No two people experience atopic dermatitis exactly the same. In some, it starts in childhood–maybe even infancy. For others, it starts in adolescence. Still, others will have their first flares in their 50s. Adults of Asian ancestry often develop thick plaques of eczema. Adult African Americans often develop eczema with patches of pale hypopigmentation or dark patches of hyperpigmentation. Triggers, severity, and response to treatment vary widely, also.
The disorder has plagued and intrigued both patients and physicians for thousands of years. Eczema-like symptoms were even mentioned in the earliest-known medical document, the Ancient Egyptian Ebers Papyrus. The Ebers Papyrus mentions different remedies for eczema, including the application of the pure element sulfur for its antimicrobial, anti-inflammatory properties.
Today, questions about atopic dermatitis remain: what causes it? How can it be prevented? Can we predict who will get it? These questions take on a certain urgency in light of the evidence that prevalence of atopic dermatitis is increasing globally. Costs for treating atopic dermatitis are increasing exponentially.
Atopic dermatitis is linked to several underlying factors that may or may not coincide. Those factors include skin barrier dysfunction, heredity, immunology, faulty or lazy suppressor genes, environment, and dysbiosis of the skin microbiome.
The Skin Barrier
Your skin is your body’s largest organ, comprising an estimated 15% of your body weight. It is your body’s first defense against pathogens and harmful particles in the environment. It is protected by a barrier called the stratum corneum, made of flattened, interlinking cells called corneocytes. Epidermal cells are brick-like, and they flatten as they mature and rise to the surface of the skin.
The corneocytes are connected by proteins and lipids that keep the cells hydrated and impermeable to moisture. This means that water from the atmosphere cannot swell the skin cells and damage them; it also means that water cannot migrate out of the skin cells to the environment, a process known as transepidermal water loss (TEWL).
Dysfunctional skin barrier
All together, the interlocking corneocytes, as well as the proteins and lipids between them, are responsible for your skin’s barrier function. One of the most universal characteristics of atopic dermatitis is compromised barrier function.
Filaggrin is one of the most important proteins involved in the skin’s barrier function. In the stratum corneum, filaggrin breaks down into amino acids, urea, sugars, and other components of the natural moisturizing factor (NMF).
The NMF is hygroscopic, drawing moisture into the skin as needed. Filaggrin breakdown can be accelerated or slowed by environmental factors such as heat and humidity, allowing for appropriate hydration in response to environmental changes.
Many people with atopic dermatitis suffer from either insufficient filaggrin production or disordered filaggrin break-down. When this happens, skin cannot maintain hydration. It becomes dry and easily irritated, triggering the development of atopic dermatitis symptoms.
Skin barrier dysfunction is not always rooted in problems with filaggrin production. Lamellar bodies in the stratum corneum secrete fatty acids, ceramides, and cholesterol. While filaggrin break-down and the NMF draw moisture into the skin cells, these lipids and fatty acids are hydrophobic. They repel water, thus preventing the evaporation of moisture from skin cells. This function also prevents large molecules from permeating the skin from the outside.
When the lamellar bodies do not manufacture or secrete enough of one or more of these fatty acids or lipids, the skin is subject to excess TEWL as well as external damage.
The very term atopic dermatitis implies an immunological basis for the disorder. The word atopic was coined in 1923 by immunologists Robert Cooke and Arthur Coca from the Greek atopia, meaning “out of place” (“any place dermatitis” is another metaphor for atopic dermatitis) It was meant to describe what they called “strange diseases–” specifically asthma and allergic rhinitis.
Cooke and Coca hypothesized that these disorders were caused by the immune system being either oversensitized or undersensitized to normally harmless antigens in the environment (such as pollens, animal dander, and dust). Their work revolutionized immunology and the study of allergy.
Ten years later, Dermatologists Fred Wise and Marion Sulzberger noted the frequency with which these “strange diseases” occurred alongside dermatitis in their patients. They borrowed Cooke’s and Coca’s term to describe this skin condition.
