Efficacy and Safety of Adalimumab Long-Term Administration with Immunosuppressants at Juvenile Idiopathic Arthritis without Systemic Manifestations

Background: Treatment of patients with juvenile idiopathic arthritis (JIA) is one of the most complex and urgent problems of rheumatology.

Objective: Our aim was to evaluate the efficacy and safety of adalimumab therapy combined with immunosuppressants in patients with JIA without systemic manifestations.

Methods: A monocentre observational comparative study was held. We studied the results of treatment of patients with JIA being treated with adalimumab combined with immunosuppressants (n = 215) and methotrexate (n = 200). The efficacy of the therapy was evaluated using the paediatric criteria of the American College of Rheumatology (ACRpedi) and remission criteria by C. Wallace during 5 years.

Results: After 6 and 12 months the remission of articular syndrome was registered in 72 and 81% of patients treated with adalimumab combined with immunosuppressants, and in 53 and 65% treated with methotrexate. Laboratory indicators of the disease activity corresponded to the reference values after 6 months in 73 and 48%, after 12 months — in 94 and 68% of patients in the comparison groups, respectively. After 6 and 12 months of supervision the activity according to the CHAQ questionnaire was fully recovered in 63 and 79%; 47 and 62% of children. After 1 month the improvement according to the ACRpedi30/50/70 criteria was registered in 87/54/25% of the observed treated with adalimumab. After 6 months the ACRpedi30/50/70 index was 93/89/76% and 63/57/47% for adalimumab therapy with immunosuppressants and methotrexate, respectively. Adalimumab combined with immunosuppressants more quickly than methotrexate induced the stage of inactive disease/remission — after 5 (3; 8) and 12 (6; 18) months, respectively (p < 0.001). After 6 and 12 months of supervision the stage of inactive disease/remission was reported in 43 and 47% of patients treated with adalimumab combined with immunosuppressants, and in 9 and 38% of patients receiving the methotrexate therapy. Adalimumab and methotrexate were well tolerated by 58 and 73% of patients with JIA without systemic manifestations. The adverse events were reported in 42 and 27% of patients, but became the reason for drug dechallenge only in 6 and 10% of patients.

Conclusion: Adalimumab combination therapy combined with immunosuppressants has faster and more evident anti-inflammatory effect than the treatment with classical immunosuppressant methotrexate.

1. Baranov AA. Pediatrics. Clinical guidelines. Мoscow: GEOTAR-Media; 2009. p. 387–420. (In Russ).

2. Cassidy JT, Petty RE, Laxer RM, Lindsley CB. Textbook of pediatric rheumatology. 6th edn. Philadelphia: Saunders Elsevier; 2011. 794 p.

3. Hashkes PJ, Laxer RM. Medical treatment of juvenile idiopathic arthritis. JAMA. 2005;294(13):1671–1684. doi: 10.1001/jama.294.13.1671.

4. Horneff G. Update on biologicals for treatment of juvenile idiopathic arthritis. Exp Opin Biol Ther. 2013;13(3):361–376. doi: 10.1517/14712598.2013.735657.

5. El-Gabalawy HS, Lipsky PE. Why do we not have a cure for rheumatoid arthritis? Arthritis Res. 2004;4 (Suppl 3):297–301. doi: 10.1186/ar568.

6. Foster HE, Marshall N, Myers A, et al. Outcome in adults with juvenile idiopathic arthritis: a quality of life study. Arthritis Rheum. 2003;48(3):767–775. doi: 10.1002/art.10863.

7. Minden K, Niewerth M, Listing J, et al. Long-term outcome in patients with juvenile rheumatoid arthritis. Arthritis Rheum. 2002;46(9):2392–2401. doi: 10.1002/art.10444.

8. Woo P, Wilkinson N, Prieur AM, et al. Open label phase 2 trial of single, ascending doses of MRA in Caucasian children with severe systemic juvenile idiopathic arthritis: proof of principle of efficacy of IL-6 receptor blocade in this type of arthritis and demonstration of prolonged clinical improvement. Arthritis Res Ther. 2005;7:1281–1288.

9. Alexeeva EI, Baranov AA. Guidelines on biological therapy. Moscow; 2011. p. 247. (In Russ).

10. 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. (Hobooken). 2011;63(4):465–482. doi: 10.1002/acr.20460.

11. Nasonov EL, Karataev DE. The use of genetically engineered biological drugs for the treatment of rheumatoid arthritis: general overview (lecture). Nauchno-prakticheskaja revmatologiya. 2013;51(2):163–169. (In Russ).

12. de Vries HS, van Oijen MG, Driessen RJ, et al. Appropriate infliximab infusion dosage and monitoring: results of a panel meeting of rheumatologists, dermatologists and gastroenterologists. Brit J Clin Pharmacol. 2011;71(1):7–19. doi: 10.1111/j.1365-2125.2010.03760.x.

13. Alonso-Ruiz A, Pijoan JI, Ansuategui E, et al. Tumor necrosis factor alpha drugs in rheumatoid arthritis: systematic review and metaanalysis of efficacy and safety. BMC Musculoskelet Disord. 2008;9(1):52. doi: 10.1186/1471-2474-9-52.

14. Breedveld FC, Weisman MH, Kavanaugh AF, et al. The PREMIER study a multicenter, randomized, double blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum. 2006;54:26–37.

15. Kievit W, Adang EM, Fransen J. The effectiveness and medication costs of three antitumour necrosis factor alpha agents in the treatment of rheumatoid arthritis from prospective clinical practice data. Ann Rheum Dis. 2008;67(9):1229–1234. doi: 10.1136/ard.2007.083675.

16. Burmester GR, Mariette X, Montecucco C, et al. Adahmumab alone and in combination with disease-modifying antirheumatic drugs for the treatment of rheumatoid arthritis in clinical practice the Research in Active Rheumatoid Arthritis (ReAct) trial. Ann Rheum Dis. 2007;66(6):732-739. doi: 10.1136/ard.2006.066761.

17. Weinblatt ME, Keystone EC, Furst DE, et al. Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum. 2003;48:35–45. doi: 10.1002/art.546.

18. Karataev DE, Nasonov EL, Luchichina EL. The efficacy and safety of adalimumab treatment in patients with active rheumatoid arthritis resistant to standard therapy: results of the Russian national study. Terapevticheskii arkhiv. 2012;8:22–28. (In Russ).

19. Lovell DJ, Ruperto N, Goodman S, et al. Adalimumab with or without methotrexate in juvenile rheumatoid arthritis. N Engl J Med. 2008;359(8):810–820. doi: 10.1056/nejmoa0706290.

20. Ruperto N, Lovell DJ, Goodman S, et al. Long-term efficacy and safety of adalimumab in children with juvenile rheumatoid arthritis (JRA): data over two years of treatment in a phase III study. Abstract presented at: 8th Annual European League Against Rheumatism (EULAR 2007). Barcelona, Spain; 2007. Abstract THU0195.

21. Kingsbury DJ, Pierre Quartier DJ, Karunaratne PM, et al. Safety, effectiveness, and pharmacokinetics of adalimumab in children with polyarticular juvenile idiopathic arthritis aged 2 to 4 years. Clin. Rheumatol. 2014. doi: 10.1007/s10067-014-2498-1.

22. Ruperto N, Lovell DJ, Reiff A, et al. OLE DE038: Long-Term Efficacy and Safety of ADA for up to 6 years in Patients with JIA. ACR11. Arthritis Rheum. 2011;63(10). Аbstr. 265.