Biologics Therapy in Paediatric Rheumatology

Rheumatology study day 2014Alice 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• ≥ 1 joint with evidence of synovitis• Exclusion of infection/ vasculitis

Radiology imaging of JointsSynovial cytologyANA/RF/ HLAB27

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)

Management

Physiotherapy

Occupational therapist

Rheum Nurse

podiatrist

Clinical Psychologist

orthopaedic

school

growthExercises

Education

Social worker

Medical treatment

Play therapist

Information

career

Transitional

Ophthalmologist

Education

Management

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

Core Set Criteria Active Joint Counts

Restricted Joint Counts

Physician Global Assessment Score

Parental VAS

CHAQ

ESR

Which biologics agent should be used?

Current views on pathogenesis of Inflammatory Arthritis- 1

Smolen, J.S. et al., 2007. Lancet, Published online June13

Co- Stimulatory inhibitor- abatacept

Current views on pathogenesis of Inflammatory Arthritis - 2

Smolen, J.S. et al., 2007. Lancet, Published online June13

Anti TNF- EtanerceptInfliximab

Anti IL1 and IL6-AnakinraTocilizumab

Anti-CD20 rituximab

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

A possible positive feedback cycle contributes to perpetuation of chronic inflammation in sJIA

Anti IL1 and IL6-AnakinraTocilizumab

Therapeutic Indications - UKEtanercept

(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 arthritiswww.emc.medicines.org.uk

Nomenclature

‒ ximab chimeric antibody

‒ zumab humanised antibody

‒ umab human antibody

‒ cept fusion protein

Structure of Etanercept

Human TNF Receptors

Human Antibody

sTNFR:FcActivatedmacrophage Target

cell

Signal

sTNFR

TNFTNFR

sTNFR:Fc

Etanercept - Mode of Action

Etanercept - Mode of Action

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

Etanercept

• German Etanercept registry- n=1300 66% for 4 years of treatment

• Dutch Registry n=146 38% complete remission

Etanercept

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

compliance

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

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

Infliximab

• Lovell Ruperto 2007/ 2010n=122ACR pedi 50/70- 70%/52% at wk 52Infusion reaction 32%

Discontinued 34% Only 30% continue to wk 204

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 childflares of arthritis, pneumonia

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

Adalimumab

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

Tocilizumab

• Recombinant human interleukin 6 receptor antibody

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

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

Cherish Trial for poly JIA

Anakinra• Anti IL 1 receptor antagonist

• Lequerre et al 2008 in SOJIAn=20, Duration 6 monthsDose 1-2mg/kg/dayACR paed 50 in 20% AE in 4 patients with severe skin reaction, infection

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

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

Abatacept (CTLA4-Ig)A receptor immunoglobulin fusion protein

Adapted from Kremer, J.M., 2004. Rheum Dis Clin N Am, 30, pp. 381–391

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

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 FDA88% also received immuno-suppressiveLymphoma, leukaemia, melanoma and solid tumour

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

• 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-sactumor, myelodysplasia, bladder cancer (1 case each)

Types of malignancy

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

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