RELEVANT DISCLOSURES. Consultant for Galderma Research grant from Ceragenix Investigator on Novartis study Research grant from Celgene

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1 Novel Therapeutics in Atopic Dermatitis Eric Simpson, MD,MCR Associate Professor, Dermatology Oregon Health & Science University RELEVANT DISCLOSURES Consultant for Galderma Research grant from Ceragenix Investigator on Novartis study Research grant from Celgene OBJECTIVES 1. Improve Long-term Control of AD 2. Understand the role of allergen avoidance 3. Prevent Staphylococcal infections Dr.S: Your patient with eczema called again. States skin flaring again. Wants another Kenalog shot. Dr.S: Pts mother called again. Wants to know what food is causing her daughter s eczema. Dr.S: Pts father called. States he is getting pus bumps and yellow crusting. Skin starting to flare. 4. Can eczema onset be prevented? Dr.S: Pt s mom is pregnant. Can she do anything to prevent having another kid with eczema? Fewer call backs mean more time for 1

2 Initial Visit is Education STEROID PHOBIA - Discuss risk of not treating INDUCING CLEARANCE CAUSATION AND FOOD ALLERGY - Skin barrier disease - Allergy associated but not the cause WRITE OUT CLEARANCE PROTOCOL SCHEDULE 1 WEEK FOLLOW-UP 1 WEEK LATER NOW WHAT? FLARE PREVENTION STRATEGIES Barrier Devices FLARE PREVENTION Mild Disease Bathe as often as they want Mild cleansers to diaper area and scalp Moisturize! Moisturize! Moisturize! Do emollients really work? Moisturizers I Use Few allergens, good oil content Cetaphil Cream Plain petrolatum Plastibase Aquaphor QUESTIONS Are these products better than petrolatum-based products? - Compliance? - TEWL? - Hydration? Can they be used to better prevent AD flares? Baseline Use 50g 2

3 FLARE PREVENTION STRATEGIES Role of Devices Sinclair Pharmaceuticals (UK) Hyaluronic acid Extract of Vitis vinifera Studies in mild-mod disease - 70% clear or almost clear - Better than vehicle - Vehicle an irritant? Atopiclair Questions Active vs placebo creams with detectable differences? EPICERAM Ceramides, cholesterol and fatty acids EPICERAM International Symposium of Atopic Dermatitis, % of placebo needed steroid rescue- placebo an irritant? Improve skin barrier? Marketed late 2008 Compete with calcineurin inhibitors as steroid-sparing agent EPICERAM Remaining Questions No intent-to-treat analysis - 5 drop-outs in Epiceram group Not designed as an equivalency study - Lack of superiority does not mean equivalency MimyX Stiefel Palmitamide MEA - Fatty acid - Binds to cannabinoid receptors Equivalent to 1% hydrocortisone but with purported barrier repair abilities No placebo-controlled studies Does the molar ratio matter clinically? 3

4 Eucerin alone Mimyx + Eucerin 29 days 43 days DEVICES May have modest anti-inflammatory properties Could use to treat mild disease, but why? Median time to first flare: - MimyX Cream + emollient 48% longer remission 25% greater incidence of flare with emollient only vs skin treated with MimyX Cream (P<0.051). Too expensive for use as moisturizer If interested or scared patient, use one instead of TCI for steroid-sparing agent FLARE PREVENTION STRATEGIES Role of Devices Pimecrolimus used for early disease vs vehicle Steroid used for flares Proportion of Subjects Without Flare ~65% vs 37% More subjects in PIM group without flares Reduced steroid use Wahn, U. et al. Pediatrics 2002;110:e2 FLARE PREVENTION Topical Steroids 3 studies including pediatric and adult patients evaluating topical fluticasone to prevent relapses Used on healed sites and early disease All 3 studies with same conclusions Copyright 2002 American Academy of Pediatrics PROBABILITY OF NO RELAPSE Pediatrics, 2008 RCT of 295 patients aged with AD Cleared on 1 month of fluticasone cream or ointment Time to relapse: 6 weeks in vehicle group >16 weeks in steroid group HR~6 Median time to relapse Fluticasone 2X/week to healed sites vs. placebo control Can you do this with TCI s? 4

5 Intermittent Anti-inflammatory If using more than days per month topical steroid, add TCI s For severe disease: - clearance protocol, - then either 2X/week topical steroid OR - 3X/week TCI to healed sites and increase to bid to early disease WRITE IT OUT! FLARE PREVENTION STRATEGIES Role of Devices 2008 Oral abx did not help in infected or noninfected eczema (3 studies) Antimicrobial soaps, creams, or bath additives did not help (7 studies) Antimicrobials added to topical steroids reduced staph counts but did not improve the eczema (9 studies) Bleach baths 2X/week 5-10 minutes % (0.5cup 6% bleach in 40 gallon tub) - Mupirocin nasal 5 days each month - Placebo controlled BLEACH BATH STUDY Allocation concealment not specified Not clear if ITT analysis performed Baseline severity differed between groups Co-treatments not listed Only a trend in lower IGA scores were noted and not reported Was it the bleach baths or the mupirocin? Good start, more data are needed FLARE PREVENTION STRATEGIES Role of Devices PROBIOTICS Cultures of bacteria that are beneficial to the gut microflora Normal gut microflora may be an important inhibitor of Th2 responses may correct abnormal atopic microflora and promote Th1 responses SYSTEMATIC REVIEW Michail, 2008 Mean change of 3.01 in SCORAD (1-102 scale) SCORAD for moderate AD=25 Doubtful clinical significance 5

