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| ==Overview== | | ==Overview== |
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| | The mainstay of treatment for atopic dermatitis depends upon the severity of the disease and is treated with combination of conservative and medical therapy. The goals of treatment include elimination of aggravating factors, skin barrier function repair, maintaining skin hydration and pharmacologic treatment of skin inflammation. |
| Atopic dermatitis is a chronic inflammatory skin disorder with an immunologic background and occurs in patients with a personal or family history of atopy (i.e., asthma or allergic rhinitis).<ref name="MihmSoter1976">{{cite journal|last1=Mihm|first1=Martin C|last2=Soter|first2=Nicholas A|last3=Dvorak|first3=Harold F|last4=Austen|first4=K Frank|title=The Structure Of Normal Skin And The Morphology Of Atopic Eczema|journal=Journal of Investigative Dermatology|volume=67|issue=3|year=1976|pages=305–312|issn=0022202X|doi=10.1111/1523-1747.ep12514346}}</ref> It is caused by either skin barrier dysfunction or immune dysregulation of the adaptive and innate immune response leading to an enhanced IgE-mediated, systemic Th2 response. The skin barrier is invaded by exogenous substances, including allergens, irritants and microbes; and brick wall-like’ structure of the stratum corneum is further compromised. Systemically, a dysfunctional innate and adaptive immune response causes further damage to the epidermis<ref name="pmid20109730">{{cite journal |vauthors=Barnes KC |title=An update on the genetics of atopic dermatitis: scratching the surface in 2009 |journal=J. Allergy Clin. Immunol. |volume=125 |issue=1 |pages=16–29.e1–11; quiz 30–1 |date=January 2010 |pmid=20109730 |pmc=2874322 |doi=10.1016/j.jaci.2009.11.008 |url=}}</ref>.
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| ==Pathophysiology==
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| ===Physiology===
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| The normal physiology of atopic Dermatitis can be understood as follows:
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| '''Epidermal barrier function:'''
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| * '''Epidermis''': It directly interfaces with the environment and acts as the 1st line of defense. It is primarily dependent on structure and composition of the most outermost layer of the skin, i.e. Stratum corneum. It protects the body from irritants, allergens, microbes and pathogens from invading the skin as well as preventing the excess water loss.<ref name="pmid25131691">{{cite journal |vauthors=Elias PM, Wakefield JS |title=Mechanisms of abnormal lamellar body secretion and the dysfunctional skin barrier in patients with atopic dermatitis |journal=J. Allergy Clin. Immunol. |volume=134 |issue=4 |pages=781–791.e1 |date=October 2014 |pmid=25131691 |pmc=4186911 |doi=10.1016/j.jaci.2014.05.048 |url=}}</ref>
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| ** Tightly packed corenocytes layers in the stratum corneum.
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| ** Intercellular lipid bilayers.
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| ** Corneocytes layers embedded in the extracellular matrix derived from lipid lamellae.
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| ** Natural Moisturising Factors, maintains the water retention in the stratum corneum
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| ** Antimicrobial peptides production
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| * '''Filaggrin protien:''' Encoded by FLG gene on chromosome 1q21(contains the genes of the epidermal differentiation complex (EDC) and is the main component required to form corneocytes in the stratum corneum.<ref name="pmid19386895">{{cite journal |vauthors=Sandilands A, Sutherland C, Irvine AD, McLean WH |title=Filaggrin in the frontline: role in skin barrier function and disease |journal=J. Cell. Sci. |volume=122 |issue=Pt 9 |pages=1285–94 |date=May 2009 |pmid=19386895 |pmc=2721001 |doi=10.1242/jcs.033969 |url=}}</ref>
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| ** Pro-filaggrin is required for the formation of dense cytoplasmic granules, which along with other proteins forms the corneocytes, that acts as primary unit for barrier function of the skin.
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| ** Pro-filaggrin undergoes extensive phosphorylation and dephosphorylation, to produce Filaggrin monomers, to interact and aggregate with the keratin filaments and provide
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| ** The degraded products of Filaggrin protein are one of the major components of Natural Moisturising Factors(NMF), which prevents excess water loss from the stratum corneum
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| ** The degraded products of Filaggrin protein also maintain the acidic pH of the SC, required to regulate the activity of enzymes in stratum corneum.
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| * '''Proteins related to tight junctions''': These transmembrane proteins are present in the stratum granulosum of the epidermis and compose together to form tight junctions. e.g. claudin-1, occludin, junctional adhesion molecule, etc.<ref name="pmid211635152">{{cite journal |vauthors=De Benedetto A, Rafaels NM, McGirt LY, Ivanov AI, Georas SN, Cheadle C, Berger AE, Zhang K, Vidyasagar S, Yoshida T, Boguniewicz M, Hata T, Schneider LC, Hanifin JM, Gallo RL, Novak N, Weidinger S, Beaty TH, Leung DY, Barnes KC, Beck LA |title=Tight junction defects in patients with atopic dermatitis |journal=J. Allergy Clin. Immunol. |volume=127 |issue=3 |pages=773–86.e1–7 |date=March 2011 |pmid=21163515 |pmc=3049863 |doi=10.1016/j.jaci.2010.10.018 |url=}}</ref>
