vspВопросы современной педиатрииCurrent Pediatrics1682-55271682-5535Издательство «ПедиатрЪ»10.15690/vsp.v17i5.1954vsp-1954Research ArticleОРИГИНАЛЬНАЯ СТАТЬЯORIGINAL ARTICLESРанние прогностические факторы ответа на терапию адалимумабом у пациентов с ювенильным идиопатическим артритом без системных проявлений: проспективное когортное исследованиеEarly Predictors of the Response to Adalimumab Therapy in Patients With Juvenile Idiopathic Arthritis Without Systemic Manifestations: A Prospective Cohort Studyhttps://orcid.org/0000-0002-3874-4721АлексееваЕ. И.AlexeevaEkaterina I.

Алексеева Екатерина Иосифовна - доктор медицинских наук, профессор, член-корреспондент РАН, заведующая ревматологическим отделением НМИЦ здоровья детей, декан педиатрического факультета Первого МГМУ имени И.М. Сеченова.

119991, Москва, Ломоносовский пр-т, д. 2, стр. 1; тел.: +7 (499) 134-02-97

alekatya@yandex.ruДворяковскаяТ. М.DvoryakovskayaTatyana M.ИсаеваК. Б.IsaevaKseniya B.

Moscow.

СлепцоваТ. В.SleptsovaTatyana V.

Moscow.

ДенисоваР. В.DenisovaRina V.

Moscow.

https://orcid.org/0000-0002-6150-0880СолошенкоМ. А.SoloshenkoMargarita A.

Moscow.

ЛомакинаО. Л.LomakinaOlga L.

Moscow.

https://orcid.org/0000-0002-8959-1606ФетисоваА. Н.FetisovaAnna N.

Moscow.

РудницкаяМ. Г.RudnickayaMariya G.

Moscow.

ВаньковаД. Д.VankovaDariya D.

Moscow.

ДьяконовЮ. М.DyakonovYuri M.АльшевскаяА. А.AlshevskayaAlina A.

Новосибирск.

Novosibirsk.

МоскалёвА. В.MoskalevAndrei V.

Новосибирск.

Novosibirsk.

https://orcid.org/0000-0003-0367-6017МамутоваА. В.MamutovaAnna V.

Moscow.

Научный медицинский исследовательский центр здоровья детей; Первый Московский государственный медицинский университет им. И.М. Сеченова (Сеченовский Университет)РоссияNational Medical Research Center for Children’s Health; Sechenov First Moscow State Medical University (Sechenov University)Russian FederationНаучный медицинский исследовательский центр здоровья детейРоссияNational Medical Research Center for Children’s HealthRussian FederationПервый Московский государственный медицинский университет им. И.М. Сеченова (Сеченовский Университет)РоссияSechenov First Moscow State Medical University (Sechenov University)Russian FederationНаучно-исследовательский центр биостатистики и клинических исследованийРоссияResearch Center for Biostatistics and Clinical TrialsRussian Federation201801122018175381388Copyright © Алексеева Е.И., Дворяковская Т.М., Исаева К.Б., Слепцова Т.В., Денисова Р.В., Солошенко М.А., Ломакина О.Л., Фетисова А.Н., Рудницкая М.Г., Ванькова Д.Д., Дьяконов Ю.М., Альшевская А.А., Москалёв А.В., Мамутова А.В., 20182018Алексеева Е.И., Дворяковская Т.М., Исаева К.Б., Слепцова Т.В., Денисова Р.В., Солошенко М.А., Ломакина О.Л., Фетисова А.Н., Рудницкая М.Г., Ванькова Д.Д., Дьяконов Ю.М., Альшевская А.А., Москалёв А.В., Мамутова А.В.Alexeeva E.I., Dvoryakovskaya T.M., Isaeva K.B., Sleptsova T.V., Denisova R.V., Soloshenko M.A., Lomakina O.L., Fetisova A.N., Rudnickaya M.G., Vankova D.D., Dyakonov Y.M., Alshevskaya A.A., Moskalev A.V., Mamutova A.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://vsp.spr-journal.ru/jour/article/view/1954

