Atopic Dermatitis: Practice Essentials, Background, Pathophysiology (original) (raw)

Practice Essentials

Atopic dermatitis (AD) is a chronic, pruritic inflammatory skin condition (see image below) that typically affects the face (cheeks), neck, arms, and legs but usually spares the groin and axillary regions. AD usually starts in early infancy, but also affects a substantial number of adults. AD is commonly associated with elevated levels of immunoglobulin E (IgE). That it is the first disease to present in a series of allergic diseases—including food allergy, asthma, and allergic rhinitis, in order—has given rise to the “atopic march” theory, which suggests that AD is part of a progression that may lead to subsequent allergic disease at other epithelial barrier surfaces. [1, 2]

Atopic dermatitis. Flexural involvement in childho

Atopic dermatitis. Flexural involvement in childhood atopic dermatitis.

Signs and symptoms of atopic dermatitis

Incessant pruritus (itchiness) is the only symptom of AD. The disease typically has an intermittent course with flares and remissions occurring, often for unexplained reasons.

Primary physical findings include the following:

The eczematous changes and its morphology are seen in different locations, depending on the age of the patient (ie, infant, child, or adult).

The following is a constellation of symptoms and features commonly seen in AD:

See Clinical Presentation for more detail.

Diagnosis of atopic dermatitis

The following features should be considered in the diagnosis of AD in accordance with the American Academy of Dermatology (AAD) 2014 Guidelines [3] :

Essential features (must be present) are as follows:

Important features (supports the diagnosis) are as follows:

Associated features (nonspecific but suggest the diagnosis of AD) are as follows:

Exclusionary conditions (conditions that should be excluded) are as follows:

Additional considerations in the diagnosis of AD are as follows:

See Workup for more detail.

Management of atopic dermatitis

Agents typically used to treat AD include the following:

Other treatments that have been tried include the following:

Nonmedical measures that may be helpful include the following:

See Treatment and Medication for more detail.

eMedicine Logo

Background

Atopic dermatitis (AD) is a pruritic skin condition of unknown origin that usually starts in early infancy (an adult-onset variant is recognized); it is characterized by pruritus, eczematous lesions, xerosis (dry skin), and lichenification (thickening of the skin and an increase in skin markings).

AD may be associated with other atopic (immunoglobulin E [IgE]–associated) diseases (eg, acute allergic reaction to foods, asthma, urticaria, and allergic rhinitis). [8] AD has enormous morbidity, and the incidence and prevalence appear to be increasing. Further, AD is the first disease to present in a series of allergic diseases such as food allergy, asthma, and allergic rhinitis (in order), provoking the “atopic march” theory, which suggests that early or severe AD and cutaneous sensitization to environmental allergens may lead to subsequent allergic disease at other epithelial barrier surfaces (eg, gastrointestinal or respiratory tract). This hypothesis is supported by cross-sectional and longitudinal studies. [1]

eMedicine Logo

Pathophysiology

Despite recent advances in the understanding of the genetics of atopic dermatitis (AD), the pathophysiology remains poorly defined. Two main hypotheses have been proposed regarding the development of inflammation that leads to AD. The first suggests a primary immune dysfunction resulting in IgE sensitization, allergic inflammation, and a secondary epithelial barrier disturbance. The second proposes a primary defect in the epithelial barrier leading to secondary immunologic dysregulation and resulting in inflammation.

In healthy individuals, balance exists between important subsets of T cells (eg, Th1, Th2, Th17, Th22). The primary immune dysfunction hypothesis invokes an imbalance in the T cell subsets, with Th2 cells predominating; this results in the production of type 2 cytokines such as interleukin (IL)–4, IL-5, and IL-13, causing an increase in IgE from plasma cells. Later, in persons with chronic AD, the Th1 cells have been shown to predominate. More recently, Th17 cells have been found to be elevated in patients with AD. [9] Although primarily considered a Th2 cell‒associated cytokine-mediated disease, the precise contributions of Th1 and Th17 cell responses remain to be fully defined.

In addition to the role of T and B cells in AD, other innate immune cells have also been implicated in the pathogenesis of AD, including eosinophils and mast cells. [10, 11] More recently, basophils and newly identified innate immune cells called group 2 innate lymphoid cells (ILC2s) have been shown to underlie the pathogenesis of AD. [12, 13, 14, 15, 16] Together, basophils and ILC2s are critical sources of the type 2 cytokines IL-4, IL-5, and IL-13. [12, 13] Further, these cells appear to be potently regulated by a family of epithelial cell‒derived cytokines directly released from damaged keratinocytes, including thymic stromal lymphopoietin (TSLP), IL-25, and IL-33. [17] Taken together, these studies highlight a new paradigm in which, in addition to classical adaptive Th2 cells, innate type 2 immune cells play critical roles in the etiology of AD through interactions with epidermal-derived cytokines.

