RETROSPECTIVE ANALYSIS OF EFFICACY AND SAFETY OF HYPODERMIC METHOTREXATE INJECTIONS IN PATIENTS WITH JUVENILE IDIOPATHIC ARTHRITIS

Aim: to assess efficacy and safety of hypodermic methotrexate injections in children aged from 1,5 to 16 years old with juvenile idiopathic arthritis (JIA) without extra-articular manifestations. Patients and methods: the results of treatment of 104 patients with JIA without systemic manifestations (61 girls and 43 boys) aged 5,0 (1,5–16) years old being followed-up in the rheumatology department of FSFI «SCCH» of RAMS were analyzed. The mean duration of the disease at the moment of methotrexate first administration was 6 months. Efficacy of methotrexate therapy was assessed according to the pediatric criteria for improvement of the American College of Rheumatology. The percentage of non-active stage and medicinal remission achievement were considered to be the target characteristics of therapy efficacy. Results: 61 patients (59%) were maintained in the study during 1 year. In 12 months of treatment remission according to C. Wallace criteria was induced in 39 of 104 (38%) children. In 22 (21%) of patients who failed to achieve remission in 1 year of treatment, 70% improvement was observed. Side effects were found in 45 (43%) of children: mild and moderate — in 33 (32%), severe — in 12 (12%) of patients. In 9 patients methotrexate was withdrawn due to intolerance of the drug. These patients as well as 34 children with resistance to performed treatment were administered genetically engineered biological agents. Conclusions: hypodermic injections of methotrexate are highly efficient in patients with JIA without extra-articular manifestations. Early administration at the dose of 15 mg/m² of body surface as well as appropriate selection of administration form induced remission and allowed to prevent of disability development in 38% of children.

1. Cassidy J., Petty R. Texbook of paediatric rheumatology, 6th еd. Philadelphia: Saunders Elsevier. 2010. 9 p.

2. Alekseeva E. I., Litvitskii P. F. Revmatoidnyi artrit. Etiologiya, patogenez. Klinika. Algoritmy diagnostiki i lecheniya [Rheumatoid Arthritis. Etiology and Pathogenesis. Clinical Pictire. Scheme of Diagnosis and Treatment]. Moscow, Vedi, 2007. 359 p.

3. Denisova R. V., Alekseeva E. I., Al'bitskii V.Yu., Vinyarskaya I. V., Valieva S. Voprosi sovremennoi pediatrii — Current Pediatrics. 2009; 8 (3): 18–26.

4. Baranov A. A., Nasonov E. L., Alekseeva E. I., Erdes Sh. F., Il'in A. G. Voprosi sovremennoi pediatrii — Current Pediatrics. 2007; 6 (1): 6–8.

5. Kroot E. J. A., van Leeuwen M. A., van Rijswijk M. H. et al. No increased mortality in patient with rheumatoid arthritis: up to 10 years of follow-up from disease onset. Ann. Rheum. Dis. 2000; 59: 954–958.

6. Klinicheskie rekomendatsii. Revmatologiya. Pod red. E. L. Nasonova [Clinical Recommendations. Rheumatology. Edited by E. L. Nasonov]. Moscow, GEOTAR-Media, 2005. pp. 25–71, 120–140.

7. Beukelman T., Patkar N. M., Saag K. G., Tolleson-Rinehart S., Cron R. Q., Morgan Dewitt E., 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. Arthr. Care Res. 2011; 63 (4): 465–482.

8. Fleischmann R. Safety and efficacy of disease-modifying antirheumatic agents in rheumatoid arthritis and juvenile rheumatoid arthritis. Exp. Opin. Drug. Saf. 2003; 2 (4): 347–365.

9. Baranov A. A., Alekseeva E. I., Bzarova T. M., Valieva S. I., Denisova R. V., Isaeva K. B., Karagulyan N. A., Litvitskii P. F., Mitenko E. V., Sleptsova T. V., Fetisova A. N., Chistyakova E. G., Taibulatov N. I., Morev S.Yu. Voprosi sovremennoi pediatrii — Current Pediatrics. 2013; 12 (1): 37–56.

10. Hashkes P. J., Laxer R. M. Medical treatment of juvenile idiopathic arthritis. JAMA. 2005; 294 (13): 1671–1684.

11. Nasonov E. L. Protivovospalitel'naya terapiya revmaticheskikh boleznei [Preventive Therapy of Rheumatic Diseases]. Moscow, M-Siti, 1996. 345 p.

