Dynamics of Destructive Joint Changes in Juvenile Idiopathic Arthritis in Children who Received Methotrexate or Methotrexate-Tocilizumab Combination: a Cohort Study

Background. Destructive joint damages in juvenile arthritis inevitably lead to persistent disability in adulthood. These consequences can be avoided by resorting to early therapy of the disease.

Objective. Our aim was to assess the dynamics of destructive joint changes in juvenile idiopathic arthritis (JIA) in children, depending on a basic therapy.

Methods. We studied the treatment results of children with systemic-onset JIA with active joint syndrome without active  systemic manifestations hospitalized in the regional clinical  cardiological health center. JIA activity criteria at the time of  hospitalization: 3 joints with active arthritis; the assessment of the disease activity by a doctor 3 points out of 10; the assessment of  wellbeing by the patient or a parent 3 points out of 10; the  appointment of basic therapy no later than 6 months from the  disease onset. Treatment results were compared in the groups of  methotrexate (hospitalization from January 2008 to December 2010) and methotrexate + tocilizumab (January 2014 — September 2016). The main outcome of JIA therapy was the severity of joint  destruction in 6, 12 and 24 months as determined by the modified  Sharpe ratio according to radiographs obtained from patients' medical records.

Results. The study groups were comparable in terms of sex and age of the patients, JIA onset age, the disease activity at the time of  hospitalization, and the initial assessment of joint destruction —  (median) 165 (131; 187) and 162 (124; 171) (p = 0.116). Under  pressure of therapy, the modified Sharpe score in the group of  methotrexate monotherapy was higher than in the group of combined therapy: in 6 months — 142 (126; 163) and 87 (72; 112) (p < 0.001); in 12 months — 166 (121; 210) and 75 (29; 89) (p <  0.001); in 24 months — 165 (113; 198) and 52 (26; 73) (p <  0.001). At the first administration of tocilizumab, 4 children had nausea and abdominal pain, and 3 children had headache.

Conclusion. Basic therapy with methotrexate and tocilizumab  inhibits the destruction of joints in patients with systemic-onset JIA  with active joint syndrome without active systemic manifestations.

1. Ювенильный артрит. Клинические рекомендации для педиатров: Детская ревматология / Под ред. Баранова А.А., Алексеевой Е.И. — М.: ПедиатрЪ; 2013. — 120 с. [Yuvenil’nyi artrit. Klinicheskie rekomendatsii dlya pediatrov: Detskaya revmatologiya. Ed by Baranov A.A., Alexeeva E.I. Moscow: Paediatrician Publishers; 2013. 120 p. (In Russ).]

2. Алексеева Е.И., Бзарова Т.М. Алгоритм диагностики и лечения ювенильного артрита // Вопросы современной педиатрии. — 2010. — Т. 9. — № 6 — С. 78–104. [Alexeeva EI, Bzarova TM. Algorithm of diagnostics and treatment of juvenile arthritis. Current pediatrics. 2010;9(6):78–104. (In Russ).]

3. van Dijkhuizen EH, Wulffraat NM. Prediction of methotrexate efficacy and adverse events in patients with juvenile idiopathic arthritis: a systematic literature review. Pediatr Rheumatol Online J. 2014;12:51. doi: 10.1186/1546-0096-12-51.

4. Boers M. Understanding the window of opportunity concept in early rheumatoid arthritis. Arthritis Rheum. 2003;48(7): 1771–1774. doi: 10.1002/art.11156.

5. Kearsley-Fleet L, McErlane F, Foster HE, et al. Effectiveness and safety of TNF inhibitors in adults with juvenile idiopathic arthritis. RMD Open. 2016;2(2):e000273. doi: 10.1136/rmdopen-2016-000273.

6. Beukelman T, Patkar NM, Saag KG, et al. 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 (Hoboken). 2011;63(4):465–482. doi: 10.1002/acr.20460.

7. Виноградова Н.А. Влияние комбинированной терапии глюкокортикостероидами и метотрексатом на суставную деструкцию при ревматоидном артрите: Автореф. дисс. ... канд. мед. наук. — М.; 2004. [Vinogradova NA. Vliyanie kombinirovannoi terapii glyukokortikosteroidami i metotreksatom na sustavnuyu destruktsiyu pri revmatoidnom artrite. [dissertation abstract] Moscоw; 2004. (In Russ).] Доступно по: http://www.dissercat.com/content/vliyaniekombinirovannoi-terapii- glyukokortikosteroidami-i-metotreksatomna-sustavnuyu-destr. Ссылка активна на 12.11.2017.

8. Wallace CA, Sherry DD, Mellins ED, Aiken RP. Predicting remission in juvenile rheumatoid arthritis with methotrexate treatment. J Rheumatol. 1993;20(1):118–122.

9. Reiff A, Shaham B, Wood BP, et al. High dose methotrexate in the treatment of refractory juvenile rheumatoid arthritis. Clin Exp Rheumatol. 1995;13(1):113–118.

10. Harel L, Wagner-Weiner L, Poznanski AK, et al. Effects of methotrexate on radiologic progression in juvenile rheumatoid arthritis. Arthritis Rheum. 1993;36(10):1370–1374. doi: 10.1002/art.1780361007.

