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Introduction: Systemic sclerosis (SSc) is a severe autoimmune disease characterized by progressive fibrosis of multiple organs and associated with high mortality [1]. Up to 40% of patients develop painful calcinosis cutis, defined by calcium-phosphate deposition in the skin. The pathogenesis of this complication remains unclear and no established therapy exists [2]. Calciprotein particles (CPPs) are nanoscale complexes composed of calcium, phosphate, and fetuin-A, and are already known to be taken up by monocytes, leading to increased production of pro-inflammatory cytokines [3], [4]. CPPs may therefore represent a mechanistic link between mineral dysregulation, inflammation, fibrosis, and ectopic calcification. However, their role in systemic sclerosis remains unknown.

Methods: To investigate this, circulating CPPs in the serum of SSc patients (n=33) and healthy controls (n=22) were directly stained with OsteoSense, a fluorophore-conjugated bisphosphonate, and quantified using imaging flow cytometry. Additionally, key parameters of calcium-phosphate metabolism and disease activity were analyzed. These include, among others, ionized calcium, phosphate, magnesium, parathyroid hormone, serum albumin, total protein, and renal function parameters.

Results: Our results show that 30% of the SSc patients had increased CPP concentrations above the range of the healthy control group (>1.76 x 107 particles/ml, **p=0.0037, Fisher’s exact test), corresponding to an odds ratio of approximately 20. Notably, the highest levels of CPPs were observed in SSc patients with calcinosis cutis compared to the healthy control group (n=5 vs. n=22, mean=2.4 x 107 particles/ml vs. 1.19 x 107 particles/ml, **p=0.002). Moreover, SSc patients showed elevated levels of parathyroid hormone (mean=4.51 pmol/l vs. 3.56 pmol/l, *p=0.017) as well as decreased concentrations of ionized calcium (mean=1.233 mmol/l vs. 1.258 mmol/l, *p=0.03). The observed decrease in ionized calcium in SSc patients contradicts the physiological regulatory function of elevated parathyroid hormone levels and therefore suggests a dysregulation of mineral metabolism.

Conclusion: In conclusion, our results suggest that CPPs may play a relevant role in the pathogenesis of calcinosis cutis and that their increased concentration might reflect a disturbed calcium buffering capacity of serum contributing to the disease. In addition, elevated CPP levels could stimulate monocytes to release pro-fibrotic and pro-calcific cytokines, thereby promoting fibrosis that provides a permissive environment for calcium-phosphate deposition.

Disclosures: None declared.

References

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