In terms of AD-associated itch, Th2 cells are known to be significant sources of the itch-inducing cytokine or pruritogen IL-31. [18] Emerging clinical trials data indicate that blocking this pathway may be a key mechanism by which atopic itch can be treated clinically. Additionally, a 2017 study identified that neuronal, rather than immune, signaling of the type 2 cytokines IL-4 and IL-13 critically regulate AD-associated itch. [19] Indeed, the dual IL-4 and IL-13 blocker, dupilumab, has emerged as a highly effective treatment for AD, which received FDA approval in March of 2017. Thus, blocking cytokine-nerve interactions with targeted biologic therapies has emerged as a novel therapeutic strategy in AD.

The epidermal barrier dysfunction hypothesis suggests that AD patients develop AD as a result of skin barrier defects that allow for the entry of antigens, resulting in the production of inflammatory cytokines. Some authors question whether such antigens can also be absorbed from the gut (eg, from food) and/or the lungs (eg, from house dust mites). Xerosis and ichthyosis are known to be associated signs in many AD patients. Clinically, 37-50% of people with ichthyosis vulgaris have atopic disease and up to 37% of people with AD have clinical evidence of ichthyosis vulgaris. Mutations in the gene encoding filaggrin, a key epidermal barrier protein, cause ichthyosis vulgaris and are the strongest known genetic risk factors for the development of AD. [20, 21]

Further, filaggrin mutations are associated with early-onset AD and with airway disease in the setting of AD. [22] One mechanism by which filaggrin defects may influence inflammation is by the release of epithelial cell‒derived cytokines, including TSLP, IL-25, and IL-33, which are all known to be up-regulated in the context of AD. [23, 24, 25, 26] TSLP has been shown to be a potent promoter of basophil and ILC2 responses in the skin, while IL-25 and IL-33 preferentially elicit ILC2s. [12, 13, 16] Although filaggrin is strongly linked to AD, mutations are only found in 30% of European patients, begging the question of whether other genetic variants may also be responsible for some of the findings in the pathogenesis of AD. Indeed, genetic variants of TSLP have been shown to interact with mutations in filaggrin to influence AD disease persistence in patients. [27]

In AD, transepidermal water loss is increased. Whether the primary immune dysregulation causes secondary epithelial barrier breakdown or primary epithelial barrier breakdown causes secondary immune dysregulation that results in disease remains unknown. However, given the fact that filaggrin is critical for epithelial integrity, it is now thought that loss of filaggrin function leads to increased transepidermal penetration of environmental allergens, increasing inflammation and sensitivity and potentially leading to the atopic march. [28]

eMedicine Logo

Etiology of Atopic Dermatitis

Genetics [29, 30]

A family history of atopic dermatitis (AD) is common. The strongest known genetic risk factor for developing AD is the presence of a loss-of-function mutation in filaggrin. More recently, genome-wide association studies (GWAS) have identified susceptibility loci at 11q13.5 in European populations, at 5q22.1 and 1q21.3 in a Chinese Han population, and at 20q13.33 in both Chinese Han and German populations. A recent meta-analysis of GWAS studies in European populations identified SNPs rs479844 near OVOL1, rs2164983 near ACTL9, and rs2897442 in intron 8 of KIF3A. Many of these loci contain genes that encode proteins involved in epidermal proliferation and differentiation or inflammatory cytokines.

Infection

The skin of patients with AD is colonized by S aureus. Clinical infection with S aureus often causes a flare of AD, and S aureus has been proposed as a cause of AD by acting as a superantigen. Similarly, superinfection with herpes simplex virus can also lead to a flare of disease and a condition referred to as eczema herpeticum.

Hygiene

The hygiene hypothesis is touted as a cause for the increase in AD. This attributes the rise in AD to reduced exposure to various childhood infections and bacterial endotoxins. [31, 32]

Climate

AD flares occur in extremes of climate. Heat is poorly tolerated, as is extreme cold. A dry atmosphere increases xerosis. Sun exposure improves lesions, but sweating increases pruritus. These external factors act as irritants or allergens, ultimately setting up an inflammatory cascade.

Food antigens

The role of food antigens in the pathogenesis of AD is controversial, both in the prevention of AD and by the withdrawal of foods in persons with established disease. Because of the controversy regarding the role of food in AD, most physicians do not withdraw food from the diet. Nevertheless, acute food reactions (urticaria and anaphylaxis) are commonly encountered in children with AD.

Probiotics [33]

The role of probiotics in the diet of patients with AD remains controversial.

Aeroallergens

A role for aeroallergens and house dust mites has been proposed, but this awaits further corroboration.