12. Tynjala P., Vahasalo P., Tarkiainen M., Kroger L., Aalto K., Malin M., Putto-Laurila A., Honkanen V., Lahdenne P. Aggressive combination drug therapy in very early polyarticular juvenile idiopathic arthritis (ACUTE-JIA): a multicentre randomised open-label clinical trial. Ann. Rheum. Dis. 2011; 70.

13. Visvanathan S., Wagner C., Marini J. C., Lovel D. J., Martini A., Petty R., Cuttica R., Woo P., Espada G., Gattorno M., Apaz M. T., Baildam E., Fasth A., Gerloni V., Lahdenne P., Quartier P., Saurenmann R., Travers S., Mendelsohn A., Xu S., Giannini E. H., Ruperto N. for the Paediatric Rheumatology International Trials Organization (PRINTO) and the Pediatric Rheumatology Collaborative Study Group (PRCSG). The effect of infliximab plus methotrexate on the modulation of inflammatory disease markers in juvenile idiopathic arthritis: analyses from a randomized, placebo-controlled trial. Pediatr. Rheumatol. 2010; 8: 24.

14. Alarcon G. S. Methotrexate: Its use for the treatment of rheumatoid arthritis and other rheumatic disorders. In: Arthritis and Allied Conditions. A Text book of rheumatology, 13th Edn. W. J. Koopman (еd.). Baltimore, Philadelphia, London: Williams & Wilkins. 1997; 1: 679–698.

15. Cronstein B. N. The mechanism of action of methotrexate. Rheum. Dis. Clin. North Am. 1997; 23: 739–755.

16. Tambic-Bukovac L., Malcic I., Prohic A. Personal experience with methotrexate in the treatment of idiopathic juvenile arthritis. Rheumatism. 2002; 49 (1): 20–24.

17. Cassidy J. T. Outcomes research in the therapeutic use of methotrexate in children with chronic peripheral arthritis. J. Pediatr. 1998; 133: 179–180.

18. Klein A., Kaul I., Foeldvari I., Ganser G., Urban A., Horneff G. Efficacy and safety of oral and parenteral methotrexate therapy in children with juvenile idiopathic arthritis: an observational study with patients from the German Methotrexate Registry. Arthr. Care Res. (Hoboken). 2012; 64 (9): 1349–1356.

19. Ramanan A. V., Whitworth P., Baildam E. M. Use of methotrexate in juvenile idiopathic arthritis. Arch. Dis. Child. 2003; 88: 197–200.

20. Yokota S. Classification and treatment strategy for juvenile idiopathic arthritis. Therapy. 1999; 81: 766–772.

21. Giannini E. H., Brewer E. J., Kuzmina N. et al. Methotrexate in resistant juvenile rheumatoid arthritis. Results of the USA-USSR double-blind, placebo-controlled trial. The Pediatric RheumatologyCollaborative Study Group and The Cooperative Children’s Study Group. N. Engl. J. Med. 1992; 326: 1043–1049.

22. Woo P., Southwood T. R., Prieur A. M. et al. Randomized, placebocontrolled, crossover trial of low-dose oral methotrexate in children with extended oligoarticular or systemic arthritis. Arthr. Rheum. 2000; 43 (8): 1849–1857.

23. Silverman E., Mouy R., Spiegel L. et al. Leflunomide or methotrexate for juvenile rheumatoid arthritis. N. Engl. J. Med. 2005; 352: 1655–1666.

24. Albertioni F., Flato B., Seideman P. et al. Methotrexate in juvenile rheumatoid arthritis. Evidence of age dependent pharmacokinetics. Eur. J. Clin. Pharmacol. 1995, 47 (6): 507–511.

25. Tukova J., Chladek J., Nemcova D. et al. Methotrexate bioavaila bility after oral and subcutaneous administration in children with juvenile idiopathic arthritis. Clin. Exp. Rheumatol. 2009; 27 (6): 1047–1053.

26. Ruperto N., Murray K. J., 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: 2191–2201.

27. Alsufyani K., Ortiz-Alvarez O., Cabral D. A. et al. The role of subcutaneous administration of methotrexate in children with juvenile idiopathic arthritis who have failed oral methotrexate. J. Rheumatol. 2004; 31 (1): 179–182.

28. Kugathasan S., Newman A. J., Dahms B. B. et al. Liver biopsy findings liver in patients with juvenile rheumatoid arthritis receiving longterm, weekly methotrexate therapy. J. Pediatr. 1996; 128 (1): 149– 151.

29. Cron R. Q., Sherry D. D., Wallace C. A. Methotrexate-induced hypersensitivity pneumonitis in a child with juvenile rheumatoid arthritis. J. Pediatr. 1998; 132 (5): 901–902.