arthritis: advice and recommendations from the MARAJIA expert consensus meeting

PICO research questions and recommendations Grade of evidence Supporting references
Research question 1: Efficacy and safety of methotrexate in juvenile idiopathic arthritis
 1. MTX is recommended as the first-line treatment in oligoarthritis that persists despite nonsteroidal anti-inflammatory drugs (NSAIDs) and intraarticular steroid (IAS) therapy, and in polyarticular disease 1A [2,3,4, 7,8,9,10,11,12,13,14,15, 20, 21, 23,24,25]
  MTX is also recommended in systemic arthritis with predominant joint inflammation, without active systemic features 4C [2,3,4, 7,8,9,10,11,12,13,14,15, 20,21,22,23,24,25]
 2. Clinical and laboratory monitoring of MTX toxicity is recommended every 4-8 weeks initially, and then every 12-16 weeks, unless risk factors are present 4C [1, 4, 12, 21, 26,27,28,29,30,31,32,33,34,35,36,38,38, 40,41,42]
Research question 2: Dosages of methotrexate in juvenile idiopathic arthritis
 3. A dose of 10-15 mg/m2/week is recommended. 5D [7, 9, 42]
  Further increases in MTX dosage have not been associated with additional therapeutic benefit 1A  
Research question 3: Route of administration of methotrexate in juvenile idiopathic arthritis
 4. MTX may be given orally or subcutaneously once a week. If high doses (15 mg/m2/week) are requested, the subcutaneous route is preferable due to increased bioavailability 4C [9, 21, 43,44,45,46,47,48,49]
Research question 4: Tapering and discontinuation of methotrexate in juvenile idiopathic arthritis
 5. MTX could be discontinued after 6 months of stable remission 1A [50,51,52]
Research question 5: Folic acid supplementation for the prevention of methotrexate toxicity in patients with juvenile idiopathic arthritis
 6. Folic or folinic acid supplementation is recommended to prevent MTX side effects. 1A [53,54,55,56,57, 59,60,61,62]
  The advised dose is approximately one third of the MTX dose, at least 24 hours after the weekly dose of MTX for folinic acid; for folic acid 1 mg/day skipping the day when MTX is administered 4C  
Research question 6: Efficacy of methotrexate in uveitis associated with juvenile idiopathic arthritis
 7. MTX is recommended for the treatment of JIA-related uveitis refractory to topical treatment 4C [63,64,65,66,67,68,69,70,71,72, 74,75,76,77,78,79]
Research question 7: Add-on therapy with biologic drugs in juvenile idiopathic arthritis not responding to methotrexate
 8. The combination of MTX with a TNF-α inhibitor is recommended in patients who had an inadequate clinical response to MTX alone 3B [11, 48, 80, 83,84,85, 88, 89]
  Combination therapy is safe and may reduce the development of anti-drug antibodies 2B [83, 88,89,90]
Research question 8: Molecular elements and genetic markers of response to methotrexate in juvenile idiopathic arthritis – Biomarkers
 9. No recommendation is made regarding the use of biomarkers in current clinical practice   [91,92,93,94,95,96,97,98,99,100,101]
Research question 9: Use of vaccination in patients with juvenile idiopathic arthritis treated with methotrexate
 10. Vaccination with non-live vaccines is not contraindicated during MTX treatment 2B [101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119]
  No recommendation can be formulated for live-attenuated vaccines, but the available data for measles, mumps, rubella (MMR) booster indicate that it is safe and adequately immunogenic   
  1. Abbreviations: IAS intra-articular steroid, JIA juvenile idiopathic arthritis, MMR measles, mumps, rubella, MTX methotrexate, NSAIDs nonsteroidal anti-inflammatory drugs, TNF-α tumor necrosis factor-α