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Recovery of Bone Marrow Function in VEXAS Syndrome-potential Role for Romiplostim

2023; Wolters Kluwer; Volume: 7; Issue: 8 Linguagem: Inglês

10.1097/hs9.0000000000000934

2572-9241

Adam Al‐Hakim, Alyssa Cull, Joanna Topping, Fatima Nadat, Joanna Milek, Razan Alhefzi, Michael McDermott, Roger G. Owen, Catherine Cargo, James A. Poulter, David G. Kent, Sinisa Savic,

Vascular Anomalies and Treatments

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a recently reported late-onset hematoinflammatory disorder occurring predominantly in older men, due to acquired mutations in the X-linked UBA1 gene.1 An emerging category of hematoinflammatory disorders are broadly defined as diseases caused by somatic mutations restricted to the blood, but results in systemic inflammation with multiorgan involvement and are associated with abnormal and/or premalignant bone marrow (BM) changes.2 The inflammatory manifestations are driven in part by activation of the NLRP3 inflammasome and release of proinflammatory cytokines such as interleukin (IL)-1β, IL-18, and IL-6.3 The hematological manifestations include vacuoles in erythroid and myeloid precursors, macrocytosis, and multilineage cytopenias. Most patients are diagnosed with clonal cytopenia of unknown significance, with 31%–50% of cases also fulfilling diagnostic criteria for myelodysplastic syndrome (MDS).4,5 Typical inflammatory manifestations include fever, weight loss, skin lesions, lung disease, joint involvement, and inflammatory eye disease, while VEXAS can clinically mimic inflammatory syndromes such as Sweet's syndrome (acute febrile neutrophilic dermatosis), relapsing polychondritis, and polyarteritis nodosa.4,5 The best characterized and, to date, most common pathogenic variants lead to substitution of methionine at position 41, (UBA1 p.Met41 [p.Met41Leu/Thr/Val]), which is the start codon for translation of the cytoplasmic, enzymatically active, isoform of UBA1 (UBA1b). Consequently, there is loss of intracellular homeostasis due to dysregulated ubiquitination. The mutation is found in multipotent hematopoietic progenitors, with putative selection pressure conferred by the mutation driving a high variant allele fraction (VAF) in myeloid cells, while lymphocytes generally do not survive with the mutation.6 VEXAS syndrome is associated with significant morbidity, and for the 32% of patients who develop transfusion dependence, the risk of mortality is increased by 4.5-fold.4 Presently, the only potentially curative treatment is allogenic hematopoietic stem cell transplantation (ASCT), with numerous other medical therapies used for symptomatic control only. Here, we describe a case of VEXAS syndrome, P22 from the original cohort published in 2020,1 who has undergone spontaneous resolution of their trilineage cytopenia and inflammatory manifestations, despite the persistence of the pathogenic UBA1 mutation. The patient is a 76-year-old male who initially presented with macrocytic anemia 10 years earlier. The anemia was later found to be part of his VEXAS syndrome, subsequently diagnosed in 2020. He had a difficult clinical course due to trilinage cytopenia and a variety of inflammatory complications, including suspected polymyalgia rheumatica and relapsing polychondritis (Figure 1). He was not deemed suitable for ASCT due to initial uncertainty about the diagnosis and the presence of significant comorbidities. His treatment has largely been supportive and aimed at controlling inflammatory complications and cytopenia. He became transfusion dependent in June 2015 and subsequently developed severe thrombocytopenia. His anemia and thrombocytopenia were initially presumed to be immune-mediated and he was therefore treated with intravenous immunoglobulin and later rituximab, without success. He had a nondiagnostic BM examination on several occasions. Retrospective investigations showed the presence of the pathogenic UBA1 Met41Leu mutation with similar VAFs in all BM samples.Figure 1.: Summary of clinical progress