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KATIE THOMAS
NYT Syndicate
David Fajgenbaum was the fittest of his friends at the University of Pennsylvania's medical school, a 6-foot-3 gym addict and former quarterback at Georgetown. His mammoth hands seemed more suited to spiraling footballs than the fine fingerwork a doctor-in-training might need. He had endurance to match, taking multiple hits and returning to the field to play on.
"This guy was a physical specimen," said his former roommate, Grant Mitchell, who used to walk to work with him. When they would arrive at the hospital for his obstetrics rotation, his friend recalled,"he would basically coerce me into doing pull-ups on the tree outside."
In July 2010, that all changed. The 25-year-old woke up at night drenched in sweat. His lymph nodes were swollen. He felt stabs of abdominal pain, and odd red bumps began sprouting across his chest. Most bizarre of all, he felt very tired ” so tired that he began slipping into empty exam rooms between patients, stealing five-minute naps to get through the day.
"Guys, I think I'm dying," he recalled telling his friends.
A visit to the emergency room confirmed his fears. A doctor told him that his liver, kidneys and bone marrow were not working properly. Even more troubling, the doctor had no idea why his body was failing.
"What do you think is going on?" he remembers the doctor asking him.
Pursuing the answer to that question, it turned out, would become his life's work. It would transform Fajgenbaum from a patient on the brink of death five times, whose illness stumped specialist after specialist, to one of the leading researchers in his field. He has even used himself as his own test subject, and may have discovered a treatment for his rare disease.
His story, which has been circulating inside medicine, is more than one person's remarkable journey, however. It offers a look into the world of rare diseases, a corner of medicine that continues to frustrate ” and flummox ” those who seek cures for obscure conditions. About 95 percent of all rare diseases have no approved drug treatments. When Fajgenbaum's brain started slowing down, Mitchell said, the severity of the illness sunk in.
"I would ask him a simple question, and he would answer in a couple words, like 30 seconds to a minute later," he said.
Mitchell and the other medical students scoured textbooks and the internet, searching for clues. The top medical experts at Penn, meanwhile, were not having much more luck. Lymphoma was just one theory. Others thought it might be a severe case of lupus or even mononucleosis. But test after test was inconclusive.
Finally, the doctors tried a huge dose of steroids. Slowly, his body began to fight its way back. His kidneys and liver began functioning again, and the extra fluid receded. Seven weeks after he was admitted, Fajgenbaum walked out of the hospital. It was September 2010.
"I remember asking the doctor, saying, 'What was this?'" he said."And I remember the doctor saying, 'We don't know what it was, but let's just hope it doesn't come back.'"
It took only one month for symptoms to come rushing back, while he was convalescing at his childhood home in Raleigh, North Carolina. Doctors there shipped a piece of his lymph node to the Mayo Clinic in Minnesota, where pathologists finally pinpointed his disease. The condition, called Castleman disease, was so rare that doctors at the hospital in Raleigh had no experience with it.
Castleman disease had been known since the 1950s but has remained largely a mystery. A hallmark of the condition is enlarged lymph nodes, and most people with the disease ” about two-thirds ” have a form that affects just one part of the body and can usually be cured through surgery. The form ravaging Fajgenbaum's body ” multicentric Castleman disease ” is even more rare and deadly.
Over the next few years, Fajgenbaum alternated between extended periods of relative health and frightening relapses. His condition stumped even leading experts in the disease, people like Dr Frits van Rhee of Little Rock, Arkansas, who has treated the largest number of patients ” about 100 ” with Castleman.
The tools van Rhee and others had were blunt and harmful in their own right. More than once, Fajgenbaum underwent a devastating, 21-day course of chemotherapy that annihilated his immune system in an effort to knock his disease into remission.
Fajgenbaum was also granted emergency access to siltuximab, a drug that Johnson & Johnson was developing for people with his form of multicentric Castleman disease, which would be approved in 2014. That year, in 2011, van Rhee secured a rare exception to try it on Fajgenbaum.
But the drug, like other previous treatments, did not work.
Fajgenbaum was undaunted. With the zeal he once devoted to bench-pressing a personal best ” 375 pounds, reached six months before he first fell ill ” he dove into the scientific research on Castleman disease and began to familiarise himself with the world's top experts.
One of the people he called was Dr Thomas Uldrick, a clinical researcher at the National Cancer Institute who had studied multicentric Castleman disease. The two struck up a correspondence.
"Clearly he was a very bright medical student, and he was scared of dying from this disease," Uldrick recalled.
