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David Saadoun

Publications and source records attributed to David Saadoun.

At least 19 recordsLinked to original sources
PubMed2006

Increased risks of lymphoma and death among patients with non-hepatitis C virus-related mixed cryoglobulinemia.

BACKGROUND: Data on essential mixed cryoglobulinemia (MC) are scarce, and most date back to studies before 1989 (ie, before the discovery of hepatitis C virus [HCV] infection). Our objective was to describe the spectrum of MC in the era of HCV infection. METHODS: Retrospective study from a single university hospital's database of 1434 patients who tested positive for MC between January 1989 and December 2003. RESULTS: One hundred thirty-three patients (9%) with persistent MC without HCV were included in the study. Sixty-five of 133 patients who fulfilled the criteria for MC vasculitis were compared with 118 patients with HCV-related MC vasculitis. The patients without HCV had increased frequencies of renal involvement and B-cell non-Hodgkin lymphoma (NHL), lower gammaglobulin levels, and higher death rates. Twenty-three of the patients had B-cell NHL (primarily of the lymphoplasmocytic and marginal zone types), and 8 patients had Sjögren syndrome. In multivariate analysis, a cryoglobulin level higher than 0.6 g/L (odds ratio [OR], 1.44) and the presence of MC vasculitis (OR, 4.3) and hypogammaglobulinemia (OR, 6.7) were independently associated with B-cell NHL. After a mean follow-up of 49.4 months, 18 (14%) of 133 patients had died, primarily of sepsis. In multivariate analysis, age at diagnosis older than 60 years (OR, 1.06) and renal involvement (OR, 5.20) were independently associated with death. CONCLUSION: Patients with non-HCV-related MC vasculitis have a poor outcome and have a 4-fold increased risk of developing B-cell NHL.

Adult↗
PubMed2006

Regulatory and effector T cell activation levels are prime determinants of in vivo immune regulation.

Little is known about the in vivo conditions in which CD4+CD25+ regulatory T cells (T(reg)) exert their suppressive effect in nonlymphopenic mice. To this end, we analyzed T(reg)-mediated suppression of expansion and cytokine production at different levels of Ag-specific CD4+CD25- T cell activation. Using Ab-mediated depletion of endogenous T(reg), we show that basal immunosuppression is dependent on effector T cell activation. These polyclonal T(reg), which were poorly activated in our immunization conditions, were effective in weak but not high T cell activation context. In contrast, the same immunization conditions led to proliferation of cotransferred Ag-specific T(reg). Those efficiently inhibited T cell proliferation and cytokine production even in strong T cell activation context. Interestingly, T(reg) selectively suppressed expansion or cytokine production depending on the experimental approach. The importance of the immune context for efficient suppression is further supported by the observation that T(reg) depletion exacerbated diabetes of NOD mice only at the early stage of the disease. Overall, our study suggests that T(reg)-mediated suppression depends on the relative activation of T(reg) and effector T cells in vivo. This balance may be a critical factor in the regulation of immune responses.

Adoptive Transfer↗
PubMed2006

Cryoglobulinaemia vasculitis in patients coinfected with HIV and hepatitis C virus.

OBJECTIVE: To describe mixed cryoglobulinaemia (MC) vasculitis in patients coinfected with hepatitis C virus (HCV) and HIV. DESIGN: Retrospective multicentre study through the GERMIVIC Database of 4005 HIV/HCV-coinfected patients. METHODS: The characteristics and outcome of 11 HIV/HCV-coinfected patients with MC vasculitis were analysed and compared with those of 118 HCV-infected patients with MC vasculitis. RESULTS: The mean age was 46 years (SD, 14), with 82% male. The median initial CD4 cell count was 367 cells/microl (range, 252-846). After a mean follow-up of 44.4 months, two deaths (18%) were noted. Clinical manifestations of MC included polyneuropathy in seven (64%), purpura in four (36%), arthralgia in four (36%), and kidney involvement in three (27%). Six patients received combination treatment with interferon-alfa and ribavirin, three of whom had sustained HCV virological response and were complete clinical responders. Four patients received corticosteroids and two showed a partial clinical response. Regardless of the HIV virological response, antiretroviral therapy did not improve MC vasculitis. Compared with patients with HCV monoinfection, coinfected patients were younger (P < 0.001), more frequently male (P = 0.03), more frequently intravenous drug users (P < 0.001), had higher HCV viraemia (P = 0.004), higher liver necroinflammation (P = 0.03), higher gammaglobulinaemia (P < 0.001) and lower cryoglobulin level (P = 0.03). The clinical manifestations of MC vasculitis did not differ significantly between the two groups. CONCLUSION: There was a beneficial effect of anti-HCV therapy for HIV/HCV-coinfected patients with MC vasculitis.