and treatment responses. Timeline of symptoms and complications development, investigations, and treatment responses. BM = bone marrow; Bx = biopsy; CRP = C-reactive protein; CT = computer tomography; DVT = deep vein thrombosis; LCV = leukocytoclastic vasculitis; PLT = platelets; PMR = polymyalgia rheumatica; PUO = pyrexia of unknown origin; RBC = red blood cells.In 2020, he was briefly treated with eltrombopag, which was ineffective and subsequently commenced on the thrombopoietin receptor agonist (TPO-RA), romiplostim, for thrombocytopenia. He continues to receive monthly romiplostim (Suppl. Figure S1). The full blood count before his final transfusion in November 2021 showed a hemoglobin (Hb) of 110 g/L, platelets (PLT) 80 × 109/L, mean corpuscular volume (MCV) 114, lymph 0.67 × 109/L. Over subsequent months, these have spontaneously improved to normal levels (Hb 156, PLT 188, and lymph 1.10), although the MCV remains elevated at 110 (Suppl. Figure S1). The patient's inflammatory symptoms are well-controlled despite his prednisolone being weaned down to its current level of 6 mg/day. Further reduction is limited by the patient complaining of severe fatigue. A synacthen test indicated that this is likely due to secondary adrenal insufficiency, but since the test was done while the patient was still receiving 6 mg of prednisolone (<5 mg daily is required for the test to be fully valid), the diagnosis remains unconfirmed. The patient's latest C-reactive protein (CRP) readings (November 2022 and January 2023) demonstrate well-controlled inflammation with CRP [email protected]; Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen N, Denmark); Andres Jimenez Kaufmann ([email protected]; Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen N, Denmark); Sara Garcia ([email protected]; Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen N, Denmark); Philippe Hupé ([email protected]; Institut Curie, U900 Inserm, PSL Research University, UMR144 CNRS, Paris, France & Mines Paris Tech, Fontainebleau, France); Fanny Coffin ([email protected]; Institut Curie, U900 Inserm, PSL Research University, Paris, France & Mines Paris Tech, Fontainebleau, France); Apolline Gallois ([email protected]; Institut Curie, U900 Inserm, PSL Research University, Paris, France & Mines Paris Tech, Fontainebleau, France); Henri de Soyres ([email protected]; Institut Curie, U900 Inserm, PSL Research University, Paris, France & Mines Paris Tech, Fontainebleau, France); Julien Roméjon (julien.romé[email protected]; Institut Curie, U900 Inserm, PSL Research University, Paris, France & Mines Paris Tech, Fontainebleau, France); Aura Moreno Vega ([email protected]; OWKIN, Biotec, Paris, France); Marc Dubourdeau ([email protected]; AMBIOTIS SAS - Toulouse – France); Karoline Krause ([email protected]; Charité - Universitätsmedizin Berlin, Institut für Allergieforschung, 12203 Berlin, Germany); Dirk Foell ([email protected]; Department of Pediatric Rheumatology and Immunology, University of Muenster, Muenster, Germany); Christoph Kessel ([email protected]; Department of Pediatric Rheumatology and Immunology, University of Muenster, Muenster, Germany); Katerina Laskari ([email protected]; Rheumatology Unit, 1st Department of Propaedeutic Internal Medicine, Joint Academic Rheumatology Program, University of Athens, Medical School, Athens, Greece); Andreakos Evangelos ([email protected]; Laboratory of Immunobiology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece); Paul Van Daele ([email protected]; Department of internal medicine and department of immunology, Erasmus MC, Rotterdam, The Netherlands); Clementien Vermont ([email protected]; Department of internal medicine and department of immunology, Erasmus MC, Rotterdam, The Netherlands); Rogier van Wijck ([email protected]; Department of Pathology & Clinical Bioinformatics); Sigrid Swagemakers ([email protected]; Department of Pathology & Clinical Bioinformatics); Peter van der Spek ([email protected]; Department of Pathology & Clinical Bioinformatics); Stefan Erkeland ([email protected]; Department