A study led by Krembil researchers reveals that currently recommended doses of the steroid medication prednisone are more effective at treating the disease than lower doses.
Prednisone is the most common drug prescribed to treat lupus nephritis—an autoimmune disease in which the body’s immune system attacks the kidney. The disease causes inflammation at sites in the kidney—known as glomeruli—that filter and cleanse the blood.
Because steroid drugs can cause a number of serious side effects, such as cataracts, diabetes and osteoporosis, efforts are underway to minimize the amount of prednisone that is prescribed to individuals with lupus. Two recent studies have suggested that low doses of the drug might be effective at treating lupus nephritis.
“These studies were preliminary. They enrolled very few participants and did not fully establish the link between drug dose and symptom improvement, so we saw the need for a larger and more thorough investigation,” says Dr. Murray Urowitz, senior author of the study and Senior Scientist at UHN’s Schroeder Arthritis Institute.
Working with a team of Krembil researchers that included Senior Scientist Dafna Gladman, Dr. Urowitz led a study involving 206 individuals with lupus nephritis. The researchers split the participants into two groups based on their prednisone dose: a medium dose group (30 mg/day or less) and a high dose group (40 mg/day or more). The 2 groups were matched for demographic features, lupus disease factors and other therapies used.
The study followed the patients over three years. As is standard for treatment with prednisone, doses were lowered over time. The dose reductions were not the same for both groups: the drug levels in high dose group were lowered to a greater extent so that, by one year after the start of treatment, prednisone levels were lower in this group than in the original medium dose group.
The results revealed that around 62% of individuals in the high dose group experienced complete remission (i.e., disappearance of the signs of disease) at the one-year mark—versus only around 38% in the medium dose group. Furthermore, there was no difference observed between the two groups in terms of harmful side effects.
“Our findings reveal that high prednisone doses—40 mg or more per day—within the first six months are beneficial for treating lupus nephritis, and that lower doses do not provide additional benefits or fewer side effects,” concludes Dr. Urowitz.
This work was supported by the Canadian Institutes of Health Research, the Lou and Marissa Rocca Family, the Mark and Diana Bozzo Family, Lupus Canada and the UHN Foundation.
Tselios K, Gladman DD, Al-Sheikh H, Su J, Urowitz MB. Medium versus high initial prednisone dose for remission induction in lupus nephritis: A propensity score matched analysis. Arthritis Care Res (Hoboken). 2021 Mar 4. doi: 10.1002/acr.24592.
Welcome to the latest issue of Research Spotlight.
As Canada’s largest research hospital, UHN is a national and international source for discovery, education and patient care. This newsletter highlights top research advancements across UHN and from over 1000 researchers appointed at our institutes.
Stories in this month’s issue:
● A New Therapeutic Strategy: Molecule found to halt the growth of aggressive cancer stem cells in experimental models.
● Controlling Type 1 Diabetes: A drug used to lower blood sugar may reduce the need for insulin pump users to count carbs.
● Wired Differently: Brain circuitry features may explain why men and women experience chronic pain differently.
● Disrupting the Status Quo: Study reveals the need for medical schools to demonstrate commitment to inclusion from day one.
● 2020 Krembil Annual Report is Here: Read the latest annual report to learn how Krembil is making progress from promise.
As the pandemic continues, several studies from around the world have reported an increased risk of COVID-19 among individuals affected with cancer. And cancer patients comprise a higher proportion of COVID-19 cases than expected.
To understand why, a study led by Dr. Fei-Fei Liu at the Princess Margaret Cancer Centre looked at whether genes known to facilitate viral entry into the body were expressed differentially in healthy versus cancer tissues in adults and children.
“Specific factors found on the surface and inside of our cells help the SARS-CoV-2 virus gain entry during a COVID-19 infection,” explains Dr. Liu. “Given the increased COVID-19 infectivity rates among cancer patients, we suspected that these factors were elevated during cancer.”
Using available large-scale genomic datasets, the team evaluated the expression of three critical factors for entry—ACE2, TMPRSS2 and CTSL—in various healthy and cancerous human tissues.
They found that expression of these SARS-CoV-2 viral entry genes was increased in respiratory, gastrointestinal and genitourinary tract tissues in individuals with cancer versus health individuals. Furthermore, expression of these genes were lower in cancer tissues from children compared to those from adults.
The team further investigated why cancer patients experience more severe COVID-19 symptoms than the general population. They assessed whether radiotherapy—a common cancer treatment that uses radiation to destroy cancer cells—hindered the body’s natural defense mechanisms that are needed to fight the virus.
The team’s findings revealed that radiotherapy did weaken immune defenses and did so by changing the expression of genes involved in immunity. These changes were restored to normal a few weeks post-treatment. Similar effects were observed with chemotherapy as well.
“Further work is needed to understand whether it would be beneficial for clinicians to adjust the timing of radiotherapy or chemotherapy for cancer patients during an active COVID-19 infection in order to minimize their impact on immune system function,” says Dr. Liu.
