Pivotal Role of mTOR in Non-Skin Manifestations of Psoriasis.

Psoriasis is a chronic inflammatory condition affecting 2% of the Western population. It includes diverse manifestations influenced by genetic predisposition, environmental factors, and immune status. The sustained activation of mTOR is a key element in psoriasis pathogenesis, leading to an uncontrolled proliferation of cytokines. Furthermore, mTOR activation has been linked with the transition from psoriasis to non-skin manifestations such as psoriatic arthritis and cardiovascular events. While therapies targeting pro-inflammatory cytokines have shown efficacy, additional pathways may offer therapeutic potential. The PI3K/Akt/mTOR pathway, known for its role in cell growth, proliferation, and metabolism, has emerged as a potential therapeutic target in psoriasis. This review explores the relevance of mTOR in psoriasis pathophysiology, focusing on its involvement in cutaneous and atheromatous plaque proliferation, psoriatic arthritis, and cardiovascular disease. The activation of mTOR promotes keratinocyte and synovial cell proliferation, contributing to plaque formation and joint inflammation. Moreover, mTOR activation may exacerbate the cardiovascular risk by promoting pro-inflammatory cytokine production and dysregulation lipid and glucose metabolism. The inhibition of mTOR has shown promise in preclinical studies, reducing skin inflammation and plaque proliferation. Furthermore, mTOR inhibition may mitigate cardiovascular risk by modulating cholesterol metabolism and attenuating atherosclerosis progression. Understanding the role of mTOR in psoriasis, psoriatic arthritis, and cardiovascular disease provides insight into the potential treatment avenues and sheds light on the complex interplay of the immune and metabolic pathways in these conditions.

[Neonatal lupus erythematosus, a clinical case]. / Lupus eritematoso neonatal, caso clínico.

Neonatal lupus erythematosus (NLE) is a very rare autoimmune disease, occurring in neonates born to mothers who present auto-antibodies to cytoplasmic antigens of Sjögren's syndrome. In most cases, the clinical course is benign toward spontaneous resolution, but there is a group of patients who develop severe involvement of the cardiac conduction system, therefore, early detection is critical. OBJECTIVE: To describe a clinical case of neonatal lupus erythematosus emphasizing the importance of timely diagnosis in the patient and the mother. CLINICAL CASE: A 33-year-old woman, with a history of hypertension, came to the dermatology department for her 15-day-old male neonate who presented a recent onset of round, erythematous, raised-edged, and non-scaling plaques consistent with NLE. Cardiac conduction involvement was ruled out. Newborn's laboratory tests showed moderate neutropenia, mild increase of transaminases, and positive anti-Ro and anti-La antibodies. On directed anamnesis, the mother reported a personal history of symptoms consistent with connective tissue disease, such as fatigue, alopecia, and xerophthalmia. Antinuclear antibodies from the mother showed titers of 1/1280 in a speckled pattern, positive anti-double-stranded DNA antibodies, and anti-Ro and Anti-La antibodies. Schirmer Test was consistent with dry eye, therefore, Systemic Lupus Erythematosus associated with Sjögren's Syndrome was diagnosed. The infant was followed up for 5 months with remission of cutaneous manifestations and normalization of laboratory tests. CONCLUSION: Although cutaneous manifestations of NLE are benign and transient in the newborn, these can be associated with other life-threatening manifestations that require an active search and prompt management by the medical team. A 25% of mothers of newborns with NLE are asymptomatic or unaware of their SLE diagnosis before delivery, so timely diagnosis of NLE leads to the diagnosis of asymptomatic mothers, improving their follow-up and treatment.

Non-Canonical WNT/Wnt5a Pathway Activity in Circulating Monocytes of Untreated Psoriatic Patients: An Exploratory Study of Its Association with Inflammatory Cytokines and Cardiovascular Risk Marker-ADAMTS7.

