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Objective.Genetic and environmental backgrounds influence the development of rheumatoid arthritis (RA). In Latin America, epidemiologic data are scarce. We aimed to determine the prevalence of RA in Chile in a population-based study.Methods.The National Health Survey was a cross-sectional household survey with a stratified multistage probability sample of 6233 participants performed between August 2016 and March 2017. A screening instrument for RA was applied to a random sample of 3847 subjects > 30 years old. Positive screening was defined by at least 1 of the following: 2 swollen joints for at least 4 consecutive weeks (past/present), and/or a diagnosis of arthritis in the past. Individuals with positive screening had rheumatoid factor, anticitrullinated protein antibodies, and C-reactive protein measured, as well as clinical examination performed by a rheumatologist. Self-report of doctor-diagnosed RA was also performed.Results.The screening questionnaire was applied to 2998 subjects. A positive screening was found for 783 (22.1%). Among subjects with positive screening, 493 (66%) had a clinical evaluation performed by a rheumatologist. Using the American College of Rheumatology/European League Against Rheumatism 2010 classification criteria, prevalence was 0.6% (95% CI 0.3–1.2). Prevalence was higher in women, and 3.3% of subjects self-reported having RA.Conclusion.According to this national population-based study, RA prevalence in Chile is 0.6% (0.3–1.2), a value similar to what has been found in developed countries and slightly lower than some Latin American countries. Self-reporting leads to overestimating RA.

This study aimed to illustrate how a new methodology to assess clinical trial outcome measures using a longitudinal item response theory–based model (IRM) could serve as an alternative to mixed model repeated measures (MMRM). Data from the EXACT (Exacerbation of chronic pulmonary disease tool) which is used to capture frequency, severity, and duration of exacerbations in COPD were analyzed using an IRM. The IRM included a graded response model characterizing item parameters and functions describing symptom-time course. Total scores were simulated (month 12) using uncertainty in parameter estimates. The 50th (2.5th, 97.5th) percentiles of the resulting simulated differences in average total score (drug minus placebo) represented the estimated drug effect (95%CI), which was compared with published MMRM results. Furthermore, differences in sample size, sensitivity, specificity, and type I and II errors between approaches were explored. Patients received either oral danirixin 75 mg twice daily (n = 45) or placebo (n = 48) on top of standard of care over 52 weeks. A step function best described the COPD symptoms-time course in both trial arms. The IRM improved precision of the estimated drug effect compared to MMRM, resulting in a sample size of 2.5 times larger for the MMRM analysis to achieve the IRM precision. The IRM showed a higher probability of a positive predictive value (34%) than MMRM (22%). An item model–based analysis data gave more precise estimates of drug effect than MMRM analysis for the same endpoint in this one case study. Supplementary Information The online version contains supplementary material available at 10.1208/s12248-021-00600-1.

To evaluate the different definition of refractoriness in uveitis in the literature.We systematically searched the literature in order to identify definitions of refractory noninfectious uveitis in adult patients. A search strategy in the databases of MEDLINE and Scopus was used to find articles published between January 2005 and October 2018.Definitions of corticosteroids-refractoriness were related to two main concepts: persistence of inflammation despite the use of corticosteroid and recurrences above a dosage threshold. In terms of immunomodulatory therapy and biologic agents, we observed a great variety of definitions: persistence of inflammation, number of attacks, side effects or complications, symptoms, and best-corrected visual acuity.The results of this systematic review demonstrate the current lack of consensus on the definition for refractory uveitis, regardless of the treatment being used and revealed a new terminology based on a comprehensive and operational definition for each specific category of refractoriness.

Conventional radiography of hands has been the imaging technique used for the early diagnosis of rheumatoid arthritis, considering its easy access and ability to reveal structural damage. However, it does not provide information about inflammatory activity or prognosis of this disease. On the other hand, magnetic resonance imaging is becoming the technique of choice for the early diagnosis of this disease and for the assessment of treatment response. It has a better sensitivity for the detection of inflammatory findings that cannot be identified with physical examination, analytical and conventional imaging techniques. This article reports the imaging protocol for magnetic resonance of the hands used at our institution for the diagnosis and follow-up of patients with rheumatoid arthritis. We also review the main imaging findings of the disease.

Lupus nephritis (LN) is one of the most serious manifestations of systemic lupus erythematosus (SLE). Based on studies showing the potential role of heme oxygenase-1 (HO-1), an enzyme that catalyzes the degradation of heme and has anti-inflammatory properties in SLE development, we decided to explore HO-1 in LN. Accordingly, we evaluated HO-1 levels and function in circulating and infiltrating monocytes and neutrophils of LN patients. HO-1 levels were assessed in peripheral monocytes of LN patients and controls by flow cytometry and immunofluorescence microscopy. Phagocytosis and the production of reactive oxygen species (ROS) were evaluated to determine the effect of HO-1 in monocyte function. In addition, renal biopsies with proliferative LN were used to identify HO-1 in infiltrating cells and renal tissue by immunofluorescence and immunohistochemistry. Biopsies of healthy controls (HC) and patients who underwent nephrectomy were included as controls. Circulating pro-inflammatory monocytes and activated neutrophils were increased in LN patients. HO-1 levels were decreased in all subsets of monocytes and in activated neutrophils. LN monocytes showed increased phagocytosis and higher production of ROS than those of HC. When HO-1 was induced, phagocytosis and ROS levels became similar to those of HC. HO-1 was mostly expressed in renal tubular epithelial cells (RTEC). Renal tissue of LN patients showed lower levels of HO-1 than HC, whereas infiltrating immune cells of LN showed lower levels of HO-1 than biopsies of patients who had renal surgery. HO-1 is decreased in circulating monocytes and activated neutrophils of LN patients. HO-1 levels modulate the phagocytosis of LN monocytes and ROS production. HO-1 expression in RTEC might be an attempt of self-protection from inflammation.

Systemic lupus erythematosus (SLE) is an autoimmune disease with unrestrained T‐cell and B‐cell activity towards self‐antigens. Evidence shows that apoptotic cells (ApoCells) trigger an autoreactive response against nuclear antigens in susceptible individuals. In this study, we focus on generating and characterizing tolerogenic dendritic cells (tolDCs) to restore tolerance to ApoCells. Monocyte‐derived dendritic cells (DCs) from healthy controls and patients with SLE were treated with dexamethasone and rosiglitazone to induce tolDCs. Autologous apoptotic lymphocytes generated by UV irradiation were given to tolDCs as a source of self‐antigens. Lipopolysaccharide (LPS) was used as a maturation stimulus to induce the expression of co‐stimulatory molecules and secretion of cytokines. TolDCs generated from patients with SLE showed a reduced expression of co‐stimulatory molecules after LPS stimulation compared with mature DCs. The same phenomenon was observed in tolDCs treated with ApoCells and LPS. In addition, ApoCell‐loaded tolDCs stimulated with LPS secreted lower levels of interleukin‐6 (IL‐6) and IL‐12p70 than mature DCs without differences in IL‐10 secretion. The functionality of tolDCs was assessed by their capacity to prime allogeneic T cells. TolDCs displayed suppressor properties as demonstrated by a significantly reduced capacity to induce allogeneic T‐cell proliferation and activation. ApoCell‐loaded tolDCs generated from SLE monocytes have a stable immature/tolerogenic phenotype that can modulate CD4+ T‐cell activation. These properties make them suitable for an antigen‐specific immunotherapy for SLE.

