Meaningful improvements from a new drug for rheumatoid arthritis patients

Mark Genovese led an international clinical trial of an experimental medication that improved the condition of rheumatoid arthritis patients who had failed to get relief from other therapies. Norbert von der Groeben

In a large trial led by a Stanford investigator, an experimental drug produced clinically meaningful improvements for rheumatoid arthritis patients unresponsive to existing treatments.

Rheumatoid arthritis patients getting little or no relief from conventional small-molecule drugs and injectable biologic drugs saw substantial improvement in their condition from daily use of an experimental compound in a large 24-week study led by a Stanford University School of Medicine investigator

A paper describing the results of the double-blind, randomized phase-3 clinical trial was published July 23 in JAMA.

“For patients who haven’t done well on other therapies, these findings are cause for optimism, enthusiasm and hope,” said Mark Genovese, MD, professor of immunology and rheumatology and principal investigator of the study.

Stanford Health Care offers services to rheumatoid arthritis patients through its immunology and rheumatology clinic. As clinical chief, Genovese spends three half-days per week in the clinic, where he regularly sees and treats rheumatoid arthritis patients.

He is the paper’s lead author. The senior author is Tsutomu Takeuchi, MD, PhD, professor of rheumatology and clinical immunology at Keio University School of Medicine in Tokyo, Japan.

Rheumatoid arthritis is a progressive, systemic autoimmune disease affecting at least 1 in every 100 people worldwide. For reasons that aren’t understood, 3 of every 4 people with the disorder are women. While its most visible hallmarks are pain, stiffness, inflammation and eventual deterioration of joints, patients also are at heightened risk for cardiovascular disease and other inflammatory complications.

In clinical trials, about 70% of rheumatoid arthritis patients have appeared to benefit initially from small-molecule therapies in a pill form, such as methotrexate, said Genovese, who is the James W. Raitt M.D. Professor. However, “in the real world, adherence to any of them is more like 50%,” he said. Patients for whom the conventional small-molecule drugs fail are switched to pricey, injectable, bioengineered-protein drugs, including three of the world’s top-15 biggest-selling drugs in dollar sales. But these drugs, too, fail among about half the rheumatoid arthritis patients who use them, Genovese said.

Selective JAK-1 inhibitor

The experimental compound, filgotinib, is a selective JAK-1 inhibitor. It works by preferentially blocking 1 of a set of 4 closely related enzymes required for certain inflammatory signaling processes within cells. Two other compounds that are similar in mechanism of action to filgotinib but that impede JAK enzyme family members less selectively are licensed in the United States for use by rheumatoid arthritis patients, but only at low doses or with warning labels due to side effects.

This novel drug works exceptionally well in patients who’ve already failed traditional therapies for rheumatoid arthritis.

The trial was conducted in 114 centers in 15 countries, mostly in North America and Europe. The 449 participants averaged 56 years of age, and about 80% of them were female. They were randomized to 1 of 3 study arms, in which they received daily doses of either 200 milligrams of filgotinib, 100 milligrams of filgotinib or a placebo for 24 weeks. All participants had moderately to severely active rheumatoid arthritis despite treatment with one or more biologic therapies.

The primary goal of the study was to observe whether there was an improvement at 12 weeks into the trial of at least 20% on a measure of joint swelling and tenderness called the ACR20 that was established by the American College of Rheumatology. An important secondary outcome was a score indicating low disease activity in 28 predetermined joints on a test called the DAS28-CRP.

Compared with the placebo group, a significantly greater proportion of participants on both the high- and low-dose filgotinib regimens achieved the primary endpoint: a 20% improvement in symptoms as measured by the ACR20. Sixty-six percent of participants on 200 milligrams of filgotinib, and 57.5% of those on 100 milligrams, fulfilled this criterion, versus only 31.1% of those on placebo.

Of equal or even greater importance, Genovese said, was the participants’ improvement on the DAS28-CRP at both 12 and 24 weeks. By 12 weeks, 40.8% of those on the 200 milligram dose of filgotinib and 37.3% of those on 100 milligrams had reached the status of low disease activity as measured by the DAS28-CRP, as opposed to only 15.5% of those on the placebo regimen. These outcomes continued or improved over the course of the trial. By 24 weeks, 48.3% of the high-dose filgotinib recipients and 37.9% of those on the low dose had reached low-disease-activity status.

