22 research outputs found
New diagnostic and prognostic marker in membranous nephropathy
La GlomĂ©rulonĂ©phrite extra-membraneuse est une maladie auto-immune rare mais grave qui conduit dans 30% des cas Ă une insuffisance rĂ©nale chronique terminale nĂ©cessitant le recours Ă la dialyse ou la greffe rĂ©nale. Dans les suites dâune greffe, la GEM rĂ©cidive dans 30 Ă 40% des cas. En 2009, lâĂ©quipe du Pr. Salant en collaboration avec notre Ă©quipe a montrĂ© que 70% des patients prĂ©sentant une GEM Ă©taient porteurs dâanticorps (Ac) dirigĂ©s contre le rĂ©cepteur des phospholipases A2 (PLA2R1). Le titre dâanticorps est corrĂ©lĂ© Ă lâactivitĂ© de la maladie. Il nâexiste actuellement aucun biomarqueur permettant de prĂ©dire lâĂ©volution de la fonction rĂ©nale dâun patient lors de sa prise en charge : dans 30% des cas les patients prĂ©sentent une rĂ©mission spontanĂ©e sans traitement immunosuppresseur. Le traitement de la GEM repose sur un traitement symptomatique et une rĂ©Ă©valuation aprĂšs 6 mois. En cas de maladie active persistante, il faut dĂ©buter un traitement immunosuppresseur. Dans les formes graves, cette pĂ©riode dâobservation de 6 mois peut ĂȘtre Ă lâorigine de lĂ©sions irrĂ©versibles. Nous avons validĂ© un test ELISA permettant de quantifier les Ac anti-PLA2R1 au cours du suivi de patients porteurs dâune GEM. Ce test nous a permis de montrer sur une cohorte de 15 patients greffĂ©s dans les suites dâune GEM quâun titre dâAc anti-PLA2R1 persistant aprĂšs la greffe Ă©tait associĂ© Ă un risque de rĂ©cidive de la maladie sur le greffon. Nous avons ensuite produit dans des cellules HEK les orthologues de PLA2R1 (les rĂ©cepteurs humain, lapin et murin).Membranous Nephropathy (MN) is a major cause of nephrotic syndrome in adults. It is a rare but severe kidney disease with different etiologies and outcomes. In most cases (85%), the disease is idiopathic (iMN) and has an autoimmune origin. One third of patients develop end-stage kidney disease and are on kidney transplant waiting list. MN recurred in 30% after transplantation. Another third enter in spontaneous remission under renin-angiotensin system blockade. The treatment of iMN is controversial. KDIGO guidelines recommend a supportive symptomatic treatment with RAS-blockade and diuretics in all patients with iMN, and immunosuppressive therapy in case of renal function deterioration or persistent nephrotic syndrome. Therefore, immunosuppressive treatments are often started only after significant and potentially irreversible complications. No biological markers can predict clinical outcome and orient therapy. A major breakthrough was the discovery of autoantibodies to the phospholipase A2 receptor (PLA2R1, 180 kDa) in 70% of iMN patients in 2009, which has now allowed to develop diagnosis and prognosis tests for better medical care. During my PhD, I have first participated to the development of an ELISA which is now commercially available. I then used this latter to demonstrate that persistent anti-PLA2R1 activity can predict iMN recurrence after transplantation in a retrospective cohort of 15 patients. We then screened 50 patients with iMN on native kidney for their cross-reactivity to human (h), rabbit (rb) and mouse (m) PLA2R1 by western blot (WB) and antigen-specific ELISAs
Nouveaux marqueurs diagnostiques et pronostiques dans la glomĂ©rulonĂ©phrite extra-membraneuse : suivi des anticorps anti-PLA2R1 chez le greffĂ© rĂ©nal : caractĂ©risation des Ă©pitopes reconnus par les anticorps anti-PLA2R1 : identification dâune nouvelle cible antigĂ©nique
Membranous Nephropathy (MN) is a major cause of nephrotic syndrome in adults. It is a rare but severe kidney disease with different etiologies and outcomes. In most cases (85%), the disease is idiopathic (iMN) and has an autoimmune origin. One third of patients develop end-stage kidney disease and are on kidney transplant waiting list. MN recurred in 30% after transplantation. Another third enter in spontaneous remission under renin-angiotensin system blockade. The treatment of iMN is controversial. KDIGO guidelines recommend a supportive symptomatic treatment with RAS-blockade and diuretics in all patients with iMN, and immunosuppressive therapy in case of renal function deterioration or persistent nephrotic syndrome. Therefore, immunosuppressive treatments are often started only after significant and potentially irreversible complications. No biological markers can predict clinical outcome and orient therapy. A major breakthrough