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Viscosupplementation in the olderpatient with osteoarthritis
VISCOSUPPLEMENTATION IN THE OLDER PATIENT WITH OSTEOARTHRITIS CHARLES WEISS, MD
Osteoarthritis of the knee is the leading cause of disability in the elderly. This localized, painful condition is often accompanied by decreased elastoviscosity of the intraarticular synovial fluid due to decreased hyaluronan molecular weight and/or concentration. Viscosupplementation attempts to restore viscoelastic homeostasis to the arthritic joint to reduce pain and restore function. Recently, two low-molecular weight (MW) hyaluronans and one cross-linked high-MW hyaluronan (hylan) have been approved for the intraarticular treatment of this disease in the United States. Five weekly intraarticular injections are recommended for both low-MW hyaluronans. They have been proven effective in reducing knee pain in mild to moderate disease, equivalent to NSAIDS. They are as effective as corticosteroids, are of slower onset, and have longer duration of effect. Three weekly injections are recommended for the hylan product. It has been proven effective in mild to advanced disease and is as or more effective than NSAIDS and more effective than corticosteroids. Definitive comparative studies of these products have not been published. Viscosupplementation has been shown to be very safe. Local transient knee pain and/or swelling (2-4%) per injection, without long-term sequelae have been the only significant adverse events No systemic effects, viral transmission, drug interaction, or mortality have been associated with this treatment. It is recommended that viscosupplementation be considered after the failure of exercise and local or systemic analgesic treatment in the elderly osteoarthritic knee, particularly when gastrointestinal, renal, or cardiovascular comorbidities or drug interactions may exist. KEY WORDS: viscosupplementation, hyaluronan, hylan, elastoviscous, osteoarthritis Copyright 2002, Elsevier Science (USA). All rights reserved.
Osteoarthri.tis (OA) of the knee is the leading cause of disability among persons over 65 years of age in the United States. 1 Recently, two hyaluronan and one hyaluronan derivative (hylan) have been approved in the U.S. for intraarticular treatment of this disease. This article will outline the history, activity of hyaluronans in the joint, the results of clinical studies, and the integration of viscosupplementation into the OA treatment paradigm.
From the Department of Orthopaedics, University of Miami School of Medicine, Miami, FL; and the Department of Orthopaedic Surgery, University of Pittsburgh, Shadyside Medical Center, Pittsburgh, PA. Address reprint requests to Charles Weiss, MD, 6431 Pine Tree Drive Circle, Miami Beach, FL 33141. Tel: + 1-305-867-5401; fax: + 1-305-8680209. E-mail: [email protected]. Copyright 2002, Elsevier Science (USA). All rights reserved. 1048-6666/02/1202-0000535.00/0 doi:10.1053/otor.2002.36174
million. At a concentration of 0.3 m g / m L , these molecular solutions completely fill their solvents; therefore, normal synovial fluid consists of a crowded, overlapping, entangled polyanionic molecular network that influences every cell, fibril, molecule, and ion that enters or attempts to enter the joint space (Fig 1). A concentrated layer of hyaluronan covers ~and is imbibed into the articular surface (the lamina splendens) and the synovium. This layer acts as a molecular filter inhibiting the movement and distribution of molecules such as fibrinogen and immunoglobins into the joint. 3,4 The high MW and concentration of hyaluronan in normal human synovial fluid confers elastoviscous properties, which influence its physiologic function. When subjected to low rates of deformation, slow-movement molecules configurationally adjust, line up parallel to the direction of flow (pseudoplasticity), and dissipate energy through viscous flow and heat. When subjected to high rates of deformation (slow walking), the molecules a r e unable to configurationally adjust, become increasingly entangled, and act as an elastic solid storing energy (Fig 2). The synovial fluid of arthritic joints has lowered elastoviscosity due to decreased MW a n d / o r concentration, and behaves predominantly as a viscous fluid without the tissue protective properties of an elastic solid. 5 The activities of cells involved in the pathogenesis of OA are affected by the rheological properties of the hyaluronan matrix that bathes them. High elastoviscous hyaluronan affects cells of the lymphomyeloid system by decreasing cell migration, mitosis, pinocytosis, phagocytosis, prostaglandin, and bradykinin release, lymphocyte activation, fibroblast migration, and stabilizes nociceptor
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Operative Techniques in Orthopaedics, Vol 12, No 2, 2002: pp 124-130
VISCOSUPPLEMENTATION: HYALURONAN ACTIVITY IN JOINTS Thirty-five years ago, Balazs suggested that some types of osteoarthritic pain were associated with decreased elastoviscous properties of hyaluronan in the joint. 2 He subsequently hypothesized that the addition of exogenous viscoelastic hyaluronan to these joints, viscosupplementation, could reduce pain and improve function by restoring joint homeostasis. 3 Hyaluronan is a polyanion composed of repeating units of N-acetylglucosamine and glucuronic acid. Its concentration in normal synovial fluid is 3-4 m g / m L with an average molecular weight (MW) of 5
Hyaluronan Molecular Network
Hyaluronan Molecule
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Fig 1. The hyaluronan molecule (HA) is composed of repeating disaccharide units that form a spherical random coil molecule of approximately 3,000-A diameter. The individual molecules overlap at concentrations greater than 0.3 mg/mL to form an entangled molecular network,
activity; it is a very effective free radical scavenger. Synovial fluid of low elastoviscous properties, as found in osteoarthritic joints, has the reverse effect. Synoviocytes are stimulated to synthesize hyaluronan in vitro by the
addition of exogenous high-MW hyaluronan, whereas the addition of low-MW hyaluronan does not have this effect.6 The medical use of hyaluronan was made possible by E.A. Balazs" purification of a noninflammatory fraction of sodium hyaluronan. 7 It had a MW of 2-3 million and reduced pain in surgically induced knee cartilage injury in dogs and monkeys and in the arthritic joints of race horses. 8 Subsequent studies showed that the synovial fluid in these arthritic joints had decreased elastoviscous properties, which returned to normal in those that responded Lovtscosupplementation. This response was dependent on the elastoviscosity of the hyaluronan injected into the joint. 9 Later studies in Japan confirmed that increased elastoviscosity of exogenously introduced hyaluronan reduced pain and pain mediators (bradykinin and prostaglandin E2) in experimentally produced arthritis. 6 The first studies of viscosupplementation in humans for the treatment of OA were conducted from 1969 to 1973. The hyaluronan, Healon ® (Biotrics, Arlington, MA), used in these investigations had an average MW of 2-3 million and was produced by Biotrics and subsequently was manufactured and distributed by Pharmacia for veterinary use as Hyartil-Vet® (Pharmacia, Uppsala, Sweden). It was produced from rooster combs as are all hyaluronan-approved products in the U.S. today. Overall, Healon® was effective in relieving pain in patients who had high levels of pain, mild to moderate disease on X-ray, and symptomatic arthritis of relatively recent onset. In patients with more advanced disease it was less effective,s° In 1987, two hyaluronan products of tow elastoviscosity (MW 500,000-800,000) became available commercially to treat arthritic joints: Artz TM manufactured by Seikagaku in Japan and Hyalgan®, manufactured by Fidia in Italy. Because more than 90% of hvaluronan molecules in normal synovial fluids are more titan 2 million, MW products of 2 million or more will be classified as high MW and those below 2 million will be classified as low MW. In 1997, HyaIgan@ and in 2001, Supartz TM two low-MW hyaluronans, and in 1997 one high-MW hylauronan derivative (hylan G-F 20), Synvisc® (Genzyme Biosurgery, Cambridge, MA), were approved for file treatment of OA of the knee in the United States (Fig 3).
A
B
Fig 2. Molecular basis for the elastoviscous properties of HA. (A) the application of a low-strain frequency force (1) to a HA solution causes the randomly organized HA molecules (2) to orient in the direction of flow (3). This orientation allows extremely viscous HA solutions to flow through narrow gauge needles. (B) The application of a high-strain frequency force (high rate of deformation) (1) does not allow the HA molecules time to reorient. Therefore, the energy of the impact is stored elastically in the compressed molecular network (2). At a distance from the point of highest strain frequency (3,4) a slow, viscous flow is established, and then molecular orientation (random coils) are restored. VISCOSUPPLEMENTATION IN THE OLDER PATIENT WITH OSTEOARTHRITIS
125
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Hyaluronan (MW 1.2 mi )
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Fig 3. The MW distribution of HA in normal and OA synovial fluid and in viscosupplementation products.
