Journal of Dermatology for Physician Assistants

The official journal of the Society of Dermatology Physician Assistants

Chronic Pruritus: Etiologies, Pathophysiology, and Therapeutic Options

By Cristina M. Foschi, BS, and Peter Lio, MD, FAAD

ABSTRACT
The purpose of this article is to discuss the pathogenesis of itch along with the four general categories of chronic pruritus in patients, how to clinically assess itch, and treatment options for each category of itch.

Histamine-driven and non-histamine-driven itch can be further subdivided into dermatologic, neuropathic, psychogenic, and systemic types of itch, each with evidence for certain therapies. There are several important categories of itch that can inform treatment approaches, some with significant evidence behind them, but gaps in both understanding and treatment remain.

CME Credit Available: This program has been reviewed and is approved for a maximum of 1 hours of AAPA Category I CME credit by the Physician Assistant Review Panel. Approval is valid for 1 year from the issue date of March 1, 2022. This program was planned in accordance with AAPA’s CME Standards for Enduring Material Programs and for Commercial Support of Enduring Material Programs. SDPA members may access the post-test at https://www.dermpa.org/JDPA_Exams  JDPA CME is a free member-only offer. Not a member? Join SDPA today.

Learning Objectives:
1. Describe the four general categories of itch.
2. Explore the key pathogenesis for itch.
3. Illustrate common assessments used for analyzing itch.
4. Discuss traditional and upcoming therapies for itch symptoms.

INTRODUCTION
Itch, or pruritus, is a common presenting symptom seen with inflammatory skin diseases such as atopic dermatitis (AD), psoriasis, urticaria, neurodermatitis, prurigo, and cutaneous pruritus along with other dermatologic conditions such as seborrheic dermatitis or scabies. It is the most common symptom seen in dermatology with estimates showing that more than one-third of patients suffer from itch.1Pereira MP, Stander S. Assessment of severity and burden of pruritus. Allergol. Int. 2017; 66(1): 3-7. doi: 10.1016/j.alit.2016.08.009 However, itch is also seen in patients with neuropathic, psychogenic and systemic conditions. There are two general types of itch which follow distinct pathways: acute itch, which often relies on the histaminergic pathway, and chronic itch, which generally is mediated via the non-histaminergic pathway.2Elmariah SB. Adjunctive management of itch in atopic dermatitis. Dermatol. Clin. 2017; 35(3): 373-94. doi: 10.1016/j.det.2017.02.011,3Rinaldi G. The itch-scratch cycle: a review of the mechanisms. Dermatol Pract Concept. 2019; 9(2): 90-7. doi: 10.5826/dpc.0902a03

When the sensation of itch occurs for more than six weeks, it is defined as chronic pruritus, and this can have a significant effect on a patient’s well-being by reducing sleep quality, affecting mood, and negatively impacting quality of life (QoL).4Yosipovitch G, Rosen JD, Hasimoto T. Itch: from mechanism to (novel) therapeutic ap-proaches. J. Allergy Clin. Immunol. 2018; 142(5): 1375-90. doi: 10.1016/j. jaci.2018.09.005,5Kremer AE, Mettang T, Weisshaar E. Non-dermatological challenges of chronic itch. Acta Derm. Venereol. 2020; 100(2): adv00025. doi: 10.2340/00015555-3345 In addition, chronic itch has a prevalence of approximately 10 percent, is more prevalent in the elderly, and is difficult to treat, representing a significant social and economic burden to patients.6Yonova D. Pruritus in certain internal diseases. Hippokratia. 2007; 11(2): 67-71. PMID: 19582180 The cause of chronic itch has been historically divided into four categories: dermatologic (associated with primary skin diseases such as AD), neuropathic (associated with nerve fibers such as brachioradial pruritus and small-fiber polyneuropathy), psychogenic (associated with psychiatric conditions such as generalized anxiety disorder and delusions of parasitosis), or systemic (associated with hematologic diseases, end-stage renal disease [ESRD], and cholestasis).3Rinaldi G. The itch-scratch cycle: a review of the mechanisms. Dermatol Pract Concept. 2019; 9(2): 90-7. doi: 10.5826/dpc.0902a034Yosipovitch G, Rosen JD, Hasimoto T. Itch: from mechanism to (novel) therapeutic approaches. J. Allergy Clin. Immunol. 2018; 142(5): 1375-90. doi: 10.1016/j. jaci.2018.09.005

It is important that clinicians identify the underlying condition producing itch in order to select the most appropriate therapy for relief. Here, we discuss the pathogenesis of itch, describe the four categories of chronic pruritus, outline tools for clinically assessing itch in patients, and list treatment options for each category of itch.

