Editor’s note: Tuhina Neogi, MD PhD, is professor at the Boston University School of Medicine and in the School of Public Health, US, as well as chief of Rheumatology at Boston Medical Center. After completing her medical training at the University of Toronto, Canada, Neogi moved to Boston to complete her PhD in the School of Public Health at Boston University. As a rheumatologist and epidemiologist, Neogi focuses her research primarily on risk factors and pain mechanisms underlying knee osteoarthritis. In addition to her clinical work and research, Neogi plays a key role in mentoring trainees and junior faculty in musculoskeletal disease-related research. Neogi took time to talk with Lincoln Tracy, a research fellow from Monash University, Australia, to discuss the problem of osteoarthritis pain, her research, and more. Below is an edited transcript of their conversation.
What was your path to becoming a rheumatologist?
The path really began before I started my internal medicine training, when I couldn’t decide between pediatrics and internal medicine. In the end, I chose internal medicine. Then, when I got to the point where I had to choose a specialty, I had a difficult time choosing between nephrology and rheumatology. In an alternative universe, I might be a pediatric nephrologist! But what really drew me to rheumatology is that you need to be a very good clinician. Rheumatic diseases can affect any organ system or body part, and the diseases can affect individuals at all stages across their lifespan. And, because rheumatic diseases are often chronic diseases, you get to develop relationships with your patients over time as you are seeing them in an outpatient setting.
Intellectually, I really enjoy the detective work in rheumatology – trying to put the puzzle pieces together to make a diagnosis. And the pathophysiology of rheumatic diseases is very interesting, particularly with the autoimmune rheumatic diseases where there have been dramatic advances in immunology and immunology-based therapies. In addition, you virtually can’t go anywhere without meeting someone who has an issue with a rheumatic condition or their joints – it’s such a huge public health burden. It keeps things interesting.
How did you become involved in osteoarthritis research?
When I was a rheumatology trainee, I was doing basic science in the lab on a mouse model of Kawasaki disease [which is characterized by inflammation in the blood vessels (vasculitis), especially in the coronary arteries], and I thought I was going to end up as a basic science vasculitis researcher. Eventually, I started doing more and more clinical research and realized that’s what I wanted to pursue as an academic career. So I sought out clinical research training in epidemiology and biostatistics because I realized that, just like for bench research, one also needs rigorous training for clinical research. I chose to go to Boston University to train under David Felson, who has a recognized track record for training clinical researchers in rheumatology.
My initial interest was still in vasculitis, but while working in Boston I got to learn more and more about osteoarthritis. The more I learned about it, the more I saw the need there is in osteoarthritis research. The huge public health burden of osteoarthritis as the most common arthritis worldwide was something I hadn’t considered as a trainee. Yet there was only a minimal array of known risk factors for such a common disease. And while there were numerous advances in other rheumatic diseases, treatment options in osteoarthritis were limited, and a lot was not yet understood about its pathophysiology. It was at this point that I started drifting into osteoarthritis research and made that my primary focus. This is a common story – rheumatology trainees are much more interested in diseases like vasculitis and lupus, whereas diseases like osteoarthritis are not as clinically interesting, as we don’t have much in our armamentarium to offer patients.
How big of a problem is osteoarthritis?
According to the Global Burden of Disease study, more than 300 million people have osteoarthritis. I’ve heard that, in the upcoming study, this number will be updated to over 500 million people worldwide – that’s about 10% to 15% of adult populations from country to country. This number is as high, or higher than, conditions like diabetes and heart disease.
In the United States, it’s estimated that about 100 million people have chronic pain, and about 30% of those have osteoarthritis. Joint pain and arthropathies [diseases of the joint] are now the number one cause for doctor’s office visits, of which osteoarthritis is a major contributor. It used to be hypertension, but patients don’t go to see their doctors because they feel their blood pressure; they go because the doctor tells them to come in for a blood pressure check. The fact that joint pain and arthropathies are now number one on the list indicates that this is the most important issue or complaint that patients have.
Another really amazing statistic is that in the United States, osteoarthritis is now the third most common hospital admission/discharge diagnosis, behind childbirth-related admissions and sepsis, and ahead of cardiovascular disease. But why is osteoarthritis number three? It’s largely because of joint replacement surgery, indicating how much of a burden there is on the public health system because we don’t have adequate treatments for osteoarthritis. This huge burden is exacerbated by the fact that osteoarthritis is a chronic disease that people live with for decades, which further compounds the lack of adequate therapies to prevent or halt its progression, and to address the symptoms of the disease.
