P134 Developing a potential composite pharmacodynamic serum marker of skin severity in systemic sclerosis
Authors: Roblin Elen , Clark Kristina E N , Beesley Claire , Ong Voon H , Denton Christopher P 
Published: April 2024

Abstract

Background/Aims
Previously, through multilevel and high dimensional analysis, we derived a composite biomarker for modified Rodnan Skin Score (mRSS) in systemic sclerosis (SSc) patients using a derivation cohort (BIOPSY). This identified 4 blood proteins (COMP, COL4A1, TNC and SPON1) that independently correlated with mRSS and also with skin gene and dermal blister expression at a separate 12-month timepoint. These proteins likely reflect overlapping aspects of SSc skin pathobiology that are not overly influenced by other disease compartments. In the present study, we undertake technical and biological validation of this novel composite marker in well characterised SSc patients.

Methods
COMP (DCMP0, R&D Systems), COL4A1 (CSB-EL005741HU, Cusabio), TNC (ab213831, Abcam) and SPON1 (CSB-EL022599HU, Cusabio) were examined in serum samples from diffuse cutaneous SSc (dcSSc) cases in two independent cohorts of patients, BIOPSY (n = 33) and MODERNISE (n = 37). The BIOPSY cohort was previously used to derive the composite marker and MODERNISE was a novel validation cohort. Later, early dcSSc patients from both cohorts were combined into a third analysis group (n = 36). Multiple regression analysis derived a formula for a composite biomarker score which predicted mRSS based on serum ELISA results.

Results
Serum concentration positively correlated with mRSS for COMP and TNC, particularly in early dcSSc patients (COMP, r = 0.10, p = 0.05; TNC, r = 0.13, p = 0.03). No significant correlation was observed for COL4A1 (r = 0.03, p = 0.34). Interpretable data could not be obtained for SPON1 due to technical limitations of the ELISA. Confirming previous results multiple regression analysis derived a formula for the prediction of mRSS using the three remaining serum proteins (r = 0.15, p = 0.009). mRSS = 9.896 + 0.01719(COMP) - 0.006481(COL4A1) - 0.002318(TNC). Patients receiving mycophenolate mofetil showed numerically lower serum concentrations of COMP (p = 0.16), COL4A1 (p = 0.32), TNC (p = 0.15) and a lower composite biomarker score (p = 0.22) with increasing treatment duration in early dcSSc cases (Table 1).

Conclusion
Our results confirm this novel three-protein composite serum marker predicts skin severity in SSc better than each individual analyte. After further validation, this blood-based approach may help evaluate treatment response to standard immunosuppression. Further work will establish utility of this composite measure as a predictive or prognostic biomarker.

Disclosure
E. Roblin: None. K.E.N. Clark: None. C. Beesley: None. V.H. Ong: None. C.P. Denton: Consultancies; C.P.D. has received consulting fees from Arxx Therapeutics, Roche, Janssen, GlaxoSmithKline, Bayer, Sanofi, Galapagos, Boehringer Ingelheim, CSL Behring and Acceleron. Honoraria; C.P.D. has received honoraria from Janssen, Boehringer Ingelheim, and Corbus. Grants/research support; C.P.D. has received research grants to the institution from Servier, Horizon, Arxx Therapeutics and GlaxoSmithKline.