Confronting Issues and Challenges Beneath the Surface: Biology and Pathophysiology of Eczema

Pathophysiology of AD, featuring Brian Kim, MD, MTR, FAAD

Itch-Scratch Cycle and Its Impact on Patients

The itch-scratch cycle can be vicious for patients with atopic dermatitis (AD), starting with either an itchy or inflammatory sensation and triggering the desire to scratch to relieve the sensation (Figure 1). In severe cases of AD, this cycle is very difficult to control.

In AD, having inflammation in the skin is enough to cause damage to the skin barrier. We also know that many individuals with AD have a defective barrier due to genetics. Scratching only aggravates inflammation and the damaged barrier further, causing the release of epidermal cytokines that then activate cells in the dermis, which, in turn, release even more proinflammatory factors that then propagate inflammation and itch (Figure 2). These cytokines, including IL-4, IL-13, and IL-31, are classically associated with AD and allergic inflammation. They also translate what happens in the immune system to the nervous system, thereby promoting itch. 

Research has validated these pathways as therapeutically important. We see this with the advanced therapeutics that are either available or in development; these emerging options have shown a very profound effect on itch. This is probably, in part, due to disruption of the neuroimmune interaction between the immune system and the nervous system.

Addressing the itch-scratch cycle, first and foremost, requires the patient to understand their disease. After that, my care plan typically is very homeopathic in that the most important component is a multifaceted multidisciplinary approach. Overall, the patient should be empowered to fully understand what phase their disease is in at each moment and how to appropriately address these moments. For example, there are times when the barrier is more important than the itch. In these cases, heavy moisturization becomes the primary modality in order to prevent transepidermal water loss (TEWL) and further damage. There are other moments in which the patient will need to differentiate between having dry skin and having inflammation. Sometimes treating itch means treating the inflammation playing a role in its presentation. The appropriate course of action with inflammation, then, would be to be more aggressive with topical corticosteroid application. The day-to-day treatment can be time and context dependent. Different approaches may be needed at different times and should be adjusted through a shared decision-making process with the patient.

Immune Axes and Their Importance in Eczema

Essentially, there are three different immune axes. The first is what we call the type 1 immune system, which is critical for protecting against viral and certain forms of bacterial infections. Cytokines associated with a type 1 response include IL-2, interferon (IFN) γ, tumor necrosis factor (TNF) α. Another axis is the type 2 immune response. This seems to be a very ancient form of immunity against worm parasites. Type 2 largely is not that important in modern day, but it has become more of a problem through diseases, such as eczema, in which cytokines such as IL-4, IL-5, and IL-13 can cause an inflammatory response. Then, there is the third arm, referred to as type 3 or as T_H17. This response is responsible for the production of cytokines IL-17 and IL-22, and it is necessary to some degree for bacterial infections but also very important for antifungal infections. What we know is that all of these different parts of the immune system can go wrong and cause different diseases, whether it is eczema with type 2 or psoriasis with T_H17.

Eczema is a relatively clean type 2 immune disease, as evidenced by the effectiveness of the therapies that block type 2 cytokines. However, it is also a complex disease. We think that, in addition to the type 2 response, patients start to acquire other immune responses that increasingly become a pathologic component of AD. In those patients, blocking some of these other pathways now becomes important, potentially, for treating their disease. The contribution of type 1 or T_H17 responses and subsequent inhibition of those axes in eczema likely comes down to practicality. For example, the cytokines that promote the type 1 pathways, such as IFN-γ and TNF-α, are very important to overall health, and suppression can have critical adverse effects. We think there is some ability to get around this limitation through a partial blockade, and that is probably what Janus kinase (JAK) inhibitors do. JAK inhibitors, in particular, are broader and likely block enough of the various different pathways to get a composite effect.

In addition, there is at least some significant contribution of T_H22, though the immunology is not entirely clear. We know that there are increased levels of IL-22 in AD. We also know that blocking it will probably have some amount of therapeutic effect, but we do not know exactly how that is happening because the lack of evidence on how IL-22 is specifically pathologic.

Most recently, two very distinct pathways have been discovered that clearly mediate chronic itch vs acute itch. Acute itch is allergen-mediated whereas chronic likely is not, and we are finding that the stimulated neurons and involved immune cells are different. With this knowledge, we have to start considering that there are multiple different pathways operative in AD. We already see this in our clinical practice; we have patients that have chronic itch but who also have acute itch, but then others with only chronic itch and no acute itch. There are additional layers to the disease as well; some people get staphylococcal infections that itch vs some who have staphylococcal infections and have pain.

The point being is eczema is not just one rash and just one itch—it is probably many rashes and many itches with varying combinations and presentations. If a patient is lucky, one product can treat it all. However, for many of our patients, you might need one, two, or three therapies to address the different components of AD.

The Complexity and Burden of Itch

Itch considerably affects patients with eczema, but it also affects individual patients differently. As previously discussed, itch is a very important, and in some ways the most important, component of AD. It helps drive an inflammatory response that keeps the scratch cycle going, so we need to capture itch in a holistic sense. We now have technologies that can objectively measure scratching in an effective way, and these technologies will likely highlight the hidden morbidities of itch in eczema that we currently do not realize.

