1) Williams HJ, et al : Comparison of low-dose oral pulse methotrexate and placebo in the treatment of rheumatoid arthritis. A controlled clinical trial. Arthritis Rheum, 28 : 721-730, 1985
2) Weinblatt ME, et al : Efficacy of low-dose methotrexate in rheumatoid arthritis. N Engl J Med, 312 : 818-822, 1985
3) Furst DE, et al : Increasing methotrexate effect with increasing dose in the treatment of resistant rheumatoid arthritis. J Rheumatol, 16 : 313-320, 1989
4) Schnabel A, et al : Tolerability of methotrexate starting with 15 or 25mg/week for rheumatoid arthritis. Rheumatol Int, 14 : 33-38, 1994
5) Pavy S, et al : Methotrexate therapy for rheumatoid arthritis : clinical practice guidelines based on published evidence and expert opinion. Joint Bone Spine, 73 : 388-395, 2006
6) Visser K, et al : Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis : integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative. Ann Rheum Dis, 68 : 1086-1093, 2009
7) Visser K & van der Heijde D : Optimal dosage and route of administration of methotrexate in rheumatoid arthritis : a systematic review of the literature. Ann Rheum Dis, 68 : 1094-1099, 2009
8) Mouterde G, et al : Optimizing methotrexate therapy in rheumatoid arthritis : a systematic literature review. Joint Bone Spine, 78 : 587-592, 2011
9) 柏崎禎夫, 他 : 慢性関節リウマチに対するL-377 (メトトレキサートカプセル) の至適投与量検討試験. 炎症, 16 : 437-458, 1996
11) Thompson RN, et al : A controlled two-centre trial of parenteral methotrexate therapy for refractory rheumatoid arthritis. J Rheumatol, 11 : 760-763, 1984
12) Hobl EL, et al : A randomized, double-blind, parallel, single-site pilot trial to compare two different starting doses of methotrexate in methotrexate-naive adult patients with rheumatoid arthritis. Clin Ther, 34 : 1195-1203, 2012
13) Dhir V, et al : Randomized controlled trial comparing 2 different starting doses of methotrexate in rheumatoid arthritis. Clin Ther, 36 : 1005-1015, 2014
14) Bergstra SA, et al : Meta-Regression of a Dose-Response Relationship of Methotrexate in Monoand Combination Therapy in Disease-Modifying Antirheumatic Drug-Naive Early Rheumatoid Arthritis Patients. Arthritis Care Res (Hoboken), 69 : 1473-1483, 2017
15) Bergstra SA, et al : Similar short-term clinical response to high-dose versus low-dose methotrexate in monotherapy and combination therapy in patients with rheumatoid arthritis. Arthritis Res Ther, 19 : 258, 2017
16) Emery P, et al : Evaluating drug-free remission with abatacept in early rheumatoid arthritis : results from the phase 3b, multicentre, randomised, active-controlled AVERT study of 24 months, with a 12-month, double-blind treatment period. Ann Rheum Dis, 74 : 19-26, 2015
17) Burmester GR, et al : Tocilizumab in early progressive rheumatoid arthritis : FUNCTION, a randomised controlled trial. Ann Rheum Dis, 75 : 1081-1091, 2016
18) Westhovens R, et al : Filgotinib in combination with methotrexate or as monotherapy versus methotrexate monotherapy in patients with active rheumatoid arthritis and limited or no prior exposure to methotrexate : the phase 3, randomised controlled FINCH 3 trial. Ann Rheum Dis, 80 : 727-738, 2021
19) van Vollenhoven R, et al : Efficacy and Safety of Upadacitinib Monotherapy in Methotrexate-Naive Patients With Moderately-to-Severely Active Rheumatoid Arthritis (SELECT-EARLY) : A Multicenter, Multi-Country, Randomized, Double-Blind, Active Comparator-Controlled Trial. Arthritis Rheumatol, 72 : 1607-1620, 2020
20) Lee EB, et al : Tofacitinib versus methotrexate in rheumatoid arthritis. N Engl J Med, 370 : 2377-2386, 2014
21) Fleischmann R, et al : Baricitinib, Methotrexate, or Combination in Patients With Rheumatoid Arthritis and No or Limited Prior Disease-Modifying Antirheumatic Drug Treatment. Arthritis Rheumatol, 69 : 506-517, 2017
22) Gaujoux-Viala C, et al : Optimal methotrexate dose is associated with better clinical outcomes than non-optimal dose in daily practice : results from the ESPOIR early arthritis cohort. Ann Rheum Dis, 76 : 2054-2060, 2017
