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Abstract Background Tuberous sclerosis complex (TSC) is a multisystem neurocutaneous syndrome with variable phenotypes. Recent updates of TSC diagnostic criteria reaffirmed the defined genetic diagnostic criterion as the finding of a pathogenic DNA alteration in either TSC1 or TSC2 genes. It also slightly modified definite clinical diagnostic criteria. TSC-associated skin lesions in infancy are important clinical signs to select individuals with possible TSC for a closer clinical follow-up and genetic testing. Objective To raise awareness of the updated TSC diagnosis criteria; to assess the frequency of skin lesions in TSC patients as well as the first dermatological presentation; and to associate the findings with either TSC1 or TSC2 mutations. Methods Observational cross-sectional study. Clinical and genetic data were retrospectively collected from 37 TSC patients from a Brazilian University Hospital. Patients with skin signs were examined and prospectively assessed for 12 months. Results The earliest cutaneous lesions were hypomelanotic macules, which together with angiofibromas were the most frequent dermatological lesions. The total pathogenic DNA alteration ratio between TSC2 and TSC1 genes was 8:1. The frequency of a TSC2 pathogenic variant was 10-fold greater in the presence of ungual fibromas. Study limitations Small sample and a limited number of patients with TSC1 pathogenic variants. Conclusion Clinicians should be knowledgeable about TSC updated diagnostic criteria. Patients need to be followed up by a multidisciplinary team and treated accordingly. Early detection of cutaneous lesions is important for TSC diagnosis. A significant association between TSC2 gene pathogenic alterations and ungual fibromas is described.

Abstract Background Histopathology can be crucial for diagnosis of inflammatory nail diseases. Longitudinal excision and punch biopsies are the most used techniques to obtain the tissue sample. However, there is a low clinical-histopathological correlation, besides the risk of nail dystrophy. Tangential excision biopsy (TB) is a well-established technique for the investigation of longitudinal melanonychia. TB could also be used to evaluate diseases in which histopathological changes are superficial, as in psoriasis. Objective To study the value of TB in the histopathological diagnosis of nail psoriasis. Methods This is a prospective and descriptive study of the clinical-histopathological findings of samples from the nail bed or matrix and nail plate of 13 patients with clinical suspicion of nail psoriasis. Biopsies were obtained through partial nail avulsion and TB. Results In nine patients, the hypothesis of psoriasis was confirmed by histopathology; in one, the criteria for diagnosing nail lichen planus were fulfilled. The tissue sample of only one patient did not reach the dermal papillae, and, in four of 13 patients, the adventitial dermis was not sampled. No patient developed onychodystrophy after the procedure. Study limitations In three patients, the clinical and, consequently, histopathological nail changes were subtle. Also, in one patient’s TB didn’t sample the dermal papillae. Conclusions TB is a good option to assist in the histopathological diagnosis of nail psoriasis, especially when appropriate clinical elements are combined. Using this technique, larger and thinner samples, short postoperative recovery time, and low risk of onychodystrophy are obtained.

Abstract Hailey-Hailey disease is a rare genodermatosis described in 1939, with an autosomal dominant inheritance pattern, characterized by compromised adhesion between epidermal keratinocytes. It has an estimated prevalence of 1/50,000, with no gender or race predilection. It results from a heterozygous mutation in the ATP2C1 gene, which encodes the transmembrane protein hSPA1C, present in all tissues, with preferential expression in keratinocytes. Mutations in the ATP2C1 gene cause changes in the synthesis of junctional proteins, leading to acantholysis. It usually begins in adulthood, with isolated cases at the extremes of life. It manifests as vesico-bullous lesions mainly in the flexural areas, which develop into erosions and crusts. Chronic lesions may form vegetative or verrucous plaques. Pruritus, a burning feeling and pain are common. It evolves with periods of remission and exacerbation, generally triggered by humidity, friction, heat, trauma and secondary infections. The diagnosis is based on clinical and histopathological criteria: marked suprabasal acantholysis, loosely joined keratinocytes, giving the appearance of a “dilapidated brick wall”, with a few dyskeratotic cells. The acantholysis affects the epidermis and spares the adnexal epithelia, which helps in the differential diagnosis with pemphigus vulgaris. Direct immunofluorescence is negative. The main differential diagnoses are Darier disease, pemphigus vegetans, intertrigo, contact dermatitis, and inverse psoriasis. There is no cure and the treatment is challenging, including measures to control heat, sweat and friction, topical medications (corticosteroids, calcineurin inhibitors, antibiotics), systemic medications (antibiotics, corticosteroids, immunosuppressants, retinoids and immunobiologicals) and procedures such as botulinum toxin, laser and surgery. There is a lack of controlled clinical trials to support the choice of the best treatment.