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CLINICAL EFFICACY OF LOW-MW H Y L A L U R O N A N S l O -la Supartz T M is a 1% solution of hyaluronan with an average MW of 800,000 (620,000-1,170,000). Recommended treatment is 5 weekly injections of 25 mg (2.5 million) each. Short-term clinical trials (4-8 weeks } in Japan showed that 50-84% of patients receiving Artz T M improved. In a 6-month effectiveness study 80% of patients responded with 43.5% graded excellent; however, an average of 13.7 injections were given per patient. 1°-~3 A 1-year study in Sweden found no significant benefit for Artz T M in the intent-to-treat population except in the subgroup of patients over 60 years of age with Lequesne Index greater than 1014 and a 1-year trial failed to show significant benefit. ~s The safety and efficacy of Supartz T M for treatment of OA of the knee in the U.S. was "based on an integrated analysis of 5 randomized, multicenter, blinded placebo controlled clinical trials" in 5 countries (Australia, France, Germany, Sweden, and the United Kingdom). There were 123 centers, 1155 patients, mean age 62 with 63% being female. Treatment regimen consisted of 5 weekly injections. The French study included a 3-injection arm. The results of the German study for paracetamol consumption revealed no significant difference, as did the UK and Swedish studies for protocol-specific primary analysis. Individual study results for Lequesene score as Repeated Measures of Analysis of Covariance (ANCOVA) of mean reduction from baseline over all visits or after the 5-week visit revealed that only the Australian and UK studies showed statistical significance (P < .05), whereas the French 3- and 5-injection series, as well as the German and Swedish studies, showed no significant statistical difference from control. The integrated analysis of all 5 studies for Lequesne score, however, did show a statistically significant improvement in the SupartzTM=treated patients. 16 Hyalgan® is a low elastoviscous 1% solution of hyaluronan (MW 500,000-730,000). The recommended treatment regimen is 5 injections of 20 mg hyaluronan in 2 mL, given once a week, Eight placebo controlled studies and 3 studies comparing Hyalgan® to corticosteroid injections have been published. 1°-13 Three studies of 8 weeks dura-
1 26
tion showed that 75-88% of patients responded to Hyalgan® injections, 30-50% responded to placebo and 3 or 5 injections was better than one injection. A 5-injection, 5-month efficacy study failed to show a significant difference between Hyalgan® and placebo except for a decrease in the use of rescue NSAIDS. A 48-week, 4-injection blinded study showed Hyalgan@ to be very effective for rest pare and mildly effective for pain on movement compared with placebo. A 52-week, 4-injection, controlled, open label study showed Hyalgan® treated patients better for all parameters at 7 weeks. At i year, there was no difference from control at rest or exercise VAS pain; however, they were better b y physician global assessment and Lequesne Index. In a second 52-week study, 19 I-Iyalgan@ treated and placebo knees were arthroscopically evaluated before treatment and 1 year later. Patients receiving Hyalgan® had better ~clinical and arthroscopic results. A U.S., 3-armed, 26-week study, compared 5 weekly injections of Hyalgan® to 5 placebo injections and to Naproxen in 495 patients, mean age 63.7 of which 58.4% were female. This study showed small, but substantially significant improvement in an analysis of completers in the Hyalgan® primary efficacy measure (pain on a 50-foot walk) and in the categorical assessment of pain by the patient compared with placebo and no difference compared with N a p r o x e n J In two open studies, Hyalgan® was compared with 6-methylprednisolone acetate (40 rag) injections and showed that pain relief with Hyalgan® was as effective, longer lasting, but of slower onset. A double-blind, controlled study showed no statistically significant difference but a trend in favor of Hyalgan®. 12 In summation, low-MW hyaluronans have been shown to be more effective than placebo and as effective as NSAIDs and intraarticular corticosteroids for mild to moderate OA in the elderly patient. In the 1980S, Balazs et al. developed a family of crosslinked hyaluronan~ polymers (hylans) in which neither the carboxylate nor the acetamido group of hyaluronan is chemically modified. 18 Hylan G-F 20 (Synvisc®) is the specific hylan composition formulated to behave as a synovial prosthesis. It consists of 80% hylan A by volume (an elastoviscous fluid, a~erage M W 6 million) and 20% hytan
CHARLESWEISS
I00
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80
2O
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3O
60
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"G
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so
~,
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g.. Fig 4. Elastic and viscous behavior of normal and osteoarthritic synovial fluid compared with Iow-MW HA and a hylan viscosupplement.
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Hyaluronan (0.5 million MW)
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Frequency (Hz)
B (a hydrated water insoluble gel containing 99.5% of water). It has similar physicochemical properties to the synovial fluid found in healthy young adults, being highly elastic over a wide range of strain frequencies, intraarticular residence time is extended compared with native hyaluronan and low-MW hyaluronans, 6,1s and it has the same permeability, biocompatibility, and lack of immunogenicity as unmodified hyaluronan. It behaves predominantly as an elastic solid, whereas other hyaluronan viscosupplements remain predominately viscous fluids throughout all physiologic ranges 6 (Fig 4). Neurophysiologic studies demonstrated that the increased discharge frequencies of the medial articular nerve after inflammatory and mechanical stimulation were significantly reduced after intraarticular injection of hylan G-F 20, but not after nonelastoviscous degraded hylan G-F 20 was injected. This was most pronounced during movement of the inflamed joint; thus, elastoviscosity directly influenced nociceptors responsible for pain perception. 19,2° Other factors: repeated dilution of noxious stimuli, polyaniordc lavage, and repeated mechanical and possible physiochemical stimulation of synovial lining celIs play a role in the reduction of pain. CLINICAL
EFFICACY
OF HYLAN
G-F 20
The safety and efficacy of hylan G-F20 (Synvisc®) in the treatment of OA of the knee has been evaluated in seven prospective double-blind controlled studies, average patient's age 61 with over 60% female: 3 vs. saline, 1 vs. arthrocentesis, 2 vs. NSAID, and 1 vs, low-MW hyaluronan. 11-13Seven additional studies have been reported: one multi-center retrospective study; one retrospective study comparing Artz® to Synvisc®, one open label ~tudy vs. saline, 3 prospective open label studies in advanced disease, and one prospective single-blind study vs. corticosteroid• The first two studies showed that two bi-weekly Synvisc@ injections were significantly better than control b y
week 4 and remained so through week 12 (P < .05), and 3 injections were significantly better than two by week 8 and remained so through week 12. In a multi-center study, more than 50% of Synvisc® treated patients were symptom-free at 12 weeks and significantly (P < •001) better than saline controls. At 26 weeks these improvements continued for weight-bearing pain, night pain, decreased activity, and reduced use of rescue treatment (P <- .05)Y In a U.S. trial, patients who worsened after withdrawal of NSAID were considered a flare population. Patients with inflammatory disease were specifically included in this study• Synvisc@ was better than arthrocentesis in pain relief (P K •0001) and reduction of effusion (P < •005)• At 26-36 weeks, patients who had two courses of treatment had significant reductions in pain with motion (P < .02), rest pain (P < •05), and overall pain (P K .05). In the flare population there was significant (P < .05) improvement in Synvisc@ treated knees with >50% improvement in pain on motion, rest pain, night pain, walking, and overall pain. 22 Two studies compared Synvisc@ to NSAID. In the first there were 3 arms: one received NSAID plus 3 weekly arthrocentesis, the second received Synvisc@ plus placebo pills, and the third received NSAID plus Synvisc@. At 12 weeks Synvisc@ was at least equivalent to NSAID in improving pain parameters and overall assessment• By 26 weeks both Synvisc@ groups were statistically superior to NSAID in percent of symptom-free patients. Repeat-measures analysis demonstrated statistically significant improvement of Synvisc@ vs. NSAID alone (P < .05) with regard to overall pain level. 2s A second study compared Synvisc® to diclofenac. There were 3 s t u d y groups: the first received 3 injections of Synvisc@ plus a placebo pill, the second received diclofenac plus 3 arthrocentesis, and the third received 3 arthrocentesis and a placebo pill. At 3 months there was significant improvement (P < .03) of Synvisc® over double control for all parameters of the WOMAC and no statistical significance between diclofenac and control. The Le-
VISCOSUPPLEMENTATION IN THE OLDER PATIENT WITH OSTEOARTHRITIS
127
