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

Abstract

Methotrexate (MTX), the anchor drug in the current treatment strategy for rheumatoid arthritis (RA), was first approved for treatment of RA in Japan in 1999 at the recommended dose of 6–8 mg/week; it was approved as first-line drug with the maximum dose of 16 mg/week in February 2011. However, more than half of Japanese patients with RA are unable to tolerate a dose of 16 mg/week of MTX. Moreover, some serious adverse events during the treatment with MTX, such as pneumocystis pneumonia (PCP) and lymphoproliferative disorders (LPD) have been observed much more frequently in Japan than in other countries. Therefore, this article, an abridged English translation summarizing the 2016 update of the Japan College of Rheumatology (JCR) guideline for the use of MTX in Japanese patients with RA, is not intended to be valid for global use; however, it is helpful for the Japanese community of rheumatology and its understanding might be useful to the global community of rheumatology.

Keywords:

• Guideline
• Japan College of Rheumatology
• methotrexate
• rheumatoid arthritis

Introduction

Methotrexate (MTX) is the anchor drug in current treatment strategy for rheumatoid arthritis (RA) [1,2]. In Japan, MTX was first approved for refractory RA in adults in 1999 at the recommended dose of 6–8 mg/week. In February 2011, MTX was approved for adult RA with the maximum dose up to 16 mg/week, and as first-line conventional synthetic disease-modifying anti-rheumatic drug (csDMARD). The Japan College of Rheumatology (JCR) subcommittee on the guideline for the use of MTX in patients with RA published the first Japanese version of the guideline in 2011 and updated it in 2016. Since the adverse events during the treatment with MTX in Japan are rather serious and unique, such as pneumocystis pneumonia (PCP) and lymphoproliferative disorders (LPD), and its maximum dose is limited, it is important to publish the guideline in English for better understanding of the use of MTX for RA in Japan. This article is an abridged English translation summarizing the 2016 update of the JCR guideline for the use of MTX in Japanese patients with RA with a minimal update, and it is not intended to be valid for global use.

Indications, contraindications, and precautions

The paradigm of ‘Treat to Target (T2T)’ [1], in which long-term health-related quality of life is maximized by estimating disease activity and adjusting the therapy accordingly until reaching the target, has been widely accepted, and the first-line use of MTX as the anchor drug for the treatment of RA has been recommended [2]. The evidences from clinical trials on Japanese patients with poorly prognostic RA treated with first-line MTX therapy have been accumulated [3,4]. Therefore, MTX should be considered as the first choice among csDMARDs to maintain a balance between risk factors associated with MTX treatment, such as advanced age and comorbidities and benefits obtained by prompt control of disease activity (Table 1). In addition, MTX should be used as far as possible in patients who are likely to develop a functional disorder or its progression despite optimal dose of other csDMARDs for 2–3 months.

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.

Contraindications for MTX include severe hematological and lymphatic disorders, namely, myelodysplasia, aplastic anemia, pure red cell aplasia, LPD within recent 5 years, and severe leukopenia or thrombocytopenia (white blood cell [WBC] count <3000/uL, platelet count <50,000/uL) [5]; hepatic disorders, namely, acute or chronic active viral hepatitis B or C, and liver cirrhosis; severe renal disorders, including end-stage kidney disorder requiring dialysis with estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m²; and severe respiratory disorders diagnosed with hypoxemia (PaO₂ < 70 Torr in room air), % vital capacity <80% as estimated using lung function test, or severe pulmonary fibrosis as seen on the chest radiographs.

