Recommendations for optimizing methotrexate treatment for patients with rheumatoid arthritis

Alfonso E Bello, Elizabeth L Perkins, Randy Jay, Petros Efthimiou, Alfonso E Bello, Elizabeth L Perkins, Randy Jay, Petros Efthimiou

Abstract

Methotrexate (MTX) remains the cornerstone therapy for patients with rheumatoid arthritis (RA), with well-established safety and efficacy profiles and support in international guidelines. Clinical and radiologic results indicate benefits of MTX monotherapy and combination with other agents, yet patients may not receive optimal dosing, duration, or route of administration to maximize their response to this drug. This review highlights best practices for MTX use in RA patients. First, to improve the response to oral MTX, a high initial dose should be administered followed by rapid titration. Importantly, this approach does not appear to compromise safety or tolerability for patients. Treatment with oral MTX, with appropriate dose titration, then should be continued for at least 6 months (as long as the patient experiences some response to treatment within 3 months) to achieve an accurate assessment of treatment efficacy. If oral MTX treatment fails due to intolerability or inadequate response, the patient may be "rescued" by switching to subcutaneous delivery of MTX. Consideration should also be given to starting with subcutaneous MTX given its favorable bioavailability and pharmacodynamic profile over oral delivery. Either initiation of subcutaneous MTX therapy or switching from oral to subcutaneous administration improves persistence with treatment. Upon transition from oral to subcutaneous delivery, MTX dosage should be maintained, rather than increased, and titration should be performed as needed. Similarly, if another RA treatment is necessary to control the disease, the MTX dosage and route of administration should be maintained, with titration as needed.

Keywords: bioavailability; dosing; gastrointestinal; polyglutamation; subcutaneous.

Conflict of interest statement

Disclosure Alfonso Bello served as a speaker for Abbvie, speaker and advisory board for Pfizer and Medac Pharma, and consultant and speaker for Horizon Pharma and Mallinckrodt. Elizabeth Perkins served as a consultant for Medac Pharma, Pfizer Inc, Lilly, USA, LLC, Amgen Inc, and Antares Pharma Inc. Randy Jay served as a consultant for Medac Pharma. Petros Efthimiou served as a speaker and consultant for Medac Pharma. The authors report no other conflicts of interest in this work.

Figures

Figure 1
Figure 1
Results from the TEMPO trial at 3 years of follow-up: probability plots of changes in total Sharp scores. Note: Republished with permission of John Wiley and Sons Inc from van der Heijde D, Klareskog L, Landewé R, et al. Disease remission and sustained halting of radiographic progression with combination etanercept and methotrexate in patients with rheumatoid arthritis. Arthritis Rheum. 2007;56(12):3928–3939. © 2007, American College of Rheumatology permission conveyed through Copyright Clearance Center, Inc.
Figure 2
Figure 2
Percentages of patients who achieved a response according to ACR20/50/70 criteria after 2 years of treatment in the TEAR trial. Notes: Patients received immediate combination therapy, initial MTX therapy with transition to combination therapy, or MTX monotherapy. There were no statistically significant differences among groups. Republished with permission of John Wiley and Sons Inc., from O’Dell JR, Curtis JR, Mikuls TR, et al. Validation of the methotrexate-first strategy in patients with early, poor-prognosis rheumatoid arthritis: results from a two-year randomized, double-blind trial. Arthritis Rheum. 2013;65(8):1985–1994.© 2013, American College of Rheumatology, permission conveyed through Copyright Clearance Center, Inc. Abbreviation: ACR, American College of Rheumatology; MTX, methotrexate.
Figure 3
Figure 3
Results of a retrospective analysis of 103 patients with RA. Notes: Significant improvement in disease control was observed following transition from oral to subcutaneous MTX (40 patients were switched because of inadequate efficacy; 63 were switched because of gastrointestinal side effects). Republished with permission of John Wiley and Sons Inc., from Hameed B, Jones H. Subcutaneous methotrexate is well tolerated and superior to oral methotrexate in the treatment of rheumatoid arthritis. Int J Rheum Dis. 2010;13(4):e83–e84.© 2010 Asia Pacific League of Associations for Rheumatology and Blackwell Publishing Asia Pty Ltd, permission conveyed through Copyright Clearance Center, Inc. Abbreviations: RA, rheumatoid arthritis; MTX, methotrexate; DAS28, Disease Activity Score for 28 Joints.
