An immunogenomic exome landscape of triple positive primary antiphospholipid patients.

Primary antiphospholipid syndrome is characterized by thrombosis and autoantibodies directed against phospholipids or associated proteins. The genetic etiology of PAPS remains unknown. We enrolled 21 patients with thromboembolic events associated to lupus anticoagulant, anticardiolipin and anti ß2 glycoprotein1 autoantibodies. We performed whole exome sequencing and a systematic variant-based analysis in genes associated with thrombosis, in candidate genes previously associated with APS or inborn errors of immunity. Data were compared to public databases and to a control cohort of 873 non-autoimmune patients. Variants were identified following a state-of-the-art pipeline. Enrichment analysis was performed by comparing with the control cohort. We found an absence of significant HLA bias and genetic heterogeneity in these patients, including when testing combinations of rare variants in genes encoding for proteins involved in thrombosis and of variants in genes linked with inborn errors of immunity. These results provide evidence of genetic heterogeneity in PAPS, even in a homogenous series of triple positive patients. At the individual scale, a combination of variants may participate to the breakdown of B cell tolerance and to the vessel damage.

The course of non-infectious uveitis in pregnancy: a retrospective study of 79 pregnancies.

PURPOSE: The study aims to describe the course and management of non-infectious uveitis during pregnancy and postpartum period in European populations. METHODS: A retrospective observational study in two tertiary centers in France was performed. Pregnant patients during the follow-up of a non-infectious uveitis as well as those with new-onset uveitis were included. The medical records were analyzed with a systematic collection of the characteristics of the uveitis, the treatment and evolution of the uveitis, and the course of the pregnancy including obstetric complications. RESULTS: Seventy-nine pregnancies in 59 women were included: 48 patients (68 pregnancies) were followed for uveitis and 11 had a new-onset uveitis diagnosis. Most patients had idiopathic uveitis (32.2%) or sarcoid uveitis (27.1%). Among the patients followed for uveitis at the time of conception, there were 18 relapses (26.5%) requiring treatment escalation. Relapses occurred mainly in the two first trimester (n = 12) or during the postpartum period (n = 5) and were significantly associated with an active uveitis at the time of conception (OR = 9.2, 95% CI [1.57-48.4], p = 0.01). The characteristics of the new-onset uveitis were similar to those already existing before pregnancy. Obstetric complications occurred in 25 pregnancies (31.6%), mainly gestational hypertension and gestational diabetes. CONCLUSION: The frequency of non-infectious uveitis relapses decreases as pregnancy progresses, in agreement with data from other non-European studies. However, multidisciplinary monitoring should be advised, especially to uncontrolled patients at the time of conception.

Off-label use of biologics for the treatment of refractory and/or relapsing granulomatosis with polyangiitis.

OBJECTIVE: To describe the efficacy and safety of off-label use of biologics for refractory and/or relapsing granulomatosis with polyangiitis (GPA). METHODS: We conducted a French retrospective study including GPA patients who received off-label biologics for refractory and/or relapsing disease after failure of conventional immunosuppressive regimens. RESULTS: Among 26 patients included, 18 received infliximab (IFX), 2 adalimumab (ADA) and 6 abatacept (ABA). Biologics were initiated in median as 4th-line therapy (IQR 3-6) for relapsing and/or refractory disease in 23 (88%) and/or significant glucocorticoid-dependency in 8 cases (31%). At biologics initiation, median (IQR) BVAS and prednisone dose in anti- TNF-α and ABA recipients were 7 (3-8) and 2 (1-6), and 20 (13-30) mg/day and 20 (15-25) mg/day, respectively. Clinical manifestations requiring biologics were mainly pulmonary and ENT manifestations in 58% each. Anti-TNF-α and ABA were continued for a median duration of 8 months (IQR 6-13) and 11 months (IQR 6-18) respectively. Anti-TNF-α recipients showed remission, partial response and treatment failure in 10%, 30% and 60% at 6 months, and 25%, 20% and 55% at 12 months, respectively. ABA recipients showed remission, partial response and treatment failure in 17%, 33% and 50% at 6 months and 17%, 33% and 50% at 12 months. One patient treated with IFX experienced life-threatening reaction while one patient treated with ABA experienced a severe infection. CONCLUSION: This real-life study suggests that off-label use of anti-TNF-α and abatacept shows efficacy in less than 50% of refractory and/or relapsing GPA.

Intermediate uveitis, an ophthalmological manifestation of systemic disease.

