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Higher Lupus-Associated Flare Risk Seen in Patients With Normal-Looking Skin


This new research may help investigators prevent skin lesions.

New research into the skin cells of patients with lupus offers insights into the underlying mechanisms that appear to prime the skin for inflammation and lesions.

Writing in Science Translational Medicine, the authors said their findings could help investigators better understand how to prevent skin lesions and other types of inflammatory responses in patients with lupus.

About 70% of patients with systemic lupus erythematosus (SLE) will be affected by cutaneous lupus erythematosus (CLE), which is associated with disfiguring skin lesions, the investigators noted. Some patients experience skin lesions even when their underlying SLE is controlled by medication. However, the investigators explained that little is known about what causes CLE-related skin lesions to occur.

One theory is that abnormalities in nonlesional skin may be a driving factor. Previous research has suggested that increased type I interferon production and dysfunction of Langerhans cells may play a role, but the authors said contributions from other skin cells and the communication links that lead to dysfunction are not well understood.

The investigators decided to look at biopsies of normal-looking skin and lesional skin from 7 patients with lupus, using-single cell RNA sequencing. Their analysis showed that both lesional and prelesional skin have a type-I interferon-rich environment that affects gene transcription across skin types and distorts cell-to-cell communication networks.

“This really starts to piece the puzzle together of how inflammation seen in lupus patients may be related to skin exposures such as [ultraviolet] light,” said J. Michelle Kahlenberg, Md, PhD, senior study author, in a statement announcing the findings. “We were able to see the properties of normal-looking skin in unparalleled resolution, suggesting that the skin is primed for inflammatory reactions.”

Those inflammatory properties were found both in the epidermal keratinocytes and in the fibroblasts of the skin samples from patients with CLE. The analysis showed that samples from healthy controls did not bear the same type-I interferon signature.

Kahlenberg said the findings are particularly helpful in light of the development of therapies that can block interferon signaling in lupus. “So, validating this abnormality in the interferon pathway could be essential for determining the best course of treatment for scores of lupus patients,” she said.

The authors also examined blood samples from patients with CLE, finding that CD16+ monocytes travel from the blood into the skin of patients, where they appear to gain a proinflammatory phenotype, which the investigators characterize as “cell education.”

Allison C. Billi, MD, PhD, a dermatologist at University of Michigan Health and the study’s co–first author, said the findings help explain how the immune dysfunction of lupus leads to skin lesions.

“These interferon-educated immune cells seem to be priming many different cell types in the skin to overreact to stimuli with excessive inflammatory responses, manifesting as disfiguring skin lesions,” she said, in the statement. “We don’t yet know all of the stimuli that can tip the balance and precipitate these rashes, but UV light certainly appears to be one of them.”

Kahlenberg said learning how monocytes change when they get to the skin from the blood suggests more research is also needed to see whether a similar process occurs in other lupus-involved organs.


Billi AC, Ma F, Plazyo O, et al. Nonlesional lupus skin contributes to inflammatory education of myeloid cells and primes for cutaneous inflammation. Sci Transl Med. Published online April 27, 2022. doi:10.1126/scitranslmed.abn2263

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