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Biologics Therapy in Paediatric Rheumatology

Biologics Therapy in Paediatric Rheumatology. Rheumatology study day 2014 Alice Chieng. 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 . JIA Diagnosis. History >6 weeks <16 yrs

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Biologics Therapy in Paediatric Rheumatology

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  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. Management

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

  7. 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

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

  9. Which biologics agent should be used?

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

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

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

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

  14. Therapeutic Indications - UK www.emc.medicines.org.uk

  15. Nomenclature • ximab chimeric antibody • zumab humanised antibody • umab human antibody • cept fusion protein

  16. Structure of Etanercept Human TNF Receptors Human Antibody

  17. sTNFR:Fc Activated macrophage Target cell TNFR TNF sTNFR Signal sTNFR:Fc Etanercept - Mode of Action

  18. Etanercept - Mode of Action

  19. 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

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

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

  22. 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, Lovellet al 2008

  23. 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

  24. 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

  25. 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

  26. 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

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

  28. Tocilizumab • Recombinant human interleukin 6 receptor antibody

  29. Tocilizumab • n=56, 8mg /kg 2 wkly infusion • ACR pedi 30/50/70- 91/82/68% • CRP<50 in 2weeks in 86% • Wk48, 98% still on medication • ACR pedi 30/50/70- 98/94/90% Yokota et al

  30. 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

  31. Cherish Trial for poly JIA

  32. 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

  33. 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

  34. 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

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

  36. 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

  37. 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

  38. 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

  39. Types of malignancy • 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)

  40. 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

  41. 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

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