A recent toast to James Watson highlights a tolerance for bigotry many want excised from the scientific community.
Patients with the rare autoimmune condition, highlighted in the Oscar-nominated film The Big Sick, currently have limited treatment options.
March 1, 2018|
FLICKR, BAGOGAMESReaders take note: movie spoilers ahead
In the movie The Big Sick, based on real events that happened to its two Academy Award-nominated scriptwriters, the character Emily falls gravely ill and is put into a medically induced coma as doctors race to treat what they believe is an antibiotic-resistant infection. When they finally diagnose her with a rare autoimmune condition called adult-onset Still’s disease, treating the symptoms seems trivial, and Emily is soon out of the coma and back on her feet.
It turns out that treating Still’s in real life isn’t always so simple. Some patients’ symptoms aren’t immediately resolved by first-line treatments, and many experience periodic flare-ups after the initial bout of symptoms. But a Swiss trial reported last month (February 22) in the Annals of the Rheumatic Diseases moves a potential new treatment for the condition closer to the market. It blocks the inflammatory cytokine interleukin 18 (IL-18), which is elevated in Still’s patients.
“We still don’t really understand adult onset Still’s disease very well,” says University of California, San Francisco, rheumatologist Andrew Gross. Its causes aren’t known, although there may be an infectious trigger. And as depicted in the movie, the condition can be challenging to diagnose. With symptoms such as high fever, fluid around the lungs, and liver inflammation, “it mimics a lot of different things, including cancer as well as infections,” Gross tells The Scientist. But, he adds, the severity of the fictional Emily’s condition, true to the filmmaker’s, is unusual: It’s more typical that patients aren’t ill enough to be hospitalized, but spend months or even years visiting doctors before they are correctly diagnosed.
Diagnosis can be particularly complicated for patients who have macrophage activation syndrome, a life-threatening complication more often associated with infection, writes Cleveland Clinic rheumatologist Apostolos Kontzias, who was not involved in the new study, in an email to The Scientist. “Often times, Still’s patients go through a diagnostic Odyssey before they reach a solid diagnosis which unfortunately is one of exclusion,” he notes.
Often times, Still’s patients go through a diagnostic Odyssey before they reach a solid diagnosis which unfortunately is one of exclusion.—Apostolos Kontzias
Once diagnosed, Still’s patients are commonly treated with corticosteroids to tamp down acute symptoms. Some respond better to the drugs than others, and if a high dose is needed, it can cause many side effects, says Cem Gabay, a rheumatologist at the University of Geneva. Other treatment options include the arthritis drug methotrexate, and antagonists of the cytokines IL-1 and IL-6. But some patients experience repeated flare-ups of the disease, even with a combination of these treatments, Gabay says. He and collaborators decided to test out a drug that blocks a different cytokine: IL-18, levels of which tend to be very high in Still’s disease.
The drug, tadekinig alfa, was originally developed for rheumatoid arthritis, but had not proved to be effective for that condition in clinical testing. It was purchased from a pharmaceutical company by Swiss startup AB2 Bio, which funded the study (Gabay also receives consultant fees from AB2 Bio and owns shares in it).
Twenty-three patients with active Still’s who had symptoms of the disease even after treatments with steroids or other available treatments were injected with tadekinig alfa three times per week for 12 weeks. The most common side effect was irritation at the injection site, although two patients experienced more severe local reactions, and about half of the participants’ symptoms improved: their fevers resolved, and levels of circulating C-reactive protein, a marker of inflammation, were either normalized or dropped by at least half. “Having 50 percent response in this difficult-to-treat group of patients is very encouraging for future clinical trials,” says Gabay. This study did not include a control arm, but the research group is hoping to start a Phase 3 trial next year.
Although he cautions the results are “preliminary,” Gross, who was not involved in the study, says it’s exciting when “one more therapeutic agent gets added to the arsenal” for a disease with limited treatments. Even if the drug isn’t ultimately successful, he says, the studies on it give more insight into the role of IL-18 in Still’s disease, and the cytokine’s viability as a therapeutic target.
Whatever its fate in the drug development pipeline, the drug has already delivered a dramatic outcome for one family, Gabay says: Several years ago, his team learned about a three-month-old baby in the U.S. who was suffering from a severe case of a rare inflammatory disease that, like Still’s, involves high levels of IL-18. “This child was in ICU, she was three months old—everybody was desperate because she was not responding to corticosteroids [or] different drugs,” he says. AB2 Bio provided tadekinig alfa under compassionate use; the girl is now three years old and healthy. Gabay says the case is an early indication that the drug may work for other conditions in additon to Still’s.
C. Gabay et al., “Open-label, multicentre, dose-escalating phase II clinical trial on the safety and efficacy of tadekinig alfa (IL-18BP) in adult-onset Still’s disease,” Annals of the Rheumatic Diseases, doi:10.1136/annrheumdis-2017-212608, 2018.