Similarities and differences in peripheral itch and pain pathways in atopic dermatitis.

Atopic dermatitis (AD) is predominantly characterized by intense itching, but concomitant skin pain is experienced by more than 40% of patients. Patients with AD display considerable somatosensory aberrations, including increased nerve sensitivity to itch stimuli (hyperknesis), perception of itch from innocuous stimuli (alloknesis), or perception of pain from innocuous stimuli (allodynia). This review summarizes the current understanding of the similarities and differences in the peripheral mechanisms underlying itch and pain in AD. These distinct yet reciprocal sensations share many similarities in the peripheral nervous system, including common mediators (such as serotonin, endothelin-1, IL-33, and thymic stromal lymphopoietin), receptors (such as members of the G protein-coupled receptor family and Toll-like receptors), and ion channels for signal transduction (such as certain members of the transient receptor potential [TRP] cation channels). Itch-responding neurons are also sensitive to pain stimuli. However, there are distinct differences between itch and pain signaling. For example, specific immune responses are associated with pain (type 1 and/or type 3 cytokines and certain chemokine C-C [CCL2, CCL5] and C-X-C [CXCL] motif ligands) and itch (type 2 cytokines, including IL-31, and periostin). The TRP melastatin channels TRPM2 and TRPM3 have a role in pain but no known role in itch. Activation of µ-opioid receptors is known to alleviate pain but exacerbate itch. Understanding the connection between itch and pain mechanisms may offer new insights into the treatment of chronic pain and itch in AD.

Cutaneous Components Leading to Pruritus, Pain, and Neurosensitivity in Atopic Dermatitis: A Narrative Review.

Atopic dermatitis (AD) is a chronic, relapsing immunoinflammatory skin condition characterized by sensations such as pruritis, pain, and neuronal hypersensitivity. The mechanisms underlying these sensations are multifactorial and involve complex crosstalk among several cutaneous components. This review explores the role these components play in the pathophysiology of atopic dermatitis. In the skin intercellular spaces, sensory nerves interact with keratinocytes and immune cells via myriad mediators and receptors. These interactions generate action potentials that transmit pruritis and pain signals from the peripheral nervous system to the brain. Keratinocytes, the most abundant cell type in the epidermis, are key effector cells, triggering crosstalk with immune cells and sensory neurons to elicit pruritis, pain, and inflammation. Filaggrin expression by keratinocytes is reduced in atopic dermatitis, causing a weakened skin barrier and elevated skin pH. Fibroblasts are the main cell type in the dermis and, in atopic dermatitis, appear to reduce keratinocyte differentiation, further weakening the skin barrier. Fibroblasts and mast cells promote inflammation while dermal dendritic cells appear to attenuate inflammation. Inflammatory cytokines and chemokines play a major role in AD pathogenesis. Type 2 immune responses typically generate pruritis, and the type 1 and type 3 responses generate pain. Type 2 responses and increased skin pH contribute to barrier dysfunction and promote dysbiosis of the skin microbiome, causing the proliferation of Staphyloccocus aureus. In conclusion, understanding the dynamic interactions between cutaneous components in AD could drive the development of therapies to improve the quality of life for patients with AD.

Maintenance of Investigator's Static Global Assessment Response with Once-Daily Crisaborole in Participants with Mild to Moderate Atopic Dermatitis.

INTRODUCTION: Treatments for atopic dermatitis (AD) often fail to achieve lasting disease control. In the CrisADe CONTROL phase III study (ClinicalTrials.gov: NCT04040192), participants aged ≥ 3 months with mild to moderate AD treated with once-daily (QD) crisaborole, following initial treatment success with crisaborole twice daily (BID), had longer periods of flare-free maintenance, a higher number of flare-free days, and a lower number of flares compared with those who received vehicle. The study was an exploratory analysis of data on the maintenance of response per Investigator's Static Global Assessment (ISGA; ISGA score of 0 [clear] or 1 [almost clear]) during the CrisADe CONTROL study through week 52. METHODS: Exploratory endpoints were the time to ISGA response during the open-label run-in period, and the maintenance of ISGA response and the severity and duration of flares during the double-blind maintenance period. Outcomes were stratified by age (participants aged 3 months to < 12 years and ≥ 12 years) and duration of crisaborole BID treatment (< 4 weeks or ≥ 4 weeks) during the open-label run-in period. RESULTS: During the open-label run-in period, the median time to ISGA response was 41.5 days. From week 4 to week 52 of the double-blind maintenance period, the proportion of participants who maintained ISGA response was greater with crisaborole versus vehicle, and this difference was statistically significant up to week 36 (P < 0.05). Duration of flare periods during the maintenance period were 54.1 and 54.0 days for the vehicle and crisaborole-treated groups, respectively. Numerically fewer crisaborole-treated participants experienced a flare with an ISGA score of ≥ 2 compared with vehicle-treated participants (64.8% vs. 74.4%, respectively). Findings were comparable across most subgroups. CONCLUSIONS: Adult and pediatric participants with mild to moderate AD at baseline who had achieved responder criteria (treatment success) with crisaborole BID during the run-in period maintained response per ISGA with crisaborole QD during the double-blind maintenance period through week 52. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04040192.

