Background Systemic sclerosis (SSc) is characterized by excessive extracellular matrix (ECM) deposition in the skin, as well as autoantibody production, release of various cytokines, and T-cell activation. Several lines of evidence indicate a potential role for B cells in the pathogenesis of SSc through effects on autoantibody production, T-cell activation, and fibrosis, among others. Accordingly, targeting B cells could effectively reduce ECM deposition and the inflammatory background of this disease.
Objectives In animal models of SSc, decreased B-cell function following CD19 inhibition led to reduced skin thickness and a reduction in autoantibody production, which is consistent with the expression of CD19 on plasma cells (PC), the major source of antibody production. Therefore, our goal was to investigate the effect of CD19 inhibition on PC levels and collagen expression in the skin of SSc patients.
Methods We evaluated skin biopsies obtained from a Phase I clinical trial of MEDI-551, an anti-CD19 antibody expected to deplete PC and B cells. Skin biopsies were collected pre-treatment (baseline) and at 29 days post-treatment with either MEDI-551 or placebo. To evaluate PC, we used whole genome microarray analysis of sorted cellular fractions to identify a panel of genes expressed predominantly in PC. To account for the multiple collagen types involved in skin fibrosis, a collagen score was calculated as the median expression of three collagen genes, COL1A1, COL3A1, and COL5A1.
Results In patients with SSc, the collagen score was positively correlated with the modified Rodnan skin score (mRSS) disease activity measure at baseline (r=0.67, p=0.004), highlighting the role of collagen expression in SSc disease severity. Additionally, we identified a positive correlation between the PC signature and the collagen score at baseline (r=0.60, p=0.001). Following anti-CD19 treatment, the collagen score and the PC signature were both inhibited in skin as much as 90%, with a median inhibition of 35% and 50%, respectively. No change in the PC signature or collagen score was observed following placebo treatment. Interestingly, the inhibition of the PC signature was positively correlated with inhibition of the collagen score in all patients (r=0.80, p=0.001).
Conclusions The positive correlation observed between inhibition of the PC signature and inhibition of this collagen score in scleroderma skin supports a role for PC in the pathogenic mechanism of this disease. These preliminary results need to be validated in a larger cohort of patients to determine if changes in PC signature and the collagen score could predict those who respond to treatment with PC-depleting therapeutics.
Disclosure of Interest K. Streicher Shareholder of: MedImmune; AstraZeneca, C. Morehouse Shareholder of: MedImmune; AstraZeneca, C. Groves Shareholder of: MedImmune; AstraZeneca, B. Rajan Shareholder of: MedImmune; AstraZeneca, F. Pilataxi Shareholder of: MedImmune; AstraZeneca, K. Lehmann Shareholder of: MedImmune; AstraZeneca, P. Brohawn Shareholder of: MedImmune; AstraZeneca, B. Higgs Shareholder of: MedImmune; AstraZeneca, K. McKeever Shareholder of: MedImmune; AstraZeneca, L. Richman: None Declared, B. Jallal Shareholder of: MedImmune; AstraZeneca, R. Herbst Shareholder of: MedImmune; AstraZeneca, Y. Yao Shareholder of: MedImmune; AstraZeneca, K. Ranade Shareholder of: MedImmune; AstraZeneca
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