Background: Genetic and environmental backgrounds influence the development of rheumatoid arthritis (RA) and its frequency has regional variations. In Latin America epidemiologic data are scarce. Objectives: We aimed to determine the prevalence of RA in Chile as part of the National Health Survey (ENS, Encuesta Nacional de Salud). Methods: ENS was a cross-sectional household survey with a stratified multistage probability sample of 6,233 participants performed between August 2016 and March 2017. A screening instrument for RA was applied to a random sample of 3,700 subjects >30 years old.1, 2 Positive screening was defined by at least one of the following: (i) 2 swollen joints for at least 4 consecutive weeks (past or present) and/or (ii) a diagnosis of arthritis in the past. Individuals with positive screening had Rheumatoid Factor, Anti-citrullinated protein antibodies, and C-reactive protein measured and clinical examination was performed by a rheumatologist. Self-report of doctor-diagnosed RA was also performed. Results: The screening questionnaire was applied to 2,998 subjects. Seven hundred and thirty-eight (22.1%) had a positive screening. Among the subjects with a positive screening 493 (66%) had consulted a rheumatologist. Thirty-one subjects had RA according to the ACR/EULAR 2010 classification criteria, which corresponds to 0.6% (95%CI 0.3, 1.2). Three point three per cent reported having RA. Prevalence was higher in women and in high SES. Conclusion: According to this national population-based study RA prevalence in Chile is 0.6% (0.3, 1.2). This is similar to the prevalence previously reported in developed countries, which is noteworthy given the differences in sociodemographic characteristics which exist compared to Chile. Self-reporting leads to an important overestimation of RA. Our study suggests there is a higher risk of RA in subjects with high SES in this region. References [1] MacGregor AJ, Riste LK, Hazes JMW, Silman AJ. Low prevalence of rheumatoid arthritis in Black Caribbeans compared with Whites in inner city Manchester. Ann Rheum Dis 1994;53:293–7 [2] Carmona L, et al. The prevalence of rheumatoid arthritis in the general population of Spain. Rheumatology (Oxford). 2002;41(1):88-95. Disclosure of Interests: josefina duran: None declared, loreto massardo Speakers bureau: Werfen, carolina llanos: None declared, sergio iacobelli: None declared, Paula Burgos: None declared, Raquel Aguilera: None declared, maria eugenia martinez: None declared, marcela cisternas: None declared, macarena armstrong: None declared, mirentxu iruretagoyena: None declared, francisco radrigan: None declared, alvaro passi: None declared, pablo riedemann: None declared, camila cifuentes: None declared, lucero hagedorn: None declared, natalia crisostomo: None declared, alvaro cisternas: None declared, paula margozzini: None declared

Background: Teaching rheumatology to undergraduate students is every day more challenging. In order to motivate new generations and use time more efficiently, we explored new methods to incorporate active learning in our rheumatology course. Therefore, we developed a video library and turned the classical lectures into flipped classrooms. Objectives: To evaluate the impact of this new teaching method of rheumatology in a cohort of medical students at Pontificia Universidad Catolica de Chile School of Medicine. Methods: Fundamental lectures of rheumatology were recorded, edited and uploaded to YouTube, so the students were able to easily access the lessons from different electronic devices. A total of 10 videos were created, with an average duration of 6 minutes. A cohort of 120 fourth-year medical students took the rheumatology course between May 28th and June 11th of 2018. They were asked to watch the videos before the class, and during the classroom time the teacher could work on clinical classes, complement the information about the topic and answer questions. At the end of the course, the students evaluated this new methodology with a final online and anonymous survey. Performance analysis of each video was obtained from YouTube Analytics. Results: Seventy-two students completed the survey at the end of the course (60%). One hundred percent thought that watching the videos before the class was useful for their learning. Moreover, 70 students (97%) would like to continue using flipped classrooms in the future, and 1/3 of them would even use them to replace traditional lectures. Overall, the rheumatology was evaluated with a 6.8 score in a 1 – 7 scale. A 100% of this cohort approved the course. Average view duration of all videos was 4:37 minutes. Twenty-two students added positive comments about the use of flipped classroom in this course, and appreciated the videos were short enough to watch them before attending lectures. Conclusion: Advances in technology have allowed developing innovating ways to teach. Flipped classroom encourages students to adopt a more active role in the learning process. This new methodology seems to be well accepted by students and shows a promising way to motivate new generations to learn rheumatology. Acknowledgement: Supported by FONDEDOC Grant, Pontificia Universidad Catolica de Chile Disclosure of Interests: None declared

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the presence of autoantibodies against nuclear antigens, immune complex deposition, and tissue damage in the kidneys, skin, heart and lung. Because of the pathogenic role of antinuclear antibodies and autoreactive T cells in SLE, extensive efforts have been made to demonstrate how B cells act as antibody-producing or as antigen-presenting cells that can prime autoreactive T cell activation. With the discovery of new innate immune cells and inflammatory mediators, innate immunity is emerging as a key player in disease pathologies. Recent work over the last decade has highlighted the importance of innate immune cells and molecules in promoting and potentiating SLE. In this review, we discuss recent evidence of the involvement of different innate immune cells and pathways in the pathogenesis of SLE. We also discuss new therapeutics targets directed against innate immune components as potential novel therapies in SLE.

