mrjСовременная ревматологияModern Rheumatology Journal1996-70122310-158XIMA-PRESS, LLC10.14412/1996-7012-2020-3-146-149mrj-1037Research ArticleОБЗОРЫREVIEWSЧто мы знаем о возможности предсказания потенциальной эффективности и безопасности метотрексата путем определения концентрации его метаболитов при ревматоидном артрите?What do we know about the possibility of predicting the potential efficacy and safety of methotrexate, by measuring the concentration of its metabolites in rheumatoid arthritis?ГридневаГ. И.GridnevaG. I.

Галина Игоревна Гриднева

115522, Москва, Каширское шоссе, 34А

Galina Igorevna Gridneva

34A, Kashirskoe Shosse, Moscow 115522

gigridneva@mail.ruАроноваЕ. С.AronovaE. S.

115522, Москва, Каширское шоссе, 34А

34A, Kashirskoe Shosse, Moscow 115522

СыгыртаВ. С.SygyrtaV. S.

115522, Москва, Каширское шоссе, 34А

34A, Kashirskoe Shosse, Moscow 115522

КудрявцеваА. В.KudryavtsevaA. V.

115522, Москва, Каширское шоссе, 34А

34A, Kashirskoe Shosse, Moscow 115522

НурбаеваК. С.NurbaevaK. S.

115522, Москва, Каширское шоссе, 34А

34A, Kashirskoe Shosse, Moscow 115522

ФГБНУ «Научно-исследовательский институт ревматологии им. В.А. Насоновой»РоссияV.A. Nasonova Research Institute of RheumatologyRussian Federation202021092020143146149Copyright © Гриднева Г.И., Аронова Е.С., Сыгырта В.С., Кудрявцева А.В., Нурбаева К.С., 20202020Гриднева Г.И., Аронова Е.С., Сыгырта В.С., Кудрявцева А.В., Нурбаева К.С.Gridneva G.I., Aronova E.S., Sygyrta V.S., Kudryavtseva A.V., Nurbaeva K.S.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://mrj.ima-press.net/mrj/article/view/1037

Ревматоидный артрит (РА) характеризуется прогрессирующим течением с формированием деформаций суставов и развитием тяжелых функциональных нарушений. Наиболее благоприятные условия для изменения течения болезни складываются в первые месяцы после ее начала. Метотрексат (МТ) занимает ведущее место в терапии РА. Назрела необходимость в разработке инструментов, которые позволят предсказывать эффективность и переносимость МТ на самых ранних этапах лечения РА. Концентрация активных метаболитов МТ рассматривается как потенциальный биомаркер, с помощью которого возможно предсказать, каким будет ответ на терапию этим препаратом.

В статье приводится анализ наиболее актуальных работ, посвященных изучению концентрации активных метаболитов МТ – полиглутаматов (МТПГ) у больных РА. Показано, что представленные исследования не охватывают все возможности терапевтического лекарственного мониторинга, в частности определение содержания МТПГ в мононуклеарах в динамике. Необходимы дальнейшие исследования с целью разработки объективного подхода к назначению МТ у больных РА.

Rheumatoid arthritis (RA) is characterized by a progressive course with the formation of joint deformities and the development of severe functional disorders. The most favorable conditions for changing the course of the disease emerge in the first months after its onset. Methotrexate (MTX) occupies a leading position in the treatment of RA. There is a need to develop tools that will be able to predict the efficacy and tolerability of MTX at the earliest stages of RA treatment. The concentration of active metabolites of MTX is considered as a potential biomarker that enables one to predict what response to therapy with this drug will be.

The paper analyzes the most relevant works devoted to the study of the concentration of active MTX metabolites polyglutamates (MTX PGs) in patients with RA. It is shown that the presented studies do not cover all the possibilities of therapeutic drug monitoring, in particular the determination of the levels of MTX PGs in mononuclear cells over time. Further investigation is needed to develop an objective approach to prescribing MTX in RA patients.