6 COCHRANE SYSTEMATIC REVIEW PROBIOTICS FOR AD TREATMENT Boyle RJ, 2008 Reviewed 12 studies Effect size of 2.46 (P=0.33) Not effective Cases of bowel ischemia and infection reported (pneumonia, sepsis, meningitis) PROBIOTIC ORAL THERAPY FOR AD Inconsistent results for both treatment and prevention If any effect, likely small A role of gut flora on immune dysregulation not established Need further information on strain effects, potency, viability, storage FLARE PREVENTION STRATEGIES Role of Devices DUST MITE AVOIDANCE WHEN TO ADDRESS ALLERGY 9 RCT s One with some benefit - +IgE to egg - Egg avoidance group did better If immediate urticarial lesions develop within 30 minutes of eating. Parent concerned about eczema flaring after a food despite good skin care. RAST for milk, egg, soy, wheat, peanut, fish Otherwise, redirect focus to good skin care! VITAMIN D, of course! Upregulate AMP s and immunomodulatory effects Upregulates cathelicidins in AD (Hata, JACI, 2008) Slight improvement in AD (Sidbury, BJD 2008) More Vit D as infant, more atopy (Back, Acta 2009) SUMMARY Eczema Flare Prevention Simple soak and smear works. Education and follow-up in a week. Incorporate TCI s to early recurrence for moderate disease. Use twice weekly steroid or three times weekly tacrolimus oint to NORMAL skin to prevent flares in moderate-severe patients. Can Atopic Dermatitis Be Prevented? Replace low levels of vitamin D 6

7 Evidence Barrier Protection from Birth can Prevent AD Early use of petrolatum protective in one study (Macharia, 1991) Aquaphor prevents dermatitis in prematures prevent flares of AD What are current guidelines for skin care of newborn? Birth, September 2005 Two research questions - How does the use of soap and detergents affect newborn skin? - Consequences of moisturizer use? No studies identified examining skin care of the term newborn Guidelines say no emollient needed unless dry skin apparent Table 3. Follow-up time of cohort (n=22) Table 4. Main clinical outcomes from study Outcome Result Adverse events None AD (ITT) (n=22) 6 (22.7%) AD excluding 3 (15.0%) drop-outs Average age of 11.0 months AD onset (n=3) CURRENT PREVENTION STUDY SYSTEMIC THERAPY OTHER SYSTEMICS 150 neonates, 2 centers Prospective intervention trial 3 emollients and a control group 6 months of follow-up Feasibility endpoints - Willingness to randomize - Adherence - Contamination of control group Skin barrier endpoints Severe disease or severe flares - Cyclosporine first line need 5mg/kg - Transition to NBUVB or MTX with some overlap Moderate disease - NBUVB, MTX, azathioprine, mycophenolate - Rosiglitazone? IFN-gamma if recalcitrant Rituximab, omalizumab, alefacept if all other options fail- use with caution Anti-IL-5 did not work (Oldhoff, 2005) Anti-IL-4 Anti-TSLP Phosphodiesterase inhibitors Anti-P40 (IL-12) ACKNOWLEDGEMENTS ACKNOWLEDGEMENTS ATOPIC DERMATITIS SYSTEMIC TREATMENT LADDER SEVERE DISEASE- Cyclosporine MOD-SEVERE / MAINTENANCE - NBUVB National Eczema Association OREGON CLINICAL + TRANSLATIONAL RESEARCH INSTITUTE VERY REFRACTORY 7

8 AZATHIOPRINE (Imuran) (Berth Jones, et al. BJD, 2002) (Meggitt SJ, et al. Lancet,2006) Purine analog 2 RCTs show 25%-37% improvement Less expensive than other immunosuppressants Can use in children AZATHIOPRINE Basics Dose approx 2-2.5mg/kg Watch drug interactions: ACE inhibitors, allopurinol, anticoagulants Need baseline thiopurine methyltransferase (TPMT) level nmol/h/ml RBC : 1mg/kg - >7.5 nmol/h/ml RBC: 2.5mg/kg AZATHIOPRINE Side Effects Nausea most common Myelosuppression Elevated transaminases- 10% Hypersensitivity reaction- fever and myalgias AZATHIOPRINE Side Effects/Monitoring Skin cancer- aggressive SCC s Infection Lymphoma none reported in derm pts (<600g total) Monitor blood count, chemistries, liver, and urinalysis ATOPIC DERMATITIS SYSTEMIC TREATMENT LADDER SEVERE DISEASE- Cyclosporine MOD-SEVERE / MAINTENANCE - NBUVB - Azathioprine VERY REFRACTORY MYCOPHENOLATE MOFETIL Murray ML and Cohen JB. J Clin and Exp Derm, 2006 Inhibits inosine monophosphate dehydrogenase Case reports/series/open-label studies only Efficacy variable but generally modest results - Case series of 5 pts without improvement (Hansen, BJD, 2000) More expensive than azathioprine, less data MYCOPHENOLATE MOFETIL Update Heller M, BJD, 2007 Children with severe AD at NYU 14 pts, only 1 did not respond 8 pts with at least 90% improvement No infectious complications and well-tolerated MYCOPHENOLATE MOFETIL Basics Adult dose is g per day divided bid Pediatric dosing: mg/kg daily - or 1200 mg/m 2 daily MYCOPHENOLATE MOFETIL Advantages May not have increased lymphoma risk seen with azathioprine (Robson R, Am J Transplant 2005) No renal toxicity like cyclosporine Can use in children 8