Abstract Background Anti-desmoglein (Dsg)1 is produced in pemphigus foliaceus (PF), affecting exclusively the skin. Pemphigus vulgaris (PV) shows the production of anti-Dsg3 in the mucosal form, and anti-Dsg1 and 3 in the mucocutaneous form. Anti-Dsg3 autoantibodies have been rarely reported in PF. Objectives To determine the factors associated with the production and pathogenicity of anti-Dsg3 in PF. Methods Comparative analytical study of three patients groups: 16 PF-anti-Dsg3+, and 42 PF-anti-Dsg3(-) and 22 PV treatment-naïve cases. Serum was used in the anti-Dsg1 and 3 ELISA, and in immunoblotting (IB) with human epidermis extract. The expression of Dsg1 and 3 in paraffin sections was analyzed by immunohistochemistry (IHC). HLA-DRB1 alleles were compiled from a database. Results In the PF-anti-Dsg3+ group: age range similar to that of the PV group (p > 0.9999); predominance of the generalized form of PF (p = 0.002); anti-Dsg3 titers lower than those of PV (p < 0.0001); IB confirmed Dsg3 identification in one (8.33%) of 12 patients; IHC showed exclusive cytoplasmic internalization of Dsg1; HLA-DRB1 alleles of susceptibility to PF, with the absence of alleles associated with PV, in the five typed patients. Study limitations Most of the patients in the PF-anti-Dsg3+ group were undergoing treatment. Conclusion The presence of anti-Dsg3 antibodies in PF was related to older age (comparable to that of PV) and the generalized form of PF. The non-pathogenicity of anti-Dsg3 antibodies in PF can be attributed to the low serum anti-Dsg3 titers, the lack of Dsg3 internalization as detected by IHC, and the absence of PV-associated HLA-DRB1 alleles.

Abstract Background Merkel cell polyomavirus (MCPyV), a human polyomavirus that is unequivocally linked to merkel cell carcinoma (MCC), has been found in association with keratinocytes carcinomas (KC), especially basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC). Nevertheless, there is scarce information about the possible involvement of MCPyV in the development of KC. Objectives To assess the presence of MCPyV DNA and Large-T Antigen (LT-Ag) via Polymerase Chain Reaction (PCR) and Immunohistochemistry (IHC) in cases of KC, and to correlate its presence with immunohistochemical markers p16, p53, and ki67, tumor type and subtype, sun-exposed location, and epidemiological data. Methods The prevalence of MCPyV DNA, LT-Ag, and immunohistochemical markers p16, p53, and ki67 was assessed by PCR and Immunohistochemistry (IHC) in 127 cases of KC, these results were correlated with tumor type and subtype, sun-exposed location, and epidemiological data. Results The MCPyV DNA was detected in 42.57% (43 of 101) cases by PCR, the LT-Ag was detected in 16.4% (20 of 122) of cases, p16 in 81.5% (97 of 119), p53 in 66.4% (83 of 125), ki67 in 89% (73 of 82). No correlation between MCPyV LT-Ag and DNA confronted with tumor type, subtype, location site, and immunohistochemical markers was found. A single correlation between the MCPyV LT-Ag and cSCC tumors and peri-tumoral lymphocyte cells was noted. Study limitations Further steps need to be taken to better evaluate the MCPyV influence and its possible role in KC carcinogenesis, as the evaluation of the virus genome state, the gene sequence that encodes LT-Ag in the KC tumor cells, and in situ hybridization for viral DNA or RNA in these cells. Conclusions Despite the frequent detection of MCPyV in KC, the data available so far does not support the hypothesis of a causal relationship between them.

