n Feature Article

Rate of Adverse Reactions to More Than 1 Series of Viscosupplementation

Tracy A. Webber, MD; Anthony E. Webber, MD; Elizabeth Matzkin, MD

abstract Full article available online at Healio.com/Orthopedics. Search: 20120327-26

Viscosupplementation, hyaluronic acid treatment, is an ancillary method for treating patients with symptomatic stage I or II osteoarthritis. Previous studies reported that local reactions occurred more frequently in patients receiving .1 course of treatment compared with patients receiving their first course of treatment. One (2%) of 42 first series patients and 4 (21%) of 19 of repeated series patients had adverse reactions severe enough to seek unscheduled care.

This study was performed to determine whether patients receiving .1 series of visco- supplementation had an increased adverse reaction rate. A retrospective chart review was performed on all patients who received .1 series of viscosupplementation during the study. A local adverse reaction was defined as acute swelling and pain in the knee, with no injury or trauma within 72 hours after hyaluronic acid injection.

Twenty-eight knees received .1 series of viscosupplementation. The adverse reaction rate to second series injections was 1.28% (3.57% of knees). The adverse reaction rate to >3 series was 0.9% (6.67% of knees). This adverse reaction rate was significantly less than the 21% reported in previous studies for multiple series injections (z521.90; P,.05) and is not significantly different than the 2% rate of adverse reactions reported for first series injections. No significant difference existed in the adverse reaction rates between 2 series and >3 series of viscosupplementation.

The current study suggests that the rate of adverse reaction was low at 1.28% of second series viscosupplementation.

Dr Webber (Tracy) is from Tufts University School of Medicine, Dr Webber (Anthony) is from the Department of Orthopedics, Faulkner Hospital, and Dr Matzkin is from the Department of Orthopedics, Brigham and Women’s Hospital, Boston, Massachusetts. Drs Webber (Tracy), Webber (Anthony), and Matzkin have no financial relationships to disclose. Correspondence should be addressed to: Anthony E. Webber, MD, Department of Orthopedics, Faulkner Hospital, 1153 Center St, Ste 54, Boston MA 02130 ([email protected]). doi: 10.3928/01477447-20120327-26

