[Main Types of Cysts in Dermatopathology: Part 2]. / Principales tipos de quistes en dermatopatología: Parte 2.

This is the second article in a two-part series published in this journal, in which we examine the histopathological characteristics, as well as the differential diagnosis, of the main entities that present as cystic and pseudocystic structures in cutaneous biopsy. In this second article, we address ciliated cutaneous cysts, branchial cysts, Bartholin's cysts, omphalomesenteric cysts, thymic cysts, thyroglossal duct cysts, synovial cysts, and median raphe cysts, as well as mucocele, ganglion, and auricular and digital myxoid pseudocysts.

Monocyte-to-High-Density Lipoprotein Ratio Is Associated with Systemic Inflammation, Insulin Resistance, and Coronary Subclinical Atherosclerosis in Psoriasis: Results from 2 Observational Cohorts.

Systemic inflammation or insulin resistance drive atherosclerosis. However, they are difficult to capture for assessing cardiovascular risk in clinical settings. The monocyte-to-high-density lipoprotein ratio (MHR) is an accessible biomarker that integrates inflammatory and metabolic information and has been associated with poorer cardiovascular outcomes. Our aim was to evaluate the association of MHR with the presence of subclinical atherosclerosis in patients with psoriasis. The study involved a European and an American cohort including 405 patients with the disease. Subclinical atherosclerosis was assessed by coronary computed tomography angiography. First, MHR correlated with insulin resistance through homeostatic model assessment for insulin resistance, with high-sensitivity CRP and with 18F-fluorodeoxyglucose uptake in spleen, liver, and bone marrow by positron emission tomography/computed tomography. MHR was associated with both the presence of coronary plaques >50% of the artery lumen and noncalcified coronary burden, beyond traditional cardiovascular risk factors (P < .05). In a noncalcified coronary burden prediction model accounting for cardiovascular risk factors, statins, and biologic treatment, MHR added value (area under the curve base model = 0.72 vs area under the curve base model plus MHR = 0.76, P = .04) within the American cohort. These results suggests that MHR may detect patients with psoriasis who have subclinical burden of cardiovascular disease and warrant more aggressive measures to reduce lifetime adverse cardiovascular outcomes.

Clinical and Real-World Effectiveness of Mogamulizumab: A Narrative Review.

Mogamulizumab (MOG) is an antibody targeting the CCR4 receptor, authorized for relapsed or refractory peripheral T-cell (PTCL) and cutaneous T-cell lymphomas (CTCL). Its adoption in guidelines and endorsement by FDA and EMA established it as a systemic treatment, especially for advanced disease stages due to its comparatively lower toxicity. Clinical trials and real-world evidence have underscored its efficacy in advanced CTCLs, including mycosis fungoides and Sézary syndrome; PTCLs; and adult T-cell leukemia/lymphoma (ATLL), showcasing positive outcomes. Notably, the drug has demonstrated significant response rates, disease stability, and extended periods of progression-free survival, suggesting its applicability in cases with multiple treatment lines. Its safety profile is generally manageable, with adverse events (AEs) primarily related to the skin, infusion-related reactions, drug eruptions, autoimmune diseases, and skin disorders. The latter seem to appear as CCR4 can promote the skin-specific homing of lymphocytes, and MOG is directed against this receptor. While combination with immunostimulatory agents like interferon alpha and interleukin 12 has shown promising results, caution is urged when combining with PD1 inhibitors due to the heightened risk of immune-mediated AEs. The introduction of MOG as a systemic treatment implies a significant advancement in managing these diseases, supported by its favorable safety profile and complementary mechanisms.

Dose reduction is a feasible strategy in patients with plaque psoriasis who achieve sustained response with secukinumab: a retrospective, multicenter cohort study in daily practice setting.

