Atopic Dermatitis Position Paper SLaai

Atopic Dermatitis Position Paper SLaai

1. ATOPIC DERMATITIS Position Paper

2. Revista Alergia México 2014; 61: 178-211 Jorge Sánchez, Bruno Páez , A Macías, C Olmos, A de Falco http://www.revistasmedicasmexicanas.com.mx/nieto/Alergia/2014/jul-sep/pisition.paper_atopic.pdf

3. Atopic dermatitis (AD) Atopic dermatitis affects a large part of the population, particularly children under 5 years . It usually precedes the development of other allergic diseases such as : Food allergy Asthma, Rhinitis and/or conjunctivitis  It is considered an important risk factor for these diseases .

4. Evaluation and management of AD Should be comprehensive and must include all participants in the process of health care P atients Families Health care system

5. The environmental characteristics of the tropics and subtropics make it necessary to create a guideline addressed to the particularities of atopic dermatitis in Latin America.

6. Methodology I The committee of atopic dermatitis of the Latin American Society of Allergy Asthma and Immunology (SLAAI) developed this guideline. The committee organized a table of contents that was divided into sections, reviewed by at least two committee members. The points regarding the diagnosis and management were defined by vote using the Delphi method. This guideline had a process of external validation to assess the clarity of the concepts and their applicability.

7. Methodology II Each management section concludes with a summary of the topic, which includes the strength of the recommendation and a statement of the group based on current evidence in Latin America. To facilitate understanding by health care staff and patients, recommendations on the diagnosis and treatment were divided into “strong”, “moderate” or “weak” according to the GRADE system (Grading of Recommendations Assessment, Development and Evaluation).

8. Strength of recommendation GRADE

9. Definitions I We use the nomenclature proposed by the World Allergy Organization (WAO) in 2004. According to the recommendation of the WAO, the general term for a local inflammation of the skin should be “dermatitis”. While proposing the term “eczema” to replace the term previously used as “syndrome eczema/dermatitis”. Johansson SG et al. J Allergy Clin . Immunol . 2004; 113:832-836

10. Definitions II They also recommend limiting the use of the term “atopic eczema” when a mediation IgE is demonstrated in the pathophysiology of the disease, and “ nonatopic eczema” when it is discarded. While confirmatory immunological studies are done, they recommend only using the term eczema.

11. However, in many countries of Latin America the term “dermatitis” is used as equivalent to “eczema”, so in this guideline they are used a common term

12. Epidemiology – AD The most common skin allergic disease . Affecting 1% to 20% of population . It has an onset in 80% of cases in children under 2 years of age . No significant differences between genders in the first years of life . It is most frequent in women (60%) than in men (40%) after 6 years .

13. Atopic dermatitis Usually tends to remission symptoms before 5 years in 40% to 80% of patients, and in 60% to 90% at 15 years of age. This disease has been recognized as an important risk factor for the development of other allergic diseases such as food allergy, rhinitis and asthma. Barnetson RS, Rogers M. BMJ 2002; 324:1376-1379

14. Atopic dermatitis Kemp et al observed that stress and psychiatric problems in patients with moderate to severe dermatitis were higher than those in patients with diabetes mellitus. Kemp AS Pharmacoeconomics 2003;21:105-113

15. Prevalence and incidence studies in Latin America (LA) The ISAAC study (International Study of Asthma and Allergies in Childhood) observed that among children aged 6-7 years, the presence of “actual eczema” varied from 0.9% in Jodhpur (India) to 22.5% in Quito (Ecuador). Among children between 13-14 years, the prevalence ranged from 0.2% in Tibet (China) to 24.6% in Barranquilla (Colombia). Odhiambo JA et al J Allergy Clin Immunol 2009;124(6):1251-1258

16. Causes of increased prevalence of AD in LA Multiple causes… Latin American factors as high exposure to mites, and the high genetic heterogeneity .