Abstract Background Hidradenitis suppurativa (HS) is a chronic inflammatory disease that leads to the formation of nodules, abscesses and fistulas, with the formation of scars and fibrosis, causing significant impairment in patient quality of life. The diagnosis is clinical, using scores to classify the severity of the condition; currently the most recommended classification is the International Hidradenitis Suppurativa Severity Scoring System (IHS4). Doppler ultrasound has been used to complement the clinical evaluation of patients with HS. It is possible to observe subclinical lesions that change the staging, the severity of the case, and its treatment, either clinical or surgical. Correct treatment is essential to minimize the consequences of this disease for the patient. Objective To establish an outpatient protocol for the use of Doppler ultrasound in the care of patients with HS. Methods A narrative review of the literature was carried out on the use of Doppler ultrasound in patients with hidradenitis suppurativa; a referring protocol and technique orientations for imaging assessment in HS were created. Results Recommendation to perform ultrasound evaluation of symptomatic areas eight weeks after using antibiotics and four, 12, and 24 weeks after starting immunobiologicals; apply SOS-HS ultrasound severity classification. Study limitations The review did not cover all literature on ultrasound and HS; no systematic review was carried out, but rather a narrative one. Conclusions The correct assessment of patients staging must be carried out using dermatological ultrasound to avoid progression to scars and fibrosis, which compromise patients quality of life.

Abstract Prurigo is a reactive, hyperplastic skin condition characterized by pruritic papules, plaques, and/or nodules. The temporal classification includes acute/subacute and chronic disease (≥ 6 weeks), with different clinical variants, synonymies, and underlying etiological factors. The immunology of chronic prurigo shows similarities with atopic dermatitis due to the involvement of IL-4 and IL-13, IL-22, and IL-31. Treatment includes antihistamines, topical steroids, dupilumab, and JAK inhibitors. Several conditions manifest clinically as prurigo-like lesions, and the correct clinical diagnosis must precede correct treatment. Furthermore, chronic prurigos represent a recalcitrant and distressing dermatosis, and at least 50% of these patients have atopic diathesis, the treatment of which may induce adverse effects, especially in the elderly. The quality of life is significantly compromised, and topical treatments are often unable to control symptoms and skin lesions. Systemic immunosuppressants, immunobiologicals, and JAK inhibitors, despite the cost and potential adverse effects, may be necessary to achieve clinical improvement and quality of life. This manuscript reviews the main types of prurigo, associated diseases, their immunological bases, diagnosis, and treatment.

Abstract Background The treatment for atopic dermatitis (AD) has been the focus of clinical research, and behavioral intervention is considered an indispensable treatment method. To our knowledge, no relevant meta-analysis has evaluated the effects of behavioral interventions on atopic dermatitis. Objectives To evaluate the effects of behavioral interventions on atopic dermatitis. Methods The authors searched PubMed, EMBASE, and Cochrane CENTRAL to retrieve relevant RCTs (up to Feb 2022). The search strategy involved a combination of related keywords. The Cochrane Q and I2 statistics were used to assess heterogeneity. Results Six RCTs involving seven reports with 246 patients were included. The results suggested that behavioral interventions could relieve eczema severity (correlation coefficient [r = −0.39]; p < 0.001) and scratching severity significantly (r = −0.19; p = 0.017), while not affect itching intensity (r = −0.02; p = 0.840). A sensitivity analysis confirmed the robustness of the results. Study limitations An important limitation of this study was the insufficient number of RCTs and the limited sample size. In addition, the study lacked a control group receiving a type of intervention other than the experimental protocol. Another limitation was the short duration of follow-up. Conclusions This study suggests that behavioral interventions could be effective in treating atopic dermatitis by reducing eczema and scratching severity. Additionally, habit-reversal behavioral therapy may be more effective for treating atopic dermatitis.

