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.

Cardiac involvement in anti-MDA5 dermatomyositis: a case-based review.

Among myositis-specific antibodies, anti-melanoma differentiation-associated gene 5 (anti-MDA5) is one of the antibodies with a unique spectrum that is expressed principally in clinically amyopathic dermatomyositis (CADM) and, to a lesser extent, in dermatomyositis (DM). In addition to muscle and classical skin involvement, patients with anti-MDA5 DM/CADM are characterized by the expression of rapidly progressive interstitial lung diseases, vasculopathic lesions, and non-erosive arthritis. Although cardiac involvement has been described in other inflammatory myopathies, such as myocarditis, pericarditis, and conduction disorders, in anti-MDA5 DM/CADM patients, heart disease is infrequent. We report a case of a young male presenting with constitutional symptoms, polyarthritis, skin ulcers, and mild muscle weakness who developed an episode of high ventricular rate atrial fibrillation during his hospitalization. The anti-MDA5 DM diagnosis was supported by increased muscular enzymes, positive anti-MDA5 and anti-Ro52 antibodies, and the presence of organizing pneumonia. He was treated with high-dose glucocorticoids, rituximab, and beta-blocker drugs and received pharmacological cardioversion, which improved his myopathy symptoms and stabilized his heart rhythm. Here, we describe eight similar cases of anti-MDA5 DM/CADM with cardiac involvement. The case presented and the literature reviewed reveal that although rare, physicians must be aware of cardiac disease in patients with suggestive symptoms to guarantee early assessment and treatment, thereby reducing life-treating consequences.

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.

Perfil demográfico y clínico de la poliarteritis nodosa sistémica y cutánea en un grupo de pacientes pediátricos de Medellín, 2010-2019 / Demographic and clinical profile of systemic and cutaneous Polyarteritis nodosa in a group of pediatric patients in Medellin, 2010-2019

Resumen Objetivo: describir las principales características demográficas y clínicas de los pacientes pediátricos con poliarteritis nodosa (PAN). Metodología: estudio descriptivo retrospectivo. Resultados: se obtuvieron las historias clínicas de menores de 18 años con diagnóstico de vasculitis o PAN atendidos entre el 2010 y 2019 en dos hospitales de Medellín. Se incluyeron 19 pacientes, 11 clasificados como PAN cutánea (PANC) según la definición de la Liga Europea contra el Reumatismo y la Sociedad Europea de Reumatología Pediátrica, y 8 como PAN sistémica (PANS) acorde con los criterios de Ankara 2008. El 57,9 % fueron varones (n = 11). La mediana de la edad en el diagnóstico fue 10 años (3-17 años) y del tiempo de seguimiento: 15 meses (0-105 meses). Las manifestaciones más frecuentes fueron nódulos subcutáneos (84,2 %), fiebre (57,9 %), artralgias (57,9 %) y dolor en las pantorrillas (52,6 %). Los pacientes con PANS presentaron más pérdida de peso y hemoglobina baja. 5 niños cursaron con úlceras (26,3 %) cuatro con PANC; 2 exhibieron necrosis lingual (10,5 %) y 2 necrosis digital (10,5 %), todos con PANC. El promedio de la PCR fue de 10,2 mg/dl (0,33-45,3) y, de la eritrosedimentación: 74 mm/hora (15-127 mm/hora). En las imágenes hubo un realce meníngeo, aneurismas intrahepáticas y mesentéricos, entre otros hallazgos. Todos recibieron esteroides sistémicos. Ninguno falleció. Conclusión: en esta serie, la PAN pediátrica fue más común en niños de edad escolar. La PANC fue más frecuente que la PANS. Las manifestaciones más descritas fueron los nódulos subcutáneos, las mialgias, la fiebre, las artralgias y el dolor en las pantorrillas. Aunque se ha considerado la PANC como una enfermedad benigna, estos pacientes pueden requerir tratamiento con glucocorticoides e inmunosupresores.

