4. sCD163
Early recognition of MAS remains a diagnostic challenge and research focused on the potential diagnostic application of specific biomarkers apart from ferritin. Soluble (s) CD163 is the soluble counterpart of CD163 receptor for the hemoglobin-haptoglobin complex located on M2 macrophage cell membrane and represents a marker of M2 macrophage activation and differentiation. The shedding and quick release of CD163 is induced by several pro-inflammatory stimuli such as TNF-α, oxidative stress and lipopolysaccharide and several studies demonstrated the prognostic role of sCD163 in conditions characterized by high systemic inflammatory burden, like sepsis or acute respiratory distress syndrome requiring mechanical ventilation (75, 76). Moreover, convincing evidence supports the potential role of sCD163 as biomarker of MAS (77, 78). In this setting, activated or hemophagocytic CD163+ macrophages within bone marrow aspirates were demonstrated to precede MAS development in subjects with sJIA, thus suggesting the pivotal role of macrophage activation in MAS through the induction of hemophagocytosis and hypercytokinemia (79). Of note, serum sCD163 levels are significantly increased in patients with sJIA associated with MAS in comparison to patients with active disease without MAS, in particular at disease onset, follow the clinical course in response to treatment and, of note, correlate with other surrogate biomarkers of systemic inflammatory burden, like sCD125 and ferritin (80). Similar increases of sCD163 have been depicted in patients with AOSD, in particular in the group with active disease, and levels were similar as for patients with sepsis (81). Interestingly, sCD163 levels positively correlated with ferritin serum levels only in AOSD patients, suggesting a direct involvement of macrophage in ferritin production in these conditions (82). Moreover, a recent study demonstrated that systemic lupus erythematosus patients with MAS display significantly higher levels of sCD163 in comparison to patients with other severe disease manifestations, like lupus nephritis, autoimmune haemolytic anaemia or immune thrombocytopenia, with sCD163 levels correlating with disease activity (82). Levels of sCD163 may also serve as marker to differentiate primary HLH and MAS. In a recent study, the serum levels of sCD163 were markedly increased in patients with MAS as compared to pHLH patients, thus hypothesizing that the macrophage activation in MAS is higher than in pHLH (83). Thus, in MAS, the massive IL-1β release triggers a close autocrine loop leading to cytokine storm with dramatic IL-6, IL-18 and ferritin production and, consequently, sCD163 spreading from macrophages. Surely, deeper understanding of this complex pathogenic pattern related to massive cytokine release may lead to targeted therapies and improved patient prognosis (84).