By week 12 of the trial, 22.4% of high-dose and 25.5% of low-dose filgotinib recipients, but only 8.1% of placebo recipients, had DAS28-CRP scores indicating outright remission. By week 24, high-dose recipients had a remission rate of 30.6%; low-dose recipients, 26.1%; and placebo recipients, 12.2%.

Improvement seen early on

The drug’s benefits to participants became apparent soon after the trial’s onset. “We could see improvements as early as two weeks into the trial,” Genovese said.

Also telling was a substantial difference among the study arms in how many participants completed the 24-week trial. Of the 148 participants in the placebo arm, 51 dropped out before completion. Only 20 of the 148 high-dose recipients and 34 of the 153 low-dose recipients dropped out.

Investigators’ early concerns about increased susceptibility to infections, or the re-emergence of active forms of prior infections, such as tuberculosis or shingles, were assuaged by the relative smattering of such adverse events, compared with placebo.

Notably, patients for whom at least three different biologic therapies provided insufficient relief did as well in this trial as those who’d derived insufficient relief from just one biologic therapy, Genovese said. “We found that those high levels of response were independent of how many drugs you’d failed, and independent of which drugs you’d failed,” he said.

Overall response rates to filgotinib appear to surpass those of the other commercially available JAK inhibitors at doses approved for use in the United States, he said.

“This novel drug works exceptionally well in patients who’ve already failed traditional therapies for rheumatoid arthritis,” he said.

Learn more: Novel rheumatoid arthritis drug succeeds in clinical trial


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Electro stimulation of the vagus nerve could provide a novel treatment approach for patients with rheumatoid arthritis

via NRAS – National Rheumatoid Arthritis Society

The results of a pilot study presented today at the Annual European Congress of Rheumatology (EULAR 2019) suggest that electro stimulation of one of the nerves connecting the brain to the body (the vagus nerve), could provide a novel treatment approach for patients with rheumatoid arthritis.

“This is a really exciting development. For many patients suffering from rheumatoid arthritis, current treatments don’t work, or aren’t tolerated,” said Professor Thomas Dörner, Chairperson of the Scientific Programme Committee, EULAR. “These results open the door to a novel approach to treating not only rheumatoid arthritis, but other chronic inflammatory diseases. This is certainly an area for further study.”

The vagus nerve is the longest and the most complex of the 12 pairs of cranial nerves that originate from the brain. The name ‘vagus’ comes from the latin word for ‘wandering’. This is because the vagus nerve wanders from the brain into the organs of the neck, chest and abdomen.

Recent advances in neuroscience and immunology have mapped circuits in the brain that regulate immune responses. In one of the circuits, the ‘inflammatory reflex’, signals are transmitted in the vagus nerve that inhibit the production of cytokines including tumor necrosis factor (TNF), an inflammatory molecule that is a major therapeutic target in rheumatoid arthritis. It is thought that, by stimulating the activity of this inflammatory reflex, innate immune responses can be modulated without abolishing them or producing significant immunosuppression.

In this pilot study, a novel miniaturised neurostimulator called a MicroRegulator was implanted into 14 patients with rheumatoid arthritis who had failed on at least two biologics or targeted oral therapies with different mechanisms of action. Patients were randomised to three groups who were either placebo, stimulated once daily, or stimulated four times a day for 12 weeks. At the end of the study, the patients who received once-daily stimulation were shown to have a better response than those on four-times-daily stimulation with two thirds meeting the EULAR good or moderate response criteria and a mean change in DAS28-CRP of -1.24. The mean change in DAS28-CRP* in the placebo group was 0.16.1

Cytokines (a broad and loose category of small proteins that are important in cell signalling) were also measured in the study with the actively stimulated groups showing a decrease of more than 30% in levels of Interleukin (IL) 1?, IL-6, and TNF-?. Implantation and stimulation were generally well tolerated with no device or treatment-related SAEs and two surgery-related adverse events that resolved without clinically significant effects.