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iscosupplementation, a hyaluron- injections after a 6-month latency period, al10 established. A local adverse reaction ic acid treatment, is an ancillary which is the time required by most insur- was defined as acute swelling and pain in Vmethod for treating patients with ance plans between treatments. the knee, with no injury or trauma with- symptomatic stage I or II osteoarthritis, Previous studies, most notably that in 72 hours after viscosupplementation. as demonstrated by radiographs. As ar- conducted by Leopold et al,10 reported Painless effusions identified clinically at ticular degeneration occurs, the level of that local reactions occurred more often in routine follow-up were not considered re- hyaluronic acid in the joint decreases, patients who received more .1 course of actions.10 leading to knee pain. Hyaluronic acid de- treatment compared with patients receiving All intra-articular injections were per- rivatives injected intra-articularly increase their first course of treatment. One of 42 formed using an aseptic technique with the elasticity and viscosity of the synovial (2%) first series patients and 4 of 19 (21%) a 22-gauge needle by the orthopedic sur- fluid to the density of healthy synovial repeated series patients had adverse reac- geons (A.W., E.M.) in these 2 practices. If fluid, leading to a decrease in osteoarthritic tions severe enough to seek unscheduled an effusion existed, the fluid was drained pain and an improvement in mobility.1-2 care. An acute local reaction was defined as using a straight-leg superolateral approach, Viscosupplementation temporarily relieves an acute onset of pain and swelling in the and the viscosupplement was injected us- the symptoms of mild osteoarthritis based knee that occurred within 72 hours after the ing the same needle but a separate syringe, on the Visual Analog Score (VAS) and Hylan G-F 20 injection in the absence of as recommended by the manufacturers. If Western Ontario and McMaster Universtiy another cause, such as acute trauma. These no effusion existed, the injection was ad- Osteoarthrits Index (WOMAC) scores.1-4 acute local reactions caused severe pain ministered using a flexed-knee anterome- Viscosupplementation can significantly and limitation of activity and were treated dial or anterolateral approach. Of the 28 improve pain during load, pain at rest, and with aspiration and corticosteroid injec- knees injected with Hylan G-F 20, 28 of duration of walking activity vs baseline3 tions that relieved the symptoms.10 the first series knees and 25 of the second and can significantly increase patients’ The purpose of this study was to de- series knees were injected with Synvisc activity levels.4 Higher-molecular-weight termine the risk of adverse reactions in following the manufacturer’s instructions products, such as Hylan G-F 20 (Synvisc; patients receiving more .1 series of treat- and received a series of 3 weekly injec- Genzyme Biosurgery, Ridgefield, New ment with viscosupplementation. tions of 2 mL of Hylan G-F 20. The other Jersey), are superior to other formulations 3 second series knees were injected with of hyaluronic acid viscosupplemenatation Materials and Methods Synvisc-One, which is 1 injection of 6 mL because they require fewer injections and After Institutional Review Board ap- of Hylan G-F 20. Conrozier et al11 dem- have a decreased risk of infection com- proval, all patients who received .1 series onstrated that one 6-mL injection is as ef- pared with lower-molecular-weight hy- of treatment with viscosupplementation ficacious as three 2-mL injections 1 week aluronic products.5 When the efficacy of from the orthopedic departments at Tufts apart. After patients received injections, Hylan G-F 20 was compared with sodium Medical Center and Orthopaedic Associates they were instructed to ice their knees and hyaluronate, the clinical effectiveness and at the Faulkner Hospital between July 2004 to not participate in strenuous activities for patient satisfaction was significantly better and July 2009 were identified. 1 to 2 days. Patients who had adverse reac- in patients who received Hylan G-F 20.6 A retrospective chart review was per- tions were asked about the circumstances In addition, treating osteoarthritis formed, and data were collected, includ- of their symptoms to determine possible with Hylan G-F 20 can prolong the time ing: patients’ ages, sexes, arthritic knee causation. before total knee arthroplasty (TKA) is compartments (medial, lateral, patello- Excel 2004 for Mac version 11.5.8 necessary by 2 years.7 It has decreased femoral), which knees were injected with (Microsoft, Redmond, Washington) was pain and improved stiffness and physical hyaluronic acid viscosupplementation, the used for data management and statisti- functioning in patients who have previ- number of series of hyaluronic acid visco- cal analysis. The percentage comparison ously undergone arthroscopic surgeries supplementation patients underwent, and function was used to calculate z scores to and partial meniscectomies.8,9 Hylan G-F adverse reactions. In addition, informa- test for significant differences in propor- 20 is a commonly used. Treatment in- tion was collected on whether the patients tions between pooled local adverse reac- volves 3 weekly intra-articular injections. previously received steroid injections or tions in the current study and in the previ- Recently, single-injection hyaluronic acid whether they underwent arthroscopic sur- ous study by Leopold et al.10 The rate of therapy has been approved and is avail- gery or TKA since completing treatment adverse reactions between our first series able for use (Synvisc-One; Genzyme with viscosupplementation. and their first series, our second series and Biosurgery). If results are beneficial, pa- Local adverse reactions were identified their first series, and our second series tients are able to receive another series of using the same guidelines that Leopold et and their multiple series were compared.