ревматоидный артритметотрексатполиглутаматмониторингrheumatoid arthritismethotrexatepolyglutamatedrug monitoringReferencesОлюнин ЮА. Ранний ревматоидный артрит. Современные аспекты диагностики и лечения. Современная ревматология. 2010;4(1):65-70. doi: 10.14412/1996-7012-2010-590Olyunin YuA. Early rheumatoid arthritis: current aspects of its diagnosis and treatment. Sovremennaya revmatologiya = Modern Rheumatology Journal. 2010;4(1):65-70. (In Russ.). doi: 10.14412/1996-7012-2010-590Contreras-Yanez I, Pascual-Ramos V. Window of opportunity to achieve major outcomes in early rheumatoid arthritis patients: how persistence with therapy matters. Arthritis Res Ther. 2015 Jul 11;17(1):177. doi: 10.1186/s13075-015-0697-z.Contreras-Yanez I, Pascual-Ramos V. Window of opportunity to achieve major outcomes in early rheumatoid arthritis patients: how persistence with therapy matters. Arthritis Res Ther. 2015 Jul 11;17(1):177. doi: 10.1186/s13075-015-0697-z.Van Nies JA, Tsonaka R, Gaujoux-Viala C, et al. Evaluating relationships between symptom duration and persistence of rheumatoid arthritis: does a window of opportunity exist? Results on the Leiden early arthritis clinic and ESPOIR cohorts. Ann Rheum Dis. 2015 May;74(5):806-12. doi: 10.1136/annrheumdis-2014-206047.Van Nies JA, Tsonaka R, Gaujoux-Viala C, et al. Evaluating relationships between symptom duration and persistence of rheumatoid arthritis: does a window of opportunity exist? Results on the Leiden early arthritis clinic and ESPOIR cohorts. Ann Rheum Dis. 2015 May;74(5):806-12. doi: 10.1136/annrheumdis-2014-206047.Raza K, Filer A. The therapeutic window of opportunity in rheumatoid arthritis: does it ever close? Ann Rheum Dis. 2015 May;74(5): 793-4. doi: 10.1136/annrheumdis-2014-206993.Raza K, Filer A. The therapeutic window of opportunity in rheumatoid arthritis: does it ever close? Ann Rheum Dis. 2015 May;74(5): 793-4. doi: 10.1136/annrheumdis-2014-206993.Van der Linden MP, le Cessie S, Raza K, et al. Long-term impact of delay in assessment of patients with early arthritis. Arthritis Rheum. 2010 Dec;62(12):3537-46. doi: 10.1002/art.27692.Van der Linden MP, le Cessie S, Raza K, et al. Long-term impact of delay in assessment of patients with early arthritis. Arthritis Rheum. 2010 Dec;62(12):3537-46. doi: 10.1002/art.27692.Насонов ЕЛ. Метотрексат при ревматоидном артрите – 2015: новые факты и идеи. Научно-практическая ревматология. 2015;53(4):421-33. doi: 10.14412/1995-4484-2015-421-433Nasonov EL. Methotrexate in rheumatoid arthritis – 2015: new facts and ideas. Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice. 2015;53(4):421-33. (In Russ.). doi: 10.14412/1995-4484-2015-421-433Goodman S. Measuring methotrexate polyglutamates. Clin Exp Rheumatol. 2010 Sep-Oct;28(5 Suppl 61):S24-6.Goodman S. Measuring methotrexate polyglutamates. Clin Exp Rheumatol. 2010 Sep-Oct;28(5 Suppl 61):S24-6.Chabner BA, Allegra CJ, Curt GA, et al. Polyglutamation of methotrexate. Is methotrexate a prodrug? J Clin Invest. 1985 Sep; 76(3):907-12.Chabner BA, Allegra CJ, Curt GA, et al. Polyglutamation of methotrexate. Is methotrexate a prodrug? J Clin Invest. 1985 Sep; 76(3):907-12.Tishler M, Caspi D, Graff E, et al. Synovial and serum levels of methotrexate during methotrexate therapy of rheumatoid arthritis. Br J Rheumatol. 