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| * '''Other protiens''': filaggrin-2, corneodesmosin, desmoglein-1, desmocollin-1, transglutaminase-3 are also part of skin barrier related proteins.<ref name="pmid21211653">{{cite journal |vauthors=Broccardo CJ, Mahaffey S, Schwarz J, Wruck L, David G, Schlievert PM, Reisdorph NA, Leung DY |title=Comparative proteomic profiling of patients with atopic dermatitis based on history of eczema herpeticum infection and Staphylococcus aureus colonization |journal=J. Allergy Clin. Immunol. |volume=127 |issue=1 |pages=186–93, 193.e1–11 |date=January 2011 |pmid=21211653 |pmc=3059191 |doi=10.1016/j.jaci.2010.10.033 |url=}}</ref>
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| '''Immune response:'''
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| * '''Cutaneous immune response''': It acts as first line barrier and constitutes the rapid response mechanism to the invading allergen or pathogen. It recognizes the microbes through receptors known as pattern recognition receptors (PRRs). Cutaneous immune response includes following 4 elements:<ref name="pmid233742592">{{cite journal |vauthors=Kuo IH, Yoshida T, De Benedetto A, Beck LA |title=The cutaneous innate immune response in patients with atopic dermatitis |journal=J. Allergy Clin. Immunol. |volume=131 |issue=2 |pages=266–78 |date=February 2013 |pmid=23374259 |doi=10.1016/j.jaci.2012.12.1563 |url=}}</ref>
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| ** Physical: stratum corneum and the tight junctions in stratum granulosum . The maintenance and repair of epithelial barriers, is mediated through the activation of PRRs by the innate immune system.<ref name="pmid15236188">{{cite journal |vauthors=Cario E, Gerken G, Podolsky DK |title=Toll-like receptor 2 enhances ZO-1-associated intestinal epithelial barrier integrity via protein kinase C |journal=Gastroenterology |volume=127 |issue=1 |pages=224–38 |date=July 2004 |pmid=15236188 |doi= |url=}}</ref>
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| ** Chemical: antimicrobial proteins including antimicrobial peptides (AMPs), S100 protiens, cytokines as well as chemokines, innate lymphoid cells group 2 (ILC-2), toll-like receptors (TLRs),keratinocytes, filaggrin degraded products, and neutrophils.<ref name="pmid23374259">{{cite journal |vauthors=Kuo IH, Yoshida T, De Benedetto A, Beck LA |title=The cutaneous innate immune response in patients with atopic dermatitis |journal=J. Allergy Clin. Immunol. |volume=131 |issue=2 |pages=266–78 |date=February 2013 |pmid=23374259 |doi=10.1016/j.jaci.2012.12.1563 |url=}}</ref>,<ref name="pmid232231422">{{cite journal |vauthors=Kuo IH, Carpenter-Mendini A, Yoshida T, McGirt LY, Ivanov AI, Barnes KC, Gallo RL, Borkowski AW, Yamasaki K, Leung DY, Georas SN, De Benedetto A, Beck LA |title=Activation of epidermal toll-like receptor 2 enhances tight junction function: implications for atopic dermatitis and skin barrier repair |journal=J. Invest. Dermatol. |volume=133 |issue=4 |pages=988–98 |date=April 2013 |pmid=23223142 |pmc=3600383 |doi=10.1038/jid.2012.437 |url=}}</ref>
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| ** Microbiome: skin-resident normal microbial flora including bacteria, fungi, and viruses. Protects from invading microbes and pathogens and modulates the balance between inflammation and immune responses.<ref name="pmid279740402">{{cite journal |vauthors=Lynch SV, Pedersen O |title=The Human Intestinal Microbiome in Health and Disease |journal=N. Engl. J. Med. |volume=375 |issue=24 |pages=2369–2379 |date=December 2016 |pmid=27974040 |doi=10.1056/NEJMra1600266 |url=}}</ref>
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| ** Immunological: Immune response includes both non specific and immediate response (innate immunity) and highly specific and late response (adaptive immunity).
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| * '''Adaptive Immune response''':The character and magnitude of adaptive immune system is determined by innate immune response by interactions with the epidermal elements and activation of TLRs<ref name="pmid19078985">{{cite journal |vauthors=De Benedetto A, Agnihothri R, McGirt LY, Bankova LG, Beck LA |title=Atopic dermatitis: a disease caused by innate immune defects? |journal=J. Invest. Dermatol. |volume=129 |issue=1 |pages=14–30 |date=January 2009 |pmid=19078985 |doi=10.1038/jid.2008.259 |url=}}</ref>
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| * '''Thymic stromal lymphopoietin:''' Thymic stromal lymphopoietin (TSLP) is considered as "a master switch for allergic inflammation"<ref name="pmid16432252">{{cite journal |vauthors=Liu YJ |title=Thymic stromal lymphopoietin: master switch for allergic inflammation |journal=J. Exp. Med. |volume=203 |issue=2 |pages=269–73 |date=February 2006 |pmid=16432252 |pmc=2118215 |doi=10.1084/jem.20051745 |url=}}</ref>, and is highly expressed by epithelial cells and epidermal keratinocytes<ref name="pmid22270071">{{cite journal |vauthors=Takai T |title=TSLP expression: cellular sources, triggers, and regulatory mechanisms |journal=Allergol Int |volume=61 |issue=1 |pages=3–17 |date=March 2012 |pmid=22270071 |doi=10.2332/allergolint.11-RAI-0395 |url=}}</ref> . It is an IL-7-like cytokine, which stimulates the differentiation of naïve T helper cells into inflammatory Th2 cells<ref name="pmid164322522">{{cite journal |vauthors=Liu YJ |title=Thymic stromal lymphopoietin: master switch for allergic inflammation |journal=J. Exp. Med. |volume=203 |issue=2 |pages=269–73 |date=February 2006 |pmid=16432252 |pmc=2118215 |doi=10.1084/jem.20051745 |url=}}</ref>.
