Somatic Mutations in UBA1 Define a Distinct Subset of Relapsing Polychondritis Patients With VEXAS.
Journal
Arthritis & rheumatology (Hoboken, N.J.)
ISSN: 2326-5205
Titre abrégé: Arthritis Rheumatol
Pays: United States
ID NLM: 101623795
Informations de publication
Date de publication:
10 2021
10 2021
Historique:
received:
26
11
2020
accepted:
18
03
2021
pubmed:
30
3
2021
medline:
10
11
2021
entrez:
29
3
2021
Statut:
ppublish
Résumé
Somatic mutations in UBA1 cause a newly defined syndrome known as VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome). More than 50% of patients currently identified as having VEXAS met diagnostic criteria for relapsing polychondritis (RP), but clinical features that characterize VEXAS within a cohort of patients with RP have not been defined. We undertook this study to define the prevalence of somatic mutations in UBA1 in patients with RP and to create an algorithm to identify patients with genetically confirmed VEXAS among those with RP. Exome and targeted sequencing of UBA1 was performed in a prospective observational cohort of patients with RP. Clinical and immunologic characteristics of patients with RP were compared based on the presence or absence of UBA1 mutations. The random forest method was used to derive a clinical algorithm to identify patients with UBA1 mutations. Seven of 92 patients with RP (7.6%) had UBA1 mutations (referred to here as VEXAS-RP). Patients with VEXAS-RP were all male, were on average ≥45 years of age at disease onset, and commonly had fever, ear chondritis, skin involvement, deep vein thrombosis, and pulmonary infiltrates. No patient with VEXAS-RP had chondritis of the airways or costochondritis. Mortality was greater in VEXAS-RP than in RP (23% versus 4%; P = 0.029). Elevated acute-phase reactants and hematologic abnormalities (e.g., macrocytic anemia, thrombocytopenia, lymphopenia, multiple myeloma, myelodysplastic syndrome) were prevalent in VEXAS-RP. A decision tree algorithm based on male sex, a mean corpuscular volume >100 fl, and a platelet count <200 ×10 Mutations in UBA1 were causal for disease in a subset of patients with RP. This subset of patients was defined by disease onset in the fifth decade of life or later, male sex, ear/nose chondritis, and hematologic abnormalities. Early identification is important in VEXAS given the associated high mortality rate.
Substances chimiques
UBA1 protein, human
0
Ubiquitin-Activating Enzymes
EC 6.2.1.45
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1886-1895Subventions
Organisme : NIAMS NIH HHS
ID : ZIA-AR-041199
Pays : United States
Organisme : NIAMS NIH HHS
ID : ZIA-AR-041199
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Published 2021. This article is a U.S.Government work and is in the public domain in the USA.
Références
Beck DB, Ferrada MA, Sikora KA, Ombrello AK, Collins JC, Pei W, et al. Somatic mutations in UBA1 and severe adult-onset autoinflammatory disease. N Engl J Med 2020;383:2628-38.
Dion J, Costedoat-Chalumeau N, Sène D, Cohen-Bittan J, Leroux G, Dion C, et al. Relapsing polychondritis can be characterized by three different clinical phenotypes: analysis of a recent series of 142 patients. Arthritis Rheumatol 2016;68:2992-3001.
Shimizu J, Yamano Y, Kawahata K, Suzuki N. Relapsing polychondritis patients were divided into three subgroups: patients with respiratory involvement (R subgroup), patients with auricular involvement (A subgroup), and overlapping patients with both involvements (O subgroup), and each group had distinctive clinical characteristics. Medicine (Baltimore) 2018;97:e12837.
Ferrada M, Rimland CA, Quinn K, Sikora K, Kim J, Allen C, et al. Defining clinical subgroups in relapsing polychondritis: a prospective observational cohort study. Arthritis Rheumatol 2020;72:1396-402.
Washio K, Oka M, Ohno K, Shimizu H, Kawano S, Kunisada M, et al. Case of recurrent Sweet's syndrome in a patient with relapsing polychondritis and myelodysplastic syndrome. J Dermatol 2012;39:731-3.
Erden A, Bilgin E, Kilic L, Sari A, Armagan B, Buyukasik Y, et al. Remission of relapsing polychondritis after successful treatment of myelodysplastic syndrome with azacitidine: a case and review of the literature. Drug Metab Pers Ther 2018;33:105-8.
Hall R, Hopkinson N, Hamblin T. Relapsing polychondritis, smouldering non-secretory myeloma and early myelodysplastic syndrome in the same patient: three difficult diagnoses produce a life threatening illness. Leuk Res 2000;24:91-3.
Hebbar M, Brouillard M, Wattel E, Decoulx M, Hatron PY, Devulder B, et al. Association of myelodysplastic syndrome and relapsing polychondritis: further evidence. Leukemia 1995;9:731-3.
Heo SW, Cho KH, Ryu JI, Chung SH, Kim CG, Kim SG, et al. A case of relapsing polychondritis associated with myelodysplastic syndrome with erythroid hypoplasia/aplasia. Korean J Intern Med 2003;18:251-4.
Kamboj AK, Cotter TG, Varghese C. Relapsing polychondritis with myelodysplastic syndrome: a case report. Am J Med 2017;130:e107-8.
