PROGNOSTIC FACTORS FOR THE RESPONSE TO TOCILIZUMAB THERAPY IN PATIENTS WITH JUVENILE IDIOPATHIC ARTHRITIS WITHOUT SYSTEMIC MANIFESTATIONS: A COHORT STUDY

Background. To assign genetically engineered biologic drugs, we need data on the predictors for response to therapy. Prognostic factors for the response to tocilizumab in patients with juvenile idiopathic arthritis (JIA) without systemic symptoms are poorly studied.

Objective. Our aim was to reveal early predictors for the response to tocilizumab therapy in patients with JIA without systemic symptoms.

Methods. A retrospective cohort study enrolled patients with JIA without systemic symptoms who received tocilizumab therapy between July 2009 and August 2017. We assessed the association between the initial demographic, clinical, and laboratory parameters in patients and the best response (according to the ACR90 criteria) to treatment after a year.

Results. The study included 95 (girls 85%) patients; the mean age was 10.3 (6.0; 13.6). During the first year of therapy, 71 (75%), 55 (58%), 38 (40%), and 22 (23%) patients achieved the improvement according to ACR30/50/70/90 criteria, respectively; 22 (23%) patients reached disease inactive stage according to the Wallace criteria. When performing multivariate analysis, the following improvement predictors were revealed based on the ACR90 criteria after a year of treatment: decrease in serum C-reactive protein level during the first month of therapy [odds ratio (OR) 1.024; 95% confidence interval (CI) 1.007–1.051], decrease in disease activity score on the visual analogue scale according to the parent/patient assessment (OR 1.048; 95% CI 1.005–1.105), early onset of the disease (OR 0.38; 95% CI 0.16–0.72), persistent oligoarthritis according to the ILAR (OR 9.9; 95% CI 1.5–109.3). During the first year of tocilizumab administration, neutropenia was registered in one patient, leukopenia — in three cases, and urticaria — in one case.

Conclusion. The variant of JIA, the age at the disease onset, and the disease course pattern in the first month of tocilizumab therapy are the predictors of treatment efficacy throughout the year.

1. Giancane G, Consolaro A, Lanni S, et al. Juvenile idiopathic arthritis: diagnosis and treatment. Rheumatol Ther. 2016;3(2): 187–207. doi: 10.1007/s40744-016-0040-4.

2. Davies R, Gaynor D, Hyrich KL, Pain CE. Efficacy of biologic therapy across individual juvenile idiopathic arthritis subtypes: a systematic review. Semin Arthritis Rheum. 2017;46(5):584–593. doi: 10.1016/j.semarthrit.2016.10.008.

3. Martini A. It is time to rethink juvenile idiopathic arthritis classification and nomenclature. Ann Rheum Dis. 2012;71(9):1437–1439. doi: 10.1136/annrheumdis-2012-201388.

4. Ringold S, Weiss PF, Beukelman T, et al. 2013 update of the 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: recommendations for the medical therapy of children with systemic juvenile idiopathic arthritis and tuberculosis screening among children receiving biologic medications. Arthritis Rheum. 2013;65(10):2499–2512. doi: 10.1002/art.38092.

5. Federal’nye klinicheskie rekomendatsii po vedeniyu patsientov s yunosheskim artritom. Soyuz pediatrov Rossii; 2017. (In Russ). Доступно по: http://www.pediatr-russia.ru/sites/default/files/file/kr_yua.pdf. Ссылка активна на 01.07.2018.

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. Dueckers G, Guellac N, Arbogast M, et al. [Evidence and consensus based treatment guidelines 2010 for juvenile idiopathic arthritis by the German Society of Paediatric Rheumatology. (In German).] Klin Padiatr. 2011;223(6):386–394. doi: 10.1055/s0031-1287837.

8. Frampton JE. Tocilizumab: a review of its use in the treatment of juvenile idiopathic arthritis. Paediatr Drugs. 2013;15(6):515–531. doi: 10.1007/s40272-013-0053-1.