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A .05 significance level was used for all reactions to first series injections reported series of Synvisc. Average time from ar- statistical tests. Significance levels are for by Waddell et al12 and our second series throscopic surgery to beginning Synvisc 1-tailed tests. injections. This adverse reaction was in a was 29.8 months (range, 5 months-13 78-year-old woman who placed heat on years). Of the 28 knees, 5 (17.9%) under- Results her knee following the first injection of went TKA after Synvisc. Average time Twenty-two patients (28 knees) re- her second series, resulting in increased was 3.8 months after completing 4.8 se- ceived .1 series of Hylan G-F 20. Eleven pain and swelling. Treatment consisted ries of Synvisc treatment. Fifty percent (15 knees) patients were women and 11 of ice, elevation, and nonsteroidal anti- of the patients who had adverse reactions (13 knees) patients were men. Mean age inflammatory drugs (NSAIDs), with reso- had previous arthroscopic surgeries, and was 61.3 years (range, 38-86 years). lution of the symptoms the following day. neither patient had a TKA. Fourteen knees were left knees and 14 The second series was completed the fol- were right knees; 6 patients received bi- lowing week, and the patient subsequently Discussion lateral injections. Radiographs revealed had 3 more Synvisc treatments, with no Acute local reactions following injec- osteoarthritic changes on 25 medial, 12 further adverse reactions tions of viscosupplementation have been lateral, and 23 patellofemoral compart- No local adverse reactions to third se- reported following first and multiple series ments. Radiographs showed that 4 pa- ries injections occurred., but 1 local ad- of injections.5,12-16 However, a definition of tients were affected in 1 compartment (all verse reaction to a fourth series injection a local adverse reaction has not been used medial), and 8 patients had tricompart- occurred. The frequency of local adverse consistently in the literature. For instance, mental osteoarthritis (Table). reactions to a fourth series was 3.57% of a study looking at the tolerability and ef- Of the 28 knees, 28 completed 2 se- injections (10% of knees, and 12.5% of fectiveness of Hylan G-F 20 included 4253 ries, 15 completed 3 series, 10 completed patients). A 53-year-old woman called the patients and reported that treatment-related 4 series, 7 completed 5 series, 3 com- day after her first injection of the fourth adverse events occurred in 4.2% of patients pleted 6 series, and 1 completed 9 series series and reported that her knee was pain- (2.4% of injections), but they defined an of treatment with viscosupplementation. ful and swollen, with no redness or fever. adverse event as joint effusion, joint swell- Mean total number of series completed It was presumed to be an allergic pseu- ing, arthralgia, joint warmth, and injection- was 3.36. All first and second series injec- doseptic reaction, and the patient did not site erythema.14 This is a broader definition tions were with Synvisc. One patient un- complete the rest of the series. Treatment in which the reactions could be from the derwent 2 series of Synvisc followed by 3 consisted of rest, ice, elevation, and injection or osteoarthritis itself, not the na- series of Orthovisc (Anika Therapeutics, NSAIDs, with resolution of the symptoms ture of the injected product. Woburn, Massachusetts), and another pa- over the next few days. She began another This is similar to the low-threshold tient received 5 series of Synvisc followed fourth series with Orthovisc a month later. definition of “pain, warmth, and swell- by 1 series of Hyalgan (Sanofi-Aventis, The rate of adverse reactions to fourth se- ing lasting up to 3 weeks” that Puttick et Bridgewater, New Jersey). During a ries Synvisc injections is similar to that al13 used when they reported the rate of fourth series injection with Synvisc, 1 pa- accepted in the literature for first series adverse events for first series injections to tient had an adverse reaction and discon- adverse reactions and to our rate for sec- be 27% of patients and 11% of injections. tinued treatment with Synvisc. She fin- ond series adverse reactions.12 These milder symptoms do not hinder the ished her fourth series with Orthovisc. All No adverse reactions occurred after treatment or prognosis of patients. other injections were with Synvisc. Mean fifth, sixth, or ninth series injections. When a product safety review report- time between the first and second series of In addition to determining the rate of ed that the most common adverse events treatment was 8.8 months (Table). adverse reactions to multiple series of with hyaluronic acid were mild injection One patient had a local adverse re- viscosupplementations, previous and site pain and swelling. Rare accounts were action to a second series injection. The subsequent knee treatments of each pa- reported of severe acute inflammatory frequency of adverse reactions to second tient were investigated. Twenty-one of reactions and pseudoseptic knees with series injections was 1.28% (3.57% of 28 (75%) knees had received steroid Synvisc. This was believed to be caused knees and 4.54% of patients). This rate injections prior to their first series of by antibodies to chicken proteins found of adverse reactions to second series in- Synvisc. Both patients who experienced in Hylan G-F 20. However, Synvisc dem- jections is significantly less than the 21% local adverse reactions received ste- onstrated a favorable safety protocol in reported in by Leopold et al10 for multiple roid injections previously. In addition, clinical trials and practice when compared series injections (z521.90; P,.05). No 12 (42.9%) of 28 knees had undergone with other standard therapies for manag- difference existed in the rate of adverse arthroscopic surgery prior to their first ing osteoarthritic knee pain.17

