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1. Renal Recovery for Patients with ANCA-Associated Vasculitis and Low eGFR in the ADVOCATE Trial of Avacopan

Author

Cortazar, F. B., Niles, J. L., Jayne, D. R. W., Merkel, P. A., Bruchfeld, A., Yue, H., Schall, T. J., Bekker, P., Peh, C. A., Chakera, A., Cooper, B., Kurtkoti, J., Langguth, D., Levidiotis, V., Luxton, G., Mount, P., Mudge, D., Noble, E., Phoon, R., Ranganathan, D., Ritchie, A., Ryan, J., Suranyi, M., Rosenkranz, A., Lhotta, K., Kronbichler, A., Demoulin, N., Bovy, C., Hellemans, R., Hougardy, J., Sprangers, B., Wissing, K., Pagnoux, C., Barbour, S., Brachemi, S., Cournoyer, S., Girard, L., Laurin, L., Liang, P., Philibert, D., Walsh, M., Tesar, V., Becvar, R., Horak, P., Rychlik, I., Szpirt, W., Dieperink, H., Gregersen, J., Ivarsen, P., Krarup, E., Lyngsoe, C., Rigothier, C., Augusto, J., Belot, A., Chauveau, D., Cornec, D., Jourde-Chiche, N., Ficheux, M., Karras, A., Klein, A., Maurier, F., Mesbah, R., Moranne, O., Neel, A., Quemeneur, T., Saadoun, D., Terrier, B., Zaoui, P., Schaier, M., Benck, U., Bergner, R., Busch, M., Floege, J., Grundmann, F., Haller, H., Haubitz, M., Hellmich, B., Henes, J., Hohenstein, B., Hugo, C., Iking-Konert, C., Arndt, F., Kubacki, T., Kotter, I., Lamprecht, P., Lindner, T., Halbritter, J., Mehling, H., Schonermarck, U., Venhoff, N., Vielhauer, V., Witzke, O., Szombati, I., Szucs, G., Garibotto, G., Alberici, F., Brunetta, E., Dagna, L., De Vita, S., Emmi, G., Gabrielli, A., Manenti, L., Pieruzzi, F., Roccatello, D., Salvarani, C., Dobashi, H., Atsumi, T., Fujimoto, S., Hagino, N., Ihata, A., Kaname, S., Kaneko, Y., Katagiri, A., Katayama, M., Kirino, Y., Kitagawa, K., Komatsuda, A., Kono, H., Kurasawa, T., Matsumura, R., Mimura, T., Morinobu, A., Murakawa, Y., Naniwa, T., Nanki, T., Ogawa, N., Oshima, H., Sada, K., Sugiyama, E., Takeuchi, T., Taki, H., Tamura, N., Tsukamoto, T., Yamagata, K., Yamamura, M., van Daele, P., Rutgers, A., Teng, Y., Walker, R., Chua, I., Collins, M., Rabindranath, K., de Zoysa, J., Svensson, M., Grevbo, B., Kalstad, S., Little, M., Clarkson, M., Molloy, E., Pamplona, I. A., Anton, J., Lucia, V. B., Ciggaran, S., Cid, M. C., Encarnacion, M. D., Oliveras, X. F., Soler, M. J., Rusinol, H. M., Praga, M., Porras, L. Q., Segarra, A., Segelmark, M., Soveri, I., Thomaidi, E., Westman, K., Neumann, T., Burnier, M., Daikeler, T., Dudler, J., Hauser, T., Seeger, H., Vogt, B., Jayne, D., Burton, J., Al Jayyousi, R., Amin, T., Andrews, J., Baines, L., Brogan, P., Dasgupta, B., Doulton, T., Flossmann, O., Griffin, S., Harper, J., Harper, L., Kidder, D., Klocke, R., Lanyon, P., Luqmani, R., Mclaren, J., Makanjuola, D., Mccann, L., Nandagudi, A., Selvan, S., O'Riordan, E., Patel, M., Patel, R., Pusey, C., Rajakariar, R., Robson, J., Robson, M., Salama, A., Smyth, L., Sznajd, J., Taylor, J., Merkel, P., Sreih, A., Belilos, E., Bomback, A., Carlin, J., Chen Lin, Y. C., Derebail, V., Dragoi, S., Dua, A., Forbess, L., Geetha, D., Gipson, P., Gohh, R., Greenwood, G. T., Hugenberg, S., Jimenez, R., Kaskas, M., Kermani, T., Kivitz, A., Koening, C., Langford, C., Marder, G., Mohamed, A., Monach, P., Neyra, N., Niemer, G., Niles, J., Obi, R., Owens, C., Parks, D., Podoll, A., Rovin, B., Sam, R., Shergy, W., Silva, A., Specks, U., Spiera, R., Springer, J., Striebich, C., Swarup, A., Thakar, S., Tiliakos, A., Tsai, Y., Waguespack, D., Wasko, M. C., Cortazar, F, Niles, J, Jayne, D, Merkel, P, Bruchfeld, A, Yue, H, Schall, T, Bekker, P, Peh, C, Chakera, A, Cooper, B, Kurtkoti, J, Langguth, D, Levidiotis, V, Luxton, G, Mount, P, Mudge, D, Noble, E, Phoon, R, Ranganathan, D, Ritchie, A, Ryan, J, Suranyi, M, Rosenkranz, A, Lhotta, K, Kronbichler, A, Demoulin, N, Bovy, C, Hellemans, R, Hougardy, J, Sprangers, B, Wissing, K, Pagnoux, C, Barbour, S, Brachemi, S, Cournoyer, S, Girard, L, Laurin, L, Liang, P, Philibert, D, Walsh, M, Tesar, V, Becvar, R, Horak, P, Rychlik, I, Szpirt, W, Dieperink, H, Gregersen, J, Ivarsen, P, Krarup, E, Lyngsoe, C, Rigothier, C, Augusto, J, Belot, A, Chauveau, D, Cornec, D, Jourde-Chiche, N, Ficheux, M, Karras, A, Klein, A, Maurier, F, Mesbah, R, Moranne, O, Neel, A, Quemeneur, T, Saadoun, D, Terrier, B, Zaoui, P, Schaier, M, Benck, U, Bergner, R, Busch, M, Floege, J, Grundmann, F, Haller, H, Haubitz, M, Hellmich, B, Henes, J, Hohenstein, B, Hugo, C, Iking-Konert, C, Arndt, F, Kubacki, T, Kotter, I, Lamprecht, P, Lindner, T, Halbritter, J, Mehling, H, Schonermarck, U, Venhoff, N, Vielhauer, V, Witzke, O, Szombati, I, Szucs, G, Garibotto, G, Alberici, F, Brunetta, E, Dagna, L, De Vita, S, Emmi, G, Gabrielli, A, Manenti, L, Pieruzzi, F, Roccatello, D, Salvarani, C, Dobashi, H, Atsumi, T, Fujimoto, S, Hagino, N, Ihata, A, Kaname, S, Kaneko, Y, Katagiri, A, Katayama, M, Kirino, Y, Kitagawa, K, Komatsuda, A, Kono, H, Kurasawa, T, Matsumura, R, Mimura, T, Morinobu, A, Murakawa, Y, Naniwa, T, Nanki, T, Ogawa, N, Oshima, H, Sada, K, Sugiyama, E, Takeuchi, T, Taki, H, Tamura, N, Tsukamoto, T, Yamagata, K, Yamamura, M, van Daele, P, Rutgers, A, Teng, Y, Walker, R, Chua, I, Collins, M, Rabindranath, K, de Zoysa, J, Svensson, M, Grevbo, B, Kalstad, S, Little, M, Clarkson, M, Molloy, E, Pamplona, I, Anton, J, Lucia, V, Ciggaran, S, Cid, M, Encarnacion, M, Oliveras, X, Soler, M, Rusinol, H, Praga, M, Porras, L, Segarra, A, Segelmark, M, Soveri, I, Thomaidi, E, Westman, K, Neumann, T, Burnier, M, Daikeler, T, Dudler, J, Hauser, T, Seeger, H, Vogt, B, Burton, J, Al Jayyousi, R, Amin, T, Andrews, J, Baines, L, Brogan, P, Dasgupta, B, Doulton, T, Flossmann, O, Griffin, S, Harper, J, Harper, L, Kidder, D, Klocke, R, Lanyon, P, Luqmani, R, Mclaren, J, Makanjuola, D, Mccann, L, Nandagudi, A, Selvan, S, O'Riordan, E, Patel, M, Patel, R, Pusey, C, Rajakariar, R, Robson, J, Robson, M, Salama, A, Smyth, L, Sznajd, J, Taylor, J, Sreih, A, Belilos, E, Bomback, A, Carlin, J, Chen Lin, Y, Derebail, V, Dragoi, S, Dua, A, Forbess, L, Geetha, D, Gipson, P, Gohh, R, Greenwood, G, Hugenberg, S, Jimenez, R, Kaskas, M, Kermani, T, Kivitz, A, Koening, C, Langford, C, Marder, G, Mohamed, A, Monach, P, Neyra, N, Niemer, G, Obi, R, Owens, C, Parks, D, Podoll, A, Rovin, B, Sam, R, Shergy, W, Silva, A, Specks, U, Spiera, R, Springer, J, Striebich, C, Swarup, A, Thakar, S, Tiliakos, A, Tsai, Y, Waguespack, D, and Wasko, M