Tobacco

A study by Lee et al suggested a correlation between early and/or current exposure to cigarette smoking and adult onset of AD. [34] The study also determined that exposure to tobacco smoke in childhood is linked to adult onset of AD.

eMedicine Logo

Epidemiology of Atopic Dermatitis

Frequency

United States

The prevalence rate for atopic dermatitis (AD) is 10-12% in children and 0.9% in adults. More recent information examining physician visits for AD in the United States from 1997-2004 estimates a large increase in office visits for AD occurred. In addition, blacks and Asians visit more frequently for AD than whites. Note that this increase involves all disease under the umbrella of AD and it has not been possible to allocate which type has increased so rapidly. [35]

International

The prevalence rate of AD is rising, and AD affects 15-30% of children and 2-10% of adults. This figure estimates the prevalence in developed countries. In China and Iran, the prevalence rate is approximately 2-3%. The frequency is increased in patients who immigrate to developed countries from underdeveloped countries. [36]

Race

AD affects persons of all races. Immigrants from developing countries living in developed countries have a higher incidence of AD than the indigenous population, and the incidence is rapidly rising in developed countries.

Sex

The male-to-female ratio for AD is 1:1.4.

Age

In 85% of cases, AD occurs in the first year of life; in 95% of cases, it occurs before age 5 years. The incidence of AD is highest in early infancy and childhood. The disease may have periods of complete remission, particularly in adolescence, and may then recur in early adult life.

In the adult population, the rate of AD frequency is 3% or higher, but onset may be delayed until adulthood.

eMedicine Logo

Prognosis

Most patients with this skin condition improve; this can occur at any age. While the frequency of atopic dermatitis (AD) is as high as 20% in childhood, [37] it is 0.9% in adults. One third of patients develop allergic rhinitis. One third of patients develop asthma.

In a longitudinal study of 7157 children and adolescents with AD from the Pediatric Eczema Elective Registry, researchers found that symptoms of mild to moderate AD are likely to persist into the teen years or beyond. [38, 39, 40]

Approximately two-thirds of the patients were followed for at least 2 years and the rest were followed for at least 5 years. From ages 2 to 26 years, more than 80% of patients reported having continued symptoms and/or use of topical medications to control symptoms. By age 20, approximately half of the patients had experienced at least one 6-month symptom- and medication-free period. Living in southern states, having a relative with an atopic illness, and exposure to pollen, wool, pets, cigarettes, fumes, some foods or drinks, and soaps/detergents were linked to persistent symptoms. [38, 39, 40]

Mortality/morbidity

Incessant itch and work loss in adult life is a great financial burden. A number of studies have reported that the financial burden to families and government is similar to that of asthma, arthritis, and diabetes mellitus. In children, the disease causes enormous psychological burden to families and loss of school days. Sleep disturbance is common in AD patients, owing to the incessant pruritus. Sleep disturbances can significantly impact quality of life. Mortality due to AD is unusual.

Kaposi varicelliform eruption (eczema herpeticum) is a well-recognized complication of AD. It usually occurs with a primary herpes simplex infection, but it may also be seen with recurrent infection. Vesicular lesions usually begin in areas of eczema and spread rapidly to involve all eczematous areas and healthy skin. Lesions may become secondarily infected. Timely treatment with acyclovir ensures a relative lack of severe morbidity or mortality.

Another cause of Kaposi varicelliform eruption is vaccination with vaccinia for the prevention of small pox, but because this is no longer mandatory, patients with AD do not develop the sequelae of eczema vaccinatum that has been seen in the past. It was usually contracted by the patient from the vaccination of themselves or their close relatives. This condition had a high mortality rate (up to 25%). In the current climate of threats of bioterrorism, vaccination may once again become necessary, and physicians should be aware of eczema vaccinatum in this setting.

Note that chickenpox vaccine does not carry the same risk as herpes simplex and vaccinia.

Bacterial infection with S aureus or Streptococcus pyogenes is not infrequent in the setting of AD_._ The skin of patients with AD is colonized by S aureus. Colonization does not imply clinical infection, and physicians should only treat patients with clinical infection. The emergence of methicillin-resistant S aureus (MRSA) may prove to be a problem in the future in these patients. Eczematous and bullous lesions on the palms and soles are often infected with beta-hemolytic group A Streptococcus.

Urticaria and acute anaphylactic reactions to food occur with increased frequency in patients with AD. The food groups most commonly implicated include peanuts, eggs, milk, soy, fish, and seafood. In studies in peanut-allergic children, the vast majority were atopic.

Latex and nickel allergy is more common in patients with AD than in the general population.

Of AD patients, 30% develop asthma and 35% have nasal allergies.

eMedicine Logo

Patient Education

Frequently reinforce treatment and maintenance regimens with patients. Advise patients to contact the National Eczema Association for Science and Education at 4460 Redwood Hwy, Suite 16-D, San Rafael, CA 94903-1953.

Inform patients that treatment of this skin condition does not produce cure but good itch control can be achieved

Show videos to patients that show how to apply medication and that discuss the role of moisturization. A randomized controlled trial by Armstrong et al demonstrated improved patient education and clinical outcome in patients who watched a video on atopic dermatitis (AD) compared with those who received a pamphlet. [41] The study emphasized the importance of lifestyle changes and daily care in the successful treatment of AD.