Summary Objective: To describe the main demographic and clinical characteristics of patients who were diagnosed with childhood polyarteritis nodosa (PAN). Methods: A descriptive study was conducted using retrospective data Results: The clinical registries from patients under 18th years with vasculitis or PAN diagnosis attended between 2010 and 2019 in two Medical Centers from Medellín were obtained. Nineteen patients were included: eleven classified as cutaneous PAN (PANC) according to the definition of the European League Against Rheumatism and the European Society of Pediatric Rheumatology and eight as systemic PAN according to Ankara 2008 Criteria. 57.9% were male. The median age at diagnosis was ten years (3-17), and the median follow-up period was 15 months (0-105). The most common clinical characteristics were subcutaneous nodules (84.2%), fever (57.9%), arthralgias (57.9%), and calf pain (52.6%). SPAN patients had more frequent weight loss and lower hemoglobin. Five patients had ulcers (26.3%), four of them with CPAN; two patients had lingual necrosis (10.5%), and two digital necrosis (10.5%), all of them also with CPAN. CRP mean was 10.2 mg/dl (0.33-45.3) and mean erythrocyte sedimentation rate (ESR) was 74 mm/h (15-127 mm/h). Meningeal enhancing, intrahepatic, and mesenteric aneurism, among others, were reported in diagnostic images. All patients required treatment with systemic glucocorticoid. None of the patients died during the follow-up period. Conclusions: In this pediatric series from Medellín-Colombia, PAN was more common in boys of school age. CPAN was more frequent than SPAN. The clinical characteristics most reported were subcutaneous nodules, myalgias, arthralgias, and calf pain. Although CPAN has been considered a benign disease, these patients may require systemic glucocorticoid and immunosuppressive therapy.

Ultrasonido Doppler de arterias temporales en pacientes con arteritis de células gigantes: estado del arte y revisión sistemática de la literatura / Temporal artery Doppler ultrasound in patients with giant cell arteritis: State of the art and systematic review of the literature

RESUMEN La arteritis de células gigantes es una vasculitis que afecta de manera predominante a vasos de gran calibre y aparece en personas mayores de 50 arios. Su presentación clínica incluye cefalea, alteraciones auditivas o síntomas similares a polimialgia reumática. En su forma más grave puede causar pérdida de visión uni- o bilateral, secundaria a neuropatía óptica isquémica de tipo arterítico. En la actualidad, el estándar de referencia para su diagnóstico es la biopsia de arterias temporales, procedimiento que no es inocuo y que puede tener como complicaciones infección, lesión nerviosa o sangrado, entre otras. Entre las técnicas no invasivas de diagnóstico, el ultrasonido y el Doppler de arterias temporales han tomado un rol cada vez más importante en el diagnóstico de esta entidad, dado que son pruebas benignas, con nulos efectos adversos y, a través de estrategias como las clínicas fast-track apoyadas en este método diagnóstico, se ha logrado reducir las complicaciones isquémicas de la enfermedad.

ABSTRACT Giant cell arteritis is a vasculitis that predominantly affects large calibre vessels, and usually appears in people over 50 years-old. Its clinical presentation includes headache, hearing impairment, or polymyalgia rheumatica-like symptoms. In its most severe form, it can cause uni- or bilateral vision loss secondary to arteritic ischaemic optic neuropathy. Currently, the gold standard for its diagnosis is the temporal artery biopsy, a procedure that is not harmless and may have complications such as infection, nerve injury, bleeding, among others. Among non-invasive diagnostic methods, the ultrasound and temporal artery Doppler have gained a predominant role in the diagnosis of giant cell arteritis, as it is a benign test with no adverse effects. Through strategies such as «fast-track¼ clinics, supported by this diagnostic method, a reduction has been achieved in ischaemic complications of the disease.

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.

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.

Factors associated with active tuberculosis in Colombian patients with systemic lupus erythematosus: a case-control study.

