Impairment of quality of life in patients with antiphospholipid syndrome.

OBJECTIVES: Health-related quality of life (HRQoL) has not been fully explored in antiphospholipid syndrome (APS); therefore, we compared HRQoL between APS patients and the general population and assessed the impact of thromboembolic history. METHODS: HRQoL was measured in a multicentre cohort study by the Medical Outcomes Study Short-Form 36 (MOS-SF-36) questionnaire. HRQoL scores were compared to the French general population norms. Factors significantly associated with an impaired HRQoL were identified. RESULTS: A total of 115 patients with aPL and/or systemic lupus erythematosus (SLE) were included (mean age 42.7 ± 14.1 years old, 86 women). In 53 patients APS was diagnosed. Compared to general population norms, patients with APS had an impaired HRQoL. SLE-associated APS patients had the worst HRQoL scores (physical component summary (PCS)=40.8 ± 10.6; mental component summary (MCS)=40.6 ± 16.5) in comparison with SLE or aPL patients without thromboembolic history. In APS patients, history of arterial thrombosis significantly impaired HRQoL (PCS score: 42.2 ± 9.4 vs 49.2 ± 8.5; MCS score: 33.9 ± 13.7 vs 44.6 ± 10.3). CONCLUSION: Compared to the general population, APS patients experienced a lower HRQoL. In these patients, a history of arterial thrombosis significantly impaired HRQoL. Therefore, measurements of HRQoL should be included in APS patient management to assess the burden of the disease from a patient's perspective and to provide patients with the support they need.

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.

[Behçet's disease in obstetrics and gynecology]. / Maladie de Behçet en gynécologie-obstétrique.

Behçet's disease is a multisystemic disease of unknown origin characterized by a recurrent bipolar aphtosis (oral and genital) associated with vascular, digestive or articular symptoms. Gynecologists can be faced to this disease at any time of the life of their patients, including during the pregnancy. Given that the first demonstrations of the disease can be genital, they are in the front line to evoke this diagnosis. They thus have to know the main characteristics of the disease to make the diagnosis and to organize a multidisciplinary management. During pregnancy, the treatment of the disease is to be adapted to avoid teratogenic drugs, and adapt the doses of the treatment.

Value of (18)F-FDG-PET/CT in patients with fever of unknown origin and unexplained prolonged inflammatory syndrome: a single centre analysis experience.

OBJECTIVE: The aim of our study was to evaluate the diagnostic contribution of (18)F-fluoro-deoxyglucose ((18)F-FDG)-positron emission tomography (PET)/computed tomography (CT) in patients with fever of unknown origin (FUO) or unexplained prolonged inflammatory syndrome (UPIS) in real life. PATIENTS AND METHODS: We performed a retrospective study including 14 patients with FUO or UPIS hospitalised in our institution (Strasbourg University Hospital, France) between January 2005 and July 2006. (18)F-FDG-PET/CT was considered helpful when abnormal results allowed an accurate diagnosis. RESULTS: (18)F-FDG-PET/CT was helpful in half the patients (7/14) for final diagnosis. A diagnosis was reached in 87.5% of the patients (7/8) with an abnormal (18)F-FDG-PET/CT but only in 50% of the patients (3/6) with a normal (18)F-FDG-PET/CT. Conventional chest and abdominal CT was performed in 13 patients before ordering (18)F-FDG-PET/CT. We considered that (18)F-FDG-PET/CT was essential to establish the final diagnosis in only 23% of the patients (3/13) since neither chest nor abdominal CT identified abnormalities consistent with the final diagnosis. However, among the three patients, two were diagnosed with large vessel vasculitis and one patient with local prosthetic infection. CONCLUSIONS: Our study supports the potential interest of (18)F-FDG-PET/CT in the diagnostic workup of FUO and UPIS as it helped establish a fine diagnosis in half of the cases. However, (18)F-FDG-PET/CT appeared to be essential to the final diagnosis in only 23% of the cases. In our opinion, this protocol should be performed as a second level test, especially when conventional CT is normal or is unable to discriminate between active and silent lesions.