For patient education resources, see Eczema (Atopic Dermatitis).

eMedicine Logo

  1. Spergel JM. From atopic dermatitis to asthma: the atopic march. Ann Allergy Asthma Immunol. 2010 Aug. 105(2):99-106; quiz 107-9, 117. [QxMD MEDLINE Link].
  2. Carlsten C, Dimich-Ward H, Ferguson A, Watson W, Rousseau R, Dybuncio A, et al. Atopic dermatitis in a high-risk cohort: natural history, associated allergic outcomes, and risk factors. Ann Allergy Asthma Immunol. 2013 Jan. 110(1):24-8. [QxMD MEDLINE Link].
  3. [Guideline] Eichenfield LF, Tom WL, Chamlin SL, Feldman SR, Hanifin JM, Simpson EL, et al. Guidelines of care for the management of atopic dermatitis: section 1. Diagnosis and assessment of atopic dermatitis. J Am Acad Dermatol. 2014 Feb. 70(2):338-51. [QxMD MEDLINE Link].
  4. Heller M, Shin HT, Orlow SJ, Schaffer JV. Mycophenolate mofetil for severe childhood atopic dermatitis: experience in 14 patients. Br J Dermatol. 2007 Jul. 157(1):127-32. [QxMD MEDLINE Link].
  5. Van Velsen SG, Haeck IM, Bruijnzeel-Koomen CA. Severe atopic dermatitis treated with everolimus. J Dermatolog Treat. 2009. 20(6):365-7. [QxMD MEDLINE Link].
  6. Feldman SR. Adherence must always be considered: is everolimus really ineffective as a treatment for atopic dermatitis?. J Dermatolog Treat. 2009. 20(6):317-8. [QxMD MEDLINE Link].
  7. Huang JT, Abrams M, Tlougan B, Rademaker A, Paller AS. Treatment of Staphylococcus aureus colonization in atopic dermatitis decreases disease severity. Pediatrics. 2009 May. 123(5):e808-14. [QxMD MEDLINE Link].
  8. Jansen CT, Haapalahti J, Hopsu-Havu VK. Immunoglobulin E in the human atopic skin. Arch Dermatol Forsch. 1973 May 28. 246(4):209-302. [QxMD MEDLINE Link].
  9. Koga C, Kabashima K, Shiraishi N, Kobayashi M, Tokura Y. Possible pathogenic role of Th17 cells for atopic dermatitis. J Invest Dermatol. 2008 Nov. 128 (11):2625-30. [QxMD MEDLINE Link].
  10. Molfino NA, Gossage D, Kolbeck R, Parker JM, Geba GP. Molecular and clinical rationale for therapeutic targeting of interleukin-5 and its receptor. Clin Exp Allergy. 2011 Sep 23. [QxMD MEDLINE Link].
  11. Hershko AY, Suzuki R, Charles N, Alvarez-Errico D, Sargent JL, Laurence A, et al. Mast cell interleukin-2 production contributes to suppression of chronic allergic dermatitis. Immunity. 2011 Oct 28. 35 (4):562-71. [QxMD MEDLINE Link].
  12. Kim BS, Siracusa MC, Saenz SA, Noti M, Monticelli LA, Sonnenberg GF, et al. TSLP elicits IL-33-independent innate lymphoid cell responses to promote skin inflammation. Sci Transl Med. 2013 Jan 30. 5 (170):170ra16. [QxMD MEDLINE Link].
  13. Kim BS, Wang K, Siracusa MC, Saenz SA, Brestoff JR, Monticelli LA, et al. Basophils promote innate lymphoid cell responses in inflamed skin. J Immunol. 2014 Oct 1. 193 (7):3717-25. [QxMD MEDLINE Link].
  14. Roediger B, Kyle R, Yip KH, Sumaria N, Guy TV, Kim BS, et al. Cutaneous immunosurveillance and regulation of inflammation by group 2 innate lymphoid cells. Nat Immunol. 2013 Jun. 14 (6):564-73. [QxMD MEDLINE Link].
  15. Imai Y, Yasuda K, Sakaguchi Y, Haneda T, Mizutani H, Yoshimoto T, et al. Skin-specific expression of IL-33 activates group 2 innate lymphoid cells and elicits atopic dermatitis-like inflammation in mice. Proc Natl Acad Sci U S A. 2013 Aug 20. 110 (34):13921-6. [QxMD MEDLINE Link].
  16. Salimi M, Barlow JL, Saunders SP, Xue L, Gutowska-Owsiak D, Wang X, et al. A role for IL-25 and IL-33-driven type-2 innate lymphoid cells in atopic dermatitis. J Exp Med. 2013 Dec 16. 210 (13):2939-50. [QxMD MEDLINE Link].
  17. Kim BS. Innate lymphoid cells in the skin. J Invest Dermatol. 2015 Mar. 135 (3):673-8. [QxMD MEDLINE Link].
  18. Cevikbas F, Wang X, Akiyama T, Kempkes C, Savinko T, Antal A, et al. A sensory neuron-expressed IL-31 receptor mediates T helper cell-dependent itch: Involvement of TRPV1 and TRPA1. J Allergy Clin Immunol. 2014 Feb. 133 (2):448-60. [QxMD MEDLINE Link].
  19. Oetjen LK, Mack MR, Feng J, et al. Sensory Neurons Co-opt Classical Immune Signaling Pathways to Mediate Chronic Itch. Cell. 2017 Sep 21. 171 (1):217-228.e13. [QxMD MEDLINE Link].
  20. Osawa R, Akiyama M, Shimizu H. Filaggrin gene defects and the risk of developing allergic disorders. Allergol Int. 2011 Mar. 60(1):1-9. [QxMD MEDLINE Link].
  21. Smith FJ, Irvine AD, Terron-Kwiatkowski A, et al. Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat Genet. 2006 Mar. 38(3):337-42. [QxMD MEDLINE Link].
