Knee Osteoarthritis: Overview of Current and Evolving Treatment

Editor’s Note:  Dr. Michael D. Clayman, CEO of Flexion Therapeutics Inc., wrote one of the most cogent descriptions of the osteoarthritic knee disease process and state of treatment we’ve ever read. It is our pleasure and honor to share it with the readers of Orthopedics This Week.

Osteoarthritis (OA) of the knee is a disease that has afflicted humankind for millennia.¹ Perhaps that helps explain why it is so often accepted as an inevitable part of the aging process—a nuisance that just needs to be tolerated as we “get old.”

However, the reality is that OA is a serious medical condition which significantly increases morbidity and mortality.² It demands attention, and failure to effectively manage OA² can result in a cascade of negative health consequences that not only impact quality of life but can lead to unneeded suffering and death.

A Large and Growing Health Concern

To start, it is important to put OA in proper context.

It is a disease that affects more than 30 million Americans.³ The number of people diagnosed with OA is only expected to grow in the years ahead due to several demographic and societal factors, including the aging of the U.S. population, increases in the number of overweight and obese individuals, people living sedentary lifestyles and the long-term effects of knee injuries in aging athletes.^1,4

OA of the knee (OAK) is a common type of OA, and more than 15 million Americans were treated for OAK in 2016.⁵

At the current rate of growth, OAK will likely be the fourth leading cause of disability by 2020.⁶ Significantly, the average age of physician-diagnosed OAK has fallen by 16 years, from 72 in the 1990s to 56 in the 2010s.⁷

Given that there is no cure for OAK, earlier diagnosis is likely to result in more people living longer with painful disease symptoms.⁷

Finally, but alarmingly, OAK imposes an annual economic burden which now amounts to more than $185 billion in annual U.S. expenditures.⁸

The Cascade of Consequences

It Starts With Pain Leading to Reduced Physical Activity

The benefits of exercise are well established. In fact, studies show that as little as 15 minutes per day of moderate physical activity, such as brisk walking, reduced all-cause mortality by 14%,⁹ and there is a documented reduction in the incidence of coronary disease events in people who are more physically active.¹⁰

However, patients with OAK may limit or avoid physical activity.¹¹

Part of the progressive nature of OA is that the downward spiral can start slowly and almost imperceptibly. As the disease advances, pain generally increases, and many patients simply do not obtain sufficient pain relief.^{12, 13}

In fact, one in four people with knee OA have daily pain while walking, 47% have difficulty or are unable to climb stairs, and 74% have difficulty or are unable to kneel, stoop or crouch.¹⁴ These limitations can have broad detrimental health effects, as physical activity can improve overall health and decrease comorbidities in patients with OAK.^15-17

OAK Exacerbates Other Chronic Diseases and May Lead to Excess Mortality

In addition to its direct effects on knee pain and function, OA is also associated with other health effects and increases in cardiovascular disease.² A meta-analysis of published literature found a statistically significant increased risk of developing diabetes mellitus in patients with OA compared with patients without OA.¹⁸

In patients with both OA and diabetes, OA-related walking difficulty is a significant risk factor for diabetes complications.¹⁹ Cross-sectional analysis of data from the National Health and Nutrition Examination Survey found that more than half of adult OA patients had metabolic syndrome.²⁰ Another study found that 80% of OAK patients were overweight or obese, and that more pain was reported in patients with higher body mass indices (BMI).²¹ Increased BMI (>27 kg/m²) is also significantly associated with both OAK progression and knee pain and is also a risk factor for poor three-year outcomes in OAK patients with respect to Western Ontario and McMaster Universities Arthritis Index (WOMAC) function.^22-24

Importantly, OAK is associated not only with an increase in the incidence of other significant health conditions, but strikingly, with excess mortality.²

A recent study found that excess mortality in OA patients may result from reduced levels of physical activity due to involvement of lower limb joints.²⁶ Perhaps not surprisingly, given the impact of exercise on cardiovascular health, the majority of excess mortality is associated with the adverse effect of walking disability on cardiovascular health.² These findings highlight the importance of maintaining or improving mobility as a way to prevent early death in OAK patients.

