Philippe Musette

Université de Rouen, Mont-Saint-Aignan, Upper Normandy, France

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Publications (96)494.8 Total impact

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    ABSTRACT: Regulatory B cells (B-reg) produce IL-10 and suppress inflammation in both mice and humans, but limited data on the phenotype and function of these cells have precluded detailed assessment of their contribution to host immunity. In this article, we report that human B-reg cannot be defined based on a phenotype composed of conventional B cell markers, and that IL-10 production can be elicited in both the CD27(+) memory population and naive B cell subset after only a brief stimulation in vitro. We therefore sought to obtain a better definition of IL-10-producing human B-regs using a multiparameter analysis of B cell phenotype, function, and gene expression profile. Exposure to CpG and anti-Ig are the most potent stimuli for IL-10 secretion in human B cells, but microarray analysis revealed that human B cells cotreated with these reagents resulted in only ∼0.7% of genes being differentially expressed between IL-10(+) and IL-10(-) cells. Instead, connectivity map analysis revealed that IL-10-secreting B cells are those undergoing specific differentiation toward a germinal center fate, and we identified a CD11c(+) B cell subset that was not capable of producing IL-10 even under optimal conditions. Our findings will assist in the identification of a broader range of human pro-B-reg populations that may represent novel targets for immunotherapy.
    Journal of immunology (Baltimore, Md. : 1950). 07/2014;
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    ABSTRACT: Background Drug reaction with eosinophilia and systemic symptoms (DRESS) may relapse following introduction of drugs structurally unrelated to the initial culprit drug. Objective To assess the frequency and characteristics of recurrent drug eruptions in patients with history of DRESS. Methods Patients who had developed adverse cutaneous reaction after DRESS occurrence were recruited from the regional database of Upper Normandy in France. Rate of recurrences were compared with patients with Toxic Epidermal Necrolysis (TEN) and Stevens–Johnson syndrome (SJS) patients during the same time frame. ResultsOf the 60 cases of DRESS collected, 15 (25%) with recurrences were retained for analysis. Seven patients had a single recurrence, whereas eight patients had several relapses. In the patients with pre-existing DRESS, recurrences were incomplete, corresponding to cutaneous rash in 13 cases and associated with eosinophilia in seven cases. Internal organ involvement was observed in two cases. In contrast, a single recurrence was found out of 61 patients with TEN/SJS. Conclusion Incomplete recurrences with structurally unrelated culprit drugs are a frequent phenomenon in DRESS patients.
    Journal of the European Academy of Dermatology and Venereology 03/2014; · 2.69 Impact Factor
  • JAMA dermatology. 12/2013;
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    ABSTRACT: We have identified a spliced mRNA transcript of CD20 (named D393-CD20) which was associated with resistance to RTX in primary B cell from patients with lymphoma and leukaemia. In the present work, we wished to investigate whether D393-CD20 variant was expressed by B cells from patients with pemphigus. Ten patients with bullous pemphigoid and twenty-five patients with pemphigus were included. All patients were responder to conventional immunosuppressive agents or rituximab (n=11). Efficacy of B-cell activation by Pokeweed Mitogen was assessed by CD86 expression using a FACS Canto II flow cytometer. mRNA CD20 expression study was then performed using RT-PCR assay allowing first to discriminate wild type (wt)-CD20 and D393-CD20 transcript. Although wt-CD20 expression was always detected, we were unable to detect D393-CD20, even after B cell activation or RTX treatment. Our results suggest that D393-CD20 transcript may be a molecular marker of B cell malignancies rather than auto-immune disease like pemphigus. Further study of RTX-non responders or -escaping PV patients are thus still required to appreciate whether D393-CD20 expression may be detected under the pressure of RTX therapy. This article is protected by copyright. All rights reserved.
