Risk factors for non-melanoma skin cancer development in renal transplant recipients: a 40 year retrospective study in Croatia.

AIM: To determine the prevalence of non-melanoma skin cancer (NMSC) and disease-specific risk factors in renal transplant recipients (RTRs). METHODS: This retrospective cohort study enrolled 1232 RTRs (736 men) treated in University Hospital Center Zagreb over 40 years. The effect of sex, age at transplantation, geographic residence, dialysis vintage, and the type of immunosuppressive therapy on NMSC occurrence was investigated. RESULTS: The prevalence of NMSC was 6.81%. Overall, 60.7% of patients developed basal cell carcinoma (BCC) and 30.9% of patients developed cutaneous squamous cell carcinoma (cSCC). Only 8.3% developed both tumors. The BCC:cSCC ratio was 1.76:1. The risk for NMSC was 50% higher in men. Patients older than 50 years at transplantation were at greater risk for NMSC development. Residence in an area with higher ultraviolaet radiation (UV) exposure and dialysis vintage before transplantation did not influence NMSC development. Cyclosporine and azathioprine treatment conferred a greater risk for NMSC than tacrolimus or mycophenolate mofetil treatment. CONCLUSION: RTRs are at high risk for NMSC development. Sex, age at transplantation, and type of immunosuppressive therapy play a role in tumor development.

New and Emerging Targeted Therapies for Hidradenitis Suppurativa.

Hidradenitis suppurativa (HS) is a chronic, recurrent, inflammatory skin disease deriving from the hair follicles. The formation of inflammatory nodules, abscesses, fistulas, and sinus tracts is characterized by a large inflow of key pro-inflammatory mediators, such as IFN-γ, TNF-α, IL-1, IL-17, and IL-12/23. Adalimumab is currently the only Food and Drug Administration (FDA)- and European Medicines Agency (EMA)-approved biologic therapy for moderate to severe HS in adults and adolescents. However, the long-term effectiveness of this TNF-α inhibitor in HS patients has shown to be highly variable. This review aims to review the evidence for emerging therapies that target the main pro-inflammatory cytokines in HS pathogenesis. A review of the literature was conducted, using the PubMed and Google Scholar repositories, as well as Clinicaltrials.gov. Presently, the most promising biologics in phase III trials are anti-IL-17 antibodies, secukinumab, and bimekizumab. Furthermore, an anti-IL-1 biologic, bermekimab, is currently in phase II trials, and shows encouraging results. Overall, the clinical efficacies of all new targeted therapies published up to this point are limited. More studies need to be performed to clarify the precise molecular pathology, and assess the efficacy of biological therapies for HS.

The association between clinical and laboratory findings of bullous pemphigoid and dipeptidyl peptidase-4 inhibitors in the elderly: a retrospective study.

AIM: To evaluate the association between the use of dipeptidyl peptidase-4 inhibitors (DPP4I) and clinical and laboratory findings of bullous pemphigoid (BP) in patients treated at the European Reference Network - Skin Reference Centre in Croatia. METHODS: This retrospective study enrolled 82 patients treated for BP at the Department of Dermatovenereology, University Hospital Center Zagreb from January 2015 to December 2019. Clinical features of BP, presence of comorbidities, and laboratory findings of anti-BP antibodies and eosinophilia were analyzed in three groups of BP patients: 1) diabetes mellitus (DM) type II patients treated with DPP4I, 2) DM type II patients not treated with DPP4I, and 3) non-DM type II patients. RESULTS: The average age and anti-BP180 titer were similar in all three groups. DPP4I group had a slightly lower eosinophil level in both peripheral blood (4.89%) and biopsy specimens (87.5%), but the difference was not significant. The prevalence of inflammatory BP in DPP4I group was 76.5%. DPP4I group had significantly higher percentage of patients with chronic renal failure and dementia (52.9% and 11.8%, respectively) compared with non-DPP4I DM (14.3% and 0%, respectively) and non-DM type II patients (15.7% and 0%, respectively). CONCLUSION: BP patients treated with DPP4I and those not treated with DPP4Is did not significantly differ in laboratory findings. However, DPP4I treatment was associated with an inflammatory subtype of BP and a higher prevalence of dementia and chronic renal failure. These findings warrant further research into the association of BP and DM with dementia and chronic renal failure.

