The Bleeding Edge of Itch Research

Scientists have been scratching at the familiar, annoying phenomenon long enough now to produce a new crop of promising itch drugs.

Scratching an itch can be extremely satisfying—even pleasurable—but persistent, long-term itching makes millions of people miserable. Scientifically, the question of what causes us to itch has left scientists scratching their heads for centuries.  

That’s ironic, given that the first medical definition of itch came in 1660, when the German physician Samuel Haffenreffer described it as “an uncomfortable sensation that provokes a desire to scratch.” He was spot on, and that remains the best definition to this day. But despite Haffenreffer’s early clarity, our understanding of itch progressed very little in the centuries since. 

Itch was historically associated with a lack of personal hygiene or, worse, insanity, and therefore largely ignored or dismissed in the early days of medicine. And even over the last century, as we have gotten better at diagnosing the infections, skin conditions, or nerve damage that can cause it, itchiness has not gotten the attention it deserves.

Now things are changing. Some researchers have begun to consider itch to be a disease in its own right, rather than just a symptom. And recent progress in neuroscience coupled with a strong interest in the pharmaceutical industry over the past 10 years has led to major advances in our understanding of the science of itch. A handful of itch therapeutics have already been approved for use by the U.S. Food and Drug Administration (FDA), and there are a dozen or so more in the pipeline, which offers some hope (and relief) to people who suffer. 

Rethinking the itch

Whereas pain alerts us to potentially life-threatening injuries, itch, and the scratching that it induces, likely evolved as a defence mechanism against disease-carrying insects, plant toxins, and other noxious environmental substances. But it can become pathological, and when it does, those experiencing it can become miserable. Chronic itch can cause prolonged loss of sleep and lead to the development of symptoms of depression. It can, therefore, be extremely debilitating, and can have a negative impact on quality of life comparable to that of chronic pain. Chronic itch, defined as itching that persists for more than 6 weeks, is estimated to affect up to 15% of the population. And so this niggling sensation represents a huge unmet clinical need. 

“Compared to pain, itch is understudied.”

“Compared to pain, itch is understudied,” says Hoghzan Hu of the Center for the Study of Itch and Sensory Disorders at the Washington University School of Medicine in St. Louis. “We have so many patients and family members asking questions that we don’t know how to answer. We have painkillers but we still don’t have itch killers.”

Until very recently, itch was widely considered to be just a mild form of pain. The two sensations do indeed have much in common, but there are important differences between them. Both are detected and transmitted by peripheral neurons called C-fibers, which have cell bodies located just behind the spinal cord. These cells possess a single, small diameter fiber that splits into two branches soon after emanating from the cell body, with one branch projecting out towards the skin surface, and the other entering the back of the spinal cord, where it connects to a secondary cell that projects up to the brain. 

In 1997, a team of researchers in Germany and Sweden reported the discovery of C-fibers in human skin that appeared to be specific for itch, and to respond to histamine, the “classic” itch molecule, with sustained activity. Fifteen years later, researchers at Johns Hopkins University School of Medicine identified a subpopulation of pain-sensing cells specifically linked to itch, and subsequent research has identified cell surface receptors that are specific for other itch molecules.  

The distinction between itch and pain is blurry, however. The discovery of C-fibers activated by histamine suggested that itch has its own dedicated sensory pathway, but itching is often accompanied by painful burning, tingling, or stinging sensations, and itch-sensitive C-fibers (or pruriceptors) also express certain pain-sensing membrane proteins, so some of them may transmit both pain and itch signals. Thus, itch researchers are entertaining two hypotheses, one stating that there are C-fibers dedicated to itch alone, the other that the intensity of C-fiber activity is key, such that weaker or stronger activation of C-fibers causes itch or pain, respectively.   

Itching involves crosstalk between the nervous and immune systems, with molecules called cytokines being key players in the process. Cytokines are a diverse family of small proteins that function as signaling molecules. In the skin, they are secreted by mast cells and Langerhans cells, which are closely associated with sensory nerve endings. Interleukin-31, discovered in 2004, was one of the first cytokines shown to trigger itching by acting directly on C-fibers. Mice genetically engineered to overproduce interleukin-31 develop immune-triggered hair loss and severe itching that results in skin lesions due to excessive scratching. A study published last year shows that a cytokine called oncostatin M can sensitize itch-sensitive C-fibers.

“Itch is very complex,” says Hu. “It’s like a railway, with cells at different levels from the skin, to your spinal cord, then to your cortex, and problems anywhere can cause itch. Skin alone contains so many different components, including keratinocytes [skin cells], numerous immune cells, and small diameter and large diameter sensory fibers.” 

In their own work, Hu and his colleagues have identified skin cells called Merkel cells      (which typically respond to light touch) as key players in age-related chronic itch. In 2018, they reported that Merkel cells send fast signals via large diameter nerve fibers into the spinal cord to inhibit itch sensations. Their latest findings, published in July 2022, show that pruriceptors reorient their nerve endings towards Merkel cells to drive itching.