Figure 4
Figure 4
Results from a single-center, open-label, randomized, 2-period, 2-sequence, single-dose, crossover study in 4 dose groups (7.5, 15, 22.5, and 30 mg) with 54 healthy adults treated with oral and subcutaneous MTX. Note: © 2014 Clinical and Experimental Rheumatology. Reproduced from Pichlmeier U, Heuer KU. Subcutaneous administration of methotrexate with a prefilled autoinjector pen results in a higher relative bioavailability compared with oral administration of methotrexate. Clin Exp Rheumatol. 2014;32(4):563–571. Abbreviations: MTX, methotrexate; SC, subcutaneous; AUC, area under the curve.
Figure 5
Figure 5
Percentage of patients achieving (A) DAS28 remission and (B) DAS28 low disease activity at baseline and at 6, 12, and 24 months. Note: DAS28 remission was defined as DAS28 <2.6; low disease activity was defined as DAS28 >2.6 and <3.2. Reproduced from Gallo G, Brock F, Kerkmann U, Kola B, Huizinga TW. Efficacy of etanercept in combination with methotrexate in moderate-to-severe rheumatoid arthritis is not dependent on methotrexate dosage. RMD Open. 2016;2(1):e000186. Copyright © 2016 with permission from BMJ Publishing Group Ltd. Abbreviations: DAS28, Disease Activity Score for 28 Joints; ETN, etanercept; MTX, methotrexate.

References

    1. Chan ES, Cronstein BN. Molecular action of methotrexate in inflammatory diseases. Arthritis Res. 2002;4(4):266–273.
    1. Singh JA, Saag KG, Bridges SL, Jr, et al. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol. 2016;68(1):1–26.
    1. Smolen JS, Landewé R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis. 2014;73(3):492–509.
    1. Todoerti M, Maglione W, Bernero E, et al. Systematic review of 2008–2012 literature and update of recommendations for the use of methotrexate in rheumatic diseases, with a focus on rheumatoid arthritis. Reumatismo. 2013;65(5):207–218.
    1. Rau R, Herborn G. Benefit and risk of methotrexate treatment in rheumatoid arthritis. Clin Exp Rheumatol. 2004;22(5 suppl 35):S83–S94.
    1. Verstappen SM, Lunt M, Bunn DK, Scott DG, Symmons DP. In patients with early inflammatory polyarthritis, ACPA positivity, younger age and inefficacy of the first non-biological DMARD are predictors for receiving biological therapy: results from the Norfolk Arthritis Register. Ann Rheum Dis. 2011;70(8):1428–1432.
    1. Davis JM, 3rd, Knutson KL, Skinner JA, et al. A profile of immune response to herpesvirus is associated with radiographic joint damage in rheumatoid arthritis. Arthritis Res Ther. 2012;14(1):R24.
    1. Drouin J, Haraoui B, 3e Initiative Group Predictors of clinical response and radiographic progression in patients with rheumatoid arthritis treated with methotrexate monotherapy. J Rheumatol. 2010;37(7):1405–1410.
    1. Shiozawa K, Yamane T, Murata M, et al. MMP-3 as a predictor for structural remission in RA patients treated with MTX monotherapy. Arthritis Res Ther. 2016;18:55.
    1. Sokka T. Increases in use of methotrexate since the 1980s. Clin Exp Rheumatol. 2010;28(5 suppl 61):S13–S20.
    1. Pincus T, Gibson KA, Castrejón I. Update on methotrexate as the anchor drug for rheumatoid arthritis. Bull Hosp Jt Dis. 2013;71(Suppl 1):S9–S19.
    1. Rohr MK, Mikuls TR, Cohen SB, Thorne CJ, O’Dell JR. The underuse of methotrexate in the treatment of RA: a national analysis of prescribing practices in the U.S. Arthritis Care Res (Hoboken) 2016 Nov 18; Epub.