Eczema underlines, in a very poignant way, how itch can be played down even by the patient. Just because the patient does not seem to be acutely bothered by their itch does not mean that it is trivial within their overall disease. A patient aged 7 years may say that his level of itching is okay, but if he is not sleeping well because he is up scratching all night long, that could have effects on his schooling, attention, mood, and overall health. We need to go further into the role of itch in AD,because the implications of what this does in patients may be much bigger than we realized.

I am in the camp that believes AD is the rash that itches. It goes back to the idea that there are inflammatory cascades that are set off in the skin that mediate both chronic and acute itch. These inflammatory mediators then just bombard the nerves, playing a role in the infamous itch-scratch cycle. Our available and emerging advanced therapies disrupt that process with good effectiveness, and current research is looking at other strategies, such as altering IL-1 blockage or mast cells.

We recently uncovered the unexpected role of basophils. When I was in medical school, basophils were referred to as a vestigial cell of unknown function and significance; now we know basophils are rather significant and, in some ways, the circulating counterparts of mast cells. But they are also very different by the way in which they are stimulated and “get angry” despite having a very similar machinery to mast cells. Although they are not in eczematous skin, basophils can be rapidly recruited into the skin, bringing with them IL-4 and promoting inflammation. Surprisingly, they then promote itch not through those cytokines but through other molecules, such as leukotrienes by binding allergens through IgE.

While itch undoubtedly is a burden on patients with eczema, I have some ambivalence about patients overly emphasizing their itch, because I do not want them to be taken hostage by their disease. However, patients need to know if there are certain triggers that set off their itch (Table 1). When flares happen, patients should be encouraged to take note of its qualities: How bad it is? How severe it is? Is it affecting sleep? What makes it go away? If patients can at least track those terrible periods and the associated characteristics, that can be helpful to understanding the course of their disease as the clinician. Often what happens is that patients show up and they say their AD was bad 3 months ago and that it is under control now, making it a guessing game as to how to proceed with care. 

As discussed earlier, treatment should heavily involve education and improving the patient’s understanding of their disease. The more we can empower the patient, the better their outcomes may be, allowing us to give them more tools at their disposal to handle their itch and AD.

Skin Biology of Eczema, featuring Peter Lio, MD, FAAD

Skin Barrier Deficiency

We often talk about the skin as the interface with the outside world. One of its primary functions is to keep water and other nutrients inside our body and protect us from allergens, irritants, and pathogens—bacteria, viruses, fungi—that could potentially cause trouble. In AD, there often is barrier damage or dysfunction. One way to describe it is leaky skin; instead of having organized tight junctions, the epidermis is open, allowing water to escape and allergens, irritants, and potentially abnormal pathogens to get in the skin (Figure 3).

One thing that is fascinating is the role of the mutation of FLG, the gene that encodes for filaggrin protein, in patients with eczema. A lack of filaggrin and/or incorrect filaggrin correlates with a much higher risk of developing AD. It is interesting to see this potential connection between a genetic mutation and the leaky skin, but the truth is this notion does not account for every patient with AD. In various populations, there may be different loci playing a role, and there are different types of barrier functions (Table 2), such as the microbiome and biodiversity; the chemical layer, which prefers to keep our skin somewhat acidic at 4.5 pH; and the immune layer, which responds to infection and inflammation. If any of these functions are abnormal, then we can have trouble as seen in AD.

Under normal circumstances with healthy skin, TEWL should be a very low number. Even when adjusting for variability between anatomical locations and time of day, healthy skin should have minimal moisture leaving and thus maintain skin hydration. When that barrier is leaky, then TEWL increases significantly. There are other skin conditions that also probably have barrier problems too, including psoriasis, acne, rosacea, ichthyosis, and allergic contact dermatitis. We know from studying dermatologic diseases that anytime the skin is inflamed, dry, or under duress, this makes it susceptible to further irritation or infection from external factors. Moisturization becomes critical to preventing excessive TEWL and restoring the skin’s barrier functions.

However, one of the things we often hear from patients with AD is that no matter how much moisturizer they apply, it never seems to be enough to resolve their dry, itchy skin. This is likely an index that the skin cannot hold the water in. Think of it as if you were trying to fill up a strainer; the water just keeps pouring through and the strainer is ineffective at holding it in. We see a similar concept with the leaky gut, wherein there is a permeability in the gut that seems to be associated with a number of gastrointestinal diseases. There is some thought that there could be a similar issue in the respiratory epithelium with asthma as well. It is interesting to note that while we focus on the skin as dermatologists, we do see some similarities to these barrier problems across different conditions, and atopy seems to put our patients at risk for multiple layers of trouble.

Correcting barrier dysfunction in the vast majority of patients with AD is reliant on using moisturizer liberally and frequently. If we suggest to our patients some of the moisturizers that are designed to help restore and strengthen the skin barrier and act as a temporary barrier (Table 3), most patients will see a net positive effect. 

Microbiome Dysbiosis

We know that the microbiome differs from individual to individual, but it also differs based on the location on an individual body. The microbiome of the mouth is very different to the microbiome on the arm, which is different to the one on the legs or the groin. We know that diversity of the microbiome really does seem to be a positive trait, and having a good diversity correlates with general health and stability.