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Table Adverse Reaction Rate

No. Patient Previous Previous Total Adverse Arthroplasty No./Sex Age, y Knee Compartment Steroid Scope Synvisc Series Injections Reaction After 1/M 57 R Med, Lat, PF Y Y 2 6 N N 2/F 52 L Med, PF N Y 2 6 N N 3/M 54 R Med, Lat, PF Y N 2 6 N Y 4/M 54 L Med, PF Y N 3 9 N N 5/F 57 R Med, PF Y N 2 6 N Y 6/M 67 R Med, Lat, PF Y N 2 6 N N 7/M 67 L Med, Lat, PF N N 2 6 N N 8/M 53 R Med, Lat Y N 2 6 N N 9/M 86 R Med, Lat, PF Y Y 3 9 N Y 10/M 84 R Med, PF N N 2 6 N N 11/M 84 L Med, PF N N 4 12 N Y 12/M 72 L M, PF Y N 5 15a N N 13/F 78 L Med, PF Y N 5 15 Yb 2 (4) N 14/M 53 L Med Y N 2 4c N N 15/F 66 R Med, Lat, PF Y Y 3 9 N N 16/M 49 R Med, Lat, PF N Y 5 13d N N 17/M 49 L Med Y Y 5 13d N N 18/F 72 R Med Y N 2 4c N N 19/F 72 L Med Y N 2 4c N N 20/F 61 L Med, Lat, PF Y Y 6 18e N N 21/M 64 L Med, PF Y Y 2 6 N N 22/F 38 R Med, PF N Y 9 27 N Y 23/F 38 L Lat, PF N Y 6 18 N Y 24/F 57 R Lat, PF Y Y 4 12 N N 25/F 58 R Lat, PF Y N 3 9 N N 26/F 53 R Med, PF Y Y 4 13f Yg 4 (10) N 27/F 60 L Med, PF Y N 3 9 N Y 28/F 62 L Med, PF Y Y 2 6 N N Mean 61.3 75% 42.90% 3.36 9.75 17.90% Abbreviations: F, women; L, left; Lat, lateral; M, men; Med, medial; N, no; PF, patellofemoral; R, right; Y, yes. a First and second series Synvisc, third, fourth and fifth series Orthovisc (Anika Therapeutics, Woburn, Massachusetts). bPatient had knee pain and swelling after heating it postinjection. This was the first injection of her second series. Patient finished her second series and had 3 subsequent series with Synvisc and no other reactions. cFirst series Synvisc (Genzyme Biosurgery, Ridgefield, New Jersey), second series Synvisc-One (Genzyme Biosurgery). dFirst to fourth series Synvisc, fifth series Synvisc-One. eFirst to fifth series Synvisc, sixth series Hyalgan (Sanofi-Aventis, Bridgewater, New Jersey). fPatient had an adverse reaction to the first injection of her fourth series of Synvisc; she discontinued the series and began a new fourth series with Orthovisc 7 weeks later. gPatient had an allergic pseudoseptic reaction to the first injection of her fourth series. She did not complete the series and was treated with a fourth series of Orthovisc.