OBJECTIVE: To identify factors associated with active tuberculosis (TB) in patients with systemic lupus erythematosus (SLE). METHODS: We performed a retrospective case-control study in two tertiary care teaching hospitals in Medellín, Colombia. From January 2007 to December 2017, a total of 268 patients with SLE were included. SLE patients with TB (cases) were matched 1:3 with SLE patients without TB (controls) by disease duration and the date of the hospitalization in which the diagnosis of TB was made (index date of cases) to the nearest available rheumatology hospitalization in the matched controls (± 2 years). Conditional univariable and multivariable logistic regression analyses were performed. RESULTS: Sixty-seven cases and 201 controls were assessed. Only pulmonary TB occurred in 46.3%, only extrapulmonary TB in 16.4% and disseminated TB in 37.3% of cases. Multivariable logistic regression analysis showed that lymphopenia (OR, 2.91; 95% CI 1.41-6.03; P = 0.004), 12-month cumulative glucocorticoid dose ≥ 1830 mg (OR, 2.74; 95% CI 1.26-5.98; P = 0.011), and having been treated with ≥ 2 immunosuppressants during the last 12 months (OR, 2.81; 95% CI 1.16-6.82; P = 0.022) were associated with TB after adjusting for age, sex, ethnicity, disease duration, disease activity, and comorbidity index. A trend towards an association of kidney transplantation with TB was also found (OR, 3.77; 95% CI 0.99-14.30; P = 0.051). CONCLUSION: Among SLE patients, cumulative glucocorticoid dose, lymphopenia, and the use of ≥ 2 immunosuppressants during the last 12 months were associated with active TB infection. Key Points • Among SLE patients, a cumulative dose of glucocorticoids equivalent to 5 mg/day of prednisone during the last 12 months is independently associated with the development of TB. • The use of two or more immunosuppressants during the last 12 months is also a risk factor for TB infection development is SLE patients. • Lymphopenia is predominant in SLE patients with TB, being especially profound in those with disseminated TB. • Renal transplant recipients with SLE also have an elevated risk of TB.

Urinary levels of ceruloplasmin and monocyte chemoattractant protein-1 correlate with extra-capillary proliferation and chronic damage in patients with lupus nephritis.

BACKGROUND AND AIM: There are few studies of urinary biomarkers and histopathologic features in lupus nephritis (LN). The aim was to analyze the correlation between a wide panel of urinary biomarkers and serum concentrations of anti C1q antibodies with histological items of activity and chronicity on kidney biopsy in LN patients. METHODS: Patients with systemic lupus erythematosus (SLE) according to American College of Rheumatology (ACR) criteria were included. LN diagnosis was based on ACR criteria. Histologic features of activity and chronicity indices were analyzed according to the Austin classification. Serum Anti C1q levels were determined by commercial ELISA. Urinary levels of transferrin, ceruloplasmin (CP), VCAM-1, TWEAK, monocyte chemoattractant protein-1 (MCP-1), neutrophil gelatinase-associated lipocalin (NGAL), and alpha-1-acid glycoprotein were measured by commercial ELISA. RESULTS: We included 120 SLE patients (81% female, mean age 33.1 ± 9.3 years, 59.4% Mestizo, 37.8% Afro-Latin American): 64% had LN. Kidney biopsy was performed in 55 patients, but only 37 were made in our center. Anti C1q antibodies were associated with endocapillary proliferation. In patients with cellular crescents, urinary concentrations of CP were significantly higher. In patients with a chronicity index (CI) ≥ 4, fibrous crescents, tubular atrophy, and interstitial fibrosis, urinary MCP-1 levels were higher. CONCLUSIONS: In SLE patients, serum anti C1q antibodies and urinary CP were associated with activity on kidney biopsy and MCP-1 with chronic damage. This panel of biomarkers could be validated in larger, multi-ethnic population as a complementary tool for better stratification of LN patients. Key Points • Urinary biomarkers are complementary useful tools for the assessment of SLE patients. • Urinary levels of CP correlated with activity findings on kidney biopsy in LN patients. • Urinary levels of MCP-1 correlated with chronic damage, especially with fibrous crescents, tubular atrophy, and interstitial fibrosis.

