Researchers identify new target for rheumatoid arthritis

Researchers at Hospital for Special Surgery have identified a potential new target for drugs to treat patients with rheumatoid arthritis (RA), a protein known as IRHOM2. The finding could provide an effective and potentially less toxic alternative therapy to tumor necrosis factor-alpha blockers (TNF-blockers), the mainstay of treatment for rheumatoid arthritis, and could help patients who do not respond to this treatment. Efforts to develop drugs that hone in on this new target are underway.

“This study is an elegant example of the capacity of basic science cell biologists to work with translational rheumatologists to address a clinically relevant question at a basic level,” said Jane Salmon, M.D., Collette Kean Research Chair and co-director, Mary Kirkland Center for Lupus Research at Hospital for Special Surgery (HSS) in New York City, and an author of the study. “We have identified a clinically relevant target that can be applied to patients in the near term.” The study will appear online, ahead of print, on January 25, in the Journal of Clinical Investigation and in the February 2013 print issue.

Rheumatoid arthritis, an autoimmune disease, is triggered, in large part, by TNF-alpha, a small signaling protein usually involved in launching protective systemic inflammatory responses. With excessive TNF production, however, immune cells can become activated inappropriately and cause tissue inflammation. This produces a number of diseases, including RA. While TNF-blockers help many RA patients, these treatments are very expensive, and some patients do not respond. For this reason, researchers have been searching for alternative targets in patients with inflammatory diseases against which drugs can be directed.

“TNF can be thought of as a balloon tethered to the surface of cells. To work, it must be cut loose by signaling scissors called TACE (TNF-alpha converting enzyme),” said Carl Blobel, M.D., Ph.D., program director of the Arthritis and Tissue Degeneration Program at HSS. While blocking TACE could be another way to treat rheumatoid arthritis, researchers know this strategy would likely have side effects since patients lacking TACE are prone to skin infections and intestinal lesions.

Earlier this year, HSS investigators demonstrated that the TACE scissors are regulated by molecules called IRHOM1 and IRHOM2, which are thought to wrap around TACE and help it mature into functional scissors. They also demonstrated that mice that are genetically engineered to lack IRHOM2 lack functional TACE on the surface of their immune cells and don’t release TNF. Surprisingly, these mice are healthy, and do not develop skin or intestinal defects.

Rheumatoid Arthritis Statistics
It is estimated that about 2.1 million adults in the United States have rheumatoid arthritis. The disease occurs in all races and ethnic groups but is much more common in women than in men. Although the disease occurs most often in older people, children and young adults can also develop it. According to some recent statistics, the overall number of new rheumatoid arthritis cases may be decreasing.

Gender and Ethnicity
Rheumatoid arthritis occurs in all races and ethnic groups. The disease often begins in middle-age and occurs with increased frequency in older people. About 80 percent of all patients develop rheumatoid arthritis between the ages of 35 and 50. However, children and young adults also develop it.
Like some other forms of arthritis, rheumatoid arthritis occurs much more frequently in women than in men. About two to three times as many women as men have the disease.

In the current study, HSS researchers set out to investigate why this paradox exists. After examining tissues of IRHOM2-deficient mice, they found that IRHOM2 regulates TACE on immune cells, whereas IRHOM1 is responsible for helping TACE mature elsewhere in the body, such as in brain, heart, kidney, liver, lung and spleen cells. “IRHOM2 appears to have a more restrictive and exclusive function in immune cells,” said Dr. Blobel.

The researchers then set out to determine whether blocking IRHOM2 could be a strategy to treat RA. They used a mouse model that mimics human rheumatoid arthritis in mice genetically engineered to be deficient in IRHOM2. They found that these rodents did not develop inflammatory arthritis and were otherwise healthy.

“When we tested mice that don’t have IRHOM2 in a model for inflammatory arthritis, we found they were protected and they were protected as well as mice that didn’t have any TNF,” said Dr. Blobel. “Because TNF is the driver of rheumatoid arthritis in human disease, as evidenced by how well anti-TNF drugs work, we feel that this provides a completely new angle on blocking TNF release. It would be wonderful to be able to inactivate TACE in a tissue-specific manner and IRHOM2 provides a unique mechanism for us to do so.”

Some Rheumatoid Arthritis statistics are better than others

-  Recent Rheumatoid Arthritis statistics now estimate that a larger number of people have RA than expected: about 1.5 million in the US.

-  Yesterday was an exciting landmark for Rheumatoid Arthritis Warrior. Our Facebook Fan Page reached 5,000 fans! That has to be my favorite statistic of this year so far! I’m not happy there are so many people with RA, but I’m so glad we are finding each other.

-  This month, the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR) adopted new guidelines for Rheumatoid Arthritis. Spokesmen say that this could make the diagnosis of Rheumatoid Arthritis more likely to occur earlier. The emphasis is on the numbers here with a point system for qualifying to be considered “definite RA”, explained at this link. Numbers on test results will certainly be in the spotlight for patients hoping for that lucky 6. I’m still hoping this will be good news overall.

-  There is a shortage of rheumatologists and the numbers are shocking about how much worse it will get. In 2005, there were 4,946 rheumatologists in the US seeing adult patients. The demand for rheumatologists is expected to continue to increase. By 2025, the demand will exceed supply by 2,576 adult rheumatologists and 33 pediatric rheumatologists according to the statistics in this report in Arthritis and Rheumatism.

-  Mortality figures were discussed last week on the blog especially as relates to Rheumatoid Arthritis and heart disease. Most deaths due to RA are not recorded as such; it’s the secondary symptoms which usually are named. Imagine my surprise when I stumbled across this map of Rheumatoid Arthritis statistics on mortality.

-  There is a 3 year old press release that is still one of the most compelling Rheumatoid Arthritis statistics. According to that document, “RA is the most common form of inflammatory arthritis and costs society more than $80 billion each year. The disease affects more than one in every 200 Americans. However, research funding for RA averages as little as $25.90 per patient and remains significantly low compared to other chronic diseases that affect far fewer people like lupus, diabetes and multiple sclerosis, which average $330.00 per patient.”

Using drugs that inactivate IRHOM2 in humans, clinicians will be able to block the function of TACE only in immune cells. “We can prevent the deleterious contribution of TACE to rheumatoid arthritis patients and preserve its protective function in skin and intestines,” said Dr. Blobel. “With IRHOM2, we have a unique and unprecedented opportunity to inactive TACE only in certain cell types, and not in others, and there is currently no other effective way of doing that.”

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