Cover Story | Musculoskeletal

Developing Effective, Targeted Intra-articular Therapy

By Marie Rosenthal MS

An estimated 60% of lameness cases—a leading cause of performance loss—are attributed to osteoarthritis. Cricket Russillo, DVM, ISELP-Cert, discussed ways to develop effective, targeted treatment plans for lameness patients that need intra-articular therapy.

The decision to treat with intra-articular therapy can be multilayered and nuanced. Many factors may influence that decision, including efficacy, cost, and owner experiences and preferences. Performance schedule can also be an important consideration in professional horses. The disease and its severity, the horse’s age, and its comorbidities (eg, endocrinopathies) will also come into play.

“On top of these aspects of our case, there is the ever-expanding menu of choice,” said Dr. Russillo, a veterinarian and owner of High Performance Equine, which services patients in Northern Virginia and Florida. “It’s not just corticosteroids anymore. Now we have hemoderivatives, orthobiologics, non-biologic substances, and choices between autologous or allogeneic options.

“We must consider the variables across the tissue types, our patient as an individual, the unique set of circumstances, and the particular diagnosis of joint disease,” Dr. Russillo said at the 71st AAEP Annual Convention in Denver. Here are some considerations.

Articular cartilage
Different tissues, including articular cartilage, synovial membrane, synovial fluid and subchondral bone, support the function of the synovial joints. Joint injury occurs because of inflammation, direct trauma or cytokine-driven damage to the articular cartilage and bone, she explained.

By keying in on the pathophysiology, veterinarians will be better able to identify therapeutic options. For example, the function of articular cartilage is to facilitate movement and absorb shock. The breakdown of the articular cartilage aggravates joint disease, causing pain, inflammation and impaired joint function. “In response to injury, the activation of chondrocytes, synoviocytes and immune cells cause the release of key pro-inflammatory cytokines,”
Dr. Russillo explained.

These cytokines promote inflammation and matrix degradation, and can increase the production of prostaglandins, enzymes and free radicals.

“All this inflammation has to be controlled before we can begin the repair process. We have to remember that while the repair process will attempt to regenerate cartilage, the process is inherently flawed due to the poor regenerative capacity of articular cartilage,” she said.

Instead of healthy cartilage, fibrocartilage and scare tissue are formed. “This tissue is inherently less robust and is prone to further degradation when placed under future stress,” Dr. Russillo explained. It lacks a direct blood supply, which limits its ability to repair itself.

Therefore, the goal should be to protect cartilage integrity as much as possible, which is typically done by arresting that inflammatory cascade.

Choosing a therapy will depend on how much the disease has progressed. “Is this early-onset inflammation a response to the onboarding of training in a young horse, or is this an aged athlete suffering from more progressed cartilage degeneration? We need to keep this in mind as we choose our therapy and manage our client expectations,” Dr. Russillo said.

Options that support the health of articular cartilage in a younger horse might include the use of chondroprotective agents such as glycosaminoglycans and hyaluronic acid, pentosan polysulfate, and other nutraceuticals and/or nonsteroidal medications.

To limit inflammation, however, direct therapy at the root cause of inflammation—those pro-inflammatory cytokines.

“This is where the hemoderivative orthobiologics come into play,” Dr. Russillo said. These products can reduce the activity of the pro-inflammatory cytokines, contribute growth factors, and stimulate chondrocytes and promote extracellular matrix synthesis. Hemoderivatives that contain the molecule alpha-2-macroglobulin may also reduce the activity of proteases, aggrecanases and metalloproteinases.

Another orthobiologic therapy consists of mesenchymal stromal cells derived from bone marrow or adipose tissue. These cells can be autologous or allogeneic and can modulate the joint environment. The benefits of these stem cell therapies, especially when combined with arthroscopic surgery or a previous injection of hemoderivative therapy, holds the promise of chondrogenesis and tissue repair, she said.

However, these options are not always user-friendly, nor are they available to all practitioners.

Synovial membrane
The synovial membrane plays a critical role in the onset and progression of joint inflammation, as well as its repair. It nourishes the avascular cartilage and provides lubrication within the intimal layer of the synovium.
“If we suspect that inflammation of the synovium is our principal issue contributing to joint disease, there are at least 2 avenues for therapy. One, blunt the pro-inflammatory cytokine- and protease-driven inflammation, or number 2, look for a therapy that might manipulate the interplay of M1 and M2 synovial macrophage polarization,” Dr. Russillo said.
Intra-articular options worth consideration include corticosteroids, which can mitigate inflammation. Orthobiologics can also reduce the inflammatory responses of interleukins and growth factors, and a recent study showed that polyacrylamide gel might promote synovial macrophages toward the M2 type to repair and restore joint homeostasis.