1989 Oct;28(5):422-3.Tishler M, Caspi D, Graff E, et al. Synovial and serum levels of methotrexate during methotrexate therapy of rheumatoid arthritis. Br J Rheumatol. 1989 Oct;28(5):422-3.Bannwarth B, Pehourcq F, Schaeverbeke T, Dehais J.Clinical pharmacokinetics of low-dose pulse methotrexate in rheumatoid arthritis. Clin Pharmacokinet. 1996 Mar;30(3):194-210.Bannwarth B, Pehourcq F, Schaeverbeke T, Dehais J.Clinical pharmacokinetics of low-dose pulse methotrexate in rheumatoid arthritis. Clin Pharmacokinet. 1996 Mar;30(3):194-210.Dalrymple JM, Stamp LK, O'Donnell JL, et al. Pharmacokinetics of oral methotrexate in patients with rheumatoid arthritis. Arthritis Rheum. 2008 Nov;58(11):3299-308. doi: 10.1002/art.24034.Dalrymple JM, Stamp LK, O'Donnell JL, et al. Pharmacokinetics of oral methotrexate in patients with rheumatoid arthritis. Arthritis Rheum. 2008 Nov;58(11):3299-308. doi: 10.1002/art.24034.De Rotte MC, den Boer E, de Jong PH, et al. Methotrexate polyglutamates in erythrocytes are associated with lower disease activity in patients with rheumatoid arthritis. Ann Rheum Dis. 2015 Feb;74(2):408-14. doi: 10.1136/annrheumdis-2013-203725. Epub 2013 Dec 2.De Rotte MC, den Boer E, de Jong PH, et al. Methotrexate polyglutamates in erythrocytes are associated with lower disease activity in patients with rheumatoid arthritis. Ann Rheum Dis. 2015 Feb;74(2):408-14. doi: 10.1136/annrheumdis-2013-203725. Epub 2013 Dec 2.Danila MI, Hughes LB, Brown EE, et al. Measurement of erythrocyte methotrexate polyglutamate levels: ready for clinical use in rheumatoid arthritis? Curr Rheumatol Rep. 2010 Oct;12(5):342-7. doi: 10.1007/s11926010-0120-3.Danila MI, Hughes LB, Brown EE, et al. Measurement of erythrocyte methotrexate polyglutamate levels: ready for clinical use in rheumatoid arthritis? Curr Rheumatol Rep. 2010 Oct;12(5):342-7. doi: 10.1007/s11926010-0120-3.Halilova KI, Brown EE, Morgan SL, et al. Markers of treatment response to methotrexate in rheumatoid arthritis: where do we stand? Int J Rheumatol. 2012;2012: 978396. doi: 10.1155/2012/978396. Epub 2012 Jul 9.Halilova KI, Brown EE, Morgan SL, et al. Markers of treatment response to methotrexate in rheumatoid arthritis: where do we stand? Int J Rheumatol. 2012;2012: 978396. doi: 10.1155/2012/978396. Epub 2012 Jul 9.Kremer JM. Still trying to understand methotrexate. J Rheumatol. 2014 Nov;41(11): 2099-101. doi: 10.3899/jrheum.141081Kremer JM. Still trying to understand methotrexate. J Rheumatol. 2014 Nov;41(11): 2099-101. doi: 10.3899/jrheum.141081Stamp LK, O'Donnell JL, Chapman PT, et al. Determinants of red blood cell methotrexate polyglutamate concentrations in rheumatoid arthritis patients receiving long-term methotrexate treatment. Arthritis Rheum. 2009 Aug;60(8):2248-56. doi: 10.1002/art.24653.Stamp LK, O'Donnell JL, Chapman PT, et al. Determinants of red blood cell methotrexate polyglutamate concentrations in rheumatoid arthritis patients receiving long-term methotrexate treatment. Arthritis Rheum. 2009 Aug;60(8):2248-56. doi: 10.1002/art.24653.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 Dec;49(12): 2337-45. doi: 10.1093/rheumatology/keq216. Epub 2010 Aug 16.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 Dec;49(12): 2337-45. doi: 10.1093/rheumatology/keq216. Epub 2010 Aug 16.