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.

Trends of Diagnosis, Disease Course, and Treatment of Atopic Dermatitis 2012-2021: Real-World Data from a Large Healthcare Provider.

In the last decade, new treatments for atopic dermatitis (AD) have emerged. We aimed to describe trends of the diagnosis, disease course, and treatment of AD over a decade (2012-2021) using data from Maccabi Healthcare Services (a 2.7-million-member healthcare provider in Israel). The AD prevalence was stable (4.0% on 31 December 2021 vs. 4.3% on 31 December 2012). The annual AD incidence was also stable (5.8/1000 in 2012 and 5.7/1000 in 2021). AD-related treatment use was highest in the first year post-diagnosis, and it included, among children (n = 87,414) vs. adults (n = 36,865), low-potency topical corticosteroids (TCS) (41.8% vs. 27.1%), mid-potency TCS (30.1% vs. 28.1%), high-potency TCS (34.9% vs. 60.3%), topical calcineurin inhibitor (10.8% vs. 10.1%), phosphodiesterase-4-inhibitor (0.3% vs. 0.7% overall; approved in 2019), phototherapy (0.1% vs. 2.3%), and systemic/biologic treatments (13.0% vs. 13.3%). Among children diagnosed in 2012 and followed through to 2021 (n = 5248), 21.5% had ≥1 AD diagnosis/treatment 10 years later (among 3223 adults: 38.3%). We conclude that the incidence and prevalence rates of AD were comparable to those in similar database studies and remained relatively stable over the past decade. The results underscore the burden of medication use among children and adults, particularly in the first year after AD diagnosis, and the low rate of AD diagnosis among patients originally diagnosed as children 10 years earlier.

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.

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.

Potential application of PS-OCT in the safety assessment of non-steroidal topical creams for atopic dermatitis treatment.

Crisaborole 2% ointment is a non-steroidal treatment for mild-moderate atopic dermatitis (AD) and may produce fewer adverse effects than topical corticosteroids (TCS). We used PS-OCT to quantify dermal collagen at baseline and after 29 days of treatment with crisaborole and betamethasone valerate (BMV), in 32 subjects. PS-OCT detected a mean increase 1 × 10-6, 95% CI (6.3, 1.37) × 10-6 in dermal birefringence following TCS use (p < 0.0001, ad-hoc, not powered), whereas a change of -4 × 10-6, 95% CI (-32, 24) × 10-6 was detected for crisaborole (p = 0.77, ad-hoc, not powered). These results could suggest a differential effect on dermal collagen between the two compounds. PS-OCT may thus find an important role in safety assessment of novel AD treatment' and larger trials are warranted.

Narrative Review of the Pathogenesis of Stasis Dermatitis: An Inflammatory Skin Manifestation of Venous Hypertension.

INTRODUCTION: Stasis dermatitis (SD), also known as venous dermatitis, is a form of inflammatory dermatitis of the lower extremities that typically occurs in older individuals and represents a cutaneous manifestation of venous hypertension. Venous hypertension (also known as sustained ambulatory venous pressure) is most often due to retrograde blood flow, which occurs due to calf muscle pump failure. This failure is most commonly secondary to incompetent venous valves, valve destruction, or obstruction of the venous system. Many of the common symptoms associated with SD are caused by inflammatory processes. METHODS: This review summarizes the pathogenesis and key role of inflammation in SD by reviewing inflammatory biomarkers associated with SD. The literature was selected though a high-level PubMed search focusing on keywords relating to inflammation associated with SD. RESULTS: Venous reflux at the lower extremities causes venous hypertension, which leads to chronic venous insufficiency. High venous pressure due to venous hypertension promotes the local accumulation and extravasation of inflammatory cells across the vascular endothelium. Leukocyte trapping in the microcirculation and perivascular space is associated with trophic skin changes. Cell adhesion molecules are linked with the perpetuated influx of activated leukocytes into inflammatory sites. Here, inflammatory cells may influence the remodeling of the extracellular matrix by inducing the secretion of proteinases such as matrix metalloproteinases (MMPs). The increased expression of MMPs is associated with the formation of venous leg ulcers and lesions. Phosphodiesterase 4 activity has also been shown to be elevated in individuals with inflammatory dermatoses compared to healthy individuals. DISCUSSION: Because inflammation is a key driver of the signs and symptoms of SD, several of the highlighted biomarkers of inflammation represent potential opportunities to target and interrupt molecular pathways of cutaneous inflammation and, therefore, remediate the signs and symptoms of SD. CONCLUSION: Understanding the pathogenesis of SD may help clinicians identify drivers of inflammation to use as potential targets for the development of new treatment options.

