The definition of pruritus, more commonly known as itch, was introduced by a German physician named Samuel Hafenreffer in 1660 as an “unpleasant sensation that elicits the desire or reflex to scratch.”1 Chronic pruritus affects approximately 15–20% of the U.S. population and accounts for more than 7 million outpatient visits per year in the U.S.2 In addition to its high prevalence, chronic pruritus affects multiple quality of life (QoL) parameters, including mood, concentration, eating habits, sexual function and sleep.3-5 Indeed, QoL studies have shown equivalence in terms of impact of chronic pain and chronic itch on QoL measures.6
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Despite the high burden of itch-associated conditions on both society and the individual, itch as a medical problem remains an overlooked epidemic because the etiology of itch remains poorly understood. Even 354 years after Hafenreffer initially defined pruritus, treatments remain limited, with no FDA-approved medications for use in humans.
It’s widely appreciated that chronic pruritus underlies multiple dermatologic conditions, such as atopic dermatitis (AD), contact dermatitis and psoriasis. Beyond the skin, pruritus is associated with a variety of systemic medical conditions, including, but not limited to, chronic kidney disease (CKD), liver dysfunction, malignancy, various infections and even psychiatric disease (see Table 1). Recent scientific advances have revealed previously unrecognized itch-specific pathways that are regulated by particular mediators, including neurotransmitters, pharmacologic agents and inflammatory cytokines (see Figure 1).7,8 Although off-label treatments can be employed, more investigation is needed to develop definitive therapeutics to appropriately target chronic pruritus. Recent scientific discoveries have led to a greater understanding of the mechanisms underlying the sensation of itch, which will invariably inform the design of novel treatments in the future.
Pathophysiology of Itch
Classically, itch was viewed as a mild form of pain. As a result, the prevailing wisdom was that the same neurologic pathways mediated both pain and itch. The identification of histamine-responsive neurons in the periphery revealed for the first time that distinct itch-sensitive, pain-independent pathways were present.9,10 However, it was widely appreciated that antihistamines, although effective in certain forms of itch (e.g., urticaria-associated itch), were ineffective in the treatment of many forms of chronic pruritus. These clinical observations provoked the hypothesis that perhaps histamine-independent pathways were present.
Acute itch, as seen in response to arthropod bites & poison ivy, is transient in nature. In contrast, chronic itch is highly debilitating & its etiology is often difficult to define.
Indeed, in 2009 Liu et al identified the Mas-related G protein-coupled receptor (Mrgpr) as a novel family of histamine-independent itch receptors expressed in the dorsal root ganglia (DRG).11 Subtypes of Mrgprs have been identified in both mice and humans.12 Further, MrgprA3 is activated by the drug chloroquine, which has been associated with the development of itch in patients.11 Beyond the peripheral nervous system (PNS), Sun et al identified the first receptor that mediates itch in the central nervous system (CNS), namely gastrin-releasing peptide receptor (GRPR).13 This seminal discovery identified that itch can be regulated both in the periphery, where exogenous pruritogenic stimuli may be encountered, as well as centrally in the spinal cord itself.
Collectively, these emerging studies demonstrate that the factors and pathways regulating itch are much more heterogeneous than previously recognized (see Figure 1). This new scientific paradigm of itch biology may help us to better understand and conceptualize the different forms of itch and their potential treatments.
Emerging studies demonstrate that the factors & pathways regulating itch are much more heterogeneous than previously recognized.
Categories of Itch
Acute itch, as seen in response to arthropod bites and poison ivy, is transient in nature. In contrast, chronic itch is highly debilitating and its etiology is often difficult to define. Chronic itch, defined as lasting greater than six weeks, accompanies a number of inflammatory skin diseases, such as AD and psoriasis, as well as systemic conditions, such as CKD and cholestasis.14 The presentation of chronic itch can be divided into five different clinical categories to help organize the clinical approach, diagnosis and treatment:15
- Systemic itch;
- Neuropathic itch;
- Psychogenic itch;
- Idiopathic itch; and
- Dermatologic itch.
In this review, we briefly outline our current understanding of each category of chronic itch and its potential treatments. Further, we highlight chronic pruritus as a problem in the context of rheumatologic and autoimmune diseases. Although the five categories of chronic itch overlap at times in terms of their pathophysiology and treatments, this structure allows for a systematic and logical clinical approach (see Table 1).
The causes of systemic itch are broad and include renal failure, cholestasis and other related hepatic diseases, malignancies, endocrine disorders, systemic infection and exposure to specific drugs. Although a variety of medical conditions underlie chronic itch due to systemic causes, a common theme among these disorders is that a systemic factor is either overproduced or inadequately metabolized and excreted to mediate the itch response. In the following section, we highlight current concepts and treatments regarding a few forms of the most common causes of systemic itch.
