Pathophysiology of Itch

Synopsis

Chronic itch is a clinically challenging yet scientifically remarkable and complex process. Increasing understanding of the pathophysiology of chronic itch is leading to targeted therapeutic approaches that are now dramatically improving quality of life. This improvement will accelerate as the tools of basic and clinical research continue to be applied to this previously intractable problem.

The pathophysiology of chronic itch differs markedly from the physiology of acute itch. Acute itch physiology is encompassed by stimulation of sensory neural fibers in the skin resulting in a signal being sent to the brain that is interpreted as itch followed by a motor response to scratch such that the stimulus that initiated the cycle is removed (1). Chronic itch is filled with complexity, redundancy and dynamic processes (2). There is no single chronic itch but rather distinct and overlapping chronic itches. A detailed understanding of the pathophysiology that underlies chronic itches is now leading to targeted therapeutic approaches for distinct itches and is making a difference in the clinic.

At the clinical level, chronic itches are defined as those lasting six weeks or longer. Everyone with atopic dermatitis itches. While there are commonalities between their itches, the itches also differ by a variety of measures. These include the quality and severity of the sensation, components of burning, pricking, stinging and pain (3). Scratching can be pleasurable and may or may not relieve the itch until pain is generated on account of localized removal of the epidermis. In chronic urticaria, itch is a given although scratching is neither pleasurable nor helpful with the response primarily related to rubbing. In other inflammatory conditions, such as psoriasis, itch may or may not be a feature. In systemic conditions that are not necessarily considered inflammatory, such as chronic liver and chronic kidney diseases, itch can be intense but may not be associated with specific skin manifestations and neither the sensation of itch nor its location is uniform. Add to these the itches, entirely not understood and for which no therapeutic approaches are regularly beneficial, that result from the emerging use of immune checkpoint inhbitors to treat cancer (4). Next the neurogenic or neuropathic itches, including brachioradial pruritus and notalgia paresthetica, which may be associated with nerve compression rather than a conventional inflammatory component, and herpes zoster, which does. Finally, there are psychogenic itches associated with conditions ranging from depression or obsessions to delusions of parasitosis in which the entire process may be localized in the brain, raising the question whether targeting the periphery can have an impact. Chronic itch is thus associated with a broad range of clinical entities that can arise in distinct anatomic locations. Therapeutic approaches that restore homeostasis or interrupt the flow of immunologic or neurosensory information in the area may be of benefit for particular itches.

At the environmental, biochemical, molecular and cellular levels, a vast number of waypoints exist between the skin and brain. At the wide entrance to the funnel are exogenous agents, including components of the microbiome and larger environmental stimuli such as arthropods and plants, in addition to irritants and materials with different pH, moisture content and temperature. These interface with endogenous components comprising the skin barrier, keratinocytes and a plethora of immune cells, each of which has an interactive conversation with one another and with sensory fibers that transmit histamine-dependent and histamine-independent itch. This conversation includes direct cell-cell communication, selective granule release, as well as numerous mediators, receptors and channels that can be shared directly or through family members across the many different cell types. The sensory fibers extend to dorsal root ganglia outside of the spinal cord and then synapse with second order neurons in the spinal cord. While the funnel may be squeezed at this point, that view is again simplistic given the extensive excitatory and inhibitory neural circuitry, together with the contribution of microglia, in the spinal cord. These conversations in the spinal cord converge to brain regions with the funnel ultimately narrowing as the sensation as itch is interpreted (5). However, with the possible exception of histamine accounting for urticaria in some patients, there are no examples in which either the mediators of chronic itch or biomarkers have been definitively correlated with a particular itch. The lack of clarity with respect to the contribution of individual components to chronic itch presents an opportunity ripe for analysis via the application of proteomic, metabolomic and next generation sequencing approaches. It is logical to posit that comparative proteomics and metabolomics if applied to populations of patients with itchy and non-itchy primary biliary cirrhosis or chronic kidney disease might allow for the mediators to be determined. Chronic itch is thus associated with distinct but interacting environmental, biochemical, molecular and cellular components. Again, therapeutic approaches that restore homeostasis or effectively interrupt the flow of information between these components may be of benefit for particular itches.

