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

• Published in: Journal of investigative dermatology Vol. 138; no. 6; pp. 1301 - 1310
• Main Authors: Hinchcliff, Monique, Toledo, Diana M., Taroni, Jaclyn N., Wood, Tammara A., Franks, Jennifer M., Ball, Michael S., Hoffmann, Aileen, Amin, Sapna M., Tan, Ainah U., Tom, Kevin, Nesbeth, Yolanda, Lee, Jungwha, Ma, Madeleine, Aren, Kathleen, Carns, Mary A., Pioli, Patricia A., Whitfield, Michael L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2018
• Subjects: Adult; Biopsy; Case-Control Studies; Cell Count; Chemokine CCL2 - immunology; Chemokine CCL2 - metabolism; Female; Gene Expression Profiling; Humans; Immunosuppressive Agents - pharmacology; Immunosuppressive Agents - therapeutic use; Longitudinal Studies; Male; Middle Aged; Mycophenolic Acid - pharmacology; Mycophenolic Acid - therapeutic use; Myeloid Cells - drug effects; Myeloid Cells - immunology; Prospective Studies; Scleroderma, Systemic - drug therapy; Scleroderma, Systemic - immunology; Scleroderma, Systemic - pathology; Skin - cytology; Skin - drug effects; Skin - immunology; Skin - pathology; Transcriptome - drug effects; Transcriptome - immunology; Treatment Outcome; SSc; mDC; NES; MMF; mRSS; DC
• ISSN: 0022-202X; 1523-1747; 1523-1747
• DOI: 10.1016/j.jid.2018.01.006

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.