Acute Posterior Multifocal Placoid Pigment Epitheliopathy as the Initial Manifestation of Sarcoidosis

Purpose: To report an undiagnosed case of systemic sarcoidosis manifesting with bilateral acute posterior multifocal placoid pigment epitheliopathy (APMPPE). Case Report: A 26-year-old Caucasian man was referred for management of unilateral visual loss together with a paracentral scotoma developing 2 weeks after a flu-like syndrome. Clinical signs and ancillary diagnostic investigations suggested APMPPE. Laboratory tests demonstrated elevated serum angiotensin converting enzyme and lysozyme levels. Chest CT-scan disclosed moderate hilar lymph node calcifications but QuantiFERON-TB gold test was negative and bronchoalveolar lavage and biopsies were unremarkable. Accessory salivary gland biopsy disclosed epithelioid and gigantocellular granuloma formation without caseum, confirming a diagnosis of sarcoidosis. The fellow eye was involved a few days later and the patient complained of dyspnea. Echocardiography disclosed severe granulomatous myocardial infiltration and high dose corticosteroids and intravenous cyclophosphamide were initiated. Systemic treatment controlled both cardiac and ocular lesions, and was tapered accordingly. Conclusion: The constellation of "white dot syndromes" and systemic symptoms necessitates a general work-up to exclude granulomatous disorders such as sarcoidosis or tuberculosis. Delayed diagnosis of cardiac sarcoidosis may have life-threatening consequences and the ophthalmologist may be the first physician to diagnose the condition

Ultrasensitive serum interferon-α quantification during SLE remission identifies patients at risk for relapse

International audienceObjectives Maintenance of remission has become central in the management of systemic lupus erythematosus (SLE). The importance of interferon-alpha (IFN-α) in the pathogenesis of SLE notwithstanding, its expression in remission has been poorly studied as yet. To study its expression in remission and its prognostic value in the prediction of a disease relapse, serum IFN-α levels were determined using an ultrasensitive single-molecule array digital immunoassay which enables the measurement of cytokines at physiological concentrations.Methods A total of 254 SLE patients in remission, according to the Definition of Remission in SLE classification, were included in the study. Serum IFN-α concentrations were determined at baseline and patients were followed up for 1 year. Lupus flares were defined according to the Safety of Estrogens in Lupus Erythematosus: National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index Flare Index, whereas the Kaplan-Meier analysis and Cox regression analysis were used to estimate the time to relapse and to identify baseline factors associated with time to relapse, respectively.Results Of all patients in remission, 26% displayed abnormally high IFN-α serum levels that were associated with the presence of antibodies specific for ribonucleoprotein (RNP), double stranded (ds)DNA and Ro/SSA60, as well as young age. Importantly, elevated-baseline IFN-α serum levels and remission duration were associated in an independent fashion, with shorter time to relapse, while low serum levels of complement component 3 and anti-dsDNA Abs were not.Conclusion Direct serum IFN-α assessment with highly sensitive digital immunoassay permits clinicians to identify a subgroup of SLE patients, clinically in remission, but at higher risk of relapse

In Antisynthetase Syndrome, ACPA Are Associated With Severe and Erosive Arthritis: An Overlapping Rheumatoid Arthritis and Antisynthetase Syndrome

International audienceAbstract: Anticitrullinated peptide/protein antibodies (ACPA), which are highly specific for rheumatoid arthritis (RA), may be found in some patients with other systemic autoimmune diseases. The clinical significance of ACPA in patients with antisynthetase syndrome (ASS), a systemic disease characterized by the association of myositis, interstitial lung disease, polyarthralgia, and/or polyarthritis, has not yet been evaluated with regard to phenotype, prognosis, and response to treatment. ACPA-positive ASS patients were first identified among a French multicenter registry of patients with ASS. Additionally, all French rheumatology and internal medicine practitioners registered on the Club Rhumatismes et Inflammation web site were asked to report their observations of ASS patients with ACPA. The 17 collected patients were retrospectively studied using a standardized questionnaire and compared with 34 unselected ACPA-negative ASS patients in a case–control study. All ACPA-positive ASS patients suffered from arthritis versus 41% in the control group (P 7-year mean follow-up, extra-articular outcomes and survival were not different. ACPA-positive ASS patients showed an overlapping RA–ASS syndrome, were at high risk of refractory erosive arthritis, and might experience ASS flare when treated with antitumor necrosis factor drugs. In contrast, other biologics such as anti-CD20 mAb were effective in this context, without worsening systemic involvements

