[Posted 14/Sep/2023]

AUDIENCE: Dermatology, Oncology, Family Medicine

KEY FINDINGS: In addition, Rab7a overexpression is accompanied by reduced migration capacity. Taken together, the study emphasizes that alterations in lysosomal properties facilitate the malignant phenotype and declares the targeting of lysosomal function as a future therapeutic approach.

BACKGROUND: Lysosomes are central in cell homeostasis and participate in macromolecular degradation, plasma membrane repair, exosome release, cell adhesion/migration, and apoptosis. In cancer, alterations in lysosomal function and spatial distribution may facilitate disease progression.

DETAILS: In this study, authors show enhanced lysosomal activity in malignant melanoma cells compared with that in normal human melanocytes. Most lysosomes show perinuclear location in melanocytes, while they are more dispersed in melanoma, with retained proteolytic activity and low pH also in the peripheral population. Rab7a expression is lower in melanoma cells than in melanocytes, and by increasing Rab7a, lysosomes are relocated to the perinuclear region in melanoma. Exposure to the lysosome-destabilizing drug L-leucyl-L-leucine methyl ester causes higher damage in the perinuclear subset of lysosomes in melanomas, whereas differences in subpopulation susceptibility cannot be found in melanocytes. Interestingly, melanoma cells recruit the endosomal sorting complex required for transport-III core protein CHMP4B, involved in lysosomal membrane repair, rather than initiate lysophagy. However, when the perinuclear lysosomal position is promoted by Rab7a overexpression or kinesore treatment, lysophagy is increased.

Copyright © The Authors. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology. All rights reserved.

Source: Eriksson, I., Vainikka, L., Waster, P., et al. (2023). Lysosomal Function and Intracellular Position Determine the Malignant Phenotype in Malignant Melanoma. Journal of Investigative Dermatology. 2023; 143 (9): 1769-1778. Published: September, 2023. DOI: 10.1016/j.jid.2023.01.036.

A Randomized Controlled Trial In A Real-World Setting

[Posted 21/Sep/2023]

AUDIENCE: Dermatology, Family Medicine

KEY FINDINGS: Combining adalimumab with surgery resulted in greater clinical effectiveness and improved quality of life after 12 months in patients with moderate to severe hidradenitis suppurativa.

BACKGROUND: Adalimumab, the only biologic registered for hidradenitis suppurativa, shows clinical response in up to 60% of patients, leaving many patients in need for other treatment options such as surgery. Aim of the study is to compare the clinical effectiveness of adalimumab combined with surgery vs adalimumab monotherapy in patients with moderate to severe hidradenitis suppurativa.

DETAILS: A pragmatic Randomized Controlled Trial was performed from August 2018 to July 2022. Primary outcome was the difference in mean International Hidradenitis Suppurativa Severity Score System reduction after 12 months of treatment with the difference in mean Dermatology Life Quality Index reduction as a key secondary outcome. Thirty-one patients were included per arm. The mean International Hidradenitis Suppurativa Severity Score System at baseline was 23.9 ± 10.7 in the surgery group and 20.9 ± 16.4, in the monotherapy group. After 12 months of treatment the surgery group had a significantly greater reduction in International Hidradenitis Suppurativa Severity Score System compared with the monotherapy group (-19.1 ± 11.3 vs -7.8 ± 11.8, P < .001). Moreover, the surgery group showed a greater reduction in Dermatology Life Quality Index after treatment compared with the monotherapy group (-8.2 ± 6.2 vs -4 ± 7.7, P = .02). Limitations: The study follow-up was too short to assess surgical recurrence rates.

Copyright © Elsevier Ltd. All rights reserved.

Source: Aarts, P., van Huijstee, J. C., van der Zee, H. H., et al. (2023). Adalimumab In Conjunction With Surgery Compared With Adalimumab Monotherapy For Hidradenitis Suppurativa: A Randomized Controlled Trial In A Real-World Setting. Journal of the American Academy of Dermatology. 2023; 89(4): 677-684. Published: October, 2023. DOI: 10.1016/j.jaad.2023.04.034.

