Study identifies alternate path for inflammation that could improve RA treatment

(Press-News.org) PULLMAN, Wash. — The class of anti-inflammatory drugs known as TNF-inhibitors has brought relief to many sufferers of rheumatoid arthritis, but they don't work for up to 4 of every 10 patients.

New research led by Washington State University may have discovered why: a “backdoor” pathway of inflammation that sidesteps medicines that lock the front door.

The findings, published in the journal Cellular & Molecular Immunology, suggest new avenues for improving the treatment of rheumatoid arthritis, a debilitating autoimmune disease where the body attacks its own joints. The disease affects roughly 1% of the world’s population, and the discovery could have positive implications for rheumatoid arthritis as well as other autoimmune diseases.

The research team found that a lesser-known inflammatory signal triggered by proteins known as TWEAK and Fn14 play an important role in the inflammatory response. The main protein involved in arthritis is Tumor Necrosis Factor, or TNF; over the past quarter-century, a range of biologic drugs known as TNF inhibitors, which block signaling in that pathway, have come onto the market.

The new study found that TWEAK and Fn14 signaling team up with TNF to amplify inflammation. When both signals are active, inflammation surges. When the Fn14 receptor-mediated pathway is blocked, that TNF-driven surge quiets dramatically. 

“It’s kind of like a back-door entry or an alternate route,” said Salah-uddin Ahmed, professor and associate dean for research and graduate education in the College of Pharmacy and Pharmaceutical Sciences and corresponding author of the new publication. “If you shut the main door for TNF, it has other ways to cause inflammation.”

The discovery could herald good news for the millions of people afflicted by rheumatoid arthritis worldwide. Many of those patients have gotten effective relief from the five TNF inhibitors that have been approved by the FDA, a class of drugs that has grown rapidly since their introduction.

They are also prescribed for conditions such as ankylosing spondylitis, Crohn’s disease, ulcerative colitis, and others. It is estimated that the market for the drugs in 2024 was about $25 billion.

“These are fantastic for the majority of patients, but roughly 30% to 40% of patients don’t respond,” Ahmed said.

Also, among those who do respond, some will see the effectiveness of the drugs decline.

The new publication grows from several years of research led by a former graduate student in Ahmed’s lab, Farheen Shaikh, who was the first author on the paper. The researchers wanted to explore the biological reasons that TNF inhibitors aren’t always effective; it was known that TWEAK was a part of the large protein superfamily of TNF—an evolutionarily related group of proteins with a common ancestor—but the relationship between them was not well-understood.

The team examined human tissues, as well as data from rat studies, to explore the molecular communications involved in the inflammatory process. They discovered that TWEAK can exploit its own protein receptor—Fn14—to cause inflammation.

“What we found was when you block Fn14 or knock down Fn14, the power of TNF to cause inflammation was reduced significantly,” Ahmed said. “This was telling us TNF heavily relied on this receptor to cause inflammation.”

This “crosstalk” between TNF and Fn14—the alternate route for inflammation—was first described in the new publication.

Ahmed now plans to investigate a couple of different pathways for developing potential therapeutics — one would target the two inflammatory pathways together, and the other would focus on the Fn14 path. Given the role of TNF in other autoimmune diseases, further study of the Fn14 function could shine a light on other illnesses, as well, he said. 

“This is almost like a partner in crime for TNF,” he said.

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