A double-blinded randomised control study to compare the effectiveness and safety of intralesional vitamin D3 with intralesional triamcinolone and its correlation with tissue expression of vitamin D receptors in patients with keloid.

Intralesional steroids commonly used for keloid treatment have adverse effects like cutaneous atrophy and telangiectasias. Safer and more effective therapies are needed. Preliminary studies suggest intralesional vitamin D as a potential alternative treatment. The aim of this study was to compare efficacy and safety of intralesional vitamin D with triamcinolone for keloids, and correlate tissue expression of vitamin D receptors (VDRs) with treatment outcomes. Sixty patients were randomly assigned to two groups: Group A (intralesional vitamin D) and Group B (intralesional triamcinolone). Four injections were given at 4-week intervals, with an 8-week follow-up. Biopsies were taken pre- and post-treatment to examine VDR expression levels and treatment response correlation. The primary outcome of interest was the proportion of patients achieving a 50% reduction in Vancouver Scar Scale (VSS). Secondary outcomes included incidence of adverse effects, and changes in VDR expression before and after treatment. Baseline VSS scores were 9.73 ± 1.01 (vitamin D group) and 10.13 ± 1.07 (triamcinolone group). After treatment, mean VSS decreased to 5.17 ± 0.59 (vitamin D group, p < 0.001) and 4.77 ± 0.77 (triamcinolone group, p < 0.001), with significantly better response in latter (p = 0.03). More than 50% reduction in VSS score was higher in the triamcinolone group (76.7% vs. 50%, p = 0.032). No recurrences were noted during the 8-week follow-up. Hypopigmentation (80% vs. 36.7%, p < 0.001) and atrophy (73.3% vs. 40%, p = 0.009) were more common in the triamcinolone group. No significant difference in pre- and post-treatment VDR receptor expression was observed in either group. Both triamcinolone acetonide and vitamin D were effective for keloids. Triamcinolone was more efficacious, whereas vitamin D was safer, suggesting it as a viable alternative for keloid management.

Giant corneal keloid following Descemet stripping automated endothelial keratoplasty for the treatment of corneal decompensation secondary to trauma.

PURPOSE: This report aims to present a case of corneal keloid caused by chronic corneal insult after trauma and Descemet stripping automated endothelial keratoplasty (DSAEK). CASE PRESENTATION: A 35-year-old male with a history of vision loss in the right eye was referred to our hospital. The patient underwent Ahmed Glaucoma Valve Implantation to alleviate elevated intraocular pressure after ocular trauma to the same eye. One year following the procedure, the eye developed endothelial failure, leading to the performance of Descemet's Stripping Automated Endothelial Keratoplasty (DSAEK) with repositioning of the shunt tube. Upon initial examination, a well-circumscribed elevated white opaque lesion involving the central corneal surface of the RE was observed. Based on the patient's clinical history, slit lamp examination, and UBM findings, the diagnosis of corneal keloid was established. Superficial keratectomy was performed. Histopathological analysis confirmed the diagnosis of corneal keloid. Following the procedure, BCVA improved slightly. However, 3 months later, the patient underwent a penetrating keratoplasty for visual rehabilitation. CONCLUSION: Corneal keloids should be considered following any form of ocular trauma, particularly in cases involving ocular surgery. Diagnosing corneal keloids can sometimes be challenging due to the variety of potential differentials; however, by carefully evaluating the patient's medical history and clinical presentation, we can effectively narrow down the differential diagnosis of corneal conditions.

The role of IL-17 and Th17 cells in keloid pathogenesis.

