Cardiac involvement in the catastrophic antiphospholipid syndrome (CAPS): Lessons from the "CAPS registry".

OBJECTIVE: To analyze the demographic, clinical, and laboratory characteristics of catastrophic antiphospholipid syndrome (CAPS) patients with cardiac involvement, and to identify the factors associated with this cardiac involvement. MATERIAL AND METHODS: Based on the analysis of the "CAPS Registry", the demographic, clinical, and serological characteristics of patients with cardiac involvement were analyzed. Cardiac involvement was defined as heart failure, valvular disease, acute myocardial infarction, pericardial effusion, pulmonary arterial hypertension, systolic dysfunction, intracardiac thrombosis, and microvascular disease. Univariate and multivariate analysis was used for multiple comparisons. RESULTS: 749 patients (293 [39 %] women and mean age 38.1 ± 16.2 years) accounting for 778 CAPS events were included, of them 404 (52 %) had cardiac involvement. The main cardiac manifestations were heart failure in 185/377 (55 %), valve disease in 116/377 (31 %), and acute myocardial infarction in 104/378 (28 %). Of 58 patients with autopsy/biopsy, 48 (83 %) had cardiac thrombotic microangiopathy, Stroke (29% vs. 21 %, p = 0.012), transient cerebral vascular accident (2% vs. 1 %, p = 0.005), pulmonary infarction (26% vs. 3 %, p = 0.017), renal infarction (46% vs. 35 %, p = 0.006), acute kidney injury (70% vs. 53 %, p < 0.001), and livedo reticularis (24% vs. 17 %, p = 0.016) were significantly more frequent during CAPS events with versus without heart involvement. Multivariate analysis identified acute kidney injury (OR 1.068, IC 95 % 1.8-4.8, p < 0.001) as the only clinical characteristics that were, independently, associated with cardiac involvement in CAPS events. Cardiac involvement was not related to higher mortality. CONCLUSIONS: Cardiac involvement is frequent in CAPS, with association with kidney involvement, and it is not related to higher mortality. The presence of cardiac microthrombosis was demonstrated in most biopsies/autopsies performed.

Innovative cellular therapies for autoimmune diseases: expert-based position statement and clinical practice recommendations from the EBMT practice harmonization and guidelines committee.

Autoimmune diseases (ADs) are characterized by loss of immune tolerance, high chronicity, with substantial morbidity and mortality, despite conventional immunosuppression (IS) or targeted disease modifying therapies (DMTs), which usually require repeated administration. Recently, novel cellular therapies (CT), including mesenchymal stromal cells (MSC), Chimeric Antigen Receptors T cells (CART) and regulatory T cells (Tregs), have been successfully adopted in ADs. An international expert panel of the European Society for Blood and Marrow Transplantation and the International Society for the Cell and Gene Therapy, reviewed all available evidence, based on the current literature and expert practices, on use of MSC, CART and Tregs, in AD patients with rheumatological, neurological, and gastroenterological indications. Expert-based consensus and recommendations for best practice and quality of patient care were developed to support clinicians, scientists, and their multidisciplinary teams, as well as patients and care providers and will be regularly updated.

Organ damage is a major determinant of work productivity impairment in Behçet's Syndrome: a post-hoc analysis of the BODI validation study.