quesne index demonstrated statistically significant improvement of Synvisc® over diclofenac and control. There was no difference between diclofenac and controlY In a two-and-one-half year multi-center retrospective study of 336 patients, (122 bilateral), 56 knees had a second course. The mean age was 65 years and disease duration 7 years. Seventy seven percent of the knees were rated better or much better and 2% were worse. After a second course 87% of knees were better and 4% worse. The mean time to retreatment was 8.2 months. Treatment was effective across the entire spectrum of disease with 58% of patients with Kellgren-Lawrence grade (KLG) IV arthritis rated better or much better. Up to 90% of patients with less severe disease were better and over 70% of patients were able to use less NSAIDs. 2s In an open label 12 week, study (56% had Larsen grades III and IV), all outcome measures: night pain, weightbearing pain, overall improvement were significantly improved (P = .0001) from 1-12 weeks post-treatment. 26 A prospective randomized double-blind 3-injection multi-center trial compared the clinical efficacy of Synvisc® to Artz®. At 12 weeks patients Synvisc® patients were significantly better (P < .05) in all primary outcome measures (overall condition, most painful knee movement, weight-bearing pain, and overall pain) as well as symptom-free patients. 27 A retrospective study of 200 patients, who received either 5 weekly injections of Hyalgan® or 3 weekly injections of Synvisc®, showed both groups were significantly better than before treatment i:n weight-bearing pain, mobility, and pain at rest. Synvisc® was significantly better than Hyalgan® in relief of pain on weight-bearing~ mobility (P < .03), and night-time pain (P < .005). 28 Three prospective open studies were performed in late stage disease~ In Canada 60 patients on the queue for total knee arthroplasty (TKA), all had grade IV KLG arthritis, chronic disabling pain, mean age was 67 years and 65% were female. At 1 year there was a significant improvement in the WOMAC A, B, and C scores (P < .02), and 38% were able to delay surgery. 29 In a U.S. prospective study of 108 patients, all were candidates for TKA having failed NSAIDs, corticosteroids and conservative treatment. Eighty-three percent had KLG IV and 13% had grade IfI OA. The Hospital for Special Surgery Rating Scale was utilized pretreatment and at 1, 3, 6, and 12 months and every 6 months thereafter. 52% of eligible patients did not undergo TKA at 2.6 years. 3° In a study of 123 knees in 90 patients (65% female average ag e 74 + _ years) 75% had KLG IV arthritis, 85% failed NSAIDs, two thirds failed interarticular corticosteroids, and one third failed arthroscopic debridement. Sixty-five percent of patients were better 6 months after treatment and 46% at 1 year; 64% of patients better at 1 year remained so at 2 years. Thirty-three knees had a retreatment (mean time 15 months) and 78% remained better 12 months later. There was a fifty-two percent decrease in the number of TKAs. 3~ One randomized single-blind study compared 3 injections of Synvisc® to one injection of Aristopan® (Triamcinoloixe Hexacetonide 40 rag) for 26 weeks. At 12 weeks, Synvisc® treated knees were statistically significantly su128
perior for WOMAC AI, WOMAC C, total WOMAC, and VAS overall. These statistically significant improvements persisted at week 26, except for the WOMAC AI, which, however, was still improved. 32 In summation, high-MW hylan G-F 20 has been shown to be more effective than placebo, NSAIDs, and corticosteroids in the treatment of mild to advanced OA to the knee in elderly patients.
THE OA TREATMENT PARADIGM OA of the knee is a local nonfatal disabling disease. Its treatment is based on the principles of doing no harm, relieving pain, and restoring function. To appropriately position viscosupplementation in the elderly patient, it is important to consider its efficacy and safety compared with other standard treatments. To date, the only adverse events (AEs) of significance are transient reactions of pain and or effusions without permanent sequelae. The mean prevalences of AEs per injection in controlled clinical trials was 2.6% for Artz TM, 4.2% for Hyalgan®, 2.3% for Synvisc® and were similar to saline controls¢i-!3 These local AEs usually occur within 48 hours of injection, and are occasionally accompanied by an inflammatory response. They usually resolve with rest, ice, analgesics, and occasionally arthrocentesis a n d / o r corticosteroid injection. 12 Two thirds of patients who had AEs post,Synvisc® injection had a subsequent AE-free injection, and 69% were clinically improved. There were no permanent sequelae and no evidence of an immune response.25 There are occasional reports of increased incidences of AEs with both low-; and high, MW viscosupplementsJ2,~ 3 The etiology of theses AEs is poorly understood. It may be related to the physical characteristics of the viscosupplement, injection technique, or postinjection physical activity. There has been no alteration of urine or blood tests, no drug inter, action, no systemic pharmacologic activity, no sepsis, and no allergic responses. 12 Extra-articular injections, may also contribute to the incidence of local tissue reactions, with the suprapatellae medial approach with t h e knee partially bent, having a si~ificant increase in the number of AEs.25 In the author's experience after strict aseptic t e c ~ i q u e , if there is an effusion, a suprapatellae lateral approach with the knee in extenSion util~ing a 20-gauge needle, is most effective. If no fluid comes back, the needle may be plugged therefore inject a small amount of air (<1 mL), If thereis no effusion either the knee extended suprapatellae or an infer0,patellar lateral approachi w i t h the knee bent to 90 o is! i effective i To check that the needle is in the joint, inject some air, which can be heard a n d / o r felt w~thin the joint. This technique assures that the needle is i n the joint cavity: and not in capsule or fat pad. NSA!DS are the ~tQst commonly used medication for OA pain, most of these occurring in patients being treated for arthritis. In the United States it is linked to 16,500 deaths ~ u a l l y ~ 3 Gastrointestinal ulcerations occur in 9-30% of patients~on NSA!DS for more than 2 weeks and 10% of; these develop obstruction, perf0ration, or hemorrhage.~ This risk is: heightened a n d additional problems such as nephrotoxici~ (4%), edema ( 4 0 ) , hyperkalemia (20/0):, and llyponatre~ia (7%)in ~ e e!derly> 4 Hypertension (5 m m increase in diastolic pressure) occurs in 1% of CHARLES WEISS
the p a t i e n t s t a k i n g N S A I D s ) a n d increases the risk of stoke b y 67% a n d c o r o n a r y a r t e r y disease b y 15%. s5,36 R e c e n t r e v i e w s s u g g e s t i n c r e a s e d risks of M I w i t h selective COX-2 inhibitors, 37 as well as i n c r e a s e d risks of g a s t r o i n testinal ulcers. 3s All of the c a r d i o v a s c u l a r c o m p l i c a t i o n s are i n c r e a s e d b y d r u g interactions, ie, A C E inhibitors, Beta blockers, c a l c i u m c h a n n e l blockers, a n d diuretics c o m m o n l y u s e d in the t r e a t m e n t of h y p e r t e n s i o n a r r h y t h m i a s , or c o n g e s t i v e failure in the elderly. C o n s i d e r i n g the lethal a n d debilitating s y s t e m i c effects of these d r u g interactions, it is a p p r o p r i a t e to u s e v i s c o s u p p l e m e n t a t i o n b e f o r e N S A I D s in p a t i e n t s w i t h these risk factors. Jntraarticular corticosteroids h a v e b e e n u s e d i n O A joints fo r a l m o s t 50 y e a r s despite the lack of e v i d e n c e of l o n g - t e r m efficacy, a n d significant s y s t e m i c a n d local side effects139 A single injection of intra-articular steroids c a n s u p p r e s s stress r e s p o n s e s w i t h s u p p r e s s i o n of e n d o g e n o u s cortisone p r o d u c t i o n for 10-30 days. It often m a k e s the c o n t r o l of h y p e r t e n s i o n a n d diabetes m o r e difficult, causes d e c r e a s e d l i g a m e n t strength, m a y cause s t e r o i d a r t h r o p a ' t h y a n d a v a s c u l a r necrosis, a n d h a s a n infection r a t e of 1 in 14,000 (almost 20 times m o r e f r e q u e n t t h a n that r e p o r t e d after v i s c o s u p p l e m e n t a t i o n w i t h hylans). Postinjection flares ( p a i n a n d swelling) s u b s i d i n g in 1-3 d a y s , o c c u r s in 2%, sim!!ar t o v i s c o s u p p l e m e n t a t i o n . H y p e r s e n s i t i v i t y a n d a case of a n a p h y l a x i s w e r e r e p o r t e d in 199Z 39 C o n s i d e r i n g these s y s t e m i c a n d local r e s p o n s e s , c o r t i c o s t e r o i d s s h o u l d be l i M t e d to t h o s e cases w h e r e there is a clear i n f l a m m a t o r y o r a c u t e crystalline a r t h r o p a t h y . T o r n k n e e a r t h r o p l a s t y is o n e of the m o s t successful p r o c e d u r e s i n o r t h o p a e d i c s t o d a y ; h o w e v e r , it h a s significant m 0 r b i d i t y a n d mortality. The d e a t h rate f r o m p u l m o n a r y e m b o l i s m is o v e r 0.2%. 4° A p p r o x i m a t e l y 47% of p a t i e n t s will d e v e l o p a d e e p v e i n t h r o m b o s i s , d e s p i t e p r o p h y ! a x i s a n d 24% of t h e s e p a t i e n t s will h a v e a p o s t - t h r o m b o s i s s y n d r o m e . 4~ O v e r the life time o f the p r o s t h e s i s 1% of p a t i e n t s w i l l d e v e l o p a joint infection that r e q u i r e s r e m o v a l 6f the prosthesis. 42 T e n p e r c e n t are likely to requ!re r e v i s i o n s u r g e r y , a n d 5% of p a t i e n t s h a v e unsatisf a c t o r y results d u e t o j o i n t stiffness.