  22. Palmer CN, Irvine AD, Terron-Kwiatkowski A, et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet. 2006 Apr. 38(4):441-6. [QxMD MEDLINE Link].
  23. Hvid M, Vestergaard C, Kemp K, Christensen GB, Deleuran B, Deleuran M. IL-25 in atopic dermatitis: a possible link between inflammation and skin barrier dysfunction?. J Invest Dermatol. 2011 Jan. 131 (1):150-7. [QxMD MEDLINE Link].
  24. Savinko T, Matikainen S, Saarialho-Kere U, Lehto M, Wang G, Lehtimäki S, et al. IL-33 and ST2 in atopic dermatitis: expression profiles and modulation by triggering factors. J Invest Dermatol. 2012 May. 132 (5):1392-400. [QxMD MEDLINE Link].
  25. Soumelis V, Reche PA, Kanzler H, Yuan W, Edward G, Homey B, et al. Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol. 2002 Jul. 3 (7):673-80. [QxMD MEDLINE Link].
  26. Brandt EB, Sivaprasad U. Th2 Cytokines and Atopic Dermatitis. J Clin Cell Immunol. 2011 Aug 10. 2(3):[QxMD MEDLINE Link]. [Full Text].
  27. Margolis DJ, Kim B, Apter AJ, Gupta J, Hoffstad O, Papadopoulos M, et al. Thymic stromal lymphopoietin variation, filaggrin loss of function, and the persistence of atopic dermatitis. JAMA Dermatol. 2014 Mar. 150 (3):254-9. [QxMD MEDLINE Link].
  28. Kubo A, Nagao K, Amagai M. Epidermal barrier dysfunction and cutaneous sensitization in atopic diseases. J Clin Invest. 2012 Feb 1. 122(2):440-7. [QxMD MEDLINE Link]. [Full Text].
  29. Sun LD, Xiao FL, Li Y, et al. Genome-wide association study identifies two new susceptibility loci for atopic dermatitis in the Chinese Han population. Nat Genet. 2011 Jun 12. 43(7):690-4. [QxMD MEDLINE Link].
  30. Paternoster L, Standl M, Chen CM, et al. Meta-analysis of genome-wide association studies identifies three new risk loci for atopic dermatitis. Nat Genet. 2011 Dec 25. 44(2):187-92. [QxMD MEDLINE Link]. [Full Text].
  31. Williams H, Flohr C. How epidemiology has challenged 3 prevailing concepts about atopic dermatitis. J Allergy Clin Immunol. 2006 Jul. 118(1):209-13. [QxMD MEDLINE Link].
  32. Zutavern A, Hirsch T, Leupold W, Weiland S, Keil U, von Mutius E. Atopic dermatitis, extrinsic atopic dermatitis and the hygiene hypothesis: results from a cross-sectional study. Clin Exp Allergy. 2005 Oct. 35(10):1301-8. [QxMD MEDLINE Link].
  33. Weston S, Halbert A, Richmond P, Prescott SL. Effects of probiotics on atopic dermatitis: a randomised controlled trial. Arch Dis Child. 2005 Sep. 90(9):892-7. [QxMD MEDLINE Link].
  34. Lee CH, Chuang HY, Hong CH, et al. Lifetime exposure to cigarette smoking and the development of adult-onset atopic dermatitis. Br J Dermatol. 2011 Mar. 164(3):483-9. [QxMD MEDLINE Link]. [Full Text].
  35. Horii KA, Simon SD, Liu DY, Sharma V. Atopic dermatitis in children in the United States, 1997-2004: visit trends, patient and provider characteristics, and prescribing patterns. Pediatrics. 2007 Sep. 120(3):e527-34. [QxMD MEDLINE Link].
  36. Williams HC, Pembroke AC, Forsdyke H, Boodoo G, Hay RJ, Burney PG. London-born black Caribbean children are at increased risk of atopic dermatitis. J Am Acad Dermatol. 1995 Feb. 32(2 Pt 1):212-7. [QxMD MEDLINE Link].
  37. Leung DY, Bieber T. Atopic dermatitis. Lancet. 2003 Jan 11. 361(9352):151-60. [QxMD MEDLINE Link].
  38. Fox S. Atopic Dermatitis Symptoms in Children Are Persistent. Medscape Medical News. Available at https://www.medscape.com/viewarticle/823090. Accessed: April 15, 2014.
  39. Margolis JS, Abuabara K, Bilker W, Hoffstad O, Margolis DJ. Persistence of Mild to Moderate Atopic Dermatitis. JAMA Dermatol. 2014 Apr 2. [QxMD MEDLINE Link].
  40. Silverberg JI. Persistence of Childhood Eczema Into Adulthood. JAMA Dermatol. 2014 Apr 2. [QxMD MEDLINE Link].
  41. Armstrong AW, Kim RH, Idriss NZ, Larsen LN, Lio PA. Online video improves clinical outcomes in adults with atopic dermatitis: a randomized controlled trial. J Am Acad Dermatol. 2011 Mar. 64(3):502-7. [QxMD MEDLINE Link].
  42. Garmhausen D, Hagemann T, Bieber T, Dimitriou I, Fimmers R, Diepgen T, et al. Characterization of different courses of atopic dermatitis in adolescent and adult patients. Allergy. 2013 Apr. 68(4):498-506. [QxMD MEDLINE Link].
  43. Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol (Stockh). 1980. 92 (suppl):44-7.
