Scientists forge new weapon to fight rheumatoid arthritis
Vancouver’s Augurex offers simple diagnostic test for early detection
A chance conversation between two scientists in a cafeteria lineup sparked a discovery that could improve the lives of millions of people with rheumatoid arthritis.
When Walter Maksymowych and Aziz Ghahary started trading thoughts about parallels between the healing of wounds in burn patients and healing in joint destruction, it occurred to Maksymowych that a “sibling” of a protein in Ghahary’s research could play a role in rheumatoid arthritis.
Maksymowych is a professor of medicine specializing in rheumatology at the University of Alberta; Aziz Ghahary is now a professor in the University of B.C.’s Department of Surgery and director of the B.C. Firefighters Burn and Wound Healing Laboratory.
“Often at universities we are all working in silos, very focused on our own research,” Maksymowych said. “It really is fortuitous that it was quite a long lineup for a sandwich. It really led to some remarkable work.”
When Maksymowych examined the joint fluid of patients with rheumatoid arthritis, they soon found a unique and previously unexamined protein, one that occurs naturally and harmlessly inside of cells, but outside of cells triggers a cascade of autoimmune reactions, proteins and enzymes that attack joint tissue.
Fast forward 10 years and the discovery of the apparent role of protein 14-3-3η in rheumatoid arthritis has yielded a test that detects rheumatoid arthritis earlier and more reliably than ever, a test that is now in commercial production by the Vancouver-based biotech firm Augurex.
The blood-borne proteins and antibodies normally used to diagnose rheumatoid arthritis may be absent in about 33 to 40 per cent of patients.
That limited the effectiveness of the most widely used tests for early detection and meant many people had joint damage before a proper diagnosis was made.
The JOINTstat test offered by Augurex helps to close that gap by looking for that previously unknown marker for the disease.
The protein is detectable in many patients well before their symptoms meet the criteria for rheumatoid arthritis, said Anthony Marotta, chief scientific officer for Augurex.
Recently published research based on a Japanese study of 149 patients suggests that drug treatments that eliminate the 14-3-3η protein from the blood result in better patient outcomes, meaning the simple and inexpensive test can be used to assess the effectiveness of treatments by measuring the protein in the blood, allowing doctors to adjust quickly when treatments are not effective.
More importantly, the research suggests that 14-3-3η itself is a “bad actor” in the development of the disease and therefore an important new target for drug treatment.
“If a drug treatment can reduce the 14-3-3η protein to undetectable levels (in a patient’s blood), we are confident we are using the right approach,” said Maksymowych.
With earlier detection and the “precision treatment” allowed by their discovery, Maksymowych believes the remission rate for rheumatoid arthritis, currently about 30 per cent, could double to 60 per cent or higher.
The tests developed to monitor 14-3-3η may also help many patients in remission live their lives without drugs, which can cost as much as $20,000 a year.
“This is a huge change, because we have the ability to achieve remission with current treatments,” said Maksymowych.
Once a patient is in remission, regular surveillance for 14-3-3η could be used as an “early warning signal” to prevent relapse, he said.
A next-generation test due out in the new year for both the 14-3-3η protein and the 14-3-3 antibody could push early detection as high as 93 per cent, according to data presented last year at a European congress of the world’s leading rheumatologists and since published in the peer-reviewed Journal of Rheumatology.
Maksymowych believes that 93 per cent may really be 100.
“We are starting to wonder if those last seven per cent of people who are negative for all four (conventional blood factor and JOINTstat) tests have rheumatoid arthritis at all,” he said. “They may have something else.”
In Canada, the JOINTstat test developed by Augurex is available through LifeLabs on a patient-pay basis for about $75. The test is offered by Quest Diagnostics in the United States and has become available for clinical use in Europe, Japan and Australia.
While early detection and treatment of rheumatoid arthritis is known to lead to more effective treatment and symptom control, the 14-3-3 family of proteins and antibodies may also help guide the development of more effective treatments personalized to the specific needs of each patient.
Marotta and co-founder CEO Norma Biln formed Augurex in 2006 to identify and develop early stage discoveries in the biomarker space. Augurex licensed the discovery from the University of B.C. after becoming convinced of its commercial and clinical potential in meetings with Ghahary, Maksymowych and their research partners.
As the Augurex immunoassay test was refined, it soon became apparent that 14-3-3η is a “very strong differential signal” in patients with rheumatoid arthritis. “You want to see that, so you don’t end up with a lot of false positives,” said Marotta.
With funding from the National Research Council of Canada’s Industrial Research Assistance Program, they undertook studies to prove that their target protein was part of the mechanism of disease and not simply a bystander.
“We could see that when 14-33η was added to cells in concentrations similar to those in the body, that it caused those cells to produce factors linked to the process of the disease,” he said.
The protein 14-3-3η is the first of four closely related markers Marotta and Biln believe have clinical importance to rheumatoid arthritis, potentially aiding the development of robust tools for diagnosis and treatment.
“It’s very rewarding to see a discovery move from bench to bedside and help the people it was intended for,” said Biln.
Augurex is also in the early stages of developing a drug to suppress 14-3-3η in rheumatoid arthritis patients.