Figure 9. Click to enlarge.
Hyaluronic acid is also known as sodium hyaluronate, or hyaluronan (the more correct term). Hyaluronic acid (HA) is a glycosaminoglycan (previously discussed) (Fig 9). It is a normal component of joints but it is generally agreed that there is some depletion of the amount in diseased joints and certainly the function.
Figure 10. Click to enlarge.
HA is an integral component of both synovial fluid and articular cartilage in normal joints. Synovial fluid HA is produced by the synovial cells of the synovial membrane. Other HA that is incorporated in the matrix of articular cartilage is synthesized locally by the chondrocyte. HA confers the property of viscoelasticity to synovial fluid and is responsible for boundary lubrication in the synovial membrane and also is a factor in the lubrication of articular cartilage. HA also influences the composition of the synovial fluid by acting as a high molecular weight barrier over the synovial membrane (called steric hindrance) and preventing active plasma components and leukocytes (white blood cells) from the joint cavity (Fig 10). It is also felt that solutions containing HA change the attraction of various other inflammatory cells. The HA that is in the articular cartilage is important in acting as a backbone for aggregations of proteoglycan molecules (discussed above) and aiding in the compressive stiffness of the articular cartilage.
Possible mechanisms of action of sodium hyaluronate that is injected – Beneficial effects after intra-articular administration of HA have been reported in a number of studies in the horse as well as other animals. However, the mechanism through which beneficial effects have been achieved remains controversial. The therapeutic effect of exogenously administered HA may result from the supplementation of the actions of depleted or depolymerized (decreased molecular weight) endogenous (formed naturally by the joint tissues) HA or alternatively result from other properties that have been suspected based on experimental work (discussed later).
It has been assumed by many for a long time that the primary therapeutic effect is by supplementation of depleted HA. However, while alterations in synovial fluid HA concentration and molecular weight in various joint diseases have been described, the results are conflicting. Generally there is a reduction in synovial HA concentration and molecular weight with equine joint disease. On the other hand, a recent study from equine joints with acute traumatic synovitis is not significantly different in HA concentration than from normal fluids. In the same recent study, the molecular weight of synovial fluid HA was not significantly different from normal equine joints compared with those of acute or chronic arthritis.
It is known that the half-life (time for half of the drug to be eliminated) of intra-articular HA injected into normal equine joints is 96 hours. This half-life is reduced in diseased joints. It is felt that although most of this HA is rapidly cleared from the joint, some remains associated with the synovial membrane and that it provides beneficial activity in the intercellular spaces of the synovial membrane. We know that HA has direct anti-inflammatory effects in inhibiting inflammatory cells. It has also been suggested that HA may also reduce interactions of enzymes or cytokines through the steric hindrance project. It is most recently felt that the decreased inflammatory cell activity is through interaction of HA with cell receptors on the white blood cells. Our research with intravenous hyaluronic acid leads us to suspect that the receptor mechanism is important.
It has been commonly proposed that the injection of HA into a diseased or injured joint results in increased synthesis of high molecular weight endogenous HA by the synoviocytes. Much of this work relies on in vitro (laboratory studies with tissue taken from the animal) evidence. These results, however, fit well with our clinical observations of a fairly long term effect when we know that the drug is not lost in the joint fluid (very long, or even less in the blood stream).
The use of intra-articular HA in clinical equine joint disease – The clinical use of HA for intra-articular treatment of equine joint disease was published in 1970 from Sweden in which cases of traumatic degenerative equine arthritis were treated with methylprednisolone acetate (a corticosteroid) versus HA/methylprednisolone acetate combination in 20 racing Thoroughbreds and Standardbreds. The investigators concluded that the combination of HA and methylprednisolone acetate (Depo-Medrol) resulted in a better and more lasting improvement than the corticosteroid alone. In 1976, other Swedish veterinarians published on the treatment of equine traumatic arthritis with intra-articular HA alone in 54 joints of 45 racehorses previously treated unsuccessfully by other means. Through a one year observation period, 38 of 45 horses were free of lameness and 32 returned to the racetrack after treatment. Since these early reports, numerous clinical and experimental studies have been conducted to evaluate the efficacy of HA in the treatment of equine joint disease. These clinical reports have generally supported the use of HA but in many of them, the evaluations are subjective (personal feeling) and the definitions for what success is are absent. The duration of post-treatment observation periods are varied and some studies were of short duration. A number of the studies have implied that HA is successful in the treatment of osteoarthritis but in most instances, joints have not had x-ray changes and blocked out with intra-articular analgesia (more typical of synovitis and capsulitis).
There have been some more objective studies in the horse done with bilateral osteochondral fractures created by arthrotomy and also chemically-induced synovitis. In one study a positive response was seen, whereas in the other no response was seen. There have been various studies in other experimental animals in which a chondroprotective (beneficial effects that protect the cartilage from degeneration) effect has been proposed. However, in a recent study in sheep the work implied that after injecting hyaluronic acid intra-articularly the sheep moved better and put more weight on the limb but degenerative changes occurred in the articular cartilage.
It is the subjective feeling of the author that mild to moderate synovitis and capsulitis will respond well to intra-articular hyaluronic acid, particularly in the fetlock joint. However, recent experience with intravenous hyaluronic acid has led to it being used more commonly in this fashion.
Intravenous Hyaluronic Acid (Legend)
A new formulation of HA for intravenous use has been approved recently in horses. It is marketed by Bayer as a product called Legend. My subjective impression is the drug can be very useful and in some instances has a more obvious beneficial effect than the intra-articular drug.
Figure 11a. Total protein concentrations on day 71. Significant differences (P less than 0.05) are noted by the same letters. Click to enlarge.
Figure 11b. Prostaglandin E2 concentrations on day 72. Same letters indicate significant differences (P less than 0.05). Click to enlarge.
Figure 11c. Synovial membrane scores of cellular infiltration. Significant differences (P less than 0.05) between groups are identified by the same letters. Click to enlarge.
Figure 11c. Synovial membrane scores of celular infiltration. Significant differences (P less than 0.05) between groups are identified by the same letters. Click to enlarge.
Figure 12. Click to enlarge.
We recently completed an experimental investigation of intravenously administered HA using a carpal chip model with the horses exercised on a treadmill. Twelve horses were used and six received 40 mg of Legend intravenously on days 13, 20 and 27 after chip fracture and six horses were treated similarly with a placebo of physiologic saline. Seventy-two days after surgery, the joints subjected to osteochondral fragmentation had increased synovial fluid total protein, glycosaminoglycan and prostaglandins E2 levels compared to contralateral joints without fragments. They also had increased synovial membrane inflammation. With treatment with intravenous HA, there were significantly reduced levels of synovial fluid total protein and prostaglandin E2 compared to joints with fragments in nontreated horses and also reduced synovial membrane cellular infiltration and vascularity (Fig 11a-d). Last but not least, horses treated with intravenously administered sodium hyaluronate were also determined to have a reduced degree of lameness compared to nontreated horses. We also showed no deleterious effects on articular cartilage.
The results of this study were very impressive but we still don’t know the mechanism as to why intravenous HA is achieving benefit. The time that HA lasts in the blood stream is extremely short, so we assume at this stage that the beneficial effects must be due to the HA localizing in the synovial membrane and working through receptors stimulating other events. We do know that the synovial membrane has an excellent blood supply so that intravenous administration may provide more access to the synovial membrane cells than intra-articular administration. A possible mechanism is illustrated in Figure 12.