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Many studies reported the rate of lo- series subgroup improved by 41%, the re- tion. In one study, Synvisc, Hyalgan, and cal adverse events to second series injec- peat series subgroup improved by 35%, Supartz were injected into the air pouches tions to be lower than the 21% of patients and the appropriate care group improved of mouse knees to histologically exam- reported by Leopold et al.10 In a study by 14%. Both subgroups improved sig- ine the local inflammatory reactions. All of 71 patients with a mean time of 19.6 nificantly over the appropriate care group, 3 showed a significant increase in total months between first and second series, and no significant differences existed in membrane cellularity, but an antibody Waddell et al15 reported the incidence of the number of adverse events between the response only occurred with Synvisc. local adverse reactions to second series single and repeat course groups.18 This Ottavini et al22 concluded that this anti- was 1 (1.4%) of 71 patients. This patient study supports the hypothesis of the cur- body response could be directed against did not discontinue the study due to this rent study that Synvisc should be used a nonhyaluronic part of Synvisc, a pos- adverse event, supporting the repeated use for the treatment of osteoarthritis and that sible reason why adverse reactions occur of Synvisc if the patient has had a previ- multiple courses can be given if pain con- in Synvisc patients more often than with ous favorable clinical response. This study tinues. Repeat series continue to reduce other viscosupplementations. is consistent with the data collected in the pain, prolonging the time until TKA is Another study observed granuloma- current study, supporting the theory that needed. tous inflammation after Hylan G-F 20 in 6 multiple courses of Synvisc are well tol- The literature has also looked at a patients and concluded that Synvisc may erated. Waddell et al12 later reported that 12-month follow-up on patients treated be responsible for synovitis.23 However, the incidence of treatment-related adverse with a second course of Hylan G-F 20. Marino et al24 rebutted by stating that this events was 3.4% of patients (0.8% of in- Patients improved significantly from inflammation could be from miniscule jections) in the first series, 13.1% of pa- baseline on the WOMAC and VAS index levels of contaminants in the Hylan G-F tients (4.3% of injections) in the second at 26 weeks and 52 weeks after injection, 20 injection. The synovial fluid analysis series, and 17.3% of patients (5.4% of in- supporting the repeated use of Hylan G-F of a patient with a large knee effusion af- jections) in the third series. 20 with patients who previously had suc- ter injection with viscosupplementation The current study documented the ad- cessful results with Synvisc.16 Synvisc revealed intracellular rhomboid crystals verse reaction rate to second series injec- continues to relieve pain with repeated typical of pseudogout.2 tions to be less than the incidence found by series, and injections should continue to Another possible cause of local adverse Leopold et al10 and Waddell et al.12 The fre- be given if a patient has done well with reactions from Hylan G- F20 injections quency of adverse events was similar to the previous series. could be injection technique. If the visco- incidence of first series adverse reactions Most patients avoid TKA if nonopera- supplements are not properly administered reported by the manufacturers. Waddell et tive treatments are available for the treat- into the joints and are instead injected into al16 reported that 7.2% patients (2.2% of ment of osteoarthritis. After activity modi- the fat pads of knees, local inflammatory injections) experience adverse events in fication, physical therapy, and the use of reactions occur.25 Viscosupplements must the first series. Therefore, the data from the NSAIDs, choices for treating osteoarthri- be delivered into the joints and not into the current study support the hypothesis that tis are corticosteroid injections and vis- anterior fat pads or subsynovial tissues. no increased chance exists of experienc- cosupplementation injections. Leopold et Looking at the accuracy of needle place- ing an adverse event if one continues with al19 reported no significant difference with ment into the intra-articular space of the multiple series of injections. No difference respect to pain relief at 6-month follow- knee using fluoroscopic imaging on 240 exists in the rate of adverse reactions to first up when comparing these fundamentally consecutive injections by 1 orthopedic vs repeated series of Hylan G-F 20 injec- different intra-articular injections. Two surgeon in the absence of knee effusions, tions. randomized controlled trials found that 71% of anterolateral, 75% of anterome- Raynauld et al18 conducted a random- viscosupplementation was superior to cor- dial, and 93% of lateral midpatellar injec- ized controlled trial, in which 255 patients ticosteroids when evaluating the duration tions entered the knee joint space.26 This were randomized to an appropriate care of pain relief.20,21 Seventy-five percent of supports the theory that needle placement group and an appropriate care with Hylan the patients in the current study received is correlated with adverse reactions rates. G-F 20 group, to determine the effec- steroid injections prior to the start of their Lussier et al4 concluded that the incidence tiveness of Synvisc. The group receiving treatment with Hylan G-F 20. Time to of adverse reactions is significantly influ- Synvisc was subdivided into patients who TKA is delayed when patients are treated enced by injection technique, although received 1 course of treatment and patients with Synvisc.7 69% of their patients who experienced who received >2 courses of treatment. Local adverse reactions are a the po- adverse events still improved clinically. If Using the WOMAC pain scale, the single tential side effect of viscosupplementa- an adverse event occurred, one cannot as-

