Unless you have rheumatoid arthritis, an autoimmune condition that causes the body to attack its own tissue, destroying the synovial lining inside of joints.

That eventually leads to erosion of cartilage and bone, a painful and often debilitating condition that can make the simplest tasks – like opening a jar or buttoning a shirt – challenging if not impossible.

So far, science has a clear picture of what it looks like to live with rheumatoid arthritis. But researchers still don’t know what sparks the autoimmune disorder at the heart of it.

“Growing evidence indicates that metabolic dysfunction in lymphocytes may be an important factor,” said Dr. Aaron Marshall, professor and head of immunology at the Max Rady College of Medicine, Rady Faculty of Health Sciences. “But this has not been studied in B cells from rheumatoid arthritis patients.”

With a recent grant of $100,000 ($50,000 per year for two years) from the Arthritis Society Canada, Marshall and his Rady Faculty coinvestigators Dr. Hani El-Gabalawy and Dr. Liam O’Neil now have the initial funds they need to launch a project that could help change the lives of hundreds of thousands of Canadians.

Their project, “Understanding how sugar fuels autoimmune disease,” involves exploring how autoantibody-producing B cells promote the cycle of inflammation that leads to joint damage in rheumatoid arthritis patients.

“This is innovative research that could open a new area of research and identify new approaches to treat and prevent worsening of rheumatoid arthritis,” said Marshall.

The funds are from the Arthritis Society Canada through an Ignite Innovation Grant, a unique program that encourages people to take bold chances by testing out new ideas or theories, especially those that are considered risky, but have the potential for significant rewards if successful.

“We hope to identify specific metabolic inhibitor drugs that can shut down disease-promoting B cells,” said Marshall. “And as many new medicines are being developed to target metabolic enzymes for treatment of cancer, our results may spark collaborations with industry to develop or repurpose such medicines to benefit rheumatoid arthritis patients.”

The Ignite Innovation Grant is awarded at the start of a project, which means that if the research is deemed feasible, preliminary data is not necessary and researchers like Marshall and his team can hit the ground running.

“It was great to be able to move very quickly from a new idea to a funded project to actually test it!” said Marshall. “I hope this will launch a new research direction in my lab and in the arthritis research field.”

“I’m humbled,” said Dr. Vidyanand Anaparti, a research associate in the department of internal medicine at the Max Rady College of Medicine. “I’m honoured my research made the list.”

But this isn’t the first time Anaparti’s work has made the annual list highlighting research breakthroughs in the area of arthritis. Anaparti’s findings have been featured on the list for 2019 and 2020. 

The research that most recently made the list began 12 years ago, when samples of synovial tissue were collected from the knees of 17 patients with early rheumatoid arthritis. Synovial tissue is a connective tissue that surrounds joints. It’s where rheumatoid arthritis begins, Anaparti said.  

After the synovial tissue was collected, the patients’ clinical data was gathered over 12 years and the scientists discovered that the patients could be placed into two groups. One group of patients had significantly high levels of matrix metalloproteinase (MMP) and the other group of patients had low levels. MMP is a group of enzymes that break down proteins found in spaces between cells in tissues. The enzymes were responsible for tissue degradation of synovial tissue and increased inflammation, Anaparti said.  

The research team observed that people with high MMP responded well to treatment, had lower joint inflammation and a reduction in swollen joint count than those who had low MMP levels. The study was published in Frontiers of Medicine last year.

“We can predict by analyzing the genes expressed in the tissue biopsy of an individual who will respond to treatment better and who will resist treatment,” Anaparti said. “We need to collect more samples and conduct more studies to validate our model, but this is definitely a big start and a step closer to a precision medicine based approach to treating rheumatoid arthritis.”

Dr. Siân Bevan, chief science officer, Arthritis Society Canada, said that one in five Manitobans has arthritis and it’s time to transform how we understand and treat this disease.

“By revealing new insights about the molecular features and outcomes of people with rheumatoid arthritis, this research could help tackle the common problem of patients going through trial-and-error cycles before finding the best treatment for them,” Bevan said.

This research will not only benefit patients but the health-care system as well, Anaparti said. The system will save money because patients won’t be on treatments that don’t work for them, he said.

“My sincerest congratulations to Vidyanand on this important accomplishment,” said Dr. Hani El-Gabalawy, professor of internal medicine and immunology at the Max Rady College of Medicine, who is Anaparti’s supervisor along with Dr. Neeloffer Mookherjee, professor of internal medicine and immunology. “The basic and translational research he has undertaken at the Manitoba Centre for Proteomics and Systems Biology provided new insights into how the early molecular and cellular patterns found in the inflamed joints can predict the outcomes of rheumatoid arthritis up to 15 year later.”