    1. Yazici Y, Shi N, John A. Utilization of biologic agents in rheumatoid arthritis in the United States: analysis of prescribing patterns in 16,752 newly diagnosed patients and patients new to biologic therapy. Bull NYU Hosp Jt Dis. 2008;66(2):77–85.
    1. Curtis JR, Zhang J, Xie F, et al. Use of oral and subcutaneous methotrexate in rheumatoid arthritis patients in the United States. Arthritis Care Res (Hoboken) 2014;66(11):1604–1611.
    1. Detert J, Klaus P. Biologic monotherapy in the treatment of rheumatoid arthritis. Biologics. 2015;9:35–43.
    1. O’Dell JR, Cohen SB, Thorne JC, Mikuls TR. Changing use of methotrexate (MTX) and biologics in the treatment of rheumatoid arthritis (RA) in the United States (US): results of a comprehensive pharmaceutical claims analysis; Presented at: EULAR/Annual European Congress of Rheumatology; June 8–11; 2016; London.
    1. Desai RJ, Solomon DH, Liu J, Kim SC. Secular trends in use of disease modifying anti-rheumatic drugs for the treatment of rheumatoid arthritis in the United States [abstract] [Accessed October 24, 2016];Arthritis Rheumatol. 2015 67(suppl 10) webpage on the Internet. Available from: .
    1. Engel-Nitz NM, Ogale S, Kulakodlu M. Use of anti-tumor necrosis factor therapy: a retrospective study of monotherapy and adherence to combination therapy with non-biologic disease-modifying anti-rheumatic drugs. Rheumatol Ther. 2015;2(2):127–139.
    1. Desai RJ, Rao JK, Hansen RA, Fang G, Maciejewski ML, Farley JF. Predictors of treatment initiation with tumor necrosis factor-a inhibitors in patients with rheumatoid arthritis. J Manag Care Spec Pharm. 2014;20(11):1110–1120.
    1. Zhang J, Xie F, Delzell E, et al. Trends in the use of biologic agents among rheumatoid arthritis patients enrolled in the US medicare program. Arthritis Care Res (Hoboken) 2013;65(11):1743–1751.
    1. Manara M, Bianchi G, Bruschi E, et al. Adherence to current recommendations on the use of methotrexate in rheumatoid arthritis in Italy: results from the MARI study. Clin Exp Rheumatol. 2016;34(3):473–479.
    1. Idolazzi L, Adami S, Capozza R, et al. Suboptimal methotrexate use in rheumatoid arthritis patients in Italy: the MARI study. Clin Exp Rheumatol. 2015;33(6):895–899.
    1. Tian H, Cronstein BN. Understanding the mechanisms of action of methotrexate: implications for the treatment of rheumatoid arthritis. Bull NYU Hosp Jt Dis. 2007;65(3):168–173.
    1. Milne GR, Palmer TM. Anti-inflammatory and immunosuppressive effects of the A2A adenosine receptor. ScientificWorldJournal. 2011;11:320–339.
    1. Emery P, Sebba A, Huizinga TW. Biologic and oral disease-modifying antirheumatic drug monotherapy in rheumatoid arthritis. Ann Rheum Dis. 2013;72(12):1897–1904.
    1. Taylor P, van Vollenhoven R, Aletaha D. Optimising patient outcomes throughout the rheumatoid arthritis patient journey: the exception, the standard, and the rule. EMJ Rheumatol. 2016;3:36–47.
    1. Lopez-Olivo MA, Siddhanamatha HR, Shea B, Tugwell P, Wells GA, Suarez-Almazor ME. Methotrexate for treating rheumatoid arthritis. Cochrane Database Syst Rev. 2014;6:CD000957.
    1. Hazlewood GS, Barnabe C, Tomlinson G, Marshall D, Devoe D, Bombardier C. Methotrexate monotherapy and methotrexate combination therapy with traditional and biologic disease modifying antirheumatic drugs for rheumatoid arthritis: abridged Cochrane Systematic Review and network meta-analysis. BMJ. 2016;353:i1777.
    1. Klareskog L, van der Heijde D, de Jager JP, 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. 2004;363(9410):675–681.
