The Pathophysiology of Itch and Upcoming Therapeutics

Itch is a top patient-reported symptom that dermatologists encounter daily. However, a tough itch patient often elicits uncertainty, anxiety, and trepidation among us. This is no fault of our own—until recently there have been very few options available and, in many cases, the evidence for these therapies is limited to case reports and uncontrolled studies. We were taught to prescribe antihistamines, but nonsedating antihistamines have little efficacy outside of chronic urticaria and do not target the underlying pathophysiology of itch for most conditions. Although sedating antihistamines may provide transient relief of itch in some patients, mostly via sedation, there are reports that long-term use of anticholinergic drugs, such as diphenhydramine or even 10 mg of doxepin nightly, is associated with an increased risk of dementia.¹ Other off-label agents prescribed, such as cyclosporine, prednisone, or intramuscular steroids, also have unfavorable safety profiles, and neuromodulating agents, such as antidepressants, gabapentin, and naltrexone, have limited evidence and sedative effects.

During every itch clinic that I have, I ask myself if I have a good reason for picking whichever therapy I choose. What is truly driving the patient’s itch and which one of the many therapies is best for them? Now, with a flurry of studies recently completed or ongoing, we are amid a paradigm shift in our understanding of the pathophysiology of itch. This change in our approach has been largely driven by an unprecedented pipeline of antipruritic therapies at the bedside. Here we will touch on new paradigms in itch pathophysiology and discuss recently approved and upcoming therapeutics.

Itch Pathophysiology
Itch sensation is transmitted at the skin interface by unmyelinated type C and thinly myelinated A  cutaneous nerve fibers.² The cell bodies of these nerves reside in the dorsal root ganglion and synapse at the spinal cord before relaying the itch message to the brain. As demonstrated in Figure 1, there is crosstalk between immune mediators involving various cytokines, such as IL-4, IL-13, and IL-31, and neural mediators, such as substance P and mu/kappa opioids, which are involved in itch transmission.

Because there are a variety of new agents attempting to modulate many of these targets, we need to understand what separates different forms of itch in human chronic pruritic diseases. Itch was previously categorized as being on immune, neuropathic, and systemic disease spectrums that were thought to have distinct and unique etiologies (Figure 2). With recent research, the precision medicine movement is starting to better understand human itch subtypes.

Here are a few examples of human itch subtyping, which is transforming our understanding of the pathophysiology and management of chronic itch:

• Chronic pruritus of unknown origin (CPUO) is an umbrellaterm that lacks standardized nomenclature and a uniform understanding of diagnosis and management. CPUO was recently found to have varying endotypes that are more biased toward immune- or neural-biased etiologies. Patients who have increased blood eosinophils, and often increased IgE, are more likely to respond to immunomodulator therapy, such as methotrexate or off -label dupilumab, than patients who do not have upregulation of type 2 inflammation. Patients without upregulation of type 2 inflammation may be more likely to respond to neurally targeted therapies such as gabapentin.³ Some cases of patients with CPUO are generalized neuropathic pruritus, which is indistinguishable from immunosenescent forms of itch with prominent type 2 inflammation. Research on biomarkers is ongoing to predict the relative contribution of immune and neural dysregulation in itch responses.

• Prurigo nodularis (PN) is a pruritic inflammatory skin disease with hyperkeratotic, itchy nodules on the trunk and extremities. The pathogenesis of PN varies on the neuroimmune spectrum, with endotypes that have greater blood inflammation or neural etiologies, such as spinal disc disease and myelopathy.⁴ Additionally, recent studies show unique endotypes of patients with PN who have upregulated or normal plasma levels of IL-13.⁵

• There are also subsets of patients with systemic and neuropathic etiologies of pruritus that respond to treatment with dupilumab.^6,7

These findings highlight the need for further phenotyping of human chronic pruritic diseases to better personalize antipruritic therapies. Since dupilumab was approved in 2017, it has been used both on and off label, transforming the management of atopic dermatitis (AD) and many other pruritic conditions. Successful cases and ongoing trials with dupilumab are reported frequently in a variety of chronic pruritic conditions, from PN to chronic spontaneous urticaria and CPUO, demonstrating the powerful role of the antipruritic effects of type 2 inflammation in human itch conditions.