Vasculitis crioglobulinémica y artritis psoriásica: reporte de caso de una inusual asociación / Cryoglobulinemic vasculitis and psoriatic arthritis: case report of an unusual association

Se presenta el caso de un paciente de 47 años con antecedente de artritis psoriásica (AP) de 9 años de evolución en quien se encuentra compromiso renal, hipocomplementemia, neuropatía periférica, lesiones necróticas acrales y crioglobulinas positivas. Luego de realizar el abordaje diagnóstico se concluye que el cuadro clínico corresponde a una vasculitis crioglobulinémica concomitante a la AP. Se expone además del caso una revisión de la literatura referente a la presencia de estas 2 enfermedades en un solo paciente

We report the case of a 47-year-old man with a 9-year history of psoriatic arthritis (PsA) in whom we detected renal involvement, hypocomplementemia, peripheral neuropathy, acral necrotic lesions and positive cryoglobulins. The results of the diagnosis led us to conclude that the clinical picture corresponded to cryoglobulinemic vasculitis concomitant with PsA. In addition, we present a review of the literature on the presence of these two diseases in a single patient

Cryoglobulinemic vasculitis and psoriatic arthritis: Case report of an unusual association. / Vasculitis crioglobulinémica y artritis psoriásica: reporte de caso de una inusual asociación.

We report the case of a 47-year-old man with a 9-year history of psoriatic arthritis (PsA) in whom we detected renal involvement, hypocomplementemia, peripheral neuropathy, acral necrotic lesions and positive cryoglobulins. The results of the diagnosis led us to conclude that the clinical picture corresponded to cryoglobulinemic vasculitis concomitant with PsA. In addition, we present a review of the literature on the presence of these two diseases in a single patient.

Proinflammatory Differentiation of Macrophages Through Microparticles That Form Immune Complexes Leads to T- and B-Cell Activation in Systemic Autoimmune Diseases.

Patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) demonstrate increased circulating microparticles (MP). These vesicles, primarily those that form immune complexes (MP-IC), may activate monocytes. We evaluated the effect of MP and MP-IC in the differentiation of monocytes to macrophages (monocyte-derived macrophages; MDM) and for consequences in autologous lymphocyte activation. Monocytes from healthy controls (HC) and patients with RA and SLE that differentiated into MDM in the presence of MP-IC showed a proinflammatory (M1-like) profile, which was more evident using MP-IC from patients with RA than those from patients with SLE. Notably, MDM from HC and patients with RA that differentiated with MP-IC were more prone to M1-like profile than those from patients with SLE. In HC and patients with RA, monocyte differentiation using MP-IC decreased the frequency of MDM that bound/internalized latex beads. The M1-like profile did not completely revert following IL-4 treatment. The effect of M1-like MDM on T lymphocytes stimulated with phytohemagglutinin was further evaluated. MDM differentiated with MP enhanced the proliferation of T cells obtained from patients with RA compared with those differentiated with MP-IC or without vesicles. Neither MP nor MP-IC induced interferon (IFN)-γ+ and tumor necrosis factor (TNF)-α+ T cells in patients with RA. Conversely, unlike MDM differentiated with or without MP, MP-IC enhanced the proliferation and increased the frequencies of IFN-γ+CD4+ T, TNF-α+CD4+ T, and IFN-γ+CD8+ T cells in patients with SLE. The co-culture of B cells with MDM obtained from patients with RA and SLE and differentiated with MP-IC increased the expression of B-cell activation markers and prevented B lymphocyte death. Strikingly, only for patients with SLE, these responses seemed to be associated with a significant increase in B-cell activating factor levels, high plasmablast frequency and immunoglobulin production. These results showed that MP-IC from patients with systemic autoimmune diseases favored the polarization of MDM into a proinflammatory profile that promotes T-cell activation, and additionally induced B-cell activation and survival. Therefore, the effect of MP-IC in mononuclear phagocytes may be an important factor for modulating adaptive responses in systemic autoimmune diseases.