This work was supported by the Canadian Institutes of Health Research, the Government of Ontario, the Ministry of Science and Technology of Taiwan, the Ontario Institute for Cancer Research and The Princess Margaret Cancer Foundation. FF Liu holds the Peter and Shelagh Godsoe Chair in Radiation Medicine. TJ Pugh holds a Tier 2 Canada Research Chair in Translational Genomics.
Kwan JYY, Lin LT, Bell R, Bruce JP, Richardson C, Pugh TJ, Liu FF. Elevation in viral entry genes and innate immunity compromise underlying increased infectivity and severity of COVID-19 in cancer patients. Sci Rep. 2021 Feb 25. doi: 10.1038/s41598-021-83366-y.
Vision researchers at the Donald K. Johnson Eye Institute have shed light on patient experiences surrounding a prosthetic device-based treatment for complex corneal conditions.
Corneal conditions, such as irregularly shaped corneas and corneal degeneration, are a leading cause of eye disease and vision loss. These conditions cause eye discomfort and impaired vision, and are commonly treated with artificial tears, anti-inflammatory drugs and specialized contact lenses. Patients with severe conditions that do not respond to traditional treatments have recently benefitted from a new therapy called PROSE—Prosthetic Replacement of the Ocular Surface Ecosystem.
PROSE involves daily use of a custom-designed lens that covers the cornea and rests on the white of the eye, called the sclera. The space between the lens and the cornea is filled with saline solution, which the patient replaces each time they insert the lens. PROSE treatment reduces eye discomfort, improves vision and promotes cornea healing.
PROSE is a relatively new treatment in Canada, and research is needed to better understand patient experiences surrounding PROSE device fitting and use.
A research team led by Krembil Clinician Investigators Drs. Allan Slomovic and Clara Chan analyzed medical records from 78 adults who underwent PROSE device fitting at the Kensington Eye Institute in Toronto. The team analyzed what symptoms and diagnoses led to PROSE treatment, previous devices used and vision improvements that patients experienced with PROSE.
The researchers found that doctors recommended PROSE for patients with a variety of complex corneal conditions. Prior to PROSE treatment, patients commonly experienced blurry vision, light sensitivity, eye pain and glare and saw rainbows around lights. Most patients had previously tried conventional contact lenses, but these lenses often failed to improve vision or were uncomfortable.
In addition to identifying common diagnoses and symptoms leading to PROSE treatment, the researchers found that PROSE significantly improved visual acuity—the sharpness or clarity of one’s vision. The researchers also found that patients could comfortably wear the PROSE device for long periods of time, often for at least five hours each day.
“PROSE is an effective treatment for patients who do not benefit from traditional therapies,” says Dr. Chan. “Reducing the debilitating eye pain and vision loss associated with corneal diseases can dramatically improve patients’ quality of life.”
This work was supported by the UHN Foundation.
Wong BM, Garg A, Trinh T, Mimouni M, Ramdass S, Liao J, Chandrakumar M, Chan CC, Slomovic AR. Diagnoses and Outcomes of Prosthetic Replacement of the Ocular Surface Ecosystem Treatment-A Canadian Experience. Eye Contact Lens. 2021 Mar 16. doi: 10.1097/ICL.0000000000000779.
On Wednesday, April 14, 2021, UHN celebrated the launch of the Max Planck–University of Toronto Centre (MPUTC) for Neural Science and Technology.
The MPUTC is the third Max Planck Centre in Canada, continuing a 50-year-long history of successful scientific collaboration between Canada and Germany.
Led by Co-Directors Dr. Taufik Valiante (Krembil Brain Institute) and Dr. Joyce Poon (Max Planck Institute for Microstructure Physics), the Centre brings together experts in the fields of engineering, physics, neuroscience, neuroinformatics and neuromedicine. It also serves as a link between the Max-Planck-Gesellschaft, the University of Toronto, University Health Network and participating hospitals—the Hospital for Sick Children and the Centre for Addiction and Mental Health.
“The partnership between these research institutions and hospitals will support the development of new tools and experiments that are relevant to the human brain,” says Dr. Valiante. “There is a great sense of societal urgency surrounding brain research, and we are confident that the MPUTC will accelerate breakthroughs in this field.”
Graduate trainees will have the opportunity to enroll in a joint PhD program at the MPUTC. This program will enable students to spend the first year of their PhD studies at the University of Toronto followed by up to three additional years at a participating Max Planck Institute.
Krembil has committed to funding three joint PhD program studentships, during which students will be supervised by Krembil Brain Institute scientists.
For more information, visit the Centre’s website here.
Researchers at the Toronto General Hospital Research Institute have shown that the diabetes medication empagliflozin can eliminate the need for insulin pump users to track their carbohydrate intake.
People with type 1 diabetes do not produce insulin, a hormone required to control the amount of sugar in the blood. In addition to diet and exercise, many people with type 1 diabetes require lifelong insulin therapy to control their blood sugar levels.
