The Impact of Health Inequities on Population-Based Breast Cancer Survival in a Colombian Population, 2008-2015.

OBJECTIVE: To obtain breast cancer survival estimates in Manizales, Colombia, considering socioeconomic level, health insurance regime and residential area, while adjusting for age, histology and stage at diagnosis. METHODS: Analytical cohort study based on breast cancer incident cases recorded by the Population-based Manizales Cancer Registry between 2008-2015. Patients were followed-up for 60 months. Cause-specific survival was calculated using the Kaplan-Meier method for variables of interest, with the Wilcoxon-Breslow-Gehan test for differences. Cox multivariate regression models were fitted. RESULTS: 856 breast cancer cases were included. The 5-year cause-specific survival for the entire cohort was 78.2%. It was higher in women with special/exception health insurance, high socioeconomic level, <50 years old, ductal carcinoma, and stages I and II. Residential area did not impact survival. In Cox models, the subsidized health insurance regime (HR: 4.87 vs contributory) and low socioeconomic level (HR: 2.45 vs high) were predictors of the hazard of death in women with breast cancer, adjusted for age, histology, stage and interactions age-stage and insurance-stage. A positive interaction (synergistic effect modification) between health insurance regime and stage regarding to survival was observed. CONCLUSION: Socioeconomic factors significantly contribute to the inequities in breast cancer survival, independent of the stage at diagnosis. This suggests the need for comprehensive interventions to remove barriers to accessing the health system. This research provides evidence of survival gaps mediated by certain social determinants of health and generates data on the overall performance of the Colombian health system.

NETosis Secondary to the Use of Levamisole-Adulterated Cocaine: A Likely Underlying Mechanism of Vasculopathy.

Background: Since 2010, several cases of a new vasculopathy induced by the use of levamisole-adulterated cocaine (LAC) have been reported. This vasculopathy is characterized by retiform purpura, earlobe necrosis, multisystem compromise, and multiple autoantibodies. Given its similarity to antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, LAC-associated vasculopathy is postulated to be mediated by pathophysiologic processes resulting from neutrophil cell death by NETosis, a phenomenon previously described in ANCA vasculitis. This study tries to establish the presence of NETosis induced by cocaine, levamisole, or both. Methodology. Neutrophils were isolated from the peripheral blood of healthy controls by Ficoll-Hystopaque density gradient centrifugation followed by dextran sedimentation. Cell viability and purity were evaluated by flow cytometry after staining with PI/DiOC6 and labeling with fluorescent anti-CD45/anti-CD3 monoclonal antibodies (mAbs), respectively. Neutrophils were exposed to levamisole, cocaine, a cocaine-levamisole mixture, and sera pools from healthy controls and patients with LAC-associated vasculopathy. NETosis was then assessed by flow cytometry after staining cells with Sytox Green, Hoechst-33342, and fluorescent antineutrophil elastase (NE) and antimyeloperoxidase (MPO) mAbs. In addition, NETosis was morphologically confirmed by fluorescence microscopy. Proinflammatory cytokine levels in culture supernatants and reactive oxygen species (ROS) synthesis were determined by flow cytometry. The involvement of calcium and muscarinic receptors in cell death induction was evaluated in parallel experiments carried out in the presence of 1,2-bis (o-aminophenoxy) ethane-N, N, N', N'-tetraacetic acid (BAPTA) and hyoscine butylbromide (HBB), their respective inhibitors. Results: Cocaine, levamisole, and a cocaine-levamisole mixture induced neutrophil cell death. DNA/MPO extrusion and cell morphology patterns were consistent with NETosis. Neither proinflammatory cytokines nor ROS behaved as proNETotic factors. Preliminary results suggested that muscarinic receptors and calcium-dependent signals were involved in LAC-induced NETosis. Conclusions: Cocaine, levamisole, and a cocaine-levamisole mixture can induce NETosis through mechanisms involving muscarinic receptors and calcium-dependent pathways.

B cell-targeted polylactic acid nanoparticles as platform for encapsulating jakinibs: potential therapeutic strategy for systemic lupus erythematosus.

Background: B cells are pivotal in systemic lupus erythematosus and autoimmune disease pathogenesis. Materials & methods: To address this, Nile Red-labeled polylactic acid nanoparticles (NR-PLA NPs) loaded with the JAK inhibitor baricitinib (BARI), specifically targeting JAK1 and JAK2 in B cells, were developed. Results: Physicochemical characterization confirmed NP stability over 30 days. NR-PLA NPs were selectively bound and internalized by CD19+ B cells, sparing other leukocytes. In contrast to NR-PLA NPs, BARI-NR-PLA NPs significantly dampened B-cell activation, proliferation and plasma cell differentiation in healthy controls. They also inhibited key cytokine production. These effects often surpassed those of equimolar-free BARI. Conclusion: This study underscores the potential of PLA NPs to regulate autoreactive B cells, offering a novel therapeutic avenue for autoimmune diseases.