Adult↗
PubMed2006

Antiviral therapy for hepatitis C virus--associated mixed cryoglobulinemia vasculitis: a long-term followup study.

OBJECTIVE: To evaluate the long-term efficacy of anti-hepatitis C virus (HCV) therapy in patients with HCV-associated mixed cryoglobulinemia (HCV-MC) vasculitis and to assess the factors associated with clinical remission of MC. METHODS: This was a single-center study of 72 consecutive patients who received treatment with IFN alfa-2b (3 million IU 3 times a week; n = 32 patients) or PEGylated IFN alfa-2b (PEG-IFN alfa-2b) (1.5 mug/kg/week; n = 40 patients), both in combination with oral ribavirin (600-1,200 mg/day), for at least 6 months. Logistic regression was used to assess factors associated with clinical remission of MC. RESULTS: The mean +/- SD duration of followup after discontinuation of antiviral therapy was 39.7 +/- 24.4 months. Eight deaths (11.1% of patients) occurred during the study, primarily as a result of cardiovascular disease, liver disease, or infection. A complete clinical response of the MC occurred in 45 patients (62.5%), a sustained virologic response occurred in 58.3%, and cryoglobulins cleared in 45.8%. Compared with patients treated with IFN alfa-2b plus ribavirin, those receiving PEG-IFN alfa-2b plus ribavirin had a higher sustained clinical (67.5% versus 56.3%), virologic (62.5% versus 53.1%), and immunologic (57.5% versus 31.3%) response, regardless of HCV genotype and viral load. In multivariate analyses, an early virologic response (odds ratio 3.53 [95% confidence interval 1.18-10.59]) was independently associated with a complete clinical response of MC. A glomerular filtration rate <or=70 ml/minute (odds ratio 0.18 [95% confidence interval 0.05-0.67]) was negatively associated with a complete clinical response of MC. CONCLUSION: PEG-IFN alfa-2b plus ribavirin should be considered as induction therapy for HCV-MC vasculitis. An early virologic response and the absence of renal insufficiency are the key factors in the clinical response.

Aged↗
PubMed2006

Cryoglobulinemia is associated with steatosis and fibrosis in chronic hepatitis C.

The relationship between cryoglobulin and severity of liver lesions is debated. No study has focused on the relationship between cryoglobulin, liver steatosis, and fibrosis. The aim of this study was to determine the relationship between cryoglobulins and liver lesions (necroinflammation, fibrosis, and steatosis) in patients with hepatitis C virus (HCV) infection. Four hundred and thirty-seven consecutive patients with untreated chronic hepatitis C who had been admitted for liver biopsy were included in the study. Risk factors for fibrosis and steatosis were assessed. The mean age was 50.9 +/- 13.8 years, and 49% were male. Cryoglobulin was present in 286 patients, 103 of whom had vasculitis. One hundred and eighty-six patients (43%) had steatosis greater than 10%, and 110 (25%) had advanced fibrosis (Metavir score F3-F4). On multivariate analysis, cryoglobulin increased by nearly threefold the risk of having advanced fibrosis and steatosis greater than 10%. Steatosis greater than 10% was associated with a higher body mass index (P < .001), HCV genotype 3 (P < .001), cryoglobulin (P = .002), and advanced liver fibrosis (P = .009). Advanced fibrosis (F3-F4) was associated with a higher level of gamma-glutamyltransferase (P = .04), cryoglobulin (P < .001), a high grade of necroinflammation (Metavir score A2-A3) (P < .001), and steatosis higher than 10% (P = .04). In conclusion, our study shows an independent association between cryoglobulin and steatosis as well as advanced fibrosis.

Adult↗
PubMed2006

Hepatitis C virus eradication followed by HBeAg to anti-HBe seroconversion after pegylated interferon-alpha2b plus ribavirin treatment in a patient with hepatitis B and C coinfection.

