Table 1:
Serum biomarkers Investigated in Sarcoidosis and Their Potential Clinical Utility
| Biomarker | Significance | Sensitivity | Specificity | Diagnostic value | Prognosis | Treatment response | Comment |
|---|---|---|---|---|---|---|---|
| Serum Angiotensin-Converting Enzyme (ACE) | Marker of granulomatous inflammatory burden | 22%−83% | Low | Limited | Undefined | Undefined | Sensitivity varies based on disease manifestations and presence/absence of a 287 base-pair deletion within ACE gene. Serial measurements can be useful in disease follow-up. Interpretation of ACE levels may be confounded by use of drugs or immunosuppressants. Measurement of serum ACE is not useful in patients taking ACE inhibitors. |
| Serum soluble IL-2 receptor (sIL-2R) | Marker of T lymphocytes activation | ~80% (81%−98% for uveitis) | Low | Not fully established | + | Undefined | High diagnostic value in patients with uveitis. Potential useful for staging and/or marker of disease severity. Serial measurements can be useful in disease follow-up. High sIL-2R levels may predict relapse after infliximab therapy. Renal insufficiency may alter sIL-2R levels |
| Serum and urinary calcium | Marker of granulomatous inflammatory activity | Hypercalcemia: 3.6%−16% Hypercalciuria: 6.4%−33% |
Undefined | + | Undefined | Hypercalcemia and hypercalciuria are more common in men. Rare in patients with Löfgren’s syndrome. Hypercalcemia and hypercalciuria are associated with lower rates of spontaneous resolution and higher rate of relapses. | |
| Lysozyme | Marker of granulomas burden | 69%−80% | 60%−90.7% | Limited | Undefined | + | Serial measurements may be useful for monitoring response to systemic anti-inflammatory treatment. Elevated serum levels of lysozyme are also present in patients with tuberculosis, asbestosis and silicosis. Lysozyme levels should be interpreted with caution in patients with renal impairment. |
| Bronchoalveolar lavage (BAL) fluid lymphocytosis | CD4 activated T lymphocytes are the immunological hallmark of sarcoidosis | 71%−85% | 68%−93% | + | Uncertai n | Uncertain | Higher percentages of BAL lymphocytes may be associated with a more favorable disease course |
| BAL CD4+/CD8+ ratio | CD4+ T cell accumulation is the main feature of sarcoidosis granulomatous inflammation | 54%−80% | 59%−80% | + (highly specific when >3.5) | + | Uncertain | High CD4+/CD8+ ratios are associated with acute sarcoidosis and more favorable prognosis. Higher CD4+/CD8+ ratios are found in patients carrying the HLA-DRB1*03 genotype, which is associated with good prognosis. |
| BAL CD103+CD4+/CD4+ ratio | CD103+ cells are involved in fibrogenic inflammation | 63%−81% | 76%−78% | + (particularly if associated with a high CD4+/CD8+ ratio | Uncertain | Undefined | The CD103+CD4+/CD4+ ratio is typically reduced (<0.2) in sarcoidosis. Potentially useful as a marker of disease severity and prognosis, often seen in association with more advanced radiographic stages and worse outcome. |
| Additional, less established biomarkers | |||||||
| Chitotriosidase | Marker of disease activity | 89%−100% | About 90% | − | Uncertain | Uncertain | Potentially useful as a marker of severity and prognosis (highest levels are found in patients with persistent disease). Serial measurements can be useful in monitoring disease course. Interpretation of chitotriosidase levels may be confounded by corticosteroid treatment. |
| Th17 (CCR4+/CXCR3−) CD4+ T cells | Key players in many inflammatory disease | Undefined | Undefined | Undefined | + | Undefined | Higher BAL level of Th17+ cells have been found in patients developing chronic disease. |
| Serum Amyloid A (SSA) | SSA depositions are found in sarcoid granulomas | Undefined | Undefined | Uncertain | + | Undefined | Elevated serum SSA levels are found in patients with more active disease, severe lung function impairment and need for systemic therapy. |
| CXCL9 and CXCL10 | Stimulation of T cell migration to sites of inflammation | Undefined | Undefined | Uncertain | Uncertain | Undefined | Increased in BAL and serum from patients with sarcoidosis. Might predict disease outcome. Inversely correlated with lung function (FVC and DLCO). |
Table 1 summarizes “conventional” biomarkers as well as “potential” biomarkers for future use. Biomarkers could benefit sarcoidosis care in several ways: diagnosis, assessment of severity, prediction of disease behavior, prognosis, response to treatment and relapse. Unfortunately, none of the available biomarkers is sufficiently sensitive nor specific to be routinely used in clinical practice.