The leading cause of death in psoriasis is cardiovascular disease. The determinants that induce the increase in this risk are not known. The systemic inflammatory process is dependent on lymphocytes and monocytes, as has been proposed. However, adaptation modules such as mTOR have recently been mentioned as having a role. Other factors, such as WNT and its non-canonical WNT5a-inducing pathway, are relevant in inflammation, cell migration, and neoangiogenesis. Thus, we studied circulating monocytes from untreated severe psoriatic patients and characterized inflammatory cytokines, chemokines, mTOR activity, and the cardiovascular risk marker ADAMTS7. Peripheral blood from ten severely psoriatic patients (Psoriasis severity index greater than 10) was extracted and age- and sex-matched with healthy subjects. Surface and intracellular flow cytometry were performed for cytokine, chemokine receptors, and mTOR activity. ADAMTS7 was measured using ELISA. Psoriatic patients had a higher frequency of WNT5a+ cells in monocytes, which also had higher levels of IL-1ß, IL-6, CXCR3, CCR2, and phosphorylated S6R protein. We found that M1 monocytes are dominant in the WNT5a+ cell group, and intracellular levels of WNT5a were also augmented. Levels of WNT5a were correlated with ADAMTS7, a blood marker related to the pathogenesis of atheromatosis. WNT5a could be relevant to the cardiovascular risk of psoriatic patients considering its association with higher levels of inflammatory cytokines, chemokine receptors and the pro-atherogenic profile of circulating monocytes.

New Markers for Cardiovascular Disease in Psoriatic Patients: Preliminary Study on Monocyte Phenotype, ADAMTS7, and mTOR Activity.

Psoriasis is a skin disease with occasional involvement of non-cutaneous territories. Beyond the usual, cardiovascular events are more frequent in these patients and correlate only partially with disease activity, suggesting the presence of other unknown factors. We selected ten psoriatic patients without treatment in the last year and matched them for age and gender with eleven healthy subjects. Ficoll-extracted mononuclear cells were analyzed with flow cytometry for monocyte surface phenotype markers, intracellular NFκB/inflammasome-dependent interleukins, and chemotaxis receptor CXCR3. Using ELISA, patient serum was evaluated for ADAMTS7 and CXCL10. Inflammatory M1 monocytes showed higher levels of IL-1ß and IL-6 in psoriatic patients. M2 monocytes also showed higher levels of intracellular inflammatory cytokines. Nevertheless, IL-6 values were higher compared to other monocytes and IL-1ß. The mTORC activation markers ADAMTS7 and S6Rp were higher in psoriatic patients than in healthy controls. In psoriatic patients, serum levels of ADAMTS7 were elevated, and M2 monocytes showed a distinct inflammatory response with higher relative levels of NFκB-dependent IL-6 and less activity of the CXCR3-CXCL10 chemotactic pathway. These data suggest pathways with potential markers for prediction and early detection of cardiovascular risk in psoriatic patients.

Cardiovascular Disease-Associated Skin Conditions.

According to data from the American Heart Association and the World Health Organization, cardiovascular disease (CVD) is the most frequent cause of premature death. Several inflammatory and non-inflammatory skin diseases have been associated with metabolic syndrome and cardiovascular risk (CVR). Here, we classified these conditions into traditionally CVR-associated and those that have been linked to a lesser degree. Psoriasis and hidradenitis suppurativa are commonly associated with CVD, sharing common inflammatory pathways and a higher prevalence of traditional cardiovascular risk factors. Many other diseases could be associated indirectly - with no common pathogenic features with the atheromatous disease - but share a higher prevalence of standard cardiovascular risk and chronic inflammatory state. This review aims to highlight the associated cardiovascular risk that exists for some dermatologic diseases and sensitize cardiologists, dermatologists, and first care providers to implement risk factor control promptly.

Diffuse Lymphadenopathy Syndrome as a Flare-Up Manifestation in Lupus and Mixed Connective Tissue Disease Following Mild COVID-19.

BACKGROUND Manifestations of Coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 virus, are highly variable among healthy populations. In connective tissue disease patients, the spectrum of clinical manifestations is even broader. In mild COVID-19 patients, diffuse lymphadenopathy (DL) has not been described as a late manifestation, and only severe COVID-19 has been associated with lupus flare-ups. Herein, we report 3 cases of connective tissue disease patients that presented with DL after diagnosis and complete resolution of mild COVID-19 disease. CASE REPORT Case 1. A 28-year-old man with inactive lupus, mixed connective tissue disease (MCTD), and a history of lung and cutaneous involvement. He presented with fever, polyarthralgia, and multiple lymphadenopathies 3 weeks after COVID-19 disease resolution. After evaluation, immunosuppressive treatment was initiated, with rapid response. Case 2. A 25-year-old woman with inactive lupus with a history of articular, hematologic, and cutaneous involvement. Four weeks after resolution of COVID-19 disease, she presented with malaise and cervical lymphadenopathies. After laboratory testing and imaging, she was treated for lupus flare-up, with rapid response. Case 3. A 68-year-old woman with inactive lupus with a history of articular and cutaneous involvement. Four weeks after COVID-19 resolution, she presented with malaise and cervical and axillary lymphadenopathies. After extensive evaluation, immunosuppressive treatment resulted in a rapid response. CONCLUSIONS After 3 to 4 weeks of mild, outpatient-treated COVID-19 and complete resolution of symptoms, 3 patients with connective tissue disease presented diffuse lymphadenopathy associated with inflammatory and constitutional symptoms. Infectious and neoplastic causes were thoroughly ruled out. All patients responded to reintroduction of or an increase in immunosuppressive therapy. We recommend considering the diffuse lymphadenopathy as a possible post-acute COVID-19 syndrome (PACS) manifestation in these patients, mainly when they are in the inactive phase.