BACKGROUND: Biological therapy dose modification is a common practice in the long-term treatment of plaque psoriasis. OBJECTIVE: The objective of the study was to determine prevalence, characteristics of patients, effectiveness, treatment survival of secukinumab dose reduction (SEC-DR) strategy and assess its safety and cost implications. METHODS: A retrospective, observational, multicenter cohort study was conducted in patients with plaque psoriasis treated with secukinumab and up to 2 years of follow-up. RESULTS: In 63/347 patients with an initial standard dose regimen, SEC-DR was tried at any moment in 18.2% of them after sustained response. In 51 patients, the interval between administrations was increased while in 12 patients, monthly dose was reduced to 150 mg. Successful SEC-DR was achieved in 77.8% of the patients, with sustained PASI response to the end of the study. Survival of secukinumab treatment and safety profile were not compromised by DR. The use of DR saved 33% of the cost, including failures in which standard treatment was resumed. LIMITATIONS: The proper of the study designed and the arbitrary definition of "DR success." CONCLUSION: Off-label SEC-DR strategy was used in patients with sustained response to standard dose regimen; this strategy showed long-term efficacy without compromising treatment survival or worsening the safety profile while also being cost saving.

Treatment of Psoriasis Patients with Latent Tuberculosis Using IL-17 and IL-23 Inhibitors: A Retrospective, Multinational, Multicentre Study.

BACKGROUND: Tuberculosis has a major global impact. Immunocompetent hosts usually control this disease, resulting in an asymptomatic latent tuberculosis infection (LTBI). Because TNF inhibitors increase the risk of tuberculosis reactivation, current guidelines recommend tuberculosis screening before starting any biologic drug, and chemoprophylaxis if LTBI is diagnosed. Available evidence from clinical trials and real-world studies suggests that IL-17 and IL-23 inhibitors do not increase the risk of tuberculosis reactivation. OBJECTIVE: To evaluate psoriasis patients with treated or untreated newly diagnosed LTBI who received IL-17 and IL-23 inhibitors and the tolerability/safety of tuberculosis chemoprophylaxis. METHODS: This is a retrospective, observational, multinational study from a series of 14 dermatology centres based in Portugal, Spain, Italy, Greece and Brazil, which included adult patients with moderate-to-severe chronic plaque psoriasis and newly diagnosed LTBI who were treated with IL-23 or IL-17 inhibitors between January 2015 and March 2022. LTBI was diagnosed in the case of tuberculin skin test and/or interferon gamma release assay positivity, according to local guideline, prior to initiating IL-23 or IL-17 inhibitor. Patients with prior diagnosis of LTBI (treated or untreated) or treated active infection were excluded. RESULTS: A total of 405 patients were included; complete/incomplete/no chemoprophylaxis was administered in 62.2, 10.1 and 27.7% of patients, respectively. The main reason for not receiving or interrupting chemoprophylaxis was perceived heightened risk of liver toxicity and hepatotoxicity, respectively. The mean duration of biological treatment was 32.87 ± 20.95 months, and only one case of active tuberculosis infection (ATBI) was observed, after 14 months of treatment with ixekizumab. The proportion of ATBI associated with ixekizumab was 1.64% [95% confidence interval (CI): 0-5.43%] and 0% for all other agents and 0.46% (95% CI 0-1.06%) and 0% for IL-17 and IL-23 inhibitors, respectively (not statistically significant). CONCLUSIONS: The risk of tuberculosis reactivation in patients with psoriasis and LTBI does not seem to increase with IL-17 or IL-23 inhibitors. IL-17 or IL-23 inhibitors should be preferred over TNF antagonists when concerns regarding tuberculosis reactivation exists. In patients with LTBI considered at high risk for developing complications related to chemoprophylaxis, this preventive strategy may be waived before initiating treatment with IL-17 inhibitors and especially IL-23 inhibitors.

Dermatologist-like explainable AI enhances trust and confidence in diagnosing melanoma.