What are the risk factors for osteoarthritis, and which of them are modifiable?
Increasing age and female gender are risk factors, but obesity and knee injury are the strongest modifiable risk factors for the development of knee osteoarthritis. So maintaining a healthy weight, and knee injury prevention, are important in trying to reduce the risk of knee osteoarthritis. Leg length discrepancy, where there is a noticeably unequal leg length, is another risk factor for lower extremity osteoarthritis. Similarly, congenital hip dysplasia and bone shape abnormalities are also risk factors. There is a genetic predisposition to osteoarthritis, but the genetic component hasn’t been fully elucidated yet. Various nutritional factors have also been investigated as risk factors, but these haven’t really been proven in randomized trials. There’s still a lot to learn about potential risk factors.
What are the mechanisms that cause osteoarthritis pain?
There has been a lot of debate surrounding the structure-symptom discordance in osteoarthritis pain. Some people can have terrible-looking X-rays of their knees, but their pain doesn’t seem to be concordant with the severe nature of the radiographic appearance. At the same time, other people have relatively good-looking radiographs, yet they experience severe pain. This discordance has contributed to a long-standing debate about whether the pathology is important in experiencing symptoms in osteoarthritis.
When I was a research fellow, I took advantage of there being two knees within the body as a natural experiment. If one individual has pain and another individual doesn’t, we don’t know if the pain is caused by something going on in the knees or if there is something different at a personal level between the two people. But if for an individual one knee has pain and the other doesn’t, it points to something being unique in the painful knee that’s not in the non-painful knee. We were able to show that if you inherently control for all the between-person differences, the severity of structural pathology is linearly associated with symptoms.
What this indicates is that when you are doing large-scale studies and comparing across individuals, if you don’t account for the other factors that contribute to the between-person pain differences, you lose the ability to see that pathology does contribute to symptoms. However, it also highlights the fact that pathology is not the sole contributor to the pain experience. The thinking in osteoarthritis is that there is some element of nociception that is contributing to the pain experience. That seems to make sense when you think about the early stages of osteoarthritis, when pain is present primarily with weight-bearing activities. But later in the disease, some people develop persistent pain, even pain at rest or with normal range of motion. This suggests that there are alterations in neurobiological mechanisms that contribute to the pain experience, even when we don’t expect nociception to be the predominant driver.
Together with Lisa Carlesso, you recently sought to identify pain susceptibility phenotypes that contribute to persistent knee pain in knee osteoarthritis. What were the results of this study?
We were very lucky to have this unique database where we could collect data longitudinally. For this specific study, we looked at people who were initially free from persistent knee pain to understand what factors, apart from knee osteoarthritis pathology, might predispose an individual to developing chronic osteoarthritis pain. We wanted to look at factors that we know are associated with pain experience, such as depressive symptomology, coping skills, catastrophizing, and poor sleep. We also looked at QST [quantitative sensory testing] measures.
We performed a latent class analysis to identify whether there are different clusters of these characteristics in different groups of individuals. We were really surprised to see that our four different clusters of individuals were similar on depressive symptoms, sleep, widespread pain, and catastrophizing. The clusters were more differentiated based on the patterns of QST abnormalities. We evaluated our four clusters that we identified at baseline to see who developed persistent knee pain over two years, and found that the cluster that had low pressure pain thresholds at the knee and the wrist, meaning they had higher degrees of pain sensitization, had almost a twofold increased risk of developing persistent pain two years later. Interestingly, the people who had the most enhanced temporal summation did not have an increased risk of developing persistent knee pain over two years.
So what we came away with from this study was that, while certain factors contribute to the pain experience, they may not predispose to developing persistent pain. On the other hand, pain sensitization does appear to predispose to developing persistent pain. This goes back to the question of whether this is an inducible state or an inherent trait, such as, perhaps, related to genetics or some other factor that precedes the symptom experience. Now we need to look at other cohorts in a longitudinal fashion to see whether this finding is unique to a US-based cohort. Nonetheless, these findings have implications for understanding the transition from acute to chronic pain.
Given that osteoarthritis can affect different joints throughout the body, are there differences between hand and knee osteoarthritis? Or are they largely the same condition except for the body area affected?
