Help! What s the Answer? FRM F027 - Translating Evidence into Practice: Atopic Dermatitis Guidelines

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1 Help! What s the Answer? FRM F027 - Translating Evidence into Practice: Atopic Dermatitis Guidelines Christine T. Lauren, M.D. Assistant Professor of Dermatology and Pediatrics Columbia University, New York, NY

2 Disclosures No relevant conflicts of interest Off-label uses of systemic medications will be discussed

3 Learning Objectives Formulate treatment regimens for atopic dermatitis of varying severities Select pediatric patients that may benefit from systemic therapy Demonstrate knowledge of traditional and emerging topical and systemic therapy Recognize limitations of data with regards to dosing, duration of therapy and long term sequelae of systemic therapies in pediatric patients with AD Address common patient and family concerns about atopic dermatitis management

4 Sidbury R et al. J Am Acad Dermatol Aug;71(2):

5 Phototherapy Recommendations Second line treatment after failure of TCS and TCI Can be used as maintenance of chronic disease Can combine with select topical and systemic therapies** Should be performed under guidance of supervising physician Dosing based on MED and/or Fitzpatrick type Medical, physical or psychologic impact Sidbury R et al. J Am Acad Dermatol Aug;71(2):

6 Phototherapy NB-UVB nm Efficacy, availability, tolerability BB-UVB nm UVA +/- psoralen In-office Home units in special circumstances Peak therapeutic effectiveness of UVB nm Below 300 nm risk of erythema or severe burning Sidbury R et al. J Am Acad Dermatol Aug;71(2):

7 Phototherapy: Adverse Effects* Sunburn like symptoms Redness, burning, stinging, pruritus, tenderness Actinic damage NMSC (MC with PUVA) HSV reactivation Cataracts (MC with UVA) Photosensitive eruptions, photo-onycholysis *Psoralen increases photosensitivity, systemic side effects includes HA, nausea, vomiting

8 Phototherapy: Considerations in Children Concerns Apprehension Cooperation Shielding Tips and Tricks Spaceship X marks the spot Parent in box Still as a statue

9 Phototherapy Dosing Sidbury R et al. J Am Acad Dermatol Aug;71(2):

10 Indications for Systemic Therapy Moderate to severe atopic dermatitis (AD) Significant psychosocial impact Sleep disturbance, school performance, interpersonal relationships, quality of life Failure of first and second line therapies Emollients, Topical steroids, Topical calcineurin inhibitors Phototherapy Contact dermatitis excluded Sidbury R et al. J Am Acad Dermatol Aug;71(2):

11 Systemic Therapy in Pediatric Patients: Safety 101 No FDA approved systemic agents for use in pediatric AD * Continue additional first line therapies to minimize dose and duration of therapy Once efficacy achieved, lower to minimally effective dose Live vaccination avoidance Vaccinations may be less efficacious Vaccinate household members Conventional immunosuppressants require baseline and frequent monitoring during initiation and dose adjustments TB, hepatitis screening CBC with diff, LFTs, BMP, lipids

12 Systemic Steroids in AD Systemic steroids should be avoided Short term use should ONLY be considered only when other systemic or phototherapy are being initiated Short courses may lead to flares Increase in disease severity Consideration of short and long term adverse effects Decreased vertical growth Osteoporosis

13 Systemic Steroids (when used) Formulations Prednisone, prednisolone for oral use tablet and solution Triamcinolone intramuscular injection Dosing: 0.5-1mg/kg/d with taper Additional considerations Vitamin D and calcium supplementation Gastrointestinal prophylaxis Antibiotic prophylaxis for opportunistic infections

14 Cyclosporine (CSA) Calcineurin inhibitor Inhibits T cells and IL-2 production FDA approved age 6 months transplant rejection Europe approved AD age 16 and up Use in atopic dermatitis first reported 1991 Time to improvement: 2-6 weeks Nature 397, (11 February 1999)

15 Cyclosporine (CSA) Dosing Dosing 2.5-5mg/kg/d mg adult Higher initial dose more rapid response Available as 100mg/1ml suspension Modified microemulsion (Neoral) More rapid onset Greater initial efficacy Tapering when improvement FDA time limit 1 year continuous therapy Transition to first line therapies