Artificial intelligence (AI) systems have been shown to help dermatologists diagnose melanoma more accurately, however they lack transparency, hindering user acceptance. Explainable AI (XAI) methods can help to increase transparency, yet often lack precise, domain-specific explanations. Moreover, the impact of XAI methods on dermatologists' decisions has not yet been evaluated. Building upon previous research, we introduce an XAI system that provides precise and domain-specific explanations alongside its differential diagnoses of melanomas and nevi. Through a three-phase study, we assess its impact on dermatologists' diagnostic accuracy, diagnostic confidence, and trust in the XAI-support. Our results show strong alignment between XAI and dermatologist explanations. We also show that dermatologists' confidence in their diagnoses, and their trust in the support system significantly increase with XAI compared to conventional AI. This study highlights dermatologists' willingness to adopt such XAI systems, promoting future use in the clinic.

[Main Types of Cysts in Dermatopathology: Part 1]. / Principales tipos de quistes en dermatopatología: parte 1.

Cystic structures represent one of the most common findings in dermatopathology. These encompass both cystic tumors and pseudocysts resulting from the accumulation of certain substances, such as mucin. In a two-part series (of which this is the first part), we have reviewed the principal types of cysts and pseudocysts that may be observed in cutaneous biopsies, examining their histopathological features and primary differential diagnoses. This first part encompasses infundibular cysts, eruptive dermoid cysts, pigmented follicular cysts, pilonidal cysts, tricholemmal cysts, milium cysts, hybrid cysts, bronchogenic cysts, as well as steatocystoma, hydrocystoma, and comedones.

Safety of biologic therapy in combination with methotrexate in moderate to severe psoriasis: a cohort study from the BIOBADADERM registry.

BACKGROUND: Safety is an important consideration in decisions on treatment for patients with moderate-to-severe psoriasis and the study of drug safety is the main purpose of the BIOBADADERM registry. The combination of a biologic agent and a conventional systemic drug [generally methotrexate (MTX)] is a common treatment in clinical practice. However, there is a paucity of evidence from real-world practice on the safety of such combination regimens in the treatment of psoriasis. OBJECTIVES: The primary objective of this study was to ascertain whether the use of regimens combining biologic drugs with MTX in the management of moderate-to-severe psoriasis increases the risk of adverse events (AEs) or serious AEs (SAEs). We compared monotherapy using tumour necrosis factor (TNF), interleukin (IL)-17 and IL-23 inhibitors with the use of the same drugs in combination with MTX. METHODS: Using data from the BIOBADADERM registry, we compared biologic monotherapies with therapies that were combined with MTX. We estimated adjusted incidence rate ratios (aIRR) using a random effects Poisson regression with 95% confidence intervals for all AEs, SAEs, infections and serious infections and other AEs by system organ class. RESULTS: We analysed data from 2829 patients and 5441 treatment cycles, a total of 12 853 patient-years. The combination of a biologic with MTX was not associated with statistically significant increases in overall risk of AEs or SAEs in any treatment group. No increase in the total number of infections or serious infections in patients receiving combined therapy was observed for any group. However, treatment with a TNF inhibitor combined with MTX was associated with an increase in the incidence of gastrointestinal AEs (aIRR 2.50, 95% CI 1.57-3.98; P < 0.002). CONCLUSIONS: The risk of AEs and SAEs was not significantly increased in patients with moderate-to-severe psoriasis receiving different classes of biologic drugs combined with MTX compared with those on biologic monotherapy.

Corrigendum: The paradigm of IL-23-independent production of IL-17F and IL-17A and their role in chronic inflammatory diseases.

[This corrects the article DOI: 10.3389/fimmu.2023.1191782.].

Association of the Complement System with Subclinical Atherosclerosis in Psoriasis: Findings from an Observational Cohort Study.

Psoriasis is a chronic and inflammatory disease that affects the skin and joints and is associated with multiple comorbidities and cardiovascular risk factors. Consequently, patients with psoriasis have an increased risk of cardiovascular diseases such as atherosclerosis, a chronic pathology that shares common inflammatory and immune-response mechanisms with psoriasis, including vascular inflammation and complement activation. To better understand the relationship between atherosclerosis and psoriasis, a proteomics study followed by a bioinformatics analysis was carried out, with a subsequent validation step using ELISA and western blotting. When the plasma from patients with psoriasis alone was compared with that from patients with psoriasis and atherosclerosis, 31 proteins of interest related to the complement system and oxygen transport were identified. After the validation phase, 11 proteins appeared to define the presence of subclinical atherosclerosis in patients with psoriasis, indicating the importance of complement cascades in the development of atherosclerotic plaques in individuals with psoriasis. These results are a step forward in understanding the pathological pathways implicated in the cardiovascular risk associated with this population, which may represent an interesting starting point for developing predictive tools that improve the follow-up of these patients and design more effective therapies.

