vspВопросы современной педиатрииCurrent Pediatrics1682-55271682-5535Издательство «ПедиатрЪ»10.15690/vsp.v14.i4.1386vsp-1077Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESСпособна ли терапия метотрексатом предотвращать развитие увеита у пациентов с ювенильным идиопатическим артритом: результаты ретроспективного исследованияCan the Methotrexate Therapy Prevent the Development of Uveitis in Patients with Juvenile Idiopathic Arthritis: Results of a Retrospective StudyКостикМ. М.KostikM. M.

кандидат медицинских наук, доцент, доцент кафедры госпитальной педиатрии Санкт-Петербургского государственного педиатрического медицинского университета Адрес: 194100, Санкт-Петербург, ул. Литовская, д. 2, тел.: +7 (812) 416-52-98

kost-mikhail@yandex.ruГайдарЕ. В.GaydarE. V.ДубкоМ. Ф.DubkoM. F.МасаловаВ. В.MasalovaV. V.СнегирёваЛ. С.SnegirevaL. S.ЧиковаИ. А.ChikovaI. A.ИсуповаЕ. А.IsupovaE. A.НикитинаТ. Н.NikitinaT. N.СерогодскаяЕ. Д.SerogodskayaE. D.КалашниковаО. В.KalashnikovaO. V.РавеллиА.RavelliA.ЧасныкВ. Г.ChasnykV. G.Санкт-Петербургский государственный педиатрический медицинский университет, Санкт-Петербург, Российская ФедерацияРоссияSaint-Petersburg State Pediatric Medical University, Saint-Petersburg, Russian FederationRussian FederationИнститут Г. Газлини, Генуя, Италия Университет Генуи, Генуя, ИталияРоссияGiannina Gaslini Institute, Genoa, Italy University of Genoa, Genoa, ItalyRussian Federation201523092015144477482Copyright © Костик М.М., Гайдар Е.В., Дубко М.Ф., Масалова В.В., Снегирёва Л.С., Чикова И.А., Исупова Е.А., Никитина Т.Н., Серогодская Е.Д., Калашникова О.В., Равелли А., Часнык В.Г., 20152015Костик М.М., Гайдар Е.В., Дубко М.Ф., Масалова В.В., Снегирёва Л.С., Чикова И.А., Исупова Е.А., Никитина Т.Н., Серогодская Е.Д., Калашникова О.В., Равелли А., Часнык В.Г.Kostik M.M., Gaydar E.V., Dubko M.F., Masalova V.V., Snegireva L.S., Chikova I.A., Isupova E.A., Nikitina T.N., Serogodskaya E.D., Kalashnikova O.V., Ravelli A., Chasnyk V.G.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/1077

Увеит является одним из наиболее частых внесуставных проявлений ювенильного идиопатического артрита (ЮИА). В настоящее время изучается возможность снижения риска развития увеита у детей с ЮИА при применении метотрексата.

Цель исследования

Цель исследования: проанализировать результаты терапии детей с ЮИА, изучив связь применения метотрексата с риском развития увеита.

Методы

Методы: проведено ретроспективное неконтролируемое исследование. Изучены истории болезни пациентов с ЮИА, которые лечились на протяжении не менее 2 лет с момента дебюта заболевания. Сравнивали результаты лечения больных, получавших и не получавших метотрексат (базовая терапия — нестероидные противовоспалительные лекарственные препараты и внутрисуставные инъекции глюкокортикоидов). Учитывали установленные случаи развития увеита.

Результаты

Результаты: в исследовании проанализированы результаты наблюдения281 ребенка с ЮИА. В группе метотрексата развитие увеита зафиксировано у 22/191 (11,5%), в группе сравнения — у 42/90 (46,7%) больных (ОШ 6,7; 95% ДИ 3,7–12,3). Время между дебютом ЮИА и развитием увеита в сравниваемых группах не различалось и составило 24 (12; 67) и 17 мес (7; 35), соответственно (р = 0,232). Многофакторный регрессионный анализ показал, что основными предикторами развития увеита были олигоартикулярный вариант течения ЮИА (ОР = 1,89), позитивность по антинуклеарному фактору (ОР = 2,14), дебют ЮИА в возрасте до 5 лет (ОР = 2,56), женский пол (ОР = 1,82) и отсутствие в схеме терапии метотрексата (ОР = 0,24).