Exhausted Cytotoxic Control of Epstein-Barr Virus in Human Lupus

Systemic Lupus Erythematosus (SLE) pathology has long been associated with an increased Epstein-Barr Virus (EBV) seropositivity, viremia and cross-reactive serum antibodies specific for both virus and self. It has therefore been postulated that EBV triggers SLE immunopathology, although the mechanism remains elusive. Here, we investigate whether frequent peaks of EBV viral load in SLE patients are a consequence of dysfunctional anti-EBV CD8+ T cell responses. Both inactive and active SLE patients (n = 76 and 42, respectively), have significantly elevated EBV viral loads (P = 0.003 and 0.002, respectively) compared to age- and sex-matched healthy controls (n = 29). Interestingly, less EBV-specific CD8+ T cells are able to secrete multiple cytokines (IFN-γ, TNF-α, IL-2 and MIP-1β) in inactive and active SLE patients compared to controls (P = 0.0003 and 0.0084, respectively). Moreover, EBV-specific CD8+ T cells are also less cytotoxic in SLE patients than in controls (CD107a expression: P = 0.0009, Granzyme B release: P = 0.0001). Importantly, cytomegalovirus (CMV)-specific responses were not found significantly altered in SLE patients. Furthermore, we demonstrate that EBV-specific CD8+ T cell impairment is a consequence of their Programmed Death 1 (PD-1) receptor up-regulation, as blocking this pathway reverses the dysfunctional phenotype. Finally, prospective monitoring of lupus patients revealed that disease flares precede EBV reactivation. In conclusion, EBV-specific CD8+ T cell responses in SLE patients are functionally impaired, but EBV reactivation appears to be an aggravating consequence rather than a cause of SLE immunopathology. We therefore propose that autoimmune B cell activation during flares drives frequent EBV reactivation, which contributes in a vicious circle to the perpetuation of immune activation in SLE patients

Lupus systémique induit par la silice cristalline (analyse détaillée de la littérature illustrée de deux observations cliniques)

La physiopathologie des maladies auto-immunes et du lupus érythémateux systémique (LES) en particulier est souvent résumée comme l interaction d un terrain génétique prédisposant et d évènements environnementaux agissant comme facteur déclenchant. L exposition à la silice cristalline est un des risques environnementaux associés au lupus les mieux documentés, bien que largement méconnu des cliniciens. La causalité de l exposition à la silice dans le développement de certains cas de LES semble maintenant clairement établie. Elle repose aussi bien sur des données épidémiologiques aux méthodes variées, révélant une relation dose-effet, que sur des arguments physiopathologiques étayant la plausibilité de l association. L épidémiologie du LES induit par la silice (Si-LES) est bien documentée et permet de proposer la description de deux profils de Si-LES : le Si-LES patent et le Si-LES occulte. Ces études devront être complétées à l avenir de données pronostiques et thérapeutiques. La physiopathologie du Si-LES repose sur un modèle animal cohérent ; les rôles centraux du macrophage et de l apoptose y semblent clairement établis. Les travaux futurs devront s attacher à mieux cerner le rôle des différentes populations lymphocytaires (lymphocytes T régulateurs, lymphocytes Th17) et à comprendre le rôle des facteurs génétiques prédisposants.Cette monographie est complétée de l analyse de deux observations cliniques de LES induit par la silice, en illustrant les difficultés diagnostiques. Les conséquences du Si-LES, à la fois sociales et médicales, plaident en faveur d une reconnaissance comme maladie professionnelle, au même titre que le syndrome d Erasmus.PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocSudocFranceF

