VEXAS syndrome as a new differential diagnosis of late onset spondyloarthritis

Article title: Syndrome VEXAS comme nouveau diagnostic différentiel de la spondyloarthrite du sujet âgé

First author: Jain H

Journal: MEDITERRANEAN JOURNAL OF RHEUMATOLOGY

Link to the article: https://pubmed.ncbi.nlm.nih.gov/39463879/

Author of the abstract: Philippe Mertz

VEXAS syndrome (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) is an autoinflammatory disease associated with somatic mutations in the UBA1 gene, mainly observed in people over the age of 50. This gene encodes a key enzyme in the ubiquitination process, whose dysfunction leads to the activation of several inflammatory pathways. Signs suggestive of VEXAS syndrome include macrocytic anemia, neutrophilic dermatoses (such as Sweet's syndrome), pulmonary and ophthalmological involvement, thrombosis, and various rheumatological manifestations. The latter often present as arthralgia or mono-, oligo-, or polyarthritis.

Spondyloarthritis in older individuals is a rare condition that can be axial and/or peripheral, with an inflammatory component that is often more pronounced than in younger individuals. It requires the elimination of certain specific differential diagnoses, including microcrystalline rheumatism, rhizomelic pseudo-polyarthritis, giant cell arteritis, and paraneoplastic rheumatism.

The authors report the case of a 67-year-old man living in India with peripheral polyarthritis associated with chronic inflammatory low back pain. Skin lesions had also been observed for a month, and biopsy revealed neutrophilic dermatosis, which responded well to corticosteroid therapy. Rheumatological tests showed the presence of HLA B27, active bilateral sacroiliitis on MRI, synovitis of the wrists, and bilateral retrocalcaneal bursitis. Initial treatment with sulfasalazine and NSAIDs failed, and the introduction of methotrexate at 15 mg/week was also ineffective. Further investigations revealed macrocytic anemia (Hb = 8.3 g/dL, MCV = 106 fL) associated with a biological inflammatory syndrome (CRP = 38 mg/L). These abnormalities led to Sanger sequencing of the UBA1 gene, confirming the diagnosis of VEXAS syndrome due to the p.Met41Leu mutation. Corticosteroid therapy combined with sulfasalazine at 1 mg/day controlled the joint symptoms.

Two other cases of spondyloarthritis in older patients associated with VEXAS syndrome have been reported:

A 57-year-old man living in France, presenting with a similar clinical picture, including peripheral polyarthritis, bilateral sacroiliitis, HLA-B27 positivity, and biological inflammatory syndrome (2). When the first inflammatory symptoms appeared at the age of 57 in 2010, treatment with anti-TNF alpha initially provided good control of the symptoms. Subsequently, he developed acute anterior uveitis, chondritis of the ear and nose, chronic inflammatory bowel disease (IBD), and neutrophilic dermatosis. Several lines of treatment were attempted without lasting success, including methotrexate, azathioprine, cyclophosphamide, baricitinib, infliximab, tocilizumab, anakinra, and ustekinumab. Finally, a combination treatment of intravenous immunoglobulins (2 g/kg every 4 weeks) and secukinumab (300 mg every 4 weeks) proved effective. The diagnosis of VEXAS syndrome associated with the Met41Thr mutation was made retrospectively in 2020.

A 74-year-old Caucasian man with a recent history of venous thrombosis in the lower limbs presented with inflammatory low back pain with bilateral sacroiliitis on MRI, macrocytic anemia (Hb = 8.8 g/dL and MCV = 101 fL), but without significant biological inflammatory syndrome (3). He subsequently developed progressive anemia (Hb = 8.5 g/dL and MCV = 100 fL), purpura of the lower limbs, erythema nodosum, and chondritis of the ear. He was diagnosed with VEXAS syndrome associated with the Met41Thr mutation of the UBA1 gene. After several treatments failed, including tocilizumab complicated by abscessed diverticulitis, azacitidine at the standard dose of 75 mg/m²/day led to a significant reduction in corticosteroid therapy (from 40 mg/day to 5 mg/day) and clinical improvement of symptoms.