Subjects
avacopan, Clinical Research, renal recovery, Nephrology, low eGFR, complement 5a receptor, complement, ANCA-associated vasculiti
Abstract

INTRODUCTION: In the 330-patient ADVOCATE trial of avacopan for the treatment of antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, in which 81% of patients had renal involvement, estimated glomerular filtration rate (eGFR) increased on average 7.3 ml/min per 1.73 m(2) in the avacopan group and 4.1 ml/min per 1.73 m(2) in the prednisone group (P = 0.029) at week 52. This new analysis examines the results in the patient subgroup with severe renal insufficiency at enrollment into the trial, i.e., eGFR ≤20 ml/min per 1.73 m(2). METHODS: eGFR was determined at baseline and over the course of the trial. Changes in eGFR were compared between the 2 treatment groups. RESULTS: In ADVOCATE, 27 of 166 patients (16%) in the avacopan group and 23 of 164 patients (14%) in the prednisone group had a baseline eGFR ≤20 ml/min per 1.73 m(2). At week 52, eGFR increased on average 16.1 and 7.7 ml/min per 1.73 m(2) in the avacopan and prednisone groups, respectively (P = 0.003). The last eGFR value measured during the 52-week treatment period was ≥2-fold higher than baseline in 41% of patients in the avacopan group compared to 13% in the prednisone group (P = 0.030). More patients in the avacopan group versus prednisone group had increases in eGFR above 20, 30, and 45 ml/min per 1.73 m(2), respectively. Serious adverse events occurred in 13 of 27 patients (48%) in the avacopan group and 16 of 23 patients (70%) in the prednisone group. CONCLUSION: Among patients with baseline eGFR ≤20 ml/min per 1.73 m(2) in the ADVOCATE trial, eGFR improved more in the avacopan group than in the prednisone group.

Published
2023

3. Pregnancy outcomes in women with primary Sjögren's syndrome: an analysis of data from the multicentre, prospective, GR2 study

Author

Grégoire Martin de Frémont, Nathalie Costedoat-Chalumeau, Estibaliz Lazaro, Rakiba Belkhir, Gaëlle Guettrot-Imbert, Nathalie Morel, Gaétane Nocturne, Anna Molto, Tiphaine Goulenok, Elisabeth Diot, Laurent Perard, Nicole Ferreira-Maldent, Maelle Le Besnerais, Nicolas Limal, Nihal Martis, Noémie Abisror, Odile Debouverie, Christophe Richez, Vincent Sobanski, François Maurier, Gaëtan Sauvetre, Hervé Levesque, Marie-Agnès Timsit, Nathalie Tieulié, Pauline Orquevaux, Boris Bienvenu, Matthieu Mahevas, Thomas Papo, Céline Lartigau-Roussin, Elodie Chauvet, Emilie Berthoux, Françoise Sarrot-Reynauld, Loïc Raffray, Marion Couderc, Nicolas Martin Silva, Noémie Jourde-Chiche, Nicolas Belhomme, Thierry Thomas, Vincent Poindron, Viviane Queyrel-Moranne, Juliette Delforge, Camille Le Ray, Emmanuelle Pannier, Xavier Mariette, Véronique Le Guern, Raphaèle Seror, Alexandra AUDEMARD-VERGER, Emmanuel AZZI, Béatrice BANNEVILLE, Antoine BAUDET, Constance BEAUDOUIN BAZIRE, Cristina BELIZNA, Alexandre Belot, Ygal BENHAMOU, Alice Berezné, Fanny BERNARD-GUERVILLY, Sabine BERTHIER, Holy BEZANAHARY, Lisa BIALE, Adrien BIGOT, Claire BLANCHARD-DELAUNAY, Anne CALAS, Julien CAMPAGNE, Pascal CATHEBRAS, Claire CAZALETS, Benjamin CHAIGNE, Olivia CHANDESRIS, Jérémy CHATELAIS, Emmanuel CHATELUS, Fleur COHEN, Bernard Combe, Céline COMPARON, Pascal COQUERELLE, Louise DAMIAN, Eric DAUGAS, Mathilde DE MENTHON, Claire DE MOREUIL, Estelle DELATTRE, Azeddine DELLAL, Catherine Deneux-Tharaux, Amélie DENIS, Camille DEPROUW, Emmanuelle DERNIS, Alban DEROUX, Sandra DESOUCHES, Philippe Dieudé, Guillaume DIREZ, Maxime Dougados, Marine DRIESSEN, Aurélie DU THANH, Laetitia DUNOGEANT, Cécile DURANT, Cécile-Audrey DUREL, Isabelle DURIEU, Florence EBOUE, Elisabeth Elefant, Olivier FAIN, Bruno FAUTREL, René-Marc FLIPO, Aline FRAZIER, Antoine FROISSART, Sophie GEORGIN-LAVIALLE, Elisabeth GERVAIS, Bertrand GODEAU, François Goffinet, Anne GOMPEL, Laure GOSSEC, Philippe GOUPILLE, Claire GRANGE, Constance GUILLAUD-DANIS, Eric HACHULLA, Sabine HOEFSLOOT, Aurélie HUMMEL, Patrick JEGO, Stéphanie JOBARD, Laurence JOSSELIN-MAHR, Marc LAMBERT, Vincent LANGLOIS, Delphine LARIVIERE, Claire LARROCHE, Augustin LATOURTE, Christian LAVIGNE, Thomas LE GALLOU, Gaëlle LEROUX, Jean Guillaume LETAROUILLY, Frédéric LIOTÉ, Laurence Loeuillet, Jonathan London, Valentine Loustau, Pierre LOZAC'H, Emmanuel MAHEU, Hélène MAILLARD, Hubert MAROTTE, Agathe MASSEAU, Arsène MEKINIAN, Sara Melboucy Belkhir, Corinne Miceli-Richard, Martin MICHAUD, Marc MICHEL, Olivier MORANNE, Chafika MORATI-HAFSAOUI, Guillaume MOULIS, Luc MOUTHON, Barbara NICOLAS, Jacky Nizard, Jérémy ORA, Rodérau OUTH, Elisabeth PASQUIER, Jean-Loup PENNAFORTE, Antoinette PERLAT, Hélène PETIT-BAUER, Evangeline PILLEBOUT, Jean-Maxime PIOT, Agnès PORTIER, Olivier Pourrat, Xavier PUECHAL, Gregory PUGNET, Manon REDONDIN, Alexis REGENT, Mélanie RORIZ, Laurent SAILLER, Léa SAVEY, Marc SCHERLINGER, Nicolas SCHLEINITZ, Jérémie Sellam, Loïc Sentilhes, Aude SERVAIS, Perrine SMETS, Christelle SORDET, Martin SOUBRIER, Katia STANKOVIC-STOJANOVIC, Geoffrey URBANSKI, Véronique VEIT, Emmanuelle WEBER, and Cécile YELNIK

Subjects
Rheumatology, Immunology, Immunology and Allergy
Published
2023

4. Categorization of patients with systemic lupus erythematosus using disease activity, patient-reported outcomes, and transcriptomic signatures

Author

Elisabeth Jouve, Noémie Jourde-Chiche, Laurent Chiche, and Robin Arcani

Subjects
Transcriptome, Disease activity, Text mining, Categorization, Rheumatology, business.industry, Medicine, General Medicine, business, Bioinformatics
Abstract

Objective Patients with systemic lupus erythematosus (SLE) display symptoms that are not always related to disease activity and may distort clinical trial results. Recently, a clinical categorization based on the presence of type 1 (inflammatory manifestations) and/or type 2 (widespread pain, fatigue, depression) symptoms has been proposed in SLE. Our aim was to develop a type 2 score derived from the Short-Form health survey (SF-36) to categorize SLE patients and to compare immunological and transcriptomic profiles between groups. Methods Seventeen items from the SF-36 were selected to build a type 2 score for 50 SLE patients (100 visits; LUPUCE cohort) and the SLEDAI was used to define type 1 symptoms. Patients were categorized in four groups: minimal (no symptoms), type 1, type 2 and mixed (both type 1 and type 2 symptoms). Clinical, immunological and transcriptomic profiles were compared between the groups. Results Type 2 scores ranged from 0 to 31, with a cut-off value of 14 (75th percentile). The sample categorization was: minimal in 39%, type 1 in 37%, type 2 in 9% and mixed in 15%. Type 2 patients were older than minimal patients and had a longer disease duration than type 1 and mixed patients. Immunological data and modular interferon signatures did not differ between the groups. Conclusion Patients with SLE can be categorized into four clinical groups using the SLEDAI score and our SF-36-derived type 2 score. This categorization is non-redundant with immunological or transcriptomic profiles and could prove useful to stratify patients in clinical trials.