“He would wake up at 5:30 a.m. every morning to go into the lab and start on his research. Then head to the OR at 7:00 a.m. where he had a full patient load,” says Will Falk.

The three-year professorship was inspired by the Centennial Fellowship, a two-year award that allowed Rudy Falk to study in Stockholm with highly respected immunologists.

“What we try to do is give young scientists protected time for research while still establishing themselves as physicians,” says Will Falk.

This year’s recipient, assistant professor of internal medicine and immunology, Liam O’Neil [BSc/09, MD/12] embodies Falk’s zeal for research and clinical practice. While in medical school, O’Neil thought he would practice as a physician full-time. However, while working with different mentors throughout his career, he found himself gravitating more towards research. 

“The more you learn about medicine and disease, the more you realize how little we actually know about diseases such as rheumatoid arthritis. I think that combined with the right mentorship really facilitated my interest in pursuing a research career,” O’Neil says.

This professorship will allow him to study the causes of rheumatoid arthritis and investigate how to possibly prevent the disease once a person has developed the autoantibodies. Working with O’Neil on this study is Dr. Hani El-Gabalawy, professor of internal medicine and immunology and Endowed Rheumatology Research Chair, who also nominated O’Neil for the professorship.

“He has been a huge mentor for me. I certainly would not have applied without his support, he really believed in me,” says O’Neil.

Rheumatoid arthritis affects only about 1 per cent of the population, but around 2 – 3 per cent of people who live in Indigenous communities, where O’Neil and El-Gabalawy have been focusing their research.

O’Neil says the increase in the affliction of rheumatoid arthritis in these communities is likely due to genetics and environmental factors. By observing individuals who are more likely to develop rheumatoid arthritis and observing what may be causing those individuals to develop the disease, they may be able to pinpoint how to prevent the disease.

He and El-Gabalawy are using a combination of nutritional supplements, curcumin, vitamin D and omega 3 to treat people who have rheumatoid arthritis antibodies to see if they can be used as a preventative measure.

O’Neil hopes that this award will bring attention not only to his research on rheumatoid arthritis but also to careers that combine research and clinical practice.

“There’s not many people who take on clinical duties but also engage heavily in doing research. It’s not a common career path so I really saw this professorship award as an opportunity to promote the department and the research we are doing,” says O’Neil. “There is no replacement for physicians engaged in an active research program. I think it’s really important that we continue to promote these types of careers as being viable for individuals who are early in their training programs.”

O’Neil finds working with patients to be one of the most rewarding aspects of his job. He asks them to participate in his research to learn more about what they can do to prevent or treat their disease. 

The project has received a one-year grant from The Winnipeg Foundation Innovation Fund, which supports cutting-edge, collaborative medical research in the Rady Faculty of Health Sciences.

Rheumatoid arthritis (RA) is an autoimmune disease that causes swelling of the joints. Before patients develop RA, they develop autoantibodies and joint symptoms such as pain and stiffness, without swelling.

“Our research team wants to understand if Manitobans who are at high risk to develop RA have differences in their joints that can be detected by thermal imaging,” says the study’s leader, Dr. Liam O’Neil, assistant professor of internal medicine and immunology.  

“A state-of-the-art thermal camera, which UM will acquire for this research, can detect very small increases in temperature – one of the most important features of inflammation. We think that before RA starts, at-risk individuals will show changes to their joints that can be captured by the thermal camera, but not necessarily by physical examination.”

The highly sensitive camera will produce better-quality images than have been attained in most previous studies applying thermal imaging to RA, O’Neil says.  

O’Neil is collaborating on the study with Dr. Pingzhao Hu, associate professor of biochemistry and medical genetics, Dr. Hani El-Gabalawy, professor of internal medicine and immunology, and Dr. Dylan MacKay, assistant professor of community health sciences.

The interdisciplinary team will use deep learning, a form of artificial intelligence, to analyze the thermal images. They will “teach” a computer to interpret the images, recognize inflammation, and develop an automatic method to determine whether the images are from a healthy person or someone at high risk to develop RA.

“This study will use leading-edge technology and has the potential for high impact in the short term, making it an ideal fit for support from The Winnipeg Foundation Innovation Fund,” says Dr. Peter Nickerson, vice-dean research of the Rady Faculty of Health Sciences. “The new thermal camera will also be an asset for other UM researchers with an interest in thermography.”