    1. van der Heijde D, Klareskog L, Rodriguez-Valverde V, et al. Comparison of etanercept and methotrexate, alone and combined, in the treatment of rheumatoid arthritis: two-year clinical and radiographic results from the TEMPO study, a double-blind, randomized trial. Arthritis Rheum. 2006;54(4):1063–1074.
    1. van der Heijde D, Klareskog L, Landewé R, et al. Disease remission and sustained halting of radiographic progression with combination etanercept and methotrexate in patients with rheumatoid arthritis. Arthritis Rheum. 2007;56(12):3928–3939.
    1. Moreland LW, O’Dell JR, Paulus HE, et al. A randomized comparative effectiveness study of oral triple therapy versus etanercept plus methotrexate in early aggressive rheumatoid arthritis: the treatment of Early Aggressive Rheumatoid Arthritis Trial. Arthritis Rheum. 2012;64(9):2824–2835.
    1. O’Dell JR, Curtis JR, Mikuls TR, et al. Validation of the methotrexate-first strategy in patients with early, poor-prognosis rheumatoid arthritis: results from a two-year randomized, double-blind trial. Arthritis Rheum. 2013;65(8):1985–1994.
    1. van Vollenhoven RF, Ernestam S, Geborek P, et al. Addition of infliximab compared with addition of sulfasalazine and hydroxychloroquine to methotrexate in patients with early rheumatoid arthritis (Swefot trial): 1-year results of a randomised trial. Lancet. 2009;374(9688):459–466.
    1. van Vollenhoven RF, Geborek P, Forslind K, et al. Conventional combination treatment versus biological treatment in methotrexate-refractory early rheumatoid arthritis: 2 year follow-up of the randomised, non-blinded, parallel-group Swefot trial. Lancet. 2012;379(9827):1712–1720.
    1. Pincus T, Furer V, Sokka T. Underestimation of the efficacy, effectiveness, tolerability, and safety of weekly low-dose methotrexate in information presented to physicians and patients. Clin Exp Rheumatol. 2010;28(5 suppl 61):S68–S79.
    1. Durán J, Bockorny M, Dalal D, LaValley M, Felson DT. Methotrexate dosage as a source of bias in biological trials in rheumatoid arthritis: a systematic review. Ann Rheum Dis. 2016;75(9):1595–1598.
    1. Yamanaka H, Ishiguro N, Takeuchi T, et al. Recovery of clinical but not radiographic outcomes by the delayed addition of adalimumab to methotrexate-treated Japanese patients with early rheumatoid arthritis: 52-week results of the HOPEFUL-1 trial. Rheumatology (Oxford) 2014;53(5):904–913.
    1. Wasko MC, Dasgupta A, Hubert H, Fries JF, Ward MM. Propensity-adjusted association of methotrexate with overall survival in rheumatoid arthritis. Arthritis Rheum. 2013;65(2):334–342.
    1. Tornero Molina J, Ballina García FJ, Calvo Alén J, et al. Recommendations for the use of methotrexate in rheumatoid arthritis: up and down scaling of the dose and administration routes. Reumatol Clin. 2015;11(1):3–8.
    1. 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. 2009;68(7):1094–1099.
    1. Nair SC, Jacobs JW, Bakker MF, et al. Determining the lowest optimally effective methotrexate dose for individual RA patients using their dose response relation in a tight control treatment approach. PLoS One. 2016;11(3):e0148791.
    1. Herman RA, Veng-Pedersen P, Hoffman J, Koehnke R, Furst DE. Pharmacokinetics of low-dose methotrexate in rheumatoid arthritis patients. J Pharm Sci. 1989;78(2):165–171.
    1. Yee SW, Gong L, Badagnani I, Giacomini KM, Klein TE, Altman RB. SLC19A1 pharmacogenomics summary. Pharmacogenet Genomics. 2010;20(11):708–715.
    1. Laverdière C, Chiasson S, Costea I, Moghrabi A, Krajinovic M. Polymorphism G80A in the reduced folate carrier gene and its relationship to methotrexate plasma levels and outcome of childhood acute lymphoblastic leukemia. Blood. 2002;100(10):3832–3834.
    1. Shea B, Swinden MV, Tanjong Ghogomu E, et al. Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. Cochrane Database Syst Rev. 2013;5:CD000951.