Keloids are characterized histologically by excessive fibroblast proliferation and connective tissue deposition, and clinically by scar tissue extending beyond the original site of skin injury. These scars can cause pruritus, pain, physical disfigurement, anxiety, and depression. As a result, keloid patients often have a diminished quality of life with a disproportionate burden on ethnic minorities. Despite advances in understanding keloid pathology, there is no effective Food and Drug Administration (FDA)-approved pharmacotherapy. Recent studies have highlighted the possible pathologic role of T helper (Th)17 cells and interleukin (IL)-17 in keloid formation, as well as their implication in other inflammatory disorders. This systematic review characterizes the role of Th17 cells and IL-17 in keloid pathogenesis, highlighting this pathway as a potential therapeutic target. Adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a comprehensive search on PubMed, Embase, MEDLINE, and Web of Science databases on June 5, 2024. The search included terms related to Th17 cells, IL-17, and keloids. Thirteen studies met the inclusion criteria, comprising basic science and bioinformatic studies focusing on Th17 cells and IL-17. Key findings include increased Th17 cell infiltration and IL-17 expression in keloids, IL-17's role in amplifying the inflammatory and fibrotic response via the promotion of IL-6 expression, and IL-17's involvement in upregulating fibrotic markers via SDF-1 and HIF-1α pathways. IL-17 also activates the transforming growth factor beta (TGF-ß)/Smad pathway in keloid fibroblasts. Th17 cells and IL-17 significantly contribute to the inflammatory and fibrotic processes in keloid pathogenesis. Therefore, targeting the IL-17 pathway offers a potential new therapeutic target to improve keloid patients' outcomes. Future research could further elucidate the role of Th17 cells and IL-17 in keloid pathogenesis and assess the safety and efficacy of targeting this pathway in human studies.

Assessment of the efficacy and safety of auricular keloids excision followed by 5-aminolevulinic acid photodynamic therapy.

BACKGROUND: Auricular keloids are a significant clinical challenge, which adversely affect the life of the patient at the level of aesthetic and psychological well-being. Despite various treatment modalities, a universally effective therapy has yet to be established. Photodynamic therapy (PDT) offers a promising approach by inhibiting the abnormal proliferation of fibroblasts while minimizing damage to surrounding healthy cells and tissues. This study evaluates the clinical outcomes of auricular keloid patients treated with excision followed by 5-aminolevulinic acid photodynamic therapy (ALA-PDT). METHODS: This study included 8 patients diagnosed with auricular keloids based on pathological examination and clinical presentation. Following surgical excision of the auricular keloids, topical 5-ALA solution was applied for 4 hours. Then each lesion was irradiated with 120 J/cm² using a red LED (635-nm laser) for 20 minutes. Patients received 3-5 courses of 5-aminolevulinic acid photodynamic therapy (ALA-PDT) during and after the surgery. RESULTS: Among the 8 patients treated, auricular keloids were completely controlled with the combination therapy. During a follow-up period of 2.7 years (range: 1.8-4.1 years), all patients exhibited excellent outcomes with no recurrence of keloids. CONCLUSIONS: The combination of surgical excision and 5-aminolevulinic acid photodynamic therapy (ALA-PDT) is an effective and safe treatment for auricular keloids. This combined approach shows promise as an alternative clinical treatment for managing auricular keloids.

Secondary corneal keloid: a report of two cases.

We conducted clinical and histological evaluations on two male patients who presented with corneal keloid. One patient had a history of corneal trauma due to contact with boiling sunflower oil, while the other had undergone pterygium removal. Upon slit lamp examination, the corneal lesions were identified as single, well-circumscribed, pearly white nodules with a smooth surface. We successfully removed these nodules using a combination of superficial keratectomy and the application of mitomycin C. Light microscopy analysis of the excised nodules revealed hyperplastic epithelium, disrupted Bowman's layer, and irregularly arranged abundant collagen fibers within the stroma. Notably, there was no recurrence of the lesions in either case within six months following the surgical excision. Secondary corneal keloids should be considered as a potential diagnosis in patients with elevated corneal nodules, especially when there is a history of ocular surface trauma or surgery.

Update on the Pathogenesis of Keloid Formation.

Keloids are abnormal skin growths occurring in a significant portion of the global population. Despite their pervasiveness, the underlying pathophysiology of this scarring process is yet to be fully understood. In this review article, we delve into the current literature on the pathophysiological mechanisms of keloids. We take a top-down approach, first looking at host factors such as genetics and endocrine factors and then taking a more granular approach describing specific control factors such as germline keloid predisposition variants, epigenetics and transcriptomics, inflammatory and immune dysregulation, and the role of profibrotic and angiogenic cell signaling pathways. We then discuss current knowledge gaps, propose further research avenues, and explore potential future treatment options considering our increased understanding of keloid pathogenesis.

Phosphodiesterase 4 is overexpressed in keloid epidermal scars and its inhibition reduces keratinocyte fibrotic alterations.

