[COMPREHENSIVE GUIDELINES AND INDICATIONS FOR DIGITAL MONITORING OF PATIENTS AT HIGH-RISK FOR MELANOMA: A POSITION PAPER BY THE ISRAELI ASSOCIATION FOR DERMATOLOGY].

INTRODUCTION: Early detection may lead to reduced morbidity and mortality from melanoma. This study aims to establish guidelines for selecting patients suitable for digital monitoring of skin lesions. METHODS: A literature review was conducted, followed by consensus among experts appointed by the Israeli Dermatology Association. RESULTS: Two effective methods for early melanoma diagnosis were identified: Total-body photography (TBP) and digital dermoscopy. TBP involves capturing clinical images of the entire skin area for long-term monitoring (6-12 months). Digital dermoscopy focuses on close-up images of distinct lesions for short-term monitoring (3-4 months). Various risk factors for melanoma were identified, including genetic and familial factors, as well as demographic and phenotypic characteristics. Based on these risk factors and feasibility of clinical follow-up, a comprehensive list of indications for TBP was developed, categorized into three groups based on the expected level of benefit. Digital dermoscopy surveillance is recommended for patients with flat or slightly raised skin lesions showing dermoscopic features that do not definitively indicate melanoma. DISCUSSION: TBP significantly improves early melanoma detection, enhancing sensitivity and specificity while reducing unnecessary biopsies. However, due to its high cost and limited coverage by the Israeli public health care system, prioritizing patients who would benefit most from TBP is crucial. The compiled list of indications aligns with international recommendations and provides further details within the article.

Epidemiological and Clinical Characteristics of Adult and Pediatric Patients with Chronic Spontaneous Urticaria.

Chronic spontaneous urticaria (CSU) is when lesions occur for ≥6 weeks. However, its underlying mechanism remains unclear. CSU prevalence is similar in adult and pediatric patients; nevertheless, few data are available on CSU characteristics in pediatric patients. We aimed to describe the epidemiology, clinical features, and treatment approach of CSU in pediatrics and adults. In this cross-sectional study, 193 patients with CSU were treated at the Sheba Medical Center, Israel, in 2009-2022. The information collected includes age at diagnosis, reported triggers, atopic co-morbidities, autoimmune co-morbidities, treatments and their response, family background, laboratory tests, and follow-up duration. The study group was divided into pediatrics (aged ≤ 18) and adults. Metabolic syndrome was most prevalent in adults as against atopy in pediatrics. Autoimmune co-morbidities were observed in 34.7% and 34.8% of adults and pediatrics, respectively. Inflammatory bowel disease and thyroid disease were the most common in pediatrics and adults, respectively. Systemic treatments other than antihistamines were administered more frequently in adults. Adults with autoimmune disease required second-line treatment with immunomodulators compared to those without it. Co-morbidities were more common in adults than in pediatrics. Patients with autoimmune co-morbidities may be more challenging to manage; thus, escalation to biologics should be considered soon.

Diagnostic delay, comorbid hidradenitis suppurativa and the prognostic value of bacterial culture in folliculitis decalvans: A cohort study.

BACKGROUND: Folliculitis decalvans (FD) is a type of primary neutrophilic cicatricial alopecia often leading to irreversible hair loss. Data on its epidemiology, clinical features, outcomes, and prognostic factors are limited. OBJECTIVE: To evaluate a cohort of patients with FD and identify characteristics of severe disease and prognostic factors which impede remission. PATIENTS AND METHODS: This retrospective cohort study included 192 patients diagnosed with FD and followed for at least six months at a tertiary center between 2010 and 2020. RESULTS: There was a diagnostic delay averaging 22.2 (± 29.7) months. Comorbid follicular occlusion disorders were common. Bacterial cultures were positive in 45.6% of the cases, with Staphylococcus (S.) aureus being the most common pathogen. Severe disease was associated with comorbid hidradenitis suppurativa and a positive bacterial culture, particularly S. aureus. 50.7% of patients experienced complete remission: 32% within the first six months of treatment and 18.7% later during follow-up. Relapses were frequent. Negative prognostic factors for achieving remission included younger age and a positive bacterial culture. CONCLUSIONS: There is a need for the education of dermatologists to reduce the diagnostic delay. Screening FD patients for comorbid hidradenitis suppurativa and obtaining bacterial cultures is important for treatment planning.

