Autoreactivity to self-antigens LL37 and ADAMTSL5 influences the clinical response to risankizumab in psoriatic patients.

The autoantigens LL37 and ADAMTSL5 contribute to induce pathogenetic T-cells responses in a subset of psoriatic patients. Whether the presence of LL37-and/or ADAMTS5-reactive T-cells influences the clinical response to treatment is still unknown. The aim of the study is to evaluate the clinical responses to the anti-IL-23 risankizumab in LL37 and/or ADAMTSL5-reactive patients in comparison with non-reactive ones and to assess whether genetics (HLA-Cw06.02) or BMI influences the response to treatment. Patients were screened at baseline for the presence of circulating LL37 or/and ADAMTSL5-reactive T-cells and were treated as per protocol with risankizumab. Effectiveness data (PASI scores) were collected at weeks 4, 16, 28, 40 and 52. Data were also analyzed based on HLA-Cw06.02 status and BMI. The overall response to treatment of patients with autoreactivity to LL37 or ADAMTSL5 did not differ compared to the non-reactive cohort as measured as PASI75/90/100 at different time points; however, subjects that had autoreactive T-cells to both LL37 and ADAMTS5 demonstrated suboptimal response to treatment starting at week16. HLA-Cw06:02+ patients demonstrated faster response to risankizumab at week 4 compared to HLA-Cw06:02-. Additionally, the response to treatment was influenced by the BMI with slower responses seen in overweight and obese patients at week 4 and week16. In conclusion, while the presence of either LL37-and ADAMTS5-reactive circulating T-cells do not influence the clinical response to risankizumab, the presence of the double reactivity to both LL37 and ADAMTS5 decreases the clinical responses. Moreover, we evidenced that HLA-Cw06+ respond faster to IL-23 inhibition and that BMI, associated to autoreactivity, can influence the speed in response.

Short-, mid- and long-term efficacy of dupilumab in moderate to severe atopic dermatitis: a real life multicenter Italian study on 2576 patients.

BACKGROUND: The efficacy and safety of dupilumab in atopic dermatitis (AD) have been defined in clinical trials but limited real-world evidence on long term treatment outcomes are currently available to inform clinical decisions. OBJECTIVES: to describe long-term effectiveness and safety of dupilumab up to 48 months in patients with moderate-to-severe AD. METHODS: a multicenter, retrospective, dynamic cohort study was conducted to assess long term effectiveness and safety of dupilumab in patients with moderate to severe AD in a real-world setting. Predictors of minimal disease activity (MDA) optimal treatment target criteria (defined as the simultaneous achievement of EASI90, itch NRS score ≤1, sleep NRS score ≤1 and DLQI ≤1) were investigated. RESULTS: 2576 patients were enrolled from June 2018 to July 2022. MDA optimal treatment target criteria were achieved by 506 (21.91%), 769 (40.63%), 628 (50.36%), 330 (55.37%) and 58 (54.72%) of those that reached 4, 12, 24, 36 and 48 months of follow-up, respectively. Logistic regression revealed a negative effect on MDA achievement for conjunctivitis and food allergy at all timepoints. Adverse events (AE) were mild and were observed in 373 (15.78%), 166 (7.02%), 83 (6.43%), 27 (4.50%) and 5 (4.55%) of those that reached 4, 12, 24, 36 and 48 months of follow-up. Conjunctivitis was the most frequently reported AE during the available follow-up. AE led to treatment discontinuation in <1% of patients during the evaluated time periods. CONCLUSION: High long-term effectiveness and safety of dupilumab were confirmed in this dynamic cohort of patients with moderate to severe AD, regardless of clinical phenotype and course at baseline. Further research will be needed to investigate the effect of Th2 comorbidities and disease duration on the response to dupilumab and other newer therapeutics for AD.

Hidradenitis suppurativa presents a methylome dysregulation capable to explain the pro-inflammatory microenvironment: Are these DNA methylations potential therapeutic targets?

