Can the Methotrexate Therapy Prevent the Development of Uveitis in Patients with Juvenile Idiopathic Arthritis: Results of a Retrospective Study

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

1. 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.

2. Rosenberg K. D., Feuer W. J., Davis J. L. Ocular complications of paediatric uveitis. Ophthalmology. 2004; 111: 2299–2306.

3. De Boer J., Wulffraat N., Rothova A. Visual loss in uveitis of childhood. Brit. J. Ophthalmol. 2003; 87: 879–884.

4. 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.

5. Ravelli A., Martini A. Juvenile idiopathic arthritis. Lancet. 2007; 369: 767–778.

6. 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.

7. 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.

8. 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.

9. 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.

10. 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.

11. 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.

12. 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.

13. Heiligenhaus A., Minden K., Foll D., Pleyer U. Uveitis in Juvenile Idiopathic Arthritis. Dtsch. Arztebl. Int. 2015; 112 (6): 92–100.

14. Wentworth B. A., Freitas-Neto C. A., Foster C. S. Management of pediatric uveitis. F1000 Prime Rep. 2014; 6: 41.

15. 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.

16. 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.

17. Foeldvari I., Wierk A. Methotrexate is an effective treatment for chronic uveitis associated with juvenile idiopathic arthritis. J. Rheumatol. 2005; 32: 362–365.

18. 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.

19. 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.

20. 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.

21. 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.

22. 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.

23. 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.

24. 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.

25. 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.

26. 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.

27. 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.

28. 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.