11. Prieur AM, Malleson PN, Kimura Y. Systemic arthritis. In: Szer LS, Kimura Y, Malleson PN, Southwood TR, editors. Arthritis in children and adolescents: juvenile idiopathic arthritis. NY, USA: Oxford University Press; 2006. pp. 210–222.

12. Szer LS, Kimura Y, Malleson PN, Southwood TR, editors. Arthritis in children and adolescents: juvenile idiopathic arthritis. NY, USA: Oxford University Press; 2006. 456 p.

13. Вакуленко О.Ю., Кричевская О.А., Эрдес Ш.Ф. Про грессирование деструкции суставов у больных ревматоидным артритом // Научно-практическая ревматология. — 2011. — № 3 — С. 69–74. [Vakulenko OYu, Krichevskaya OA, Erdes ShF. Progression of joint destruction in patients with rheumatoid arthritis. Rheumatology Science and Practice. 2011; (3):69–74. (In Russ).] doi: 10.14412/1995-4484-2011-575.

14. Brunner HI, Ruperto N, Zuber Z, et al. Efficacy and safety of tocilizumab in patients with polyarticular-course juvenile idiopathic arthritis: results from a phase 3, randomised, double-blind withdrawal trial. Ann Rheum Dis. 2015;74(6):1110–1117. doi: 10.1136/annrheumdis-2014-205351.

15. Родионовская С.Р., Никишина И.П. «Эра метотрексата» в детской ревматологии // Вопросы современной педиатрии. — 2006. — Т. 5. — № 3 — С. 31–39. [ Rodionovskaya SR, Nikishina IP. «Methotrexate era» in children rheumatology. Current pediatrics. 2006;5(3):31–39. (In Russ).]

16. Матвеева Н.В., Манеров Ф.К., Котович М.М. Применение высоких доз метотрексата в лечении системных форм ревматоидного артрита у детей // Мать и дитя в Кузбасе. — 2005. — № 1 — С. 16–19. [Matveeva NV, Manerov FK, Kotovich MM. Primenenie vysokikh doz metotreksata v lechenii sistemnykh form revmatoidnogo artrita u detei. Mat’ i ditya v Kuzbase. 2005;(1): 16–19. (In Russ).]

17. Матюнова А.Е. Факторы риска деструктивных повреждений суставов у детей с ювенильным идиопатическим артритом: Автореф. дисс. ... канд. мед. наук. — Новосибирск; 2013. [Matyunova AE. Faktory riska destruktivnykh povrezhdenii sustavov u detei s yuvenil’nym idiopaticheskim artritom. [dissertation abstract] Novosibirsk; 2013. (In Russ).] Доступно по: http://medical-diss.com/medicina/faktoryriska-destruktivnyh- povrezhdeniy-sustavov-u-detey-s-yuvenilnymidiopaticheskim-artritom. Ссылка активна на 12.11.2017.

18. Кричевская О.А., Горячев Д.В., Смирнов А.В., Эрдес Ш.Ф. Некоторые методы оценки прогрессирования рентгенологических проявлений ревматоидного артрита // Научно- практическая ревматология. — 2007. — Т. 45. — № 2 — С. 56–63. [Krichevskaya OA, Goryachev DV, Smirnov AV, Erdes SF. Methods of rheumatoid arthritis radiological progression assessment. Rheumatology Science and Practice. 2007;45(2):56–63. (In Russ).] doi: 10.14412/1995-4484-2007-839.

19. rlsnet.ru [интернет]. Справочник «Электронная энциклопедия лекарств». Серия РЛС. 2017 [доступ от 21.11.2017]. [Spravochnik «Elektronnaya entsiklopediya lekarstv». Seriya RLS. 2017 (In Russ).] Доступ по ссылке https://www.rlsnet.ru/.

20. Ravelli A. The time has come to include assessment of radiographic progression in juvenile idiopathic arthritis clinical trials. J Rheumatol. 2008;35(4):553–557.

21. 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.

22. Насонов Е.Л., Насонова В.А. Ревматология. Национальное руководство. — М.: ГЭОТАР-Медиа; 2008. 282 с. [Nasonov EL, Nasonova VA. Revmatologiya. Natsional’noe rukovodstvo. Moscow: Geotar-Media; 2008. 282 p. (In Russ).]

23. Giancane G, Consolaro A, Lanni S, et al. Radiographic damage in hands and wrists of patients with juvenile idiopathic arthritis after 29 years of disease duration. Pediatr Rheumatol Online J. 2017;15(1):20. doi: 10.1186/s12969-017-0151-7.

24. Ravelli A, Ioseliani M, Norambuena X, et al. Adapted versions of the Sharp/van der Heijde score are reliable and valid for assessment of radiographic progression in juvenile idiopathic arthritis. Arthritis Rheum. 2007;56(9):3087–3095. doi: 10.1002/art.22835.

25. 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.

26. Shepherd J, Cooper K, Harris P, et al. The clinical effectiveness and cost-effectiveness of abatacept, adalimumab, etanercept and tocilizumab for treating juvenile idiopathic arthritis: a systematic review and economic evaluation. Health Technol Assess. 2016;20(34):1–222. doi: 10.3310/hta20340.

27. Brennan P, Harrison В, Barrett Е. A simple algorithm to predict the development of radiological erosions in patients with early rheumatoid arthritis: prospective cohort study. BMJ. 1996; 313(7055):471–476. doi: 10.1136/bmj.313.7055.471.