Jay M. Patel, BSc1 and Harry Dao Jr., MD, FAAD2
1Department of Neuroscience and Medical Scientist Training Program, Baylor College of Medicine, Houston, TX, USA
2Department of Dermatology, Baylor College of Medicine, Houston, TX, USA
Conflict of interest:
The authors have no conflicts to disclose.
Chronic pruritus remains a difficult condition to treat with many non-specific therapeutic options. Recent scientific discoveries have elucidated the physiology associated with pruritus. Combined with clinical and experimental trials with immune-modulatory agents, chronic pruritus now has novel treatment options with known mechanisms of action. This review goes over recent scientific progress in understanding the molecular mechanisms governing pruritus, the cross-talk between the immune and nervous systems that regulate itch, and central nervous pathways and projections affected by itch. In light of these recent discoveries, we briefly discuss a growing body of data from relevant clinical trials investigating immunomodulatory drugs targeting specific interleukin receptors (IL-4/13/31) and intracellular signaling (e.g., Janus kinase) pathways. We focus on the physiological processes that control this complex physical and emotional experience, as well as the role of newer drugs used to treat chronic itch.
chronic pruritus, neuro-immune interaction, dorsal root ganglion, IL-4, IL-13, IL-31, IL-4Ra, dupilumab, ruxolitinib, tofacitinib, nemolizumab, Janus kinase
Chronic pruritus (CP) is a debilitating condition defined as itch lasting longer than 6 weeks.1 Causes of CP include both dermatologic and non-dermatologic diseases leading to involvement of the entire body (generalized) or specific areas (localized).1 Treatment methods are often trial-error based in order to determine an optimal regimen to reduce symptoms. Generally, CP can be divided into broad categories of origin: dermatologic (e.g., atopic dermatitis and psoriasis), systemic (e.g., chronic kidney disease and cholestasis), neuropathic (e.g., post-herpetic itch), or psychogenic (e.g., obsessive-compulsive disorder and drug use).2 Importantly, non-dermatologic causes can also present with skin findings due to the itch-scratch cycles and, therefore, can be masked by dermatitis. While CP is often a feature of inflammatory skin diseases, it can also stem from idiopathic causes, which are not marked by inflammatory processes.3 Thus, the mechanisms of CP are multifaceted and numerous activating mediators of itch are known, including histamine and substance P.4 Ultimately, the physiology of itch sensation results in the activation of peripheral sensory neurons.
Neuronal Physiology of Itch
The sensation of itch is initially transmitted through unmyelinated C-nerve fibers in the dermis and epidermis.5 These nerve fibers can be activated by numerous molecules including those involved in acute itch sensation, such as substance P, proteinases, and histamine. Although antihistamines are effective in reducing itch from mast cell degranulation, they have little to no effect in CP.6 Additionally, not all C-nerve fibers that transmit itch are histamine responsive.7 Specifically, the only group of neurons that have thus far been identified as required for itch transmission are those expressing gastrin-releasing peptide receptor (GRPR).8
Recent work identified the central nervous system circuits that GRPR neurons utilize to transmit itch sensation to the brain in a mouse model.9 By utilizing retrograde neuronal labeling in combination with immediate early gene expression (c-fos) after inducing itch, Mu et al. identified the spinoparabrachial pathway to be activated by pruritus.9 Additionally, they identified direct monosynaptic connections between GRPR sensory neurons and projection neurons from the spinal cord to the parabrachial nucleus (PBN).9 Further, inhibition of these projections resulted in diminished scratching when mice were treated with histamine.9 Remaining work by Mu et al. focused on the PBN, a region of the brain stem implicated in arousal, thermoregulation, taste, and now itch.10-12
The researchers identified that neurons in the PBN are activated by itch, and that modulation of these neurons could alter itch-induced scratching when administering pruritogens like histamine or chloroquine to mice.9 They also discovered that glutamatergic signaling in the PBN was required for itchinduced scratching.9 Genetic deletion of the vesicular glutamate transporter resulting in an inability to release glutamate by PBN neurons resulted in the loss of itch-induced scratching for six different pruritogens including the 1-fluoro-2,4-dinitrobenzene (DNFB) induced chronic itch model.9 Overall, this work identified the PBN as a key relay station for the central nervous system processing of itch and, moreover, elucidated a necessary role for local glutamatergic signaling for itch-induced scratching for both acute and chronic pruritus models. Understanding the neuronal circuit of itch aids in clarifying the physiology of non-dermatologic causes of itch and begins to uncover novel target cell-types for treatments. Future experiments should focus on the genetic expression pattern of these neurons to identify drug targets to modulate the neuronal activity of these itch-sensing neurons. Although brain region specific alteration of neurotransmission is not currently a viable option for the treatment of pruritus, novel therapies targeting the neuroimmune interaction have begun to be utilized in the treatment of CP.13-17