CONCLUSIONS Viscosupplementation is an effective and recognized treatment for O A of the knee, as T r e a t m e n t s h o u l d start w i t h p a t i e n t e d u c a t i o n , w e i g h t loss, exercise, braces, canes, t o p ical analgesics, a n d s i m p l e analgesics s u c h as a c e t a m i n o p h e n . In e l d e r l y p a t i e n t s o n m e d i c a t i o n s (ACE inhibitors, diuretics, Beta blockers, a n d soon), w h o h a v e h y p e r t e n sion, renal, c a r d i o - p u l m o n a r y , or g a s t r o i n t e s t i n a l disease, this s h o u l d b e f o l l o w e d b y v i s c o s u p p t e m e n t a t i o n . For the r e m a i n d e r , short c o u r s e s of N S A I D s m a y be a p p r o p r i a t e . The us e of intraarticular corticosteroids s h o u l d be res e r v e d f o r t h o s e patients w h o h a v e a n acute crystalline a r t h r o p a t h y o r a r e c u r r e n t i n f l a m m a t o r y c o m p o n e n t of their arthritis, Certainly v i s c o s u p p l e m e n t a t i o n s h o u l d be considered before joint arthroplasty or surgical intervention.
REFERENCES 1. Arthritis Prevalence and Activity Limitations--United States, 1990. Morbidity Mortality Weekly Report 43:24:433-438, 1994
2. Balazs EA, Watson D, Duff IF, et al: Hyaluronic acid in synoviaI fluid. I. Molecular parameters of hyaluronic acid in normal and arthritic human fluids. Arthritis Rheum 10:357-376, 1967 3. Balazs EA, Denlinger JL: Viscosupplementation: A new concept in the treatments of osteoarthritis. J Clin Rheum 39:3-9, 1993 4. Levick JR: Synovia] fluid: Determinants of vol~tme turnover and material concentration, in Kuettner KE, Peyron JG, Scheleyerbach R, et al (eds): Articular Cartilage and Osteoarthritis. New York, Raven Press, 1992, pp 529-541 5. Balazs EA: The physica] properties of synovial fluid and the special role of hvaluronic acid, in Helfet AJ (ed I: Disorders of the Knee, i st ed. Philadelphia, JB Lippincott, 1974, pp 63-75 6. Weiss C, Band P: Basic principles tmderlying the development of viscosupplementafton for the treatment of osteoarthritis. J Clin Rheum 5:$2-Sll, 1999 (suppl) 7. Denlinger, JL: Hyaluronan and its derivatives as viscoelastics in medicine, in Laruent TC (ed): The Chemistry, Biology and Medical Applications of Hyaluronan and its Derivatives: Proceedings of the Wenner-Gren Foundation International Symposium, Sept 18-21, 1996, Stockholm, Sweden, London, Portland Press, 1997, pp 235-242 8. Rydell N, Balazs EA: Effect of the intra-articular injection of hyab uronic acid on the clinical symptoms of osteoarLhfitis and on granulation tissue formation. Clin Orthop 80:25-32, 1971 9. Balazs EA. Denlinger JL: Sodium hyalttronate and joint function. J Equine Vet Sci 5:217-228, 1985 10. Peyron, JG: Intraarticular hyaluronan injections in the treatment of osteoarthritis: State of the art review. J R h e u m V 20:10-15, 1993 (suppl) 11. Peyron ]G: Viscosupplementation for the treatment of osteoarthritis of the knee with hyaluronan and hylans: Rationale and state of the art, in Tanaka S. Hamanishi C (eds): Advances in Osteoarthritis. Springer, Tokyo, 1999, pp 213-236 12. Adams ME, Lussier AJ, Peyron JG: A risk-benefit assessment of injections of hylattronan and its derivatives in the treatment of osteoarthritis of the knee. Drug Safety 2:115-130, 2000 13. Rosier RN, O'Keefe RJ: Hyaluronic acid therapy, in Price CT (ed): Instructional Course Lectures, vo149. Rosemont, IL, American Academy of Orthopaedic Surgeons, 2000, pp 495-502 14. Kahlberg L, Lohmander LS, Ryd L: Intraarticular injections of hyluronan in patients with cartilage abnormalities and knee pain: A one year double-blind, ptacebo-comrolled study. Arthr Rheum 37:521528, 1994 15. Lohmander LS, Dalen N, Englund G, et ah Intra-articular hyaluronan injections in*the treatment of osteoarthritis of the knee: A randomized, double-blind, placebo controlled, multicenter trial. Ann Rheum DiS 55:424-431, 1996 16. SupartzT M FDA Labeling. 17. Airman RD, Moskowitz R: The Hyalgan Study Group: Intraarticular sodium hyaluronate (Hyalgan®) in the treatment of patients with osteoarthritis of the knee: A randomized clinical trial. J Rheumatol 25:2203-12, 1998 18. Balazs EA, Leshchiner E, Larsen NE, Band, P. Hyaluronan biomaterials: Medical applications, in Wise DL, Trantoto DT, Altobelli DE, et al (eds): Encyclopedic Handbook of Biomaterials and Bioengineermg, vol 2. New York, Marcel Dekker, 1995, pp 1693-1715 19. Belmonte C, Pozo MA, Balazs EA: Modulation by hyaluronan and its derivatives (hylans) of sensory nerve activity signaling articular pain. in Laurent TC (ed): The Chemistry, Biology, and Medical Applications of Hyaluronan and its Derivatives, vol 72. Proceedings of the Wenner-Gren Foundation international Symposium, Sept 18-21, 1996, Stockholm, Sweden. London, Portland Press, 1997, pp 205-217 20. Pozo MA, Balazs EA, Belmonte C: Reduction of sensory responses to passive movements of inflamed knee joints by hylan, a hyaluronan derivative. Exp Brain IRes 116:3-9, 1997 21. Wohig M, Dichut A, Maier R, eta!: Viscosupplementation with hylan G-F20: A 26-week controlled trial of efficacy and safety in the osteoarthritis of the knee. Clin Ther 20:410-423, 1998 22. Moreland LW: New therapeutic Options for treating knee osteoarthrifts. Pharmacy Therapeutics 20:238-245, 1999 23. Adams. M: Viseosupplementation as an alternative to conventional treatment for the management of osteoarthritis of the knee. J Clin Rheumatol 5:SI8-$23, 1999 (suppl) 24. Dixon DJ', HOMeG: The Primary Study Group. Double-blind double control comparison of viscosupplementation with hylan G-F20 (Syn-
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visc®) against diclofenac and control in knee osteoarthritis. J Rheum 37:155, 1998 (suppl 1) Lussier A, Cividino AA, McFarlane CA, Olyszynski WP, Potasher wJ, de Medicis R: Viscosupplementation with hylan for the treatment of osteoarthritis: Findings from clinical practice in Canada. J Rheumatol 23:1579-1585, 1996 Wobig M, Beks P, Dichut A, et ah Openqabel multicenter trial of the safety and efficacy of viscosupplementation with hylan G-F20 (Synvise) in primary osteoarthritis of the knee. J Clin Rheumatol 5:$24$31, 1999 (suppl) Wobig M, Bach G, Beks P, et ah ]~he role of elastoviscosity in the efficacy of vlscosupplementation for osteoarthritis of the knee: A comparison of hylan G-F20 and a lower-molecular-weight hyaluronan, Clin Ther 21:1549-1562, 1999 Sripada P, Pritchard C, Banks PF: Comparison of efficacy of hyaluronan and hylan G-F20 in osteoarthritis. ACR Abstract No. 1353, Nov. 1999 Bell M, Fallaha M, Lenczner E, et ah Viscosupplementation with hylan G-F20 in total knee replacement candidates: An effective pain management therapy that may delay surgery, Osteoarthritis Re~ search Society International, Vienna, Austria, Sept 16-19, 1999 Miller EH, Snyder MA, Heidt RS, et ah Analysis of the results of viscosupplementation with hylan G-F20 in the treatment of osteoarthritis of the knee. A prospective study of 108 patients. American Academy of Orthopaedic Surgeons. Anaheim, CA, Feb 4-8, 1999 (abstr) Weiss C: The treatment of osteoarthritis of the knee with hylan G-F20 m orthopaedic practice. 5~ Osteoarthritis Cartilage 8:$86, 2000 (suppl) Lanzer WL, Schuster RT: A randomized single-blind comparison of the efficacy and safety of Synvisc® (hylan G-F 20) and Aristopan® (Triamcinoloine Hexacetonide) in patients with osteoarthritis (OA/of