“Our pilot study suggests this novel MicroRegulator device is well tolerated and reduces signs and symptoms of rheumatoid arthritis,” said Mark Genovese, M.D., James W. Raitt Endowed Professor of Medicine, Stanford University, Stanford, California, USA. “These data support the study of this device in a larger placebo-controlled study as a novel treatment approach for rheumatoid arthritis and possibly other chronic inflammatory diseases.”

This study follows a proof-of-concept study which used reprogrammed epilepsy stimulators on the vagus nerve to demonstrate reduced systemic inflammation and improved disease activity in 17 patients with rheumatoid arthritis.

The study included 14 patients with active rheumatoid arthritis who had had an insufficient response to more than two biological disease modifying anti-rheumatic drugs (bDMARDs) or JAK inhibitors with more than two modes of action. All patients remained on stable background of methotrexate. The first three patients were implanted and stimulated after three weeks, following safety review board approval, the remaining 11 patients were implanted and randomised to one minute of stimulation once-daily, one minute of stimulation four times daily, or one minute of placebo stimulation.

Learn more: Vagus nerve stimulation study shows significant reduction in rheumatoid arthritis symptoms


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Could gum disease have an impact on Alzheimer’s disease, rheumatoid arthritis and aspiration pneumonia?

The mouth of a person with severe gum disease. Bacteria involved in periodontitis have been linked with Alzheimer’s disease, aspiration pneumonia, rheumatoid arthritis and other common disorders.
Image courtesy of Jan Potempa, University of Louisville.

Scientists trace path of bacterial toxins from the mouth to the brain and other tissues

Researchers are reporting new findings on how bacteria involved in gum disease can travel throughout the body, exuding toxins connected with Alzheimer’s disease, rheumatoid arthritis and aspiration pneumonia. They detected evidence of the bacteria in brain samples from people with Alzheimer’s and used mice to show that the bacterium can find its way from the mouth to the brain.

The bacterium, Porphyromonas gingivalis, is the bad actor involved in periodontitis, the most serious form of gum disease. These new findings underscore the importance of good dental hygiene as scientists seek ways to better control this common bacterial infection.

“Oral hygiene is very important throughout our life, not only for having a beautiful smile but also to decrease the risk of many serious diseases,” said Jan Potempa, PhD, DSc, a professor at the University of Louisville School of Dentistry and head of the department of microbiology at Jagiellonian University in Krakow, Poland. “People with genetic risk factors that make them susceptible to rheumatoid arthritis or Alzheimer’s disease should be extremely concerned with preventing gum disease.”

While previous researchers have noted the presence of P. gingivalis in brain samples from Alzheimer’s patients, Potempa’s team, in collaboration with Cortexyme, Inc., offers the strongest evidence to date that the bacterium may actually contribute to the development of Alzheimer’s disease. Potempa will present the research at the American Association of Anatomists annual meeting during the 2019 Experimental Biology meeting, held April 6-9 in Orlando, Fla.

The researchers compared brain samples from deceased people with and without Alzheimer’s disease who were roughly the same age when they died. They found P. gingivaliswas more common in samples from Alzheimer’s patients, evidenced by the bacterium’s DNA fingerprint and the presence of its key toxins, known as gingipains.

In studies using mice, they showed P. gingivalis can move from the mouth to the brain and that this migration can be blocked by chemicals that interact with gingipains. An experimental drug that blocks gingipains, known as COR388, is currently in phase 1 clinical trials for Alzheimer’s disease. Cortexyme, Inc. and Potempa’s team are working on other compounds that block enzymes important to P. gingivalis and other gum bacteria in hopes of interrupting their role in advancing Alzheimer’s and other diseases.

The researchers also report evidence on the bacterium’s role in the autoimmune disease rheumatoid arthritis, as well as aspiration pneumonia, a lung infection caused by inhaling food or saliva.

P. gingivalis‘s main toxins, the enzymes the bacterium need to exert its devilish tasks, are good targets for potential new medical interventions to counteract a variety of diseases,” said Potempa. “The beauty of such approaches in comparison to antibiotics is that such interventions are aimed only at key pathogens, leaving alone good, commensal bacteria, which we need.”

P. gingivalis commonly begins to infiltrate the gums during the teenage years. About one in five people under age 30 have low levels of the bacterium in their gums. While it is not harmful in most people, if it grows to large numbers the bacteria provoke the body’s immune system to create inflammation, leading to redness, swelling, bleeding and the erosion of gum tissue.