17. Pathophisiology I Complex and multifactorial disease . It is currently known that not only Th2 and IgE-mediated hypersensitivity are involved. Also the Th1 and even an autoimmune response. Multiple genes may be involved in its development, conferring risk or protection between populations. Several genes from the immune system has been involved (STAT-6, RANTES, TGF-beta);20-22 Filaggrin gene is located in the locus 1q21.

18. Pathophisiology II Two main points are present in all phenotypes: An alteration of the integrity of the skin barrier An immune inflammatory process .

19. Alteration of the skin barrier I The skin is a physical barrier that prevents the entry of multiple agents as organic and inorganic contaminants. Alterations in proteins or cells involved in the barrier function carry the entry of microorganisms, irritants and allergens, leading to a neuroimmune -inflammatory response with the consequent development of symptoms such as ITCHING.

20. Alteration of the skin barrier II Dermatitis : S ubstance P Nerve growth factor (NGF) Vasoactive intestinal polypeptid (VIP) Exposure and stimulation of Malpighian receptors Accelerated apoptosis of keratinocytes  colonization of bacteria ( S Aureus )

21. Immunological alterations in AD Langerhans cells Myeloid dendritic cells Inflammatory dendritic epidermal cells Favor an inflammatory response and present allergens to immature T lymphocytes (both CD4 + and CD8 +) which are activated and become mature T cells specific for the allergen that generated activation.

22. Risk factors according ISAAC in Europe Family history of atopy Personal development of asthma Urban environment Early sensitization to food and aeroallergens High socioeconomic strata Few family members

23. Study FRAAT ( Risk factors for asthma and atopy in the tropics ) Birth cohort consists of 326 children from the lowest socioeconomic strata (lower income of $200 per month) of Cartagena (Colombia), and who have strong African ancestry. None of the children at age of three had developed atopic dermatitis Protective factors : Genetic inheritance Low sanitary conditions Greater exposure to endotoxin Acevedo N et al. BMC Pulm Med 2012; 12:13

24. ISAAC in Latin America The frequency of dermatitis in Barranquilla is one of the highest in Latin America. One possibility is that in some cities in Latin America, the onset of dermatitis is later (> 3 years) similar to that found in some European countries Dei-Cas I et al. Clin Exp Dermatol 2009;34:299-303

25. The concept of “atopic march” and the “hygiene hypothesis” in Latin America Favoring the development of allergic diseases : Rapid urbanization in Latin American countries Economic development Improvement of water quality Health coverage I ncreasing adoption of Western lifestyle with consequent changes in diet Number of infections  Th1 Th2

26. Helminthes infection in LA Appears to have an important role in sensitization and some respiratory allergies. Has been demonstrated in some cohorts in Brazil, Colombia and Ecuador. Figueiredo CA et al J Allergy Clin Immunol 2013;131:1064-1068 Figueiredo CA et al Clin Immunol 2011; 139:57-64

27. Diagnosis There is not a definitive diagnostic test. Based on a set of clinical symptoms and signs : - Pruritus - Eczematous lesions with periods of exacerbation and control. The distribution of eczema can change with time. In children under 2 years the involvement of the face and the extensor regions is usually more common that in the elderly, where the involvement of the folds becomes more relevant.

28. Williams criteria are based in original Hanifin and Rafka criteria Pruritus Distribution and typical morphology (facial involvement and extension areas in children, and in the areas of flexion in adults) Chronic or recurrent symptoms and Personal or family history of asthma, rhinitis and/or dermatitis For diagnosis, it is essential the presence of pruritus and at least two of the other criteria.

29. Diagnosis Hanifin and Rafka proposed to support the diagnosis in the presence of at least three “minor criteria”: Xerosis Pityriasis alba Cheilitis Follicular hyperkeratosis White dermatographism Ichthyosis High total IgE Conjunctivitis Tendency to skin infections Facial erythema Dennie Morgan bifold Sensitization to food Contact dermatitis Seborrheic dermatitis

30. Severity Among the most frequently used are: SCORAD (Severity Scoring of Atopic Dermatitis) EASI (Eczema Area and Severity Index POEM (Patient-Oriented Eczema Measure).