Заключение

Заключение: лечение метотрексатом может приводить к снижению риска развития увеита у пациентов с ЮИА. Для подтверждения этой гипотезы необходимо проведение рандомизированных исследований.

Background

Background: Uveitis is one of the most common extra-articular manifestations of juvenile idiopathic arthritis (JIA). Currently, the possibility of reducing the risk of uveitis in children with JIA by using methotrexate has been studied.

Objective

Objective: Our aim was to analyze the results of treatment of children with JIA by studying the relation between the use of methotrexate and the risk of uveitis.

Methods

Methods: A retrospective uncontrolled study. The case histories of patients with JIA who were treated for at least 2 years after the onset of the disease were studied. The results of treatment of patients who received and who did not receive methotrexate were studied (standard therapy — non-steroidal anti-inflammatory drugs and intra-articular injections of glucocorticoids). The established cases of uveitis were taken into account.

Results

Results: The study analyzed the results of observation of 281 children with JIA. In the methotrexate group, uveitis was detected in 22/191 (11.5%), and in the control group — in 42/90 (46.7%) of patients (OR 6.7; 95% CI 3.7–12.3). The time period between the onset of JIA and development of uveitis in two groups under study was the same and equal to 24 (12; 67) and 17 months (7; 35), respectively (p = 0.232). Multivariate regression analysis showed that the main predictors of uveitis were oligoarticular course of JIA (HR = 1.89), positive antinuclear antibody test (HR = 2.14), onset of JIA under the age of 5 (HR = 2.56), female gender (HR = 1.82),and the absence of methotrexate in the therapy (HR = 0.24).

Conclusion

Conclusion: The treatment with methotrexate may reduce the risk of uveitis in patients with JIA. To confirm this hypothesis, randomized studies are needed.

