Biologics Therapy in Paediatric
Rheumatology
Rheumatology study day 2014
Alice Chieng
• Prevalence of JIA 400:100,000
• Incidence of JIA 10-:100,000
Mannere et al
Kunamo et al
• Greater Manchester 100 new cases per year
JIA Diagnosis
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History >6 weeks
<16 yrs
≥ 1 joint with evidence of synovitis
Exclusion of infection/ vasculitis
Radiology imaging of Joints
Synovial cytology
ANA/RF/ HLAB27
JIA Classification
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Systemic
Polyarticular
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Oligoarticular
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Psoriatic arthritis
Enthesitis-related arthritis
Other arthritis
RF +ve
RF –ve
persistent
extended
ILAR ( International League of Associations for Rheumatology 2001)
Management
Family
response
Intra
articular
steroid
injections
New
diagnosis
JIA child
MDT
involvement
Medical
intervention
Education
Management
orthopaedic
Physiotherapy
Occupational
therapist
podiatrist
Medical
treatment
growth
Exercises
school
Transitional
Education
Education
Information
Clinical
Psychologist
Social
worker
Rheum Nurse
Ophthalmologist
career
Play therapist
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
Co- Stimulatory
inhibitor- abatacept
Smolen, J.S. et al., 2007. Lancet, Published online June13
Current views on pathogenesis of
Inflammatory Arthritis - 2
Anti IL1 and IL6Anakinra
Tocilizumab
Anti TNFEtanercept
Infliximab
Anti-CD20
rituximab
Smolen, J.S. et al., 2007. Lancet, Published online June13
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 IL6Anakinra
Tocilizumab
Therapeutic Indications - UK
Etanercept
Rheumatoid arthritis
(Enbrel)
Ankylosing spondylitis
Psoriatic arthritis
Plaque psoriasis
Polyarticular juvenile idiopathic arthritis
Infliximab
Rheumatoid arthritis
(Remicade)
Ankylosing spondylitis
Psoriatic arthritis
Plaque psoriasis
Crohn’s disease
Ulcerative colitis
Adalimumab
Rheumatoid arthritis
(Humira)
Ankylosing spondylitis
Psoriatic arthritis
Crohn’s disease
Psoriasis
Poly articular Juvenile Idiopathic arthritis
www.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
Etanercept - Mode of Action
Activated
macrophage
sTNFR:Fc
Target
cell
TNF
Signal
sTNFR:Fc
Etanercept - Mode of Action
Etanercept
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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 registryn=1300
66% for 4 years of treatment
• Dutch Registry
n=146
38% complete remission
Etanercept
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BNDR Biologics New Drug Registry
N=483
69% remained on drug after 2 years
20.7% discontinued- poor efficacy, non
compliance
Etanercept- Adverse Events
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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/ 2010
n=122
ACR pedi 50/70- 70%/52% at wk 52
Infusion 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 child
flares 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
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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
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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 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
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 30/5055/30%
• 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
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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 FDA
88% also received immuno-suppressive
Lymphoma, leukaemia, melanoma and solid tumour
Malignancies
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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
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)
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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