Transla&onal Opportuni&es

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Philomena Pitts
5 years ago
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Suppor&ng the UK s Transla&onal Research in Paediatric Rheumatology

Rheumatology n Juvenile idiopathic arthri&s n Juvenile Dermatomyosi&s n

n Complex diseases n Biological basis n Biomarkers n Small(ish) cohorts

rheumatology are intrinsic in our day to day clinical care of patients at

Research as a Standard to be expected All children and young people should

conducted clinical study from point of diagnosis onwards, and have the

inves&ga&on into the cause of their condi&on including pharmacovigilance

1 Suppor&ng the UK s Transla&onal Research in Paediatric Rheumatology Experience of the UK s Paediatric Rheumatology Clinical Studies Group West Midlands Annual Mee.ng Birmingham, 4 th July 03 Professor Michael W Beresford Chair of UK s MCRN/Arthri.s Research UK Paediatric Rheumatology Clinical Studies Group Paediatric Rheumatology n Juvenile idiopathic arthri&s n Juvenile Dermatomyosi&s n Juvenile- onset SLE n Childhood Scleroderma n Vasculi&s. n Complex diseases n Biological basis n Biomarkers n Small(ish) cohorts Knowledge of disease mechanism and clinical trials of new drugs in rheumatology are intrinsic in our day to day clinical care of patients at Alder Hey UK Paediatric Rheumatology Clinical Studies Group Clinical Research as a Standard to be expected All children and young people should be given an opportunity to be enrolled in a clinical trial or well conducted clinical study from point of diagnosis onwards, and have the opportunity to contribute towards a consented biobank for subsequent inves&ga&on into the cause of their condi&on including pharmacovigilance and drug safety studies What are the key clinical research priori&es that will change clinical prac&ce in Paediatric Rheumatology? Topic Specific Groups In JIA, JDM, vasculi.s, JSLE, etc Beresford MW, Cleary AG, Foster HE, Hutchinson E, Baildam EM, Davies K; Rheumatology 00

CSG s Topic Specific Groups UK Paediatric Rheumatology CSG Auto Inflammatory

Dermatomyositis Juvenile Idiopathic Arthritis And associated uveitis

ve efforts in areas of priority in transla.

disciplinary Exper&se International Networks Commercial BSPAR Topic Groups JIA

Group Childhood Scleroderma Non-inflammatory s Vasculitis PorTolio Development &

. JDM Na&onal Registry Etc Thornton J, Beresford MW, et al Rheumatology

c Diseases Safety and Efficacy All Biologics Associated bio- bank All paediatric

s Trial Randomised controlled trial of the clinical effec.

2 CSG s Topic Specific Groups UK Paediatric Rheumatology CSG Auto Inflammatory Diseases Bone Health Consumer Involvement Formulations & Pharmacy Juvenile Dermatomyositis Juvenile Idiopathic Arthritis And associated uveitis Juvenile-onset SLE Fostering collabora.ve efforts in areas of priority in transla.onal medicine UK Paediatric Rheumatology Clinical Studies Group Mul&- disciplinary Exper&se International Networks Commercial BSPAR Topic Groups JIA JSLE JDM Biologics Registries Childhood Arthri&s Prospec&ve Study UK JSLE Study Group Childhood Scleroderma Non-inflammatory s Vasculitis PorTolio Development & Priori&es Etc.. JDM Na&onal Registry Etc Thornton J, Beresford MW, et al Rheumatology 008;47:63-66 Safety of Biologic Use in UK Children with Rheuma.c Diseases Safety and Efficacy All Biologics Associated bio- bank All paediatric rheuma.c disease h_p:// JIA- Uvei.s Trial Randomised controlled trial of the clinical effec.veness, safety and cost effec.veness of an.- TNF therapy for the treatment of JIA- associated uvei.s Government / Charitable funding Inves.gator led Partnership with Industry Related Bio- bank / biomarkers of outcome Challenge facing Paediatric Rheumatology New opportunities Growing expectation Driving forwards care and understanding

Phase Strand et al Nat Rev 007;6:7-9 Wilkinson et al Arch. Dis. Child.

discontinuation earlier due to disease remission), Intermediate response (more than 0% improvement from

earlier due to ineffectiveness or intolerance) % meet ACR70 at year Otten MH et al. JAMA.

008; 39:80-80 Cytokine Pathways in Arthri&s Commercial of Biologics Biologic JIA Sub- type Year Therapy

Nature Reviews Immunology 7, 49-44 Adalimumab Poly JIA 008 Abatacept Poly JIA 008 Tocilizumab Systemic JIA

Golimumab Poly JIA Open, not in UK Canakinumab Systemic JIA On going; NEJM Canakinumab Long term and

Associated Open Periodic Syndromes (CAPS) Rituximab Polyangii.s or microscopic Just opened polyangii.s. Tocilizumab Systemic JIA Safety issues Just opened Tocilizumab Systemic and Poly JIA - st global recruit!