In this study, a new approach to treating autoimmune diseases, particularly systemic lupus erythematosus, was investigated by focusing on a type of immune cell called B cells. Special nanoparticles (NPs) labeled with Nile Red (NR) and made from polylactic acid (PLA) were created. These NPs were loaded with a drug called baricitinib (BARI), which targets specific proteins (JAK1 and JAK2) in B cells. This was done to determine if these NPs could help control the behavior of B cells, which are important in autoimmune diseases. First, these NPs remained stable for a long time (30 days). The NR-labeled PLA NPs (NR-PLA NPs) were also good at attaching to and entering a specific type of B cell called CD19⁺ B cells while leaving other types of immune cells alone. The use of NR-PLA NPs loaded with BARI produced exciting results. These NPs were better at reducing the activity, growth and transformation of B cells into plasma cells compared with the drug BARI by itself. They also stopped the production of certain immune system signals called cytokines, which are usually overactive in autoimmune diseases. This work suggests that PLA NPs could be a promising way to control overactive B cells that contribute to autoimmune diseases like systemic lupus erythematosus. This could open a new and exciting path for developing treatments for these conditions.

Estilo cognitivo en la dimension de dependencia-independencia de campo de estudiantes universitarios del área de Manizales / Cognitive Style in the Field Dependence-independence Dimension of University Student from the Manizales Area

Resumen El presente artículo reporta un estudio que busca identificar el estilo cognitivo en la dimensión de independencia-dependencia de campo en una población estudiantil universitaria y establecer sus asociaciones con el género y la carrera que cursan. La muestra total fue de 1.379 estudiantes (797 mujeres y 582 hombres), de tres universidades del área metropolitana de Manizales, Colombia, de 18 carreras profesionales, quienes respondieron la prueba SG-EFT que permite identificar el nivel de independencia de campo. Se llevaron a cabo pruebas t de Student y análisis de varianza para examinar diferencias por género y carrera. Los resultados indican diferencias significativas en los puntajes de la prueba por carrera universitaria en independencia del género, y a su vez, se discuten en relación con resultados previos y sus implicaciones para la construcción del perfil del estudiante en cada carrera.

Abstract This paper reports a study that seeks to identify the cognitive styles, in the field independence-dependence dimension, in a university student population and to establish its associations with gender and career. The total sample consisted of 1.379 students (797 females and 582 males) from three universities in the metropolitan area of Manizales (Colombia), from 18 professional careers, who answered the SG-EFT test which measures levels of field independence. Analyses of variance and t- Student tests were carried out to examine differences by gender and career. Significant differences in the SG-EFT scores were found regarding career choice, independently of gender. Results are discussed with respect to previous findings and their implications for the construction of the student profile in each career.

Lupus enteritis: A 10-year experience in a single Latin American center.

OBJECTIVE: The objective is to compare the clinical and laboratory characteristics of systemic lupus erythematosus (SLE) patients with and without lupus enteritis (LE) and to identify the factors associated with the occurrence of LE. METHODS: We performed a retrospective, case-control study in hospitalized patients with SLE who were admitted to our tertiary hospital between January 2012 and December 2021. Sixteen LE patients (cases) were matched (1:3 ratio) for sex and birth year with 48 non-LE patients (controls). Univariable and multivariable logistic regression analyses were used to identify the variables associated with LE. RESULTS: Of 2,479 SLE patients who were admitted to our hospital as inpatients, 16 (0.65%) were diagnosed as having LE. All patients, cases and controls, were of Mestizo ethnicity. SLE was diagnosed simultaneously with the first episode of LE in 10 (62.5%) patients. The median time from SLE diagnosis to the first episode of LE was 7 (IQR 0-78) months. LE patients had a shorter median disease duration [7 (0-78) vs 34 (9.5-79) months], and a significantly longer hospital stay (28.3 ± 15.8 vs 6.5 ± 7.9 days, p < 0.001) than non-LE patients. Most LE patients (93.8%) had concomitant lupus nephritis. LE patients had higher SLEDAI-2K scores than those without LE (20.5 ± 9.4 vs 9.8 ± 10.4, p < 0.001). By multivariable analysis, a higher SLEDAI-2K score (OR 1.10, 95% CI 1.02-1.18; p = 0.015) was independently associated with LE occurrence after adjusting for cutaneous involvement, lymphocyte count, serum creatinine, and serum complement C4. Recurrence was observed in two patients (12.5%), both with a bowel wall thickening > 8 mm. The two patients with large intestine-dominant LE developed intestinal pseudo-obstruction. No patient had life-threatening complications (intestinal hemorrhage, infarction, or perforation), and there were no deaths induced directly by LE itself. CONCLUSION: In patients of Mestizo ethnicity, LE occurs during the early course of SLE, frequently is one of the presenting manifestations of SLE, and in most cases, it presents with concomitant lupus nephritis. Higher levels of disease activity at diagnosis were independently associated with LE occurrence and when recurrences occur, they do so in the context of severe wall thickness.

Relevance of non-criteria antiphospholipid antibodies titers among patients with antiphospholipid syndrome and patients with systemic lupus erythematosus.