OBJECTIVES: To evaluate the prevalence, magnitude, and potential determinants of work productivity impairment in patients with Behçet's Syndrome (BS), focusing on the role of irreversible organ damage. METHODS: A post-hoc analysis of the BS overall damage index (BODI) prospective validation study was performed. Demographics and clinical features were recorded in all patients. The Work Productivity and Activity Impairment: General Health (WPAI: GH) questionnaire was administered to assess the work limitation and the BODI to measure organ damage. The independent effect of BS features on WPAI: GH outcomes was evaluated by regression analysis. RESULTS: Out of 148 patients, 34.5% were unemployed, with age (OR 1.035) and BODI score (OR 1.313 for 1-unit increase) as the only factors significantly (p< 0.05) associated with the unemployment state. An overall work impairment was reported in about 64.2% of the employed patients. Indeed, 22.7% reported missing work h due to their health (absenteeism), with a mean time loss of 34.4%; whereas 60.2% declared a reduced performance at work because of their health (presenteeism), with a mean productivity impairment of 45.4%. Ocular damage was associated with absenteeism (ß 0.225); female sex (ß 0.260), physician global assessment of disease activity (ß 0.502) and an increased BODI score (ß 0.166 for 1-point increase) with presenteeism; fibromyalgia (ß 0.246), physician global assessment (ß 0.469), and musculoskeletal damage (ß 0.325) with overall work impairment. CONCLUSIONS: Disease activity and organ damage accrual remarkably affect work productivity in BS patients. Achieving remission and preventing damage accrual are crucial and complementary objectives.

Ex vivo confocal microscopy detects basic patterns of acute and chronic lesions using fresh kidney samples.

Background: Ex vivo confocal microscopy is a real-time technique that provides high-resolution images of fresh, non-fixed tissues, with an optical resolution comparable to conventional pathology. The objective of this study was to investigate the feasibility of using ex vivo confocal microscopy in fusion mode (FuCM) and the haematoxylin and eosin (H&E)-like digital staining that results for the analysis of basic patterns of lesion in nephropathology. Methods: Forty-eight renal samples were scanned in a fourth-generation ex vivo confocal microscopy device. Samples were subjected to confocal microscopy imaging and were then processed using conventional pathology techniques. Concordance between the techniques was evaluated by means of the percentage of agreement and the κ index. Results: Agreement between conventional microscopy and H&E-like digital staining was strong (κ = 0.88) in the evaluation of acute tubular damage and was substantial (κ = 0.79) in the evaluation of interstitial fibrosis, interstitial inflammation, arterial and arteriolar lesions. H&E-like digital staining also allows rapid identification of extracapillary proliferation (κ = 0.88), necrosis and segmental sclerosis (κ = .88) in the glomerular compartment, but the results reported here are limited because of the small number of cases with these glomerular findings. Conclusions: FuCM proved to be as effective as conventional techniques in evaluating the presence of acute tubular necrosis and interstitial fibrosis changes, but in fresh tissue. The ease of acquisition of ex vivo confocal microscopy images suggests that FuCM may be useful for rapid evaluation of kidney biopsies and to restructure the clinical workflow in renal histopathology.

COVID-19 coagulopathy and antiphospholipid syndrome

The presence of thrombotic events in COVID-19 patients has been described since the beginning of the pandemic. This association has been confirmed in most of the reported studies. Autopsy reports have shown that most thromboses are located in the lung, although they have also been observed in other organs such as the skin and kidneys. SARS-CoV2 infection induces a generalized prothrombotic state, which is attributed to a combination of factors such as hypoxia, excess cellular apoptosis, and mainly to overactivation of the immune system. Among immune-mediated prothrombotic situations, antiphospholipid syndrome (APS) stands out. Recurrent thrombotic events are observed in APS in the presence of antiphospholipid antibodies (aPL). There are numerous studies that report high prevalence of aPL in patients with COVID-19 infection. However, the results show discrepancies in the data on the prevalence of aPL, and its role in the pathogenesis of thrombosis in these patients. This could be due to the heterogeneity of the detection procedures for aPL or to transient elevations of non-pathogenic aPL levels in the context of infection. In this review we try to clarify the role of aPL in COVID-19 infection, and attempt to answer the question of whether it is a coagulopathy of its own, or secondary to APS.

