Hyaluronan Preparations Used for Viscosupplementation in the Joints

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The first hyaluronan preparation used for intra-articular injection was the so-called non-inflammatory fraction of the natrium salt of hyaluronan (NIF-NaHA) and it had an average molecular weight of 2-3 million. This name was given to this highly purified preparation because it was distinctly different from the other fraction of the molecule that caused inflammatory reactions in various tissues used for testing such as the vitreus of the owl monkey, the peritoneal cavity of mouse and the horse joint. The test carried out in the monkey eye was the most sensitive and reproducible. The acute inflammatory reaction is similar to an endotoxin-induced inflammation but is not a result of the endotoxin content of the hyaluronan preparations because the endotoxin content of these hyaluronan preparations was very low even before they were fractionated. Nor was the very small amount of protein and nucleic acid impurities the cause of inflammation. The monkey vitreous test became the standard between 1970 and 1990 for all hyaluronan preparations used in ophthalmic surgery and for intra-articular injection in human and veterinary medicine (103,104). Because this test was expensive it was replaced in the 1990s with a much less sensitive and less expensive test using injections into the vitreus or anterior chamber of rabbit eyes.

At the time NIF-NaHA, a high molecular weight (average MW 2-3 million) hyaluronan, was developed the biological role of this molecule was perceived in a much broader spectrum than simply in mechanical terms. In 1971 the author of this chapter wrote: "The proposed biological role of hyaluronic acid will be discussed in four areas of matrix function: (a) mechanical function; (b) regulation of transport and distribution of molecules; (c) development and maintenance of matrix assembly; and (d) control of cell assembly" (79). The importance of the mechanical properties meant that 'hyaluronic acid provides the matrix with mechanical shock and vibration absorbing system of high permeability, transparency and deformability'. The regulatory role of hyaluronan in transport and distribution of molecules meant that 'the extended (polyanionic) coil structure of hyaluronic acid can serve as a filter and prevent or slow the passage of water and solutes through its domain. The effect is called the sieve or dynamic filtration effect'. The regulation of matrix assembly by hyaluronan means that it can 'under certain conditions influence the formations and mechanical stability of collagen fibrils' as well as 'the development and maintenance of the ordered structures of matrix' (79). The goal of developing hyaluronan for therapeutic purposes was to engineer the intercellular matrix and thereby influence tissue healing and regeneration. Matrix engineering was coined to describe the implantation or injection of crowded molecular networks of hyaluronan in solutions ($ 1%) or in the form of dry sheaths and hydrated membranes into the liquid or solid intercellular spaces of tissue compartments where disease or aging has altered or destroyed the normal matrix structure. In the case of the therapeutic application in painful arthritis this meant two steps. The first was to remove the pathological synovial fluid or exudate that contained hyaluronan of lower-than-normal concentration and with molecules of much lower molecular weight and broader polydispersity than present in healthy fluid. The second was to replace the fluid removed with NIF-NaHA made of hyaluronan molecules that, as closely as possible, resembled those present in the healthy fluid. Since the technology in the early 1970s was not available to produce sterile NIF-NaHA with an average molecular weight of 6 million or greater and with a narrow polydispersity comparable to that present in healthy synovial fluid, an adjustment of the concentration had to be made. By increasing the concentration to 10 mg/mL, the rheological properties of the preparation became closer to those of the healthy synovial fluid. In contrast, the concentration in the healthy joint is only 3-4 mg/mL. This was the first hyaluronan preparation marketed for veterinary medicine worldwide in the late 1970s and extensively tested in more than two dozen clinical trials in human osteoarthritis between 1968 and 1980 (Biotrics, Inc., Arlington, MA and Pharmacia AB, Uppsala, Sweden, under the trade names Healon® and Hylartil®). The very early exploratory human and veterinary clinical trials were published (80,105-107), but the later and more extensive human clinical trials were not, and this product was never marketed for treatment of painful osteoarthritis in humans.