Omega-3 Versus Omega-6 Polyunsaturated Fatty Acids in the Prevention and Treatment of Inflammatory Skin Diseases.

Omega-3 (ω-3) and omega-6 (ω-6) polyunsaturated fatty acids (PUFAs) are nowadays desirable components of oils with special dietary and functional properties. Their therapeutic and health-promoting effects have already been established in various chronic inflammatory and autoimmune diseases through various mechanisms, including modifications in cell membrane lipid composition, gene expression, cellular metabolism, and signal transduction. The application of ω-3 and ω-6 PUFAs in most common skin diseases has been examined in numerous studies, but their results and conclusions were mostly opposing and inconclusive. It seems that combined ω-6, gamma-linolenic acid (GLA), and ω-3 long-chain PUFAs supplementation exhibits the highest potential in diminishing inflammatory processes, which could be beneficial for the management of inflammatory skin diseases, such as atopic dermatitis, psoriasis, and acne. Due to significant population and individually-based genetic variations that impact PUFAs metabolism and associated metabolites, gene expression, and subsequent inflammatory responses, at this point, we could not recommend strict dietary and supplementation strategies for disease prevention and treatment that will be appropriate for all. Well-balanced nutrition and additional anti-inflammatory PUFA-based supplementation should be encouraged in a targeted manner for individuals in need to provide better management of skin diseases but, most importantly, to maintain and improve overall skin health.

Epidermolysis Bullosa Acquisita-Current and Emerging Treatments.

Epidermolysis bullosa acquisita (EBA) is a rare chronic autoimmune subepidermal blistering disease of the skin and mucous membranes, usually beginning in adulthood. EBA is induced by autoantibodies to type VII collagen, a major component of anchoring fibrils in the dermal-epidermal junction (DEJ). The binding of autoantibodies to type-VII collagen subsequently leads to the detachment of the epidermis and the formation of mucocutaneous blisters. EBA has two major clinical subtypes: the mechanobullous and inflammatory variants. The classic mechanobullous variant presentation consists of skin fragility, bullae with minimal clinical or histological inflammation, erosions in acral distribution that heal with scarring, and milia formation. The inflammatory variant is challenging to differentiate from other autoimmune bullous diseases, most commonly bullous pemphigoid (BP) but also mucous membrane pemphigoid (MMP), Brunsting-Perry pemphigoid, and linear IgA dermatosis. Due to its recalcitrance conventional treatment of epidermolysis bullosa acquisita is shown to be demanding. Here we discuss novel therapeutic strategies that have emerged and which could potentially improve the quality of life in patients with EBA.

Epidemiology of hidradenitis suppurativa.

Hidradenitis suppurativa (HS) is a chronic, inflammatory, recurrent skin disease affecting hair follicles in predominantly intertriginous areas, characterized by deep, painful nodules and abscesses, fistulas, sinus tracts, and scarring. The estimated global prevalence of HS is highly variable, as revealed in a growing body of published literature, and ranges from 0.053% to 4.1%. In North American and European patients, HS is three times more common in women than men, whereas in South Korea and Japan, male predominance is found. The disease most frequently manifests itself between the ages of 18 and 29. Numerous published studies have reported the association between smoking, obesity, and HS, although there are limitations in confirming the causal relationship due to the retrospective design of the available studies. Case-control studies have frequently evaluated the association between HS, metabolic syndrome, and other systemic comorbidities. Due to increased mental health problems, a higher risk of suicide in patients with HS has been reported. We provide up-to-date evidence about the epidemiology, genetic and environmental risk factors, comorbidities, and quality of life of patients with HS. The divergence in HS frequency, possibly due to differences in populations and methodologies, remains to be explained in future worldwide studies.

The genetic aspects of hidradenitis suppurativa.

