VEXAS Syndrome in a Moroccan Patient: A Story of a Two-year Diagnostic Lag

doi:10.21203/rs.3.rs-4999965/v1

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Case Report

VEXAS Syndrome in a Moroccan Patient: A Story of a Two-year Diagnostic Lag

https://doi.org/10.21203/rs.3.rs-4999965/v1

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Background: VEXAS syndrome, also known as Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome, is a newly identified genetic condition characterized by a combination of autoinflammatory symptoms and myeloid dysplasia. The initial description was documented in 2020, and since then, there has been an increasing number of cases and series reported globally.

Case presentation: In this report, we present a case of VEXAS syndrome in an 88-year-old male patient. The patient has a p.Met41Val mutation in the UBA1 gene, with notable skin, joint, and lung involvement. As far as we know, this is the first documentation of VEXAS syndrome in Morocco and Africa. This condition may exhibit characteristics of recurrent fever, neutrophilic dermatitis, arthritis, and chondritis, along with cytopenias and myelodysplastic syndrome. The p.Met41Val mutation is known to be associated with severe clinical presentation and poor prognosis, with less chondritis involvement and more undifferentiated inflammatory syndrome, as seen in the described case.

Conclusions: Vexas syndrome represents a prototype for a new classification of diseases, although it is still insufficiently identified in many underdeveloped countries, especially in Africa, it should be considered in elderly males with unexplained fever associated with systemic manifestations and worsening hematologic abnormalities.

VEXAS syndrome

myelodysplastic syndrome

autoinflammation

immune dysregulation

genetics

Myelodysplastic syndrome is frequently linked to autoimmunity and inflammation, to the point where it can be considered that myelodysplastic syndrome and autoimmune disorders are two sides of the same coin and share the exact underlying mechanisms [1]. Dysregulation of the immunological environment and impaired levels of inflammatory cytokines, such as tumor necrosis factor-α, interferon-γ, interleukin (IL)-6, IL-8, and IL-17, appear to play a pivotal role in the pathogenesis of the disease [2]. In this context, VEXAS syndrome stands out as a notable example.

VEXAS syndrome stands for Vacuoles, E1 Enzyme, X-linked, Auto-inflammatory, and Somatic. This syndrome is a newly identified condition resulting from a mutation in the UBA1 gene. It causes an acquired auto-inflammatory disease in adults. VEXAS was first reported in 2020 in 25 men with adult-onset inflammatory disease and myeloid dysplasia [1].

Clinical manifestations vary widely and are characterized by inflammatory and hematological involvement, defining a new category of hemato-inflammatory disease [2]. The most common signs include fever, skin lesions, arthritis, chondritis, cytopenias (macrocytic anemia, thrombocytopenia), infiltrative lung disease, and venous thrombosis [3].

Systemic involvement is important because it makes other diagnoses like polyarteritis nodosa, relapsing polychondritis, or sweet syndrome more likely [3].

It causes significant morbidity and reduced life expectancy, and the standards of care remain undefined, but interest in this newly described disease is worldwide [2].

This article describes the first case of VEXAS syndrome reported in Morocco and Africa to the best of our knowledge, where the impact of the clinician’s flair and the crucial contribution of genetics to diagnosis are underscored. The patient’s written consent was obtained.

We report the case of an 88-year-old patient initially admitted to intensive care for febrile respiratory distress. His medical history included high blood pressure and a COVID-19 infection the previous year.

The history of the disease dates back a few weeks, with the onset of an anemic syndrome, bone pain, and oedematous polyarthritis (RS3PE-like) in the context of a deteriorating general condition.

While in the hospital, he had recurrent febrile spikes with no individualized germ. He also had painful erythematous skin lesions (figure 1) and oedematous polyarthritis (figure 2).

The biological workup showed macrocytic anemia and lymphopenia. There was a significant inflammatory syndrome with a C-reactive protein of 240 mg/L, elevated ferritinemia, hypoalbuminemia, hyper-alpha 1/alpha 2 proteins, and polyclonal hypergammaglobulinemia on protein electrophoresis. All tests for infectious markers have shown negative results.