16 CSA: Adverse Effects and Monitoring Adverse effects: Nephrotoxicity, hypertension Nausea, diarrhea, hepatic anomalies, myalgia, arthralgia Hypertrichosis, gingival hyperplasia, headache, tremor Drug interactions Increased risk infection, skin cancer and lymphoma Monitoring Blood pressure: x2, then at each visit Screening and ongoing laboratory studies CBC, CMP, lipids, Mg, Phos, Uric Acid q2 weeks for 2 months, then monthly

17 Cyclosporine For Pediatric AD Retrospective chart review 15 pediatric patients Starting dose 2.8 ± 0.6 mg/kg/d 80% response rate Duration of therapy 7-15 months Duration of therapy longer in patients that did not relapse 17.7 ± 10.7 months vs 10.2 ± 2.7 months Sibbald et al. Pediatr Dermatol Jan-Feb;32(1):36-40

18 CSA For Pediatric AD Prospective randomized open parallel group 40 pediatric patients with severe AD ages 2-16 Short 12 week courses versus continuous therapy for 1 year Max dose 5mg/kg/d Efficacy both groups not statistically significantly different 7/21 controlled with 2 short courses, 3/21 after 1 course More consistent control in continuous arm Harper et al. Br J Dermatol Jan;142(1):52-8.

19 CSA for Pediatric AD Retrospective chart review 63 pediatric patients Mean starting dose 4.27mg/kg/d 4 weeks: good to excellent 64%, poor 36% Duration 4.6 months (range months) Prolonged remission in 20% Poor outcome associated with egg allergy, elevated eosinophil level Hernandez-Martin etal. JEADV Nov 29. Epub ahead of print

20 Azathioprine (AZA) Purine analog inhibits DNA synthesis FDA approved for RA and transplant rejection Off-label use in AD Time to improvement: up to 12 weeks Dosing 1-4mg/kg/d in children Based on TPMT (thiopurine methyl-transferase) level Escalated therapy Pills must be compounded into suspension Nature Clinical Practice Gastroenterology & Hepatology (2006) 3,

21 AZA: Adverse Effects Myelotoxicity GI: nausea, vomiting, bloating, anorexia, cramping, elevated LFT Increased risk infection, lymphoma, skin cancer Hypersensitivity reactions Monitoring Baseline and follow-up laboratory screening CBC, CMP, Mg, Uric Acid q2 weeks for 2-3 months, then monthly Tb screening Thiopurine methyltransferase (TPMT) level Level should be reassessed if change in clinical status

22 Azathioprine in Pediatric AD Prospective study 12 pediatric patients moderate severe AD 1 Low TPMT 1.0mg/kg/d vs normal TPMT 2.5mg/kg/d 11/12 response 3 change TPMT level Prospective monitoring 82 children 2 Mean age 8.3 years Max doses 1.5mg/kg/d low TPMT vs 2.4mg/kg/d normal TPMT 41% lab anomalies 20% clinical adverse effects 6% stopped due to AE (labs anomalies, HA, infection) No irreversible or fatal effects 1 Caufield M Tom W. J Am Acad Dermatol Jan;68(1): Fuggle et al. J Am Acad Dermatol Jan;72(1):

23 Methotrexate (MTX) Anti-folate metabolite FDA approved for oncologic and inflammatory indications Off-label treatment of refractory AD Dosing based on use in psoriasis 7.5mg - 25 mg weekly mg/kg May be divided into 3 q12 hr doses Oral, subcutaneous and intramuscular formulations Injectable has better bioavailability 0.1ml of 25mg/ml = 2.5mg Test dose may be given Nature Reviews Cancer 5, Average time until efficacy 10 weeks Consider discontinuation if no response weeks Tapering when improvement Transition to first line therapies

24 MTX: Adverse Effects and Monitoring Adverse effects Nausea, vomiting, stomatitis Alopecia Bone marrow suppression Risk of pulmonary side effects Idiosyncratic pneumonitis early, pulmonary fibrosis late Consider candidacy in patients with asthma Hepatotoxicity Risk of lymphoma, skin cancer Pregnancy Category X Drug interactions NSAIDs, Bactrim Monitor cumulative dosing Stratify risk factors for hepatotoxicity Baseline and ongoing monitoring Baseline CBC, LFT, BUN/Cr, hepatitis serologies, pregnancy testing Repeat CBC, LFT after test dose, every 1-2 weeks for 2-4 weeks, then space to every 3-4 months 1-2 weeks after dose escalations BUN/Cr twice yearly Folic Acid to limit hematologic and GI toxicity 1mg daily, may increase to 5mg daily

