Single-cell RNA sequencing gives insight to dermatomyositis treatment

Dermatomyositis is a rare and devastating autoimmune disease primarily affecting the skin and skeletal muscle.

While both can affect the muscle, dermatomyositis and lupus show many overlapping clinical and pathological features in their associated skin rashes but a differing response to available therapeutics.

Better understanding of the immunopathology in dermatomyositis, the cellular characteristics and the modular differences in lesional and non-lesional skin in dermatomyositis and lupus patients can give insight for more effective treatments.

At University of Michigan Health, a team of researchers led by Michelle Kahlenberg, M.D., Ph.D., Vice Chair of Research for the Department of Internal Medicine and Michael H. and Maricia S. Klein Professor of Rheumatic Disease at U-M Health observed distinct differences in the skin of dermatomyositis patients using single-cell RNA sequencing.

The study published in Science Translational Medicine, analyzed lesional and non-lesional lupus and dermatomyositis skin, healthy control skin and peripheral blood.

The findings revealed a unique, inflammatory monocyte population within the skin and blood of dermatomyositis patients.

These monocytes contributed to endothelial dysfunction and apoptosis.

“Our research demonstrated a pervasive type one interferon signature in dermatomyositis and lupus skin that likely explains some overlapping features such as photosensitivity,” said Kahlenberg.

“However, the endothelial cells in dermatomyositis rashes looked unhealthy, which is was not observed to the same extent in the lupus skin.”

Further testing their theory of monocyte-endothelial cell interplay in dermatomyositis skin, Kahlenberg and team introduced medical inhibition of the JAK1 protein to the data set.

Upon JAK1 inhibition, endothelial cell death and inflammatory signature were reversed in dermatomyositis endothelial cells, highlighting JAK1protein inhibition as a therapeutic avenue of treatment.

“Together, this data provides a comprehensive cross-disease characterization of lesional and non-lesional skin in dermatomyositis and gives evidence on why JAK1 inhibition may offer therapeutic hope for dermatomyositis patients,” said Kahlenberg.

The next steps for Kahlenberg’s team will include further mechanistic testing of JAK1 inhibition as a treatment method for dermatomyositis with the intention of opening a better treatment pathway for dermatomyositis patients.

Additional authors: Grace A. Osborne, Elisabeth A. Pedersen, Rachel Bogle, Mio Nakamura, Lam C. Tsoi, Allison C. Billi, Johann E. Gudjonsson, Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA. Lin Zhang, Feiyang Ma, Amanda N. Victory, Amy Hurst, Bin Xu, Vladimir Ogenenovski, Benjamin Klein, Pei-Suen Tsou, Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA. Mehranz Gharee-Kermani, Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA and the Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA. Jessica L. Turnier, Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA and the Division of Rheumatology, Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109, USA. Celine C. Berthier, Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.

Funding/disclosures: Funding for this work was received through the Lupus Research Alliance (to J.M.K.), Bristol Myers Squibb (to J.M.K. and J.E.G.), and the National Institutes of Health NIAMS (National Institute of Arthritis and Musculoskeletal and Skin Diseases) through R01 AR071384 (to J.M.K.), K24 AR076975 (to J.M.K.), and AI130025 (to J.E.G.); the U-M Skin Biology and Diseases Resource Center P30 AR075043 (to J.E.G.); and NIAID (National Institute of Allergy and Infectious Diseases) through P01 AI179251 (to J.M.K. and J.E.G.) and R01AI183620 (to J.E.G. and P.-S.T.). Funding was also received through the Taubman Institute Innovative Program (to J.M.K. and J.E.G.), the Department of Defense (to P.T.), and the LEO Foundation (to P.T.). Other funding included effort support by a NIAMS K23 Career Development Grant (K23AR080789) to J.L.T. and the German Research Foundation (KL3612/1-1) to B.K.

Paper cited: “Dermatomyositis is characterized by JAK1-mediated monocyte-driven vasculopathy and inflammation,” Science Translational Medicine. DOI: 10.1126/scitranslmed.aea9007

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