Published
2023

5. Weaning of maintenance immunosuppressive therapy in lupus nephritis (WIN-Lupus): results of a multicentre randomised controlled trial

Author

Noemie Jourde-Chiche, Nathalie Costedoat-Chalumeau, Karine Baumstarck, Anderson Loundou, Laurence Bouillet, Stéphane Burtey, Valérie Caudwell, Laurent Chiche, Lionel Couzi, Laurent Daniel, Christophe Deligny, Bertrand Dussol, Stanislas Faguer, Pierre Gobert, Guillaume Gondran, Antoine Huart, Aurélie Hummel, Emilie Kalbacher, Adexandre Karras, Marc Lambert, Véronique Le Guern, Ludivine Lebourg, Sandrine Loubière, Hélène Maillard-Lefebvre, François Maurier, Micheline Pha, Viviane Queyrel, Philippe Remy, Françoise Sarrot-Reynauld, David Verhelst, Eric Hachulla, Zahir Amoura, Eric Daugas, Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
Immunosuppression Therapy, Lupus Erythematosus, Outcome Assessment, [SDV]Life Sciences [q-bio], Systemic, Immunology, Weaning, Mycophenolic Acid, Lupus Nephritis, General Biochemistry, Genetics and Molecular Biology, Health Care, Treatment Outcome, Rheumatology, Recurrence, Azathioprine, Humans, Lupus Erythematosus, Systemic, Immunology and Allergy, Glucocorticoids, Immunosuppressive Agents, Hydroxychloroquine
Abstract

International audience; ObjectivesLupus nephritis (LN) is a frequent complication of systemic lupus erythematosus (SLE). Severe (proliferative) forms of LN are treated with induction immunosuppressive therapy (IST), followed by maintenance IST, to target remission and avoid relapses. The optimal duration of maintenance IST is unknown. The WIN-Lupus trial tested whether IST discontinuation after 2‒3 years was non-inferior to IST continuation for two more years in proliferative LN.MethodsWIN-Lupus was an investigator-initiated multicentre randomised controlled trial. Patients receiving maintenance IST with azathioprine or mycophenolate mofetil for 2–3 years, and hydroxychloroquine, were randomised (1:1) into two groups: (1) IST continuation and (2) IST discontinuation. The primary endpoint was the relapse rate of proliferative LN at 24 months. Main secondary endpoints were the rate of severe SLE flares, survival without renal relapse or severe flare, adverse events.ResultsBetween 2011 and 2016, 96 patients (out of 200 planned) were randomised in WIN-Lupus: IST continuation group (n=48), IST discontinuation group (n=48). Relapse of proliferative LN occurred in 5/40 (12.5%) patients with IST continuation and in 12/44 (27.3%) patients with IST discontinuation (difference 14.8% (95% CI −1.9 to 31.5)). Non-inferiority was not demonstrated for relapse rate; time to relapse did not differ between the groups. Severe SLE flares (renal or extrarenal) were less frequent in patients with IST continuation (5/40 vs 14/44 patients; p=0.035). Adverse events did not differ between the groups.ConclusionsNon-inferiority of maintenance IST discontinuation after 2‒3 years was not demonstrated for renal relapse. IST discontinuation was associated with a higher risk of severe SLE flares.Trial registration numberNCT01284725.

Published
2022

10. Characterisation of a high-risk profile for maternal thrombotic and severe haemorrhagic complications in pregnant women with antiphospholipid syndrome in France (GR2): a multicentre, prospective, observational study

Author

Anne Murarasu, Gaëlle Guettrot-Imbert, Véronique Le Guern, Cécile Yelnik, Viviane Queyrel, Nicolas Schleinitz, Nicole Ferreira-Maldent, Elisabeth Diot, Geoffrey Urbanski, Emmanuelle Pannier, Estibaliz Lazaro, Odile Souchaud-Debouverie, Pauline Orquevaux, Nicolas Belhomme, Nathalie Morel, Elodie Chauvet, François Maurier, Maëlle Le Besnerais, Noemie Abisror, Tiphaine Goulenok, Françoise Sarrot-Reynauld, Alban Deroux, Elisabeth Pasquier, Claire de Moreuil, Holy Bezanahary, Laurent Pérard, Nicolas Limal, Vincent Langlois, Anne Calas, Bertrand Godeau, Christian Lavigne, Eric Hachulla, Fleur Cohen, Ygal Benhamou, Loïc Raffray, Mathilde de Menthon, Nathalie Tieulié, Vincent Poindron, Luc Mouthon, Maddalena Larosa, Elisabeth Eléfant, Loic Sentilhes, Anna Molto, Catherine Deneux-Tharaux, Nathalie Costedoat-Chalumeau, Emmanuel Azzi, Béatrice Banneville, Antoine Baudet, Constance Beaudouin-Bazire, Cristina Belizna, Rakiba Belkhir, Alice Berezne, Emilie Berthoux, Sabine Berthier, Lisa Biale, Boris Bienvenu, Claire Blanchard-Delaunay, Pascal Cathebras, Claire Cazalets, Benjamin Chaigne, Olivia Chandesris, Jérémy Chatelais, Emmanuel Chatelus, Pascal Coquerelle, Marion Couderc, Juliette Delforge, Amélie Denis, Sandra Desouches, Philippe Dieudé, Guillaume Direz, Marine Driessen, Aurélie Du Thanh, Laetitia Dunogeant, Cécile Durant, Isabelle Durieu, Marc Fabre, Olivier Fain, René-Marc Flipo, Aline Frazier, Antoine Froissart, Sophie Georgin-Lavialle, Elisabeth Gervais, Anne Gompel, Laure Gossec, Phillipe Goupille, Claire Grange, Constance Guillaud-Danis, Aurélie Hummel, Moez Jallouli, Patrick Jego, Stéphane Jobard, Laurence Josselin-Mahr, Noémie Jourde-Chiche, Anne-Sophie Korganow, Marc Lambert, Delphine Lariviere, Claire Larroche, Céline Lartigau-Roussin, Augustin Latourte, Thomas Le Gallou, Gaëlle Leroux, Hervé Levesque, Frédéric Lioté, Jonathan London, Valentine Loustau, Emmanuel Maheu, Matthieu Mahevas, Hélène Maillard, Xavier Mariette, Hubert Marotte, Nicolas Martin-Silva, Nihal Martis, Agathe Masseau, Arsène Mekinian, Sara Melboucy-Belkhir, Martin Michaud, Marc Michel, Chafika Morati-Hafsaoui, Jacky Nizard, Jérémy Ora, Jean-Loup Pennaforte, Antoinette Perlat, Hélène Petit Bauer, Evangeline Pillebout, Jean-Maxime Piot, Agnès Portier, Gregory Pugnet, Manon Redondin, Alexis Regent, Christophe Richez, Mélanie Roriz, Laurent Sailler, Gaëtan Sauvêtre, Léa Savey, Vincent Sobanski, Christelle Sordet, Martin Soubrier, Katia Stankovic Stojanovic, Thierry Thomas, Marie-Agnès Timsit, and Vassilis Tsatsaris

Subjects
Rheumatology, Immunology, Immunology and Allergy
Published
2022

15. Aortitis is an under-recognized manifestation of antiphospholipid syndrome: A case report and literature review

Author

Thomas Escoda, Julia George, Pierre-André Jarrot, Rodolphe Jean, Karin Mazodier, Frederick Sanderson, Pascale Poullin, Ludivine Saby, Noémie Jourde-Chiche, Gilles Kaplanski, and Laurent Chiche

Subjects
Adult, Aortitis, Rheumatology, Pregnancy, immune system diseases, Microcirculation, Antibodies, Antiphospholipid, Humans, Lupus Erythematosus, Systemic, Female, Thrombosis, Antiphospholipid Syndrome, skin and connective tissue diseases
Abstract

Aortitis is a classic manifestation of large vessel vasculitis. Antiphospholipid syndrome (APS), sometimes known as Hughes syndrome, is an acquired autoimmune disorder that manifests clinically as recurrent venous or arterial thrombosis. Patients with APS may also suffer from various underlying diseases, most frequently systemic lupus erythematosus (SLE). Catastrophic antiphospholipid syndrome (CAPS) is a rare but serious complication of APS characterized by failure of several organs due to diffuse microcirculatory thrombi. Its main manifestations involve the kidneys, lungs, heart and central nervous system, and require early diagnosis and rapid therapeutic management. While APS can affect virtually any blood vessel, aortitis is not a known symptom of APS. We report the case of a 36-year-old patient with APS and SLE who presented with CAPS during pregnancy, with no concomitant SLE flare. The first manifestation of CAPS was aortitis, preceding renal, cardiac and haematological manifestations. The outcome was favourable with combined treatment including corticosteroids, anticoagulants, plasma exchange and rituximab. We then carried out a literature search for papers describing the presence of aortitis in APS and/or SLE. In the cases of aortic involvement identified in the literature, including another case of CAPS, the occurrence of aortitis in SLE, often associated with the presence of antiphospholipid antibodies/APS, suggests that aortitis should be considered as an under-recognized manifestation and potential non-criterion feature of APS.

