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Biomedical subjects

Loïc Guillevin

Publications and source records attributed to Loïc Guillevin.

At least 19 recordsLinked to original sources
PubMed2007

Churg-Strauss syndrome.

PURPOSE OF REVIEW: Churg-Strauss syndrome is a small-vessel necrotizing vasculitis typically characterized by asthma, lung infiltrates, extravascular necrotizing granulomas and hypereosinophilia. The most recent clinical studies on its pathogenesis and therapeutic management are reviewed here. RECENT FINDINGS: French and Italian clinical studies found that the clinical characteristics of patients with Churg-Strauss syndrome differed according to their antineutrophil cytoplasmic autoantibody status: cardiomyopathy predominated in antineutrophil cytoplasmic autoantibody-negative patients while necrotizing glomerulonephritis was more often observed in antineutrophil cytoplasmic autoantibody-positive patients. These histologically documented findings suggest the existence of different Churg-Strauss syndrome subtypes, characterized by the predominance of distinct pathogenetic mechanisms. To date, following the therapeutic recommendations for Churg-Strauss syndrome (i.e. corticosteroids and, when required, immunosuppressants), patient outcomes are good, with 5-year survival exceeding 90%, but often with the need to continue low-dose corticosteroids to control residual asthma. SUMMARY: The precise pathogenetic mechanisms of Churg-Strauss syndrome are only partly elucidated. Recent results suggest that antineutrophil cytoplasmic autoantibodies are probably more involved in the vasculitic manifestations of Churg-Strauss syndrome (e.g. glomerulonephritis) whereas eosinophil tissue infiltration and associated cytotoxicity would be responsible for cardiomyopathy. If confirmed, these results could support individual therapeutic stratification according to the clinical pattern. Furthermore, some patients may benefit from new biologic therapies under development, for example antiinterleukin-5 or antiimmunoglobulin E monoclonal antibodies.

Adrenal Cortex Hormones↗
PubMed2006

Sjogren's syndrome is associated with and not secondary to systemic sclerosis.

OBJECTIVES: When Sjögren's syndrome (SS) is secondary to rheumatoid arthritis, the sicca syndrome is less serious and anti-SSA/SSB antibodies are found less frequently than in primary SS (pSS). When SS is associated with systemic lupus erythematosus, clinical and serological patterns are similar to those of pSS. We aimed to determine whether SS, accompanying systemic sclerosis (SSc), could be considered secondary to or associated with SSc and whether the coexistence of both modifies the severity and the outcome of each disease. PATIENTS AND METHODS: A retrospective multicentric study was conducted to compare (i) characteristics and complications of SS between 27 patients with SS and SSc (SS-SSc) and 202 patients with pSS, and (ii) the characteristics of SSc and complications between the SS-SSc group and 94 patients with SSc alone. RESULTS: SS features were similar in both SS-SSc and pSS patients, except for peripheral neuropathy and arthritis, which was more common in SS-SSc than in the pSS patients (P = 0.02 and 0.05, respectively). SSc appears to be less severe in patients with SS-SSc than SSc alone with a lower frequency of lung fibrosis (P = 0.05). Compared with patients with pSS or SSc alone, SS-SSc patients were more likely to have another autoimmune disorder and other autoantibodies (SS-SSc vs pSS, P = 0.02 and P = 0.03, respectively). CONCLUSION: SS seems to be associated with and not secondary to SSc. SS associated with SSc has the same features as pSS, but SSc seems to be less serious. Moreover, the association of SS and SSc is frequently accompanied by a spreading of autoimmunity.

Adult↗
PubMed2006

Accumulation of hydrogen peroxide is an early and crucial step for paclitaxel-induced cancer cell death both in vitro and in vivo.

Intracellular events following paclitaxel binding to microtubules that lead to cell death remain poorly understood. Because reactive oxygen species (ROS) are involved in the cytotoxicity of anticancer agents acting through independent molecular targets, we explored the role of ROS in paclitaxel cytotoxicity. Within 15 min after in vitro exposure of A549 human lung cancer cells to paclitaxel, a concentration-dependent intracellular increase in O(o)(2)(-) and H(2)O(2) levels was detected by spectrofluorometry. Addition of N-acetylcysteine (NAC) or glutathione, two H(2)O(2) scavenger, induced a 4-fold increase in paclitaxel IC(50). Delaying NAC co-incubation by 4 hr, resulted in a 3-fold reduction in cell protection. The glutathione synthesis inhibitor, buthionine sulfoximine significantly increased paclitaxel cytotoxicity and H(2)O(2) accumulation, but did not modify O(o)(2)(-) levels. Co-incubation with diphenylene iodonium suggested that paclitaxel induced-O(o)(2)(-) production was in part associated with increased activity of cytoplasmic NADPH oxidase. Concomitant treatment with inhibitors of caspases 3 and 8 increased cell survival but did not prevent the early accumulation of H(2)O(2.) To evaluate the role of ROS in paclitaxel antitumoral activity, mice were injected with LLC1 lung cancer cells and treated with paclitaxel i.p. and/or NAC. The antitumoral activity of paclitaxel in mice was abolished by NAC. In conclusion, the accumulation of H(2)O(2) is an early and crucial step for paclitaxel-induced cancer cell death before the commitment of the cells into apoptosis. These results suggest that ROS participate in vitro and in vivo to paclitaxel cytotoxicity.