At the conceptual level, chronic itch may result from peripheral or central sensitization (6), terms borrowed from the chronic pain field. In peripheral sensitization, chronic itch develops from activation of pruriceptors, akin to nociceptors that respond to pain. Chronic exposure to pruritogens or inflammatory mediators that are associated with itch enhances the responsiveness of pruriceptive nerve fibers. Peripheral sensitization leads to increased action potential firing and transmitter release in the dorsal horn of the spinal cord, where somatosensory information is processed. Mediators released from microglia in the dorsal horn modulate the activity of neurons in the vicinity. The heightened activity of dorsal horn neurons leads to heightened excitability and is termed central sensitization. It is possible that sensitization is a parallel to long-term potentiation associated with learning and memory. Sensitization is considered responsible for exaggerated responses to itchy stimuli and is termed hyperknesis. Sensitization contributes to itch elicited by normally non-pruritic stimuli, or alloknesis. Peripheral and central sensitization may well be associated with epigenetic changes but have not yet been reported. Therapeutic approaches that allow for reversal or modulation of epigenetic changes are likely to be of benefit in chronic itch associated with sensitization.

The paragraphs above are purposely general. There are extensive lists of components that are considered to be part of the itch pathways (7). These lists reveal the current state of knowledge but are not yet complete enough to generate a convincing gestalt as to the physiology of itch and thus the pathophysiology. That does not imply a lack of progress. The literature is replete with in vitro studies that replicate portions of itch pathways. In in vivo studies, especially those that employ state-of-the-art genetic models in mice, spontaneous itch develops or, when stimuli provided over a few days to a few weeks, scratching bouts counted, and considered chronic itch. These models are limited with respect to clinical correlates as none accurately recapitulates chronic itch in patients although they do reveal that a plethora of channels, receptors and mediators contribute to chronic itch that is associated with cutaneous inflammation or neural pathways. A limited selection of this plethora includes transient receptor potential channels, sodium channels, ligand-gated ionotropic and metabotropic receptors, toll-like receptors, cytokine receptors and a series of G-protein coupled receptors (GPCR) including the gastrin-releasing peptide receptor, neurokinin 1 receptor, members of the mas-related GPCR family, the neuropeptide Y, opiate receptors and, when known, their respective ligands. All of these contribute to itch and in certain cases, its modulation.

As might be expected, treatment approaches that correct or interrupt the flow of information between the skin and dorsal root ganglia have been shown to be effective for the chronic itches associated with inflammatory skin diseases, Corticosteroids have long been used to reduce inflammation with the benefit of relieving itch, demonstrating a link between the immune and nervous systems. Blocking the activity of interleukin-31 rapidly alleviates itch in patients with atopic dermatitis while inflammation is maintained, perhaps allowing for unlinking the immune and nervous systems (8). Blocking the IL-4/IL-13 pathway is effective at treating the inflammatory aspects of many, but not all, patients with atopic dermatitis (9). The relief of itch from this therapeutic approach may result from the anti-inflammatory activity as well as blockade of IL-4 receptors expressed on sensory nerves. This possibility is supported by the demonstration that an inhibitor of Janus-associated kinases (JAKs), which are downstream of IL-4 receptor activation, appears to be effective in examples of chronic idiopathic pruritus (10).

Finely targeted approaches are increasingly available for some chronic itches of inflammatory skin disease. Less targeted approaches are used for the treatment of neurogenic, neuropathic or psychogenic itches. This therapeutic paucity will change as more is learned about the processes underlying these conditions. In summary, detailed understanding of the pathophysiology of chronic itch is becoming achievable. This understanding should lead to safe, effective and targeted therapeutics. To paraphrase Winston Churchill, we are near the end of the beginning of understanding chronic itch.

Key Points.

• Chronic itch has a major negative impact on quality of life.

• There are chronic itches, not only one chronic itch.

• The pathophysiology of chronic itch is becoming increasingly understood.

• This understanding is being driven by findings in basic and clinical research combined with clinical responses to new classes of therapeutic agents that specifically target cytokines, receptors and channels.