In hepatitis B or hepatitis C endemic areas, the number of patients with dual infections is substantial. In such patients, interferon-alpha plus ribavirin can achieve sustained hepatitis C virus (HCV) clearance and hepatitis B e antigen (HBeAg) seroconversion. Pegylated interferon (PegIFN), an established treatment for hepatitis C, is currently increasingly recognized as an efficient therapy for hepatitis B. No case of successful use of PegIFN plus ribavirin has yet been reported, however, in hepatitis B virus (HBV) and HCV coinfection. We report on a 32-year-old man, of Kampuchean origin, with chronic hepatitis B, as documented by the presence of hepatitis B surface antigen with HBeAg, who was coinfected with HCV genotype 1. On therapy with PegIFN-alpha2b plus ribavirin, HCV RNA became undetectable at week 17. At the end of the 48 weeks of treatment, HCV RNA was still undetectable, HBV DNA was reduced and HBeAg remained positive. Twelve weeks after the end of treatment, HBV DNA reduction was followed by HBeAg to anti-HBe seroconversion. Two years after the end of treatment, HCV RNA and HBV DNA were still undetectable, and HBeAg to anti-HBe seroconversion was maintained. We conclude that the combination of PegIFN plus ribavirin may induce suppression of both viral infections.

Adult↗
PubMed2006

[Systemic vasculitis due to hepatitis C virus].

Hepatitis C virus (HCV) is the leading cause of chronic liver disease in industrialized countries. HCV also causes a variety of extrahepatic disorders, of which systemic vasculitis, of the cryoglobulin or polyarteritis nodosa type, is the most severe. This article reviews the main diagnostic, pathophysiologic and therapeutic aspects of HCV-induced systemic vasculitis.

Cryoglobulinemia↗
PubMed2005

Hepatitis B virus genotypes and extrahepatic manifestations.

BACKGROUND/AIMS: This study aimed at correlating the presence of extrahepatic manifestations with hepatitis B virus (HBV) genotypes in patients with chronic HBV infection. METHODS: This was a national (France), multicenter, retrospective, cross-sectional study. HBV genotypes were determined in 190 patients HBsAg-positive for at least 6 months and documented before any treatment. RESULTS: Patients were aged 42+/-15 years and mainly male (77%). Alcohol intake was high in 6% of them, ALT elevated in 73%; 27% were cirrhotic. All HBV genotypes were found, mainly A (24%), D (29%), C (11%), and E (10%). Thirty (16%) patients had clinical extrahepatic manifestations, mainly sensory-motor deficiency, sicca syndrome, myalgia, glomerulonephritis, and arthralgia-arthritis. Their presence was not related to any epidemiologic, viral (including genotypes) or hepatic factor, but to a higher platelet count (P=0.004). Twenty-nine (15%) patients had biological extrahepatic manifestations, mainly anti-smooth muscle, antinuclear, and anti-nucleosome antibodies. Their presence was related only to anti-HBe antibodies positivity (P=0.007) or elevated platelet count (P=0.003). Carrying precore mutant HBV increased by 2.8 folds the risk to have at least one extrahepatic biological manifestation. CONCLUSIONS: No relationships between HBV genotypes and the presence of extrahepatic manifestations were evidenced in patients with chronic HBV infection.

Adolescent↗
PubMed2005

Severe pulmonary arterial hypertension as initial manifestation of intravascular lymphoma: case report.

Intravascular lymphoma (IVL) is a rare and usually fatal disease that belongs to the class of high-grade malignant lymphomas and which is characterized by proliferation of neoplastic lymphoid cells exclusively within the lumina of small blood vessels. Its polymorphic and nonspecific clinical manifestations make antemortem diagnosis very difficult. We report herein a case of IVL revealed by fatal, precapillary, pulmonary arterial hypertension and associated with long-lasting fever. Extensive investigation of the usual causes of pulmonary arterial hypertension was negative. The diagnosis of intravascular lymphoma was made on postmortem analysis, revealing diffuse and sometimes complete obliterations of the lumina of small blood vessels by large B-cell lymphoma, including pulmonary capillaries. Thus, we propose that IVL must be added to the spectrum of etiologies of subacute pulmonary arterial hypertension, notably in the context of associated fever, both entities requiring emergency diagnosis. For this purpose, blood collected via pulmonary capillary-wedge aspiration for cytologic examination may be associated with right-sided heart catheterization when this latter procedure is suitable.

Aged↗
PubMed2005

PEGylated interferon alfa-2b and ribavirin treatment in patients with hepatitis C virus-related systemic vasculitis.