23) Smolen JS, et al : Treating rheumatoid arthritis to target : 2014 update of the recommendations of an international task force. Ann Rheum Dis, 75 : 3-15, 2016
24) van der Heijde DM, et al : Prognostic factors for radiographic damage and physical disability in early rheumatoid arthritis. A prospective follow-up study of 147 patients. Br J Rheumatol, 31 : 519-525, 1992
25) Singh JA, et al : 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken), 64 : 625-639, 2012
28) Strand V, et al : Treatment of active rheumatoid arthritis with leflunomide compared with placebo and methotrexate. Leflunomide Rheumatoid Arthritis Investigators Group. Arch Intern Med, 159 : 2542-2550, 1999
29) Grigor C, et al : Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study) : a single-blind randomised controlled trial. Lancet, 364 : 263-269, 2004
30) Verstappen SM, et al : Intensive treatment with methotrexate in early rheumatoid arthritis : aiming for remission. Computer Assisted Management in Early Rheumatoid Arthritis (CAMERA, an open-label strategy trial). Ann Rheum Dis, 66 : 1443-1449, 2007
31) Tanaka Y, et al : Efficacy and safety of baricitinib in Japanese patients with rheumatoid arthritis : Subgroup analyses of four multinational phase 3 randomized trials. Mod Rheumatol, 28 : 583-591, 2018
32) Tanaka Y, et al : Efficacy and safety of peficitinib (ASP015K) in patients with rheumatoid arthritis and an inadequate response to conventional DMARDs : a randomised, double-blind, placebo-controlled phase III trial (RAJ3). Ann Rheum Dis, 78 : 1320-1332, 2019
33) Takeuchi T, et al : Efficacy and safety of peficitinib (ASP015K) in patients with rheumatoid arthritis and an inadequate response to methotrexate : results of a phase III randomised, double-blind, placebo-controlled trial (RAJ4) in Japan. Ann Rheum Dis, 78 : 1305-1319, 2019
34) Seideman P : Methotrexate--the relationship between dose and clinical effect. Br J Rheumatol, 32 : 751-753, 1993
35) Wegrzyn J, et al : Better efficacy of methotrexate given by intramuscular injection than orally in patients with rheumatoid arthritis. Ann Rheum Dis, 63 : 1232-1234, 2004
36) Takahashi C, et al : Association of erythrocyte methotrexate-polyglutamate levels with the efficacy and hepatotoxicity of methotrexate in patients with rheumatoid arthritis : a 76-week prospective study. RMD Open, 3 : e000363, 2017
38) 「リウマトレックス(R) 適正使用情報 Vol.21-重篤な副作用および死亡症例の発現状況-, -特定使用成績調査の最終報告-」, ファイザー株式会社, 2015年6月
39) 抗リウマチ剤 メトジェクト(R) 皮下注7.5/10/12.5/15mg シリンジ添付文書. 日本メダック株式会社, エーザイ株式会社, 2022
40) Braun J, et al : Comparison of the clinical efficacy and safety of subcutaneous versus oral administration of methotrexate in patients with active rheumatoid arthritis : results of a six-month, multicenter, randomized, double-blind, controlled, phase IV trial. Arthritis Rheum, 58 : 73-81, 2008
41) Stamp LK, et al : Effects of changing from oral to subcutaneous methotrexate on red blood cell methotrexate polyglutamate concentrations and disease activity in patients with rheumatoid arthritis. J Rheumatol, 38 : 2540-2547, 2011
42) Schiff MH, et al : Head-to-head, randomised, crossover study of oral versus subcutaneous methotrexate in patients with rheumatoid arthritis : drug-exposure limitations of oral methotrexate at doses > 15mg may be overcome with subcutaneous administration. Ann Rheum Dis, 73 : 1549-1551, 2014
43) Li D, et al : Subcutaneous administration of methotrexate at high doses makes a better performance in the treatment of rheumatoid arthritis compared with oral administration of methotrexate : A systematic review and meta-analysis. Semin Arthritis Rheum, 45 : 656-662, 2016
44) Li CKH, et al : Safety and Tolerability of Subcutaneous Methotrexate in Routine Clinical Practice. Arthritis Care Res (Hoboken), 73 : 1306-1311, 2021
45) Tanaka Y, et al : Efficacy and tolerability of subcutaneously administered methotrexate including dose escalation in long-term treatment of rheumatoid arthritis in a Japanese population. Mod Rheumatol : doi : 10.1093/mr/roac103, 2022