Endothelial activation and injury by microparticles in patients with systemic lupus erythematosus and rheumatoid arthritis.

BACKGROUND: Endothelial activation and damage is commonly observed in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) and is related to development of atherosclerosis and cardiovascular diseases. Different components of the immune system seem to participate in the endothelial injury, such as generation of autoantibodies and formation of immune complexes (ICs). Microparticles (MPs) and their immune complexes (MPs-ICs) are increased in the circulation of patients with SLE and RA; therefore, we propose these extracellular vesicles could interact and modulate the function of endothelial cells. Hence, the effect of MPs and MPs-ICs from patients with SLE and RA in endothelial cells was evaluated. METHODS: Macrovascular and microvascular endothelial cells were exposed to MPs and MPs-ICs from healthy donors and patients with SLE and RA. Vesicles uptake/binding, expression of adhesion molecules, cytokine and chemokine production, monocyte adherence, and alterations of endothelial monolayer were evaluated by flow cytometry and fluorescence microscopy. RESULTS: Endothelial cells internalized MPs and MPs-ICs and increased CD54 and CD102 expression and CCL2, CCL5, and IL-6 production after the treatment with these extracellular vesicles, which led to an increase in the adherence of classic monocytes. These vesicles also induced low expression of VE-cadherin in membrane, depolymerization of actin filaments, and formation of intercellular spaces, which led to endothelial death and increased permeability after MPs and MPs-ICs exposure. CONCLUSIONS: MPs and MPs-ICs from patients with SLE and RA increase adhesion molecules expression, chemokine production, and structural alterations in macrovascular and microvascular endothelial cells. Therefore, high counts of these vesicles in patients would promote endothelial alterations and secondary tissue leukocyte infiltration.

Clinical Profile of Levamisole-Adulterated Cocaine-Induced Vasculitis/Vasculopathy: A 30-Case Series.

OBJECTIVES: The aims of this study were to describe clinical and laboratory manifestations of patients with levamisole-adulterated cocaine-induced vasculitis/vasculopathy and to propose a skin classification according to the distribution and severity of lesions. METHODS: We report the characteristics of 30 patients admitted with levamisole-adulterated cocaine-induced vasculitis/vasculopathy in 4 high-complexity institutions in Colombia, from December 2010 to May 2017. We compare our findings with the main published series. RESULTS: Median age was 31 years (interquartile range, 27-38 years) with a male-to-female ratio of 5:1. Eighty-three percent of the patients had retiform purpura affecting the limbs, buttocks, face, or abdomen; 73% had ear necrosis, 50% cutaneous ulcers, 17% genital necrosis, 13% oral ulcers, and 10% digital necrosis. Cutaneous involvement was classified according to the frequency of the compromised corporal area, and purpuric lesions were stratified in 4 grades of severity. Anti-neutrophil cytoplasmic autoantibodies were positive in 85% of the cases, lupus anticoagulant in 73%, and antinuclear autoantibodies in 57%; rheumatoid factor was negative in all cases. We found nephritis in 17 cases (57%). Prednisolone was used in most of the patients (70%), with other immunosuppressive agents being used in a lower percentage. Improvement was observed in 93% of the patients, but symptoms recurred in 40%, attributed to relapses in consumption. End-stage chronic renal disease developed in 10% of the cases, and 1 patient died. CONCLUSIONS: Because of rising cocaine consumption and levamisole adulteration frequency, levamisole-adulterated cocaine-induced vasculitis/vasculopathy is becoming more common. Detailed characterization of skin involvement coupled with multiple antibody positivity is essential for a diagnosis. Renal involvement is frequent, clinically and histologically heterogeneous, and potentially serious.