31. SCORAD The scale goes from 0 to 104 points, and ranks as “mild”, “moderate”, and “severe” Scale : Mild < 15 puntos Moderate 16-40 Severe > 40

32. Dermatitis classification divides patients in : Intrinsic Extrinsic Normal IgE Phenotypes High levels of total IgE (generally accepted > 200 kU /L), or a demonstrated sensitization to aeroallergens or food allergens.

33. Population characteristics in Latin America A big part of the NON-ALLERGIC population in Latin American cities seem to have total IgE levels above 200 kU /L, so this cutoff would not serve as a criterion for classifying dermatitis as intrinsic or extrinsic. This higher concentration of total IgE in the tropical population seems to be due to the high frequency of helminthes infections.

34. Phenotypes according to immunological changes. Parallel to the better understanding of the pathophysiology of AD, a more accurate classification has been developed to allow, through the use of multiple biomarkers, a greater certainty in the prediction of the evolution of dermatitis, and also to define a more effective treatment for each patient.

35. Phenotype I Th1 Response  Expression of cytokines: IL-1 IL-6 TNF-beta Dendritic cells with few exilon receptors in the membrane Predominates in patients classified with intrinsic dermatitis and in patients with extrinsic dermatitis during inter-critical periods

36. Phenotype II Predominance of Th2 response  Airborne and food allergen sensitization This process : - associated with asthma - lower remission rate - greater severity - associated with defects in filaggrin gene May be suspected : palmar hiperlineality eczema herpeticum

37. Phenotype III Presence of an autoimmune response mediated by IgE. It is suggested that this may be due to the homology between human proteins and allergens from other species Represent the most serious phase in a patient with dermatitis as a result of the persistent exposure to intrinsic allergens

38. These three processes represent different “ endo -phenotypes” of the dermatitis Their identification would predict the likelihood of remission and the treatment required (whether or not avoidance of allergenic sources, treatment with topical or systemic immunomodulators , etc.).

39. These processes may occur separately, can also be different stages of a single process Process 1 Th1 response Process 2 Th2 response Process 3 S ensitization to auto- allergens

40. Classification according to age of presentation 80% of the cases begin before age 2 43.2% had a complete remission between 2 and 7 years 18.7% persisted with symptoms 38.3% had a intermittent pattern Illi S et al, JACI,2004 Factors related to persistence early onset ( before the 1er year of life ) AD severity lower respiratory symptoms

41. Classification according to age of presentation 20% of the cases begin >14 years Only few studies about adult AD 45% of the adult AD begin before age 6 18% of the adult AD begin after 20 years Higher sensitization and total IgE level Higher persistence Garmhausen et al. Allergy , 2013

42. Laboratory test Total IgE Higher level in AD patients Biomarker associated with Persistence ( Kawamoto N et al; Lui FT et al ) Severity ( Antunez C et al, Laske N et al ) Rate of sensitization ( Laske N et al ) Topical and systemic treatment response It may persist elevated even with a AD improvement Other causes of elevated total IgE should be considered

43. Laboratory test Total IgE Indication : Evaluation and monitoring of the patients with extrinsic and intrinsic AD Committee recommendation : Weak May be used in children < 6 months with severe symptoms and children >5 years with persistent symptoms Particular considerations in Latin America : It is necessary to know normal total IgE in different regions of Latin America before performing this test routinely

44. Laboratory test Allergen sensitization AD patients are sensitized to a large number of sources than patients with asthma or rhinitis ( Johnke H, Pediatr Allergy Immunol 2006) Sensitization to food occurs in the first years of life and then it is replaced by sensitization to aeroallergens ( Acevedo N, BMC Pulm Med 2012) In tropical zones , mites sensitization could start early in life ( before the first year ) ( Acevedo N, BMC Pulm Med 2012, López N, Eur resp J, 2002) Specific IgE (mites and cat dander ) in Europa: has been related with AD severity ( Schöfer T, JACI 1999) High specific IgE in AD patients has been associated with an increased risk of food allergic reactions ( Hill DJ, Pediatr Allergy Immunol 2008; Wahn U Pediatr Allergy Immunol 2008 )

