Table 2.

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

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	[2–4, 7–15, 20, 21, 23–25]
MTX is also recommended in systemic arthritis with predominant joint inflammation, without active systemic features	4C	[2–4, 7–15, 20–25]
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, 26–38, 40–42]
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, 43–49]
Research question 4: Tapering and discontinuation of methotrexate in juvenile idiopathic arthritis
5. MTX could be discontinued after 6 months of stable remission	1A	[50–52]
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	[53–57, 59–62]
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	[63–72, 74–79]
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, 83–85, 88, 89]
Combination therapy is safe and may reduce the development of anti-drug antibodies	2B	[83, 88–90]
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		[91–101]
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	[101–119]
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

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