More than a decade later, Italian and Japanese researchers started clinical trials with NIF-NaHA that had a very low average molecular weight (0.5-0.8 million) with very broad polydispersity (108,109). Unlike the pathological human synovial fluid this preparation did not have the high molecular weight component but only the very low one. Fig. 6 shows the polydispersity of hyaluronan in the human synovial fluid of a healthy knee joint compared with various hyaluronan preparations used as therapeutics for arthritic pain (110). Note than hylan A (avg MW 6 million) most closely resembles the polydispersity of the healthy synovial fluid; next is Hylartilw (avg MW 2.5 million), then

Orthovisc (avg MW 1.2 million), Artzal (avg MW 0.7 million) and Hyalgan (avg MW 0.5 million). Hylartil was the first hyaluronan in clinical tests for human and equine arthritis and was marketed for veterinary use in the late 1970s. Artz® (or Artzal® or Supartz® ) and Hyalgan® (avg MW 0.5 million) were first marketed for human osteoarthritis in 1986 in Japan and Italy (Seikagaku SPH,

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Side Effects Supartz Injections

molecular mass

Figure 6 Polydispersity of some hyaluronan products used for viscosupplementation. Hylartil® was the first hyaluronan product clinically tested for the treatment of osteoarthritis in humans and marketed for veterinary medicine. Hylan A is the fluid component of hylan G-F 20, representing 80% per volume of the product (average molecular weight 6 million). The average molecular weight of Orthovisc® is 1.2 million and that of Artzal® is 0.75 million. The dotted line represents the polydispersity of hyaluronan in a healthy human synovial fluid, obtained from the knee joint. The polydispersity was analyzed by agarose gel electrophoresis according to the method described in Ref. 110.

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Figure 6 Polydispersity of some hyaluronan products used for viscosupplementation. Hylartil® was the first hyaluronan product clinically tested for the treatment of osteoarthritis in humans and marketed for veterinary medicine. Hylan A is the fluid component of hylan G-F 20, representing 80% per volume of the product (average molecular weight 6 million). The average molecular weight of Orthovisc® is 1.2 million and that of Artzal® is 0.75 million. The dotted line represents the polydispersity of hyaluronan in a healthy human synovial fluid, obtained from the knee joint. The polydispersity was analyzed by agarose gel electrophoresis according to the method described in Ref. 110.

Japan and Fidia SpA, Italy). It is important to note the fundamental differences in the distribution of molecules of various sizes in these preparations and compare them with the hyaluronan in the healthy fluid. Fig. 7 demonstrates the difference in polydispersity of the healthy and osteoarthritic fluids (5). The important fact is that all osteoarthritic synovial fluids ever studied have a considerable amount of hyaluronan with high molecular weight ($ 2 million). Therefore, the pathological change, as far as the polydispersity of hyaluronan is concerned, is the appearance of various amounts of hyaluronan molecules with molecular weights between 0.3 and 2 million (110-113).

Fig. 8 (5) demonstrates the proportion of elasticity and viscosity as functions of frequency of the same hyaluronan preparations (Hylartil®, Orthovisc®, Artzal®) as shown in Fig. 6. As expected from the polydispersity data, preparations that have higher and narrower distribution of molecular weight will show greater elastic properties at the higher frequency range. This is only if the concentration of hyaluronan is same or similar.

Neither of the above hyaluronan preparations fulfilled the original criteria for viscosupplementation. Therefore in the early 1980s the author decided to n o

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Figure 7 The polydispersity of hyaluronan in the synovial fluid of the knee of a healthy and an osteoarthritic patient demonstrated in agarose gel electrophoresis according to Lee and Cowman (110). The relative mobility, obtained from densitometry measurements and MW distribution, is based on electrophoretic analysis of hyaluronan standards with known average molecular weight (from Ref. 5).