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| ==Pathogenesis==
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| It is understood that atopic dermatitis is the result of either skin barrier dysfunction or by immune dysregulation.<ref name="pmid21682749">{{cite journal |vauthors=Boguniewicz M, Leung DY |title=Atopic dermatitis: a disease of altered skin barrier and immune dysregulation |journal=Immunol. Rev. |volume=242 |issue=1 |pages=233–46 |date=July 2011 |pmid=21682749 |pmc=3122139 |doi=10.1111/j.1600-065X.2011.01027.x |url=}}</ref>
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| '''Epidermal barrier dysfunction(outside-in hypothesis):'''<ref name="pmid183290874">{{cite journal |vauthors=Elias PM, Hatano Y, Williams ML |title=Basis for the barrier abnormality in atopic dermatitis: outside-inside-outside pathogenic mechanisms |journal=J. Allergy Clin. Immunol. |volume=121 |issue=6 |pages=1337–43 |date=June 2008 |pmid=18329087 |pmc=2706021 |doi=10.1016/j.jaci.2008.01.022 |url=}}</ref>
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| * The major factors to abnormal skin barrier include loss-of-function mutations in the filaggrin gene (FLG) causing Filaggrin deficiency<ref name="pmid19720210">{{cite journal |vauthors=Howell MD, Kim BE, Gao P, Grant AV, Boguniewicz M, DeBenedetto A, Schneider L, Beck LA, Barnes KC, Leung DY |title=Cytokine modulation of atopic dermatitis filaggrin skin expression |journal=J. Allergy Clin. Immunol. |volume=124 |issue=3 Suppl 2 |pages=R7–R12 |date=September 2009 |pmid=19720210 |doi=10.1016/j.jaci.2009.07.012 |url=}}</ref>, tight junction abnormalities<ref name="pmid21163515">{{cite journal |vauthors=De Benedetto A, Rafaels NM, McGirt LY, Ivanov AI, Georas SN, Cheadle C, Berger AE, Zhang K, Vidyasagar S, Yoshida T, Boguniewicz M, Hata T, Schneider LC, Hanifin JM, Gallo RL, Novak N, Weidinger S, Beaty TH, Leung DY, Barnes KC, Beck LA |title=Tight junction defects in patients with atopic dermatitis |journal=J. Allergy Clin. Immunol. |volume=127 |issue=3 |pages=773–86.e1–7 |date=March 2011 |pmid=21163515 |pmc=3049863 |doi=10.1016/j.jaci.2010.10.018 |url=}}</ref>, more alkaline surface pH,<ref name="pmid18329087">{{cite journal |vauthors=Elias PM, Hatano Y, Williams ML |title=Basis for the barrier abnormality in atopic dermatitis: outside-inside-outside pathogenic mechanisms |journal=J. Allergy Clin. Immunol. |volume=121 |issue=6 |pages=1337–43 |date=June 2008 |pmid=18329087 |pmc=2706021 |doi=10.1016/j.jaci.2008.01.022 |url=}}</ref> microbial colonization, altered protease activity in the stratum corneum.<ref name="pmid16815133">{{cite journal |vauthors=Cork MJ, Robinson DA, Vasilopoulos Y, Ferguson A, Moustafa M, MacGowan A, Duff GW, Ward SJ, Tazi-Ahnini R |title=New perspectives on epidermal barrier dysfunction in atopic dermatitis: gene-environment interactions |journal=J. Allergy Clin. Immunol. |volume=118 |issue=1 |pages=3–21; quiz 22–3 |date=July 2006 |pmid=16815133 |doi=10.1016/j.jaci.2006.04.042 |url=}}</ref><ref name="pmid23374260">{{cite journal |vauthors=McAleer MA, Irvine AD |title=The multifunctional role of filaggrin in allergic skin disease |journal=J. Allergy Clin. Immunol. |volume=131 |issue=2 |pages=280–91 |date=February 2013 |pmid=23374260 |doi=10.1016/j.jaci.2012.12.668 |url=}}</ref><ref name="pmid22951058">{{cite journal |vauthors=Margolis DJ, Apter AJ, Gupta J, Hoffstad O, Papadopoulos M, Campbell LE, Sandilands A, McLean WH, Rebbeck TR, Mitra N |title=The persistence of atopic dermatitis and filaggrin (FLG) mutations in a US longitudinal cohort |journal=J. Allergy Clin. Immunol. |volume=130 |issue=4 |pages=912–7 |date=October 2012 |pmid=22951058 |pmc=3462287 |doi=10.1016/j.jaci.2012.07.008 |url=}}</ref><ref name="pmid22521249">{{cite journal |vauthors=Morizane S, Yamasaki K, Kajita A, Ikeda K, Zhan M, Aoyama Y, Gallo RL, Iwatsuki K |title=TH2 cytokines increase kallikrein 7 expression and function in patients with atopic dermatitis |journal=J. Allergy Clin. Immunol. |volume=130 |issue=1 |pages=259–61.e1 |date=July 2012 |pmid=22521249 |pmc=3387356 |doi=10.1016/j.jaci.2012.03.006 |url=}}</ref>
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| * Skin barrier abnormalities lead to the permeability of epidermis, causing entry of antigens or pathogens, microbial colonization most notably by staphylococcus aureus and herpes simplex virus (HSV); leading to the production of inflammatory cytokines and Impaired production of antimicrobial peptides.<ref name="pmid23712284">{{cite journal |vauthors=Leung DY |title=New insights into atopic dermatitis: role of skin barrier and immune dysregulation |journal=Allergol Int |volume=62 |issue=2 |pages=151–61 |date=June 2013 |pmid=23712284 |doi=10.2332/allergolint.13-RAI-0564 |url=}}</ref>
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| *It leads to increased trans-epidermal water loss, and decreased levels of ceramides and water binding.<ref name="pmid19494826">{{cite journal| author=Cork MJ, Danby SG, Vasilopoulos Y, Hadgraft J, Lane ME, Moustafa M et al.| title=Epidermal barrier dysfunction in atopic dermatitis. | journal=J Invest Dermatol | year= 2009 | volume= 129 | issue= 8 | pages= 1892-908 | pmid=19494826 | doi=10.1038/jid.2009.133 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19494826 }} </ref>
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| *Severe atopic dermatitis have been associated with higher levels of trans-epidermal water loss.<ref name="pmid21137118">{{cite journal |vauthors=Flohr C, England K, Radulovic S, McLean WH, Campbel LE, Barker J, Perkin M, Lack G |title=Filaggrin loss-of-function mutations are associated with early-onset eczema, eczema severity and transepidermal water loss at 3 months of age |journal=Br. J. Dermatol. |volume=163 |issue=6 |pages=1333–6 |date=December 2010 |pmid=21137118 |doi= |url=}}</ref>
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| '''Immune dysregulation (inside-out’ hypothesis):'''<ref name="pmid183290872">{{cite journal |vauthors=Elias PM, Hatano Y, Williams ML |title=Basis for the barrier abnormality in atopic dermatitis: outside-inside-outside pathogenic mechanisms |journal=J. Allergy Clin. Immunol. |volume=121 |issue=6 |pages=1337–43 |date=June 2008 |pmid=18329087 |pmc=2706021 |doi=10.1016/j.jaci.2008.01.022 |url=}}</ref>:
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| *'''Innate immune response:'''
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| **Pathogens or tissue damage activate pattern recognition receptors including toll-like receptors (TLRs), induce a release of inflammatory mediators, including AMPs, cytokines, and chemokines<ref name="pmid23223142">{{cite journal |vauthors=Kuo IH, Carpenter-Mendini A, Yoshida T, McGirt LY, Ivanov AI, Barnes KC, Gallo RL, Borkowski AW, Yamasaki K, Leung DY, Georas SN, De Benedetto A, Beck LA |title=Activation of epidermal toll-like receptor 2 enhances tight junction function: implications for atopic dermatitis and skin barrier repair |journal=J. Invest. Dermatol. |volume=133 |issue=4 |pages=988–98 |date=April 2013 |pmid=23223142 |pmc=3600383 |doi=10.1038/jid.2012.437 |url=}}</ref>
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| **Defective cutaneous innate immune mediated epidermal barrier repair and maintenance may alter skin-resident normal microbial flora and lead to severe inflammation as demonstrated with atopic dermatitis patients colonized with ''Staphylococcus aureus''<ref name="pmid22310478">{{cite journal |vauthors=Kong HH, Oh J, Deming C, Conlan S, Grice EA, Beatson MA, Nomicos E, Polley EC, Komarow HD, Murray PR, Turner ML, Segre JA |title=Temporal shifts in the skin microbiome associated with disease flares and treatment in children with atopic dermatitis |journal=Genome Res. |volume=22 |issue=5 |pages=850–9 |date=May 2012 |pmid=22310478 |pmc=3337431 |doi=10.1101/gr.131029.111 |url=}}</ref>
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| **In intact skin barrier, antimicrobial peptides(AMPs) are regulated by cytokines, IL-17 and IL- 22, which are secreted by Th17 T and Th22 cells. This effect is suppressed in patients with atopic dermatitis.<ref name="pmid21315950">{{cite journal |vauthors=Macias ES, Pereira FA, Rietkerk W, Safai B |title=Superantigens in dermatology |journal=J. Am. Acad. Dermatol. |volume=64 |issue=3 |pages=455–72; quiz 473–4 |date=March 2011 |pmid=21315950 |doi=10.1016/j.jaad.2010.03.044 |url=}}</ref>
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| *'''Adaptive immune response:'''
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| **Increased allergen penetration through the damaged epidermis leading to a Th2-type milieu is thought to explain the critical link between barrier defect of atopic dermatitis patients with FLG mutations and Th2 polarization<ref name="pmid216827492">{{cite journal |vauthors=Boguniewicz M, Leung DY |title=Atopic dermatitis: a disease of altered skin barrier and immune dysregulation |journal=Immunol. Rev. |volume=242 |issue=1 |pages=233–46 |date=July 2011 |pmid=21682749 |pmc=3122139 |doi=10.1111/j.1600-065X.2011.01027.x |url=}}</ref>.
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| **Enhanced expression of Th2, Th17 and Th22 cytokines, characterize the acute initiation of atopic dermatitis lesions<ref name="pmid25282559">{{cite journal |vauthors=Leung DY, Guttman-Yassky E |title=Deciphering the complexities of atopic dermatitis: shifting paradigms in treatment approaches |journal=J. Allergy Clin. Immunol. |volume=134 |issue=4 |pages=769–79 |date=October 2014 |pmid=25282559 |pmc=4186710 |doi=10.1016/j.jaci.2014.08.008 |url=}}</ref>.
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| **Epidermal barrier function is regulated through Th2 and Th22 cytokines (IL-4, IL-13, IL-31, and IL-22) by:<ref name="pmid252825593">{{cite journal |vauthors=Leung DY, Guttman-Yassky E |title=Deciphering the complexities of atopic dermatitis: shifting paradigms in treatment approaches |journal=J. Allergy Clin. Immunol. |volume=134 |issue=4 |pages=769–79 |date=October 2014 |pmid=25282559 |pmc=4186710 |doi=10.1016/j.jaci.2014.08.008 |url=}}</ref>
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| ***stimulating epidermal hyperplasia
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| ***inhibiting the expression of terminal keratinocyte differentiation genes (eg, ''FLG'', loricrin, involucrin)
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| ***suppressing the production of AMPs
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| *'''Thymic stromal lymphopoietin:'''
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| **Defective skin barrier and enhanced epidermal protease activity, which is reported in atopic dermatitis, promote TSLP production and Th2 response, leading to atopic dermatitis-like inflammation<ref name="pmid222700712">{{cite journal |vauthors=Takai T |title=TSLP expression: cellular sources, triggers, and regulatory mechanisms |journal=Allergol Int |volume=61 |issue=1 |pages=3–17 |date=March 2012 |pmid=22270071 |doi=10.2332/allergolint.11-RAI-0395 |url=}}</ref>.
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| **''TSLP'' polymorphisms have been linked to the severity of atopic dermatitis.
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| **TSLP genetic variants are associated with atopic dermatitis and eczema herpeticum.<ref name="pmid20466416">{{cite journal |vauthors=Gao PS, Rafaels NM, Mu D, Hand T, Murray T, Boguniewicz M, Hata T, Schneider L, Hanifin JM, Gallo RL, Gao L, Beaty TH, Beck LA, Leung DY, Barnes KC |title=Genetic variants in thymic stromal lymphopoietin are associated with atopic dermatitis and eczema herpeticum |journal=J. Allergy Clin. Immunol. |volume=125 |issue=6 |pages=1403–1407.e4 |date=June 2010 |pmid=20466416 |pmc=2925504 |doi=10.1016/j.jaci.2010.03.016 |url=}}</ref>
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| **In patients with defective skin barrier due to FLG mutations, TSLP genetic variants are associated with reduced probability of having persistent atopic dermatitis<ref name="pmid24401911">{{cite journal |vauthors=Margolis DJ, Kim B, Apter AJ, Gupta J, Hoffstad O, Papadopoulos M, Mitra N |title=Thymic stromal lymphopoietin variation, filaggrin loss of function, and the persistence of atopic dermatitis |journal=JAMA Dermatol |volume=150 |issue=3 |pages=254–9 |date=March 2014 |pmid=24401911 |pmc=4414492 |doi=10.1001/jamadermatol.2013.7954 |url=}}</ref>.
