Biomarkers in the Diagnosis and Prognosis of Sarcoidosis: Current Use and Future Prospects

Abstract

Sarcoidosis is a heterogeneous disease in terms of presentation, duration, and severity. Due to this heterogeneity, it is difficult to align treatment decisions. Biomarkers have proved to be useful for the diagnosis and prognosis of many diseases, and over the years, many biomarkers have been proposed to facilitate diagnosis, prognosis, and treatment decisions. Unfortunately, the ideal biomarker for sarcoidosis has not yet been discovered. The most commonly used biomarkers are serum and bronchoalveolar lavage biomarkers, but these lack the necessary specificity and sensitivity. In sarcoidosis, therefore, a combination of these biomarkers is often used to establish a proper diagnosis or detect possible progression. Other potential biomarkers include imaging tools and cell signaling pathways. Fluor-18-deoxyglucose positron emission tomography and high-resolution computed tomography have been proven to be more sensitive for the diagnosis and prognosis of both pulmonary and cardiac sarcoidosis than the serum biomarkers ACE and sIL-2R. There is an upcoming role for exploration of signaling pathways in sarcoidosis pathogenesis. The JAK/STAT and mTOR pathways in particular have been investigated because of their role in granuloma formation. The activation of these signaling pathways also proved to be a specific biomarker for the prognosis of sarcoidosis. Furthermore, both imaging and cell signaling biomarkers also enable patients who might benefit from a particular type of treatment to be distinguished from those who will not. In conclusion, the diagnostic and prognostic path of sarcoidosis involves many different types of existing and new biomarker. Research addressing biomarkers and disease pathology is ongoing in order to find the ideal sensitive and specific biomarker for this disease.

Keywords: biomarkers; bronchoalveolar lavage; future biomarkers; imaging biomarkers; sarcoidosis; serum.

Figure 1

An integrated overview of serum and bronchoalveolar lavage fluid biomarkers produced by cells of the innate and adaptive immune system, involved in the formation of granulomas in sarcoidosis. The sarcoidosis granuloma consists of a tightly formed core of epithelioid and multinucleated-giant cells (MGCs) encircled especially by T helper (Th) cells, but also by B cells, macrophages and dendritic cells (DCs). During this granuloma formation a variety of biomarkers is released by these inflammatory cells. Macrophages are key players in granuloma formation and produce a number of inflammatory biomarkers [e.g., serum angiotensin-converting enzyme (sACE), lysozyme, neopterin, CD163, C-C motive chemokine ligand 18 (CCL18), serum amyloid A (SAA)]. Macrophages activate T-cells by presenting a triggering antigen, which results in an upregulated expression of soluble interleukin 2 receptor (sIL-2R). Apart from T-cells, B-cells also have shown to play a role in granuloma formation. Crucial for the B-cell maturation and function is the biomarker B-cell activating factor (BAFF). All these biomarkers may be useful for the diagnosis and prognosis of sarcoidosis. Figure created with Biorender.com.

Figure 2

(A) ¹⁸F-fluorodeoxyglucose (FDG) by positron emission tomography (PET) activity and improvement in pulmonary function. Correlation between high activity of pulmonary parenchyma on ¹⁸F-FDG PET (maximum standardized uptake value [SUV_max]) at baseline and improvement in forced vital capacity (FVC) in patients with a pulmonary treatment indication (R = 0.62, p = 0.0004). Reproduced and modified from (134) with permission. (B) Example of a PET-CT scan of a sarcoidosis patient with pulmonary involvement, before (i) and after (ii) 6 months of infliximab therapy.