детиювенильный идиопатический артритувеитрискметотрексатchildrenjuvenile idiopathic arthritisuveitisriskmethotrexate.ReferencesSaurenmann R. K., Levin A. V., Feldman B. M., Rose J. B., Laxer R. M., Schneider R., Silverman E. D. Prevalence, risk factors, and outcome of uveitis in juvenile idiopathic arthritis: a long-term follow-up study. Arthritis Rheum. 2007; 56: 647–657.Saurenmann R. K., Levin A. V., Feldman B. M., Rose J. B., Laxer R. M., Schneider R., Silverman E. D. Prevalence, risk factors, and outcome of uveitis in juvenile idiopathic arthritis: a long-term follow-up study. Arthritis Rheum. 2007; 56: 647–657.Rosenberg K. D., Feuer W. J., Davis J. L. Ocular complications of paediatric uveitis. Ophthalmology. 2004; 111: 2299–2306.Rosenberg K. D., Feuer W. J., Davis J. L. Ocular complications of paediatric uveitis. Ophthalmology. 2004; 111: 2299–2306.De Boer J., Wulffraat N., Rothova A. Visual loss in uveitis of childhood. Brit. J. Ophthalmol. 2003; 87: 879–884.De Boer J., Wulffraat N., Rothova A. Visual loss in uveitis of childhood. Brit. J. Ophthalmol. 2003; 87: 879–884.Cordero-Coma M., Yilmaz T., Onal S. Systematic review of antitumor necrosis factor-alpha therapy for treatment of immunemediated uveitis. Ocul. Immunol. Inflamm. 2013; 21 (1): 19–27.Cordero-Coma M., Yilmaz T., Onal S. Systematic review of antitumor necrosis factor-alpha therapy for treatment of immunemediated uveitis. Ocul. Immunol. Inflamm. 2013; 21 (1): 19–27.Ravelli A., Martini A. Juvenile idiopathic arthritis. Lancet. 2007; 369: 767–778.Ravelli A., Martini A. Juvenile idiopathic arthritis. Lancet. 2007; 369: 767–778.Calandra S., Gallo M. C., Consolaro A., Pistorio A., Lattanzi B., Bovis F., Muratore V., De Marco R., Martini A., Ravelli A. Female sex and oligoarthritis category are not risk factors for uveitis in Italian children with juvenile idiopathic arthritis. J. Rheumatol. 2014; 41 (7): 1416–1425.Calandra S., Gallo M. C., Consolaro A., Pistorio A., Lattanzi B., Bovis F., Muratore V., De Marco R., Martini A., Ravelli A. Female sex and oligoarthritis category are not risk factors for uveitis in Italian children with juvenile idiopathic arthritis. J. Rheumatol. 2014; 41 (7): 1416–1425.Verazza S., Allegra M., Lattanzi B., Dalpra S., Magni-Manzoni S., Pistorio A., Oliveira S., Castell E., Arguedas O., Martini A., Ravelli A. Time of onset of iridocyclitis (IC) in children with juvenile idiopathic arthritis (JIA). Pediatr. Rheumatol. Online J. 2008; 6 (Suppl. 1): 77.Verazza S., Allegra M., Lattanzi B., Dalpra S., Magni-Manzoni S., Pistorio A., Oliveira S., Castell E., Arguedas O., Martini A., Ravelli A. Time of onset of iridocyclitis (IC) in children with juvenile idiopathic arthritis (JIA). Pediatr. Rheumatol. Online J. 2008; 6 (Suppl. 1): 77.Zannin M. E., Buscain I., Vittadello F., Martini G., Alessio M., Orsoni J. G., Breda L., Rigante D., Cimaz R., Zulian F. Timing of uveitis onset in oligoarticular juvenile idiopathic arthritis (JIA) is the main predictor of severe course uveitis. Acta Ophthalmol. 2012; 90: 91–95.Zannin M. E., Buscain I., Vittadello F., Martini G., Alessio M., Orsoni J. G., Breda L., Rigante D., Cimaz R., Zulian F. Timing of uveitis onset in oligoarticular juvenile idiopathic arthritis (JIA) is the main predictor of severe course uveitis. Acta Ophthalmol. 2012; 90: 91–95.Angeles-Han S. T., Pelajo C. F., Vogler L. B., Rouster-Stevens K., Kennedy C., Ponder L., McCracken C., Lopez-Benitez J., Drews-Botsch C., Prahalad S. CARRA Registry Investigators. Risk markers of juvenile idiopathic arthritis-associated uveitis in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry. J. Rheumatol. 2013; 40 (12): 2088–2096.Angeles-Han S. T., Pelajo C. F., Vogler L. B., Rouster-Stevens K., Kennedy C., Ponder L., McCracken C., Lopez-Benitez J., Drews-Botsch C., Prahalad S. CARRA Registry Investigators. Risk markers of juvenile idiopathic arthritis-associated uveitis in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry. J. Rheumatol. 2013; 40 (12): 2088–2096.American academy of pediatrics. Guidelines for ophthalmic examinations in children with juvenile rheumatoid arthritis. Section on Rheumatology and Section on Ophthalmology. Pediatrics. 1993; 92: 295–329.American academy of pediatrics. Guidelines for ophthalmic examinations in children with juvenile rheumatoid arthritis. Section on Rheumatology and Section on Ophthalmology. Pediatrics. 