45. Laboratory test Allergen sensitization Colombian study : Correlation between the pattern of sensitization to aeroallergens and the development of AD and asthma Other allergen sources must be consered in Latin America : corn , tomato and pork A right interpretation of the test result is neccessary in order to increased the patient adherence to therapy and the quality of life Sánchez J, Revista Alergia México 2012 Sánchez J, Allergol Immunopathol 2013

46. Laboratory test Allergen sensitization Microbial proteins : 50-80% sensitization to the AD patients It has been correlated with the AD severety A greater sensitization to Malazzasia fufur has been observed in the AD patients ; a clear correlation with severity is not demostrated Response against autoallergens ( Hom s ) appears to be specific of AD severe which could be important in predicting the prognosis

47. Laboratory test Allergen sensitization Indication : Diagnosis and monitoring of AD patients Identification of environmental sources exacerbating symptoms Committee recommendation : Aeroallergens : strong . All patients with dermatitis Food allergens : strong . Only when a clinical suspicion or AD severe or persistente. The test battery should be consistent with the geographical area Particular considerations in Latin America : There are many studies about aeroallergens but only a few about food allergens in specific regions

48. Laboratory test Patch tests with food and/ or aeroallergens Food Tests have been carried out with milk , egg , soy, wheat … Drawback . Wide range in predictive values and lack of standardization Adventages Easy to perform It can reduce the requeriment for provocation tests and avoid unnecessary restriction diets Aeroallergens The main experience with mites patch tests Lack of standardizations so the routinely use is not recommended ( Isolauri E, JACI 1996; Niggemann B, Allergy 2000; Vanto T, Allergy 1999; Niggemann B, JACI 1999; Majamaa H, Allergy 1999; Darsow U, Allergy 2004

49. Laboratory test Patch tests with food and/ or aeroallergens Indication : Evaluation and monitoring of AD patients When delayed reactions with food or aerollergens are suspected Committee recommendation : Food : moderate . Useful in patients with negative IgE response or late- onset symptoms Aeroallergens : weak . Few controled studies . Specific batteries of allergens should be used Particular considerations in Latin America : Only a few studies but in favor of its use Standardization of the technique is necessary

50. Laboratory test Patch with standard battery and other types of patch 15-30% of AD patients suffer from contact dermatitis This test is very useful in patients with strong suspition of exacerbation by contac allergens or persistent symptoms without response to treatment Considered a false positive result in AD In some occasions a photo-pach test must be performed It is important to know that if non standarizated contacts are used , pacth tests in 10 healthy controls must be performed White JM, Clin Exp Allergy 2012; Spiewak R, Curr Opin Allergy Immunol 2012

51. Laboratory test Patch with standard battery and other types of patch Indication : Patients with suspicion of AD Patients with severe and persistent AD refractory to medical treatment Committee recommendation : Standard battery : strong Other types of patch : moderate Particular considerations in Latin America : Useful as diagnosis support in AD Rodrigues DF, An Bras Dermatol 2012; Blancas-Espinosa R, Contact Dermatitis 2006; Rivas A, Revista Asociación Colombiana Dermatologia 2011)

52. Laboratory test Provocation and food elimination diets The provocation test with food is considered the gold standard for identifying if a suspected food is the cause of the patient´s symptoms Due to the potential risk of this test, it is carried out when skin prick test and laboratory test cannot clarify the diagnosis In many cases are carried out elimination diets for 4-6 weeks to assess the AD evolution ; if doubt persists then a challenge test could be performed

53. Laboratory test Provocation and food elimination diets Indication : When skin prick test and laboratory test cannot clarify the diagnosis Committee recommendation : Strong After elimination diet , if doubt persists , a provocation must be performed Particular considerations in Latin America : There are few studies about this subject . It is necessary to establish protocols with native foods Madrigal BI, Rev Aler Mex 1996)

54. Laboratory test Complementary studies -CSC, electrolytes determination , liver function or kidney function …. : They are not inicated as routined exams They could be indicated as part of the follow up when immunosupressants or sistemic steroids are been administrated - Skin biopsia: useful for differencial diagnosis

