Systemic perturbation of cytokine and chemokine networks in Erdheim-Chester disease: a single-center series of 37 patients

Immunopathogenesis of Erdheim-Chester disease (ECD), a rare non-Langerhan

Serum vascular endothelial growth factor is associated with cardiovascular involvement and response to therapy in Erdheim-Chester disease

Erdheim-Chester disease (ECD) is a rare histiocytosis, considered to be an inflammatory myeloid neoplasm. Tropism for specific involvements of the disease remains unexplained. Vascular endothelial growth factor-A (VEGF) is implicated in cancer pathophysiology and mutations of the RAS oncogene have been shown to induce upregulation of VEGF gene expression. We therefore hypothesized that VEGF might play a particular role in ECD pathophysiology. We conducted a retrospective, single-center study to assess serum VEGF (sVEGF) concentrations and determine whether they were associated with the characteristics of ECD patients, and to determine whether VEGF was expressed by histiocytes. We evaluated 247 ECD patients, 53.4% of whom had sVEGF levels above the normal range (>500 pg/mL). Patients with high sVEGF levels more frequently had cardiac and vascular involvement (58.3% vs. 41.4%, P=0.008 and 70.5% vs. 48.3%, P=0.0004, respectively). In treatment-naïve patients (n=135), the association of C-reactive protein >5 mg/L and sVEGF >500 pg/mL was strongly associated with vascular involvement (odds ratio=5.54 [95% confidence interval: 2.39-13.62], P<0.001), and independently associated with cardiac involvement (odds ratio=3.18 [95% confidence interval: 1.34-7.83], P=0.010) after adjustment for the presence of the BRAF V600E mutation. Changes in sVEGF concentration on treatment were associated with a response of cardiac involvement on consecutive cardiac magnetic resonance images. All histological samples analyzed (n=24) displayed histiocytes with intracytoplasmic expression of VEGF, which was moderate to high in more than 90% of cases. Our study suggests a role for VEGF in cardiac and vascular involvement in ECD

Cytokine Profiles in Sepsis Have Limited Relevance for Stratifying Patients in the Emergency Department: A Prospective Observational Study

INTRODUCTION: Morbidity, mortality and social cost of sepsis are high. Previous studies have suggested that individual cytokines levels could be used as sepsis markers. Therefore, we assessed whether the multiplex technology could identify useful cytokine profiles in Emergency Department (ED) patients. METHODS: ED patients were included in a single tertiary-care center prospective study. Eligible patients were >18 years and met at least one of the following criteria: fever, suspected systemic infection, ≥ 2 systemic inflammatory response syndrome (SIRS) criteria, hypotension or shock. Multiplex cytokine measurements were performed on serum samples collected at inclusion. Associations between cytokine levels and sepsis were assessed using univariate and multivariate logistic regressions, principal component analysis (PCA) and agglomerative hierarchical clustering (AHC). RESULTS: Among the 126 patients (71 men, 55 women; median age: 54 years [19-96 years]) included, 102 had SIRS (81%), 55 (44%) had severe sepsis and 10 (8%) had septic shock. Univariate analysis revealed weak associations between cytokine levels and sepsis. Multivariate analysis revealed independent association between sIL-2R (p = 0.01) and severe sepsis, as well as between sIL-2R (p = 0.04), IL-1β (p = 0.046), IL-8 (p = 0.02) and septic shock. However, neither PCA nor AHC distinguished profiles characteristic of sepsis. CONCLUSIONS: Previous non-multiparametric studies might have reached inappropriate conclusions. Indeed, well-defined clinical conditions do not translate into particular cytokine profiles. Additional and larger trials are now required to validate the limited interest of expensive multiplex cytokine profiling for staging septic patients

Cryofibrinogenemia: new insights into clinical and pathogenic features.