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic, systemic, inflammatory skin condition with elusive pathogenesis that affects therapeutic intervention directly. OBJECTIVE: To characterize epigenetic variations in cytokines genes contributing to HS. METHODS: Epigenome-wide DNA methylation profiling with the Illumina Epic array was performed on blood DNA samples from 24 HS patients and 24 age- and sex-matched controls to explore DNA methylation changes in cytokine genes. RESULTS: We identified 170 cytokine genes including 27 hypermethylated CpG sites and 143 genes with hypomethylated sites respectively. Hypermethylated genes, including LIF, HLA-DRB1, HLA-G, MTOR, FADD, TGFB3, MALAT1 and CCL28; hypomethylated genes, including NCSTN, SMAD3, IGF1R, IL1F9, NOD2, NOD1, YY1, DLL1 and BCL2 may contribute to the pathogenesis of HS. These genes were enriched in the 117 different pathways (FDR p-values ≤ 0.05), including IL-4/IL-13 pathways and Wnt/ß-catenin signalling. CONCLUSIONS: The lack of wound healing, microbiome dysbiosis and increased tumour susceptibility are all sustained by these dysfunctional methylomes, hopefully, capable to be targeted in the next future. Since methylome describes and summarizes genetic and environmental contributions, these data may represent a further step towards a feasible precision medicine also for HS patients.

Adult-Onset Linear Morphea (en coupe de sabre) of the Face Successfully Treated with Photoactivated Low-Temperature Platelet-Rich Plasma: A Valid Therapeutic Option.

Localized scleroderma (also known as morphea) is a chronic autoimmune disorder characterized by depressed, fibrotic, and dyschromic cutaneous lesions. It has a significant impact on the patient's daily life due to the unaesthetic evolution of the cutaneous lesions. Morphea is clinically divided into linear, circumscribed (plaque), generalized, pansclerotic, and mixed forms. Linear morphea en coupe de sabre (LM) usually arises in childhood. However, in about 32% of cases, it may arise in adulthood, showing a more aggressive course with also an increased risk of systemic involvement. Methotrexate is the first-line treatment for LM, although systemic steroids, topical agents (corticosteroids and calcineurin inhibitors), hyaluronic acid injections, and hydroxychloroquine or mycophenolate mofetil are valid therapeutic options. In any case, these treatments are not always effective and sometimes can be associated with important side effects and/or not tolerated by the patients. In this spectrum, platelet-rich plasma (PRP) injection can be considered a valid and safe alternative since PRP injections in the skin induce the release of anti-inflammatory cytokines and growth factors, thus reducing inflammation and increasing collagen remodeling. Herein, we describe a successful treatment of an adult-onset LM en coupe de sabre with photoactivated low-temperature PRP (Meta Cell Technology Plasma) sessions, showing an important local improvement of the lesion and patient satisfaction.

Carbapenem Resistance in Gram-Negative Bacteria: A Hospital-Based Study in Egypt.

Background and Objectives: The global spread of carbapenem resistance and the resulting increase in mortality forced the World Health Organization (WHO) to claim carbapenem-resistant enterobacteriaceae (CRE) as global priority pathogens. Our study aimed to determine the prevalence of carbapenemase-encoding genes and major plasmid incompatibility groups among Gram-negative hospital-based isolates in Egypt. Material and Methods: This cross-sectional study was carried out at Mansoura University Hospitals over 12 months, from January to December 2019. All the isolates were tested for carbapenem resistance. The selected isolates were screened by conventional polymerase chain reaction (PCR) for the presence of carbapenemase genes, namely blaKPC, blaIMP, blaVIM, and blaNDM-1. PCR-based plasmid replicon typing was performed using the commercial PBRT kit. Results: Out of 150 isolates, only 30 (20.0%) demonstrated carbapenem resistance. Klebsiella pneumoniae was the most resistant of all isolated bacteria, and blaNDM was the predominant carbapenemases gene, while the most prevalent plasmid replicons were the F replicon combination (FIA, FIB, and FII) and A/C. Plasmids were detected only in Klebsiella pneumoniae, Escherichia coli, Enterobacter cloacae, and Pseudomonas aeruginosa. Remarkably, we found a statistically significant association between carbapenemase genes and plasmid replicons, including blaNDM, IncA/C, and IncX. Conclusions: Our study demonstrated an alarming rise of plasmid-mediated carbapenem-resistant bacteria in our locality. The coexistence of resistance genes and plasmids highlights the importance of a targeted antibiotic surveillance program and the development of alternative therapeutic options at the local and international levels. Based on our results, we suggest a large-scale study with more Enterobacteriaceae isolates, testing other carbapenemase-encoding genes, and comparing the replicon typing method with other plasmid detection methods. We also recommend a national action plan to control the irrational use of antibiotics in Egypt.

Cutaneous Toll-like Receptor 9 Pre-Defines Hydroxychloroquine Dosage in Patients with Both Discoid and Subacute Lupus Erythematosus.

