Abstract Anti-synthetase syndrome (ASS) is an autoimmune condition defined by the presence of anti-aminoacyl-tRNA synthetase antibodies and clinical features such as interstitial lung disease (ILD), myositis, arthritis, and mechanic’s hands. Among these antibodies, anti-EJ has a particularly strong association with ILD, which can be the predominant one. Diagnosis requires a high clinical suspicion and comprehensive serology, especially in patients with idiopathic interstitial pneumonia. The following case illustrates a complex presentation of ASS. A 59-year-old woman with a 25-pack-year smoking history presented for evaluation of progressive dyspnea over one year. Her condition worsened significantly following a hospitalization for pneumonia, requiring discharge on 4 L/min supplemental oxygen. Despite this, her symptoms progressed, prompting a specialist referral. She reported severe exertional dyspnea, a productive cough, xerostomia, and profound difficulty performing activities of daily living. Physical examination revealed bilateral lower-lobe crackles and digital skin changes. Pulmonary function testing demonstrated a restrictive ventilatory defect with a severely reduced diffusing capacity for carbon monoxide (DLCO). High-resolution computed tomography (HRCT) of the chest showed findings consistent with nonspecific interstitial pneumonia (Fig.1). Autoimmune serology was positive for anti-EJ, anti-RNA Polymerase III, anti-RNP, anti-SS-A, ANA and rheumatoid factor. The combination of anti-EJ antibody and ILD confirmed the diagnosis of ASS as the dominant driver of her severe pulmonary involvement. The additional antibodies defined a severe overlap connective tissue disease, incorporating features of systemic sclerosis (anti-RNA Polymerase III) and mixed connective tissue Disease (anti-RNP). Her clinical course was complicated by progressive hypoxic respiratory failure, with oxygen requirements rising to 6 L/min. Echocardiography and right heart catheterization revealed moderate pulmonary hypertension (mean PA pressure 32 mmHg, PVR 4.87 WU), attributed to combined group 1 and group 3 mechanisms. Initial management included methotrexate and prednisone. Over subsequent visits, methotrexate was changed to mycophenolate mofetil for maintenance immunosuppression. This change resulted in significant clinical improvement. Her oxygen requirements decreased to 2 L/min, with markedly improved exercise tolerance. This case illustrates a severe overlap connective tissue disease where ASS is the primary phenotype. It highlights the importance of comprehensive serological testing in guiding diagnosis and management. Aggressive immunosuppression with mycophenolate mofetil was effective, leading to significant clinical stabilization and underscoring the need for a tailored treatment approach in complex connective tissue disease-associated ILD. The patient continues follow-up with the lung transplant and pulmonary hypertension teams, with plans to initiate inhaled treprostinil and participate in pulmonary rehabilitation. This abstract is funded by: none
G et al. (Fri,) studied this question.