Published
2022

16. Liver Transplantation Using Allografts With Recent Liver Blunt Trauma: A Nationwide Audit From the French CRISTAL Biomedicine Agency Registry

Author

Florian, Seckler, Célia, Turco, Kayvan, Mohkam, Pietro, Addeo, Fabien, Robin, François, Cauchy, Charlotte, Maulat, Raffaele, Brustia, Brice, Paquette, François, Faitot, Delphine, Weil Verhoeven, Anne, Minello, Zaher, Lakkis, Vincent, Di Martino, Marianne, Latournerie, Laurence, Chiche, Mehdi, El Amrani, Petru, Bucur, Francis, Navarro, Sophie, Chopinet, Mircea, Chirica, Johan, Gagnière, Antonio, Iannelli, Gaëlle, Cheisson, Christophe, Chardot, Daniele, Sommacale, Fabrice, Muscari, Federica, Dondero, Laurent, Sulpice, Philippe, Bachellier, Olivier, Scatton, Jean Yves, Mabrut, Bruno, Heyd, and Alexandre, Doussot

Subjects
Transplantation
Abstract

In the current setting of organ shortage, brain-dead liver donors with recent liver trauma (RLT) represent a potential pool of donors. Yet, data on feasibility and safety of liver transplantation (LT) using grafts with RLT are lacking.All liver grafts from brain-dead donors with RLT proposed for LT between 2010 and 2018 were identified from the nationwide CRISTAL registry of the Biomedicine Agency. The current study aimed at evaluating 1-y survival as the primary endpoint.Among 11 073 LTs, 142 LTs (1.3%) using grafts with RLT were performed. These 142 LTs, including 23 split LTs, were performed from 131 donors (46.1%) of 284 donors with RLT proposed for LT. Transplanted grafts were procured from donors with lower liver enzymes levels (P 0.001) and less advanced liver trauma according to the American Association for the Surgery of Trauma liver grading system (P 0.001) compared with not transplanted grafts. Before allocation procedures, 20 (7%) of 284 donors underwent damage control intervention. During transplantation, specific liver trauma management was needed in 19 patients (13%), consisting of local hemostatic control (n = 15), partial hepatic resection on back-table (n = 3), or perihepatic packing (n = 1). Ninety-day mortality and severe morbidity rates were 8.5% (n = 12) and 29.5% (n = 42), respectively. One-year overall and graft survival rates were 85% and 81%, and corresponding 5-y rates were 77% and 72%, respectively.Using liver grafts from donors with RLT seems safe with acceptable long-term outcomes. All brain-dead patients with multiorgan trauma, including liver injury, should be considered for organ allocation.

Published
2022

17. Immune-checkpoint inhibitor use in patients with cancer and pre-existing autoimmune diseases

Author

Alice Tison, Soizic Garaud, Laurent Chiche, Divi Cornec, and Marie Kostine

Subjects
Biological Products, Rheumatology, Antirheumatic Agents, Neoplasms, Humans, Symptom Flare Up, Immune Checkpoint Inhibitors, Immunosuppressive Agents, Autoimmune Diseases, Retrospective Studies
Abstract

Immune-checkpoint inhibitors (ICIs) have dramatically changed the management of advanced cancers. Designed to enhance the antitumour immune response, they can also cause off-target immune-related adverse events (irAEs), which are sometimes severe. Although the efficacy of ICIs suggests that they could have wide-ranging benefits, clinical trials of the drugs have so far excluded patients with pre-existing autoimmune disease. However, evidence is accumulating with regard to the use of ICIs in this 'at-risk' population, with retrospective data suggesting that they have an acceptable safety profile, but that there is a risk of disease flare or other irAE occurrence. The management of immunosuppressive drugs at ICI initiation in patients with autoimmune disease (or later in instances of disease flare or irAE) remains a question of particular interest in clinical practice, in which there is always a search for the balance between protecting against autoimmunity and ensuring a good tumour response. Although temporary use of immunosuppressants seems safe, prolonged use or use at ICI initiation might hamper the antitumour immune response, prompting clinicians to use the minimal efficient immunosuppressive regimen. However, a new paradigm is emerging, in which inhibitors of TNF or IL-6 could have synergistic effects with ICIs on tumour response, while also preventing severe irAEs. If confirmed, this 'decoupling' effect on toxicity and efficacy could change therapeutic practice in this field. Knowledge of the current use of ICIs in patients with pre-existing autoimmune disease, particularly with regard to the use of immunosuppressive drugs and/or biologic DMARDs, can help to guide clinical practice.

Published
2022

18. Thrombosis of Medium-Sized and Large Arteries During Covid-19 Infection: Results of the COVIVASC Study

Author

Raphael Coscas, Maxime Dubosq, Johanna Charton, Salma El Batti, Julien Gaudric, Fabien Koskas, Laurent Chiche, Thibault Couture, Jean-Michel Davaine, Yves Castier, Pierre Cerceau, Mostafa EL Hajjam, Patricia Samb, Alain Beauchet, Lamiae Grimaldi, Isabelle Javerliat, Olivier Goeau-Brissonniere, Jean-Marc Alsac, Ilaria Onorati, Emmanuel Martinod, Pascal Desgranges, Joseph Touma, Frédéric Cochennec, Quentin Pellenc, Pierre Julia, and Marc Coggia

Subjects
Male, Treatment Outcome, SARS-CoV-2, Humans, COVID-19, Thrombosis, Surgery, Arteries, General Medicine, Cardiology and Cardiovascular Medicine
Abstract

COVID-19 infection is associated not only with venous thromboses but also with arterial thromboses (COV-ATs) in relation with an endothelial dysfunction, a coagulopathy and rhythm disorders. The incidence, the topography, and the prognosis of COV-ATs remain poorly known. The objective of this study was to report the overall experience of the Greater Paris University Hospitals (Assistance Publique - Hopitaux de Paris, AP-HP) during the first pandemic wave of COVID-19 infection.After approval by the ethics committee, a study using the AP-HP clinical data warehouse was carried out between March and May 2020. Overall, 124,609 patients had a polymerase chain reaction for COVID-19 in our hospitals, of which 25,345 were positive. From 20,710 exploitable stays, patients tested positive for COVID who presented an episode of acute COV-AT (except coronary and intracranial arteries) were selected on the basis of the French medical classification for clinical procedures codes. The data are presented as absolute values with percentages and/or means with standard deviation.Over the studied period, 60 patients (aged 71±14 years, 42 men) presented a COV-AT at the time of their hospitalization, an incidence of 0.2%. The arterial complication occurred 3±7 days after the COVID infection and was inaugural in 30% of the cases (n = 18). The sites of COV-AT were the lower extremities (n = 35%, 58%), the abdominal aorta (n = 10%, 17%), the thoracic aorta (n = 7%, 12%), the upper limbs (n = 7%, 12%), the cerebral arteries (n = 7%, 12%), the digestive arteries (n = 6%, 10%), the renal arteries (n = 2%, 3%), and the ophthalmic artery (n = 1%, 2%). Multiple COV-ATs were observed in 13 patients (22%). At the time of diagnosis, 20 (33%) patients were in intensive care, including six (10%) patients who were intubated. On computed tomography angiography, COVID lesions were classified as moderate and severe in 25 (42%) and 21 (35%) cases, respectively. Revascularization was attempted in 27 patients (45%), by open surgery in 16 cases, using endovascular techniques in 8 cases and with a hybrid approach in three cases. Six patients (22%) required reinterventions. The duration of hospitalization was 12±9 days. Early mortality (in-hospital or at 30 days) was 30% (n = 18). Nine (15%) patients presented severe nonlethal ischemic complications.Arterial involvement is rare during COVID-19 infection. The aorta and the arteries of the limbs are the privileged sites. The morbi-mortality of these patients is high. Future studies will have to determine if the systematization of anticoagulation therapy decreases the incidence and the severity of the condition.