“In [age-related] dry skin conditions, losing this inhibition promotes itch,” says Hu, “and not only have you lost this inhibitory component, but you also change the connections between Merkel cells and C-fibers. Normally there’s no connection, but in the inflammatory state, the C-fiber grows towards the Merkel cells, forming a synapse-like structure.”   

Hu adds that these surprising new findings put Merkel cells on the map as key players in age-related itch. “Nobody ever thought that a touch spot could become an itch spot.” 

Drugging the itch     

The new understanding of itch biology points to several different treatment strategies, and there is already some progress on this front. One approach is to use antibodies to neutralize the cytokines that activate itch receptors. Eli Lilly’s lebrikizumab, for example, is an antibody that binds to interleukin-13. It was developed as an experimental immunosuppressant for the treatment of asthma, in which it is associated with improved lung function. Last year, Lilly announced the results of a third phase 3 study showing that the drug also demonstrates significant skin improvement and itch relief in people with moderate to severe eczema when combined with corticosteroid creams.

Another approach is to block cytokine receptors with antibodies. In 2015, researchers in Japan published results from the first trial of CIM331, an antibody that binds to the human interleukin-31 receptor, reporting that a single injected dose was safe and well tolerated in healthy volunteers, and also reduced itching in a small number of patients with eczema. These results were subsequently replicated in a larger and longer phase 2 trial

Sanofi’s dupilumab is another human monoclonal antibody that binds to the interleukin-4 receptor and inhibits signaling by interleukin-4 and interleukin-13. Already approved for the treatment of moderate to severe eczema in adults, dupilumab has just received FDA approval for use in children 6 months to 5 years old, and the company claims it is currently “the first and only biologic medicine approved to treat moderate to severe [eczema] from infancy to adulthood.” It has also just been accepted for priority review in adults with prurigo nodularis, a chronic inflammatory skin disease that causes the formation of hard itchy lumps, most commonly on the arms, legs, upper back, and abdomen.  

Besides targeting the pro-itch cytokines and blocking their receptors with antibodies, there are drugs that inhibit the “downstream” biochemical pathways activated by those itch receptors. Abrocitinib, a small molecule which was developed by Pfizer and has just been approved by the FDA as a treatment for eczema, works in this way. It binds to and inhibits an intracellular enzyme called JAK1 kinase.

Eczema is one of the most common itch conditions, affecting nearly 32 million in the U.S., or approximately 10% of the country’s population. It is also one of the best understood, and is known to occur when the immune system overreacts to allergens or irritants, leading to dry, inflamed, and itchy skin. “Eczema is a model to understand itching,” says Brian Kim, director of the Mark Lebwohl Center for Neuroinflammation and Sensation at the Icahn School of Medicine in New York. “It’s a classic rash that itches with a straightforward, causal sequence of events. If you get rid of the inflammation the itch goes away.” 

Itch drugs in the pipeline

The head game

Popular culture has long imbued itchiness as a psychological metaphor with bold—even desirable—traits, like wanderlust or a strong sexual appetite. But the truth is much darker. Itch does have a strong psychological component, and it sometimes occurs in the apparent absence of a physical cause, while still being highly debilitating. For example, people with delusional parasitosis hold the false, unshakable belief that they are infested with insects or parasites. This leads them to scratch and pick at their skin incessantly or, in the most severe cases, use pesticides as a treatment or even mutilate themselves. 

“Patients will come in with a zip locked bag containing lint, hairs, and other regular household items, saying they pulled them out of their skin,” says Kim. “We’ve even recorded patients scratching throughout the night while they sleep. It’s so stereotyped that I’m convinced something is happening in the brain.”

“If we can better understand itch we may better understand conditions like heartburn, migraine, fibromyalgia, and irritable bowel syndrome.”

Some dermatologists and psychiatrists believe that Morgellons disease, which superstar folk singer Joni Mitchell says she suffers from, is actually a form of delusional parasitosis. There is, however, some evidence to suggest that Morgellons is in fact a reaction to Borrelia burgdorferi, the same bacterium that causes Lyme disease.

As recently as 10 years ago, Kim says, the prevailing view among clinicians was that itch is one symptom and that every disease that causes itch would in time be treated in the same way. The reality is far more complicated, however. Some conditions may involve overlapping itch-causing mechanisms that can be treated with the same methods, but many others are likely to have unique underlying causes that require specialized, targeted treatments. 

“If you have an allergy, the mast cells kick in, but inflammatory itch is completely different,” Hu says. “Now that we have a bigger picture, we can pinpoint which cells and molecules are important for each type of itch, and what can be targeted.” 

But there’s still a long way to go, he says. “Chronic itch is a severe and debilitating disease for many people, and we need more scientists working on this and more resources to improve their quality of life.”

Further research will surely provide a deeper understanding of itch biology, which may point to newer, as yet unknown strategies for developing itch treatments. And advances in our understanding of itch may also help clinicians to see a wide variety of other poorly understood ailments in a new light. “I’m starting to believe that a lot of things which were classically defined as pain may actually be more akin to itch,” says Kim. “It may be a scientific paradigm for irritability, and if we can better understand itch, we may better understand conditions like heartburn, migraine, fibromyalgia, and irritable bowel syndrome.”

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