In Knee OA, Adding Hyaluronic Acid (HA) Vs. Cross-Linked HA to Intra-Articular Platelet-Rich Plasma Did Not Differ for Pain at 6 Months

Huang H-Y, Hsu C-W, Lin G-C, Lin H-S, Chou Y-J, Liou I-H, Sun S-F. Comparing efficacy of a single intraarticular injection of platelet-rich plasma (PRP) combined with different hyaluronans for knee osteoarthritis: a randomized-controlled clinical trial. BMC Musculoskelet Disord. 2022 Nov 4;23(1):954. Question: In patients with knee osteoarthritis (OA), what is the effect of adding hyaluronic acid (HA) versus a cross-linked HA to a single intra-articular injection of platelet-rich plasma (PRP) on pain? Design: Randomized (allocation concealed), blinded (patients and outcome assessors), controlled trial with 6 months of follow-up. Setting: Kaohsiung Veterans General Hospital, Taiwan. Patients: 99 patients aged 20 to 85 years (mean age, 61 years; 64% women) who had symptomatic knee OA (knee pain ≥30 mm on a 100-mm [worst pain] visual analog scale [VAS] for >6 months despite nonoperative treatment) and radiographs in the past 6 months showing Kellgren-Lawrence grade-2 knee OA. Exclusion criteria were orthopaedic surgery on the target knee, spine, or lower limb; disabling hip or foot OA; knee instability; joint effusion or marked valgus/varus deformity; intra-articular injections into the target knee in the past 6 months; or treatment with anticoagulants or antiaggregants. 96% of patients completed follow-up at 6 months. Intervention: Patients were allocated to a single intra-articular injection of HA, 2.5 mL (Artz; Seikagaku), followed immediately by a single intra-articular injection of PRP, 3 mL (n = 50); or cross-linked HA, 3 mL (HYAJOINT Plus; SciVision Biotech), followed by PRP, 3 mL (n = 49), using an anterolateral approach with the knee in 90° of flexion. Patients stopped analgesic or nonsteroidal anti-inflammatory drugs 7 days before baseline and were not to use analgesics, chondroprotective supplements, or physiotherapy during the trial. Acetaminophen, 4 g/day, was allowed as rescue treatment. Main outcome measures: The primary outcome was pain (VAS; score range 0 [no pain] to 100 [worst imaginable pain]). Secondary outcomes included the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Lequesne index, single-leg stance test (SLS), and adverse events. Main results: Key efficacy outcomes at 6 months are reported in Table I. The groups did not differ for pain at 1, 3, or 6 months. At 6 months, the HA + PRP group had less knee stiffness and shorter SLS time compared with the cross-linked HA + PRP group. No serious adverse events were reported. TABLE I - Single intra-articular platelet-rich plasma (PRP) injection with hyaluronic acid (HA) versus a cross-linked HA in patients with knee osteoarthritis (intention-to-treat analysis)* Outcomes Mean Adjusted mean between-group difference at 6 months (95% CI) HA + PRP Cross-linked HA + PRP Pain† 11.9 8.7 2.8 (−3.0 to 8.6) WOMAC-total‡ 16.4 19.5 −2.5 (−7.4 to 2.3) WOMAC-pain‡ 3.2 3.9 −0.6 (−1.6 to 0.4) WOMAC-stiffness‡ 1.3 1.8 −0.6 (−0.1 to −1.0) WOMAC-function‡ 11.8 13.9 −1.4 (−5.0 to 2.2) Lequesne index§ 5.0 5.8 −0.8 (−2.1 to 0.5) Single-leg stance#(sec) 37.4 44.8 −13.8 (−23.0 to −4.6) *CI = confidence interval, WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index.†Visual analog scale, score range 0 (no pain) to 100 (worst imaginable pain).‡24-item scale, score range 0 (best condition) to 96 (worst condition); subscales for pain (5 items, score range 0 to 20), stiffness (2 items, score range 0 to 8), and physical function (17 items, score range 0 to 68).§Knee pain severity in past week; score range 0 (no pain) to 24 (worst pain).#Static balance test of time standing on the study leg. Conclusion: In knee OA, adding HA versus cross-linked HA to a single intra-articular injection of PRP did not differ for pain at 6 months. Source of funding: Kaohsiung Veterans General Hospital Research Fund, Taiwan. For correspondence: Shu-Fen Sun, Department of Physical Medicine and Rehabilitation, Kaohsiung Veterans General Hospital, Taiwan. E-mail address: [email protected]. Commentary The randomized controlled trial by Huang and colleagues compared the efficacy of 2 viscosupplementation injections delivered with PRP in patients with moderate knee OA. Basic science studies have shown that both leukocyte-poor PRP and HA injections may have anti-inflammatory and chondroprotective effects that may ameliorate the symptoms of knee OA. Furthermore, studies have reported favorable outcomes with high-molecular-weight and biologically fermented HA compared with low-molecular-weight avian-derived formulations3. The results of the current trial suggest that delivery of PRP with either of these 2 HA formulations is safe and effective based on patient-reported outcomes (PROs). The cross-linked HA formulation with PRP improved static balance (SLS scores) for up to 6 months after injection, but the groups were largely equivalent in other PROs assessed through 6 months. The trial provides reasonable-quality evidence that PRP and HA treatment is an effective treatment option for patients with moderate OA of the knee (Kellgren-Lawrence grade 2), aligning with the results of Ciapini et al. of favorable outcomes for 6 months after PRP plus HA treatment1. It does not, however, provide any insights as to whether combined treatment with PRP and HA is more effective than either of these treatments alone. A recent systematic review by Belk et al. suggested that PRP or concentrated bone marrow aspirate is more effective in isolation than with HA injection2. The trial results are not broadly generalizable because patients with more severe radiographic arthritic changes were excluded, and all patients received 1 specific formulation of leukocyte-poor PRP with approximately 2.4 times the baseline platelet concentration. Future studies would benefit from additional treatment groups for each HA and PRP treatment alone, as well as corticosteroid injections, which are still frequently prescribed for patients with knee OA. In addition, assessment of structural changes based on serial radiographic and/or magnetic resonance imaging would be invaluable to assess if these treatments offer benefits beyond symptomatic relief. A recent randomized controlled trial by Küçükakkaş et al.3 reported greater knee femoral cartilage thickness with HA injection compared with PRP injection.

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