La presencia de eventos trombóticos en los pacientes con COVID-19 se describió desde el inicio de la pandemia, asociación que ha sido confirmada en la mayoría de los estudios reportados. Los informes de necropsias han puesto de manifiesto que la mayoría de las trombosis se localiza en el pulmón, aunque también se han observado en otros órganos, como la piel y los riñones. La infección por SARS-CoV-2 induce un estado protrombótico generalizado que se atribuye a una conjunción de factores como la hipoxia, el exceso de apoptosis celular y, sobre todo, una hiperactivación del sistema inmune. Entre las situaciones protrombóticas inmunomediadas destaca el síndrome antifosfolipídico, en el cual se observan eventos trombóticos de repetición en presencia de anticuerpos antifosfolipídicos (AAF). Existen numerosos estudios que reportan una elevada prevalencia de AAF en los pacientes con infección por la COVID-19; sin embargo, los resultados muestran discordancias en los datos de prevalencia de AAF y su rol en la patogenia sobre la trombosis en estos pacientes, lo que que podría deberse a la heterogeneidad de los procedimientos de detección de los AAF o a elevaciones transitorias de los niveles de AAF no patogénicos en el contexto de la infección. En esta revisión se busca aclarar el papel de los AAF en la infección por COVID-19, intentando responder a la pregunta de si se trata de una coagulopatía propia o es secundaria a un síndrome antifosfolipídico.

Kidney biopsy in lupus nephritis after achieving clinical renal remission: paving the way for renal outcome assessment.

The role of repeat kidney biopsy in lupus nephritis (LN) with renal remission is unclear. The aim of this study was to assess this role in a real-life scenario. This retrospective, single-centre study included 56 patients with LN diagnosed from 1998 to 2019, with an initial kidney biopsy (KB1) at the onset of LN and a second kidney biopsy (KB2) after achieving renal remission. A total of 51 (91.1%) patients were women with a median age of 29.9 years [interquartile range (IQR) 23.4-40.6] at the time of LN diagnosis. KB2s were performed after 41.1 months (IQR 30.1-52.5) of KB1. At the time of KB2, complete renal response was achieved in 51 (91.1%) patients. The median activity index decreased from a baseline value of 6.5 (IQR 2.8-11) to 0 (IQR 0-2) (P < .001). The chronicity index worsened from 1 (IQR 0-2) to 2 (IQR 1-3) (P = .01). In patients with proliferative/mixed forms at KB2, the chronicity index median value increased to 3 (IQR 1.5-4), as well as interstitial fibrosis and tubular atrophy [Formula: see text]25%, from 5.4% to 13.5%. Persistent histological active LN (activity index ≥2) was present in 11 (19.6%) KB2s. There were no differences when comparing immunological parameters between both groups (activity index ≥2 versus <2) at KB2, nor in the percentage of patients who presented renal flare. Immunosuppressive treatment was withdrawn in 35 (62.5%) patients and maintained/switched in 21 (37.5%). Afterward, new renal flare occurred in 9 patients per group (25.7% and 43%, respectively), after a median time of 39 months (IQR 6.5-55) and 7 months (IQR 6-30), respectively. There was no difference in the number of patients who developed chronic kidney disease [n = 14 (25%)] according to the treatment. In conclusion, KB2 provides valuable information to guide immunosuppressive maintenance therapy.

Accrual of organ damage in Behçet's syndrome: trajectory, associated factors, and impact on patients' quality of life over a 2-year prospective follow-up study.