46) Hoekstra M, et al : Bioavailability of higher dose methotrexate comparing oral and subcutaneous administration in patients with rheumatoid arthritis. J Rheumatol, 31 : 645-648, 2004
47) Korber H,et al : Bioavailability and pharmacokinetics of methotrexate (MTX) and its metabolite 7-hydroxy MTX after low dose MTX (25mg) in patients with chronic rheumatic diseases. Arthritis Rheum, 35 Suppl : S142, 1992
48) Freeman-Narrod M, et al : Comparison of serum concentrations of methotrexate after various routes of administration. Cancer, 36 : 1619-1624, 1975
49) Teresi ME, et al : Methotrexate bioavailability after oral and intramuscular administration in children. J Pediatr, 110 : 788-792, 1987
50) Bianchi G, et al : Methotrexate and Rheumatoid Arthritis : Current Evidence Regarding Subcutaneous Versus Oral Routes of Administration. Adv Ther, 33 : 369-378, 2016
51) Hoekstra M, et al : Splitting high-dose oral methotrexate improves bioavailability : a pharmacokinetic study in patients with rheumatoid arthritis. J Rheumatol, 33 : 481-485, 2006
52) Katchamart W, et al : Canadian recommendations for use of methotrexate in patients with rheumatoid arthritis. J Rheumatol, 37 : 1422-1430, 2010
53) Rath T & Rubbert A : Drug combinations with methotrexate to treat rheumatoid arthritis. Clin Exp Rheumatol, 28 : S52-S57, 2010
54) Dale J, et al : Combination therapy for rheumatoid arthritis : methotrexate and sulfasalazine together or with other DMARDs. Nat Clin Pract Rheumatol, 3 : 450-8 ; quiz, following 478, 2007
55) Fraenkel L, et al : 2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Care Res (Hoboken), 73 : 924-939, 2021
56) Smolen JS, et al : EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs : 2019 update. Ann Rheum Dis, 79 : 685-699, 2020
57) Tugwell P, et al : Combination therapy with cyclosporine and methotrexate in severe rheumatoid arthritis. The Methotrexate-Cyclosporine Combination Study Group. N Engl J Med, 333 : 137-141, 1995
58) Marchesoni A, et al : Radiographic progression in early rheumatoid arthritis : a 12-month randomized controlled study comparing the combination of cyclosporin and methotrexate with methotrexate alone. Rheumatology (Oxford), 42 : 1545-1549, 2003
59) Capell HA, et al : Combination therapy with sulfasalazine and methotrexate is more effective than either drug alone in patients with rheumatoid arthritis with a suboptimal response to sulfasalazine : results from the double-blind placebo-controlled MASCOT study. Ann Rheum Dis, 66 : 235-241, 2007
60) Dougados M, et al : Combination therapy in early rheumatoid arthritis : a randomised, controlled, double blind 52 week clinical trial of sulphasalazine and methotrexate compared with the single components. Ann Rheum Dis, 58 : 220-225, 1999
61) Haagsma CJ, et al : Combination of methotrexate and sulphasalazine vs methotrexate alone : a randomized open clinical trial in rheumatoid arthritis patients resistant to sulphasalazine therapy. Br J Rheumatol, 33 : 1049-1055, 1994
62) Haagsma CJ, et al : Combination of sulphasalazine and methotrexate versus the single components in early rheumatoid arthritis : a randomized, controlled, double-blind, 52 week clinical trial. Br J Rheumatol, 36 : 1082-1088, 1997
63) Kremer JM, et al : Concomitant leflunomide therapy in patients with active rheumatoid arthritis despite stable doses of methotrexate. A randomized, double-blind, placebo-controlled trial. Ann Intern Med, 137 : 726-733, 2002
64) Lehman AJ, et al : A 48-week, randomized, double-blind, double-observer, placebo-controlled multicenter trial of combination methotrexate and intramuscular gold therapy in rheumatoid arthritis : results of the METGO study. Arthritis Rheum, 52 : 1360-1370, 2005
65) Kremer JM, et al : Tacrolimus in rheumatoid arthritis patients receiving concomitant methotrexate : a six-month, open-label study. Arthritis Rheum, 48 : 2763-2768, 2003
66) Kitahama M, et al : Efficacy of adjunct tacrolimus treatment in patients with rheumatoid arthritis with inadequate responses to methotrexate. Mod Rheumatol, 23 : 788-793, 2013