PATHOPHYSIOLOGY
Physiologic itch begins at the skin with a pruritogen that activates receptors on small itch-selective unmyelinated C fibers which are G protein-coupled receptors (GPCRs).4Yosipovitch G, Rosen JD, Hasimoto T. Itch: from mechanism to (novel) therapeutic approaches. J. Allergy Clin. Immunol. 2018; 142(5): 1375-90. doi: 10.1016/j. jaci.2018.09.005 In addition to this pathway, two subtypes of itch-sensitive neurons exist: histaminergic and non-histaminergic neurons.4Yosipovitch G, Rosen JD, Hasimoto T. Itch: from mechanism to (novel) therapeutic approaches. J. Allergy Clin. Immunol. 2018; 142(5): 1375-90. doi: 10.1016/j. jaci.2018.09.005 These itch signals ascend through the spinal cord in separate tracts and have different patterns of brain activation.6Yonova D. Pruritus in certain internal diseases. Hippokratia. 2007; 11(2): 67-71. PMID: 19582180The histaminergic pathway is involved in acute itch as histamine is released primarily by mast cells which bind to histaminergic neurons (afferent C-fibers) which then release neuropeptides such as calcitonin gene-related protein (CGRP) and substance P.2Elmariah SB. Adjunctive management of itch in atopic dermatitis. Dermatol. Clin. 2017; 35(3): 373-94. doi: 10.1016/j.det.2017.02.011 This causes local vasodilation, plasma extravasation and mast cell degranulation, which produces skin reactions such as urticaria and erythema.

In contrast, chronic itch is induced by the non-histaminergic pathway in which these neurons are elicited by pruritogens such as proteases, cytokines, or chemokines. In allergic and inflammatory conditions, there is an increased T helper type 2 (Th2) immune response and production of cytokines such as interleukin (IL)-31 that induce itch. This alternative pathway does not appear to promote the same intense inflammatory response compared to the histaminergic pathway.3 Rinaldi G. The itch-scratch cycle: a review of the mechanisms. Dermatol Pract Concept. 2019; 9(2): 90-7. doi: 10.5826/dpc.0902a03 Thymic stromal lymphopoietin (TSLP), which is secreted primarily by epidermal keratinocytes, is another key cytokine in promoting the Th2 immune response and induces itch by binding to neurons. Scratching the itch then induces epidermal keratinocytes to further express TSLP and this perpetuates a positive feedback loop of itching and scratching.3 Rinaldi G. The itch-scratch cycle: a review of the mechanisms. Dermatol Pract Concept. 2019; 9(2): 90-7. doi: 10.5826/dpc.0902a03 IL-4 and IL-13 are additional cytokines that are involved in Th2 immunity and induce chronic itch by activating sensory neurons through the IL-4 receptor subunit alpha, which is a shared subunit for both IL-4 and IL-13 along with Janus kinase (JAK).

After processing in the spinal cord, itch signals ascend through the spinothalamic tract to the thalamus and through the spinoparabrachial pathway to the parabrachial nucleus.3 Rinaldi G. The itch-scratch cycle: a review of the mechanisms. Dermatol Pract Concept. 2019; 9(2): 90-7. doi: 10.5826/dpc.0902a03 The signal is then projected to the primary and secondary somatosensory cortices. These areas contribute to the localization, intensity, and recognition of itch.

The mechanisms of neuropathic, psychogenic, and systemic itch are not well understood. Neuropathic itch occurs mainly due to damaged central or peripheral afferent nerves. It is a type of itch that is also accompanied by localized neuropathic symptoms such as pain and paresthesia likely due to damage of itch-inhibiting neurons.3 Rinaldi G. The itch-scratch cycle: a review of the mechanisms. Dermatol Pract Concept. 2019; 9(2): 90-7. doi: 10.5826/dpc.0902a03 Psychogenic itch is a diagnosis of exclusion where another reason for itch is not found, and mental health symptoms are present. Imbalances of serotonin, opioids, and dopamine may play a role in this pathway.3 Rinaldi G. The itch-scratch cycle: a review of the mechanisms. Dermatol Pract Concept. 2019; 9(2): 90-7. doi: 10.5826/dpc.0902a03 Finally, systemic itch is an itch that originates from organs other than the skin. Conditions that can cause this include hematologic disease, hepatobiliary disease, and ESRD.5Kremer AE, Mettang T, Weisshaar E. Non-dermatological challenges of chronic itch. Acta Derm. Venereol. 2020; 100(2): adv00025. doi: 10.2340/00015555-3345

Hematologic itch is usually aquatogenic, or occurs after a warm shower. While a confirmed mechanism is unknown, it is thought to be due to the up-regulation of serotonin receptors.5Kremer AE, Mettang T, Weisshaar E. Non-dermatological challenges of chronic itch. Acta Derm. Venereol. 2020; 100(2): adv00025. doi: 10.2340/00015555-3345 Other hematologic conditions that can induce pruritus include malignancy such as Hodgkin’s lymphoma which is thought to be due to release of basophils, histamine, and leukopeptidase from white blood cells.6 Interestingly, both iron deficiency and hemochromatosis where iron levels are elevated can cause itch.6Yonova D. Pruritus in certain internal diseases. Hippokratia. 2007; 11(2): 67-71. PMID: 19582180 Cholestatic pruritus is due to the accumulation of bile salts that then trigger histamine and lysophosphatidic acid release, which are powerful pruritogens. In addition, cholestatic patients have higher levels of endogenous opioids due to a diseased liver that can contribute to systemic itch. Itch seen in ESRD is very common and is thought to be due to increased levels of uremic toxins along with the up-regulation of endogenous opioids.5Kremer AE, Mettang T, Weisshaar E. Non-dermatological challenges of chronic itch. Acta Derm. Venereol. 2020; 100(2): adv00025. doi: 10.2340/00015555-3345