Systemic lupus erythematosus (SLE), a complex and heterogeneous autoimmune disease, represents a significant challenge for both diagnosis and treatment. Patients with SLE in Latin America face special problems that should be considered when therapeutic guidelines are developed. The objective of the study is to develop clinical practice guidelines for Latin American patients with lupus. Two independent teams (rheumatologists with experience in lupus management and methodologists) had an initial meeting in Panama City, Panama, in April 2016. They selected a list of questions for the clinical problems most commonly seen in Latin American patients with SLE. These were addressed with the best available evidence and summarised in a standardised format following the Grading of Recommendations Assessment, Development and Evaluation approach. All preliminary findings were discussed in a second face-to-face meeting in Washington, DC, in November 2016. As a result, nine organ/system sections are presented with the main findings; an 'overarching' treatment approach was added. Special emphasis was made on regional implementation issues. Best pharmacologic options were examined for musculoskeletal, mucocutaneous, kidney, cardiac, pulmonary, neuropsychiatric, haematological manifestations and the antiphospholipid syndrome. The roles of main therapeutic options (ie, glucocorticoids, antimalarials, immunosuppressant agents, therapeutic plasma exchange, belimumab, rituximab, abatacept, low-dose aspirin and anticoagulants) were summarised in each section. In all cases, benefits and harms, certainty of the evidence, values and preferences, feasibility, acceptability and equity issues were considered to produce a recommendation with special focus on ethnic and socioeconomic aspects. Guidelines for Latin American patients with lupus have been developed and could be used in similar settings. Fil: Pons Estel, Bernardo A.. Centro Regional de Enfermedades Autoinmunes y Reumáticas; Argentina Fil: Bonfa, Eloisa. Universidade de Sao Paulo; Brasil Fil: Soriano, Enrique R.. Instituto Universitario Hospital Italiano de Buenos Aires. Rectorado.; Argentina Fil: Cardiel, Mario H.. Centro de Investigación Clínica de Morelia; México Fil: Izcovich, Ariel. Hospital Alemán; Argentina Fil: Popoff, Federico. Hospital Aleman; Argentina Fil: Criniti, Juan M.. Hospital Alemán; Argentina Fil: Vásquez, Gloria. Universidad de Antioquia; Colombia Fil: Massardo, Loreto. Universidad San Sebastián; Chile Fil: Duarte, Margarita. Hospital de Clínicas; Paraguay Fil: Barile Fabris, Leonor A.. Hospital Angeles del Pedregal; México Fil: García, Mercedes A.. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina Fil: Amigo, Mary Carmen. Centro Médico Abc; México Fil: Espada, Graciela. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina Fil: Catoggio, Luis J.. Hospital Italiano. Instituto Universitario. Escuela de Medicina; Argentina Fil: Sato, Emilia Inoue. Universidade Federal de Sao Paulo; Brasil Fil: Levy, Roger A.. Universidade do Estado de Rio do Janeiro; Brasil Fil: Acevedo Vásquez, Eduardo M.. Universidad Nacional Mayor de San Marcos; Perú Fil: Chacón Díaz, Rosa. Policlínica Méndez Gimón; Venezuela Fil: Galarza Maldonado, Claudio M.. Corporación Médica Monte Sinaí; Ecuador Fil: Iglesias Gamarra, Antonio J.. Universidad Nacional de Colombia; Colombia Fil: Molina, José Fernando. Centro Integral de Reumatología; Colombia Fil: Neira, Oscar. Universidad de Chile; Chile Fil: Silva, Clóvis A.. Universidade de Sao Paulo; Brasil Fil: Vargas Peña, Andrea. Hospital Pasteur Montevideo; Uruguay Fil: Gómez Puerta, José A.. Hospital Clinic Barcelona; España Fil: Scolnik, Marina. Instituto Universitario Hospital Italiano de Buenos Aires. Rectorado.; Argentina Fil: Pons Estel, Guillermo J.. Centro Regional de Enfermedades Autoinmunes y Reumáticas; Argentina. Hospital Provincial de Rosario; Argentina Fil: Ugolini Lopes, Michelle R.. Universidade de Sao Paulo; Brasil Fil: Savio, Verónica. Instituto Universitario Hospital Italiano de Buenos Aires. Rectorado.; Argentina Fil: Drenkard, Cristina. University of Emory; Estados Unidos Fil: Alvarellos, Alejandro J.. Hospital Privado Universitario de Córdoba; Argentina Fil: Ugarte Gil, Manuel F.. Universidad Cientifica del Sur; Perú. Hospital Nacional Guillermo Almenara Irigoyen; Perú Fil: Babini, Alejandra. Instituto Universitario Hospital Italiano de Buenos Aires. Rectorado.; Argentina Fil: Cavalcanti, André. Universidade Federal de Pernambuco; Brasil Fil: Cardoso Linhares, Fernanda Athayde. Hospital Pasteur Montevideo; Uruguay Fil: Haye Salinas, Maria Jezabel. Hospital Privado Universitario de Córdoba; Argentina Fil: Fuentes Silva, Yurilis J.. Universidad de Oriente - Núcleo Bolívar; Venezuela Fil: Montandon De Oliveira E Silva, Ana Carolina. Universidade Federal de Goiás; Brasil Fil: Eraso Garnica, Ruth M.. Universidad de Antioquia; Colombia Fil: Herrera Uribe, Sebastián. Hospital General de Medellin Luz Castro de Gutiérrez; Colombia Fil: Gómez Martín, DIana. Instituto Nacional de la Nutrición Salvador Zubiran; México Fil: Robaina Sevrini, Ricardo. Universidad de la República; Uruguay Fil: Quintana, Rosana M.. Hospital Provincial de Rosario; Argentina. Centro Regional de Enfermedades Autoinmunes y Reumáticas; Argentina Fil: Gordon, Sergio. Hospital Interzonal General de Agudos Dr Oscar Alende. Unidad de Reumatología y Enfermedades Autoinmunes Sistémicas; Argentina Fil: Fragoso Loyo, Hilda. Instituto Nacional de la Nutrición Salvador Zubiran; México Fil: Rosario, Violeta. Hospital Docente Padre Billini; República Dominicana Fil: Saurit, Verónica. Hospital Privado Universitario de Córdoba; Argentina Fil: Appenzeller, Simone. Universidade Estadual de Campinas; Brasil Fil: Dos Reis Neto, Edgard Torres. Universidade Federal de Sao Paulo; Brasil Fil: Cieza, Jorge. Hospital Nacional Edgardo Rebagliati Martins; Perú Fil: González Naranjo, Luis A.. Universidad de Antioquia; Colombia Fil: González Bello, Yelitza C.. Ceibac; México Fil: Collado, María Victoria. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Sarano, Judith. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Retamozo, Maria Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; Argentina Fil: Sattler, María E.. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; Argentina Fil: Gamboa Cárdenas, Rocio V.. Hospital Nacional Guillermo Almenara Irigoyen; Perú Fil: Cairoli, Ernesto. Universidad de la República; Uruguay Fil: Conti, Silvana M.. Hospital Provincial de Rosario; Argentina Fil: Amezcua Guerra, Luis M.. Instituto Nacional de Cardiologia Ignacio Chavez; México Fil: Silveira, Luis H.. Instituto Nacional de Cardiologia Ignacio Chavez; México Fil: Borba, Eduardo F.. Universidade de Sao Paulo; Brasil Fil: Pera, Mariana A.. Hospital Interzonal General de Agudos General San Martín; Argentina Fil: Alba Moreyra, Paula B.. Universidad Nacional de Córdoba. Facultad de Medicina; Argentina Fil: Arturi, Valeria. Hospital Interzonal General de Agudos General San Martín; Argentina Fil: Berbotto, Guillermo A.. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; Argentina Fil: Gerling, Cristian. Hospital Interzonal General de Agudos Dr Oscar Alende. Unidad de Reumatología y Enfermedades Autoinmunes Sistémicas; Argentina Fil: Gobbi, Carla Andrea. Universidad Nacional de Córdoba. Facultad de Medicina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Gervasoni, Viviana L.. Hospital Provincial de Rosario; Argentina Fil: Scherbarth, Hugo R.. Hospital Interzonal General de Agudos Dr Oscar Alende. Unidad de Reumatología y Enfermedades Autoinmunes Sistémicas; Argentina Fil: Brenol, João C. Tavares. Hospital de Clinicas de Porto Alegre; Brasil Fil: Cavalcanti, Fernando. Universidade Federal de Pernambuco; Brasil Fil: Costallat, Lilian T. Lavras. Universidade Estadual de Campinas; Brasil Fil: Da Silva, Nilzio A.. Universidade Federal de Goiás; Brasil Fil: Monticielo, Odirlei A.. Hospital de Clinicas de Porto Alegre; Brasil Fil: Seguro, Luciana Parente Costa. Universidade de Sao Paulo; Brasil Fil: Xavier, Ricardo M.. Hospital de Clinicas de Porto Alegre; Brasil Fil: Llanos, Carolina. Universidad Católica de Chile; Chile Fil: Montúfar Guardado, Rubén A.. Instituto Salvadoreño de la Seguridad Social; El Salvador Fil: Garcia De La Torre, Ignacio. Hospital General de Occidente; México Fil: Pineda, Carlos. Instituto Nacional de Rehabilitación; México Fil: Portela Hernández, Margarita. Umae Hospital de Especialidades Centro Medico Nacional Siglo Xxi; México Fil: Danza, Alvaro. Hospital Pasteur Montevideo; Uruguay Fil: Guibert Toledano, Marlene. Medical-surgical Research Center; Cuba Fil: Reyes, Gil Llerena. Medical-surgical Research Center; Cuba Fil: Acosta Colman, Maria Isabel. Hospital de Clínicas; Paraguay Fil: Aquino, Alicia M.. Hospital de Clínicas; Paraguay Fil: Mora Trujillo, Claudia S.. Hospital Nacional Edgardo Rebagliati Martins; Perú Fil: Muñoz Louis, Roberto. Hospital Docente Padre Billini; República Dominicana Fil: García Valladares, Ignacio. Centro de Estudios de Investigación Básica y Clínica; México Fil: Orozco, María Celeste. Instituto de Rehabilitación Psicofísica; Argentina Fil: Burgos, Paula I.. Pontificia Universidad Católica de Chile; Chile Fil: Betancur, Graciela V.. Instituto de Rehabilitación Psicofísica; Argentina Fil: Alarcón, Graciela S.. Universidad Peruana Cayetano Heredia; Perú. University of Alabama at Birmingahm; Estados Unidos

Background Systemic lupus erythematous (SLE), is an autoimmune disease characterized by autoantibody synthesis and inflammation. During disease course, up to 70% of SLE patients will develop LN. Emerging evidence has demonstrated that infiltrating monocytes and macrophages are associated with LN pathogenesis. We have previously demonstrated that HO-1, a haem-degrading enzyme with anti-inflammatory properties is decreased in peripheral monocytes of SLE patients. Therefore, we decided to explore the contribution of HO-1 expression to LN pathogenesis. Objectives To explore the role of HO-1 in modulating innate immunity through a cytoprotective effect in monocytes of LN nephritis patients. Accordingly, we examined the expression of HO-1 in circulating monocytes, and the effect of HO-1 induction in reactive oxygen species (ROS) production and the phagocytic activity of monocytes from peripheral blood of LN patients and healthy controls (HC). Methods SLE patients with proliferative LN confirmed by renal biopsy (Class III, IV or V ISN/RPS) were recruited at Hospital Clinico of PUC. All individuals signed an informed consent form. Monocytes were purified from peripheral blood mononuclear cells (PBMCs) of LN patients and HC using pan-monocytes MACS kit. Subpopulations of monocytes and HO-1 expression were measured by FACS. ROS was determined using CellRox Kit. The phagocytic ability of monocytes was assessed by FACS and the total phagocytosis was calculated as the percentage of cells with engulfed beads. Results We found that monocytes from LN patients show significant differences when compared to HC in all the parameters analyzed. The percentage of CD16+ inflammatory monocytes was higher in LN patients (6.72±0.98%) compared to HC (4.07±0.48%) (p Conclusions Decreased HO-1 expression in circulating monocytes of LN patients leads to higher ROS production and phagocitic activity. ROS level and phagocytosis are reduced when we induce HO-1 expression with CoPP. We propose that HO-1 induction might exert a cytoprotective role in LN by regulating innate immunity. FONDECYT N° 1150173. Acknowledgements We would like to extend our appreciation to all the volunteers that participated in this study. Disclosure of Interest None declared

International audience; Accumulating evidence suggests a close bidirectional communication and regulation between the neu-roendocrine and immune systems. Thyroid hormones (THs) can exert responses in various immune cells, e.g., monocytes, macrophages, natural killer cells, and lymphocytes, affecting several inflammation-related processes (such as, chemotaxis, phagocytosis, reactive oxygen species generation, and cytokines production). The interactions between the endocrine and immune systems have been shown to contribute to pathophysiological conditions, including sepsis, inflammation, autoimmune diseases and viral infections. Under these conditions, TH therapy could contribute to restoring normal physiological functions. Here we discuss the effects of THs and thyroid stimulating hormone (TSH) on the immune system and the contribution to inflammation and pathogen clearance, as well as the consequences of thyroid pathologies over the function of the immune system.

