CRYOFIBRINOGEN-ASSOCIATED SYSTEMIC SCLEROSIS: POSSIBLE CORRELATIONS WITH SCLERODERMA DIGITAL ULCERS AND PULMONARY ARTERIAL HYPERTENSION

BackgroundCryofibrinogenemia (CF) is a rare disorder characterized by the presence of an abnormal protein in the plasma that precipitates when cooled and redissolves at room temperature (1). CF is rarely symptomatic, therefore it is often underestimated. Nevertheless, the cryoprecipitation of native fibrinogen could induce thrombotic occlusion of small and medium sized vessels; as a consequence, this condition could become potentially lethal without the proper treatments. CF is classified into an essential and secondary form. The association of CF with Systemic Sclerosis (SSc) is described in literature (2-4); however, the role of this phenomenon it is not completely clarified, especially because some clinical aspects could be similar in both conditions.ObjectivesThe aim of our study was to analyze the clinical, laboratory, instrumental and therapeutic features of SSc patients with cryofibrinogenemia, with particular attention to the possible prevention strategy and appropriate therapy of SSc digital ulcers.Methods101 SSc patients (M:F 1:13) referring to the SSc Unit-Rheumatology Unit of our University Hospital have been tested both for cryofibrinogen and cryoglobulins from February 2020 to January 2022. Clinical, laboratory, instrumental features and ongoing therapies were collected.ResultsPatients with diffuse cutaneous form, limited cutaneous form, and sine-scleroderma subsets were 20 (19,8%), 79 (78,2%), and 2 (2,0%), respectively. The overall positivity for CF was 69,3%, of which 90,7% as isolated CF and 9,3% in addition to cryoglobulins. No correlation between CF positivity and positivity for rheumatoid factor, Scl-70, CENP B, anti-fibrillarin, anti-U1RNP, anti-Th/To, anti-Ku, anti-MDA5, anti-mitochondrial, anti-SSA, anti-SSB, anti-citrullinated peptide, anti-phospholipids, anti-CORE, and anti-HCV antibodies was observed. An inverse correlation trend between CF positivity and anti-RNAP3 antibodies positivity (OR=0.0577, 95% CI 0.0029-1.1537, p=0.0620) was noted. No significant correlation between CF positivity and interstitial lung disease, pulmonary arterial hypertension (PAH), history of digital ulcers, and amputation was recorded; however, considering cryocrit sample ≥1%, a correlation between the presence of an estimated pulmonary arterial systolic pressure (ePASP) higher than 30 mmHg and the positivity of CF was obtained (OR = 2.71, 95% CI 1.01-7.28, p=0.0482). The same association was achieved if we considered patients without endothelin receptor antagonist therapy (n=47) and CF positivity (OR=6.19, 95% CI 1.19-32.2, p=0.0304). Furthermore, no correlation between CF positivity and the presence of digital ulcers at the moment of the blood sampling was verified; however, if we stratified patients according to their ongoing treatments (absence of an endothelin receptor antagonists therapy plus PDE5 inhibitors), a significant correlation between digital ulcers and CF positivity emerged (OR=8.14, 95% CI 1.03-64,5, p=0.0470, n=91).ConclusionOur preliminary results on this issue are extremely interesting as they can open new perspectives on the identification of cryofibrinogen as possible prognostic marker that could be involved in the pathogenesis of scleroderma digital ulcers and PAH. Moreover, therapies which are currently used for the treatment of PAH and the management of digital ulcers, could determine circulating cryofibrinogen disappearance, with possible challenging future impact on SSc therapeutic approaches.References[1]Michaud M, Pourrat J. Cryofibrinogenemia. J Clin Rheumatol Pract Rep Rheum Musculoskelet Dis. aprile 2013;19(3):142–8.[2]Kao L, Weyand C. Vasculitis in Systemic Sclerosis. Int J Rheumatol. 30 settembre 2010;2010:e385938.[3]Kocoloski A et al, Successful management of secondary cryofibrinogenaemia using bosentan therapy. Rheumatol Oxf Engl. 1 ottobre 2018;57(10):1868–70.[4]Barrett MC et al, Cryofibrinogenaemia and acute gangrene in systemic sclerosis. Postgrad Med J. ottobre 1986;62(732):935–6.Disclosure of InterestsNone declared