A Retrospective Cohort Study

[Posted 7/Sep/2023]

AUDIENCE: Dermatology, Family Medicine

KEY FINDINGS: Lymecycline 600 mg daily for 3 months can be used as an adjunct in cases of leprosy resistance and treatment failure among multibacillary patients. Lymecycline significantly reduced bacillary index, recurrence of skin lesions, and nerve function impairment through its possible immunomodulatory, antiapoptotic, and neuroprotective effects.

BACKGROUND: Hansen's disease or leprosy is a chronic, infectious disease that has locally and globally afflicted all populations. Despite standard treatment with multidrug therapy (WHO-MDT), the incidence of drug resistance has been an increasingly prevalent global problem in leprosy management. This study compared the effectiveness between lymecycline with WHO-MDT and standard WHO-MDT in leprosy treatment.

DETAILS: The research is a retrospective cohort study at a tertiary hospital from January 2011 to July 2021. Pre- and post-treatment bacillary index, presence of new lesions, nerve function impairment, and leprosy reactions were obtained through chart review. The results showed a significant difference in bacteriological index (BI) in both groups at the end of the treatment. However, a higher reduction in BI was noted for the lymecycline group. For the group that took WHO-MDT alone, BI decreased by 0.7 (P < 0.001) whereas patients who took lymecycline and WHO-MDT had a BI difference of 3 (P 0.001) upon completion of treatment. A significant decrease in the recurrence of lesions (P = 0.006) and nerve function impairment (P = 0.038) was also noted in the lymecycline group whereas there was no significant difference in leprosy reactions between the two groups.

Copyright © John Wiley & Sons Ltd. All rights reserved.

Source: Diaz, J. C. D., BAbad-Venida, L., Espinoza-Thaebtharm, A., et al. (2023). Comparison Between Lymecycline With Multidrug Therapy and Standard Multidrug Regimen (WHO-MDT) In The Treatment of Multibacillary Leprosy Patients: A Retrospective Cohort Study. Int J Dermatol. 202; 62(9): 1186-1192. Published: September, 2023. DOI: 10.1111/ijd.16767.

Post Hoc Analysis Results from a Phase III Trial

[Posted 30/Aug/2023]

AUDIENCE: Dermatology, Family Medicine

KEY FINDINGS: Treatment with dupilumab provides significant and sustained improvements within 2 weeks in AD signs, symptoms, and QoL in almost all children with severe AD, including those who did not achieve clear or almost clear skin by week 16.

BACKGROUND: Children with severe atopic dermatitis (AD) have a multidimensional disease burden. Objective of the trial was to assess the clinically meaningful improvements in AD signs, symptoms, and quality of life (QoL) in children aged 6-11 years with severe AD treated with dupilumab compared with placebo.

DETAILS: R668-AD-1652 LIBERTY AD PEDS was a randomized, double-blinded, placebo-controlled, parallel-group, phase III clinical trial of dupilumab with concomitant topical corticosteroids (TCS) in children aged 6-11 years with severe AD. This post hoc analysis focuses on 304 patients receiving either dupilumab or placebo with TCS and assessed the percentage of patients considered responsive to dupilumab treatment at week 16. At week 16, almost all patients receiving dupilumab + TCS (95%) demonstrated clinically meaningful improvements in AD signs, symptoms, or QoL compared with placebo + TCS (61%, p 0.0001). Significant improvements were seen as early as week 2 and sustained through the end of the study in the full analysis set (FAS) and the subgroup of patients with an Investigator’s Global Assessment score greater than 1 at week 16.

Copyright © Springer Nature. All rights reserved.

Source: Siegfried, E. C., Cork, M. J., Katoh, N., et al. (2023). Dupilumab Provides Clinically Meaningful Responses in Children Aged 6-11 Years with Severe Atopic Dermatitis: Post Hoc Analysis Results from a Phase III Trial. Am J Clin Dermatol. 2023; 4: 787-798. Published: September, 2023. DOI: 10.1007/s40257-023-00791-7.

[Posted 25/Aug/2023]

AUDIENCE: Dermatology, Family Medicine

KEY FINDINGS: These data demonstrate that fibroblast expression of hMMP1 is a critical mediator of dermal aging and creates a dermal microenvironment that promotes keratinocyte tumor development.