Published
2022

19. Quand le loup sème le doute, le cochon perd la foi

Author

C. Stavris, L. Chiche, C. Charpin, P. Dukan, C. Doncarli, H. Drouet, M. Delord, L. Renard, J. Allemand, S. Caillères, N. Talbi, P. Halfon, F. Retornaz, and A. Servettaz

Subjects
Gastroenterology, Internal Medicine
Published
2022

22. Supplemental Material - Complex relationships between inflammatory manifestations/type 1 and type 2 symptoms in systemic lupus erythematosus: A narrative literature review

Author

Escoda, Thomas, Jourde-Chiche, Noémie, Granel, Brigitte, Cornec, Divi, and Chiche, Laurent

Subjects
111702 Aged Health Care, FOS: Health sciences
Abstract

Supplemental Material for Complex relationships between inflammatory manifestations/type 1 and type 2 symptoms in systemic lupus erythematosus: A narrative literature review by Thomas Escoda, Noémie Jourde-Chiche, Brigitte Granel, Divi Cornec, and Laurent Chiche in Lupus

Published
2023
Full Text
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23. Towards adaptive structuring of the lupologist’s consultation to transform the care pathway of systemic lupus erythematosus

Author

Laurent Chiche, Guillemette Thomas, Noémie Chiche, and Thomas Escoda

Subjects
Complementary and alternative medicine, Pharmaceutical Science, Pharmacology (medical)
Abstract

Systemic lupus erythematosus (SLE) is a complex autoimmune disease, which can be clinically heterogeneous in the same patient over the disease process and has an unpredictable evolution. Although its prevalence is increasing, SLE remains a rare disease with frequent extra-articular manifestations managed by multiple specialists. Among these, the internist is a key player in the overall coordination of the care pathway. The dramatic improvement in the short-term prognosis of SLE observed over the past few decades has favoured the emergence of more chronic disease-associated morbidities, especially infectious, cardiovascular and/or related to sequelae, notably renal. Thus, every lupologist is confronted with the difficulty of having to address, in an educational, individualised but also systematic way, a certain number of key items on which the short-, medium- and long-term medical future of patients who develop SLE at a relatively young age depend. In recent years, in addition to the creation of a network of reference centres and the drafting of regularly updated national therapeutic guidelines and therapeutic education programs, international consensus about the factors to consider in SLE patients has been reached, including the definition of therapeutic objectives according to a treat-to-target (T2T) strategy. However, the translation of these new objectives/paradigms in real-life has encountered a number of difficulties. As part of a multidisciplinary team involving SLE patients, we developed practical tools in the form of CHECKLISTs addressing the problems of refractory SLE (D2T), the management of comorbidities and toxicities (BASICs), and, more recently, therapeutic de-escalation with a shared medical decision (T2U). It appears that there is an opportunity to transform the care pathway of SLE patients by allowing the implementation of these tools within adaptive structuring of the consultation, which has the advantage of defining a starting point within the care pathway as a common denominator for lupologists, regardless of their specialty or where they work.

Published
2023

25. Delirium in Adults With COVID-19–Related Acute Respiratory Distress Syndrome

Author

Raphael, Bernard-Valnet, Eva, Favre, Adriano, Bernini, Mauro, Oddo, Jean-Daniel, Chiche, Renaud A, Du Pasquier, and Andrea O, Rossetti

Subjects
Adult, Respiratory Distress Syndrome, Intensive Care Units, Critical Illness, Humans, COVID-19, Delirium, Neurology (clinical), Respiration, Artificial, Retrospective Studies
Abstract

Background and ObjectivesNeurologic complications have been associated with COVID-19, including delirium. Such complications have been reported to be frequent among intensive care unit (ICU)-admitted patients. We hypothesized that the rate of neurologic complications would be higher in COVID-19 associated acute respiratory distress syndrome (ARDS) than those who develop ARDS from a different cause.MethodsWe conducted a retrospective cohort study in the adult ICU of Lausanne University Hospital, including all consecutive patients fulfilling the Berlin criteria for ARDS hospitalized between December 2017 and June 2021, stratifying exposure between COVID-19 or not. The primary outcome was delirium onset during ICU stay, defined by the confusion assessment method (CAM-ICU). Exploratory outcomes included development of neurologic complications of the central nervous system (stroke, hemorrhage, and vasculitis), critical illness weakness, and 30- and 180-day all-cause mortality.ResultsThree hundred eleven patients were included in the study (253 with COVID-19 and 58 with other causes) and CAM-ICU could be assessed in 231 (74.3% in COVID-19 vs 74.1% in non-COVID-19). The proportion of patients developing delirium was similar in patients with COVID-19 and controls in univariate comparison (69.1% vs 60.5%,p= 0.246). Yet, patients with COVID-19 had a higher body mass index, lower ICU severity, longer mechanical ventilation, and higher sedation doses (propofol and dexmedetomidine). After adjusting for these factors in a multivariable analysis, the risk of delirium remained comparable across groups (adjusted OR [95% CI]: 0.86 [0.35–2.1]). Similarly, COVID-19–related ARDS had no effect on all-cause mortality at 30 days (adjusted OR: 0.87 [0.39–1.92]) and 180 days (adjusted OR: 0.67 [0.33–1.35]). Finally, neurologic complications affecting the CNS (adjusted OR: 1.15 [0.25–5.29]) and critical illness weakness (adjusted OR: 2.99 [0.97–9.1]) were not higher in the COVID-19 group.DiscussionCompared with other etiologies, patients with COVID-19 did not have higher incidence of delirium and other neurologic complications, after accounting for underlying disease severity in patients with ARDS. Management of COVID-19–associated ARDS needed longer invasive ventilation and higher sedation, which could explain higher rates of delirium in uncontrolled studies.

Published
2022

26. Kindlin‐1 drives early steps of breast cancer metastasis

Author

Florian Bonin, Aurélie Chiche, Zakia Tariq, Paula Azorin, Sébastien Nola, Rosette Lidereau, and Keltouma Driouch

Subjects
Cancer Research, Skin Neoplasms, Oncology, Humans, Breast Neoplasms, Female, Melanoma
Published
2022