BACKGROUND: This study aimed to investigate the trajectory of damage accrual, associated factors, and impact on health-related quality of life (HR-QoL) in a multicenter cohort of patients with Behçet's syndrome (BS) over 2 years of follow-up. METHODS: Patients recruited in the BS Overall Damage Index (BODI) validation study were prospectively monitored for 2 years and assessed for damage accrual, defined as an increase ≥1 in the BODI score, and HR-QoL was evaluated by the SF-36 questionnaire. Logistic and multiple linear regression models were built to determine factors associated with damage accrual and impairment in the different SF-36 domains. RESULTS: During follow-up, 36 out of 189 (19.0%) patients had an increase ≥1 in the BODI score with a mean (SD) difference of 1.7 (0.8) (p <0.001). The incidence rate of damage accrual was stable over time, regardless of the disease duration. Out of 61 new BODI items, 25 (41.0%) were considered related to glucocorticoid (GC) use. In multivariate analysis, duration of GC therapy (OR per 1-year 1.15, 95% CI 1.07-1.23; p <0.001) and occurrence of ≥1 disease relapse (OR 3.15, 95% CI 1.09-9.12; p 0.038) were identified as predictors of damage accrual, whereas the use of immunosuppressants showed a protective effect (OR 0.20, 95% CI 0.08-0.54, p<0.001). Damage accrual was independently associated with the impairment of different physical domains and, to a greater extent, in emotional domains of the SF-36 questionnaire. Female sex, higher disease activity, and fibromyalgia were also significantly associated with impairment in HR-QoL. CONCLUSION: In BS, organ damage accrues over time, also in long-standing disease, resulting in an impairment of the perceived physical and mental health. Adequate immunosuppressive treatment, preventing disease flares and minimizing exposure to GCs have a crucial role in lowering the risk of damage accrual.

Catastrophic antiphospholipid syndrome / Síndrome antifosfolípido catastrófico

ABSTRACT The antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by the development of thrombotic events and/or obstetric morbidity in the presence of antiphospholipid antibodies (aPL), such as the lupus anticoagulant (LA), anticardiolipin antibodies (aCL) or anti- β 2-glycoprotein I antibodies (a β2 GPI). In 1992, Ronald A. Asherson described a very aggressive clinical variant of this syndrome characterized by the development of multiple thrombotic manifestations, simultaneously or in a short period of time. The term catastrophic APS was proposed and since then it is known by this name.

RESUMEN El síndrome antifosfolípido (SAF) es una enfermedad sistêmica autoinmune, caracterizada por el desarrollo de eventos trombóticos y/o morbilidad obstétrica en presencia de anticuerpos antifosfolípidos (aPL), tales como el anticoagulante lúpico (AL), los anticuerpos anticardiolipina (aCL) o anticuerpos anti- β2-glicoproteína I (aβ2GPI). En 1992, Ronald A. Asherson describió una variante clínica muy agresiva de este síndrome, caracterizada por el desarrollo de múltiples manifestaciones trombóticas, de manera simultánea o dentro de un corto periodo de tiempo. Se propuso entonces el término SAF catastrófico y desde entonces se le ha conocido por ese nombre.

Understanding tubulointerstitial injury and repair mechanisms paves the way for renal outcome improvement in lupus nephritis / Entender la lesión tubulointersticial y los mecanismos de reparación será la vía para mejorar los desenlaces renales en nefritis lúpica

ABSTRACT Despite improvements in patient survival and quality of life, long-term renal survival has not changed significantly in the recent decades and nephritis relapses affect over 50% of patients with lupus nephritis. Renal fibrosis affecting the tubulointerstitial compartment is a central determinant of the prognosis of any kidney disease. Notwithstanding this evidence, the current 2003 ISN/RPS classification still focuses on glomerular pathology and does not include a mandatory score with clear subcategories of the tubulointerstitial injury in the biopsy. The pathogenesis, and the morphological and molecular characteristics of this process in patients with lupus nephritis will be considered, together with a discussion about the concepts the clinician needs to efficiently address in this injury during daily practice and in future clinical trials. Both tubulointerstitial inflammation and fibrosis are strongly correlated with poor renal outcomes in lupus nephritis, regardless of the extent of glomerular damage. Therefore, it is essential to develop reliable and noninvasive approaches to predict which patients are most likely to develop CKD so that appropriate interventions can be adopted before ESRD is established. Currently, no ideal method for monitoring kidney fibrosis exists, since repeated renal biopsies are invasive. Promising methods for assessing and monitoring fibrosis non-invasively include imaging techniques, such as magnetic resonance imaging or ex vivo confocal microscopy, integrated in computational and digital pathology techniques. Finally, beyond specific immunosuppressive treatment in Lupus Nephritis, identifying and treating cardiovascular risk factors should be a cornerstone of treatment in these patients.