DIAGNOSIS OF ITCH
Assessment of pruritus can be challenging as the sensation is subjective and there are many components that must be considered, such as other sensory symptoms, location, and duration. The International Forum for the Study of Itch (IFSI) established a classification system that divides chronic pruritus into three categories upon physical examination: 1) chronic pruritus on inflamed skin 2) chronic pruritus on normal skin, and 3) chronic pruritus with severe scratch lesions.1Pereira MP, Stander S. Assessment of severity and burden of pruritus. Allergol. Int. 2017; 66(1): 3-7. doi: 10.1016/j.alit.2016.08.009

Many scales have been developed to assess pruritus intensity. Mono-dimensional scales include the numerical rating scale (NRS) in which patients are asked to rate their itch from 0 (no itch) to 10 (worst imaginable itch) and the visual analogue scale (VAS) where patients indicate the intensity of their itch by marking on a 10cm-long, ruler-shaped scale using the same values as the NRS.7Rosen JD, Fostini AC, Yosipovitch G. Diagnosis and management of neuropathic itch. Dermatol. Clin. 2018; 36(3): 213-224. doi: 10.1016/j.det.2018.02.005 Scores below 3.0 on both of these scales are associated with mild itch while scores higher than 6.9 are associated with severe itch.9Rosen JD, Fostini AC, Yosipovitch G. Diagnosis and management of neuropathic itch. Dermatol. Clin. 2018; 36(3): 213-224. doi: 10.1016/j.det.2018.02.005

However, these scales only provide the itch intensity at a specific point in time and thus are not as useful in understanding the larger outside-of-clinic picture.

Multidimensional scales, such as the 5-D itching scale (degree, duration, direction, disability, and distribution) evaluates many components of pruritus. The Itch-free Days (IFD) questionnaire, which was recently validated, contains questions that describe many parameters related to itch course and calculates a score to compare the results from different time points of assessment.1Pereira MP, Stander S. Assessment of severity and burden of pruritus. Allergol. Int. 2017; 66(1): 3-7. doi: 10.1016/j.alit.2016.08.009 Another instrument is the pruritus-specific Patient Benefit Index (PBI-P), which has been developed to determine the benefits gained from treatment and degree of global satisfaction. It assesses the relevance of 27 possible therapeutic benefits for patients before treatment and the extent to which they were met post-treatment. This has been validated for chronic pruritus patients and has a high correlation with scores from VAS.

In addition to using these questionnaire tools, management of pruritus includes first taking a thorough medical history and performing a physical examination. To rule out systemic causes of itch, the British Association of Dermatology recommends initial blood tests, including a full blood cell count, iron levels, thyroid function tests, urea and electrolyte levels, liver function tests, and an autoimmune screen to help diagnosis or exclude systemic causes.3 Rinaldi G. The itch-scratch cycle: a review of the mechanisms. Dermatol Pract Concept. 2019; 9(2): 90-7. doi: 10.5826/dpc.0902a03 In addition, a thorough history can provide information about the origin of pruritus such as trauma or comorbidities and a detailed skin examination is required to rule out primary dermatologic conditions that cause itch.9Rosen JD, Fostini AC, Yosipovitch G. Diagnosis and management of neuropathic itch. Dermatol. Clin. 2018; 36(3): 213-224. doi: 10.1016/j.det.2018.02.005

TYPES OF ITCH AND THERAPEUTIC OPTIONS
A general guideline of the categories of chronic pruritus along with initial steps in therapeutic management is outlined in Figure 1, with a more detailed description below.

DERMATOLOGIC ITCH
Inflammatory skin disorders causing dermatologic itch including AD are primarily driven by a type 2 immune axis response through cytokines IL-33, TSLP, IL-4, IL-5, IL-13, and IL-31.10 Elevated levels of type 2 cytokines also promote production of immunoglobulin E (IgE), activation of mast cells, and release of histamine which can cause urticaria.10Erickson S, Heul AV, Kim BS. New and emerging treatments for inflammatory itch. Ann. Allergy Asthma Immunol. 2021; 126(1): 13-20. doi: 10.1016/j. anai.2020.05.028

Reducing inflammatory mediators in the skin is crucial to reducing pruritus and achieving control in these conditions. Traditionally, psoriasis has been considered a non-pruritic dermatosis compared to AD, however, studies have demonstrated that itch is present in psoriasis and can have a debilitating impact on patient well-being.11Elewski B, Alexis AS, Lebwohl A, Stein Gold L, Pariser D, Del Rosso J, et al. Itch: an under-recognized problem in psoriasis. JEADV. 2019; 33(8): 1465-76. doi: 10.1111/jdv.15450

Substances that have been associated with pruritus in psoriasis include nerve growth factor (NGF), substance P, CGRP, and neuropeptide Y (NPY). While the exact pathogenesis of psoriatic pruritus is not clear, extensive itching of the skin can cause the development of new psoriatic lesions in response to trauma, known as the Koebner phenomenon.11Elewski B, Alexis AS, Lebwohl A, Stein Gold L, Pariser D, Del Rosso J, et al. Itch: an under-recognized problem in psoriasis. JEADV. 2019; 33(8): 1465-76. doi: 10.1111/jdv.15450 Additional causes of dermatologic itch include the severe, persistent itch that manifests with scabies. Many pathophysiologic mechanisms have been proposed for the severity of this itch which involve both type I (immediate) and type IV (delayed) hypersensitivity reactions.12Kim HS, Hashimoto T, Fischer K, Bernigaud C, Chosidow O, Yosipovitch G. Scabies itch: an update on neuroimmune interactions and novel targets. JEADV. 2021; 35(9): 1765-76. doi: 10.1111/jdv.17334