Mycosis Fungoides in Solid-Organ Transplant Recipients: A Multicenter Retrospective Cohort Study.

BACKGROUND: Mycosis fungoides (MF) in solid-organ transplant recipients (SOTRs) is rare, with limited data on disease characteristics. OBJECTIVE: The aim was to study the characteristics of MF in SOTRs with an emphasis on the immunosuppressive therapy. METHODS: A retrospective cohort of patients diagnosed with MF, who were also SOTRs, were followed at 3 cutaneous lymphoma outpatient clinics, between January 2010 and February 2022. RESULTS: Ten patients were included (7 male; median ages at transplantation and at diagnosis of MF were 33 and 48 years, respectively; 40% were diagnosed before the age of 18 years). Median time from transplantation to diagnosis of MF was 8 years (range 0.5-22). Transplanted organs and immunosuppressive treatments included: liver (n = 5; 4 treated with tacrolimus, 1 with tacrolimus and prednisone), kidney (n = 3), liver and kidney (n = 1), and heart (n = 1), all treated with mycophenolic acid, tacrolimus, and prednisone. Nine had early-stage MF (IA - 4, IB - 5; 40% with early folliculotropic MF), treated with skin-directed therapies, in 2 combined with acitretin, achieving partial/complete response. One patient had advanced-stage MF (IIIA) with folliculotropic erythroderma, treated with ultraviolet A and narrow-band ultraviolet B with acitretin, achieving partial response. Immunosuppression was modified in 3. At last follow-up (median 4 years, range 1-8), no stage progression was observed; 5 had no evidence of disease, 5 had active disease (IA/IB - 4, III - 1). CONCLUSIONS: MF in SOTRs is usually diagnosed at an early stage, with overrepresentation of folliculotropic MF, and of children. Immunosuppressive therapy alterations, not conducted in most patients, should be balanced against the risk of organ compromise/rejection. Disease course was similar to MF in immunocompetent patients, during the limited time of follow-up.

The Implications of a Dermatopathologist's Report on Melanoma Diagnosis and Treatment.

An accurate and comprehensive histopathology report is essential for cutaneous melanoma management, providing critical information for accurate staging and risk estimation and determining the optimal surgical approach. In many institutions, a review of melanoma biopsy specimens by expert dermatopathologists is considered a necessary step. This study examined these reviews to determine the critical primary histopathology Breslow score in which a histopathology review would be most beneficial. Histopathology reports of patients referred to our institute between January 2011 and September 2019 were compared with our in-house review conducted by an expert dermatopathologist. The review focused on assessing fundamental histologic and clinical prognostic features. A total of 177 specimens underwent histopathology review. Significant changes in the Breslow index were identified in 103 cases (58.2%). Notably, in many of these cases (73.2%), the revised Breslow was higher than the initially reported score. Consequently, the T-stage was modified in 51 lesions (28.8%). Substantial discordance rates were observed in Tis (57%), T1b (59%), T3a (67%) and T4a (50%) classifications. The revised histopathology reports resulted in alterations to the surgical plan in 15.3% of the cases. These findings emphasize the importance of having all routine pathologies of pigmented lesions referred to a dedicated cancer center and reviewed by an experienced dermatopathologist. This recommendation is particularly crucial in instances where the histopathology review can potentially alter the diagnosis and treatment plan, such as in melanoma in situ and thinner melanomas measuring 0.6-2.2 mm in thickness. Our study highlights the significant impact of histopathology reviews in cutaneous melanoma cases. The observed changes in Breslow scores and subsequent modifications in T-stage classification underline the need for thorough evaluation by an expert dermatopathologist, especially in cases of melanoma in situ and thin melanomas. Incorporating such reviews into routine practice within dedicated cancer centers can improve diagnostic accuracy and guide appropriate treatment decisions, ultimately leading to better patient outcomes.

