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International Journal of Molecular... Jun 2024Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases, with an increasing number of targeted therapies available. While biologics to treat...
Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases, with an increasing number of targeted therapies available. While biologics to treat AD exclusively target the key cytokines of type 2 immunity, Janus kinase inhibitors target a broad variety of cytokines, including IFN-γ. To better stratify patients for optimal treatment outcomes, the identification and characterization of subgroups, especially with regard to their IFNG expression, is of great relevance, as the role of IFNG in AD has not yet been fully clarified. This study aims to define AD subgroups based on their lesional IFNG expression and to characterize them based on their gene expression, T cell secretome and clinical attributes. RNA from the lesional and non-lesional biopsies of 48 AD patients was analyzed by RNA sequencing. Based on IFNG gene expression and the release of IFN-γ by lesional T cells, this cohort was categorized into three IFNG groups (high, medium, and low) using unsupervised clustering. The low IFNG group showed features of extrinsic AD with a higher prevalence of atopic comorbidities and impaired epidermal lipid synthesis. In contrast, patients in the high IFNG group had a higher average age and an activation of additional pro-inflammatory pathways. On the cellular level, higher amounts of M1 macrophages and natural killer cell signaling were detected in the high IFNG group compared to the low IFNG group by a deconvolution algorithm. However, both groups shared a common dupilumab response gene signature, indicating that type 2 immunity is the dominant immune shift in both subgroups. In summary, high and low IFNG subgroups correspond to intrinsic and extrinsic AD classifications and might be considered in the future for evaluating therapeutic efficacy or non-responders.
Topics: Dermatitis, Atopic; Humans; Interferon-gamma; Female; Male; Adult; Middle Aged; Antibodies, Monoclonal, Humanized; Macrophages; T-Lymphocytes; Killer Cells, Natural
PubMed: 38892346
DOI: 10.3390/ijms25116158 -
International Journal of Molecular... May 2024Stress exposure worsens allergic inflammatory diseases substantially. Mast cells (MCs) play a key role in peripheral immune responses to neuroendocrine stress mediators...
Stress exposure worsens allergic inflammatory diseases substantially. Mast cells (MCs) play a key role in peripheral immune responses to neuroendocrine stress mediators such as nerve growth factor (NGF) and substance P (SP). Mast cell proteases (MCPs) and cholinergic factors (Chrna7, SLURP1) were recently described to modulate MC stress response. We studied MCPs and Chrna7/SLURP1 and their interplay in a mouse model for noise induced stress (NiS) and atopic dermatitis-like allergic inflammation (AlD) and in cultured MC lacking Chrna7. We found that the cholinergic stress axis interacts with neuroendocrine stress mediators and stress-mediator cleaving enzymes in AlD. SP-cleaving mMCP4+ MC were upregulated in AlD and further upregulated by stress in NiS+AlD. Anti-NGF neutralizing antibody treatment blocked the stress-induced upregulation in vivo, and mMCP4+ MCs correlated with measures of AlD disease activity. Finally, high mMCP4 production in response to SP depended on Chrna7/SLURP1 in cultured MCs. In conclusion, mMCP4 and its upstream regulation by Chrna7/SLURP1 are interesting novel targets for the treatment of allergic inflammation and its aggravation by stress.