Stasis dermatitis is a skin disease that affects the legs, most often of older people, with chronic venous insufficiency. Chronic venous insufficiency is when veins cannot return blood from the legs back to the heart. This leads to high blood pressure in veins and causes blood in those veins to flow backwards. If stasis dermatitis is left untreated, complications, including skin ulcers, can result. Other skin symptoms of stasis dermatitis include itchiness, scaling, and discoloration. Such skin symptoms can have a negative effect on a person's quality of life. Inflammation that lasts a long time is likely the main link between the skin changes seen in people with stasis dermatitis and the increased pressure in leg veins. Several molecules are associated with the inflammation observed in stasis dermatitis, including white blood cells, matrix metalloproteinases, phosphodiesterase 4, and interleukin-31. Treatment for stasis dermatitis should focus both on the underlying chronic venous insufficiency and the associated skin issues. Identifying inflammatory markers and pathways could help treat the signs and symptoms associated with stasis dermatitis, including the skin symptoms.

Characteristics of Atopic Dermatitis Patients Treated with Crisaborole: Real-World Data from a Large Healthcare Provider Database in Israel.

Background: In recent years, new treatments dedicated to atopic dermatitis (AD) have become available in Israel, including crisaborole, a small molecule with unique benzoxaborole chemistry. Objective: To describe baseline characteristics, history of AD therapies, and use of health-care services of early crisaborole users in real-world settings. Methods: A retrospective cohort study was performed using the data of a large health provider in Israel. AD patients treated with crisaborole since it became commercially available in Israel in July 2019 through end of Sep 2020, were included. Baseline demographics and clinical characteristics, prior AD-related treatments and healthcare resource utilization were collected. Results: A total of 441 patients were included (57.8% females, median age = 21.1y; interquartile range = 10.5-40.8). In 62.1%, a dermatologist prescribed the first dispensed crisaborole. Median time from AD diagnosis to crisaborole treatment was 6.6 years. Up to 12 months prior to crisaborole treatment, low-, mid- and high-potency TCS were used by 30.8%, 31.1% and 55.8% of patients, respectively. Treatments related to moderate-to-severe AD were dispensed to 38.5% of patients in the prior 5 years. Asthma and allergic rhinitis were documented among 22.2% and 37.2%, respectively. In the past year, patients had a median of 9 visits to primary care physicians, 84.6% visited a dermatologist (≥5 visits: 12.9%). Conclusion: While crisaborole is indicated for mild-to-moderate disease, results suggest that a significant proportion of patients had history of advanced AD therapies suggestive of moderate-to-severe AD.

Multilocus sequence typing (MLST) of Escherichia coli O78 strains.

Strains of Escherichia coli serotype O78 are associated with many diseases, including invasive infections, in humans and farm animals. The clonal relationship between strains from different hosts is therefore important for assessing the risk of zoonotic infections. Here we propose a multilocus sequence typing scheme for E. coli, based on six housekeeping genes. Preliminary, but significant, results indicate that clonal division in E. coli O78 strains is host independent, and closely related clones reside in different hosts. There was a positive correlation between virulence and clonal origin.