The levels of C3 and C4 were within the normal range, and the immunological testing, which included tests for anti-nuclear antibodies, rheumatoid factor, anti-citrullinated protein antibodies, and anti-proteinase 3/MPO antibodies, yielded negative results. The levels of vitamins B9 and B12 were normal.

A temporal artery ultrasound did not find signs of temporal arteritis. A thoracic-abdominal-pelvic CT scan was performed to search for a possible neoplastic cause, finding diffuse interstitial lung disease (figure 3).

18F-FDG PET/CT images (figure 4 and 5) demonstrated intense FDG uptake in the bone marrow with bilateral basal pulmonary hypermetabolism associated with non-hypermetabolic pleurisy.

He was prescribed empirical antibiotherapy and corticosteroids, and then he was released from the hospital.

During the follow-up of 18 months, he had many flares (repeated fevers, cutaneous and joint inflammatory manifestations, and persistent anemia). The patient exhibited the clinical profile of VEXAS syndrome, including being male, having an age of onset between the fifth and seventh decade, experiencing macrocytic anemia, and displaying systemic inflammatory characteristics. Since the genetic confirmation was delayed due to the non-availability of genetic tests in our settings, the patient was treated periodically with corticosteroids with a temporary improvement.

A bone marrow biopsy showed no tumor infiltration or granuloma, only generalized oedematocongestive changes. No vacuoles were detected in the anatomopathological examination of the bone marrow.

Nevertheless, the presence of cytopenias, fever, and skin lesions in addition to the persistent inflammatory syndrome indicated a potential diagnosis of VEXAS syndrome.

Genetic analysis was finally carried out, and the sample was analyzed abroad, revealing a mutation affecting methionine-41of the UBA1 gene (c.121 A>G; p.Met41 valine [Val]), and we made a final diagnosis of VEXAS syndrome.

Presently, the patient consistently attends our clinic for routine examinations. The patient is stabilized with corticosteroids and colchicine.

In October 2020, a group of researchers led by D.B. Beck identified and described a novel autoinflammatory syndrome, which they named "VEXAS syndrome" (Vacuoles, E1 enzyme, X-linked, Auto-inflammatory, Somatic) [3]. To identify this new disease, they used a technique not yet widely employed in genetics. Typically, new mutations are identified through exome analysis, preferably in a trio setting with the index case and its parents. In this study, the authors have employed a genotype-driven strategy to bypass the challenging analysis of phenotypes. They begin by identifying genotypic communities within potentially relevant genes. In the original study, the authors focused on the ubiquitination genes, including UBA1, in US exome databases. They identified 3 patients with an acquired mutation inactivating UBA1. Once the mutation had been identified, they searched specifically for it in patients belonging to unidentified autoinflammatory disease cohorts. They found 25 patients whose phenotypic analysis showed similarities [3]. Numerous publications have followed the initial description of the disease worldwide [4-10], except for the African region. We report here the first Moroccan and African case of VEXAS syndrome in the area. The diagnosis delay was about 2 years.

The pathophysiological mechanism of VEXAS syndrome is based on altered ubiquitination (3), a protein activation process playing a central role in intracellular signaling and DNA repair, usually mediated by the enzymes E1 (of which there is only one sub-form), E2 and E3 (of which there are over 600 sub-forms) [3]. The formation of this E1 enzyme is usually ensured by the expression of the UBA1 gene, which has both nuclear and cytoplasmic expression. Mutation of the cytoplasmic isoform (UBA1b) leads to a ubiquitination defect in affected cells (unfolded protein response, autophagy dysregulation), as well as the appearance of cytoplasmic vacuoles typical of the disease [3].

Due to this intrinsic dysregulation, VEXAS patients display high levels of proinflammatory cytokines in their peripheral blood, including IL-1 and IL-18. This indicates the activation of the inflammasome and the dysregulation of myeloid cells. Gene expression studies show an increase in the activity of TNF- and NF-κB signaling pathways, which may be responsible for promoting cell death and inflammation [11].