Ингибиторы фактора  некроза опухоли  альфа  широко используют  в лечении ювенильного  идиопатического артрита (ЮИА). Для  достижения  максимальной  эффективности  генно-инженерных биологических  препаратов  необходимо изучение прогностических факторов ответа на терапию. Цель исследования — определить ранние предикторы ответа на терапию адалимумабом у пациентов с ЮИА без системных проявлений. Методы. В проспективном когортном исследовании  анализировали результаты  лечения пациентов с ЮИА без системных проявлений, которым назначали адалимумаб в период с августа 2008 по август 2014 г. Изучали связи исходных демографических показателей, а также исходных и зарегистрированных через 1 мес лечения клинических и лабораторных показателей с наилучшим (ремиссия по критериям Wallace) ответом на терапию через 1 год. Результаты. За первый год терапии ремиссия по критериям Wallace была достигнута  у 94 (43,9%) из 214 больных. При многофакторном анализе  предикторами достижения ремиссии через 1 год терапии адалимумабом были улучшение по критерию АКР70 после 1 мес терапии [отношение шансов (ОШ) 3,3; 95% доверительный интервал (ДИ) 1,7–6,7)], наличие увеита в анамнезе (ОШ 1,86; 95% ДИ 1,03–3,33), уменьшение числа суставов с активным артритом после 1 мес терапии (ОШ 1,09; 95% ДИ 1,02–1,16). На фоне терапии инъекционные реакции в виде боли отмечены у 36 (16,8%) из 214 пациентов, инфекционные заболевания ЛОР-органов — у 85 (39,7%), дыхательных  путей — у 17 (7,9%), тубинфицирование  — у 13 (6,1%) детей. Заключение. Наличие увеита в анамнезе, быстрая редукция числа суставов с активным артритом и высокий уровень ответа на лечение после 1 мес терапии адалимумабом являются предикторами достижения  пациентами ремиссии в течение первого года лечения.

Background. Tumour necrosis factor alpha inhibitors are widely used in the treatment  of juvenile idiopathic arthritis (JIA). To achieve maximum efficiency of genetically engineered biologic drugs, it is necessary to study predictors of the response to therapy. Objective. Our aim was to identify early predictors  of the response  to adalimumab therapy in patients with JIA without systemic manifestations. Methods. A prospective cohort study analysed treatment results of patients with JIA without systemic manifestations, who were prescribed adalimumab for the period from August 2008 to August 2014. We studied the relationship between baseline demographic indicators as well as baseline and registered after one month of treatment clinical and laboratory parameters and the best (remission according to the Wallace criteria) response to therapy after one year. Results. In the first year of therapy, 94 (43.9%) of 214 patients achieved remission according to the Wallace criteria. In a multivariate analysis, predictors of achieving remission after one year of adalimumab therapy were the improvement according to the ACR70 criterion after one month of therapy [odds ratio (OR) 3.3; 95% confidence interval (CI) 1.7–6.7], a history of uveitis (OR 1.86; 95% CI 1.03–3.33), a decrease in the number of joints with active arthritis after one month of therapy (OR 1.09; 95% CI 1.02–1.16). During therapy, injection reactions in the form of pain were observed in 36 (16.8%) of 214 patients, infectious diseases of ENT organs — in 85 (39.7%), of the respiratory tract — in 17 (7.9%), and tubinfection — in 13 (6.1%) children. Conclusion. The presence of uveitis, rapid reduction in the number of joints with active arthritis and a high level of response to treatment after one month of adalimumab therapy are predictors for achieving remission during the first year of treatment.