RESUMEN A pesar de las mejoras en la sobrevida de los pacientes y su calidad de vida, la sobrevida renal en el largo plazo no ha cambiado significativamente durante las últimas décadas, y las recidivas nefríticas afectan a más del 50% de los pacientes con nefritis lúpica. La fibrosis renal, que afecta el compartimiento tubulointersticial, es un factor determinante central en el pronóstico de todas las patologías renales. A pesar de la evidencia, la actual clasificación ISN/RPS del 2003 todavía se concentra en la patología glomerular y no incluye un score obligatorio con claras subcategorías de la lesión tubulointersticial en la biopsia. Se hablará de la patogenia y las características morfológicas y moleculares de este proceso en pacientes con nefritis lúpica, así como de los conceptos que el clínico necesita para abordar esta lesión de manera eficiente en su práctica cotidiana y en los estudios clínicos a futuro. Tanto la inflamación tubulointersticial como la fibrosis se relacionan fuertemente con desenlaces renales pobres en la nefritis lúpica, con independencia de la extensión del dañío glomerular. Resulta por lo tanto esencial desarrollar sistemas confiables y no invasivos para predecir cuáles pacientes tendrán mayor probabilidad de desarrollar enfermedad renal crónica, a fin de realizar las intervenciones apropiadas antes de que se establezca la enfermedad renal terminal (ERT). En la actualidad, no existe un método ideal para monitorear la fibrosis renal, dado que las biopsias repetidas son procedimientos invasivos. Algunos de los métodos promisorios para evaluar y monitorear la fibrosis de manera no invasiva son las técnicas de imágenes, tales como la resonancia magnética o la microscopía confocal ex vivo, integradas en técnicas de patología computarizadas y digitales. Finalmente, más allá del tratamiento inmunosupresor específico para la nefritis lúpica, identificar y tratar los factores de riesgo cardiovascular deberá ser uno de los pilares de tratamiento en estos pacientes.

Treat to target in systemic lupus erythematosus / Tratamiento por objetivos en el lupus eritematoso sistémico

ABSTRACT Systemic lupus erythematosus (SLE) is the most representative disorder within systemic autoimmune diseases. The treat-to-target strategy in SLE was established half a decade ago and, since then, remarkable advances have been made. An international consensus has defined and unified the term remission and also low disease activity has been proposed as an alternative and, perhaps, more realistic target. Both of them have proven to be meaningful in terms of improving several outcomes, and have opened the path for future research in clinical trials.

RESUMEN El lupus eritematoso sistémico (LES) es el trastorno más representativo dentro de las enfermedades autoinmunes sistémicas. La estrategia de tratamiento por objetivos en el LES se estableció hace media década y desde entonces se han producido notables avances. Un consenso internacional ha definido y unificado el término remisión y también se ha propuesto la baja actividad de la enfermedad como un objetivo alternativo y quizás más realista. Ambos han demostrado ser significativos en cuanto a la mejora de varios resultados y han abierto el camino para futuras investigaciones en ensayos clínicos.

The Rheumatology Drugs for COVID-19 Management: Which and When?

INTRODUCTION: While waiting for the development of specific antiviral therapies and vaccines to effectively neutralize the SARS-CoV2, a relevant therapeutic strategy is to counteract the hyperinflammatory status, characterized by an increase mainly of interleukin (IL)-1ß, IL-2, IL-6, IL-7, IL-8, and tumor necrosis factor (TNF)-α, which hallmarks the most severe clinical cases. 'Repurposing' immunomodulatory drugs and applying clinical management approved for rheumatic diseases represents a game-changer option. In this article, we will review the drugs that have indication in patients with COVID-19, including corticosteroids, antimalarials, anti-TNF, anti-IL-1, anti-IL-6, baricitinib, intravenous immunoglobulins, and colchicine. The PubMed, Medline, and Cochrane Library databases were searched for English-language papers concerning COVID-19 treatment published between January 2020 and October 2020. Results were summarized as a narrative review due to large heterogeneity among studies. In the absence of specific treatments, the use of immunomodulatory drugs could be advisable in severe COVID-19 patients, but clinical outcomes are still suboptimal. An early detection and treatment of the complications combined with a multidisciplinary approach could allow a better recovery of these patients.