One of the major goals in the research of autoimmune diseases is to develop specific therapies to regulate the expression and function of gene products that could contribute to restoring tolerance to self-constituents and replace conventional systemic immunosuppression, which is associated with important undesired side effects. Although significant progress has been made on the understanding of the pathogenesis of autoimmunity, therapies for these ailments have not seen a change. During the last decade, different strategies such as pharmacologic or gene therapy modulation of heme oxygenase-1 (HO-1) and the administration of its metabolic product, carbon monoxide (CO), have been shown to display beneficial immunoregulatory and cytoprotective properties. In different experimental autoimmune conditions, such as Experimental autoimmune encephalomyelitis, type-1 diabetes and systemic lupus erythematosus, genetic or pharmacological modulation of HO-1, as well as delivery of CO have shown to ameliorate disease progression. Furthermore, it has been demonstrated that dendritic cell and monocyte function can be modulated by HO-1 and/or CO. In this article, recent data related to the immunoregulatory properties of HO-1/CO will be discussed, focusing on their potential therapeutic use to treat autoimmune diseases.

Background— A recent case-control study suggested a benefit of hydroxychloroquine (HCQ) in lowering the risk of cardiac manifestations of neonatal lupus (cardiac-NL) in pregnancies of anti-SSA/Ro–positive patients with systemic lupus erythematosus. A historical cohort assembled from 3 international databases was used to evaluate whether HCQ reduces the nearly 10-fold increase in risk of recurrence of cardiac-NL independently of maternal health status. Methods and Results— Two hundred fifty-seven pregnancies of anti-SSA/Ro-positive mothers (40 exposed and 217 unexposed to HCQ) subsequent to the birth of a child with cardiac-NL were identified from 3 databases (United States, England, and France). Exposure was defined as the sustained use of HCQ throughout pregnancy with initiation before 10 weeks of gestation. The recurrence rate of cardiac-NL in fetuses exposed to HCQ was 7.5% (3 of 40) compared with 21.2% (46 of 217) in the unexposed group ( P =0.050). Although there were no deaths in the exposed group, the overall case fatality rate of the cardiac-NL fetuses in the unexposed group was 21.7%. In a multivariable analysis that adjusted for database source, maternal race/ethnicity, and anti-SSB/La status, HCQ use remained significantly associated with a decreased risk of cardiac-NL (odds ratio, 0.23; 95% confidence interval, 0.06–0.92; P =0.037). Similar results were obtained with propensity score analysis, an alternative approach to adjust for possible confounding by indication. Conclusion— Aggregate data from a multinational effort show that in mothers at high risk of having a child with cardiac-NL, the use of HCQ may protect against recurrence of disease in a subsequent pregnancy.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple functional alterations affecting immune cells, such as B cells, T cells, dendritic cells (DCs) and monocytes. During SLE, the immunogenicity of monocytes and DCs is significantly up-regulated, promoting the activation of self-reactive T cells. Accordingly, it is important to understand the contribution of these cells to the pathogenesis of SLE and the mechanisms responsible for their altered functionality during disease. One of the key enzymes that control monocyte and DC function is haem oxygenase-1 (HO-1), which catalyses the degradation of the haem group into biliverdin, carbon monoxide and free iron. These products possess immunosuppressive and anti-inflammatory capacities. The main goal of this work was to determine HO-1 expression in monocytes and DCs from patients with SLE and healthy controls. Hence, peripheral blood mononuclear cells were obtained from 43 patients with SLE and 30 healthy controls. CD14(+) monocytes and CD4(+) T cells were sorted by FACS and HO-1 expression was measured by RT-PCR. In addition, HO-1 protein expression was determined by FACS. HO-1 levels in monocytes were significantly reduced in patients with SLE compared with healthy controls. These results were confirmed by flow cytometry. No differences were observed in other cell types, such as DCs or CD4(+) T cells, although decreased MHC-II levels were observed in DCs from patients with SLE. In conclusion, we found a significant decrease in HO-1 expression, specifically in monocytes from patients with SLE, suggesting that an imbalance of monocyte function could be partly the result of a decrease in HO-1 expression.

Objective Cutaneous disease associated with placental transport of maternal anti-SSA/Ro or anti-SSB/La antibodies is transient, and children often appear to be otherwise healthy. However, the impact of this manifestation of neonatal lupus (NL) on the risk of cardiac disease occurring in a future pregnancy is critical for family counseling and for powering preventive trials. The purpose of this study was to determine the recurrence rates of NL, with specific focus on cardiac NL following cutaneous NL in a child enrolled in the Research Registry for Neonatal Lupus (RRNL). Methods Fifty-eight families who were enrolled in the RRNL met the following inclusion criteria for our study: maternal anti-SSA/Ro or anti-SSB/La antibodies, a child with cutaneous NL, and a pregnancy subsequent to the child with cutaneous NL. Results The majority of the 58 mothers (78%) were Caucasian. Of 77 pregnancies that occurred following the birth of a child with cutaneous NL, the overall recurrence rate for any manifestation of NL was 49% (95% confidence interval [95% CI] 37–62%); 14 pregnancies (18.2%) were complicated by cardiac NL, 23 (29.9%) by cutaneous NL, and 1 (1.3%) by hematologic/hepatic NL. A subset analysis was restricted to the 39 children who were born after the initial child with cutaneous NL had been enrolled in the RRNL. The overall recurrence rate for NL was 36% (95% CI 20–52%); 5 pregnancies (12.8%) were complicated by cardiac NL and 9 (23.1%) by cutaneous NL. There were no significant differences in the following maternal risk factors for having a subsequent child with cardiac or cutaneous NL: age, race/ethnicity, anti-SSB/La status, diagnosis, use of nonfluorinated steroids, or breastfeeding. The sex of the subsequent fetus did not influence the development of cardiac or cutaneous NL. Conclusion Based on data from this large cohort, the identification of cutaneous NL in an anti-SSA/Ro antibody–exposed infant is particularly important, since it predicts a 6–10-fold risk of a subsequent child developing cardiac NL.

Objective Identifying the frequency of recurrent cardiac manifestations of neonatal lupus (NL) in a second child is critical to understanding the pathogenesis of anti-SSA/Ro–mediated injury and would improve counseling strategies regarding future pregnancies and power the design of clinical prevention trials. Accordingly, this study was undertaken to address the recurrence rates of cardiac NL and associated risk factors in a large US-based cohort. Methods Families enrolled in the Research Registry for Neonatal Lupus were evaluated for rates of recurrence of cardiac NL and potential risk factors, with a focus on pregnancies immediately following the birth of an affected child. Results The overall rate of recurrence of cardiac NL in 161 pregnancies of 129 mothers with anti-SSA/Ro antibodies was 17.4% (95% confidence interval 11.1–23.6%). Analysis of the potential risk factors among 129 mothers with a pregnancy immediately following the birth of a child with cardiac NL showed that the maternal diagnosis was not associated with the outcome in a subsequent pregnancy. In this group, 23% of mothers who were either asymptomatic or had an undifferentiated autoimmune syndrome, compared with 14% of mothers with systemic lupus erythematosus or Sjogren's syndrome, had a second child with cardiac NL (P = 0.25). The recurrence rate was not statistically significantly different in mothers who had taken steroids compared with those who had not taken steroids (16% versus 21%; P = 0.78). The antibody status of the mother was not predictive of outcome in subsequent pregnancies. Moreover, death of the first child with cardiac NL was not predictive of recurrence of cardiac NL in a subsequent pregnancy (P = 0.31). The risk of cardiac NL was similar between male and female children (17.2% versus 18.3%; P = 1.0). Conclusion In this cohort, the overall recurrence rate for cardiac NL was 17%. The recurrence rate appeared to be unaffected by maternal health, use of steroids, antibody status, severity of cardiac disease in the first affected child, or sex of the subsequent child.

