Molecular characterisation of progressive pulmonary sarcoidosis: protocol for a longitudinal multi-centre study to develop peripheral blood circulating biomarkers for predicting pulmonary sarcoidosis progression

Introduction Sarcoidosis is a heterogeneous granulomatous disease with highly variable clinical trajectories, yet no validated biomarkers exist to distinguish progressive sarcoidosis (P-sarcoidosis) from non-progressive disease (NP-sarcoidosis). This lack of tractable biomarkers limits early risk stratification and impedes therapeutic decision-making. Preliminary data from our group suggest that P-sarcoidosis and NP-sarcoidosis may be differentiated by blood-derived and peripheral blood mononuclear cell (PBMC)-derived molecular signatures, as well as ex vivo granuloma biogenesis in response to putative disease-causing antigens. This protocol describes a multi-omic study aimed at identifying mechanistically grounded, clinically translatable biomarkers that distinguish P-sarcoidosis from NP-sarcoidosis.Methods and analysis We will perform an integrative proteomic and transcriptomic analysis across three biological compartments: ex vivo granuloma model, PBMCs and plasma. Participants with clinically adjudicated P-sarcoidosis or NP-sarcoidosis will provide blood samples for multi-omic profiling. P-sarcoidosis versus NP-sarcoidosis phenotype will be assessed based on changes in spirometry, diffusing capacity for carbon monoxide, chest radiography and need for treatment for pulmonary symptoms. Patient-reported outcomes will also be recorded. Data-driven computational approaches will be used to identify molecular pathways associated with granuloma formation and disease persistence and to develop a classifier that distinguishes P-sarcoidosis from NP-sarcoidosis. Rigorous internal validation, feature-selection procedures and statistical controls for high-dimensional data will be applied. Candidate biomarkers emerging from multi-compartment integration will be prioritised based on biological coherence, reproducibility and clinical feasibility.Ethics and dissemination The study protocol has been approved by the Biomedical Research Alliance of New York, serving as a single Institutional Review Board (IRB) for the project (IRB # 23–02-503), as well as at National Jewish Health (IRB# HS-4091), University of Minnesota (STUDY00020121/SITE00002051) and The Ohio State University (IRB# 2023X0140). All participants will provide informed consent prior to enrolment. Results will be disseminated through peer-reviewed publications, scientific conferences and presentations to patients and advocacy groups. De-identified datasets and analytic workflows will be shared in accordance with institutional policies and data-sharing agreements.