Pathophysiology and clinical aspects of the itch (2023/2024)

Learning outcomes

The aim of the course is to discuss the neuro-physiological mechanisms of itching, the main chemical mediators involved, the clinical relevance of the symptom, the main diseases in which the symptom is dominant and the therapeutic aspects of itching in the main pathologies.

Pruritus is defined as an unpleasant sensation that provokes the desire to scratch. Pruritus is a common
symptom of numerous inflammatory skin diseases, and it can be severe enough to interfere with sleeping
and daily activities, and impact markedly on patients’ quality of life. Chronic pruritus (CP) is defined
clinically by its persistence for more than 6 weeks and it is a frequent complaint in the general population,
with a 13.5-16.8% point prevalence. CP can be classified on the basis of its underlying aetiology as
dermatological, systemic, neurological, somatoform or multifactorial [3] . The neurophysiology and basic
mechanisms underlying CP have been recently elucidated using animal models and with clinical studies,
contributing to new pathophysiological and therapeutic concepts. CP is a common symptom of a
heterogeneous spectrum of cutaneous inflammatory skin diseases, which have been recently re-classified
according to their immune response pattern, based on specific cellular and cytokine signatures.
The itch sensation usually originates around the dermo-epidermal junction by the activation of selective or
specific nerve endings called pruriceptors. Then, itch is processed and transmitted by specific pathways
through nerves and the spinal cord to the brain. At least two classes of primary afferent C fibers transmit
itch, mechano-insensitive C fibers and mechano-responsive polymodal C-nociceptor units, as well as thinly
myelinated Aδ fibers afferents. Specific receptors located on these fibers can be activated by a large
number of endogenous itch-inducing agents released by keratinocytes, immune cells or neighbouring
neuronal afferent and exogenous agents, such as proteases released by Staphylococcus aureus. These
sensory neurons have cell bodies in the dorsal root ganglion (DRG) and project primary afferents to the
skin, and they send projections to the dorsal horn of the spinal cord, where they synapse with second- or
third-order neurons, that come together to form part of the spinothalamic tract, which then ascends up to
the thalamus and proceed to the somatosensory and the anterior cingulate cortex. Second- and third-order
neurons in the spinal cord may have either excitatory or inhibitory functions. Pathways of itch are complex
and not fully established. Moreover, pruritus and pain pathways are largely overlapped and interrelated,
though the exact relationships are still a matter of debate. Several chemical pruritogens and some physical
stimuli have been experimentally used to elicit itch to investigate pruritus pathways and test potential anti-
pruritic drugs. However, no objective methods to elicit and to evaluate itch have been standardized.
Pruritus is a common symptom of several skin diseases, both inflammatory and neoplastic. Pruritus may
have a tremendous impact on the patients’ quality of life and strongly interfere with sleep, social and work
activities. We review the role of type-2 inflammation and immunity in the pathogenesis of chronic pruritic
conditions of the skin. Type 2 cytokines, including IL-4, IL-13, thymic stromal lymphopoietin, periostin, IL-
31, IL-25 and IL-33 are released by mast cells, innate lymphoid cells 2, keratinocytes and type 2 T
lymphocytes and are master regulators of chronic itch. These cytokines may act as direct pruritogen on
primary sensory neurons (pruriceptors) or alter the sensitivity to other itch mediators Type 2 inflammation-
and immunity-dominated skin diseases, including atopic dermatitis, prurigo nodularis, bullous pemphigoid,
scabies, parasitic diseases, urticaria, and Sézary syndrome are indeed conditions associated with most
severe pruritus. In contrast, in other skin diseases, such as scleroderma, lupus erythematosus, hidradenitis
suppurativa, and acne, type 2 inflammation is less represented, and pruritus is milder or variable. Th2
inflammation and immunity have evolved to protect against parasites, and thus, the scratching response
evoked by pruritus may have developed to alert about the presence and to remove parasites from the skin
surface.

Interview