What is Hyaluronan (HA)?
Hyaluronan, also known as sodium hyaluronate and hyaluronic acid, is a naturally occurring polysaccharide present in the fluid inside normal joints. Slightly different synthetic formulations. (e.g. Synvisc, Hyalgan and Artzal) have been marketed as treatments for mild to moderate knee osteoarthritis Treatment consists of a series of weekly injections into the joint, and it may take up to two months to see the full effect of treatment. At this time, HA is approved only for use in the knee, but studies are underway looking at other joints, such as the base of the thumb, and HA has been used experimentally in the hip, shoulder, temporo-mandibular joint in the jaw, and the sacro-iliac joint in the low back.
How does HA work?
In normal knees, high levels of HA in the joint fluid make it thick and viscous, allowing the fluid to act as a lubricant and shock absorber, protecting the knee from damage during everyday stress. However, in joints with OA, the level of HA in the joint fluid is lower, and the fluid becomes thinner and less dense. Injectable HA is a thick, jelly-like substance, and it was initially believed that HA treatment worked simply by replicating the physiologic state of normal knees -- like putting new oil into a rusted ball bearing. However, further human and animal studies show that synthetic injectable HA only briefly remains inside the joint before absorption by the body; after a week, almost none is left in the joint. This makes it unlikely that HA's long-term therapeutic properties relate to its physical ability to diffuse high impact loads.
The actual reason for its ability to improve pain in some patients is unknown, and is probably due to a combination of factors. Synthetic HA may stimulate the body to produce more natural HA, or it may act as a scavenger, mopping up destructive inflammatory products produced by the damaged joint. It may also inhibit production of inflammatory molecules which can lead to pain and further joint destruction.
What are the main side-effects?
After over 5 million injections, the most serious events reported associated with synthetic HA use are two instances of anaphylactoid reactions, which resolved without further problems. A large series of 1537 HA injections showed that minor local reactions at the injection site or in the knee occurred in 2.7% of patients, with no major complications A recent study of 1489 knees treated with HA confirmed these low rates of adverse events. Swelling of the knee after HA injection has been documented and responds well to corticosteroids. There may be an increased risk of acute local reactions with repeated series of HA injections. Most randomized controlled trials show no difference in side effects between HA and placebo injections,,. One large controlled trial showed a slight increase in injection site reactions with HA compared to placebo, although only <1% of patients on HA chose to stop treatment due to such reactions.
Other investigators have noted an amorphous intracellular material in the joint in patients with acute inflammatory reactions after HA injections, which might represent a foreign-body type reaction. All these reactions resolved with intra-articular steroids and aspiration. One report describes six cases of granulomatous inflammation occurring in patients after HA injection, suggesting that HA may actually cause a more recalcitrant type of inflammation in some people. Given the millions of injections of HA that have occurred worldwide over the past decade, it is doubtful that this is a significant risk of treatment. Although existing studies do not suggest an increased risk of joint infection with the use of HA, any intra-articular injection has the potential to introduce infection into the joint space. However, this is exceedingly uncommon when the injection is performed by an experienced physician under sterile conditions; the estimate of infection due to a corticosteroid injection is 1/ 17,000-1/50,000.
Does it matter which formulation is used?
HA comes in a variety of molecular weight preparations: moderate molecular weight native preparations, (e.g. Hyalgan 0.5-0.73 kDa, Artzal 0.5-1.0 kDa, and Orthovisc 1.5 kDa.) and high molecular weight cross-linked preparations (e.g. Synvisc 7 kDa). Although claims have been made that high weight preparations, which better approximate the weight of natural occurring HA, may work better, this does not appear to be the case. The only double blind placebo controlled trial comparing different molecular weight preparations (Artzal and Synvisc) showed no difference in efficacy between the two brands.
What are the data in knee osteoarthritis?
The data supporting the use of HA in knee OA are controversial. While many individual studies conclude that HA improves pain and function in some people with mild to moderate knee OA,, there is some disagreement as to whether it works better than corticosteroid injections, oral medication such as non-steroidal anti-inflammatories, or even placebo injections,. For example, one recent retrospective study comparing HA to intra-articular steroids found patients using HA had less pain than those using steroids one year after the injections. However, another prospective randomized trial found that, although both treatments were moderately effective, there was no difference between steroids and HA at 6 months.
A number of OA experts do not find the existing data compelling enough to promote the use of HA in knee OA. However, a recent meta-analysis found that Synvisc does work in the treatment of knee OA. In this review, the beneficial effect of this HA appears to be clinically important, being detectable at 1-4 weeks and further developing between 5-13 weeks.
Whether these disagreements of opinion are due to flaws in study design, interpretation of results, or actual effectiveness of HA remains a point of contention. However, given the existing evidence, the enormous negative impact OA can have on a person's quality of life, and the very low risk of side-effects with HA, it remains a reasonable treatment option for some patients who have failed other conservative therapies.
Is HA disease-modifying for OA?
There are animal studies suggesting treating with HA may be beneficial to cartilage. Rabbits who were given experimental OA had less severe cartilage damage at 9 weeks if they were also treated with HA. In rabbits undergoing partial meniscectomy, HA increased meniscal regrowth and slowed further cartilage degradation. However, many positive reports are balanced by others that showed no effect of HA on cartilage,. This may be a result of timing: HA given right after trauma to the joint did not appear to be beneficial, whereas giving it later made it more likely that there would be improvements in the cartilage,.
In humans, some open label trials show that HA can improve or halt the destructive joint changes associated with OA. After receiving HA, some patients had increased thickness of the superficial amorphous cartilage layer six months later. Another trial suggested that treatment of HA decreased the rate of cartilage degradation compared with conventional therapy. While these are provocative data, whether or not HA has long-term structural benefits on joint architecture needs to be confirmed in rigorous prospective randomized controlled trials.
Who might benefit from a trial of HA?
All patients with symptomatic knee OA should initially have appropriate physical therapy and try oral medications such as non-steroidal anti-inflammatories, COX-2 inhibitors, or acetaminophen. Corticosteroid injections may also be useful in some patients. Although existing studies have not conclusively identified a sub-set of patients who might benefit most from HA treatment, it is important to note that most studies exclude patients with severe OA, as most researchers feel HA is not effective in patients with end-stage joint destruction.
In patients with mild to moderate knee OA in whom the above therapies have not worked, or who cannot take them due to other medical problems, options for treatment of knee OA are limited. In these patients, a trial of HA is reasonable. There are no data to suggest that if one brand of HA does not work, it is worth trying another. Cost is also an important factor, as each course of HA costs hundreds of dollars. Although most insurance policies do cover HA, patients should always check with their pharmacy coverage before starting a course of therapy.
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