|
|
| Line 4: |
Line 4: |
|
| |
|
| ==Overview== | | ==Overview== |
|
| | The majority of patients with [disease name] are asymptomatic. |
| 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>.
| |
|
| |
|
| ==Pathophysiology==
| | OR |
| ===Physiology===
| |
| The normal physiology of atopic dermatitis can be understood as follows:
| |
|
| |
|
| '''Epidermal barrier function:'''
| | The hallmark of [disease name] is [finding]. A positive history of [finding 1] and [finding 2] is suggestive of [disease name]. The most common symptoms of [disease name] include [symptom 1], [symptom 2], and [symptom 3]. Common symptoms of [disease] include [symptom 1], [symptom 2], and [symptom 3]. Less common symptoms of [disease name] include [symptom 1], [symptom 2], and [symptom 3]. |
| * '''Epidermis''': It directly interfaces with the environment and acts as the 1st line of defense. It is primarily dependent on the 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>
| |
| ** Tightly packed corneocytes layers in the stratum corneum.
| |
| ** Intercellular lipid bilayers.
| |
| ** Corneocytes layers embedded in the extracellular matrix derived from lipid lamellae.
| |
| ** Natural Moisturising Factors, maintains the water retention in the stratum corneum
| |
| ** Antimicrobial peptides production
| |
| * '''Filaggrin proteins:''' Encoded by filaggrin gene ''FLG'' 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>
| |
| ** Pro-filaggrin is required for the formation of dense cytoplasmic granules, which along with other proteins forms the corneocytes, that acts as a primary unit for the barrier function of the skin.
| |
| ** Pro-filaggrin undergoes extensive phosphorylation and dephosphorylation, to produce Filaggrin monomers, to interact and aggregate with the keratin filaments and permits extensive crosslinking, to form a highly insoluble keratin matrix.<ref name="pmid193868952">{{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>
| |
| ** 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
| |
| ** The degraded products of filaggrin protein also maintain the acidic pH of the stratum corneum, required to regulate the activity of enzymes.
| |
| * '''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>
| |
| * '''Other proteins''': 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>
| |
| '''Immune response:'''
| |
| * '''Cutaneous immune response''': It acts as the 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). The cutaneous immune response includes the 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>
| |
| ** Physical: stratum corneum and the tight junctions in stratum granulosum. The maintenance and repair of epithelial barriers are 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>
| |
| ** Chemical: antimicrobial proteins including antimicrobial peptides (AMPs), S100 proteins, 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>
| |
| ** 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>
| |
| ** Immunological: Immune response includes both non-specific and immediate response (innate immunity) and highly specific and late response (adaptive immunity).
| |
|
| |
|
| * '''Adaptive Immune response''': | | ==History and Symptoms== |
| ** The character and magnitude of the adaptive immune system is determined by the 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>
| | *The majority of patients with [disease name] are asymptomatic. |
| | OR |
| | *The hallmark of [disease name] is [finding]. A positive history of [finding 1] and [finding 2] is suggestive of [disease name]. The most common symptoms of [disease name] include [symptom 1], [symptom 2], and [symptom 3]. |
| | *Symptoms of [disease name] include [symptom 1], [symptom 2], and [symptom 3]. |
| | ===History=== |
| | Patients with [disease name]] may have a positive history of: |
| | *[History finding 1] |
| | *[History finding 2] |
| | *[History finding 3] |
|
| |
|
| * '''Thymic stromal lymphopoietin:'''
| | ===Common Symptoms=== |
| ** 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>.
| | Common symptoms of [disease] include: |
| ** 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>. | | *[Symptom 1] |
| | *[Symptom 2] |
| | *[Symptom 3] |
|
| |
|
| ==Pathogenesis== | | ===Less Common Symptoms=== |
| | | Less common symptoms of [disease name] include |
| 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>
| | *[Symptom 1] |
| | | *[Symptom 2] |
| '''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>
| | *[Symptom 3] |
| * 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>
| |
| | |
| * 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>
| |
| | |
| * Skin barrier abnormalities also 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>
| |
| | |
| * Severe atopic dermatitis has 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>
| |
| '''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>:
| |
| * '''Innate immune response:'''
| |
| **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>
| |
| **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>
| |
| **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>
| |
| * '''Adaptive immune response:'''
| |
| **Increased allergen penetration through the damaged epidermis leading to a Th2-type milieu is thought to explain the critical link between the 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>.
| |
| **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>.
| |
| **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>
| |
| ***stimulating epidermal hyperplasia
| |
| ***inhibiting the expression of terminal keratinocyte differentiation genes (eg, ''FLG'', loricrin, involucrin)
| |
| ***suppressing the production of AMPs
| |
| * '''Thymic stromal lymphopoietin:'''
| |
| **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>.
| |
| **''TSLP'' polymorphisms have been linked to the severity of atopic dermatitis.
| |
| **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>
| |
| **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>.