The extent of tubulointerstitial inflammation is an independent predictor of renal survival in lupus nephritis.

BACKGROUND AND OBJECTIVE: Lupus nephritis (LN) is a major complication in patients with systemic lupus erythematosus (SLE). Tubulointerstitial injury is an inflammatory process that, if not attenuated, can promote renal damage. Despite this, the current 2003 ISN/RPS "glomerulocentric" classification does not include a score for tubulointerstitial injury. We sought to establish predictors for tubulointerstitial injury and to determine their influence on renal outcomes. METHODS: This is a retrospective study of a cohort of 166 patients with biopsy-proven LN diagnosed in a Spanish referral center, with a median follow-up of 86 months. Chronic tubulointerstitial lesions were defined as interstitial fibrosis and tubular atrophy (IF/TA), whereas tubulointerstitial inflammation (TII) was defined as an acute interstitial lesion. Activity (0-24) and chronicity (0-12) indices were assigned. OUTCOME: Composite outcome, defined as advanced CKD or development of kidney failure. RESULTS: The prevalence of tubulointerstitial lesions was 69.3%. Eighty-one of the biopsies had features of tubulointerstitial inflammation and only 6 of these 81 (7%) patients had moderate/severe tubulointerstitial inflammation. The incidence of interstitial fibrosis and tubular atrophy was 56.6%. Renal survival was shorter in patients with moderate/severe as compared with absent/mild interstitial fibrosis and tubular atrophy (median: 15-19 years, p = 0.009). In the Cox regression model, the grade of interstitial fibrosis and tubular atrophy was independently associated with shorter renal survival (hazard ratio: 3.9, 95% CI 1.4-10.5; p = 0.008) after adjusting for degree of IF/TA and hypertension or diabetes. CONCLUSIONS: The extent of tubulointerstitial inflammation emerged as an independent predictor of renal survival after adjusting for the grade of interstitial fibrosis and tubular atrophy and co-morbid conditions including hypertension or diabetes. Regarding disease duration at the time of renal biopsy, no significant association was found between the interstitial fibrosis and tubular atrophy groups. The results reported herein need to be validated in future studies to include also groups of patients who usually have a worse prognosis. Consensus on histological classification is needed to aid in defining prognosis.

Deletions in VANGL1 are a risk factor for antibody-mediated kidney disease.

We identify an intronic deletion in VANGL1 that predisposes to renal injury in high risk populations through a kidney-intrinsic process. Half of all SLE patients develop nephritis, yet the predisposing mechanisms to kidney damage remain poorly understood. There is limited evidence of genetic contribution to specific organ involvement in SLE.1,2 We identify a large deletion in intron 7 of Van Gogh Like 1 (VANGL1), which associates with nephritis in SLE patients. The same deletion occurs at increased frequency in an indigenous population (Tiwi Islanders) with 10-fold higher rates of kidney disease compared with non-indigenous populations. Vangl1 hemizygosity in mice results in spontaneous IgA and IgG deposition within the glomerular mesangium in the absence of autoimmune nephritis. Serum transfer into B cell-deficient Vangl1+/- mice results in mesangial IgG deposition indicating that Ig deposits occur in a kidney-intrinsic fashion in the absence of Vangl1. These results suggest that Vangl1 acts in the kidney to prevent Ig deposits and its deficiency may trigger nephritis in individuals with SLE.