Насонов ЕЛ, редактор. Российские клинические рекомендации. Ревматология. Москва: ГЭОТАР-Медиа; 2019.Nasonov EL, editor. Rossiiskie klinicheskie rekomendatsii. Revmatologiya [Russian clinical guidelines. Rheumatology]. Moscow: GEOTAR-Media; 2019.Stamp L, Roberts R, Kennedy M, et al. The use of low dose methotrexate in rheumatoid arthritis – are we entering a new era of therapeutic drug monitoring and pharmacogenomics? Biomed Pharmacother. 2006 Dec;60(10):678-87. Epub 2006 Oct 20.Stamp L, Roberts R, Kennedy M, et al. The use of low dose methotrexate in rheumatoid arthritis – are we entering a new era of therapeutic drug monitoring and pharmacogenomics? Biomed Pharmacother. 2006 Dec;60(10):678-87. Epub 2006 Oct 20.Pan S, Stamp LK, Duffull SB, et al. Assessment of the relationship between methotrexate polyglutamates in red blood cells and clinical response in patients commencing methotrexate for rheumatoid arthritis. Clin Pharmacokinet. 2014 Dec;53(12): 1161-70. doi: 10.1007/s40262-014-0179-5.Pan S, Stamp LK, Duffull SB, et al. Assessment of the relationship between methotrexate polyglutamates in red blood cells and clinical response in patients commencing methotrexate for rheumatoid arthritis. Clin Pharmacokinet. 2014 Dec;53(12): 1161-70. doi: 10.1007/s40262-014-0179-5.Cronstein BN. Going with the flow: methotrexate, adenosine, and blood flow. Ann Rheum Dis. 2006 Apr;65(4):421-2. doi: 10.1136/ard.2005.049601.Cronstein BN. Going with the flow: methotrexate, adenosine, and blood flow. Ann Rheum Dis. 2006 Apr;65(4):421-2. doi: 10.1136/ard.2005.049601.Angelis-Stoforidis P, Vajda FJ, Christophidis N. Methotrexate polyglutamate levels in circulating erythrocytes and polymorphs correlate with clinical efficacy in rheumatoid arthritis. Clin Exp Rheumatol. 1999 May-Jun;17(3):313-20.Angelis-Stoforidis P, Vajda FJ, Christophidis N. Methotrexate polyglutamate levels in circulating erythrocytes and polymorphs correlate with clinical efficacy in rheumatoid arthritis. Clin Exp Rheumatol. 1999 May-Jun;17(3):313-20.Dervieux T, Greenstein N, Kremer J. Pharmacogenomic and metabolic biomarkers in the folate pathway and their association with methotrexate effects during dosage escalation in rheumatoid arthritis. Arthritis Rheum. 2006 Oct;54(10):3095-103. doi: 10.1002/art.22129.Dervieux T, Greenstein N, Kremer J. Pharmacogenomic and metabolic biomarkers in the folate pathway and their association with methotrexate effects during dosage escalation in rheumatoid arthritis. Arthritis Rheum. 2006 Oct;54(10):3095-103. doi: 10.1002/art.22129.Dervieux T, Furst D, Lein DO, et al. Pharmacogenetic and metabolite measurements are associated with clinical status in patients with rheumatoid arthritis treated with methotrexate: results of a multicentred cross sectional observational study. Ann Rheum Dis. 2005 Aug;64(8):1180-5. doi: 10.1136/ard.2004.033399. Epub 2005 Jan 27.Dervieux T, Furst D, Lein DO, et al. Pharmacogenetic and metabolite measurements are associated with clinical status in patients with rheumatoid arthritis treated with methotrexate: results of a multicentred cross sectional observational study. Ann Rheum Dis. 2005 Aug;64(8):1180-5. doi: 10.1136/ard.2004.033399. Epub 2005 Jan 27.Hobl EL, Jilma B, Erlacher L, et al. A short-chain methotrexate polyglutamate as outcome parameter in rheumatoid arthritis patients receiving methotrexate. Clin Exp Rheumatol. Mar-Apr 2012;30(2):156-63. Epub 2012 Apr 13.Hobl EL, Jilma B, Erlacher L, et al. A short-chain