While research into OAK has linked it with increases in both morbidity and mortality, concomitant health conditions themselves may exacerbate OAK. For example, OAK progression, measured by annualized joint space narrowing, has been shown to be significantly greater in OAK patients with Type 2 diabetes compared with OAK patients who do not have Type 2 diabetes.²⁷

Exercise Cuts Pain in OAK Patients

Physical activity can be an important tool for mitigating the effects of the cascade of consequences that result from OAK and is the first-line intervention to decrease pain and functional limitations in OA.¹⁵ Exercise can provide pain relief and functional benefits for patients with OAK, regardless of their age, pain or functional level or disease state.¹⁶

In patients with OAK, exercise has been shown to result in an absolute reduction of 12 points on a 0-100-point pain scale and an absolute improvement of 10 points on a 0-100-point scale of physical function.¹⁶

The importance of physical activity in managing OA is underscored by its inclusion in the clinical practice guidelines from the American College of Rheumatology, the American Academy of Orthopaedic Surgeons and the Osteoarthritis Research Society International and is also recommended by the Centers for Disease Control and Prevention as a way to improve pain, function, mood and quality of life.^{15, 17}

Given the limiting effects of pain on physical activity, new OAK therapies that effectively relieve pain have the potential to play a critical role in enabling patients to increase their levels of physical activity.

The Evolving Treatment Paradigm

When patients initially present to physicians with OAK, their symptoms are typically treated with oral medications such as nonsteroidal anti-inflammatory drugs (NSAIDS).

These treatments, however, provide only relatively modest pain relief^{12, 13} and many come with black box warnings that describe serious, sometimes fatal side effects.

Opioids continue to be prescribed for patients with OA despite the well-known and potentially devastating risks associated with this class and that they are only modestly efficacious in OA pain.²⁸

Alarmingly, recent studies have found that in patients who were prescribed a medication for their OA pain, over 70% were eventually prescribed an opioid²⁹and almost 20% of patients leave their first medical appointment for OA with an opioid prescription.³⁰  

As patients exhaust their oral treatment options they typically advance to intra-articular (IA) therapies in the form of corticosteroids or hyaluronic acids (HA). Immediate-release steroids have served as the standard of care since the 1950s, and the first HA was approved as a medical device for the treatment of OA in 1997.

For too many, the inadequacies of the current OAK treatment paradigm eventually dictate total knee replacement (TKR).

In fact, roughly 50% of all patients diagnosed with OAK will eventually undergo TKR.³¹

Obviously, undergoing major surgery is something that patients would likely prefer to avoid, but they are driven to this decision by pain, reduced functionality and its effect on other health conditions.

So, new treatments that can effectively address OA knee pain have the potential to make a real and important difference in their lives.

Until recently there has been relatively little innovation in terms of new medicines for OA.

However, from last year’s approval of a microsphere-based intra-articular treatment for OAK pain developed by the company I lead, Flexion Therapeutics, to clinical trials investigating anti-nerve growth factor (NGF) antibodies,³² human fibroblast growth factors³³ and newer studies evaluating WNT pathways³⁴ and the potential of ultra-pure trans-capsaicin,³⁵ industry has renewed its focus on OAK through a variety of modalities which may offer meaningful analgesia.

Furthermore, at Flexion, we are now advancing a preclinical, investigational gene therapy which can be administered locally to stimulate the production of an anti-inflammatory protein, interleukin-1 receptor antagonist (IL-1Ra) within the joint.

We believe, that durable, on-demand suppression of inflammation holds the potential to both reduce pain and modify disease progression.³⁶

While far from an exhaustive list, these examples serve to illustrate some of the ways in which industry is now responding to this area of need.

Summary:  OAK is a painful, progressive and incurable disease which places a tremendous burden on society. Yet only recently have the serious health and economic implications from this condition fully been recognized. Insufficient pain relief from OAK can lead patients to limit or avoid physical activity, contributing to a cascade of consequences. Therefore, it is essential that patients are well-educated about the disease and its impacts so they are equipped to have informed discussions with their caregivers. It is critical that they obtain appropriate clinical intervention which effectively addresses their pain for extended periods, improves their quality of life and allows them to engage in activities that can reduce the risks of both morbidity and excess mortality associated with OA.

In the longer term, with the continued development of new approaches that not only provide symptomatic relief but also delay and disrupt disease progression, perhaps we will dispel the notion that OA is an “inevitable part of aging” and recast it as one of many chronic diseases that are being effectively treated by modern medicine.

For more information:  https://flexiontherapeutics.com/

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