Acetylcysteine↗
PubMed2006

Marked efficacy of a therapeutic strategy associating prednisone and plasma exchange followed by rituximab in two patients with refractory myopathy associated with antibodies to the signal recognition particle (SRP).

We report two patients with myopathy associated with anti-signal recognition particle Ab, refractory to conventional therapy, who were treated with prednisone and plasma exchange, followed by rituximab. A marked response was observed in both patients, with partial to complete recovery of muscle strength, which was sustained.

Adult↗
PubMed2006

Anti-endothelial cell antibodies from patients with limited cutaneous systemic sclerosis bind to centromeric protein B (CENP-B).

By using a quantitative immunoblotting technique on protein extracts of human macrovascular and microvascular endothelial cells, we have analyzed the self-reactive repertoires of IgG from 20 patients with limited cutaneous SSc, 40 patients with diffuse SSc and 60 age- and sex-matched healthy controls. Serum IgG from 15/20 patients with limited cutaneous SSc and anti-centromere antibodies bound to at least one of the two 75- and 85-kDa protein bands in the different endothelial cell extracts, whereas IgG from healthy controls or patients with diffuse SSc did not. N-terminal sequencing of the 75- and 85-kDa bands identified CENP-B as the sole antigen in both bands. Moreover, IgG from all of the SSc patients who recognized the 75- and/or 85-kDa bands bound to a full-length recombinant CENP-B protein as assessed by ELISA, whereas IgG from other SSc patients did not. The main target of anti-endothelial cell antibodies in patients with limited cutaneous SSc is the nuclear and ubiquitous protein CENP-B.

Antibody Specificity↗
PubMed2006

A cohort study of enfuvirtide immunological and virological efficacy in clinical practice.

The aim of the study was to evaluate, under routine circumstances, the immunological and virological efficacy of antiretroviral regimens containing enfuvirtide in multi-class experienced HIV-1 infected patients. This retrospective monocentric study analyzed the clinical, immunological, and virological data of 18 HIV-1 infected patients who started enfuvirtide and completed at least 3 months of therapy. Following 3 months of enfuvirtide therapy, 11 (61%) patients had HIV-1 RNA below 400 copies/ml, among whom 8 (44%) patients below 50 copies/ml. In the ten patients still receiving enfuvirtide after 12 months, the median increase in CD4 cell count was 159 cells/microl (range, -25 to +301) and the mean decrease in HIV-1 RNA was 2.5 +/- 1.4 log(10) copies/ml; in six of these patients, viral load remained below 50 copies/ml. Five patients discontinued enfuvirtide for virological failure but none as a consequence of adverse event. Mutations located within the 36-45 amino acid domain of HR1 region of gp41 and associated to enfuvirtide resistance were found in all seven patients with persistent viral replication. In addition, a new mutation, A50V, emerged in one patient with late viral rebound. Its disappearance after treatment discontinuation suggests that it could play a role in resistance to enfuvirtide. In conclusion, enfuvirtide may be a good therapeutic option as rescue therapy in treatment-experienced patients. However, the mutations conferring resistance to enfuvirtide develop rapidly when viral load is not controlled confirming that enfuvirtide should be prescribed in association with an active background regimen.

Adult↗
PubMed2006

[Mandibular resorption, an underdiagnosed manifestation of systemic scleroderma].

INTRODUCTION: Systemic sclerosis (SSc) is sometimes associated with bone resorption that can reach the mandible. CASES: We report here the cases of two women (aged 47 and 57 years) with SSc diagnosed 13 and 26 years earlier, respectively. Both presented marked mandibular bone resorption. The first had prominent interstitial lung disease, and the second, who died within a few months, had severe left ventricular dysfunction due to SSc. DISCUSSION: Mandibular resorption is a rare but probably underdiagnosed manifestation of SSc. In addition to its esthetic effects, it can cause severe disability.

Bone Resorption↗
PubMed2006

[Diagnosis of lymphocytopenia].

Lymphopenia is defined as a peripheral lymphocyte count lower than 1500/mm3 in adults and 4500/mm3 in children younger than eight months of age. We propose a classification of lymphopenia according to the mechanism involved: lymphocyte production defects, including primary immune deficiencies and immune deficiencies secondary to malnutrition or zinc deprivation; excess catabolism, due to causes including radiotherapy, chemotherapy, immunosuppressive therapy, HIV infection, and systemic lupus erythematosus; abnormal lymphocyte trapping, including mainly splenomegaly, certain viral infections, septic shock, extended burns, systemic granulomatosis, and corticosteroids; other causes of lymphocytopenia, with mechanisms that remain poorly understood: ethnicity (Ethiopians), lymphoma, renal insufficiency, and idiopathic CD4 lymphocytopenia.