methotrexate polyglutamate as outcome parameter in rheumatoid arthritis patients receiving methotrexate. Clin Exp Rheumatol. Mar-Apr 2012;30(2):156-63. Epub 2012 Apr 13.Takahashi C, Kaneko Y, Okano Y, et al. Association of erythrocyte methotrexatepolyglutamate levels with the efficacy and hepatotoxicity of methotrexate in patients with rheumatoid arthritis: a 76-week prospective study. RMD Open. 2017 Jan 3;3(1): e000363. doi: 10.1136/rmdopen-2016-000363Takahashi C, Kaneko Y, Okano Y, et al. Association of erythrocyte methotrexatepolyglutamate levels with the efficacy and hepatotoxicity of methotrexate in patients with rheumatoid arthritis: a 76-week prospective study. RMD Open. 2017 Jan 3;3(1): e000363. doi: 10.1136/rmdopen-2016-000363Sandhu A, Dhir V, Bhatnagar A, et al. High Methotrexate Triglutamate Level Is an Independent Predictor of Adverse Effects in Asian Indian Rheumatoid Arthritis Patients A Preliminary Study. Ther Drug Monit. 2017 Apr;39(2):157-63. doi: 10.1097/FTD.0000000000000375.Sandhu A, Dhir V, Bhatnagar A, et al. High Methotrexate Triglutamate Level Is an Independent Predictor of Adverse Effects in Asian Indian Rheumatoid Arthritis Patients A Preliminary Study. Ther Drug Monit. 2017 Apr;39(2):157-63. doi: 10.1097/FTD.0000000000000375.Stamp LK, O'Donnell JL, Chapman PT, et al. Methotrexate polyglutamate concentrations are not associated with disease control in rheumatoid arthritis patients receiving long-term methotrexate therapy. Arthritis Rheum. 2010 Feb;62(2):359-68. doi: 10.1002/art.27201.Stamp LK, O'Donnell JL, Chapman PT, et al. Methotrexate polyglutamate concentrations are not associated with disease control in rheumatoid arthritis patients receiving long-term methotrexate therapy. Arthritis Rheum. 2010 Feb;62(2):359-68. doi: 10.1002/art.27201.Murosaki T, Nagatani K, Sato T, et al. Prediction of the therapeutic response to methotrexate at 24 weeks by methotrexatepolyglutamates concentration in erythrocytes at 8 weeks in patients with rheumatoid arthritis. Mod Rheumatol. 2017 May;27(3):411-16. doi: 10.1080/14397595.2016.1208137Murosaki T, Nagatani K, Sato T, et al. Prediction of the therapeutic response to methotrexate at 24 weeks by methotrexatepolyglutamates concentration in erythrocytes at 8 weeks in patients with rheumatoid arthritis. Mod Rheumatol. 2017 May;27(3):411-16. doi: 10.1080/14397595.2016.1208137Dervieux T, Kremer JM, Weinblatt ME. Differing contribution of methotrexate polyglutamates to adalimumab blood levels as compared with etanercept. Ann Rheum Dis. 2019 Sep;78(9):1285-86. doi: 10.1136/annrheumdis-2018-214860. Epub 2019 Mar 18.Dervieux T, Kremer JM, Weinblatt ME. Differing contribution of methotrexate polyglutamates to adalimumab blood levels as compared with etanercept. Ann Rheum Dis. 2019 Sep;78(9):1285-86. doi: 10.1136/annrheumdis-2018-214860. Epub 2019 Mar 18.Dervieux T, Kremer J, Brady K, et al. Enhanced Methotrexate Polyglutamation in Japanese as Compared to Caucasian Rheumatoid Arthritis Patients Starting Methotrexate [abstract]. Arthritis Rheumatol. 2019; 71(suppl 10):2401.Dervieux T, Kremer J, Brady K, et al. Enhanced Methotrexate Polyglutamation in Japanese as Compared to Caucasian Rheumatoid Arthritis Patients Starting Methotrexate [abstract]. Arthritis Rheumatol. 2019; 71(suppl 10):2401.

The authors declare that there are no conflicts of interest present.