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the knee. American Academy of Orthopaedic Surgeons, Dallas, TX, Feb. 13-17, 2002 Wolfe MM, Lichtenstein DR, Singh G: Gastrointestinal toxicity of nonsteroidal anti-iruqammatory drugs. N Engl J Med 340:1888-1899, 1999. Whelton A, Maurath CJ, Verburg KM, et al: Renal safety and tolerability of celecoxib, a novel cyclooxygenase-2 inhibitor. Am J Ther 7:159-175, 2000 Collins R, Pete R, MacMahon S: Blood pressure, stroke, and coronary heart disease: Part 2. Lancet 335:827-838, 1990 Collins R, Peto R, MacMahon S: Blood pressure, stroke and coronary heart disease. Part 2. short-term reductions in blood pressure: overview of randomized drug trials in their epidemiological context. Lancet 335:765~774, 1990 Mukherjee D, Nissen SE, Topol EJ: Risk of cardiovascular associated with selective COX-2 inhibitors. JAMA 286:954-959, 2001 Juni P, Rutjes AS, Dieppe PA: Are selective Cox2 irfl~ibitors superior to traditional non-steroidal anti-inflammatory drugs? Adequate analysis of the class trial indicates that this rosy not be the case. Br Med J 324:1287-1288, 2002 Rozental TD, Sculco TP: Intra-articular corticosteroids: An updated overview. Am J Orthop 20:18-23, 2000 Clagett GP, Anderson FA Jr, Geert SW: Prevention of venous thron~tboembolism. 5th ACCP Consensus Conference on Antithrombotic Therapy. Chest 114:5315-5605, 1998 (suppl) Hass S: Deep vein thrombosis: Beyond the operating table. Orthopedics 23:629-632, 2000 (suppl) Wilson G, Kelley K, Thornhiss TS: Infection a s a complication of total knee replacement arthroplasty. J Bone Joint Surg 72A'878-883, 1990 Altman RD, Hochberg MC, Moskowitz RW, et ah Recommendation for medical management of osteoarthriti s of the hip and knee. Arth Rheum 43:1905-1915, 2000
CHARLES WEISS
Osteoarthritis of the knee is the leading cause of disability in the elderly. This localized, painful condition is often accompanied by decreased elastoviscosity of the intraarticular synovial fluid due to decreased hyaluronan molecular weight and/or concentration. Viscosupplementation attempts to restore viscoelastic homeostasis to the arthritic joint to reduce pain and restore function. Recently, two low-molecular weight (MW) hyaluronans and one cross-linked high-MW hyaluronan (hylan) have been approved for the intraarticular treatment of this disease in the United States. Five weekly intraarticular injections are recommended for both low-MW hyaluronans. They have been proven effective in reducing knee pain in mild to moderate disease, equivalent to NSAIDS. They are as effective as corticosteroids, are of slower onset, and have longer duration of effect. Three weekly injections are recommended for the hylan product. It has been proven effective in mild to advanced disease and is as or more effective than NSAIDS and more effective than corticosteroids. Definitive comparative studies of these products have not been published. Viscosupplementation has been shown to be very safe. Local transient knee pain and/or swelling (2-4%) per injection, without long-term sequelae have been the only significant adverse events No systemic effects, viral transmission, drug interaction, or mortality have been associated with this treatment. It is recommended that viscosupplementation be considered after the failure of exercise and local or systemic analgesic treatment in the elderly osteoarthritic knee, particularly when gastrointestinal, renal, or cardiovascular comorbidities or drug interactions may exist. KEY WORDS: viscosupplementation, hyaluronan, hylan, elastoviscous, osteoarthritis Copyright 2002, Elsevier Science (USA). All rights reserved.
Osteoarthri.tis (OA) of the knee is the leading cause of disability among persons over 65 years of age in the United States. 1 Recently, two hyaluronan and one hyaluronan derivative (hylan) have been approved in the U.S. for intraarticular treatment of this disease. This article will outline the history, activity of hyaluronans in the joint, the results of clinical studies, and the integration of viscosupplementation into the OA treatment paradigm.
From the Department of Orthopaedics, University of Miami School of Medicine, Miami, FL; and the Department of Orthopaedic Surgery, University of Pittsburgh, Shadyside Medical Center, Pittsburgh, PA. Address reprint requests to Charles Weiss, MD, 6431 Pine Tree Drive Circle, Miami Beach, FL 33141. Tel: + 1-305-867-5401; fax: + 1-305-8680209. E-mail: [email protected]. Copyright 2002, Elsevier Science (USA). All rights reserved. 1048-6666/02/1202-0000535.00/0 doi:10.1053/otor.2002.36174
million. At a concentration of 0.3 m g / m L , these molecular solutions completely fill their solvents; therefore, normal synovial fluid consists of a crowded, overlapping, entangled polyanionic molecular network that influences every cell, fibril, molecule, and ion that enters or attempts to enter the joint space (Fig 1). A concentrated layer of hyaluronan covers ~and is imbibed into the articular surface (the lamina splendens) and the synovium. This layer acts as a molecular filter inhibiting the movement and distribution of molecules such as fibrinogen and immunoglobins into the joint. 3,4 The high MW and concentration of hyaluronan in normal human synovial fluid confers elastoviscous properties, which influence its physiologic function. When subjected to low rates of deformation, slow-movement molecules configurationally adjust, line up parallel to the direction of flow (pseudoplasticity), and dissipate energy through viscous flow and heat. When subjected to high rates of deformation (slow walking), the molecules a r e unable to configurationally adjust, become increasingly entangled, and act as an elastic solid storing energy (Fig 2). The synovial fluid of arthritic joints has lowered elastoviscosity due to decreased MW a n d / o r concentration, and behaves predominantly as a viscous fluid without the tissue protective properties of an elastic solid. 5 The activities of cells involved in the pathogenesis of OA are affected by the rheological properties of the hyaluronan matrix that bathes them. High elastoviscous hyaluronan affects cells of the lymphomyeloid system by decreasing cell migration, mitosis, pinocytosis, phagocytosis, prostaglandin, and bradykinin release, lymphocyte activation, fibroblast migration, and stabilizes nociceptor
124
Operative Techniques in Orthopaedics, Vol 12, No 2, 2002: pp 124-130
VISCOSUPPLEMENTATION: HYALURONAN ACTIVITY IN JOINTS Thirty-five years ago, Balazs suggested that some types of osteoarthritic pain were associated with decreased elastoviscous properties of hyaluronan in the joint. 2 He subsequently hypothesized that the addition of exogenous viscoelastic hyaluronan to these joints, viscosupplementation, could reduce pain and improve function by restoring joint homeostasis. 3 Hyaluronan is a polyanion composed of repeating units of N-acetylglucosamine and glucuronic acid. Its concentration in normal synovial fluid is 3-4 m g / m L with an average molecular weight (MW) of 5
Hyaluronan Molecular Network
Hyaluronan Molecule
~
1 3000A
~bC)
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.O~
""
~
~ /11201 H O ~ o .