9 MYCOPHENOLATE MOFETIL Side Effects Gastrointestinal Anemia, leukopenia Urinary symptoms, weakness and headaches Infections Congenital malformations and 17 cases PML - SLE and tx pts on immunosuppression Monitor chemistries, blood count and urinalysis, liver function (Fiorentino, 2006) ATOPIC DERMATITIS SYSTEMIC TREATMENT LADDER SEVERE DISEASE- Cyclosporine MOD-SEVERE / MAINTENANCE - NBUVB - Azathioprine - Mycophenolate - MTX - Rosiglitazone - Photopeheresis VERY REFRACTORY METHOTREXATE 20 patients with 44.3% reduction in SCORAD (Lyakhovitsky A, J Eur Acd Derm Vener, 2009) 20 pts, over half had 70% improvement - Goujon C, Eur J Derm, adults with mean 53% improvement - Weatherhead SC, Br J Dermatol, 2007 Alternative dosing mg 4 consecutive days per week - Increase to 5mg 4 days per week Can use in children mg/kg q week PHOTOPHERESIS Sand M, Dermatology 2007 ROSIGLITAZONE (Avandia) Behshad, Arch Derm, 2008 ATOPIC DERMATITIS SYSTEMIC TREATMENT LADDER 4 previous case reports showed efficacy 7 adult patients with severe disease 1 cycle every 2 weeks No concomitant topical therapy Mean SCORAD reduced from 77.7 to 55.6 PPAR are hormone receptors Glucose homeostasis Anti-inflammatory effects and regulate skin barrier 5 patients with some improvement SEVERE DISEASE- Cyclosporine MOD-SEVERE / MAINTENANCE - NBUVB - MTX - Mycophenolate mofetil - Azathioprine - Rosiglitazone? VERY REFRACTORY - Biologics - Photopheresis THE BIOLOGICS FOR AD THE BIOLOGICS FOR AD JAAD, 2009 INTERFERON-GAMMA Inhibits production of Th2 cytokines Dose is 50ug/m 2 SQ nightly Actimmune.com Expensive 2 RCT s showed 30%-50% improvement (Hanifin, JAAD 1993) (Jang, JAAD, 2000) 9

10 IFN-GAMMA Side Effects/Monitoring Flu-like symptoms common - Improve over time or with decrease in dose - Dose at bedtime with acetaminophen Significant SE rare- Neutropenia/leukopenia Monitor blood counts, transaminases, blood chemistries OMALIZUMAB FOR AD (Xolair) Krathen, RA, et al. JAAD Aug Lane, JE, et al. JAAD Jan Vigo PG, JAAD, 2006 Belloni B, JACI 2007 Anti-IgE antibody Approved for allergic asthma 24 total patients with conflicting results Cannot neutralize high levels of IgE IgE likely not critical to pathogenesis.1% anaphylaxis rate TNF INHIBITORS IN AD Elevated serum and tissue TNF levels in AD patients Etanercept not effective- 2 pts (Buka RL, JAAD 2005) Etanercept was effective- 2 pts (Rullan, J Drugs Derm 2009) Infliximab 7/9 pts dropped out (Jacobi A, JAAD 2005) 6 patients reported with AD-like eruptions after starting infliximab (Chan, 2004 and Wright, 2003) ALEFACEPT (Amevive) 2 open label studies Moul DK, JAAD 2008 (9 patients) - 30mg IM X 16 weeks - 1 patient with EASI 50, 1 with EASI 90 Simon D, JACI 2008 (10 patients) - 15mg IM X 12 weeks - 78% EASI improvement at week 12-86% improvement at Week 22 RITUXIMAB Simon D, et al. JACI, 2008 Anti CD 20 antibody Targets B cells 6 adult patients with severe disease 2 IV infusions 1g, 2 weeks apart RITUXIMAB Simon D, et al. JACI, 2008 EASI decreased by 70% and sustained No change in IgE levels No severe adverse events Marked reduction in B and T cells in skin Case series 2 patients with minimal effect (Sediva, JACI 2008) BIOLOGICS FOR ATOPIC DERMATITS IFN-gamma for severe recalcitrant disease not stabilized by other agents Could try rituximab, alefacept, or omalizumab. Use with caution. No other biologic shows promise yet - IL-4 mutein (SID, 2007) - IL-12/23?, IL-17? IL-18? - Skin barrier drugs? 10