BACKGROUND: There is an increasing interest in the study of non-criteria antiphospholipid antibodies (aPL) including antibodies targeting domain 1 of the B2 glycoprotein 1 (anti-D1 B2GP1) and antibodies anti phosphatidylserine/ prothrombin (PS/PT). OBJECTIVES: Our aim was to analyze a panel of conventional and non-criteria aPL in a cohort of patients with systemic lupus erythematosus (SLE) and primary antiphospholipid syndrome (APS), to describe if there are differences in aPL titers among groups, to evaluate clinical associations including risk of recurrent events of novel aPL. METHODS: Observational study that evaluated at baseline antibodies against anti-D1 B2GP1 and anti PS/PT. Anti-D1 B2GP1 antibodies were tested using a chemiluminescent immunoassay. IgG and IgM anti PS/PT, aCL and anti B2GP1 by ELISA techniques. Therefore, patients were followed in order to identify new thrombotic events. RESULTS: 133 patients with SLE and 23 with primary APS patients were included. Main APS manifestations were DVT (27%), obstetric morbidity (22%) and arterial thrombosis (10.1%). IgM anti PS/PT antibodies levels were (20.6 - 127) vs 21.9 (11.2 - 39.2) U/ml, p<0.001 in primary APS vs SLE with APS, respectively. Anti-D1 B2GP1, IgG and IgM anti PS/PT were associated with thrombotic and non-thrombotic manifestations. During follow-up, IgG B2GP1 were related with a significant cumulative risk of thrombosis. CONCLUSIONS: We found significant differences in serum titers of non-criteria aPL among patients with primary APS vs SLE with APS. Whether non-criteria aPL antibodies titers are useful to differentiate patients with primary and secondary APS requires further analysis in other populations.

Predictive Factors of Hospital-Acquired Bacterial Infections in Patients With Systemic Lupus Erythematosus.

OBJECTIVE: We aimed to identify the predictive factors of hospital-acquired bacterial infections in patients with systemic lupus erythematosus (SLE). METHODS: This chart review study included patients with SLE who were hospitalized between 2009 and 2020 for reasons other than infection. The outcome was defined as any infection confirmed using any bacterial isolation method or diagnosed by treating physicians and required treatment with intravenous antibiotics. For statistical analysis, logistic regression analyses were performed. RESULTS: In total, 1678 patients (87.6% women) were included. The median age was 33 years (interquartile range, 24-47 years). The incidence of hospital-acquired infections was 13.9% (233 infections). Age, Systemic Lupus Erythematosus Disease Activity Index score, Systemic Lupus International Collaborating Clinics damage score, blood urea nitrogen and C-reactive protein levels, dosage of steroid in the previous month, recent use of 1 or more immunosuppressants, admission with a central venous catheter (or dialysis catheter), and use of central venous catheter or bladder catheter in the first 5 days were the predictive factors of nosocomial infections. CONCLUSION: The patients' infection risk profile should be assessed to accurately determine the risk-benefit balance of any therapeutic intervention, minimize exposure to steroids and immunosuppressants, and maintain a low threshold for the early diagnosis of infections. Further studies should assess whether the modification of some identified factors could reduce the incidence of nosocomial infections.

Importancia de los títulos de anticuerpos antifosfolípidos no criterio entre pacientes con síndrome antifosfolípido primario y pacientes con lupus eritematoso sistémico / Relevance of non-criteria antiphospholipid antibodies titers among patients with antiphospholipid syndrome and patients with systemic lupus erythematosus

Antecedentes: Hay un interés creciente en el estudio de los anticuerpos antifosfolípidos (aPL) no criterio, incluyendo anticuerpos contra el dominio 1 de la B2 glicoproteína 1 (anti-D1 B2GP1) y anticuerpos antifosfatidilserina/protrombina (PS/PT). Objetivos: Nuestro objetivo fue analizar un panel de aPL convencionales y no criterio en una cohorte de pacientes con lupus eritematoso sistémico (LES) y síndrome antifosfolípido primario (SAF), para describir si hay diferencias en los títulos de aPL entre los grupos, y evaluar asociaciones clínicas incluyendo el riesgo de eventos recurrentes con aPL novedosos. Metodología: Estudio observacional que evaluó los anticuerpos anti-D1 B2GP1 y anti-PS/PT de manera basal. Los anticuerpos anti-D1 B2GP1 se evaluaron a través de inmunoanálisis por quimioluminiscencia. Los anticuerpos anti-PS/PT, anticardiolipinas (aCL) y anti-B2GP1 fueron evaluados por técnicas de ELISA. Finalmente, los pacientes fueron seguidos en el tiempo para identificar nuevos eventos trombóticos. Resultados: Se incluyeron 133 pacientes con LES y 23 pacientes con SAF primario. Las principales manifestaciones de SAF fueron TVP (27%), morbilidad obstétrica (22%) y trombosis arterial (10,1%). Los títulos de anticuerpos anti-PS/PT IgM fueron 46,5 (20,6-127) vs. 21,9 (11,2-39,2) U/ml, p<0,001, en pacientes con SAF primario vs. LES con SAF secundario, respectivamente. Los anti-D1 B2GP1, anti-PS/PT IgG e IgM se asociaron con manifestaciones trombóticas y no trombóticas. Durante el seguimiento, los anticuerpos IgG B2GP1 se relacionaron con un riesgo acumulativo significativo de trombosis. Conclusiones: Se encontraron diferencias estadísticamente significativas en títulos séricos de aPL no criterio en pacientes con SAF primario vs. pacientes con LES y SAF secundario. Si los títulos de aPL no criterio son útiles para diferenciar entre SAF primario y SAF secundario, se requieren más análisis en otras poblaciones para poder confirmar si los títulos de aPL no criterio.

