Introduction: Antisynthetase syndrome (ASyS) is a rare autoimmune disorder belonging to the spectrum of idiopathic inflammatory myopathies, with an estimated incidence of 0.56 cases per 100,000 person-years and a prevalence of 9.21 per 100,000 inhabitants. It is characterized by the presence of autoantibodies directed against aminoacyl-tRNA synthetases. Among them, the anti-PL-7 antibody is uncommon and is associated with a high frequency of severe interstitial lung disease (ILD) and an unfavorable prognosis.

Case Presentation: We report the case of a 41-year-old man with no significant past medical history who presented with proximal muscle weakness and elevated muscle enzymes, findings consistent with inflammatory myopathy. He was initially treated with corticosteroids and cyclophosphamide, followed by maintenance therapy with azathioprine. Several months later, during a subsequent hospitalization, he developed progressive dyspnea and was diagnosed with antisynthetase syndrome (ASyS) with anti-PL-7 positivity, confirmed through an extended myopathy antibody panel, associated with interstitial lung disease (ILD), pulmonary hypertension, and signs of myopathy. Immunosuppressive therapy was adjusted, but with poor clinical response, leading to progression of ILD and worsening pulmonary hypertension. A new therapeutic adjustment with cyclophosphamide was initiated, achieving clinical stability and hospital discharge.

Conclusions: This case highlights the importance of early clinical suspicion and an aggressive therapeutic approach in antisynthetase syndrome (ASyS), particularly in the presence of the anti-PL-7 antibody, a marker of poor prognosis and strong association with interstitial lung disease (ILD). Timely identification of this variant allows for individualized immunosuppressive management and may improve patients’ clinical outcomes. This report underscores the need to include anti-PL-7 serology in the evaluation of patients with ILD of undetermined cause.