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).