68) Hara M, et al : Safety and efficacy of combination therapy of iguratimod with methotrexate for patients with active rheumatoid arthritis with an inadequate response to methotrexate : an open-label extension of a randomized, double-blind, placebo-controlled trial. Mod Rheumatol, 24 : 410-418, 2014
69) Ichikawa Y, et al : Therapeutic effects of the combination of methotrexate and bucillamine in early rheumatoid arthritis : a multicenter, double-blind, randomized controlled study. Mod Rheumatol, 15 : 323-328, 2005
70) Odderskov C, et al : Methotrexate pharmacokinetic is influenced by co-administration of cyclosporin in rheumatoid arthritis patients. Results from a randomized clinical trial. Scand J Clin Lab Invest, 80 : 185-190, 2020
71) Choy EH, et al : Factorial randomised controlled trial of glucocorticoids and combination disease modifying drugs in early rheumatoid arthritis. Ann Rheum Dis, 67 : 656-663, 2008
72) Lee WS, et al : Efficacy and safety of low-dose tacrolimus for active rheumatoid arthritis with an inadequate response to methotrexate. Korean J Intern Med, 31 : 779-787, 2016
73) Shin K, et al : Efficacy and safety of add-on tacrolimus versus leflunomide in rheumatoid arthritis patients with inadequate response to methotrexate. Int J Rheum Dis, 22 : 1115-1122, 2019
74) Takeuchi T, et al : Post-marketing surveillance of the safety and effectiveness of tacrolimus in 3,267 Japanese patients with rheumatoid arthritis. Mod Rheumatol, 24 : 8-16, 2014
76) Breedveld FC, et al : The PREMIER study : A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum, 54 : 26-37, 2006
77) Klareskog L, et al : Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis : double-blind randomised controlled trial. Lancet, 363 : 675-681, 2004
78) van Riel PL, et al : Efficacy and safety of combination etanercept and methotrexate versus etanercept alone in patients with rheumatoid arthritis with an inadequate response to methotrexate : the ADORE study. Ann Rheum Dis, 65 : 1478-1483, 2006
79) Kameda H, et al : Continuation of methotrexate resulted in better clinical and radiographic outcomes than discontinuation upon starting etanercept in patients with rheumatoid arthritis : 52-week results from the JESMR study. J Rheumatol, 38 : 1585-1592, 2011
81) Keystone EC, et al : Golimumab, a human antibody to tumour necrosis factor {alpha} given by monthly subcutaneous injections, in active rheumatoid arthritis despite methotrexate therapy : the GO-FORWARD Study. Ann Rheum Dis, 68 : 789-796, 2009
82) Maini RN, et al : Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate. Arthritis Rheum, 54 : 2817-2829, 2006
83) Dougados M, et al : Clinical, radiographic and immunogenic effects after 1 year of tocilizumab-based treatment strategies in rheumatoid arthritis : the ACT-RAY study. Ann Rheum Dis, 73 : 803-809, 2014
85) Genovese MC, et al : Sarilumab Plus Methotrexate in Patients With Active Rheumatoid Arthritis and Inadequate Response to Methotrexate : Results of a Phase III Study. Arthritis Rheumatol, 67 : 1424-1437, 2015
86) Burmester GR, et al : Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH) : a randomised, double-blind, parallel-group phase III trial. Ann Rheum Dis, 76 : 840-847, 2017
87) Matsubara T, et al : Abatacept in combination with methotrexate in Japanese biologic-naive patients with active rheumatoid arthritis : a randomised placebo-controlled phase IV study. RMD Open, 4 : e000813, 2018
88) Jansen JP, et al : Comparative efficacy of biologics as monotherapy and in combination with methotrexate on patient reported outcomes (PROs) in rheumatoid arthritis patients with an inadequate response to conventional DMARDs--a systematic review and network meta-analysis. Health Qual Life Outcomes, 12 : 102, 2014 systematic review and network meta-analysis. Health Qual Life Outcomes, 12 : 102, 2014
89) Buckley F, et al : Comparative Efficacy of Novel DMARDs as Monotherapy and in Combination with Methotrexate in Rheumatoid Arthritis Patients with Inadequate Response to Conventional DMARDs : A Network Meta-Analysis. J Manag Care Spec Pharm, 21 : 409-423, 2015