Genetic aspects have a substantial role in hidradenitis suppurativa (HS) pathogenesis. A positive family history of HS occurs in about one-third of HS cases and is significantly higher in patients with early onset of the disease. Recent twin studies have shown a high heritability in HS, fortifying the importance of genetic factors in disease pathogenesis. Based on existing knowledge on the genomics of HS, the disease can be categorized as familial HS, sporadic, syndromic HS, and "HS plus" associated with other syndromes. In familial HS, autosomal dominant transmission is proposed, and monogenic inheritance is rare. This monogenic trait is related to mutations of γ-secretase component genes and Notch signaling or defects in inflammasome function. With newly discovered gene mutations, such as those related to innate and adaptive immunity, skin microbiome, inflammasome, epidermal homeostasis, and keratinization pathway, we can define HS as a polygenic, multifactorial, autoinflammatory disease. To fully elucidate the genetic aspects of HS, we need extensive, long-term global collaborations.

The Association Between Hidradenitis Suppurativa and Diet: An Update.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition characterized by painful inflammatory lesions, predominantly affecting areas of the skin rich in apocrine glands, such as inguinal, axillary, submammary, and anogenital regions, with an estimated global prevalence between 1%-4%. The treatment of HS is challenging with various treatment modalities employed to control the disease. Since the condition is chronic and life-impairing, many patients have looked for ways to complement their conventional treatment procedures with non-medical interventions, among which dietary interventions have been of particular interest. Researchers have looked for ways to connect the gastrointestinal system with the skin through the ˝skin-gut axis concept˝ introducing a strong association between the microbiome of the gastrointestinal system and the skin. In addition, diet stimulation of insulin and IGF-1 (insulin-like growth factor 1) may impact signaling pathways playing a role in HS pathogenesis. Patients have tried various dietary interventions to alleviate their symptoms of inflammation and suppuration. Among the different dietary approaches that have been described are paleo, autoimmune, Mediterranean, and elimination diet regimes. Dietary supplements have become the mainstay of lifestyle factors aimed at improving the clinical signs and symptoms of HS. This review aims to synthesize and present the current findings on diet as a modifiable factor in HS, helping the patients to navigate through the data and helping them make informed choices on their healthy lifestyles.

Post-COVID Telogen Effluvium.

Recently, the number of patients with acute telogen effluvium (ATE), among other forms of hair loss, has increased in comparison with previous years. The COVID-19 pandemic, taking place during this period, may be the cause of this phenomenon. The exact mechanisms by which this virus causes hair loss are not entirely understood; still, the most likely cause is an excessive release of proinflammatory cytokines during SARS-CoV-2 infection. This process can trigger the development of telogen effluvium (TE) by damaging hair matrix cells. Additionally, the psychosocial condition of patients recovering from COVID-19 will have deteriorated, contributing to hair loss. Based on data collected until now, post-COVID TE is expected to improve without any treatment. Although there is no specific treatment for post-COVID TE, eliminating psychophysical stress, managing systemic complications, and explaining the course of the condition to the patient will potentially improve and speed up the hair recovery process.

Dermatologic Adverse Events in Oncologic Therapies.

During recent decades, the number of patients diagnosed with cancer has been increasing. Conventional treatments, which comprise chemotherapy, radiotherapy, surgery, and hormonal treatment, represent improvements in effectiveness and safety of administration and continue to be the standard model of treating malignancies. Advances in oncology have enabled the development of newer therapies such as immunotherapy and targeted therapy. However, numerous adverse events continue to emerge, including dermatologic adverse events, which significantly impact the course of treatment, treatment outcomes, and patient quality of life. Alopecia occurs most commonly, along with mucositis, xerosis, pruritus, hyperpigmentation, acral erythema, nail changes, and many others. The early detection, monitoring, and adequate treatment of these adverse events could prevent reduction, interruption, or permanent discontinuation of oncologic therapies. Herein we review various dermatologic adverse events that may occur due to the therapy applied, present their possible treatments, and emphasize the need to evaluate their impact on patient quality of life.

Genetic risk factors in melanoma etiopathogenesis and the role of genetic counseling: A concise review.