~
r /
~
~/1o
HNCOCH8
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j._
/
.0-"7
"~../_...---/----.~' _ / '
Na+_O~O// ~o
N.AcetyI-D-Glucosornine
, "o"
Na-D-Glucuronate
Fig 1. The hyaluronan molecule (HA) is composed of repeating disaccharide units that form a spherical random coil molecule of approximately 3,000-A diameter. The individual molecules overlap at concentrations greater than 0.3 mg/mL to form an entangled molecular network,
activity; it is a very effective free radical scavenger. Synovial fluid of low elastoviscous properties, as found in osteoarthritic joints, has the reverse effect. Synoviocytes are stimulated to synthesize hyaluronan in vitro by the
addition of exogenous high-MW hyaluronan, whereas the addition of low-MW hyaluronan does not have this effect.6 The medical use of hyaluronan was made possible by E.A. Balazs" purification of a noninflammatory fraction of sodium hyaluronan. 7 It had a MW of 2-3 million and reduced pain in surgically induced knee cartilage injury in dogs and monkeys and in the arthritic joints of race horses. 8 Subsequent studies showed that the synovial fluid in these arthritic joints had decreased elastoviscous properties, which returned to normal in those that responded Lovtscosupplementation. This response was dependent on the elastoviscosity of the hyaluronan injected into the joint. 9 Later studies in Japan confirmed that increased elastoviscosity of exogenously introduced hyaluronan reduced pain and pain mediators (bradykinin and prostaglandin E2) in experimentally produced arthritis. 6 The first studies of viscosupplementation in humans for the treatment of OA were conducted from 1969 to 1973. The hyaluronan, Healon ® (Biotrics, Arlington, MA), used in these investigations had an average MW of 2-3 million and was produced by Biotrics and subsequently was manufactured and distributed by Pharmacia for veterinary use as Hyartil-Vet® (Pharmacia, Uppsala, Sweden). It was produced from rooster combs as are all hyaluronan-approved products in the U.S. today. Overall, Healon® was effective in relieving pain in patients who had high levels of pain, mild to moderate disease on X-ray, and symptomatic arthritis of relatively recent onset. In patients with more advanced disease it was less effective,s° In 1987, two hyaluronan products of tow elastoviscosity (MW 500,000-800,000) became available commercially to treat arthritic joints: Artz TM manufactured by Seikagaku in Japan and Hyalgan®, manufactured by Fidia in Italy. Because more than 90% of hvaluronan molecules in normal synovial fluids are more titan 2 million, MW products of 2 million or more will be classified as high MW and those below 2 million will be classified as low MW. In 1997, HyaIgan@ and in 2001, Supartz TM two low-MW hyaluronans, and in 1997 one high-MW hylauronan derivative (hylan G-F 20), Synvisc® (Genzyme Biosurgery, Cambridge, MA), were approved for file treatment of OA of the knee in the United States (Fig 3).
A
B
Fig 2. Molecular basis for the elastoviscous properties of HA. (A) the application of a low-strain frequency force (1) to a HA solution causes the randomly organized HA molecules (2) to orient in the direction of flow (3). This orientation allows extremely viscous HA solutions to flow through narrow gauge needles. (B) The application of a high-strain frequency force (high rate of deformation) (1) does not allow the HA molecules time to reorient. Therefore, the energy of the impact is stored elastically in the compressed molecular network (2). At a distance from the point of highest strain frequency (3,4) a slow, viscous flow is established, and then molecular orientation (random coils) are restored. VISCOSUPPLEMENTATION IN THE OLDER PATIENT WITH OSTEOARTHRITIS
125
0.12
0.1
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Fig 3. The MW distribution of HA in normal and OA synovial fluid and in viscosupplementation products.
.-
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CLINICAL EFFICACY OF LOW-MW H Y L A L U R O N A N S l O -la Supartz T M is a 1% solution of hyaluronan with an average MW of 800,000 (620,000-1,170,000). Recommended treatment is 5 weekly injections of 25 mg (2.5 million) each. Short-term clinical trials (4-8 weeks } in Japan showed that 50-84% of patients receiving Artz T M improved. In a 6-month effectiveness study 80% of patients responded with 43.5% graded excellent; however, an average of 13.7 injections were given per patient. 1°-~3 A 1-year study in Sweden found no significant benefit for Artz T M in the intent-to-treat population except in the subgroup of patients over 60 years of age with Lequesne Index greater than 1014 and a 1-year trial failed to show significant benefit. ~s The safety and efficacy of Supartz T M for treatment of OA of the knee in the U.S. was "based on an integrated analysis of 5 randomized, multicenter, blinded placebo controlled clinical trials" in 5 countries (Australia, France, Germany, Sweden, and the United Kingdom). There were 123 centers, 1155 patients, mean age 62 with 63% being female. Treatment regimen consisted of 5 weekly injections. The French study included a 3-injection arm. The results of the German study for paracetamol consumption revealed no significant difference, as did the UK and Swedish studies for protocol-specific primary analysis. Individual study results for Lequesene score as Repeated Measures of Analysis of Covariance (ANCOVA) of mean reduction from baseline over all visits or after the 5-week visit revealed that only the Australian and UK studies showed statistical significance (P < .05), whereas the French 3- and 5-injection series, as well as the German and Swedish studies, showed no significant statistical difference from control. The integrated analysis of all 5 studies for Lequesne score, however, did show a statistically significant improvement in the SupartzTM=treated patients. 16 Hyalgan® is a low elastoviscous 1% solution of hyaluronan (MW 500,000-730,000). The recommended treatment regimen is 5 injections of 20 mg hyaluronan in 2 mL, given once a week, Eight placebo controlled studies and 3 studies comparing Hyalgan® to corticosteroid injections have been published. 1°-13 Three studies of 8 weeks dura-
1 26
tion showed that 75-88% of patients responded to Hyalgan® injections, 30-50% responded to placebo and 3 or 5 injections was better than one injection. A 5-injection, 5-month efficacy study failed to show a significant difference between Hyalgan® and placebo except for a decrease in the use of rescue NSAIDS. A 48-week, 4-injection blinded study showed Hyalgan@ to be very effective for rest pare and mildly effective for pain on movement compared with placebo. A 52-week, 4-injection, controlled, open label study showed Hyalgan® treated patients better for all parameters at 7 weeks. At i year, there was no difference from control at rest or exercise VAS pain; however, they were better b y physician global assessment and Lequesne Index. In a second 52-week study, 19 I-Iyalgan@ treated and placebo knees were arthroscopically evaluated before treatment and 1 year later. Patients receiving Hyalgan® had better ~clinical and arthroscopic results. A U.S., 3-armed, 26-week study, compared 5 weekly injections of Hyalgan® to 5 placebo injections and to Naproxen in 495 patients, mean age 63.7 of which 58.4% were female. This study showed small, but substantially significant improvement in an analysis of completers in the Hyalgan® primary efficacy measure (pain on a 50-foot walk) and in the categorical assessment of pain by the patient compared with placebo and no difference compared with N a p r o x e n J In two open studies, Hyalgan® was compared with 6-methylprednisolone acetate (40 rag) injections and showed that pain relief with Hyalgan® was as effective, longer lasting, but of slower onset. A double-blind, controlled study showed no statistically significant difference but a trend in favor of Hyalgan®. 12 In summation, low-MW hyaluronans have been shown to be more effective than placebo and as effective as NSAIDs and intraarticular corticosteroids for mild to moderate OA in the elderly patient. In the 1980S, Balazs et al. developed a family of crosslinked hyaluronan~ polymers (hylans) in which neither the carboxylate nor the acetamido group of hyaluronan is chemically modified. 18 Hylan G-F 20 (Synvisc®) is the specific hylan composition formulated to behave as a synovial prosthesis. It consists of 80% hylan A by volume (an elastoviscous fluid, a~erage M W 6 million) and 20% hytan
CHARLESWEISS
I00
7O
9O
10 Hylan G-F 20 (6 millkm MW)
80
2O
70
3O
60
- 4O
"G
50
so
~,
40
~" 60
g
~
g.. Fig 4. Elastic and viscous behavior of normal and osteoarthritic synovial fluid compared with Iow-MW HA and a hylan viscosupplement.
