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Scientific Article   |    
Increased Frequency of Acute Local Reaction to Intra-Articular Hylan GF-20 (Synvisc) in Patients Receiving More Than One Course of Treatment
Seth S. Leopold, MD; Winston J. Warme, MD , Lieutenant Colonel; Patrick D. Pettis, LVN; Susan Shott, PhD
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Investigation performed at the Orthopaedic Surgery Service, William Beaumont Army Medical Center, El Paso, Texas

Seth S. Leopold, MD
Department of Orthopaedics and Sports Medicine,
University of Washington Medical Center, 1959 N.E. Pacific Street, Box 356500, Seattle, WA 98195. E-mail address: leopold@u.washington.edu

Lieutenant Colonel Winston J. Warme, MD, Medical Corps, U.S. Army
Patrick D. Pettis, LVN
Orthopaedic Surgery Service, William Beaumont Army Medical Center, 5005 North Piedras Street, 3rd Floor, El Paso, TX 79920

Susan Shott, PhD
Biostatistics Unit, Obstetrics and Gynecology, Rush-Presbyterian-St. Luke's Medical Center, 1653 West Congress Parkway, Chicago, IL 60612

The authors did not receive grants or outside funding in support of their research or preparation of this manuscript. They did not receive payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.

The views expressed in this work are those of the authors and do not reflect the official policy of the Department of Defense or the United States Government.

J Bone Joint Surg Am, 2002 Sep 01;84(9):1619-1623
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Abstract

Background: Intra-articular knee injections with hylan GF-20 (Synvisc) have been shown to provide temporary relief of osteoarthritic symptoms. Several studies have suggested that repeated courses of treatment with this product may be administered without an increase in the likelihood of an adverse reaction. The present study was performed to test the hypothesis that the likelihood of a painful reaction to hylan GF-20 does not increase in patients who receive more than one course of treatment.

Methods: The records of all patients who had received more than one course of treatment with hylan GF-20 were compared with a group of patients who had received only one course of treatment during the same fifteen-month period at a single center. The single-course group was prospectively enrolled and followed, as part of an ongoing randomized trial. The two groups were compared with respect to several demographic and clinical parameters as well as with respect to the frequency of painful acute local reactions following injections of hylan GF-20.

Results: Local reactions to hylan GF-20 occurred significantly more often in patients who had received more than one course of treatment than they did in patients who had received only a single course of treatment; the reactions occurred in four (21%) of nineteen patients in the former group and in one (2%) of the forty-two patients in the latter (p = 0.029). All of the reactions were severe enough to cause the patient to seek unscheduled care. Following corticosteroid injection, the reactions abated without apparent sequelae. With the numbers available, no significant differences were detected between the multiple-course and single-course groups in terms of age, gender, body-mass index, or severity or bilaterality of the disease.

Conclusions: The present study suggests that it may be reasonable to counsel patients who have been treated with a course of hylan GF-20 and who desire an additional course that the likelihood of a painful acute local reaction to the medication appears to be increased. Additional study of the frequency of acute local reactions following repeated courses of hylan GF-20 and investigation of the mechanisms of those reactions are warranted.

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    These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
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    Duane C. Heald
    Posted on June 23, 2004
    A Randomized Comparison of Hylan G-F 20 and Sodium Hyaluronate
    USAF

    To the Editor:

    We read with interest “Increased Frequency of Acute Local Reaction to Intra-articular Hylan G-F 20 (Synvisc) in Patients Receiving More than One Course of Treatment” (2002;84-A:1619-23), by Leopold et al. and the subsequent letters the article stimulated. These focused on the increased frequency of pseudoseptic reactions to hylan G-F 20 (Synvisc). There have been four additional reports,(1-4) all associated with hylan G-F 20, since that publication, but there have been no published reports, to our knowledge that have investigated the naturally derived sodium hyaluronate products (Hyalgan or Supartz).

    Pseudoseptic reactions are clinically distinct from inflammatory reactions, which can occur following any intra-articular injection(5). The preponderance of clinical reports (1-5) and preclinical data (6-9) is substantial, and considerable support for an immunological component to these reactions exists (5-10).

    We conducted a prospective, single-blinded, comparative study evaluating 5 or 3 weekly injections of sodium hyaluronate (Hyalgan) or hylan G-F 20 (Synvisc), respectively. Our results further support the findings of Leopold et al., and suggest that these are hylan-specific reactions. Seventy-four patients with painful knee osteoarthritis were randomly assigned to receive sodium hyaluronate or hylan G-F 20 and completed at least one follow-up visit (6 weeks). The primary outcome measure was a 10 -cm visual analog scale assessment of pain following a 50-foot walk. Follow-ups were scheduled at 12, 18, 26 and 38 weeks following therapy. Sixty percent of the patients completing their Week 5 follow-up completed the Week 38 visit, and the majority of patients demonstrated significant improvement in pain (>20%) from baseline, with no significant difference between the treatments. While 2/38 (5.3%) patients in the hylan G-F 20 group (114 injections) developed pseudoseptic reactions, none of the patients in the sodium hyaluronate group (0/36 patients, 180 injections) reported such reactions.

    Estimates in the literature of the frequency of pseudoseptic reactions have ranged from 1.8% to 27% of treated patients (5) with higher rates associated with repeat treatment courses. The impacts of subclinical reactions and additional sequelae (chronic granulomatous reactions) need to be considered when counseling patients considering repeat treatment with hylan G-F 20.

    References 1. Tomas GJ, Lopez MP, Alegre J. Acute adverse reaction to hylan G-F 20: comment on the article by Martens. Arthritis Rheum. 2003;48:866. 2. Brown DJ, Wood EV, Hannah HM, Teanby D. A prospective comparative study of the safety and efficacy of sodium hyaluronate (HyalganÒ) and hylan G-F 20 (SynviscÒ) in a clinical practice [letter]. Arthritis Rheum. 2003 (In Press) 3. Noain E, Sancez-Villares J, Lasanta P, Gonzalez rteaga F. Acute local reaction to intra-articular infiltration with Synvisc (Hylan GF20). About two cases [Spanish]. An Sist Sanit Navar. 2003;26:283-5. 4. Shannon PD, Morton A. Reactions to hylan G-F 20 viscosupplementation are not a class effect. J Bone Joint Surg. 85-A:2050-1. 5. Goldberg VM, Coutts, RD. Pseudoseptic Reactions to Hylan viscosupplementation: Diagnosis and Management. Clin Orthop. 2004;419:130- 137. 6. Synvisc® PMA [Premarket Approval Application. Summary of Safety and Effectiveness Data]. Available at: ttp://www.fda.gov/cdrh/pdf/p940015.pdf. Accessed October 1, 2003. 7. Bucher W, Otto T, Hamburger MI. Differentiation of hyaluronate products by qualitative differences in their immunogenicity in rabbits: possible mechanism for product-specific severe adverse reactions? Arthritis Rheum. 2002;46:2543-4. 8. Schiavinato A, Finesso M, Abatangelo G. Comparison of the effects of intra-articular injections of hyaluronan and its chemically cross-linked derivative (hylan G-F 20) in normal rabbit knee joints. Clin Exp Rheumatol. 9. Sasaki M, Miyazaki Y, Takahashi T. Hylan G-F20 induces delayed foreign body inflammation in Guinea pigs and rabbits. Toxicol Pathol. 2003;31:321- 5. 10. Puttick MP, Wade JP, Chalmers A, Connell DG, Rangno KK. Acute local reactions after intraarticular hylan for osteoarthritis of the knee. J Rheumatol. 1995;22:1311-4.

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