Pyoderma gangrenosum and impact on quality of life: A narrative review.

Pyoderma gangrenosum (PG) is an autoinflammatory disorder typically characterized by progressive ulcers with dense neutrophilic infiltrates in the absence of infectious causes. The chronic nature of this disease significantly impacts the patients' quality of life (QoL). Yet there is currently a dearth of information in the literature regarding standardised treatment guidelines and the impact of PG on patients' QoL. We conducted a literature search on PubMed using the terms "pyoderma gangrenosum" AND "quality of life." We identified nine relevant articles that provide insight into which domains are affected and what treatment can improve QoL. The most common domains involved are physical, emotional, and psychological. Patients tend to feel depressed/anxious, isolated, and embarrassed secondary to PG manifestations. Comorbidities such as Crohn's disease, monoclonal gammopathy of dermatologic significance, and ulcerative colitis can worsen the impact on these patients' QoL. Pain is also a significant contributor to decreasing patients' QoL. Treatments such as topical steroids, adalimumab, and canakinumab may help improve QoL scores. We believe this information can help clinicians guide the care of patients with PG and highlight the need for more studies and clinical trials focusing on PG treatments' impact on QoL.

A narrative review of studies assessing the quality of life in patients with generalized pustular psoriasis.

Generalized pustular psoriasis (GPP) is a clinical entity distinct from psoriasis, associated with a poor clinical prognosis, often resulting in severe systemic complications and mortality. The relapsing nature of the disease with recurrent or intermittent flares imposes a significant burden on patients' quality of life (QoL). Although inadequately studied, QoL data in GPP patients has been a recent point of investigation. We conducted a literature search on PubMed/MEDLINE using the following search terms: 'generalized pustular psoriasis' OR 'pustular psoriasis' AND 'quality of life'. We identified 12 relevant articles that provide insight into the large impact of GPP on the QoL of patients, the burden of the disease and the treatment, and the success of new treatment options in making a clinically important difference to QoL. This review illustrates a need for routine assessment of the QoL in interventional clinical trials for GPP and during physician encounters. This information can help guide clinicians on how to tailor the treatment approach from the patient's perspective or illustrate whether new therapies offer meaningful benefits to patient care as we enter an era of exciting new treatments for this challenging condition.

Novel assessment of lip redness and microcirculation using optical coherence tomography after dermal filler injection.

OBJECTIVES: Lip filler injections are one of the most popular procedures in esthetic dermatology. In this study, we used three-dimensional colorimetric photography to assess lip color and optical coherence tomography-angiography (OCT-A), a noninvasive alternative to histopathology, to evaluate microcirculation after hyaluronic acid (HA) injection. The pain of the injection procedure was also assessed. METHODS: An average of 0.85cc of the total volume of HA with lidocaine was injected into the upper and lower lip of eighteen young (<30yo) and nine postmenopausal healthy women. OCT-A, two-dimensional, and three-dimensional images were acquired immediately before (visit 1) and 15 days after injection (visit 2). Custom-made software was used to analyze the imaging data to detect vessel morphology and redness changes. The Wong-Baker FACES pain rating scale (0-10) was used to score the subject procedural pain. RESULTS: For young and old subjects, three-dimensional lip volume was greater than the injected volume. OCT-A images of the lips showed higher vessel density and thickness, reaching statistical significance in the younger cohort. The overall trend of increased redness assessed by three-dimensional colorimetric imaging and increased vascularity evaluated by OCT-A imaging were similar. However, the correlation was not statistically significant for standard two-dimensional digital photography. The average pain score after the first needle insertion and overall procedure were 2.9 and 3.5, respectively. CONCLUSIONS: The results suggest an increased microvasculature network observed in OCT-A images in young females. The increased blood vessel density and thickness observed by OCT-A after HA lip filler injection is associated with increased lip redness and volume as assessed by colorimetric three-dimensional photography; however, more research is needed to confirm these findings. This study presents OCT-A as a novel noninvasive tool to investigate changes in lip microvascularity after HA filler injection and indicates that HA filler procedures may affect lip vascularity.

Gene expression profiling of laminin α3-blocked keratinocytes reveals an immune-independent mechanism of blistering.

