Combined GDF-15 and Lung Ultrasound for Subclinical ILD Screening in Rheumatoid Arthritis and Systemic Sclerosis

Interstitial lung disease (ILD) represents one of the most severe extra-articular and systemic manifestations of Rheumatoid Arthritis (RA) and Systemic Sclerosis (SSc). ILD significantly increases morbidity and remains a leading cause of mortality in both disease entities.

Accumulating evidence demonstrates a high prevalence of subclinical interstitial lung disease, occurring in up to 33% of patients with rheumatoid arthritis and 50% of patients with systemic sclerosis. Therefore, Early detection during this subclinical window is paramount to initiate timely immunomodulatory or antifibrotic therapies before irreversible fibrotic replacement occurs.

Although high-resolution computed tomography (HRCT) of the chest remains the gold standard for diagnosing interstitial lung disease, its high cost and associated radiation exposure restrict its utility as a routine screening tool for all patients, particularly in resource-limited settings. Consequently, there is a clinical demand for a validated, non-invasive, radiation-free, and cost-effective triage tool to screen populations at risk and identify those who genuinely require diagnostic HRCT evaluation.

Growth Differentiation Factor-15 (GDF-15), a stress-responsive cytokine belonging to the Transforming Growth Factor-beta (TGF-β) superfamily, has emerged as a novel systemic biomarker reflective of cellular stress, inflammation, and fibrogenesis . GDF-15 is significantly elevated in active systemic autoimmune conditions such as Behcet disease, Inflammatory bowel disease and Sjogren's disease . Importantly, GDF-15 is overexpressed in pulmonary epithelial cells during active fibrogenesis and serves as a key circulating biomarker in idiopathic pulmonary fibrosis as well as connective tissue disease-associated ILD and pulmonary hypertension.

As a cellular stress cytokine, serum GDF-15 reflects the distinct pathogenetic mechanisms driving ILD in each condition:

RA-ILD: Mucosal citrullination and anti-CCP immune complex deposition 2022induce alveolar epithelial injury and inflammatory cytokine release. Here, elevated GDF-15 primarily reflects acute epithelial stress and immune-mediated inflammatory intensity.

SSc-ILD: Microvascular damage and endothelial apoptosis trigger TGF-β signaling and myofibroblast expansion. Here, GDF-15 acts downstream of TGF-β, reflecting chronic endothelial ischemia and fibrogenesis.

Concurrently, point-of-care Lung Ultrasound (LUS) has revolutionized bedside assessment in rheumatology. LUS detects interstitial pulmonary changes-specifically B-lines and pleural line irregularities-with exceptional sensitivity. Recent evidence highlights that LUS achieves remarkable diagnostic accuracy compared to HRCT in both RA-ILD and SSc-ILD.

While GDF-15 reflects early molecular and cellular fibrotic activity and LUS identifies early structural lung affection, whether combining these two non-invasive modalities yields superior diagnostic accuracy for subclinical ILD screening compared to either modality alone remains unexplored. Combining a molecular circulating marker with a physical point-of-care imaging tool could establish a robust triage model for outpatient rheumatology clinics. Therefore, this is a diagnostic accuracy study to determine the outcomes of this combination.

Inclusion criteria

• Adult patients (≥18 years) with confirmed diagnosis of RA or SSc.
• Absence of overt, unexplained respiratory symptoms (e.g., severe resting dyspnea, chronic cough) or known diagnosed clinical ILD (subclinical population).

Exclusion criteria

• Active respiratory tract infection or acute exacerbation of pulmonary disease.
• Other causes of pulmonary fibrosis such as history of heavy smoking (>15 pack-years) or significant environmental/occupational exposure known to induce pulmonary fibrosis.
• Pre-existing primary chronic lung diseases (e.g., COPD, bronchial asthma, active tuberculosis, severe bronchiectasis).