1. Biologics Therapy in Paediatric Rheumatology Rheumatology study day 2014 Alice Chieng

2. Prevalence of JIA 400:100,000 Mannere et al Incidence of JIA 10-:100,000 Kunamo et al Greater Manchester 100 new cases per year

3. JIA Diagnosis History >6 weeks <16 yrs ≥ 1 joint with evidence of synovitis Exclusion of infection/ vasculitis Radiology imaging of Joints Synovial cytology ANA/RF/ HLAB27

4. JIA Classification Systemic Polyarticular RF +ve RF –ve Oligoarticularpersistent extended Psoriatic arthritis Enthesitis-related arthritis Other arthritis ILAR ( International League of Associations for Rheumatology 2001)

5. JIA child Family response New diagnosis MDT involvement Education Medical intervention Intra articular steroid injections Management

7. Physiotherapy Occupational therapist Rheum Nurse podiatrist Clinical Psychologist orthopaedic school growth Exercises Education Social worker Medical treatment Play therapist Information career Transitional Ophthalmologist Education Management

8. Medical treatment Depends on subtypes of JIA Intra articular steroid injections DMARD: methotrexate/ sulphasalazine/ leflunomide Biologics NICE guidance Failure or intolerance to DMARD by 3 months, Active joint disease

10. Core Set Criteria  Active Joint Counts  Restricted Joint Counts  Physician Global Assessment Score  Parental VAS  CHAQ  ESR

11. Which biologics agent should be used?

12. Current views on pathogenesis of Inflammatory Arthritis- 1 Smolen, J.S. et al., 2007. Lancet, Published online June13 Co- Stimulatory inhibitor- abatacept

13. Current views on pathogenesis of Inflammatory Arthritis - 2 Smolen, J.S. et al., 2007. Lancet, Published online June13 Anti TNF- Etanercept Infliximab Anti IL1 and IL6- Anakinra Tocilizumab Anti-CD20 rituximab

14. Secretion of IL ‑ 1β by monocytes in inflammatory diseases in SOJIA

15. A possible positive feedback cycle contributes to perpetuation of chronic inflammation in sJIA Anti IL1 and IL6- Anakinra Tocilizumab

16. Therapeutic Indications - UK Etanercept (Enbrel) Rheumatoid arthritis Ankylosing spondylitis Psoriatic arthritis Plaque psoriasis Polyarticular juvenile idiopathic arthritis Infliximab (Remicade) Rheumatoid arthritis Ankylosing spondylitis Psoriatic arthritis Plaque psoriasis Crohn’s disease Ulcerative colitis Adalimumab (Humira) Rheumatoid arthritis Ankylosing spondylitis Psoriatic arthritis Crohn’s disease Psoriasis Poly articular Juvenile Idiopathic arthritis www.emc.medicines.org.uk

17. Nomenclature ‒ ximabchimeric antibody ‒ zumabhumanised antibody ‒ umabhuman antibody ‒ ceptfusion protein

18. Structure of Etanercept Human TNF Receptors Human Antibody

19. Etanercept - Mode of Action

21. Etanercept Etanercept in Children with polyarticular JRA 0.4mg/kg twice weekly ACR 30 pedi- 74% 82% discontinue coticosteroids or taper below 5mg/day Safety: 0.12 events per patient year Lovell DJ, Giannini EH et al 2006

22. Etanercept German Etanercept registry- n=1300 66% for 4 years of treatment Dutch Registry n=146 38% complete remission

23. Etanercept BNDR Biologics New Drug Registry N=483 69% remained on drug after 2 years 20.7% discontinued- poor efficacy, non compliance

24. Etanercept- Adverse Events Injection site reaction 39% URTI 35% SAE 15% include severe infection Malignancy and demyelination is rare New onset uveitis and Cronhs Diseases Tauber et al 2006, Giannini 2009, Lovell et al 2008

26. Infliximab chimeric human–mouse monoclonal antibody directed against TNF-α 6 mg/kg at 0, 2 and 4 weeks 4-8 weeks interval after apoptosis of cells bearing TNF-α Not licensed or FDA approved JIA Crohns >6 yrs

27. Infliximab Lovell Ruperto 2007/ 2010 n=122 ACR pedi 50/70- 70%/52% at wk 52 Infusion reaction 32% Discontinued 34% Only 30% continue to wk 204