BACKGROUND: Epidermal remodeling and hypertrophy are hallmarks of skin fibrotic disorders, and keratinocyte to mesenchymal (EMT)-like transformations drive epidermis alteration in skin fibrosis such as keloids and hypertrophic scars (HTS). While phosphodiesterase 4 (PDE4) inhibitors have shown effectiveness in various fibrotic disorders, their role in skin fibrosis is not fully understood. This study aimed to explore the specific role of PDE4B in epidermal remodeling and hypertrophy seen in skin fibrosis. METHODS: In vitro experiments examined the effects of inhibiting PDE4A-D (with Roflumilast) or PDE4B (with siRNA) on TGFß1-induced EMT differentiation and dedifferentiation in human 3D epidermis. In vivo studies investigated the impact of PDE4 inhibition on HOCl-induced skin fibrosis and epidermal hypertrophy in mice, employing both preventive and therapeutic approaches. RESULTS: The study found increased levels of PDE4B (mRNA, protein) in keloids > HTS compared to healthy epidermis, as well as in TGFß-stimulated 3D epidermis. Keloids and HTS epidermis exhibited elevated levels of collagen Iα1, fibronectin, αSMA, N-cadherin, and NOX4 mRNA, along with decreased levels of E-cadherin and ZO-1, confirming an EMT process. Inhibition of both PDE4A-D and PDE4B prevented TGFß1-induced Smad3 and ERK1/2 phosphorylation and mesenchymal differentiation in vitro. PDE4A-D inhibition also promoted mesenchymal dedifferentiation and reduced TGFß1-induced ROS and keratinocyte senescence by rescuing PPM1A, a Smad3 phosphatase. In vivo, PDE4 inhibition mitigated HOCl-induced epidermal hypertrophy in mice in both preventive and therapeutic settings. CONCLUSIONS: Overall, the study supports the potential of PDE4 inhibitors, particularly PDE4B, in treating skin fibrosis, including keloids and HTS, shedding light on their functional role in this condition.

The diagnostic value and associated molecular mechanism study for fibroblast-related mitochondrial genes on keloid.

PURPOSE: This study aims to reveal the mechanism of fibroblast-related mitochondrial genes on keloid formation and explore promising signature genes for keloid diagnosis. METHOD: The distribution of fibroblasts between the keloid sample and control sample based on three keloid datasets, followed by the differentially expressed genes (DEGs) investigation and associated enrichment analysis. Then, hub genes were explored based on DEGs, mitochondrial genes from an online database, as well as fibroblast-related genes that were revealed by WCGNA. Subsequently, signature genes were screened through machine learning, and their diagnostic value was validated by nomogram. Moreover, the targeted drugs and related transcriptional regulation of these genes were analyzed. Finally, the verification analysis was performed on signature genes using qPCR analysis. RESULT: A total of totally 329 DEGs were revealed based on three datasets, followed by enrichment analysis. WGCNA revealed a total of 258 fibroblast-related genes, which were primarily assembled in functions like muscle tissue development. By using machine learning, we screened four signature genes (ACSF2, ALDH1B1, OCIAD2, and SIRT4) based on eight hub genes (fibroblast-related mitochondrial genes). Nomogram and validation analyses confirmed the well-diagnostic performance of these four genes in keloid. Immune infiltration and drug correlation analyses showed that SIRT4 was significantly associated with immune cell type 2 T helper cells and molecular drug cyclosporin. All these findings provided new perspectives for the clinical diagnosis and therapy of keloid. CONCLUSION: The fibroblast-related mitochondrial genes including SIRT4, OCIAD2, ALDH1B1, and ACSF2 were novel signature genes for keloid diagnosis, offering novel targets and strategies for diagnosis and therapy of keloid.

The role of apoptosis, immunogenic cell death, and macrophage polarization in carbon ion radiotherapy for keloids: Targeting the TGF-ß1/SMADs signaling pathway.