International audienceOBJECTIVE: Cryofibrinogenemia is an under-recognized cryoprotein that can be life-threatening when untreated. Our aim was to describe the prevalence and clinical findings of patients with cryofibrinogenemia and to clarify the mechanisms involved. METHODS: Between 1996 and 2006, 2312 patients were tested for cryofibrinogenemia in a single university hospital. A total of 515 patients had positive test results, of whom 455 (88.3%) had an associated cryoglobulin. RESULTS: Sixty patients (11.7%) with persistent cryofibrinogenemia and without cryoglobulin were included in the study. Main clinical manifestations related to cryofibrinogenemia included purpura (46.6%), skin necrosis (36.6%), and arthralgia (31.6%) with cold sensitivity in 40%. Overall thrombotic events occurred in up to 40% of cases. Cryofibrinogen plasma concentration was 2 times greater in patients with thrombotic events (P=.012). Complications included gangrene (5%), septicemia (5%), and leg amputation (3.3%). Complete remission of cryofibrinogenemia was achieved in 78% of patients receiving antithrombotic agents, steroids, or immunosuppressants, whereas 41.6% of patients experienced a relapse after a median time of 9 months (range 7-42 months). After a mean follow-up of 85 months, 3 patients died of sepsis (n=2) and cardiovascular disease (n=1). Fibrinolysis status analyzed in a patient with cryofibrinogenemia showed an increase in fibrinolysis inhibitor levels, plasminogen activator inhibitor-1, alpha-2 macroglobulin, and euglobulin lysis time, which normalized after fibrinolytic therapy. CONCLUSION: Essential cryofibrinogenemia represents 12% of all the cryoproteins at Pitie-Salpêtriere Hospital. Thrombotic events are frequent and could be associated with the amount of plasma cryofibrinogen. Defects in the fibrinolysis process might lead to cryofibrinogen accumulation and clotting in small and medium arteries

Cryofibrinogen in patients with hepatitis C virus infection.

International audienceBACKGROUND: Mixed cryoglobulin is usually associated with hepatitis C virus (HCV) infection and might cause systemic vasculitis. The presence and impact of cryofibrinogen, another cryoprotein, in the serum of HCV-infected patients have not yet been evaluated. The objective was to study the prevalence and the clinical and therapeutic impacts of cryofibrinogen in HCV-infected patients. METHODS: A total of 143 consecutive HCV-infected (RNA+) patients (including 57 patients with HCV-related vasculitis) were screened for cryofibrinogen and cryoglobulin (positive if >0.05 g/L). The main characteristics and outcome were evaluated according to the cryofibrinogen/cryoglobulin status at baseline. RESULTS: At baseline, 53 of 143 patients (37%) were cryofibrinogen positive, most of whom (47/53 [89%]) were also cryoglobulin positive. Only 37 of 90 cryofibrinogen-negative patients (41%) were cryoglobulin positive (P<.001). In patients with HCV-related vasculitis, 28 of 57 (49%) were cryofibrinogen positive compared with 25 of 86 patients (29%) without vasculitis (P=.03). There was a higher rate of renal involvement in cryofibrinogen-negative/cryoglobulin-positive patients than in cryofibrinogen-positive/cryoglobulin-positive patients (10/25 [40%] vs 3/27 [11%], respectively; P=.02). After a mean follow-up of 32.6 months, among patients who were cryofibrinogen positive at baseline, 12 of 26 (46%) of those who received an HCV treatment were cryofibrinogen negative at the end of follow-up compared with 4 of 16 (25%) of those who did not receive antiviral drugs. Most patients who became cryofibrinogen negative also became cryoglobulin negative (93%). CONCLUSION: Cryoproteins, including cryoglobulin and cryofibrinogen, are frequently found in the serum of HCV-infected patients. In such patients, a positive cryofibrinogen status is closely related to the presence of cryoglobulin at baseline and after antiviral therapy

Cryoglobulinemia after the era of chronic hepatitis C infection

International audienceObjectives: Historically chronic hepatitis C virus (HCV) infection accounted for the majority of mixed cryoglobulinemia (MC). The advent of direct-acting antivirals (DAA) against HCV has dramatically changed the management and the prevalence of chronic HCV infection. We aimed to describe the spectrum of MC in the era of DAA agents.Methods: We performed a longitudinal cohort study between 2011 and 2018 from a single-center French university hospital's database of 15 970 patients screened for MC. Epidemiological, clinical and immunological data of MC were recorded. We evaluated the incidence and evolution of MC before and after the era of DAA agents and compared HCV and non-HCV related MC.Results: Among 742 patients who tested positive for cryoglobulin, 679 [mean age 55.5 years, 54.5% female and 381 (56.1%) with chronic HCV infection] patients with persistent MC were included in the study. 373 (54.9%) had type II and 306 (45.1%) type III cryoglobulin, and 139 (21.5%) had cryoglobulinemia vasculitis (CryoVas). The incidence of MC decreased steadily with 395 and 284 incident cases during 2011-2014 and 2015-2018, respectively. In 2011, the leading cause was chronic HCV infection (62.5% of all MC). Currently, autoimmune diseases [systemic lupus erythematosus (28.9%) and Sjögren's syndrome (10.7%)] are the main cause of MC. The incidence of CryoVas was similar between HCV-and non HCV-related MC.Conclusion: Direct-acting antivirals have dramatically changed the landscape and the incidence of MC