28. The genetic landscape and clinical spectrum of nephronophthisis and related ciliopathies

Author

Friederike Petzold, Katy Billot, Xiaoyi Chen, Charline Henry, Emilie Filhol, Yoann Martin, Marina Avramescu, Maxime Douillet, Vincent Morinière, Pauline Krug, Cécile Jeanpierre, Kalman Tory, Olivia Boyer, Anita Burgun, Aude Servais, Remi Salomon, Alexandre Benmerah, Laurence Heidet, Nicolas Garcelon, Corinne Antignac, Mohamad Zaidan, Sophie Saunier, Tania Attié-Bitach, Valerie Comier-Daire, Jean-Michel Rozet, Yaacov Frishberg, Brigitte Llanas, Michel Broyer, Nabil Mohsin, Marie-Alice Macher, Nicole Philip, Véronique Baudouin, Damian Brackman, Chantal Loirat, Marina Charbit, Maud Dehennault, Claude Guyot, Pierre Bataille, Mariet Elting, Georges Deschenes, Andrea Gropman, Geneviève Guest, Marie-France Gagnadoux, Philippe Nicoud, Pierre Cochat, Bruno Ranchin, Albert Bensman, Anne-Marie Guerrot, Bertrand Knebelmann, Ilmay Bilge, Danièle Bruno, Stéphane Burtey, Caroline Rousset Rouvière, Valérie Caudwell, Denis Morin, Hélène Dollfus, Anne Maisin, Christian Hamel, Eric Bieth, Sophie Gie, Judith Goodship, Gwenaelle Roussey, Hermine La Selve, Hubert Nivet, Lucie Bessenay, Mathilde Caillez, Jean Bernard Palcoux, Stéphane Benoît, Philippe Dubot, Marc Fila, Fabienne Giuliano, Daouya Iftene, Michele Kessler, Theresa Kwon, Anine Lahoche, Audrey Laurent, Anne-Laure Leclerc, David Milford, Thomas Neuhaus, Sylvie Odent, Philippe Eckart, Dominique Chauveau, Patrick Niaudet, Horacio Repetto, Sophie Taque, Alexandra Bruel, Alexandra Noel-Botte, Emma Allain Launay, Lisa Allard, Dany Anlicheau, Anne-Laure Adra, Arnaud Garnier, Arvind Nagra, Remy Baatard, Justine Bacchetta, Banu Sadikoglu, Christine Barnerias, Anne Barthelemy, Lina Basel, Nader Bassilios, Hedi Ben Maiz, Fatma Ben Moussa, Faïza Benmati, Romain Berthaud, Aurélia Bertholet, Dominique Blanchier, Jean Jacques Boffa, Karim Bouchireb, Ihab Bouhabel, Zakaria Boukerroucha, Guylhène Bourdat-Michel, Odile Boute, Karine Brochard, Roseline Caumes, Siham Chafai Elalaoui, Bernard Chamontin, Marie Caroline Chastang, Christine Pietrement, Christine Richer, Christophe Legendre, Karin Dahan, Fabienne Dalla-Vale, Damien Thibaudin, Maxime Dauvergne, Salandre Davourie, Martin Debeukelaer, Jean Daniel Delbet, Constantinos Deltas, Denis Graber, Nadège Devillars, Boucar Diouf, Martine Doco Fenzy, Jean-Luc André, Dominique Joly, Alan Fryer, Laetitia Albano, Elisabeth Cassuto, Aline Pincon, Ana Medeira, Annabelle Chaussenot, Anne Mensire-Marinier, Francois Bouissou, Stephane Decramer, Armand Bottani, Aurélie Hummel, Alexandre Karras, Avi Katz, Christine Azema, Bénédicte Janbon, Bernard Roussel, Claude Bonniol, Christiophe Mariat, Gérard Champion, Deborah Chantreuil, Nicolas Chassaing, Christiane Mousson, Christine Baudeau, Delphine Hafdar Cuntz, Cyril Mignot, Laurene Dehoux, Didier Lacombe, Thierry Hannedouche, Elodie Mérieau, Emmanuelle Charlin, Eric Gauthier, Florent Plasse, Stanislas Faguer, Fanny Lebas, Florence Demurger, Francesco Emma, François Cartault, Geneviève Dumont, Nathalie Godefroid, Vincent Guigonis, Sophie Hillaire, Jaap Groothoff, Jan Dudley, Noémie Jourde-Chiche, Khalil El Karoui, Saoussen Krid, Krier Coudert, Larbi Bencheick, Laurent Yver, Marie-Pierre Lavocat, Le Monies De Sagazan, Valerie Leroy, Lise Thibaudin, Liz Ingulli, Lorraine Gwanmesia, Lydie Burglen, Marie-Hélène Saïd-Menthon, Marta Carrera, Mathilde Nizon, Catherine Melander, Michel Foulard, Monique Blayo, Jacques Prinseau, Nadine Jay, Nathalie Brun, Nicolas Camille, François Nobili, Olivier Devuyst, Ouafa Ben Brahim, Paloma Parvex, Laurence Perrin Sabourin, Philippe Blanc, Philippe Vanhille, Pierre Galichon, Sophie Pierrepont, Vincent Planquois, Gwenaelle Poussard, Claire Pouteil Noble, Radia Allal, Raphaelle Bernard, Raynaud Mounet, Rémi Cahen, Renaud Touraine, Claire Rigothier, Amélie Ryckewaert, Mathieu Sacquepee, Salima El Chehadeh, Charlotte Samaille, Shuman Haq, Ari Simckes, Stéphanie Lanoiselée, Stephanie Tellier, Jean-François Subra, Sylvie Cloarec, Julie Tenenbam, Thomas Lamy, Valérie Drouin Garraud, Huguette Valette, Vanina Meyssonnier, Rosa Vargas-Poussou, Yves Snajer, Sandrine Durault, Emmanuelle Plaisier, Etienne Berard, Fadi Fakhouri, Ferielle Louillet, Paul Finielz, Michel Fischbach, Bernard Foliguet, Hélène Francois-Pradier, Florentine Garaix, Marion Gerard, Gianfranco Rizzoni, Brigitte Gilbert, Denis Glotz, Astrid Godron Dubrasquet, Jean-Pierre Grünfeld, Guillaume Bollee, Michelle Hall, Sverker Hansson, Damien Haye, Hélène Taffin, Friedhelm Hildebrandt, Maryvonne Hourmand, Hümya Kayserili, Ivan Tack, Marie Line Jacquemont, Jennifer Fabre-Teste, Cliff Kashtan, Kkoen Van Hoeck, Alexandre Klein, Yannick Knefati, Nine Knoers, Martin Konrad, Alain Lachaux, Isabelle Landru, Gilbert Landthaler, Philippe Lang, Patrick Le Pogamp, Tristan Legris, Catherine Didailler, Thierry Lobbedez, Loïc de Parscau, Lucile Pinson, Hervé Maheut, Marc Duval-Arnould, Marlène Rio, Marie-Claire Gubler, Pierre Merville, Guillaume Mestrallet, Maite Meunier, Karine Moreau, Jérôme Harambat, Graeme Morgan, Georges Mourad, Niksic Stuber, Odile Boespflug-Tanguy, Olivier Dunand, Olivier Niel, Nacera Ouali, Paolo Malvezzi, Pauline Abou Jaoude, Solenne Pelletier, Julie Peltier, M.B. Petersen, Philippe Michel, Philippe Rémy, Jean-Baptiste Philit, Valérie Pichault, Thierry Billette de Villemeur, Bernard Boudailliez, Bruno Leheup, Claire Dossier, Djamal-Dine Djeddi, Yves Berland, Bruno Hurault de Ligny, Susan Rigden, Christophe Robino, Annick Rossi, Sabine Sarnacki, Messaoud Saidani, Albane Brodin Sartorius, Elise Schäfer, Sztriha Laszlo, Marie-Christine Thouret, Angélique Thuillier-Lecouf, Howard Trachtman, Claire Trivin, Michel Tsimaratos, Rita Van Damme-Lombaerts, Marjolaine Willems, Michel Youssef, Ariane Zaloszyc, Alexis Zawodnik, and Marie-Julia Ziliotis

Subjects
Nephrology
Abstract

Nephronophthisis (NPH) is an autosomal-recessive ciliopathy representing one of the most frequent causes of kidney failure in childhood characterized by a broad clinical and genetic heterogeneity. Applied to one of the worldwide largest cohorts of patients with NPH, genetic analysis encompassing targeted and whole exome sequencing identified disease-causing variants in 600 patients from 496 families with a detection rate of 71%. Of 788 pathogenic variants, 40 known ciliopathy genes were identified. However, the majority of patients (53%) bore biallelic pathogenic variants in NPHP1. NPH-causing gene alterations affected all ciliary modules defined by structural and/or functional subdomains. Seventy six percent of these patients had progressed to kidney failure, of which 18% had an infantile form (under five years) and harbored variants affecting the Inversin compartment or intraflagellar transport complex A. Forty eight percent of patients showed a juvenile (5-15 years) and 34% a late-onset disease (over 15 years), the latter mostly carrying variants belonging to the Transition Zone module. Furthermore, while more than 85% of patients with an infantile form presented with extra-kidney manifestations, it only concerned half of juvenile and late onset cases. Eye involvement represented a predominant feature, followed by cerebellar hypoplasia and other brain abnormalities, liver and skeletal defects. The phenotypic variability was in a large part associated with mutation types, genes and corresponding ciliary modules with hypomorphic variants in ciliary genes playing a role in early steps of ciliogenesis associated with juvenile-to-late onset NPH forms. Thus, our data confirm a considerable proportion of late-onset NPH suggesting an underdiagnosis in adult chronic kidney disease.

Published
2023

29. Beyond the kidney biopsy: genomic approach to undetermined kidney diseases

Author

Thomas Robert, Laure Raymond, Marine Dancer, Julia Torrents, Noémie Jourde-Chiche, Stéphane Burtey, Christophe Béroud, and Laurent Mesnard

Subjects
Transplantation, Nephrology
Abstract

Background and objectives According to data from large national registries, almost 20 to 25% of patients with end-stage kidney disease have an undetermined kidney disease (UKD). Recent data have shown that monogenic disease-causing variants are under-diagnosed. We performed exome sequencing (ES) on UKD patients in our center to improve the diagnosis rate. Design, setting, participants, and measurements ES was proposed in routine practice for patients with UKD including kidney biopsy from January 2019 to December 2021. Mutations were detected using a targeted bioinformatic customized kidney gene panel (675 genes). The pathogenicity was assessed using American College of Medical Genetics guidelines. Results We included 230 adult patients, median age 47.5 years. Consanguinity was reported by 25 patients. A family history of kidney disease was documented in 115 patients (50%). Kidney biopsies were either inconclusive in 69 patients (30.1%) or impossible in 71 (30.9%). We detected 28 monogenic renal disorders in 75 (32.6%) patients. Collagenopathies was the most common genetic kidney diagnosis (46.7%), with COL4A3 and COL4A4 accounting for 80% of these diagnoses. Tubulopathies (16%) and ciliopathies (14.7%) yielded respectively the second and third genetic kidney diagnosis category and UMOD-associated nephropathy as the main genetic findings for tubulopathies (7/11). Ten of the 22 patients having ES ‘first’ eventually received a positive diagnosis, thereby avoiding 11 biopsies. Among the 44 patients with glomerular, tubulo-interstitial or vascular nephropathy, 13 (29.5%) were phenocopies. The diagnostic yield of ES was higher in female patients (p = 0.02) and in patients with a family history of kidney disease (p Conclusion Genetic diagnosis has provided new clinical insights by clarifying or reclassifying kidney disease etiology in over a third of UKD patients. Exome ‘first’ may have a significant positive diagnostic yield, thus avoiding invasive kidney biopsy; moreover, the diagnostic yield remains elevated even when biopsy is impossible or inconclusive. ES provides a clinical benefit for routine nephrological healthcare in patients with UKD.