HMGB1+ microparticles present in urine are hallmarks of nephritis in patients with systemic lupus erythematosus.

Non-classical monocytes infiltrate the kidney parenchyma and participate in tissue damage in patients with lupus nephritis (LN). Circulating microparticles (MPs) seem to play critical roles in the activation of monocytes in systemic lupus erythematosus (SLE) patients. This study aims to characterize the phenotypes of MPs and monocyte subsets in LN patients and to determine their potential to discriminate between SLE patients with and without LN. Blood and urine samples from SLE patients were collected. In monocyte subsets from whole blood samples several phenotypic markers were evaluated. MPs were isolated from platelet-poor plasma and urine by centrifugation. This phenotypic marker characterization was performed using multiparametric flow cytometry. We observed that patients with active LN have lower counts of non-classical monocytes than do those without renal involvement. All monocyte subsets exhibited lower expression of CX3CR1 and ICAM-1 in LN than in patients without LN. High frequencies of MP-HMGB1+ and MP-HLA-DR+ were detected in circulation and urine of LN patients. Although MP-HMGB1+ , MP-HLA-DR+ , and MP-CX3CR1+ from urine were able to discriminate between patients with and without LN, only urinary MP-HMGB1+ were different between patients with active and inactive LN. Therefore, these vesicles may be useful as biomarkers of LN.

Platelet-derived microparticles generated in vitro resemble circulating vesicles of patients with rheumatoid arthritis and activate monocytes.

Patients with rheumatoid arthritis (RA) have increased amount of platelet-derived microparticles (PMPs) positive for citrullinated peptides (CPs) that form immune complexes (PMPs-ICs). Monocytes are important inflammatory mediators that play a role in the clearance of PMPs-ICs. We aimed to generate PMPs-ICs in vitro and determine its effect on monocytes from patients with RA and healthy individuals (HI). PMPs from patients showed platelet markers, mitochondria content, and phosphatidylserine exposure similar to PMPs from HI. However, patients had a higher frequency of IgG+ and CPs+ vesicles than HI. PMPs-ICs generated in vitro were similar to the circulating vesicles of patients with respect to IgG- and CPs-positivity. PMPs-ICs induced pro-inflammatory cytokines and CX3CR1 expression in monocytes from HI, and IL-10 and CD36 upregulation in monocytes from patients. These results suggest that PMPs-ICs induce activation of monocytes, with a pro-inflammatory response in HI and a more tolerant response in cells of patients with RA.

Extracellular vesicles are associated with the systemic inflammation of patients with seropositive rheumatoid arthritis.

Patients with rheumatoid arthritis (RA) and autoantibodies, such as rheumatoid factor and those against cyclic citrullinated peptides, are designated as seropositive and have a more severe disease with worse prognosis than seronegative RA patients. Understanding the factors that participate in systemic inflammation, in addition to articular commitment, would allow better treatment approaches for prevention of RA comorbidities and disease reactivation. We evaluated whether monocyte subsets and extracellular vesicles (EVs) could contribute to this phenomenon. Seropositive patients had higher levels of proinflammatory cytokines than those of seronegative patients and healthy controls (HCs); however, this systemic inflammatory profile was unrelated to disease activity. High frequencies of circulating EVs positive for IgG, IgM, CD41a, and citrulline, together with altered counts and receptor expression of intermediate monocytes, were associated with systemic inflammation in seropositive patients; these alterations were not observed in seronegative patients, which seem to be more similar to HCs. Additionally, the EVs from seropositive patients were able to activate mononuclear phagocytes in vitro, and induced proinflammatory cytokines that were comparable to the inflammatory response observed at the systemic level in seropositive RA patients; therefore, all of these factors may contribute to the greater disease severity that has been described in these patients.