was the discovery of autoantibodies to the phospholipase A2 receptor (PLA2R1, 180 kDa) in 70% of iMN patients in 2009, which has now allowed to develop diagnosis and prognosis tests for better medical care. During my PhD, I have first participated to the development of an ELISA which is now commercially available. I then used this latter to demonstrate that persistent anti-PLA2R1 activity can predict iMN recurrence after transplantation in a retrospective cohort of 15 patients. We then screened 50 patients with iMN on native kidney for their cross-reactivity to human (h), rabbit (rb) and mouse (m) PLA2R1 by western blot (WB) and antigen-specific ELISAs.La GlomĂ©rulonĂ©phrite extra-membraneuse est une maladie auto-immune rare mais grave qui conduit dans 30% des cas Ă une insuffisance rĂ©nale chronique terminale nĂ©cessitant le recours Ă la dialyse ou la greffe rĂ©nale. Dans les suites dâune greffe, la GEM rĂ©cidive dans 30 Ă 40% des cas. En 2009, lâĂ©quipe du Pr. Salant en collaboration avec notre Ă©quipe a montrĂ© que 70% des patients prĂ©sentant une GEM Ă©taient porteurs dâanticorps (Ac) dirigĂ©s contre le rĂ©cepteur des phospholipases A2 (PLA2R1). Le titre dâanticorps est corrĂ©lĂ© Ă lâactivitĂ© de la maladie. Il nâexiste actuellement aucun biomarqueur permettant de prĂ©dire lâĂ©volution de la fonction rĂ©nale dâun patient lors de sa prise en charge : dans 30% des cas les patients prĂ©sentent une rĂ©mission spontanĂ©e sans traitement immunosuppresseur. Le traitement de la GEM repose sur un traitement symptomatique et une rĂ©Ă©valuation aprĂšs 6 mois. En cas de maladie active persistante, il faut dĂ©buter un traitement immunosuppresseur. Dans les formes graves, cette pĂ©riode dâobservation de 6 mois peut ĂȘtre Ă lâorigine de lĂ©sions irrĂ©versibles. Nous avons validĂ© un test ELISA permettant de quantifier les Ac anti-PLA2R1 au cours du suivi de patients porteurs dâune GEM. Ce test nous a permis de montrer sur une cohorte de 15 patients greffĂ©s dans les suites dâune GEM quâun titre dâAc anti-PLA2R1 persistant aprĂšs la greffe Ă©tait associĂ© Ă un risque de rĂ©cidive de la maladie sur le greffon. Nous avons ensuite produit dans des cellules HEK les orthologues de PLA2R1 (les rĂ©cepteurs humain, lapin et murin)
Les auto-anticorps dirigés contre le récepteur des phospholipases A2 de type M sont-ils prédictifs d'une récidive de glomérulonéphrite extramembraneuse en transplantation rénale ?
NICE-BU MĂ©decine Odontologie (060882102) / SudocSudocFranceF
Diagnostic significance of antineutrophil cytoplasmic antibody (ANCA) titres: a retrospective case-control study
Objectives To investigate the reliability of elevated titres of antineutrophil cytoplasmic antibody (ANCA) and to identify a cut-off titre in discriminating between ANCA-associated vasculitides (AAV) and its mimickers.Methods This retrospective observational single-centre study included patients over 18 years with positive myeloperoxidase (MPO)-ANCA and/or proteinase 3 (PR3)-ANCA immunoassays over an 8-year period (January 2010 to December 2018), via their electronic medical files. Patients were classified according to the 2022 ACR/EULAR criteria and alternative diagnoses categorised either as non-AAV autoimmune disorders (ANCA-AI) or disorders without autoimmune features (ANCA-O). Findings from the AAV group were compared with those of ANCA-AI and ANCA-O groups and followed by a multivariate logistic stepwise regression analysis of features associated with AAV.Results 288 ANCA-positive patients of which 49 had AAV were altogether included. There was no difference between patients between the ANCA-AI (n=99) and the ANCA-O (n=140) groups. The AUC for titres discriminating AAV from mimickers was 0.83 (95% CI, 0.79 to 0.87). The best threshold titre, irrespective of PR3-ANCA or MPO-ANCA, was 65âU/mL with a negative predictive value of 0.98 (95% CI, 0.95 to 1.00). On multivariate analysis, an ANCA titre â„65âU/mL was independently associated with AAV with an OR of 34.21 (95% CI 9.08 to 129.81; p<0.001). Other risk factors were: pulmonary fibrosis (OR, 11.55 (95% CI, 3.87 to 34.47, p<0.001)), typical ear nose and throat involvement (OR, 5.67 (95% CI, 1.64 to 19.67); p=0.006) and proteinuria (OR, 6.56 (95% CI, 2.56 to 16.81; p<0.001)).Conclusion High PR3/MPO-ANCA titres can help to discriminate between AAV and their mimickers in patients presenting with small-calibre vasculitides, with a threshold titre of 65âU/mL and above