Laminin-332 pemphigoid is a rare and chronic autoimmune blistering disease which results in subepidermal blisters and erosive lesions predominantly localized to mucous membranes. As histologic inflammation is variable and non-complement-fixing IgG antibodies against laminin-332 are the predominant class of autoantibodies deposited at the epidermal basement membrane zone, we hypothesized that complement-independent pro-inflammatory and blistering pathways existed similarly to that previously shown in bullous pemphigoid. As autoantibodies to laminin α3 are most prevalent, we studied the major cellular response to blockade of laminin α3 using a well-characterized monoclonal antibody (P3H9-2). RNA-seq revealed upregulation of numerous desmosomal genes (DSG1, DSG3, DSC1, DSC3 and DSP) as well as KRT1 and KRT10. Additionally, P3H9-2-treated cells demonstrated downregulation of most hemidesmosomal genes. A pro-inflammatory response was not appreciated. Using pharmacological inhibitors, we identified both protein kinase C and NOTCH as key regulators of P3H9-2 induced differentiation. We lastly utilized 3D human skin equivalents to determine whether blockade of laminin α3 would lead to delayed blistering, consistent with keratinocyte differentiation. Significant blistering was noted after 72 h of treatment, with only minimal separation at 24 h. In summary, blockade of laminin α3 alters keratinocyte differentiation, representing a potential complement-independent mechanism of blistering.

The role of Dipeptidyl Peptidase-4 in cutaneous disease.

Dipeptidyl peptidase-4 (DPP4) is a multifunctional, transmembrane glycoprotein present on the cell surface of various tissues. It is present in multiple molecular forms including cell surface and soluble. The role of DPP4 and its inhibition in cutaneous dermatoses have been a recent point of investigation. DPP4 exerts a notable influence on T-cell biology, the induction of skin-specific lymphocytes, and the homeostasis between regulatory and effector T cells. Moreover, DPP4 interacts with a broad range of molecules, including adenosine deaminase, caveolin-1, CXCR4 receptor, M6P/insulin-like growth factor II-receptor and fibroblast activation protein-α, triggering downstream effects that modulate the immune response, cell adhesion and chemokine activity. DPP4 expression on melanocytes, keratinocytes and fibroblasts further alters cell function and, thus, has crucial implications in cutaneous pathology. As a result, DPP4 plays a significant role in bullous pemphigoid, T helper type 1-like reactions, cutaneous lymphoma, melanoma, wound healing and fibrotic disorders. This review illustrates the multifactorial role of DPP4 expression, regulation, and inhibition in cutaneous diseases.

Treatment of Pain in Keloids Using Only a Long-Pulsed 1064 nm Nd:YAG Laser.

BACKGROUND AND OBJECTIVE: Keloids are benign lesions arising from overproduction of the extracellular matrix and abnormal collagen deposition by dermal fibroblasts. This altered wound healing typically occurs in response to dermal trauma. Keloid treatment poses a challenge due to the variable nature of treatment response, which can be affected by the size, appearance, and associated symptoms of erythema, pruritus, and pain. Recently, successful treatment of keloids has been reported using the Nd:YAG laser in conjunction with 5-fluorouracil and intralesional corticosteroids. We present a series of patients with symptomatic keloids, who we treated with only a 1064 nm Nd:YAG laser. STUDY DESIGN/MATERIALS AND METHODS: Eight patients of Fitzpatrick skin types I-VI presented for treatment of keloids with associated symptoms of pain. The keloids were most commonly located on the trunk, and seven patients had intralesional steroid injections prior to presentation with persistence of symptoms. Patient treatment consisted of two passes under a long-pulsed 1064 nm Nd:YAG laser with a 10 mm spot size, a fluence of 18-19 J/cm2 , and 60 ms pulse duration every 3-8 weeks. Patient-reported pain scores were collected before and after treatment. RESULTS: Following treatment, transient erythema and mild edema were noted at the treatment site. All patients reported improvement in the symptoms of pain, with an average of a 5-point reduction using a 10-point scale (R: 2-10). Five out of eight patients had total resolution of their pain. An average of 3.25 treatments (R:1-5) were needed for patients to first notice an improvement in the pain. A Wilcoxon signed-rank test showed that treatment with a 1064 nm laser elicited a statistically significant improvement in pain in individuals with keloids (Z = 2.46, P = 0.01). No patients in our study suffered any scarring or pigment changes as a result of these treatments. CONCLUSION: Keloids are a common condition with variable rates of treatment satisfaction. Lasers have been used in an attempt to improve clinical appearance and associated symptoms. We report a significant reduction in pain for patients treated exclusively with a 1064 nm Nd:YAG laser. Lasers Surg. Med. © 2020 Wiley Periodicals LLC.