BACKGROUND: Fragmentation, disorganization, and depletion of the collagen-rich dermal extracellular matrix are hallmarks of aged human skin. These deleterious alterations are thought to critically mediate many of the prominent clinical attributes of aged skin, including thinning, fragility, impaired wound healing, and a propensity for carcinoma.

DETAILS: Matrix metalloproteinase-1 (MMP1) initiates the cleavage of collagen fibrils and is significantly increased in dermal fibroblasts in aged human skin. To investigate the role of elevated MMP1 in skin aging, we generated a conditional bitransgenic mouse (type I collagen alpha chain 2; human MMP1 [Col1a2; hMMP1]) that expresses full-length, catalytically active hMMP1 in dermal fibroblasts. hMMP1 expression is activated by a tamoxifen-inducible Cre recombinase that is driven by the Col1a2 promoter and upstream enhancer. Tamoxifen induced hMMP1 expression and activity throughout the dermis Col1a2:hMMP1 mice. At 6 months of age, Col1a2; hMMP1 mice displayed loss and fragmentation of dermal collagen fibrils, which was accompanied by many of the features of aged human skin, such as contracted fibroblast morphology, reduced collagen production, increased expression of multiple endogenous MMPs, and proinflammatory mediators. Interestingly, Col1a2; hMMP1 mice displayed substantially increased susceptibility to skin papilloma development.

Copyright © The Authors. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology. All rights reserved.

Source: Quan, T., Xia, W., He, T., et al. (2023). Matrix Metalloproteinase-1 Expression in Fibroblasts Accelerates Dermal Aging and Promotes Papilloma Development in Mouse Skin. Journal of Investigative Dermatology. 2023; 143(9): 1700-1707. Published: September, 2023. DOI: 10.1016/j.jid.2023.02.028.

A Network Meta-Analysis of 221 Randomized Controlled Trials

[Posted 17/Aug/2023]

AUDIENCE: Family Medicine, Dermatology

KEY FINDINGS: The most effective treatment for acne is oral isotretinoin, followed by triple therapies containing a topical retinoid, BPO, and an antibiotic. Research presents detailed comparisons of each intervention to serve as a practical database.

BACKGROUND: Acne is an extremely common skin disease with an estimated global prevalence of 9.4%. Authors aimed to provide comprehensive comparisons of the common pharmacological treatments for acne.

DETAILS: Randomized controlled trials comparing the efficacy of pharmacological therapies for acne vulgaris in patients of any age and sex and with a treatment duration of >2 weeks were included. PubMed and Embase databases were searched from inception until February 2022. Our prespecified primary end points were mean percentage reduction in total, inflammatory, and noninflammatory lesions. Treatment ranking was determined by P values. There were 210 articles describing 221 trials and 37 interventions included in the analysis. Our primary analysis of percentage reduction in total lesion count had 65,601 patients enrolled. Across all trials, the mean age was 20.4 years. The median duration of treatment was 12 weeks. The median total, inflammatory, and noninflammatory lesion counts were 72, 27, and 44, respectively. The most effective treatment was oral isotretinoin (mean difference [MD] = 48.41; P = 1.00), followed by triple therapy containing a topical antibiotic, a topical retinoid, and benzoyl peroxide (BPO) (MD = 38.15; P = .95) and by triple therapy containing an oral antibiotic, a topical retinoid, and BPO (MD = 34.83; P = .90). For monotherapies, oral or topical antibiotics or topical retinoids have comparable efficacy for inflammatory lesions, while oral or topical antibiotics have less effect on noninflammatory lesions.

Copyright © Annals of Family Medicine, Inc. All rights reserved.

Source: Huang, C. Y., Chang, I. J., Bolick, N., et al. (2023). Comparative Efficacy of Pharmacological Treatments for Acne Vulgaris: A Network Meta-Analysis of 221 Randomized Controlled Trials. The Annals of Family Medicine. 2023; 21(4): 358-369 Published: July/August, 2023. DOI: 10.1370/afm.2995.