The so-called “atopic march” refers to the fact that having one atopic disorder–allergic rhinitis, asthma, or atopic dermatitis–predisposes patients to the development of the others.
“A common progression is childhood eczema, then asthma, with allergic rhinitis developing by age 30,” says Dr. Steve Harlan, a board-certified dermatologist.
Atopy, Inflammation, and The Immune System
Atopy is the result of an immune response that results in itching, then inflammation. In atopic dermatitis, redness, increased itching, swelling, and oozing are signs of this inflammation.
Inflammation itself is just a sign that your body is trying to protect or heal itself from injury or disease. Sometimes, though, inflammation is rooted in immune system dysregulation. It occurs where there is no real threat, or it continues long after a threat has been neutralized. This is what happens with atopic dermatitis.
A Coordinated Defense
The introduction of an antigen to your tissues immediately sets off an elaborate chain of signals and responses. Injured cells activate pattern recognition receptors (PRR) that are responsible for distinguishing between the body’s own cells and those of pathogens.
Cells such as Langerhans cells, which are localized to your skin, then release chemicals called inflammatory mediators. These chemicals recruit neutrophils, macrophages, and other immune system cells to help them repel the intruder and heal the injured tissues.
Each of these cells plays a designated role in defense against antigens and repair of injured tissues. Some of them cause dilation of blood vessels, which encourages increased blood flow to the injured tissues. Some work to draw fluids to the tissues to facilitate healing.
When your immune system responds to antigens, some cells isolate those antigens, and others break them down. Macrophages gather the remnants of the invading cells when they are broken down. They then “present” the antigen’s molecular information to helper T cells.
These cells ferry the molecular code of the antigen, as presented by the macrophages, to the lymph nodes, where they activate T cells. The T cells then signal the B cells that generate antibodies against those specific antigens. The antibodies involved in atopic disorders are collectively called immunoglobulin E, or IgE.
Inflammation is the outward result of this well-coordinated response. Injured tissues are repaired through this process, while the offending antigen is ejected. The inflammation resolves once this is accomplished, usually over the course of days.
For people with atopic disorders, this response can be triggered by antigens that would not normally provoke a reaction. In addition, the immune cells never seem to get the order to stand down; the inflammation persists chronically, along with its attendant symptoms.
Atopic Dermatitis and Autoimmune Disorders
Many studies over the past few years have indicated a strong correlation between atopic dermatitis and several autoimmune diseases. These diseases include hypothyroidism, lupus, Crohn’s Disease, in addition to diseases that affect the skin, such as alopecia areata and vitiligo.
Atopic dermatitis seems to be more prevalent among people with two co-occurring autoimmune diseases than it is among those with only one autoimmune disease. Atopic dermatitis often precedes an autoimmune disorder diagnosis; this seems to be especially true for people who develop eczema before adulthood.
Autoimmune disorders are disorders of the adaptive immune system, also known as the “acquired immune system.” We are not born with an adaptive immune system; it develops as we are exposed to antigens. It engineers specific antibodies to specific antigens, often giving us immunity to any future attacks by related antigens.
In people with autoimmune disorders, the immune system manufactures antibodies to its own tissues. The result is damage to those tissues, which triggers more inflammation.
Atopic dermatitis and autoimmune disorders each feature immune system dysregulation. Dysfunction in helper T cells, which are activated in both innate and adaptive immune responses, is found in both atopic dermatitis and autoimmune disease. Research into the correlation between atopic dermatitis and autoimmune disorders is ongoing.
Atopic dermatitis is not in and of itself an autoimmune disorder. Having atopic dermatitis does not guarantee the development of an autoimmune disorder, nor vice versa.
Atopic dermatitis is largely a disease of the innate immune system, a defense against pathogens that includes your skin, mucus membranes, and cells such as neutrophils, macrophages, and dendritic cells. You are born with this defense system; it is nonspecific and does not target individual antigens.