детиювенильный идиопатический артриттерапияпредикторы ответагенно-инженерный биологический препаратадалимумабchildrenjuvenile idiopathic arthritistherapyresponse predictorsgenetically engineered biologic drugadalimumabНе указан.Not specifiedReferencesGiancane G, Alongi A, Ravelli A. Update on the pathogenesis and treatment of juvenile idiopathic arthritis. Curr Opin Rheumatol. 2017;29(5):523–529. doi: 10.1097/BOR.0000000000000417.Giancane G, Alongi A, Ravelli A. Update on the pathogenesis and treatment of juvenile idiopathic arthritis. Curr Opin Rheumatol. 2017;29(5):523–529. doi: 10.1097/BOR.0000000000000417.Blandizzi C, Gionchetti P, Armuzzi A, et al. The role of tumour necrosis factor in the pathogenesis of immune-mediated diseases. Int J Immunopathol Pharmacol. 2014;27(1 Suppl):1–10. doi: 10.1177/03946320140270S101.Blandizzi C, Gionchetti P, Armuzzi A, et al. The role of tumour necrosis factor in the pathogenesis of immune-mediated diseases. Int J Immunopathol Pharmacol. 2014;27(1 Suppl):1–10. doi: 10.1177/03946320140270S101.Ringold S, Weiss PF, Beukelman T, et al. 2013 update of the 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: recommendations for the medical therapy of children with systemic juvenile idiopathic arthritis and tuberculosis screening among children receiving biologic medications. Arthritis Rheum. 2013;65(10):2499–2512. doi: 10.1002/art.38092.Ringold S, Weiss PF, Beukelman T, et al. 2013 update of the 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: recommendations for the medical therapy of children with systemic juvenile idiopathic arthritis and tuberculosis screening among children receiving biologic medications. Arthritis Rheum. 2013;65(10):2499–2512. doi: 10.1002/art.38092.Союз педиатров России. Федеральные клинические рекомендации по ведению пациентов с юношеским артритом. — М.; 2017. Доступно по: http://www.pediatr-russia.ru/sites/default/files/file/kr_yua.pdf. Ссылка активна на 12.10.2018.Soyuz pediatrov Rossii. Federal’nye klinicheskie rekomendatsii po vedeniyu patsientov s yunosheskim artritom. Moscow; 2017. (In Russ). Доступно по: http://www.pediatr-russia.ru/sites/default/files/file/kr_yua.pdf. Ссылка активна на 12.10.2018.Mourao AF, Santos MJ, Melo Gomes JA, et al. Effectiveness and long-term retention of anti-tumour necrosis factor treatment in juvenile and adult patients with juvenile idiopathic arthritis: data from Reuma. pt. Rheumatology (Oxford). 2016;55(4):697–703. doi: 10.1093/rheumatology/kev398.Mourao AF, Santos MJ, Melo Gomes JA, et al. Effectiveness and long-term retention of anti-tumour necrosis factor treatment in juvenile and adult patients with juvenile idiopathic arthritis: data from Reuma. pt. Rheumatology (Oxford). 2016;55(4):697–703. doi: 10.1093/rheumatology/kev398.Burmester GR, Panaccione R, Gordon KB, et al. Adalimumab: long-term safety in 23 458 patients from global clinical trials in rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis and Crohn’s disease. Ann Rheum Dis. 2013;72(4):517–524. doi: 10.1136/annrheumdis-2011-201244.Burmester GR, Panaccione R, Gordon KB, et al. Adalimumab: long-term safety in 23 458 patients from global clinical trials in rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis and Crohn’s disease. Ann Rheum Dis. 2013;72(4):517–524. doi: 10.1136/annrheumdis-2011-201244.Solari N, Palmisani E, Consolaro A, et al. Factors associated with achievement of inactive disease in children with juvenile idiopathic arthritis treated with etanercept. J Rheumatol. 2013;40(2): 192–200. doi: 10.3899/jrheum.120842.Solari N, Palmisani E, Consolaro A, et al. Factors associated with achievement of inactive disease in children with juvenile idiopathic arthritis treated with etanercept. J Rheumatol. 2013;40(2): 192–200. doi: 10.3899/jrheum.120842.Кайлина А.Н., Огородова Л.М., Часовских Ю.П., Кремер Е.Э. Показатели системы матриксных металлопротеиназ (ММП-2, ММП-9, ТИМП-1) при ювенильных артритах у детей // Вестник Российской академии медицинских наук. — 2013. — Т. 68. — № 7 — С. 36–40. doi: 10.15690/vramn.v68i7.710.Kailina AN, Ogorodova LM, Chasovskikh YP, Kremer EЕ. Indices of matrix metalloproteinases (MMP-2, MMP-9, TIMP-1) with juvenile arthritis in children. Annals of the Russian academy of medical sciences. 