Prevalence and burden of atopic dermatitis involving the head, neck, face, and hand: A cross sectional study from the TARGET-DERM AD cohort.

BACKGROUND: Atopic dermatitis (AD) is severely burdensome, and there has been poor characterization of any differences in impact based on the area affected. OBJECTIVE: To estimate the prevalence and HRQoL impact of head/face/neck/hand (HFNH) involvement among patients with moderate-to-severe atopic dermatitis. METHODS: All TARGET-DERM AD registry patients with moderate/severe Investigator Global Assessment (vIGA-AD) were assessed using the Patient Oriented SCORing Atopic Dermatitis, Patient Oriented Eczema Measure (POEM) and the (Children's) Dermatology Life Quality Index ((C)DLQI). RESULTS: 541 participants met the criteria (75.0% adults) and 84% (N = 453) reported HFNH involvement. HFNH and non-HFNH involved participants had similar characteristics; 55.2% female and 46.9% White. Compared to the non-HFNH involved, the involved had severe vIGA-AD (28.5% vs 16.3%, P = .02) and higher median body surface area affected (15% vs 10%, P ≤ .01) and were twice as likely to have higher (C)DLQI and POEM scores. LIMITATIONS: This was an analysis of real-world and patient reported outcome data. CONCLUSION: Real-world HFNH involved AD patients were associated with significantly worse quality of life, POEM/(C)DLQI, and more severe disease. Detailed assessments of specific areas affected by AD are needed to personalize treatment.

Do Atopic Dermatitis Patient-Reported Outcomes Correlate With Validated Investigator Global Assessment? Insights From TARGET-AD Registry.

BACKGROUND: Research examining associations between the clinician-reported validated Investigator Global Assessment for AD (vIGA-AD) and patient-reported disease burden is sparse. This study aims to evaluate the relationship between vIGA-AD with patient-reported disease severity and quality of life (QoL). METHODS: A cross-sectional analysis was conducted using a September 2021 data cut from the TARGET-DERM AD study, a real-world, longitudinal cohort of children, adolescents, and adults with AD enrolled at 44 academic and community dermatology and allergy sites in the US. Clinical AD severity was measured using vIGA-AD while disease severity and QoL were assessed by the Patient Oriented Eczema Measure (POEM) and (Children's) Dermatology Life Quality Index (C/DLQI), respectively. Patient characteristics, clinical- and patient reported-outcomes were assessed by stratified POEM and C/DLQI categories using descriptive statistics. Associations with vIGA-AD were evaluated using unadjusted and adjusted ordinal logistic regression and linear regression models. RESULTS: The analysis cohort (n=1,888) primarily consisted of adults (57%), females (56%), and patients with private insurance (63%). Unadjusted analyses suggest that clinical AD severity was associated with age, with more adolescents and adults having moderate/severe vIGA-AD than pediatric patients. Clinical AD severity was also associated with disease severity, with greater POEM scores observed at greater vIGA-AD severity levels (r = 0.496 and 0.45 for adults and pediatrics, respectively). Clinical AD severity and QoL were positively correlated, with greater CDLQI/DLQI scores at greater vIGA-AD severity levels (r = 0.458 and 0.334 for DLQI and CDLQI, respectively). After adjusting for demographics and other risk factors, vIGA-AD continued to show significant associations with POEM and DLQI/CDLQI. Compared to patients with clear/almost clear disease, adults and pediatrics with moderate-to-severe AD were 8.19 and 5.78 times as likely to be in a more severe POEM category, respectively. Similarly, compared to patients with clear/almost clear disease, adults and pediatrics with moderate/severe AD were 6.69 and 3.74 times as likely to be in a more severe DLQI/CDLQI category. Adjusted linear regression analyses of DLQI in adults showed significant differences by vIGA-AD level, with mild AD and moderate/severe AD associated with a 2.26-point and 5.42-point greater DLQI relative to clear/almost clear AD. CONCLUSIONS: In this real-world study of patients with AD, greater clinician-reported disease severity is positively correlated with higher patient-reported disease severity and lower QoL. J Drugs Dermatol. 2023;22(4): doi:10.36849/JDD.7473 Access Supplementary Material here Citation: Guttman-Yassky E, Bar J, Rothenberg Lausell C, et al. Do atopic dermatitis patient-reported outcomes correlate with validated investigator global assessment? Insights from TARGET-AD registry. J Drugs Dermatol. 2023;22(4):344-355. doi:10.36849/JDD.7473.

Upadacitinib plus topical corticosteroids in atopic dermatitis: Week 52 AD Up study results.