Approach to the so-called "Invisible Dermatosis": When Subtle Histopathological Findings Guide Diagnosis.

ABSTRACT: Invisible dermatosis is a concept that can be applied either to clinical or histopathological findings. We will focus on the dermatopathological aspect of this invisible dermatosis that can be seen as dermatosis with subtle histopathological findings that are mandatory to known to stablish the diagnosis. With a proper approach facing in depth the different skin layers from stratum corneum to subcutaneous tissue combined with some especial stains, special investigations and mostly a proper clinicopathological correlation, the problem of missing out a diagnosis can be decreased. We will review the general aspects for diagnosis and the peculiar findings of an in-depth review of them because it is important to note that minor changes on a skin biopsy do not mean it is disease free. We will review classic clues, we will add some new useful ones, and we will also provide a guide on the special stains helpful, such as periodic acid-Schiff when facing fungi, orcein-Giemsa and van Gieson when altered elastic fibers are suspected, or Pearl and Masson Fontana when an altered skin pigmentation is suspected.

A 3-dimensional histology computer model of malignant melanoma and its implications for digital pathology.

BACKGROUND: Historically, cancer diagnoses have been made by pathologists using two-dimensional histological slides. However, with the advent of digital pathology and artificial intelligence, slides are being digitised, providing new opportunities to integrate their information. Since nature is 3-dimensional (3D), it seems intuitive to digitally reassemble the 3D structure for diagnosis. OBJECTIVE: To develop the first human-3D-melanoma-histology-model with full data and code availability. Further, to evaluate the 3D-simulation together with experienced pathologists in the field and discuss the implications of digital 3D-models for the future of digital pathology. METHODS: A malignant melanoma of the skin was digitised via 3 µm cuts by a slide scanner; an open-source software was then leveraged to construct the 3D model. A total of nine pathologists from four different countries with at least 10 years of experience in the histologic diagnosis of melanoma tested the model and discussed their experiences as well as implications for future pathology. RESULTS: We successfully constructed and tested the first 3D-model of human melanoma. Based on testing, 88.9% of pathologists believe that the technology is likely to enter routine pathology within the next 10 years; advantages include a better reflectance of anatomy, 3D assessment of symmetry and the opportunity to simultaneously evaluate different tissue levels at the same time; limitations include the high consumption of tissue and a yet inferior resolution due to computational limitations. CONCLUSIONS: 3D-histology-models are promising for digital pathology of cancer and melanoma specifically, however, there are yet limitations which need to be carefully addressed.

Pancreatic panniculitis revisited: A series of 34 patients.

BACKGROUND: Pancreatic panniculitis is a rare form of panniculitis generally associated with acute or chronic pancreatitis, and less frequently with pancreatic carcinoma. Clinically, it presents with subcutaneous nodules usually located in the lower extremities, however, it presents an almost pathognomonic histopathological finding with enzymatic fat necrosis in the adipose tissue. METHODS: In this retrospective case series of five hospitals, biopsy specimens of cutaneous lesions of pancreatic panniculitis were reviewed. Clinical information was obtained through medical records. RESULTS: A total of 34 cases were included, 23 women and 11 men, aged between 31 and 92 years. The most common associated pancreatic disease was acute pancreatitis (23 cases) and its main triggering cause was gallstones (17 cases). In two patients it was related to chronic pancreatitis and six cases were associated with malignancy. Histopathological findings were always the key to diagnosis. In the biopsies reviewed, mostly lobular panniculitis with the characteristic necrosis of the adipocytes was observed. In addition, nine of the cases presented with Splendore-Hoeppli phenomenon. CONCLUSIONS: We present the largest series of pancreatic panniculitis. Clinically, the female predominance and biliary lithiasis as the main cause of acute pancreatitis are to be emphasized. Histopathologically, a peripheral eosinophilic striated rim surrounding aggregates of ghost adipocytes consistent with Splendore-Hoeppli is an additional clue to its diagnosis.