25 Methotrexate In Pediatric AD Retrospective review 31 pediatric patients age 3-18 in New Zealand 1 Starting doses 5mg age 0-5 years 10mg age 6-14 years 15mg age years 75% effective or very effective (reduced SCORAD, decreased topical steroid use) Improvement by week 8-12 Mean duration treatment 14 months 14% nausea, 14% non-significant elevation LFT Case series 25 pediatric patients mg weekly 76% clear or almost clear after 10.5 months 1 Deo et al. Int J Dermatol Aug;53(8): Roberts et al. Australas J Dermatol 2010; 51:

26 MTX vs CSA In Pediatric AD Randomization 40 children Egypt moderate-severe AD Age 8-14 MTX 7.5mg weekly vs Cyclosporine 2.5mg/kg/d Slower onset of effect with methotrexate No statistical difference in SCORAD reduction Adverse effects mild both groups El-Khalawany et al. Eur J Pediatr (2013) 172:

27 MTX vs AZA In AD 42 adult patients randomized AZA ( mg/kg/d) vs MTX ( mg/wk) for 12 weeks Similar improvement week 12 and 24 Blood abnormalities more common AZA group AD patients with filaggrin loss-of-function mutations show good but lower responses to immunosuppressive 1 Schram et al. J Allergy Clin Immunol Aug;128(2): Roekevisch et al. BJD Nov 19. doi: /bjd [Epub ahead of print]

28 MycophenolateMofetil (MMF) Off-label use for treatment of refractory AD Variability in reported effectiveness Blocks purine biosynthesis pathway of cells via inhibition of inosine monophosphate dehydrogenase This image cannot currently be displayed. Nature Reviews Microbiology 2, (September 2004) Dosing 30-50mg/kg/d, BID dosing Ranges from 0.5-3g/d Capsule, suspension Mycophenolate sodium (enteric coated) tablet (MPA) Relapse rate unknown

29 MMF: Adverse Effects and Monitoring Nausea, vomiting, diarrhea, abdominal discomfort Headaches, fatigue Bone marrow suppression, elevated LFTs, genitourinary symptoms Infections, especially viral and bacterial Lymphoma and other malignancies have not reported in children on monotherapy Monitoring at baseline and ongoing CBC, CMP q2 weeks x 2 then q2 months Baseline PPD, hepatitis serologies, pregnancy testing

30 MMF in Pediatric AD Retrospective review 14 children with severe recalcitrant AD age 2-16 Dosing 30-50mg/kg/d divided BID ( mg/m2) Initial dosing 12-40mg/kg/d divided, titrated to effect Response 29% complete clearance, 29% partial clearance, 35% response, 7% no response Initial response within 8 weeks (mean 4 weeks) Maximum response 8-12 weeks (mean 9 weeks) Duration 2-24 months (mean 8 months) No adverse effects Heller et al., Br J Dermatol Jul;157(1):

31 MMF vs AZA in Pediatric AD Retrospective chart review 28 pediatric patients AZA 1mg/kg/d (low TPMT) vs 3mg/kg/d (normal TPMT) MMF mg/kg/d Both effective in treating moderate to severe AD Lower rates of laboratory abnormalities with MMF Similar rates of cutaneous infections Waxweiler WT et al. Pediatr Dermatol.2011 Nov-Dec;28(6):

32 TREAT Survey European TREatment of Severe ATopicEczema in Children Taskforce European survey treatment of severe atopic dermatitis in children 44.8% response rate 343/765 pediatric dermatology society members 71% utilize systemic therapy Variation in systemic treatment strategies First line: cyclosporine 43%, corticosteroids 30.7%, azathioprine 21.7% Second line: cyclosporine 33.6% Third line: methotrexate 26.2% Proudfoot et al. BJD (2013) 169,

33 TREAT-US TREatmentof ATopiceczema (TREAT) U.S. and Canada Survey Survey to members of Society of Pediatric Dermatology 45.9% response rate (133/290 invited participants) 86.5% used systemic therapy for pediatric AD First line: cyclosporine 45.2%, methotrexate 29.6% Cyclosporine 3-5mg/kg/d over 4-12 months Second line: methotrexate 31.3%, mycophenolate mofetil 30.4% Third line: azathioprine 33%, mycophenolate mofetil 24% Barriers to use: side effect profile and perceived long term risk toxicity Discontinue with slow taper Poster Presentation. Society for Pediatric Dermatology 41th Annual Meeting. Boston, MA. July 11, JAAD 2017 Feb;76(2):