CKD is one of the main causes of systemic itch and is often referred to as renal pruritus. Renal pruritus affects up to 58% of patients with renal failure.16 It can be either intermittent or constant and most commonly affects the back, in addition to the head, arms and abdomen.17 Although the pathophysiology is unknown, multiple hypotheses have been suggested. For example, it has been proposed that immune dysregulation underlies renal pruritus, based on the observation that patients respond to immunosuppressive light therapy.18
Beyond the immune system, the accumulation of calcium, magnesium and phosphate due to a lack of renal clearance has also been hypothesized as a contributor. In support of this, symptoms often improve following interventions that normalize electrolytes, such as parathyroidectomy.19
More recently, serotonin and endogenous opioids have also been implicated in renal pruritus.20 Based on these observations, current therapies attempt to target a variety of these underlying processes. In renal pruritus, immunologic treatments include thalidomide, pentoxifylline, doxepin and broadband UVB therapy, which have demonstrated efficacy.21-24 Additionally, selective serotonin reuptake inhibitors (SSRIs), naltrexone and nalfurafine have also been employed to target serotonin and opioid dysregulation.25,26 Gabapentin with dialysis has also been shown to be very effective in multiple studies.27,28 However, universal treatments for renal pruritus remain limited.
Itch is a key determinant of the efficacy of new biologic therapeutics in psoriasis.
Another common systemic cause of chronic pruritus is liver disease. Specifically, diseases resulting in cholestasis are the most common cause of chronic itch in this context.29,30 For example, over 69% of patients with primary biliary cirrhosis report pruritus as a symptom.31 Cholestasis-associated pruritus is widespread and intractable, and can be severe enough to warrant liver transplantation.32 Although the pruritogens are unknown, bile salt and their metabolites are believed to be involved. One hypothesis is that pruritogens secreted into bile are converted in the liver and gut to modulate endogenous serotoninergic and opioidergic systems linked to pruritus.33 Treatment of cholestatic pruritus starts with addressing the etiology of liver disease, including gallstone removal or treatment with cholestyramine, which binds bile salts, or rifampin, which inhibits bile acid production.34,35 Additionally, naltrexone, which targets the opioidergic system, has demonstrated some efficacy.36 More recently, the potent neuronal activator lysophosphatidic acid (LPA) has been found to be elevated in sera of patients with cholestasis and pruritus and represents a potential future drug target.37 Similar to renal pruritus, the mechanisms of cholestatic pruritus and other hepatic etiologies still require further investigation for the development of definitive, targeted treatments.
Importantly, independent of end-organ dysfunction causing systemic chronic pruritus, medications should always be considered potential culprits. It is widely appreciated that opioids, calcium channel blockers (CCBs), β-adrenergic blockers and NSAIDs can induce pruritus.38 Hydroxychloroquine, an antimalarial that is often employed in the treatment of rheumatologic diseases, has also been reported to cause pruritus. As highlighted earlier, recent studies by Liu et al have revealed that this is mediated specifically via activation of Mrgpr on itch sensory neurons.11 Therefore, it’s imperative that patients be evaluated for long-term use of medications that may induce their chronic pruritus. Although we review only a few contributors to systemic pruritus, many etiologies exist. Therefore, when working up chronic pruritus, these should should be considered and have been reviewed extensively elsewhere.15,39,40
In contrast to systemic chronic itch, which is likely mediated by circulating factors or pruritogens, neuropathic itch derives from pathology along the afferent nervous system.41 The nervous system can be activated either centrally or peripherally. Tumors or degenerative diseases of the CNS (e.g., multiple sclerosis) can lead to centrally mediated mechanisms of pruritus.42
More commonly, neuropathic itch is triggered within the PNS. For example, viral damage to peripheral neurons is thought to mediate postherpetic itch in a manner similar to postherpetic neuralgia.43,44
Another example of peripherally mediated pruritus includes notalgia paresthetica, which presents as chronic, localized itch most often on the central back. Although the exact etiology remains unknown for notalgia paresthetica, it has been theorized that sensory nerve entrapment, involving the posterior rami of the T2 to T6 nerve root, occurs due to degenerative changes in the vertebrae.45 In a similar fashion, brachioradial pruritus manifests as chronic, intermittent pruritus along the arms and is thought to be caused by nerve impingement along the cervical spine.46
For the treatment of neuropathic itch, a variety of neuromodulators are employed empirically. For example, topical capsaicin has been shown to improve symptoms in notalgia parasthetica.47 The mechanism of action of capsaicin is activation of the sensory nerve receptor TRPV1, which leads to depletion of substance P and neuronal desensitization.48 For postherpetic itch and brachioradial pruritus, gabapentin has demonstrated efficacy as well.49 Its mechanism of action is believed to be via binding of the α2δ1 subunit of voltage-dependent calcium channels in dorsal horn postsynaptic cells.50
Other treatments attempted in neuropathic itch include oxcarbazepine, botulinum toxin or, in the case of nerve entrapment, physical therapy and/or surgery.
Psychogenic pruritus is a diagnosis of exclusion that presents in association with an underlying psychiatric disorder, such as obsessive-compulsive disorder (OCD), anxiety disorder or substance abuse.41 Associated conditions include neurotic excoriations or excoriation disorder, which is now recognized in the DSM-V manual.51 These diseases are strongly influenced by variations in life events and stress. Typical findings include excoriations, erosions, ulcers and scarring in areas of the body that can be easily manipulated by the patient, such as the extensor surfaces and face.52 Delusions of parasitosis, a relatively uncommon psychiatric condition, presents with the patient having a fixed belief that he or she has been infested with arthropods or parasites.53 The patient suffers from these delusions and consciously produces self-inflicted wounds as a result.