Synovial fluid
The synovial fluid plays a crucial role in providing nutrients to the cartilage, reducing friction and maintaining joint health. It provides lubrication for joint movement, nutrients for the articular cartilage and removal of metabolic waste.

“If synovial fluid loses its protective and nutritive properties, it becomes a medium for inflammation, pain and cartilage degradation,” Dr. Russillo said.

In response to this inflammation, there is increased synovial fluid production with high levels of pro-inflammatory cytokines, prostaglandin E2, and nitrous oxide, which further degrade the cartilage. Excess synovial fluid contributes to increased joint effusion, which leads to joint pressure, pain and stiffness.

“If we consider synovial fluid as our target tissue for therapy, our best lever to pull would be in manipulating the level of hyaluronic acid,” she said. Direct injection of hyaluronic acid into the joint can improve the viscosity and lubrication of the synovial fluid, allowing smoother joint motion and protecting cartilage.

However, an injection alone is not enough. Most cases will also require the administration of IV hyaluronic acid and systemic polysulfated glycosaminoglycans, which may improve synovial fluid quality and joint health. Younger horses with minimal joint disease are most likely to benefit from this strategy.

Subchondral bone
Comprised of 2 principal parts—a compact subchondral bone plate and a more elastic subchondral trabecular bone component—the subchondral bone plays an integral part in joint stability and load distribution. The subchondral bone is highly adaptive and responds to mechanical loading through the coordinated activity of osteoclasts and osteoblasts.

Excess repetitive stress can lead to pathological changes within the subchondral bone that contribute to the development and progression of equine joint disease, and these injuries are common in equine athletes, regardless of their discipline, according to Dr. Russillo.

There are several pathways in which subchondral bone lesions may precede—and potentially drive—cartilage degeneration. For example, alterations in the subchondral bone, such as sclerosis or cyst formation, can decrease shock absorption. The release of pro-inflammatory cytokines in response to subchondral bone injury can also affect the health of the overlying cartilage.

Once the tissue’s adaptive capabilities have been exceeded, the coordinated action of osteoclasts and osteoblasts becomes uncoupled. Osteoclasts act to remove diseased bone over weeks, while the reparative process of replacement of bone by osteoblasts occurs more slowly over months. This effectively creates a transient osteopenia.

Pathology of subchondral bone is difficult and can be difficult to recognize in practice. In earlier stages, radiographs may be unremarkable, but they may show sclerosis or lysis in advanced stages. Advanced tools, like magnetic resonance imaging and computed tomography, are instrumental in diagnosing subchondral bone disease. However, advanced imaging is not always available, and owners cannot always afford them. So, recognizing subchondral bone disease may depend on the practitioner having an index of suspicion about the source of the lameness.

Still, clients might not like the best therapy option—exercise modification. “The complete bone repair cycle can take up to 120 days, and we practitioners need to be mindful about returning horses to training during this stage,” Dr. Russillo said.

Explain to clients that exercise modification doesn’t mean complete rest; controlled hand-walking or turnout exercise during the initial phase of repair is recommended. Some level of movement can be beneficial as the horse approaches a return to training. A water treadmill could aid in the reintroduction of training. “Alternatively, incorporating water treadmill exercise as the horse is back into full training can be a way of helping to prevent re-injury,” she said.
The extra-label use of systemic bisphosphonates can be considered, but these medications should not be given until the complete repair cycle has been performed by the osteoclast.

Shockwave therapy is sometimes used, although the evidence for its benefit in subchondral bone disease is low, she said.
It is important to explain to owners that it takes time for the joint to repair.

No one-size-fits-all option
There is no one-size-fits-all therapy for managing these cases, but veterinarians can create a treatment plan based on the pathophysiology of the damaged tissue, knowing that some of the options can modify the disease-causing mechanisms of more than 1 tissue. For example, the hemoderivatives that reduce inflammation through pro-inflammatory mediators can affect cartilage health and synovial homeostasis. Often, combination therapy is the best answer, Dr. Russillo added.

“In some cases, combining therapies over time can deliver maximal benefits,” she said. “Using this tailored method, we can develop a more effective individualized treatment strategy to improve both outcomes and client satisfaction.” MeV