Japan College of Rheumatology guideline for the use of methotrexate in patients with rheumatoid arthritis

Figures & data

Table 1. 2016 Update of the JCR recommendations for the use of MTX in patients with RA.

1. MTX should be considered as the first choice among csDMARDs based on the risk-benefit balances in patients with poor-prognostic RA.

2. The switch to or the addition of MTX should be considered in patients not reaching the treatment target despite the optimal dose of other csDMARDs for 2–3 months.

3. MTX is contraindicated in pregnancy; in case of hypersensitivity to MTX; pleural effusion or ascites; severe infection or severe hematological, lymphatic, hepatic, renal, or respiratory disorders. MTX should be administered with particular caution in elderly patients and those with hypoalbuminemia or less severe organ disorders as described above.

4. Principally, MTX should be started with an oral dose of 6–8 mg/week. The initial dose should be determined based on the risk factors for adverse events, disease activity, and poor-prognostic factors. A dose of 8 mg/week MTX is recommended especially for non-elderly patients with poor-prognostic factors.

5. The dose of MTX should be escalated by 2 mg/week after 4 weeks usually in patients not reaching the treatment target. The dose of MTX may be escalated by 2 mg/week in every 2 weeks or by 4 mg/week in every 4 weeks in non-elderly patients with high disease activity and poor-prognostic factors.

6. The dose of MTX should be escalated to 10–12 mg/week in tolerable patients without risk factors for adverse events. The dose of MTX may be escalated maximally to 16 mg/week in patients showing insufficient response, although the addition of other csDMARDs or biological DMARDs (bDMARDs) may also be considered.

7. The weekly MTX dose may be administered as one single dose or divided into 2–3 doses every 12 h for 1–2 d. The divided dosing is preferable rather than non-divided dosing for more than 8 mg of MTX per week.

8. The addition of other csDMARDs to MTX therapy is a therapeutic choice for patients not reaching the treatment target despite the sufficient dose (usually at least 10–12 mg/week) of MTX for 3–6 months. Bucillamine, salazosulfapyridine, iguratimod, and tacrolimus are the recommended csDMARDs based on the evidences of the additive efficacy.

9. The addition of bDMARDs to MTX therapy is a therapeutic choice for patients not reaching the treatment target despite the sufficient dose (usually at least 10–12 mg/week) of MTX for 3–6 months. The addition of bDMARDs to MTX therapy, rather than switching to bDMARDs only, has been recommended in view of the effectiveness.

10. The addition of targeted synthetic DMARDs (tsDMARDs) to MTX therapy may be a therapeutic choice in patients showing insufficient response to MTX.

11. The dose of MTX may be kept unchanged with the addition of other csDMARDs, bDMARDs or tsDMARDs, namely up to 16 mg/week, which is the same as its use in monotherapy. The MTX dose can be reduced in patients with risk factors for infectious diseases. Further dose-escalation of MTX (maximum up to 16 mg/week) may be a therapeutic choice in patients showing insufficient response to MTX-anchored combination therapy.

12. The supplementation of folic acid should be considered along with the continuation of MTX therapy because of its effectiveness for the prevention and treatment of liver dysfunction, gastrointestinal symptoms, and stomatitis. Folic acid supplementation is especially recommended for patients receiving more than 8 mg of MTX per week, elderly patients at higher risk of adverse events or those with renal insufficiency.

13. Folic acid (Foliamin^®) up to 5 mg/week should be given after 24–48 h of the latest MTX administration. Folinic acid (Leucovorin^®), instead of folic acid, should be used for the treatment of severe MTX-related adverse events.

14. Prior to MTX therapy, the assessment of RA activity and risk factors for MTX-related adverse events should be completed by history taking; physical examination; blood tests for complete blood cell count (CBC), erythrocyte sedimentation rate (ESR), and blood chemistry; immunological tests; chest X-ray; and screening tests for hepatitis viruses and tuberculosis (TB).