The overall approach to the treatment of psychogenic itch is to treat the underlying psychiatric disorder with anxiolytics, antidepressants and/or other neuroleptics. Patients typically need to see their primary physician regularly to develop strong therapeutic rapport. Once the patient is willing, a psychiatric referral is highly helpful, if not essential.
Idiopathic itch is defined as chronic itch in the absence of specific skin disease and lack of any evidence of underlying disease in the aforementioned categories.54 We include what has been described as pruritus of the elderly within this category because many aging conditions are not necessarily defined as distinct disease entities.55 Although the mechanism is unknown, it has been suggested that chronic generalized pruritus develops in response to gradual loss of skin barrier function, immunosenescence of the skin immune system and sensory neuropathy.56
Initial treatments can include restoring skin barrier function with cream- or ointment-based emollients and gentle atopic skin care. In severe cases, treatment by ‘soak and smear’ with topical steroids as well as steroid-sparing systemic agents such as azathioprine can be helpful.57 Similar to psychogenic itch, this is a diagnosis of exclusion and the astute physician must ensure no underlying systemic or inflammatory conditions are present.
Dermatologic (& Rheumatologic) Itch
Pruritus results most commonly from an inflammatory pathology in the skin. Atopic dermatitis, chronic urticaria, cutaneous T cell lymphoma (CTCL) and autoimmune skin conditions are often associated with chronic pruritus. Understanding the molecular basis of dermatologic itch will likely yield new targeted treatments. Recent studies have demonstrated that inflammatory cytokines, such as thymic stromal lymphopoietin (TSLP) (derived from keratinocytes) and IL-31 (derived from T helper type 2 cells), directly bind itch sensory neurons, suggesting that atopic itch may be targeted therapeutically (see Figure 1).58,59
In chronic idiopathic urticaria (CIU), activation of mast cells has been implicated in the pathogenesis of itch via the binding of IgE onto cell surface FcεRIα receptors.60 Indeed, this has been supported by recent clinical trials demonstrating that omalizumab, an anti-FcεRIα monoclonal antibody, is highly effective in the treatment of CIU-associated itch.61 Collectively, these studies demonstrate that the identification of novel immunologic pathways that mediate itch hold great promise for future treatments (see Figure 1).
In terms of autoimmune and rheumatologic skin disease, psoriasis is the most common and affects 1–3% of the population. It presents with silvery, scaly plaques, generally on extensor surfaces.62 The prevalence of pruritus among patients with psoriasis ranges from 64–97%, and the intensity of itch severity correlates with the development of lesional plaques.63-67 Although T helper type 17 (Th17) cell responses have emerged as dominant mechanisms underlying psoriasis, the definitive pathway by which itch is elicited remains poorly defined.68,69 Notwithstanding this, itch is a key determinant of the efficacy of new biologic therapeutics in psoriasis.
Beyond psoriasis, other autoimmune conditions affecting the skin have been associated with decreased QoL due to pruritus, including morphea, systemic sclerosis and dermatomyositis.70-73 In a recent study, among 959 patients with systemic sclerosis, 42.6% reported pruritus, and its presence was significantly associated with skin and gastrointestinal involvement of disease.74 This suggests that pruritus may be an indicator of systemic disease burden. In the context of cutaneous lupus erythematosus (CLE) and dermatomyositis (DM), a recent study demonstrated that DM has a much stronger association with pruritus than lupus and may help to distinguish between those individuals with CLE and DM.73 Further, improvement of DM disease severity is associated with improvement in pruritus and QoL.75 This is consistent with prior studies demonstrating that pruritus is a significant contributor to QoL in DM patients.76,77
Taken together, these studies demonstrate that the burden of chronic pruritus in rheumatologic diseases is significant and multifaceted. A unifying theme of pruritus associated with autoimmune disease is that it is another measure of disease activity and adequate treatment of the underlying process is essential to improvement of the symptom.
In summary, we have highlighted five broad categories of itch: 1) systemic, 2) neuropathic, 3) psychogenic, 4) idiopathic and 5) dermatologic. Itch associated with rheumatologic disease is generally manifested in the latter category. The potential causes of chronic pruritus in most patients are multifactorial.
Overall, stratifying the potential causes of pruritus allows for a systematic approach, aiding the provider in developing a better understanding of the underlying diseases, pathophysiology and potential treatments. Emerging studies are revealing previously unrecognized pathways that regulate itch and hold great promise for new, targeted treatments.
Shivani V. Tripathi, MD, is a clinical research fellow in the Division of Dermatology at Washington University School of Medicine in St. Louis, Mo.
Brian S. Kim, MD, MTR, is assistant professor of medicine (dermatology) in the Department of Medicine/Division of Dermatology at Washington University School of Medicine in St. Louis, Mo.
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