Melanoma is a highly aggressive cancer originating from melanocytes. Its etiopathogenesis is strongly related to genetic, epigenetic, and environmental factors. Melanomas encountered in clinical practice are predominantly sporadic, whereas hereditary melanomas account for approximately 10% of the cases. Hereditary melanomas mainly develop due to mutations in the CDKN2A gene, which encodes two tumor suppressor proteins involved in the cell cycle regulation. CDKN2A, along with CDK4, TERT, and POT1 genes, is a high-risk gene for melanoma. Among the genes that carry a moderate risk are MC1R and MITF, whose protein products are involved in melanin synthesis. The environment also contributes to the development of melanoma. Patients at risk of melanoma should be offered genetic counseling to discuss genetic testing options and the importance of skin UV protection, avoidance of sun exposure, and regular preventive dermatological examinations. Although cancer screening cannot prevent the development of the disease, it allows for early diagnosis when the survival rate is the highest.

Maskne: A New Entity in the COVID-19 Pandemic.

The term "maskne" has been coined during the ongoing COVID-19 pandemic, designating acne associated with prolonged protective mask-wearing. Maskne is a variant of acne mechanica caused by mask-induced mechanical injury (pressure, friction, and rubbing) and occlusion. The additional factors influencing the onset of maskne include genetics, environmental factors, duration of mask-wearing, the type of mask, and previous facial skin disease. The prevalence of maskne is increasing since masks are the most commonly used personal protective equipment in the general population. Furthermore, wearing masks in public tends to become the "new normal" even in the post-pandemic period. Hence, the problem of maskne could become even more significant. This review aims to provide a comprehensive view of current knowledge on prevalence, pathogenesis, prevention, and treatment of maskne.

Pemphigus-The Crux of Clinics, Research, and Treatment during the COVID-19 Pandemic.

Pemphigus is a rare autoimmune disease characterised by the production of pathogenic autoantibodies in response to different desmosome proteins. The pathophysiological process leads to the development of blisters and erosions on mucosal and/or skin surfaces. The classical clinical variants of pemphigus are pemphigus vulgaris and pemphigus foliaceus. A diagnostic delay is very common in pemphigus, especially among patients with mucosal involvement. However, in recent years we have witnessed considerably fewer patients with extensive mucocutaneous manifestations, since patients with oral lesions are referred to dermatologists to start the treatment much sooner than they had been previously. Among non-classical variants of pemphigus, unusual cases with discrepancies between autoantibody profiles and clinics challenge the "desmoglein compensation theory". The identification of several other autoantigens that perform a role in the pathogenesis of different variants of pemphigus will progress immunodermatology towards an approach that will determine personalized pemphigus subtypes for each patient. Comorbidities among patients are primarily associated with the prolonged use of corticosteroids and other immunosuppressive agents. The SARS-CoV-2 pandemic raised concerns regarding the immunosuppressive effects of treatment and the risk of a more complicated COVID-19 infection, as well as on the ability to develop an adequate vaccine response.

Understanding the Relationship Between Smoking and Hidradenitis Suppurativa.

Hidradenitis suppurativa (HS) is a chronic skin disease affecting hair follicles in intertriginous areas, characterized by deep, recurrent, painful nodules and abscesses, fistulae, sinus tracts, and scarring. With a prevalence of 1-4%, HS is not an uncommon disease. Several risk factors have been linked with the development of HS, such as genetic predisposition, smoking, and obesity, leading to the hypothesis that HS develops as a result of environmental triggers in a genetically susceptible individual. Smoking has been recognized as one of the environmental factors with the most impact on HS. This review aims to provide a comprehensive and holistic view on how smoking habits affect the incidence, severity, treatment, and pathophysiology of HS. A growing body of published literature has reported the association between smoking and HS, despite limitations in proving the causal relationship due to the retrospective design of the available studies. There is a consensus that patients with HS who are active smokers have a higher number of affected body areas than patients with HS who do not smoke or have stopped smoking. Similarly, it is recommended for patients with HS to discontinue tobacco use because of its association with weaker treatment response. Studies on the pathophysiological mechanism of smoking on the skin show that tobacco smoke with many of its chemicals as well as nicotine promote the proinflammatory cytokines found in HS lesions, activate the nicotinic acetylcholine (nAChRs) and aryl hydrocarbon receptors (AHRs), and further suppress Notch signaling pathway.

Nonprescription acne vulgaris treatments: Their role in our treatment armamentarium-An international panel discussion.

