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Doctor Diagnoses Rare Complication and Saves a Life

Pediatric rheumatologist, Edward Behrens, MD, is unraveling the mysteries of a life-threatening syndrome that strikes children with arthritis.

By Jennifer Davis

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Hayley O’Keefe doesn’t remember much about Thanksgiving Day in 2004. But her mother, Colleen, can recall every detail.

Soon after the family woke up that holiday morning, Colleen watched in terror as her 13-year-old daughter lost feeling in her left side, lost her speech, lost consciousness and lapsed into a coma.

All her life, Hayley had suffered from an autoimmune disease that brought on regular, high fevers and skin inflammation that led to welts and rashes. But neither her doctors nor her parents had ever witnessed the kind of crisis that Hayley was experiencing that morning.

“It was so fast,” her mother says. “Every organ in her body was involved. Her brain, liver, pancreas,” Colleen remembers. “We did think she was going to die.”

Local physicians airlifted Hayley, who is from New Jersey, to Children's Hospital of Philadelphia where she was treated by Edward Behrens, MD, a pediatric rheumatologist who has received research funding from the Arthritis Foundation since 2007, first as a post-doctoral fellow and in 2010 as the recipient of an Innovative Research Grant.

“He’s amazing. First of all he saved her life. But on top of that, he’s just really compassionate and really cares,” Colleen says about Dr. Behrens.

A Challenging Diagnosis, Too Often Missed

The O’Keefes consider themselves lucky that they found a doctor who recognized what was happening, which turned out to be a mysterious and rare condition called macrophage activation syndrome, or MAS.

Little is known about MAS except that it can kill within hours and that it tends to strike about 10 percent of children who have systemic juvenile idiopathic arthritis, or JIA. (Though it is most commonly seen in children with JIA, cases have also been described in adults and children with other kinds of rheumatic and autoimmune diseases.)

Dr. Behrens believes MAS was first recognized in the medical literature as culture-negative sepsis because it shared many of the same characteristics as the life-threatening, body-wide infection, in which bacteria overwhelm the bloodstream.

 

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Doctor Diagnoses Rare Complication and Saves a Life

Pediatric rheumatologist, Edward Behrens, MD, is unraveling the mysteries of a life-threatening syndrome that strikes children with arthritis.

By Jennifer Davis


Hayley O’Keefe doesn’t remember much about Thanksgiving Day in 2004. But her mother, Colleen, can recall every detail.

Soon after the family woke up that holiday morning, Colleen watched in terror as her 13-year-old daughter lost feeling in her left side, lost her speech, lost consciousness and lapsed into a coma.

All her life, Hayley had suffered from an autoimmune disease that brought on regular, high fevers and skin inflammation that led to welts and rashes. But neither her doctors nor her parents had ever witnessed the kind of crisis that Hayley was experiencing that morning.

“It was so fast,” her mother says. “Every organ in her body was involved. Her brain, liver, pancreas,” Colleen remembers. “We did think she was going to die.”

Local physicians airlifted Hayley, who is from New Jersey, to Children's Hospital of Philadelphia where she was treated by Edward Behrens, MD, a pediatric rheumatologist who has received research funding from the Arthritis Foundation since 2007, first as a post-doctoral fellow and in 2010 as the recipient of an Innovative Research Grant.

“He’s amazing. First of all he saved her life. But on top of that, he’s just really compassionate and really cares,” Colleen says about Dr. Behrens.

A Challenging Diagnosis, Too Often Missed

The O’Keefes consider themselves lucky that they found a doctor who recognized what was happening, which turned out to be a mysterious and rare condition called macrophage activation syndrome, or MAS.

Little is known about MAS except that it can kill within hours and that it tends to strike about 10 percent of children who have systemic juvenile idiopathic arthritis, or JIA. (Though it is most commonly seen in children with JIA, cases have also been described in adults and children with other kinds of rheumatic and autoimmune diseases.)

Dr. Behrens believes MAS was first recognized in the medical literature as culture-negative sepsis because it shared many of the same characteristics as the life-threatening, body-wide infection, in which bacteria overwhelm the bloodstream.


