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Cureus Nov 2023Hidradenitis suppurativa (HS) is a multifactorial disease involving the skin and subcutaneous tissues characterized by deep-seated, painful nodules and abscesses with... (Review)
Review
Hidradenitis suppurativa (HS) is a multifactorial disease involving the skin and subcutaneous tissues characterized by deep-seated, painful nodules and abscesses with draining sinus tracts. It affects mostly younger individuals between the ages of 18 and 34. The discomfort and embarrassment that patients affected by HS experience negatively impact their daily lives. It is associated with decreased quality of life and high rates of comorbid depression and anxiety. The rate of depression in HS was reported to be as high as 26%. Its pathogenesis is multifactorial and as such requires a multimodal approach to treatment, which subsequently is reviewed here. Moreover, the pathogenesis of HS is complex and only partially understood. Autoinflammation is the key driver of disease development and is linked with dysregulated inflammasome activation with the subsequent production of inflammatory cytokines. Genetics and cutaneous microbiome play a role in the development of chronic inflammation and lesion formation. Risk factors such as obesity, metabolic syndrome, diabetes, and smoking also add to the systemic inflammation. Targeting these risk factors is a key aspect of the treatment of HS. Lifestyle modifications are used in conjunction with pharmacotherapy and procedures to effectively manage the disease.
PubMed: 38146560
DOI: 10.7759/cureus.49390 -
Modern Pathology : An Official Journal... Nov 2023Fusion genes involving homologs of protein kinase C (PKC) have been identified in a variety of tumors. We report the clinical and histologic presentation of 51 cutaneous...
Fusion genes involving homologs of protein kinase C (PKC) have been identified in a variety of tumors. We report the clinical and histologic presentation of 51 cutaneous melanocytic neoplasms with a PKC fusion gene (involving PRKCA in 35 cases, PRKCB in 15 cases, and PRKCG in a single case). Most tumors were in young adults (median age, 29.5 years; range, 1-73 years) but some presented in newborns. Histologically, 42 tumors were classified as benign, presenting predominantly as biphasic dermal proliferation (88%) with nests of small melanocytes surrounded by fibrosis with haphazardly arranged spindled and dendritic melanocytes, resembling those reported as "combined blue nevi." Most tumors (60%) were heavily pigmented and in 15%, hyperpigmented epithelioid melanocytes were present at the dermoepidermal junction. Two lesions were paucicellular and showed marked sclerosis. Three tumors, including 2 proliferating nodules, were considered intermediate grade. Six tumors had sheets of atypical melanocytes infiltrating the dermis and were classified as melanomas. Two of the melanomas displayed loss of BAP1 nuclear expression. The median follow-up time was 12 months, with 1 patient alive with metastatic disease and 1 dying of their melanoma. These results suggest that melanocytic tumors with PKC fusion genes have characteristic histopathologic features, which are more similar to blue nevi than to pigmented epithelioid melanocytomas. As is the case with GNA-mutated blue nevi, they can progress to melanomas via BAP1 inactivation and metastasize.
Topics: Infant, Newborn; Young Adult; Humans; Adult; Nevus, Blue; Biomarkers, Tumor; Melanoma; Skin Neoplasms; Protein Kinase C
PubMed: 37474004
DOI: 10.1016/j.modpat.2023.100286 -
The Journal of Allergy and Clinical... Jan 2024Prurigo nodularis (PN) is a chronic neuroimmune skin disease characterized by bilaterally distributed pruritic hyperkeratotic nodules on extremities and trunk....
BACKGROUND
Prurigo nodularis (PN) is a chronic neuroimmune skin disease characterized by bilaterally distributed pruritic hyperkeratotic nodules on extremities and trunk. Neuroimmune dysregulation and chronic scratching are believed to both induce and maintain the characteristic lesions.
OBJECTIVES
This study sought to provide a comprehensive view of the molecular pathogenesis of PN at the single-cell level to identify and outline key pathologic processes and the cell types involved. Features that distinguish PN skin from the skin of patients with atopic dermatitis were of particular interest. We further aimed to determine the impact of the IL31RA antagonist, nemolizumab, and its specificity at the single-cell level.
METHODS
Single-cell RNA-sequencing of skin from 15 healthy donors and nonlesional and lesional skin from 6 patients each with PN and atopic dermatitis, combined with spatial-sequencing using the 10x Visium platform. Integration with bulk RNA-sequencing data from patients treated with nemolizumab.
RESULTS
This study demonstrates that PN is an inflammatory skin disease characterized by both keratinocyte proliferation and activation of profibrotic responses. This study also demonstrates that the COL11A1 fibroblast subset is a major contributor to fibrosis and is predominantly found in the papillary dermis of PN skin. Activation of fibrotic responses is the main distinguishing feature between PN and atopic dermatitis skin. This study further shows the broad effect of nemolizumab on PN cell types, with a prominent effect driving COL11A1 fibroblast and keratinocyte responses toward normal.
CONCLUSIONS
This study provides a high-resolution characterization of the cell types and cellular processes activated in PN skin, establishing PN as a chronic fibrotic inflammatory skin disease. It further demonstrates the broad effect of nemolizumab on pathological processes in PN skin.
Topics: Humans; Prurigo; Dermatitis, Atopic; Skin; Chronic Disease; RNA; Pruritus
PubMed: 37506977
DOI: 10.1016/j.jaci.2023.07.005 -
Journal of the American Academy of... Mar 2024Janus kinase 1 inhibition may alleviate hidradenitis suppurativa (HS)-associated inflammation and improve symptoms. (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and safety of the oral Janus kinase 1 inhibitor povorcitinib (INCB054707) in patients with hidradenitis suppurativa in a phase 2, randomized, double-blind, dose-ranging, placebo-controlled study.
BACKGROUND
Janus kinase 1 inhibition may alleviate hidradenitis suppurativa (HS)-associated inflammation and improve symptoms.
OBJECTIVE
To assess efficacy and safety of povorcitinib (selective oral Janus kinase 1 inhibitor) in HS.
METHODS
This placebo-controlled phase 2 study randomized patients with HS 1:1:1:1 to receive povorcitinib 15, 45, or 75 mg or placebo for 16 weeks. Primary and key secondary end points were mean change from baseline in abscess and inflammatory nodule count and percentage of patients achieving HS Clinical Response at week 16.
RESULTS
Of 209 patients randomized (15 mg, n = 52; 45 mg, n = 52; 75 mg, n = 53; placebo, n = 52), 83.3% completed the 16-week treatment. At week 16, povorcitinib significantly reduced abscess and inflammatory nodule count from baseline (least squares mean [SE] change: 15 mg, -5.2 [0.9], P = .0277; 45 mg, -6.9 [0.9], P = .0006; 75 mg, -6.3 [0.9], P = .0021) versus placebo (-2.5 [0.9]). More povorcitinib-treated patients achieved HS Clinical Response at week 16 (15 mg, 48.1%, P = .0445; 45 mg, 44.2%, P = .0998; 75 mg, 45.3%, P = .0829) versus placebo (28.8%). A total of 60.0% and 65.4% of povorcitinib- and placebo-treated patients had adverse events.
LIMITATIONS
Baseline lesion counts were mildly imbalanced between groups.
CONCLUSION
Povorcitinib demonstrated efficacy in HS, with no evidence of increased incidence of adverse events among doses.
Topics: Humans; Hidradenitis Suppurativa; Abscess; Janus Kinase 1; Treatment Outcome; Severity of Illness Index; Double-Blind Method
PubMed: 37871805
DOI: 10.1016/j.jaad.2023.10.034