9. De Benedetti F, Ruperto N, Zuber Z, et al. PReS-FINAL-2180: Efficacy and safety of tocilizumab (TCZ) in patients with polyarticularcourse juvenile idiopathic arthritis (pcJIA): 2-year data from CHERISH. Pediatr Rheumatol Online J. 2013;11(Suppl 2):O15. doi: 10.1186/1546-0096-11-S2-O15.

10. Kearsley-Fleet L, Davies R, Lunt M, et al. Factors associated with improvement in disease activity following initiation of etanercept in children and young people with Juvenile Idiopathic Arthritis: results from the British Society for Paediatric and Adolescent Rheumatology Etanercept Cohort Study. Rheumatology (Oxford). 2016;55(5): 840–847. doi: 10.1093/rheumatology/kev434.

11. Solari N, Palmisani E, Consolaro A, et al. Factors associated with achievement of inactive disease in children with juvenile idiopathic arthritis treated with etanercept. J Rheumatol. 2013;40(2): 192–200. doi: 10.3899/jrheum.120842.

12. Alexeeva EI, Namazova-Baranova LS, Bzarova TM, et al. Predictors of the response to etanercept in patients with juvenile idiopathic arthritis without systemic manifestations within 12 months: results of an open-label, prospective study conducted at the National Scientific and Practical Center of Children’s Health, Russia. Pediatr Rheumatol Online J. 2017;15(1):51. doi: 10.1186/s12969-017-0178-9.

13. Tsang AC, Roth J, Gottlieb C. Tocilizumab for severe chronic anterior uveitis associated with juvenile idiopathic arthritis in a pediatric patient. Ocul Immunol Inflamm. 2014;22(2):155–157. doi: 10.3109/09273948.2013.866254.

14. Tappeiner C, Heinz C, Ganser G, Heiligenhaus A. Is tocilizumab an effective option for treatment of refractory uveitis associated with juvenile idiopathic arthritis? J Rheumatol. 2012;39(6):1294–1295. doi: 10.3899/jrheum.120010.

15. 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.

16. Kostik MM, Chikova IA, Isupova EA, et al. The use of tocilizumab in 40 patients with polyarticular juvenile idiopathic arthritis: the results of a retrospective study. Current pediatrics. 2017;16(2):148–155. (In Russ). doi: 10.15690/vsp.v16i2.1716.

17. 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.

18. Giannini EH, Ruperto N, Ravelli A, et al. Preliminary definition of improvement in juvenile arthritis. Arthritis Rheum. 1997;40(7): 1202–1209. doi: 10.1002/art.1780400703.

19. Wallace CA, Giannini EH, Huang B, et al. American College of Rheumatology provisional criteria for defining clinical inactive disease in select categories of juvenile idiopathic arthritis. Arthritis Care Res (Hoboken). 2011;63(7):929–936. doi: 10.1002/acr.20497.

20. Swart JF, van Dijkhuizen EH, Wulffraat NM, de Roock S. Clinical Juvenile Arthritis Disease Activity Score proves to be a useful tool in treat-to-target therapy in juvenile idiopathic arthritis. Ann Rheum Dis. 2018;77(3):336–342. doi: 10.1136/annrheumdis-2017-212104.

21. van Dijkhuizen EH, Wulffraat NM. Early predictors of prognosis in juvenile idiopathic arthritis: a systematic literature review. Ann Rheum Dis. 2015;74(11):1996–2005. doi: 10.1136/annrheumdis-2014-205265.

22. Bakry R, Horneff G. THU0529 Methotrexate treatment response in non-systemic juvenile idiopathic arthritis. Ann Rheum Dis. 2017;76(Suppl 2):406–407. doi: 10.1136/annrheumdis-2017-eular.3530.

23. Sieper J, Porter-Brown B, Thompson L, et al. OP0166 Tocilizumab (TCZ) is not effective for the treatment of ankylosing spondylitis (AS): results of a phase 2, international, multicentre, randomised, doubleblind, placebo-controlled trial. Ann Rheum Dis. 2013;71(Suppl 3): 110–111. doi: 10.1136/annrheumdis-2012-eular.1849.

24. Yokota S, Imagawa T, Mori M, et al. Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial. Lancet. 2008;371(9617):998–1006. doi: 10.1016/S01406736(08)60454-7.