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. 2021 Dec;13(1_suppl):376S-386S.
doi: 10.1177/19476035211025815. Epub 2021 Sep 13.

Risk of Severe Acute Localized Reactions for Different Intraarticular Hyaluronic Acid Knee Injections in a Real-World Setting

Kevin L Ong  1 , Jack Farr  2 , Andrew S Gudeman  2 , Iain R Murray  3 , Louis F McIntyre  4 , Charles D Hummer  5 , Wilson Ngai  6 , Edmund Lau  7 , Roy D Altman  8 , Seth L Sherman  9
Affiliations

Risk of Severe Acute Localized Reactions for Different Intraarticular Hyaluronic Acid Knee Injections in a Real-World Setting

Kevin L Ong et al. Cartilage. 2021 Dec.

Abstract

Objective: Case reports of severe acute localized reactions (SALR) following intraarticular (IA) hyaluronic acid (HA) injections for knee osteoarthritis (OA) have been described. We compared surrogate SALR measures between patients using hylan G-F 20 and specific non-hylan G-F 20 HA products.

Design: Knee OA patients were identified from the Optum Clinformatics dataset (January 2006 to June 2016), stratified into hylan G-F 20 and non-hylan G-F 20 HA users, matched by single or multiple injection products. Occurrences of surrogate SALR measures including inflammation/infection, intraarticular corticosteroid (CS) injections, arthrocentesis/aspiration, arthrotomy/incision and drainage, and arthroscopy were evaluated within 3 days post-HA.

Results: Based on 694,404 HA injections, inflammation/infection rate was rare within 3 days of HA (up to 0.03%), with no statistical differences between hylan G-F 20 and non-hylan G-F 20 groups (matched by single or multiple injection products). The risk of knee arthrotomy/incision and drainage, arthroscopy, or arthrocentesis for hylan G-F 20 (2 mL) 3 weekly injection patients was lower than Hyalgan/Supartz and Orthovisc patients, but greater than Euflexxa patients. Overall, we found that Hylan G-F 20 (2 mL) 3 weekly injection had lower SALR rates compared to Hyalgan/Supartz and Orthovisc. However, Hylan G-F 20 (2 mL) 3 weekly injection had slightly higher rates of SALR when compared to Euflexxa. Among the single injection products, Hylan G-F 20 (6 mL) single injection had lower rates of SALR than Monovisc and Gel-One.

Conclusions: This study shows no clear correlation between avian-derived or cross-linked products and SALR and provides evidence against avian-derived products or crosslinking as a source for these reactions.

Keywords: hyaluronic acid; inflammatory reaction; knee osteoarthritis; localized reactions; pseudosepsis.

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Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: KLO, EL: Employees of Exponent, Inc., a scientific and engineering consulting firm. Exponent received funding from Sanofi US for this study.

KLO: Exponent has been paid fees for his consulting services on behalf of such companies and suppliers (Medtronic, Stryker Orthopaedics, Sanofi, Ferring Pharmaceuticals, Pacira Pharmaceuticals, St. Jude Medical, Relievant Medsystems, International Society for the Advancement of Spine Surgery, SI-Technology, LLC, Bioventus, Zimmer Biomet, Joerns Healthcare, SpineFrontier, Ethicon, DJO, Ossur, Karl Storz Endoscopy-America, Rex Medical, Smith & Nephew, Covidien).

JF: Research support from Active Implants, Arthrex, Episurf, Fidia, JRF Ortho, Moximed, Norvartis, Organogenesis, Samumed, Vericel, Zimmer Biomet; Paid consultant for Aesculap/B. Braun, Cartiheal, Cook Biotech Inc., Exactech, Moximed, Organogenesis, Regentis, Samumed Inc., ZKR Orthopedics; Editorial or governing board for American Journal of Orthopedics, Cartilage; Paid presenter/speaker for Arthrex, Organogenesis, Vericel; IP royalties for Arthrex Inc., Biopoly LLC, Moximed, Organogenesis; Stocks/stock options for MedShape Inc., Ortho Regenerative Tech Inc.; Publishing royalties, financial or material support for Springer, Thieme Medical Publishers.

ASG: Nothing to disclose.

IRM: Editorial or governing board for Bone and Joint Research, Journal of Bone and Joint Surgery–British.