That’s a really good question, but it’s one that we still don’t have an answer for. We know from a symptomatic perspective that knee osteoarthritis is very prevalent, and the symptomatic aspects are very well studied compared to osteoarthritis in other areas. But radiographic hand osteoarthritis, where there are visible changes in the joint on an X-ray, is much more common than radiographic knee osteoarthritis. The pathology of osteoarthritis is similar across body sites, but it’s not yet clear if it’s the same mechanisms occurring in the hand and the knee. So while the pathologic structural features of cartilage loss, osteophytes [bone spurs], synovitis [inflammation of the synovial membrane], and so on occur in any joint affected by osteoarthritis, whether the mechanism by which that pathology occurs in the knee, hip, or hand is the same or different is not yet clear.
You were part of the core executive committee that published the American College of Rheumatology guideline for the management of osteoarthritis of the hand, hip, and knee. What are some of the key takeaways from that guideline?
For those who have read the guideline, they’ll see that the term “non-pharmacological” does not appear anywhere. This is because we want to achieve an international consensus on recognizing that semantics and language matter to our patients. Describing a therapy as a “non”-therapy makes it sound like they aren’t receiving the definitive therapy. So saying non-pharmacologic therapy makes it sound like pharmacologic therapy is the definitive treatment. We were very careful in our messaging to elevate the importance of physical or mind-body approaches; these are just as important as pharmacological approaches that a patient or provider might consider. Healthcare providers woefully underutilize advice about weight loss, exercise, and physical therapy, which are the foundational mainstays of knee osteoarthritis management.
While there are strong recommendations for weight loss and physical activity, the main takeaway is that despite years and years and years of research and numerous trials, we still have a paucity of effective pharmacological treatments for osteoarthritis. What I find really striking is that when you look through the guideline, there are so few approaches that are strongly recommended or conditionally recommended. Yet at the same time, we have a lot of approaches that are strongly recommended against or conditionally recommended against. This highlights the terrible situation that we're in, where we have a highly prevalent and disabling disease, but we have very few effective management options to offer for patients in whom weight loss, physical activity, physical therapy, and a few pharmacologic agents are insufficient.
Having an inadequate armamentarium of options and the underutilization of weight loss and physical activity can have unintended adverse consequences. Andrew Stokes, an early-career investigator I work with here in Boston, looked at prescription analgesics for people who have arthritis or chronic low back pain from 1996 to 2016 using a US-based database. We found that NSAIDs and COX-2 inhibitors were the most prescribed treatments until Vioxx came off the market in 2004. After this, there was a marked drop-off in prescription of NSAIDs and COX-2 inhibitors, related to concerns about side effects of these agents, and there has been a concomitant and dramatic increase in the prescription of opioids. More recently, we see that more and more providers are nervous about opioids and there is movement to address the opioid epidemic. But this may inadvertently lead to a pain epidemic, where patients don’t have enough options to adequately manage their pain.
Looking forward, what are some of the questions you hope will be answered in the osteoarthritis field in the next five to 10 years?
I don’t think there’s going to be a single magic bullet for osteoarthritis. So we need to have better ways of phenotyping what’s going on at an individual level, not only from a disease pathology perspective but also with regards to other contributors to the pain experience, to develop an evidence-based way of managing the patient as a whole. Another area is to learn more about what pathologic lesions contribute to the progression of osteoarthritis, what are incidental findings, and what is part of healthy aging of the joint. If you think about kidney function, for example, there are natural declines with age, but these aren’t considered pathologic until they reach a certain threshold. Perhaps most importantly, I hope that we develop effective treatments to halt the disease and even prevent its onset.
Lincoln Tracy is a research fellow and freelance writer based in Melbourne, Australia. You can follow him on Twitter @lincolntracy.
Additional Reading
Kolasinski SL, Neogi T, Hochberg MC, Oatis C, Guyatt G, Block J, Callahan L, Copenhaver C, Dodge C, Felson D, Gellar K, Harvey WF, Hawker G, Herzig E, Kwoh CK, Nelson AE, Samuels J, Scanzello C, White D, Wise B, Altman RD, DiRenzo D, Fontanarosa J, Giradi G, Ishimori M, Misra D, Shah AA, Shmagel AK, Thoma LM, Turgunbaev M, Turner AS, Reston J.
Arthritis Rheumatol. 2020 Feb;72(2):220-233.
Stokes A, Berry KM, Hempstead K, Lundberg DJ, Neogi T
JAMA Netw Open. 2019 Dec; 2(12):e1917228.
Carlesso LC, Segal NA, Frey-Law L, Zhang Y, Lu N, Nevitt M, Lewis CE, Neogi T
Arthritis Rheumatol. 2019 Apr; 71(4):542-549.
The epidemiology and impact of pain in osteoarthritis.
Neogi T.
Osteoarthritis Cartilage. 2013 Sep;21(9):1145-53.