    Experimental Dermatology 12/2013; · 3.58 Impact Factor
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    ABSTRACT: Pemphigus is a severe blistering condition of the skin and mucosa caused by autoantibodies directed against desmogleins, which are a type of keratinocyte adhesion protein. B cell depletion by rituximab has short-term efficacy against pemphigus. We aimed to assess the long-term course of pemphigus patients after B cell depletion and to understand the immunological mechanisms that mediate long-lasting remissions. We evaluated the clinical course of 22 pemphigus patients treated with rituximab after a 79-month median follow-up and compared the anti-desmoglein B cell response and B and T lymphocyte subpopulations and repertoire between patients who achieved complete remission (CR) and those who had incomplete remission (IR). Thirteen patients (59%) experienced CR during the study, including 10 patients off treatment and 3 patients with prednisone doses <10 mg/day; 9 patients had IR. A marked increase was observed in the ratio of CD19CD27 naïve B cells to CD19CD27 memory B cells. Indeed, patients in CR had a fourfold higher number of transitional B cells and interleukin-10-secreting regulatory B cells than those in IR. Furthermore, CR was associated with modification of the initial B cell repertoire and the disappearance of desmoglein-specific circulating immunoglobulin G-positive (IgG) B lymphocytes, whereas a skewed B cell repertoire was observed in patients in IR. Thus, a blockage of B cell maturation, a prolonged repopulation with naïve B cells, and a delayed reappearance of memory B cells, which resulted in the disappearance of circulating desmoglein-specific IgG B lymphocytes, contribute to the long-lasting effectiveness of rituximab for treating pemphigus.
    Science translational medicine 03/2013; 5(175):175ra30. · 10.76 Impact Factor
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    ABSTRACT: We have reviewed 47 drug rash with eosinophilia and systemic symptoms (DRESS) cases associated to strontium ranelate reported up to March 2011 to the Marketing Holder. The main signs were skin rash, fever, face oedema hypereosinophilia and liver involvement. For ten patients, persistence of DRESS symptoms was reported at the latest news obtained, and DRESS was identified as the direct cause of death in one case. The maximum incidence of DRESS associated with strontium ranelate was 1/24,112 [95 % CI (1/14,859; 1/42,194)] newly treated patients in France. Because DRESS is a severe drug reaction, the occurrence of a rash in a patient treated with strontium ranelate should lead to prompt and permanent treatment discontinuation. INTRODUCTION: This study aims to describe cases of DRESS reported to the Marketing Authorisation Holder worldwide for patients receiving strontium ranelate by practitioner or by regulatory authorities. METHODS: Spontaneously reported hypersensitivity events from the strontium ranelate pharmacovigilance database since marketing authorisation (2004) to March 2011 were reviewed by an expert committee. Cases of DRESS were classified as established, probable, possible or no DRESS according to expert judgement. National incidences of DRESS were estimated in relation to the number of newly treated patients. RESULTS: Up to March 2011, 325 cases of strontium ranelate-induced hypersensitivity events were assessed from which 47 DRESS cases were confirmed. Mean age was 68.7 years and besides skin rash, the main signs and symptoms were hypereosinophilia, liver involvement, fever and face oedema. Median time to skin reaction was 33.5 days after treatment start. Most patients (62 %) recovered at the time of reporting or were recovering. For ten patients, persistence of DRESS symptoms was reported at the latest news obtained. Relapses were observed in a single case. The mortality rate was 8.5 %. The maximum incidence of DRESS associated with strontium ranelate was 1/24,112 [95 % CI (1/14,859; 1/42,194)] newly treated patients in France. CONCLUSION: DRESS is a well-identified and characterised adverse reaction to strontium ranelate. This risk should be integrated in the risk-benefit balance evaluation of patient treatment, and the occurrence of a rash should lead to prompt and permanent treatment discontinuation with careful follow-up.
    Osteoporosis International 01/2013; · 4.04 Impact Factor
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    ABSTRACT: The syndrome termed 'Drug Reaction with Eosinophilia and Systemic Symptoms' (DRESS) is an unpredictable, life-threatening condition associated with adverse reactions to therapy. Although the etiology of DRESS is poorly understood, genetic susceptibility markers have been identified within the HLA complex and there are several prevailing models of pathogenesis. Modification of host antigens by haptens (drugs or their metabolites), or non-covalent drug binding to endogenous proteins (the p-i concept), may drive pro-inflammatory immune responses in patients. Alternatively, a viral trigger for DRESS has been proposed based on the concomitant detection of herpesviruses and the recent demonstration of Epstein-Barr virus-specific immune responses in DRESS patients. In the present review, we discuss the latest findings concerning the pathogenesis of drug reactions and known risk factors for DRESS.
