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.

Balancing medical education in aesthetics: Review and debate.

The demand for minimally invasive cosmetic procedures is rising, and the public and other physicians deem dermatologists as top providers of these services. Given these expectations, dermatologic residency training must equip resident physician trainees to care for the growing population of patients with aesthetic concerns. As it stands, formal hands-on cosmetic dermatology training in residency is lacking specific structure. Educational, cultural, time, and monetary barriers exist, among others, which restrict residents from attaining proficiency in cosmetic dermatology procedures prior to graduation. This may adversely impact patient safety and deter graduates from offering aesthetic procedures. The standardization of core residency competencies in minimally invasive cosmetic procedures is fundamental to guarantee patient safety and satisfaction while ensuring practitioner competence. The balance between these elements is essential for optimal patient care. We review and debate modifying and strengthening the current curriculum requirements while presenting means to overcome barriers.

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.

Rescuing medical education in times of COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic has caused widespread disruptions in various sectors of medicine, including medical education. Although the necessary focus has been on patient care and public safety and the long-lasting impact of COVID-19 remains to be determined, the impact on medical education warrants further attention and action. While it seems minuscule compared with the toll the global pandemic has caused worldwide, the impact on medical education, including graduate medical education, carries the potential to alter career progression and outcomes. We have assessed the effects of COVID-19 on dermatology clinics, residency education, and medical education, exploring recommendations and actions taken by governing bodies and offering additional suggestions of our own.

A Review of Acquired Autoimmune Blistering Diseases in Inherited Epidermolysis Bullosa: Implications for the Future of Gene Therapy.

Gene therapy serves as a promising therapy in the pipeline for treatment of epidermolysis bullosa (EB). However, with great promise, the risk of autoimmunity must be considered. While EB is a group of inherited blistering disorders caused by mutations in various skin proteins, autoimmune blistering diseases (AIBD) have a similar clinical phenotype and are caused by autoantibodies targeting skin antigens. Often, AIBD and EB have the same protein targeted through antibody or mutation, respectively. Moreover, EB patients are also reported to carry anti-skin antibodies of questionable pathogenicity. It has been speculated that activation of autoimmunity is both a consequence and cause of further skin deterioration in EB due to a state of chronic inflammation. Herein, we review the factors that facilitate the initiation of autoimmune and inflammatory responses to help understand the pathogenesis and therapeutic implications of the overlap between EB and AIBD. These may also help explain whether corrections of highly immunogenic portions of protein through gene therapy confers a greater risk towards developing AIBD.

Complementary and alternative medicine treatments for common skin diseases: A systematic review and meta-analysis.

BACKGROUND: Complementary and alternative medicine (CAM) treatments are growing in popularity as alternative treatments for common skin conditions. OBJECTIVES: To perform a systematic review and meta-analysis to determine the tolerability and treatment response to CAM treatments in acne, atopic dermatitis (AD), and psoriasis. METHODS: PubMed/Medline and Embase databases were searched to identify eligible studies measuring the effects of CAM in acne, AD, and psoriasis. Effect size with 95% confidence interval (CI) was estimated using the random-effect model. RESULTS: The search yielded 417 articles; 40 studies met the inclusion criteria. The quantitative results of CAM treatment showed a standard mean difference (SMD) of 3.78 (95% CI [-0.01, 7.57]) and 0.58 (95% CI [-6.99, 8.15]) in the acne total lesion count, a SMD of -0.70 (95% CI [-1.19, -0.21]) in the eczema area and severity index score and a SMD of 0.94 (95% CI [-0.83, 2.71]) in the scoring of atopic dermatitis score for AD, and a SMD of 3.04 (95% CI [-0.35, 6.43]) and 5.16 (95% CI [-0.52, 10.85]) in the Psoriasis Area Severity Index score for psoriasis. LIMITATIONS: Differences between the study designs, sample sizes, outcome measures, and treatment durations limit the generalizability of data. CONCLUSIONS: Based on our quantitative findings we conclude that there is insufficient evidence to support the efficacy and the recommendation of CAM for acne, AD, and psoriasis.

Hidradenitis suppurativa is associated with acne keloidalis nuchae: a population-based study.

The association between acne keloidalis nuchae (AKN) and hidradenitis suppurativa (HS) is yet to be investigated. To determine the link between AKN and HS using a large computerized health maintenance database. A cross-sectional study design was used to assess the prevalence of HS in patients with AKN and in control participants matched by age, sex, and ethnicity. A total of 2677 participants with AKN and 13,190 control participants were studied. An increased prevalence of HS was observed in the AKN group compared to the control group (1.0% vs. 0.3%, respectively; OR, 3.6; 95% CI 2.2-5.8; P < 0.001), especially among those younger than 20 years (OR, 10.2; 95% CI 3.1-34.2; P < 0.001), and females (OR, 15.7; 95% CI 3.1-78.8; P < 0.001). After adjusting for confounding factors, the multivariate analysis demonstrated a persistent association of AKN with HS (adjusted OR, 3.6; 95% CI 2.1-5.9; P < 0.001). This study demonstrated a significant association between AKN and HS in an Israeli population. The threshold for diagnosis of HS among patients with AKN must be lowered in patients presenting with concerning symptoms. Further observational studies in other patient populations will help confirm this relationship.

Dermatologist transitions: Academics into private practices and vice versa.

National experience demonstrates that most physicians will undergo a job change within the first few years of practice. Due to shifting payment models, personal preferences, and financial burden, among other factors, job transitions between private practice and academic medicine are expected. With the rising shortage of dermatologists and an increase in demand for dermatologic services, this particular topic is salient due to the impact on patient care, graduate medical education, and advances in research and medicine. The balance between these elements is fundamental for the future of dermatologic education and care. We address the challenges faced by dermatologists in both the academic and private practice settings, while offering insight into the motivations and barriers in the transition between the two.

