Introduction Atopic dermatitis AD is a
Atopic dermatitis (AD) is a common chronic relapsing disease with intense itch. AD usually accompanies a personal or familial history of allergic diseases, including allergic rhinitis, asthma, and allergic conjunctivitis. Itch is the cardinal symptom of AD. It severely interferes with the life quality of patients and their caregivers and it may impair school and work performance and trigger anxiety and depression. The prevalence of AD is estimated to be 6–9% in Taiwan. While the exact pathogenesis of AD remains to be investigated, both impairment of the skin barriers and aberrant immune activation play significant roles in its pathogenesis.
Itch perception: From skin initiation to cgrp activation Itch is a unique perception that provokes one to desire to scratch to get rid of noxious stimuli. Cough, which may be induced by noxious chemicals or particles, is a similar action used to expel such stimuli. The epidermis is innervated by small unmyelinated C fiber. The perception of itch is transmitted from the peripheral free nerve endings (C fiber) in the epidermis back to the neuron body in the dorsal root ganglion located at the spinal cord. Subsequently, a synapse in the spinal cord transmits the signal in the contralateral spinothalamic tract to the thalamus, and eventually the signal radiates to the cortical neurons. In skin, the propagation of itch could result from both inflammatory and noninflammatory diseases. AD is a prototypic inflammatory skin disease that is always accompanied by intense itching. People affected by other inflammatory skin diseases, such as lupus erythematosus and pityriasis lichenoides, may or may not experience itch. Among the noninflammatory skin diseases, some diseases (e.g., uremic pruritus) may cause itch, but others (e.g., stable vitiligo) may not. In diseases with inflammatory conditions, immune factors may play a significant role in the initiation of itch. On the other hand, in those diseases with noninflammatory conditions, neurogenic factors may play a more significant role in itch pathophysiology. Several functional imaging studies have been performed to observe the functional activation of itch signals in the brain. However, different diseases associated with itching can cause differences in the activation of the brain cortex. Furthermore, histamine-induced or non-histamine-induced itch causes differences in the chronological and topological activation of the brain cortex. Based on the principle of near-infrared spectroscopy, one of our previous studies demonstrated that brain cortex activation, reflected by changes in oxygenated and deoxygenated hemoglobin levels, in histamine-induced itch is distinctly different from push–pull gauge-induced pain.
Impaired skin barrier and itch perception AD is characterized by the impairment of the skin barrier. The epidermis is an intact tissue that protects the human body from harsh outside environments and is fully organized with ordered differentiated keratinocytes and has a densely packed corneal layer equipped with “brick and mortar.” However, the impaired skin barrier in AD allows the entry of potential allergens, which subsequently aggravate the inflammatory responses and thereby further deteriorate the impaired skin barrier, creating a vicious cycle. Filaggrin, an important protein that binds to keratins associated with keratinocyte differentiation, is important to the integrity of the skin barrier. In AD, approximately half of the patients are affected by the mutations in filaggrin. The loss or mutation of filaggrin, which decreases the skin\'s ability to hold water, impairs skin barrier function. On the other hand, enhancing the barrier function of the skin increases the therapeutic effects on AD. We previously found an association between barrier dysfunction, an increase in transepidermal water loss (TEWL), and itch intensity. The greater the TEWL, the worse the itch. In fact, increased TEWL has been positively correlated with an increase in skin pH, promoting the activity of serine proteases to their disruption of the skin barrier and inducing pruritus.