In addition, the scabies mite produces proteins such as serine protease which digests skin proteins and contributes to the breakdown of the epidermal barrier, evoking itch.13Kim HS, Hashimoto T, Fischer K, Bernigaud C, Chosidow O, Yosipovitch G. Scabies itch: an update on neuroimmune interactions and novel targets. JEADV. 2021; 35(9): 1765-76. doi: 10.1111/jdv.17334 While in children and adults AD is one of the most common causes of pruritus in this category, xerosis, or dry skin, is the most common cause of dermatologic-related itch in the elderly and has been reported in 69 percent of elderly chronic itch patients.10 Xerosis should be considered in all elderly patients as many common drugs can cause pruritus in this population, such as calcium channel blockers and hydrochlorothiazide.14Berger TG, Shive M, Harper M. Pruritus in the older patient. JAMA. 2013; 310(22): 2443-50. doi: 10.1001/jama.2013.282023

In addition, other skin conditions are more common in elderly patients which can cause pruritus including bullous pemphigoid and mycosis fungoides.13Berger TG, Shive M, Harper M. Pruritus in the older patient. JAMA. 2013; 310(22): 2443-50. doi: 10.1001/jama.2013.282023 The therapeutic ladder in this type of itch generally follows topicals, then phototherapy, and, finally, systemics.

Topical Treatments. Chronic skin disorders are associated with an impaired skin barrier, which allows for moisture to leak out of the skin causing dry, itchy skin characterized by redness, flakes, and a rough texture.15Yosipovitch G, Misery L, Proksch E, Metz M, Stander S, Schmeltz M. Skin barrier dam-age and itch: review of mechanisms, topical management and future directions. Acta Derm. Venereol. 2019; 99(13): 1201-09. doi: 10.2340/00015555-3296

Topical therapy is the foundation of treatment for skin-barrier related pruritus and includes emollients, corticosteroids, and other immunomodulators.14Yosipovitch G, Misery L, Proksch E, Metz M, Stander S, Schmeltz M. Skin barrier dam-age and itch: review of mechanisms, topical management and future directions. Acta Derm. Venereol. 2019; 99(13): 1201-09. doi: 10.2340/00015555-3296

Effective emollients consist of water and lipids which act to rehydrate the skin and are first-line therapy for skin-barrier related itch.14Yosipovitch G, Misery L, Proksch E, Metz M, Stander S, Schmeltz M. Skin barrier dam-age and itch: review of mechanisms, topical management and future directions. Acta Derm. Venereol. 2019; 99(13): 1201-09. doi: 10.2340/00015555-3296 Topical corticosteroids reduce pruritus in inflammatory skin conditions and are perhaps best utilized in more localized pruritic disease. These have been an essential method of therapy for acute inflammatory flares with multiple systematic reviews demonstrating that high-potency class I steroids significantly improve atopic itch within a few days of application.16Yarbrough KB, Neuhaus KJ, Simpson EL. The effects of treatment on itch in atopic derma-titis. Dermatol. Ther. 2013; 26(2): 110-9. doi: 10.1111/dth.12032

Due to adverse effects from chronic use such as skin atrophy, telangiectasias, and changes in pigmentation, however, alternatives are preferred to minimize continuous use of topical steroids.15Yarbrough KB, Neuhaus KJ, Simpson EL. The effects of treatment on itch in atopic dermatitis. Dermatol. Ther. 2013; 26(2): 110-9. doi: 10.1111/dth.12032 Calcineurin inhibitors, such as tacrolimus and pimecrolimus, are immunomodulators that have been shown to reduce AD-related pruritus in multiple studies.2Elmariah SB. Adjunctive management of itch in atopic dermatitis. Dermatol. Clin. 2017; 35(3): 373-94. doi: 10.1016/j.det.2017.02.011

,15Yarbrough KB, Neuhaus KJ, Simpson EL. The effects of treatment on itch in atopic dermatitis. Dermatol. Ther. 2013; 26(2): 110-9. doi: 10.1111/dth.12032 This therapy offers an alternative targeted anti-inflammatory treatment without the side effects associated with corticosteroid use, and can thus be used more chronically. Crisaborole, a topical phosphodiesterase-4 (PDE4) inhibitor recently approved for use in AD, is another anti-inflammatory agent. PDE4 regulates multiple pro-inflammatory signals by degrading cyclic adenosine monophosphate in cells. This medication improved disease severity and pruritus with a favorable safety profile in those with mild to moderate AD.17

Phototherapy. Ultraviolet-A (UV-A), Narrow-Band Ultraviolet-B (nbUV-B), and psoralen and UVA (PUVA) improve pruritus by reducing nerve fiber density and semaphorin 3A levels in the epidermis.4 This is an effective and safe treatment in dermatologic itch, such as psoriasis, as it reduces T cells and IgE-binding in the dermis.2 Phototherapy also reduces the density of epidermal sensory nerves which can contribute to a direct antipruritic effect.2 A systematic review demonstrated that UV phototherapy with UVB, combined UVA and UVB (UVAB), nbUVB, and high intensity UVA can be useful for management of AD.15 However, not all studies demonstrate that UV therapy improves pruritus and multiple sessions per week are required for clearance, which can be time consuming and cumbersome to patients.