55. Active management FIRST LINE MANAGEMENT Skin care and hydratation Dry skin is one of the main signs of AD due to - filaggrin defects - lack of intercell lipids and other stratum corneum alterations In consequence , a lack of continuity of SKIN BARRIER occurs in AD Briot A, J Exp Med 2009

56. Active management FIRST LINE MANAGEMENT Bathing : Removes debris of the skin that could stimulate the bacterial growth It is recommended very short bath ( about 5 minutes) with slightly cold water to reduce xerosis and mechanical irritation Add sodium hypochlorite into bath water in patients with history of skin infection or risk of skin infection ) aprox . 1 or 2 drops / liter of water prevent balterial growth Using bath salts or oils in final two minutes of the bath could improve skin hydratation and skin cleansing Avoid soaps and use neutral cleansing Huang JT, Pediatrics 2009

57. Active management FIRST LINE MANAGEMENT If a chielitis exits , moisturizing lipsticks are recommended Keep nails short to prevent stcraching during sleep Baggy clothing made of cotton is the best in order to avoid irritation and heat There are a few controlled studies in relation to adjuvant treatment ( moisturizing , general recommendatios , cleansing products …) Méndez-Cabeza J. MEDIFAM 2003

58. Active management FIRST LINE MANAGEMENT Moisturizers appear to reduce S everity of AD exacerbations ( Breternitz M, Skin Pharmacol Physiol 2008) B acterial infections ( Verallo-Rovell VM, Dermatitis 2008 ) S teroid requirement ( Grimalt R, Dermatology 2007; Szczepanowska J Pediatr Allergy Immunol 2008) It is recommended to apply twice a day ; one of them after bathing or shower ( Chiang C, Pediatr Dermatol 2009) Choosing the best depend on AD extension AD severity patient´s tolerance ( Varothai S, Asian Pac j Allergy Immunol 2013

59. Active management FIRST LINE MANAGEMENT Moisturizers It’s considered a pillar in the treatment of AD Another important factor in a good adherence is the cost of the product E xplain to the patient how to use moisturizers and apply the right amount Rule of the fingers could be used : The amount of cream that covers a thumb must be cover the palm of hand ),

60. Active management FIRST LINE MANAGEMENT Moisturizers V aseline is considered a AD moisturizers with a excellent cost / efficacy relation Disadventages : it has an oily consistency and it produce a sense of heat and sweat retention Urea products impprove the skin renewal but tend to be less tolerated than others , specially in areas with open lesions Urea is recommended on skin with lichenification . Some creams contain natural ingredients ( nuts , oats …) with a small risk of sensitization Lodén M, Acta Derm Venereol 2002 Lack G, N Engl J Med 2003

61. Active management FIRST LINE MANAGEMENT Moisturizers Indication In all AD patients The frecuency and the amount depend on the severity Committe recomendation Strong Choose the product that facilitate the better adherence Particular considerations in Latin America : At the moment , these products are not covered by the health systems in the most countries . Factors such as cost / benefit must be considered to ensure a good adherence and a better response

62. "For anti-inflammatory treatment, topical steroids remain the cornerstone in the management of dermatitis" Topical steroids First line management

63. Topical steroids Reduce the risk of infection by S. aureus Lower frequency of systemic side effects Few controlled studies supporting their uses or how to use them Different schemes have been proposed in the use of steroids Active management FIRST LINE MANAGEMENT

64. Schemes proposed in the use of steroids: Potency and regions Active management FIRST LINE MANAGEMENT Topical steroids

65. Schemes proposed in the use of steroids: Minimum possible time Switch to medium or low power steroids according to the control of the patient. Prolonged periods in wide body extensions (even mild steroids) can have similar risk of adverse effects than oral or intravenous steroids. Intermittent treatment appears to reduce this risk even with high potency steroids Active management FIRST LINE MANAGEMENT Topical steroids