OBJECTIVE: Type II mixed cryoglobulinemia (MC) is a systemic vasculitis usually associated with hepatitis C virus (HCV), which may involve the skin, kidneys, and nervous system. Molecular evidence of antigen-driven B cell proliferation is definitively provided in HCV-associated type II MC, and HCV appears to be the key trigger. The present trial was established to investigate the efficacy of therapy with PEGylated interferon alfa-2b (PEG-IFN alfa-2b) plus ribavirin in patients with HCV-related MC vasculitis. METHODS: Nine consecutive patients with HCV-related MC received PEG-IFN alfa-2b (1.5 microg/kg/week) subcutaneously plus oral ribavirin (800-1,200 mg/day) for at least 6 months. The response to treatment was analyzed by comparing clinical, immunologic, and virologic parameters at the initial evaluation with those observed during followup. RESULTS: The mean +/- SD duration of therapy with PEG-IFN alfa-2b plus ribavirin was 13.5 +/- 2.8 months. After a mean period of 18.6 months following discontinuation of treatment, all 9 patients are alive. Seven patients (78%) had a sustained virologic response and were complete clinical responders. Serum cryoglobulin disappeared in 5 of 9 patients (56%), and complement levels normalized in 80% of the patients. One patient had a partial virologic response with a complete clinical response. In another patient, a clinical relapse of MC vasculitis occurred in association with the reappearance of HCV RNA. Treatment was well tolerated, and no patient had side effects for which discontinuation of therapy was required. CONCLUSION: Treatment with PEG-IFN alfa-2b plus ribavirin can achieve a complete clinical response in most patients with HCV-related MC vasculitis. Complete clinical response correlates with the eradication of HCV and requires a shorter treatment period than that previously reported for IFNalpha plus ribavirin.

Aged↗
PubMed2005

Involvement of chemokines and type 1 cytokines in the pathogenesis of hepatitis C virus-associated mixed cryoglobulinemia vasculitis neuropathy.

OBJECTIVE: To examine the expression profiles of a large number of genes within typical vasculitic nerve lesions in patients with mixed cryoglobulinemia (MC) vasculitis in order to better characterize the molecules involved in cellular tissue activation and trafficking. METHODS: The quantitative expression of 19 genes coding for cytokines, chemokines, and their receptors in the nerve lesions of 9 patients with hepatitis C virus (HCV)-associated MC vasculitis, 7 with idiopathic polyarteritis nodosa (PAN) (rheumatic disease controls), and 8 patients with noninflammatory idiopathic neuropathy (noninflammatory neuropathy controls) was assessed using a real-time reverse transcriptase-polymerase chain reaction procedure. RESULTS: Compared with the noninflammatory controls, HCV-MC vasculitis patients had a significantly higher expression of Th1 cytokines in vasculitic nerve lesions (mean +/- SEM fold increase 33.7 +/- 11.6 for interferon-gamma and 7.2 +/- 1.9 for tumor necrosis factor alpha), whereas Th2 cytokines were absent (interleukin-4 [IL-4], IL-5, and IL-13) or were not significantly different (IL-10). Chemokines involved in T cell and monocyte trafficking were also significantly up-regulated in the HCV-MC vasculitis patients (mean +/- SEM fold increase 27.4 +/- 8.3 for macrophage inflammatory protein 1alpha [MIP-1alpha], 19.9 +/- 5.7 for MIP-1beta, and 7.2 +/- 1.5 for CXCR3). Compared with patients with idiopathic PAN, there was a trend toward higher expression of MIP-1alpha and CXCR3 in HCV-MC vasculitis patients (mean +/- SEM fold increase 27.4 +/- 8.3 versus 5.3 +/- 3.4 for MIP-1alpha and 7.2 +/- 1.5 versus 2.5 +/- 0.9 for CXCR3). CONCLUSION: This study is the first to demonstrate a role of cellular immunity and Th1 lymphocytes in the pathogenesis of HCV-MC vasculitic nerve lesions.

Adult↗
PubMed2005

Hepatitis C virus infection and mixed cryoglobulinaemia vasculitis: a review of neurological complications.

Chronic liver disease caused by hepatitis C virus (HCV) infection is commonly associated with extrahepatic manifestations, mainly mixed cryoglobulinaemia. Neurological complications in HCV-infected patients occur predominantly in the peripheral nervous system. Peripheral neuropathy in HCV infection is primarily associated with mixed cryoglobulinaemia. Central nervous system (CNS) involvement is more rarely reported. In this review, peripheral and CNS involvement associated with chronic HCV infection are described. The underlying mechanisms and treatment possibilities are discussed.

Brain Diseases↗
PubMed2005

Central nervous system involvement in hepatitis C virus cryoglobulinemia vasculitis: a multicenter case-control study using magnetic resonance imaging and neuropsychological tests.