    Current opinion in immunology 10/2012; · 10.88 Impact Factor
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    Archives of dermatology 04/2012; 148(4):543-4. · 4.76 Impact Factor
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    ABSTRACT: The Drug Reaction with Eosinophilia and Systemic Symptom (DRESS) is a severe adverse drug-induced reaction. Diagnosing DRESS is challenging due to the diversity of cutaneous eruption and organs involved. We used the RegiSCAR scoring system that grades DRESS cases as "no," "possible," "probable," or "definite" to classify cases reported in the literature. We also analyzed the clinical course and treatments of the cases. A total of 44 drugs were associated with the 172 cases reported between January 1997 and May 2009 in PubMed and MEDLINE. The most frequently reported drug was carbamazepine, and the vast majority of cases were classified as "probable/definite" DRESS cases. Hypereosinophilia, liver involvement, fever, and lymphadenopathy were significantly associated with "probable/definite" DRESS cases, whereas skin rash was described in almost all of the cases, including "possible cases." Culprit drug withdrawal and corticosteroids constituted the mainstay of DRESS treatment. The outcome was death in 9 cases. However, no predictive factors for serious cases were found. This better knowledge of DRESS may contribute to improve the diagnosis and management of this syndrome in clinical practice.
    The American journal of medicine 07/2011; 124(7):588-97. · 5.30 Impact Factor
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    ABSTRACT: Cutaneous adverse reactions are reported for many therapeutic agents and, in general, are observed in between 0% and 8% of treated patients depending on the drug. Antiosteoporotic agents are considered to be safe in terms of cutaneous effects, however there have been a number of case reports of cutaneous adverse reactions which warrant consideration. This was the subject of a working group meeting of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis in April 2009, which focused on the impact of cutaneous adverse reactions and drug-induced hypersensitivity in the management of postmenopausal osteoporosis. This position paper was drafted following these discussions and includes a flowchart for their recognition. Cutaneous adverse reactions observed with antiosteoporotic agents were reviewed and included information from case reports, regulatory documents and pharmacovigilance. These reactions ranged from benign effects including exanthematous or maculopapular eruption (drug rash), photosensitivity and urticaria, to the severe and potentially life-threatening reactions of angioedema, drug rash with eosinophilia and systemic symptoms (DRESS), Stevens Johnson syndrome and toxic epidermal necrolysis. A review of the available evidence demonstrates that cutaneous adverse reactions occur with all commonly used antiosteoporotic treatments. Notably, there are reports of Stevens Johnson syndrome and toxic epidermal necrolysis for bisphosphonates, and of DRESS and toxic epidermal necrolysis for strontium ranelate. These severe reactions remain very rare (<1 in 10,000 cases). In general, with proper management and early recognition, including immediate and permanent withdrawal of the culprit agent, accompanied by hospitalization, rehydration and systemic corticosteroids if necessary, the prognosis is positive.
    Therapeutic advances in musculoskeletal disease 02/2011; 3(1):31-41.
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    ABSTRACT: The inflammation which occurs around the silicone prosthesis is a complex process that can provoke the failure of the device and compromise the health of the implanted patient. Toll-like receptors (TLRs), which are transmembrane proteins, are now known to act in the innate immune response and in endogenous inflammation. The aim of our study was to assess the role of TLR4 in the foreign body reaction to a silicone shell prosthesis. Disks of shell silicone prosthesis were implanted in the subcutaneous tissue of C57BL6-TLR4-/- and C57BL6-WT mice. At day 14, inflammatory cell infiltrate and vessel sections around the prosthesis were less numerous in TLR4-/- than in WT mice. A histomorphometric analysis showed that the capsule around the implant was 1.96-fold less thick in depleted TLR4 than in wild-type mice. In addition, vascular endothelial growth factor and transforming growth factor 1 were underexpressed in the surrounding tissue of the prosthesis in TLR4-/- mice. Our study suggests, from this foreign body response model against silicone in mice, that TLR4 plays a key role in the reaction process around silicone implants.