66. Schemes proposed in the use of steroids: High potency steroids: Should be used only in patients with moderate to severe AD Should be avoided in the facial, folds and perennial regions Should be used with caution in children under two years ? FIRST LINE MANAGEMENT Active management Topical steroids

67. Schemes proposed in the use of steroids: Steroid use with moisturizer seems to improve the power of the steroid and increase the time of its effect on the skin + Topical steroids Active management FIRST LINE MANAGEMENT

68. Recommendation of the Committee. Strong. Particular considerations in Latin America. Latin America has a wide variety of steroids It must be taken into account the characteristics of the tropics and subtropics regions when choosing the consistency (cream, ointment, etc.) to improve patient adherence. FIRST LINE MANAGEMENT Active management Topical steroids

69. In practice, they can be used for the same indications as a steroid of medium ( tacrolimus 1%) or low power ( tacrolimus 0.03%, pimecrolimus 1%) Advantages: Lower risk of adverse effects Not cause skin atrophy in continuous treatment Calcineurin inhibtors Active management FIRST LINE MANAGEMENT

70. Recommendation of the Committee. Strong Particular considerations in Latin America. Currently in most Latin American countries both tacrolimus and pimecrolimus are available. FIRST LINE MANAGEMENT Active management Calcineurin inhibtors

71. “In the last two decades several controlled studies showing that a significant percentage of patients with atopic dermatitis can benefit from this therapy" First line management Allergen-specific immunotherapy

72. ACTIONS Significant reduction in symptoms compared to placebo (by SCORAD) Significant increase in IgG4 Allergen-specific immunotherapy Active management FIRST LINE MANAGEMENT

73. Indication . Patients with persistent moderate or severe atopic dermatitis who have a clear relationship of exacerbation with aeroallergens. Recommendation of the Committee . Moderate. Particular considerations in Latin America . Studies support the efficacy and safety of using the specific allergen immunotherapy with Dermatophagoides farinae and Dermatophagoides pteronyssinus S tudies using other common allergen sources in the region, as Blomia tropicalis , Dermatophagoides siboney and some pollen grains are needed. FIRST LINE MANAGEMENT Active management Allergen-specific immunotherapy

74. “Since the skin of patients with dermatitis is very sensitive, many agents can act as irritants increasing the inflammatory process and therefore should be avoided" First line management Enviromental and dietary control

75. Environmental control Irritants substances: Soap, detergent, some creams, polluted air Control the temperature and humidity is necessary Allergenic sources witch patients are sensitized must be avoided Prophylactic restrictions without clinical relevance are not recommended Removal of pets: unless there is clear clinical relationship and sensitization is demonstrated Enviromental and dietary control FIRST LINE MANAGEMENT

76. Dietary control Top Ten allergenic foods Restricted diet should be very careful High prevalence of irrelevant sensitizations Nutritional problems Enviromental and dietary control FIRST LINE MANAGEMENT

77. FIRST LINE MANAGEMENT Enviromental and dietary control

78. “Have been used for many years … but controlled studies show minimal or no effect" Second line management Antihistamines

79. NO EFFECT? Other mechanisms? IL-33? First-generation: Sedative effect Risk of side effects: drowsiness; low concentration Second-generation: Loratadine , cetirizine , fexofenadine : some impact on pruritus Antihistamines Active management SECOND LINE MANAGEMENT

80. Active management SECOND LINE MANAGEMENT Antihistamines

81. “Because the high risk of adverse effects (cataracts, osteoporosis, height), is not recommended for prolonged use” Second line management Systemic steroids

82. High relapse rate after suspension, compared with other immunosuppressants , like cyclosporine Adjust the dose according the weight Reduce the dose as soon as possible No standard way to do this Systemic steroids Active management SECOND LINE MANAGEMENT

83. Active management SECOND LINE MANAGEMENT Systemic steroids

84. “Mild to moderate AD had a significant improvement over the summer, with relapses in the other seasons” Second line management Sun exposure and phototherapy