Molecular Massx 10"6

Figure 7 The polydispersity of hyaluronan in the synovial fluid of the knee of a healthy and an osteoarthritic patient demonstrated in agarose gel electrophoresis according to Lee and Cowman (110). The relative mobility, obtained from densitometry measurements and MW distribution, is based on electrophoretic analysis of hyaluronan standards with known average molecular weight (from Ref. 5).

develop hyaluronan with an average molecular weight (with narrow polydispersity) similar to or even greater than that of the native hyaluronan. This new hyaluronan derivative that could be produced with an average molecular weight of 6-25 million was given the generic name of hylan A. A cross-linked gel of hyaluronan called hylan B was also developed (37-39). The mixture of these two hyaluronan derivatives (8 volumes hylan A of 10 mg/ mL concentration and 2 volumes of hylan B of 0.5 mg/mL concentration) became the formulation of hylan G-F 20 (Synvisc®, Biomatrix, Inc., Ridgefield, NJ and since 2000, Genzyme Corp., Cambridge, MA). This is today the only viscosupplementation product available worldwide to patients that has rheological properties similar to the healthy human synovial fluid since it was first marketed in Canada in 1993 (98). Shear, extensional and squeeze flow experiments on hyaluronan (as present in the joint) suggest that the hyaluronan in healthy synovial fluid has a combination of rheological properties which make it remarkably effective for tissue and cell protection in the joint. The hylan A and hylan B system (hylan G-F 20) was studied with the same rheological methods (114). The authors of these studies interpreted this special mixture of hylan A and hylan B as "successfully mimicking over long periods, the behavior in joints of healthy synovial fluid".

Many other hyaluronan preparations have recently been made available to patients worldwide, but most of them have elastoviscous properties comparable

Hyaluronic Acid Matrix Implantation
Figure 8 Proportion of elasticity and viscosity in hyaluronan preparations as a function of the frequency at which the measurement of the elastic (G0) and viscous (G0/) dynamic moduli is made. For more details see legend of Fig. 3 (from Ref. 5).

to those of the lower molecular weight component of the pathological synovial fluid (for review see Refs. 115 and 116).

C. Clinical Use of Hyaluronan for Alleviating Joint Pain

The principal symptom that brings the patient to the doctor is local pain in the joint that may be initiated by movements (with load or not) or present in the resting joint. All treatments by drugs or surgery are aimed at alleviating this pain. Viscosupplementation is the latest, if by now not a very new, therapeutic paradigm targeted as a local analgesic treatment. Since its introduction to veterinary and human medicine by clinical trials and marketing in the late 1970s, viscosupplementation has met with enthusiastic support and also doubtful criticism. While millions of patients have been treated worldwide and dozens of drug companies have conducted and financed laboratory and clinical research to define its efficacy, safety and mode of action, the question of which patients benefit the most from this local treatment remains unanswered. There are several well-defined reasons for this. First is the lack of general recognition that there are fundamental differences between the hyaluronan preparations used today. It is surprising that this fact is seldom noted when the efficacy of various preparations is considered.

It is generally accepted that there is a lower limit of elastoviscosity of a hyaluronan preparation below which it is not effective in viscosupplementation. There have been several clinical trials where hyaluronan (10mg/mL concentration) with average molecular weight of less than 100,000 was used as control. The developer of one of the lowest average molecular weight hyaluronan (Artz® 750,000) always emphasized that their preparation was efficacious because it was made of 'high molecular weight' hyaluronan (108). This means that the hyaluronan preparation that has efficacy over physiological salt solution must have elastoviscous properties at least at the level of the lowest observed in pathological synovial fluids. In some clinical studies, hyaluronan (1%) with average molecular weight of 100,000 or even lower was used as a control. The difficulty lies in the differentiation of the efficacy levels (effect size) between the various hyaluronan preparations and between a control treatment using physiological salt solutions or low average molecular weight hyaluronan of the same volume and with the same injection frequency. It is also generally accepted that a control treatment is not equivalent to a classic placebo ('sugar pill') because if it is properly used, it combines the removal of the exudate from the joint and its replacement with the physiological salt solution, thereby washing out and diluting pain-causing agents in the joint. Indeed with all hyaluronan preparations used for viscosupplementation a sizable number of patients respond to physiological salt solution treatment with analgesia, which in some cases is long lasting (weeks). This is not surprising in view of the long-lasting analgesic effect of diagnostic arthroscopy, a procedure during which the joint is washed out with a large volume of physiological saline solution.