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| == Genetics ==
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| Recent studies has established strong strong genetic association with atopic dermatitis. Twin studies have indicated high heritability of atopic dermatitis with a concordance rate of 72–86 % for monozygotic twins compared with 21–23 % percent for dizygotic twins.<ref name="pmid27004062">{{cite journal |vauthors=Al-Shobaili HA, Ahmed AA, Alnomair N, Alobead ZA, Rasheed Z |title=Molecular Genetic of Atopic dermatitis: An Update |journal=Int J Health Sci (Qassim) |volume=10 |issue=1 |pages=96–120 |date=January 2016 |pmid=27004062 |pmc=4791162 |doi= |url=}}</ref>
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| Genes involved in the pathogenesis of atopic dermatitis include:<ref name="pmid270040623">{{cite journal |vauthors=Al-Shobaili HA, Ahmed AA, Alnomair N, Alobead ZA, Rasheed Z |title=Molecular Genetic of Atopic dermatitis: An Update |journal=Int J Health Sci (Qassim) |volume=10 |issue=1 |pages=96–120 |date=January 2016 |pmid=27004062 |pmc=4791162 |doi= |url=}}</ref>
| | ==Conservative Therapy== |
|
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| * '''Filaggrin Gene mutation''':
| | {| class="wikitable" |
| ** Located on chromosome 1q21 (epidermal differentiation complex) loss-of-function mutations in the filaggrin gene FLG, is strongly associated with broad range of skin and allergic diseases including atopic dermatitis<ref name="pmid21991953">{{cite journal |vauthors=Irvine AD, McLean WH, Leung DY |title=Filaggrin mutations associated with skin and allergic diseases |journal=N. Engl. J. Med. |volume=365 |issue=14 |pages=1315–27 |date=October 2011 |pmid=21991953 |doi=10.1056/NEJMra1011040 |url=}}</ref>. Mutation in this gene is also responsible for ichthyosis vulgaris and pachyonychia congenita.<ref name="pmid17657246">{{cite journal |vauthors=Liao H, Waters AJ, Goudie DR, Aitken DA, Graham G, Smith FJ, Lewis-Jones S, McLean WH |title=Filaggrin mutations are genetic modifying factors exacerbating X-linked ichthyosis |journal=J. Invest. Dermatol. |volume=127 |issue=12 |pages=2795–8 |date=December 2007 |pmid=17657246 |doi=10.1038/sj.jid.5700971 |url=}}</ref> The common genetic variant R510X and 2282del4 are very strongly associated with atopic dermatitis.<ref name="pmid16550169">{{cite journal |vauthors=Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H, Lee SP, Goudie DR, Sandilands A, Campbell LE, Smith FJ, O'Regan GM, Watson RM, Cecil JE, Bale SJ, Compton JG, DiGiovanna JJ, Fleckman P, Lewis-Jones S, Arseculeratne G, Sergeant A, Munro CS, El Houate B, McElreavey K, Halkjaer LB, Bisgaard H, Mukhopadhyay S, McLean WH |title=Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis |journal=Nat. Genet. |volume=38 |issue=4 |pages=441–6 |date=April 2006 |pmid=16550169 |doi=10.1038/ng1767 |url=}}</ref>
| | |+ |
| ** FLG Gene mutation is associated with developing atopic dermatitis at early age(≤8 years), but is not associated with late childhood or adulthood atopic dermatitis.<ref name="pmid25314673">{{cite journal |vauthors=Rupnik H, Rijavec M, Korošec P |title=Filaggrin loss-of-function mutations are not associated with atopic dermatitis that develops in late childhood or adulthood |journal=Br. J. Dermatol. |volume=172 |issue=2 |pages=455–61 |date=February 2015 |pmid=25314673 |doi=10.1111/bjd.13477 |url=}}</ref>
| | !'''Elimination of exacerbating factors''' |
| * '''SPINK5 and LEKTI gene''':
| | !'''Maintaining skin hydration''' |
| ** Located on chromosome 5q32, Serine Protease Inhibitor Kazal-Type 5 (SPINK5) gene encodes a protease inhibitor Lymphoepithelial Kazal-Type-Related Inhibitor (LEKTI), which is involved in converting profilaggrin into filaggrin and is responsible for marinating the permeability of normal skin.<ref name="pmid270040622">{{cite journal |vauthors=Al-Shobaili HA, Ahmed AA, Alnomair N, Alobead ZA, Rasheed Z |title=Molecular Genetic of Atopic dermatitis: An Update |journal=Int J Health Sci (Qassim) |volume=10 |issue=1 |pages=96–120 |date=January 2016 |pmid=27004062 |pmc=4791162 |doi= |url=}}</ref>
| | !'''Controlling pruritus''' |
| ** LEKTI deficiency leads to enhanced cleavage of intercellular attachments, decreased corneocyte cohesion and impaired skin barrier function.<ref name="pmid168151332">{{cite journal |vauthors=Cork MJ, Robinson DA, Vasilopoulos Y, Ferguson A, Moustafa M, MacGowan A, Duff GW, Ward SJ, Tazi-Ahnini R |title=New perspectives on epidermal barrier dysfunction in atopic dermatitis: gene-environment interactions |journal=J. Allergy Clin. Immunol. |volume=118 |issue=1 |pages=3–21; quiz 22–3 |date=July 2006 |pmid=16815133 |doi=10.1016/j.jaci.2006.04.042 |url=}}</ref>
| | |- |
| * '''MHC (or HLA) genes'''
| | | |
| * '''Innate Immune system genes''':
| | * Avoid trigger factors such as low humidity, overheating of skin |
| ** CARD4 (or NOD1) gene: Caspase recruitment domain – containing protein (CARD) 4
| | * Treating stress and anxiety |
| ** CARD15 (or NOD2) gene
| | * Avoid exposure to solvents and detergents |
