Fatigue in Sjögren’s Disease - Integrating Biomedical and Psychosocial Aspects: A Narrative Review

Fatigue is a prevalent and disabling symptom in Sjögren's disease (SjD), yet its pathogenesis remains poorly understood and inadequately managed. This narrative review addresses a critical gap in knowledge by conceptualizing SjD-related fatigue as a bidimensional phenomenon driven by both biomedical and psychosocial mechanisms, and framed within the model of persistent somatic symptoms (PSS). In this narrative review, findings from immunology, neuroendocrinology, psychology, and clinical research were synthesized to examine predisposing, triggering, and maintaining factors contributing to SjD-related fatigue. Particular attention was given to studies exploring immune dysregulation, neuroimmune signaling, autonomic imbalance, and psychological traits. Findings indicate that biomedical contributors-such as pro-inflammatory cytokine (e.g., interleukin [IL]-1β, IL-36α), neuroendocrine dysfunction, dysbiosis, and genetic predispositions-interact with psychosocial vulnerabilities, including early-life adversity, personality profiles, maladaptive coping strategies, and mood disorders. These interactions foster self-reinforcing loops of symptom persistence. Notably, current treatments targeting isolated domains yield limited success. Nonetheless, integrated strategies-ranging from biologics and cytokine modulators to exercise, cognitive behavioral therapy, and neuro-modulatory interventions-have demonstrated promise, particularly when aligned with the PSS framework. This narrative review underscores the need for a paradigm shift in fatigue management, advocating for multidimensional assessment and personalized, multimodal interventions. By illuminating the duality of SjD-related fatigue, this narrative review provides a roadmap for more effective diagnosis, research, and patient-centered care.