Detection in whole blood of autoantibodies for the diagnosis of connective tissue diseases in near patient testing condition

International audienceA novel technology, photonic ring immunoassay (PRI), for detecting 12 autoantibodies simultaneously in whole blood in less than 15 minutes was evaluated by comparing results from 235 clinically diagnosed patients with standard laboratory tests. The overall agreement was greater than 91% for 10 of the 12 assays, with positive percent agreement greater than 89% for 9 of the assays and negative percent agreement greater than 91% for 10 of them. Thus, the clinical sensitivities and specificities were similar for the 2 methods. In addition, 199 normal blood donors were tested on the ANA 12 PRI, yielding specificities greater than 97.5% for all assays. This proof of concept study shows that this new system is suitable for point of care testing for clinically useful autoantibodies, allowing the doctor to have test results in minutes rather than days

Clinical Phenotypes of Patients with Anti-DFS70/LEDGF Antibodies in a Routine ANA Referral Cohort

Objective. To analyze the clinical value of anti-DFS70 antibodies in a cohort of patients undergoing routine antinuclear antibodies (ANAs) testing. Methods. Sera with a dense fine speckled (DFS) indirect immunofluorescence (IIF) pattern from 100 consecutive patients and 100 patients with other IIF patterns were tested for anti-DFS70 antibodies by a novel chemiluminescence immunoassay (CIA) and for ANA by ANA Screen ELISA (both INOVA). Results. Among the 100 patients with a DFS IIF pattern, 91% were anti-DFS70 positive by CIA compared to 3% in the comparator group . The CIA and IIF titers of anti-DFS antibodies were highly correlated (rho = 0.89). ANA by ELISA was positive in 35% of patients with the DFS IIF pattern as compared to 67% of patients with other patterns . Only 12.0% of patients with DFS pattern and 13.4% with DFS pattern and anti-DFS70 antibodies detected by CIA had systemic autoimmune rheumatic disease (SARD). Only 5/91 (5.5%) patients with anti-DFS70 antibodies had SARD and their sera were negative on the ANA Screen ELISA. Conclusion. Although anti-DFS70 antibodies cannot exclude the presence of SARD, the likelihood is significantly lower than in patients with other IIF patterns and should be included in test algorithms for ANA testing.Peer Reviewe

Clinical Phenotypes of Patients with Anti-DFS70/LEDGF Antibodies in a Routine ANA Referral Cohort

International audienceObjective. To analyze the clinical value of anti-DFS70 antibodies in a cohort of patients undergoing routine antinuclear antibodies (ANAs) testing.Methods. Sera with a dense fine speckled (DFS) indirect immunofluorescence (IIF) pattern from 100 consecutive patients and 100 patients with other IIF patterns were tested for anti-DFS70 antibodies by a novel chemiluminescence immunoassay (CIA) and for ANA by ANA Screen ELISA (both INOVA).Results. Among the 100 patients with a DFS IIF pattern, 91% were anti-DFS70 positive by CIA compared to 3% in the comparator group . The CIA and IIF titers of anti-DFS antibodies were highly correlated (rho = 0.89). ANA by ELISA was positive in 35% of patients with the DFS IIF pattern as compared to 67% of patients with other patterns . Only 12.0% of patients with DFS pattern and 13.4% with DFS pattern and anti-DFS70 antibodies detected by CIA had systemic autoimmune rheumatic disease (SARD). Only 5/91 (5.5%) patients with anti-DFS70 antibodies had SARD and their sera were negative on the ANA Screen ELISA.Conclusion. Although anti-DFS70 antibodies cannot exclude the presence of SARD, the likelihood is significantly lower than in patients with other IIF patterns and should be included in test algorithms for ANA testing