He also began collaborating with van Rhee, who knew Fajgenbaum was a different kind of patient after he arrived armed with charts, graphs, timelines and slide presentations.
"There are patients who keep meticulous records," van Rhee said with a chuckle,"but he was definitely in the top one percent."
In spring 2013, Fajgenbaum earned his medical degree, and a few months later he entered the Wharton School at Penn, reasoning that, to solve the tangled mystery of Castleman disease, business smarts would serve him well. But in December of that year he got sick again, with his blood platelets dropping so low that he barely avoided a fatal brain bleed.
This time, though, he was able to use his relapse to further his search for a cure.
For months, Fajgenbaum had been collecting weekly blood samples that served as snapshots of his immune system, tabulating the results in a spreadsheet and adding them to a detailed slide presentation that he had been preparing since he received the diagnosis. And when it was clear the disease had returned, he persuaded his doctors to remove a piece of a lymph node, test it and save it for future research.
After a round of chemotherapy, he improved enough to be discharged and started looking into what secrets the tests might reveal. It turned out that five months before he started noticing symptoms in December, his T cells ” one of the key weapons in the body's immune arsenal ” had starting activating, preparing for a fight even though there was no apparent threat. Then, about three months before his relapse, he noticed that he had started producing more VEGF, a protein that instructs the body to make more blood vessels, and is another sign of an immune system gearing up.
These two hints gave him an idea: Maybe the problem was with one of the body's communication lines, the one that triggered production of VEGF and also told the T cells to begin activating. If Fajgenbaum could get his body to shut down that communication line ” known as the mTOR pathway ” he might be able to stop his immune system from overreacting and prevent a relapse. The discovery was exhilarating.
"I felt like I was part of steering the ship," Fajgenbaum said."This time I was part of this team."
With this major clue in hand, he and his doctors turned to potential treatments, existing drugs that were known to shut down the mTOR pathway. The one that seemed the best option was practically hiding in plain sight. Sirolimus, also known as Rapamune, was commonly given to kidney transplant patients to prevent their bodies from rejecting the organ. The drug had been on the market for years and was known to have few serious side effects.
"I wouldn't think I ever could have prescribed this to another patient, or told a patient to try it, because we just didn't have very much data," Fajgenbaum said."But at this stage, I'd had four episodes, and I'd failed everything the doctors had ever given me."
In January 2014, he stopped taking his old cancer drugs and started on sirolimus. Six months passed, then a year. The weekly blood tests showed that his immune system was returning to normal.
Fajgenbaum, his health improving, returned to the other challenges that were hampering progress in the field of Castleman disease. He started the Castleman Disease Collaborative Network, a nonprofit whose mission was to prioritise and coordinate research into the disease, which operates out of the Perelman School of Medicine at Penn. Fajgenbaum, an assistant professor of medicine at the school, and his collaborators assembled an advisory panel of the world's experts in the disease and set an agenda for answering the most pressing questions.
In medical research, discoveries come slowly and take twists and turns that no one saw coming. Seasoned researchers have learned to rein in their optimism and to know that true breakthroughs can take years, if not decades, to realise. Not Fajgenbaum.
"I almost wish that every disease had a David to be a part of the charge," said Dr Mary Jo Lechowicz, a professor at the Emory University School of Medicine, who has studied Castleman disease and serves on the network's advisory board.
These days, Fajgenbaum, now 31, walks through the hallways of Penn's medical centre, his frame again projecting the easy confidence of the athlete he once was. But he jokes that he would have to pull out photos of his days as a quarterback to explain to people why his friends still call him the Beast.
Now, he said, every time he tries to exercise, his mind wanders back to an email he needs to write or a call he needs to make."It's not because I don't have the energy to do it; it's because all of my energy is going toward this disease," he said.
Not everyone is convinced that sirolimus is what has been keeping him healthy. Van Rhee noted that while the results in Fajgenbaum are promising, his is just one case and treatments need to be proven in many more people.
"I think the finding is very interesting," he said,"but we need to see whether a similar mechanism is active in other patients."
But Fajgenbaum said he grew more confident every day that it is the drug that is helping. He has begun sharing his experience with more doctors and researchers, is conducting laboratory tests to see if the drug is likely to work in other patients and has started writing an article about his experience for a medical journal. Soon, he hopes, doctors will begin prescribing the drug to other patients.
Fajgenbaum is optimistic about the drug's chances but is aware medical science is unpredictable.
"Who knows; maybe it will work for only a small percentage," he said."So we've still got a lot of work ahead of us."