Background: There is an increasing interest in the study of non-criteria antiphospholipid antibodies (aPL) including antibodies targeting domain 1 of the B2 glycoprotein 1 (anti-D1 B2GP1) and antibodies anti phosphatidylserine/ prothrombin (PS/PT). Objectives: Our aim was to analyze a panel of conventional and non-criteria aPL in a cohort of patients with systemic lupus erythematosus (SLE) and primary antiphospholipid syndrome (APS), to describe if there are differences in aPL titers among groups, to evaluate clinical associations including risk of recurrent events of novel aPL. Methods: Observational study that evaluated at baseline antibodies against anti-D1 B2GP1 and anti PS/PT. Anti-D1 B2GP1 antibodies were tested using a chemiluminescent immunoassay. IgG and IgM anti PS/PT, aCL and anti B2GP1 by ELISA techniques. Therefore, patients were followed in order to identify new thrombotic events. Results: 133 patients with SLE and 23 with primary APS patients were included. Main APS manifestations were DVT (27%), obstetric morbidity (22%) and arterial thrombosis (10.1%). IgM anti PS/PT antibodies levels were (20.6 - 127) vs 21.9 (11.2 - 39.2) U/ml, p<0.001 in primary APS vs SLE with APS, respectively. Anti-D1 B2GP1, IgG and IgM anti PS/PT were associated with thrombotic and non-thrombotic manifestations. During follow-up, IgG B2GP1 were related with a significant cumulative risk of thrombosis. Conclusions: We found significant differences in serum titers of non-criteria aPL among patients with primary APS vs SLE with APS. Whether non-criteria aPL antibodies titers are useful to differentiate patients with primary and secondary APS requires further analysis in other populations.(AU)

Predictors of severe hemolytic anemia and its impact on major outcomes in systemic lupus erythematosus: Data from a multiethnic Latin American cohort.

OBJECTIVE: To determine the predictors of the occurrence of severe autoimmune hemolytic anemia (AIHA) and its impact on damage accrual and mortality in SLE patients. METHODS: Factors associated with time to severe AIHA (hemoglobin level ≤7 g/dL) occurring from the onset of SLE symptoms were examined by Cox proportional hazards regressions. The association of severe AIHA with mortality was examined by logistic regression analyses while its impact on damage was by negative binomial regression. RESULTS: Of 1,349 patients, 49 (3.6%) developed severe AIHA over a mean (SD) follow-up time of 5.4 (3.8) years. The median time from the first clinical manifestation to severe AIHA was 111 days (IQR 43-450). By multivariable analysis, male sex (HR 2.26, 95% CI 1.02-4.75, p = 0.044), and higher disease activity at diagnosis (HR 1.04, 95% CI 1.01-1.08, p = 0.025) were associated with a shorter time to severe AIHA occurrence. Of the SLEDAI descriptors, only hematologic (leukopenia and/or thrombocytopenia) showed a certain trend toward significance in the multivariable analysis (HR 2.36, 95% CI 0.91-6.13, p = 0.0772). Severe AIHA contributed neither to damage nor to mortality. CONCLUSIONS: Severe AIHA occurs during the early course of SLE. Male sex and higher disease activity at diagnosis emerged as independent predictors of a shorter time to severe AIHA occurrence. Although not statistically significant, hematological abnormalities at SLE diagnosis could predict the occurrence of severe AIHA in a shorter time. Damage and mortality did not seem to be impacted by the occurrence of severe AIHA.

Altered B cell phenotype and CD27+ memory B cells are associated with clinical features and environmental exposure in Colombian systemic lupus erythematosus patients.

Background: B lymphocytes are dysregulated in Systemic Lupus Erythematosus (SLE) including the expansion of extrafollicular B cells in patients with SLE of African American ancestry, which is associated with disease activity and nephritis. The population of Colombia has a mixture of European, Native American, and African ancestry. It is not known if Colombian patients have the same B cell distributions described previously and if they are associated with disease activity, clinical manifestations, and environmental exposures. Objective: To characterize B cell phenotype in a group of Colombian Systemic Lupus Erythematosus patients with mixed ancestry and determine possible associations with disease activity, clinical manifestations, the DNA methylation status of the IFI44L gene and environmental exposures. Materials and methods: Forty SLE patients and 17 healthy controls were recruited. Cryopreserved peripheral B lymphocytes were analyzed by multiparameter flow cytometry, and the DNA methylation status of the gene IFI44L was evaluated in resting Naive B cells (rNAV). Results: Extrafollicular active Naive (aNAV) and Double Negative type 2, DN2 (CD27- IgD- CD21- CD11c+) B cells were expanded in severe active patients and were associated with nephritis. Patients had hypomethylation of the IFI44L gene in rNAV cells. Regarding environmental exposure, patients occupationally exposed to organic solvents had increased memory CD27+ cells (SWM). Conclusion: aNAV and DN2 extrafollicular cells showed significant clinical associations in Colombian SLE patients, suggesting a relevant role in the disease's pathophysiology. Hypomethylation of the IFI44L gene in resting Naive B cells suggests that epigenetic changes are established at exceedingly early stages of B cell ontogeny. Also, an alteration in SWM memory cells was observed for the first time in patients exposed to organic solvents. This opens different clinical and basic research possibilities to corroborate these findings and deepen the knowledge of the relationship between environmental exposure and SLE.