    1. Whittle SL, Hughes RA. Folate supplementation and methotrexate treatment in rheumatoid arthritis: a review. Rheumatology (Oxford) 2004;43(3):267–271.
    1. Griffith SM, Fisher J, Clarke S, et al. Do patients with rheumatoid arthritis established on methotrexate and folic acid 5 mg daily need to continue folic acid supplements long term? Rheumatology (Oxford) 2000;39(10):1102–1109.
    1. Medley S, Dolan AL, Coakley G. How safe is starting high dose methotrexate?; Presented at EULAR/Annual European Congress of Rheumatology; June 10–13, 2009; Copenhagen Denmark. Abstract SAT0150.
    1. Lampropoulos CE, Orfanos P, Bournia VK, et al. Adverse events and infections in patients with rheumatoid arthritis treated with conventional drugs or biologic agents: a real world study. Clin Exp Rheumatol. 2015;33(2):216–224.
    1. Hobl EL, Mader RM, Jilma B, et al. A randomized, double-blind, parallel, single-site pilot trial to compare two different starting doses of methotrexate in methotrexate-naïve adult patients with rheumatoid arthritis. Clin Ther. 2012;34(5):1195–1203.
    1. Ruperto N, Murray KJ, Gerloni V, et al. A randomized trial of parenteral methotrexate comparing an intermediate dose with a higher dose in children with juvenile idiopathic arthritis who failed to respond to standard doses of methotrexate. Arthritis Rheum. 2004;50(7):2191–2201.
    1. Ringold S, Weiss PF, Colbert RA, et al. Childhood Arthritis and Rheumatology Research Alliance consensus treatment plans for new-onset polyarticular juvenile idiopathic arthritis. Arthritis Care Res (Hoboken) 2014;66(7):1063–1072.
    1. Soubrier M, Puéchal X, Sibilia J, et al. Evaluation of two strategies (initial methotrexate monotherapy vs its combination with adalimumab) in management of early active rheumatoid arthritis: data from the GUEPARD trial. Rheumatology (Oxford) 2009;48(11):1429–1434.
    1. Bykerk VP, Akhavan P, Hazlewood GS, et al. Canadian Rheumatology Association recommendations for pharmacological management of rheumatoid arthritis with traditional and biologic disease-modifying antirheumatic drugs. J Rheumatol. 2012;39(8):1559–1582.
    1. Hameed B, Jones H. Subcutaneous methotrexate is well tolerated and superior to oral methotrexate in the treatment of rheumatoid arthritis. Int J Rheum Dis. 2010;13(4):e83–e84.
    1. Bianchi G, Caporali R, Todoerti M, Mattana P. Methotrexate and rheumatoid arthritis: current evidence regarding subcutaneous versus oral routes of administration. Adv Ther. 2016;33(3):369–378.
    1. Branco JC, Barcelos A, de Araújo FP, et al. Utilization of subcutaneous methotrexate in rheumatoid arthritis patients after failure or intolerance to oral methotrexate: a Multicenter Cohort Study. Adv Ther. 2016;33(1):46–57.
    1. Pichlmeier U, Heuer KU. Subcutaneous administration of methotrexate with a prefilled autoinjector pen results in a higher relative bioavailability compared with oral administration of methotrexate. Clin Exp Rheumatol. 2014;32(4):563–571.
    1. Dervieux T, Zablocki R, Kremer J. Red blood cell methotrexate polyglutamates emerge as a function of dosage intensity and route of administration during pulse methotrexate therapy in rheumatoid arthritis. Rheumatology (Oxford) 2010;49(12):2337–2345.
    1. Hornung N, Ellingsen T, Attermann J, Stengaard-Pedersen K, Poulsen JH. Patients with rheumatoid arthritis treated with methotrexate (MTX): concentrations of steady-state erythrocyte MTX correlate to plasma concentrations and clinical efficacy. J Rheumatol. 2008;35(9):1709–1715.
    1. Dervieux T, Furst D, Lein DO, et al. Polyglutamation of methotrexate with common polymorphisms in reduced folate carrier, aminoimidazole carboxamide ribonucleotide transformylase, and thymidylate synthase are associated with methotrexate effects in rheumatoid arthritis. Arthritis Rheum. 2004;50(9):2766–2774.