One of the most common causes of CP is atopic dermatitis (AD) and the role of the immune system, particularly driven by type 2 T helper (Th2) cellular responses and cytokines. Specifically, interleukin (IL)-31 has been identified as a potent pruritogen, and IL-4 and IL-13 drive skin inflammation leading to AD like features and itch.18,19 Work in the past year from Oetjen and colleagues has furthered our understanding of how these interleukins act specifically on neurons and co-opt downstream signaling mechanisms to mediate itch.3
Oetjen et al. identified expression of interleukin receptors (IL-4Ra, IL13Ra1, and IL31Ra) on both human and mouse dorsal root ganglion (DRG) neurons.3 It is important to note that both IL-4 and IL-13 bind to the IL-4Ra receptor. Utilizing intracellular calcium indicator dyes, their work demonstrated that both human and mice DRG neurons were directly activated by IL-4 and IL-13.3 Overall, DRG responsive neurons represented a small subset of histamine positive neurons and were mainly small diameter <18 um neurons.3 Interestingly, while DRG neurons were responsive to these interleukins, IL-4 and IL-13 were not acute pruritogens and did not potently induce itch-like behavior in rodents compared to IL-31.3 However, when paired with administration of acute pruritogens like histamine, IL-4 caused increased itching bouts compared with histamine alone.3 This evidence suggests that IL-4 and IL-13 could act to sensitize neurons and lower the threshold for itch.3
To test the necessity of IL-4 and IL-13 in the development of CP, the researchers genetically deleted the IL-4Ra receptor from DRG neurons. They subsequently discovered that in a calcipotriol mouse model of AD, both scratching behavior and histological changes due to dermatitis were ameliorated.3 They also identified Janus kinase (JAK) signaling as the downstream mediator of IL-4Ra signaling in DRG neurons similar to immune cells expressing the receptor. Loss of neuronal JAK signaling produced similar results as the loss of IL-4Ra receptor in mice.3 Most remarkably, however, was the discovery that in parallel to the genetic loss of JAK signaling, exogenous delivery of ruxolitinib, a JAK inhibitor, produced similar results, and was beneficial in reducing scratching in a non-inflammatory itch rodent model.3 Overall, their findings identified a novel neuro-immune system cross-talk, whereby interleukin activation of sensory neurons mediated itch through the JAK intracellular signaling cascade.
Immune-Modulatory Agents in Chronic Pruritus Associated Disorders
Using their basic science findings as rationale, Oetjen et al. set-up an experimental trial to explore if JAK signaling might be a novel therapeutic target in chronic idiopathic pruritus (CIP) patients with no overt signs of inflammation. In this short investigation, the researchers treated five CIP patients with oral tofacitinib, a JAK inhibitor, and found a significant reduction in their itching as quantified by a 0-10 numerical rating scale.3 This finding is summarized in Table 1.
Other recent clinical trials have also focused on specific immune modulators to treat moderate-to-severe AD in patients who have failed conventional topical treatments to alleviate their itch symptoms. These have included blockade of IL-4Ra receptor, JAK, or IL-31Ra receptor signaling.13-17,20 Select clinical and experimental trials utilizing these drugs are presented in Table 1. Overall, there appears to be positive treatment responses to these treatments with minimal side effects. Dupilumab, an IL-4Ra receptor antagonist, has been the most studied, with large-scale clinical trials showing dose dependent improvements in symptoms. Based on the phase 2 trials, weekly subcutaneous 300 mg with topical glucocorticoids appears to elicit the best response, however, the measured outcomes used between trials are different and subject numbers vary greatly. Dupilumab was recently approved by the US Food and Drug Administration on March 28, 2017 for moderate-to-severe eczema (AD) at an initial dose of 600 mg (two 300 mg injections) followed by 300 mg injections every other week.21 Tofacitinib has also been assessed in clinical and experimental trials in both ointment and oral forms, and demonstrated signs of improvement in both AD and CIP. Although the oral tofacitinib trials are very small and neither placebo controlled nor blinded, they did show improvement of symptoms in both AD and CIP patients as measured by body surface involvement and itch cessation, respectively. Lastly, a recent trial published on nemolizumab, an IL-31Ra antagonist, reported a dose-dependent response in pruritus reduction.
Review of Key Messages
- Neuro-immune system interactions play a key role in CP.
- IL-4/IL-13 signaling through the IL-4Ra receptor on peripheral sensory neurons and downstream Janus kinase-signal transducer of activation (JAK-STAT) pathway signaling lowers the threshold for itch.
- Treatments targeting IL-31R, IL-4Ra, and intracellular JAK signaling for CP may in part induce clinical relief of itch through their action on peripheral sensory neurons.