Dermatologic manifestations of pediatric cardiovascular diseases: Skin as a reflection of the heart.

Cutaneous disease can often be an initial clue of an underlying cardiovascular disease. Many congenital conditions (ie, Noonan syndrome with multiple lentigines, Carney complex, and Fabry disease) and acquired conditions may present initially with specific cutaneous features that should prompt clinicians to conduct a full cardiac workup. Given the extensive number of conditions with both cardiovascular and cutaneous findings, this review will focus on diseases with cardiocutaneous pathology with hopes of raising clinician awareness of these associations to decrease morbidity and mortality, as several of these diseases often result in fatal outcomes.

IgA pemphigus: A systematic review.

BACKGROUND: The clinical, histologic, and immunopathologic features of IgA pemphigus have not been studied on a large scale. OBJECTIVE: To synthesize existing data on the epidemiologic, clinical, histologic, and immunologic features of IgA pemphigus. METHODS: We performed a systematic review using MEDLINE, Embase, and Web of Science databases. Case reports and series of patients with IgA pemphigus were included. RESULTS: A total of 119 eligible studies, comprising 137 patients with IgA pemphigus with a mean age of 51.5 ± 21.0 years, were included. Most patients presented with vesicles (80.8%), pustules (75.0%), and circinate plaques (63.6%). Pruritus was present in 65.6% of reported patients. Intercellular deposition of IgA was noted in almost all patients (97.0%), and the remaining 3.0% of patients had IgA positivity on indirect immunofluorescence or enzyme-linked immunosorbent assay confirming the diagnosis. IgA circulating intercellular antibodies were detected in only 66.7% patients. IgA gammopathy and ulcerative colitis were associated with IgA pemphigus in 9.5% and 6.6% patients, respectively. Oral dapsone and corticosteroids were the mostly commonly used treatments. LIMITATIONS: Results are mainly based on case reports and small case series. CONCLUSIONS: The diagnosis of IgA pemphigus may be considered in patients presenting with vesiculopustular eruption and circinate plaques with truncal and extremity involvement.

Aesthetic Outcomes of Nasal Burow's Grafts With Interdomal Sutures After Mohs Micrographic Surgery.

BACKGROUND: Post-Mohs reconstruction of distal nasal defects is challenging. Many repair options exist, each with advantages and disadvantages. Utilization of a Burow's graft in combination with manipulation of the underlying nasal cartilages with interdomal sutures is an underreported yet effective repair option. OBJECTIVE: To present the authors' experience with Burow's grafts facilitated by interdomal sutures for repair of nasal defects after Mohs micrographic surgery (MMS). MATERIALS AND METHODS: Patients who underwent repair with Burow's grafts and interdomal sutures from 2013 to 2017 at a single university were identified. Demographics, follow-up, and complications were recorded. Two independent, board-certified dermatologists evaluated photographs for cosmesis and alar symmetry. RESULTS: Thirty-one patients were identified. A total of 5/31 patients (16.1%) experienced minor complications without permanent sequelae. A total of 4/31 (12.9%) patients underwent cosmetic revision. No incidences of pincushioning, nasal valve dysfunction, or graft necrosis occurred. Aesthetic ratings were good to excellent with mean visual analog score of 80.8. Alar symmetry was excellent. CONCLUSION: A Burow's full-thickness skin graft facilitated by an interdomal suture to maintain nasal tip orientation and projection is an elegant repair technique for distal nasal oncologic defects with good to excellent aesthetic outcomes. It should be considered in the armamentarium for repair of distal nasal defects after MMS.

Combination of Melolabial Interpolation Flap and Nasal Sidewall and Cheek Advancement Flaps Allows for Repair of Complex Compound Defects.