34 Oral Antihistamines in Pediatric AD Nonsedating antihistamines NOT recommended in management of atopic dermatitis Short term use of sedating antihistamines for management of sleep loss Adverse Effects Sedation School performance Anticholinergic Does not substitute for first line therapies

35 Future Guidelines Section 5. Management and treatment with biologics and targeted therapy

36 dupilumab nemolizumab X X X crisaborole apremilast X omalizumab

37 Phosphodiesterase Inhibitors Peripheral leukocytes from patients with AD display elevated phosphodiesterase-4 (PDE) levels PDE4 also found in keratinocytes, Langerhans cells, dendritic cells, T helper cells, monocytes, eosinophils J Drugs Dermatol. 2016;15(4):

38 Crisaborole2% Ointment Topical phosphodiesterase-4 (PDE-4) inhibitor Small molecule penetrates into skin FDA approved December 14, 2016 Age 2 and older Mild to moderate AD BID dosing Side effects Burning and stinging 4% Contact urticaria <1%

39 Apremilast Oral phosphodiesterase 4 (PDE4) inhibitor FDA approved 2014 for adults with psoriatic arthritis and moderate to severe psoriasis Titrated over 5 days to dosing of 30mg PO BID Diarrhea, headache, URI, nausea most common Increase incidence of depression Weight loss Cytochrome P450 interaction

40 Apremilast in AD Phase 2 study (NCT ) completed in adult AD population Open label pilot studies adults AD 16 adults moderate-severe AD 1 20mg BID improved DQLI and pruritus 30mg BID improved EASI, DQLI and pruritus Case report in pediatrics 4 8-year-old male with atopic triad Failed topicals, prednisone, omalizumab Treated with 30mg daily Relief of his intense pruritus in 2 weeks No adverse effects reported 10 adults AD or ACD 2 20mg BID 20% IGA improvement 2 points, 10% EASI-75, 10% EASI-50 Case reports adult AD 3 4 adult patients AD, 1 foot dermatitis 30mg BID Improvement of pruritus and skin disease 1 Arch Dermatol Aug;148(8): J Drugs Dermatol Mar;11(3): J Am Acad Dermatol Jul;77(1): Case Rep Dermatol 2016;8:

41 Dupilumab Human monoclonal antibody to IL-4 receptor alpha Blocks signaling of IL-4 and IL-13

42 Dupilumab in AD Phase 3 trials: SOLO1 and SOLO2 >1300 adults moderate to severe AD poorly controlled topically 300 mg SQ weekly or every other week for 16 weeks after loading dose 600mg Primary endpoint clear or almost clear in ~37% vs 9% Secondary endpoints severity (EASI-75), pruritus, QOL, depression Significant pruritus by week 2 Simpson EL et al. N Engl J Med Dec 15;375(24): Epub 2016 Sep 30.

43 NEJM 375;24

44 Dupilumab in AD Late breaking abstracts AAD 2017 Open label Phase 2a trial in pediatric AD age 6-18 (age 6-11 and age 12-18) 1 Single dose then multiple weekly doses 2 mg/kg and 4 mg/kg Improvement in EASI scores and pruritus Liberty AD CHRONOS: Randomized Phase 3 Clinical Trial: Dupilumab and Concurrent TCS 2 > 700 adult patients moderate to severe AD Treatment 300mg SQ every other week (106), weekly (319) or placebo (315) + TCS Primary endpoint clear or almost clear 39% vs 12% at Week 16 sustained Week 52 EASI % vs 22% at Week 16 sustained at Week 52 Improvements in QoL, sleep, pruritus 1 Cork MJ et al. Pharmacokinetics, Safety, and Efficacy of Dupilumab in a Pediatric Population with Moderate-to-Severe Atopic Dermatitis: Results from an Open-Label Phase 2a Trial In session: F072 Late-breaking research: Clinical studies/pediatric. American Academy of Dermatology 75 nd Annual Meeting, Orlando FL. March 4, Lancet Jun 10;389(10086):

45 Dupilumab: Adverse Effects Injection site reaction, conjunctivitis AD flares and skin infections appear more frequent in placebo 2 deaths in dupilumab group (asthma exacerbation, depression) 1 death CHRONOS study dupilumab group (MVA)

