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Introduction Systemic sclerosis (SSc) is an autoimmune disease characterized by immune dysregulation, vasculopathy, and fibrosis. High-risk patients, particularly those with diffuse cutaneous involvement (dcSSc) and interstitial lung disease (ILD), may benefit from early intensive immunosuppressive therapy during the inflammatory phase of the disease. We hypothesized that soluble immune checkpoints (sICPs) reflect immune activation and serve as biomarkers for disease activity and treatment response.Material and Methods Plasma levels of 15 sICPs (including sPD-1, sTIM-3, sBTLA, sCD25, sCD137, sIDO), cytokines, B cell activating factor (BAFF) and dephosphorylated-uncarboxylated Matrix Gla Protein (dp-ucMGP) were analyzed in a prospective SSc cohort (n=35). A high-risk subset (n=14) received an intensified immunosuppressive regimen consisting of therapeutic plasma exchange (TPE), cyclophosphamide, and maintenance therapy with mycophenolate mofetil or rituximab in cases of intolerance. Samples were obtained at baseline, 6, and 12 months. Correlations with clinical variables and treatment response were assessed using non-parametric statistics and principal component analysis (PCA).Results Patients selected for intensified treatment had a distinct inflammatory profile with elevated levels of sICPs and BAFF, while CRP levels did not differ. sICPs correlated positively with dp-ucMGP, indicating a link between vascular dysfunction and immune activation. Classical pro-inflammatory cytokines (e.g., IL-6, TNFalpha), however, showed weak correlations with disease severity. Longitudinal analysis showed a significant decline in most sICPs within 6 months of treatment, whereas cytokine levels remained stable. Survival and pulmonary function were preserved during a median follow-up of 4.5 years.Conclusions sICPs reflect T cell dysregulation and disease severity in SSc more accurately than classical cytokines. Early intervention in inflammatory, high-risk patients may prevent long-term clinical deterioration. The observed decline of sICPs following treatment supports their potential as early biomarkers of treatment response. Moreover, the correlation between sICPs and dp-ucMGP suggests a mechanistic link between vascular and immune pathology in SSc.