Phase I/II study of rheumatoid arthritis drug used in systemic sclerosis shows signs of efficacy, and RNA technology plays key role in discovery

Systemic sclerosis – or scleroderma that affects the skin and internal organs – is one of the rarest autoimmune diseases, affecting around 100,000 people (mostly women) in the United States. However, systemic sclerosis is devastating — it has the highest death rate among rheumatic diseases, according to Dinesh Khanna MBBS, M.Sc., director of the Michigan Medicine Scleroderma Program.

And with no approved treatments available for this subset of scleroderma patients, rheumatology researchers are constantly looking for opportunities to use resources and technologies that have been shown to be beneficial in the treatment of other autoimmune and rheumatic diseases.

One resource that clinicians at Michigan Medicine and the University of Pittsburgh recently explored in early-stage systemic sclerosis was an FDA-approved rheumatoid arthritis drug, tofacitinib. Their goals for the study were to determine if the drug was safe for patients and to understand how the drug would work mechanically at the cellular level in the disease.

“We first wanted to understand if there was a clinical benefit of tofacitinib for patients, but we were also asking what the differences are between healthy skin cells and systemic sclerosis cells…how does the drug work ? Khanna said.

In their new study published in JCI Insight, the researchers found that tofacitinib was well tolerated in patients with early-onset systemic sclerosis and found that the drug primarily affected the protein, interferon, in both fibroblasts and keratinocyte cells.

The sample size for the study consisted of 15 patients with early diffuse cutaneous systemic sclerosis – patients with hardening of the skin and organ problems. Of the total participants, 10 patients received 5 milligrams of tofacitinib twice daily, and the rest received placebo in a randomized, double-blind, placebo-controlled trial.

During the 24-week trial period, researchers found no patients who experienced serious adverse effects at or before the end of the trial. Additionally, to measure the effectiveness of tofacitinib, modified Rodnan skin score (mRSS) and other measures were used with patients to measure improvement throughout the trial.

These results showed that the mean mRSS score and other measures improved over the course of the trial. Additionally, placebo patients started open-label tofacitinib after 24 weeks and there was continued improvement over the next 24 weeks, indicating improvement in the measure.

“We are delighted to see that the drug is safe to use and can potentially be repurposed for the treatment of systemic sclerosis,” Khanna said, “but what made this study innovative was the use of technology single cell. »

Study participants underwent a skin biopsy at the start of the trial and then again six weeks after receiving tofacitinib or placebo. Next, the clinicians used the relatively new technology – single-cell RNA sequencing – to observe the mechanism of tofacitinib at work in the skin cells of trial participants.

“This work highlights the ability of single-cell RNA sequencing to determine how disease states are maintained and how various skin cell populations, both fibroblasts, skin cells and immune cells, communicate, providing power unparalleled in addressing disease mechanisms, and how drugs, like tofacitinib, work in disease where they have not been used before,” said Johann Gudjonsson MD, Ph.D., professor of dermatology and collaborator at this study.

In addition to finding out how tofacitinib inhibits cells that help form connective tissue (fibroblasts) and skin cells (keratinocytes), the researchers found that the drug had minimal effect on T cells – the important white blood cells. which are essential to the immune system.

“Because we found that the drug worked on one part (the fibroblast and keratinocyte mechanism), we are now investigating whether we can combine tofacitinib with another drug with a complementary mechanism in action, to treat early-onset systemic sclerosis. without causing toxicity,” explained Khanna.

To learn more about the drug, researchers will need to conduct a more robust study and trial to see if their recent findings are true.

“Through this combined effort between Michigan Medicine and the University of Pittsburgh, we know the drug is safe, and we know the technology (RNA sequencing) is doable, now we can start using the technology and find out what type of therapies we can mix and match which will bring benefits to patients,” Khanna said.

Other authors include Cristina Padilla, Lam C. Tsoi, Vivek Nagaraja, Puja P. Khanna, Tracy Tabib, J. Michelle Kahlenberg, Amber Young, Suiyuan Huang, Johann E. Gudjonsson, David A. Fox, and Robert Lafyatis.

The study was funded by Pfizer Inc as an Investigator Initiated Grant to Dr. Khanna. Pfizer, Inc. played no role in the collection, analysis and interpretation of the data. Dr. Khanna was supported by NIH/NIAMS R01 AR070470 and NIH/NIAMS K24 AR063120. JMK, JEG, and LCT are supported by the Taubman Medical Research Institute and NIH P30 AR075043. LCT was also supported by NIH/NIAMS K01 AR072129.

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