O’Neil anticipates that the study results will help those who are at risk for rheumatoid arthritis, and their doctors, better understand their often-troubling symptoms.

“By revealing more about how RA develops, the findings will contribute to the search for early treatments to prevent this chronic disease,” he adds. “Thermal imaging may also help researchers understand if preventative treatments are working, and help predict who is most likely to respond to treatment.”

The researchers hope to obtain future funding for a larger, longitudinal study. They propose to follow a cohort of patients, using thermal imaging and other methods to examine the relationship between the patients’ early, pre-clinical signs of rheumatoid arthritis and the clinical onset of the disease.  

The interdisciplinary team is one of only four research groups in Canada to receive funding from CIHR’s Human Immunology Research Teams grant, an initiative to study autoimmune diseases with the goal of improving the knowledge of the human immune system.

“We’re delighted to receive this CIHR funding, but we also recognize the challenges ahead in undertaking such an interdisciplinary project,” said Dr. Hani El-Gabalawy, professor of medicine and immunology and Endowed Rheumatology Research Chair, Max Rady College of Medicine.

The project, titled Prediction and prevention of rheumatoid arthritis in First Nations People, has three aims. The first aim is to improve biomarkers in predicting whether someone will develop rheumatoid arthritis.

El-Gabalawy, the project’s principal investigator, said that rheumatoid arthritis “starts before it starts.” Meaning that before someone develops sore, stiff or swollen joints, and a diagnosis can be made by a doctor, the person has biomarkers in their blood that show their immune system isn’t functioning properly, he said.

The biomarker could be present for up to 10 years before the person develops any symptoms, El-Gabalawy said. However, not everyone who has these biomarkers will develop rheumatoid arthritis. So part of what the research team is trying to do with this first aim is to find better ways of predicting who will develop rheumatoid arthritis.

The project builds on team members’ previous research that showed that rheumatoid arthritis is very common in some First Nations families. El-Gabalawy said that the disease can be particularly damaging and resistant in First Nations people.

Aim two of the project will be a randomized clinical trial in First Nations communities to see whether the combination of turmeric, omega-3 and vitamin D can reduce the risk of rheumatoid arthritis based on biomarkers developed through the first aim. In support of this approach, team members’ previous research showed that this combination of supplements helped prevent inflammatory arthritis in mice.

Co-investigator Dr. Dylan Mackay, an assistant professor in the department of community health sciences and a clinical trialist with the George & Fay Yee Centre for Healthcare Innovation, said that if the results of the trial are favourable, it could mean that treatment costs could be reduced or avoided with the trio of affordable supplements.

“Some of the modern rheumatoid treatments are incredibly expensive,” said Mackay, who is a lead on the clinical trial. “Finding lower cost alternatives that maintain the health of people would be fantastic.”

Researchers will screen about 1,500 people to find under 200 people with biomarkers to be eligible for the study.

The third aim will look at the experience of First Nations people as they progress through the clinical trial from start to finish. Amanda Fowler-Woods, a PhD candidate in the department of community health sciences, Max Rady College of Medicine, said that there have been clinical trials done with Indigenous people before but this would be the first-ever study to gather their experiences.

“We want to know if Indigenous peoples are feeling like research is still not being done in a good way, because if you look at history, that makes perfect sense,” said Fowler-Woods, who is a lead on the third aim. “Our peoples weren’t treated well. Scientific experiments were done on Indigenous peoples, not with them. And the results of that have been traumatic, so this is an opportunity to actually get constant feedback on what we are doing good, and what we are not doing good on.”

Fowler-Woods said that this is also a chance to build a framework for how to combine Indigenous methodologies with quantitative research so scientists are not only doing research with First Nations people but they’re taking care of their spirits, and protecting and honouring who they are.

“It excites me that the communities will feel respected, and they’ll start to see that there’s a possibility that research is actually working to help,” Fowler-Woods said.

El-Gabalawy said that one of the things that thrills him about this project is that it brings seasoned scientists – like Dr. Aaron Marshall, head of the department of immunology, Dr. John Wilkins, professor of internal medicine and director of the Manitoba Centre for Proteomics and Systems Biology, and Dr. Neeloffer Mookherjee, associate professor within the departments of internal medicine and immunology – together with up-and-comers like Fowler-Woods, Mackay, Dr. Liam O’Neil, assistant professor of internal medicine, and Dr. Vidyanand Anaparti, a post-doctoral fellow in the Max Rady College of Medicine.

“I’m excited because this project leverages lots of different expertise at the University of Manitoba,” Mackay said. “I’m glad that CIHR recognized that and funded the project.”