Three mutations have been identified in methionine-41 (p.Met41 Leu/Thr/Val), resulting in the expression of a non-functional isoform responsible for variable clinical phenotypes [11]. Our patient presented with a missense mutation p.Met41/Val, and he is more likely to have a more severe prognosis. Recent studies [4,12] have shown that patients with the p.Met41/Val mutation have a lower survival rate (approximately 76.7% after five years) compared to the group of patients with p.Met41 Leu mutations.

Clinically, the patient exhibited two distinct features: joint manifestations resembling RS3PE arthritis and pulmonary infiltrates leading to severe respiratory distress, which was the main reason for his hospital admission.

Joint involvement is frequent, with arthralgia and/or arthritis. Although it is often reported in the literature, it remains poorly described. VEXAS syndrome can mimic or be associated with different rheumatologic diseases such as erosive rheumatoid arthritis, HLA-B27 spondyloarthritis [13], systemic lupus [14] or still disease [15]...

Lung involvement is frequently observed in individuals with VEXAS syndrome. A meta-analysis has included 269 patients with VEXAS syndrome. The most commonly described pulmonary manifestation was infiltrates (43.1%; n = 116), followed by pleural effusion (7.4%n = 2020) and idiopathic interstitial pneumonia (3.3%; n = 9) [16]. Pulmonary manifestations in VEXAS syndrome seem non severe, responsive to corticosteroids [16], and do not lead to pulmonary fibrosis [17].

Frequent cases of chondritis, particularly in the ears and nose, have been described in a third of VEXAS cases, but this feature was absent in our patient. This cartilage damage seems less associated with the UBA1 p.Met41Val mutation [5,11,1218].

This case demonstrates a significant delay in diagnosis of almost two years, despite a high level of clinical suspicion for VEXAS syndrome. The delay can be attributed to the inadequate knowledge and expertise of our anatomopathologists and hematologists regarding this new condition, along with the lack of modern genetic testings. Furthermore, genetic testings are currently not included in health insurance coverage in our country.

Vexas syndrome serves as a model for a novel category of illnesses, yet it remains insufficiently diagnosed in numerous developing nations, particularly in Africa. This is primarily attributed to the absence of accessible genetic testings and the limited awareness of this disease among internists, rheumatologists, hematologists, and anatomopathologists.

However, it is crucial to assess elderly male patients who have long-lasting or recurring fevers associated with different systemic symptoms and worsening blood abnormalities, a lack of response to treatment, and a need for high doses of glucocorticoids, as they may potentially have VEXAS.

Ethics approval and consent to participate:

Informed and written consent has been obtained from the patient. This report have been performed in accordance with the Declaration of Helsinki.

Consent for publication:

Consent for publication was obtained from the patient.

Availability of data and materials:

All data generated or analysed during this study are included in this published articleThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request

Competing interests:

The authors declare that they have no competing interests

Funding:

No funding was obtained

Authors’ contribution:

AA analyzed the patient data and drafted the manuscript. HH analyzed and interpreted the patient data regarding the hematological abnormalities. LZ was a participant in the redaction of the manuscript. DK collected and analyzed the patient data. AN revised the manuscript. AAB analyzed and interpreted the patient data regarding the immunological dysregulation. All authors read and approved the final manuscript

Acknowledgements:

All authors acknowledge Dr Amine Azzaz for his assistance in providing us with articles published about VEXAS syndrome.

Hochman MJ, DeZern AE. Myelodysplastic syndrome and autoimmune disorders: two sides of the same coin? Lancet Haematol. 1 juill 2022;9(7):e523‑34.
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Guerrero-Bermúdez CA, Cardona-Cardona AF, Ariza-Parra EJ, Arostegui JI, Mensa-Vilaro A, Yague J, et al. Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome (VEXAS syndrome) with prominent supraglottic larynx involvement: a case-based review. Clin Rheumatol. nov 2022;41(11):3565‑72.
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Delplanque M, Aouba A, Hirsch P, Fenaux P, Graveleau J, Malard F, et al. USAID Associated with Myeloid Neoplasm and VEXAS Syndrome: Two Differential Diagnoses of Suspected Adult Onset Still’s Disease in Elderly Patients. J Clin Med. 27 nov 2021;10(23):5586.
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No competing interests reported.

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VEXAS Syndrome in a Moroccan Patient: A Story of a Two-year Diagnostic Lag

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