Kristīne Ivanova ^1,2* Maksims Zolovs ^1,3 Kaj Blennow ^4,5,6 Henrik Zetterberg ^4,7,8,9 Nataļja Kurjāne ^1,2 Viktorija Ķēniņa ^1,2

• ¹ Riga Stradiņš University, Riga, Latvia
• ² Pauls Stradins Clinical university hospital, Riga, Latvia
• ³ Daugavpils University, Daugavpils, Latvia
• ⁴ Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
• ⁵ Hôpitaux Universitaires Pitié Salpêtrière, Paris, France
• ⁶ First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, China
• ⁷ Department of Neurodegenerative Disease, Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London, London, England, United Kingdom
• ⁸ Hong Kong Center for Neurodegenerative Diseases, Hong Kong University of Science and Technology, Kowloon, Hong Kong, SAR China
• ⁹ Wisconsin Alzheimer's Institute, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States

Introduction. Systemic sclerosis (SSc) is a rare autoimmune disease with multiple organ involvement; however, the contribution of the nervous system (NS) remains relatively understudied. There are no specific data on the role of the autoimmune response and inflammation in the development of peripheral nerve system (PNS) damage in SSc and markers to assess this damage have yet to be identified.Objectives. The primary objective of this study was to define the autoimmune mechanisms that lead to neuropathy by identifying antibodies (Abs) that target certain component of the NS or are associated with SSc. The secondary objective was to identify markers of NS damage that correlate with the detection and progression of polyneuropathy (PNP).Methods. This study included patients diagnosed with SSc who met ACR/EULAR 2013 classification criteria at two leading Latvian hospitals between January 2016 and December 2021. Patients underwent a nerve conduction study (NCS). The SSc-associated Abs, Abs against myelin-associated glycoprotein (MAG) and anti-ganglioside Abs (GM1, GM2, GD1a, GD1b and GQ1b) were analysed. Potential serum PNS biomarkersneurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), fibroblast growth factor 21 (FGF21) and growth/differentiation factor 15 (GDF15) -were measured.Results. We recruited 103 Caucasian patients diagnosed with SSc. SSc-associated Abs did not differ significantly between patients with and without PNP (p > 0.05). Anti-MAG and anti-ganglioside Abs in patients with PNP did not present a significant increase above the reference range. NfL, GFAP and GDF15 were significantly elevated in the presence of PNP (p < 0.05), with a moderate to high effect size (r = 0.36-0.65). Our regression analysis revealed a strong association between the HAQ-DI score, older age, male gender and the risk of developing PNP. Conclusions. The development of PNP in patients with SSc is most likely due to ageing, natural progression and the sequelae of the disease. Several serum biomarkers -NfL, GFAP and GDF15could be used as relevant diagnostic biomarkers for PNP in patients with SSc. Future studies are warranted to validate the diagnostic efficacy of these biomarkers and to unravel the complex interplay of factors leading to PNP in patients with SSc.