Molecular Predictors of Rheumatoid Arthritis Relapse

Ruth Williams in The Scientist:

Studies of blood samples from four rheumatoid arthritis patients collected over years has led to the discovery of an RNA profile that predicts an imminent flare-up of symptoms, according to a report in the New England Journal of Medicine today (July 15). The transcriptional signature also indicates that a type of fibroblast previously linked to the disease becomes enriched in the blood before migrating to the joints to wreak havoc. “The work is clearly a breakthrough in how patients with [rheumatoid arthritis] might be managed in the future,” Lawrence Steinman of Stanford University writes in an email to The Scientist. If such an RNA test were commercially developed, then “via a home test involving a mere finger stick, markers that precede a flare [would be] identified. This would allow the individual to consult with their physician and take necessary measures to avert such a flare,” continues Steinman, who studies autoimmune diseases but was not involved in the study.

Rheumatoid arthritis, in which the body’s immune system attacks the joints to cause swelling, stiffness, and pain, exhibits a waxing and waning of symptoms, as do many other autoimmune diseases. Even with treatment to suppress certain immune cells or cytokines, it is common for a patient to experience a couple of relapses each year, says study author Dana Orange, a clinical rheumatologist and researcher at Rockefeller University in the laboratory of Robert Darnell. Relapses in the disease are debilitating and can make life hard to plan, explains Orange. Patients “just don’t know when they are going to be blind-sided and incapacitated with a flare,” she says. Orange, Darnell, and colleagues therefore sought a way to predict such occurrences. Being a dynamic molecule, RNA “lends itself to profiling changes over time,” says Darnell, whose research focuses on RNA regulation in autoimmune and other diseases. “What we wanted to do,” he says, “was to design a study where we could have the RNA before a patient gets sick with a flare . . . to try and get signatures of what might be the antecedents.”

To this end the team recruited patients, via an ad in a newspaper, who were willing to collect tiny samples of their own blood—a few drops via a finger stick—each week and keep diaries of their symptoms. The patients also had clinical evaluations once a month. The team then sequenced the messenger RNA content of a selection of the blood samples—those representing baseline conditions and the weeks immediately prior to, during, and after a flare—to see whether and how the transcriptomes varied with the waxing and waning of symptoms. A total of 162 samples, taken from four patients over the course of one to four years, were sequenced and analyzed computationally. When they looked at the weeks preceding a flare up, “what jumped out was that something changed from the baseline,” says Darnell.  Two weeks prior to a relapse, the team detected a change in the RNA profile that was consistent with an increased abundance of immune cells. “That gave us a hint that we were on the right track and that was exciting,” says Darnell,  “but the big excitement came when we were looking at week -1.”

“There was a unique set of genes that were unexpected—they had signatures of stem cells and mesenchymal cells,” Darnell continues, and “it was not clear exactly what to make of that.”

More here.