Background/Purpose: Case reports of severe acute localized reactions (SALR) following intra-articular (IA) hyaluronic acid (HA) injections for knee osteoarthritis (OA) have been described. These have been speculated to be related to the crosslink of hylan or an allergic reaction to avian-derived hyaluronan, but reactions have also been reported for non-crosslinked, non-animal, and/or naturally derived HA. We compared surrogate SALR measures between patients using hylan G-F 20 and specific non-hylan G-F 20 HA products.

Methods: Knee OA patients were identified from the Optum Clinformatics dataset (Jan 2006-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, intra-articular corticosteroid (CS) injections, arthrocentesis/aspiration, arthrotomy/incision and drainage, arthroscopy, and office visits were evaluated (with ICD/CPT codes) within three days of HA use, adjusting for demographics and clinical factors. These were stratified by single/multiple injection products and evaluated for claims that had a corresponding knee OA diagnosis (knee OA related), as well as those that did not (any diagnosis).

Results: A total of 694,404 HA injections were included in the study. Inflammation/infection rate (with any diagnosis) was rare within three days of HA use (hylan G-F 20 (3-injection): 0.02%; Euflexxa: 0.03%; Hyalgan/Supartz: 0.02%; Orthovisc: 0.02%; hylan G-F 20 (1-injection): 0.02%; Monovisc: none; Gel-One: none) (Figs. 1 and 2); no statistical differences between hylan G-F 20 and non-hylan G-F 20 groups were observed (Table 1). The risk of arthrocentesis was greater for hylan G-F 20 (3-injection; 1.4%) than Euflexxa patients (1.1%) (adjusted hazard ratio (AHR) 1.48; p< 0.001), but lower than Hyalgan/Supartz (2.9%) (AHR 0.53; p< 0.001) and Orthovisc (2.4%) (AHR 0.80; p< 0.001) patients. When considering the collective occurrence of any of the surrogate SALR outcomes, the risk was found to be similar between hylan G-F 20 (3-injection) and Euflexxa cohorts (p=0.062), except when limited to those with corresponding knee OA diagnoses (AHR 1.24 for hylan G-F 20; p< 0.001). The overall risks were lower for hylan G-F 20 (3-injection) than Hyalgan/Supartz (p< 0.001) or Orthovisc (p< 0.001) patients and lower for hylan G-F 20 (1-injection) than Monovisc (p< =0.007) or Gel-One patients (p< =0.012).

Conclusion: The present study examined potential SALR risk in a real-world setting of almost 700,000 HA injections. Diagnoses of inflammation or infection diagnoses were extremely rare (0 to 0.03%) within three days of HA injections. While our arthrocentesis results are consistent with a randomized controlled trial (Kirchner 2006), which reported a greater rate of local reactions in terms of effusions, in hylan G-F 20 (3-injection) than Euflexxa patients, the collective risk of any of the surrogate SALR outcomes was not found to be significantly different between hylan G-F 20 and non-hylan G-F 20 products (single or multiple injection products).

Figure 1. Surrogate SALR outcomes within three days post-injection for hylan G-F 20 (3-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 (3-injection) group, respectively).

Figure 2. Surrogate SALR outcomes within three days post-injection for hylan G-F 20 (1-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 (1-injection) group, respectively).

Figure 3. Adjusted likelihood of clinical encounters within three days post-injection for the hylan G-F 20 groups compared to other non-hylan G-F 20 product groups, stratified by single and multiple injection products. 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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ACR Meeting Abstracts - https://acrabstracts.org/abstract/risk-of-severe-acute-localized-reactions-for-different-intra-articular-hyaluronic-acid-knee-injections-in-a-real-world-setting/