Abstract Background Cutaneous squamous cell carcinoma (CSCC) is one of the most common types of skin cancer worldwide. Therefore, the identification of biomarkers associated with CSCC progression could aid in the early detection of high-risk squamous cell carcinoma and the development of novel therapeutic strategies. Objective This study aimed to investigate the expression patterns of silent mating type Information Regulation 2 homolog 6 (SIRT6) in CSCC and its clinical significance. Methods The protein expression level of SIRT6 in tissues was detected by immunohistochemistry, and the correlation between SIRT6 expression and clinicopathological parameters in CSCC patients was analyzed. The relative expression of SIRT6 in CSCC cell lineage and tissue specimens was determined by western blotting and PCR. The effect of SIRT6 silencing on cell proliferation was evaluated using cell counting kit 8. Wound healing, transwell method, and flow cytometry were used to investigate the migration, invasion, and cell cycle distribution/apoptosis of CSCC cells after SIRT6 silencing, respectively. Western blot was used to detect the expression of EMT (Epithelial-Mesenchymal Transition), cycle, apoptosis, and other related proteins. Results The high expression of SIRT6 was correlated with the location of cancer tissue and Broder staging in CSCC patients. Knockdown of SIRT6 inhibited the proliferation, migration, invasion and EMT of CSCC cells, and promoted their apoptosis, with cells blocked in G1 phase. Study limitations No animal experiments were conducted to further verify the results. Conclusion Decreased expression of SIRT6 can inhibit the occurrence and development of CSCC.

Abstract Objective To evaluate the effects of rosacea on ocular surface changes such as alterations in dry eye parameters, corneal densitometry, and aberrations, in comparison with healthy controls. Methods A total of 88 eyes of 44 patients diagnosed with rosacea and 88 eyes of 44 healthy controls were enrolled in this cross-sectional study. All participants underwent a comprehensive dermatologic and ophthalmic examination and Tear Break-Up Time (TBUT) and Schirmer-1 tests were performed. The rosacea subtype and Demodex count and OSDI scores of all participants were recorded. Corneal topographic, densitometric, and aberrometric measurements were obtained using the Scheimpflug imaging system. Results The mean age of the 44 patients was 41.2 ± 11.0 years of whom 31 (70.5%) were female. The mean TBUT and Schirmer-1 test values were significantly decreased and OSDI scores were significantly increased in the rosacea group compared to healthy controls (p < 0.01 for all). The most common subtype of rosacea was erythematotelangiectatic rosacea (70.4%). The severity grading of rosacea revealed that 18 (40.9%) patients had moderate erythema. The median (min-max) Demodex count was 14.0 (0-120) and the disease duration was 24.0 (5-360) months. The comparison of the corneal densitometry values revealed that the densitometry measurements in all concentric zones, especially in central and posterior zones were higher in rosacea patients. Corneal aberrometric values in the posterior surface were also lower in the rosacea group compared to healthy controls. The topographic anterior chamber values were significantly lower in the rosacea group. Study limitations Relatively small sample size, variable time interval to hospital admission, and lack of follow-up data are among the limitations of the study. Future studies with larger sample sizes may also enlighten the mechanisms of controversial anterior segment findings by evaluating rosacea patients who have uveitis and those who do not. Conclusion Given the fact that ocular signs may precede cutaneous disease, rosacea is frequently underrecognized by ophthalmologists. Therefore, a comprehensive examination of the ocular surface and assessment of the anterior segment is essential. The main priority of the ophthalmologist is to treat meibomian gland dysfunction and Demodex infection to prevent undesired ocular outcomes.

Abstract Chronic ulcers significantly affect the quality of life of patients and impose a high cost on the healthcare system. The therapeutic management should be comprehensive, taking into consideration the etiological diagnosis of the wound and the characteristics of the wound bed when deciding on a therapeutic proposal appropriate to the healing phase, correcting factors that delay healing. During the epithelialization phase, repair techniques with grafts are recommended to shorten re-epithelialization time, improve the quality of scar tissue, and achieve adequate pain management. Currently, due to the reported benefits of skin appendages, the technique of follicular unit auto-grafting obtained with a scalp punch is among the chosen strategies for wound repair. This is a minimally invasive, outpatient practice, whose technique has advantages over the donor site, patients recovery and well-being.

