Table 1

Multinational recommendations for the use of methotrexate in RA.

Recommendation

Level of evidence

Grade of recommendation

Selected references


1

The 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 × ray (obtained within the previous year); consider serology for HIV, hepatitis B/C, blood fasting glucose, lipid profile and pregnancy test.

4

C

[39,231-237]

2

Oral methotrexate should be started at 10 to 15 mg/week, with escalation of 5 mg every 2 to 4 weeks up to 20 to 30 mg/week, depending on clinical response and tolerability; parenteral administration should be considered in the case of inadequate clinical response or intolerance.

2b

B

[238-242]

3

Prescription of at least 5 mg folic acid per week with methotrexate therapy is strongly recommended.

1a-

A

[207,243-245]

4

When starting methotrexate or increasing the dose, ALT with or without AST, creatinine and CBC should be performed every 1 to 1.5 months until a stable dose is reached and every 1 to 3 months thereafter; clinical assessment for side effects and risk factors should be performed at each visit.

4

C

[39,233,246-250]

5

Methotrexate 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 normalization. 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.

2b

C

[237,250-252]

6

Based on its acceptable safety profile, methotrexate is appropriate for long-term use.

2b

B

[253-258]

7

In DMARD-naïve patients the balance of the efficacy/toxicity favors methotrexate monotherapy over combination with other conventional DMARDs; methotrexate should be considered as the anchor for combination therapy when methotrexate monotherapy does not achieve disease control.

1a-

A

[7,57,259-263]

8

Methotrexate can be safely continued in the perioperative period in RA patients undergoing elective orthopedic surgery.

1b

B

[264,265]

9

Methotrexate should not be used for at least three months before planned pregnancy for men and women and should not be used during pregnancy or breast feeding

4

C

[266-268]


Adapted by permission from BMJ Publishing Group Limited. [Ann Rheum Dis, Visser K et al. 2009, 68:1086-1093]. Evidence-based recommendations for the use of methotrexate in daily clinical care of rheumatic disorders, issued by 751 rheumatologists from 17 countries through systematic review of the literature, discussion and voting. Levels of evidence and grades of recommendation were determined according to those established by the Oxford Centre for Evidence Based Medicine [269], as follows: level 1a - systematic review (SR; with homogeneity) of randomized clinical trials (RCTs); level 1b - individual RCT (with narrow confidence interval); level 1c - all or none; level 2a - SR (with homogeneity) of cohort studies; level 2b - individual cohort study (including low quality RCT); level 2c - 'outcomes' research, ecological studies; level 3a - SR (with homogeneity) of case-control studies; level 3b - individual case-control study; level 4 - case-series (and poor quality cohort and case-control studies); level 5 - expert opinion without explicit critical appraisal or based on physiology, bench research or 'first principles'; a minus sign (-) can be added to a particular level, to denote that it fails to provide a conclusive answer because of either a single result with a wide confidence interval or a SR with troublesome heterogeneity. Grade of recommendation A - consistent level 1 studies; grade of recommendation B - consistent level 2 or 3 studies or extrapolations from level 1 studies; grade of recommendation C - level 4 studies or extrapolations from level 2 or 3 studies; grade of recommendation D - level 5 evidence or troublingly inconsistent or inconclusive studies of any level. ALT, alanine aminotransferase; AST, aspartate aminotransferase; CBC, complete blood count; DMARD, disease-modifying antirheumatic drug; RA, rheumatoid arthritis; SD, standard deviation; ULN, upper limit of normal.

Romão et al. BMC Medicine 2013 11:17   doi:10.1186/1741-7015-11-17

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