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J Invest Dermatol. 2018 Jun;138(6):1301-1310. doi: 10.1016/j.jid.2018.01.006. Epub 2018 Jan 31.

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

Author information

1
Department of Medicine, Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA; Institute of Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. Electronic address: m-hinchcliff@northwestern.edu.
2
Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA.
3
Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA.
4
Department of Medicine, Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
5
Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
6
Celdara Medical LLC, Lebanon, New Hampshire, USA.
7
Institute of Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA; Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
8
Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA; Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA. Electronic address: Michael.L.Whitfield@Dartmouth.edu.

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.

PMID:
29391252
DOI:
10.1016/j.jid.2018.01.006

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