Background and Objectives: Cutaneous lupus erythematosus (CLE) presents clinically heterogeneous manifestations, partially explained by the different expression of Toll-like receptors (TLRs) type 8 and 9, located to endosomal compartments where they are poised to recognize microbial nucleic acids. This disease is empirically treated with hydroxychloroquine (HCQ), which is hallmarked with a safe and effective profile, but induces a slow and sometimes clinically insufficient therapeutic response. Currently, no biomarkers predictive of response are validated or even proposed in the scientific literature. We aimed to evaluate endosomal TLR type 7, 8 and 9 as predictive biomarkers of HCQ efficacy. Materials and Methods: We conducted a case-control study comparing CLE patients retrospectively assigned to three subgroups based on 3-6-month Cutaneous LE Disease Area and Severity Index (CLASI) reduction upon treatment with HCQ (I = <40% vs. II = 40-80% vs. III = >80%). Before HCQ, lesional skin specimens were collected in untreated CLE and through immunohistochemistry; TLR-7, -8 and -9 expression was evaluated in the epidermis and the lymphocytic infiltrate was evaluated in the dermis. Results: Sixty-six lesional skin biopsies were compared with healthy controls. CLE patients displayed lower epidermal expression of total TLR 8 and 9 as well as infiltrating TLR-8, TLR9 + lymphocytes compared to controls. High HCQ responders differed from low responders for TLR-9 positivity (high vs. low) and for the lymphocytic dermal infiltrate (high vs. low). Conclusions: TLR9 could be envisaged as a possible biomarker to predict HCQ response level and dosage in CLE patients.

New onset atopic dermatitis and psoriasis in the same patients under biologic treatments: The role of systemic treatments as a possible trigger.

Atopic dermatitis (AD) and psoriasis (PsO) are among the most common diseases in the daily clinical practice. Usually, AD and PsO are reported as two diseases that cannot coexist in the same patient because this requires the activation of opposing inflammatory pathways. Anyway, some reports highlight how AD and PsO may coexist in the same patient or develop consequently. In this short report we collected 12 patients that developed new AD or PsO. Among them, eight patients (n = 8; 3M:5F) with a previous diagnosis of PsO, developed subsequently an AD with a mean time of onset of 71.5 months. Out of eight patients, four patients where in treatment with ustekinumab, one with ixekizumab, two with adalimumab, and one with guselkumab. All new onset AD have been treated with topical medicaments, except one case that performed dupilumab. Contrariwise, four patients with a baseline AD developed a PsO with a mean time of onset of 25 months. Two AD patients were under dupilumab treatment, while the other two patients performed only topical treatments. All patients showed an improvement of the new onset PsO with topical treatment only. This report highlights how AD and PsO are not mutually exclusive diseases. The mechanisms by which AD patients develop PsO or psoriatic patients develop AD are still not very clear; some triggers can promote these processes, such as systemic therapies. Therefore, clinicians should carefully evaluate any changes in these patients, in order to reach a correct diagnosis and carry out a relative treatment.

Syphilis: a mini review of the history, epidemiology and focus on microbiota.

Syphilis is a chronic systemic infectious disease caused by the spirochaete bacterium Treponema pallidum(syphilis treponeme). In recent decades there has been a drastic increase in cases of syphilis,with a relative increase in scientific interest in this regard. However, the data concerning the studyof microbiota in syphilis are few and very scattered.This brief review provides a quick update on the disease, with particular attention to the role of themicrobiota, an aspect not always adequately considered in the evaluation of the pathology. The usualcoexistence of different sexually transmitted diseases in the same patients led us to delve also intothe possible role of the microbiota in the pathogenesis of syphilis; indeed, not all sexual contactslead to infections, suggesting that host immunity and local microbiota could modulate the historyof sexually transmitted disease. In both males and females, alteration of the microbiota may be involvedin syphilis as well as in the other sexually transmitted diseases. Finally, since 9% of the totalproteome of T. pallidum is spent for transportome, the latter may provide essential nutrients, makingT. pallidum able to adapt to a diverse range of microenvironments and stresses in the human host.

Case Report of Dermoscopic Aspects and Reflectance Confocal Microscopy Description of Segmental Leiomyoma and Relative Management.