Psori Silk in Mild to Moderate Psoriasis: A Randomized Phase I-II Trial Study.

In patients with mild to moderate psoriasis, topical corticosteroids are usually the first-line of treatment; however, they are not suitable for long-term use. The purpose of this study was to assess the efficacy and safety of a multi-fruit-and-vegetable compound, Psori Silk, in the treatment of patients with psoriasis. This was a randomized double-blind trial comprising 12 weeks of treatment with Psori Silk versus a vehicle, and a 4-week follow-up. The primary endpoint was 50% reduction in the modified Psoriasis Area and Severity Index (MPASI 50) score at week 12, while the secondary endpoint was quality of life assessment using the Dermatology Life Quality Index (DLQI). The Psori Silk group consisted of 23 patients with 34 lesions to be treated versus 22 patients in the vehicle group with 36 lesions. The MPASI 50 score was observed in 59% patients in the active group versus 22.7% patients in the vehicle group (P < 0.001). A mean 33% DLQI improvement was observed in 65.2% patients in the active group versus 27.2% patients in the vehicle group (P < 0.001). Mild and temporary discomfort at the site of application was reported in 39% patients in the active group versus 23% patients in the vehicle group. Psori silk appears to be an effective and safe treatment option for mild to moderate plaque psoriasis.

Bath psoralen plus ultraviolet-A photochemotherapy for chronic graft-versus-host disease: a retrospective cohort study.

BACKGROUND: Chronic graft-versus-host disease is a severe complication of allogeneic stem cell and bone marrow transplantation. First-line immunosuppressive agents, such as steroids, are used to prevent this disease; however, they have multiple side effects. Therefore, bath psoralen plus ultraviolet-A (PUVA) is an alternative second-line treatment. This study aimed to evaluate the clinical efficacy of bath PUVA for managing chronic graft-versus-host disease. METHODS: This retrospective, case-control study included 14 patients with extensive cutaneous chronic graft-versus-host disease, resistant to systemic corticosteroid, treated with bath PUVA. Major and partial responses were defined as clinical improvements of >70% and 50-70%, respectively. We analyzed the graft-versus-host disease clinical presentation and timing after allogeneic stem cell and bone marrow transplantation, bath PUVA doses, background diseases, additional treatments, and adverse effects. RESULTS: We observed eight major (three lichenoid and five sclerodermatoid) and six partial (three lichenoid and three sclerodermatoid) responses after a mean of 28 treatment sessions. After 6 to 25 months, four of the eight patients with sclerodermatoid lesions and all those with lichenoid lesions experienced relapse but responded to additional treatment cycles. CONCLUSIONS: Bath PUVA is well-tolerated and effective for extensive cutaneous chronic graft-versus-host disease. It allows rapid tapering of adjuvant immunosuppressants; however, most patients require prolonged maintenance phototherapy.

Coexistence of malignancies in pemphigus vulgaris.

Pemphigus vulgaris (PV) is a rare autoimmune intraepidermal bullous disease. PV has a major effect on morbidity as well as quality of life. There is sparse literature regarding the association between pemphigus vulgaris (PV) and comorbid malignancies. In this study we aimed to assess the risk of malignancy in a cohort of patients with PV and characterize PV-associated malignancies. Data were collected from two tertiary referral centers between the years 2008 and 2019 and compared with the national cancer registry. Of 164 patients with PV, 19 were diagnosed with malignancy: seven prior to PV diagnosis and 12 after. All cancers, solid and hematological, displayed higher incidences compared to the general population (p <0.001). In conclusion, we demonstrated higher rates of malignancies among patients with PV than in the general population. These observations suggest the need for careful assessment and follow up of patients with PV, given the possibility of associated malignancies.

Biological treatment for bullous pemphigoid.