Causes of Hospitalization in Systemic Lupus Erythematosus: A Narrative Review.

Hospitalizations are frequent in Systemic Lupus Erythematosus (SLE) and carry a significant economic burden. The focus of this review was to summarize the information available on the main causes of SLE hospitalizations over recent decades. A literature review was conducted, using PubMed and Scopus, for articles related to SLE hospital admissions from 1981 onward. Active disease/ flare and infection were the leading causes of admission across the study period. More recently, other comorbidities gained relevance, such as cardio and cerebrovascular disease, pregnancy-related morbidity, adverse drug reactions, thromboembolic events, malignancy and renal, pulmonary and gastrointestinal disease. African and Southeast Asian studies seemed to display particularly high percentages of patients admitted with active disease/flare, while European and North American studies appeared to report more admissions due to comorbidities and accumulated disease/treatment damage. Some data support a temporal change of certain admission causes, but the limited number, heterogeneity and variance among studies weakens a consistent analysis. In conclusion, despite the developments in SLE management, causes of hospitalization have not prominently changed across recent decades.

Long-term follow-up of antiphospholipid syndrome: real-life experience from a single center.

OBJECTIVE: The objective of this paper is to assess the prevalence of the main clinical manifestations and laboratory features at disease onset and during the ensuing 10 years of a large cohort of patients with antiphospholipid syndrome (APS) from a single center. METHODS: The study included all consecutive APS patients followed longitudinally in our center from 2003 to 2013. Descriptive statistics for demographics, clinical and laboratory features and mortality were performed. RESULTS: A total of 160 patients were included. Most of them, 128 (78.8%), were women and the mean (SD) age at diagnosis was 39.1 (14.0) years. The majority of them, 104 (65.0%), had primary APS, 36 (22.5%) had APS associated with systemic lupus erythematous, and 20 (12.5%) had APS associated with other autoimmune disease. During the study period, thrombotic events occurred in 27 (16.9%) patients, the most common being strokes, nonbacterial thrombotic endocarditis and deep venous thrombosis. Regarding obstetric morbidity, 18 women (14.3%) became pregnant and 90% of pregnancies succeeded in having live births. The most common obstetric complication was early pregnancy loss (15% of pregnancies). Prematurity (11.1% of live births) and intrauterine growth restriction (5.6% of live births) were the most frequent fetal morbidities. Ten (6.3%) patients died and the most frequent causes of death were severe thrombosis, hemorrhage, and cancer. Three (0.9%) cases of catastrophic APS occurred. The survival probability at 10 years was 93.8%. CONCLUSIONS: Patients with APS develop significant morbidity and mortality despite current treatment. It is imperative to identify prognostic factors and therapeutic measures to prevent these complications.

Genome-wide whole blood transcriptome profiling in a large European cohort of systemic sclerosis patients.

OBJECTIVES: The analysis of annotated transcripts from genome-wide expression studies may help to understand the pathogenesis of complex diseases, such as systemic sclerosis (SSc). We performed a whole blood (WB) transcriptome analysis on RNA collected in the context of the European PRECISESADS project, aiming at characterising the pathways that differentiate SSc from controls and that are reproducible in geographically diverse populations. METHODS: Samples from 162 patients and 252 controls were collected in RNA stabilisers. Cases and controls were divided into a discovery (n=79+163; Southern Europe) and validation cohort (n=83+89; Central-Western Europe). RNA sequencing was performed by an Illumina assay. Functional annotations of Reactome pathways were performed with the Functional Analysis of Individual Microarray Expression (FAIME) algorithm. In parallel, immunophenotyping of 28 circulating cell populations was performed. We tested the presence of differentially expressed genes/pathways and the correlation between absolute cell counts and RNA transcripts/FAIME scores in regression models. Results significant in both populations were considered as replicated. RESULTS: Overall, 15 224 genes and 1277 functional pathways were available; of these, 99 and 225 were significant in both sets. Among replicated pathways, we found a deregulation in type-I interferon, Toll-like receptor cascade, tumour suppressor p53 protein function, platelet degranulation and activation. RNA transcripts or FAIME scores were jointly correlated with cell subtypes with strong geographical differences; neutrophils were the major determinant of gene expression in SSc-WB samples. CONCLUSIONS: We discovered a set of differentially expressed genes/pathways validated in two independent sets of patients with SSc, highlighting a number of deregulated processes that have relevance for the pathogenesis of autoimmunity and SSc.

