New NEA Research: What Factors Influence Clinical Trial Participation for…
The findings highlight the differences between what adults value for themselves in clinical trial participation versus what parents find important for their children.
Published On: Jul 30, 2021
Last Updated On: Jan 3, 2023
Itch is often described as the hallmark of atopic dermatitis (AD) with nearly 100% of people with AD reporting itch as one of their major symptoms. Itch leads to scratching behavior, which can be extremely disruptive and difficult to overcome. Itch and scratching have been shown to negatively impact sleep, physical activity, daily functioning at work or school, social life and mental health (depression, anxiety, suicidal ideation), leading to an overall reduced quality of life.1,2
Researching itch has not been easy. Dr. Gil Yosipovitch, a professor at the University of Miami and renowned clinician and researcher on itch, said, “The general knowledge in the beginning was that AD is an immune disease. We had very limited understanding of the mechanisms of neural transmission of itch.” Dr. Brian Kim, professor of dermatology at Mount Sinai University, followed up by saying, “People did not understand that itch itself is a disease. It is very difficult to get money to support your research when no one believes you are studying a real disease.”
In spite of the difficulties, several dedicated itch researchers have established that many different mechanisms underlie itch in AD, with keratinocytes (i.e., the main structural cells of the skin), as well as various immune cells, nerves and the brain all playing their part. How all these different cells and systems might communicate and interact remains an area of active research, but it is becoming clearer that all these systems do talk to each other (Figure 1).
Thinking about how the skin functions has greatly evolved over the last several years. “We used to think about the skin as just a brick-and-mortar structure that blocked environmental stimuli,” said Dr. Kim. “In recent years, we’ve come to appreciate that the skin itself is an immune organ, a part of the innate immune system.” Dr. Kim added that “the brick-and-mortar wall structure actually integrates directly with the immune system. Nerves rapidly sense and modulate dedicated responses to alert the body that there is something wrong. The nerves interface and are integrated with the immune system to generate a fluid, sophisticated response. The skin structure, immune system and neurons are integrated, not siloed.”
The skin is a sensory organ and itch is one way the skin experiences interaction with the environment.3 When skin is healthy, the outer cells that form the skin barrier, called the stratum corneum, keep foreign material out of the skin – allergens and pathogens cannot penetrate. Healthy skin also has nerve endings that stop at the dermis, the layer of tissue underneath the epidermis.
However, when the skin barrier is disrupted (as in AD), allergens and pathogens can get into the skin, increasing inflammation.4 When the stratum corneum is compromised, keratinocytes release signals that cause nerve endings in skin to activate.
Nerve fibers found in the skin are called pruriceptors, which act as a kind of “antennae” to constantly sample the environment and send signals along neurons to the spinal cord and brain for interpretation.5 In acute itch, like a bug bite, mast cells release histamine, which can activate a special set of nerve fibers (C-nerve fibers) that then connect to the spinal nerves and up to the brain. For this kind of itch, antihistamines can be applied topically or taken systemically to reduce the itch. However, antihistamines typically do not work to relieve itch in AD4, suggesting that another set of non-histaminergic nerve fibers are responsible for the itch.
Brain imaging has shown that the areas of the brain involved in emotions, reward and memory of negative experiences, as well as processing of pain, are activated in AD itch significantly more than in healthy individuals.4 Dr. Yosipovitch said, “Emotional states such as stress, anxiety and mood changes can affect the skin-inflammation-nerve-brain axis. For example, they can aggravate itch in AD by damaging the skin barrier, increasing inflammation and increasing nerve sensitivity.”
Experiencing itch causes the desire to scratch, which can temporarily provide itch relief. However, reward mechanisms in the brain become activated with scratching, which can induce people to feel an intense sense of pleasure associated with scratching. This can lead to the “itch-scratch cycle” which is extremely destructive to the skin and worsens the symptoms of AD. Recent studies have shown that two different types of nerves become activated in the brain when a person itches and scratches their skin – the gamma-aminobutyric acid (GABA) nerves and the dopaminergic (DA) nerves.6 The GABA neurons are what causes the brain to process the disturbed feeling associated with itch and the DA neurons mediate the pleasure feeling associated with scratching. The DA neurons only become activated after scratching, meaning that if a person who feels itch does not scratch, only the unpleasant feelings of itch will be perceived. Inhibiting the activation of the DA nerves resulted in reduced scratching behavior in mice, suggesting that blocking these nerves therapeutically could reduce the itch-scratch cycle. Blocking the GABA nerves could also reduce the unpleasant sensations associated with itch and reduce the desire to scratch.6
Keratinocytes are also an active part of the immune system; they have the ability to release signaling molecules that talk to other immune cells and nerves. It has long been known that AD is caused by a defective skin barrier and an amplified immune reaction that is impacted by genetics, the environment and the specific types of immune cells that become activated7,8, but keratinocytes play a direct role in itch, too. Keratinocytes secrete active proteins called enzymes, specifically kallikreins (KLK) that cut up other proteins. Under normal conditions in healthy skin the KLKs act to cause the top layer of skin to slough off, so that the skin does not get too thick. However certain kallikreins, specifically KLK7, KLK8, KLK10 and KLK11 are upregulated in wounded skin in AD8, and with increased activation of these KLKs there is too much cell-sloughing and the barrier becomes reduced.
Interestingly, in a mouse model of AD that lacks expression of KLK7, the mice still get AD and have an enhanced immune reaction, but these animals have a markedly reduced scratching response. KLK7 itself was found to activate nerves implicated in itch without involvement of the immune system.8 Dr. Kim was an author on this study and said, “The reduction in itchiness in these mice was really striking, but we still do not know what exactly KLK7 is doing. We are excited to continue this research because pharmaceutical companies have been very interested and want to find ways to selectively block KLK7 to reduce itch.”