Background: Bullous pemphigoid (BP) is the most common autoimmune subepidermal bullous disease. Topical or systemic corticosteroids are often used as the first-line treatment. However, long-term corticosteroid use may lead to significant side effects. Therefore, various adjuvant immunosuppressant therapies are used as steroid-sparing agents, with accumulating reports of biological treatments for severely recalcitrant BP. Objective: To describe the clinical and immunological features of a series of patients with recalcitrant BP treated with immunobiological therapies. To assess the efficacy and safety of their therapies. Methods: Patients receiving biological treatment for BP from two centers were assessed. Here, we described the clinical, immunopathological, and immunofluorescence findings of adult patients with BP and analyzed the clinical response and adverse events associated with various biological therapies. Results: We identified nine eligible patients treated with rituximab (seven), omalizumab (three), or dupilumab (one). The mean age at diagnosis was 60.4 years, the average BP duration before biologic initiation was 1.9 years, and the average previous treatment failure was 2.11 therapies. The mean follow-up period from the first biological treatment to the last visit was 29.3 months. Satisfactory response, defined as clinical improvement, was achieved in 78% (7) of the patients, and total BP clearance was achieved in 55% (5) of the patients at the last follow-up visit. Additional rituximab courses improved the disease outcomes. No adverse events were reported. Conclusions: Efficient and safe novel therapies can be considered in recalcitrant steroid-dependent BP non-responsive to conventional immunosuppressant therapies.

White epidermal nevus as an early sign of tuberous sclerosis complex-A case series.

Tuberous sclerosis complex (TSC) is a rare genetic disease with neurocutaneous manifestations, often presenting initially to the dermatology clinic. We report a cohort of neonates who presented with a novel finding of white epidermal nevus and were eventually diagnosed with TSC. White epidermal nevus may be yet another dermatological finding that may aid in the early diagnosis of TSC.

Bullous pemphigoid and dipeptidyl peptidase-4 inhibitors: evaluation of clinical course and treatment response.

BACKGROUND: Dipeptidyl peptidase-4 inhibitors (DPP4is), drugs used to treat type 2 diabetes mellitus (DM2), show a significant association with bullous pemphigoid (BP) development. OBJECTIVES: To evaluate the clinical course and development of BP among patients with DM2 treated with DPP4is. METHODS: This retrospective cohort study included all the patients with BP and comorbid DM2 who visited Sheba Medical Center during 2015-2020. RESULTS: Among 338 patients with BP, 153 were included in our study. In 92 patients, BP diagnosis was attributed to the use of DPP4is. The patients with DPP4i-associated BP had fewer neurological and cardiovascular comorbidities and higher blistered body surface area (BSA) at first presentation, with noticeable upper and lower limb involvement. These patients were younger and more responsive to treatment, with a greater reduction in their BSA score after 2 months of treatment. CONCLUSIONS: The clinical features of patients with BP treated with DPP4is were initially more severe; however, during follow-up, a marked clinical improvement was noticed, especially among patients who had ceased the drug. Therefore, although withdrawal of the drug may not impose disease remission, it can alleviate the disease course and avert the need for treatment escalation.

Cutaneous Leishmaniasis Caused by Leishmania infantum, Israel, 2018-2021.

Cutaneous leishmaniasis (CL) is endemic to Israel. Previously, CL caused by Leishmania infantum had been reported in Israel only once (in 2016). We report 8 L. infantum CL cases; 7 occurred during 2020-2021. None of the patients had systemic disease. L. infantum CL may be an emerging infection in Israel.

A horse or a zebra? Unusual manifestations of common cutaneous infections in primary immunodeficiency pediatric patients.