We evaluated the efficacy of dexamethasone (DEX) in anti-SSA/Ro-exposed fetuses newly diagnosed with congenital heart block. Previous use of DEX has been anecdotal with varying reports of therapeutic benefit. This was a multicenter, open-label, nonrandomized study involving 30 pregnancies treated with DEX (22 with third-degree block, 6 with second-degree block, 2 with first-degree block) and 10 untreated (9 with third-degree block, 1 with first-degree block). Initial median ventricular rates, age at diagnosis, and degree of cardiac dysfunction were similar between groups. Six deaths occurred in the DEX group. There was no reversal of third-degree block with therapy or spontaneously. In fetuses treated with DEX, 1/6 with second-degree block progressed to third-degree block and 3 remained in second-degree block (postnatally 1 paced, 2 progressed to third degree); 2 reverted to normal sinus rhythm (NSR; postnatally 1 progressed to second degree). DEX reversed the 2 fetuses with first-degree block to NSR by 7 days with no regression at discontinuation. Absent DEX, the 1 with first-degree block detected at 38 weeks had NSR at birth (overall stability or improvement in 4 of 8 in the DEX group vs 1 of 1 in the non-DEX group). Median gestational birth age was 37 weeks in the DEX group versus 38 weeks in the non-DEX group (p = 0.019). Prematurity and small size for gestational age were restricted to the DEX group. Pacemaker use and growth parameters at birth and 1 year were similar between groups. In conclusion, these data confirm the irreversibility of third-degree block and progression of second- to third-degree block despite DEX. A potential benefit of DEX in reversing first- or second-degree block was supported in rare cases but should be weighed against potential steroid side effects such as growth restriction.

UNLABELLED 166 patients with congenital dislocation of the hip, ranging from 10 months to 5 years old, were operated between 1958 and 1971. 140 patients were women (84%) and 26 patients were men (16%). 96 patients had unilateral and 70 patients had bilateral dislocation; that makes a total of 236 dislocated hips. 61 patients with bilateral hip dislocation were operated simultaneously on both hips. All the patients were treated with adductor tenotomy and open reduction through Smith Petersen incision with section or elongation of the psoas tendon. The postoperative immobilization consisted in a period of one month pelvic toecast followed by 2 plaster casts with abduction rod during 3 to 5 months. The postoperatory follow-up ranged from 9 years to 26 years, 2 months; average 14 years, 5 months. The clinical evaluation comprises pain, hip mobility, gait and muscle power. RESULTS excellent 138 (59%); good 66 (28%); fair 29 (12%); and poor 3 (1%). The radiological evaluation considered: Mose; acetabular femoral head index; Wiberg's CD-angle; cervico-diaphysiary angle and radial quotient. RESULTS normal 5 (2%); excellent 44 (19%); good 78 (33%); subtotal 54%; fair 90 (38%), and poor 19 (8%). Complications (hips); infections 12 (5%); 3 of them deep ones (1%); residual subluxation 19 (8%); reluxation 1 (0.5%). Isquemic necrosis Grade II of Tonnis 31 (13%); Grade III 2 (1%) and Grade IV 1 (0.5%).

International audience; Systemic lupus erythematosus (SLE) is a heterogeneous disease in which excessive inflammation, autoantibodies and complement activation lead to multisystem tissue damage. The contribution of the individual genetic composition has been extensively studied, and several susceptibility genes related to immune pathways that participate in SLE pathogenesis have been identified. It has been proposed that SLE takes place when susceptibility factors interact with environmental stimuli leading to a deregulated immune response. Experimental evidence suggests that such events are related to the failure of T-cell and B-cell suppression mediated by defects in cell signalling, immune tolerance and apoptotic mechanism promoting autoimmunity. In addition, it has been reported that dendritic cells (DCs) from SLE patients, which are crucial in the modulation of peripheral tolerance to self-antigens, show an increased ratio of activating/inhibitory receptors on their surfaces. This phenotype and an augmented expression of co-stimulatory molecules is thought to be critical for disease pathogen-esis. Accordingly, tolerogenic DCs can be a potential strategy for developing antigen-specific therapies to reduce detrimental inflammation without causing systemic immunosuppression. In this review article we discuss the most relevant data relative to the contribution of DCs to the triggering of SLE.

Dendritic cells (DCs) play a key role in the activation of the immune response against pathogens, as well as in the modulation of peripheral tolerance to self-antigens (Ags). Furthermore, an imbalance in the activating/inhibitory receptors expressed on the surface of DCs has been linked to increased susceptibility to develop autoimmune diseases underscoring their immunogenicity potential. It has been described that modulation of activating or inhibitory molecules expressed by DCs, such as CD86, TLRs, PDL-1 and FcγRs, can define the immunogenic phenotype. On the other hand, T cell tolerance can be achieved by tolerogenic DCs, which have the capacity of blocking undesired autoimmune responses in several experimental models, mainly by inducing T cell anergy, expansion of regulatory T cells and limiting B cell responses. Due to the lack of specific therapies to treat autoimmune disorders and the tolerogenic capacity of DCs shown in experimental autoimmune disease models, autologous tolDCs are a potential therapeutic strategy for fine-tuning the immune system and reestablishing tolerance in human autoimmune diseases. New advances in the role of DCs in systemic lupus erythematosus (SLE) pathogenesis and the identification of pathogenic self-Ags may favor the development of novel tolDC based therapies with a major clinical impact. In this review, we discuss recent data relative to the role of DCs in systemic autoimmune pathogenesis and their use as a therapy to restore tolerance. Fil: Mackern Oberti, Juan Pablo. Pontificia Universidad Católica de Chile; Chile. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina Fil: Llanos, Carolina. Pontificia Universidad Católica de Chile; Chile Fil: Vega, Fabián. Pontificia Universidad Católica de Chile; Chile Fil: Salazar-Onfray, Flavio. Universidad de Chile; Chile Fil: Riedel, Claudia A.. Universidad Andrés Bello; Chile. Inserm; Francia Fil: Bueno, Mirian Susana. Pontificia Universidad Católica de Chile; Chile. Inserm; Francia Fil: Kalergis, Alexis. Pontificia Universidad Católica de Chile; Chile. Inserm; Francia

Summary Systemic lupus erythematosus is characterized by the presence of circulating anti-nuclear antibodies (ANA) and systemic damage that includes nephritis, haematological manifestations and pulmonary compromise, among others. Although major progress has been made in elucidating the molecular mechanisms responsible for autoimmunity, current therapies for lupus have not improved considerably. Because the exposure of carbon monoxide (CO) has been shown to display beneficial immunoregulatory properties in different immune-mediated diseases, we investigated whether CO therapy improves lupus-related kidney injury in lupus mice. MRL-Faslpr lupus mice were exposed to CO and disease progression was evaluated. ANA, leucocyte-infiltrating populations in spleen, kidney and lung and kidney lesions, were measured. CO therapy significantly decreased the frequency of activated B220+ CD4− CD8− T cells in kidneys and lungs, as well as serum levels of ANA. Furthermore, we observed that CO therapy reduced kidney injury by decreasing proliferative glomerular damage and immune complexes deposition, decreased proinflammatory cytokine production and finally delayed the impairment of kidney function. CO exposure ameliorates kidney and lung leucocyte infiltration and delays kidney disease in MRL-Faslpr lupus mice. Our data support the notion that CO could be explored as a potential new therapy for lupus nephritis.

To investigate the influence of -308 tumour necrosis factor-alpha (TNFalpha) promoter polymorphism and circulating TNFalpha levels in the clinical response to adalimumab treatment in patients with rheumatoid arthritis (RA).Eighty-one patients with active RA were genotyped for the -308 TNFalpha polymorphism by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis and subdivided into two groups for each polymorphism (G/A and G/G genotype). All received 40 mg of adalimumab subcutaneously every other week. We compared the groups' clinical responses to adalimumab at 8, 16, and 24 weeks using the Disease Activity Score in 28 joints (DAS28).Both groups showed a significant improvement from baseline. A significant difference between groups was found at week 24. We found that 88.2% of G/G versus 68.4% of G/A for the -308 polymorphism were DAS28 responders (p = 0.05). The score improvement at week 24 was 2.5 +/- 1.3 in the G/G group and 1.8 +/- 1.3 in the G/A group for the -308 polymorphism (p = 0.04). The median of serum TNFalpha levels of the G/A group were lower than those of the G/G group, and statistically different at weeks 8 and 24 (p0.039 and p0.043). When comparing baseline levels to those achieved at 8, 16, and 24 weeks for the whole group, only responder patients showed a statistically significant overall increase in TNFalpha over time (p0.000001).A relationship between DAS28 improvement, the -308 G/G polymorphism, and increased circulating TNFalpha levels was found in Chilean RA patients treated with adalimumab.