85. Sun exposure: 15 a 20 minutes (7:00-8:00 am; 3:00 - 4:00 pm) – beneficial effect High temperature and humidity in tropics can exacerbate pruritus Sun exposure and phototherapy SECOND LINE MANAGEMENT

86. Phototherapy: Controlled environments - 40 to 50% of substancial improvements Mechanisms (not clear): Antimicrobial effect Inhibiting the Langehans cells activity Production of Vitamin D Wavelengths types: UVA1, UVB, UVB broadband UVB can use in children Side effects: Burns, hyper pigmentation, fatigue, nausea , h eadache Sun exposure and phototherapy SECOND LINE MANAGEMENT

87. Sun exposure and phototherapy SECOND LINE MANAGEMENT

88. “This therapy is clinically effective, but with high relapse rate” Second line management Cyclosporine A

89. Cyclosporine A: Mechanisms : Potent inhibitors of T lymphocytes immune responses Clinical response is observed after 2 weeks, reaching great effect at 2 to 3 months Risks: Nephrotoxicity and hypertension Side effects: Nausea, paresthesias , abdominal pain Active management SECOND LINE MANAGEMENT

90. SECOND LINE MANAGEMENT Active management Cyclosporine A

91. “Although there are numerous report showing its positive effect in patients with AD, there are few controlled studies” Third line management Mycophenolate mofetil

92. Mycophenolate mofetil : Mechanisms : Inhibitors of purine synthesis; Stop the division of diverse cell lines , including lymphocytes Side effects: Nausea, vomiting, herpes and retinitis Active management THIRD LINE MANAGEMENT

93. Active management THIRD LINE MANAGEMENT Mycophenolate mofetil :

94. “Several controlled studies supported it , use especially in severe cases in p opulation over 6 years of age” Third line management Azathioprine

95. Azathioprine : Mechanisms : Not know High incidence of adverse effects Nausea, vomiting and abdominal pain Clinical response: 4 to 8 weeks Active management THIRD LINE MANAGEMENT

96. Active management THIRD LINE MANAGEMENT Azathioprine :

97. “There are few controlled studies for AD treatment. Therefore the appropriate dose and frequency of adverses effects is limited” Third line management Methrotrexate

98. Methrotrexate : Mechanisms : Inhibitor of dihydrofolatereductase , it prevents the activity of thymidilate synthetase necessary for the incorporation of nucleotide dTMP into DNA Efficacy similar to Azathioprine 10 to 25 mg/week Active management THIRD LINE MANAGEMENT

99. Active management THIRD LINE MANAGEMENT Methrotrexate :

100. Probiotics and prebiotics Pro Contra Kalliomäki et al: Lactobacillus rhamnosus Dotterud et al: Lactobacillus sp Osborn , Cochrane Review 2007: reduction in eczema, but not enough to recommend Williams et al Bath- Hextal , Cochrane Review 2012 Osborn , Cochrane Review 2013: more studies are needed Kalliomäki , Lancet 2003. Osborn , Cochrane Database Syst Rev. 2007 Dotterud , Br J Dermatol 2010. Williams, Clin Exp Dermatol 2010 Bath- Hextal , Cochrane Database Syst Rev 2012, Osborn , Cochrane Database Syst Rev. 2013 Active management FOURTH LINE MANAGEMENT

101. Omalizumab Conflicting evidence: studies with promising results and some without clinical effect. Some reports suggest good results even with high levels of IgE Caruso , Allergy 2010. Park, Ann Dermatol 2010. Lane , J Am Acad Dermatol 2006. Belloni , JACI 2007. Sheinkopf , Allergy Asthma Proc 2008. Heil , J Dtsch Dermatol Ges 2010. Iyengar , Int Arch Allergy Immunol 2013 Active management FOURTH LINE MANAGEMENT

102. Interferon gamma One study compared high dose, low dose and placebo, with good results in the 2 groups treated with interferon gamma. Adverse effects: transient fever, myalgias , respiratory distress, elevated transaminases and lipid profile. Jang , J Am Acad Dermatol 2004. Active management FOURTH LINE MANAGEMENT