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome (VEXAS syndrome) with prominent supraglottic larynx involvement: a case-based review.

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome (VEXAS syndrome) is a recently described genetic disorder that gathers autoinflammatory symptoms and myeloid dysplasia. The first description was reported in 2020, and subsequently, a growing number of cases have been described worldwide. Herein, we describe a case of a 72-year-old male patient with VEXAS syndrome with p.Met41Val mutation of the UBA1 gene, prominent supraglottic larynx involvement, and costochondritis. To our knowledge, this is the first report of VEXAS syndrome in Colombia and South America. This disease could present features of relapsing polychondritis, polyarteritis nodosa, giant cell arteritis, and Sweet syndrome, associated with hematologic involvement, including cytopenias, myelodysplastic syndrome, or thromboembolic disease. Supraglottic larynx chondritis and costochondritis are atypical manifestations. These features were proposed previously to differentiate relapsing polychondritis from VEXAS syndrome but are not entirely reliable like in the case described. A diagnosis of VEXAS should be considered in male patients with incomplete or complete features of the previously described conditions, refractory to treatment, requiring high-dose glucocorticoids, and associated progressive hematologic abnormalities. Key Points • VEXAS syndrome is a recently described genetic (somatic mutations in UBA1 gene) disorder that gathers autoinflammatory and hematologic manifestations. • VEXAS syndrome should be considered in male patients with incomplete or complete features of relapsing polychondritis, polyarteritis nodosa, giant cell arteritis, and Sweet syndrome, refractory to treatment, associated with hematologic involvement, including cytopenias, myelodysplastic syndrome, or thromboembolic disease. • Glucocorticoids ameliorate symptoms effectively. However, other treatment options are limited due to a lack of evidence. Traditional immunosuppressants and biological therapy have been used empirically with limited efficacy and a transient effect. Bone marrow transplant offers a curative approach, but it has high morbidity and mortality.

Modulation of B cell activation by extracellular vesicles and potential alteration of this pathway in patients with rheumatoid arthritis.

BACKGROUND: Extracellular vesicles are involved in the intercellular communication of the immune system. In rheumatoid arthritis (RA), these structures are considered a source of autoantigens that drive proinflammatory responses of innate immune cells. A high concentration of circulating medium/large size extracellular vesicles (m/lEVs) and m/lEVs forming immune complexes (m/lEV-ICs) have been associated with disease activity and systemic inflammation in patients with RA. B cells are central components of RA immunopathology because of their involvement in the production of autoantibodies, antigen presentation, and cytokine production. However, the effect of m/lEVs on B cell function in the context of RA and other autoimmune diseases remains unknown. METHODS: We evaluated the effect of m/lEVs obtained from healthy donors (HD) and patients with RA on B cell responses in vitro. In addition, we evaluated the effect of pre-exposition of monocyte-derived macrophages (MDM) to m/lEVs on activation of autologous B cells from HD and patients. RESULTS: The presence of m/lEVs reduced the frequency of CD69+ and CD86+ B cells from HD activated by an agonist of antigen receptor. This regulation of the B cell activation markers by m/lEVs was partially dependent on phosphatidylserine binging. These m/lEVs also reduced the proliferation, calcium mobilization, and global phosphorylation of tyrosine. Similar responses were observed in B cells from patients with RA. However, the presence of m/lEVs promoted high antibody levels in B cells cultured with T cell-dependent stimuli by 7 days. In addition, despite the direct inhibitory effect of m/lEVs on early B cell responses, when B cells were cocultured with autologous MDM previously exposed to m/lEVs or m/lEV-ICs, an increased frequency of CD69+ B cells from patients with RA was observed, albeit not with cells from HD. CONCLUSIONS: These data together suggest that m/lEVs have a direct modulatory effect in early responses of B cells through B cell receptor that can potentially fail in patients with RA because of the impact of these vesicles over cells of the innate immune system. This phenomenon can potentially contribute to the loss of tolerance and disease activity in patients with RA.

T cell metabolism and possible therapeutic targets in systemic lupus erythematosus: a narrative review.