MTX should be administered in elderly patients with particular caution. Patients with infectious diseases or those susceptible to them may need appropriate vaccination and/or prophylactic medications. Patients with mild leukopenia (3000/μL ≤ WBC <4000/μL), thrombocytopenia (50,000/μL ≤ platelet <100,000/μL) or with a history of drug-induced bone marrow disorder should receive MTX therapy along with folic acid supplementation. Therapies other than MTX should be fully considered for patients with a history of LPD. A reduced dosing of MTX with folic acid supplementation should be considered for patients with hypoalbuminemia (<3 g/dL), because those are susceptible to dose-dependent adverse events, such as pancytopenia due to delayed clearance of MTX [6]. Patients with habitual drinking should be instructed to avoid alcohol as much as possible. Patients who show a positive test for hepatitis B virus (HBV) surface antigen (HBs-Ag) or HBV-DNA should receive anti-viral therapy prior to starting the MTX treatment after consulting with a hepatology/gastroenterology expert [7]. Patients who show a positive test result for hepatitis C virus (HCV) antibodies should be referred to a hepatology/gastroenterology expert to discuss the risk-benefit from MTX treatment. When the levels of liver transaminases (aspartate aminotransferase [AST] or alanine aminotransferase [ALT]) and alkaline phosphatase (ALP) are greater than 2-fold of the upper limit of normal without any positive tests for hepatitis viruses, intensive evaluation should be carried out before the commencement of MTX therapy, and if needed, MTX should be initiated at a lower dose along with folic acid supplementation. Renal function should be evaluated by estimating eGFR, creatinine clearance, or cystatin C, and in the patients with renal dysfunction (eGFR <60 mL/min/1.73 m² or equivalent), the therapy should be started with a reduced dose of MTX along with folic acid supplementation. A consultation with a respiratory expert should be considered for patients whose chest X-rays show possible signs of interstitial pneumonia, chronic obstructive pulmonary disease (COPD) or non-tuberculous mycobacterium (NTM) infection.

The dosing of methotrexate

Based on the global evidences on the use of MTX, it has been recommended that the initial optimal dose of MTX should be 10–15 mg/week [8,9], and this has been confirmed by subsequent systematic literature reviews [10,11]. The comparison among 2, 6, and 9 mg/week doses of MTX in terms of efficacy and safety was performed to determine the optimal clinical dose of MTX in Japanese patients with RA [12]. It was observed that the dose of 2 mg/week of MTX was less effective than other doses, whereas, 9 mg/week of MTX showed numerically greater, but statistically insignificant improvement in some clinical parameters compared with 6 mg/week of MTX. However, leukopenia and liver dysfunction were more frequently observed in patients receiving 9 mg/week of MTX than in those receiving 6 mg/week, which led to the maximum approved dose of MTX as 8 mg/week for patients with RA in 1999. After the approval of 16 mg/week as the maximum dose in 2011, the C-OPERA trial was conducted, in which MTX therapy was started with the dose of 8 mg/week and was escalated by 4 mg at every 4th week up to 16 mg/week by week 8 [4]. As a result, the efficacy and safety of protocol starting from 8 mg/week of MTX was confirmed in Japan. Clinical trials for comparing the effectiveness of parenteral MTX up to 10 versus 25 mg/week [13] and oral MTX up to 10 versus 25 mg/week as the initial dose [14] showed that MTX >15 mg/week is not needed as a starting dose of the therapy. In addition, the dose of MTX has been escalated from 7.5 mg/week to the maximum until week 8 in the escalation-protocols of many clinical trials on biological DMARDs (bDMARDs) versus MTX [15,16]. With respect of the T2T strategy aiming at the achievement of therapeutic goal within 6 months [1], 6–8 mg/week of MTX is appropriate for Japanese patients as the initial dose of the MTX therapy. For non-elderly patients with high disease activity and poor-prognostic factors or refractory arthritis, starting MTX therapy with the dose of 8 mg/week is recommended.