BACKGROUND: Acne vulgaris (acne), a common inflammatory skin disorder, has its peak incidence between 14 and 19 years of age, with girls frequently developing acne earlier than boys. Over recent years, persistent acne is becoming more prevalent in adult women. OBJECTIVES: This review and panel discussion addresses challenges in acne management, particularly in adult women. The role which nonprescription acne treatment can play is explored when used as monotherapy or as an adjunctive treatment for acne of all severity. METHODS: The best available evidence on nonprescription acne treatment was coupled with the opinion of an international expert panel of dermatologists to adopt statements and recommendations discussed in this review. RESULTS: All severity of acne has a significant burden on patients. Addressing environmental factors that are important for the individual with acne may help to educate, prevent, effectively manage, and maintain acne, as per the panel. They agreed that the adult female acne population has unique needs because of their aging skin and social environment. Nonprescription acne treatment products may help to balance the efficacy and tolerability of prescription acne treatment. Currently, there are no specific guidelines for how to use nonprescription acne treatment products in these patients. CONCLUSION: The panel agreed that guidelines including nonprescription acne treatment either as monotherapy for mild acne or in combination with prescription treatments for more severe acne would address a significant unmet need.

Hypertrophic lupus erythematosus: case report.

Discoid lupus erythematosus is the most common form of cutaneous lupus erythematosus. It is more common in women than in men, in individuals between 20 and 40 years of age. It is an inflammatory autoimmune disease in which genetically predisposed individuals are stimulated by hormonal and a variety of exogenous factors including UV radiation, stress, infections, and even temperature changes. Lesions are characterized by erythema, hyperkeratosis and atrophy. Typical sites are light-exposed areas, i.e. forehead, nose, cheeks, upper part of the back, upper chest, and dorsal aspects of the hands and feet. A case of lupus erythematosus hypertrophicus with very good and rapid treatment results with antimalarials and topical corticosteroid is presented.

Dermatologic medication in pregnancy.

In female body, a vast number of skin changes occur during pregnancy. Some of them are quite distressing to many women. Therefore, performing treatment for physiologic skin changes during pregnancy with antiinfective agents, glucocorticosteroids, topical immunomodulators, retinoids, minoxidil, etc., is discussed. Drug administration during pregnancy must be reasonable.

Grover's Disease in a Kidney Transplant Recipient.