PURPOSE: Intermediate uveitis is frequently indicative associated with systemic disease. In addition to the initial evaluation of the patient with intermediate uveitis, we sought to determine the role of longitudinal follow-up in improving the diagnosis of systemic disease associated with intermediate uveitis. METHOD: Retrospective analysis of a cohort of 51 patients with intermediate uveitis followed for 5 to 13 years. RESULTS: Upon initial evaluation, an underlying disease associated with the intermediate uveitis was found in nine out of the 51 patients. Among the remaining patients, after at least 5 years of follow-up, eight new associated diagnoses were revealed (primarily inflammatory diseases and cancers). CONCLUSION: These results suggest that the initial work-up of the patient with intermediate uveitis is not sufficiently sensitive and that careful follow-up of these patients considerably improves the diagnosis of associated disease.

[Immunological aspects of the antiphospholipid syndrome]. / Aspects immunologiques du syndrome des antiphospholipides.

Antiphospholipid antibodies constitute a group of heterogeneous antibodies, which mainly recognize complexes made of proteins and anionic phospholipids. The nature of these complexes is currently better defined, as well as known, the structure of the antiphospholipid antibodies owing to the analysis of the monoclonal forms of these antibodies which were also studied both in terms of their precise specificities and cross-reactivity. However, the origin of these autoantibodies is not clearly understood, as well as the possible link between antiphospholipid antibodies present in healthy individuals, and those observed in autoimmune diseases. Only a fraction of antiphospholipid antibodies are pathogenic and directly responsible for the clinical manifestations of the antiphospholipid syndrome, but there is, to date, no biological test able to accurately detect pathogenic antiphospholipid antibodies. The diverse mechanisms which link these autoantibodies to the occurrence of symptoms, mainly during obstetrical complications, are better understood, and suggest new therapeutic avenues.

Evidence for heterogeneity of the obstetric antiphospholipid syndrome: thrombosis can be critical for antiphospholipid-induced pregnancy loss.

BACKGROUND: Antiphospholipid antibodies are associated with thrombosis and repeated pregnancy losses during the antiphospholipid syndrome. Several experimental findings indicate that purified antiphospholipid antibodies are directly responsible for inflammation-induced pregnancy losses, or for disruption of the annexin A5 shield at the trophoblastic interface. We previously showed that passive transfer of CIC15, a monoclonal antiphospholipid antibody binding to cardiolipin and annexin A5 that was isolated from a patient with primary antiphospholipid syndrome, induces fetal resorption in pregnant mice. OBJECTIVES: To investigate the mechanisms of CIC15-induced pregnancy loss. METHODS/RESULTS: We show that CIC15 induces fetal loss through a new mechanism that is probably related to procoagulant activity. The time course is different from those of previously described models, and histologic analysis shows that the placentas are devoid of any sign of inflammation but display some signs of thrombotic events. Despite these differences, the CIC15 and 'inflammatory' models share some similarities: lack of FcγRI/III dependency, and the efficacy of heparin in preventing fetal losses. However, this latter observation is here mostly attributable to anticoagulation rather than complement inhibition, because fondaparinux sodium and hirudin show similar efficiency. In vitro, CIC15 enhances cardiolipin-induced thrombin generation. Finally, using a combination of surface-sensitive methods, we show that, although it binds complexes of cardiolipin-annexin A5, CIC15 is not able to disrupt the two-dimensional ordered arrays of annexin A5. CONCLUSIONS: This human monoclonal antibody is responsible for pregnancy loss through a new mechanism involving thrombosis. This mechanism adds to the heterogeneity of the obstetric antiphospholipid syndrome.

[Invasive Streptococcus agalactiae infections in non-pregnant adults]. / Les infections invasives à Streptococcus agalactiae chez l'adulte (femme enceinte exclue).

OBJECTIVES: Streptococcus agalactiae (Group B streptococcus) is a major cause of invasive diseases in non-pregnant adults, particularly in the elderly and those with underlying conditions. We describe these conditions and clinical characteristics of patients followed in our teaching hospital. METHODS: We retrospectively reviewed clinical records of 64 patients with S. agalactiae-related invasive infection, hospitalized between January 1997 and January 2006. RESULTS: The mean age of patients was 59 (+/-17 years). The H:F sex ratio was 1.06. At least one underlying condition was found in 90.6%. Diabetes mellitus (43.7%), peripheral vascular disease (34.4%), myocardial ischemia (20.3%) and malignant neoplasms (20.3%) were among the most frequent conditions. The mean index of comorbidity (Charlson) was 2.5 (+/-2). Common clinical manifestations included infection of the urinary tract (32.8%), skin and soft-tissue (25%), and osteoarthritis (21.9%). Bacteremia occurred in 31.2% with no identified source in 2 patients. During the first month, 2 cases of endocarditis, 1 case of meningitis, and 4 deaths occurred. CONCLUSION: We confirm the importance of underlying diseases in the emergence of S. agalactiae infections.