Clinical advances and multifactorial pathophysiological mechanisms of neuropsychiatric comorbidity in systemic sclerosis

Abstract

This review addresses the high prevalence of depression and anxiety in systemic sclerosis (SSc), as well as the core biological, psychological and social mechanisms underlying such psychiatric comorbidities, The prevalence of clinically significant depression or anxiety disorders reaches 30%–50% among patients with SSc who satisfy corresponding diagnostic criteria. Established risk factors encompass multi-organ involvement (e.g., lung fibrosis, digital ulcers), chronic pain, physical disability and disease-related stigma. Three key pathophysiological mechanisms drive this comorbidity: immune dysregulation induces neuroinflammation via pro-inflammatory cytokines (IL-6, TNF-α), pathogenic autoantibodies and gut-brain axis disruption; cerebral microvascular damage and chronic hypoxia impair emotion-regulating neural circuits; tissue fibrosis and persistent stress over activate the HPA axis, forming a pathogenic cycle connecting systemic inflammation, glucocorticoid resistance and negative mood. Clinical management of SSc should extend beyond conventional antidepressants and cognitive behavioral therapy to include integrated rheumatology-psychiatry care, IL-6/JAK-targeted biologics and transcutaneous vagus nerve stimulation (tVNS), all designed to ameliorate patients’ physical and psychiatric symptoms simultaneously. In conclusion, psychiatric comorbidity in SSc stems from the intricate interplay of biological, psychological and social factors. Elucidating these mechanisms facilitates the development of targeted therapeutic strategies that address both systemic SSc manifestations and associated mental health conditions, thereby enhancing patients’ health-related quality of life and long-term psychiatric outcomes.