Recently Approved Antipruritic Therapies

The translational revolution of itch therapeutics has a heavy focus on modulating type 2 inflammation but now also spans to many novel immune and neurally targeted mechanisms of action. Recently approved antipruritic therapies include:

• Abrocitinib (100 mg- and 200-mg doses) and upadacitinib (15-mg and 30-mg doses) are selective oral Janus-kinase (JAK) 1 inhibitors recently approved for AD that rapidly reduce pruritus within days. A welcome oral addition to the therapeutic armamentarium for chronic itch, these agents are more targeted than traditional oral therapies for AD, such as methotrexate, cyclosporine, or steroids, while also allowing for rapid itch control.^8,9

• Ruxolitinib 1.5% topical cream contains a selective inhibitor of JAK1 and JAK2 and is approved for AD.¹⁰ It results in rapid and sustained itch relief via the blockade of several itch causing cytokines, such as IL-4, IL-13, and IL-31, that are also present on sensory nerves. Interestingly, ruxolitinib 1.5% cream has a faster onset and greater sustained antipruritic and inflammatory relief compared with a dermatology mainstay, triamcinolone 0.1% cream, without the risk of local atrophy and hypopigmentation.¹¹

• Tapinarof 1% topical cream contains a novel aryl hydrocarbon receptor (AhR) agonist that was recently approved for the treatment of plaque psoriasis and is also undergoing phase 3 trials in AD, with positive phase 2b studies.^12,13 AhR agonism reduces IL-17, has inhibitor activity on IL-4/13-mediated STAT6 activation, and may have a longer term remittive effect via depletion of tissue resident memory T cells.^14,15

• Tralokinumab is a fully human monoclonal antibody administered via subcutaneous injection that neutralizes IL-13 and is approved for the treatment of AD. Tralokinumab has significant effects on itch intensity, with 20% and 25% of patients experiencing a daily 4-point or greater drop in itch intensity on the pruritus numerical rating scale compared with 10.3% and 9.5% patients in the placebo groups, respectively (data from ECZTRA 1 and ECZTRA 2 phase 3 studies).¹⁶

• Intravenous difelikefalin is a selective agonist of kappa opioid receptors that was recently approved for relieving itch in patients with chronic kidney disease-associated pruritus. In phase 3 trials, patients received injections of difelikefalin at the end of hemodialysis sessions 3 times per week.¹⁷

• Roflumilast 0.3% topical cream contains a novel phosphodiesterase-4 inhibitor (PDE-4) and is now approved for plaque psoriasis in patients aged 12 and older. In studies to date, roflumilast has shown early onset of itch relief.¹⁸ PDE-4 is able to inhibit immune responses from Th1, Th2, and Th17 pathways, suggesting a broader antipruritic and anti-inflammatory effect among multiple inflammatory skin diseases.¹⁹

Upcoming Antipruritic Therapeutics

Antipruritic therapies in development include:

• Nemolizumab is a monoclonal antibody in development for AD and PN that targets the IL-31 receptor, which is involved in the pathogenesis of chronic itch in a variety of conditions. IL-31 is thought to be one of the “master itch cytokines,” with expression in human dorsal root ganglions and on the neuroimmune interface. In a phase 2 trial of nemolizumab in PN, patients experienced a 53.6% reduction in itch intensity by week 8, with an antipruritic response remaining even at 10 weeks off treatment.²⁰

• Lebrikizumab is a monoclonal antibody that targets IL-13 with significant antipruritic activity. Eblasakimab is also a novel monoclonal antibody that targets the IL-13 receptor α1 subunit. OX40 is a costimulatory molecule expressed on activated effector T and memory T cells that promotes type 2 inflammatory responses.²¹ There are several agents in early development, with a potential for longer lasting itch relief being explored in large-scaled studies.

• Oral difelikefalin is a kappa opioid receptor agonist being studied for pruritus in notalgia paresthetica, AD, and chronic liver disease-associated pruritus. Nalbuphine extended release is a mixed mu opioid receptor antagonist and kappa opioid receptor agonist being investigated for pruritus associated with chronic liver/kidney disease and PN. This is a similar mixed opioid antagonist/agonist mechanism to butorphanol nasal spray, which is used for severe pain but can also relieve severe forms of intractable itch as a rescue therapy.²² This therapy has potent central nervous system activity, with accompanying risks of sedation, dizziness, and confusion, as well as abuse and addiction.

Conclusion
There are a variety of therapies becoming available for our patients with chronic itch. Although inflammatory itch is now largely treatable, there is a major need for targeted, safe therapies for neuropathic itch, which remains one of the great unmet needs in pruritus clinical management.