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SAN DIEGO—The next era of rheumatoid arthritis (RA) therapy could involve combining anti-tumor necrosis factor (anti-TNF) drugs with drugs that target molecules regulating the destructive potential of synovial fibroblasts, or even with anti-angiogenic drugs, said a pioneer of RA biologics therapy at the 2017 ACR/ARHP Annual Meeting Nov. 3–8.
Ravinder N. Maini, MD, professor of rheumatology at the Kennedy Institute of the Imperial College of London in London, England, and integral to the development of TNF inhibitors, said the treatment of diseases from cancer to RA has been headlined by the clever use of combinations, and he suspects the next phase of RA treatment will prove no different. His remarks came in his Paul Klemperer Memorial Lecture.
“We should look at the combination of anti-TNF—which is well understood, well studied, we know it works—with nonimmune targets that I think offer the best prospects for the next phase of conquering rheumatoid arthritis,” he said. Some of those other targets include anti-MMP14 and anti-cadherin11, or even, eventually, “a good anti-angiogenic drug that doesn’t harm patients.”
In his talk, Dr. Maini traced the unlikely arc of the research that led to anti-TNF therapies becoming such a therapeutic boon to patients, as well as an economic boon.
“This story is unusual,” he said, “because it permitted my colleague, Marc Feldmann, and me to actually see this story from the ground when it was pure speculation, conceptual, based on observations in preclinical experiments, to being able to provide it in patient experiments through a unique collaboration we were able to build with a biotechnology company.”
He was a research fellow nearly 40 years ago as he worked to understand “cell-mediated immunity,” the idea that the inflammatory process of RA was mediated by lymphocytes that had to be in contact with the cells that responded in order for the events to unfold. That concept was eventually found to not be an effective way to think about RA treatment development.
He and Dr. Feldmann eventually grew interested in the cytokines that could be detected with new technology, and “every probe we used on rheumatoid tissues demonstrated the presence of all the cytokines we had access to.”
Dr. Maini, who receives royalties related to anti-TNF therapy, said that at the time, it seemed “impossible” that any one of these cytokines could be responsible for driving the entire complex process that happens in a RA joint. But in preclinical experiments in vitro and in an animal model, TNF was found to drive the inflammatory response, and its blockade became a premier candidate for therapy. The two researchers started contacting “every biotech company and every pharmaceutical company” that had access to TNF inhibitors.
‘To make any sense of this kind of data, we’re going to need big data & artificial intelligence.’ —Dr. Maini
TNF was developed to treat cancer, but proved unsuccessful. Anti-TNF drugs were originally developed as a potential treatment for sepsis, and there were high hopes it could treat septic shock, but neither application panned out.
Eventually, a few patients received the anti-TNF drug the researchers obtained from a biotech company. And Dr. Maini said he’ll never forget “Patient 6” in an experimental study, who he said marked a crucial point in the era of RA biologics. The patient, a 20-year-old woman with relatively recent RA onset, had such trouble walking it was hard to live a normal life. In a video shot four weeks after injection of the drug now known as infliximab, she was walking so well she seemed light of foot.
Today, at tertiary centers remission is possible in 30% of patients and at least low disease activity in 80%.
“There’s been a huge change, which is reflected in real life in rheumatology clinics, and in the experience of general practitioners worldwide who have access to modern therapies,” Dr. Maini said, not due only to biologics, but also to much better use of synthetic disease-modifying anti-rheumatic drugs in a treat-to-target fashion.
But Dr. Maini remains preoccupied with better outcomes, both through scientific advances and through prevention by curbing tobacco use, consumption of sugary drinks, high-salt diets and other factors.
“Some people tell me, ‘Why are you fussing? You’ve done the work. It’s finished, it’s done, you don’t need to do anymore,’” he said. “I think that’s a very, very short-sighted view, because in fact, even this very optimistic picture tells us there are a number of patients who aren’t doing well.”
New technologies will drive the field forward, he said. With advances such as CRISPR (i.e., clustered regularly interspaced short palindromic repeats) genome editing and single-cell mass cytometry, researchers will need powerful technology to take advantage of an avalanche of information.
“That’s a formidable amount of data if you think about it,” he said, “And to make any sense of this kind of data, we’re going to need big data and artificial intelligence. Thank goodness big data and artificial intelligence are keeping pace with laboratory breakthroughs.”
The ultimate therapy, he said, would look similar to penicillin—a treatment that remains simple and brief.
“We really do need something that, basically with short-term exposure, leads to a long-term benefit,” he said. “That’s the ideal.”
Thomas R. Collins is a freelance writer living in South Florida.