    Acta biomaterialia 01/2011; 7(5):2047-52. · 5.68 Impact Factor
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    ABSTRACT: Drug-induced hypersensitivity syndrome or DRESS is an uncommon but potentially severe cutaneous adverse drug reaction. This cutaneous drug adverse reaction has some particular characteristics: a small number of culprit drugs, long delay (three to six weeks) for development after the first drug intake, responsibility of some viruses, especially Human Herpesvirus 6 (HHV6). The awareness of this cutaneous adverse reaction has increased during the last years with a better knowledge including the relationship between some drugs and reactivation of Herpesviruses, antiviral immune response, and genetic background. The identification of DRESS is important for rheumatologist who is often using drugs at risk for DRESS (allopurinol, salazopyrine, antiépileptiques…). This recognition enables a rapid diagnosis and a proper management of this syndrome.
    Revue du Rhumatisme Monographies 01/2011; 78(3):197-200.
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    ABSTRACT: IL-10-producing regulatory B cells have been identified in mice and shown to downregulate inflammation, making them potentially important for maintenance of tolerance. In this study, we isolated B cells from human blood and spleen, and showed that after a short period of ex vivo stimulation a number of these cells produced IL-10. The IL-10-producing B cells did not fall within a single clearly defined subpopulation, but were enriched in both the memory (CD27(+)) and the transitional (CD38(high)) B-cell compartments. Combined CpG-B+anti-Ig stimulation was the most potent IL-10 stimulus tested. B cells stimulated in this way inhibited CD4(+)CD25(-) T-cell proliferation in vitro by a partially IL-10-dependent mechanism. These findings imply that manipulating IL-10 production by human B cells could be a useful therapeutic strategy for modulating immune responses in humans.
    European Journal of Immunology 10/2010; 40(10):2686-91. · 4.97 Impact Factor
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    ABSTRACT: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe, drug-induced reaction that involves both the skin and the viscera. Evidence for reactivation of herpes family viruses has been seen in some DRESS patients. To understand the immunological components of DRESS and their relationship to viral reactivation, we prospectively assessed 40 patients exhibiting DRESS in response to carbamazepine, allopurinol, or sulfamethoxazole. Peripheral blood T lymphocytes from the patients were evaluated for phenotype, cytokine secretion, and repertoire of CD4+ and CD8+ and for viral reactivation. We found Epstein-Barr virus (EBV), human herpes virus 6 (HHV-6), or HHV-7 reactivation in 76% of the patients. In all patients, circulating CD8+ T lymphocytes were activated, exhibited increased cutaneous homing markers, and secreted large amounts of tumor necrosis factor-alpha and interferon-gamma. The production of these cytokines was particularly high in patients with the most severe visceral involvement. In addition, expanded populations of CD8+ T lymphocytes sharing the same T cell receptor repertoire were detected in the blood, skin, liver, and lungs of patients. Nearly half of these expanded blood CD8+ T lymphocytes specifically recognized one of several EBV epitopes. Finally, we found that the culprit drugs triggered the production of EBV in patients' EBV-transformed B lymphocytes. Thus, cutaneous and visceral symptoms of DRESS are mediated by activated CD8+ T lymphocytes, which are largely directed against herpes viruses such as EBV.
    Science translational medicine 08/2010; 2(46):46ra62. · 10.76 Impact Factor
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    ABSTRACT: In pemphigus vulgaris (PV), IgG autoantibodies against the ectodomain of desmoglein 3 (Dsg3) have been shown to be directly responsible for the loss of keratinocyteadhesion. The aim of the present study was to study the effect of the B cell depleting anti-CD20 monoclonal antibody, rituximab, on the profile of pathogenic IgG against distinct regions of the Dsg3 ectodomain in 22 PV patients who were followed up clinically and serologically by Dsg3 ELISA over 12-24 months. Prior to rituximab, all the 22 PV patients showed IgG against Dsg3 (Dsc3EC1-5). Specifically, 14/22 showed IgG reactivity against the Dsg3EC1 subdomain, 5/22 patients against Dsg3EC2, 7/22 against Dsg3EC3, 11/22 against Dsg3EC4, and 2/22 against Dsg3EC5. Within 6 months after rituximab, all the patients showed significant clinical improvement and reduced IgG against Dsg3 (5/22) and the various subdomains, that is, Dsg3EC1 (7/22), Dsg3EC2 (3/22), Dsg3EC3 (2/22), sg3EC4 (2/22), and Dsg3EC5 (0/22). During the entire observation period, 6/22 PV patients experienced a clinical relapse which was associated with the reappearance of IgG against previously recognized Dsg3 subdomains, particularly against the Dsg3EC1. Thus, in PV, rituximab only temporarily depletes pathogenic B cell responses against distinct subdomains of Dsg3 which reappear upon clinical relapse.