We report the case of a 50-year-old man who presented with systemic vasculitis associated with Fasciola hepatica infection. The patient presented with severe skin, kidney, spleen, ophthalmic, and neurological compromise. An immunological examination for primary vasculitis was negative and other infections were discounted by microbiological and serological analyses. The patient was treated with steroids without clinical response. The Fasciola hepatica infection was confirmed by the presence of specific immunoglobulin G (IgG) serum antibodies detected by a quantitative enzyme-linked immunosorbent assay (ELISA) with an optical density (OD) of 0.483 OD units (normal value

Longitudinal studies aimed at evaluating patients clinical response to specific therapeutic treatments are frequently summarized in incomplete datasets due to missing data. Multivariate statistical procedures use only complete cases, deleting any case with missing data. MI and MIANALYZE procedures of the SAS software perform multiple imputations based on the Markov Chain Monte Carlo method to replace each missing value with a plausible value and to evaluate the efficiency of such missing data treatment. The objective of this work was to compare the evaluation of differences in the increase of serum TNF concentrations depending on the ‐308 TNF promoter genotype of rheumatoid arthritis (RA) patients receiving anti-TNF therapy with and without multiple imputations of missing data based on mixed models for repeated measures. Our results indicate that the relative efficiency of our multiple imputation model is greater than 98% and that the related inference was significant (p-value < 0.001). We established that under both approaches serum TNF levels in RA patients bearing the G/A ‐308 TNF promoter genotype displayed a significantly (p-value < 0.0001) increased ability to produce TNF over time than the G/G patient group, as they received successively doses of anti-TNF therapy. Key terms: multiple imputation, mixed model, TNF polymorphism.

Systemic autoimmune diseases can damage nearly every tissue or cell type of the body. Although a great deal of progress has been made in understanding the pathogenesis of autoimmune diseases, current therapies have not been improved, remain unspecific and are associated with significant side effects. Because dendritic cells (DCs) play a major role in promoting immune tolerance against self-antigens (self-Ags), current efforts are focusing at generating new therapies based on the transfer of tolerogenic DCs (tolDCs) during autoimmunity. However, the feasibility of this approach during systemic autoimmunity has yet to be evaluated. TolDCs may ameliorate autoimmunity mainly by restoring T cell tolerance and, thus, indirectly modulating autoantibody development. In vitro induction of tolDCs loaded with immunodominant self-Ags and subsequent cell transfer to patients would be a specific new therapy that will avoid systemic immunosuppression. Herein, we review recent approaches evaluating the potential of tolDCs for the treatment of systemic autoimmune disorders.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that is characterized by the over production of auto-antibodies against nuclear components. Thus, SLE patients have increased morbidity and, mortality compared to healthy individuals. Available therapies are not curative and are associated with unwanted adverse effects. During the last few years, important advances in immunology research have provided rheumatologists with new tools for designing novel therapies for treating autoimmunity. However, the complex nature of SLE has played a conflicting role, hindering breakthroughs in therapeutic development. Nonetheless, new advances about SLE pathogenesis could open a fruitful line of research. Dendritic cells (DCs) have been established as essential players in the mechanisms underlying SLE, making them attractive therapeutic targets for fine-tuning the immune system. In this review, we discuss the recent advances made in revealing the mechanisms of SLE pathogenesis, with a focus on the use of DCs as a target for therapy development.

International audience; Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple alterations affecting the normal function of immune cells, such as lymphocytes, dendritic cells (DCs) and monocytes. Although the understanding of autoimmunity has significantly increased, the breakthrough in effective therapies has been modest, making necessary the development of new therapeutic strategies. Here we propose that a new potential target for therapy is haem oxygenase-1 (HO-1), an enzyme that catalyses the degradation of the haem group into biliverdin, carbon monoxide (CO) and Fe 2+. These products exhibit immunosuppressive and anti-inflammatory effects, which can contribute to improving tolerance during organ transplantation. Because HO-1 is highly expressed by immune cells involved in SLE pathogenesis, such as monocytes and DCs, we evaluated whether induction of HO-1 expression or the administration of CO could ameliorate disease in the FccRIIb knockout (KO) mouse model for SLE. We found that CO administration decreased the expansion of CD11b + cells, prevented the decline of regulatory T cells and reduced anti-histone antibodies observed in untreated FccRIIb KO mice. Furthermore, CO-treated animals and HO-1 induction showed less kidney damage compared with untreated mice. These data suggest that HO-1 modulation and CO administration can ameliorate autoimmunity and prevent the lupus symptoms shown by FccRIIb KO mice, highlighting HO-1 as a potential new target for autoimmune therapy.

Objective. The autopsy and clinical information on children dying with anti-SSA/Ro-associated cardiac manifestations of neonatal lupus (cardiac NL) were examined to identify patterns of disease, gain insight into pathogenesis and enhance the search for biomarkers and preventive therapies. Methods. A retrospective analysis evaluating reports from 18 autopsies of cardiac NL cases and clinical data from the Research Registry for Neonatal Lupus was performed. Results. Of the 18 cases with autopsies, 15 had advanced heart block, including 3 who died in the second trimester, 9 in the third trimester and 3 post-natally. Three others died of cardiomyopathy without advanced block, including two dying pre-natally and one after birth. Pathological findings included fibrosis/calcification of the atrioventricular (AV) node, sinoatrial (SA) node and bundle of His, endocardial fibroelastosis (EFE), papillary muscle fibrosis, valvular disease, calcification of the atrial septum and mononuclear pancarditis. There was no association of pathology with the timing of death except that in the third-trimester deaths more valvular disease and/or extensive conduction system abnormalities were observed. Clinical rhythm did not always correlate with pathology of the conduction system, and the pre-mortem echocardiograms did not consistently detect the extent of pathology. Conclusion. Fibrosis of the AV node/distal conduction system is the most characteristic histopathological finding. Fibrosis of the SA node and bundle of His, EFE and valve damage are also part of the anti-Ro spectrum of injury. Discordance between echocardiograms and pathology findings should prompt the search for more sensitive methods to accurately study the phenotype of antibody damage.

Background— Cardiac manifestations of neonatal lupus include conduction disease and, rarely, an isolated cardiomyopathy. This study was initiated to determine the mortality and morbidity of cardiac neonatal lupus and associated risk factors in a multi–racial/ethnic US-based registry to provide insights into the pathogenesis of antibody-mediated injury and data for counseling. Methods and Results— Three hundred twenty-five offspring exposed to maternal anti-SSA/Ro antibodies with cardiac neonatal lupus met entry criteria. Maternal, fetal echocardiographic, and neonatal risk factors were assessed for association with mortality. Fifty-seven (17.5%) died, 30% in utero. The probability of in utero death was 6%. The cumulative probability of survival at 10 years for a child born alive was 86%. Fetal echocardiographic risk factors associated with increased mortality in a multivariable analysis of all cases included hydrops and endocardial fibroelastosis. Significant predictors of in utero death were hydrops and earlier diagnosis, and of postnatal death were hydrops, endocardial fibroelastosis, and lower ventricular rate. Isolated heart block was associated with a 7.8% case fatality rate, whereas the concomitant presence of dilated cardiomyopathy or endocardial fibroelastosis quadrupled the case fatality rate. There was a significantly higher case fatality rate in minorities compared with whites, who were at a lower risk of hydrops and endocardial fibroelastosis. Pacing was required in 70%; cardiac transplantation was required in 4 children. Conclusion— Nearly one fifth of fetuses who develop cardiac neonatal lupus die of complications predicted by echocardiographic abnormalities consistent with antibody-associated disease beyond the atrioventricular node. The disparity in outcomes observed between minorities and whites warrants further investigation.

