Idiopathic Pulmonary Fibrosis Associated with Circulating Autoantibodies: A Chinese Cohort of a Long-Term Follow-Up Study
This retrospective cohort study investigated the clinical significance of circulating autoantibodies in patients diagnosed with idiopathic pulmonary fibrosis (IPF) over a nine-year follow-up period. The research aimed to determine whether the presence of autoantibodies in IPF correlates with distinct clinical characteristics, radiological patterns, disease progression, or survival outcomes.
Background and Rationale
Interstitial pneumonia with autoimmune features (IPAF) is a term describing patients with interstitial lung disease (ILD) who exhibit features suggestive of connective tissue disease (CTD) but do not meet formal CTD diagnostic criteria. The IPAF classification incorporates clinical, serological, and morphological domains. Notably, the usual interstitial pneumonia (UIP) pattern on high-resolution computed tomography (HRCT) is excluded from the IPAF morphological criteria. Consequently, patients with UIP and positive autoantibodies lacking additional clinical features of autoimmune disease are classified as having IPF rather than IPAF. Prior studies report that approximately 22% of IPF patients harbor circulating autoantibodies, yet the clinical implications of this finding remain unclear. This study addressed critical gaps by comparing long-term outcomes, radiographic features, and disease behavior between IPF patients with and without autoantibodies.
Study Design and Methodology
The study enrolled 222 IPF patients diagnosed between October 2010 and October 2019 at Nanjing Drum Tower Hospital, China. Diagnoses were established through multidisciplinary review per the 2018 IPF guidelines, requiring exclusion of alternative ILD causes and confirmation of UIP via HRCT or histopathology. Key HRCT features included subpleural/basal predominance, honeycombing, and reticular opacities.
Patients were stratified into two groups: those with positive autoantibodies (n=66, 29.73%) and those without (n=156, 70.27%). Autoantibody panels included antinuclear antibodies (ANAs), rheumatoid factor (RF), and anti-neutrophil cytoplasmic antibodies (ANCAs). Clinical data collected at baseline included demographics, smoking history, laboratory parameters (e.g., immunoglobulin G [IgG], erythrocyte sedimentation rate [ESR]), pulmonary function tests (PFTs), and HRCT findings. Transplant-free survival, defined as time from diagnosis to death, lung transplantation, or last follow-up (censored December 2019), was analyzed.
Key Findings
Baseline Characteristics
The cohort comprised predominantly males (91.44%) with a mean age of 67.85 years. Smoking history was comparable between groups (56.76% overall). Among autoantibody-positive patients, ANAs were most prevalent (53.03%), followed by RF (31.82%) and ANCAs (15.15%).
Laboratory Markers
Autoantibody-positive patients exhibited significantly higher IgG levels (15.55 ± 5.01 g/L vs. 13.32 ± 3.89 g/L, P=0.025) and elevated ESR (median 24.50 mm/h vs. 19.00 mm/h, P=0.049) compared to seronegative counterparts. These findings suggest heightened immune activation in antibody-positive IPF.
Radiographic Features
HRCT analysis revealed traction bronchiectasis more frequently in seronegative patients (21.15% vs. 9.09%, P=0.034). No differences were observed in honeycombing, reticulation, or distribution patterns. The higher prevalence of traction bronchiectasis—a marker of fibrosis severity—in seronegative patients implies potential pathophysiological distinctions between subgroups.
Pulmonary Function and Disease Progression
Baseline PFTs, including forced vital capacity (FVC) and diffusion capacity for carbon monoxide (DLCO), showed no significant differences. Longitudinal analysis using linear mixed models demonstrated comparable rates of FVC and DLCO decline between groups, indicating similar disease progression trajectories.
Treatment Patterns
Immunosuppressive therapies (e.g., corticosteroids, azathioprine) and antifibrotic agents (pirfenidone, nintedanib) were administered at similar frequencies in both groups. Treatment responses did not differ, suggesting autoantibody status does not guide therapeutic decisions in current practice.
Survival Outcomes
Over a median follow-up of 44.57 months, 42.79% of patients died, with three undergoing lung transplantation. Transplant-free survival did not differ between seropositive and seronegative groups (median 18.50 vs. 17.00 months, P=0.238). Kaplan-Meier curves corroborated equivalent survival probabilities (P=0.238), challenging the hypothesis that autoantibodies confer prognostic significance in IPF.
Discussion
Autoantibodies and Immune Dysregulation in IPF
The study reinforces that autoantibodies, particularly ANAs, are common in IPF but lack definitive clinical utility. Elevated IgG and ESR in seropositive patients highlight immune dysregulation, potentially involving Fcγ receptor-mediated pathways or complement activation. However, these serological abnormalities did not translate to distinct phenotypes or accelerated progression.
Radiographic and Pathological Correlations
The higher prevalence of traction bronchiectasis in seronegative patients contrasts with prior IPAF studies, where nonspecific interstitial pneumonia (NSIP) predominates. This discrepancy underscores the need for histopathological comparisons between seropositive and seronegative IPF, as UIP’s exclusion from IPAF criteria may oversimplify autoimmune-associated fibrosis.
Survival and Classification Challenges
Consistent with Collins et al. (2017), this study found no survival difference between IPF patients with or without autoantibodies. This contrasts with Ghang et al. (2019), who associated ANCA positivity with better outcomes, suggesting regional or methodological variability. The findings advocate for refining IPAF criteria to encompass UIP patients with autoimmune features, as current classifications may overlook clinically relevant subgroups.
Limitations
The retrospective design, reliance on HRCT over biopsy, and heterogeneous follow-up intervals limit causal inferences. Additionally, autoantibody titers and specific subtypes (e.g., ANA patterns) were not analyzed, potentially obscuring subtype-specific effects.
Conclusion
This long-term study demonstrates that circulating autoantibodies in IPF are associated with elevated IgG and ESR but do not independently influence disease progression or survival. The findings question the prognostic value of autoantibodies in IPF and highlight the need for revised classification frameworks integrating UIP with autoimmune features. Future research should prioritize prospective designs, histopathological correlations, and mechanistic studies elucidating immune pathways in fibrogenesis.
doi.org/10.1097/CM9.0000000000001834
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