Q:

6/30/2014
A middle aged woman was referred by an orthopedist to r/o Synvisc (sodium hyaluronate) allergy because her knee swelled dramatically within 24 hours after injection into her right knee and they want to know if this could be an allergy. I cannot find any information on testing for this product. Do you know of any?

A:

Thank you for your inquiry.

Synvisc is hyaluronan synthesized from chicken combs. Large local reactions to Synvisc are not infrequent. We have dealt with a similar inquiry recently on our Ask the Expert website. I think that the answer to the previous inquiry will be helpful to you as well. Therefore, for your convenience, I have copied it below.

In addition, here is a link to the package insert information for Synvisc which you can access free of charge should you wish more detailed information about the product per se.

As you can see from the previous response, the mechanism of action regarding the production of large local reactions to Synvisc is unknown.

Thank you again for your inquiry and we hope this response is helpful to you.

Previous Inquiry: Reaction to the injection of hylan (Synvisc)
Question:
2/23/2014
53 year-old woman presents with history of reaction to Synvisc. Pt receives injections for OA. 24 hours after receiving injection of Synvisc in both knees, developed localized erythema, swelling and pain of both knee joints. At 48 hrs reaction worse and given articular injection of steroid. Has received multiple injections of Hyalgan in past with no adverse effect. Can patients develop delayed hypersensitity reactions to hyaluronan derivatives? Should she avoid future injections? Utility of patch testing to material?

Answer:
Thank you for your inquiry.

As you can see from the Synvisc package insert quote and the abstracts copied below, we can conclude the following:

Large local, apparently inflammatory reactions occur with significant frequency due to the injection of Synvisc. These reactions are more likely to occur after repeated injections. Attempts to define an immunologic response, and test, have not to date, to my knowledge, been successful.

Based upon these observations, it is not unlikely that your patient will react to another injection, but unfortunately, there does not appear to be any test that would allow you to predict the risk of such a recurrence.

Thank you again for your inquiry and we hope this response is helpful to you.

PACKAGE INSERT
"Overall Injected Knee Safety Summary: The safety profile of Synvisc-One is similar to the clinical and Post-marketing experience seen with SYNVISC (3 injection regiment) where pain,swelling and effusion were the most frequently occurring AEs in the injected knee. There have been post-marketing reports for SYNVISC indicating that in some cases the joint effusion may be large and can cause pronounced pain; it is important to remove and to analyze the fluid to rule out infection or crystalline arthropathies. These types of severe AEs were not observed in either the initial or repeat treatment phase of the Synvisc-One trial."

Increased Frequency of Acute Local Reaction to Intra-Articular Hylan GF-20 (Synvisc) in Patients Receiving More Than One Course of Treatment, The Journal of Bone & Joint Surgery, Volume 84, Issue 9, 2002
Seth S. Leopold, MD; Winston J. Warme, MD , Lieutenant Colonel; Patrick D. Pettis, LVN; Susan Shott, PhD 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.

Assessment of Immunologic Mechanisms for Flare Reactions to Synvisc(R)
Clinical Orthopaedics & Related Research: January 2006 - Volume 442 - Issue - pp 187-194
Marino, Andrew A PhD; Waddell, David D MD; Kolomytkin, Oleg V PhD; Pruett, Stephen PhD; Sadasivan, Kalia K MD; Albright, James A MDAbstract
Intraarticular injection of SynviscR for treatment of knee pain sometimes results in an acute local reaction (flare). We tested the hypothesis that the flare was a Type-1 hypersensitivity reaction as manifested by the presence of SynviscR antibodies in the synovial fluid and serum and by an increase in the concentration of the mast-cell enzyme tryptase in the synovial fluid. Our second objective was to determine whether the ratio of CD4+ to CD8+ lymphocytes in the synovial fluid was increased, as would be expected in a Type-4 hypersensitivity reaction. The study population was a prospective, consecutive series of 16 patients who had a flare, and 20 control patients. We found no differences in product-specific antibodies in the synovial fluid or serum between patients with flares and patients without flares. The mean tryptase level in the synovial fluid of patients with flares, 3.8 ± 0.8 µg/L, was not different from the corresponding level in the control patients. The CD4+/CD8+ ratio in the synovial fluid was more than eight times greater in patients with flares. Flares that sometimes occur after treatment with SynviscR are probably not Type-1 (antibody-mediated) hypersensitivity reactions, but may be Type-4 (cell-mediated) hypersensitivity reactions.

J Rheumatol. 2002 Dec;29(12):2611-4.
Are there distinctive inflammatory flares after hylan g-f 20 intraarticular injections?
Pullman-Mooar S1, Mooar P, Sieck M, Clayburne G, Schumacher HR.
Author information
1MCP/Hahneman University School of Medicine, Philadelphia, Pennsylvania, USA.
Abstract
Objective: This survey was designed to examine features of a group of patients with acute painful joint effusions following hylan G-F 20 (Synvisc) knee injections.
Methods: Eight patients with painful local reactions after intraarticular hylan G-F 20 injections for knee osteoarthritis were evaluated clinically, with detailed synovial fluid analysis, and followed for outcome.
Results: Leukocyte counts ranged from 3150 to 103,000/mm3. Crystals were seen in one patient. Inflammatory knee effusions occurred from 1 to 48 h after injections, but never with first injections. Synovial fluid volumes were 30 to 71 mm(3). Three patients had shiny clumps (not further characterized) that were noted in leukocytes on Wright stained smears. Most patients were treated with aspiration and depot steroids. Five of the 8 patients had moderate or greater improvement at 6 months.
Conclusion: The majority of the occasional dramatic episodes of inflammation after hylan G-F 20 injection do not seem to be related to crystals. No detrimental lasting results were noted. The absence of post-hylan flares following the first intraarticular injection in this small series suggests that sensitization to or accumulation of hylan G-F 20 or its breakdown products may play an etiologic role in these flares.

Sincerely,
Phil Lieberman, M.D.

AAAAI - American Academy of Allergy Asthma & Immunology