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Autoinflammatory disorders
Efficacy and safety of targeted therapies in VEXAS syndrome: retrospective study from the FRENVEX
  1. Jerome Hadjadj1,
  2. Yann Nguyen2,
  3. Dalila Mouloudj1,
  4. Rim Bourguiba3,4,
  5. Mael Heiblig5,
  6. Hassina Aloui3,
  7. Chloe McAvoy1,
  8. Valentin Lacombe6,
  9. Samuel Ardois7,
  10. Corrado Campochiaro8,
  11. Alexandre Maria9,
  12. Cyrille Coustal9,
  13. Thibault Comont10,
  14. Estibaliz Lazaro11,
  15. Francois Lifermann12,
  16. Guillaume Le Guenno13,
  17. Hervé Lobbes13,
  18. Vincent Grobost13,
  19. Roderau Outh14,
  20. Julien Campagne15,
  21. Anais Dor-Etienne15,
  22. Alice Garnier16,
  23. Yvan Jamilloux17,
  24. Antoine Dossier18,
  25. Maxime Samson19,
  26. Sylvain Audia19,
  27. Barbara Nicolas19,
  28. Alexis Mathian20,
  29. Baptiste de Maleprade21,
  30. Benjamin De Sainte-Marie22,
  31. Benoit Faucher22,
  32. Jean-David Bouaziz23,
  33. Jonathan Broner24,
  34. Cyril Dumain24,
  35. Carole Antoine25,
  36. Benjamin Carpentier26,
  37. Brice Castel27,
  38. Celine Lartigau-Roussin28,
  39. Etienne Crickx29,
  40. Geoffroy Volle29,
  41. Damien Fayard30,
  42. Paul Decker31,
  43. Thomas Moulinet31,
  44. Anael Dumont32,
  45. Alexandre Nguyen32,
  46. Achille Aouba32,
  47. Jean-Philippe Martellosio33,
  48. Matthieu Levavasseur34,
  49. Sebastien Puigrenier35,
  50. Pascale Antoine35,
  51. Jean-Thomas Giraud36,
  52. Olivier Hermine37,
  53. Carole Lacout6,
  54. Nihal Martis38,
  55. Jean-Denis Karam39,
  56. Francois Chasset40,
  57. Laurent Arnaud41,
  58. Paola Marianetti42,
  59. Christophe Deligny43,
  60. Thibaud Chazal44,
  61. Pascal Woaye-Hune45,
  62. Murielle Roux-Sauvat46,
  63. Aurore Meyer47,
  64. Pierre Sujobert48,
  65. Pierre Hirsch49,
  66. Noemie Abisror1,
  67. Pierre Fenaux50,
  68. Olivier Kosmider51,
  69. Vincent Jachiet1,
  70. Olivier Fain1,
  71. Benjamin Terrier52,
  72. Arsène Mekinian1,
  73. Sophie Georgin-Lavialle3
  74. FRENVEX
    1. 1 Sorbonne Université, service de médecine interne, Hôpital Saint-Antoine, AP-HP, Paris, France
    2. 2 Service de médecine interne, Hôpital Beaujon, AP-HP.Nord, Université Paris Cité, Clichy, France
    3. 3 Médecine Interne, CEREMAIA, Sorbonne Université, Hospital Tenon, Paris, France
    4. 4 Université Tunis el Manar, Faculté de médecine de Tunis, Tunis, Tunisia
    5. 5 Hématologie, Hôpital Lyon Sud - HCL, Pierre-Bénite, France
    6. 6 Department of Internal Medicine, University Hospital Centre Angers, Angers, Pays de la Loire, France
    7. 7 Médecine interne, CHU Rennes, Rennes, France
    8. 8 Unit of Immunology, Rheumatology, Allergy ad Rre Disesaes. IRCCS San Raffaele Hospital. Vita-Salute Vita-Salute San Raffaele University, Milan, Italy
    9. 9 Department of Internal Medicine - Multi-organ Diseases, St Eloi Hospital, Montpellier University Hospital, Univ Montpellier, Montpellier, France
    10. 10 Service de médecine interne IUCT-Oncopole, CHU Toulouse, Université Paul Sabatier, Toulouse, France
    11. 11 Internal Medicine, CHU de Bordeaux, Bordeaux, Nouvelle-Aquitaine, France
    12. 12 Service de médecine interne, Centre Hospitalier Dax, Dax, Nouvelle-Aquitaine, France
    13. 13 Médecine Interne, CHU Estaing, Clermont-Ferrand, Auvergne-Rhône-Alpes, France
    14. 14 Service de médecine interne et générale, Perpignan University, Perpignan, France
    15. 15 Médecine Interne, Hôpital Robert Schuman, Metz, France
    16. 16 Hematology Department, Nantes University Hospital, Nantes, France
    17. 17 Department of Internal Medicine, Hôpital Universitaire de la Croix-Rousse, Hospices Civils de Lyon, University Claude Bernard Lyon 1, Lyon, France
    18. 18 Service de Médecine Interne, Hôpital Bichat-Claude-Bernard, APHP, Paris, France
    19. 19 Service de Médecine Interne et Immunologie Clinique, Centre de Référence Constitutif des Maladies Auto-immunes et Auto-inflammatoires Rares de l’adulte, CHU Dijon-Bourgogne, Dijon,France; Université de Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, Dijon, France