BACKGROUND: Primary (week 16) results from the ongoing phase 3, double-blind AD Up study (NCT03568318) demonstrate a positive benefit-risk profile for upadacitinib + topical corticosteroid (TCS) in patients with moderate-to-severe atopic dermatitis. OBJECTIVE: We evaluated the efficacy and safety of upadacitinib + TCS through 52 weeks. METHODS: Patients aged 12 to 75 years with chronic moderate-to-severe atopic dermatitis (≥10% of body surface area affected, Eczema Area and Severity Index [EASI] ≥16, Validated Investigator's Global Assessment for atopic dermatitis [vIGA-AD] ≥3, and Worst Pruritus Numerical Rating Scale [WP-NRS] score ≥4) were randomized 1:1:1 to once-daily upadacitinib 15 mg + TCS, upadacitinib 30 mg + TCS, or placebo (PBO) + TCS (rerandomized at week 16 to upadacitinib + TCS). Safety and efficacy, including proportion of patients experiencing ≥75% improvement in EASI (EASI-75), vIGA-AD of clear/almost clear with improvement ≥2 grades (vIGA-AD 0/1), and WP-NRS improvement ≥4, were assessed through week 52. Missing data were primarily handled by nonresponse imputation incorporating multiple imputation for missing values due to coronavirus disease 2019 (COVID-19). RESULTS: Of 901 patients, 300 were randomized to upadacitinib 15 mg + TCS, 297 to upadacitinib 30 mg + TCS, and 304 to PBO + TCS. For all end points, efficacy for upadacitinib 15 mg + TCS and upadacitinib 30 mg + TCS at week 16 was maintained through week 52. At week 52, the proportions of patients treated with upadacitinib 15 mg + TCS and upadacitinib 30 mg + TCS who experienced EASI-75 were 50.8% and 69.0%, respectively; 33.5% and 45.2%, respectively, experienced vIGA-AD 0/1; and 45.3% and 57.5%, respectively, experienced WP-NRS improvement ≥4. Upadacitinib + TCS was well tolerated through 52 weeks; no new important safety risks beyond the current label were observed. No deaths were reported; major adverse cardiovascular events and venous thromboembolic events were infrequent (≤0.2/100 patient-years). CONCLUSIONS: Results through 52 weeks demonstrate long-term maintenance of efficacy and a favorable safety profile of upadacitinib + TCS in patients with moderate-to-severe AD.

Compensatory network changes in the dentate gyrus restore long-term potentiation following ablation of neurogenesis in young-adult mice.

It is now well established that neurogenesis in the rodent subgranular zone of the hippocampal dentate gyrus continues throughout adulthood. Neuroblasts born in the dentate subgranular zone migrate into the granule cell layer, where they differentiate into neurons known as dentate granule cells. Suppression of neurogenesis by irradiation or genetic ablation has been shown to disrupt synaptic plasticity in the dentate gyrus and impair some forms of hippocampus-dependent learning and memory. Using a recently developed transgenic mouse model for suppressing neurogenesis, we sought to determine the long-term impact of ablating neurogenesis on synaptic plasticity in young-adult mice. Consistent with previous reports, we found that ablation of neurogenesis resulted in significant deficits in dentate gyrus long-term potentiation (LTP) when examined at a time proximal to the ablation. However, the observed deficits in LTP were not permanent. LTP in the dentate gyrus was restored within 6 wk and this recovery occurred in the complete absence of neurogenesis. The recovery in LTP was accompanied by prominent changes within the dentate gyrus, including an increase in the survival rate of newborn cells that were proliferating just before the ablation and a reduction in inhibitory input to the granule cells of the dentate gyrus. These findings suggest that prolonged suppression of neurogenesis in young-adult mice results in wide-ranging compensatory changes in the structure and dynamics of the dentate gyrus that function to restore plasticity.

Deletion of the L-type calcium channel Ca(V) 1.3 but not Ca(V) 1.2 results in a diminished sAHP in mouse CA1 pyramidal neurons.

Trains of action potentials in CA1 pyramidal neurons are followed by a prolonged calcium-dependent postburst afterhyperpolarization (AHP) that serves to limit further firing to a sustained depolarizing input. A reduction in the AHP accompanies acquisition of several types of learning and increases in the AHP are correlated with age-related cognitive impairment. The AHP develops primarily as the result of activation of outward calcium-activated potassium currents; however, the precise source of calcium for activation of the AHP remains unclear. There is substantial experimental evidence suggesting that calcium influx via voltage-gated L-type calcium channels (L-VGCCs) contributes to the generation of the AHP. Two L-VGCC subtypes are predominately expressed in the hippocampus, Ca(V) 1.2 and Ca(V) 1.3; however, it is not known which L-VGCC subtype is involved in generation of the AHP. This ambiguity is due in large part to the fact that at present there are no subunit-specific agonists or antagonists. Therefore, using mice in which the gene encoding Ca(V) 1.2 or Ca(V) 1.3 was deleted, we sought to determine the impact of alterations in levels of these two L-VCGG subtypes on neuronal excitability. No differences in any AHP measure were seen between neurons from Ca(V) 1.2 knockout mice and controls. However, the total area of the AHP was significantly smaller in neurons from Ca(V) 1.3 knockout mice as compared with neurons from wild-type controls. A significant reduction in the amplitude of the AHP was also seen at the 1 s time point in neurons from Ca(V) 1.3 knockout mice as compared with those from controls. Reductions in both the area and 1 s amplitude suggest the involvement of calcium influx via Ca(V) 1.3 in the slow AHP (sAHP). Thus, the results of our study demonstrate that deletion of Ca(V) 1.3, but not Ca(V) 1.2, significantly impacts the generation of the sAHP.