  44. Chopra R, Vakharia PP, Sacotte R, Patel N, Immaneni S, White T, et al. Severity strata for Eczema Area and Severity Index (EASI), modified EASI, Scoring Atopic Dermatitis (SCORAD), objective SCORAD, Atopic Dermatitis Severity Index and body surface area in adolescents and adults with atopic dermatitis. Br J Dermatol. 2017 Nov. 177 (5):1316-1321. [QxMD MEDLINE Link].
  45. Schram ME, Spuls PI, Leeflang MM, Lindeboom R, Bos JD, Schmitt J. EASI, (objective) SCORAD and POEM for atopic eczema: responsiveness and minimal clinically important difference. Allergy. 2012 Jan. 67 (1):99-106. [QxMD MEDLINE Link].
  46. Silverberg JI, Gelfand JM, Margolis DJ, Fonacier L, Boguniewicz M, Schwartz LB, et al. Severity strata for POEM, PO-SCORAD, and DLQI in US adults with atopic dermatitis. Ann Allergy Asthma Immunol. 2018 Oct. 121 (4):464-468.e3. [QxMD MEDLINE Link].
  47. Schmitt J, Chen CM, Apfelbacher C, et al. Infant eczema, infant sleeping problems, and mental health at 10 years of age: the prospective birth cohort study LISAplus. Allergy. 2011 Mar. 66(3):404-11. [QxMD MEDLINE Link].
  48. Nikkels AF, Piérard GE. Occult varicella. Pediatr Infect Dis J. 2009 Dec. 28(12):1073-5. [QxMD MEDLINE Link].
  49. Haeck IM, Rouwen TJ, Timmer-de Mik L, et al. Topical corticosteroids in atopic dermatitis and the risk of glaucoma and cataracts. J Am Acad Dermatol. 2011 Feb. 64(2):275-81. [QxMD MEDLINE Link].
  50. Heil PM, Maurer D, Klein B, Hultsch T, Stingl G. Omalizumab therapy in atopic dermatitis: depletion of IgE does not improve the clinical course - a randomized, placebo-controlled and double blind pilot study. J Dtsch Dermatol Ges. 2010 Dec. 8(12):990-8. [QxMD MEDLINE Link].
  51. Beck LA, Thaçi D, Hamilton JD, Graham NM, Bieber T, Rocklin R, et al. Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. N Engl J Med. 2014 Jul 10. 371 (2):130-9. [QxMD MEDLINE Link].
  52. Thaçi D, Simpson EL, Beck LA, Bieber T, Blauvelt A, Papp K, et al. Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebo-controlled, dose-ranging phase 2b trial. Lancet. 2016 Jan 2. 387 (10013):40-52. [QxMD MEDLINE Link].
  53. Simpson EL, Bieber T, Guttman-Yassky E, Beck LA, Blauvelt A, Cork MJ, et al. Two Phase 3 Trials of Dupilumab versus Placebo in Atopic Dermatitis. N Engl J Med. 2016 Dec 15. 375 (24):2335-2348. [QxMD MEDLINE Link].
  54. Simpson EL, et al. Dupilumab efficacy and safety in adolescents with moderate-to-severe atopic dermatitis: Results from a multicenter, randomized, placebo-controlled, double-blind, parallel-group, Phase 3 study (abstract #4640). Presented at the 27th European Academy of Dermatology and Venereology (EADV) Congress. September 15, 2018. Paris, France. [Full Text].
  55. Paller AS, Siegfried E, Gooderham M, Beck LA, Boguniewica M, Sher L, et al. Dupilumab significantly improves atopic dermatitis in children aged 6 to 12 years: Results from phase 3 trial (LIBERTY AD PEDS) (abstract 215). Presented at Revolutionizing Atopic Dermatitis 2020 virtual meeting. April 5, 2020. [Full Text].
  56. Brunk D. FDA Gives Nod to Tralokinumab for Adults With Moderate to Severe AD. Medscape Medical News. Available at https://www.medscape.com/viewarticle/965674. December 28, 2021; Accessed: January 4, 2022.
  57. Paller AS, Flohr C, Cork M, Bewley A, Blauvelt A, Hong HC, et al. Efficacy and Safety of Tralokinumab in Adolescents With Moderate to Severe Atopic Dermatitis: The Phase 3 ECZTRA 6 Randomized Clinical Trial. JAMA Dermatol. 2023 Jun 1. 159 (6):596-605. [QxMD MEDLINE Link]. [Full Text].
  58. AnaptysBio. AnaptysBio Reports Positive Topline Proof-of-Concept Data from Phase 2a Clinical Trial of ANB020 in Atopic Dermatitis. Available at https://ir.anaptysbio.com/phoenix.zhtml?c=254208&p=irol-newsArticle&ID=2305583. October 10, 2017; Accessed: November 13, 2017.
  59. Schwartz DM, Bonelli M, Gadina M, O'Shea JJ. Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases. Nat Rev Rheumatol. 2016 Jan. 12 (1):25-36. [QxMD MEDLINE Link].
  60. AbbVie. AbbVie's Upadacitinib (ABT-494) Meets Primary Endpoint in Phase 2b Study in Atopic Dermatitis. Available at https://news.abbvie.com/news/abbvies-upadacitinib-abt-494-meets-primary-endpoint-in-phase-2b-study-in-atopic-dermatitis.htm. September 7, 2017; Accessed: November 13, 2017.
  61. Papp K, Szepietowski JC, Kircik L, Toth D, Eichenfield LF, Leung DYM, et al. Efficacy and safety of ruxolitinib cream for the treatment of atopic dermatitis: Results from 2 phase 3, randomized, double-blind studies. J Am Acad Dermatol. 2021 Oct. 85 (4):863-872. [QxMD MEDLINE Link]. [Full Text].