Keloids, characterized by excessive extracellular matrix (ECM) deposition and aberrant fibrous tissue proliferation, present significant therapeutic challenges due to their recalcitrant and recurrent nature. This study explores the efficacy of Carbon Ion Radiotherapy (CIRT) as a novel therapeutic approach for keloids, focusing on its impact on fibroblast proliferation, apoptosis induction, immunogenic cell death (ICD), macrophage polarization, and the TGF-ß/SMAD signaling pathway. Utilizing a murine model of keloid formed by subcutaneous injection of zeocin in C57BL/6 mice, we demonstrated that CIRT effectively reduces collagenous fiber synthesis and collagen production in keloid tissues. Further, CIRT was shown to inhibit keloid fibroblast proliferation and to induce apoptosis, as evidenced by increased expression of apoptosis-related proteins and confirmed through flow cytometry and TUNEL assay. Notably, CIRT induced mitochondrial stress, leading to enhanced immunogenicity of cell death, characterized by increased expression of ICD markers and secretion of interferon-γ. Additionally, CIRT promoted a shift from M2 to M1 macrophage polarization, potentially reducing TGF-ß release and mitigating ECM deposition. Our findings suggest that CIRT mediates its therapeutic effects through the inhibition of the TGF-ß/SMAD signaling pathway, thereby attenuating ECM formation and offering a promising avenue for keloid treatment. This study underscores the potential of CIRT as an innovative strategy for managing keloids, highlighting its multifaceted impact on key cellular processes involved in keloid pathogenesis.

Suction-Based Optical Coherence Elastography for the Biomechanical Characterization of Pathological Skin Conditions: A Pilot Study.

Accurate characterization of mechanical properties is crucial in the evaluation of therapeutic effects for problematic skin conditions. A pilot study was carried out using a novel optical coherence elastography (OCE) device, combining mechanical characterization through suction-based deformation and imaging through optical coherence tomography. Using AI-assisted image segmentation and a power-law model, we were able to describe the mechanical behavior, comparing with measurements from the most commonly used commercial instrument (Cutometer) and subjective analyses of stiffness using the Patient and Observer Scar Assessment Scale. Twenty subjects were included with either keloids or hypertrophic scars. Measurements were fast and produced no discomfort. Mechanical and structural (epidermal thickness and rugosity) descriptors in pathologic skin conditions differed significantly from those in control tissue. We showed for the first time, the clinical feasibility of this novel suction-based OCE device in evaluating mechanical and structural properties in pathological skin conditions such as scars.

Dual Drug Therapy Versus Single Drug Therapy in Prevention of Pinna Keloid Recurrence.

Keloids are fibroproliferative disorders caused due to injury to skin. The recurrence rate has been found to be as high as 100% even after surgical excision. The high recurrence rate has led to the need for various adjuvant therapies as a single approach alone has not been found to be efficient in preventing recurrence. This attributes to the need for a multimodal approach. Steroids are found to be useful in preventing recurrence. To evaluate the efficacy of the combination of hyaluronidase with corticosteroid injection compared to corticosteroid injection alone in the prevention of recurrence of keloid after surgical excision. This randomized controlled study was conducted in the Department of Otorhinolaryngology among 50 patients with ear keloids who underwent surgical excision. Patients were divided into two groups. One group was given Triamcinolone injection alone and the other was given Triamcinolone with Hyaluronidase on postoperative weeks 1, 2, and 3. Patients were followed up for 6 months and recurrence was noted and compared. Statistical analysis was done and the results were considered significant with a p-value of less than 0.05. Of the total 50 patients, there were a total of eight male and 39 female patients. In a single therapy group, recurrence was noted in one patient after 3 months and in three more patients after 6 months. In the group with combination therapy, there was no recurrence after 3 months but three patients had recurrence after 6 months. Triamcinolone and hyaluronidase injection protected from recurrence for about 3 to 5 months after which patients had recurrence. Further studies are recommended with prolonged duration of hyaluronidase injection.

Evidence of a causal relationship between blood pressure and pathological scars: a bidirectional Mendelian randomization study.