Years before atopic dermatitis became a recognized disorder, Cooke and Coca recognized familial patterns in atopic disorders. A child with allergic rhinitis was likely to have a parent or sibling with either allergic rhinitis or asthma.
This same link was observed with atopic dermatitis. Having a family member with an atopic disorder is one of the biggest risk factors for developing atopic dermatitis.
However, the relationship between heredity and atopic dermatitis is variable and unpredictable. It is not caused by a singular gene that must be present in both parents to be passed along to the child. A number of different genes may be involved in the development of atopic dermatitis, and inheriting mutations on one or more of these genes does not guarantee the development of the disorder.
The sequencing of the human genome opened new doors for researching disease and heredity.
Genome-wide association studies (GWAS) allow scientists to examine the entire genome (all of the DNA) of a given group. A GWAS enables researchers to pinpoint susceptibility loci, or heritable mutations that increase risk of a disease.
Scientists have identified several different susceptibility loci implicated in the development of atopic dermatitis. This includes mutations on genes related to both inflammation and the skin’s barrier function.
Heredity and Filaggrin
The synthesis of filaggrin depends upon a precursor protein called profillagrin. A gene called the FLG gene is responsible for the synthesis of profillagrin. In a manner of speaking, the FLG gene gives the body the code for making profilaggrin.
Mutations on the FLG gene do not provide the correct code for synthesizing profilaggrin. These faulty “instructions” lead to inadequate production of profilaggrin, and by extension, filaggrin.
The genetic variation that causes inadequate synthesis of profilaggrin can be passed by a parent to their child. This inherited mutation, though, is not an inevitable guarantee that a person will experience eczema. Simultaneously, not everyone who develops eczema has inherited the mutation, although there is a very strong correlation between the two.
Heredity and the Lamellar Bodies
Earlier, we discussed how the lamellar bodies, as well as the fatty acids and lipids they secrete, contribute to the skin’s barrier function. Dysfunction in the lamellar bodies can lead to TEWL, as well as openness to external irritants and pathogens. Recent studies have found mutations on a gene called TMEM79 in Irish atopic dermatitis patients who had not inherited FLG mutations.
TMEM79 encodes the production of the protein mattrin, shortages of which are associated with defective lamellar body secretions in mouse studies.
Genetics and Inflammation
Several different genes are involved in regulating the body’s immune response and shutting down inflammation. A mutation on any of these genes can predispose a person to chronic inflammation; like the genetic variations regulating the skin’s protective proteins, these mutations can be passed from parent to child.
A recent GWAS of people with atopic dermatitis identified ten new susceptibility loci for eczema. Each of these susceptibility loci is also associated with adaptive immune system regulation.
The Skin Microbiome
Our skin is populated with countless microbial organisms, or microbiota. These organisms comprise your skin’s microbiome, which includes normal flora bacteria and yeast. Facial pores can also contain a few microscopic arthropods called demodex . These microbiota exist in balance when the skin is healthy.
When the skin’s microbiome is out of balance, disease-causing bacteria overpopulate the skin. Skin scrapings taken from people with atopic dermatitis often show increased yeast and Demodex organisms.
During atopic dermatitis flares, the skin is usually overpopulated by Staphylococcus aureus, which especially contributes to inflammation and strong reactions from our immune system. Flared atopic dermatitis nearly always cultures out this strain of staph.
The microbiome and the skin barrier are closely related. Studies suggest that dysfunction in one could contribute to problems with the other. The microbiome also seems to play a role in lowering inflammation, while inflammation likewise appears to unbalance the microbiome.
Environment and Atopic Dermatitis
Environment plays a key role in the development of atopic dermatitis and the severity of its symptoms. The skin’s barrier function and microbiome can be directly influenced by factors such as extreme heat, harsh wind, or humidity. Perspiration on the skin can flare poorly-controlled atopic dermatitis. Environmental factors can also trigger the over- or -underexpression of genes associated with inflammation.