1993; 92: 295–329.Cassidy J., Kivlin J., Lindsley C., Nocton J. The Section on Rheumatology, and the Section on Ophthalmology. Ophthalmic examinations in children with juvenile rheumatoid arthritis. Pediatrics. 2006; 117: 1843–1845.Cassidy J., Kivlin J., Lindsley C., Nocton J. The Section on Rheumatology, and the Section on Ophthalmology. Ophthalmic examinations in children with juvenile rheumatoid arthritis. Pediatrics. 2006; 117: 1843–1845.Heiligenhaus A., Niewerth M., Ganser G., Heinz C., Minden K. and German Uveitis in Childhood Study Group. Prevalence and complications of uveitis in juvenile idiopathic arthritis in a populationbased nation-wide study in Germany: suggested modification of the current screening guidelines A. Rheumatology (Oxford). 2007; 46 (6): 1015–1019.Heiligenhaus A., Niewerth M., Ganser G., Heinz C., Minden K. and German Uveitis in Childhood Study Group. Prevalence and complications of uveitis in juvenile idiopathic arthritis in a populationbased nation-wide study in Germany: suggested modification of the current screening guidelines A. Rheumatology (Oxford). 2007; 46 (6): 1015–1019.Heiligenhaus A., Minden K., Foll D., Pleyer U. Uveitis in Juvenile Idiopathic Arthritis. Dtsch. Arztebl. Int. 2015; 112 (6): 92–100.Heiligenhaus A., Minden K., Foll D., Pleyer U. Uveitis in Juvenile Idiopathic Arthritis. Dtsch. Arztebl. Int. 2015; 112 (6): 92–100.Wentworth B. A., Freitas-Neto C. A., Foster C. S. Management of pediatric uveitis. F1000 Prime Rep. 2014; 6: 41.Wentworth B. A., Freitas-Neto C. A., Foster C. S. Management of pediatric uveitis. F1000 Prime Rep. 2014; 6: 41.Giannini E. H., Brewer E. J., Kuzmina N., Shaikov A., Maximov A., Vorontsov I., Fink C. W., Newman A. J., Cassidy J. T., Zemel L. S. Methotrexate in resistant juvenile rheumatoid arthritis. Results of the U.S.A.–U.S.S.R. double-blind, placebo-controlled trial. The Pediatric Rheumatology Collaborative Study Group and The Cooperative Children’s Study Group. N. Engl. J. Med. 1992; 326: 1043–1049.Giannini E. H., Brewer E. J., Kuzmina N., Shaikov A., Maximov A., Vorontsov I., Fink C. W., Newman A. J., Cassidy J. T., Zemel L. S. Methotrexate in resistant juvenile rheumatoid arthritis. Results of the U.S.A.–U.S.S.R. double-blind, placebo-controlled trial. The Pediatric Rheumatology Collaborative Study Group and The Cooperative Children’s Study Group. N. Engl. J. Med. 1992; 326: 1043–1049.Ruperto N., Murray K. J., Gerloni V., Wulffraat N., de Oliveira S. K., Falcini F., Dolezalova P., Alessio M., Burgos-Vargas R., Corona F., Vesely R., Foster H., Davidson J., Zulian F., Asplin L., Baildam E., Consuegra J. G., Ozdogan H., Saurenmann R., Joos R., Pistorio A., Woo P., Martini A. Pediatric Rheumatology International Trials Organization. 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.Ruperto N., Murray K. J., Gerloni V., Wulffraat N., de Oliveira S. K., Falcini F., Dolezalova P., Alessio M., Burgos-Vargas R., Corona F., Vesely R., Foster H., Davidson J., Zulian F., Asplin L., Baildam E., Consuegra J. G., Ozdogan H., Saurenmann R., Joos R., Pistorio A., Woo P., Martini A. Pediatric Rheumatology International Trials Organization. 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.Foeldvari I., Wierk A. Methotrexate is an effective treatment for chronic uveitis associated with juvenile idiopathic arthritis. J. Rheumatol. 2005; 32: 362–365.Foeldvari I., Wierk A. Methotrexate is an effective treatment for chronic uveitis associated with juvenile idiopathic arthritis. J. Rheumatol. 2005; 32: 362–365.Heiligenhaus A., Mingels A., Heinz C., Ganser G. Methotrexate for uveitis associated with juvenile idiopathic arthritis: value and requirement for additional anti-inflammatory medication. Eur. J. Ophthalmol. 2007; 17 (5): 743–748.Heiligenhaus A., Mingels A., Heinz C., Ganser G. Methotrexate for uveitis associated with juvenile idiopathic arthritis: value and requirement for additional anti-inflammatory medication. Eur. J. Ophthalmol. 2007; 17 (5): 743–748.Simonini G., Paudyal P., Jones G. T., Cimaz R., Macfarlane G. J. Current evidence of methotrexate efficacy in childhood chronic uveitis: a systematic review and meta-analysis approach. Rheumatology (Oxford). 