BACKGROUND: The paramedian forehead flap (PMFF) is the repair of choice for large nasal defects involving multiple cosmetic subunits. However, the PMFF may not be optimal for all patients. The combination of a melolabial interpolation flap (MLIF) and a nasal sidewall flap may serve as an alternative. OBJECTIVE: To present the surgical technique and aesthetic outcomes of the alternative reconstruction for surgical defects of the lower nose. MATERIALS AND METHODS: Fourteen patients with multisubunit nasal Mohs defects reconstructed alternatively were identified from 2 academic centers in this retrospective case series. Illustrations and photographs were used to demonstrate surgical technique and outcomes. Final aesthetic results were analyzed using the Patient and Observer Scar Assessment Scale. RESULTS: The physician observer rated the scar outcome a mean score of 10.9 ± 3.3. Patients rated their results as a mean of 9.1 ± 4.7. The mean "Patient" Overall Opinion score was 2.3 ± 2.6 and the mean "Observer" Overall Opinion score was 1.9 ± 0.9. No patients reported problems with nasal airflow or obstruction, and cosmetic complications such as pincushioning or alar buckling were not observed. CONCLUSION: The combined MLIF and nasal sidewall flap is an alternative repair for complex distal nasal defects.

C-type lectin receptor expression is a hallmark of neutrophils infiltrating the skin in epidermolysis bullosa acquisita.

Introduction: Inflammatory epidermolysis bullosa acquisita (EBA) is characterized by a neutrophilic response to anti-type VII collagen (COL7) antibodies resulting in the development of skin inflammation and blistering. The antibody transfer model of EBA closely mirrors this EBA phenotype. Methods: To better understand the changes induced in neutrophils upon recruitment from peripheral blood into lesional skin in EBA, we performed single-cell RNA-sequencing of whole blood and skin dissociate to capture minimally perturbed neutrophils and characterize their transcriptome. Results: Through this approach, we identified clear distinctions between circulating activated neutrophils and intradermal neutrophils. Most strikingly, the gene expression of multiple C-type lectin receptors, which have previously been reported to orchestrate host defense against fungi and select bacteria, were markedly dysregulated. After confirming the upregulation of Clec4n, Clec4d, and Clec4e in experimental EBA as well as in lesional skin from patients with inflammatory EBA, we performed functional studies in globally deficient Clec4e-/- and Clec4d-/- mice as well as in neutrophil-specific Clec4n-/- mice. Deficiency in these genes did not reduce disease in the EBA model. Discussion: Collectively, our results suggest that while the upregulation of Clec4n, Clec4d, and Clec4e is a hallmark of activated dermal neutrophil populations, their individual contribution to the pathogenesis of EBA is dispensable.

Inhibition of dipeptidyl-peptidase 4 induces upregulation of the late cornified envelope cluster in keratinocytes.

Dipeptidyl-peptidase 4 (DPP4) is a multifunctional type II transmembrane glycoprotein that is expressed on various cell surfaces. While DPP4 inhibitors have a therapeutic role in the treatment of diabetes mellitus, they are an independent risk factor in the development of bullous pemphigoid. Contrarily, there are reports of improvement in psoriasis with DPP4 inhibition. We investigated the effect of DPP4 inhibition on primary human keratinocytes to determine whether DPP4 modulates keratinocyte inflammatory signaling and keratinocyte homeostasis. We performed RNA sequencing of primary adult human keratinocytes treated with DPP4 inhibitor, identifying 424 differentially expressed genes. Gene ontology analysis revealed significant enrichment of epidermal differentiation and cornified envelope genes. Using three-dimensional organotypic cultures and a pan-late cornified envelope 2 (LCE2) antibody, we demonstrate a dose dependent relationship between DPP4 inhibition and increased expression of LCE2 during epidermal development. The late cornified envelope gene clusters are expressed at the late stages of epithelial development, responding to stimuli such as calcium and ultraviolet light. While its biologic function is not fully understood, mutations in LCE3B/LCE3C confer a 40% increased risk in the development of plaque psoriasis. While we did not identify significant modulation of keratinocyte inflammatory markers, DPP4 inhibition increased expression of the late cornified envelope may offer a potential alternative therapeutic mechanism in psoriasis.