Humans↗
PubMed2006

[Diagnosis of primary immunodeficiency in adult patients].

The molecular bases of approximately one hundred primary immune deficiencies (PID) have been identified over the last 15 years. In adults, the diagnosis of PID cannot be evoked before ruling out acquired immunodeficiencies, which are far more frequent. The search for specific PIDs may be oriented by the type of agent responsible for severe and/or recurrent infection. More rarely, other clinical manifestations such as granulomatosis, autoimmune manifestations, hemophagocytic syndrome, lymphoproliferation, or solid tumors may also lead to the identification of PID.

Adult↗
PubMed2006

[Systemic sclerosis: pathophysiology of a multifaceted disease].

Systemic sclerosis is a rare disease characterized by vascular hyperreactivity and collagen deposition. Endothelial cell, fibroblast and lymphocyte abnormalities have been reported in systemic sclerosis. Fibroblast dysfunction is characterized by uncontrolled activation of the transforming growth factor-beta (TGF-beta) pathway and excess synthesis of both connective tissue growth factor (CTGF) and free radicals. These promote the accumulation of extracellular matrix. Endothelial cells produce excess quantities of endothelin 1 and inducible NO synthase. They also undergo early apoptosis. Oxidative stress appears to play a major role in disease progression. Increased levels of interleukin 4, a profibrotic cytokine, have been detected in plasma and skin of systemic sclerosis patients. Autoantibodies are detectable in the serum of almost all systemic sclerosis patients. Some are directed against well-identified ubiquitous nuclear proteins and have no demonstrated pathogenic role. Other autoantibodies bind to endothelial cells or fibroblasts and may have a pathogenic role.

Adult↗
PubMed2006

[Interstitial lung disease in systemic sclerosis].

Interstitial lung diseases (ILD) associated with systemic sclerosis (SSc) are mainly encountered in patients with diffuse disease, although they may also be seen in patients with limited cutaneous SSc. ILD screening must be performed regularly, with high-resolution computed tomography and pulmonary function tests (TLCO). Up to 75% of patients with diffuse SSc develop a form of ILD. ILD remains stable in most patients and does not worsen. The nonspecific nature of SSc-associated ILD makes it different from idiopathic ILD and helps to explain its better prognosis. Nonetheless, ILD is one of the two leading causes of death in SSc patients. Treatment of SSc-associated ILD is not yet well codified. Antifibrotic treatments have not proved beneficial, and the efficacy of cyclophosphamide, which has been used to treat this condition for 15 years, has been shown to be very limited against SSc-associated ILD. A subgroup of patients with rapidly progressive ILD might benefit from intravenous cyclophosphamide pulses in association with 15 mg/d prednisone.

Anti-Inflammatory Agents↗
PubMed2006

[Scleroderma renal crisis].

Scleroderma renal crisis (SRC) occurs in patients with systemic sclerosis (SSc) and is defined by otherwise unexplained rapidly progressive renal insufficiency associated with oliguria or rapidly progressive arterial hypertension or both. SRC is a rare and severe complication of SSc, most often encountered during the first 4 years of disease, almost only in patients with diffuse SSc. Factors predicting SRC were identified, including high-dose corticosteroid administration. Use of angiotensin-converting enzyme inhibitors (ACEI) has dramatically impressed the prognosis of SRC, but it mortality rate is still high. Treatment aims at normalizing blood pressure as soon as possible. ACEI should always be used, and additional anti-hypertensive agents, including calcium channel blockers and alpha- and beta-blockers, may be useful. Renal replacement therapy may be needed, but often (for almost half of patients) only temporarily.

Acute Kidney Injury↗
PubMed2006

[Therapeutic management of systemic sclerosis].

UNLABELLED: Improved understanding of the pathophysiology of systemic sclerosis (SSc) opens new therapeutic avenues in its treatment. The efficacy of disease-modifying agents remains limited however, and none has yet demonstrated its ability to improve survival in a prospective randomized trial. RESULTS: of traditional antifibrotic agents such as colchicine and D-penicillamine are disappointing. Cyclophosphamide (CYC) seems to be beneficial in interstitial lung disease associated with SSc. Organ-specific therapies may produce dramatic benefits. Examples include angiotensin-converting enzyme inhibitors for renal failure and epoprostenol for primary pulmonary hypertension. Several new therapeutic approaches are currently under evaluation, including high-dose CYC followed by peripheral stem cell transplantation, vasodilators, and antiinflammatory and antifibrotic agents. Physical therapy and rehabilitation may help to treat disability and loss of function in SSc patients.

Acute Kidney Injury↗