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sume that the treatment with Hylan G-F 3. Kotz R, Kolarz G. Intra-articular hyaluronic Hylan G-F 20 in 4253 patients with osteoar- acid: duration of effect and results of re- thritis of the knee in clinical practice. Curr 20 was not successful. peated treatment cycles. Am J Orthop (Belle Med Res Opin. 2005; 21(8):1261-1269. Mead, NJ) This study demonstrated that the risk . 1999; 28(11 suppl):5-7. 15. Waddell DD, Cefalu CA, Bricker DC. An of adverse reaction after multiple series 4. Lussier A, Cividino AA, McFarlane CA, open-label study of a second course of Hylan of hyaluronic acid treatment is 1.28%. Olszynski WP, Potashner WJ, De Medicis G-F 20 for the treatment of pain associated R. Viscosupplementation with hylan for the with knee osteoarthritis. Curr Med Res Opin. Limitations of this study include biases treatment of osteoarthritis: findings from 2003; 19(6):499-507. J Rheumatol involved in a retrospective review. In ad- clinical practice in Canada. . 16. Waddell DD, Cefalu CA, Bricker DC. A 1996; 23(9):1579-1585. dition, 28 patients received multiple series second course of Hylan G-F 20 for the treat- 5. Adams ME, Lussier AJ, Peyron JG. A risk-ben- ment of osteoarthritic knee pain: 12-month of Synvisc injections. A larger sample size efit assessment of injections of hyaluronan and patient follow-up. J Knee Surg. 2005; could have provided more confidence in its derivatives in the treatment of osteoarthritis 18(1):7-15. Drug Saf the data. Also, multiple surgeons were of the knee. . 2000; 23(2):115-130. 17. Hamburger MI, Lakhanpal S, Mooar PA, Os- involved, and thus injection technique 6. Raman R, Dutta A, Day N, Sharma HK, ter D. Intra-articular hyaluronans: a review Shaw CJ, Johnson GV. Efficacy of Hylan G-F of product-specific safety profiles. Semin Ar- was not standardized. All surgeons used a 20 and Sodium hyaluronate in the treatment thritis Rheum. 2003; 32(5):296-309. sterile technique and followed the manu- of osteoarthritis of the knee–a prospective 18. Raynauld JP, Goldsmith CH, Bellamy N, et facturer’s recommendations. Now that randomized clinical trial [published online al. Effectiveness and safety of repeat courses ahead of print April 21, 2008]. Knee. 2008; Synvisc One is available, adverse reac- of Hylan G-F 20 in patients with knee os- 15(4):318-324. teoarthritis. Osteoarthritis Cartilage. 2005; tions may differ due to the increased vol- 7. Waddell DD, Bricker DC. Total knee replace- 13(2):111-119. ume of the injection and the decreased ment delayed with Hylan G-F 20 use in pa- 19. Leopold SS, Redd BB, Warme WJ, Wehrle J Manage tients with grade IV osteoarthritis. PA, Pettis PD, Shott S. Corticosteroid com- number of injections required for each Care Pharm . 2007; 13(2):113-121. pared with hyaluronic acid injections for the series. 8. Zietz PM, Selesnick H. The use of Hylan G-F treatment of osteoarthritis of the knee. A pro- If patients experience positive results 20 after knee arthroscopy in an active patient spective, randomized trial. J Bone Joint Surg with a first series of viscosupplementa- population with knee osteoarthritis. Arthros- Am. 2003; 85(7):1197-1203. copy. 2008; 24(4):416-422. tion, then a second series can be consid- 20. Jones AC, Pattrick M, Doherty S, Doherty 9. Huskin JP, Vandekerckhove B, Delince P, et M. Intra-articular hyaluronic acid compared ered with no increased risk compared al. Multicentre, prospective, open study to to intra-articular triamcinolone hexacetonide with a first series of hviscosupplementa- evaluate the safety and efficacy of Hylan G-F in inflammatory knee osteoarthritis. Osteoar- tion. Patients in this study received up to 20 in knee osteoarthritis subjects presenting thritis Cartilage. 