Dear Editor, It is not unusual for patients with renal insufficiency to develop skin pathologies. There are reports in the literature of increased incidence of calciphylaxis, pruritus, perforating dermatoses, and porphyria cutanea tarda in this patient population (1). Although it is quite rare, Grover's disease (GD) has been reported in several patients with renal insufficiency, but only once in a renal transplant recipient (2). The disease follows three patterns: persistently pruritic, transient eruptive, or a chronic asymptomatic course (3). Common risk factors concomitant with disease prevalence are immunosuppression, HIV, hemodialysis, viral and bacterial infections, malignancies, and other skin pathologies like contact and atopic dermatitis (4). A 60-year-old woman had a family history of polycystic kidney disease and was subsequently diagnosed in 1997. The patient had concomitant hepatic involvement and a stable aneurysm of the anterior cerebral artery. Consequently, the patient preemptively received a kidney transplant in 2015. The immunosuppressive therapy consisted of tacrolimus, mycophenolate mofetil, and prednisone with basiliximab induction. In 2017, a biopsy of the right thigh demonstrated squamous cell carcinoma in situ measuring 1×1cm in size. The lesion was treated with surgical excision. The patient also exhibited an erythematous brown macule with undefined borders on the left side of the nose with a size of 12 mm; it was later determined to be actinic keratosis. The lesion was treated successfully with cryotherapy. During this period, a fever prompted a PCR for BK virus DNA which showed a substantial amount of copies, measuring 28,850 copies/mL in urine and 98 copies/mL in blood. The mycophenolate dose was reduced, and tacrolimus trough concentration was maintained at between 3 and 5 µg/L. In 2018 the patient presented with multiple pruritic erythematous papules located on the trunk. Upon histological biopsy, there was dominant suprabasal acantholysis with numerous cells separating from the epithelium. Furthermore, there was a moderate amount of mononuclear infiltrate in the upper portion of the dermis and sparse suprabasal clefts (Figure 1). Clinical presentation and histologic examination were consistent with Grover's disease. The patient was treated topically with betamethasone cream twice daily for four weeks. The skin changes persisted for only a few weeks. The pathophysiological mechanism causing GD is still unknown. It is usually only a transient skin condition that lasts no more than a few weeks, but there have been more chronic cases lasting for years, particularly in patients on hemodialysis (5). The lesions commonly affect the chest area but may spread to diffusely envelope the body as erythematous papules, pustules, lichenoid lesions, or vesicles (2). Grover characterized 4 different subtypes based on the pathohistological findings as Darier-like (the most common), pemphigus vulgaris-like, Hailey-Hailey-like, or spongiotic subtype (3). The histological patterns are not exclusive to one patient and may even be found concomitantly in a single lesion. The condition is definitively diagnosed through histology, showing distinctive acantholysis along the epidermis with dyskeratosis that is described as "corps ronds" and "grains" (3). Grover's disease is more prevalent in middle-aged Caucasian men than any other group, with a 1.6-2.1 gender ratio (6). It was originally thought that the disease was caused by dysfunctional eccrine sweat glands, as the ailment was more common in patients that had increased perspiration either due to environmental heat, fever, or extensive bedrest. This idea was reinforced by histological evidence of atrophied sweat glands in uremic patients with renal insufficiency (7). Moreover, a case series and case report described remissions of GD in their patients on hemodialysis that received a renal transplant (5,8). However, subsequent studies have not supported an association with sweat dysfunction and disease development, while others have only managed to attribute sweat gland dysfunction as the primary trigger in 20-30% of cases (9). Conversely, cold dry air and xerosis cutis is thought to trigger the disease because it is four times more likely to be diagnosed in the winter months (10). Ultraviolet radiation has been identified as an exacerbating factor for GD, which could have been the trigger for onset of disease in our patient as demonstrated by her squamous cell carcinoma and actinic keratosis (11). Despite immunosuppression being a risk factor for GD, as shown by its association in patients with HIV, bone marrow transplantation, hemodialysis, and hematological malignancies, GD has been reported only once in the literature after a renal transplant (2,4). As our case, that patient developed GD a few years after transplant without an obvious trigger and the lesions appeared as red papules that were disseminated over the anterior thorax. Their patient's cutaneous lesion resolved spontaneously after 2 weeks and never returned in the 2.5-year follow-up period. Their patient has had two renal allografts over a 20 year timespan, while ours had had her graft for only two years. The immunosuppressive regimen was slightly different: cyclosporine, azathioprine, and methylprednisolone versus our combination of tacrolimus, mycophenolate mofetil, and prednisone. Grover's disease can be treated conservatively by avoiding risk factors such as UV light and sweating as well as and applying moisturizing emollients which may cause the lesion to resolve spontaneously. Medical therapy consists of topic corticosteroids, topical vitamin D analogues, oral retinoids, and oral corticosteroids, PUVA, and methotrexate for resistant cases (6,12). When a patient exhibits pruritic papules of the skin, GD should be considered in differential diagnosis, especially in kidney transplant patients and those on hemodialysis. While the condition is rare, increased recognition in this patient population will allow for studies to further characterize this poorly understood disease.

Correlation between Family History and the Age of Onset of Childhood Acne in Relation to Sex and Type of Acne.

Acne vulgaris is a common chronic skin disorder of the pilosebaceous unit with a wide range of clinical presentations, which depend on the age of onset of acne, sex, family history of acne, and genetic factors, especially the genes affecting keratinization and desquamation. This retrospective study investigated pediatric acne using the patients' past medical history, with patients aged from newborns to 15 years of age. Acne were further stratified by 5 parameters: sex, age, family history, acne type, and localization. Our main aim was to investigate the possible association between selected parameters and the presence or absence of family history of acne. We did not find statistically significant correlation between sex, age of onset, and positive family history of acne. Furthermore, we did not find any association between age of onset and family history according to family members (mother/father/brother or sister). However, we found statistically significant correlation between sex and type of acne. This retrospective analysis of pediatric acne in Croatia did not reveal statistically significant correlation between positive family history and sex, age of onset, and clinical type of acne. In analyzing the correlation between family history and localization of acne, however, we found that the number of patients with acne localized on both the face and trunk and positive family history was statistically significant higher than expected.