Drs. Akihiro Nakamura and Nigil Haroon
Drs. Akihiro Nakamura and Nigil Haroon study axial spondyloarthritis (SpA), a painful and debilitating form of arthritis that causes inflammation in the spine, joints, eyes, gut and skin. (Photos: UHN)

Susan Rivers was only 10 years old when she began experiencing pain in the joints in her legs.

After many years of suffering and few answers, Susan was diagnosed with ankylosing spondylitis, a painful and inflammatory form of axial spondyloarthritis (SpA), which affects one per cent to two per cent of Canadians and causes inflammation in the spine, joints, eyes, gut and skin.

In a new paper recently published in the journal Science Translational Medicine, researchers at the Schroeder Arthritis Institute at UHN have made a discovery that could lead to new treatments for SpA.

"We currently have very few therapeutic options for the majority of patients living with SpA and this is a debilitating disease that directly impacts quality of life," says Dr. Nigil Haroon, a rheumatologist, co-Director of the Spondylitis Program and senior author on the paper.

"Although several treatments including biologic drugs have been approved for SpA, 40 per cent to 50 per cent of patients do not respond to any treatments and develop severe pain and abnormal new bone formation," says Dr. Akihiro Nakamura, first author on the paper and a spondylitis fellow and PhD candidate in Dr. Haroon's lab. "So, there is a desperate need to find new treatments that are effective and cover all of the clinical symptoms of SpA."

The study focuses on the role of the macrophage migration inhibitory factor (MIF), which functions as a protein that induces an inflammatory or immune response in the body. Until now, the role that MIF plays in the disease progression of SpA was unknown.

In this study, researchers observed that the expression of MIF and its receptor CD74, is increased in the blood and tissues of pre-clinical models. They also found that human neutrophils (a type of white blood cell that induces the immune system's response) from SpA patients secreted higher concentrations of MIF, compared to healthy individuals. This, in turn, drives other cells to cause more inflammation.

"What this means is that if the body has been exposed to a trigger, too much MIF could be produced in susceptible individuals that could then lead to a diagnosis of SpA later in life," explains Dr. Haroon. "If we can block the excess production of MIF early, we may be able to induce disease remission and prevent disability and mortality linked to SpA."

In a 2017 paper, the researchers found that the concentration or expression of MIF is substantially increased in the blood, joint fluids and gut tissues of SpA patients, compared to those of a different type of arthritis patients or healthy volunteers. In the same paper, they also demonstrated that MIF might be involved in promoting the development of new bone formation.

'Treatment could be effective for a good proportion of SpA patients'

These recent findings have helped to solidify those results and take our understanding of the role of MIF in SpA, further. The specific blocker of MIF, called MIF098, successfully prevented and restricted the disease onset and development of SpA, in the pre-clinical model.

The team's next step is to focus on testing the potential of other therapies targeting MIF, which could lead to finding a novel treatment in SpA.

"Patients with SpA experience inflammation, pain, stiffness and over time, this can lead to spinal fusion and loss of mobility," says Dr. Haroon. "But it's not just the disease itself that these patients have to worry about.

"Compared to the general population, there is also a 60 per cent increased chance of stroke, and a 30 per cent increased chance of experiencing a cardiovascular event or a mental illness."

For Dr. Nakamura, a clinician from Japan, who came to the Schroeder Arthritis Institute to become a leading researcher in the area of inflammatory arthritis, these new findings are nothing short of "exciting."

"In research, once we make a new discovery, that has the potential to help many more patients than I could in my clinic, back in Japan," says Dr. Nakamura. "So that motivates me a lot."

The team is next hoping to test the efficacy of MIF blockers in patients with SpA through clinical trials, where they would look to determine the optimal concentration and administration frequency of MIF-targeted drugs for humans, as well as study potential side effects, to ensure safety.

Susan's arthritis was helped with surgery and medication, but for many patients, treatment for SpA can be far more complex.

"The drugs we have currently don't work for half of all SpA patients," says Dr. Haroon. "At the same time, rates of arthritis are going up worldwide.

"We believe this treatment could be effective for a good proportion of SpA patients including those who don't respond to other currently available treatments."

This work is supported by the Canadian Institute of Health Research, Arthritis Society, Krembil Foundation, UHN Foundation, American College of Rheumatology (ACR) Research Fund, National Institutes of Health (NIH), Natural Sciences Research Council, Canada Foundation for Innovation (CFI), Ontario Research Fund, IBM, Ian Lawson van Toch Fund, Medicine by Design Program, MiTACS Accelerate Fellowship, Spondyloarthritis Research and Treatment Network (SPARTAN), and Spondyloarthritis Research Consortium of Canada (SPARCC).

Competing Interests

Dr. Nigil Haroon acts as a consultant for Abbvie, Eli Lilly, Janssen, Novartis and UCB, none of whom have funded this study.

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