Predictive Model for Response Rate to Narrowband Ultraviolet B Phototherapy in Vitiligo: A Retrospective Cohort Study of 579 Patients.

Vitiligo is an acquired depigmenting disorder. To date, there is no predictive model for its response rate to narrowband ultraviolet B (NBUVB) phototherapy. The aim of this study was to investigate the different types of response of patients with non-segmental vitiligo undergoing NBUVB 3 times a week. Many patients who were previously considered non-responders were given the opportunity to continue the treatment. Long-term maintenance of treatment and follow-up of a cohort of 579 patients enabled different subtypes of response (very rapid, rapid, average, slow and "non-responders") to be described for the first time, and a predictive model of response to be constructed based on repigmentation rate in the first 48 sessions of NBUVB. Among those patients who did not respond during the first 48 sessions, a new subgroup of patients was found, termed "very-slow" responders, who achieved a low, but significant, level of repigmentation after 96 sessions of NBUVB.

[Parvovirus B19: A DNA virus associated with multiple cutaneous manifestations]. / Parvovirus B19: Un virus ADN asociado a múltiples manifestaciones cutáneas.

Parvovirus B19 is a community DNA virus with worldwide distribution with up to 85% seroprevalence in the elderly. There is a wide spectrum of clinical manifestations in parvovirus B19 infection of which cutaneous involvement is the most frequent one. Although most of these are self-limiting conditions, there are numerous syndromes and autoimmune diseases in which parvovirus B19 is postulated as a triggering factor, given its ability to induce the production of various autoantibodies and promote the presentation of autoantigens to T cells. This review describes the spectrum of cutaneous manifestations of parvovirus B19 infection and the evidence supporting its association with each of them. We propose a new classification of different diseases with cutaneous manifestations linked to parvovirus B19, based on the amount and quality of available evidence in the literature.

Parvovirus B19: Un virus ADN asociado a múltiples manifestaciones cutáneas / Parvovirus B19: A DNA virus associated with multiple cutaneous manifestations

Resumen El parvovirus B19 es un virus ADN comunitario distribuido a nivel mundial con seroprevalencias que alcanzan hasta 85% en el adulto mayor. Existe un amplio espectro de manifestaciones clínicas en la infección por parvovirus B19 siendo las cutáneas las más frecuentes. Si bien, la mayoría de éstas son autolimitadas, existen numerosos síndromes y enfermedades autoinmunes en los cuales se postula al parvovirus B19 como factor gatillante, dada su capacidad de inducir la producción de numerosos autoanticuerpos y promover la presentación de autoantígenos a linfocitos T. En la presente revisión se describe el espectro de manifestaciones cutáneas de la infección por parvovirus B19 y la evidencia que apoya su asociación con cada una de ellas. Se propone una clasificación de las diferentes enfermedades con manifestaciones cutáneas vinculadas al parvovirus B19, basado en la cantidad y calidad de la evidencia disponible en la literatura científica.

Parvovirus B19 is a community DNA virus with worldwide distribution with up to 85% seroprevalence in the elderly. There is a wide spectrum of clinical manifestations in parvovirus B19 infection of which cutaneous involvement is the most frequent one. Although most of these are self-limiting conditions, there are numerous syndromes and autoimmune diseases in which parvovirus B19 is postulated as a triggering factor, given its ability to induce the production of various autoantibodies and promote the presentation of autoantigens to T cells. This review describes the spectrum of cutaneous manifestations of parvovirus B19 infection and the evidence supporting its association with each of them. We propose a new classification of different diseases with cutaneous manifestations linked to parvovirus B19, based on the amount and quality of available evidence in the literature.