Background/Purpose: Transforming growth factor-beta (TGFb) has long been suspected to mediate fibrotic signals in systemic sclerosis (SSc) as it potently stimulates collagen deposition in vitro, it converts fibroblasts into myofibroblasts- a key cell in pathogenesis, and SSc skin shows highly upregulated expression of genes regulated by TGFb. We have shown recently that TGFb-regulated mRNAs, cartilage oligomeric protein (COMP) and thrombospondin 1 (THS1), are highly increased in diffuse cutaneous SSc skin and that their level of expression correlates highly and directly with the modified Rodnan skin score (MRSS).

Methods: Fresolimumab is a first-in-class pan-neutralizing anti-TGF-beta human antibody that inhibits all three isoforms of TGFb with high affinity. In the first phase of a two-phase open label dosing study, we treated 7 early dSSc patients with two doses of fresolimumab 1 mg/kg at week 0 and week 4. Patients generally tolerated the medication well with one severe adverse event of severe bleeding from a patient with known gastric antral vascular ectasia. The primary efficacy outcome of the study is a change in expression of COMP and THS1. Skin biopsies taken on the day of first treatment (before first treatment), and week 3, week 7 and week 24 after treatment were analyzed for gene expression by RT-PCR, microarray and nanostring.

Results: Most patients showed a decline in expression of THS1 and COMP in biopsies taken after treatment with this difference reaching statistical significance (p<0.05, paired t-test) for THS1 expression at 7 weeks after treatment.  Microarray analyses showed downregulation of a broader set of TGFb-regulated genes in skin, by unsupervised clustering. THS1 and COMP expression correlated very highly suggesting that these mRNAs are co-regulated. Both COMP and THS1 expression correlated highly with the MRSS, suggesting that they are good biomarkers for skin disease as we have shown previously. The high correlation between biomarker mRNA expression and the MRSS also supports the unblinded clinical scoring, which showed a rapid and dramatic fall in average MRSS from baseline=29.2 to 3 weeks=24 (p<0.05). Further decline in average MRSS was seen over follow-up visits, reaching a nadir or 20.2 at 11 weeks after first treatment.  

Conclusion: These data strongly support the utility of skin mRNA expression for assessing response to therapeutic intervention in SSc, provide direct evidence implicating TGFb in SSc pathogenesis, and show the potential for fresolimumab as a treatment for SSc skin fibrosis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/treatment-of-diffuse-systemic-sclerosis-patients-with-anti-transforming-growth-factor-beta-fresolimumab-inhibits-transforming-growth-factor-beta-regulated-gene-expression-in-skin-and-is-associated-w/