2013;68(7):36–40. (In Russ). doi: 10.15690/vramn.v68i7.710.Alexeeva EI, Namazova-Baranova LS, Bzarova TM, et al. Predictors of the response to etanercept in patients with juvenile idiopathic arthritis without systemic manifestations within 12 months: results of an open-label, prospective study conducted at the National Scientific and Practical Center of Children’s Health, Russia. Pediatr Rheumatol Online J. 2017;15(1):51. doi: 10.1186/s12969-017-0178-9.Alexeeva EI, Namazova-Baranova LS, Bzarova TM, et al. Predictors of the response to etanercept in patients with juvenile idiopathic arthritis without systemic manifestations within 12 months: results of an open-label, prospective study conducted at the National Scientific and Practical Center of Children’s Health, Russia. Pediatr Rheumatol Online J. 2017;15(1):51. doi: 10.1186/s12969-017-0178-9.Horneff G, Klein A, Klotsche J, et al. Comparison of treatment response, remission rate and drug adherence in polyarticular juvenile idiopathic arthritis patients treated with etanercept, adalimumab or tocilizumab. Arthritis Res Ther. 2016;18(1):272. doi: 10.1186/s13075-016-1170-3.Horneff G, Klein A, Klotsche J, et al. Comparison of treatment response, remission rate and drug adherence in polyarticular juvenile idiopathic arthritis patients treated with etanercept, adalimumab or tocilizumab. Arthritis Res Ther. 2016;18(1):272. doi: 10.1186/s13075-016-1170-3.Wallace CA, Giannini EH, Spalding SJ, et al. Trial of early aggressive therapy in polyarticular juvenile idiopathic arthritis. Arthritis Rheum. 2012;64(6):2012–2021. doi: 10.1002/art.34343.Wallace CA, Giannini EH, Spalding SJ, et al. Trial of early aggressive therapy in polyarticular juvenile idiopathic arthritis. Arthritis Rheum. 2012;64(6):2012–2021. doi: 10.1002/art.34343.Lee WJ, Briars L, Lee TA, et al. Use of tumor necrosis factor-alpha inhibitors in children and young adults with juvenile idiopathic arthritis or rheumatoid arthritis. Pharmacotherapy. 2016;36(12): 1201–1209. doi: 10.1002/phar.1856.Lee WJ, Briars L, Lee TA, et al. Use of tumor necrosis factor-alpha inhibitors in children and young adults with juvenile idiopathic arthritis or rheumatoid arthritis. Pharmacotherapy. 2016;36(12): 1201–1209. doi: 10.1002/phar.1856.Алексеева Е.И., Дворяковская Т.М., Исаева К.Б., и др. Прогностические факторы ответа на терапию тоцилизумабом у пациентов с ювенильным идиопатическим артритом без системных проявлений: когортное исследование // Вопросы современной педиатрии. — 2018. — Т. 17. — № 3 — С. 207–215. doi: 10.15690/vsp.v17i3.1889.Alexeeva EI, Dvoryakovskaya TM, Isaeva KB, et al. Prognostic factors for the response to tocilizumab therapy in patients with juvenile idiopathic arthritis without systemic manifestations: a cohort study. Current Pediatrics. 2018;17(3):207–215. (In Russ). doi: 10.15690/vsp.v17i3.1889.Kashchenko E, Alexeeva E, Bzarova T, et al. AB0951 Factors associated with response to adalimumab treatment in juvenile idiopathic arthritis. Ann Rheum Dis. 2017;76(Suppl 2):1387–1388. doi: 10.1136/annrheumdis-2017-eular.4011.Kashchenko E, Alexeeva E, Bzarova T, et al. AB0951 Factors associated with response to adalimumab treatment in juvenile idiopathic arthritis. Ann Rheum Dis. 2017;76(Suppl 2):1387–1388. doi: 10.1136/annrheumdis-2017-eular.4011.Алексеева Е.И., Бзарова Т.М., Валиева С.И., и др. Эффективность и безопасность длительного применения адалимумаба с иммунодепрессантами при ювенильном идиопатическом артрите без системных проявлений // Вопросы современной педиатрии. — 2015. — Т. 14. — № 4 — С. 464–476. doi: 10.15690/vsp.v14.i4.1385.Alexeeva EI, Bzarova TM, Valieva SI, et al. Efficacy and safety of adalimumab long-term administration with immunosuppressants at juvenile idiopathic arthritis without systemic manifestations. Current Pediatrics. 2015; 14(4):464–476. (In Russ). doi: 10.15690/vsp.v14.i4.1385.Wallace CA, Giannini EH, Huang B, et al. American College of Rheumatology provisional criteria for defining clinical inactive disease in select categories of juvenile idiopathic arthritis. Arthritis Care Res (Hoboken). 