A Review Comparing International Guidelines for the Management of Bullous Pemphigoid, Pemphigoid Gestationis, Mucous Membrane Pemphigoid, and Epidermolysis Bullosa Acquisita.

Autoimmune blistering disease management can be challenging as treatment modalities vary greatly and no single standard of care exists. We consolidated the recommendations of international management guidelines in order to provide optimal management suggestions to physicians. A comprehensive literature search in PubMed/MEDLINE for published blistering disease management guidelines and consensus statements was conducted in November 2019. Search terms included "guideline or guidelines" or "consensus" and "pemphigoid" or "autoimmune blistering disease" or "epidermolysis bullosa acquisita". We included guidelines from established dermatologic societies and expert consensus groups. We excluded literature reviews, guidelines established by an association without dermatologists, or those specific to a single treatment. Guidelines in all languages were considered. Eleven guidelines from dermatologic associations and consensus groups meeting our inclusion criteria were selected. Several differences between recommendations, most notably when to introduce adjuvants for refractory disease, were found in bullous pemphigoid. In mucous membrane pemphigoid, treatment was directed to the sites involved and managed with systemic corticosteroids and immunosuppressants/biologics. There was no universal consensus on the first-line treatment for epidermolysis bullosa acquisita, but a combination of immunosuppressive, anti-inflammatory, and anti-neutrophil therapy was utilized. Comparison of the management guidelines revealed underrepresentation of guidelines from developing nations and key differences between the management styles among dermatologists from Europe and Asia. We attribute these discrepancies to the time elapsed between guidelines, regional differences, and demands of the local healthcare systems.

The Role of Collagen XVII in Cancer: Squamous Cell Carcinoma and Beyond.

Alterations in the extracellular matrix (ECM) likely facilitate the first steps of cancer cell metastasis and supports tumor progression. Recent data has demonstrated that alterations in collagen XVII (BP180), a transmembrane protein and structural component of the ECM, can have profound effects on cancer invasiveness. Collagen XVII is a homotrimer of three α1 (XVII) chains. Its intracellular domain contains binding sites for plectin, integrin ß4, and BP230, while the extracellular domain facilitates interactions between the cell and the ECM. Collagen XVII and its shed ectodomain have been implicated in cell motility and adhesion and are believed to promote tumor development and invasion. A strong association of collagen XVII ectodomain shedding and tumor invasiveness occurs in squamous cell carcinoma (SCC). Aberrant expression of collagen XVII has been reported in many epithelial cancers, ranging from squamous cell carcinoma to colon, pancreatic, mammary, and ovarian carcinoma. Thus, in this review, we focus on collagen XVII's role in neoplasia and tumorigenesis. Lastly, we discuss the importance of targeting collagen XVII and its ectodomain shedding as a novel strategy to curb tumor growth and reduce metastatic potential.

Hidradenitis suppurativa and pemphigus: a cross-sectional study.

A recent study of comorbidities in hospitalized pemphigus patients in the United States has demonstrated a significant association of hidradenitis suppurativa (HS) and pemphigus, but this association has not been firmly established in other populations. A retrospective, cross-sectional study was undertaken to determine the prevalence of HS in patients with pemphigus and compare with control subjects. Regression analysis was performed to obtain ORs, and 95% CIs, to evaluate the prevalence between pemphigus patients and controls matched by age, sex, and ethnicity. Among the patients included in the study, 1985 patients had pemphigus and 9874 were control subjects. The average age of presentation of pemphigus was 72.1 ± 18.5 and the group was comprised of 59.8% females. Overall, the pemphigus group had lower rates of smoking (25.7% vs. 27.9%; P = 0.045). The prevalence of HS was greater in patients with pemphigus than in control subjects (OR 4.98; 95% CI 1.01-24.69; P < 0.001), with an even more prominent association among patients who have been prescribed "pemphigus-related treatments" (OR 6.30; 95% CI 1.27-31.22; P < 0.001). The study detected a significant association between HS and pemphigus in an Israeli population. Future prospective studies are needed to establish a temporal order of appearance and the mechanistic relationship between these entities.

Patients with pemphigus are at an increased risk of developing rheumatoid arthritis: a large-scale cohort study.

Data regarding the association between pemphigus and rheumatoid arthritis (RA) is inconclusive and yet to be firmly established. In the current study, we aimed to evaluate the risk of developing RA during the course of pemphigus. A large-scale population-based longitudinal cohort study was conducted to evaluate the hazard ratio (HR) of RA among 1985 patients with pemphigus relative to 9874 age-, sex-, and ethnicity-matched control subjects. A multivariate Cox regression model was utilized. The incidence of RA was 1.07 (95% CI, 0.62-1.72) and 0.36 (95% CI, 0.24-0.52) per 1000 person-years among patients with pemphigus and controls, respectively. The lifetime prevalence of RA was 2.3% (95% CI, 1.7-3.1%) among cases and 1.8% (95% CI, 1.5-2.0%) among controls. Patients with pemphigus were more than twice as likely to develop RA as compared to control subjects (adjusted HR, 2.54; 95% confidence interval [CI], 1.31-4.92). The increased risk was robust to a sensitivity analysis that included only cases managed by pemphigus-related systemic medications (adjusted HR, 2.56; 95% CI, 1.30-5.05). In conclusion, pemphigus is associated with an increased risk of RA. Physicians treating patients with pemphigus should be aware of this possible association. Further research is required to better understand the mechanism underlying this association.