In the immunopathogenesis of systemic lupus erythematosus (SLE), there is a dysregulation of specific immune cells, including T cells. The metabolic reprogramming in T cells causes different effects. Metabolic programs are critical checkpoints in immune responses and are involved in the etiology of autoimmune disease. For instance, resting lymphocytes generate energy through oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO), whereas activated lymphocytes rapidly shift to the glycolytic pathway. Specifically, mitochondrial dysfunction, oxidative stress, abnormal metabolism (including glucose, lipid, and amino acid metabolism), and mTOR signaling are hallmarks of T lymphocyte metabolic dysfunction in SLE. Herein it is summarized how metabolic defects contribute to T cell responses in SLE, and some epigenetic alterations involved in the disease. Finally, it is shown how metabolic defects could be modified therapeutically.

Antibodies: Friends, Foes, or Both? Lessons From COVID-19 for the Rheumatologist.

ABSTRACT: Antibodies are a fundamental tool to fight infections but are intrinsically built as a double-edged sword. One side recognizes the microbial antigen, and the other gives a call to arms to fight infection by recruiting immune cells and triggering inflammation. A balanced immune response must combine a potent neutralizing antibody and a swift disposal of the invading agent by innate immune cells with the least tissue damage possible. The longer the immune system takes to control the infection, the higher the possibility for a self-sustaining inflammatory process with potentially fatal consequences for the host. In addition to quantity, the quality of antibodies also matters, because posttranslational modifications altering the N-glycan composition in Fc fractions may help tilt the balance to the effector side, by modifying their affinity for Fc receptors in immune cells. The COVID-19 pandemic has provided a wealth of data bolstering our understanding of the rules governing the production of protective and nonprotective antibodies. Also, it has broadened our understanding of the role of viruses in triggering autoimmunity and inflammation, and widened our knowledge of the different mechanisms that can be activated by viral infection and lead to autoantibody production, inflammation, and progressive tissue damage. In addition, the COVID-19 infection has contributed a great deal to our comprehension of the role of antibodies in the causation of cytokine storms and systemic inflammatory response syndrome, also seen in patients with systemic autoimmune diseases.

Construction of a questionnaire to characterise environmental exposures in patients with systemic lupus erythematosus / Construcción de un cuestionario para caracterizar exposiciones ambientales en pacientes con lupus eritematoso sistémico

ABSTRACT Introduction: As the knowledge of systemic lupus erythematosus (SLE) advances, the need to characterise the burden of environmental exposure in patients becomes increasingly relevant. However, there is currently no tool validated to measure such exposure. For this reason, the objective of this work was the construction of a questionnaire-type tool, in order to detail the exposure to multiple environmental factors previously associated with SLE. Methods: The literature was reviewed to identify relevant environmental factors associated with SLE, and the first version of the questionnaire was constructed. After expert review and feedback, the questionnaire was consolidated and applied to 40 patients and 20 healthy controls. Finally, exploratory Rasch analysis was performed to determine the performance of the tool's response function. Results: The tool showed a favourable performance in the exploratory analysis of its psychometric properties. Additionally, it allowed the characterisation of 10 environmental factors and the differences in the frequencies of exposure between patients with SLE and healthy controls. A high co-occurrence of exposures was identified, as most of the patients had positive exposures to three or more factors simultaneously. Conclusion: A practical and easy-to-apply tool has been constructed, with a favourable performance in its psychometric properties. To our knowledge, this is the first tool in the Spanish language for the characterisation of multiple environmental exposures, and constructed explicitly for patients with SLE with a validation analysis. It enabled us to identify that most of the lupus patients were exposed to the sum of three or more environmental factors.

RESUMEN Introducción: Con el avance en el conocimiento del lupus eritematoso sistémico (LES), se hace relevante la necesidad de caracterizar la carga de la exposición ambiental en los pacientes. Sin embargo, en la actualidad no se dispone de un instrumento validado para medirlo. Por consiguiente, el objetivo de este trabajo fue la construcción de un instrumento tipo cuestionario, a fin de detallar la exposición a múltiples factores ambientales previamente asociados a LES. Métodos: Se llevó a cabo una revisión de la literatura para identificar los factores ambientales asociados a LES y se construyó la primera versión del cuestionario. El instrumento se consolidó luego de la revisión y retroalimentación por expertos y se aplicó a 40 pacientes y 20 participantes sanos. Finalmente, se hizo análisis de Rasch exploratorio para determinar el desempeño en la función de respuesta. Resultados: El instrumento mostró un desempeño favorable en sus propiedades psicométricas. Adicionalmente, permitió la caracterización de 10 factores ambientales y sus diferencias en las frecuencias de exposición entre pacientes con LES y participantes sanos. Se identificó una alta co-ocurrencia de exposiciones reflejada en que la mayoría de los pacientes mostró exposición a tres o más factores simultáneamente. Conclusión: Se construyó un instrumento práctico y de fácil aplicación, con un desempeño favorable en sus propiedades psicométricas. Este instrumento, que es el primero para la caracterización de múltiples exposiciones ambientales específicamente diseñado para pacientes con LES, validado y en idioma español, permitió identificar que la mayoría de los pacientes con lupus estuvieron expuestos a la sumatoria de tres o más factores ambientales.