L' interféron-alpha induit un lupus précoce chez la souris (NZB x NZW)F1 pré-autoimmune mais pas chez la souris normale BALB-c

Plusieurs études ont montré le rôle de l'Interferon-alpha (IFN ) dans la physiopathologie du Lupus Systémique (LS). Une majorité de patients ont des taux détectables d'IFN dans le sérum, corrélés à l'activité et à la sévérité de la maladie. L'IFN utilisé dans le traitement des hépatites virales et de certaines néoplasies induit, dans un nombre important de cas, des désordres autoimmuns et parfois un LS. Des travaux récents ont montré, dans deux modèles murins, que l'invalidation d'un gêne du récepteur aux IFN de type I atténue la maladie lupique. L'étude de l'IFN dans la maladie lupique était difficile du fait de l'absence de modèle animal convenable. Nous avons développé un modèle murin chez lequel nous délivrons in vivo, pendant plusieurs semaines, de l'IFN par le biais d'un adénovecteur. Cette surexpression d'IFN induit une accélération franche de la maladie lupique chez les souris (NZBxNZW)F1. Les anticorps anti- ADN natif sont détectés dés le 10ème jour de traitement. La protéinurie, stigmate d'une glomérulonéphrite, et la mort par insuffisance rénale surviennent pour tous les individus respectivement avant la 9ème et la 18ème semaine du traitement. L'accélération de la maladie dépend directement de la dose d'IFN délivrée. Les souris normales Balb/c soumises au même traitement ne développent aucun signe d'autoimmunité. Ce travail apporte des éléments confirmant que l'IFN est un effecteur majeur dans la physiopathologie du LS. Il démontre directement l'importance du fond génétique qui confère à l'IFN son rôle pathogénique. Ce modèle pourrait permettre de tester de nouvelles thérapeutiques et d'identifier des gènes de susceptibilité du LSRecent studies indicate that interferon-alpha (IFNa) is involved in pathogenesis of Systemic Lupus Erythematosus (SLE). Increased serum IFNa in SLE patients that correlates with both disease activity and severity has long been known. The observations that IFNa treatment of patients with cancer or viral hepatitis can cause development of anti-dsDNA autoantibodies and SLE have led to possible causative link between IFNa and lupus. Recent work has suggested a role for type I IFNs in murine lupus. Indeed, lupus-prone mice lacking the receptor for type I IFNs, have reduced lupus-like disease. However, direct proof that IFNa is sufficient to induce lupus pathogenicity is lacking. In this study, we show that in vivo adenovector-mediated delivery of murine IFNa results in preautoimmune (New Zealand Black x New Zealand White)F1, but not in normal, mice, in a rapid and severe disease with all characteristics of SLE. Anti-dsDNA Abs appeared as soon as day 10 after initiation of IFNa treatment. Proteinuria and death caused by glomerulonephritis occurred in all treated mice within, respectively, approximately 9 and 18 wk. All effects elicited by IFNa were dose dependent. Our present work not only adds evidence to the concept that type IFNa is a major effector in the pathogenesis of lupus, but also directly demonstrates a major role of the genetic background conferring to IFNa its pathogenic role. We have established a new experimental model in which lupus disease is amenable in a few weeks and which will permit to test new drugs and to dissect further the lupus autoimmune responsePARIS12-CRETEIL BU Médecine (940282101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Rôle de l'interféron alpha dans la physiopathologie du lupus (effet sur les lymphocytes B et le développement de la néphropathie)