  62. Guttman-Yassky E, et al. Once-daily upadacitinib versus placebo in adolescents and adults with moderate-to-severe atopic dermatitis (Measure Up 1 and Measure Up 2): results from two replicate double-blind, randomised controlled phase 3 trials. Lancet. 2021 Jun 5. 397 (10290):2151-2168. [QxMD MEDLINE Link].
  63. Reich K, Teixeira HD, et al. Safety and efficacy of upadacitinib in combination with topical corticosteroids in adolescents and adults with moderate-to-severe atopic dermatitis (AD Up): results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2021 Jun 5. 397 (10290):2169-2181. [QxMD MEDLINE Link].
  64. Simpson EL, et al. Efficacy and safety of abrocitinib in adults and adolescents with moderate-to-severe atopic dermatitis (JADE MONO-1): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet. 2020 Jul 25. 396 (10246):255-266. [QxMD MEDLINE Link]. [Full Text].
  65. Eichenfield LF, Flohr C, Sidbury R, Siegfried E, Szalai Z, Galus R, et al. Efficacy and Safety of Abrocitinib in Combination With Topical Therapy in Adolescents With Moderate-to-Severe Atopic Dermatitis: The JADE TEEN Randomized Clinical Trial. JAMA Dermatol. 2021 Oct 1. 157 (10):1165-1173. [QxMD MEDLINE Link]. [Full Text].
  66. Silverberg JI, et al. Efficacy and Safety of Abrocitinib in Patients With Moderate-to-Severe Atopic Dermatitis: A Randomized Clinical Trial. JAMA Dermatol. 2020 Aug 1. 156 (8):863-873. [QxMD MEDLINE Link]. [Full Text].
  67. Bieber T, Simpson EL, Silverberg JI, Thaçi D, Paul C, Pink AE, et al. Abrocitinib versus Placebo or Dupilumab for Atopic Dermatitis. N Engl J Med. 2021 Mar 25. 384 (12):1101-1112. [QxMD MEDLINE Link]. [Full Text].
  68. Paller AS, Tom WL, Lebwohl MG, Blumenthal RL, Boguniewicz M, Call RS, et al. Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. J Am Acad Dermatol. 2016 Sep. 75 (3):494-503.e4. [QxMD MEDLINE Link]. [Full Text].
  69. Eucrisa (crisaborole) [package insert]. Collegeville, Pa: Anacor Pharmaceuticals, Inc. March 2020. Available at [Full Text].
  70. Eichenfield L, Boguniewicz M, Simpson E, et al. Ann Allergy Asthma Immunol. Once-Daily Roflumilast Cream 0.15% for Atopic “Dermatitis: Pooled Results: From INTEGUMENT-1/2 Phase 3 Trials. 2023 Nov 131(5; suppl 1):S91. [Full Text].
  71. Michail S. The role of Probiotics in allergic diseases. Allergy Asthma Clin Immunol. 2009 Oct 22. 5(1):5. [QxMD MEDLINE Link]. [Full Text].
  72. Hand L. Probiotics may protect infants from allergy, but not asthma. Medscape Medical News. August 19, 2013. [Full Text].
  73. Elazab N, Mendy A, Gasana J, Vieira ER, Quizon A, Forno E. Probiotic Administration in Early Life, Atopy, and Asthma: A Meta-analysis of Clinical Trials. Pediatrics. 2013 Aug 19. [QxMD MEDLINE Link].
  74. Johnson K. Probiotics in Pregnancy, Lactation Reduce Dermatitis. Medscape Medical News. Nov 25 2014. [Full Text].
  75. [Guideline] Fiocchi A, Pawankar R, Cuello-Garcia C, et al. World Allergy Organization-McMaster University Guidelines for Allergic Disease Prevention (GLAD-P): Probiotics. World Allergy Organ J. 2015. 8 (1):4. [QxMD MEDLINE Link].
  76. Douglas D. Methotrexate assay helpful in some children with skin disease. Medscape Medical News. January 7, 2014. [Full Text].
  77. Rahman SI, Siegfried E, Flanagan KH, Armbrecht ES. The methotrexate polyglutamate assay supports the efficacy of methotrexate for severe inflammatory skin disease in children. J Am Acad Dermatol. 2013 Dec 8. [QxMD MEDLINE Link].
  78. Shi VY, Foolad N, Ornelas JN, Hassoun L, Monico G, Takeda N, et al. Comparing the Effect of Bleach and Water Baths on Skin Barrier Function in Atopic Dermatitis: A Split-Body Randomized Controlled Trial. Br J Dermatol. 2016 Feb 15. [QxMD MEDLINE Link].
  79. [Guideline] American Academy of Dermatology. Atopic dermatitis clinical guideline. Available at https://www.aad.org/practicecenter/quality/clinical-guidelines/atopic-dermatitis. 2014; Accessed: November 9, 2018.
  80. [Guideline] Berth-Jones J, Exton LS, Ladoyanni E, Mohd Mustapa MF, Tebbs VM, Yesudian PD, et al. British Association of Dermatologists guidelines for the safe and effective prescribing of oral ciclosporin in dermatology 2018. Br J Dermatol. 2019 Jun. 180 (6):1312-1338. [QxMD MEDLINE Link]. [Full Text].