-~,
3O
~
20
70 ]pr
(Running)
Hyaluronan (0.5 million MW)
10
>
80
(Walking) ~
'
90 ! O0
0.01
0.1
I
10
20
Frequency (Hz)
B (a hydrated water insoluble gel containing 99.5% of water). It has similar physicochemical properties to the synovial fluid found in healthy young adults, being highly elastic over a wide range of strain frequencies, intraarticular residence time is extended compared with native hyaluronan and low-MW hyaluronans, 6,1s and it has the same permeability, biocompatibility, and lack of immunogenicity as unmodified hyaluronan. It behaves predominantly as an elastic solid, whereas other hyaluronan viscosupplements remain predominately viscous fluids throughout all physiologic ranges 6 (Fig 4). Neurophysiologic studies demonstrated that the increased discharge frequencies of the medial articular nerve after inflammatory and mechanical stimulation were significantly reduced after intraarticular injection of hylan G-F 20, but not after nonelastoviscous degraded hylan G-F 20 was injected. This was most pronounced during movement of the inflamed joint; thus, elastoviscosity directly influenced nociceptors responsible for pain perception. 19,2° Other factors: repeated dilution of noxious stimuli, polyaniordc lavage, and repeated mechanical and possible physiochemical stimulation of synovial lining celIs play a role in the reduction of pain. CLINICAL
EFFICACY
OF HYLAN
G-F 20
The safety and efficacy of hylan G-F20 (Synvisc®) in the treatment of OA of the knee has been evaluated in seven prospective double-blind controlled studies, average patient's age 61 with over 60% female: 3 vs. saline, 1 vs. arthrocentesis, 2 vs. NSAID, and 1 vs, low-MW hyaluronan. 11-13Seven additional studies have been reported: one multi-center retrospective study; one retrospective study comparing Artz® to Synvisc®, one open label ~tudy vs. saline, 3 prospective open label studies in advanced disease, and one prospective single-blind study vs. corticosteroid• The first two studies showed that two bi-weekly Synvisc@ injections were significantly better than control b y
week 4 and remained so through week 12 (P < .05), and 3 injections were significantly better than two by week 8 and remained so through week 12. In a multi-center study, more than 50% of Synvisc® treated patients were symptom-free at 12 weeks and significantly (P < •001) better than saline controls. At 26 weeks these improvements continued for weight-bearing pain, night pain, decreased activity, and reduced use of rescue treatment (P <- .05)Y In a U.S. trial, patients who worsened after withdrawal of NSAID were considered a flare population. Patients with inflammatory disease were specifically included in this study• Synvisc@ was better than arthrocentesis in pain relief (P K •0001) and reduction of effusion (P < •005)• At 26-36 weeks, patients who had two courses of treatment had significant reductions in pain with motion (P < .02), rest pain (P < •05), and overall pain (P K .05). In the flare population there was significant (P < .05) improvement in Synvisc@ treated knees with >50% improvement in pain on motion, rest pain, night pain, walking, and overall pain. 22 Two studies compared Synvisc@ to NSAID. In the first there were 3 arms: one received NSAID plus 3 weekly arthrocentesis, the second received Synvisc@ plus placebo pills, and the third received NSAID plus Synvisc@. At 12 weeks Synvisc@ was at least equivalent to NSAID in improving pain parameters and overall assessment• By 26 weeks both Synvisc@ groups were statistically superior to NSAID in percent of symptom-free patients. Repeat-measures analysis demonstrated statistically significant improvement of Synvisc@ vs. NSAID alone (P < .05) with regard to overall pain level. 2s A second study compared Synvisc® to diclofenac. There were 3 s t u d y groups: the first received 3 injections of Synvisc@ plus a placebo pill, the second received diclofenac plus 3 arthrocentesis, and the third received 3 arthrocentesis and a placebo pill. At 3 months there was significant improvement (P < .03) of Synvisc® over double control for all parameters of the WOMAC and no statistical significance between diclofenac and control. The Le-
VISCOSUPPLEMENTATION IN THE OLDER PATIENT WITH OSTEOARTHRITIS
127
quesne index demonstrated statistically significant improvement of Synvisc® over diclofenac and control. There was no difference between diclofenac and controlY In a two-and-one-half year multi-center retrospective study of 336 patients, (122 bilateral), 56 knees had a second course. The mean age was 65 years and disease duration 7 years. Seventy seven percent of the knees were rated better or much better and 2% were worse. After a second course 87% of knees were better and 4% worse. The mean time to retreatment was 8.2 months. Treatment was effective across the entire spectrum of disease with 58% of patients with Kellgren-Lawrence grade (KLG) IV arthritis rated better or much better. Up to 90% of patients with less severe disease were better and over 70% of patients were able to use less NSAIDs. 2s In an open label 12 week, study (56% had Larsen grades III and IV), all outcome measures: night pain, weightbearing pain, overall improvement were significantly improved (P = .0001) from 1-12 weeks post-treatment. 26 A prospective randomized double-blind 3-injection multi-center trial compared the clinical efficacy of Synvisc® to Artz®. At 12 weeks patients Synvisc® patients were significantly better (P < .05) in all primary outcome measures (overall condition, most painful knee movement, weight-bearing pain, and overall pain) as well as symptom-free patients. 27 A retrospective study of 200 patients, who received either 5 weekly injections of Hyalgan® or 3 weekly injections of Synvisc®, showed both groups were significantly better than before treatment i:n weight-bearing pain, mobility, and pain at rest. Synvisc® was significantly better than Hyalgan® in relief of pain on weight-bearing~ mobility (P < .03), and night-time pain (P < .005). 28 Three prospective open studies were performed in late stage disease~ In Canada 60 patients on the queue for total knee arthroplasty (TKA), all had grade IV KLG arthritis, chronic disabling pain, mean age was 67 years and 65% were female. At 1 year there was a significant improvement in the WOMAC A, B, and C scores (P < .02), and 38% were able to delay surgery. 29 In a U.S. prospective study of 108 patients, all were candidates for TKA having failed NSAIDs, corticosteroids and conservative treatment. Eighty-three percent had KLG IV and 13% had grade IfI OA. The Hospital for Special Surgery Rating Scale was utilized pretreatment and at 1, 3, 6, and 12 months and every 6 months thereafter. 52% of eligible patients did not undergo TKA at 2.6 years. 3° In a study of 123 knees in 90 patients (65% female average ag e 74 + _ years) 75% had KLG IV arthritis, 85% failed NSAIDs, two thirds failed interarticular corticosteroids, and one third failed arthroscopic debridement. Sixty-five percent of patients were better 6 months after treatment and 46% at 1 year; 64% of patients better at 1 year remained so at 2 years. Thirty-three knees had a retreatment (mean time 15 months) and 78% remained better 12 months later. There was a fifty-two percent decrease in the number of TKAs. 3~ One randomized single-blind study compared 3 injections of Synvisc® to one injection of Aristopan® (Triamcinoloixe Hexacetonide 40 rag) for 26 weeks. At 12 weeks, Synvisc® treated knees were statistically significantly su128
perior for WOMAC AI, WOMAC C, total WOMAC, and VAS overall. These statistically significant improvements persisted at week 26, except for the WOMAC AI, which, however, was still improved. 32 In summation, high-MW hylan G-F 20 has been shown to be more effective than placebo, NSAIDs, and corticosteroids in the treatment of mild to advanced OA to the knee in elderly patients.