A French guideline on the clinical use of MTX has recommended a dose-escalation at the interval of 6 weeks in patients showing an inadequate response to MTX [8]. The clinical response rate in patients receiving MTX is 20–30% at week 4, which corresponds to approximately a half of the total response rate [17]. On the other hand, tight control for rheumatoid arthritis (TICORA) [18] and Computer-Assisted Management in Early Rheumatoid Arthritis (CAMERA) [19] studies examining the T2T strategy demonstrated higher remission rate and less radiographic progression in patients undergoing therapeutic adjustment at every 4th week as compared to those evaluated conventionally at every 12th week. Based on the tolerability of the dose-escalation protocol for MTX from the initial 7.5–8 mg/week up to 16–20 mg/week within 6–8 weeks in Japan and other countries [4,15,16], patients should be assessed every 2–4 weeks after the commencement or dose-escalation of MTX, followed by performing the dose-escalation, if necessary and tolerable, up to the maximum targeted dose within 8–12 weeks. Although the dose of MTX may be escalated up to 16 mg/week, the primarily targeted dose is 10–12 mg/week, because some clinical parameters have been shown to reach the plateau above 15 mg/week [20], and parenteral MTX showed better efficacy and fewer adverse gastrointestinal events than oral MTX at the dose above 15 mg/week [21]. The C-OPERA study in Japan was conducted with the protocol of rapid dose-escalation up to 16 mg/week by 8th week. However, the mean MTX dose during the 1st year was 11.6 mg/week (median 11.9 mg/week) and 10.5 mg/week (median 12.0 mg/week) by 1st year, and only ∼30% of patients were tolerable to 16 mg/week of MTX [4]. On the other hand, a post-marketing surveillance of dose of MTX over 8 mg/week demonstrated that dose-escalation to >8 mg/week resulted in an increase in the remission rate from 10.5 to 32.5% in 24 weeks, and from 16.9 to 47.1% in week 52 [22]. Therefore, the dose-escalation up to 10–12 mg/week of MTX has been recommended in patients showing inadequate response to 6–8 mg/week of MTX. After reaching a dose of 10–12 mg/week of MTX, a few options are available according to the risk-benefit in each patient: further dose-escalation of MTX to 16 mg/week or the addition of other csDMARDs, bDMARDs, or targeted synthetic DMARDs (tsDMARDs) to MTX therapy.

Although single dosing regimen is simple and globally popular for MTX therapy for RA, the bioavailability of oral MTX is not comparable between single and divided dosing [23–26]. Subcutaneous MTX is more effective than oral administration of 15 mg/week of MTX [27]. Furthermore, the bioavailability of subcutaneous MTX is higher than that of oral MTX by 25% even for the dose of 10 mg/week, and much more for the dose greater than 15 mg/week [28]. Thus, the fact that 10–15 mg/week dose of oral MTX is less effective than that of subcutaneous MTX may be explained by the differences in the bioavailability of the respective forms of MTX. In addition, it is reported that bioavailability of MTX is similar between single and divided dosing for the dose of 8 mg/week or less, while the dose of 25–35 mg/week of MTX has better bioavailability in divided dosing than that in single dosing [29]. Subcutaneous MTX, which is recommended for patients who are unable to tolerate oral MTX or in whom oral MTX is less effective [30], has not yet been approved for RA in Japan. Therefore, divided dosing every 12 h for 1–2 d may be beneficial for using more than 8 mg/week of MTX in terms of less GI toxicity and higher bioavailability. In fact, a post-marketing surveillance of the MTX dose over 8 mg/week in Japan revealed that approximately two-thirds of patients received 3-divided dosing for 2 d, and approximately 25% of patients received 2-divided dosing within a day, while single dose administration was observed in 4% of patients. Therefore, a dose ≤8 mg/week of MTX may be administered either as a single dose or as 2–3 divided doses for 1–2 d, while a dose >8 mg/week of MTX should be received 2–4 divided doses into every 12 h for 1–2 d.

Methotrexate combined with other disease-modifying anti-rheumatic drugs

MTX is the anchor drug, which is effective with concomitant csDMARDs in patients showing inadequate response to MTX monotherapy (MTX-IR or step-up), and in those with severe RA (parallel or step-down) [1,31–33]. Although cyclosporin A (CyA) has not been approved for RA in Japan, MTX + CyA has been reported to be effective in early RA and MTX-IR patients [34,35]. MTX + salazosulfapyridine (SASP) has been reported to be effective in early RA and SASP-IR patients [36–38], although the difference in effectiveness between MTX + SASP therapy and MTX monotherapy was modest [39]. The addition of leflunomide (LEF) [40], gold sodium thiomalate (GST) [41], tacrolimus (TAC) [42,43], as well as iguratimode (IGU: a csDMARD suppressing the production of immunoglobulins and inflammatory cytokines through the inhibition of nuclear factor-kappa B [NF-κB] activity) [44,45] to the MTX monotherapy has been effective in MTX-IR patients, although the use of GST is currently very limited in Japan. MTX + LEF therapy should be considered with caution in Japan where interstitial pneumonia associated with LEF is of serious concern [46], in addition to its additive immunosuppressive mode of action and accompanied profiles of adverse events, such as interstitial pneumonia, cytopenia, and liver dysfunction. MTX + bucillamine (BUC: a csDMARD derived from d-penicillamine), has shown a superior American College of Rheumatology 20% (ACR20) response rate and inhibition of radiographic progression as compared to BUC monotherapy or MTX monotherapy in MTX-naïve patients with early RA [47].