    Dermatology Research and Practice 01/2010; 2010:321950.
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    ABSTRACT: Drug-induced hypersensitivity or Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome is a severe cutaneous adverse drug reaction induced by a limited number of drugs. It is characterized by a clinical and laboratory picture of high fever, facial edema, skin rash, lymphadenopathy, a mononucleosis-like syndrome, hypereosinophilia, and visceral involvement, especially hepatitis. This syndrome may be life-threatening due to multiple organ failure. Its pathophysiology was recently clarified by demonstration of reactivation of herpesviruses: Human Herpesvirus 6 (HHV-6), cytomegalovirus (CMV), Epstein-Barr virus (EBV), and Human Herpesvirus 7 (HHV-7). These viral reactivations and the immune response directed against the viruses explain the clinical and laboratory manifestations of the DRESS syndrome and, in particular, the systemic manifestations associated with its severity. The pathophysiology is specific to the DRESS syndrome and is not observed during the course of other cutaneous drug reactions. The DRESS syndrome may be considered to be a model of other reactions associated with viral reactivations observed in other situations, such as in organ transplantation or in immunodepressed patients in the absence of any imputable drug.
    Revue Francaise D Allergologie - REV FR ALLERGOL. 01/2010; 50(3):171-173.
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    ABSTRACT: Cutaneous adverse reactions are reported for many treatments including antiosteoporotic agents. This position paper includes an algorithm for their recognition. With early recognition and proper management, including immediate and permanent withdrawal of the culprit agent, accompanied by hospitalization, rehydration, and systemic corticosteroids, if necessary, the prognosis is good. Cutaneous adverse reactions are reported for many therapeutic agents and observed in between 0% and 8% of treated patients depending on the drug. The antiosteoporotic agents are reputed to be safe in terms of cutaneous effects; however, there have been a number of case reports of cutaneous adverse reactions, which merit consideration. This was the subject of a Working Group meeting of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis in April 2009, to focus on the impact of cutaneous adverse reactions and drug-induced hypersensitivity in the management of postmenopausal osteoporosis. We prepared this position paper following these discussions, and include an algorithm for their recognition. We reviewed cutaneous adverse reactions observed with antiosteoporotic agents, including information from case reports, regulatory documents, and pharmacovigilance. The cutaneous adverse reactions range from benign reactions including exanthematous or maculopapular eruption (drug rash), photosensitivity, and urticaria to the severe and potentially life-threatening reactions, angioedema, drug rash with eosinophilia and systemic symptoms (DRESS), Stevens Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). Review of available evidence shows that cutaneous adverse reactions occur with all commonly used antiosteoporotic agents. Notably, there are reports of SJS and TEN for bisphosphonates, and of DRESS and TEN for strontium ranelate. These severe reactions remain very rare (<1 in 10,000 cases). With early recognition and proper management, including immediate and permanent withdrawal of the culprit agent, accompanied by hospitalization and rehydration and systemic corticosteroids if necessary, the prognosis is good.