    1. Yadlapati S, Efthimiou P. Inadequate response or intolerability to oral methotrexate: is it optimal to switch to subcutaneous methotrexate prior to considering therapy with biologics? Rheumatol Int. 2016;36(5):627–633.
    1. O’Dell JR, Mikuls TR, Taylor TH, et al. Therapies for active rheumatoid arthritis after methotrexate failure. N Engl J Med. 2013;369(4):307–318.
    1. Katchamart W, Trudeau J, Phumethum V, Bombardier C. Methotrexate monotherapy versus methotrexate combination therapy with non-biologic disease modifying anti-rheumatic drugs for rheumatoid arthritis. Cochrane Database Syst Rev. 2010;4:CD008495.
    1. Karlsson JA, Neovius M, Nilsson JÅ, et al. Addition of infliximab compared with addition of sulfasalazine and hydroxychloroquine to methotrexate in early rheumatoid arthritis: 2-year quality-of-life results of the randomised, controlled, SWEFOT trial. Ann Rheum Dis. 2013;72(12):1927–1933.
    1. Buckley F, Finckh A, Huizinga TW, Dejonckheere F, Jansen JP. 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. 2015;21:409–423.
    1. Orme ME, Macgilchrist KS, Mitchell S, Spurden D, Bird A. Systematic review and network meta-analysis of combination and monotherapy treatments in disease-modifying antirheumatic drug-experienced patients with rheumatoid arthritis: analysis of American College of Rheumatology criteria scores 20, 50, and 70. Biologics. 2012;6:429–464.
    1. Fleischmann R, Koenig AS, Szumski A, Nab HW, Marshall L, Bananis E. Short-term efficacy of etanercept plus methotrexate vs combinations of disease-modifying anti-rheumatic drugs with methotrexate in established rheumatoid arthritis. Rheumatology (Oxford) 2014;53(11):1984–1993.
    1. Singh JA, Hossain A, Tanjong Ghogomu E, Mudano AS, Tugwell P, Wells GA. Biologic or tofacitinib monotherapy for rheumatoid arthritis in people with traditional disease-modifying anti-rheumatic drug (DMARD) failure: a Cochrane Systematic Review and network meta-analysis (NMA) Cochrane Database Syst Rev. 2016;11:CD012437.
    1. Berhan A. Efficacy, safety and tolerability of tofacitinib in patients with an inadequate response to disease modifying anti-rheumatic drugs: a meta-analysis of randomized double-blind controlled studies. BMC Musculoskelet Disord. 2013;14:332.
    1. Kremer JM, Bloom BJ, Breedveld FC, et al. The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo. Arthritis Rheum. 2009;60(7):1895–1905.
    1. Zerbini C, Radominski S, Cardiel MH, et al. Efficacy and safety of tofacitinib monotherapy versus combination therapy in a Latin American subpopulation of patients with rheumatoid arthritis: a pooled phase 3 analysis [abstract] [Accessed October 24, 2016];Arthritis Rheumatol. 2015 67(suppl 10) webpage on the Internet. Available from: .
    1. Nikiphorou E, Negoescu A, Fitzpatrick JD, et al. Indispensable or intolerable? Methotrexate in patients with rheumatoid and psoriatic arthritis: a retrospective review of discontinuation rates from a large UK cohort. Clin Rheumatol. 2014;33(5):609–614.
    1. Li D, Yang Z, Kang P, Xie X. 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. 2016;45(6):656–662.
    1. Kromann CB, Lage-Hansen PR, Koefoed M, Jemec GB. Does switching from oral to subcutaneous administration of methotrexate influence on patient reported gastro-intestinal adverse effects? J Dermatolog Treat. 2015;26(2):188–190.
    1. Verstappen SM, Bakker MF, Heurkens AH, et al. Adverse events and factors associated with toxicity in patients with early rheumatoid arthritis treated with methotrexate tight control therapy: the CAMERA study. Ann Rheum Dis. 2010;69(6):1044–1048.
    1. Furst DE, Koehnke R, Burmeister LF, Kohler J, Cargill I. Increasing methotrexate effect with increasing dose in the treatment of resistant rheumatoid arthritis. J Rheumatol. 1989;16(3):313–320.