OBJECTIVE: Involvement of the central nervous system (CNS) in patients with hepatitis C virus (HCV) mixed cryoglobulinemia (MC) is rare. The mechanism by which brain lesions are produced is unclear. We investigated these phenomena by clinical evaluation (neuropsychological tests) and cerebral magnetic resonance imaging (MRI) studies in patients with HCV-MC vasculitis. METHODS: This prospective study included 40 patients with MC vasculitis and chronic active HCV infection (HCV RNA+), 11 HCV controls without MC, and 36 healthy controls, matched for sex and age. A battery of 10 standardized neuropsychological tests was administered by one experienced neuropsychiatrist. All patients underwent cerebral MRI investigation. RESULTS: Twenty-four of the 27 (89%) evaluated patients with HCV-MC had a deficiency in one or more of the 10 cognitive domains examined. The most commonly involved domains were those of attention (70%), executive functions (44%), visual construction (37%), and visual spatial functions (33%). The number of impaired cognitive functions was significantly higher in patients with MC vasculitis than in HCV controls (2.18 +/- 1.84 vs 0.87 +/- 3.1; p < 0.05). MRI analysis showed that HCV-MC patients had a higher mean number of total (7.03 +/- 9.9 vs 0.90 +/- 1.81 and 2.03 +/- 3.1; p < 0.05) and periventricular (2.4 +/- 3.0 vs 0.38 +/- 0.5 and 0.8 +/- 1.4; p < 0.05) white matter high intensity signals than HCV controls and healthy controls, respectively. CONCLUSION: The high frequency of impaired cognitive function and the extent of MRI brain abnormalities in patients with HCV-associated mixed cryoglobulinemia vasculitis strongly suggest specific inflammatory involvement of the CNS.

Adult↗
PubMed2004

Splenic lymphoma with villous lymphocytes, associated with type II cryoglobulinemia and HCV infection: a new entity?

Hepatitis C virus (HCV) has been associated with the development of B-cell non-Hodgkin lymphomas. We recently reported the regression of splenic lymphoma with villous lymphocytes (SLVL) in patients with HCV after antiviral treatment, demonstrating a direct role of HCV in lymphomagenesis. This study expands our previous results in 18 patients with chronic HCV and SLVL. Mixed cryoglobulinemia (MC) was present in all cases and was symptomatic in 13 (72%). All patients were treated with interferon alone or in association with ribavirin. Hematologic and virologic responses were correlated. Fourteen (78%) patients achieved a sustained complete hematologic response after clearance of HCV RNA. Two patients had a virologic partial response and achieved a complete hematologic response. Two virologic nonresponders achieved partial hematologic response. Regardless of the response, monoclonal immunoglobulin gene rearrangement persisted after treatment. This study underscores the role of HCV in the lymphomagenesis and the benefit of antiviral treatment for patients presenting with HCV-driven lymphoproliferations.

Cryoglobulinemia↗
PubMed2004

Predominance of type 1 (Th1) cytokine production in the liver of patients with HCV-associated mixed cryoglobulinemia vasculitis.

BACKGROUND/AIMS: Patients with hepatitis C virus (HCV) mixed cryoglobulinemia (MC) vasculitis have a higher mortality rate and more frequent incidence of cirrhosis than their cryoglobulin-negative counterparts. To compare the cytokine profile of liver-infiltrating T cells in HCV-infected patients with or without MC vasculitis. METHODS: Hepatic biopsy specimens were obtained from HCV infected patients with and without MC vasculitis. Using intracellular staining and flow cytometry, we assessed the ability of freshly isolated liver T cells from these biopsies to produce IFN-gamma, TNF-alpha, IL-2, IL-4, and IL-10 in response to stimulation with PMA and ionomycin. RESULTS: HCV-MC vasculitis patients compared to HCV-MC negative controls have an enhanced hepatic T cells production of Th1-type cytokines [i.e. TNF-alpha(30.3 +/- 13% vs. 15.5 +/- 5%, P = 0.01), IL-2 (20.2 +/- 9% vs. 10 +/- 4%, P = 0.01) and IFN-gamma (22.2 +/- 11% vs. 9.4 +/- 4%, P = 0.008)], whereas IL-10, a representative Th2-type cytokine, was significantly lower (7.2 +/- 4% vs. 17 +/- 7%, P = 0.01). CONCLUSIONS: T cell from the liver of HCV-MC vasculitis patients display a significantly augmented liver Th1 profile compared to MC-negative controls. This enhanced production of type-1 cytokines may account for a more severe course of liver disease.

Adult↗