S Georgin-Lavialle1, B Terrier2, A F Guedon3, M Heiblig4, T Comont5, E Lazaro6, V Lacombe7, L Terriou8, S Ardois9, J-D Bouaziz10, A Mathian11, G Le Guenno12,13, A Aouba14, R Outh15, A Meyer16, M Roux-Sauvat17, M Ebbo18, L P Zhao19, A Bigot20, Y Jamilloux21, V Guillotin12,13, E Flamarion22, P Henneton23, G Vial12,13, V Jachiet24, J Rossignol25, S Vinzio26, T Weitten27, J Vinit28, C Deligny29, S Humbert30, M Samson31, N Magy-Bertrand30, T Moulinet32, R Bourguiba1, T Hanslik33, C Bachmeyer1, M Sebert19, M Kostine34, B Bienvenu35, P Biscay36, E Liozon37, L Sailler38, F Chasset39, A Audemard-Verger20, E Duroyon40, G Sarrabay41, F Borlot42, C Dieval43, T Cluzeau44, P Marianetti45, H Lobbes12,13, G Boursier41, M Gerfaud-Valentin4, J Jeannel22, A Servettaz45, S Audia31, M Larue46, B Henriot47, B Faucher18, J Graveleau48, B de Sainte Marie12,13, J Galland49, L Bouillet26, C Arnaud38, L Ades19, F Carrat3, P Hirsch50, P Fenaux19, O Fain24, P Sujobert30, O Kosmider40, A Mekinian24. 1. Sorbonne Université, AP-HP, Hôpital Tenon, Service de Médecine Interne, CeRéMAIA, Paris, France. 2. Department of Internal Medicine, University of Paris, AP-HP, Cochin Hospital, Paris, France. 3. Sorbonne Université, Inserm, Institut Pierre-Louis d'Epidémiologie et de Santé Publique, Département de Santé Publique, Hôpital Saint-Antoine, AP-HP, Paris, France. 4. Department of Haematology, University Hospital of Lyon, Hospices Civils de Lyon, Lyon, France. 5. Department of Internal Medicine and Clinical Immunology, University Hospital of Toulouse, Toulouse, France. 6. Department of Internal Medicine and Infectious Diseases, Hôpital Haut-Lévêque, Bordeaux, France. 7. Department of Internal Medicine, Angers University Hospital, Angers, France. 8. Department of Internal Medicine, Lille University Hospital, Lille, France. 9. Service de Médecine Interne, CHU de Rennes, Rennes, France. 10. Université de Paris, Service de Dermatologie, Hôpital Saint Louis, AP-HP, INSERM U944, Paris, France. 11. Assistance Publique-Hôpitaux de Paris, Groupement Hospitalier Pitié-Salpêtrière, French National Referral Center for Systemic Lupus Erythematosus, Antiphospholipid Antibody Syndrome and Other Autoimmune Disorders, Service de Médecine Interne 2, Institut E3M, Paris, France. 12. Department of Internal Medicine and Clinical Immunology, University Hospital Centre of Bordeaux, Saint Andre Hospital, Bordeaux, France. 13. CHU de Clermont-Ferrand, Hôpital Estaing, Service de Médecine Interne, Clermont-Ferrand, France. 14. Department of Internal Medicine, Caen Université, Hôpital de Caen, Caen, France. 15. Service de Médecine Interne et Générale, Centre Hospitalier de Perpignan, Perpignan, France. 16. Service d'Immunologie Clinique et Médecine Interne, Nouvel Hôpital Civil, CHU Strasbourg, Strasbourg, France. 17. GHND, Centre Hospitalier Pierre Oudot, BP 40348, Bourgoin-Jallieu Cedex, France. 18. Department of Internal Medicine, Aix Marseille Université, AP-HM, Hôpital de la Timone, Marseille, France. 19. Hematology Department, AP-HP, CHU of Saint Louis, Paris, France. 