Week 39: Science Monday
Each week I receive a report showing recent publications by faculty and trainees in the department of medicine (DoM). The scholarly output of the DoM is impressive, and I am limited in what I can comment on here but encourage you to see the complete list that is updated weekly.
Trainees and junior faculty represent the future of the DoM, and as such I enjoy celebrating their accomplishments.
Assistant Project Scientist Dr. Yang Cao has been having an impressive year publishing a series of landmark papers at the intersection of cardiovascular disease and metabolic disorders. She is a member of the Lusis Laboratory, and most recently published in Science the findings from a gain- and loss-of-function mouse study which examined how the liver-derived protein, coagulation factor XI (FXI), protects against diastolic dysfunction, a key feature of heart failure with preserved ejection fraction.
FXI is a well-known regulator of blood clot formation. The recently published work describes the discovery of a new function of the FXI, whereby it circulates from the liver to the heart. In the heart, FXI cleaves and activates the extracellular matrix-associated protein, BMP7, inhibiting genes involved in inflammation and fibrosis. Dr. Cao and members of the Lusis Lab are optimistic that this pathway could be harnessed to treat heart failure, however they caution that simply elevating FXI could increase blood clot formation. More work will be needed to understand how to modulate release from the liver at physiological levels that could safely improve cardiac structure. You can explore this publication, along with two others from Dr. Cao and the Lusis Lab below.
Dr. Carlos Irwin Oronce, a fellow in the DoM's STAR Fellowship & the VA Advanced Health Services Research Fellowship and an alumni member of the UCLA National Clinicians Scholar Program, has also been having a prolific year in terms of publications. Most recently, he published a paper in the Journal of the American Geriatrics Society which examines wasteful spending arising from aducanumab dispensing in the Medicare population.
Aducanumab was recently approved for the treatment of Alzheimer’s disease and its dosing is weight-based. Given the way that doses are formulated and packaged, significant amounts of drug are wasted when doses are dispensed. Dr. Oronce sought to quantify the amount of discarded drug and potential savings that could be generated from more efficient aducanumab vial sizes.
For this study, data from the 2016 Health and Retirement Study (HRS) was used to select participants aged 65 and older with Medicare Part B insurance. The team used validated cognitive measures to identify patients with dementia or mild cognitive impairment and estimated a lower and upper bound of potentially eligible patients to receive aducanumab, using the clinical trial exclusion criteria.
The team then used the two vial sizes produced by the manufacturer, 170 mg/1.7 ml and 300 mg/3.0 ml, to calculate how much aducanumab would be needed for dosing in the lower and upper bound populations, assuming a 10 mg/kg monthly dose. They counted the number and combinations of vials needed, based on the weight of survey participants, multiplied the per-vial costs by the survey-weighted population, and summarized across categories to derive a weighted average for drug spending. The team calculated how much drug would be discarded among these patients at a national level, while assuming conservatively that only 10% of those who were eligible would realistically receive the treatment. Finally, using the estimates for how much drug would be discarded annually, they calculated the equivalent amount and spending in 300 mg/3.0 mL vials.
The study’s main findings were that a 10% drug uptake would waste hundreds of thousands of aducanumab vials annually, burdening Medicare with $115–$605 million in wasteful spending each year. Reducing the 300 mg/3.0 mL vial size by two-thirds could decrease spending on discarded drug by over 60% and save between $71-$369 million each year.
This analysis indicates that efficient vial packaging of aducanumab has the potential to reduce future cost, constrain premium growth and limit beneficiary out-of-pocket expenses. Dr. Oronce believes that a focus on value, increases the ability of health systems and insurers to meaningfully address disparities resulting from the underuse of clinically proven, but high-cost therapies.
"I have benefitted greatly from mentorship from the DoM, especially from Dr. Catherine Sarkisianand Dr. John N. Mafi. They have supported me tremendously in this study while allowing me, at the same time, to bridge the concepts linking improving value with health equity," said Dr. Oronce.
Carlos is a member of the division of general internal medicine and health services research. A highlight of their academic year is the annual Martin F. Shapiro Health Services Research Symposium. Last week, I was privileged to deliver opening remarks to our GIM-HSR scholars at the symposium, which was held on Friday, September 23 at the Luskin Conference Center.
Since its inception in 2017, the symposium has grown to become a premiere annual event presenting original research by GIM-HSR faculty with guests including notable researchers from the division, UCLA, and beyond.
This year, the symposium focused on health care, health policy, and equity and showcased a range of original projects by over a dozen junior and senior GIM faculty, as well as HSR specialist collaborators. One lively panel included Dr. David Carlisle, president & CEO of Charles R. Drew University, as well as Dr. David Eisenman, professor of medicine and public health, and Dr. Carol Mangione, chief of the division of GIM-HSR and chair of the United States Preventive Services Task Force, who discussed how to use research to impact health policy on a wider level.