Making matters worse, P. gingivalis even causes benign bacteria in the mouth to change their activities and further increase the immune response. Bacteria can travel from the mouth into the bloodstream through the simple act of chewing or brushing teeth.

The best way to prevent P. gingivalis from growing out of control is by brushing and flossing regularly and visiting a dental hygienist at least once a year, Potempa said. Smokers and older people are at increased risk for infection. Genetic factors are also thought to play a role, but they are not well understood.

Learn more: Gum bacteria implicated in Alzheimer’s and other diseases


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A surprise new treatment for rheumatoid arthritis?

Researchers Kodi S. Ravichandran (left) and Sanja Arandjelovic of the UVA School of Medicine have identified an unexpected contributor to rheumatoid arthritis that may lead to a new treatment for the painful condition.
Dan Addison | University Communications

Researchers at the University of Virginia School of Medicine have identified an unexpected contributor to rheumatoid arthritis that may help explain the painful flare-ups associated with the disease. The discovery points to a potential new treatment for the autoimmune disorder and may also allow the use of a simple blood test to detect people at elevated risk for developing the condition.

The promising discovery is among the first to emerge from the School of Medicine’s new affiliation with Inova Health, a collaboration that aims to make medical breakthroughs and advance the battle against disease. In this case, the arthritis discovery originated in the lab of UVA’s Kodi Ravichandran, PhD, and was facilitated by combining his team’s resources and expertise with that of Inova researcher Thomas Conrads, PhD, through a THRIV UVA-Inova seed grant.

Understanding Rheumatoid Arthritis

The new findings about rheumatoid arthritis came in an unexpected fashion. Sanja Arandjelovic, PhD, a research scientist in the Ravichandran group, was seeking to better understand what causes the inflammation associated with inflammatory arthritis when she noted that deleting a gene called ELMO1 alleviated arthritis symptoms in mice. This was particularly surprising because Arandjelovic and Ravichandran initially thought that loss of ELMO1 would result in increased inflammation.

“This was a complete surprise to us initially,” recalled Ravichandran, chairman of UVA’s Department of Microbiology, Immunology and Cancer Biology. “I love those kinds of results, because they tell us that, first, we did not fully comprehend the scientific problem when we began exploring it, and, second, such unexpected results challenge us to think in a different way. Given that rheumatoid arthritis affects millions of people worldwide, we felt the need to understand this observation better.”

Digging deeper into the unusual outcome, the researchers determined that ELMO1 promotes inflammation via their function in white blood cells called neutrophils. Ravichandran described neutrophils as the body’s “first line of defense” because they sense and respond to potential threats. “Normally they are good for us, against many bacterial infections,” he said. “But also there are many times when they produce a lot of friendly fire that is quite damaging to the tissues – when they hang around too long or there are too many neutrophils coming in – in this case, infiltrating into the joints during arthritis.”

The researchers also discovered that there is a natural variation in the ELMO1 gene that can prompt neutrophils to become more mobile and have the potential to invade the joints in greater numbers and induce inflammation. (The potential blood test would detect this variation.)

Here things take a particularly cool turn: Normally, doctors are reluctant to try to block the effect of genes like ELMO1 in people, because such genes can play diverse roles in the body. But Ravichandran believes that ELMO1 is different. “ELMO1 partners with very specific set of proteins only in the neutrophils but not in other cells types we tested,” he said. “So, presumably, you may be able to affect only a select cell type.” This latter result came about from a collaborative study where Conrads’ group at Inova performed sophisticated analysis of ELMO1 proteomic partners in neutrophils, many of which also have previously known links to human arthritis. This provided further validation for the role of ELMO1 in rheumatoid arthritis.

Encouragingly, blocking ELMO1 in lab mice alleviated arthritis inflammation without causing other problems, Ravichandran noted. His laboratory is now seeking to identify drugs that could inhibit the function of ELMO1 and is also designing a test for the variation (also called polymorphism) in the ELMO1 gene.

“This is another example of how fundamental basic research can lead to novel discoveries on clinically relevant problems that affect a large number of people,” Ravichandran said.