Author

Brian S Kim, MD, MTR, FAAD Sol and Clara Kest Professor, Vice Chair of Research, Site Chair, Mount Sinai West and Morningside, Director, Mark Lebwohl Center for Neuroinflammation and Sensation, The Kimberly and Eric J Waldman Department of Dermatology, Precision Immunology Institute, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai

Brian S Kim, MD, MTR, FAAD is a member of the following medical societies: American Academy of Dermatology, American Medical Association, Society for Investigative Dermatology

Disclosure: Received research grant from: Doris Duke Charitable Foundation, Celgene Corporation, LEO Pharma, and the National Institute of Arthritis Musculoskeletal and Skin Diseases (NIAMS) of the National Institutes of Health [NIH (K08AR065577 and R01AR070116)]
Consultant for AbbVie, AstraZeneca, Cara Therapeutics, Galderma, GlaxoSmithKline, Pfizer, Regeneron, Sanofi Genzyme, Trevi Therapeutics; Scientific Advisory Board for Abrax Japan, Granular Therapeutics, and Recens Medical. .

Specialty Editor Board

Richard P Vinson, MD Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA

Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Texas Medical Association, Association of Military Dermatologists, Texas Dermatological Society

Disclosure: Nothing to disclose.

Van Perry, MD Assistant Professor, Department of Medicine, Division of Dermatology, University of Texas School of Medicine at San Antonio

Van Perry, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Chief Editor

William D James, MD Emeritus Professor, Department of Dermatology, University of Pennsylvania School of Medicine

William D James, MD is a member of the following medical societies: American Academy of Dermatology, American Contact Dermatitis Society, Association of Military Dermatologists, Association of Professors of Dermatology, American Dermatological Association, Women's Dermatologic Society, Medical Dermatology Society, Dermatology Foundation, Society for Investigative Dermatology, Washington DC Dermatological Society, Atlantic Dermatologic Society, Philadelphia Dermatological Society, Pennsylvania Academy of Dermatology, College of Physicians of Philadelphia

Disclosure: Received income in an amount equal to or greater than $250 from: Elsevier
Served as a speaker for various universities, dermatology societies, and dermatology departments.

Acknowledgements

Peter Fritsch, MD Chair, Department of Dermatology and Venereology, Medical University of Innsbruck, Austria

Peter Fritsch, MD is a member of the following medical societies: American Dermatological Association, International Society of Pediatric Dermatology, and Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Bernice R Krafchik, MBChB, FRCPC Professor Emeritus, Department of Pediatrics, Section of Dermatology, University of Toronto Faculty of Medicine, Canada

Bernice R Krafchik, MBChB, FRCPC is a member of the following medical societies: American Academy of Dermatology, American Dermatological Association, Canadian Medical Association, College of Physicians and Surgeons of Ontario, Royal College of Physicians and Surgeons of Canada, and Society for Pediatric Dermatology

Disclosure: Nothing to disclose.