90) Burmester GR, et al : Sarilumab monotherapy vs sarilumab and methotrexate combination therapy in patients with rheumatoid arthritis. Rheumatology (Oxford), 61 : 2596-2602, 2022
91) Lundquist LM, et al : Efficacy and safety of tofacitinib for treatment of rheumatoid arthritis. World J Orthop, 5 : 504-511, 2014
92) Taylor PC : Clinical efficacy of launched JAK inhibitors in rheumatoid arthritis. Rheumatology (Oxford), 58 : i17-i26, 2019
93) Tanaka Y, et al : Filgotinib, a novel JAK1-preferential inhibitor for the treatment of rheumatoid arthritis : An overview from clinical trials. Mod Rheumatol, 32 : 1-11, 2022
94) Fleischmann R, et al : Upadacitinib Versus Placebo or Adalimumab in Patients With Rheumatoid Arthritis and an Inadequate Response to Methotrexate : Results of a Phase III, Double-Blind, Randomized Controlled Trial. Arthritis Rheumatol, 71 : 1788-1800, 2019
96) Smolen J, et al : Efficacy and safety of certolizumab pegol plus methotrexate in active rheumatoid arthritis : the RAPID 2 study. A randomised controlled trial. Ann Rheum Dis, 68 : 797-804, 2009
97) Tanaka Y, et al : Efficacy and safety of the anti-TNF multivalent NANOBODY(R) compound ozoralizumab in patients with rheumatoid arthritis and an inadequate response to methotrexate : A 52-week result of a phase II/III study (OHZORA trial). Mod Rheumatol : doi : 10.1093/mr/roac119, 2022
98) Tanaka Y, et al : Sarilumab plus methotrexate in patients with active rheumatoid arthritis and inadequate response to methotrexate : results of a randomized, placebo-controlled phase III trial in Japan. Arthritis Res Ther, 21 : 79, 2019
99) Schiff M, et al : Efficacy and safety of abatacept or infliximab vs placebo in ATTEST : a phase III, multi-centre, randomised, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexate. Ann Rheum Dis, 67 : 1096-1103, 2008
100) Wells AF, et al : Abatacept plus methotrexate provides incremental clinical benefits versus methotrexate alone in methotrexate-naive patients with early rheumatoid arthritis who achieve radiographic nonprogression. J Rheumatol, 38 : 2362-2368, 2011
101) Tanaka Y, et al : Phase II study of tofacitinib (CP-690,550) combined with methotrexate in patients with rheumatoid arthritis and an inadequate response to methotrexate. Arthritis Care Res (Hoboken), 63 : 1150-1158, 2011
103) Taylor PC, et al : Baricitinib versus Placebo or Adalimumab in Rheumatoid Arthritis. N Engl J Med, 376 : 652-662, 2017
104) Kameda H, et al : Efficacy and safety of upadacitinib in Japanese patients with rheumatoid arthritis (SELECT-SUNRISE) : a placebo-controlled phase IIb/III study. Rheumatology (Oxford), 59 : 3303-3313, 2020
105) Combe B, et al : Filgotinib versus placebo or adalimumab in patients with rheumatoid arthritis and inadequate response to methotrexate : a phase III randomised clinical trial. Ann Rheum Dis, 80 : 848-858, 2021
106) Koike T, et al : Postmarketing surveillance of safety and effectiveness of etanercept in Japanese patients with rheumatoid arthritis. Mod Rheumatol, 21 : 343-351, 2011
107) Koike T, et al : Safety and effectiveness of adalimumab in Japanese rheumatoid arthritis patients : postmarketing surveillance report of 7740 patients. Mod Rheumatol, 24 : 390-398, 2014
108) Taylor PC, et al : Baricitinib Versus Placebo or Adalimumab in Patients with Active Rheumatoid Arthritis (RA) and an Inadequate Response to Background Methotrexate Therapy : Results of a Phase 3 Study. Arthritis Rheumatol, 67 (Suppl 10) : abstract 2L, 2015
109) van Vollenhoven RF, et al : Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med, 367 : 508-519, 2012
110) Burmester GR, et al : Efficacy and safety of ascending methotrexate dose in combination with adalimumab : the randomised CONCERTO trial. Ann Rheum Dis, 74 : 1037-1044, 2015
111) Ornetti P, et al : Increase in methotrexate dose in patients with rheumatoid arthritis who have an inadequate response to infliximab. Ann Rheum Dis, 64 : 1379-1380, 2005
112) 「リウマトレックス(R) 特定使用成績調査- 関節リウマチに対して8mg/週を超える投与に関する調査-総括報告書」, ファイザー株式会社, 2016年2月
