Abstract Rationale Idiopathic pulmonary fibrosis (IPF) and fibrotic hypersensitivity pneumonitis (fHP) share overlapping clinical features but, unlike IPF, fHP is characterized by an identifiable antigen and may respond to immunosuppressive therapy, thus making diagnostic precision critical. Serological biomarkers linked to pathology may assist in this distinction. Epithelial injury is believed to initiate the IPF pathogenesis, damaging the underlying basement membrane (BM). Type IV collagen is a key component of BMs, and its remodeling encompasses formation and matrix metalloproteinase-mediated degradation processes, which release protein fragments into circulation. These can be quantified by serum PRO-C4 (formation) and C4M (degradation). Biomarkers reflecting type IV collagen remodeling have previously been explored as prognostic and pharmacodynamic biomarkers in IPF. The aim was to understand the clinical value of PRO-C4 and C4M and their potential as tools to differentiate between fHP and IPF. Methods NordicPRO-C4TM and nordicC4MTM were measured by competitive immunoassays in serum from fHP (n = 21) and IPF (n = 43) patients from Aarhus University Hospital. Associations to forced vital capacity (FVC%) and 6-minute-walk test distance (6MWTD) were also assessed. Patients were stratified into high and low groups according to their median type IV collagen formation or degradation level. A combined variable was created for each patient based on their number of biomarkers above the respective median (0,1 or 2). Data were analyzed using linear regression models adjusted for age and sex. Results Serum C4M (IPF; median 31.70ng/mL, HP; 27.01ng/mL, p = 0.04), but not PRO-C4 (IPF; 147.26 ng/mL, HP; 128.49ng/mL, p = 0.28), was significantly elevated in IPF compared to fHP. fHP patients with high serum PRO-C4 had significantly higher FVC% (Low; 83.1%, High; 104.5%, p = 0.027) and 6MWTD scores (Low; 443m, High; 522m, p = 0.009) compared to patients with low PRO-C4. In the combined analysis, the IPF patient group with both biomarkers above median had significantly lower 6MWT distance compared to those with no high biomarkers (0 high biomarkers; 489m, 2 high biomarkers; 410m, p = 0.015). Neither PRO-C4 nor C4M showed significant individual associations with FVC% or 6MWTD in IPF. Conclusion Baseline serum C4M could distinguish between fHP and IPF. Higher serum PRO-C4 was associated with a less severe fHP disease, whereas IPF patients with both PRO-C4 and C4M levels above their respective medians showed greater disease severity . These findings suggest distinct patterns of type IV collagen remodeling across fHP and IPF. Following further validation, type IV collagen remodeling biomarkers may aid in the diagnostic distinction between fHP and IPF. This abstract is funded by: Nordic Bioscience
Christoforidou et al. (Fri,) studied this question.