Desenlaces obstétricos en pacientes con arteritis de Takayasu: serie de casos / Pregnancy outcomes in patients with Takayasu's arteritis: Case series

RESUMEN Objetivo: La actividad y el riesgo de recaída de la arteritis de Takayasu son bajos durante la gestación. Hasta el 40% de las pacientes puede tener desenlaces obstétricos desfavorables, por lo que es importante conocer su comportamiento clínico. Describimos las características clínicas y el desenlace obstétrico de gestantes con arteritis de Takayasu atendidas en un hospital de alta complejidad. Materiales y métodos: Evaluación retrospectiva de historias clínicas de gestantes con arteritis de Takayasu atendidas en el Hospital Universitario San Vicente Fundación de Medellín, Colombia, entre 2011 y 2018. Resultados: Se incluyó en el estudio a 6 pacientes con mediana de edad al diagnóstico de 17,5 arios (RI 9,25), al parto de 24 arios (RI 8,25) y con una duración de la enfermedad de 5,5 arios (RI 10,5). Del total, 3 pacientes tenían compromiso aórtico extenso; al parto, 3 pacientes esta ban activas y requirieron inmunosupresores, 5 tenían hipertensión arterial, una desarrolló preeclampsia en el segundo trimestre, una tenía insuficiencia mitral y tricuspídea grave con disminución de la fracción de eyección del ventrículo izquierdo; 2 tenían aneurismas (arte ria subclavia izquierda y aorta ascendente). Ningún embarazo resultó en aborto ni parto pretérmino; hubo 2 óbitos fetales, uno por restricción del crecimiento intrauterino e insuficiencia placentaria, y otro de etiología desconocida; ambas pacientes con actividad de la enfermedad, afección aórtica extensa e hipertensión arterial. Fueron por cesárea 5 par tos por indicación materna; no hubo disección aórtica, rotura aneurismática ni hemorragia cerebral. Conclusión: Las pacientes con enfermedad activa y afección aórtica extensa presentaron resultados obstétricos desfavorables, lo que indica que el inadecuado control de la vasculitis genera mayores complicaciones materno-fetales.

ABSTRACT Objective: The activity and risk of relapse of Takayasu's arteritis are low during pregnancy. Up to 40% of patients may have unfavorable obstetric outcomes therefore it is important to know their clinical behavior. We describe the clinical characteristics and obstetric outcome of pregnant women with Takayasu arteritis treated in a hospital of high complexity. Materials and methods: A retrospective evaluation of medical records of pregnant patients with Takayasu's arteritis treated at Hospital Universitario San Vicente Fundación in Medellin, Colombia between 2011 and 2018. Results: Six patients with a median age at diagnosis 17.5 (RI 9.25) years, at delivery 24 (RI 8.25) years, disease duration 5.5 (RI 10.5) years. Three patients had extensive aortic involvement; at delivery, 3 patients were active and required immunosuppressants, 5 had high blood pres sure, one developed preeclampsia in the second trimester, one had severe mitral and tricus pid insufficiency with a decreased ejection fraction of the left ventricle; 2 had aneurysms (left subclavian artery and ascending aorta). No pregnancy resulted in abortion or preterm birth; there were 2 fetal deaths, one due to intrauterine growth restriction and placental insuffi ciency and another of unknown etiology; both patients with disease activity, extensive aortic condition, and arterial hypertension. Five deliveries were by cesarean section by maternal indication; there was no aortic dissection, aneurysmal rupture or cerebral hemorrhage. Conclusion: Patients with active disease and extensive aortic compromise presented unfa vorable obstetric results, suggesting that inadequate control of vasculitis leads to greater maternal-fetal complications.

Desarrollo y validación interna de un modelo de predicción clínica del riesgo de infección bacteriana nosocomial en pacientes con lupus eritematoso sistémico / Development and internal validation of a clinical prediction model of the risk of nosocomial bacterial infection in patients with systemic lupus erythematosus

RESUMEN Introducción: Los pacientes con lupus eritematoso sistémico (LES) tienen un riesgo aumen tado de padecer infecciones tanto adquiridas en la comunidad como asociadas con el cuidado de la salud. Las infecciones bacterianas son las más frecuentes y graves durante la hospitalización de estos pacientes. Objetivo: Desarrollar y validar internamente un modelo de predicción clínica de pronóstico del riesgo de infección bacteriana adquirida en el hospital en pacientes con LES, usando datos clínicos y de laboratorio obtenidos durante las primeras horas de hospitalización. Métodos: Se analizó una cohorte retrospectiva de pacientes con LES mayores de 16 arios, hos pitalizados por motivos diferentes a infección bacteriana en 2 hospitales de alta complejidad de Medellín entre 2011 y 2016. Se compararon las características de los pacientes que des arrollaron el desenlace de infección bacteriana entre el día 3 y el día 15 de hospitalización con aquellos que no lo presentaron. Las variables significativas en el análisis bivariado fueron consideradas para la construcción del modelo por medio de regresión logística multivariada. Resultados: Se incluyeron 765 episodios, de los cuales 98 (12,8%) presentaron el desenlace de interés. Se consideraron 35 predictores candidatos. Las variables incorporadas en el modelo final fueron: edad, recuento de neutrófilos, puntaje de actividad lúpica SLEDAI, uso de sonda vesical, uso de catéter venoso central en las primeras 72 h, dosis de glucocorticoides en el mes previo y el uso de un antimalárico en los 3 meses previos. La capacidad de discrimi nación del modelo fue aceptable a buena (AUC-ROC 0,74; IC 95% 0,69-0,80). La prueba de bondad de ajuste de Hosmer-Lemeshow (p = 0,637) evidenció una adecuada calibración. Conclusión: Desarrollamos un modelo de predicción clínica de pronóstico del riesgo de infec ción bacteriana nosocomial en pacientes con LES. El modelo desarrollado está compuesto por variables clínicas y de laboratorio simples disponibles en el momento del ingreso al hospital. Se requieren estudios de validación externa y de impacto clínico antes de su implementación rutinaria.