Overall, with the recent scientific discoveries describing a novel neuro-immune interaction associated with chronic pruritus, we can hypothesize that the availability of new immune-modulatory treatments for regulating peripheral sensory neurons to alter itch sensation appears promising. Given the different roles of IL-4/ IL-13 to sensitize neurons to pruritogens, IL-31 acting as an acute pruritogen, and JAK as an intracellular signaling mechanism in neurons to transmit itch independent of inflammation, the next series of obvious clinical questions include the use of combination treatments to address these different aspects of itch sensation (Figure 1 and Table 1). Since most of the JAK studies have been off-label, stronger clinical trials that test the efficacy of these inhibitors with regard to chronic pruritus are warranted. With advances in understanding the pathogenesis of pruritus, including a central nervous system pathway for itch sensation, combined with concordant trials on drugs targeting receptors and their signaling pathways, we are poised to gain an even greater understanding of the underlying biologic mechanisms that may guide the development of new and more effective treatments for chronic pruritus.
- Stander S, Weisshaar E, Mettang T, et al. Clinical classification of itch: a position paper of the International Forum for the Study of Itch. Acta Derm Venereol. 2007 87(4):291-4.
- Yosipovitch G, Bernhard JD. Clinical practice. Chronic pruritus. N Engl J Med. 2013 Apr 25;368(17):1625-34.
- Oetjen LK, Mack MR, Feng J, et al. Sensory neurons co-opt classical immune signaling pathways to mediate chronic itch. Cell. 2017 Sep 21;171(1):217-28 e13.
- Stander S, Steinhoff M, Schmelz M, et al. Neurophysiology of pruritus: cutaneous elicitation of itch. Arch Dermatol. 2003 Nov;139(11):1463-70.
- Schmelz M, Schmidt R, Bickel A, et al. Specific C-receptors for itch in human skin. J Neurosci. 1997 Oct 15;17(20):8003-8.
- Grundmann S, Stander S. Chronic pruritus: clinics and treatment. Ann Dermatol. 2011 Feb;23(1):1-11.
- Schmelz M, Schmidt R, Weidner C, et al. Chemical response pattern of different classes of C-nociceptors to pruritogens and algogens. J Neurophysiol. 2003 May;89(5):2441-8.
- Sun YG, Zhao ZQ, Meng XL, et al. Cellular basis of itch sensation. Science. 2009 Sep 18;325(5947):1531-4.
- Mu D, Deng J, Liu KF, et al. A central neural circuit for itch sensation. Science. 2017 Aug 18;357(6352):695-9.
- Kaur S, Pedersen NP, Yokota S, et al. Glutamatergic signaling from the parabrachial nucleus plays a critical role in hypercapnic arousal. J Neurosci. 2013 May 1;33(18):7627-40.
- Tokita K, Boughter JD Jr. Topographic organizations of taste-responsive neurons in the parabrachial nucleus of C57BL/6J mice: An electrophysiological mapping study. Neuroscience. 2016 Mar 1;316:151-66.
- Yahiro T, Kataoka N, Nakamura Y, et al. The lateral parabrachial nucleus, but not the thalamus, mediates thermosensory pathways for behavioural thermoregulation. Sci Rep. 2017 Jul 10;7(1):5031.
- Ruzicka T, Hanifin JM, Furue M, et al. Anti-interleukin-31 receptor A antibody for atopic dermatitis. N Engl J Med. 2017 Mar 2;376(9):826-35.
- Beck LA, Thaci D, Hamilton JD, et al. Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. N Engl J Med. 2014 Jul 10;371(2):130-9.
- Simpson EL, Bieber T, Guttman-Yassky E, et al. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2016 Dec 15;375(24):2335-48.
- Thaci D, Simpson EL, Beck LA, et al. Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebo-controlled, dose-ranging phase 2b trial. Lancet. 2016 Jan 2;387(10013):40-52.
- Levy LL, Urban J, King BA. Treatment of recalcitrant atopic dermatitis with the oral Janus kinase inhibitor tofacitinib citrate. J Am Acad Dermatol. 2015 Sep;73(3):395-9.
- Dillon SR, Sprecher C, Hammond A, et al. Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice. Nat Immunol. 2004 Jul;5(7): 752-60.
- Gittler JK, Shemer A, Suarez-Farinas M, et al. Progressive activation of T(H)2/T(H)22 cytokines and selective epidermal proteins characterizes acute and chronic atopic dermatitis. J Allergy Clin Immunol. 2012 Dec;130(6): 1344-54.
- Bissonnette R, Papp KA, Poulin Y, et al. Topical tofacitinib for atopic dermatitis: a phase IIa randomized trial. Br J Dermatol. 2016 Nov;175(5):902-11.
- FDA approves new eczema drug Dupixent. FDA News Release, March 28, 2017. Available at https://www.fda.gov/newsevents/newsroom/pressannouncements/ ucm549078.htm. Accessed July 29, 2018.