Fatigue is one of the most common symptoms in patients with Rheumatoid arthritis. In this video I will address the most common causes of fatigue and also the steps you can take to manage your fatigue and start feeling better.
its final Phase III clinical trial, a new drug for treating rheumatoid arthritis has proved to be at least as effective as the current “gold standard” treatment for this autoimmune disease. This opens up new treatment options for affected patients. The results of the international multicentre study led by MedUni Vienna were recently published in the prestigious New England Journal of Medicine.
Currently, a combination of the drugs adalimumab (which inhibits the mediator of inflammation TNF (tumour necrosis factor)) and methotrexate (a folic acid antagonist) is one of the most effective options (“gold standard”) for patients who fail to respond adequately to initial treatment with methotrexate. Despite this and other effective drug regimens, up to 25% of patients do not respond well to any of the currently available therapeutic options. The new drug olokizumab is a humanised monoclonal antibody that directly targets the interleukin-6 cytokine. This is a messenger molecule that, like TNF, activates inflammatory responses in the body and is involved in the progression of joint damage in rheumatoid arthritis. Olokizumab is the first direct inhibitor (blocker) of interleukin-6 which will soon be filed for approval for commercial use for this indication.
In this Phase III clinical trial with more than 1,600 volunteers, the efficacy of the new drug in combination with methotrexate was tested against placebo and adalimumab plus methotrexate. This new therapy proved to be more efficacious than placebo and at least as effective as the current gold standard. “The new drug helps many patients with rheumatoid arthritis who failed methotrexate to achieve so-called low disease activity, which is the primary therapeutic goal in this population. Complete disappearance of symptoms of active disease, so called remission, occurs in 1 out of 8 patients,” explains study lead Josef Smolen from the Division of Rheumatology within the Department of Medicine III at MedUni Vienna and University Hospital Vienna. “This new therapy will significantly expand the range of treatment options, since this agent has a different mode of action than all other drugs.”
“This will give us another excellent treatment opportunity for our patients,” explains Daniel Aletaha, Head of the Division of Rheumatology. “We soon will have another option for those patients who do not respond to a first or subsequent therapies.”
The new drug is about to be filed for approval in the EU and the USA within the coming year. The researchers expect it to be in clinical use soon thereafter.
About rheumatoid arthritis
Rheumatoid arthritis is a chronic autoimmune disease that primarily affects women (approximately two thirds of those affected) and is usually diagnosed between the ages of 40 and 70. Approximately 1% of the world’s population suffers from rheumatoid arthritis. The disease causes inflammation of the joints, resulting in swelling, overheating and functional impairments. If left untreated, it leads to gradual destruction of the joints and the neighbouring bone, causing misalignment, malformation, and permanent and progressive disability. Around 80,000 people in Austria suffer from this disease.
New research presented this week at ACR Convergence, the American College of Rheumatology’s annual meeting, shows that people with difficult-to-treat rheumatoid arthritis who do not have success with one Janus kinase inhibitor (JAK inhibitor) can achieve success either cycling to other JAKi medications or switching to a biologic drug. (Abstract #1442).
Rheumatoid arthritis (RA) is the most common type of autoimmune arthritis. It is caused when the immune system (the body’s defense system) is not working properly. RA causes pain and swelling in the wrist and small joints of the hand and feet. Immunosuppressive treatments for RA can stop joint pain and swelling and may prevent joint damage.
JAK inhibitors are more recent additions to treat RA, but each one works differently. Some patients who fail a first JAK inhibitor may then try one of the others. There is no data that compares the effectiveness of cycling these therapies as opposed to switching to a biologic disease-modifying antirheumatic drug (bDMARD) in patients who have failed a first JAK inhibitor.
“In real life, JAK inhibitors are being used primarily in patients who have already failed treatment with a biologic DMARD, and they have shown to be effective in these situations. Despite this, in clinical trials, there were some patients who discontinued their JAK inhibitors due to lack of efficacy or safety concerns,” says Manuel Pombo-Suarez, MD, PhD, a rheumatologist at Hospital Clinico Universitario of Santiago de Compostela, Spain, and the study’s co-author.