103. Others therapies : Contradictory results: rituximab, efalizumab , aterizumab , alafacept , mepolizumb and etanercept ; can not be recommended to all patients. Satisfactory results but not standardized: intravenous immunoglobulin, autologous serum, some herbal products; can not be recommend. Simon , JACI 2008. Sedivá , JACI 2008. Ponte, J Am Acad Dermatol 2010. Ibler , J Eur Acad Dermatol Venereol 2010. Bremmer , J Am Acad Dermatol 2009. Jee , Allergy Asthma Immunol Res 2011. Pittler , Br J Dermatol 2003. DiNicola , Clin Rev Allergy Immunol 2013. Zhang, Cochrane Database Syst Rev 2005. Active management FOURTH LINE MANAGEMENT

104. Hospital management Should be avoided because high risk of complications . Should be consider when : Involvement >50% of skin surface with moist lesions or erythrodermia Sepsis or severe cutaneus infection , disseminated or extensive Involvement of other systems : renal, respiratory , etc. Limitation to perform daily activities Failure to follow established treatment Rapid deterioration Buhles , J Dtsch Dermatol Ges 2011. Holling , J Eval Clin Pract 2010 Active management

105. Primary prevention : Vitamin D supplementation during pregnancy has contradictory results Some foods (fruits, vegetables, unsaturated fatty acids) may have a preventive effect P olyunsaturated fatty acid supplementation during pregnancy appears to reduce the risk, but further studies are needed In a meta-analysis, the presence of dogs in the house reduced the risk by 25% Reinholz , clin Exp Allergy 2012. Bäck , Acta Derm Venereol 2009 Hyppönen , Ann N Y Acad Sci 2004. Nwaru , Pediatr Allergy Immunol 2010 Foolad , JAMA Dermatol 2013. Palmer, BMJ 2012. Pelucchi , JACI 2013

106. Secondary prevention The goal is to prevent common complications such as exacerbations and bacterial superinfection . Topical antibiotics one week per month, although they appear to prevent infection, no statistically significant changes and exists the risk of antimicrobial resistance. Boguniewicz , JACI 2010. Bath- Hextall , Br J Dermatol 2010

107. Pregnancy: During second half of pregnancy, 66% of patients present exacerbation Treatment is almost like non-pregnancy, but try to use small doses of topical steroids (Category C) Only in extreme cases: calcineurin inhibitors, oral steroids, azathioprine and cyclosporine Avoid: methotrexate , mycophenolate mofetil , psolarens and PUVA therapy First-generation antihistamines (Category B): chlorpheniramine , cyproheptadine and diphenhydramine Second-generation antihistamines: loratadine seems to be a safe option, there few studies Babalola , Dermatol Ther 2013. Cho , Ann Dermatol 2010 Koutroulis , Obstet Gynecol Surv 2011. Kar , J Pharmacol Pharmacother 2012 Special situations

108. Breastfeeding : Elimination diet in the mother for food to which the child is allergic Breastfeeding seems to have a beneficial effect If the mother takes immunosuppressive drugs for dermatitis: Steroids can pass into breast milk Ideally cyclosporine should be discontinued Second-generation antihistamines approved after the sixth month of life Orru , Int J Immunopathol Pharmacol 2013. Paveglio , Clin Exp Allergy 2012. Verhasselt , Nat Med 2008 Special situations

109. Adult dermatitis: Onset after 14 years: 5-15% Tendency to have more non-allergic comorbidities It may be necessary skin biopsy and / or patch tests Garmhausen , Allergy 2013. De Bruin Weller , Clin Exp Allergy 2013 Special situations

110. Interdisciplinary management Silverberg , Pediatr Allergy Immunol 2013. Yaghmaie , JACI 2013. Kemp , Pharmacoeconomics 2003

111. Table 2. Immunosuppressive drugs

112. Table 2. Immunosuppressive drugs

113. Committee of Atopic Dermatitis Dra. Ana María Agar , Chile Dra. Milagros Lázaro, España Dr. Bruno Paes Barreto, Brasil Dra. Alejandra Macías Weinmann , México