Evaluating the etiology of interstitial lung disease (ILD) commonly involves ordering a myositis panel containing myositis-specific antibodies (MSAs), including anti-NXP-2. However, little is known about the presentation of patients with ILD and anti-NXP-2 positivity. We sought to define the course of anti-NXP-2-positive ILD in order to guide prognosis and potential treatment strategies.

We performed a retrospective chart review of patients with positive anti-NXP-2 antibodies who presented to two ILD referral centers in Boston, MA between 2012-2024. Patients were identified by query of the electronic medical record for patients positive for anti-NXP-2. We included those anti-NXP-2 positive patients with ILD on chest computed tomography (CT). Data regarding clinical presentation and disease course were abstracted from the medical record. For patients following longitudinally in the ILD clinic, we conducted survival analyses for ILD progression (composite of PFT progression, hospitalization, or death) using Kaplan-Meier curves and log-rank tests. Additionally, we used a Cox proportional-hazards model, adjusting for age, gender, forced vital capacity (FVC) at baseline, and immunosuppression to calculate hazard ratios. ILD patients with MSA-positive, NXP-2-negative ILD served as the comparator group.

31 patients were identified (mean 70 years, SD 9). Three were diagnosed with dermatomyositis (DM) prior to presentation, but the remaining had ILD as the only manifestation of connective tissue disease. Most (97%) patients were symptomatic with dyspnea and/or cough at presentation. Other autoantibody positivity was common; only 42% were positive for anti-NXP-2 alone without positivity for other autoimmune serologies, including MSAs known to be associated with ILD. Clinical follow up data were available for 28 patients for a median follow up period of 24 months (range <1 month-13 years). A majority (61%) were treated with immunosuppression, antifibrotics, or both. Over one third experienced acute exacerbation of ILD or death (N = 11, 35%). Progression-free survival was similar to that of other MSA-positive ILD patients, regardless of whether anti-NXP-2 was positive alone or co-positive for other autoantibodies.

We present the largest single series of anti-NXP-2-positive ILD. Anti-NXP-2-positive ILD can occur in the absence of DM/PM and can manifest as progressive pulmonary disease that is similar to other MSA-positive ILDs.