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.
Case series Patients: Male, 28-year-old • Female, 25-year-old • Female, 68-year-old Final Diagnosis: Lupus Symptoms: COVID-19 pneumonia with deteriration of clinical symptoms • lymphadenopathy Medication: — Clinical Procedure: — Specialty: Rheumatology Objective: Rare coexistence of disease or pathology 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 Reports: 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 lymph-adenopathies. 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.
Introduction: CD14 (monocyte differentiation antigen, LPS binding protein -endotoxin receptor) and CD16 (FcγRIII, Low-affinity receptor for IgG) define three subpopulations of circulating monocytes with different inflammatory and phagocytic capabilities. Contradictory reports exist regarding both in vivo monocyte phenotype-disease association and response of these circulating monocytes to in vitro stimulation. We analyzed phenotypic changes in circulating monocytes when stimulated with LPS (pro-inflammatory stimulus) and IL-4 (alternative inflammatory stimulus). Methods: Mononuclear cells from nine healthy donors were extracted and studied for surface and intracellular markers using flow cytometry. PBMC were extracted using Ficoll technic and immediately analyzed using flow cytometry. Pro-inflammatory interleukin IL-1β and IL-6 were measured by intracellular cytometry. Mononuclear cells were stimulated using LPS and IL-4 as previously described. Changes against non-stimulated populations were statistically analyzed. Results: Compared to non-stimulated and IL-4 stimulated monocytes, LPS-stimulated cells display a singular pattern of markers, with higher levels of intracellular IL-1β and IL-6 directly correlating with CD14+CD163-cell frequency and diminishing membrane CD163 fluorescence. CD14+CD16-classical monocytes show greater percentage of CD163-cells upon LPS stimulation. CD86 levels on monocytes' surface did not change with LPS or IL-4 stimulation. Conclusions and Discussion: We showed that CD14+CD16-classical monocytes display higher sensitivity to LPS stimulation, with more IL-1β and IL-6 levels than intermediate and non-classical monocytes. This subset also diminishes its CD163 levels on the membrane after LPS stimulation with a contemporary raise in CD163-cells, suggesting that classical monocytes preferentially acquire CD163-defined M1 characteristics upon in vitro LPS stimulation. Intermediate and non-classical monocytes respond with lower levels of interleukins and display surface proteins in an M2-type profile (CD163+).
15 BACKGROUND: CD14 (Monocyte identifying Toll-Like Receptor) and CD16 (FcyRIII co-receptor, marker of 16 inflammatory monocytes) were used to define 3 subpopulations of circulating monocytes with different attributes in terms 17 of inflammatory and phagocytic capabilities. There are contradictory reports regarding response of circulating monocytes 18 to pro-inflammatory or non-inflammatory stimuli in vitro. Here we aimed to analyze the phenotypic changes in 19 circulating monocytes when stimulated with pro and non-inflammatory stimuli. 20 METHODS: Whole blood from 9 healthy donors was extracted and studied. Monocyte subpopulations were directly 21 measured using flow cytometry with PBMC Ficoll extraction method. Pro-inflammatory interleukin IL-1β was measured 22 by intracellular cytometry. Whole blood-extracted monocytes were stimulated using LPS and IL-4 as previously 23 described. Changes against non-stimulated (N-S) populations were statistically analyzed. 24 RESULTS: Compared to N-S, LPS-stimulated monocytes display a singular milieu of markers, with higher levels of 25 intracellular IL-1β in parallel raise of CD14+CD163-/CD14+CD163+ ratio. CD163 shows positive correlation with levels 26 of IL-1β. In t-SNE (T-distributed Stochastic Neighbor Embedding) analysis, after LPS stimulation, subpopulation 27 CD14+CD16-CD163-, containing mainly classical monocytes, show a higher number of IL-1β+ cells.28 CONCLUSION: Classical monocytes, the non-inflammatory subset, show higher levels of IL-1β in response to LPS 29 narrowing down to a new subpopulation of monocytes CD14+CD16-CD163-, which correlates better with this interleukin 30 response than widely used monocytes classification. Using CD163 in addition to CD16, we were able to show that 31 classical monocytes display the most intense response to LPS. Additionally, CD163 appears to be a suitable addition to 32 CD14-CD16 classification to improve its performance. 33
