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Regarding “Intra-Articular Injections of Hyaluronic Acid or Steroid Associated With Better Outcomes Than Platelet-Rich Plasma, Adipose Mesenchymal Stromal Cell, or Placebo in Knee Osteoarthritis: A Network Meta-analysis”

Published:September 23, 2020DOI:https://doi.org/10.1016/j.arthro.2020.05.052
      We read with great interest the recent article published in the Arthroscopy by Han et al.
      • Han S.B.
      • Seo I.W.
      • Shin Y.S.
      Intra-articular injections of hyaluronic acid or steroid associated with better outcomes than platelet-rich plasma, adipose mesenchymal stromal cell, or placebo in knee osteoarthritis: A network meta-analysis.
      entitled “Intra-Articular Injections of Hyaluronic Acid or Steroid Associated With Better Outcomes Than Platelet-Rich Plasma, Adipose Mesenchymal Stromal Cell, or Placebo in Knee Osteoarthritis: A Network Meta-analysis.” We believe intra-articular injectables are an important aspect to study to optimize the nonoperative treatment of those with knee osteoarthritis, and the efficacy of this treatment has been the evaluated in multiple meta-analysis and network met-analysis.
      • Campbell K.A.
      • Saltzman B.M.
      • Mascarenhas R.
      • et al.
      Does intra-articular platelet-rich plasma injection provide clinically superior outcomes compared with other therapies in the treatment of knee osteoarthritis? A Systematic review of overlapping meta-analyses.
      • Belk J.W.
      • Kraeutler M.J.
      • Houck D.A.
      • Goodrich J.A.
      • Dragoo J.L.
      • McCarty E.C.
      Platelet-rich plasma versus hyaluronic acid for knee osteoarthritis: A systematic review and meta-analysis of randomized controlled trials.
      • Riboh J.C.
      • Saltzman B.M.
      • Yanke A.B.
      • