Background: Sarcoidosis is an unpredictable and heterogenous systemic granulomatous inflammatory disease of unknown origin. SAA is an acute-phase protein involved in the regulation of granulomatous inflammation. We aimed to investigate the role of SAA as a biomarker of disease activity and outcome in intrathoracic sarcoidosis.

Methods: We included 80 patients with newly diagnosed intrathoracic sarcoidosis. SAA was measured at baseline and compared with clinical and laboratory parameters, including established biomarkers of disease activity (sACE, IL-2R, CTO, Ca15.3, SP-D, CC16, CCL18, CXCL9, CXCL10), lung function, and radiologic extent of disease. Disease outcome was assessed after 3-5 years using the Clinical Outcome Status (COS) criteria.

Results: Baseline SAA was elevated in 40% of patients and did not correlate with established biomarkers of disease activity, lung function, or radiologic extent of disease. However, SAA correlated with CCL18, a marker of Th2 inflammation and M2 alternatively activated macrophages (Spearman's correlation coefficient 0.45), along with CTO and CXCL10. In a multivariable analysis, SAA was not an independent predictor of progressive disease. However, patients with progressive disease had higher baseline levels of SP-D and CC16 (biomarkers of alveolocapillary barrier damage), more extensive HRCT infiltrates, lung fibrosis and lower FEV1 at baseline.

Conclusions: A minority of patients with intrathoracic sarcoidosis have elevated SAA and CCL18 which may represent a distinct immune phenotype with predominant M2 macrophage inflammation and possible clinical and prognostic implications. These patients could potentially benefit from more targeted therapies.