Studies in both China and Korea have demonstrated a strong correlation between air pollution and atopic dermatitis flares with increased reports of symptoms on days with high particulate matter counts.
Winter time seems to trigger the expression of genes associated with inflammation, which corresponds with higher incidence of atopic dermatitis symptoms. Meanwhile, summer appears to mute the expressions of these genes somewhat, leading in some cases to excessive staph growth–leading to greater numbers of staph-related symptoms in the summer months.
The relationship between atopic dermatitis and environment is also obvious in cases where symptoms respond to the addition or removal of triggers such as cat dander, dust mites, or mold spores from the environment.
A Convergence of Contributors
It has so far been impossible to narrow the etiology of atopic dermatitis down to one single cause. In fact, any one of the contributing factors we’ve discussed might never lead to flares on their own. For example, patients with icthyosis have terribly dry skin, but only some of them develop atopic dermatitis. A combination of co-occurring factors might trigger a flare.
Someone with an unbalanced skin microbiome and a weakened skin barrier might never have any issues until they have to hike on a dry, windy day. Someone prone to inflammation might never have a flare until their microbiome is unbalanced by a new skincare regimen or diet. Even genetic predispositions to lamellar body dysfunction or inadequate filaggrin synthesis do not, on their own, guarantee the development of atopic dermatitis.
Ultimately, the development of atopic dermatitis depends upon several different intersections between heredity, environment, and immunology. We are still not certain of the exact nature of these intersections.
What We Do Know
While the etiology of atopic dermatitis may not yet be entirely clear, there are some firmly-established facts about the treatment and prevention of this disorder. We know, for example, that moisturizing at least twice a day is one of the most critical practices for preventing and healing eczema flares.
We also know that topical corticosteroid treatments reduce inflammation and shorten the duration and severity of flares. Unfortunately, we are also aware that prolonged topical steroid use can lead to skin atrophy as well as topical steroid withdrawal (TSW), a rebound effect that causes itching, redness, swelling, and burning when steroids are withdrawn. This presents a distinct challenge in the treatment of a chronic, frequently-relapsing disorder.
Board-certified dermatologist Dr. Steve Harlan understands the difficulty and frustration that can be involved in atopic dermatitis treatment. He developed SmartLotionⓇ, an eczema cream with the needs of his long-term atopic dermatitis patients in mind. SmartLotionⓇ combines prebiotic ingredients with 0.75% hydrocortisone to reduce inflammation while fostering healthy skin flora and improved barrier function.
SmartLotionⓇ does not cause TSW or skin atrophy, and most people can use it safely under a doctor’s supervision.
The Perfect Companion for SmartLotionⓇ
SmartLotionⓇ has a ninety-five percent success rate when combined with proper moisturizing. HarlanMD has recently released a moisturizer formulated for protecting and healing the skin barrier.
Perfect Repair™ moisturizing cream is the result of Dr. Harlan’s extensive research and years of practice. Its abundant natural ceramides support the skin’s barrier functions and prevent loss of moisture. The addition of coconut oil is an advance for eczema patients. Its complex of jojoba oil, glycerin, and grapefruit seed extract create a powerful prebiotic strategy.
Perfect Repair protects dry, damaged skin, amplifying the healing effects of SmartLotionⓇ during eczema flares. Used at least twice a day, it is a good companion for SmartLotionⓇ.
Atopic dermatitis is a complex, multidimensional disorder with several different underlying factors. Genetics, environment, and immune system dysfunction can all contribute to symptoms. Compromised skin barrier and an unbalanced skin microbiome can increase susceptibility to these other influences, and can also be caused by them.
SmartLotionⓇ and Perfect Repair™ are two indispensable tools in mitigating the effects of these intersecting factors that compound each other.
Steven Harlan MD
Board Certified Dermatologist
Inventor of SmartLotion®