Published
2023

30. FAO-supported OxPhos leukemic stem cells are sensitive to cold

Author

Emmanuel Griessinger, Diego Pereira-Martins, Marielle Nebout, Claudie Bosc, Estelle Saland, Emilie Boet, Ambrine Sahal, Johanna Chiche, Delphine Debayle, Lucille Fleuriot, Maurien Pruis, Véronique De Mas, François Vergez, Christian Récher, Gerwin Huls, Jean-Emmanuel Sarry, Jan Jacob Schuringa, and Jean-François Peyron

Abstract

Targeting mitochondrial oxidative phosphorylation (OxPhos) metabolism has revealed a potential weakness for leukemic stem cells (LSCs) that can be exploited for therapeutic purposes. Fatty acids oxidation (FAO) is a crucial OxPhos-fueling catabolic pathway for some AML and for chemotherapy-resistant AML cells. Here, we identified cold sensitivity at 4°C (cold killing challenge: CKC4), as a novel vulnerability that selectively kills FAO-supported OxPhos LSCs in Acute Myeloid Leukemia while sparing normal hematopoietic stem cells (HSCs). Cell death of OxPhos leukemic cells was induced by membrane permeabilization at 4°C while by sharp contrast, leukemic cells relying on glycolysis were resistant. Forcing glycolytic cells into OxPhos metabolism sensitized them to CKC4. We show using lipidomic and proteomic analyzes that OxPhos shapes the composition of the plasma membrane and introduce variation of 22 lipid subfamilies between cold-sensitive and cold-resistant cells. Cold sensitivity is a potential OxPhos biomarker.SignificanceThis study reveals that mitochondrial energetics fueled by FAO metabolism introduces membrane fragility upon cold exposure in OxPhos-driven AMLs and in LSCs. This novel physical property of Leukemic cells and LSCs opens new avenues for biomarker and diagnostics as well as for anti-OxPhos drug screening and LSCs targeting.One Sentence SummaryOxPhos leukemic cells die at 4°C

Published
2023

32. Une cause rare de cécité

Author

T. Escoda, C. Stavris, S. Genot, G. Thomas, F. Retornaz, and L. Chiche

Subjects
Gastroenterology, Internal Medicine
Published
2023

33. Supplementary Figure 3 from Therapy-related Myeloid Neoplasms Following PARP Inhibitors: Real-life Experience

Author

Jean-Baptiste Micol, Alexandra Leary, Christophe Marzac, Arnaud Pagès, Hervé Dombret, Christian Récher, Pierre Fenaux, Lionel Adès, Mauricette Michallet, Pierre-Marie Morice, Matthieu Duchmann, Pascal Bourquard, Marie-Pierre Gourin, Sylvain Thepot, Thomas Boyer, Marion Lepelley, Laetitia Stefani, Myrtille Thomas, Nathalie Auger, Véronique Vergé, Patricia Pautier, Félix Blanc-Durand, Nadine Morineau, Marion Loirat, Jérémy Delage, Emmanuelle Tavernier, Emilie Lemasle, Géraldine Salmeron, Jacques Vargaftig, Pierre-Yves Dumas, Edmond Chiche, Céline Berthon, Alexis Genthon, Madalina Uzunov, Sylvain Chantepie, Célestine Simand, Lauris Gastaud, Sarah Bertoli, Amine Belhabri, Gabriel Etienne, Sylvain Garciaz, Justine Decroocq, and Vincent Marmouset

Abstract

Waffle chart (%) of patients addressed for cytopenia exploration after OC exposed to a PARPi treatment from cytopenia diagnosis (A) and cytopenia diagnosis based on NGS results (B). Dot plots (C) showing the median WBC, hemoglobin, and platelet counts from patients referred for cytopenia exploration after OC exposed to a PARPi treatment according to t-MN diagnosis (“t-MN”) or not (“Cytopenia”).

Published
2023

34. Supplementary Figure 2 from Therapy-related Myeloid Neoplasms Following PARP Inhibitors: Real-life Experience

Author

Jean-Baptiste Micol, Alexandra Leary, Christophe Marzac, Arnaud Pagès, Hervé Dombret, Christian Récher, Pierre Fenaux, Lionel Adès, Mauricette Michallet, Pierre-Marie Morice, Matthieu Duchmann, Pascal Bourquard, Marie-Pierre Gourin, Sylvain Thepot, Thomas Boyer, Marion Lepelley, Laetitia Stefani, Myrtille Thomas, Nathalie Auger, Véronique Vergé, Patricia Pautier, Félix Blanc-Durand, Nadine Morineau, Marion Loirat, Jérémy Delage, Emmanuelle Tavernier, Emilie Lemasle, Géraldine Salmeron, Jacques Vargaftig, Pierre-Yves Dumas, Edmond Chiche, Céline Berthon, Alexis Genthon, Madalina Uzunov, Sylvain Chantepie, Célestine Simand, Lauris Gastaud, Sarah Bertoli, Amine Belhabri, Gabriel Etienne, Sylvain Garciaz, Justine Decroocq, and Vincent Marmouset

Abstract

Blood smear and bone marrow aspiration of patient referred for cytopenia post PARPi.

Published
2023

35. Supplementary Figure 4 from Therapy-related Myeloid Neoplasms Following PARP Inhibitors: Real-life Experience

Author

Jean-Baptiste Micol, Alexandra Leary, Christophe Marzac, Arnaud Pagès, Hervé Dombret, Christian Récher, Pierre Fenaux, Lionel Adès, Mauricette Michallet, Pierre-Marie Morice, Matthieu Duchmann, Pascal Bourquard, Marie-Pierre Gourin, Sylvain Thepot, Thomas Boyer, Marion Lepelley, Laetitia Stefani, Myrtille Thomas, Nathalie Auger, Véronique Vergé, Patricia Pautier, Félix Blanc-Durand, Nadine Morineau, Marion Loirat, Jérémy Delage, Emmanuelle Tavernier, Emilie Lemasle, Géraldine Salmeron, Jacques Vargaftig, Pierre-Yves Dumas, Edmond Chiche, Céline Berthon, Alexis Genthon, Madalina Uzunov, Sylvain Chantepie, Célestine Simand, Lauris Gastaud, Sarah Bertoli, Amine Belhabri, Gabriel Etienne, Sylvain Garciaz, Justine Decroocq, and Vincent Marmouset

Abstract

Commutation plot visualizing the mutated genes in t-MN after OC according to PARPi treatment.

Published
2023

36. Supplementary Table 3 from Therapy-related Myeloid Neoplasms Following PARP Inhibitors: Real-life Experience

Author

Jean-Baptiste Micol, Alexandra Leary, Christophe Marzac, Arnaud Pagès, Hervé Dombret, Christian Récher, Pierre Fenaux, Lionel Adès, Mauricette Michallet, Pierre-Marie Morice, Matthieu Duchmann, Pascal Bourquard, Marie-Pierre Gourin, Sylvain Thepot, Thomas Boyer, Marion Lepelley, Laetitia Stefani, Myrtille Thomas, Nathalie Auger, Véronique Vergé, Patricia Pautier, Félix Blanc-Durand, Nadine Morineau, Marion Loirat, Jérémy Delage, Emmanuelle Tavernier, Emilie Lemasle, Géraldine Salmeron, Jacques Vargaftig, Pierre-Yves Dumas, Edmond Chiche, Céline Berthon, Alexis Genthon, Madalina Uzunov, Sylvain Chantepie, Célestine Simand, Lauris Gastaud, Sarah Bertoli, Amine Belhabri, Gabriel Etienne, Sylvain Garciaz, Justine Decroocq, and Vincent Marmouset

Abstract

Univariate analysis for overall survival from t-MN diagnosis of patients from the national cohort.

Published
2023

37. Supplementary Figure 1 from Therapy-related Myeloid Neoplasms Following PARP Inhibitors: Real-life Experience

Author

Jean-Baptiste Micol, Alexandra Leary, Christophe Marzac, Arnaud Pagès, Hervé Dombret, Christian Récher, Pierre Fenaux, Lionel Adès, Mauricette Michallet, Pierre-Marie Morice, Matthieu Duchmann, Pascal Bourquard, Marie-Pierre Gourin, Sylvain Thepot, Thomas Boyer, Marion Lepelley, Laetitia Stefani, Myrtille Thomas, Nathalie Auger, Véronique Vergé, Patricia Pautier, Félix Blanc-Durand, Nadine Morineau, Marion Loirat, Jérémy Delage, Emmanuelle Tavernier, Emilie Lemasle, Géraldine Salmeron, Jacques Vargaftig, Pierre-Yves Dumas, Edmond Chiche, Céline Berthon, Alexis Genthon, Madalina Uzunov, Sylvain Chantepie, Célestine Simand, Lauris Gastaud, Sarah Bertoli, Amine Belhabri, Gabriel Etienne, Sylvain Garciaz, Justine Decroocq, and Vincent Marmouset

Abstract

Flow chart of the study displaying the three cohorts.