    1. Tishler M, Caspi D, Yaron M. Methotrexate treatment of rheumatoid arthritis: is a fortnightly maintenance schedule enough? Ann Rheum Dis. 1992;51(12):1330–1331.
    1. Luis M, Pacheco-Tena C, Cazarín-Barrientos J, et al. Comparison of two schedules for administering oral low-dose methotrexate (weekly versus every-other-week) in patients with rheumatoid arthritis in remission: a twenty-four week, single blind, randomized study. Arthritis Rheum. 1999;42(10):2160–2165.
    1. Kremer JM, Davies JM, Rynes RI, et al. Every-other-week methotrexate in patients with rheumatoid arthritis. A double-blind, placebo-controlled prospective study. Arthritis Rheum. 1995;38(5):601–607.
    1. Kremer JM, Rynes RI, Bartholomew LE. Severe flare of rheumatoid arthritis after discontinuation of long-term methotrexate therapy. Double-blind study. Am J Med. 1987;82(4):781–786.
    1. Gøtzsche PC, Hansen M, Stoltenberg M, et al. Randomized, placebo controlled trial of withdrawal of slow-acting antirheumatic drugs and of observer bias in rheumatoid arthritis. Scand J Rheumatol. 1996;25(4):194–199.
    1. ten Wolde S, Breedveld FC, Hermans J, et al. Randomised placebo-controlled study of stopping second-line drugs in rheumatoid arthritis. Lancet. 1996;347(8998):347–352.
    1. Hider SL, Silman A, Bunn D, Manning S, Symmons D, Lunt M. Comparing the long-term clinical outcome of treatment with methotrexate or sulfasalazine prescribed as the first disease-modifying antirheumatic drug in patients with inflammatory polyarthritis. Ann Rheum Dis. 2006;65(11):1449–1455.
    1. Alam MK, Sutradhar SR, Pandit H, et al. Comparative study on methotrexate and hydroxychloroquine in the treatment of rheumatoid arthritis. Mymensingh Med J. 2012;21(3):391–398.
    1. Cohen S, Cannon GW, Schiff M, et al. Two-year, blinded, randomized, controlled trial of treatment of active rheumatoid arthritis with leflunomide compared with methotrexate. Utilization of Leflunomide in the Treatment of Rheumatoid Arthritis Trial Investigator Group. Arthritis Rheum. 2001;44(9):1984–1992.
    1. Tugwell P, Wells G, Strand V, et al. Clinical improvement as reflected in measures of function and health-related quality of life following treatment with leflunomide compared with methotrexate in patients with rheumatoid arthritis: sensitivity and relative efficiency to detect a treatment effect in a twelve-month, placebo-controlled trial. Leflunomide Rheumatoid Arthritis Investigators Group. Arthritis Rheum. 2000;43(3):506–514.
    1. Burmester GR, Kivitz AJ, Kupper H, et al. Efficacy and safety of ascending methotrexate dose in combination with adalimumab: the randomised CONCERTO trial. Ann Rheum Dis. 2015;74(6):1037–1044.
    1. Burmester GR, Kivitz AJ, Van Vollenhoven RF, et al. Methotrexate dose has minimal effects on methotrexate-related toxicity in patients with early rheumatoid arthritis treated in combination with adalimumab – results of Concerto Trial. 2013. Arthritis Rheum. 2013;65(Suppl 10):2688.
    2. Presented at American College of Rheumatology/Association of Rheumatology Health Professionals Annual Meeting; San Diego, CA. October 25–30, 2013.
    1. Bykerk VP, Östör AJ, Alvaro-Gracia J, et al. Comparison of tocilizumab as monotherapy or with add-on disease-modifying antirheumatic drugs in patients with rheumatoid arthritis and inadequate responses to previous treatments: an open-label study close to clinical practice. Clin Rheumatol. 2015;34(3):563–571.
    1. DiBenedetti DB, Zhou X, Reynolds M, Ogale S, Best JH. Assessing methotrexate adherence in rheumatoid arthritis: a cross-sectional survey. Rheumatol Ther. 2015;2(1):73–84.