| ** Monocyte differentiation antigen (or CD14) gene | | * Treat skin infections such as ''Staphylococcus aureus'' and herpes simplex |
| ** MBL2 gene: mannose-binding lectin '''('''MBL2) gene | | | |
| ** Toll-like receptor( TLR2, TLR4, TLR6 and TLR 9) genes | | * '''Emollients and moisturizers''' |
| ** DEFB1 gene: human β-defensin 1
| | ** Thick creams, ointments (eg, petroleum jelly) with low/zero water content |
| * '''Adaptive immune system genes''' | | ** Immediately after 5-minute, lukewarm baths BID |
| ** '''Cytokines and related genes''':
| | * '''Bathing practices''' |
| *** IL-4 gene | | ** Warm soaking baths or showers using mild or soap-free cleansers |
| *** IL-4Rα gene
| | | |
| *** STAT6 gene (Signal transducer and activator of transcription )
| | * Conservative |
| *** IL-10 gene | | ** Tepid baths |
| *** IL-6 gene
| | ** Wet dressings (wet wraps) |
| *** TNF-α gene
| | ** Moisturizers containing anti-pruritic ingredients such as phenol, menthol, and camphor |
| *** TNF-β gene
| |
| *** IL-1α gene
| |
| *** IL-β gene
| |
| *** IFNγ gene
| |
| *** IL1RL1
| |
| *** IL-5 gene
| |
| *** IL-12 β gene
| |
| *** IL-12R β
| |
| *** IL-13 gene
| |
| *** IL-18 gene
| |
| *** TGF-β1 gene
| |
| *** GM-CSF gene
| |
| *** IL-9 gene
| |
| *** IL-9R gene
| |
| ** '''Chemokines and related genes''':
| |
| *** CCL5 gene: Chemokine (C-Cmotif) ligand 5 | |
| *** CCL11 gene
| |
| *** CCL17 gene | |
| *** CCR3 gene | |
| *** CCR4 gene | |
| *** CMA1 gene: Mast cell chymase 1 | |
| ** '''Drug-metabolizing genes'''
| |
| *** GST genes: glutathione S-transferase
| |
| *** NAT-2 gene: N-acetyl transferase
| |
| ** '''Other genes'''
| |
| *** CTLA-4
| |
| *** KLK
| |
| *** RUNX1 gene
| |
| *** IRF2 gene
| |
| *** FCER1B gene
| |
| *** PHF11 gene
| |
|
| |
|
| * | | * |
| | |} |
|
| |
|
| ==Associated Conditions== | | ==Medical Therapy== |
| Conditions associated with atopic dermatitis include:
| | *Pharmacologic medical therapies for atopic dermatitis can be classified according to the several severity scales( (i.e SCORAD index, the eczema area and severity index [EASI], and the patient-oriented eczema measure [POEM]) which includes characteristics of the rash, questions about itch, sleep, impact on daily activities, and persistence of disease. |
| | ===Atopic dermatitis=== |
|
| |
|
| *Atopic triad<ref name="pmid17692428">{{cite journal |vauthors=Kapoor R, Menon C, Hoffstad O, Bilker W, Leclerc P, Margolis DJ |title=The prevalence of atopic triad in children with physician-confirmed atopic dermatitis |journal=J. Am. Acad. Dermatol. |volume=58 |issue=1 |pages=68–73 |date=January 2008 |pmid=17692428 |doi=10.1016/j.jaad.2007.06.041 |url=}}</ref> | | * '''MIld atopic dermatitis''': |
| **Atopic dermatitis | | ** Topical corticosteroids and emollients - mainstay therapy |
| **Allergic rhinitis | | *** '''Adult''' |
| **Asthma | | **** Preferred regimen (1): [[drug name|desonide 0.05%]] top. q12h-q24h for 14-28 days |
| *Food-induced urticaria/anaphylaxis <ref name="pmid10893011">{{cite journal |vauthors=Eigenmann PA, Calza AM |title=Diagnosis of IgE-mediated food allergy among Swiss children with atopic dermatitis |journal=Pediatr Allergy Immunol |volume=11 |issue=2 |pages=95–100 |date=May 2000 |pmid=10893011 |doi= |url=}}</ref> | | **** Preferred regimen (2): [[drug name|hydrocortisone 2.5% top.]] q12h-q24h for 14-28 days |
| *Ichthyosis vulgaris<ref name="pmid18455261">{{cite journal |vauthors=Bremmer SF, Hanifin JM, Simpson EL |title=Clinical detection of ichthyosis vulgaris in an atopic dermatitis clinic: implications for allergic respiratory disease and prognosis |journal=J. Am. Acad. Dermatol. |volume=59 |issue=1 |pages=72–8 |date=July 2008 |pmid=18455261 |doi=10.1016/j.jaad.2008.03.029 |url=}}</ref> | | **** Preferred regimen (3): fluocinolone acetonide [[drug name|0.01% top.]] q12h-q24h for 14-28 days |
| *Ocular comorbidities: | | **** Alternative regimen (1) tacrolimus 0.1% top. q8h ('''0.03% for adults who do not tolerate the higher dose)''' |
| **Atopic keratoconjunctivitis<ref name="pmid24342754">{{cite journal |vauthors=Chen JJ, Applebaum DS, Sun GS, Pflugfelder SC |title=Atopic keratoconjunctivitis: A review |journal=J. Am. Acad. Dermatol. |volume=70 |issue=3 |pages=569–75 |date=March 2014 |pmid=24342754 |doi=10.1016/j.jaad.2013.10.036 |url=}}</ref> | | **** Alternative regimen (2): pimecrolimus 1% top. q8h |
| **Vernal keratoconjunctivitis<ref name="pmid25744396">{{cite journal |vauthors=Pattnaik L, Acharya L |title=A comprehensive review on vernal keratoconjunctivitis with emphasis on proteomics |journal=Life Sci. |volume=128 |issue= |pages=47–54 |date=May 2015 |pmid=25744396 |doi=10.1016/j.lfs.2015.01.040 |url=}}</ref> | | **** Alternative regimen (3) crisaborole 2% top. |
| * Wiskott-Aldrich syndrome:<ref name="pmid11800140">{{cite journal |vauthors=Bradley M, Söderhäll C, Wahlgren CF, Luthman H, Nordenskjöld M, Kockum I |title=The Wiskott-Aldrich syndrome gene as a candidate gene for atopic dermatitis |journal=Acta Derm. Venereol. |volume=81 |issue=5 |pages=340–2 |date=2001 |pmid=11800140 |doi= |url=}}</ref> | | *** '''Pediatric''' |