Another problem with clinical trials using salt solutions as a comparative treatment is the standardization of patients. The well over 100 clinical trials carried out with various hyaluronan products during the past 35 years taught us that in some clinical trials with randomly selected patients, only half respond well to the treatment and the other half respond to the control treatment or do not respond at all. Such a situation does not produce satisfactory statistical results. On the other hand, in other trials with a different group of patients, viscosupplementation shows a statistically and clinically significant benefit over the control treatment. The complexity of the evaluation of efficacy of the various hyaluronan products is shown by the fact that from the very outset, the low elastoviscosity and low average molecular weight products were tested and introduced to the market with 5-10 consecutive weekly injections required for efficacy, while the very high elastoviscous product showed efficacy after only 2 -3 weekly injections. This recommended treatment schedule was often changed under commercial pressure (cost and reimbursability) during the past decades, but the bulk of clinical trials published still demonstrates the difference.

Direct comparisons of the various hyaluronan products in one clinical trial are few and not conclusive (117). A very recent meta-analysis (118) compared the effect size (at 95% confidence intervals) of 14 low (0.6-0.9 million), two medium (2 -3 million) and three high (6 million) average molecular weight preparations. The authors' conclusion was that only two trials using the high average molecular weight (6 million) products "had an effect size of 1.55 and 1.76, suggesting efficacy equivalent to that of a total knee replacement". The authors (118) were skeptical that the effect size could be so large; however, others have in fact reported that hylan G-F 20 treatment can provide pain relief to postpone replacement therapy (119). All the remaining 17 trials, including one with the highest molecular weight product, had a median effect size varying between 0.04 and 0.58 which, according to the authors, is "equivalent to the effect of non-steroidal anti-inflammatory drugs over that of acetaminophen" (118).

In the course of the past two decades it has become more and more obvious to the author and his co-workers that another evaluation method must be found in order to define the clinical value of viscosupplementation and determine which hyaluronan preparation is the most efficacious. Viscosupplementation by definition cannot be regarded as a classical drug or hormonal therapy, even if the beneficial effect is based on a combination of physicochemical and chemical properties of the hyaluronan molecule. This is because it is a replacement therapy. It supplements a natural polymer in the joint space with the same polymer in highly purified form, only at a different concentration and/or average molecular weight than present in the pathological joint. Furthermore, as we know it today, the long-lasting analgesic effect works only if the hyaluronan supplement is applied intra-articularly and only if the exudate, if present, is first removed, and it certainly is not effective in all patients with joint pain. Therefore it should be classified as a tissue fluid replacement therapy, not very different from blood transfusion (more correctly, infusion).

In recent years, the usefulness of effectiveness studies over efficacy studies was emphasized. Effectiveness studies address broader aspects of the usefulness of therapeutic paradigms and are especially useful from a pharmaco-economical and health policy point of view (120-122). The very high average molecular weight (6 million) hylan G-F 20 preparation was studied in two independent prospective effectiveness clinical trials in Canada (123,124) and France (125). The conclusion of these effectiveness trials was that the incremental improvement in the group of patients receiving hylan G-F 20 injection intra-articularly was statistically and clinically significant for all primary and secondary outcome parameters, including the measuring of pain relief by patient and physician. A statistically significant decrease of the use of non-steroidal anti-inflammatory drugs and steroid injections was also noted. Importantly, significant decreases in gastrointestinal side effects and the use of medication to treat them were also observed.

The question of what the clinically most effective formulation of a hyaluronan product is for viscosupplementation (the combination of concentration, average molecular weight, rheological properties and volume injected) and how to select the most responsive patients will not be answered until similar effectiveness studies are also carried out on very low (<1 million) and medium (2-3 million) average molecular weight products using comparable concentrations of the polymer and comparable doses (frequency of injection and volume injected).

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