Topics: Animals; Mast Cells; Dermatitis, Atopic; Mice; Disease Models, Animal; Skin; alpha7 Nicotinic Acetylcholine Receptor; Inflammation; Peptide Hydrolases; Urokinase-Type Plasminogen Activator; Substance P; Stress, Physiological; Mice, Inbred C57BL; Nerve Growth Factor
PubMed: 38891925
DOI: 10.3390/ijms25115738 -
International Journal of Molecular... May 2024Alopecia areata (AA) is an autoimmune-mediated disorder in which the proximal hair follicle (HF) attack results in non-scarring partial to total scalp or body hair loss.... (Review)
Review
Alopecia areata (AA) is an autoimmune-mediated disorder in which the proximal hair follicle (HF) attack results in non-scarring partial to total scalp or body hair loss. Despite the growing knowledge about AA, its exact cause still needs to be understood. However, immunity and genetic factors are affirmed to be critical in AA development. While the genome-wide association studies proved the innate and acquired immunity involvement, AA mouse models implicated the IFN-γ- and cytotoxic CD8+ T-cell-mediated immune response as the main drivers of disease pathogenesis. The AA hair loss is caused by T-cell-mediated inflammation in the HF area, disturbing its function and disrupting the hair growth cycle without destroying the follicle. Thus, the loss of HF immune privilege, autoimmune HF destruction mediated by cytotoxic mechanisms, and the upregulation of inflammatory pathways play a crucial role. AA is associated with concurrent systemic and autoimmune disorders such as atopic dermatitis, vitiligo, psoriasis, and thyroiditis. Likewise, the patient's quality of life (QoL) is significantly impaired by morphologic disfigurement caused by the illness. The patients experience a negative impact on psychological well-being and self-esteem and may be more likely to suffer from psychiatric comorbidities. This manuscript aims to present the latest knowledge on the pathogenesis of AA, which involves genetic, epigenetic, immunological, and environmental factors, with a particular emphasis on immunopathogenesis.
Topics: Alopecia Areata; Humans; Animals; Hair Follicle
PubMed: 38891839
DOI: 10.3390/ijms25115652 -
American Journal of Clinical Dermatology Jul 2024Abrocitinib, an oral, once-daily, Janus kinase 1-selective inhibitor, is efficacious in moderate-to-severe atopic dermatitis with a manageable long-term safety profile. (Clinical Trial)
Clinical Trial
BACKGROUND
Abrocitinib, an oral, once-daily, Janus kinase 1-selective inhibitor, is efficacious in moderate-to-severe atopic dermatitis with a manageable long-term safety profile.
OBJECTIVE
We aimed to provide updated integrated long-term safety results for abrocitinib from available data accrued up to a maximum of almost 4 years in patients with moderate-to-severe atopic dermatitis from the JADE clinical development program.
METHODS
Analysis included 3802 patients (exposure: 5213.9 patient-years) from the phase II monotherapy study (NCT02780167) and the phase III studies JADE MONO-1 (NCT03349060), JADE MONO-2 (NCT03575871), JADE TEEN (NCT03796676), JADE COMPARE (NCT03720470), JADE DARE (NCT04345367; 200 mg only), JADE REGIMEN (NCT03627767), and JADE EXTEND (NCT03422822; data cutoff 25 September, 2021). Data from patients receiving one or more doses of abrocitinib 200 mg or 100 mg were pooled in a consistent-dose cohort (patients were allocated to receive the same abrocitinib dose throughout exposure in the qualifying parent study and/or long-term study) or a variable-dose cohort (patients received open-label abrocitinib 200 mg; responders were randomized to abrocitinib 200 mg, 100 mg, or placebo, and could then receive abrocitinib 200 mg plus topical corticosteroids as rescue therapy). Incidence rates of adverse events of special interest were assessed. Cox regression analysis of risk factors for herpes zoster and serious infections was performed.
RESULTS
Overall, this safety analysis of long-term data up to a maximum of ~ 4 years of abrocitinib exposure does not indicate any changes from the previously reported risk profile. The most frequent serious infections (per Medical Dictionary for Regulatory Activities preferred term) with consistent-dose abrocitinib 200 mg and 100 mg were herpes zoster (0.5% and 0.2%), pneumonia (0.2% with either dose), and herpes simplex (0.1% with either dose). Risk factors for herpes zoster were a history of herpes zoster, abrocitinib 200-mg dose, age ≥ 65 years, absolute lymphocyte count < 1 × 10/mm before the event, and residing in Asia. For serious infections, > 100 kg body weight was a risk factor. Incidence rate/100 patient-years (95% confidence interval) with the consistent abrocitinib 200-mg and 100-mg dose combined was higher in older (aged ≥ 65 years) patients versus younger (aged 18 to < 65 years) patients for serious adverse events (17.6 [11.7‒25.4] vs 6.7 [5.8‒7.8]), malignancy excluding non-melanoma skin cancer (2.4 [0.6‒6.0] vs 0.1 [0.0‒0.4]), non-melanoma skin cancer (2.4 [0.6‒6.1] vs 0.2 [0.1‒0.4]), lymphopenia (3.5 [1.3‒7.6] vs 0.1 [0.0‒0.3]), and venous thromboembolism (1.7 [0.4‒5.1] vs 0.1 [0.0‒0.3]). Incident rate/100 patient-years (95% confidence interval) of non-melanoma skin cancer with the consistent abrocitinib 200-mg and 100-mg dose combined was higher in current/former smokers (0.9 [0.4‒1.6]) vs never-smokers (0.0 [0.0‒0.1]).