1995; 3(4):269-273. with pain following arthroscopic meniscec- 21. Leardini G, Mattara L, Franceschini M, Perbel- 9 series of injections with positive re- Knee Surg Sports Traumatol Arthrosc tomy. . lini A. Intra-articular treatment of knee osteoar- sults, with 1 patient discontinuing treat- 2008; 16(8):747-752. thritis. A comparative study between hyaluron- ment because of an adverse reaction to a 10. Leopold SS, Warme WJ, Pettis PD, Shott ic acid and 6-methyl prednisolone acetate. Clin S. Increased frequency of acute local reac- Exp Rheumatol. 1991; 9(4):375-381. fourth series injection. Patients should be tion to intra-articular Hylan GF-20 (Synvisc) aware of the low risks of adverse reac- 22. Ottaviani RA, Wooley P, Song Z, Markel DC. in patients receiving more than one course Inflammatory and immunological responses J Bone Joint Surg Am tions to viscosupplementation and that of treatment. . 2002; to hyaluronan preparations. Study of a mu- 84(9):1619-1623. this risk does not increase with multiple rine biocompatibility model. J Bone Joint 11. Conrozier T, Jerosch J, Beks P, et al. Prospec- Surg Am. 2007; 89(1):148-157. series. A prospective follow-up study is tive, multi-centre, randomised evaluation of 23. Chen AL, Desai P, Adler EM, Di Cesare PE. currently being performed to evaluate the the safety and efficacy of five dosing regi- Granulomatous inflammation after Hylan mens of viscosupplementation with Hylan incidence of local adverse reactions to G-F 20 viscosupplementation of the knee: G-F 20 in patients with symptomatic tibio- a report of six cases. J Bone Joint Surg Am. multiple series of Synvisc-One. Arch Or- femoral osteoarthritis: a pilot study. 2002; 84(7):1142-1147. thop Trauma Surg. 2009; 129(3):417-423. 24. Marino AA, Dunn S, Waddell DD. Granulo- References 12. Waddell DD, Bricker DC. Hylan G-F 20 matous inflammation after Hylan G-F 20 vis- tolerability with repeat treatment in a large cosupplementation of the knee. J Bone Joint 1. Wang CT, Lin J, Chang CJ, Lin YT, Hou SM. J orthopedic practice: a retrospective review. Surg Am. 2003; 85(10):2051-2052. Therapeutic effects of hyaluronic acid on os- Surg Orthop Adv. 2006; 15(1):53-59. teoarthritis of the knee. A meta-analysis of 25. Zardawi IM, Chan I. Synvisc perisynovitis. randomized controlled trials. J Bone Joint 13. Puttick MP, Wade JP, Chalmers A, Connell Pathology. 2001; 33(4):519-520. Surg Am. 2004; 86(3):538-545. DG, Rangno KK. Acute local reactions after intraarticular hylan for osteoarthritis of the 26. Jackson DW, Evans NA, Thomas BM. Ac- 2. Ali Y, Weinstein M, Jokl P. Acute pseudog- knee. J Rheumatol. 1995; 22(7):1311-1314. curacy of needle placement into the intra- out following intra-articular injection of high articular space of the knee. J Bone Joint Surg molecular weight hyaluronic acid. Am J Med. 14. Kemper F, Gebhardt U, Meng T, Murray C. Am. 2002; 84(9):1522-1527. 1999; 107(6):641-642. Tolerability and short-term effectiveness of

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