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An Inside Look at OrACORe’s Newest Study on Inflammation and Osteoarthritis

Lindsey A. MacFarlane, MD, MPH

OrACORe’s newest study, INFORM (Inflammation and Osteoarthritis at the Brigham), is just getting started! Leading the project is Dr. Lindsey A. MacFarlane, MD, MPH, a practicing rheumatologist at Brigham and Women’s Hospital and a clinical investigator at OrACORe. She shared her inspiration for studying knee osteoarthritis, details on the INFORM study, and insights into grant writing and study design.

1. What first attracted you to studying knee osteoarthritis (OA)?

“I had done some work on gout in residency, and, over time, my focus shifted more to OA. That shift was mostly driven by wanting to work with [OrACORe Director Dr. Jeffrey Katz], who does OA research. It’s been a very happy transition.

Specific to the INFORM study, I think inflammation in OA is a really interesting story. People tend to think of rheumatologists as the inflammatory arthritis doctors, so it’s nice to fit in with that. I also used to moonlight at a weight management clinic, which I think piqued my interest in health issues related to obesity. Arthritis and obesity are certainly linked, but there’s still an overarching question of whether inflammation is part of that link.”

2. What treatment advances in knee OA do you hope to see in the next five years?

“I think in five years we might have new agents that manage pain, but the real quest is to identify a disease-modifying OA drug (DMOAD). Currently, in terms of non-surgical treatments, everything is geared towards minimizing pain. We don’t have a treatment that halts progression, and we really don’t have anything that reverses progression. While the holy grail would be a DMOAD, I don’t know that we are five years away from that. The first challenge is identifying and developing an agent that can prevent or reverse cartilage damage. The second challenge is determining whether halting or reversing cartilage damage translates into patients having less pain. How do you tie these two things, pain and structural damage, together?”

3. Congratulations on the INFORM grant! What questions do you hope to answer with this award?

“I’m really interested in the interplay of obesity, inflammation, and OA. Traditionally, OA is thought of as the non-inflammatory arthritis. But, more and more, it is thought that there is some role for inflammation in OA and that obesity may increase inflammation. There’s a field of research looking at obesity as an inflammatory state. Especially with knees, obesity confers a mechanical disadvantage: there’s a lot of load on the knee. Beyond mechanical load, though, the inflammatory milieu that obesity promotes may also play a role in OA.

With this grant, we hope to learn whether waist-to-hip ratio and waist circumference are associated with inflammatory knee OA. Unfortunately, body mass index (BMI) is an imperfect measure of body fat. There have been many discussions in the scientific community that waist-to-hip ratio and waist circumference are better indicators of cardiovascular health and outcomes than BMI.

A second question is whether those patients with more central adiposity and more inflammation actually respond better to steroids.”

4. How is the INFORM study structured to answer these questions?

“The first part of the project will allow us to get a sense of whether waist-to-hip ratio or waist circumference are more highly associated with knee inflammation than BMI. We’re adding an ultrasound of the knee to the ORBIT study, which already measures waist-to-hip ratio and waist circumference and collects knee MRIs. The ultrasound will show us how much knee effusion synovitis there is, which is a clinical marker of inflammation. I’ll be looking to see whether waist-to-hip ratio or waist circumference are associated with more inflammation on MRI or ultrasound.

The second part of the study will involve patients who have knee aspirations performed in clinic. I’m hopeful that the patients will undergo imaging (MRI and ultrasound) as well so that this dataset will include structural information as well as joint fluid, which is comprised of white blood cells, another marker of inflammation.

We’re starting with the ORBIT add-on because it provides such a wealth of data.”

5. What have you learned from the process of applying for this grant and designing this study?

“Patience! You get a lot of rejections along the way, and it is vital to have some level of grit. I definitely learned a lot about doing your best to incorporate feedback, especially when it’s negative, to make future work stronger. But really you just need the patience to keep applying for different opportunities.

I’ve also learned a lot about how to actually implement what’s in the grant. The grant is the dream, the ideal, and often the small details are lost. In the end, the logistics are much more complex once you start trying to recruit study subjects!

I couldn’t have done this without help from mentors and colleagues. First, the financial support is huge. As a junior investigator, it’s pretty hard to get enough grants to cover your salary. There’s a lot of financial support coming from mentors. Second, they’re training me in a new career. I didn’t come to OrACORe with a ton of experience on how to set up studies or apply for grants. Then, finally, there’s the personal support. Yes, you receive a lot of rejections. Without strong mentoring, it would be a very, very difficult path.”

6. What are you most excited about in the future of INFORM?

“I’m excited to see some data! To have enough to even put together a small abstract will be amazing.”

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