Cutaneous leiomyoma is a benign tumor, mainly composed of smooth muscle cells and arising from the arrector pili muscle of hair follicles. The diagnosis of leiomyomas is of paramount importance, as they can often be associated with underlying malignancies (e.g., renal cell carcinoma, leiomyosarcoma) and specific genetic mutations. We report the case of a 27-year-old Caucasian male patient that presented to our attention with a rare segmental and Zoosteriform type II leiomyoma. We performed an analysis of the cutaneous lesions using dermoscopy, reflectance confocal microscopy (RCM) and histology. We found that, using dermoscopy, the leiomyomas showed a dermatofibroma-like appearance with a central hypopigmented area, peripheral delicate hyperpigmentation and also erythematous areas and ectatic vessels. RCM, although not specific, showed groups of hypo-reflective areas distributed in the most superficial papillary dermis, which in histology and immunohistochemistry corresponded to the most superficial protrusions in the papillary dermis of the tumoral bundles. Finally, we discuss the management of patients with multiple leiomyomas and stress the fact that, in the cases of multiple leiomyomas, an annual sonography of the kidneys associated with dermatological and (in women) gynecological consultations are needed to ensure the early identification of an underlying tumor. A genetic consultation to detect an eventual FH mutation is recommended, but since in some cases the FH result may be negative, the above recommended controls remain always of paramount importance.

Secukinumab Exhibits Sustained and Stable Response in Patients with Moderate-to-Severe Psoriasis: Results from the SUPREME Study.

Secukinumab, a fully human monoclonal antibody, neutralizes interleukin-17A, a cornerstone cytokine driving the multiple manifestations of psoriasis. This post-hoc analysis of the SUPREME study was performed to determine the sustainability of response to secukinumab in terms of Psoriasis Area and Severity Index (PASI) 90 in patients with moderate-to-severe plaque psoriasis. Based on PASI 90 response at week 16, patients were stratified as PASI 90 responders (PASI90R, n = 337) or non-responders (PASI90NR, n = 72). At week 20, 94.2% (n = 295/313) achieved PASI 90/100 response in PASI90R, with response maintained through week 48 (89.6%, n = 189/211). An increased proportion of patients achieved PASI 90/100 response in PASI90NR (week 20: 29.9%, n = 20/67; week 48: 57.1%, n = 20/35). Overall, 64.4% patients achieved absolute PASI score = 0 at week 24 with response sustained to week 48 (66.9%). Secukinumab showed sustained and stable efficacy in maintaining PASI 90 response in patients with moderate-to-severe plaque psoriasis up to week 48.

Investigating the Safety and Efficacy of Platelet-Rich Plasma (PRP) Treatment for Female Androgenetic Alopecia: Review of the Literature.

Background: female androgenetic alopecia (FAGA) is a common cause of non-scarring alopecia in women, affecting approximately 40% of women by age 50, bearing a significant psychosocial burden on affected patients. Platelet-rich plasma (PRP) has been widely investigated as a potential effective treatment for several dermatological conditions, including male androgenetic alopecia (MAGA). However, few studies have been conducted focusing on the use of PRP in FAGA. The aim of this review was to identify reports that investigated the use of PRP for the treatment of FAGA. Methods: Electronic databases of MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) from inception to September 2020 have been searched using different combinations of the following terms: "androgenetic alopecia," "FAGA," "female pattern hair loss," "platelet-rich fibrin," "platelet-rich plasma," and "PRP". Results and conclusions: Eight (n = 8) clinical studies consistent with our research were identified. A total of 197 subjects has been enrolled in the included studies. All of them were adult female patients (mean age: 38.9) affected by female pattern hair loss. PRP is a well-tolerated procedure which showed promising results in males-only and mixed populations of AGA patients. PRP showed to produce high levels of satisfaction and improvement in the quality of life in patients affected by FAGA. In the light of this evidence, PRP may be proposed in patients who did not respond or did not tolerate topical minoxidil, as well as in combination with topical and oral treatments.

Pilot Study on the Use of the "Monocyte-Rich" Platelet-Rich Plasma in Combination with 1927 nm Fractional and 308 nm Excimer Lasers for the Treatment of Vitiligo.