L interféron alpha (IFN ) semble jouer un rôle majeur dans la pathogénie du Lupus Erythémateux Systémique (LES), maladie autoimmune fréquente et souvent grave. L administration d IFN in vivo, par le biais d un adénovecteur, accélère la maladie chez les souris susceptibles (New Zealand Black x New Zealand White)F1 (NZB/W), mais ne la déclenche pas chez les souris normales. La surexpression d IFN active la prolifération des lymphocytes B chez les deux types de souris, mais ne s accompagne, que chez la souris NZB/W, de la production intense et prolongée de cellules sécrétrices d immunoglobulines à demi-vie courte dont certaines sont de spécificité anti-ADN. Ces résultats confirment que l IFN déclenche une réponse humorale pathologique chez les animaux susceptibles et qu il existe des mécanismes de contrôle chez la souris normale. De plus, l étude comparée des souris NZB/W spontanées et traitées par IFN montre que les mécanismes de recrutement des cellules inflammatoires dans les reins sont différents entre les deux modèles. Ces données apportent des éléments nouveaux pour comprendre le rôle de l IFN dans le LES et développer de nouveaux traitements.PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Mécanismes physiopathologiques du lupus systémique

International audienceSystemic Lupus Erythematosus (SLE) is a chronic disease of heterogeneous clinical presentation characterised by the production of autoantibodies directed against nuclear antigens. Its occurrence is the result of exposure to a favorable environment and stochastic events in a lupus-prone genetic background. Both the innate and adaptive immune systems are involved. The main source of autoantigens appears to be abnormal efferocytosis. Abnormally available nuclear material initiates the immune response through activation of intra- and extracytosolic nucleic acid receptors. Interactions between dendritic cells, B cells and T cells result in the production of cytokines, antibodies and cytotoxic cells that are deleterious. Interferons, especially type I and B Lymphocyte stimulator (BLyS), have a key role in the pathogenesis of SLE. Many new drugs are in development. More directly targeted on the immunological actors involved in SLE than the corticoids and immunosuppressants currently used, these new molecules should improve the efficacy and tolerance of treatments.Le lupus systémique (LS) est une maladie chronique de présentation clinique hétérogène caractérisée par la production d’autoanticorps dirigés contre des antigènes nucléaires. Sa survenue résulte de l’exposition à un environnement favorisant et la survenue d’évènements immunologiques stochastiques sur un terrain génétique favorisant. La source principale des autoantigènes semble provenir d’une efférocytose anormale. Le matériel nucléaire anormalement disponible initie la réponse immunitaire par l’activation des récepteurs intra- et extracytosoliques aux acides nucléiques. Les interactions entre cellules dendritiques, lymphocytes B et lymphocytes T aboutissent à la production de cytokines, d’anticorps et de cellules cytotoxiques délétères pour l’organisme. Les interférons, notamment de type I et le B Lymphocyte Stimulator (BLyS), ont un rôle clé dans l’initiation et l’entretien de la réponse auto-immune. De nombreux nouveaux médicaments sont en développement. Plus ciblées sur les acteurs immunologiques impliqués dans le LS que ne le sont les corticoïdes et les immunosuppresseurs actuellement utilisés, ces nouvelles molécules devraient améliorer l’efficacité et la tolérance des traitements

Anticancer Drug-Induced Capillary Leak Syndrome

International audienceThe term capillary leak syndrome (CLS) describes the manifestations associated with an increased capillary permeability to proteins leading to an escape of plasma from the blood circulatory system to surrounding tissues, muscle, organs, or body cavities. This results clinically in the typical triad of hypotension, edema, and elevated hematocrit. The more severe cases of CLS may present with cardiovascular collapse, shock, and death. The most classic form of this pathology is represented by the idiopathic systemic CLS (SCLS) also called Clarkson's disease, but capillary leaks are also described as adverse drug reactions foremost among which are anticancer drugs. This review will focus on oncologic drugs such as gemcitabine, therapeutic growth factors or cytokines, and monoclonal antibodies (mAbs) that appear now as the strongest candidates for anticancer drug-induced CLS

Response to: ‘Presence of anti-phospholipid antibodies in COVID-19: a case series study’ by Amezcua-Guerra et al

International audienc