Systemic Sclerosis in Latvia: Patient Characteristics, Peripheral Nervous System Involvement, and Novel Biomarkers

Systemic sclerosis (SSc) is a rare systemic connective tissue disease (ORPHA code 90291) and among the most severe autoimmune rheumatic disorders, with the mortality rate 3.5 times higher than that of age-matched healthy individuals. Incidence and prevalence vary widely, with lower rates in Northern Europe; no epidemiological data have been reported for Latvia. Peripheral nervous system (PNS) involvement in SSc remains insufficiently characterised, and its pathogenesis is unclear. While ischaemia is the leading hypothesis, additional mechanisms are likely involved. Although serum autoantibodies (Abs) are a hallmark of SSc, no consistent link with PNS damage has been established. Candidate biomarkers – including neurofilament light chain (NfL), growth/differentiation factor 15 (GDF15), glial fibrillary acidic protein (GFAP), and fibroblast growth factor 21 (FGF21) – have shown potential in other conditions but have not been systematically assessed in SSc-related polyneuropathy (PNP). Likewise, metabolome studies in SSc have not addressed PNP. This study aimed to determine the prevalence of SSc in Latvia, compare it internationally, describe demographic and clinical characteristics with emphasis on PNS involvement, explore pathogenesis, and evaluate potential biomarkers. Data from both Latvian adult clinical university hospitals, which receive virtually all suspected SSc cases, were analysed. A total of 159 patients meeting ACR/EULAR 2013 criteria between 2016–2021 were identified. Point prevalence was 84.0 (95 % CI 71.9–98.1) per million, highest in the 60–69 age group. The female-to-male ratio was 4.67:1, with females being slightly older at the time of diagnosis (63.12 years versus 59.75 years). Most patients were ANA-positive (82.58 %), with anti-speckled and anti-centromere (ACA) patterns predominating. ACA positivity was more prevalent in females, whereas anti-topoisomerase I (ATA) showed no difference between the sexes. First non-Raynaud’s phenomenon symptoms typically appeared in the fifth decade. Females had earlier onset than males (46.51 ± 13.52 vs 50.5 ± 16.64 years). Despite a small male cohort (n = 18), a trend towards more severe disease was observed, with higher rates of interstitial lung disease (ILD), pulmonary hypertension (PH), and oesophageal dysmotility. Glucocorticoids were used in 68.31 % of patients, most often in diffuse cutaneous SSc (90 %), but also in limited cutaneous SSc (70.59 %) and sine scleroderma (66.67 %). PNS involvement was systematically assessed. Large fibre neuropathy (LFN) was found in 43 % of 100 patients undergoing nerve conduction studies (NCS). Of 57 patients without NCS changes, quantitative sensory testing (QST) was performed in 38, revealing small fibre neuropathy (SFN) in 29. Neuropathic pain occurred in 40.59 %, more often in LFN (47.62 %) than non-LFN (35.59 %). Neuropathic pain correlated with Total Neuropathy Score (srTNS) (r = 0.51, p < 0.001), anxiety severity (r = 0.61, p < 0.001), and lower health-related quality of life (HRQoL) (r = 0.39, p = 0.001). Analysing Abs, stratified by PNP presence, ACA (36.08 %), ATA (22.68 %), and anti-Ro52 (22.68 %) were the most frequent Abs. No Abs were significantly associated with PNP, although anti-Ro52 showed a possible protective effect. Anti-myelin-associated glycoprotein and anti-ganglioside Abs were not linked to PNP. Serum biomarker levels were significantly higher in PNP-positive patients for NfL (r = 0.62, p < 0.001), GFAP (r = 0.36, p = 0.011), and GDF15 (r = 0.65, p < 0.001), while FGF21 showed no significant difference. Metabolomic profiling revealed reduced aspartic acid, glutamic acid, valine, and citrulline (fold change > 2), and elevated glutamine in SSc patients compared to healthy controls (fold change > 1.5). When comparing SSc with and without PNP, no metabolites met strict discrimination thresholds; using lower cutoffs, PNP-positive patients showed elevated kynurenine and alanine, and reduced aspartic acid, with asparagine reduction shared with PNP-negative patients. Kynurenine and alanine changes were specific to the PNP-positive subgroup. In conclusion, SSc prevalence in Latvia is lower than in many other regions, consistent with northern European patterns. PNP is highly prevalent, with almost universal PNS involvement. Neuropathic symptoms are linked to poorer HRQoL. No SSc- or inflammatory neuropathy-associated antibodies were associated with PNP. NfL, GFAP, and GDF15 emerge as promising diagnostic biomarkers. Metabolomic profiles suggest that SSc patients with PNP represent a distinct subgroup, with kynurenine and alanine elevations pointing to potential roles for neurotoxicity, mitochondrial dysfunction, and oxidative stress in pathogenesis. The development of PNP in patients with SSc is most likely due to ageing, natural progression and the sequelae of the disease. 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. This endeavour should ultimately pave the way for novel therapeutic strategies and a more nuanced understanding of this multifaceted disease.