Plasma Chromogranin A as a marker of cardiovascular involvement in Erdheim-Chester disease

Abstract

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis (LCH) characterized by tissue infiltration with CD68(+) foamy histiocytes. TNF-related chronic inflammation and mutations in the MAP kinase signaling pathway in histiocytes are recognized as the two major pathogenic events. Among pleomorphic clinical manifestations, cardiovascular involvement is frequent and prognostically relevant. Evaluation of ECD clinical course and response to treatment is, however, still challenging. Taking advantage of the two largest cohorts of ECD patients worldwide, we investigated the relevance and the potential of circulating Chromogranin A (CgA), a pro-hormone involved in cardiovascular homeostasis and inflammation, as a biomarker of response to therapy in ECD. Consistent with other TNF-related inflammatory diseases, we found that not only TNF-α and soluble TNF-Receptors (sTNF-Rs), but also CgA plasma levels were significantly increased in ECD patients compared to controls. CgA, but not sTNF-Rs, discriminated cardiovascular involvement in ECD patients and correlated with pro-Brain Natriuretic Peptide (pro-BNP). In a single case, where a cardiac biopsy was available, CgA was found expressed by cardiomyocytes but not by infiltrating histiocytes. In four ECD patients, where serial determination of these parameters was obtained, the kinetics of sTNF-Rs and CgA paralleled response to therapy with anti-cytokine inhibitors; specifically, sTNF-Rs overlapped TNF-associated inflammation, while CgA, together with pro-BNP, closely mirrored response of cardiac disease. Our data indicate that both sTNF-Rs and CgA are linked to ECD pathophysiology. Moreover, CgA, in concert with pro-BNP, can be further exploited to fulfill the unmet clinical need of non-invasive reliable biomarkers of cardiac disease in these patients.

Keywords: Chromogranin A; Erdheim–Chester disease; TNF-α; chronic inflammation; histiocytes; soluble TNF-Receptors.

Figure 1.

Circulating CgA identifies cardiovascular involvement in ECD patients. (A) Correlation between sTNF-RI and sTNF-RII (left) and between sTNF-RI and CgA (middle) and sTNF-RII and CgA (right) was evaluated by Spearman correlation analysis in 37 ECD patients. (B) circulating CgA, sTNF-RI, and sTNF-RII levels were determined in ECD patients with (n = 8, white columns) or without (w/o) (n = 9, gray columns) cardiovascular involvement (CV) and represented as mean ±SEM . Statistical significance was assessed by ANOVA. Black columns represent the mean of healthy controls (HD) (n = 20). (C) correlation between circulating CgA, sTNF-RI, or sTNF-RII with pro-BNP values was performed by Spearman correlation analysis in 14 patients. *p < 0 .05; **p < 0 .005; ***p < 0 .001.

Figure 2.

ECD cardiomyocytes express CgA. Immunohistochemistry on ECD myocardial tissue shows a polymorphic xanto-granulomatosous process, composed of vacuolated macrophages and lymphocytes, infiltrating normal myocardial fibers (A–C); (A) Hematoxylin & Eosin staining; (B) CD68 staining is expressed by foamy macrophages; (C) 5A8 staining, directed against the NH₂ terminal vasostatin-1 domain of CgA, shows a granular staining of myocyte cytoplasm. In (D) 5A8 staining on cross-section of myocardial fibers at higher magnification.

Figure 3.

Kinetics of plasma sTNF-Rs and CgA parallel response to therapy in ECD patients. Plasma levels of sTNF-RI, sTNF-RII, TNF-α, and CgA were serially measured in four patients treated with TCZ (Patients 8 and 11) or IFX (Patients 9 and 10) and showing either response to therapy or disease progression. In the x-axis, time points corresponding to 3–6 mo intervals. Pro-BNP levels were also determined at the baseline (point 1) and at the end of the observation (point 5); dotted lines represent the cut-off value (200 ng/mL) for healthy age-matched males.