CONCLUSIONS
This safety update showed a consistent profile for abrocitinib with no new safety signals and continues to support that abrocitinib has a manageable long-term safety profile in patients with moderate-to-severe atopic dermatitis. Risk of specific adverse events was higher in certain patient populations, especially those aged ≥ 65 years. [Video abstract available.] CLINICAL TRIAL REGISTRATION: NCT02780167; study start date: April, 2016; primary completion date: March, 2017; study completion date: April, 2017. NCT03349060; study start date: 7 December, 2017; study completion date: 26 March, 2019. NCT03575871; study start date: 29 June, 2018; study completion date: 13 August, 2019. NCT03720470; study start date: 29 October, 2018; primary completion date: 27 December, 2019; study completion date: 6 March, 2020. NCT03796676; study start date: 18 February, 2019; study completion date: 8 April, 2020. NCT03627767; study start date: 11 June, 2018; primary completion date: 2 September, 2020; study completion date: 7 October, 2020. NCT04345367; study start date: 11 June, 2020; primary completion date: 16 December, 2020; study completion date: 13 July, 2021. NCT03422822; study start date: 8 March, 2018; study completion date: ongoing (estimated completion date: 31 January, 2026).
Topics: Adolescent; Adult; Aged; Female; Humans; Male; Middle Aged; Young Adult; Administration, Oral; Boron Compounds; Dermatitis, Atopic; Herpes Zoster; Janus Kinase Inhibitors; Pyrimidines; Severity of Illness Index; Sulfonamides; Treatment Outcome
PubMed: 38888681
DOI: 10.1007/s40257-024-00869-w -
Acta Dermato-venereologica Jun 2024Heat application is known to activate transient receptor potential (TRP) channels, which play a crucial role in sensory perception, including itch. In this study, the... (Randomized Controlled Trial)
Randomized Controlled Trial
Heat application is known to activate transient receptor potential (TRP) channels, which play a crucial role in sensory perception, including itch. In this study, the effect of a 5-s, 49°C heat application on itch intensity in atopic dermatitis (AD) patients was evaluated. The study comprised 2 parts: a controlled trial investigating the impact of brief heat treatment on mechanically induced itch, and a real-life study of AD patients experiencing itch attacks. A significant and immediate reduction in itch sensations following heat application was shown, with effects enduring over time. This response, however, showed notable individual variability, underscoring the potential of personalized approaches in AD treatment. Repeated applications of heat showed no habituation effect, suggesting its viability as a non-pharmacological, patient-tailored option for managing itch in AD. Further research in larger cohorts is warranted to refine treatment protocols and deepen understanding of the mechanisms involved.
Topics: Humans; Dermatitis, Atopic; Pruritus; Female; Male; Adult; Hot Temperature; Young Adult; Middle Aged; Treatment Outcome; Time Factors; Severity of Illness Index; Adolescent
PubMed: 38887031
DOI: 10.2340/actadv.v104.40127 -
JAAD Case Reports Jul 2024
PubMed: 38883166
DOI: 10.1016/j.jdcr.2024.04.023 -
Cureus May 2024Background Psoriasis is a common chronic inflammatory skin disease with an autoimmune etiology. Psoriasis has been presumed to be associated with several autoimmune...