2013; 52 (5): 825–831.Simonini G., Paudyal P., Jones G. T., Cimaz R., Macfarlane G. J. Current evidence of methotrexate efficacy in childhood chronic uveitis: a systematic review and meta-analysis approach. Rheumatology (Oxford). 2013; 52 (5): 825–831.Ayuso V. K., van de Winkel E. L., Rothova A., de Boer J. H. Relapse rate of uveitis post-methotrexate treatment in juvenile idiopathic arthritis. Am. J. Ophthalmol. 2011; 151: 217–222.Ayuso V. K., van de Winkel E. L., Rothova A., de Boer J. H. Relapse rate of uveitis post-methotrexate treatment in juvenile idiopathic arthritis. Am. J. Ophthalmol. 2011; 151: 217–222.Beukelman T., Patkar N. M., Saag K. G., Tolleson-Rinehart S., Cron R. Q., DeWitt E. M., Ilowite N. T., Kimura Y., Laxer R. M., Lovell D. J., Martini A., Rabinovich C. E., Ruperto N. 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: initiation and safety monitoring of therapeutic agents for the treatment of arthritis and systemic features. Arthritis Care Res. 2011; 63: 465–482.Beukelman T., Patkar N. M., Saag K. G., Tolleson-Rinehart S., Cron R. Q., DeWitt E. M., Ilowite N. T., Kimura Y., Laxer R. M., Lovell D. J., Martini A., Rabinovich C. E., Ruperto N. 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: initiation and safety monitoring of therapeutic agents for the treatment of arthritis and systemic features. Arthritis Care Res. 2011; 63: 465–482.Papadopoulou C., Kostik M., Bohm M., Nieto-Gonzalez J. C., Gonzalez-Fernandez M. I., Pistorio A., Martini A., Ravelli A. Methotrexate Therapy May Prevent the Onset of Uveitis in Juvenile Idiopathic Arthritis. J. Pediatr. 2013; 163: 879–884.Papadopoulou C., Kostik M., Bohm M., Nieto-Gonzalez J. C., Gonzalez-Fernandez M. I., Pistorio A., Martini A., Ravelli A. Methotrexate Therapy May Prevent the Onset of Uveitis in Juvenile Idiopathic Arthritis. J. Pediatr. 2013; 163: 879–884.Petty R. E., Southwood T. R., Manners P., Baum J., Glass D. N., Golden berg J., He X., Maldonado-Cocco J., Orozco-Alcala J., Prieur A. M., Suarez-Almazor M. E., Woo P. International League of Associa tions for Rheumatology. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J. Rheumatol. 2004; 31: 390–392.Petty R. E., Southwood T. R., Manners P., Baum J., Glass D. N., Golden berg J., He X., Maldonado-Cocco J., Orozco-Alcala J., Prieur A. M., Suarez-Almazor M. E., Woo P. International League of Associa tions for Rheumatology. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J. Rheumatol. 2004; 31: 390–392.Bloch-Michel E., Nussenblatt R. B. International Uveitis Study Group recommendations for the evaluation of intraocular inflammatory disease. Am. J. Ophthalmol. 1987; 103: 234–235.Bloch-Michel E., Nussenblatt R. B. International Uveitis Study Group recommendations for the evaluation of intraocular inflammatory disease. Am. J. Ophthalmol. 1987; 103: 234–235.Jabs D. A., Nussenblatt R. B., Rosenbaum J. T. Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am. J. Ophthalmol. 2005; 140 (3): 509–516.Jabs D. A., Nussenblatt R. B., Rosenbaum J. T. Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am. J. Ophthalmol. 2005; 140 (3): 509–516.Puchta J., Hattenbach L. O., Baatz H. Intraocular levels of methotrexate after oral low-dose treatment in chronic uveitis. Ophthalmologica. 2005; 219 (1): 54–55.Puchta J., Hattenbach L. O., Baatz H. Intraocular levels of methotrexate after oral low-dose treatment in chronic uveitis. Ophthalmologica. 2005; 219 (1): 54–55.de Smet M. D., Stark-Vancs V., Kohler D. R., Smith J., Wittes R., Nussenblatt R. B. Intraocular levels of methotrexate after intravenous administration. Am. J. Ophthalmol. 1996; 121 (4): 442–444.de Smet M. D., Stark-Vancs V., Kohler D. R., Smith J., Wittes R., Nussenblatt R. B. Intraocular levels of methotrexate after intravenous administration. Am. J. Ophthalmol. 1996; 121 (4): 442–444.Foeldvari I., Thme N., Horneff G. Methotrexate is protective against the new onset of uveitis under etanercept treatment. Data from the German Etanercept Registry. Ann. Rheum. Dis. 2010; 69 (Suppl. 3): 626.Foeldvari I., Thme N., Horneff G. Methotrexate is protective against the new onset of uveitis under etanercept treatment. Data from the German Etanercept Registry. Ann. Rheum. Dis. 2010; 69 (Suppl. 3): 626.

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