Mycophenolate Mofetil Treatment of Systemic Sclerosis Reduces Myeloid Cell Numbers and Attenuates the Inflammatory Gene Signature in Skin

Abstract

Fewer than half of patients with systemic sclerosis demonstrate modified Rodnan skin score improvement during mycophenolate mofetil (MMF) treatment. To understand the molecular basis for this observation, we extended our prior studies and characterized molecular and cellular changes in skin biopsies from subjects with systemic sclerosis treated with MMF. Eleven subjects completed ≥24 months of MMF therapy. Two distinct skin gene expression trajectories were observed across six of these subjects. Three of the six subjects showed attenuation of the inflammatory signature by 24 months, paralleling reductions in CCL2 mRNA expression in skin and reduced numbers of macrophages and myeloid dendritic cells in skin biopsies. MMF cessation at 24 months resulted in an increased inflammatory score, increased CCL2 mRNA and protein levels, modified Rodnan skin score rebound, and increased numbers of skin myeloid cells in these subjects. In contrast, three other subjects remained on MMF >24 months and showed a persistent decrease in inflammatory score, decreasing or stable modified Rodnan skin score, CCL2 mRNA reductions, sera CCL2 protein levels trending downward, reduction in monocyte migration, and no increase in skin myeloid cell numbers. These data summarize molecular changes during MMF therapy that suggest reduction of innate immune cell numbers, possibly by attenuating expression of chemokines, including CCL2.

Recent advances steer the future of systemic sclerosis toward precision medicine

“…High level of the myeloid cell chemo-attractant CCL2 has been found in the skin of SSc patients with the inflammatory subset and both CCL2 mRNA and CCL2 serum levels decreased during treatment with MMF. Finally, the same study confirmed the role of macrophages [25] and myeloid dendritic cells (mDC) in SSc pathogenesis, as their level seems to decrease during MMF treatment and correlate with inflammatory NES [13]. The use of belimumab and MMF for the treatment of SSc also showed similar results [26], although, authors did not show significant differences in mRSS improvement between patients treated with belimumab compared with placebo.…”

“…It is also suggested that racial differences can be associated with distinct subsets [11]. However, patients within the same subset may show substantial different disease evolution including organ involvement as well as a heterogeneous response to treatment [12,13]. The current ACR/EULAR classification for SSc which was proposed in 2013 has significantly higher sensitivity and specificity compared with existing classification criteria [14].…”

“…The possibility to characterize every single SSc patient in terms of peculiar molecular pathways may help to identify those patients that could benefit from drugs targeting inflammation (inflammatory subset) and/ or fibrosis (fibroproliferative subset) [16,21]. The inflammatory subset has shown a significant response to immune modulating therapies [13]. In a recent study, all enrolled patients treated with mycophenolate mofetil (MMF), who reached a modified Rodnan skin score (MRSS) improvement > 25% (defined improvers) tended to have an inflammatory pattern at baseline.…”

High-throughput quantitative histology in systemic sclerosis skin disease using computer vision

“…Serum anti-topoisomerase I, anticentromere, and anti-RNA polymerase III antibody titers were measured by indirect immunofluorescence at Specialty Laboratories, Valencia, CA. Healthy control participants were recruited from the Northwestern University clinical and research communities to match the age (within 10 years), race and sex of an SSc patient as previously described [11,17,18].…”

“…For example, DNNs perform on par with dermatopathologist review of stained skin lesion sections for diagnosis of nodular basal cell carcinomas, dermal nevi, and seborrheic keratoses [14]. In this study, we applied DNN algorithms to stained sections of skin biopsies from patients with SSc and from healthy participants [17,18]. Our goal was to test the hypothesis that DNN algorithms are sensitive to histological variation in skin biopsies and to assess the association with markers of SSc disease severity including the mRSS and two SSc gene expression biomarkers: the SSc four-gene biomarker [9] and the 4S gene expression biomarker [11].…”