Efficacy and Safety of Prolonged Rituximab Treatment in Patients with Systemic Juvenile Idiopathic Arthritis

Aim: to assess efficacy and safety of rituximab treatment in children with systemic juvenile idiopathic arthritis under prolonged follow-up. Patients and methods: results of treatment of 60 children (33 girls and 27 boys) with systemic variant of juvenile idiopathic arthritis being followed-up in rheumatology department of the Federal State Institution «Scientific Centre of Children Health» of RAMS (FSI «SCCH» RAMS) were analyzed. The mean age of children was 8,7 years. The mean duration of disease course at the moment of first rituximab administration was 5,3 years. At the beginning of rituximab therapy all children had active articular syndrome, severe systemic manifestations and significantly increased laboratory markers of activity. As the signs of improvement the authors used pediatric criteria of the American College of Rheumatology. The treatment was approved by the local ethic committee of the FSI «SCCH» RAMS; the patients’ representatives and patients older than 14 years old had signed informed agreement. Results: remission was induced in 26 of 60 (43%) patients: in 9 of them after the 1^st course of treatment, in 8 — after the 2^nd, in 6 — after the 3d and in 3 — after the 4^th. The maximal duration of remission was 5 years 4 months, minimal — 6 months. Other genetically engineered drugs were administered to 34 (57%) of the patients: due to the primary inefficiency in 15, secondary inefficiency — in 10; due to partial inefficiency — in 9 children. The drug was well-tolerated in most of the patients. Undesirable effects were represented by transfusional reactions to the rituximab infusion, infections with different severity and granulocytopenia. Conclusions: rituximab has high efficiency in patients with severe systemic variant of juvenile idiopathic arthritis. The drug induced remission in patients who had been considered almost incurable, with low status of physical and social adaptation.

1. Petty R. E., Southwood T. R., Manners P. et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J. Rheumatol. 2004; 31: 390–392.

2. Lomater C., Gerloni V., Gattinara M., Mazzotti J., Cimaz R., Fantini F. Systemic onset juvenile idiopathic arthritis: a retrospective study of 80 consecutive patients followed for 10 years. J. Rheumatol. 2000; 27: 491–496.

3. Lawrence R. C., Helmick C. G., Arnett F. C. et al. Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States. Arthritis Rheum. 1998; 41: 778–799.

4. Рабсон А., Ройт А., Делвз П. Основы медицинской иммуноло- гии. М.: Мир. 2006. С. 67, 114–125, 143–145.

5. Pillai S. The chosen few? Positive selection and the generation of naive B lymphocytes. Immunity. 1999; 10: 493–502.

6. Porakishvili N. et al. Recent progress in the understanding of B cell functions in autoimmunity. Scand. J. Immunol. 2001; 54: 30–38.

7. Jonathan C. W., Edwards M. D., Leszek Szczepaґnski et al. Efficacy of B cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N. Engl. J. Med. 2004; 350: 2572–2581.

8. Gause A., Berek C. The role of B cells in the pathogenesis of rheumatoid arthritis: potential implications for treatment. Bio-Drugs. 2001; 15: 73–79.

9. Panayi G. S. The immunopathogenesis of rheumatoid arthritis. Brit. J. Rheumatol. 1993; 32 (Suppl. 1): 4–14.

10. Edwards J. C., Cambridge G., Abrahams V. M. Do self-perpetuating B lymphocytes drive human autoimmune disease? Immunology. 1999; 97: 188–196.

11. Zhang Z., Bridges S. L., Jr. Pathogenesis of rheumatoid arthritis: role of B lymphocytes. Rheum. Dis. Clin. North Am. 2001; 27: 335–353.

12. Edwards J. C., Cambridge G. Sustained improvement in rheumatoid arthritis following a protocol designed to eplete B lymphocytes. Rheumatology (Oxford). 2001; 40: 205–211.

13. Cheson B. D., Leonard J. P. Monoclonal antibody therapy for B cell non-Hodgkin's lymphoma. N. Engl. J. Med. 2008; 359: 613–626.

14. Schulz H., Bohlius J., Skoetz N., Trelle S., Kober T., Reiser M., Dreyling M., Herold M., Schwarzer G., Hallek M., Engert A. Chemotherapy plus rituximab versus chemotherapy alone for B cell non-Hodgkin’s lymphoma. Cochr. Database Syst. Rev. 2007; 4: CD003805.

15. Jansson A. F., Sengler C., Kuemmerle J. et al. B cell depletion for autoimmune diseases in paediatric patients. Clin. Rheumatol. 2011; 30: 87–97.

16. van Vollenhoven R. F., Schechtman J., Szczepanski L. J. et al. Safety and tolerability of rituximab in patients with moderate to severe rheumatoid arthritis: Results from the dose-ranging assessment international clinical evaluation of rituximab in rheumatoid arthritis (DANCER) study. Presented at the Annual Scientific Meeting of the American College of Rheumatology in San Diego, California. November 12–17, 2005. ACR Abstract #1922.

17. Fleischmann R. M., Racewicz A. J., Schechtman J. et al. Rituximab efficacy in rheumatoid arthritis is independent of coadministration of glucocorticoids: Results from the doseranging assessment international clinical evaluation of rituximab in rheumatoid arthritis (DANCER) study. Presented at the 2005 ACR/ARHP Annual Scientific Meeting in San Diego, California. November 12–17, 2005. ACR/ARHP Abstract #263.

18. Alexeeva E., Bzarova T., Amital H. et al. Efficacy of rituximab retreatment in refractory juvenile idiopathic arthritis. Clin. Exp. Rheumatol. 2010; 29 (Suppl. 2): 378.

19. Alexeeva E., Valieva S., Bzarova T. et al. Efficacy of rituximab retreatment in refractory systemic juvenile idiopathic arthritis. Presented at the American College of Rheumatology in Chicago, Illinois. November 4–9, 2011. ACR Abstract #2626.

20. Alexeeva E., Valieva S., Bzarova T. et al. Efficacy and safety of repeat courses of rituximab treatment in patients with severe refractory juvenile idiopathic arthritis. Clin. Rheumatol. 2011; 30: 1163–1172.

21. Wallace C. A., Giannini E. H., Huang В., Itert L., Ruperto N. Childhood Arthritis Rheumatology Research Alliance (CARRA), Pediatric Rheumatology Collaborative Study Group (PRCSG) and Paediatric Rheumatology International Trials Organisation (PRINTO), American College of Rheumatology provisional criteria for defining clinical inactive disease in select categories of juvenile idiopathic arthritis. Arthritis Care Res. 2011; 63: 929–936.

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. Arthritis Rheum. 2000; 43: 1849–1857.

23. Horneff G., De Bock F., Foeldvari I. et al. Safety and efficacy of combination of etanercept and methotrexate compared to treatment with etanercept only in patients with juvenile idiopathic arthritis (JIA): preliminary data from the German JIA Registry. Ann. Rheum. Dis.