Antihistamines. The histamine-1 receptor (H1R) and histamine-4 receptor (H4R) antagonists have been implicated in the treatment of itch.10 Although antihistamines have demonstrated efficacy in relieving acute itch, particularly H1R antagonists for acute urticaria, they do not seem to be as beneficial in chronic itch conditions. In AD, histamine acts as a pruritogen through H4-receptors and other cytokine mediators, and no high-quality randomized control trials of H1-antihistamines confirm their efficacy in these patients.18 They are still sometimes used in chronic itch conditions mainly for their sedative effects. H4R antagonists have particularly demonstrated both anti-inflammatory and antipruritic effects in chronic itch. Oral H4R antagonists are currently being studied in the treatment of chronic itch in those with AD, although at this time antihistamines are not first-line in chronic pruritus patients.19

Cyclosporine. Cyclosporine binds to the intracellular receptor cyclophilin leading to decreased T-cell activation and transcription of IL-2, which is a mediator of pruritus.2 A meta-analysis demonstrated reduction in itch severity in AD cases when cyclosporine was dosed at 3mg/kg to 5mg/kg for 6 to 8 weeks.15 It is best used as a short-term solution to achieve rapid control of inflammation and itch in severe AD due to adverse effects such as renal dysfunction and hyperlipidemia.15

Purine Synthesis Inhibitors. Mycophenolate mofetil (MMF) inhibits inosine monophosphate dehydrogenase, preventing lymphocyte proliferation. This has proven to be a safe and effective option in dermatologic itch patients.2 Azathioprine is a purine analog that inhibits normal purine synthesis and DNA production, limiting T-cell and B-cell proliferation. Several randomized control trials demonstrated improvement in atopic itch after treatment with azathioprine, although the potential for lymphopenia, nausea, or gastrointestinal upset must be monitored.2 Methotrexate is an inhibitor of dihydrofolate reductase that indirectly inhibits purine synthesis and is used in those with inflammatory skin disease such as psoriasis or AD.2

IgE Antagonists. Omalizumab is a recombinant humanized anti-IgE antibody that blocks IgE binding to its receptor preventing activation of basophils and mast cells. In recent clinical trials in children with severe AD utilizing high doses of omalizumab, there was a reduction in the Eczema Area and Severity Index (EASI) compared to the control group.10

IL-4 and IL-13 Antagonists. Dupilumab is a fully human monoclonal antibody that targets the IL-4 receptor alpha, a shared receptor for IL-4 and IL-13. This drug demonstrated a remarkable reduction in pruritus severity, QoL, and AD disease severity after only two weeks of treatment compared to the placebo control group in trials and is the first targeted biologic agent approved for treatment of moderate-to-severe AD inadequately controlled with topical therapies.19-21 Similarly, studies of anti-IL-13 monoclonal antibodies tralokinumab and lebrikizumab have demonstrated promising results in those with AD. In particular, lebrikizumab reduced skin lesions and pruritus by Day 2 of treatment for adults with moderate-to-severe AD.22

IL-31 Antagonists. IL-31 was the first cytokine found to directly stimulate sensory nerves and mediate itch. The humanized anti-IL-31 receptor monoclonal antibody nemolizumab binds to the IL-31 receptor A on neurons and inhibits its signaling, alleviating pruritus directly with little to no effect on inflammation.23 Promising trials demonstrate significant reduction in pruritus as early as day 2 of treatment in moderate to severe AD with monthly administration of 0.5mg/kg to 2.0mg/kg.23

Other Blockades. Epithelial cell-derived cytokines IL-33 and TSLP have been implicated in the pathogenesis of pruritic disorders by directly stimulating sensory neurons to mediate itch, which act upstream of IL-4, IL-13, and IL-31, and represent other potential targets for treatment of dermatologic pruritus.10 Tezepelumab is an anti-TSLP monoclonal antibody that demonstrated a 50-percent reduction in EASI scores in combination with topical corticosteroids, however, this was not statistically significant.10 On the other hand, an anti-IL 33 monoclonal antibody etokimab produced improvement in those with moderate-to-severe AD after a single dose.10

Janus Kinase Inhibitors. These agents provide anti-inflammatory effects through disruption of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway used by many cytokine receptors with JAK1 expressed more in itch-specific effects.22,24 A small case series of six patients reported efficacy of oral tofacitinib (JAK1/3 selective) and a recent phase 2 clinical trial with upadacitinib, which is a JAK-1 selective inhibitor, found improvement in itch as early as Week 1 of treatment.22,24 In addition to oral JAK inhibitors, topicals such as tofacitinib and delgocitinib, also demonstrated a reduction in itch.