Researchers set to find out if there’s another therapy to control disease in patients with RA. “There is no data on the effectiveness of using a second JAK inhibitor compared to a biologic DMARD after failure of a JAK inhibitor. We must provide a solution for these patients, so we asked this question in our study to find out which treatment strategy would be appropriate,” says Pombo-Suarez.
This nested cohort study included data on 708 RA patients who failed a first JAK inhibitor and then were treated with either a second JAKi (cycling) or a biologic DMARD (switching) in routine care. There were 154 who cycled and 554 who were switched. The researchers compared effectiveness for both treatment strategies on drug retention and disease activity, which was measured by DAS-28 disease activity test scores over one year after they started their second treatment.
Patients who cycled JAK inhibitors tended to be older, had RA for a longer time, had already received more biologic DMARDs, and had a longer exposure to the first JAK inhibitor compared to patients who switched.
Cycling and switching showed similar drug survival rates after two years of follow-up. Still, researchers noticed an interesting, though not statistically significant trend: discontinuation of treatment was more likely among the patients who cycled when their reason for stopping the first JAK inhibitor was because they had an adverse event. These patients were less likely to discontinue their second JAK inhibitor if they stopped the first drug because it was ineffective. Over time, patients’ disease activity test scores evolved in a similar way in both the cycling and switching groups, and both showed improvements after one year.
“This was precisely the goal of our study: to refine treatment options after failure to a JAK inhibitor. We intend to provide an answer for a growing population of RA patients, those who have failed treatment to JAK inhibitors,” says Dr. Pombo Suarez. “Our conclusion is that in those patients, the effectiveness of cycling to another JAK inhibitor is no different than that of switching to a biologic DMARD. Interestingly, patients cycling JAK inhibitors had a ‘more difficult-to-treat’ profile.”
Using new analytic tools, researchers at University of California San Diego School of Medicine and the Icahn School of Medicine at Mount Sinai have decoded the epigenetic landscape for rheumatoid arthritis (RA), a common autoimmune disease that affects more than 1.3 million Americans. In unveiling RA’s epigenome — the proteins and molecules that decorate DNA and help turn genes on and off — scientists made a surprising discovery: an overlap between the causes of RA and Huntington’s disease, a fatal and incurable genetic brain disease.
The findings are published online in the May 15 issue of Nature Communications.
The research team, led by senior author Gary S. Firestein, MD, dean and associate vice chancellor of translational medicine at UC San Diego School of Medicine, said the unexpected connection between RA and Huntington’s disease opens up the possibility of new therapeutic targets and drugs for both conditions.
“We did not expect to find an overlap between rheumatoid arthritis and Huntington’s disease, but discovering the unexpected was the reason that we developed this technology. Now that we have uncovered this connection, we hope that it opens a door for treatment options for people living with either disease,” said Firestein.
RA is a chronic inflammatory disorder that causes pain and swelling in joints. As an autoimmune disease, it can also affect other organs, including heart and blood vessels. Treatment for RA has improved, but 10 to 20 percent of patients do not respond to any available medicines.
The investigative approach used by the research team involved developing a novel algorithm, or set of computational rules, called EpiSig, which integrated and reduced the number of epigenetic combinations in the genes of patients with RA. The team could then identify new cell signaling pathways.
“Comparing different types of epigenomic data is difficult because it involves a variety of different data subsets that cannot normally be analyzed together, including various methods in which DNA gets modified,” said Wei Wang, PhD, professor of chemistry, biochemistry and cellular and molecular medicine at UC San Diego School of Medicine.
“This methodology can also be used to find connections between other diseases, not just rheumatoid arthritis,” added Firestein. “As genes involved are discovered, researchers can potentially identify new treatment options and even repurpose existing drugs.”
Firestein and team studied the epigenome in cells from the joints of patients with RA. Patients with osteoarthritis, which is a disease of cartilage degeneration, served as a control group. Both data sets were analyzed through an expansive process that examines chromatin, DNA and histone modifications. The results produced 12 terabytes of data (12 trillion bytes) that were then analyzed using EpiSig.