Background: Patients with primary immunodeficiency disorders (PIDs) often suffer from recurrent infections because of their inappropriate immune response to both common and less common pathogens. These patients may present with unique and severe cutaneous infectious manifestations that are not common in healthy individuals and may be more challenging to diagnose and treat. Objective: To describe a cohort of patients with PIDs with atypical presentations of skin infections, who posed a diagnostic and/or therapeutic challenge. Methods: This is a retrospective study of pediatric patients with PID with atypical presentations of infections, who were treated at the immunodeficiency specialty clinic and the pediatric dermatology clinic at the Sheba Medical Center between September 2012 and August 2022. Epidemiologic data, PID diagnosis, infectious etiology, presentation, course, and treatment were recorded. Results: Eight children with a diagnosis of PID were included, five of whom were boys. The average age at PID diagnosis was 1.7 (±SD 3.2) years. The average age of cutaneous infection was 6.9 (±SD 5.9) years. Three patients were born to consanguineous parents. The PIDs included the following: common variable immunodeficiency, severe combined immunodeficiency, DOCK8 deficiency, ataxia telangiectasia, CARD11 deficiency, MALT1 deficiency, chronic granulomatous disease, and a combined cellular and humoral immunodeficiency syndrome of unknown etiology. The infections included the following: ulcerative-hemorrhagic varicella-zoster virus (two cases) atypical fungal and bacterial infections, resistant Norwegian scabies, giant perianal verrucae (two cases), and diffuse molluscum contagiosum. Conclusions: In this case series, we present unusual manifestations of infectious skin diseases in pediatric patients with PID. In some of the cases, recognition of the infectious process prompted life-saving treatment. Increasing familiarity with these dermatological manifestations, as well as keeping a high index of suspicion, is important to enabling early diagnosis of cutaneous infections in PIDs and initiation of prompt suitable treatment.

Primary Melanoma miRNA Trafficking Induces Lymphangiogenesis.

Melanoma, the deadliest cutaneous tumor, initiates within the epidermis; during progression, cells invade into the dermis and become metastatic through the lymphatic and blood system. Before melanoma cell invasion into the dermis, an increased density of dermal lymphatic vessels is observed, generated by a mechanism which is not fully understood. In this study, we show that, while at the primary epidermal stage (in situ), melanoma cells secrete extracellular vesicles termed melanosomes, which are uptaken by dermal lymphatic cells, leading to transcriptional and phenotypic pro-lymphangiogenic changes. Mechanistically, melanoma-derived melanosomes traffic mature let-7i to lymphatic endothelial cells, which mediate pro-lymphangiogenic phenotypic changes by the induction of type I IFN signaling. Furthermore, transcriptome analysis upon treatment with melanosomes or let-7i reveals the enhancement of IFI6 expression in lymphatic cells. Because melanoma cells metastasize primarily via lymphatic vessels, our data suggest that blocking lymphangiogenesis by repressing either melanosome release or type I IFN signaling will prevent melanoma progression to the deadly metastatic stage.

Prevalence, Spectrum and Clinical Implications of Malignancies in Patients with Bullous Pemphigoid.

Current research on the malignancy rate and spectrum of malignancies in patients with bullous pemphigoid is contradictory. The aims of this study were to determine the prevalence and spectrum of malignancy in patients with bullous pemphigoid and to compare demographic, clinical, therapeutic and outcome data between bullous pemphigoid patients with and without malignancy. This retrospective cohort study enrolled 335 patients (194 women and 141 men; mean age at diagnosis of bullous pemphigoid 77.5 ± 12 years) followed up at an Israeli tertiary centre between January 2009 and December 2019: 107 (32%) had malignancy and 228 (68%) did not. Malignancy occurred before and after bullous pemphigoid diagnosis in 82 (77%) and 25 (23%) patients, respectively. Bullous pemphigoid patients with cancer were older (p = 0.02) and had a higher mortality rate (p < 0.0001) than those without malignancy. The 2 groups did not differ in terms of sex, comorbidities, or clinical characteristics. Those who developed malignancy before bullous pemphigoid were younger than those who developed malignancy after bullous pemphigoid (mean age 69.3 vs 82.4 years, p < 0.0001). Overall malignancy rates did not differ between patients with bullous pemphigoid and the general population; therefore, comprehensive malignancy workup may be unnecessary. However, patients with bullous pemphigoid had a greater risk of melanoma (10.7% vs 4.3%, p = 0.0005); therefore, routine skin screening may be recommended.

The Role of Histological Examination of Nail Clipping in the Diagnosis of Onychomycosis.