Published
2023

39. Supplementary Table 2 from Therapy-related Myeloid Neoplasms Following PARP Inhibitors: Real-life Experience

Author

Jean-Baptiste Micol, Alexandra Leary, Christophe Marzac, Arnaud Pagès, Hervé Dombret, Christian Récher, Pierre Fenaux, Lionel Adès, Mauricette Michallet, Pierre-Marie Morice, Matthieu Duchmann, Pascal Bourquard, Marie-Pierre Gourin, Sylvain Thepot, Thomas Boyer, Marion Lepelley, Laetitia Stefani, Myrtille Thomas, Nathalie Auger, Véronique Vergé, Patricia Pautier, Félix Blanc-Durand, Nadine Morineau, Marion Loirat, Jérémy Delage, Emmanuelle Tavernier, Emilie Lemasle, Géraldine Salmeron, Jacques Vargaftig, Pierre-Yves Dumas, Edmond Chiche, Céline Berthon, Alexis Genthon, Madalina Uzunov, Sylvain Chantepie, Célestine Simand, Lauris Gastaud, Sarah Bertoli, Amine Belhabri, Gabriel Etienne, Sylvain Garciaz, Justine Decroocq, and Vincent Marmouset

Abstract

TP53 mutations characteristics among t-MN PARPi national cohort.

Published
2023

40. Supplementary Table 1 from Therapy-related Myeloid Neoplasms Following PARP Inhibitors: Real-life Experience

Author

Jean-Baptiste Micol, Alexandra Leary, Christophe Marzac, Arnaud Pagès, Hervé Dombret, Christian Récher, Pierre Fenaux, Lionel Adès, Mauricette Michallet, Pierre-Marie Morice, Matthieu Duchmann, Pascal Bourquard, Marie-Pierre Gourin, Sylvain Thepot, Thomas Boyer, Marion Lepelley, Laetitia Stefani, Myrtille Thomas, Nathalie Auger, Véronique Vergé, Patricia Pautier, Félix Blanc-Durand, Nadine Morineau, Marion Loirat, Jérémy Delage, Emmanuelle Tavernier, Emilie Lemasle, Géraldine Salmeron, Jacques Vargaftig, Pierre-Yves Dumas, Edmond Chiche, Céline Berthon, Alexis Genthon, Madalina Uzunov, Sylvain Chantepie, Célestine Simand, Lauris Gastaud, Sarah Bertoli, Amine Belhabri, Gabriel Etienne, Sylvain Garciaz, Justine Decroocq, and Vincent Marmouset

Abstract

Univariate analysis for overall survival from t-MN diagnosis of patients diagnosed with t-MN after OC according to PARPi exposure.

Published
2023

41. Data from Therapy-related Myeloid Neoplasms Following PARP Inhibitors: Real-life Experience

Author

Jean-Baptiste Micol, Alexandra Leary, Christophe Marzac, Arnaud Pagès, Hervé Dombret, Christian Récher, Pierre Fenaux, Lionel Adès, Mauricette Michallet, Pierre-Marie Morice, Matthieu Duchmann, Pascal Bourquard, Marie-Pierre Gourin, Sylvain Thepot, Thomas Boyer, Marion Lepelley, Laetitia Stefani, Myrtille Thomas, Nathalie Auger, Véronique Vergé, Patricia Pautier, Félix Blanc-Durand, Nadine Morineau, Marion Loirat, Jérémy Delage, Emmanuelle Tavernier, Emilie Lemasle, Géraldine Salmeron, Jacques Vargaftig, Pierre-Yves Dumas, Edmond Chiche, Céline Berthon, Alexis Genthon, Madalina Uzunov, Sylvain Chantepie, Célestine Simand, Lauris Gastaud, Sarah Bertoli, Amine Belhabri, Gabriel Etienne, Sylvain Garciaz, Justine Decroocq, and Vincent Marmouset

Abstract

Purpose:To provide insights into the diagnosis and management of therapy-related myeloid neoplasms (t-MN) following PARP inhibitors (PARPi).Experimental Design:In a French cancer center, we identified and described the profiles of 13 t-MN diagnosed among 37 patients with ovarian cancer referred to hematology consultation for cytopenia under PARPi. Next, we described these 13 t-MN post-PARPi among 37 t-MN post ovarian cancer according to PARPi exposure. Finally, we described 69 t-MN post-PARPi in a national cohort.Results:From 2016 to 2021, cumulative incidence of t-MN was 3.5% (13/373) among patients with ovarian cancer treated with PARPi. At time of hematologic consultation, patients with t-MN had a longer PARPi exposure (9 vs. 3 months, P = 0.01), lower platelet count (74 vs. 173 G/L, P = 0.0005), and more cytopenias (2 vs. 1, P = 0.0005). Compared with t-MN not exposed to PARPi, patients with t-MN-PARPi had more BRCA1/2 germline mutation (61.5% vs. 0%, P = 0.03) but similar overall survival (OS). In the national cohort, most t-MN post-PARPi had a complex karyotype (61%) associated with a high rate of TP53 mutation (71%). Median OS was 9.6 months (interquartile range, 4–14.6). In multivariate analysis, a longer time between end of PARPi and t-MN (HR, 1.046; P = 0.02), olaparib compared with other PARPi (HR, 5.82; P = 0.003) and acute myeloid leukemia (HR, 2.485; P = 0.01) were associated with shorter OS.Conclusions:In a large series, we described a high incidence of t-MN post-PARPi associated with unfavorable cytogenetic and molecular abnormalities leading to poor OS. Early detection is crucial, particularly in cases of delayed cytopenia.

Published
2023

45. Data from Association of CYP1B1 Germ Line Mutations with Hepatocyte Nuclear Factor 1α–Mutated Hepatocellular Adenoma

Author

Jessica Zucman-Rossi, Paulette Bioulac-Sage, Pierre Laurent-Puig, Claudia de Toma, Christine Bellanné-Chantelot, Jeanne Tran Van Nhieu, Catherine Buffet, Jean-Yves Scoazec, Nathalie Sturm, Yannick Bacq, Laurence Chiche, Karine Poussin, and Emmanuelle Jeannot

Abstract

Biallelic somatic mutations of TCF1 coding for hepatocyte nuclear factor 1α (HNF1α) are found in 50% of the hepatocellular adenoma (HCA) cases usually associated with oral contraception. In rare cases, HNF1α germ line mutations could also predispose to familial adenomatosis. In order to identify new genetic factors predisposing to HNF1α-mutated HCA, we searched for mutations in genes involved in the metabolism of estrogen. For 10 genes (CYP1A1, CYP1A2, CYP3A4, CYP3A5, COMT, UGT2B7, NQO1, GSTM1, GSTP1, and GSTT1), we did not find mutations nor differences in the allele distribution among 32 women presenting HNF1α-mutated adenomas compared with 58 controls. In contrast, we identified a CYP1B1 germ line heterozygous mutation in 4 of 32 women presenting HNF1α-mutated adenomas compared with none in 58 controls. We confirmed these results with the identification of four additional CYP1B1 mutations in a second series of 26 cases. No mutations were found in the control group, which was extended to 98 individuals, and only a known rare genetic variant was observed in two controls (P = 0.0003). We did an ethoxyresorufin O-deethylase assay to evaluate the functional consequence of the CYP1B1 mutations. We found reduced enzymatic activity in each CYP1B1 variant. In addition, an E229K CYP1B1 mutation was found in a woman with a germ line HNF1α mutation in a familial adenomatosis context. In this large family, all three patients with adenomatosis bore both HNF1 and CYP1B1 germ line mutations. In conclusion, our data suggested that CYP1B1 germ line–inactivating mutations might increase the incidence of HCA in women with HNF1α mutations. [Cancer Res 2007;67(6):2611–6]

Published
2023

48. Supplementary Figures 1-5 from Hypoxia-Inducible Carbonic Anhydrase IX and XII Promote Tumor Cell Growth by Counteracting Acidosis through the Regulation of the Intracellular pH

Author

Jacques Pouysségur, M. Christiane Brahimi-Horn, Nathalie M. Mazure, Frédéric Dayan, Eric Trottier, Julie Laferrière, Karine Ilc, and Johanna Chiche

Abstract

Supplementary Figures 1-5 from Hypoxia-Inducible Carbonic Anhydrase IX and XII Promote Tumor Cell Growth by Counteracting Acidosis through the Regulation of the Intracellular pH

Published
2023

49. Supplementary Figures 6-8 from Hypoxia-Inducible Carbonic Anhydrase IX and XII Promote Tumor Cell Growth by Counteracting Acidosis through the Regulation of the Intracellular pH

Author

Jacques Pouysségur, M. Christiane Brahimi-Horn, Nathalie M. Mazure, Frédéric Dayan, Eric Trottier, Julie Laferrière, Karine Ilc, and Johanna Chiche

Abstract

Supplementary Figures 6-8 from Hypoxia-Inducible Carbonic Anhydrase IX and XII Promote Tumor Cell Growth by Counteracting Acidosis through the Regulation of the Intracellular pH

Published
2023

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