    1. Grijalva CG, Chung CP, Arbogast PG, Stein CM, Mitchel EF, Jr, Griffin MR. Assessment of adherence to and persistence on disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis. Med Care. 2007;45(10 suppl 2):S66–S76.
    1. Hill J, Bird H, Johnson S. Effect of patient education on adherence to drug treatment for rheumatoid arthritis: a randomised controlled trial. Ann Rheum Dis. 2001;60(9):869–875.
    1. Homer D, Nightingale P, Jobanputra P. Providing patients with information about disease-modifying anti-rheumatic drugs: individually or in groups? A pilot randomized controlled trial comparing adherence and satisfaction. Musculoskeletal Care. 2009;7(2):78–92.
    1. Evers AW, Kraaimaat FW, van Riel PL, de Jong AJ. Tailored cognitive-behavioral therapy in early rheumatoid arthritis for patients at risk: a randomized controlled trial. Pain. 2002;100(1–2):141–153.
    1. Hazlewood GS, Thorne JC, Pope JE, et al. The comparative effectiveness of oral versus subcutaneous methotrexate for the treatment of early rheumatoid arthritis. Ann Rheum Dis. 2016;75(6):1003–1008.
    1. Scott DG, Claydon P, Ellis C. Retrospective evaluation of continuation rates following a switch to subcutaneous methotrexate in rheumatoid arthritis patients failing to respond to or tolerate oral methotrexate: the MENTOR study. Scand J Rheumatol. 2014;43(6):470–476.
    1. Ravelli A, Martini A. Methotrexate in juvenile idiopathic arthritis: answers and questions. J Rheumatol. 2000;27(8):1830–1833.
    1. Ramanan AV, Whitworth P, Baildam EM. Use of methotrexate in juvenile idiopathic arthritis. Arch Dis Child. 2003;88(3):197–200.
    1. Schiff MH, Jaffe JS, Freundlich B. Head-to-head, randomised, crossover study of oral versus subcutaneous methotrexate in patients with rheumatoid arthritis: drug-exposure limitations of oral methotrexate at doses ≥15 mg may be overcome with subcutaneous administration. Ann Rheum Dis. 2014;73(8):1549–1551.
    1. Hoekstra M, Haagsma C, Neef C, Proost J, Knuif A, van de Laar M. Bioavailability of higher dose methotrexate comparing oral and subcutaneous administration in patients with rheumatoid arthritis. J Rheumatol. 2004;31(4):645–648.
    1. Schiff M, Sadowski P. Oral to subcutaneous methotrexate dose-conversion strategies in the treatment of rheumatoid arthritis [abstract] [Accessed October 24, 2016];Arthritis Rheumatol. 2015 67(suppl 10) webpage on the Internet. Available from: .
    1. Louder AM, Singh A, Saverno K, et al. Patient preferences regarding rheumatoid arthritis therapies: a conjoint analysis. Am Health Drug Benefits. 2016;9(2):84–93.
    1. Braun J, Kästner P, Flaxenberg P, 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. 2008;58(1):73–81.
    1. Gottheil S, Thorne JC, Schieir O, et al. Early use of subcutaneous MTX monotherapy vs. MTX oral or combination therapy significantly delays time to initiating biologics in early RA. [Accessed November 18, 2016];Arthritis Rheumatol. 2016 68(suppl 10) Available from:
    1. Gallo G, Brock F, Kerkmann U, Kola B, Huizinga TW. Efficacy of etanercept in combination with methotrexate in moderate-to-severe rheumatoid arthritis is not dependent on methotrexate dosage. RMD Open. 2016;2(1):e000186.
    1. Manders SHM, van de Laar MAFJ, Rongen-van Dartel SAA, et al. Tapering and discontinuation of methotrexate in patients with RA treated with TNF inhibitors: data from the DREAM registry. RMD Open. 2015;1:e000147.
    1. Fleischmann RM, Cohen SB, Moreland LW, et al. Methotrexate dosage reduction in patients with rheumatoid arthritis beginning therapy with infliximab: the Infliximab Rheumatoid Arthritis Methotrexate Tapering (iRAMT) trial. Curr Med Res Opin. 2005;21(8):1181–1190.

Source: PubMed

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