Background Psoriasis is a common chronic inflammatory skin disease with an autoimmune etiology. Psoriasis has been presumed to be associated with several autoimmune diseases. We sought to determine the prevalence of autoimmune diseases in patients with psoriasis in a large referral tertiary care center. Methods This is a retrospective and cross-sectional chart review of patients with confirmed psoriasis diagnoses in the dermatology clinic of King Abdulaziz Medical City, Riyadh, Saudi Arabia. The electronic charts of patients were individually reviewed for autoimmune diseases such as hypothyroidism, hyperthyroidism, alopecia areata, vitiligo, atopic dermatitis, and inflammatory bowel diseases like Crohn's disease and celiac diseases. Results A total of 839 cases were included, 56.4% of whom were females. Most patients were between 31 and 50 years old (37.1%). The most common autoimmune disease was hypothyroidism (6.8%), seen more in females. The second most common autoimmune disease was alopecia areata (3.6%), followed by atopic dermatitis (2.9%). Rheumatoid arthritis, systemic lupus erythematosus, and inflammatory bowel diseases were uncommon in our cohort. Conclusion In this single-center retrospective cohort of patients with psoriasis, hypothyroidism and alopecia areata were the most commonly encountered autoimmune diseases. Larger, multi-center studies are needed to evaluate the prevalence of autoimmune diseases among patients with psoriasis.
PubMed: 38883030
DOI: 10.7759/cureus.60455 -
SAGE Open Medical Case Reports 2024Atopic dermatitis is a chronic inflammatory skin disease that may progress to erythroderma in severe cases. Biologic agents such as dupilumab have recently become the...
Atopic dermatitis is a chronic inflammatory skin disease that may progress to erythroderma in severe cases. Biologic agents such as dupilumab have recently become the mainstay of systemic treatment for moderate-to-severe cases, yet many patients remain refractory to therapy. Here, we present a case of erythrodermic atopic dermatitis, resistant to prednisone and dupilumab, with remarkably rapid achievement of remission following treatment with upadacitinib, an oral selective Janus kinase 1 inhibitor.
PubMed: 38881978
DOI: 10.1177/2050313X241260497 -
Clinical, Cosmetic and Investigational... 2024Atopic dermatitis (AD) is a frequent inflammatory condition that usually begins during early childhood, but it increasingly starts to debut, even in the elderly. Based...
Atopic dermatitis (AD) is a frequent inflammatory condition that usually begins during early childhood, but it increasingly starts to debut, even in the elderly. Based on immunoglobulin E (IgE) levels and clinical features, two subsets of this disease have been recognized: intrinsic and extrinsic. When speaking about AD, most specialists think about filaggrin (FLG) mutations resulting in epidermal barrier defects, which is the case in most atopic patients, but some have a normal barrier, as seen by imaging, and still have specific clinical lesions along with metal allergies. Specific molecules (IL-10, IFN-γ, and HBD-3) have been shown to greatly impact the interactions between internal and external factors in this peculiar form of AD. A less-known protein, suprabasin, has been highlighted as a promising explanation for nickel anomalies in intrinsic AD.
PubMed: 38881699
DOI: 10.2147/CCID.S459096 -
Clinical Immunology (Orlando, Fla.) Jun 2024Overlapping clinical and pathomechanistic features can complicate the diagnosis and treatment of inflammatory skin diseases, including psoriasis and atopic dermatitis...
Overlapping clinical and pathomechanistic features can complicate the diagnosis and treatment of inflammatory skin diseases, including psoriasis and atopic dermatitis (AD). Spatial transcriptomics allows the identification of disease- and cell-specific molecular signatures that may advance biomarker development and future treatments. This study identified transcriptional signatures in keratinocytes and sub-basal CD4 and CD8 T lymphocytes from patients with psoriasis and AD. In silico prediction of ligand:receptor interactions delivered key signalling pathways (interferon, effector T cells, stroma cell and matrix biology, neuronal development, etc.). Targeted validation of selected transcripts, including CCL22, RELB, and JUND, in peripheral blood T cells suggests the chosen approach as a promising tool also in other inflammatory diseases. Psoriasis and AD are characterized by transcriptional dysregulation in T cells and keratinocytes that may be targeted therapeutically. Spatial transcriptomics is a valuable tool in the search for molecular signatures that can be used as biomarkers and/or therapeutic targets.
PubMed: 38880200
DOI: 10.1016/j.clim.2024.110283