46 Nemolizumab Humanized antibody to IL-31 receptor A Phase 2 study in adults with moderate to severe AD patients Dosing 0.1, 0.5, 2mg/kg/dose every 4 weeks for 12 weeks Significant decrease in itch Adverse effects Flare of atopic dermatitis Nasopharyngitis Late breaking Abstract 2 Efficacy and safety of nemolizumab over 64 weeks in patients with moderate to severe AD (NCT ) Maintained improvement in pruritus and dermatitis 1- N Engl J Med Mar 2;376(9): F056 Late-breaking Research Forum Clinical Trials AAD meeting Orlando, FL 2017

47 Omalizumab in Pediatric AD Humanized monoclonal anti-immunoglobulin E antibody Binds to the IgE molecule at the high-affinity IgE receptor FDA approved moderate to severe asthma 6 years, CIU 12 years Several case reports efficacy in children in AD Efficacy in relation to IgE level and filaggrin status Randomized placebo control trial 1 8 patients age 4-22 years (mean 11.6 years) 4 omalizumab every 2-4 weeks for 24 weeks 4 placebo Reduction in IgE levels and relevant cytokines No statistically significant change in SCORAD ADAPT study: children 24 weeks 2 1 Iyengar SR et al. Int Arch Allergy Immunol. 2013;162(1): Trials May 23;18(1):231

48 Use of Antimicrobial Therapy and Systemic Therapy in AD TREAT-US and Canada Survey Before starting systemic therapy 55.7% do not test/treat 32.1% test/treat child 12.2% test/treat child/family In clinically infected children 96.5% use oral antibiotics Many use topical, intranasal, antiseptics To prevent infection 95% use dilute bleach baths prophylactically Antibiotic choice Cephalosporin first line 90% Eichenfield DZ et al. Poster Presentation. Society for Pediatric Dermatology 41th Annual Meeting. Boston, MA. July 11, 2015.

49 Antimicrobial Therapy in Pediatric AD Systemic antibiotics Treatment of bacterial infection Not recommended for treatment of non-infected or colonized patients Bacterial culture for susceptibility profiles Consideration to development of antibiotic resistance Systemic antivirals Treatment of eczema herpeticum Systemic and topical antifungals Controversial role of treatment of fungal colonization Nikkels AF Pierard GE. Dermatology. 2003;206(4):

50 Topical Antiseptics and Antimicrobials AD patients at increased risk infection Compromised physical barrier Diminished immune recognition Impaired antimicrobial peptide production 80% patient colonized with S. aureus Triggers inflammatory cascades via toxins, protease inhibitors Damages epidermal barrier and potentiates allergen penetration Topical antibiotics not recommended in treating AD Contact dermatitis Antibiotic resistance Dilute bleach baths (with intranasal mupirocin) Moderate to severe disease Maintenance

51 Mupirocin Rates Pediatric Population Percent unique isolates (n=358) MSSA (n=293) MRSA (n=65) MupS MupR Prior mupirocin use strongly correlated with resistance (OR 26.5) Additional RF MRSA, AD, EB, immunosuppression, residence in Northern Manhattan/Bronx Antimicrob Agents Chemother Jun;59(6):3350-6

52 Results: MRSA and Atopic Dermatitis Isolates from patients with atopic dermatitis were more likely to be oxacillin and mupirocin resistant MRSA (n=65) % % Atopics Non-Atopic 0 Atopics (n=44) MupS MupR Non-atopics (n=21) Antimicrob Agents Chemother Jun;59(6):3350-6

53 Contact Dermatitis in AD 1142 pediatric patients patch tested in AD, 548 controls More common Cocamidopropyl betaine Wool alcohol Lanolin Tixocortol pivalate Parthenolide Less common Methylisothiazolinone Cobalt Potassium dichromate No difference Nickel JAMA Dermatol Feb 22. [Epub ahead of print]

54 Clin Dermatol Jul - Aug;35(4):

55 Clin Dermatol Jul - Aug;35(4):

56 Take Home Points Conventional immunosuppressants can be successfully utilized in the management of pediatric AD Cyclosporine is an effective treatment choice in AD Methotrexate and azathioprine are recommended for refractory AD Mycophenolate mofetil may be an effective treatment for refractory AD Systemic steroids should be avoided given risk of rebound as well as poor long term adverse effects in pediatric patients with AD New targeted systemic therapies may provide additional efficacious treatment options for pediatric AD Consider patch testing in patients with treatment resistant atopic dermatitis