    Osteoporosis International 11/2009; 21(5):723-32. · 4.04 Impact Factor
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    ABSTRACT: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by pathogenic autoantibodies directed against nuclear Ags and immune complex deposits in damaged organs. Environmental factors have been thought to play a role in the onset of the disease. The recognition of these factors is mediated by TLRs, in particular TLR2 and TLR4 which bind pathogen-associated molecular patterns of Gram(+) and Gram(-) bacteria, respectively. We attempted to determine the role of these TLRs in SLE by creating TLR2- or TLR4-deficient C57BL/6(lpr/lpr) mice. These mice developed a less severe disease and fewer immunological alterations. Indeed, in C57BL/6(lpr/lpr)-TLR2 or -TLR4-deficient mice, glomerular IgG deposits and mesangial cell proliferation were dramatically decreased and antinuclear, anti-dsDNA, and anti-cardiolipin autoantibody titers were significantly reduced. However, the response against nucleosome remained unaffected, indicating a role of TLR2 and TLR4 in the production of Abs directed against only certain categories of SLE-related autoantigens. Analysis of B cell phenotype showed a significant reduction of marginal zone B cells, particularly in C57BL/6(lpr/lpr)-TLR4-deficient mice, suggesting an important role of TLR4 in the sustained activation of these cells likely involved in autoantibody production. Interestingly, the lack of TLR4 also affected the production of cytokines involved in the development of lupus disease.
    The Journal of Immunology 11/2009; 183(10):6207-16. · 5.52 Impact Factor
  • European Journal of Anaesthesiology 06/2009; 26(9):791-3. · 2.79 Impact Factor
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    ABSTRACT: To assess the predictive value of anti-desmoglein (Dsg) 1 and anti-Dsg3 antibody (Ab) enzyme-linked immunosorbent assay (ELISA) values for the occurrence of relapses in pemphigus. Retrospective study. Dermatology departments from 13 university hospitals in France. Patients The study population comprised 26 patients with typical clinical, histologic, and immunofluorescence findings of pemphigus, who were followed up over a 17-month period. Serial anti-Dsg1 and anti-Dsg3 Ab ELISA values were recorded during the patients' follow-up examinations and correlated with the occurrence of skin and/or mucosal relapses. A significant reduction of anti-Dsg1 (P < .001) and anti-Dsg3 (P < .001) Ab ELISA values was observed in serum samples from patients with pemphigus foliaceus or pemphigus vulgaris after the initial treatment. During the long-term follow-up, anti-Dsg1 Ab ELISA values correlated with the course of skin lesions (P = .03); the 20 U/mL cutoff for the anti-Dsg1 Ab ELISA value provided a 79% positive and an 84% negative predictive value for the occurrence of cutaneous relapses. No correlation was observed between anti-Dsg3 Ab ELISA values and the course of mucosal lesions (P = .13). Anti-Dsg3 Ab ELISA values higher than the 14-U/mL cutoff were observed in 5 of the 5 patients with relapse and in 10 of the 13 patients with ongoing mucosal remission, providing a 100% sensitivity but a poor specificity of 23%. A cutoff value of 130 U/mL for anti-Dsg3 Abs was calculated based on the receiver operating characteristics curve and provided an 84% positive and an 81% negative predictive value. Anti-Dsg1 Ab ELISA values are more closely correlated than anti-Dsg3 Ab ELISA values with the course of the disease in patients with pemphigus vulgaris or pemphigus foliaceus. This should be taken into account for the management of patients with pemphigus.
    Archives of dermatology 06/2009; 145(5):529-35. · 4.76 Impact Factor

Publication Stats

1k Citations
494.80 Total Impact Points

Institutions

  • 2005–2014
    • Université de Rouen
      Mont-Saint-Aignan, Upper Normandy, France
  • 2013
    • Hôpitaux Universitaires La Pitié salpêtrière - Charles Foix
      Lutetia Parisorum, Île-de-France, France
  • 2004–2013
    • Centre Hospitalier Universitaire Rouen
      • Service de Dermatologie
      Rouen, Upper Normandy, France
  • 2005–2012
    • Hôpital Charles-Nicolle
      Tunis-Ville, Tūnis, Tunisia
  • 2011
    • Ghent University
      • Department of Internal Medicine
      Gent, VLG, Belgium
  • 2010
    • Assistance Publique – Hôpitaux de Paris
      Lutetia Parisorum, Île-de-France, France
  • 1994–2009
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 1996–2006
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
    • Cea Leti
      Grenoble, Rhône-Alpes, France
  • 1994–1996
    • Institut Pasteur International Network
      • Département d'Immunologie de Paris
      Paris, Ile-de-France, France