LFM: Board or committee member for AAOS, Advocacy for Improvement in Mobility, Arthroscopy Association of North America, Delegate Medical Society of the State of New York, Orthopedic Practice Management, Inc., Westchester County Medical Society; Publishing royalties, financial or material support for Embody; Stock/stock options for Embody; Editorial or governing board for Orthopedics Today; Paid presenter or speaker for Sanofi-Aventis, Smith & Nephew; Paid consultant for Smith & Nephew; Employee of US Orthopedic Partners

CDH: Board or committee member for PA Orthopaedic Society; Paid consultant for Sanofi-Aventis.

WN: Employee of Sanofi US.

EL: Exponent has been paid fees for his consulting services on behalf of such companies and suppliers (Medtronic, Stryker Orthopaedics, Sanofi, Ferring Pharmaceuticals, Pacira Pharmaceuticals, Relievant Medsystems, Alcon, Boston Scientific).

RDA: Paid consultant for GlaxoSmithKline, Novartis, Pfizer, Sanofi-Aventis.

SLS: Board or committee member for AAOS, ACL Study Group, American Orthopaedic Society for Sports Medicine, Arthroscopy Association of North America, Epic Bio, International Cartilage Regeneration & Joint Preservation Society, International Society of Arthroscopy, Knee Surgery, Orthopaedic Sports Medicine, Joint Restoration Foundation; Editorial or governing board for American Journal of Orthopedics, Arthroscopy, Vericel; Paid consultant for Arthrex, Bioventus, Ceterix Orthopaedics, CONMED Linvatec, Flexion Therapeutics, GLG Consulting, JRF Ortho, Linvatec, Moximed, Olympus, RTI Surgical, Smith & Nephew, Vericel, Zimmer; Paid presenter or speaker for Arthrex, CONMED Linvatec, Flexion Therapeutics, Joint Restoration Foundation, Smith & Nephew, Vericel; Research support for Arthrex; IP royalties for CONMED Linvatec; Stock/stock options for Epic Bio, Vivorte.

Figures

Figure 1.
Figure 1.
Surrogate SALR outcomes within 3 days post-injection for the Hylan G-F 20 (2 mL) 3 weekly injection, Euflexxa, Hyalgan/Supartz, and Orthovisc patient groups (top: outcomes with any diagnosis on the claims; bottom: outcomes with knee OA diagnosis on the claims). Statistically significant differences are indicated with an asterisk (*P < 0.05; green and red for lower and greater adjusted risks in the Hylan G-F 20 (2 mL) 3 weekly injection group, respectively). SALR = severe acute localized reaction; OA = osteoarthritis; ER = emergency room; CS = corticosteroid; I&D = incision and drainage.
Figure 2.
Figure 2.
Surrogate SALR outcomes within 3 days post-injection for the Hylan G-F 20 (6 mL) single injection, Monovisc, and Gel-One patient groups (top: outcomes with any diagnosis on the claims; bottom: outcomes with knee OA diagnosis on the claims). Statistically significant differences are indicated with an asterisk (*P < 0.05; green and red for lower and greater adjusted risks in the Hylan G-F 20 (6 mL) single injection group, respectively). SALR = severe acute localized reaction; OA = osteoarthritis; ER = emergency room; CS = corticosteroid.
Figure 3.
Figure 3.
Adjusted likelihood of clinical encounters within 3 days post-injection for the Hylan G-F 20 (2 mL) 3 weekly injection group compared to other non-hylan G-F 20 (multiple injection) product groups. The reference group for each comparison is the non-hylan G-F 20 group. AHR = adjusted hazard ratio; KOA = knee osteoarthritis; ER = emergency room; Urg care = urgent care; CS = corticosteroid; IP = inpatient; OP = outpatient; I&D = incision and drainage.
Figure 4.
Figure 4.
Adjusted likelihood of clinical encounters within 3 days post-injection for the Hylan G-F 20 (6 mL) single injection group compared to other non-hylan G-F 20 (single injection) product groups. The reference group for each comparison is the non-hylan G-F 20 group. AHR = adjusted hazard ratio; KOA = knee osteoarthritis; ER = emergency room; Urg care = urgent care; CS = corticosteroid; IP = inpatient; OP = outpatient; I&D = incision and drainage.
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