Kawakami T, Kawase A, Takeuchi S, Yoshioka S, Fujimoto N, Tajima S, et al. Sweet syndrome subsequent to relapsing polychondritis and myelodysplastic syndrome in a Japanese patient. Acta Derm Venereol 2008;88:517-9.
Lavabre-Bertrand T, Navarro M. Relapsing polychondritis and myelodysplastic syndrome. Am J Hematol 1993;43:243.
Loeffler KU, McLean IW. Bilateral necrotizing scleritis and blindness in the myelodysplastic syndrome presumably due to relapsing polychondritis. Acta Ophthalmol Scand 2000;78:228-31.
Manganelli P, Delsante G, Bianchi G, Fietta P, Quaini F. Remitting seronegative symmetrical synovitis with pitting oedema in a patient with myelodysplastic syndrome and relapsing polychondritis. Clin Rheumatol 2001;20:132-5.
Salahuddin N, Libman BS, Lunde JH, Kay J, Cooper SM. The association of relapsing polychondritis and myelodysplastic syndrome: report of three cases. J Clin Rheumatol 2000;6:146-9.
Shirai T, Fujii H, Saito R, Nasu K, Kamogawa Y, Fukuhara N, et al. Relapsing polychondritis complicated by myelodysplastic syndrome is resistant to immunosuppression: comment on the article by Dion et al [letter]. Arthritis Rheumatol 2017;69:682-3.
Shirota T, Hayashi O, Uchida H, Tonozuka N, Sakai N, Itoh H. Myelodysplastic syndrome associated with relapsing polychondritis: unusual transformation from refractory anemia to chronic myelomonocytic leukemia. Ann Hematol 1993;67:45-7.
Tabary A, Lega JC, Mainbourg S, Lobbes H. Recurrent superficial vein thrombosis revealing relapsing polychondritis associated with myelodysplastic syndrome. Rheumatology (Oxford) 2020;59:3581.
Tanaka K, Nakamura E, Naitoh K, Utsunomiya I, Matsuo K, Osabe S, et al. Relapsing polychondritis in a patient with myelodysplastic syndrome. Rinsho Ketsueki 1990;31:1851-5. In Japanese.
Tomomatsu J, Hamano Y, Ando J, Komatsu N, Sugimoto K. Non-myeloablative allogenic BMT for myelodysplastic syndrome successfully controlled accompanying relapsing polychondritis [letter]. Bone Marrow Transplant 2012;47:742-3.
Van Besien K, Tricot G, Hoffman R. Relapsing polychondritis: a paraneoplastic syndrome associated with myelodysplastic syndromes. Am J Hematol 1992;40:47-50.
McAdam LP, O'Hanlan MA, Bluestone R, Pearson CM. Relapsing polychondritis: prospective study of 23 patients and a review of the literature. Medicine (Baltimore) 1976;55:193-215.
Damiani JM, Levine HL. Relapsing polychondritis: report of ten cases. Laryngoscope 1979;89:929-46.
Liu Y, Jesus AA, Marrero B, Yang D, Ramsey SE, Sanchez GA, et al. Activated STING in a vascular and pulmonary syndrome. N Engl J Med 2014;371:507-18.
Youden WJ. Index for rating diagnostic tests. Cancer 1950;3:32-5.
Leroux G, Costedoat-Chalumeau N, Brihaye B, Cohen-Bittan J, Amoura Z, Haroche J, et al. Treatment of relapsing polychondritis with rituximab: a retrospective study of nine patients. Arthritis Rheum 2009;61:577-82.
Stabler T, Piette JC, Chevalier X, Marini-Portugal A, Kraus VB. Serum cytokine profiles in relapsing polychondritis suggest monocyte/macrophage activation. Arthritis Rheum 2004;50:3663-7.
Moulis G, Pugnet G, Costedoat-Chalumeau N, Mathian A, Leroux G, Boutemy J, et al. Efficacy and safety of biologics in relapsing polychondritis: a French national multicentre study. Ann Rheum Dis 2018;77:1172-8.
Farhat R, Clavel G, Villeneuve D, Abdelmassih Y, Sahyoun M, Gabison E, et al. Sustained remission with tocilizumab in refractory relapsing polychondritis with ocular involvement: a case series. Ocul Immunol Inflamm 2020;29:9-13.
Henes JC, Xenitidis T, Horger M. Tocilizumab for refractory relapsing polychondritis-long-term response monitoring by magnetic resonance imaging [letter]. Joint Bone Spine 2016;83:365-6.
Kawai M, Hagihara K, Hirano T, Shima Y, Kuwahara Y, Arimitsu J, et al. Sustained response to tocilizumab, anti-interleukin-6 receptor antibody, in two patients with refractory relapsing polychondritis [letter]. Rheumatology (Oxford) 2009;48:318-9.
Meshkov AD, Novikov PI, Zhilyaev EV, Ilevsky ID, Moiseev SV. Tofacitinib in steroid-dependent relapsing polychondritis. Ann Rheum Dis 2019;78:e72.
Fay ME, Myers DR, Kumar A, Turbyfield CT, Byler R, Crawford K, et al. Cellular softening mediates leukocyte demargination and trafficking, thereby increasing clinical blood counts. Proc Natl Acad Sci U S A 2016;113:1987-92.