Atopic dermatitis is a skin disease that causes itchy, red, and dry patches of skin that can affect a person for a long time. Current treatments for atopic dermatitis often fail to keep the symptoms under control. Some creams and ointments applied to the skin (known as topical treatments) can ease the discomfort of atopic dermatitis. Crisaborole is a steroid-free ointment that has been shown to improve symptoms of atopic dermatitis in clinical studies. In a study called the CrisADe CONTROL trial, crisaborole was tested to see if it can keep atopic dermatitis symptoms under control. People who participated in the study were aged 3 months and older and they had mild-to-moderate atopic dermatitis. Participants were asked to use crisaborole on their itchy, red, and dry skin twice daily for 8 weeks. Patients were called "responders" if their symptoms became nearly clear or completely clear based on a doctor's assessment called the Investigator's Static Global Assessment, which rates atopic dermatitis between clear to severe. Some responders were asked to use crisaborole once daily for 52 weeks and another group of responders was asked to use a control (an ointment with no medicine) once daily for 52 weeks. Investigators looked at how long the skin remained nearly clear or completely clear during the 52 weeks. Results of this study showed that after initial treatment success with crisaborole twice daily, adult and pediatric participants who had mild-to-moderate atopic dermatitis were able to keep their skin nearly clear or completely clear with crisaborole once daily.

Stasis Dermatitis: An Overview of Its Clinical Presentation, Pathogenesis, and Management.

Stasis dermatitis is a chronic inflammatory skin disease of the lower extremities. It typically occurs in older individuals and is the cutaneous manifestation of venous hypertension caused by venous reflux. Such retrograde venous blood flow is the result of incompetent venous valves, valve destruction, or venous obstruction. Stasis dermatitis is eczematous. The associated impairment of venous valves may cause swelling of the legs, leading to serious conditions including venous ulcerations. Diagnosis can be challenging because of its clinical resemblance to other skin conditions and poor clinical recognition by physicians. The cornerstones of stasis dermatitis treatment are compression therapy to ameliorate pain and swelling, topical treatments to alleviate secondary skin changes, and interventional treatment options to correct the underlying causes of venous reflux. Given the central role of inflammation of the lower extremities in driving the cutaneous changes characteristic of stasis dermatitis, new therapeutic approaches that target the inflammation are under clinical evaluation in patients with stasis dermatitis.

Stasis dermatitis is a skin disease that can affect a person for a long time. It affects the legs of older people who have a disease called chronic venous insufficiency. This is when a person's veins have difficulty sending blood from their limbs back to their heart. Stasis dermatitis is caused by increased pressure inside a person's veins. Its signs and symptoms are skin discoloration, itch, dryness, and scaling and can be similar to the signs and symptoms of cellulitis and allergic contact dermatitis. Cellulitis is a common skin infection caused by bacteria. Cellulitis causes redness, swelling, and pain. Allergic contact dermatitis is an itchy skin rash caused by contact with something that irritates the skin. Stasis dermatitis is usually diagnosed after a healthcare provider has looked at person's skin and their medical history. Treatment for stasis dermatitis should treat the chronic venous insufficiency that causes the disease. It should also treat the skin lesions caused by stasis dermatitis. One way to treat stasis dermatitis is to reduce pain and swelling. This is done by applying pressure with compression stockings or bandages. Minor surgery can treat the venous insufficiency that causes stasis dermatitis. No treatments have been approved for the skin symptoms associated with stasis dermatitis. New ways to treat such symptoms need to be developed.

Stasis Dermatitis: The Burden of Disease, Diagnosis, and Treatment.

Stasis dermatitis (SD), an inflammatory dermatosis occurring on the lower extremities, is a cutaneous manifestation of chronic venous insufficiency (CVI). SD is associated with a significant burden of disease. Symptoms such as pain, swelling, and itching can be debilitating for patients, leading to poor sleep, loss of mobility, and the inability to perform daily activities, and can interfere with work and leisure activities. Moreover, SD is a progressive disease with serious secondary complications such as ulcerations, which increase the patients' morbidity, reduce their quality of life, and increase health care burden. Challenges in diagnosing patients may have both short- and long-term sequalae for the patients due to unnecessary treatment and management. In addition, misdiagnosis may result in hospitalizations, placing additional burden on health care professionals in terms of time and financial burden on the health care system. Compression therapy and leg elevation represent the mainstay of treatment for CVI; however, it is also difficult to self-manage, which places a substantial burden on patients and caregivers. Moreover, compression therapy may cause discomfort and exacerbate itching. Subsequent nonadherence may result in disease progression that places additional burden on the physicians who manage these patients and the health care system in terms of resources required and costs incurred. A large proportion of patients with SD develop allergic contact dermatitis because of innate immune signals and altered skin barrier predisposing to sensitization to topical prescriptions, over-the-counter medications, and compression devices used to treat SD. Other than topical corticosteroids, there are no approved pharmacological options to treat inflammation in SD.