Neurokinin Receptor Antagonists. Substance P induces pruritus by stimulating the release of pruritogens from keratinocytes and other immune cells via the neurokinin-1 (NK-1) receptor, and both substance P and the NK-1 receptors are overexpressed in chronic pruritus.25 Aprepitant, serlopitant, and tradipitant, which are NK-1 antagonists, have demonstrated significant reduction of pruritus. In particular, tradipitant exhibited a statistically significant decrease in itch in a randomized trial.25

Antimicrobial Agents. Staphylococcus-derived exotoxins and superantigens aggravate AD symptoms and are capable of directly triggering itch with the density of Staphylococcus aureus colonization correlating with disease severity.26 The regular practice of dilute bleach baths with concomitant topical mupirocin can be helpful for improving AD-related itch, however, studies have demonstrated that this may not be more effective than water baths alone.26 Since AD is associated with a higher prevalence of S. aureus colonization compared with healthy controls, anti-bacterial treatments have been considered to reduce bacterial colonization which may be inducing a flare.26 For itch induced by scabies, topical permethrin 5% cream is widely used and is effective at killing both the mite and eggs with oral ivermectin usage indicated in cases of topical failure.12 Topical hypochlorous acid (HOCl) found in bleach and a vital component of our innate immune system has demonstrated anti-microbial and anti-inflammatory properties to assist with pruritus as a topical regimen. This formulation has also been shown to decrease the activity of many cytokines that are upregulated in dermatologic itch and has demonstrated antimicrobial effects and therapeutic benefits in these conditions.27 Finally, a topical 1% colloidal oat cream formulation has demonstrated effectiveness in reducing both the EASI and Atopic Dermatitis Severity Index by lowering the prevalence of Staphylococcus species and increasing microbiome diversity.28 By serving as a probiotic and improving the diversity of the cutaneous microbiome, it can repair skin barrier defects that cause inflammatory flares.28

NEUROPATHIC ITCH
Neuropathic itch is one that arises because of disease located along the afferent neural pathway and accounts for 8 to 19 percent of patients affected by chronic pruritus.9 Those with neuropathic pruritus tend to have very severe itch and, due to sensory nerve damage, this type of itch usually presents on normal appearing skin accompanied by burning and tingling.9,29 A diagnosis of neuropathic itch is supported by an itch limited to a dermatomal distribution or an itch accompanied by other neurological signs of sensory nerve damage. Allokinesis, itch evoked by light touch, and other forms of hypersensitivity result from peripheral and central sensitization of neurons and can also be associated with neuropathic pruritus.29 Table 1 breaks down specific causes of neuropathic itch as categorized by originating in the central or peripheral nervous systems.9

Topical Neuromodulators. Topical capsaicin, a naturally occurring alkaloid derived from chilli peppers, has been used to relieve pruritus by activating transient receptor potential vanilloid 1 (TRPV1) ion channels on nociceptors which trigger the release and depletion of neuropeptides.2 The long-lasting desensitization of local nerve fibers improves pruritic symptoms, although it can cause a hot or burning sensation after application. Patches of 8% capsaicin applied for 60 minutes have demonstrated a greater and longer lasting relief of neuropathic itch in patients.9 In addition, topical cooling agents such as menthol and camphor exert their effects by activating thermosensitive channels expressed on keratinocytes and peripheral nociceptors, enhancing the sensation of cold and causing receptor desensitization which leads to analgesic and antipruritic effects.9 For mild neuropathic pruritus, topical anesthetics such as lidocaine, prilocaine, and pramoxine have demonstrated some success in treatment at a lower cost for patients.9 Additionally, there have been reports of patients with refractory brachioradial pruritus demonstrating efficacy from topical amitriptyline-ketamine in treatment of this itch. Topically, amitriptyline acts by blocking voltage-gated sodium channels and preventing the depolarization of axons, working similar to an anesthetic.29 This combination has been studied in some clinical trials with mixed results and more studies are needed to understand its utilization and dosing.

Oral Medications. Gabapentin and pregabalin can reduce central neural hyper-sensitization and thus reduce pruritic conditions in neuropathic itch.30 Gabapentin is a GABA analog that antagonizes the alpha-2-delta subunit of voltage-gated calcium channels. Gabapentin is started at low doses of 300-600mg nightly and gradually increased to achieve a total daily dose as high as 3600mg/d as tolerated.9 Less commonly, oxcarbazepine and carbamazepine have demonstrated success in the treatment of neuropathic pruritus by antagonizing voltage-gated sodium channels.9 Finally, tricyclic antidepressants, such as amitriptyline, have demonstrated improvement in neuropathic itch when dosed 5 to 10mg nightly and titrated upward.9

PSYCHOGENIC ITCH
Psychogenic pruritus is a functional itch disorder which is a compulsion to scratch otherwise normal skin due to irritating factors such as skin dryness along with psychiatric disease.31 Psychiatric diseases associated with this itch include depression, obsessive-compulsive disorder (OCD), anxiety, psychosis, and substance abuse.32 It is a diagnosis of exclusion, and it is important to first rule out dermatologic and systemic causes before undergoing medication and behavioral management, along with building a strong relationship with patients prior to navigating this conversation, as it can be challenging to explain.32

Behavioral Therapy. For those with an obsessive-compulsive component to their itch, cognitive behavior therapy (CBT) has shown to be the most effective.32 Patients work on techniques to decrease the urge to pick by removing triggers and finding alternative coping mechanisms.32