 

What puzzled doctors who thought they were treating these septic patients, however, was that they couldn’t find any bacteria or viruses that could be causing the high fever, enlarged spleen, liver failure and plummeting blood cell counts that are common to both syndromes. And antibiotics were of little help.

Researchers subsequently noticed that this subset of patients had other important differences from septic cases, including high blood levels of iron and an inflammatory marker called soluble interleukin-2 receptor or (sIL-2R).

People with MAS also have large numbers of specialized cells called hemophagocytes (heem-oh-fag-oh-sites), scavenger cells that eat red blood cells and platelets.

Stepping up to Address a Research Gap

After successfully making the diagnosis in Hayley, and saving her life with high doses of immunosuppressing drugs, Dr. Behrens says he looked to see what research was being done on MAS, and found little underway.

Dr. Behrens knew something needed to be done to help speed the diagnosis and treatment of children and adults caught in this life-threatening crisis.

He approached the Arthritis Foundation for help and got it.

“When you’re working on a rare disease and when you’re working on pediatric diseases, it’s very hard to get funding,” Dr. Behrens says. “I was a somewhat junior investigator. To break ground when you’re unproven and trying to study rare diseases is difficult. This would not have happened without the Arthritis Foundation.”

An Investment Brings Answers

At the November 2010 annual meeting of the American College of Rheumatology, Dr. Behrens will present several important new findings about the syndrome in one of the meeting’s plenary sessions.

His first announcement is that he’s conducted the first study to develop a true animal model for MAS. Because human cases are few and far between, the only way to learn about rare syndromes like MAS is to recreate them in animals, usually mice. Dr. Behrens says a separate animal model was needed to study the type of MAS doctors see in their rheumatologic patients.

Arthritis Foundation funding has also allowed him to better understand the role of hemophagocyte cells in MAS. Using a special microscope, he was able to collect and observe large numbers of these rare cells by cutting individual hemophagocytes off slides with a laser – a painstaking process called laser dissection – and gathering them in a test tube.


 

Hemophagocytes are a key characteristic of MAS. While it’s been known that they are present in MAS patients, their role has been unclear. Doctors aren’t sure if they are causing the disease or helping fight inflammation. Dr. Behrens says his research has turned up a clue in this debate because the mice in his animal model have all the features and characteristics of MAS, but they don’t have hemophagocytes.

“One of the things we see in MAS is your white blood cells drop, red blood cells drop and platelets drop. One theory is hemophagoctyes are eating those cells. But if I’m not seeing those hemophagocytes in the mice, I still see those cells drop,” Dr. Behrens says. “We have hypothesized they are involved in MAS but as a good guy. I think they might be involved in MAS but I think they are trying to help out. I think they are there to suppress disease.”

Dr. Behrens says this is the first time anyone has shown that the hemophagocyte can be separate and distinct from the disease process.

“They really are separate and I think we now have to change the way we think about that cell type,” he says. “That has implications for therapy because some of the therapies we use are to try to get rid of hemophagocytes.”

Treatments on the Horizon

He says the third major discovery is that the inflammatory molecule interferon gamma is a critical cytokine for MAS. Much like blocking the molecule tumor necrosis factor-alpha, or TNF-alpha, helps to treat patients with rheumatoid arthritis, if Dr. Behrens blocks interferon gamma in MAS, mice improve.

“That suggests if we could come up with a drug and there are potential drugs out there to block interferon gamma, that should work in patients with MAS,” Dr. Behrens says.

While he acknowledges that it takes a while to translate findings in mice to human patients, he says, he’s just getting started with this animal model and he knows it will help patients down the line.  

“We’re looking at years away for changes in practice because of something I do in mice. But it’s a first step,” Dr. Behrens says.

And it represents progress for patients like Hayley O’Keefe who wouldn’t be alive without Dr. Behrens’s research.

“This work has been successful,” Dr. Behrens says. “This would not have happened if I had not had Arthritis Foundation support.”