Modern insulin pumps can monitor blood sugar levels and automatically adjust insulin delivery based on their users’ changing needs. These pumps, called “hybrid closed loop” systems, automatically deliver small amounts of insulin throughout the day, but depend on the user to determine how much insulin to give at mealtimes. The amount of mealtime insulin that a person needs depends on the amount of carbohydrates that they consume, so it is important for insulin pump users to keep track of the carbohydrate content of their meals. Unfortunately, this process is very difficult and time-consuming.
“An easier approach to administering mealtime insulin would be to simply signal that you are about to eat a meal by pressing a button on your pump, without having to carefully count the carbohydrate content of a meal. This approach is called ‘meal announcement’,” explains Dr. Bruce Perkins, a Senior Scientist at TGHRI and the senior author of the study. “Meal announcement is simple, but the insulin doses are less precise than when you count the grams of carbohydrate in your meal.”
To address these complexities, Dr. Perkins led a study to see whether the diabetes drug empagliflozin could reduce or eliminate the need to count carbohydrates. The study enrolled thirty adults who use insulin pumps. Over two months, each participant engaged in several insulin delivery strategies, including meal announcement and carbohydrate counting, with and without empagliflozin.
When participants combined the simple meal announcement and empagliflozin, their blood sugar was as well controlled as when they counted carbohydrates. When participants counted carbohydrates, the addition of empagliflozin further improved blood sugar control, substantially increasing the time spent in the target blood sugar range.
“If insulin pump users take empagliflozin, they can replace carbohydrate counting with a simple meal announcement strategy. The empagliflozin seems to make the automated insulin system work better at mealtimes. This switch can save people time and effort, without compromising blood sugar levels,” says Dr. Perkins. “Managing blood sugar levels in type 1 diabetes can be very challenging, but the strategy that we have identified has the potential to make it a little easier.”
Dr. Perkins’ team is currently studying the impact of empagliflozin in a much longer study.
This work was supported by Diabetes Canada, the Lunenfeld Tanenbaum Research Institute at Sinai Health Systems, McGill University and the UHN Foundation. A Haidar holds a Tier 2 Canada Research Chair in Diabetes Mellitus.
Haidar A, Yale JF, Lovblom LE, Cardinez N, Orszag A, Falappa CM, Gouchie-Provencher N, Tsoukas MA, El Fathi A, Rene J, Eldelekli D, Lanctôt SO, Scarr D, Perkins BA. Reducing the need for carbohydrate counting in type 1 diabetes using closed-loop automated insulin delivery (artificial pancreas) and empagliflozin: A randomized, controlled, non-inferiority, crossover pilot trial. Diabetes Obes Metab. 2021 Feb 2. doi: 10.1111/dom.14335.
The Joint Genomics Program between UHN’s Princess Margaret Cancer Centre and the Ontario Institute for Cancer Research (OICR) will benefit from the recent accreditation of an OICR genomics facility. OICR Genomics recently passed the highest standards for clinical research set by the College of American Pathologists (CAP).
The facility is one of the few labs in the world to gain CAP accreditation for identifying mutations (i.e., changes in the genetic code) and comprehensive testing of all forms of genetic changes in whole genomes. “What sets our program apart is the amount of information that our genetic test produces. Our clinical case assay can provide whole genome sequences for normal and tumour samples from the same patient—as well as detailed data on which genes are active in the tumour,” says Dr. Carolyn Ptak, Program Manager and Quality Assurance Lead of OICR Genomics.
“By providing a complete view of the genes that are present in cancers and when these genes are turned on or off, the program will deliver profound insights on new treatments and how to tailor these to individual patients,” says Dr. Trevor Pugh, Senior Scientist at Princess Margaret Cancer Centre, and Senior Investigator and Director of Genomics at OICR.
The joint program was established to alleviate administrative hurdles and ease the transfer of samples and data between UHN and OICR for collaborative research projects. The collaboration brings together researchers involved in basic, translational and clinical research under a single coordinated vision: to facilitate the use of genomic knowledge to guide clinical management of cancer patients. The program is advancing this aim through the following actions:
An example of the research being supported by the Joint Genomics Program is a clinical trial led by Drs. Jennifer Knox and Steven Gallinger. The trial, named PASS-01, is assessing two approved treatments for metastatic pancreatic cancer, which has one of the lowest survival rates of all cancer types. The program is providing clinical-grade and detailed genomic data (i.e., sequences of the whole genome and active genes). This data will provide deep insight into the disease biology and determine whether the effectiveness of treatments can be linked to genetic features.
The accredited facility is also intended to support studies from the Marathon of Hope Cancer Centres Network, of which Princess Margaret Cancer Centre is a major partner.
“This is a landmark achievement—one that reflects this team’s strong dedication to conducting clinical genomics research of the highest quality in terms of data collection and analyses,” says Brad Wouters, EVP of Science and Research at UHN. “It is a great way to kick off our expanded joint genomics program.”
T Pugh holds a Tier 2 Canada Research Chair in Translational Genomics and is supported by an OICR Senior Investigator Award.
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