Congenital heart block (CHB), a manifestation of neonatal lupus, is associated with maternal anti-Ro/SSA and anti-La/SSB autoantibodies and recurs in ∼18% of subsequent pregnancies. This study was undertaken to investigate the effect of the idiotype:antiidiotype (Id:anti-Id) antibody ratio in the ability of intravenous immunoglobulin (IVIG) administered during subsequent pregnancies to prevent CHB.We studied 16 anti-Ro/SSA and anti-La/SSB-positive pregnant women from the Preventive IVIG Therapy for Congenital Heart Block study who had previously given birth to a child with neonatal lupus. In 3 of the mothers, the study pregnancy resulted in the birth of a child with neonatal lupus (2 with CHB and 1 with rash). Sequential serum samples were obtained from all mothers immediately before the administration of IVIG during pregnancy and were evaluated for antibodies against the major B cell epitope 349-364aa of La/SSB (idiotype) and its antiidiotypic antibodies.Following IVIG treatment, serum titers of anti-La(349-364) (Id antibodies) decreased in 80% of the mothers, and in 60% an increase in anti-Id antibodies against anti-La(349-364) was observed. The Id:anti-Id ratio was significantly higher in mothers whose offspring developed neonatal lupus compared to mothers who gave birth to a healthy child (P0.0001). Removal of anti-Id antibodies substantially increased the reactivity against La(349-364) in sera from 5 of 7 mothers tested. All IVIG preparations were examined for Id and anti-Id antibody activity. IVIG from batches administered to mothers who gave birth to a healthy child had an Id:anti-Id activity ratio of1, in contrast to that given to mothers who gave birth to a child with neonatal lupus. Addition of the IVIG preparations to the maternal sera further enhanced antiidiotypic activity (by up to 4.7-fold) in 11 of 13 patients studied.This is the first study in humans to demonstrate that IVIG influences the Id-anti-Id network of a specific pathogenic autoantibody. Specifically, we showed that IVIG enhanced the anti-Id antibody response in pregnant women with anti-La/SSB antibodies. A high Id:anti-Id ratio in both the IVIG preparation and the maternal serum may explain the absence of an effect of IVIG in preventing recurrent neonatal lupus in some cases.

Under healthy conditions, there is a balance between tolerance to self-tissue constituents and immunity against foreign antigens. Autoimmunity diseases (AD) take place when that equilibrium is disrupted and the immune response is directed to self-antigens, leading to injury or destruction of host tissues. The mechanisms conducing to the loss of immune tolerance remain largely unknown. The recent appearance of biological therapies has contributed to significant reduction in morbidity. However, currently available therapies are associated with important side effects and work only as palliative treatments. Dendritic cells (DCs) have emerged as key players in developing and maintaining adaptive immunity due to their capacity to prime and modulate T cell function. Therefore, because DCs work as central modulators of immune tolerance, it is likely that alterations in their function can lead to the onset of autoimmune-inflammatory diseases. By modulating DC function, novel pathways in antigen-specific tolerance could be established. In this article, the possible contribution of altered DC-T cell interactions to the onset of autoimmunity are discussed. In addition, we expand on the notion that some of the functions of these cells could be relevant targets for intervening therapies aimed to restore the balance or even prevent the loss of tolerance.

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease characterized by an excessive production of auto-antibodies against double-stranded DNA, nucleosomes, ribonucleoproteins and other nuclear components. Accumulation of self-reactive antibodies leads to immune complex deposition in blood vessels, activation of macrophages and complement, inflammation and subsequent tissue damage in several organs, such as the heart, kidneys, lungs and central nervous system. Although significant progress has been made in the past 30 years of research, no effective specific treatments are currently available. The course of this disease remains unpredictable and patients diagnosed with SLE face long-term treatments with the subsequent economic, social and health burden. From the immunological perspective, SLE is a genetic- and environment-controlled disease that involves almost every constituent of the immune system, including both innate and adaptive immunity. Therefore, several immune cell types and molecules could be susceptible for intervention and modulation to develop more effective and specific treatments. More importantly, such therapies are likely not to induce complete immunosuppression and show reduced side effects on patients. In this article we discuss recent work in the field of SLE pathogenesis with a focus on data that provide clues for therapy design and new treatments.

Background Based on the potential involvement of Toll-like receptor (TLR) signalling in the pathogenesis of neonatal lupus (NL), it was hypothesised that fetal exposure to hydroxychloroquine (HCQ), a TLR inhibitor, might reduce the risk of anti-SSA/Ro/SSB/La antibody-associated cardiac manifestations of NL (cardiac-NL). Methods Cardiac-NL children (N=50) and controls (N=151) were drawn from the following overlapping pregnancy studies: Research Registry for NL; PR Interval and Dexamethasone Evaluation in Cardiac-NL; and Predictors of Pregnancy Outcomes: Biomarkers in Antiphospholipid Syndrome and Systemic Lupus Erythematosus (SLE). Pregnancies met the following inclusion criteria: documentation of maternal anti-SSA/Ro/SSB/La antibodies at pregnancy, confirmation of medication use and child9s outcome, a diagnosis of SLE before pregnancy and birth by 31 December 2007. Results Seven (14%) of the cardiac-NL children were exposed to HCQ compared with 56 (37%) of the controls (p=0.002; OR 0.28; 95% CI 0.12 to 0.63). Cases and controls were similar with respect to demographic and antibody status. Multivariable analysis adjusting for birth year, maternal race/ethnicity, antibody status, non-fluorinated steroid use and prior cardiac-NL risk yielded an OR associated with HCQ use of 0.46 (95% CI 0.18 to 1.18; p=0.10). Conclusion This case–control study suggests that, in mothers with SLE with anti-SSA/Ro/SSB/La antibodies, exposure to HCQ during pregnancy may decrease the risk of fetal development of cardiac-NL. Prospective studies are needed for confirmation.

The recurrence rate of anti-SSA/Ro-associated congenital heart block (CHB) is 17%. Sustained reversal of third-degree block has never been achieved. Based on potential reduction of maternal autoantibody titers as well as fetal inflammatory responses, intravenous immunoglobulin (IVIG) was evaluated as preventive therapy for CHB.A multicenter, prospective, open-label study based on Simon's 2-stage optimal design was initiated. Enrollment criteria included the presence of anti-SSA/Ro antibodies in the mother, birth of a previous child with CHB/neonatal lupus rash, current treatment withor = 20 mg/day of prednisone, and12 weeks pregnant. IVIG (400 mg/kg) was given every 3 weeks from week 12 to week 24 of gestation. The primary outcome was the development of second-degree or third-degree CHB.Twenty mothers completed the IVIG protocol before the predetermined stopping rule of 3 cases of advanced CHB in the study was reached. CHB was detected at 19, 20, and 25 weeks; none of the cases occurred following the finding of an abnormal PR interval on fetal Doppler monitoring. One of these mothers had 2 previous children with CHB. One child without CHB developed a transient rash consistent with neonatal lupus. Sixteen children had no manifestations of neonatal lupus at birth. No significant changes in maternal titers of antibody to SSA/Ro, SSB/La, or Ro 52 kd were detected over the course of therapy or at delivery. There were no safety issues.This study establishes the safety of IVIG and the feasibility of recruiting pregnant women who have previously had a child with CHB. However, IVIG at low doses consistent with replacement does not prevent the recurrence of CHB or reduce maternal antibody titers.

Objective.To evaluate the frequency of anti-α-enolase antibodies in the sera of mothers whose children have congenital heart block (CHB), given provocative results in which α-enolase, a membrane protein, was recognized by monoclonal antibodies reactive with the peptide p200 of 52 kDa Ro/SSA in a neonatal rat heart library.Methods.An ELISA using a recombinant α-enolase protein was developed. Sera from 100 anti-Ro52+ CHB mothers in the Research Registry for Neonatal Lupus, 50 patients with systemic lupus erythematosus (SLE; 7 anti-Ro52+), and 48 healthy controls were tested for anti-α-enolase reactivity.Results.There were no significant differences in the median values obtained from CHB mothers, patients with SLE, or controls at each of the dilutions tested. Only 7 (7%) at 1:100 dilution and 2 (2%) at 1:1000 dilution of 100 CHB sera were 3 standard deviations above the mean value obtained for controls. Preincubation with recombinant Ro52 did not inhibit anti-α-enolase reactivity.Conclusion.The low frequency of anti-α-enolase antibodies in the sera of CHB mothers and the absence of apparent cross-reactivity with Ro52 suggest that antibodies to Ro52 are not likely to mediate CHB via binding to α-enolase.