Videocapsule endoscopy is useful for the diagnosis of intestinal lymphangiectasia.

We study two authentic cases of protein-losing enteropathy, the diagnosis of which was facilitated using Given M2A videocapsule endoscopy. The first case corresponded to a primary intestinal lymphangiectasia confirmed by jejunum biopsies and the second one to a protein-losing enteropathy with lymphatic abnormalities secondary to a chronic constrictive pericarditis. In the first case, the mucosa of jejunum presented with a diffuse oedematous aspect, whitish villi, white curved lines probably related to submucosal dilated lymphatics and lacteal juice. In the second case, capsule endoscopy showed oedematous aspect of jejunum mucosa associated with white curved lines similar to those observed in the first case. Videocapsule endoscopy is useful in cases of protein-losing enteropathy to identify presence of intestinal lymphangiectasia and to specify their localisation after ruling out other disorders liable to induce protein-losing gastrointestinal syndrome.

[Coagulation disorders and arterial thromboembolic events in non-small-cell lung cancer. A case report]. / Anomalies de la coagulation et événements thromboemboliques artériels dans le cancer bronchique non à petites cellules. A propos d'une observation.

Certain coagulation disorders can occur in patients with cancer and thromboembolic complications are frequent. We report the case of a 53-Year-old patient with metastatic adenocarcinoma of the lung treated with chemotherapy who presented several cerebral arterial thromboembolic events leading to death a few weeks after the initial diagnosis of cancer. This case illustrates the important role of certain satellite disorders related to coagulation activation: non-bacterial thrombotic endocarditis, disseminated intravascular coagulation, anti-phospholipid antibody syndrome. The role of anticancer chemotherapy as a favoring factor for thromboembolic events is also emphasized in patients with non-small-cell lung cancer.

[The immune system: new therapeutic targets]. / Système immunitaire: nouvelles cibles thérapeutiques.

Control of the immune reaction can become a major goal, particularly in patients with autoimmune diseases or who express alloreactivity after organ transplantation. The most important side effect of this control is an immunodeficiency, a consequence of the wide spectrum of activity of the treatment. Thus, in order to limit the infectious risks, it would appear reasonable to try to develop new more selective strategies. A better definition of the cellular and molecular mechanisms implicated in the initiation and effector phases of autoimmune diseases authorizes the development of new therapeutic approaches able to target precise points of the immune system. There are a large number of potential targets, mainly directed at orientating the cytokinic response toward an antiinflammatory profile, neutralizating proinflammatory cytokines or their receptors, inducing regulatory lymphocytes in order to normalize the state of T and B cell tolerance, and modulating cellular cooperation and lymphocytic homing by blocking adhesion molecules. Some of these new approaches have already been validated in autoimmune diseases, others will follow soon.

[Pulmonary histiocytosis, then bronchiolo-alveolar cancer in HIV-1 infection]. / Histiocytose pulmonaire, puis cancer bronchiolo-alvéolaire au cours d'une infection par VIH-1.

INTRODUCTION: Langerhans cell pulmonary histiocytosis is a rare disease, primarily enhanced by smoking, and of unclear mechanism. OBSERVATION: A 42 year-old man, smoking 25 packs-years, was infected by a type 1 human immunodeficiency virus (HIV-1). He successively developed pulmonary emphysema, Langerhans cell pulmonary histiocytosis and alveolar bronchial carcinoma of the lower right pulmonary lobe, which was fatal. DISCUSSION: We discuss the concomitance of pulmonary histiocytosis and alveolar bronchial carcinoma, exceptional in the literature, and the eventual enhancing role of HIV-1 infection. The principal incriminating factor in pulmonary histiocytosis probably remains smoking, but the HIV-1 infection may have participated in the emergence of the neoplastic pathology.