BACKGROUND: Diagnosis of onychomycosis is based on potassium hydroxide (KOH), direct smear, culture, and polymerase chain reaction. Nail clippings are rarely used as a diagnostic tool. OBJECTIVES: To evaluate nail clippings for the diagnosis of onychomycosis and to compare it to KOH smears. METHODS: Nail clipping specimens of 39 patients were collected: 34 with onychomycosis proved by positive culture and 5 from normal nails. The specimens were submitted to histological processing and then stained with periodic acid-Schiff (PAS) and Grocott-Gomori's methenamine silver (GMS) stains. For each nail, KOH smear was also performed. Two pathologists who had no information on the KOH smear and the culture results evaluated the nail clipping histology for the presence of fungal element. Their assessment was compared to the KOH smear and culture results. RESULTS: Of the 34 specimens that had positive culture, 25 were dermatophytes, 5 were molds, and 4 were candida. Clipping specimens were positive in 30 cases (88%): 23/25 dermatophyte, 4/5 molds, and 3/4 candida. Pathologists were able to classify the pathogens into dermatophytes and non-dermatophytes based on the morphology. PAS stain results were the same as GMS in evaluation of the nail specimen. KOH smear was positive in 29 nails (85%): 20/25 dermatophytes, all 5 molds, and 4 candida. In all five nails where the culture was negative, both clipping and KOH smear did not show fungal elements. CONCLUSIONS: Nail clippings can serve as a rapid, inexpensive, and reliable method for evaluation of onychomycosis, comparable to KOH smear, with the advantage of pathogen group identification.

Skin Eosinophil Counts in Bullous Pemphigoid as a Prognostic Factor for Disease Severity and Treatment Response.

Dermal infiltration of eosinophils and eosinophilic spongiosis are prominent features of bullous pemphigoid lesions. Although several observations support the pathogenic role of eosinophils in bullous pemphigoid, few studies have examined the impact of skin eosinophil counts on disease severity and treatment response. This retrospective study assessed the association between eosinophil counts in skin biopsy samples of 137 patients with bullous pemphigoid and their demographic characteristics, comorbidities, disease severity, and treatment response. There was no relationship between eosinophil count and age, sex, or disease severity at disease onset. There was a positive relationship between eosinophil counts and neurological comorbidity and a negative relationship between eosinophil counts and treatment response. At all follow-up points patients with no tissue eosinophils had a better response to treatment than patients with any tissue eosinophil count. In conclusion, skin eosinophil counts in patients with bullous pemphigoid are not correlated with disease severity at onset, but can serve as a negative prognostic marker for treatment response.

Changing spectrum of hair and scalp disorders over the last decade in a tertiary medical centre.

BACKGROUND: Hair- and scalp-related disorders (HSRDs) encompass a wide range of conditions that affect people of all ages. OBJECTIVE: To evaluate the workload and trends in HSRDs at an outpatient dermatological clinic in a tertiary medical centre over a 10-year period. METHODS: Medical records for HSRD visits to the outpatient dermatology clinic at the Sheba Medical Center, an Israeli tertiary care center, were reviewed between 1 January, 2010 and 31 December, 2020. RESULTS: There were 10,396 HSRD visits with a new-to-follow-up visit ratio of 1:1.9. The annual number of HSRD visits, as well as their proportion out of all dermatological outpatient visits, have increased from 295 (1.24%) in 2010 to 1726 (9.44%) in 2020. The patients' mean age was 35.3 years (women 39.5 years, men 28.8 years), age range 1-87 years. Over the decade, there was a growing predominance of women with an average female-to-male ratio of 2:1. The winter season accounted for 28.7% of annual visits, followed by the autumn (25.6%), summer (24.3%) and spring (21.4%). The most prevalent HSRDs included androgenetic alopecia (30.6%), alopecia areata (19.3%), telogen effluvium (15.4%), non-scarring folliculitis (15.4%), seborrheic dermatitis (14.9%), lichen planopilaris (7.1%) and folliculitis decalvans (6.6%). Androgenetic alopecia demonstrated the highest increase over the decade examined (from 17% to 32%). CONCLUSION: HSRDs account for a significant percentage of visits at a tertiary dermatology outpatient clinic. The number of HSRD visits has increased annually over the past decade. The recent advancement in diagnosis and treatment may account, at least in part, for the growing burden of HSRDs within dermatological ambulatory care.