Background: Recent advancements in basic medicine and epidemiology suggest a potential influence of blood pressure on scar formation, yet the specifics of this relationship are not fully understood. This study aims to clarify the causal link between blood pressure and the development of pathological scars using Mendelian randomization (MR). Methods: This study employed genetic variants closely linked to blood pressure as instrumental variables to explore the relationship between blood pressure and pathological scars. The inverse variance weighted (IVW) method was used for analysis. Results: Our analysis identified a notable association where higher blood pressure was correlated with a lower risk of pathological scars. Specifically, an increase in diastolic blood pressure (odds ratio [OR] per standard deviation increase: 0.67 [95% Confidence Interval [CI], 0.49-0.99]), systolic blood pressure (OR per standard deviation increase: 0.66 [95% CI, 0.46-0.93]), and hypertension (pooled OR: 0.39 [95% CI, 0.18-0.85]) were significantly associated with a reduced risk of keloids. Similarly, a genetic predisposition to hypertension (pooled OR: 0.31 [95% CI, 0.11-0.89]) was significantly associated with a reduced risk of hypertrophic scars. Neither reverse MR analysis nor Steiger's test indicated a significant reverse causal relationship between hypertension and either keloids or hypertrophic scars. Conclusion: The findings suggest a protective role of higher blood pressure against the development of pathological scars, including keloids and hypertrophic scars. However, the inconsistency observed across different MR methods warrants cautious interpretation and underscores the need for further investigation to confirm these findings.

Familial Spontaneous Keloids: Examining Thoracic Manifestations in Two Brothers.

Keloids are complex fibroproliferative disorders with diverse clinical presentations. Spontaneous keloids (SKs) represent a rare subtype that emerges without any known preceding traumatic event. This report presents a case of familial spontaneous keloids appearing on the thoracic region in two brothers with no prior history of trauma or keloid occurrence in other family members. The lesions exhibited progressive growth over several years but responded to cycles of triamcinolone treatment. This case underscores an unusual spontaneous occurrence of keloids in the thoracic region of two siblings, highlighting the potential genetic predisposition in the aetiology of these lesions. Additionally, this instance reinforces the concept that keloids can develop spontaneously without any apparent trauma in the affected area.

Comprehensive bioinformatic analysis reveals a fibroblast-related gene signature for the diagnosis of keloids.

Aim: A keloid is a fibroproliferative cutaneous disorder secondary to skin injury, caused by an imbalance in fibroblast proliferation and apoptosis. However, the pathogenesis is not fully understood. In this study, candidate genes for keloid were identified and used to construct a diagnostic model. Methods: Three datasets related to keloids were downloaded from NCBI Gene Expression Omnibus. Fibroblast-related genes were screened, and fibroblast scores for the samples were determined. Then, a weighted gene co-expression network analysis (WGCNA) was used to identify modules and genes associated with keloids and the fibroblast score. Differentially expressed genes (DEGs) between keloid and control samples were identified and compared with fibroblast-related genes and genes in the modules. Overlapping genes were evaluated using functional enrichment analyses. Signature genes were further screened, and a diagnostic model was constructed. Finally, correlations between immune cell frequences and signature genes were analyzed. Results: In total, 124 fibroblast-related genes were obtained, and the fibroblast score was an effective indicator of the sample type. WGCNA revealed five modules that were significantly correlated with both the disease state and fibroblast scores, including 1760 genes. Additionally, 589 DEGs were identified, including 16 that overlapped with fibroblast-related genes and genes identified in the WGCNA. These genes were related to cell proliferation and apoptosis and were involved in FoxO, Rap1, p53, Ras, MAPK, and PI3K-Akt pathways. Finally, a six fibroblast-related gene signature (CCNB1, EGFR, E2F8, BTG1, TP63, and IGF1) was identified and used for diagnostic model construction. The proportions of regulatory T cells and macrophages were significantly higher in keloid tissues than in controls. Conclusion: The established model based on CCNB1, EGFR, E2F8, BTG1, TP63, and IGF1 showed good performance and may be useful for keloid diagnosis.

Segmental congenital vascular anomaly with atrophy, ulceration, and scarring (SeCVAUS): Case series and review of literature.