The paradigm of IL-23-independent production of IL-17F and IL-17A and their role in chronic inflammatory diseases.

Interleukin-17 family (IL-17s) comprises six structurally related members (IL-17A to IL-17F); sequence homology is highest between IL-17A and IL-17F, displaying certain overlapping functions. In general, IL-17A and IL-17F play important roles in chronic inflammation and autoimmunity, controlling bacterial and fungal infections, and signaling mainly through activation of the nuclear factor-kappa B (NF-κB) pathway. The role of IL-17A and IL-17F has been established in chronic immune-mediated inflammatory diseases (IMIDs), such as psoriasis (PsO), psoriatic arthritis (PsA), axial spondylarthritis (axSpA), hidradenitis suppurativa (HS), inflammatory bowel disease (IBD), multiple sclerosis (MS), and asthma. CD4+ helper T cells (Th17) activated by IL-23 are well-studied sources of IL-17A and IL-17F. However, other cellular subtypes can also produce IL-17A and IL-17F, including gamma delta (γδ) T cells, alpha beta (αß) T cells, type 3 innate lymphoid cells (ILC3), natural killer T cells (NKT), or mucosal associated invariant T cells (MAIT). Interestingly, the production of IL-17A and IL-17F by innate and innate-like lymphocytes can take place in an IL-23 independent manner in addition to IL-23 classical pathway. This would explain the limitations of the inhibition of IL-23 in the treatment of patients with certain rheumatic immune-mediated conditions such as axSpA. Despite their coincident functions, IL-17A and IL-17F contribute independently to chronic tissue inflammation having somehow non-redundant roles. Although IL-17A has been more widely studied, both IL-17A and IL-17F are overexpressed in PsO, PsA, axSpA and HS. Therefore, dual inhibition of IL-17A and IL-17F could provide better outcomes than IL-23 or IL-17A blockade.

Effectiveness and safety of tildrakizumab for the treatment of psoriasis in real-world settings at 24 weeks: A retrospective, observational, multicentre study by the Spanish Psoriasis Group.

BACKGROUND: Tildrakizumab is a humanized, IgG1/κ antibody that interacts with the p19 subunit of interleukin 23. It is approved for the treatment of moderate-to-severe plaque psoriasis. Real-world evidence on the effectiveness and safety of tildrakizumab is limited. OBJECTIVES: To assess the effectiveness and safety of tildrakizumab at 24 weeks in patients with moderate-to-severe plaque psoriasis in routine clinical practice. METHODS: Retrospective, observational, multicentre study including adult patients with moderate-to-severe plaque psoriasis treated with tildrakizumab under real-life conditions. Patient data were extracted from anonymized electronic medical records. Statistical analysis was performed using SPSS22. RESULTS: A total of 190 patients were included. About 53.9% were men with a mean age of 51.45 (SD 3.9) and a mean BMI of 29.13 (SD 6.21). About 79.8% (132 out of 190) of patients had previously received biological therapy (BT) and 17.3% (33 out of 191) had psoriatic arthritis. Baseline PASI was 10.7 (SD 6.53). Up to 109 patients reached Week 24 and at this point mean baseline PASI decreased to 1.7 (SD 4.8), representing an 88.79% mean PASI reduction. At 6 months, 87.1% and 40.3% of the treated patients achieved PASI ≤3 and ≤1, respectively. At Week 24 mean BSA decreased from 13.2 (SD 10.07) to 1.6 (SD 4.40) and mean DLQI went from 12.5 (SD 7.12) to 1.2 (SD 3.27). Multivariate analysis showed no differences when effectiveness was correlated with gender, obesity, psoriatic arthritis or prior exposure to BT. The rate of adverse events (AE) was 5.9% (11 out of 190), where infections were the most frequent AE (4 out of 11). One patient suffered a haemorrhagic ictus and one patient died due to causes unrelated to the study. CONCLUSION: Tildrakizumab was effective and safe in a large cohort of patients with moderate-to-severe plaque psoriasis treated in a routine clinical setting.