ABSTRACT Introduction: Patients with systemic lupus erythematosus (SLE) have an increased risk of developing community-acquired infections, as well as those associated with health care. Bacterial infections are the most common and serious while these patients are in hospital. Objective: To develop, and internally validate, a clinical prediction model for the prognosis of the risk of hospital-acquired bacterial infection in SLE patients using clinical and laboratory data obtained during the first hours of hospital admission. Methods: An analysis was performed on retrospective cohort of patients with SLE older than 16 years and admitted for reasons other than bacterial infection in 2 highly complex hospitals in Medellín between 2011 and 2016. The characteristics of the patients who developed a bacterial infection were compared between day 3 and day 15 of hospital admission with those who did not develop one. The significant variables in the bivariate analysis were used for the construction of the model using multivariate logistic regression. Results: A total of 765 episodes were included, of which 98 (12.8%) presented the outcome of interest. Thirty-five candidate predictors were considered. The variables incorporated in the final model were: age, neutrophil count, SLEDAI lupus activity score, use of a bladder catheter, use of a central venous catheter in the first 72 h, glucocorticoid doses in the previous month, and use of an antimalarial drug in the 3 previous months. The discrimination capacity of the model was acceptable to good (AUC-ROC 0.74; 95% CI 0.69-0.80). The Hosmer-Lemeshow goodness of fit test (P = .637) suggested adequate calibration. Conclusion: A clinical prediction model of prognostic risk of nosocomial bacterial infection in patients with SLE has been developed. This model is made up of simple clinical and laboratory variables available at the time of hospital admission. External validation and clinical impact studies are required before routine implementation.

Are chimeric antigen receptor T cells (CAR-T cells) the future in immunotherapy for autoimmune diseases?

OBJECTIVE: CAR-T cell therapy has revolutionized the treatment of oncological diseases, and potential uses in autoimmune diseases have recently been described. The review aims to integrate the available data on treatment with CAR-T cells, emphasizing autoimmune diseases, to determine therapeutic advances and their possible future clinical applicability in autoimmunity. MATERIALS AND METHODS: A search was performed in PubMed with the keywords "Chimeric Antigen Receptor" and "CART cell". The documents of interest were selected, and a critical review of the information was carried out. RESULTS: In the treatment of autoimmune diseases, in preclinical models, three different cellular strategies have been used, which include Chimeric antigen receptor T cells, Chimeric autoantibody receptor T cells, and Chimeric antigen receptor in regulatory T lymphocytes. All three types of therapy have been effective. The potential adverse effects within them, cytokine release syndrome, cellular toxicity and neurotoxicity must always be kept in mind. CONCLUSIONS: Although information in humans is not yet available, preclinical models of CAR-T cells in the treatment of autoimmune diseases show promising results, so that in the future, they may become a useful and effective therapy in the treatment of these pathologies.

Plasma microparticles from patients with systemic lupus erythematosus modulate the content of miRNAs in U937 cells.

In systemic lupus erythematosus (SLE), the clearance of apoptotic cells and microparticles (MPs) is reduced. Some MPs contain molecules that can modulate immune responses. This study aimed to evaluate the presence of miR-126 and miR-146a in plasma MPs of patients with SLE (SLE MPs) and analyse the ability of MPs to modulate some events in the promonocytic U937 cell line. Circulating MPs were isolated from plasma samples of healthy controls (HCs), patients with SLE and other autoimmune diseases (OAD). MPs were analysed for size and cell origin by flow cytometry and content of miR-126 and miR-146a by RT-qPCR. MPs were then added to U937 cell cultures to evaluate changes in cell phenotype, cytokine expression, content of miR-126 and miR-146a, and levels of IRF5. Patients with active SLE (aSLE) showed an increase in concentration of plasma MPs that positively correlated with the SLEDAI (SLE Disease Activity Index) score. CD14+ MPs were significantly more abundant in patients with SLE than HCs. SLE MPs contained decreased levels of miR-146a, but the miR-126 content in aSLE MPs was increased. The miR-126 content in SLE MPs correlated positively with the SLEDAI score. The treatment of U937 cells with MPs from HCs and patients induced reduced expression of HLA-DR, CD18 and CD119, increased frequency of IL-6+ and TNF-α+ cells, accumulation of IL-8 in culture supernatants, increased miR-126 levels and decreased miR-146a content, but no change in the expression of IRF5. These findings suggest that plasma MPs, especially SLE MPs, could modulate some biological events in U937 cells.