15. After the initiation of MTX therapy, general physical examination and joint evaluation should be performed regularly for monitoring the effectiveness of MTX and for confirming its safe use. Laboratory tests, including CBC (with leukocyte differentiation and mean corpuscular volume [MCV]), ESR, C-reactive protein (CRP), blood chemistry (liver transaminases [aspartate aminotransferase (AST) and alanine aminotransferase (ALT)], alkaline phosphatase, albumin, glucose, creatinine, and blood urea nitrogen), and urinalysis every 2–4 weeks within 6 months after the start or dose-escalation of MTX. The above-mentioned laboratory tests should be repeated every 4–12 weeks in a patient under maintenance dosing after the confirmation of the effectiveness of MTX and its safe use. Chest X-ray should preferably be performed every year. The assessment of effectiveness of MTX should be based on clinical measures of disease activity as well as joint images.

16. MTX may be continued in the perioperative period for patients undergoing elective orthopedic surgery. The judgment for MTX continuation should be based on the risk-benefit balance for those undergoing other surgeries or those receiving MTX >12 mg/week.

17. Before starting MTX, patients should be informed of its adverse effects on pregnancy and fetal life, so that they can use effective contraceptive measures during MTX treatment. MTX is contraindicated for (possibly) pregnant patients. Therefore, female patients of childbearing age should be instructed to avoid pregnancy during MTX therapy and at least one menstrual cycle after the latest dosing of MTX. Moreover, use of MTX is also contraindicated during lactation.

18. When starting MTX therapy, its major adverse effects should be well explained to the patients for the prevention, early recognition, and treatment of these effects. The patient education as described above should be repeated even during MTX therapy. The evaluation of risk factors and subsequent prophylactic measures for serious side effects, such as bone marrow disorder, interstitial pneumonia, infections, and lymphoproliferative disorders (LPD) should be carried out, and these should be promptly and appropriately managed when they develop.

19. The overdosing of MTX should be avoided, because bone marrow disorder associated with MTX is often fatal. The initial MTX dose should be reduced and supplementary folic acid should be administered in high-risk patients, such as the elderly and those with renal insufficiency. The skipping of MTX when patients show signs and symptoms of dehydration or severe stomatitis should be repeatedly explained.

20. Education regarding the initial signs and symptoms of interstitial pneumonia is crucial. Patients should be instructed to see a doctor without delay when they develop dry cough, shortening of breath, or dyspnea without apparent causes. MTX-related pneumonia may develop at any time during MTX therapy. Prompt exclusion of possibilities other than MTX-related pneumonia is necessary and treatments including moderate to high dose of glucocorticoids should be started when needed.

21. The screening tests for the evaluation of the risks for infectious diseases must be performed prior to starting the MTX therapy, and accordingly adequate prophylactic treatment, such as anti-TB therapy or administration of trimethoprim/sulfamethoxazole (TMP/SMX), should be provided. Patients should be educated about signs and symptoms of infectious diseases, drug cessation, and early return visit with the aim of early diagnosis and the prevention of deterioration. Patients should be observed with a special attention to respiratory infections and herpes zoster, which are frequent and account for almost half of all infectious events. Patients receiving MTX for a long time should be managed with consideration of increasing risk for infectious diseases because of immunosuppression, aging, and existing comorbidities.

22. Possible gastrointestinal adverse events, such as stomatitis and nausea should be communicated at the commencement of MTX therapy. Supplementary folic acid and anti-emetic drugs may be effective for treating these events.

23. Liver function tests and the screening tests for hepatitis viruses (HBs-Ag, HBs-Ab, HBc-Ab, and HCV-Ab) must be performed prior to starting the MTX therapy, and adequate monitoring should be performed subsequently. Folic acid supplementation is recommended for the prevention of liver toxicity because of MTX.

24. When the signs and symptoms or laboratory investigations suggest LPD during MTX treatment, MTX as well as concomitant immunosuppressive drugs should be immediately withdrawn. Since LPD in patients with RA undergoing immunosuppressive therapy frequently results in extra-nodal lesions, referral to the division of hematology or related departments should be made. The treatment of RA after the remission of LPD should not include immunosuppressive drugs as far as possible, and MTX re-challenge and use of TNF inhibitors should be avoided.

25. The possible development and exacerbation of adverse events should be monitored during the concomitant use of drugs known to interact with MTX. Accordingly, the dose adjustment for MTX and/or concomitant drugs should be considered to deal with the development of adverse events.