3 Arthri&s: Its really quite simple.. The TNF- α Story Translating knowledge of disease into better clinical care Basic Science Early Phase Late Phase Strand et al Nat Rev 007;6:7-9 Wilkinson et al Arch. Dis. Child. 003;88;86-9 Discovery Development Infliximab Adalimumab Excellent response (inactive disease or discontinuation earlier due to disease remission), Intermediate response (more than 0% improvement from baseline, but no inactive disease) Poor response (less than 0% improvement from baseline or discontinuation earlier due to ineffectiveness or intolerance) % meet ACR70 at year Otten MH et al. JAMA. 0;306(): Ruperto N. Arthritis Rheum. 007; 6: Lovell D. NEJM. 008; 39:80-80 Cytokine Pathways in Arthri&s Commercial of Biologics Biologic JIA Sub- type Year Therapy Etanercept Poly JIA 000 Infliximab Poly JIA 007 What do they teach us? McInnes I. Nature Reviews Immunology 7, Adalimumab Poly JIA 008 Abatacept Poly JIA 008 Tocilizumab Systemic JIA Started 008; NEJM Tocilizumab Poly JIA st global recruit! Golimumab Poly JIA Open, not in UK Canakinumab Systemic JIA On going; NEJM Canakinumab Long term and withdrawal Just opening Certolizumab Poly JIA Regulatory issues pending pegol Canakinumab Cryopyrin Associated Open Periodic Syndromes (CAPS) Rituximab Polyangii.s or microscopic Just opened polyangii.s. Tocilizumab Systemic JIA Safety issues Just opened Tocilizumab Systemic and Poly JIA - st global recruit! Dosing Belimumab Juvenile- onset SLE st global recruit! Etc etc How important these drugs are for Responders Biology of their disease Phenotype / genotype Non- Responders Why not? And now JSLE JDM Scleroderma Vasculitis Beresford, Baildam. Arch Dis Child Educ Prac Ed 009;94:8-43 3

Basic Science Experimental Medicine Translating knowledge of disease into better clinical care

- system autoimmune disease More severe in children. Autoan.body produc.on against nuclear auto- an.

es Adult Rheumatologists Nurse Specialists Pa.

understanding of Childhood Lupus UK- wide popula.on Demographics and Clinical Characteris.

4 Basic Science Experimental Medicine Translating knowledge of disease into better clinical care Discovery Experimental Medicine Late Phase Development NIHR Clinical Research Network Coordinating Centre (NIHR CRN CC) Juvenile onset Systemic Lupus Erythematosus (JSLE) Severe mul.- system autoimmune disease More severe in children. Autoan.body produc.on against nuclear auto- an.gens UK Lupus in Children and Adolescents Mul.- disciplinary Sub- special.es Adult Rheumatologists Nurse Specialists Pa.ents / Parents Database developer Scien&sts JSLE Cohort Study & Repository Improving our care and understanding of Childhood Lupus UK- wide popula.on Demographics and Clinical Characteris.cs Disease ac.vity / course / damage Response to clinician s inten.on to treat Incep.on cohort through into adulthood Immunopathogenesis Biobank Repository Apoptotic material APC Targeted Approaches in SLE Anti-BlyS TACI-IG Costimulatory Factors, eg, BlyS T B Y Anti-CD0 Anti-cytokines Cytokines CTLA4-Ig Anti-CD 4

Hypothesis Neutrophil apoptosis is altered in JSLE Rapid, cons.tu.ve apoptosis, enormous poten.

c burden Increased, Dysregulated Lupus JSLE (diagnosed <7 years) SLE Juvenile Idiopathic Arthritis

0 Autoimmune, inflammatory control Non inflammatory paediatric controls Healthy, no family

009;60(8):390-40 Midgley A, Beresford MW. Lupus (0) 0 7-79.

JSLE Enhanced neutrophil apoptosis Increased nuclear autoan&gen exposure : : Increased ac&va&on of

% apoptosis at 0hrs 9 8 7 6 4 3 0 JSLE Neutrophils Midgley A, Beresford MW A&R.

5 Hypothesis Neutrophil apoptosis is altered in JSLE Rapid, cons.tu.ve apoptosis, enormous poten.al apopto.c burden Increased, Dysregulated Lupus JSLE (diagnosed <7 years) SLE Juvenile Idiopathic Arthritis (JIA) * p<0.0 Autoimmune, inflammatory control Non inflammatory paediatric controls Healthy, no family autoimmune disease Infection excluded Midgley A, Beresford MW A&R. 009;60(8): Midgley A, Beresford MW. Lupus (0) IFN- α mrna expression normalised to 8s mrna expression JSLE npl : Mechanism of Disease in JSLE Enhanced neutrophil apoptosis Increased nuclear autoan&gen exposure : : Increased ac&va&on of TLR s Dysregulated ac&va&on of PBMCs. % apoptosis at 0hrs JSLE Neutrophils Midgley A, Beresford MW A&R. 009;60(8): Midgley A, Beresford MW. Lupus (0) Midgley A, Beresford MW. Lupus (0) 0: Midgley A, Thorbinson C, Beresford MW. Rheumatology. 0 Acknowledgments All CSG Colleagues Patients and Families All Clinical Staff and Paediatric Rheumatology Units Dr E Baildam Dr G Cleary Dr L McCann Dr C Pain Rheumatology Team

University of Bristol - Explore Bristol Research. Peer reviewed version. Link to published version (if available): / X.

University of Bristol - Explore Bristol Research. Peer reviewed version. Link to published version (if available): / X. Sen, E. S., & Ramanan, A. V. (2016). Biologic drugs in pediatric rheumatology. International Journal of Rheumatic Diseases, 19(6), 533-535. https://doi.org/10.1111/1756-185x.12924 Peer reviewed version