| ** Thrombocytopenia | | **** Preferred regimen (1): [[drug name|desonide 0.05%]] top. q12h-q24h for 14-28 days |
| ** Eczema (atopic dermatitis) | | **** Preferred regimen (2): [[drug name|hydrocortisone 2.5% top.]] q12h-q24h for 14-28 days |
| ** Recurrent infections | | **** Preferred regimen (3): fluocinolone acetonide [[drug name|0.01% top.]] q12h-q24h for 14-28 days |
| *Hyper-IgE syndrome:<ref name="pmid16913276">{{cite journal |vauthors=Ohameje NU, Loveless JW, Saini SS |title=Atopic dermatitis or hyper-IgE syndrome? |journal=Allergy Asthma Proc |volume=27 |issue=3 |pages=289–91 |date=2006 |pmid=16913276 |doi= |url=}}</ref> | | **** Alternative regimen (1) tacrolimus 0.03% top. q8h ('''Children (>2years)''' |
| **Eczema (atopic dermatitis) | | **** Alternative regimen (2): pimecrolimus 1% top. q8h |
| **High serum IgE | | **** Alternative regimen (3): crisaborole 2% top. |
| **Recurrent cold abscesses | | * '''Moderate atopic dermatitis''' |
| | ** Topical corticosteroids and emollients are the mainstay of therapy |
| | *** '''Adult''' |
| | **** Preferred regimen (1): fluocinolone0.025%. q12h-q24h for 14-28 days |
| | **** Preferred regimen (2): [[drug name|triamcinolone 0.1% top.]] q12h-q24h for 14-28 days |
| | **** Preferred regimen (3): fluocinolone acetonide [[drug name|0.025% top.]] q12h-q24h for 14-28 days |
| | **** Alternative regimen (1) tacrolimus 0.1% top. q8h ('''0.03% for adults who do not tolerate the higher dose)''' |
| | **** Alternative regimen (2): pimecrolimus 1% top. q8h |
| | **** Alternative regimen (3) crisaborole 2% top. |
| | ** '''Pediatric''' |
| | *** Preferred regimen (1): fluocinolone0.025%. q12h-q24h for 14 days |
| | *** Preferred regimen (2): [[drug name|triamcinolone 0.1% top.]] q12h-q24h for 14 days |
| | *** Preferred regimen (3): fluocinolone acetonide [[drug name|0.025% top.]] q12h-q24h for 14-28 days |
| | *** Alternative regimen (1) tacrolimus 0.03% top. q8h ('''Children (>2years)''' |
| | *** Alternative regimen (2): pimecrolimus 1% top. q8h |
| | *** Alternative regimen (3) crisaborole 2% top. |
| | * '''Severe atopic dermatitis''' |
| | ** Phototherapy or systemic immunosuppressant treatment is the mainstay of therapy |
| | *** '''Adult''' |
| | **** Preferred regimen (1): Phototherapy Ultraviolet light therapy (phototherapy) with PUVA (psoralens plus ultraviolet A radiation), 3 times a week |
| | **** Preferred regimen (2): [[drug name|cyclosporine]] PO 3-5 mg/kg o.d. for 6 weeks ('''monitor BP and serum creatinine q2 weeks for three months, f/u q month)''' |
| | **** Alternative regimen (1) methotrexatePO |
| | **** Alternative regimen (2): azathioprine PO |
| | **** Alternative regimen (3) mycophenolate mofetil PO |
| | **** Alternative regimen (3) dupilumab 600 mg SQ once and then 300 mg SQ every 2 weeks thereafter |
| | *** '''Pediatric''' |
| | **** Preferred regimen (1): |
| | **** Preferred regimen (2): [[drug name|cyclosporine]] PO 3 to 5 mg/kg per day o.d. for 6 weeks ('''monitor BP and serum creatinine q2 weeks for three months, f/b q month)''' |
| | **** Alternative regimen (1) Phototherapy Ultraviolet light therapy (phototherapy) with PUVA (psoralens plus ultraviolet A radiation), 3 times a week |
| | **** Alternative regimen (2): azathioprine PO |
| | **** Alternative regimen (3) mycophenolate mofetil PO |
| | **** Alternative regimen (3) dupilumab 600 mg SQ once and then 300 mg SQ every 2 weeks thereafter |
| | * '''Severe refractory atopic dermatitis''' |
| | ** '''Adult''' |
| | *** Preferred regimen (1): Intensive topical therapy |
| | **** Soak and smear: Soak for 15 minutes in a tub of water. Apply desoximetasone 0.25% top. to the whole body, except the groin, axillae, and face |
| | **** Wet wrap therapy: desoximetasone 0.25% top. then occluded with wet wraps q12h |
| | *** Alternative regimen (1) Phototherapy: narrowband ultraviolet B or psoralen plus ultraviolet A two to three times per week |
| | *** Alternative regimen (2): cyclosporine PO 2.5 to 5 mg/kg o.d. ('''C/I -''' '''abnormal renal function, uncontrolled hypertension or infection, and malignancy''') |
| | *** Alternative regimen (3): prednisone 40 to 60 mg o.d. for one week, then taper the dose over the following two to three week |
| | *** Alternative regimen (4): methotrexate 7.5 to 25 mg single weekly dose with folic acid 1 mg o.d. |
| | *** Alternative regimen (5): azathioprine 2 to 3 mg/kg |
| | *** Alternative regimen (6): mycophenolate mofetil 1 to 2 g/day |
| | *** Alternative regimen (7): mycophenolic acid 720 to 1440 mg/day |
| | *** Alternative regimen (8) dupilumab 600 mg SQ once and then 300 mg SQ every 2 weeks thereafter |
| | ** '''Pediatric''' |
| | *** Preferred regimen (1): Intensive topical therapy |
| | **** Wet wrap therapy: desoximetasone 0.05% top. then occluded with wet wraps q12h-q24h for 2 to 14 days |
| | *** Alternative regimen (1) Phototherapy: narrowband ultraviolet B (UVB) 3 times per week ('''older children > 6 years''') |
| | *** Alternative regimen (2): cyclosporine PO 2.5 to 5 mg/kg o.d. for 2-4 months ('''monitor renal and hepatic function''') |