Background and objectives: Vitiligo is an acquired chronic and idiopathic skin disorder, characterized by selective loss of melanocytes and resulting in a cutaneous depigmentation. Treatment for vitiligo remains a challenge for dermatologists; thus, it is frustrating both for physicians and patients. The objective of this study was to evaluate a combination treatment characterized by the use of a leukocyte-rich platelet-rich plasma, which is particularly rich in monocytes (defined here as monocyte-rich PRP), in combination with a 1927 nm fraxel laser and a 308 nm excimer laser. Materials and Methods: Treatment with monocyte-rich PRP combined with 1927 nm fraxel laser and 308 nm excimer laser was performed in nine sessions in 80 days and the median follow-up of the patients was 10 months. A total of 27 Caucasian patients were included in the present study. The median age of patients was 41 years, ranging between 20 and 69 years. Results: A re-pigmentation occurred in 16 cases (59%) with a reduction of the Vitiligo Extent Score (VES) and absence of re-pigmentation in untreated areas. Performing a rank correlation between VES and re-pigmentation in the treated areas, we found that there was a significant correlation (p < 0.0001). The presence of progressive vitiligo (p = 0.1) and the anatomic areas (p = 0.1) did not influence the treatment. Untreated areas did not show any improvement of the depigmented lesions, except in one case (p < 0.0001). Conclusions: in this report, we show for the first time how PRP rich in monocytes, in combination with laser therapies, gives a long therapeutic response, which persists even after 10 months of follow-up.

Systemic immunobiological, immunosuppressant, and oncologic agents for the treatment of dermatologic diseases during the SARS-CoV-2 (COVID-19) pandemic emergency: A quick review for a quick consultation.

The precision medicine era has helped to better manage patients with immunological and oncological diseases, improving the quality of life of this class of patients. Regarding the management of these patients and positivity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), currently, limited data are available and information is evolving. In this quick review, we have analyzed the mechanisms of action and related infective risk of drugs used for the treatment of immune-mediated and oncologic skin conditions during the daily clinical practice. In general, immunosuppressant and antineoplastic agents for dermatologic treatments do not require suspension and do not require special measures, if not those commonly observed. In the case of a coronavirus disease (COVID-19) patient with complications (such as pneumonia, respiratory failure), treatment suspension should always be considered after taking into account the general condition of the patient, the risk-benefit ratio, and the pathophysiology of COVID-19 infection. The COVID-19 emergency pandemic does not imply undertreatment of existing skin conditions, which together with the SARS-CoV-2 infection may jeopardize the patient's life.

CO2 laser and photodynamic therapy: Study of efficacy in periocular BCC.

Basal cell carcinoma (BCC), the most common type of skin cancer in the world, usually arises in sun-exposed areas of the skin. The therapeutic approach to periocular BCC has changed in the last few years. Currently the treatment, considering the delicate localization of the disease, must not only ensure complete recovery from the neoplastic disease, but must also satisfy functional and aesthetic criteria. In this study we tried to evaluate the efficacy of CO2 laser and photodynamic therapy in periocular BCC.

Review of HPV-related diseases and cancers.

Human papillomavirus (HPV) is a double-stranded circular DNA virus belonging to the papillomavirus family. It is transmitted by skin-to-skin or mucosa-to-mucosa contact and enters the body via cutaneous or mucosal trauma. HPV infection is the most common sexually transmitted disease, although it is usually cured by the immune system. Worldwide, the risk of being infected at least once in a lifetime among both men and women is 50%. HPV infection causes common and anogenital warts, as well as other non-dermatological diseases. The role of HPV in cancer development has been extensively studied, primarily in cervical cancer, but also in other types of neoplasms.

Paraneoplastic Pemphigus: Insight into the Autoimmune Pathogenesis, Clinical Features and Therapy.

Paraneoplastic pemphigus is a rare autoimmune skin disease that is always associated with a neoplasm. Usually, oral, skin, and mucosal lesions are the earliest manifestations shown by paraneoplastic pemphigus patients. The pathogenesis of paraneoplastic pemphigus is not yet completely understood, although some immunological aspects have been recently clarified. Because of its rarity, several diagnostic criteria have been proposed. Besides, several diagnostic procedures have been used for the diagnosis, including indirect immunofluorescence, direct immunofluorescence, and ELISA. We reviewed the most recent literature, searching on PubMed "paraneoplastic pemphigus". We included also papers in French, German, and Spanish. We found 613 papers for "paraneoplastic pemphigus". Among them, 169 were review papers. Because of its varying clinical features, paraneoplastic pemphigus still represents a challenge for clinicians. Furthermore, diagnosis and management of paraneoplastic pemphigus requires close collaboration between physicians, including dermatologist, oncologist, and otorhinolaryngologist.