Circulating autoantibodies against the glucose-regulated protein of 78 kDa (GRP78) are present at high levels in prostate cancer patients and are a biomarker of aggressive tumor behavior. We purified the anti-GRP78 IgGs and examined their effect on 1-LN, PC-3, DU145, and LnCap human prostate cancer cells. We also evaluated its effects on the breast cancer MDA-MB231 and melanoma DM413 cell lines. The anti-GRP78 antibody binds only to cells expressing GRP78 on the surface, to a site also recognized by its physiologic agonist, activated α2-macroglobulin (α2M*). This antibody is completely specific for a peptide, including the primary amino acid sequence CNVKSDKSC, which contains a tertiary structural motif mimicking an epitope in GRP78. Tertiary structual analysis suggested the linear GRP78 primary amino acid sequence LIGRTWNDPSVQQDIKFL (Leu98-Leu115) as the putative binding site, containing the tertiary structual arrangement described above, which was confirmed experimentally. The anti-GRP78 antibodies from prostate cancer patients recognize almost exclusively this epitope. We produced animal antibodies against both these peptides, and they are able to mimic the effects of the human antibody. Our experiments also suggest this epitope as highly immunogenic, thereby explaining the specificity of the immune response against this epitope in GRP78, observed in humans. Using 1-LN cells as a model, we show that anti-GRP78 IgG purified from the sera of these patients mimics the proproliferative effects induced by α2M* via the common receptor, GRP78. Furthermore, increasing concentrations of human anti-GRP78 IgG show a dose-dependent protective effect on apoptosis induced by tumor necrosis factor α. (Cancer Res 2006; 66(23): 11424-31)

Rheumatoid arthritis (RA) is a systemic autoimmune disease that affects 0.8% of the world population, it affects the synovial membrane of joints and the clinical presentation encompasses a wide spectrum, ranging from a mild to a severe and erosive disease that causes joint and cartilage destruction which finally provokes irreversible structural damage and patient disability. In the last years, there have been important advances in the pathogenesis of this disease, the efforts have been concentrated on pro-inflammatory cytokines such as tumor necrosis factor alpha (TNFalpha). This protein guides numerous events in the synovial and systemic inflammatory process and is encoded in the Major Histocompability Complex (MHC), one of the most polymorphic of the genome. Polymorphisms affecting the TNFalpha gene and its regulatory regions are associated with RA prevalence and course. There is a possible association between these polymorphisms and the clinical response to the use of monoclonal antibodies anti-TNFalpha. The possibility that the determination of genotypes -238 and -308 may have prognostic and therapeutic consequences is debated nowadays (Rev Méd Chile 2005; 133: 1089-95).

The use of biological agents such as etanercept, infliximab, adalimumab and anakinra has been recently approved for the treatment of rheumatoid arthritis. All are effective controlling signs and symptoms and inhibiting disease progression. To overcome the problems generated by their high costs and possible participation in reactivating latent infections, other therapeutic tools are being developed. Gene therapy using expression vectors carrying genes coding for specific proteins, may interfere in key points involved in the pathogenesis of the disease. Intra-articular administration of cDNA coding for soluble TNF receptors, IL-1, or IL-1Ra decreases signs of the disease in animal models. Vectors, expressing inhibitors of signal transduction pathways involving to NF-kB and JAK-STAT-3, are effective in modulating joint inflammation in mice. The use of antigen-pulsed antigen presenting cells or dendritic cells (DC) bound to apoptosis-inducing molecules, specifically eliminates autoreactive T cells. Other novel approach attempts the development of T regulatory-inducing tolerogenic DC-based vaccines that inhibit autoreactive T cells, through the secretion of suppressing cytokines or by other mechanisms to be elucidated. Oral tolerance induction to auto-antigens is also a successful experimental strategy under study. Current research aims to control peripheral tolerance in rheumatoid arthritis patients

New therapeutic approaches that include depletion of B cells usingrituximab, a chimeric monoclonal antibody directed against the B cell specific antigen CD-20have been developed for the treatment of systemic lupus erythematosus (SLE). We report the caseof a 18 years old girl with SLE that did not respond and experienced adverse effects with the useof hydroxycloroquine, methotrexate, mycophenolate mofetil, azathioprine and high-dosesteroids. Rituximab was given weekly at 375 mg/m

Tumour necrosis factor (TNF), a cytokine mainly produced by macrophages, is associated with a broad spectrum of biological effects, mainly associated with the host defense against microbes. The TNF gene is located on chromosome six within the major histocompatibility complex (MHC). Rheumatoid arthritis (RA) is a systemic autoimmune disease where TNF plays a central role in its etiology and pathogenesis. Written medical evidence of RA can be traced at least as far back as the 17th century, while human paleopathological studies appear to show the presence of RA prior to this period. The fact that RA has experienced an increment both in severity and mortality could be explained by many causes, particularly the crucial role of the immune system. Single-nucleotide polymorphisms (SNPs) are the most common genetic variations and occur at a frequency of approximately 1 in 1000 bp throughout the genome. The -308 TNF SNP is a mutation that affects the promoter region of the TNF gene. It defines the TNF1 and TNF2 alleles, determining low and high levels of TNF expression, respectively. The presence of the TNF2 allele has also been linked to increased susceptibility to and severity in a variety of autoimmune and inflammatory disorders, including RA, systemic lupus erythematosus, and ankylosing spondylitis. Studies on the functional significance of -308 SNP have detected higher levels of TNF production by cells from TNF2-carrying individuals than cells from TNF1 individuals. This difference does not appear to be due to other genes lying within the MHC region. Since the presence of the TNF2 allele may increase the host's resistance to local infection, by increasing local production of TNF at the infection site, we may suggest that such a mutation has emerged as a selective advantage to carriers of the TNF2 allele. This hypothesis may prove itself by observing the high incidence of tuberculosis and other infectious processes in those patients treated with anti-TNF therapy. Since the human lifespan has increased, the persistence of the TNF2 allele at high frequency in the population now confers what appears to be a marked survival disadvantage. As a result of the disregulation of the immune system, the genetically-predisposed host expresses larger amounts of TNF, leading to chronic inflammatory processes and autoimmune diseases, currently more prevalent. We suggest that RA, a relatively new and increasingly frequent disease, is favored by the presence of the -308 TNF promoter polymorphism, responsible for increased TNF production.

Background Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease characterized by alterations affecting both the innate and adaptive immune systems [1]. Monocytes and dendritic cells from SLE patients display a stimulatory phenotype that promotes the activation of self-reactive T cells [2]. Monocytes are pluripotent cells capable of engulfing pathogens, releasing inflammatory molecules and presenting antigens to naive T cells. One of the key molecules that controls monocyte function is Heme oxigenase-1 (HO-1), which catalyzes the degradation of heme into biliverdin, carbon monoxide (CO) and Fe+2. CO possesses immunosuppressive and anti-inflammatory abilities [3]. Objectives Therefore, the goal of this work was to assess HO-1 expression in monocytes from SLE patients and healthy controls (HC). Methods 43 non-selected SLE patients that fulfilled the ACR criteria for SLE and 30 HC were recruited. In addition, 5 kidney-transplanted patients undergoing similar immunosuppressive treatment were included. All patients signed an informed consent form before entering the study. PBMCs were separated using the standard Ficoll centrifugation method. CD14+ monocytes and CD4+ T cells were sorted by FACS and HO-1 expression was measured by RT-PCR. HO-1 protein expression was determined by FACS. T cell activation parameters after staphylococcal enterotoxin A (SEA 50nM) stimulation were determined by FACS (IL2; CD69; CD25). Results HO-1 mRNA levels were significantly decreased in CD14+ monocytes from SLE patients compared to HC (P + T cells. To assess the immunogenic capacity of monocytes, T cell activation assays in response to SEA stimulation were performed. No significant differences in T cell activation parameters, such as IL-2 production and CD69 expression were observed between lupus patients and HC. Conclusions We found a significant decrease in HO-1 expression in monocytes from SLE patients, suggesting that an imbalance in HO-1 could play a role in SLE pathogenesis. The results obtained in kidney-transplanted patients suggest that this observation is not due to the immunosuppressive treatment. Since the results observed in SEA activation assays could be explained by defects in T cells from SLE patients, additional experiments to further evaluate the role of HO-1 in monocytes function are warranted. References Llanos, C., et al. Curr Gene Ther 2011; 11(6). Steinbach, F., et al. Ann Rheum Dis 2000; 59(4): p. 283-8. Remy, S., et al., J immunol 2009; 182(4): p. 1877-84. Disclosure of Interest None Declared