The skin’s main function is to protect the internal body from external insults. Dr. Ethan Lerner of Massachusetts General Hospital believes that the sensation of itch is a switch to turn on the immune system, leading to protection against foreign materials and pathogens from entering the skin. He said, “Scratching is pleasurable because it is the body’s way to activate the immune system.” Interactions between nerves and different types of immune cells have been shown to be involved in itch in AD.9 Neurons actively participate in recruitment and activation of immune cells by releasing chemical messengers called neuropeptides and chemokines.5 Conversely, immune cells release many signals that activate nerves to carry the feeling of itch to the spinal cord and brain.5 The interleukin IL-31, first discovered in 2004, is the cytokine most directly implicated in mediating itch. IL-31 is released by many types of immune cells including T cells, mast cells, macrophages, basophils, eosinophils and dendritic cells. Keratinocytes release IL-31, further showing how keratinocytes are part of the immune system. Blocking antibodies to IL-31 or its receptor rapidly decreased itch in mice, dogs and humans.5 Keratinocytes can also release interleukins and messengers called IL-33, IL-25, and thymic stromal lymphopoietin (TSLP), all of which activate the itch interleukins (IL-4, IL-13, and IL-31) which can then act on nerve fibers to induce itch.2,10
Exciting recent work has shown some major differences in how the immune system reacts in an acute AD flare, which is often caused by exposure to an allergen, compared to the chronic itch associated with AD. There are more immune cells called basophils circulating in the blood and localized in the skin tissue of AD patients when compared to healthy subjects.11 Basophils localize along nerve endings in skin to transmit itch signals. In AD patients, there is a subset of basophils that express high levels of the receptor to IgE, which is a signaling molecule that activates cells with high levels of the IgE receptor to release more cytokines. These basophils are primed and ready to activate the rest of the immune cells and nerves when exposed to an allergen, leading to AD flares. Basophils that have been triggered during an allergic response release a chemical called leukotriene that is involved in itch during flares.11 Researchers now understand that, in general, acute flares are mediated by cross-talk between basophils and neurons, while chronic itch is mediated by cells that release TSLP, IL-4, IL-13 and IL-31 to activate neurons.12
Many avenues are being used and explored to treat itch specifically in addition to treating AD as a whole. Topical emollients are used to manage dry skin, yet a study surveying 98 AD patients also found that for 83% of respondents, emollient treatment was also effective against itch , primarily for mild AD.13 There are topical anti-itch and anti-inflammatory treatments such as crisaborole, an anti-inflammatory product which was shown in clinical trials to reduce itch within eight days of initiating treatment.14 Topical Janus Kinase (JAK) inhibitors such as ruxolitinib, have also been shown in clinical trials to quickly reduce itchin mild to moderate AD.14 Medicinal coal tar, soybean tar, or a newly developed agent called tapinarof all block a receptor called the dioxin receptor leading to decreased pro-inflammatory cytokines and increased the skin barrier.14 Topical steroids can also reduce itch.15
Systemic therapies that target different immune cytokine pathways, such as dupilumab which targets the receptors for IL-4, blocking signaling from both IL-4 and IL-13, showed improvement in inflammation and reduced itching.13 Other IL-13 targeting monoclonal antibody-based biologics being developed such as tralokinumab and lebrikizumab also show promise for reducing itch.14 Blocking the ‘itch cytokine’ IL-31 with the biologic nemolizumab has also been shown to greatly reduce itch in clinical trials. Due to the complexity of itch it has been suggested that targeting several interleukins with combination therapy could have the greatest effect of reducing inflammation as well as itch.14 Oral JAK inhibitors, such as abrocitinib, baricitinib, and upadacitinib, that block one or more members of a signaling pathway for multiple cytokines, have also demonstrated in clinical trials the ability to reduce itch within a few days of initial treatment.14
Targeting basophils in various ways could also be a potential therapeutic approach to reducing acute flares in AD. Dr. Kim said, “Leukotriene inhibition may be a good pathway to target. Depleting basophils could improve both itch flares and food allergy.” Dr. Kim also encouraged therapeutically approaching acute vs. chronic itch differently since different cells and signals are involved.
Psychological interventions have also been associated with reduced itch and scratching in AD patients. Educating patients on the origins of itch and then providing them with coping strategies and habit-reversal techniques resulted in significantly less itch and scratching. Muscle relaxation and mindfulness training also had positive effects on reducing itch and scratching behavior.16 Interestingly, several researchers are working on the concept that the placebo effect of drug treatments can have a positive impact on itch/scratching behavior. A meta-analysis of itch-associated endpoints in clinical trials with patients treated with control formulations rather than the drugs themselves found that placebo treatment significantly reduced itch.17 Itch is highly susceptible to suggestion, so setting up a patient’s expectations and the context can impact brain regions that regulate itch, thereby resulting in the placebo working to reduce itch.17
Several Centers for the Study of Itch have arisen around the United States and in other countries, including one in St. Louis co-directed by Dr. Kim and one in Miami directed by Dr. Yosipovitch. The centers are dedicated to diagnosis, management and study of itch conditions including AD. Dr. Kim said, “I feel really lucky to be working in this field at this time. There is now a critical mass of scientists dedicated to studying itch and the level of rigor required for publishing is very high. The itch center is amazing and we are beginning to convince investors and regulatory agents that working on itch is really important.” The coming years will be exciting as new knowledge comes to light about the cross-talk between the skin, immune system, nerves and brain in regulating itch and how various therapeutics can target these different systems.
Relief for the most burdensome symptom of AD may finally be on the horizon.
Take Home Points:
Glossary of Terms
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