Recurrent Lymphocytic Pleural Effusions as an Atypical Presentation of VEXAS Syndrome: A Case Report

Background VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a recently described adult-onset autoinflammatory disorder caused by somatic mutations in the UBA1 gene. The condition predominantly affects men over 50 years of age and manifests with heterogeneous rheumatologic, dermatologic, hematologic, and systemic inflammatory features. Pulmonary manifestations occur in over half of patients, but pleural effusions are relatively uncommon.[1] Given its clinical heterogeneity and overlap with autoimmune, infectious, and hematologic diseases, diagnosis remains challenging and relies on genetic confirmation of UBA1 mutations.

Case Report A 60-year-old man presented with a 1-year history of non-productive cough, dyspnea, pleuritic chest pain, fatigue, night sweats, and 10 kg unintentional weight loss. He reported intermittent left ankle swelling, bilateral stiffness, and 2 episodes of unilateral periorbital edema responsive to short prednisone courses. Laboratory investigations revealed mild macrocytic anemia (hemoglobin 121 g/L, MCV 97.6 fL) and elevated C-reactive protein (38.7 mg/L). Autoimmune and infectious workup, including ANA, ANCA, rheumatoid factor, and extensive infectious serologies, were negative. Imaging demonstrated recurrent right-sided pleural effusions without evidence of malignancy. Thoracentesis yielded a lymphocyte-predominant exudative effusion (80% lymphocytes), with negative cultures and cytology. A subsequent contralateral pleural effusion showed similar findings. Flow cytometry identified a minor B-cell population without definitive lymphoproliferative disorder. Bone marrow biopsy revealed hypercellular marrow with trilineage hematopoiesis, megakaryocytic dysplasia, and mild fibrosis, but no lymphoma. Next-generation sequencing identified a somatic UBA1 p.Met41Thr (c.122T>C) mutation (variant allele fraction 76.6%), confirming VEXAS syndrome, along with a concurrent DNMT3A frameshift mutation (VAF 39.7%) consistent with clonal hematopoiesis. The patient was treated with oral prednisone 30-40 mg daily, resulting in complete resolution of inflammatory arthritis, improvement of constitutional symptoms, and normalization of inflammatory markers after 4 weeks. He was subsequently referred for initiation of ruxolitinib as a steroid-sparing agent.[2]

Conclusion This case highlights VEXAS syndrome as a diagnostic consideration in older men with persistent systemic inflammation, recurrent lymphocytic pleural effusions, episodic arthritis, and periorbital edema in the absence of infection, malignancy, or autoimmune disease. Pleural effusions, although uncommon, may be the primary pulmonary manifestation. Comprehensive evaluation, including next-generation sequencing for UBA1 mutations, is essential for accurate diagnosis and facilitates targeted management with glucocorticoids and steroid-sparing agents. Early recognition improves outcomes and underscores the need for multidisciplinary care.

References [1.] Al-Hakim A. Rheumatology (Oxford) 2025;64:5217-29. [2.] Heiblig M. Blood 2022;140:927-31.