BACKGROUND: Next-generation sequencing has greatly increased our understanding of vascular birthmarks. Many port-wine birthmarks are due to somatic mutations in GNAQ/GNA11 exon 183, but other genomic causes have been identified. Most congenital hemangiomas are due to somatic mutations in GNAQ/GNA11 at exon 209. Although genomically distinct, clinical overlap of congenital hemangiomas and port-wine birthmarks has occasionally been described. OBJECTIVE: We report a case series of a unique segmentally distributed vascular anomaly with overlapping characteristics of port-wine birthmarks and congenital hemangiomas with other distinctive features including ulceration, atrophy, and scarring. METHODS: This was a multicenter study with retrospective identification of patients via a detailed review of medical records. We also reviewed previously published cases. RESULTS: The clinical, histological, radiological, and genomic characteristics of 19 new and 13 previously reported cases characterized by segmental distribution, sharply demarcated borders, with variable thickening are presented. All cases had central atrophy with or without episodic ulceration. Those with genomic studies (13 out of 32) had somatic activating missense mutations in GNA11 or GNAQ codon 209. CONCLUSIONS: We describe the features and propose a descriptive name segmental congenital vascular anomaly with atrophy, ulceration, and scarring (SeCVAUS) for this condition.

Alexis® Orthopedic Protector Provides Wound Protection and Aids in Hypertrophic Scar Prevention in Total Hip Arthroplasty.

PURPOSE: Total hip arthroplasty (THA) is one of the most widely performed orthopedic surgeries. Techniques for small skin incisions and preservation of muscles and tendons have been developed. However, avoiding skin complications and muscle damage due to forced deployment and surgical manipulation is challenging. This study aimed to investigate whether the use of Alexis® Orthopedic Protector (Applied Medical Resources Corp., Rancho Santa Margarita, CA, USA) affects postoperative outcomes. METHODS: This was a retrospective cohort study including 118 patients who underwent primary THA by the same surgeon at our single institution between March 2021 and March 2023. Protectors were used alternately for each operation. Fifty-nine patients were in the protector-using group (P group), and 59 were in the nonprotector-using group (N group), with comparisons made between groups. Protectors were placed under the fascia in all patients. RESULTS: Preoperative blood tests showed no difference in renal and hepatic function between the two groups. No differences in postoperative C-reactive protein (CRP) and creatine kinase (CK) values or in the Japanese Orthopedic Association Hip Disease Evaluation Questionnaire (JHEQ) and Numerical Rating Scale (NRS) scores were observed. Postoperative redness was significantly higher in the N group than in the P group (49.2% vs. 7%). The percentage of hypertrophic scars at three months postoperatively was 18.6% in the N group and 7% in the P group. Furthermore, the Japan Scar Workshop Scar Scale (JSS) indicated that hypertrophic scars were significantly worse in the N group than in the P group (p = 0.0012). CONCLUSION: Alexis® Orthopedic Protectors can not only provide short-term wound protection but also reduce the rate and degree of hypertrophic scarring.

Zinc-Alpha-2-Glycoprotein Peptide Downregulates Type I and III Collagen Expression via Suppression of TGF-ß and p-Smad 2/3 Pathway in Keloid Fibroblasts and Rat Incisional Model.

BACKGROUND: Keloids and hypertrophic scars result from abnormal collagen accumulation and the inhibition of its degradation. Although the pathogenesis remains unclear, excessive accumulation of the extracellular matrix (ECM) is believed to be associated with the TGF-ß/SMAD pathway. Zinc-alpha-2-glycoprotein (ZAG) inhibits TGF-ß-mediated epithelial-to-mesenchymal transdifferentiation and impacts skin barrier functions. In this study, we investigated the potential of a small ZAG-derived peptide against hypertrophic scars and keloids. METHODS: The study examined cell proliferation and mRNA expression of collagen types I and III in human dermal fibroblast (HDF) cell lines and keloid-derived fibroblasts (KF) following ZAG peptide treatment. A rat incisional wound model was used to evaluate the effect of ZAG peptide in scar tissue. RESULTS: Significantly lower mRNA levels of collagen types I and III were observed in ZAG-treated fibroblasts, whereas matrix metalloproteinase (MMP)-1 and MMP-3 mRNA levels were significantly increased in HDFs and KFs. Furthermore, ZAG peptide significantly reduced protein expression of collagen type I and III, TGF-ß1, and p-Smad2/3 complex in KFs. Rat incisional scar models treated with ZAG peptide presented narrower scar areas and reduced immature collagen deposition, along with decreased expression of collagen type I, α-SMA, and p-Smad2/3. CONCLUSION: ZAG peptide effectively suppresses the TGF-ß and p-Smad2/3 pathway and inhibits excessive cell proliferation during scar formation, suggesting its potential therapeutic implications against keloids and hypertrophic scars.