    20. 20 French National Referral Center for Systemic Lupus Erythematosus, Antiphospholipid Antibody Syndrome and Other Autoimmune Disorders, Service de Médecine Interne 2, Institut E3M, Inserm UMRS, Centre d’Immunologie et des Maladies Infectieuses (CIMI-Paris), Hôpital Universitaire Pitié Salpêtrière, Paris, Île-de-France, France
    21. 21 Rhumatologie, CHU de Rouen, Rouen, Normandie, France
    22. 22 Department of Internal Medicine, Centre Hospitalier Universitaire de La Timone, Marseille, France
    23. 23 Dermatology, Hopital Saint-Louis, Paris, Île-de-France, France
    24. 24 Internal Medicine Department, University Hospital Centre Nimes, Nimes, France
    25. 25 Internal Medicine, Sainte-Anne Military Teaching Hospital, Toulon, Provence-Alpes-Côte d'Azu, France
    26. 26 Hématologie clinique, Universite Catholique de Lille Hopital Saint-Vincent de Paul, Lille, Hauts-de-France, France
    27. 27 Service de Médecine Interne et d'Immunologie clinique, Centre Hospitalier de Lourdes, Lourdes, France
    28. 28 Internal Medicine, CH Ouest Reunion, Saint Paul, France
    29. 29 Centre national de référence des cytopénies auto-immunes de l'adulte, Hôpital Henri Mondor, Fédération Hospitalo-Universitaire TRUE InnovaTive theRapy for immUne disordErs, Assistance Publique Hôpitaux de Paris (AP-HP), Université Paris Est Créteil, Créteil, France
    30. 30 University Hospital Centre Gabriel Montpied, Clermont-Ferrand, Auvergne-Rhône-Alpes, France
    31. 31 Médecine interne et immunologie clinique, CHU de Nancy, UMR 7365, IMoPA, Université de Lorraine, CNRS, Nancy, France
    32. 32 Department of Internal Medicine, University Hospital Centre Caen, Caen, Basse-Normandie, France
    33. 33 Department of Internal Medicine, Centre Hospitalier Universitaire de Poitiers, Poitiers, France
    34. 34 Dermatologie, Centre Hospitalier Genevois, Annecy, France
    35. 35 Department of Internal Medicine, Centre hospitalier de Boulogne-sur-Mer, Boulogne-sur-Mer, France
    36. 36 Internal Medicine Unit, Tarbes Hospital, Tarbes, France
    37. 37 Hematology, Hopital Necker-Enfants Malades, Paris, France
    38. 38 Internal Medicine Department, University Hospital of Nice, Archet 1 Hospital, Nice, France
    39. 39 Department of Internal Medicine Amiens University Hospital, Amiens, France
    40. 40 Sorbonne Université, Faculté de Médecine, AP-HP, Service de Dermatologie et Allergologie, Paris, France
    41. 41 Department of Rheumatology. National reference Center for rare diseases (RESO). Hôpitaux Universitaires de Strasbourg et INSERM UMR-S 1109, Strasbourg, France
    42. 42 Service de médecine interne, maladies infectieuses, immunologie clinique, Reims Champagne-Ardenne University, Reims, France
    43. 43 Service de Médecine Interne, University Hospital of Martinique, Fort-de-France, Martinique
    44. 44 Internal Medicine, The Fondation Adolphe de Rothschild Hospital, Paris, France
    45. 45 Service de Médecine interne, CHD Vendée, La Roche-sur-Yon, France
    46. 46 Service de médecine interne, Pierre Oudot Hospital of Bourgoin-Jallieu, Bourgoin-Jallieu, France
    47. 47 Service d'immunologie clinique et médecine interne, Hopitaux universitaires de Strasbourg, Strasbourg, Alsace, France
    48. 48 Hospices Civils de Lyon, Hôpital Lyon Sud, Service d'hématologie biologique, Pierre Bénite, France
    49. 49 Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, SIRIC8 CURAMUS, Hôpital Saint-Antoine, Service d'Hématologie Biologique, Paris, France
    50. 50 Hématologie, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Paris, France
    51. 51 Service d’Hématologie Biologique, DMU BioPhyGen, APHP, Paris, France
    52. 52 Médecine interne, Hôpital Cochin, AP-HP.Centre, Université Paris Cité, Paris, France
    1. Correspondence to Dr Jerome Hadjadj; jerome.hadjadj{at}aphp.fr; Professor Sophie Georgin-Lavialle; sophie.georgin-lavialle{at}aphp.fr