Learn more: Surprise rheumatoid arthritis discovery points to new treatment



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Could nanosponges treat or even prevent rheumatoid arthritis from developing?

Illustration of a neutrophil cell membrane-coated nanoparticle.

Engineers at the University of California San Diego have developed neutrophil “nanosponges” that can safely absorb and neutralize a variety of proteins that play a role in the progression of rheumatoid arthritis. Injections of these nanosponges effectively treated severe rheumatoid arthritis in two mouse models. Administering the nanosponges early on also prevented the disease from developing.

The work is published Sept. 3 in Nature Nanotechnology.

“Nanosponges are a new paradigm of treatment to block pathological molecules from triggering disease in the body,” said senior author Liangfang Zhang, a nanoengineering professor at the UC San Diego Jacobs School of Engineering. “Rather than creating treatments to block a few specific types of pathological molecules, we are developing a platform that can block a broad spectrum of them, and this way we can treat and prevent disease more effectively and efficiently.”

This work is one of the latest examples of therapeutic nanosponges developed by Zhang’s lab. Zhang, who is also affiliated with the Institute of Engineering in Medicine and Moores Cancer Center at UC San Diego, and his team previously developed red blood cell nanosponges to combat and prevent MRSA infections and macrophage nanosponges to treat and manage sepsis.

The new nanosponges are nanoparticles of biodegradable polymer coated with the cell membranes of neutrophils, a type of white blood cell.

Neutrophils are among the immune system’s first responders against invading pathogens. They are also known to play a role in the development of rheumatoid arthritis, a chronic autoimmune disease that causes painful inflammation in the joints and can ultimately lead to damage of cartilage and bone tissue.

When rheumatoid arthritis develops, cells in the joints produce inflammatory proteins called cytokines. Release of cytokines signals neutrophils to enter the joints. Once there, cytokines bind to receptors on the neutrophil surfaces, activating them to release more cytokines, which in turn draws more neutrophils to the joints and so on.

The nanosponges essentially nip this inflammatory cascade in the bud. By acting as tiny neutrophil decoys, they intercept cytokines and stop them from signaling even more neutrophils to the joints, reducing inflammation and joint damage.

These nanosponges offer a promising alternative to current treatments for rheumatoid arthritis. Some monoclonal antibody drugs, for example, have helped patients manage symptoms of the disease, but they work by neutralizing only specific types of cytokines. This is not sufficient to treat the disease, said Zhang, because there are so many different types of cytokines and pathological molecules involved.

“Neutralizing just one or two types might not be as effective. So our approach is to take neutrophil cell membranes, which naturally have receptors to bind all these different types of cytokines, and use them to manage an entire population of inflammatory molecules,” said Zhang.

“This strategy removes the need to identify specific cytokines or inflammatory signals in the process. Using entire neutrophil cell membranes, we’re cutting off all these inflammatory signals at once,” said first author Qiangzhe Zhang, a Ph.D. student in Professor Liangfang Zhang’s research group at UC San Diego.

To make the neutrophil nanosponges, the researchers first developed a method to separate neutrophils from whole blood. They then processed the cells in a solution that causes them to swell and burst, leaving the membranes behind. The membranes were then broken up into much smaller pieces. Mixing them with ball-shaped nanoparticles made of biodegradable polymer fused the neutrophil cell membranes onto the nanoparticle surfaces.

“One of the major challenges of this work was streamlining this entire process, from isolating neutrophils from blood to removing the membranes, and making this process repeatable. We spent a lot of time figuring this out and eventually created a consistent neutrophil nanosponge production line,” said Qiangzhe Zhang.

In mouse models of severe rheumatoid arthritis, injecting nanosponges in inflamed joints led to reduced swelling and protected cartilage from further damage. The nanosponges performed just as well as treatments in which mice were administered a high dose of monoclonal antibodies.

The nanosponges also worked as a preventive treatment when administered prior to inducing the disease in another group of mice.

Professor Liangfang Zhang cautions that the nanosponge treatment does not eliminate the disease. “We are basically able to manage the disease. It’s not completely gone. But swelling is greatly reduced and cartilage damage is minimized,” he said.

The team hopes to one day see their work in clinical trials.

Learn more: Neutrophil Nanosponges Soak up Proteins That Promote Rheumatoid Arthritis



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