Secondary cryofbrinogenemia is related to more severe microangiopathic involvement in systemic sclerosis: results from a retrospective observational study

Abstract The aims of this study were to investigate the prevalence of cryofbrinogenemia in a cohort of patients with systemic sclerosis (SSc) regardless of clinical manifestations, who were admitted to our hospital and determine the associations among CF positivity, disease features and ongoing therapies. This was a monocentric and retrospective study. The inclusion criteria were a diagnosis of SSc (according to the ACR/EULAR 2013 classifcation criteria), regular administration of i.v. prostanoids, and CF testing between February 2020 and February 2022. Data on demographic, clinical, and immunological features and ongoing treatments were retrospectively collected. Categorical data were compared with the chi-square test or Fisher’s exact test, while quantitative variables comparisons were carried out with Student’s t test or Mann‒Whitney test. In total, 101 SSc patients were ultimately enrolled. The majority of patients were female (92.1%) and had the limited cutaneous form of SSc (81.2%). CF positivity was observed in 69.3% of the patients, whereas only 9% presented cryoglobulins and CF. CF positivity was negatively associated to RNAP3 antibodies (p=0.027). No direct associations with specifc clinical phenotypes were observed. No associations with immunosuppressive treatments were identifed, however a positive association with nifedipine administration (p=0.040), and a negative association with endothelin receptor antagonists (ERAs) plus phosphodiesterase-5 (PDE5) inhibitors regimen (p=0.031) were observed. Macitentan administration was also associated to CF cryocrit≥1% (p=0.045). Among patients who were not treated with ERAs, an estimated pulmonary artery systolic pressure≥30 mmHg was signifcantly associated with CF positivity (p=0.025). Moreover, a cryocrit≥3% was associated with a relative risk of 3.44 (95% CI 1.26–9.39, p=0.016) for digital amputation and 5.17 (95% CI 1.18–22.6, p=0.029) for death. Isolated CF is a frequent phenomenon observed in SSc patients and is associated with a higher administration of vasoactive drugs, probably identifying a SSc clinical phenotype with a more severe microvascular involvement. Moreover, a higher cryocrit is associated with an increased risk of death and digital amputations. Screening SSc patients for CF would represent an opportunity to provide better therapeutic approaches by anticipating ERA administration in an earlier phase, thereby preventing the manifestation of severe microvascular involvement.