Phospholipase A2 Receptor 1 Epitope Spreading at Baseline Predicts Reduced Likelihood of Remission of Membranous Nephropathy
G.L. and P.R. contributed equally to this work.International audienceThe phospholipase A2 receptor (PLA2R1) is the major autoantigen in primary membranous nephropathy. Several PLA2R1 epitopes have been characterized, and a retrospective study identified PLA2R1 epitope spreading as a potential indicator of poor prognosis. Here, we analyzed the predictive value of anti-PLA2R1 antibody (PLA2R1-Ab) titers and epitope spreading in a prospective cohort of 58 patients positive for PLA2R1-Ab randomly allocated to rituximab (n=29) or antiproteinuric therapy alone (n=29). At baseline, the epitope profile (CysR, CysRC1, CysRC7, or CysRC1C7) did not correlate with age, sex, time from diagnosis, proteinuria, or serum albumin, but epitope spreading strongly correlated with PLA2R1-Ab titer (P<0.001). Ten (58.8%) of the 17 patients who had epitope spreading at baseline and were treated with rituximab showed reversal of epitope spreading at month 6. In adjusted analysis, epitope spreading at baseline was associated with a decreased remission rate at month 6 (odds ratio, 0.16; 95% confidence interval, 0.04 to 0.72; P=0.02) and last follow-up (median, 23 months; odds ratio, 0.14; 95% confidence interval, 0.03 to 0.64; P=0.01), independently from age, sex, baseline PLA2R1-Ab level, and treatment group. We propose that epitope spreading at baseline be considered in the decision for early therapeutic intervention in patients with primary membranous nephropathy
Th17-Immune Response in Patients With Membranous Nephropathy Is Associated With Thrombosis and Relapses
International audienceAlternative strategies targeting dysregulated cytokine balance could be considered for these patients at high risk of relapse
Baseline and early functional immune response is associated with subsequent clinical outcomes of PD-1 inhibition therapy in metastatic melanoma patients
Background Despite significant progress with antiprogrammed cell death protein 1 (PD-1) therapy, a substantial fraction of metastatic melanoma patients show upfront therapy resistance. Biomarkers for outcome are missing and the association of baseline immune function and clinical outcome remains to be determined. We assessed the in vitro nonspecific stimulation of immune response at baseline and during anti-PD-1 therapy for metastatic melanoma.Methods Previously untreated metastatic melanoma patients received nivolumab and radiotherapy as part of the multicentric phase II trial NIRVANA (NCT02799901). The levels of Th1, Th2 and Th17 cytokines on in vitro non-specific stimulation of innate and adaptive immune cells were measured in patient sera before treatment, and at week 2 and week 6 after the beginning of the treatment, and correlated with tumorous response, progression-free survival (PFS) and occurrence of immune-related adverse events (irAEs). The results in melanoma patients were compared with those of a cohort of 9 sex and age-matched healthy donors.Results Seventeen patients were enrolled in this ancillary study. Median follow-up was 16 months (2.2â28.4). The 12-month PFS rate was 67.7%. The incidence of irAEs of any grade was 58.8%. Without in vitro stimulation no differences in cytokines levels were observed between responders and non-responders. On in vitro stimulation, metastatic patients had lower Th1 cytokine levels than healthy donors at baseline for tumor necrosis factor-α and interferon-Îł (IFN-Îł) (1136âpg/mL vs 5558âpg/mL, p<0.0001; and 3894âpg/mL vs 17â129âpg/mL, p=0.02, respectively). Responders exhibited increasing cytokine levels from baseline to week 6. Non-responders had lower interleukin 17A (IL-17A) levels at baseline than responders (7âpg/mL vs 32âpg/mL, p=0.03), and lower IFN-Îł levels at week 6 (3.3âng/mL vs 14.5âng/mL, p=0.03). A lower level of IL-17A at week 2 and a lower level of IFN-Îł at week 6 correlated with worse PFS (p=0.04âand p=0.04 respectively). At baseline, patients who developed irAEs had higher IL-6 levels (19.3âng/mL vs 9.2âng/mL, p=0.03) and higher IL-17A levels (52.5âpg/mL vs 2.5âpg/mL, p=0.009) than those without irAEs.Conclusions Our findings indicate that cytokine levels after in vitro non-specific stimulation could be a promising biomarker to predict the outcome of PD-1 inhibition therapy
Only Follow-up of Memory B Cells Helps Monitor Rituximab Administration to Patients with NeuroMyelitis Optica Spectrum Disorders
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