Antihistamines. First-generation antihistamines, such as hydroxyzine and diphenhydramine, are used in the evening for their sedative effects in these patients. Doxepin is a TCA with strong antihistamine and sedative effects that can be useful and is usually started at 10mg nightly and then titrated up to 100mg as tolerated.32

Oral Medications. Generally, when selecting oral therapy, it is important to treat the underlying psychiatric condition in these patients. Selective serotonin reuptake inhibitors (SSRIs) such as paroxetine, sertraline, and fluvoxamine, can be effective in psychogenic pruritus.4,32 In particular, low-dose oral mirtazapine (7.5-15mg) at night can decrease neural sensitization and reduce nocturnal pruritus.4,32 For excoriation disorder in which individuals repeatedly pick at their skin, N-acetylcysteine has demonstrated effectiveness in reducing pruritic symptoms.33 In one randomized trial, this amino acid dosed at 1200-3000mg/d for 12 weeks suggested that targeting the glutamate system may reduce compulsive picking behaviors.33 In delusions of parasitosis, antipsychotics are the best choice. Aripiprazole has a lower side effect profile and is approved for both psychosis and depression, which can aid patients who also have depression in feeling less self-conscious about taking an antipsychotic for itch symptoms.32 In many studies, pimozide has been shown to be first-line treatment for delusions of parasitosis with improvements in symptoms anywhere from 3 to 8 weeks of 1 to 6mg of medication per day.32

SYSTEMIC ITCH
Systemic itch is due to underlying conditions such as ESRD, biliary liver disease, hematologic disease, malignancy, and others as outlined in Table 2. It is important to obtain lab work in patients with chronic pruritus without obvious skin manifestations including a comprehensive metabolic panel (CMP), complete blood count (CBC) with differential, alkaline phosphatase, lactate dehydrogenase, and uric acid.34 ESRD in particular is a growing problem in the elderly due to the increasing number of patients suffering from diabetes or hypertension, and chronic itch is a frequent symptom in these patients.35 Chronic itch due to systemic conditions has a decreased QoL in these individuals and thus it is important to recognize conditions and treat itch appropriately.

Topicals. Emollients such as petroleum jelly are recommended in these patients to start at least 2 to 3 times per day.35 In uremic pruritus, a randomized study found that topical glycerol 15% and paraffin 10% decreased pruritus in these patients. While moisturizers and topicals are beneficial for itch, it can be difficult for patients to apply these to a diffuse area and can often require caregiver assistance, which is not ideal.35

Phototherapy. Broadband UVB (BB-UVB) provides significant reduction in the skin content of phosphorus and reduction of pruritus scores in patients specifically with pruritus due to ESRD.35 BB-UVB therapy significantly reduced chronic itch in hemodialysis (HD) patients and the antipruritic effect occurred earlier when the weekly frequency of treatments was increased.36 BB-UVB can also be helpful in reducing itch within eight weeks of beginning treatment in patients with cholestatic liver or hematologic diseases.37

Anticonvulsants. Anticonvulsant drugs, such as gabapentin, have been implicated in systemic itch. In those with uremic pruritus due to ESRD, gabapentin had improved pruritus scores in those on HD, although the optimal therapeutic dose has not been established.38 Patients on HD need lower doses at less frequent intervals than patients with normal renal function, as gabapentin has a longer half-life in patients with chronic renal failure.38 In order to avoid adverse effects, many studies suggest that gabapentin and pregabalin should be started at lower doses and progressively titrated with close observation.30,38 Pregabalin has some advantages over gabapentin such as a higher potency and faster absorption, but there is limited evidence comparing the two.

Opioids. Opioid peptides can influence itch by binding to mu receptors, and thus excessive mu receptor stimulation from high levels of opioids can induce itch more, suggesting opioid antagonism as a potential therapeutic option.39 Topical 1% naltrexone cream has demonstrated significant reduction in patients with various systemic chronic pruritic disorders and was felt within 15-30 minutes after application lasting for 2-6 hours.40

Aprepitant. A NK-1 receptor antagonist, aprepitant has been approved for the prevention of chemotherapy-induced nausea and vomiting. In many trials, patients with pruritus due to systemic conditions such as cancers and ESRD have demonstrated symptom relief with short-term use of aprepitant for up to two weeks.41 Few patients experienced adverse effects, however, and its high cost can be an economical burden to patients.41

Other Oral Medications. Peroxisome proliferator-activated receptors (PPARs) are nuclear transcription factors that regulate numerous genes and metabolism in the liver.42 Fibrates are PPAR alpha agonists which have anti-cholestatic and anti-inflammatory effects, and bezafibrate has been shown to reduce pruritus in patients with cholestatic-induced itch by 75%.42 Finally, ileal bile acid transporter (IBAT) inhibitors can be used to interrupt the enterohepatic circulation and help pruritus. Inhibition at the terminal ileum results in reduced uptake of bile salts and increased bile salt loss with the feces. Linerixibat at 90mg/day for 3 days followed by 180 mg/day for another 2 weeks demonstrated itch intensity dropping by 57 percent.42

LIMITATIONS
At this time, there are multiple studies being done for additional therapies in all four categories of chronic pruritus, with the most in dermatologic itch. Future studies targeted toward further understanding the mechanism of the less studied types of itch such as neurogenic, psychogenic, and systemic may lead to development of more therapeutic options for these patients down the line.