28. Infliximab Adverse events 91% (71/78) reported AE 1 patient died due to JRA flare with cardiac arrest infusion reaction 32% SAE 21.8% asymptomatic TB in 1 child flares of arthritis, pneumonia

29. Adalimumab Human Anti TNF IgG monoclonal antibody Dose=24mg/m₂ subcutaneous Injection 2 weekly Lovell, Ruperto et al 2008 n=171 ACR 30/50/70 monotherapy -74/64/46% ACR 30/50/70 + mtx- 94/91/71

30. Adalimumab Safety: infection 25% Hypersensitive reaction 6% Adalumumab antibodies 16% ACR100 after 2 years: 40% More effective in uveitis associated with JIA

31. Tocilizumab Recombinant human interleukin 6 receptor antibody

32. Tocilizumab n=56, 8mg /kg 2 wkly infusion ACR pedi 30/50/70- 91/82/68% CRP<50 in 2weeks in 86% Wk 48, 98% still on medication ACR pedi 30/50/70- 98/94/90% Yokota et al

33. Tocilizumab Tender Trial- SOJIA n= 88 ACR 30 with no fever 88% ACR70/90- 89%/65% 48% reduction in coticosteroids 33 SAE- 12 attributed by tocilizumab 12 infections- 6 by tocilizumab Ruperto et al 2012

34. Cherish Trial for poly JIA

35. Anakinra Anti IL 1 receptor antagonist Lequerre et al 2008 in SOJIA n=20, Duration 6 months Dose 1-2mg/kg/day ACR paed 50 in 20% AE in 4 patients with severe skin reaction, infection

36. Anakinra IL-1 receptor antagonist 1–2 mg/kg (max 100 mg daily) by SC Rosellini et al n=80 SOJIA, poly and oligo 73% responded SOJIA, ACR 30/50- 55/30% Anajis Trial n=24, placebo/anakinra 67% responded

37. Rilonacept IL-1 R/IL1RacP/Fc fusion protein Gianinni et al n=9 ACR 50 at 2/4 wks-55/78% sustained at 24 months 2 MAS On going double blind placebo trial

38. Abatacept (CTLA4-Ig) A receptor immunoglobulin fusion protein Adapted from Kremer, J.M., 2004. Rheum Dis Clin N Am, 30, pp. 381–391

39. Abatacept Phase III double blind withdraw trial in Poly JIA 10 mg/kg IV 4 weekly, n=199 ACR 30/50/70 in 64%/50%/28% achieved SAE: 6, one ALL, 2 flares of arthritis, joint wear, Varicella Zoster, ovarian cyst AE: headache and nausea

40. Safety with anti TNF Minor URTI most common TB reported in infliximab and adalimumab Demyelinating disease, uveitis, IBD rare Drug induced lupus rare Malignancy- 48 reported by FDA 88% also received immuno-suppressive Lymphoma, leukaemia, melanoma and solid tumour

41. Malignancies Rheumatic conditions (20 cases in total, of which 5 are associated with infliximab, 14 with etanercept and 1 with adalimumab, and includes the conditions: JIA, 15 cases; ankylosing spondylitis, 3 cases; psoriatic arthritis, 1 case; sarcoidosis, 1 case) Other conditions (28 cases in total, of which 26 are associated with infliximab, 1 with etanercept and 1 with adalimumab, and includes the conditions: Crohn disease, 21 cases; ulcerative colitis, 4 cases; in utero exposure, 2 cases; unknown, 1 case) Hashkets 2010 Nature

42. Hepatosplenic T-cell lymphoma* (10 cases) Non-Hodgkin lymphoma (7 cases) Hodgkin lymphoma (6 cases) Leukemia (6 cases) Malignant melanoma (3 cases) Thyroid cancer (3 cases) Basal cell carcinoma, lymphoma with acute myeloid leukemia, leiomyosarcoma, nephroblastoma, renal cell carcinoma, liver cancer, metastatic hepatocellular carcinoma, malignant mastocytosis, neuroblastoma, colorectal cancer, yolk-sac tumor, myelodysplasia, bladder cancer (1 case each) Types of malignancy

43. Long Term Safety British Society for Paediatric and Adolescent Rheumatology Biologic and New Drug Registry for JIA All children on etanercept are on the national registry

44. Summary High cost with £8000 to £15,000 per year per patient Accessibility is variable in UK Well tolerated Transition to adults Long term safety