Characterizing the proteome of bullous pemphigoid blister fluid utilizing tandem mass tag labeling coupled with LC-MS/MS.

Bullous pemphigoid is an autoimmune blistering disease caused by autoantibodies against components of the cutaneous basement membrane zone. Autoantibodies lead to complement-dependent and -independent inflammation and blistering. Blister fluid is a valuable biologic resource, as it provides insight into both systemic and local microenvironment responses. Here, we utilized liquid chromatography with tandem mass spectrometry to characterize the bullous pemphigoid blister fluid proteome. We then depleted exosomes to better understand the exosomal versus non-exosomal proteome. We identified 339 proteins in the blister fluid of bullous pemphigoid patients. Gene ontology demonstrated enrichment of several key biologic processes including innate immune response, neutrophil degranulation, platelet degranulation, and complement activation. Exosome depletion resulted in a significant decrease in normalized reporter intensities of 192 proteins, consistent with our observation of a large number of exosomal proteins found in the blister fluid. We then compared the bullous pemphigoid blister fluid proteome to prior proteomic datasets in suction blister fluid, snake bites, and thermal burns, identifying 76 proteins unique to bullous pemphigoid. These include major basic protein, eosinophil peroxidase, galectin-10, and the immunoglobulin epsilon heavy constant region, consistent with tissue eosinophilia. We lastly validated several previously reported blister fluid exosomal components. Blister fluid in bullous pemphigoid contains a mixture of numerous biologic processes. While many of these processes are shared with blistering from alternative causes, we have identified several notable features unique to bullous pemphigoid.

Safety and Sourcing of Topical Cannabinoids: Many Questions, Few Answers.

BACKGROUND: Topical cannabinoid products are increasingly being recommended and used for a variety of dermatologic conditions. Despite this, safety and efficacy data of topical preparations are lacking, and the differences between topical and oral formulations are not well characterized. OBJECTIVE: We reviewed the literature to gather published data on topical cannabinoid products and the differences between topical and oral formulations. METHODS: The PubMed/MEDLINE literature database was searched using the terms "cannabinoids," "cannabidiol," "CBD," "topical cannabidiol," "transdermal cannabidiol," "hemp" and "skin." Results were manually screened to identify published data on topical formulations of cannabinoids or cannabidiol use, adverse effects, sourcing, and solubility. RESULTS: Topical formulations of cannabinoids might be more nuanced than oral formulations, due not only to dosing differences, but also to potential differences in transcutaneous absorption. Safety and efficacy might need to be evaluated on a product-by-product basis until universal standards for topical preparations are better established. CONCLUSION: Topical cannabinoid products might be an important addition to the dermatologic armamentarium, with the potential to dose cannabinoids directly to the skin while minimizing systemic exposure. However, before this can be done reliably, important formulation parameters must be established and verified.

Eosinophils in bullous pemphigoid.

Bullous pemphigoid (BP) is an autoimmune blistering disorder with substantial morbidity and mortality. BP is regarded as a disorder driven by IgG due to BP180 and BP230 IgG autoantibodies, yet, new advances highlight the function of eosinophils and IgE autoantibodies in BP. Evidence supports that eosinophils are involved in BP pathogenesis, notably, these include the presence of IL-5, eotaxin, and eosinophil-colony stimulating factor in blister fluid. Peripheral blood eosinophilia is present in nearly 50% of affected patients, eosinophils are found against the dermo-epidermal junction (DEJ) when BP serum is present and metalloprotease-9 is secreted at blister sites. Blister fluid of BP patients contains eosinophil granule proteins which are located along the lamina lucida of the basement membrane zone (BMZ) in patients with BP and correspond with disease clinically, eosinophil extracellular traps (EET) have been linked to DEJ splitting, IL-5 activated eosinophils cause DEJ separation when BP serum is present, and eosinophils are requisite to drive anti-BP180 IgE mediated blistering of the skin. Yet, the mechanism whereby eosinophils contribute to the pathogenesis of BP remains to be explored. In this review, we examined the role of eosinophils in BP while offering a basis to explain the pathomechanisms of eosinophils in BP.