20. Department of Internal and Clinical Medicine, University of Tours, Tours, France. 21. Department of Internal Medicine and Clinical Immunology, University Hospital of Lyon, Hospices Civils de Lyon, Lyon, France. 22. Université de Paris, Service de Médecine Interne, Paris, France. 23. Service de Médecine Vasculaire, CHU Montpellier, Montpellier, France. 24. Sorbonne Université, AP-HP, Hôpital Saint Antoine, Service de Médecine Interne et Inflammation-Immunopathology-Biotherapy Department (DMU i3), Paris, France. 25. Université de Paris, Service d'Hématologie, Necker Enfants Malades, Paris, France. 26. Service de Médecine Interne, Groupe Hospitalier Mutualiste, Grenoble, France. 27. Service de Médecine Interne, Centre Hospitalier (CHICAS), Gap, France. 28. Service de Médecine Interne, Centre Hospitalier, Chalons, France. 29. Service de Rhumatologie - Médecine Interne 5D, CHU de Martinique, Hôpital P. Zobda-Quitman, France. 30. CHU de Besançon, Service de Médecine Interne, Besançon, France. 31. Department of Internal Medicine and Clinical Immunology, Dijon University Hospital, Dijon, France. 32. Department of Internal Medicine and Clinical Immunology, Regional Competence Center for Systemic and Autoimmune Rare Diseases, Nancy University Hospital, UMR 7365, IMoPA, Lorraine University, CNRS, Vandoeuvre-lès-Nancy, France. 33. AP-HP, Hôpital Ambroise Paris, Service de Médecine Interne, Paris, France. 34. Department of Rheumatology, Hôpital Haut-Lévesque, Bordeaux, France. 35. Hôpital Saint Joseph, Service de Médecine Interne, Marseille, France. 36. Clinique Mutualiste Pessac Médecine Interne, Pessac, France. 37. Service de Médecine Interne, CHU Dupuytren, Limoges, France. 38. Department of Internal Medicine, University Hospital of Toulouse, Toulouse, France. 39. Sorbonne Université, Hôpital Tenon, Service de Dermatologie et Allergologie et Inflammation-Immunopathology-Biotherapy Department (DMU i3), Paris, France. 40. Service d'Hématologie Biologique, DMU BioPhyGen GH AP-HP, Centre-University de Paris, Paris, France. 41. Laboratory of Rare and Autoinflammatory Genetic Diseases and Reference Centre for Autoinflammatory Diseases and Amyloidosis (CEREMAIA), CHU Montpellier, University of Montpellier, Montpellier, France. 42. Service de Médecine Interne, CH Béziers, Béziers, France. 43. Service de Médecine Interne et Hématologie, CH Régional, Rochefort, France. 44. Hematology Department, CHU of Nice, Cote d'Azur University, Nice, France. 45. CHU de REIMS, Service de Médecine Interne, Maladies Infectieuses, Immunologie Clinique, Reims, France. 46. AP-HP, Service de Rhumatologie, Hôpital Henri Mondor, Créteil, France. 47. Service de Médecine Interne, Centre Hospitalier René Pleven, Dinan, France. 48. CHU de Nantes Hôtel Dieu, Service de Médecine Interne, Nantes, France. 49. Service de Médecine Interne, Hôpital Fleyriat, Centre Hospitalier Bourg-en-Bresse, France. 50. Sorbonne Université, AP-HP, Hôpital Saint Antoine, Service d'Hématologie Biologique, Paris, France.