A systematic literature review of 51 full papers and 57 abstracts demonstrated that bDMARD and MTX combination therapy with all classes of bDMARD is more efficacious than bDMARD monotherapy, despite some additional evidence on the use of bDMARD monotherapy [48]. Most of the clinical trials involving MTX + anti-tumor necrosis factor (TNF) bDMARDs, such as etanercept (ETN; TEMPO [49], and JESMR [50]), adalimumab (ADA; PREMIER [51]), and golimumab (GLM; GO-BEFORE [52] and GO-FORWARD [53]) have shown superior clinical response rates, remission rates, improvement in health assessment questionnaire-disability index (HAQ-DI), and the inhibition of radiographic progression than that shown by anti-TNF bDMARD monotherapy. Therefore, anti-TNF bDMARDs should be used in combination with MTX therapy, if not indicated otherwise. The difference in the efficacy between anti-interleukin 6 (IL-6) receptor antibody, tocilizumab (TCZ) plus MTX and TCZ monotherapy is modest as compared to that with anti-TNF bDMARDs monotherapy as reported by a recent systematic literature review and network meta-analysis [54,55]. However, a combination therapy with MTX and TCZ has been recommended in MTX-naïve and MTX-IR patients without risk factors for MTX-related adverse events based on the evidences from CHARITHMA [56], ACT-RAY [57], FUNCTION [10], and SURPRISE [58] trials. The 28-joint count disease activity score (DAS28) showed a remission rate of 61.3% in MTX-naïve patients with early RA receiving MTX + abatacept (ABT), which was greater than that in those receiving MTX monotherapy (43.1%) and ABT monotherapy (45.7%) [15], while the results in MTX-IR patients are unavailable till date.

Tofacitinib (TOF), a tsDMARD against Janus kinase (JAK), has shown superiority to placebo (ORAL Scan) [59] and comparable efficacy to ADA (ORAL Standard) [60] in MTX-IR patients. The JCR guideline has recommended using TOF in MTX-IR patients. Therefore, the addition of TOF to MTX monotherapy is an option for patients not achieving the treatment goal despite 10–12 mg/week of MTX. However, a post-marketing surveillance for the safe and effective use of TOF in Japanese patients with RA is still underway; therefore, the addition of other csDMARDs or bDMARDs may be currently preferred to using TOF.

Folic acid supplementation

A meta-analysis examining the effects of folic acid supplementation on the outcome of MTX therapy showed a decrease in the rates of development of gastrointestinal symptoms, liver dysfunction, and MTX discontinuation [61–66]. However, folic acid or folinic acid supplementation may cause exacerbation of RA in some patients [67–69]. Nevertheless, folic acid supplementation has been globally recommended for all patients with RA receiving MTX based on the evidences from the trials involving 15–25 mg/week of MTX along with 1–2 mg/d of folic acid [8,9]. Folic acid supplementation has been especially recommended for patients receiving MTX above 0.2 mg/kg/week or 8 mg/week, and for patients with high risk for MTX-related adverse events, whereas, folic acid is not necessary for the patients receiving MTX <0.15 mg/kg/week.

Folinic acid is an active form of folic acid, not requiring enzymatic activation by dihydrofolate reductase (DHFR). Therefore, the administration of folinic acid, instead of folic acid, has been recommended in severe adverse events of MTX. Generally, 10 mg of folinic acid is administered orally at every 6 h, or 6–12 mg is administered intramuscularly or intravenously at every 6 h (the daily dose of folinic acid is approximately equal to three times the weekly dose of MTX) concomitantly with hydration and urinary alkalinization until improvement in adverse events is observed.

