A case of VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) with decreased oxidative stress levels after oral prednisone and tocilizumab treatment

Abstract

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome has recently been described as an autoinflammatory disease associated with severe adult-onset inflammatory manifestations. The various clinical manifestations include recurrent high-grade fever, neutrophilic dermatoses, cutaneous vasculitis, chondritis of the ear and nose, pulmonary infiltrates, cytopenia, uveitis, gastrointestinal pain or inflammation, aortitis, hepatosplenomegaly, and hematological disorders. VEXAS syndrome is caused by somatic mutations of the ubiquitin-like modifier activating enzyme 1 (UBA1) gene in myeloid-lineage cells. It is characterized by vacuolated myeloid and erythroid progenitor cells seen by bone marrow biopsy. We report the case of a 64-year-old Japanese man with VEXAS syndrome. At age 63, he was referred to us with a recurrent erythema on the hands associated with a general fever of 38–40°C that had persisted for 4 or 5 days and had recurred about once a month for a year. The skin rash appeared 2 or 3 days after the onset of each fever episode. Computed tomography (CT) of the chest revealed bilateral hilar lymphadenopathy (BHL), and the mediastinal lymph nodes were swollen. Sarcoidosis was suspected but was ruled out by several tests. Laboratory examinations showed elevated inflammatory markers. Bone marrow examination showed the vacuolization of myeloid precursor cells. A skin biopsy revealed dense dermal, predominantly perivascular, infiltrates. These consisted of mature neutrophils admixed with myeloperoxidase-positive CD163-positive myeloid cells, lymphoid cells and eosinophils. Sequencing analysis identified the somatic UBA1 variant c.122T > C, which results in p.Met41Thr. Treatment with oral prednisone (15 mg/day) and monthly intravenous tocilizumab injections (400 mg) completely resolved the symptoms. Neutrophils are a major source of reactive oxygen species, and the present case demonstrated numerous neutrophilic infiltrates. We hypothesize that the patient might have had elevated derivatives of reactive oxygen metabolites (d-ROMs). d-ROM quantification is a simple method for detecting hydroperoxide levels, and clinical trials have proven it useful for evaluating oxidative stress. In this study, we measured serum d-ROM before and after oral prednisone and tocilizumab treatment. The levels decreased significantly during treatment.

Case report: Schnitzler-like syndrome without monoclonal gammopathy

“…However, a genetic analysis failed to establish an association of Schnitzler`s syndrome with germline or somatic mutations in the NLRP3 gene locus except in rare individual cases ( 15 , 18 , 25 – 28 ). Nevertheless, it is probable that Schnitzler’s syndrome is caused by an acquired mutation, like in VEXAS syndrome ( 29 , 30 ), or in acquired Familial Mediterranean Fever ( 31 ) and acquired NLRC4-associated CAPS ( 32 ). Interestingly, a somatic NLRP3 mutation (NLRP3: c.1709A>G (p.Tyr570Cys)) identical to that reported in a Neonatal Onset Multisystem Inflammatory Disease (NOMID, or Chronic Infantile Neurological, Cutaneous and Articular Syndrome, CINCA) case was also found in a patient with a clinical picture closely resembling Schnitzler’s syndrome, and without gammopathy and without bone pain like in our patient ( 22 ).…”

VEXAS Syndrome—Diagnostic Clues for the Dermatologist and Gaps in Our Current Understanding: A Narrative Review

“…VEXAS was initially characterized in a group of 25 adult men ( Beck et al, 2020 ), though there may be important differences in disease presentation in different demographic populations. As of June 2023, 167 distinct morphologic images of the skin and eyes had been published ( Afsahi et al, 2023 ; Alhomida et al, 2021 ; Argobi, 2022 ; Balu et al, 2023 ; Beaumesnil et al, 2022 ; Beck et al, 2020 ; Beecher et al, 2022 ; Bert-Marcaz et al, 2022 ; Ciprian, 2022 ; Collantes-Rodríguez et al, 2023 ; Cordts et al, 2022 ; Dehghan et al, 2021 ; Euvrard et al, 2021 ; Ferrada et al, 2021 ; Goyal et al, 2022 ; Hage-Sleiman et al, 2021 ; Himmelmann and Brücker, 2021 ; Islam et al, 2022 ; Khosravi-Hafshejani et al, 2022 ; Koster et al, 2021 ; Koster and Warrington, 2021 ; Lacombe et al, 2022 ; Lacombe et al, 2021a ; Legeas et al, 2023 ; Loschi et al, 2022 ; Lötscher et al, 2021 ; Magnol et al, 2021 ; Martin-Nares et al, 2022 ; Matsubara et al, 2022 ; Matsuki et al, 2022 ; Matsumoto et al, 2022 ; Mohammed et al, 2023 ; Neupane et al, 2022 ; Nguyen et al, 2022 ; Oganesyan et al, 2021 ; Pàmies et al, 2022 ; Raaijmakers et al, 2021 ; Ribereau-Gayon et al, 2022 ; Shaukat et al, 2022 ; Shimizu et al, 2022 ; Skowron et al, 2023 ; Staels et al, 2021 ; Sterling et al, 2022 ; Stiburkova et al, 2023 ; Takahashi et al, 2021 ; Topilow et al, 2022 ; Tozaki et al, 2022 ; Tsuchida et al, 2021 ; Valor-Méndez et al, 2023 ; van der Made et al, 2022 ; van Leeuwen-Kerkhoff et al, 2022 ;…”

Diacron-Reactive Oxygen Metabolites Levels Are Initially Elevated in Patients with Bullous Pemphigoid

“…Although they are important in many biological processes, they can also cause cellular damage by affecting lipids, DNA, RNA, and proteins. The balance of ROS is crucial for normal physiological function, and an imbalance can lead to oxidative stress and various diseases ( Hitomi et al, 2022 ; Pigazzani et al, 2022 ; Tozaki et al, 2022 ).…”