Hot topics in Pediatric Dermatology Yvonne Chiu, MD
Hot Topics for Pediatric Dermatology Yvonne Chiu, MD WDS Summer Meeting July 21, 2012 Disclosure Statement I, Yvonne Chiu, MD, do not have any relevant financial interest or other relationships with a commercial entity producing health-care related product and or services. Caveat Objectives Treat complex infantile hemangiomas with propranolol and appropriately monitor for adverse effects Incorporate current understanding of atopic dermatitis pathogenesis into treatment plans Counsel parents on the use of biologics in children None of the medications discussed are FDA-approved Formal research on practice gaps in pediatric dermatology are lacking Practice Gap: Highly Variable Screening and Monitoring Propranolol for Infantile Hemangioma 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Baseline Studies N = 32 ECG BP HR Echo
Practice Gap: Highly Variable Screening and Monitoring Cardiology Consult Practice Gap: Highly Variable Screening and Monitoring Admission Never 25% Always 34% N = 32 Never 47% Always 9% Sometimes 44% N = 32 Sometimes 41% Consensus Guidelines Propranolol Non-selective 1 and 2 blocker No FDA-approved indication for children Historically used for supraventricular tachycardia and congenital heart disease Adverse Effects Bradycardia Hypotension Hypoglycemia Bronchospasm Sleep disturbances Cool and mottled extremities Hyperkalemia Contraindications Cardiogenic shock Sinus bradycardia Hypotension Greater than 1 st degree heart block Heart failure Bronchial asthma Hypersensitivity to propranolol PHACE syndrome with cerebrovascular anomalies (relative)
Screening History Poor feeding Dyspnea, tachypnea, wheezing Heart murmur Family history of heart block or arrhythmia Maternal history of connective tissue disease Physical examination Heart rate, blood pressure Cardiac and pulmonary assessment Screening ECG if: Heart rate is below normal for age Arrhythmia is auscultated during exam Personal or family history of congenital heart condition or arrhythmia Maternal history of connective tissue disease Echo is not indicated as routine screening Dosing 20 mg/5 ml oral solution 1-3 mg/kg/day TID dosing >6 hours apart Initiation Inpatient hospitalization for: <8 weeks corrected gestational age OR Inadequate social support OR Comorbid medical conditions Cardiovascular Respiratory (including airway hemangiomas) Glucose issues Dose escalation recommended Monitoring With initial dose and dose increases >0.5 mg/kg/day HR and BP at baseline and 1, 2, and 3 hours after dose Blood glucose and Holter not recommended Parental Counseling Administer with feeds Avoid prolonged fasts Infants <6 weeks: q4 hours Infants 6 weeks-4months: q5 hours Infants >4 months: q6-8 hours Discontinue during illness Decreased oral intake Respiratory illness Push rehydration fluids when oral intake is decreased Recognize signs of bradycardia, hypotension, and hypoglycemia
Closing the Gap: Propranolol Perform targeted H&P prior to starting propranolol Order ECG and echo only in at-risk patients Hospitalize at initiation only those infants at high risk for complications Extensively counsel parents on safe practices Atopic Dermatitis Education as Intervention Practice Gap: Inadequate Atopic Dermatitis Education for Parents Increased TEWL Pathogenesis of AD Allergens Microbes Scratching Education as intervention Education improves compliance and decreases AD severity Infection Inflammation Filaggrin Structural role in cornified envelope Degraded into natural moisturizing factor NMF H 2 O NMF NMF H 2 O NMF Profilaggrin Mutations FLG null mutation causes ichthyosis vulgaris 15-50% of atopic dermatitis patients have a FLG mutation Copy number variation Stronger association with severe disease H 2 O H 2 O
Decreased Filaggrin Decreased structural integrity of cornified envelope Decreased NMF corneocytes shrink Proteases Proteases break down corneodesmosomes Protease inhibitors control protease activity NMF H 2 O NMF H 2 O Proteases Protease inhibitors NMF NMF H 2 O H 2 O Desquamation Increased Protease Activity Increased protease gene expression and enzyme activity Decreased protease inhibitor gene expression and enzyme activity Increased Protease Activity Results in Breakdown of corneodesmosomes Activation of protease-activated receptor 2 (PAR2) Inhibits lamellar body secretion Mediates pruritus Initiates innate inflammatory response Acid Mantle Normal skin has ph of 4-6.5 Importance of acidic ph Antimicrobial effects Favors protease inhibitor activity > protease activity Optimal for lipid-generating enzymes Elevated ph filaggrin NMF ph AD patients have higher skin ph Even in uninvolved skin Higher ph during flare Sweat increases ph
Soaps and Detergents Solubilizes lipids Promotes release of pro-inflammatory cytokines Increases ph of the skin House Dust Mites Contain proteolytic enzymes Directly activate PAR2 Mediates pruritus Initiates innate inflammatory response Inhibits lamellar body secretion Staphylococcus aureus Produce proteases Secrete enzymes that interfere with lipid lamellae Toxins and superantigens Inflammation IgE production Pruritus Topical Corticosteroids Can damage epidermal barrier Treated skin is 70% thinner than control skin Decrease lipid lamellae Induce protease expression Skin Barrier Improves With Age Skin Barrier Function Age Adult AD Childhood Only Threshold for developing AD Adaptive Immunity Innate Immunity Mast cell Basophil Eosinophil Neutrophil NK cell Macrophage Phagocytosis CD8+ T cell Kill pathogen Pathogen Dendritic cell T cell TH1 cell Pattern recognition receptor Keratinocyte Release cytokines CD4+ T cell B cell Secrete antimicrobial proteins TH2 cell Allergic reactions