Screening tests before methotrexate therapy

Prior to MTX therapy, RA activity and risk factors for MTX-related adverse events should be assessed by history taking and physical examination. The estimation of CBC, ESR, blood chemistry, C-reactive protein (CRP), and urinalysis are required as general laboratory tests. Since renal disorder is the most important among the risk factors for MTX-related adverse events, renal function should be evaluated with reference to eGFR or cystatin C in elderly patients, in those with elevated serum creatinine levels, and in those with low body weight [70]. It has been reported that many patients manifest a replication of HBV during or after the immunosuppressive therapies or chemotherapies followed by the development of hepatitis, including fatal fulminant hepatitis, and that is also the case with MTX therapy [71,72]. Therefore, the screening and monitoring of HBV, according to the guidelines for preventing HBV reactivation [73], are needed along with a referral to a gastroenterology/hepatology expert. All patients should be screened for HBs-Ag and HCV-Ab before the commencement of MTX therapy. If HBs-Ag is positive, which suggests HBV-carrier, the patient should be referred to a gastroenterology/hepatology expert for prophylactic anti-viral therapy before the initiation of MTX therapy. If HBs-Ag is negative, high sensitivity testing for HBc-Ab and HBs-Ab should be performed for investigating the possibility of resolved HBV infection. If HBc-Ab and/or HBs-Ab is positive, the screening test for HBV-DNA should be performed every 1–3 months except for vaccinated patients, showing negative reports for HBc-Ab. In addition, when ≥20 IU/mL (2.1 log copies/mL) of HBV-DNA are observed in the sample, the patient should be referred to a gastroenterology/hepatology expert for prophylactic anti-viral therapy along with continuing the MTX therapy.

History taking, chest X-ray, interferon gamma releasing assay (IGRA) or tuberculin (TB) skin test, and chest computed tomography (CT) if needed, should be performed in order to investigate the possibility of TB infection. Two types of IGRAs, namely, Quantiferon^®TB Gold (Quest Diagnostics, Secaucus, NJ) and T-SPOT^®TB (Oxford Diagnostic Laboratories, Memphis, TN) are approved in Japan for this purpose. In principle, patients who meet the below criteria should receive prophylactic chemotherapy for TB before starting MTX:

1. An abnormal shadow in chest images compatible with old TB infection.

2. History of receiving TB chemotherapy.

3. Probable latent TB infection (LTBI) based on IGRA and/or TB skin test.

4. Close contact with patients with active TB.

5. Possible active TB as advised by an expert of pulmonary medicine.

Chest X-ray is helpful in the screening of interstitial pneumonia and other lung infections, which is also helpful in comparing with that obtained for the diagnosis of the lung diseases developing during MTX therapy. When interstitial pneumonia or other pulmonary complications are suspected, percutaneous oxygen saturation (SpO₂), high-resolution CT of lung, and tests for detecting β-D-glucan and biomarkers of interstitial pneumonia should be considered in addition to physical examination of the chest. Serum anti-MAC-GPL IgA antibody test can be helpful in the patients suspected of NTM infection with Mycobacterium avium/intracellulare (Mycobacterium avium complex; MAC) [74].

Monitoring during methotrexate therapy

Safety monitoring aims at the adequate management of potentially serious or frequently observed adverse events during MTX therapy. In Japan, pancytopenia, lung injury, severe infection, and LPD are the serious MTX-related adverse events, which are of special concern [22]. Laboratory blood tests and urinalysis should be performed every 2–4 weeks within 6 months of starting the MTX therapy or dose-escalation of MTX. The frequency of these tests may be reduced to every 4–12 weeks in patients receiving constant dose of MTX. However, those with risk factors for MTX-related adverse events, such as renal disorder should be monitored more closely [75]. CBC monitoring should include WBC differentiation, to rule out the possibility of granulocytopenia and lymphocytopenia, and estimation of MCV. Blood chemistry includes estimation of AST, ALT, ALP, albumin, glucose, creatinine, and blood urea nitrogen. Transaminase elevation is the most frequently observed abnormal finding among the laboratory investigations, and the sustained elevation suggests possibility of chronic liver diseases [76]. Sustained hypoalbuminemia is a risk factor for the development of cytopenia and various infectious diseases, in addition to the implication of chronic liver diseases [77]. Chest X-ray should be obtained for investigating drug-induced lung injury and opportunistic infections, such as TB. Chest X-ray or chest CT should be performed in patients with lung comorbidities, such as interstitial pneumonia, and tests for the detection of biomarkers for interstitial pneumonia (KL-6 and SP-D) and fungal infection (β-D glucan) may be considered. Serum anti-MAC-GPL IgA antibody test can be helpful in the patients suspected of MAC infection.

