¹Charité – Campus Mitte Medizinische Klinik, Schwerpunkt Rheumatologie und Klinische Immunologie, Berlin
²Deutsches Rheuma-Forschungszentrum Berlin (DRFZ), ein Institut der Leibniz-Gemeinschaft, Berlin
³Medizinische Klinik mit Schwerpunkt Nephrologie und Internistische Intensivmedizin, Charité Campus Mitte, Berlin
⁴Universidad de Antioquia UdeA, Grupo de Immunologia Cellular e Immunogenética, Instituto de Investigaciones Médicas, Facultad de Medicina, Medellin
⁵Immanuel-Krankenhaus Abteilung für Innere Medizin/Schwerpunkt Rheumatologie, Berlin

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Introduction: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by systemic inflammation and multi-organ involvement. The heterogeneity of the disease poses a challenge for clinical assessment and treatment, indicating the need to develop personalized diagnostic and therapeutic approaches. Soluble immune checkpoint molecules (sICPs) have been identified as potential biomarkers for disease activity and treatment outcomes in autoimmune diseases [1], [2]. However, their role in SLE remains unclear.

Methods: Serum concentrations of various soluble co-stimulatory (sCD25, sCD27, sCD40L, s4-1BB, and sCD86) and co-inhibitory checkpoint molecules (sCTLA-4, sPD-1, sPD-L1, sPD-L2, sTim-3, sGal-9 and sLAG-3) were measured using a bead-based assay in 241 SLE patients who visited our departments between January 2016 and February 2023. sICPs were analyzed in relation to clinical data, including SLEDAI scores, organ-specific manifestations, long-term outcomes, and laboratory parameters (C3, C4, anti-dsDNA, and type I IFN signature/Siglec-1). Long-term remission was defined based on a comprehensive clinical assessment of disease activity and stability over time. The median disease duration was 8 years. Statistical analyses included Wilcoxon rank-sum tests, multivariate logistic regression, receiver operating characteristic (ROC) analyses, cluster analyses, and correlation matrices.

Results: Higher sCD25, sTim-3, and sGal-9 concentrations were associated with active SLE (SLEDAI >4). Multivariate analyses, adjusted for age, sex, and prednisolone dose, confirmed these molecules as reliable disease activity predictors. (Figure 1 A, B [Fig. 1]) Unsupervised Cluster analysis identified the highest concentrations of sCD25, sTim-3, and sGal-9 in an SLE subgroup with more severe disease activity (median SLEDAI 10).

Strong positive correlations were observed between sCD25, sTim-3, and sGal-9 levels, suggesting that their upregulation may be driven by interrelated mechanisms. Interestingly, these molecules were specifically elevated in patients with renal involvement and/or anemia but not in those with APS, skin, or joint manifestations. Finally, low sCD25 levels were predictive of long-term and durable remission.

Conclusion: This study identified sCD25, sTim-3, and sGal-9 as biomarkers for active SLE and specific organ involvement, particularly renal and hematologic. Low sCD25 levels were associated with durable remission, underscoring the potential as predictive and response biomarkers, and requiring further validation.

References

[1] Stefanski AL, Rincon-Arevalo H, Dressler-Steinbach I, Nomovi N, Mackert A, Aue A, Ritter J, Wiedemann A, Szelinski F, Schrezenmeier E, Kühl AA, Lino AC, Henrich W, Dörner T. Dysregulation of immune checkpoint molecules as a characteristic of autoimmune congenital heart block. Ann Rheum Dis. 2024 Oct 21;83(11):1598-600. DOI: 10.1136/ard-2024-226176
[2] Gamerith G, Mildner F, Merkel PA, Harris K, Cooney L, Lim N, Spiera R, Seo P, Langford CA, Hoffman GS, St Clair EW, Fervenza FC, Monach P, Ytterberg SR, Geetha D, Amann A, Wolf D, Specks U, Stone JH, Kronbichler A. Association of baseline soluble immune checkpoints with the risk of relapse in PR3-ANCA vasculitis following induction of remission. Ann Rheum Dis. 2023 Feb;82(2):253-61. DOI: 10.1136/ard-2022-222479