Expansion of marginal zone B cells is not sufficient for the development of renal disease in NZBxNZW F1 mice.

The mechanisms which govern the production of autoantibodies and of tissue damage during systemic lupus (SLE) are still unclear. In the NZBxNZW F1 (BW) model of SLE glomerulonephritis, the activation and commitment of B cells are thought to play a major role in disease progression. Previous analysis has suggested that these mice have a substantial increase of marginal zone (MZ) B cells before the occurrence of the disease. Owing to the probable role of this B cell subset in autoantibody production, it was important to define the possible link between this abnormality and the occurrence of kidney damage. Using cytofluorometry analysis, we followed the splenic MZ B cell phenotype in different series of mice with shared autoimmune genetic background and histologically defined renal status. By comparing BW females and BW males, NZB and NZW mice, we confirm that BW mice have an increase in MZ B cells but this MZ B cells expansion is not directly linked to tissue lesions. Genetically modified BW female mice with a restricted repertoire of B and T cell antigen receptors, and which do not develop nephritis, exhibit the same increase of MZ B cells, suggesting that this increase does not depend on a specific set of antigens. Moreover, our analysis brings to light a pre-disease state in BW males, with autoantibody production and mesangial deposits.

Recombinant vaccinia viruses expressing immunoglobulin variable regions efficiently and selectively protect mice against tumoral B-cell growth.

The variable regions of the immunoglobulin (Ig) expressed on the surface of a malignant B cell can be considered tumor-specific antigens and, as such, could be targets for immunotherapeutic approaches. However, because until now the immunization procedures have been complex and have given only partial protection, it was necessary to find new methods of immunotherapy. Here, we present a successful method of vaccination against B-cell tumors in a murine model. We produced recombinant vaccinia viruses (rVV) expressing the heavy and the light chain of surface Ig of a patient's malignant B cells and we tested the ability of these rVV to protect immunized mice against tumor growth of transfectomas producing the same human Ig. The protection of the mice was complete and specific to the variable region of the immunizing heavy chain although specific lymphoproliferative and cytotoxic responses were not detectable in vitro. The protection was strictly dependent on the presence of CD4 T cells and asialo GM1+ cells. Furthermore, tumor protection clearly required gamma-interferon and was partially inhibited by blocking the Fas-Fas ligand interaction. We also show, in a murine syngeneic model, that rVV expressing a poorly mutated Ig protects against the growth of Ig-producing tumor.

The clonal analysis of anticardiolipin antibodies in a single patient with primary antiphospholipid syndrome reveals an extreme antibody heterogeneity.

The mechanism underlying the prothrombotic state that characterizes the primary antiphospholipid syndrome proves to be difficult to define mainly because of the variety of the phospholipid and protein targets of antiphospholipid antibodies that have been described. Much of the debate is related to the use of polyclonal antibodies during the different antiphospholipid assays. To better describe the antiphospholipid antibodies, a strategy was designed to analyze the reactivity of each one antibody making up the polyclonal anticardiolipin activity, breaking down this reactivity at the clonal level. This was performed in a single patient with primary antiphospholipid syndrome by combining (1) the antigen-specific selection of single cells sorted by flow cytometry using structurally bilayered labeled anionic phospholipids and (2) the cloning of immunoglobulin (Ig) variable (V) region genes originating from individual IgG anticardiolipin-specific B cells by a single-cell polymerase chain reaction technique. The corresponding V regions were cloned in order to express human recombinant antibodies in insect cells by a baculovirus expression system. The molecular analysis, the fine specificity, and the protein cofactor dependency of the first 5 monoclonal IgG anticardiolipins are reported here. This clonal analysis reveals the extreme heterogeneity of these antibodies, which could account for the difficulties in the previous attempts to define the pathogenic antiphospholipid response. This approach should help to unravel the complex antiphospholipid immune response and the mechanism of the prothrombotic state associated with these antibodies, but it could also shed some light on their possible origins. (Blood. 2001;97:3820-3828)