Pattern Recognition Receptors Polymorphisms associated with atopic dermatitis Toll-like receptor 2 (TLR2) Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) CD14 Defects result in: Susceptibility to infection Promote TH2 inflammatory response Antimicrobial Proteins Examples Cathelicidin (LL-37, hcap18) Human defensin Produced by keratinocytes and innate immune cells Kill microbes and modulate immune response Decreased in AD Innate Immune Cells Decreased levels and functional defects of: Natural killer cells Plasmacytoid dendritic cells Neutrophils Predispose to infections Innate Immune Cells Increased levels of: Eosinophils Mast cells Basophils Aggravate inflammatory response Thymic Stromal Lymphoprotein Released by keratinocytes Triggered by mechanical stimulation and pathogens Stimulates Th2 immune response TSLP polymorphisms higher levels T Cell Response Th2 cytokines in acute AD Th1 cytokines in chronic AD Involvement of Th17 and Treg cells
Th2 Cytokines IL-4 and IL-13 Isotype switching to IgE production Decrease filaggrin expression Decrease ceramide synthesis Increase S. aureus binding Inhibit S. aureus killing Downregulate AMPs Th2 Cytokines IL-5 Activates eosinophils IL-31 Stimulates itch in sensory neurons Decreases filaggrin expression Psychological Stress Promotes Th2 and inflammatory response Activate itch neural pathways Compromises epidermal barrier How does this affect AD treatment? Increased TEWL Pathogenesis of AD Allergens Microbes Scratching Multi-Faceted Approach Restore skin barrier Anti-inflammatory medications Identifying and eliminating triggers Managing pruritus and scratching Preventing and treating superinfections Counseling and parental support Infection Inflammation
Atopic Skin Care Daily bathing Synthetic detergents (syndet) Moisturize twice daily Topical Corticosteroids Only part of the treatment regimen Children at greater risk of adverse effects Steroid Phobia Aubert-Wastiaux et al, 2011 81% fear TCS 36% are non-adherent 53% warned by pharmacist of dangers of TCS 55% warned by their physician of dangers of TCS Atrophy Hong et al, 2011 70 children with AD, 22 matched controls Compliant with TCS for at least 3 months No atrophy seen Iatrogenic Cushing Syndrome Tempark et al, 2010 Review of 23 reported cases 86% had diaper dermatitis 82% using clobetasol HPA Axis Suppression Friedlander et al, 2002 Cohort study of 51 children Fluticasone cream BID for 3-4 weeks 2 /43 had HPA axis suppression
Infection Control Bleach baths Bleach baths 1-2 times weekly ¼-½ cup of bleach in tub of water Soak, then rinse Anti-bacterial soap Repair of skin barrier with moisturizer and topical corticosteroid alone can reduce S. aureus carriage Huang J T et al. Pediatrics 2009;123:e808-e814 2009 by American Academy of Pediatrics Parental Education Quality of Life Education on pathogenesis Emphasize genetic nature and chronic course Need for lifestyle change Repeated, frequent visits Beattie and Lewis-Jones, Br J Dermatol, 2006 Closing the Gap: AD AD pathogenesis is complex but is due primarily to a barrier defect combined with immune dysregulation Treatment of AD requires attention to this complexity Improved education of parents leads to improved compliance and better disease control Biologic Therapy for Pediatric Psoriasis
Practice Gap: Overuse of Topical Steroids in Pediatric Psoriasis Practice Gap: Overuse of Topical Steroids in Pediatric Psoriasis Vogel et al., Arch Dermatol, 2012 Vogel et al., Arch Dermatol, 2012 Systemic Therapy for Pediatric Psoriasis Phototherapy Methotrexate Acitretin Cyclosporine Biologic therapy Drug Biologic Therapy in Children Infliximab Etanercept Adalimumab FDA-Approved Pediatric Indications Crohn s disease Ulcerative colitis Juvenile idiopathic arthritis Juvenile idiopathic arthritis Dosing 5 mg/kg at 0, 2, and 6 weeks, then q8 weeks 0.8 mg/kg weekly OR 0.4 mg/kg twice weekly 15 kg to <30 kg: 20 mg every other week 30 kg: 40 mg every other week Level of Evidence for Pediatric Psoriasis 2 case reports Randomized controlled trial Anecdotal (no published reports) Etanercept Trial Etanercept Trial Paller et al, NEJM, 2008 Paller et al, NEJM, 2008
Etanercept Trial Etanercept Trial 89% 61% 30% Serious adverse events Anxiety Postoperative intestinal obstruction Dehydration, abdominal pain, and abortion No opportunistic infections, malignancies, or deaths Paller et al, JAAD, 2010 Paller et al, JAAD, 2010 FDA Black Box Warnings Malignancy Risk Increased risk of lymphoma and other malignancies in children, adolescents, and young adults Serious and potentially fatal infections Listeria and Legionella added in September 2011 Tuberculosis infection McCluggage, Adol Health, Med, and Ther, 2011 Malignancy Risk Closing the Gap: Pediatric Psoriasis Topical therapy is appropriate for most children Systemic therapy should be considered for moderate-severe or recalcitrant disease Etanercept is effective but lymphoma may be a concern Diak et al, Arthritis Rheum, 2010