Systemic lupus erythematosus, endothelial progenitor cells and intracellular Ca2+ signaling: A novel approach for an old disease.

Systemic lupus erythematosus (SLE) is an autoimmune multisystem disease featured by an increased cardiovascular risk that may lead to premature patient's death. It has been demonstrated that SLE patients suffer from early onset endothelial dysfunction which is due to the impairment of endogenous vascular repair mechanisms. Vascular integrity and homeostasis are maintained by endothelial progenitor cells (EPCs), which are mobilized in response to endothelial injury to replace damaged endothelial cells. Two main EPCs subpopulations exist in peripheral blood: endothelial colony forming cells (ECFCs), which represent truly endothelial precursors and can physically engraft within neovessels, and myeloid angiogenic cells (MACs), which sustain angiogenesis in a paracrine manner. Emerging evidence indicates that ECFCs/MACs are down-regulated and display compromised angiogenic activity in SLE, thereby contributing to the pathogenesis of this disease. Intracellular calcium (Ca2+) signaling plays a crucial role in maintaining vascular integrity by stimulating migration, proliferation and tube formation in both ECFCs and MACs. Herein, we illustrate the evidences that support the role played by EPCs dysfunction in SLE. Subsequently, we discuss about the hypothesis that the Ca2+ handling machinery is compromised in SLE-derived ECFCs and MACs, thereby resulting in their reduced pro-angiogenic activity. Finally, we speculate about the proposal to exploit intracellular Ca2+ signaling to improve ECFCs' reparative phenotype and suggest this strategy as a new approach to treat SLE patients.

Prevalence of Rheumatic Diseases and Quality of Life in the Saraguro Indigenous People, Ecuador: A Cross-sectional Community-Based Study.

Rheumatic diseases are more prevalent and aggressive in indigenous population groups, providing medical attention for which poses a challenge for the rheumatologist. OBJECTIVE: To estimate the prevalence of musculoskeletal (MSK) disorders and rheumatic diseases in the Saraguro indigenous people in Ecuador, as well as to identify the main factors associated with the health status of this population. METHODS: This observational, cross-sectional study focused on the community was conducted using the COPCORD (Community-Oriented Program for Control of Rheumatic Diseases) methodology. The required data were obtained using the following instruments: (1) a screening for MSK disorders and rheumatic diseases; (2) a sociodemographic questionnaire; (3) a functional capacity Health Assessment Questionnaire Disability Index questionnaire; and (4) the quality of life EQ-5D-3L (EuroQoL) questionnaire. The rheumatologists working with the indigenous community were responsible for examining and treating study participants suffering from MSK disorders. RESULTS: The study sample comprised 2687 individuals, with mean age of 44 (SD, 19.9) years, 1690 (62.9%) of whom were women; Kichwa speakers comprised 32.4% (872), and 1244 (46.3%) reported MSK pain. The most prevalent conditions were as follows: low back pain (9.3%), hand osteoarthritis (OA, 7.2%), knee OA (6.5%), rheumatic regional pain syndrome (5.8%), fibromyalgia (1.8%), and rheumatoid arthritis (1.3%). Lower education level, unemployment, cooking with firewood, and rheumatic diseases were associated with a lower quality of life. CONCLUSIONS: Musculoskeletal disorders, rheumatic diseases, and rheumatoid arthritis were found to be highly prevalent in the studied population. Rheumatoid arthritis and hand OA had the most significant impact on the quality of life.