| | *** Alternative regimen (3): methotrexate 0.5 mg/kg PO single weekly dose with folic acid 1 mg o.d.('''up to a maximum of 25 mg per week''') |
| | *** Alternative regimen (4): methylprednisolone 0.5 mg/kg o.d. for 1-2 weeks tapered over one month |
| | '''Management of Infection:''' |
| | * '''Bacterial''' '''infections''': (most common bacteria - ''Staphylococcus. aureus'') |
| | ** Clinically infected skin: |
| | *** Mupirocin 2% top. BID for one to two weeks |
| | *** More extensive infection: oral antibiotic therapy with cephalosporins or penicillinase-resistant penicillins X two weeks |
| | ** Clinically uninfected skin: |
| | *** liquid chlorine bleach- 0.5 cup or 120 ml of 6% bleach in a full bathtub [40 gallons or 150 L] of lukewarm water |
| | * '''Viral infections:''' |
| | ** Herpes simplex: |
| | *** Acyclovir 200 or 400 mg PO five times daily |
| | *** Famciclovir 750 mg BID for one day or 1500 mg as a single dose |
| | ** molluscum contagiosum : |
| | *** cryotherapy, curettage, cantharidin, and podophyllotoxin as first-line therapeutic options |
| | * '''Fungal infections:''' |
| | ** Dermatophyte infections'''-''' topical or oral antifungals |
| | '''Controlling pruritus:''' |
| | * Preferred regimen''':''' |
| | ** Sedatives: diphenhydramine, hydroxyzine, and cyproheptadine |
| | ** Nonsedatives: fexofenadine, cetirizine or loratadine |
| | * Alternative regimen: |
| | ** Topical doxepin |
| | ** Topical calcineurin inhibitors |
| | *** Pimecrolimus 1% cream or tacrolimus 0.03% to 0.1% |
|
| |
|
| ==Gross Pathology==
| | '''Chronic inflammatory skin diseases''' |
| On gross pathology, erythema, edema and vesiculation with oozing are characteristic findings of atopic dermatitis while chronic atopic dermatitis is characterized by lichenified plaques with prominent skin markings.<ref name="MihmSoter19762">{{cite journal|last1=Mihm|first1=Martin C|last2=Soter|first2=Nicholas A|last3=Dvorak|first3=Harold F|last4=Austen|first4=K Frank|title=The Structure Of Normal Skin And The Morphology Of Atopic Eczema|journal=Journal of Investigative Dermatology|volume=67|issue=3|year=1976|pages=305–312|issn=0022202X|doi=10.1111/1523-1747.ep12514346}}</ref>
| | * Contact (allergic, irritant) |
| | * Seborrhoeic dermatitis |
| | ** onset during the 1st days or weeks of life, absence of pruritus, and presence of greasy scaling on a yellow-red base |
| | ** Involvement of the top of the scalp (cradle cap), axilla, and diaper area makes it more likely the patient has '''seborrheic dermatitis''', vs excoriated dermatitis involving the extensor surfaces, face, and trunk favour '''AE.''' |
| | * Psoriasis |
| | * Lichen simplex chronicus |
| | '''Infectious agents''' |
| | * Candida |
| | * Dermatophytes |
| | * Herpes simplex |
| | * Staphylococcus aureus |
| | * Sarcoptes scabiei |
| | ** highly pruritic, erythematous papular lesions. In most cases, the typical burrows can be found on the flexor wrists, finger webs and genitalia. Similar symptoms in other family members |
| | * HIV-associated dermatitis |
| | '''Immunologic disorders''' |
| | * Dermatitis herpetiformis |
| | * Pemphigus foliaceus |
| | * Graft-versus-host disease |
| | * Dermatomyositis |
| | '''Malignant Diseases''' |
| | * Cutaneous T-cell lymphoma (mycosis fungoides, S´ezary syndrome) |
| | * Histiocytosis X (Letterer-Siwe disease) |
| | '''Congenital disorders''' |
| | * Netherton’s syndrome |
| | * Dubowitz syndrome |
| | * Erythrokeratodermia variabilis |
| | '''Immunodeficiencies''' |
| | * Wiskott-Aldrich syndrome (immunodeficiency with thrombocytopenia and eczema) |
| | * Thymic hypoplasia (DiGeorge syndrome) |
| | * Hyper-IgE syndrome |
| | * Severe combined immunodeficiency (SCID) |
| | * Ataxia teleangiectasia |
| | '''Metabolic Diseases''' |
| | * Phenylketonuria |
| | * Tyrosinemia |
| | * Histidinemia |
| | * Zinc deficiency |
| | * Pyridoxine (vitamin B6) and niacin deficiency |
| | * Multiple carboxylase deficiency |
|
| |
|
| ==Microscopic Pathology==
| | * '''Nonallergic reaction to medication''' |
| On microscopic histopathological analysis, characteristic findings of atopic dermatitis includes:<ref name="MihmSoter19763">{{cite journal|last1=Mihm|first1=Martin C|last2=Soter|first2=Nicholas A|last3=Dvorak|first3=Harold F|last4=Austen|first4=K Frank|title=The Structure Of Normal Skin And The Morphology Of Atopic Eczema|journal=Journal of Investigative Dermatology|volume=67|issue=3|year=1976|pages=305–312|issn=0022202X|doi=10.1111/1523-1747.ep12514346}}</ref>
| | ** Infliximab |
| * '''Acute vesicular lesions''':
| |
| ** Epidermal psoriasiform hyperplasia
| |
| ** Marked intercellular edema with spongiotic vesiculation
| |
| ** Marked perivenular infiltrate
| |
| ** Epidermal infiltrate, consisting predominately of a lymphohistiocytic infiltrate in the dermis
| |
| * '''Chronic lichenified plaque''': | |
| ** Hyperkeratosis
| |
| ** psoriasiform hyperplasia
| |
| ** dyskeratosis
| |
| ** Marked thickening of the papillary dermis
| |
| ** Minimal intercellular edema | |
|
| |
|
| ==References== | | ==References== |