A Chronic Itch: Burrowing Beneath the Skin

ABOVE: © ISTOCK.COM, Rungrudee

When John (patient name changed for privacy) visited our clinic in 2019, he had been driving for five hours straight. A retired widower, John had been looking forward to relaxing in his golden years. Instead, he had spent the past two years scratching himself day and night, unable to sleep and losing his mind. John tried everything; he visited eight physicians and underwent numerous lab tests. But at the end of it all, doctors were left scratching their heads, and John, his body. 

When he read about our work on the internet, John sought our help right away. While describing his symptoms, John mentioned that his belly button was particularly itchy. Scabies like to hide in crevices such as the groin, armpits, and navel, so this was our big clue. We scraped his skin, observed it under a microscope, and there it was: a scabies mite that caused the unbearable itch. When we informed John about the diagnosis and that he would be relieved of his misery soon with a simple antiparasitic, he wept with relief. He informed us that we were literally his last hope; he had reached a breaking point where he had considered ending his life if we weren’t able to help him.  That day, John became one of the lucky few whose itch was easily treatable. For many, there is no relief. 

One thing is clear: we have only scratched the surface of the vast itch biology and neuroimmunology.

 —B­­rian Kim, Mount Sinai

For most people, an itch caused by a mosquito bite or exposure to poison ivy fortunately causes temporary suffering. However, approximately 20% of people suffer from chronic itch, which is medically defined as an itch lasting greater than six weeks. In some cases, a chronic itch can last for years.¹ 

Chronic itching is one of the most common symptoms in medicine. It is not only associated with dermatologic disorders such as eczema, hives, and psoriasis, but also with other medical conditions including chronic kidney disease, liver failure, and lymphoma. In most of these cases, some inflammatory or metabolic irritant stimulates itch nerves repeatedly. In other cases, an itch may arise from the nerves spontaneously and result in persistent rubbing, scratching, and picking. Itch has historically been one of the most overlooked medical symptoms, reflected in the limited available treatment options, most of which have only been discovered recently.²

Itch is not pain

The science underlying itching largely lagged behind due to a perfect storm of biased definitions, concepts, and perceptions. Pain, for example, is defined as physical suffering or discomfort caused by illness or injury, which conjures immediate medical connotations. In contrast, itch is defined as an uncomfortable sensation on the skin that causes a desire to scratch. In other words, it’s a mere nuisance. 

Scientific misinterpretation is also partly to blame. In 1896, the pioneering neuroscientist Max Von Frey from the Carl Ludwig Institute of Physiology observed, “It is possible to stimulate the skin in such a way as to produce a painful sensation with no preceding or accompanying pressure sensation.” He concluded that pain has its own dedicated pathways. 

         

In 1922, Von Frey came to a different conclusion about itch. Upon inducing pain in the skin with tiny spicules, he observed an itchy aftersensation. In this case, he concluded that itch is not a separate sensory modality, but rather, a mild form of pain.³ This prevailing but misguided conception of itch made researchers believe that if we simply understood pain better, we would solve the problem of itch. 

Itch is linked to social stigma due to its association with infestations such as scabies, body lice, and bed bugs. Further, people misconstrue scratching as compulsive behavior due to psychiatric illness.⁴ So, we avoid itchy people, and patients are ashamed to disclose their conditions.  

Is our social aversion to itch learned or instinctual? When researchers studied mice, they observed that pain evokes empathic consolation behavior, manifesting as licking or grooming to alleviate the suffering of the mouse in pain.^5-7 In our experiments, we observed that a mouse witnessing another mouse itch moves away from the itchy mouse. It appears that mice approach other mice in pain but avoid those that itch.  Drawing parallels, this means that humans may instinctively struggle with demonstrating empathic behavior towards individuals with chronic itch, independent of social constructs, thereby isolating the sufferer. 

An itch can be ignored, but should it?   

Patients with genetic errors in proteins responsible for pain often suffer catastrophic injuries resulting in loss of limb or life.⁸ Why have similar population genetic studies not revealed mutations responsible for itch? 

Itching is not critical for survival in the same way as pain. Few studies have reported that mutations that trigger itching result in patients itching spontaneously.^9-10 But ultimately, since we do not diagnose and treat itch widely, it is easy to miss associations in population studies. 