| |
| == Genetics ==
| |
| Recent studies have established a 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>
| |
| | |
| 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>
| |
| # '''Filaggrin Gene mutation''':
| |
| #* Located on chromosome 1q21 (epidermal differentiation complex) loss-of-function mutations in the filaggrin gene FLG, is strongly associated with a 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 an 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>
| |
| # '''SPINK5 and LEKTI gene''':
| |
| #* 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 the 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>
| |
| #* 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''':
| |
| #* CARD4 (or NOD1) gene: Caspase recruitment domain–containing protein (CARD) 4
| |
| #* CARD15 (or NOD2) gene
| |
| #* Monocyte differentiation antigen (or CD14) gene
| |
| #* MBL2 gene: mannose-binding lectin '''('''MBL2) gene
| |
| #* Toll-like receptor( TLR2, TLR4, TLR6 and TLR 9) genes
| |
| #* DEFB1 gene: human β-defensin 1
| |
| # '''Adaptive immune system genes'''
| |
| #* '''Cytokines and related genes''':
| |
| #** IL-4 gene
| |
| #** IL-4Rα gene
| |
| #** STAT6 gene (Signal transducer and activator of transcription )
| |
| #** IL-10 gene
| |
| #** IL-6 gene
| |
| #** TNF-α gene
| |
| #** 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==
| |
| Conditions associated with atopic dermatitis include:
| |
| | |
| *'''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> | |
| **Atopic dermatitis
| |
| **Allergic rhinitis
| |
| **Asthma
| |
| *'''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>
| |
| *'''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>
| |
| *'''Ocular comorbidities:'''
| |
| **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>
| |
| **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>
| |
| * '''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>
| |
| ** Thrombocytopenia
| |
| ** Eczema (atopic dermatitis)
| |
| ** Recurrent infections
| |
| *'''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>
| |
| **Eczema (atopic dermatitis)
| |
| **High serum IgE
| |
| **Recurrent cold abscesses
| |
| * '''Anemia'''<ref name="pmid26619045">{{cite journal |vauthors=Drury KE, Schaeffer M, Silverberg JI |title=Association Between Atopic Disease and Anemia in US Children |journal=JAMA Pediatr |volume=170 |issue=1 |pages=29–34 |date=January 2016 |pmid=26619045 |doi=10.1001/jamapediatrics.2015.3065 |url=}}</ref>
| |
| * '''Psychiatric disorders''':<ref name="pmid30119868">{{cite journal |vauthors=Rønnstad ATM, Halling-Overgaard AS, Hamann CR, Skov L, Egeberg A, Thyssen JP |title=Association of atopic dermatitis with depression, anxiety, and suicidal ideation in children and adults: A systematic review and meta-analysis |journal=J. Am. Acad. Dermatol. |volume=79 |issue=3 |pages=448–456.e30 |date=September 2018 |pmid=30119868 |doi=10.1016/j.jaad.2018.03.017 |url=}}</ref>
| |
| ** Depression<ref name="pmid29929155">{{cite journal |vauthors=Bao Q, Chen L, Lu Z, Ma Y, Guo L, Zhang S, Huang X, Xu S, Ruan L |title=Association between eczema and risk of depression: A systematic review and meta-analysis of 188,495 participants |journal=J Affect Disord |volume=238 |issue= |pages=458–464 |date=October 2018 |pmid=29929155 |doi=10.1016/j.jad.2018.05.007 |url=}}</ref>
| |
| ** Anxiety<ref name="pmid25795537">{{cite journal |vauthors=Cheng CM, Hsu JW, Huang KL, Bai YM, Su TP, Li CT, Yang AC, Chang WH, Chen TJ, Tsai SJ, Chen MH |title=Risk of developing major depressive disorder and anxiety disorders among adolescents and adults with atopic dermatitis: a nationwide longitudinal study |journal=J Affect Disord |volume=178 |issue= |pages=60–5 |date=June 2015 |pmid=25795537 |doi=10.1016/j.jad.2015.02.025 |url=}}</ref>
| |
| ** Suicidal ideations
| |
| ** Attention deficit hyperactivity disorder<ref name="pmid27105659">{{cite journal |vauthors=Strom MA, Fishbein AB, Paller AS, Silverberg JI |title=Association between atopic dermatitis and attention deficit hyperactivity disorder in U.S. children and adults |journal=Br. J. Dermatol. |volume=175 |issue=5 |pages=920–929 |date=November 2016 |pmid=27105659 |pmc=5216180 |doi=10.1111/bjd.14697 |url=}}</ref>
| |
| * '''Angina pectoris'''<ref name="pmid29210061">{{cite journal |vauthors=Thyssen JP, Halling-Overgaard AS, Andersen YMF, Gislason G, Skov L, Egeberg A |title=The association with cardiovascular disease and type 2 diabetes in adults with atopic dermatitis: a systematic review and meta-analysis |journal=Br. J. Dermatol. |volume=178 |issue=6 |pages=1272–1279 |date=June 2018 |pmid=29210061 |doi=10.1111/bjd.16215 |url=}}</ref>
| |
| | |
| ==Gross Pathology==
| |
| 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>
| |
| | |
| ==Microscopic Pathology==
| |
| On microscopic histopathological analysis, characteristic findings of atopic dermatitis include:<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>
| |
| * '''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== |