Abstract Background Molecularly targeted therapies, such as monoclonal antibodies (mAbs) and Janus Kinase inhibitors (JAKis), have emerged as essential tools in the treatment of dermatological diseases. These therapies modulate the immune system through specific signaling pathways, providing effective alternatives to traditional systemic immunosuppressive agents. This review aims to provide an updated summary of targeted immune therapies for inflammatory skin diseases, considering their pathophysiology, efficacy, dosage, and safety profiles. Methods The review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. A systematic search was conducted on PubMed over the past 10 years, focusing on randomized clinical trials, case reports, and case series related to targeted immune therapies in dermatology. Eligibility criteria were applied, and data were extracted from each study, including citation data, study design, and results. Results We identified 1360 non-duplicate articles with the initial search strategy. Title and abstract review excluded 1150, while a full-text review excluded an additional 50 articles. The review included 143 studies published between 2012 and 2022, highlighting 39 drugs currently under investigation or in use for managing inflammatory skin diseases. Study limitations The heterogeneity of summarized information limits this review. Some recommendations originated from data from clinical trials, while others relied on retrospective analyses and small case series. Recommendations will likely be updated as new results emerge. Conclusion Targeted therapies have revolutionized the treatment of chronic skin diseases, offering new options for patients unresponsive to standard treatments. Paradoxical reactions are rarely observed. Further studies are needed to fully understand the mechanisms and nature of these therapies. Overall, targeted immune therapies in dermatology represent a promising development, significantly improving the quality of life for patients with chronic inflammatory skin diseases.

Abstract Background 5-Fluorouracil (5-FU) is a first-line drug to treat cutaneous field cancerization (CFC). There are few clinical trials with topical colchicine (COL). Objective To evaluate the effectiveness of 0.5% COL cream versus 5% 5-FU cream in the treatment of CFC. Method This was a randomized, open, self-controlled clinical trial. Forty-five patients (90 forearms), with three to ten actinic keratoses (AK) on each forearm, used 0.5% COL cream 2×/day for seven days on one forearm, and 5% 5-FU cream 2× /day, for 21 days, on the other forearm. The dosages were defined based on previous clinical trials for each drug. Adverse effects were evaluated after 14 days and outcomes after 90 days of inclusion. The primary outcome was complete AK clearance and the secondary outcomes were: partial clearance (≥50%), reduction in AK count, assessment of the Forearm Photoaging Scale (FPS), AK Severity Score (AKSS), and adverse effects. Results After 90 days, there was complete clearance of AK in 37% (95% CI 24%-49%) and partial clearance in 85% (95% CI 76%-93%) of the forearms treated with 5-FU,versus 17% (95% CI 7%-27%) and 78% (95% CI 66%-88%) for COL (p > 0.07). There was a percentage reduction of 75% in the AK count of the forearms treated with 5-FU (95% CI 66%-83%) and 64% in those treated with COL (95% CI 55%-72%). Regarding FPS and AKSS, there was improvement in both groups, with no difference regarding FPS (p = 0.654), and 5-FU superiority for AKSS (p = 0.012). Study limitations Single-center study. Conclusions 5-FU and COL are effective for treating CFC, with neither showing superiority regarding the reduction in AK counts.

Abstract Background Neurofibromatosis type 1 (NF1) is a rare genetic disorder with a wide range of clinical manifestations, notably neurocutaneous features, that can lead to emotional and physical consequences. Objectives This study assessed the influence of sociodemographic factors and clinical features of the disease on the quality of life of Brazilian individuals with NF1. Methods This is a descriptive cross-sectional study. Data were collected from 101 individuals with NF1 using the Brazilian version of the Impact of NF1 on Quality of Life Questionnaire (INF1-QoL), a form with information on sociodemographic characteristics, and an NF1 visibility self-evaluation scale. The relationship between variables was evaluated through statistical testing, and the significance level was defined as 0.05. Results The study included 101 adults with NF1 aged 18 to 59 years, with a mean age of 35.54 years (±9.63) and a female predominance (n = 84, 83.17%). The mean total INF1-QoL score was 10.62 (±5.63), with a median of 10, minimum value of 0, and maximum of 31 points. Two characteristics of the participants were significantly associated with the quality of life: educational level (p = 0.003) and familial history of NF1 (p = 0.019). There was a statistically significant correlation between the INF1-QoL score and the degree of disease visibility (rho = 0.218; p = 0.028). Study limitations Cross-sectional study, conducted with a convenience sample and using self-reported measures. Conclusions The findings support the significant impact of NF1 on quality of life. The authors recommend multidisciplinary follow-up for patients, with adherence to anticipatory clinical care measures, adequate pain control, psychological assistance, and genetic counseling.