Abstract
BACKGROUND: A new autoinflammatory syndrome related to somatic mutations of UBA1 was recently described and called VEXAS syndrome ('Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic syndrome'). OBJECTIVES: To describe clinical characteristics, laboratory findings and outcomes of VEXAS syndrome. METHODS: One hundred and sixteen patients with VEXAS syndrome were referred to a French multicentre registry between November 2020 and May 2021. The frequency and median of parameters and vital status, from diagnosis to the end of the follow-up, were recorded. RESULTS: The main clinical features of VEXAS syndrome were found to be skin lesions (83%), noninfectious fever (64%), weight loss (62%), lung involvement (50%), ocular symptoms (39%), relapsing chondritis (36%), venous thrombosis (35%), lymph nodes (34%) and arthralgia (27%). Haematological disease was present in 58 cases (50%): myelodysplastic syndrome (MDS; n = 58) and monoclonal gammopathy of unknown significance (n = 12; all patients with MGUS also have a MDS). UBA1 mutations included p.M41T (45%), p.M41V (30%), p.M41L (18%) and splice mutations (7%). After a median follow-up of 3 years, 18 patients died (15·5%; nine of infection and three due to MDS progression). Unsupervised analysis identified three clusters: cluster 1 (47%; mild-to-moderate disease); cluster 2 (16%; underlying MDS and higher mortality rates); and cluster 3 (37%; constitutional manifestations, higher C-reactive protein levels and less frequent chondritis). The 5-year probability of survival was 84·2% in cluster 1, 50·5% in cluster 2 and 89·6% in cluster 3. The UBA1 p.Met41Leu mutation was associated with a better prognosis. CONCLUSIONS: VEXAS syndrome has a large spectrum of organ manifestations and shows different clinical and prognostic profiles. It also raises a potential impact of the identified UBA1 mutation.
BACKGROUND: A new autoinflammatory syndrome related to somatic mutations of UBA1 was recently described and called VEXAS syndrome ('Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic syndrome'). OBJECTIVES: To describe clinical characteristics, laboratory findings and outcomes of VEXAS syndrome. METHODS: One hundred and sixteen patients with VEXAS syndrome were referred to a French multicentre registry between November 2020 and May 2021. The frequency and median of parameters and vital status, from diagnosis to the end of the follow-up, were recorded. RESULTS: The main clinical features of VEXAS syndrome were found to be skin lesions (83%), noninfectious fever (64%), weight loss (62%), lung involvement (50%), ocular symptoms (39%), relapsing chondritis (36%), venous thrombosis (35%), lymph nodes (34%) and arthralgia (27%). Haematological disease was present in 58 cases (50%): myelodysplastic syndrome (MDS; n = 58) and monoclonal gammopathy of unknown significance (n = 12; all patients with MGUS also have a MDS). UBA1 mutations included p.M41T (45%), p.M41V (30%), p.M41L (18%) and splice mutations (7%). After a median follow-up of 3 years, 18 patients died (15·5%; nine of infection and three due to MDS progression). Unsupervised analysis identified three clusters: cluster 1 (47%; mild-to-moderate disease); cluster 2 (16%; underlying MDS and higher mortality rates); and cluster 3 (37%; constitutional manifestations, higher C-reactive protein levels and less frequent chondritis). The 5-year probability of survival was 84·2% in cluster 1, 50·5% in cluster 2 and 89·6% in cluster 3. The UBA1 p.Met41Leu mutation was associated with a better prognosis. CONCLUSIONS: VEXAS syndrome has a large spectrum of organ manifestations and shows different clinical and prognostic profiles. It also raises a potential impact of the identified UBA1 mutation.
Authors: Béatrice Gaugler; Arsène Mekinian; Vincent Jachiet; Laure Ricard; Pierre Hirsch; Florent Malard; Laurent Pascal; Odile Beyne-Rauzy; Pierre Peterlin; Alexandre Thibault Jacques Maria; Norbert Vey; Maud D'Aveni; Marie-Pierre Gourin; Sophie Dimicoli-Salazar; Anne Banos; Stefan Wickenhauser; Louis Terriou; Benoit De Renzis; Eric Durot; Shanti Natarajan-Ame; Anne Vekhoff; Laurent Voillat; Sophie Park; Julien Vinit; Céline Dieval; Azeddine Dellal; Vincent Grobost; Lise Willems; Julien Rossignol; Eric Solary; Olivier Kosmider; Nicolas Dulphy; Lin Pierre Zhao; Lionel Adès; Pierre Fenaux; Olivier Fain; Mohamad Mohty Journal: Clin Exp Med Date: 2022-08-11 Impact factor: 5.057