Tildrakizumab improves high burden skin symptoms, impaired sleep and quality of life of moderate-to-severe plaque psoriasis patients in conditions close to clinical practice.

BACKGROUND: Tildrakizumab (TIL) is an interleukin (IL)-23p19 inhibitor for the treatment of moderate-to-severe plaque psoriasis with long-term efficacy and safety demonstrated in Phase III trials. Studies conducted in conditions closer to clinical practice are needed. OBJECTIVES: The TRIBUTE study (open-label, Phase IV) assessed the efficacy and impact on health-related quality of life (HRQoL) of TIL 100 mg in adult moderate-to-severe psoriasis patients (naïve to IL-23/Th17 pathway inhibitors) in conditions similar to clinical practice. METHODS: Key efficacy measure was Psoriasis Area Severity Index (PASI). HRQoL was evaluated using the Dermatology Life Quality Index (DLQI) and Skindex-16. Additional patient-reported outcomes included Pain-, Pruritus- and Scaling-Numerical Rating Scale (NRS), Medical Outcome Study (MOS)-Sleep, Work Productivity and Activity Impairment (WPAI), Patient Benefit Index (PBI) and Treatment Satisfaction Questionnaire for Medication (TSQM). RESULTS: One hundred and seventy-seven patients were enrolled (six patients did not complete the study). After 24 weeks, the proportion of patients achieving PASI scores ≤ 3, PASI 75, PASI 90 and DLQI 0/1 was 88.4%, 92.5%, 74.0% and 70.4%, respectively. Skindex-16 overall score improved (mean absolute change from baseline, MACB [95%CI]: -53.3 [-58.1, -48.5]). Significant benefits (MACB [95%CI]) were found on pruritus-, pain- and scaling-NRS scores (-5.7 [-6.1, -5.2], -3.5 [-4.1, -3.0] and -5.7 [-6.2, -5.2], respectively), MOS-Sleep (-10.4 [-13.3, -7.4] Sleep problems Index II) and WPAI (-36.4 [-42.6, -30.2] activity impairment, -28.2 [-34.7, -21.7] productivity loss, -27.0 [-32.9, -21.1] presenteeism and -6.8 [-12.1, -1.5] absenteeism). 82.7% of patients reported PBI ≥ 3 and the mean (SD) global TSQM score was high (80.5 [18.5]). Only one serious treatment-emergent adverse event was reported (not-related to TIL). CONCLUSIONS: TIL 100 mg treatment after 24 weeks in conditions close to real clinical practice showed a quick and high improvement in psoriasis signs and HRQoL. Patient reported improvements in sleep outcomes and work productivity, relevant benefits and high treatment satisfaction. The safety profile was favourable and consistent with Phase III trials.

Efficacy and Safety of Dimethyl Fumarate in Patients with Moderate-to-Severe Plaque Psoriasis: Results from a 52-Week Open-Label Phase IV Clinical Trial (DIMESKIN 1).