THE OA TREATMENT PARADIGM OA of the knee is a local nonfatal disabling disease. Its treatment is based on the principles of doing no harm, relieving pain, and restoring function. To appropriately position viscosupplementation in the elderly patient, it is important to consider its efficacy and safety compared with other standard treatments. To date, the only adverse events (AEs) of significance are transient reactions of pain and or effusions without permanent sequelae. The mean prevalences of AEs per injection in controlled clinical trials was 2.6% for Artz TM, 4.2% for Hyalgan®, 2.3% for Synvisc® and were similar to saline controls¢i-!3 These local AEs usually occur within 48 hours of injection, and are occasionally accompanied by an inflammatory response. They usually resolve with rest, ice, analgesics, and occasionally arthrocentesis a n d / o r corticosteroid injection. 12 Two thirds of patients who had AEs post,Synvisc® injection had a subsequent AE-free injection, and 69% were clinically improved. There were no permanent sequelae and no evidence of an immune response.25 There are occasional reports of increased incidences of AEs with both low-; and high, MW viscosupplementsJ2,~ 3 The etiology of theses AEs is poorly understood. It may be related to the physical characteristics of the viscosupplement, injection technique, or postinjection physical activity. There has been no alteration of urine or blood tests, no drug inter, action, no systemic pharmacologic activity, no sepsis, and no allergic responses. 12 Extra-articular injections, may also contribute to the incidence of local tissue reactions, with the suprapatellae medial approach with t h e knee partially bent, having a si~ificant increase in the number of AEs.25 In the author's experience after strict aseptic t e c ~ i q u e , if there is an effusion, a suprapatellae lateral approach with the knee in extenSion util~ing a 20-gauge needle, is most effective. If no fluid comes back, the needle may be plugged therefore inject a small amount of air (<1 mL), If thereis no effusion either the knee extended suprapatellae or an infer0,patellar lateral approachi w i t h the knee bent to 90 o is! i effective i To check that the needle is in the joint, inject some air, which can be heard a n d / o r felt w~thin the joint. This technique assures that the needle is i n the joint cavity: and not in capsule or fat pad. NSA!DS are the ~tQst commonly used medication for OA pain, most of these occurring in patients being treated for arthritis. In the United States it is linked to 16,500 deaths ~ u a l l y ~ 3 Gastrointestinal ulcerations occur in 9-30% of patients~on NSA!DS for more than 2 weeks and 10% of; these develop obstruction, perf0ration, or hemorrhage.~ This risk is: heightened a n d additional problems such as nephrotoxici~ (4%), edema ( 4 0 ) , hyperkalemia (20/0):, and llyponatre~ia (7%)in ~ e e!derly> 4 Hypertension (5 m m increase in diastolic pressure) occurs in 1% of CHARLES WEISS
the p a t i e n t s t a k i n g N S A I D s ) a n d increases the risk of stoke b y 67% a n d c o r o n a r y a r t e r y disease b y 15%. s5,36 R e c e n t r e v i e w s s u g g e s t i n c r e a s e d risks of M I w i t h selective COX-2 inhibitors, 37 as well as i n c r e a s e d risks of g a s t r o i n testinal ulcers. 3s All of the c a r d i o v a s c u l a r c o m p l i c a t i o n s are i n c r e a s e d b y d r u g interactions, ie, A C E inhibitors, Beta blockers, c a l c i u m c h a n n e l blockers, a n d diuretics c o m m o n l y u s e d in the t r e a t m e n t of h y p e r t e n s i o n a r r h y t h m i a s , or c o n g e s t i v e failure in the elderly. C o n s i d e r i n g the lethal a n d debilitating s y s t e m i c effects of these d r u g interactions, it is a p p r o p r i a t e to u s e v i s c o s u p p l e m e n t a t i o n b e f o r e N S A I D s in p a t i e n t s w i t h these risk factors. Jntraarticular corticosteroids h a v e b e e n u s e d i n O A joints fo r a l m o s t 50 y e a r s despite the lack of e v i d e n c e of l o n g - t e r m efficacy, a n d significant s y s t e m i c a n d local side effects139 A single injection of intra-articular steroids c a n s u p p r e s s stress r e s p o n s e s w i t h s u p p r e s s i o n of e n d o g e n o u s cortisone p r o d u c t i o n for 10-30 days. It often m a k e s the c o n t r o l of h y p e r t e n s i o n a n d diabetes m o r e difficult, causes d e c r e a s e d l i g a m e n t strength, m a y cause s t e r o i d a r t h r o p a ' t h y a n d a v a s c u l a r necrosis, a n d h a s a n infection r a t e of 1 in 14,000 (almost 20 times m o r e f r e q u e n t t h a n that r e p o r t e d after v i s c o s u p p l e m e n t a t i o n w i t h hylans). Postinjection flares ( p a i n a n d swelling) s u b s i d i n g in 1-3 d a y s , o c c u r s in 2%, sim!!ar t o v i s c o s u p p l e m e n t a t i o n . H y p e r s e n s i t i v i t y a n d a case of a n a p h y l a x i s w e r e r e p o r t e d in 199Z 39 C o n s i d e r i n g these s y s t e m i c a n d local r e s p o n s e s , c o r t i c o s t e r o i d s s h o u l d be l i M t e d to t h o s e cases w h e r e there is a clear i n f l a m m a t o r y o r a c u t e crystalline a r t h r o p a t h y . T o r n k n e e a r t h r o p l a s t y is o n e of the m o s t successful p r o c e d u r e s i n o r t h o p a e d i c s t o d a y ; h o w e v e r , it h a s significant m 0 r b i d i t y a n d mortality. The d e a t h rate f r o m p u l m o n a r y e m b o l i s m is o v e r 0.2%. 4° A p p r o x i m a t e l y 47% of p a t i e n t s will d e v e l o p a d e e p v e i n t h r o m b o s i s , d e s p i t e p r o p h y ! a x i s a n d 24% of t h e s e p a t i e n t s will h a v e a p o s t - t h r o m b o s i s s y n d r o m e . 4~ O v e r the life time o f the p r o s t h e s i s 1% of p a t i e n t s w i l l d e v e l o p a joint infection that r e q u i r e s r e m o v a l 6f the prosthesis. 42 T e n p e r c e n t are likely to requ!re r e v i s i o n s u r g e r y , a n d 5% of p a t i e n t s h a v e unsatisf a c t o r y results d u e t o j o i n t stiffness.
CONCLUSIONS Viscosupplementation is an effective and recognized treatment for O A of the knee, as T r e a t m e n t s h o u l d start w i t h p a t i e n t e d u c a t i o n , w e i g h t loss, exercise, braces, canes, t o p ical analgesics, a n d s i m p l e analgesics s u c h as a c e t a m i n o p h e n . In e l d e r l y p a t i e n t s o n m e d i c a t i o n s (ACE inhibitors, diuretics, Beta blockers, a n d soon), w h o h a v e h y p e r t e n sion, renal, c a r d i o - p u l m o n a r y , or g a s t r o i n t e s t i n a l disease, this s h o u l d b e f o l l o w e d b y v i s c o s u p p t e m e n t a t i o n . For the r e m a i n d e r , short c o u r s e s of N S A I D s m a y be a p p r o p r i a t e . The us e of intraarticular corticosteroids s h o u l d be res e r v e d f o r t h o s e patients w h o h a v e a n acute crystalline a r t h r o p a t h y o r a r e c u r r e n t i n f l a m m a t o r y c o m p o n e n t of their arthritis, Certainly v i s c o s u p p l e m e n t a t i o n s h o u l d be considered before joint arthroplasty or surgical intervention.
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CHARLES WEISS