Evolution has not prioritized itching either. The five senses include sight, hearing, smell, taste, and touch. An itch may be mistaken as a form of touch, but researchers have found that the pathways that mediate touch differ from those that relay itch to the brain. While sensory stimuli are hard to ignore, we can suppress an itch temporarily. For instance,  patients can suppress an eczema-associated itch by eliciting pain to such an extent that they become anesthetized to the pain itself. In fact, patients will do almost anything to relieve their itch, including scratching, rubbing, picking, scraping, using hair dryers on high heat, and applying ice packs.  How does itch suppression work? 

Different kinds of sensory nerve fibers relay signals from the skin to the spinal cord where a series of interneurons, or connector neurons, are activated. From there, projection neurons send a signal to the brain where touch, heat, cold, pain, and itch can be perceived. However, there are inhibitory spinal interneurons as well. The idea that spinal nerves control which signals will be transmitted to the brain underlies the gate control theory, which was first defined in the context of pain. This theory asserts that nonpainful stimuli can suppress pain by closing the “gates” from the pain nerve fibers that carry painful input to the spinal cord.¹¹ Simply put, the brain can send signals to the spinal cord to suppress incoming pain signals.¹⁴ 

A classic example is soldiers in battle who do not feel pain when under extreme stress. Similar pathways appear to exist for itch.^15-19 Extreme mechanical, thermal, or even pain sensations can suppress an itch.^12-13 The brain itself can also suppress an itch. Many patients report that if they are highly focused on something, they can ignore their itch. Conversely, they find itching is more common at bedtime when they are less distracted by activities. There seems to be an evolutionary hierarchy among sensations, and itch is likely at the bottom. Of course, in severe forms, we lose our ability to mentally tune itch out, and that’s when the suffering becomes unbearable.

     

Neuroimmunology brought itch and therapies to the forefront  

The discovery of a series of itch-specific receptors extending from the peripheral nervous system into the spinal cord brought itch research to the forefront. These receptors are specific for itch perception, and the nerves that house them convey pain to some degree as well.^20-22 The studies that uncovered these receptors advanced the notion that itch is specific, mediated by unique pathways, and therefore is tractable for therapeutic development.

Somewhat ironically, advances in immunology rather than neurobiology inadvertently led to the most effective therapies for itch. The work from our lab and many others revealed how several inflammatory cytokines such as interleukin (IL)-4, IL-13, IL-31, IL-33, oncostatin M, and thymic stromal lymphopoietin can act like neurotransmitters on sensory neurons to promote itch.^23-28 Additionally, downstream molecules such as Janus kinases (JAKs) that relay cytokine signals classically associated with immune cells have also informed therapeutic design of anti-itch agents with the nerve as a major target. 

These findings inspired the term neuroimmunology, underscoring the increasingly blurry distinction between neurons and immune cells. Importantly, multiple therapeutics targeting these pathways in the setting of itch for conditions like atopic dermatitis, chronic spontaneous urticaria, and prurigo nodularis are now FDA-approved or are in late-stage development.^29-30 There are many more itch disorders with limited effective treatments including chronic kidney disease, liver disease, and neuropathic itch. Whether this paradigm of neuroimmunology extends to the vast array of unmet chronic itch conditions remains to be seen. 

     

An itch has emerged as an important medical paradigm that may inform of physiologies and diseases extending beyond the skin. Sensory neurons that have itch machinery are much more extensive than we previously appreciated. For example, many molecules associated with itch can be found within the vagus nerve,³¹ which regulates heart rate, breathing rate, digestion, and can sense a variety of signals from the associated organs. Such sensations may include discomfort related to irritation leading to coughing, esophageal reflux, or even nausea. In other words, itch biology provides a new and dynamic blueprint to view many unmet sensory maladies. 

Itching is more than just sensing external stimuli. For example, our team has found that molecules like JAK1 within neurons act as an internal sensor of inflammation across multiple organs.³² Also, sensory nerves directly incite or tame regulation in various tissues. This means that an itch can help us understand how our bodies process inflammation and a variety of internal stimuli, a start to a new approach in medicine.  

The fact that sensory neurons may play a previously unrecognized role in these different settings widens the scope of how and what we sense both outside and inside the body. In the future, could we treat autoimmunity via the vagus nerve?^33-34 Is modulation of skin nerves a way to alleviate irritable bowel syndrome? Is pain not simply a symptom, but driving cancer progression via the nerves?  These provocative questions could be foundations for new ways to treat many medical disorders in the future. 

One thing is clear: we have only scratched the surface of the vast itch biology and neuroimmunology.

Brian Kim is a physician-scientist and neuroimmunologist at the Icahn School of Medicine at Mount Sinai. His research focuses on the biological mechanisms of skin inflammation and itch sensation.

This article has been updated to fix a typo