INTRODUCTION: Although dimethyl fumarate (DMF) has been approved since 2017 for treatment of moderate-to-severe plaque psoriasis, limited data on its safety and efficacy are available in clinical practice. The objective was to assess the efficacy and safety of DMF in patients with moderate-to-severe plaque psoriasis through 52 weeks in conditions close to real clinical practice. METHODS: DIMESKIN 1 was a 52-week, open-label, phase IV clinical trial conducted at 36 Spanish sites. Adults with diagnosis of moderate-to-severe plaque psoriasis, treated with DMF as per its summary of product characteristics and with ≥ 1 post-baseline Psoriasis Area and Severity Index (PASI) value were included [intention-to-treat (ITT) population]. Efficacy analyses were performed for ITT population and are based on multiple imputation. RESULTS: Overall, 282 and 274 patients were included in the safety and ITT populations, respectively. At week 24, 46.0%/24.8%/10.9% of patients achieved PASI 75/90/100 response, respectively. At week 52, these percentages were 46.0%/21.9%/10.9%, respectively. Mean body surface area affected decreased from 17.4% to 6.9%/7.3% after 24/52 weeks (p < 0.001, both). A total of 42.9%/49.4% of patients had a Physician's Global Assessment 0-1 at week 24/52, respectively. Mean pruritus visual analogue scale (VAS) significantly decreased after 24 and 52 weeks (p < 0.001, both), with 56.5% and 67.6% of patients, respectively, rating a pruritus VAS < 3. At week 24/52, 61.3%/73.4% patients had a Dermatology Life Quality Index (DLQI) ≤ 5 and 34.7%/32.1% had a DLQI 0-1. The most frequent adverse events were gastrointestinal disorders (mainly diarrhea/abdominal pain in 50.0%/35.1% of patients, respectively), flushing (28.0%), and lymphopenia (31.2%), mostly mild/moderate. CONCLUSIONS: DMF significantly improves main severity and extension indexes and rates, as well as patient-reported outcomes such as pruritus and quality of life in patients with moderate-to-severe psoriasis after 24 weeks of treatment. These improvements are sustained through 52 weeks. The safety profile of DMF is similar to that previously described for fumarates. EUDRACT NUMBER: 2017-00136840.

Rosacea, microbiome and probiotics: the gut-skin axis.

Rosacea is an inflammatory skin disease involving diverse symptoms with a variable clinical progress which can severely impact the patient's quality of life as well as their mental health. The pathophysiological model of rosacea involves an unbalanced immune system predisposed to excessive inflammation, in addition to vascular and nervous alterations, being certain cutaneous microorganisms' triggers of the symptoms onset. The gut-skin axis explains a bidirectional interaction between skin and gut microbiota in some inflammatory skin diseases such as atopic dermatitis, psoriasis, or rosacea. The introduction and consolidation of the next-generation sequencing in recent years has provided unprecedented information about the microbiome. However, the characterization of the gut and skin microbiota and the impact of the gut-skin axis in patients with rosacea has been little explored, in contrast to other inflammatory skin diseases such as atopic dermatitis or psoriasis. Furthermore, the clinical evolution of patients with rosacea is not always adequate and it is common for them to present a sustained symptomatology with frequent flare-ups. In this context, probiotic supplementation could improve the clinical evolution of these patients as happens in other pathologies. Through this review we aim to establish and compile the basics and directions of current knowledge to understand the mechanisms by which the microbiome influences the pathogenesis of rosacea, and how modulation of the skin and gut microbiota could benefit these patients.

A comprehensive review on pathogenesis, associations, clinical findings, and treatment of livedoid vasculopathy.

Livedoid vasculopathy (LV) is a thrombo-occlusive vasculopathy that involves the dermal vessels. Clinically, it is characterized by the presence of painful purpuric ulcers on the lower extremities. Histopathologically, it shows intraluminal fibrin deposition and thrombosis, segmental hyalinization, and endothelial proliferation. It is important to notice that the term "atrophie blanche" is descriptive and it includes not only patients with LV but also patients with a combination of vasculitis and vasculopathy, that is, LV and medium-sized vasculitis such as cutaneous polyarteritis nodosa (PANc). Diagnosis is based on a proper clinicopathological correlation, excluding the main differential diagnosis and considering vasculitis as a mimicker or concomitant diagnosis. Coagulation disorders must also be studied although they are not found in all LV. Its frequency is reviewed as well. Treatment of LV is challenging, and different therapies have been attempted. Among them, pain management, wound care, control of cardiovascular risk factors, and both antiplatelets and anticoagulants, mostly rivaroxaban, are the main therapies used. These different therapies as well as their degree of evidence are reviewed.