Epigenetics, or “above the genome”, is the study of processes that alter the gene structure without changing the DNA sequence itself. These DNA modifications are essential to human growth and development and change throughout people’s lives. Epigenetic changes are influenced by a variety of environmental factors, including stress, activity and lifestyle choices.
“By revealing the comprehensive epigenetics behind rheumatoid arthritis, we now have a better understanding of this disease. More importantly, our new approach, could not only help patients with rheumatoid arthritis, but also people with other immune-mediated diseases,” Firestein said.
In patients with chronic inflammatory conditions, such as rheumatoid arthritis, there has been limited understanding of how this inflammation affects the brain.
A new study published in Nature Communications examines this issue.
“Rheumatoid arthritis is an inflammatory and autoimmune condition with nasty levels of inflammation that can affect a person’s joints and the rest of their body, inducing fatigue, sleep and creating cognitive difficulties,” says Andrew Schrepf, Ph.D., a research investigator at Michigan Medicine’s Chronic Pain and Fatigue Research Center and one of the lead authors of the study.
“Even though it has been assumed for a long time that the inflammation we see in blood is impacting the brain, up until this study we didn’t know precisely where and how those changes in the brain were actually happening.”
Schrepf says the effects of inflammation are more understood in short-term illnesses, but the same can’t be said for chronic conditions.
“When a person becomes sick with the flu, for example, they begin to show symptoms of the inflammation happening in their body, such as feeling lethargic and being unable to control their body temperature,” he says. “We wanted to understand what is happening in conditions where patients have inflammation for weeks, months or years, such as in rheumatoid arthritis.”
The research team used a data set of 54 rheumatoid arthritis patients carefully constructed and characterized by author Neil Basu, Ph.D., of the University of Aberdeen in the United Kingdom, Schrepf says.
“Studies such as ours are usually performed in healthy people who are induced with sickness behaviors,” Schrepf explains, calling the available data “remarkable.” “They will then do a brain scan before and after the immune insult, and the results are interesting, but to understand how it impacts people with chronic illness, we have to see the brain of someone with inflammation happening for a long period of time.”
Using functional and structural neuroimaging of the data set at baseline and six months, the research team examined whether higher levels of peripheral inflammation were associated with brain connectivity and structure.
“We took the levels of inflammation in their peripheral blood, just as it would be done clinically by a rheumatologist to monitor the severity of their disease and how it’s being controlled,” Schrepf says. “We found profound and consistent results in a couple areas of the brain that were becoming connected to several brain networks. We then looked again six months later and saw similar patterns, and this replication of results is not that common in neuroimaging studies.”
Co-first author Chelsea Kaplan, Ph.D., an anesthesiology research fellow at Michigan Medicine, then examined the functional connectivity of 264 regions of the brain and identified increased connectivity patterns in patients experiencing heightened levels of inflammation.
“In a graph theoretical analysis across the whole brain network, and correlating that with levels of inflammation, we saw a lot of convergence across methods and time points for the amount of connectivity in the inferior parietal lobule and medial prefrontal cortex,” Kaplan says.
“This showed us that the brain doesn’t operate in isolation. It also demonstrated how inflammation we measure in the periphery may be actually altering functional connections in the brain and playing a role in some of the cognitive symptoms we see in rheumatoid arthritis.”
Basu, who is a practicing rheumatologist and a researcher, notes anti-inflammatory therapeutics have evolved over the past decade and have alleviated the peripheral inflammation driving the joint pain and disability in rheumatoid arthritis. Despite such progress, patients continue to report challenging levels of symptoms such as fatigue and mood dysfunction.
“This intriguing data supports the idea that rheumatoid arthritis inflammation targets the brain and not just the joints,” Basu says. “By relating these advanced neuroimaging measures back to the patient experience, we provide evidence that the future targeting of central inflammatory pathways may greatly enhance the quality of life of patients with rheumatoid arthritis and potentially other chronic inflammatory disorders.”
Because this is one of the first studies to examine brain inflammation in rheumatoid arthritis, Schrepf says, additional research is needed on the correlation.
Basu agrees, “Further exploration into this complex space demands strong multidisciplinary and collaborative working, and this study represents a fine example of trans-Atlantic team science.”