The manifestations of VEXAS syndrome are varied and still poorly defined. It appears to be one of the new differential diagnoses to consider in cases of spondyloarthritis in older patients, particularly those aged 50 and over, given the age of onset of VEXAS syndrome and especially in the presence of a biological inflammatory syndrome, hematological abnormalities with associated anemia, particularly macrocytic anemia, or other suggestive findings such as neutrophilic dermatosis. An atypical history or the appearance of new extra-rheumatological symptoms, such as venous thrombosis, inflammatory dermatoses (particularly neutrophilic), chondritis, or pulmonary involvement, should also point to this diagnosis. In addition, resistance to initial treatment with NSAIDs may be a warning sign, especially since the hematological abnormalities associated with VEXAS syndrome may appear secondarily.

REFERENCES

Jain H, Roy D, Mavidi S, Haldar S, Mondal S, Bhattacharya P, et al. Elderly Onset Spondyloarthropathy and VEXAS Syndrome: A Case Report. Mediterr J Rheumatol. 2024 Sep;35(3):490–3.

Magnol M, Couvaras L, Degboé Y, Delabesse E, Bulai-Livideanu C, Ruyssen-Witrand A, et al. VEXAS syndrome in a patient with previous spondyloarthritis with a favourable response to intravenous immunoglobulin and anti-IL17 therapy. Rheumatology (Oxford). 2021 Sep 1;60(9):e314–5.

Pereira da Costa R, Sapinho G, Bandeira M, Infante J, Marques T, Mimoso Santos C, et al. Case report: VEXAS syndrome: an atypical indolent presentation as sacroiliitis with molecular response to azacitidine. Front Immunol. 2024;15:1403808.

Syndrome VEXAS comme nouveau diagnostic différentiel de la spondyloarthrite du sujet âgé.p

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Comparing clinical features between males and females with VEXAS syndrome: data from literature analysis of patient reports

Premier auteur: Echerbault et al.

Lien vers l'article: DOI: 10.1093/rheumatology/keae123

Abstract

Objectives: VEXAS syndrome is an autoinflammatory disease associated with a somatic mutation of the X-linked UBA1 gene in haematopoietic progenitor cells. This disorder was originally described as a disease affecting men, but rare cases of VEXAS syndrome in women have since been reported. The theoretical existence of phenotypic sex differences in this X-linked disease is debated. We compared the features of VEXAS syndrome between males and females to better understand this disorder and to improve its diagnostic accuracy in females.

Methods: From previously published clinical descriptions of VEXAS syndrome, we included studies that described patients with precise, individual VEXAS-related features. We formed a literature-based cohort of patients by collecting their clinical and biological data and compared the characteristics of male and female patients.

Results: We gathered 224 patient descriptions from 104 articles: 9 women and 215 men. Among the women, 1 had a constitutional 45,X karyotype and 4 had an acquired X monosomy in the bone marrow karyotype, while the marrow karyotype was not provided for the others. No difference was observed in the clinical or biological features according to sex. We also observed no difference in the type of UBA1 mutation or the association with myelodysplastic syndrome.

Conclusions: Our results supported the hypothesis that the UBA1 mutation should be sought under the same conditions in both sexes. As UBA1 is not subject to X-chromosome inactivation, VEXAS syndrome in females requires both UBA1 mutation and X monosomy, thus explaining the similarity between male and female VEXAS-related features and the lower prevalence of VEXAS syndrome in females.

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Vacuoles in bone marrow progenitors: VEXAS syndrome and beyond.

Valentin Lacombe, Jérome Hadjadj, Sophie Georgin-Lavialle, Christian Lavigne, Franck Geneviève, Olivier Kosmider

Summary :

The presence of vacuoles in myeloid and erythroid progenitor cells in bone marrow aspirates is a key feature of vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome. The mere observation of vacuolated progenitor cells is not specific to VEXAS syndrome; in this Viewpoint, we point out the causes to be considered in this situation. Vacuoles, in particular, can be observed in individuals with wild-type UBA1 and with persistent inflammatoryfeatures or myelodysplastic syndromes.

However, several clues support the diagnosis of VEXAS syndrome in the presence of vacuolated bone marrow progenitors: a high number of vacuolated progenitors and of vacuoles per cell, the predominance of vacuoles in early rather than late progenitors, and the vacuolisation of both myeloid and erythroid progenitors with predominance of myeloid ones. Some criteria derived from these observations have been proposed with great diagnostic performances. However, the absence or a low proportion of vacuolated cells should not prevent UBA1 gene sequencing.

Vacuoles in bone marrow progenitors: VEXAS syndrome and beyond.pdf

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