The assessment of effectiveness of MTX should be based on a comprehensive assessment of disease activity, including joint examination, and estimation of acute phase reactants. The disease activity should be initially evaluated every 4–8 weeks of MTX dose adjustment, followed by every 12 weeks in patients with sustained remission or low disease activity. In addition, relevant X-ray images of the joints should be obtained at least once a year. Ultrasound examination of the joints has been reported to be useful for the assessment of active synovitis in patients undergoing MTX therapy [78], and it may be performed in addition to the physical examination of joints.

Perioperative management

A majority of the evidences suggest that continuation of 5–12.5 mg/week of MTX in the perioperative period of elective orthopedic surgery does not produce any impact on the postoperative complications and the wound healing, but it reduces the flare rate of RA [79–86]; however, some reports indicated an increase in the rate of postoperative infections [87,88]. Since there is lack of evidences concerning the surgeries other than elective orthopedic surgery, the judgment regarding the continuation, discontinuation, and restart of MTX therapy should be based on the perioperative condition of patients (for example the status of renal function, bleeding volume, and hypoalbuminemia) and the dose of MTX (more than 12 mg/week or not).

Management during pregnancy and lactation

The exposure to MTX during pregnancy may lead to MTX-related embryopathy, which includes CNS deformity, skull bone deformity, growth deficiency of extremities, and cleft palate [89]. A report from the European League Against Rheumatism (EULAR) task force on the use of DMARDs before pregnancy and during pregnancy and lactation recommends the discontinuation of MTX 1–3 months prior to the conception [90]. It is stated in the package insert of MTX in Japan that, 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. MTX is contraindicated during lactation, because MTX has been detected in human breast milk [91–93].

The management of methotrexate-related adverse events

When MTX therapy is started, its major adverse effects and their prevention, early recognition, and treatment should be well explained to the patients. Patient education as described above should also be repeated during MTX therapy by doctors and other medical staff. The pamphlet (in Japanese) prepared by JCR (http://www.ryumachi-jp.com/pdf/mtx_2017.pdf) may be helpful for the above purpose.

Blood disorders (myelosuppression with few exceptions) are observed as MTX-related fatal outcomes in 29.5% of cases [22]. The risk factors include renal disorders [22,94–97], advanced age [22,94,96,97], folic acid deficiency [96,97], multiple concomitant drugs [95–97], hypoalbuminemia [95,97], and dehydration.

MTX-related pneumonia develops in 1–7% of RA patients [98,99] and 13% of them are fatal [100]. MTX-related pneumonia tends to develop within 1 year of the commencement of MTX therapy in Japan and other countries, although it may occur abruptly at any time during the therapy. The risk factors for MTX-related pneumonia include pre-existing rheumatoid lung, advanced age, diabetes mellitus, hypoalbuminemia, and previous use of DMARDs [101,102]. When patients develop interstitial pneumonia, MTX should be immediately discontinued, and differential diagnosis to rule out other possibilities should be performed. MTX-related pneumonia is not distinguishable from PCP on the basis of chest HRCT images alone. A publication by the Japanese Respiratory Society Committee on the formulation of Consensus statement is helpful in the diagnosis and treatment of drug-induced lung injuries [103]. Antibiotics, such as TMP/SMX 6–12 g/d are administered along with glucocorticoids. Re-exposure to MTX should be avoided because it has been reported that 25% of such patients developed repeated MTX-related pneumonia [100].