The keynote remarks were delivered by Dr. Kirsten Bibbins-Domingo, professor of epidemiology and biostatistics at UCSF and current editor of JAMA, discussing the reasons and ways to increase representation of diverse populations in clinical research trials. Dr. Martin Shapiro, a distinguished professor and chief emeritus in the DoM’s division of GIM-HSR traveled from New York to lead discussions and provide insight following each presentation. He shared closing remarks that focused on the work presented and possible future directions for division research.
Let me now share an example of research from DoM faculty, that will significantly shape health care delivery. DoM Executive Vice Chair for Equity, Diversity and Inclusion Dr. Keith Norris and Chair of the UCLA Nephrology Racial and Health Equity Committee Dr. Susanne Nicholas have served as national and local advocates for using a race-neutral estimated glomerular filtration rate (eGFR) to test kidney function in patients.
African-Americans make up 35% of people with kidney failure and use of the legacy eGFR formula may contribute to health disparities in African-American patients by providing an inaccurate individual assessment of kidney function, since the eGFR score was adjusted based on a person’s race and ethnicity. This approach is problematic since race and ethnicity are social constructs that have no direct relation to medical or physiological processes, nor does it account for individual genetic and biological factors. The overestimation of renal function in African-Americans by existing eGFR scores delays the identification of clinically significant renal disease leading to delays in treatment. Through advocacy by professional organizations that include the National Kidney Foundation and American Society of Nephrology, Dr. Norris and Dr. Nicholas have successfully championed using a race-neutral eGFR within health systems. Most recently, Dr. Nicholas spearheaded the introduction of the race-neutral eGFR at UCLA Health and Dr. Norris spoke with the Los Angeles Sentinel to raise awareness about this issue and why health systems should move forward in adopting the new formula.
We applaud their efforts to reduce barriers to accessing kidney care and invite you to read their latest publication regarding the race-neutral eGFR, “Race, ancestry, and genetic risk for kidney failure,” published in Cell Reports Medicine.
The final publication is an example of investigating the risk versus benefit of a novel therapy for rheumatoid arthritis.
Dr. Christina Charles-Schoeman, chief of rheumatology, recently published important findings from the FDA mandated post authorization, safety end-point trial, ORAL Surveillance, examining risk of major adverse cardiovascular events (MACE) with the Janus kinase (JAK) inhibitor, tofacitinib, compared to tumor necrosis factor inhibitors (TNFi), commonly prescribed and effective medications for patients with rheumatoid arthritis (RA). RA patients have a two to three-fold increased risk of cardiovascular disease, which is related to traditional CV risk factors as well as high levels of RA disease activity.
The primary analyses of ORAL Surveillance, which included over 4000 RA patients aged ≥50 years with ≥1 additional CV risk factor found an increased risk of MACE with tofacitinib versus TNFi. This “post hoc” analysis by Dr. Charles-Schoeman and colleagues, identified increased risk of MACE primarily in patients with a history of pre-existing atherosclerotic cardiovascular disease (ASCVD) (15% of patients enrolled). In patients without a history of ASCVD but with CV risk factors (85% of patients), there did not appear to be a detectable difference in risk of MACE with tofacitinib versus TNFi.
Dr. Charles-Schoeman notes this is a significant development, as tofacitibib is an important drug in controlling RA disease activity, and we want to make sure that in treating patients for this common autoimmune disease, we should not be prescribing medications that will place them at higher risk for atherosclerotic cardiovascular disease. It is important to note that the overall incidence of cardiovascular events was low across this high-risk population who were all treated actively with either tofacitinib or TNFI to control RA disease activity.
You can review the entire publication in Annals of Rheumatic Diseases. Future work by Dr. Charles-Schoeman and her team will be focusing on using biospecimens from the tofacitinib clinical trial program to identify a new biomarker of cardiovascular risk in RA patients. We look forward to reading those results!
These few examples of our faculty’s research output would not be possible without their ability to successfully compete for extramural funding. Our department has led the DGSOM in research administration and I was very pleased to learn this week that the DoM’s Director of Research Administration Catherine Rujanuruks was awarded the Chancellor’s Excellence in Service Award from the UCLA Staff Assembly.
A lifelong Bruin, Cathy began her career at UCLA in the department of life sciences over 20 years ago. She spent five years in life sciences, was described as a quiet purchaser who has now grown into a rock star in research administration in the department of medicine. She is the guiding light for over 80 staff and fund managers in over 20 divisions. She manages the biggest research portfolio at UCLA totaling over $130 million and ensures compliance and accountability for these funds. Cathy has been described as an outstanding employee who embodies the values of the Cultural North Star which encourages us all to be kind, do what is right, and make things better. We are fortunate to count on Cathy’s expertise as a research administrator and her kindness which enriches the DoM every day. Congratulations Cathy on this well-deserved recognition!
Later this month I will be rolling up my sleeves to get my flu shot AND my COVID19 booster. I hope you will sign up and get this done early. Only then can you start ignoring those reminder emails.