Background:Cardiovascular (CV) Disease is the main cause of death in Rheumatoid Arthritis (RA). Current tools like Framingham or European SCORE underestimate CV risk in RA patients. Efforts to improve the assessment including RA biomarkers (disease activity) have been only partially successful. There is a need for better biomarkers to identify AR patients at high risk for CV disease. Monocytes have an important role in plaque development. Monocytes differentiates into 2 main phenotypes M1 and M2 (1). In RA and in post-MI patients M1 monocytes are expanded (2). mTORC influences monocyte phenotypein vitroand has been associated with development of atheromatous plaque (3).Objectives:To evaluate the phenotype of circulating monocyte in RA patient with or without previous CV events (RA-CV(-)RA-CV(+)), and its possible association with mTORC activity.Methods:9 RA-CV(+)patients aged between 18 and 65 yo with RA (EULAR/ACR 2010 criteria), were paired with RA-CV(-)patients. 6 healthy individuals (HI) were also studied. Pairing criteria were classic CV risk factors (AHA 2018), sex, age, years since RA diagnosis, comorbidities, number of DMARDs previously used and use of bDMARDS. M1 and M2 circulating Monocytes were evaluated in PBMC obtained from patients and controls by flow cytometry analysis. Intracellular inflammatory cytokines (IL1, Il6) and phosphorylated S6R (P-S6R) as a measure of mTORC activation was also evaluated. M1 was defined as CD14+HLA-DR+CCR2+ and M2 CD14+CD163+CCR2-. DAS28-RCP, DAS28-ESR and Lipid profile was also measured. The differences among groups was analysed using Mann–Whitney U nonparametric. The relationship between variables with Spearman rank correlation test.Results:There were no differences in demographic, RA characteristic and CV risk factors between RA-CV (+) and RA-CV (-) patients. Male/Female 4/5, age 62±3 and 63±2 respectively. HI were younger than RA patients (32.5±7). CV events were 8 patients with MI and one Stroke. DAS28-RCP was 2.96±0.23 and 2.88±0.43 respectively. One patient in each group had failed to more than 2 sDMARDs and one in each group was receiving bDMARD. M1 circulating monocytes were expanded in RA as compared to HI. This difference was at RA-CV (+) expense. RA monocytes had higher Intracellular levels of IL-1b and IL-6 as compared to HI. M1 from RA-CV (+) had higher intracellular levels of IL-1b and IL-6 than RA-CV (-). M1 monocytes have higher levels of inflammatory cytokines than M2. P-S6R protein, (mTORC activation), was higher in RA patients than HI. The highest levels of P-S6R was observed in M1 monocytes from RA-CV(+) population.FIGURE 1.Circulating monocytes phenotype, intracellular cytokines and phosphorylated S6R in HI and RA-CV (+), RA-CV (-) and the combined RA patients. A) *=0,02; B) *=0,016; C) ****=0,0001, **=0,002; D) ****=0,0001, ***=0,0008, **=0,001, *=0,01; E) ****0,0001, **=0,002; F) ****=0,0001, **=0,001, **=0,003.Conclusion:RA-CV+ patients, have a significantly higher number of pro-inflammatory circulating monocytes, using a multiparametric classification method. These monocytes also express higher levels of inflammatory cytokines and higher activation of mTORC, which also participate in the development of atheromatous plaque, suggesting that these monocytes could be a key element in the non-clarified-yet, excess of CV risk of RA patients.References:[1] Fukui S, et al. M1 and M2 Monocytes in Rheumatoid Arthritis: A Contribution of Imbalance of M1/M2 Monocytes to Osteoclastogenesis. Front Immunol. 2017;8:1958.2. Zhuang J, et al. Comparison of circulating dendritic cell and monocyte subsets at different stages of atherosclerosis: insights from optical coherence tomography. BMC Cardiovasc Disord. 2017 Oct 18;17(1):270.Disclosure of Interests:None declared
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-1β, 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.
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