The risk factors for infectious diseases to be evaluated prior to MTX therapy include age, preexisting lung disease, extra-articular manifestations, diabetes mellitus, glucocorticoids use, and serious infection within recent 3 years [104,105], in addition to chronic infectious complications, renal disorder, bone marrow disorder, and the history of opportunistic infections. The adequate prophylaxis includes complete antibiotic therapy for active infection or necessary vaccination, such as that against pneumococcus and influenza viruses, isoniazid for LTBI, TMP/SMX, pentamidine isethionate inhalation, atovaquone for those with elevated risk for PCP, and consultation with an expert of pulmonary medicine for patients with possible NTM infection.

MTX-related liver disorders are classified as dose-dependent, principally hepatotoxic liver dysfunction and viral hepatitis reactivated or aggravated by MTX. When patients showing positive test results for HBV or HCV develop liver dysfunction, they should be referred to a gastroenterology/hepatology expert for the management including discontinuation of MTX administration. When patients without viral hepatitis show elevated AST and/or ALT levels not greater than 3-fold of the upper limit of the normal levels, reduction in the dose of MTX, or starting or increasing the dose of folic acid should be considered; whereas, for those showing elevated AST and/or ALT levels greater than 3-fold of the upper limit of normal, dose reduction or discontinuation of MTX, and starting or increasing the dose of folic acid as daily administration should be encouraged.

A 2–6 fold increased risk of malignant lymphoma in patients with RA as compared to that in the general population have been reported [106–109]. Diffuse large B-cell lymphoma (DLBCL) is the most frequently observed histological type [109], and the presence of extra-nodular lesions, such as in skin, oral cavity, pharynx, and lungs are characteristic of LPD in the patients with receiving MTX therapy [110]. Many cases of iatrogenic immunodeficiency-associated LPD demonstrating complete or partial regression of nodular or extra-nodular lesions shortly after discontinuing the administration of MTX or other immunosuppressive drugs have been reported. A recent report suggested that the elevated mean dose of MTX was a risk factor for LPD; however, the cumulative disease activity was not adjusted in that study [111].

Conflict of interest

HK has received consulting fees and/or speaker fees from AbbVie GK, Bristol-Myers Squibb, Chugai Pharmaceutical Co., Ltd., Eli Lilly and Company, Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma, Novartis Pharma K.K., and Sanofi K.K., and has received research grants from AbbVie GK, Asaki Kasei Pharma, Astellas Pharma Inc., Bristol-Myers Squibb, Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma, Novartis Pharma K.K., and Sanofi K.K.

TF has received a research grant and/or speaker fee from Pfizer Japan Inc., Ono Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Mitsubishi Tanabe Pharma, Eisai Co., Ltd., AbbVie GK, and Astellas Pharma Inc.

AN has received consulting or speaker fees from Astellas Pharma Inc., Bristol-Myers Squibb, Chugai Pharmaceutical Co., Ltd., Daiichi-Sankyo Healthcare Co., Ltd., Eisai Co., Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma, Novartis Pharma K.K., Pfizer Japan Inc., Taisho Toyama Pharmaceutical Co., Ltd., and has received research grants from Kissei Pharmaceutical Co., Ltd.

KK has received speaker fee from Mitsubishi Tanabe Pharma.

MH has received speaker fees from Mitsubishi Tanabe Pharma, Chugai Pharmaceutical Co., Ltd., and Eli Lilly and Company, research grants from Abbvie GK, Ayumi Co., Ltd., Eisai Co., Ltd., Nippon-Kayaku Co., Ltd., Taisho-Toyama Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma, and Teijin Pharma Co., Ltd.

YS has received research funding from Chugai Pharmaceutical Co., Ltd., and Teijin Pharma Co., Ltd., has received honoraria or fees for promotional materials from Pfizer Japan Inc., Eisai Co., Ltd., Asaki Kasei Pharma, and Ayumi Co., Ltd. All other authors declared no conflicts of interest.

Acknowledgments

The authors thank to Editage Japan for editing the manuscript, which fee was supported by Research on rare and intractable diseases, Health and Labour Sciences Research Grant H29-028.