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Introduction Fatigue is one of the most common and debilitating symptoms in systemic sclerosis (SSc), with a major impact on quality of life. Its genesis is multifactorial, potentially influenced by both physical and psychological comorbidities, yet it remains poorly understood. Given its subjective and multidimensional nature, we adopted an integrated approach based on SSc-related clinical features and Patient-Reported Outcome Measures (PROMs) to evaluate its clinical, functional, and psychological correlates. The aim of this study was to identify determinants and predictors of fatigue in SSc.Material and Methods We retrospectively analyzed 168 patients with SSc classified according to 2013 ACR/EULAR criteria, stratified by clinically significant fatigue (SF-36 vitality subscale less than or equal to 45). Demographic, clinical, serological, and instrumental data were collected. Disease perception was evaluated using PROMs, including Sclero-ID, HAQ, UCLA GIT 2.0, and SF-36. Statistical analysis included descriptive analysis, group comparisons and multivariable logistic regression to identify independent determinants of fatigue.Results Clinical, demographic and PROMs data are summarized in tables 1 and 2. A total of 61 patients (36.3%) reported clinically significant fatigue, of whom 29 (17.3%) had severe fatigue. Compared with patients without fatigue, those with fatigue had more telangiectasias (67% vs 50%, p=0.029), dysphagia (38% vs 16%, p=0.002), arthralgias (47% vs 27%, p=0.013), and worse dyspnea (mMRC 1±1 vs 0±1, p=0.023). Patients with fatigue consistently performed worse across nearly all PROMs, with higher disability (HAQ), worse Sclero-ID domains, more severe GI involvement (UCLA GIT 2.0), and markedly impaired quality of life across all SF-36 domains, despite comparable objective disease burden.Multivariable analysis identified dysphagia as an independent predictor of fatigue (OR 3.236, 95% CI 1.128–9.286), with trends for associations with mRSS (OR 1.099, 95% CI 0.999–1.209), digital ulcers (OR 2.938, 95% CI 0.983–8.780), and arthralgias (OR 2.158, 95% CI 0.945–4.929).Conclusions Fatigue is a key determinant of patients’ perceived health status in SSc and may confound interpretation of other PROMs, amplifying the perceived disease burden independently of measurable organ damage. Dysphagia emerged as the only independent predictor of clinically significant fatigue, hypothesizing a possible link between GI involvement and fatigue levels. However, the multifactorial nature of fatigue makes it challenging to isolate predictors, suggesting an interplay of multiple disease-related and psychological factors, stressing the need to consider fatigue in clinical practice and research.Abstract P.322 Table 1Demograghic, clinical, serological, and organ involvement characteristics of systemie selerosis patients stratified according to the presence of clinically significant fatigue (SF-36 vitality subscale SA5). Dota we reported as mean (standard deviation) oe mumbher (pereentage). P-valucs refer to compariso between groupsAbstract P.322 Table 2Comparison of Patient-Reported Outcome Meanes (PROMs) between patients with and without clinically significant fatigue (SF-36 vitality 545). Data are reported as mean (standard deviation). P-values refer to comparisoni between groups