of Immunology, Erasmus University Medical Center, Rotterdam, The Netherlands); Harmen van de Werken ([email protected]; Department of Immunology, Erasmus University Medical Center, Rotterdam, The Netherlands); Yvonne Mueller ([email protected]; Department of Immunology, Erasmus University Medical Center, Rotterdam, The Netherlands); Peter Katsikis ([email protected]; Department of Immunology, Erasmus University Medical Center, Rotterdam, The Netherlands); Michael Hofer ([email protected]; Pediatric immuno-rheumatology, Dept Pediatrics, CHUV, University Hospital of Lausanne, Lausanne, Switzerland); Cem Gabay ([email protected]; Division of Rheumatology, Department of Medicine & Department of Pathology and Immunology, HUG and University of Geneva, Faculty of Medicine, Switzerland); Helen Lachmann ([email protected]; National Amyloidosis Centre, Royal Free London NHS Foundation Trust and University College London, London, UK); Costas Papaloukas ([email protected]; Department of Biological Applications and Technology, University of Ioannina, Greece); Dimitrios I. Fotiadis ([email protected]; Unit of Medical Technology and Intelligent Information Systems, Department of Materials Science and Engineering, University of Ioannina, Greece); Dominique de Seny ([email protected]; Laboratory of Rheumatology, GIGA-Research, CHU Liège, University of Liège, 4000 Liège, Belgium); Haner Direskeneli ([email protected]; Department of Internal Medicine, Division of Rheumatology, Marmara University, School of Medicine, Istanbul, Turkey); Seza Ozen ([email protected]; Department of Pediatrics, Division of Rheumatology, Hacettepe University, Faculty of Medicine, Ankara, Turkey); Umut Kalyoncu ([email protected]; Division of Rheumatology, Department of Internal Medicine, Hacettepe University Faculty of Medicine, Ankara, Turkey); Tadej Avcin ([email protected]; Department of Allergology, Rheumatology and Clinical Immunology, University Children's Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia); Jordi Anton ([email protected]; Pediatric rheumatology. Hospital Sant Joan de Déu. Institut de Recerca Sant Joan de Déu. Universitat de Barcelona, Spain); Violeta Bittermann ([email protected]; Pediatric rheumatology. Hospital Sant Joan de Déu. Institut de Recerca Sant Joan de Déu. Universitat de Barcelona, Spain); Alina Boteanu ([email protected]; Servicio de Reumatología, Hospital Universitario Ramón y Cajal, Madrid, Spain); Fabrizio De Benedetti ([email protected]; Division of Rheumatology, Bambino Gesù Children's Hospital, IRCCS, Roma, Italy); Antonella Insalaco ([email protected]; Division of Rheumatology, Bambino Gesù Children's Hospital, IRCCS, Roma, Italy); Emanuele Bizzi ([email protected]; Internal Medicine Ospedale Fatebenefratelli, Milano, Italy); Sonia Caccia ([email protected]; Department of biomedical and clinical sciences, University of Milano, Italy); Luca Cantarini ([email protected]; Rheumatology Unit Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy); Paolo Sfriso ([email protected]; Rheumatology Unit, Department of Medicine, University of Padova, Italy); Jean-François Deleuze ([email protected]; Centre d'Etude du Polymorphisme Humain, Fondation Jean Dausset, Paris, France); Sarhan Yaiche ([email protected]; European Clinical Research Infrastructure Network). AUTHOR CONTRIBUTIONS AA and SS wrote the first draft of the article. AA, JT, FN, JM, RA, and JP processed the samples and conducted laboratory experiments and analyzed the data. RO, CC, and SS provided clinical details and care of the patient. MFM, DK, and SS provided funding and overall supervision of the study. All authors read and approved the article. DISCLOSURES DK is a Scientific Editor for HemaSphere. The remaining authors have no conflicts of interest to disclose. SOURCES OF FUNDING This project has received funding from European Union's Horizon 2020 research and innovation programme under grant agreement No 779295 (ImmunAID- Immunome project consortium for Autoinflammatory disorders). SS is supported by Senior fellowship from Kennedy Trust.