Treating patients with epidermolysis bullosa

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Treating patients with epidermolysis bullosa

• Jemima Mellerio
• Great Ormond Street Hospital and
• St Johns Institute of Dermatology
• London, UK

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Treating patients with EB

• EB and EB care in England and Wales
• What are the problems and what can we do about
  them?
• Clinical trials in EB - what is there?
• Why so few?
• What could we do?
• What is the way forward?

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Epidermolysis bullosa (EB)

• Group of inherited disorders
• Skin /- mucosal fragility
• Variable severity
• Variable non-cutaneous features
• Overall incidence of approx 1 per 20,000 births
• Estimated 5,000 with EB in UK

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Epidermolysis bullosa (EB)

• Result from mutations in genes encoding proteins
  at the dermal-epidermal junction
• Latest classification 13 different genes, many
  more clinical subtypes

Fine J-D et al. J Am Acad Dermatol 2008 58(6)
931-50
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EB care in England and Wales

• April 2002 NSCAG funding (National Specialist
  Commissioning Advisory Group) (now NCG)
• Specialist centres to develop expertise in rare
  diseases
• Funded by Department of Health
• Reciprocal arrangements with Scotland and N
  Ireland

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EB care in England and Wales
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Multidisciplinary EB care
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EB what are the problems and what can we do
about them?
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EB what are the problems and what can we do
about them?
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EB what are the problems and what can we do
about them?
Hand contractures
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EB what are the problems and what can we do
about them?
Nutrition
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EB what are the problems and what can we do
about them?
Anaemia
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EB what are the problems and what can we do
about them?
Bone health
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EB what are the problems and what can we do
about them?
Airways
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EB what are the problems and what can we do
about them?
Eyes
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EB what are the problems and what can we do
about them?
Cancer
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(No Transcript)
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So many problems
So many interventions
So little evidence
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Clinical trials in EB - what is there?

• Two double-blind placebo-controlled RCTs for oral
  tetracyclines in EB simplex
• Small numbers (n12 and n21)
• No evidence of benefit

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Clinical trials in EB - what is there?

• Two RCTs for topical interventions in EBS
• 20 aluminium chloride hexahydrate (n23)
• 5 bufexamac cream (n8)
• No evidence for benefit from either

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Clinical trials in EB - what is there?

• One RCT with phenytoin vs placebo in recessive
  dystrophic EB
• N36
• No benefit from phenytoin

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Clinical trials in EB - what is there?

• Anecdotal reports and retrospective analyses
• Small non-controlled trials with small numbers
• e.g. acceptability and efficacy of Urgotul
  dressings
• e.g. parenteral iron and erythropoietin for
  anaemia in EB
• Tolerability of oral isotretinoin in patients
  with recessive dystrophic EB

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Clinical trials in EB - what is there?

• Pilot study of low dose trimethoprim in children
  with junctional and dystrophic EB

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Clinical trials in EB - what is there?

• Pilot study of low dose trimethoprim in children
  with junctional and dystrophic EB
• Topical thymosin beta4 for wound healing in
  junctional and dystrophic EB

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Clinical trials in EB - what is there?

• Pilot study of low dose trimethoprim in children
  with junctional and dystrophic EB
• Topical thymosin beta4 for wound healing in
  junctional and dystrophic EB
• Efficacy of 2 different devices for improving
  microstomia in severe generalised recessive
  dystrophic EB

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Clinical trials in EB - what is there?

• Pilot study of low dose trimethoprim in children
  with junctional and dystrophic EB
• Topical thymosin beta4 for wound healing in
  junctional and dystrophic EB
• Efficacy of 2 different devices for improving
  microstomia in severe generalised recessive
  dystrophic EB

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Clinical trials in EB - what is there?

• Topical opioids for wound pain in EB
• Low dose amitriptyline for chronic pain in
  children with EB

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Clinical trials in EB - what is there?

• Ex vivo gene therapy for non-Herlitz junctional
  and recessive dystrophic EB

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Clinical trials - why so few?

• EB is a rare disease especially if break down
  into subtypeshard to get decent numbers
• Validity of comparing different subtypes of EB?
• Other variables e.g. temperature, infection,
  anaemia, age

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Clinical trials - why so few?

• Hard to get objective measures e.g. blister
  counts, wound healing

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Clinical trials - why so few?

• What would normal healing rate be?

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Clinical trials - why so few?

• Could evaluate before and after

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Clinical trials - why so few?

• More global measures e.g. pain diaries, QoL
  measures may not be sufficiently sensitive to
  detect real differences
• Birmingham EB Severity Score
• Sydney QoL EB index

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Clinical trials - why so few?

• May mean yet another intervention or treatment
  for patient and carers
• May be higher drop outs due to other factors e.g.
  intercurrent illness
• Extra visits for study may be unfeasible

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Clinical trials - what to do?

• Anaemia in severe forms of EB
• Parenteral iron /- erythropoietin

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Clinical trials - what to do?

• Osteoporosis in severe forms of EB
• Effects of bisphosphonates on EB bone turnover
• Potential benefits from low amplitude vibrating
  platforms

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Clinical trials - what to do?

• Cancer chemoprevention in recessive dystrophic EB
• Trial of oral retinoids tolerability and
  efficacy

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Clinical trials - what to do?

• Cancer management

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Clinical trials - what to do?

• Cancer management
• Role of imiquimod for treatment of early in situ
  tumours or palliation

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Clinical trials - what to do?

• Cancer management
• Role of Mohs micrographic surgery or sentinnel
  lymph node biopsy?

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Clinical trials - what to do?

• Cancer management
• Role of newer chemotherapeutic agents e.g. EGFR
  inhibitors and tyrosine kinase inhibitors

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Clinical trials - what to do?

• Gene, cell and protein therapy

EB gene
Skin biopsy
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Clinical trials - what to do?

• Gene, cell and protein therapy

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What is the way forward?

• UK in privileged position
• Large clinical centres for adults and children
  providing comprehensive multidisciplinary care
• Most patients with more severe forms seen
  regularly at one of these centres
• Links to excellent diagnostic services
• Invaluable role of DebRA UK

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What is the way forward?

• UK multi-centre trials much needed
• International collaboration is the way forward
  for more power and larger numbers
• Already good communication and links between EB
  centres in EU and beyond
• Need to overcome administrative and financial
  hurdles to enable clinical trials to be undertaken