    Abstract

    Objectives Vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic (VEXAS) syndrome is an adult-onset autoinflammatory disease associated with somatic ubiquitin-like modifier-activating enzyme 1 (UBA1) mutations. We aimed to evaluate the efficacy and safety of targeted therapies.

    Methods Multicentre retrospective study including patients with genetically proven VEXAS syndrome who had received at least one targeted therapy. Complete response (CR) was defined by a clinical remission, C-reactive protein (CRP) ≤10 mg/L and a ≤10 mg/day of prednisone-equivalent therapy, and partial response (PR) was defined by a clinical remission and a 50% reduction in CRP levels and glucocorticoid dose.

    Results 110 patients (median age 71 (68–79) years) who received 194 targeted therapies were included: 78 (40%) received Janus kinase (JAK) inhibitors (JAKi), 51 (26%) interleukin (IL)-6 inhibitors, 33 (17%) IL-1 inhibitors, 20 (10%) tumour necrosis factor (TNFα) blockers and 12 (6%) other targeted therapies. At 3 months, the overall response (CR and PR) rate was 24% with JAKi, 32% with IL-6 inhibitors, 9% with anti-IL-1 and 0% with TNFα blockers or other targeted therapies. At 6 months, the overall response rate was 30% with JAKi and 26% with IL-6 inhibitors. Survival without treatment discontinuation was significantly longer with JAKi than with the other targeted therapies. Among patients who discontinued treatment, causes were primary failure, secondary failure, serious adverse event or death in 43%, 14%, 19% and 19%, respectively, with JAKi and 46%, 11%, 31% and 9%, respectively, with IL-6 inhibitors.

    Conclusions This study shows the benefit of JAKi and IL-6 inhibitors, whereas other therapies have lower efficacy. These results need to be confirmed in prospective trials.

    • Biological Therapy
    • Inflammation
    • Tumor Necrosis Factor Inhibitors

    Data availability statement

    Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.

    https://doi.org/10.1136/ard-2024-225640

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      Data availability statement

      Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.

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      Footnotes

      • Handling editor Josef S Smolen

      • X @Maxime_Samson21, @MoulinetThomas, @SophieGeorgin

      • Collaborators The FRENVEX: Isabelle Melki, Lionel Ades, Lin Pierre Zhao, Alexandra Audemard, Mikael Ebbo, Odile Beyne Rauzy, Alexandre Belot, Raphaël Borie, Ygal Benhamou, Gaetan Sauvetre, Khalil El-Karoui, François Rodrigues, Louis Terriou, Jeremie Dion.

      • Contributors JH is the guarantor. JH performed research, analysed results and wrote the paper. JH and SG-L designed the study. YN performed statistical analysis. JH and DM collected the data. JH, YN and SG-L analysed results and reviewed the paper. All other authors provided clinical or biological care and reviewed the paper.

      • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

      • Competing interests None declared.

      • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

      • Provenance and peer review Not commissioned; externally peer reviewed.

      • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.