CONCLUSION
Chronic pruritus, or itch lasting more than 6 weeks, is a common presenting symptom seen in dermatology. While the pathogenesis of chronic itch due to dermatologic diseases is multifactorial and related to processes such as an over-activation of the Th2 immune response, the mechanism behind itch seen in neurologic, psychogenic, and systemic itch is less well-understood. Qualifying itch using tools such as NRS and VAS along with identifying the underlying trigger for itch are important for clinicians to pick an adequate therapy. Various topical therapies can be utilized as first-line treatments in dermatologic and neuropathic itch, while oral regimens are best for psychogenic and systemic itch. By correctly identifying the underlying cause of chronic itch, proper therapy can be selected to provide the most optimal relief for patients.

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Cristina Foschi, BS, is a fourth-year medical student at Rush Medical College in Chicago, IL applying for Dermatology residency.

Peter Lio, MD, FAAD, is a Clinical Assistant Professor of Dermatology & Pediatrics at Northwestern University Feinberg School of Medicine. Dr. Lio received his medical degree from Harvard Medical School, completed his internship in Pediatrics at Boston Children’s Hospital, and his Dermatology training at Harvard where he served as Chief Resident in Dermatology. While at Harvard, he received formal training in acupuncture. Dr. Lio is the founding director of the Chicago Integrative Eczema Center and a founding partner of Medical Dermatology Associates of Chicago. He currently serves as a board member and scientific advisory committee member for the National Eczema Association. He is a member of the American Academy of Dermatology’s Atopic Dermatitis Expert Resource Group and a founding faculty member of the Integrative Dermatology Certificate Program. He has over 200 publications and 3 textbooks.

Funding: No funding sources were secured for this article.

Disclosures: Dr. Lio reports research grants/funding from AOBiome, Regeneron/Sanofi Genzyme, and AbbVie; is on the speaker’s bureau for Regeneron/Sanofi Genzyme, Pfizer, Incyte, Eli Lilly, LEO, Galderma, and L’Oreal; reports consulting/advisory boards for Almirall, ASLAN, Concerto Biosciences, Dermavant, Regeneron/Sanofi Genzyme, Pfizer, LEO, AbbVie, Eli Lilly, Micreos, L’Oreal, Pierre-Fabre, Johnson & Johnson, Level Ex, KPAway, Menlo Therapeutics, Theraplex, IntraDerm, Exeltis, AOBiome, Realm Therapeutics, Altus Labs, Galderma, Amyris, Bodewell, Burt’s Bees. In addition, Dr. Lio has a patent pending for a Theraplex product with royalties paid and is a Board member of the National Eczema Association. Ms. Foschi has disclosed no potential conflicts of interest, financial or otherwise, relating to the content of this article.

References

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  • 2
    Elmariah SB. Adjunctive management of itch in atopic dermatitis. Dermatol. Clin. 2017; 35(3): 373-94. doi: 10.1016/j.det.2017.02.011
  • 3
    Rinaldi G. The itch-scratch cycle: a review of the mechanisms. Dermatol Pract Concept. 2019; 9(2): 90-7. doi: 10.5826/dpc.0902a03
  • 4
    Yosipovitch G, Rosen JD, Hasimoto T. Itch: from mechanism to (novel) therapeutic approaches. J. Allergy Clin. Immunol. 2018; 142(5): 1375-90. doi: 10.1016/j. jaci.2018.09.005
  • 5
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    Yonova D. Pruritus in certain internal diseases. Hippokratia. 2007; 11(2): 67-71. PMID: 19582180
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    Rosen JD, Fostini AC, Yosipovitch G. Diagnosis and management of neuropathic itch. Dermatol. Clin. 2018; 36(3): 213-224. doi: 10.1016/j.det.2018.02.005
  • 9
    Rosen JD, Fostini AC, Yosipovitch G. Diagnosis and management of neuropathic itch. Dermatol. Clin. 2018; 36(3): 213-224. doi: 10.1016/j.det.2018.02.005
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    Erickson S, Heul AV, Kim BS. New and emerging treatments for inflammatory itch. Ann. Allergy Asthma Immunol. 2021; 126(1): 13-20. doi: 10.1016/j. anai.2020.05.028
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    Elewski B, Alexis AS, Lebwohl A, Stein Gold L, Pariser D, Del Rosso J, et al. Itch: an under-recognized problem in psoriasis. JEADV. 2019; 33(8): 1465-76. doi: 10.1111/jdv.15450
  • 12
    Kim HS, Hashimoto T, Fischer K, Bernigaud C, Chosidow O, Yosipovitch G. Scabies itch: an update on neuroimmune interactions and novel targets. JEADV. 2021; 35(9): 1765-76. doi: 10.1111/jdv.17334
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    Yosipovitch G, Misery L, Proksch E, Metz M, Stander S, Schmeltz M. Skin barrier dam-age and itch: review of mechanisms, topical management and future directions. Acta Derm. Venereol. 2019; 99(13): 1201-09. doi: 10.2340/00015555-3296
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    Yarbrough KB, Neuhaus KJ, Simpson EL. The effects of treatment on itch in atopic derma-titis. Dermatol. Ther. 2013; 26(2): 110-9. doi: 10.1111/dth.12032

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