2011;63(7):929–936. doi: 10.1002/acr.20497.Wallace CA, Giannini EH, Huang B, et al. American College of Rheumatology provisional criteria for defining clinical inactive disease in select categories of juvenile idiopathic arthritis. Arthritis Care Res (Hoboken). 2011;63(7):929–936. doi: 10.1002/acr.20497.Petty RE, Southwood TR, Manners P, et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol. 2004; 31(2):390–392.Petty RE, Southwood TR, Manners P, et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol. 2004; 31(2):390–392.Giannini EH, Ruperto N, Ravelli A, et al. Preliminary definition of improvement in juvenile arthritis. Arthritis Rheum. 1997;40(7): 1202–1209. doi: 10.1002/art.1780400703.Giannini EH, Ruperto N, Ravelli A, et al. Preliminary definition of improvement in juvenile arthritis. Arthritis Rheum. 1997;40(7): 1202–1209. doi: 10.1002/art.1780400703.Swart JF, van Dijkhuizen EH, Wulffraat NM, de Roock S. Clinical Juvenile Arthritis Disease Activity Score proves to be a useful tool in treat-to-target therapy in juvenile idiopathic arthritis. Ann Rheum Dis. 2018;77(3):336–342. doi: 10.1136/annrheumdis-2017-212104.Swart JF, van Dijkhuizen EH, Wulffraat NM, de Roock S. Clinical Juvenile Arthritis Disease Activity Score proves to be a useful tool in treat-to-target therapy in juvenile idiopathic arthritis. Ann Rheum Dis. 2018;77(3):336–342. doi: 10.1136/annrheumdis-2017-212104.Burmester GR, Mease P, Dijkmans BA, et al. Adalimumab safety and mortality rates from global clinical trials of six immune-mediated inflammatory diseases. Ann Rheum Dis. 2009;68(12):1863–1869. doi:10.1136/ard.2008.102103.Burmester GR, Mease P, Dijkmans BA, et al. Adalimumab safety and mortality rates from global clinical trials of six immune-mediated inflammatory diseases. Ann Rheum Dis. 2009;68(12):1863–1869. doi:10.1136/ard.2008.102103.Murdaca G, Colombo BM, Puppo F. Adalimumab for the treatment of immune-mediated diseases: an update on old and recent indications. Drugs Today (Barc). 2011;47(4):277–288. doi: 10.1358/dot.2011.47.4.1576692.Murdaca G, Colombo BM, Puppo F. Adalimumab for the treatment of immune-mediated diseases: an update on old and recent indications. Drugs Today (Barc). 2011;47(4):277–288. doi: 10.1358/dot.2011.47.4.1576692.Anink J, Otten MH, Gorter SL, et al. Treatment choices of paediatric rheumatologists for juvenile idiopathic arthritis: etanercept or adalimumab? Rheumatology (Oxford). 2013;52(9):1674–1679. doi: 10.1093/rheumatology/ket170.Anink J, Otten MH, Gorter SL, et al. Treatment choices of paediatric rheumatologists for juvenile idiopathic arthritis: etanercept or adalimumab? Rheumatology (Oxford). 2013;52(9):1674–1679. doi: 10.1093/rheumatology/ket170.Arends S, Brouwer E, van der Veer E, et al. Baseline predictors of response and discontinuation of tumor necrosis factor-alpha blocking therapy in ankylosing spondylitis: a prospective longitudinal observational cohort study. Arthritis Res Ther. 2011;13(3):R94. doi: 10.1186/ar3369.Arends S, Brouwer E, van der Veer E, et al. Baseline predictors of response and discontinuation of tumor necrosis factor-alpha blocking therapy in ankylosing spondylitis: a prospective longitudinal observational cohort study. Arthritis Res Ther. 2011;13(3):R94. doi: 10.1186/ar3369.Martini A. It is time to rethink juvenile idiopathic arthritis classification and nomenclature. Ann Rheum Dis. 2012;71(9): 1437–1439. doi: 10.1136/annrheumdis-2012-201388.Martini A. It is time to rethink juvenile idiopathic arthritis classification and nomenclature. Ann Rheum Dis. 2012;71(9): 1437–1439. doi: 10.1136/annrheumdis-2012-201388.Rudwaleit M, Claudepierre P, Wordsworth P, et al. Effectiveness, safety, and predictors of good clinical response in 1250 patients treated with adalimumab for active ankylosing spondylitis. J Rheumatol. 2009;36(4):801–808. doi: 10.3899/jrheum.081048.Rudwaleit M, Claudepierre P, Wordsworth P, et al. Effectiveness, safety, and predictors of good clinical response in 1250 patients treated with adalimumab for active ankylosing spondylitis. J Rheumatol. 2009;36(4):801–808. doi: 10.3899/jrheum.081048.

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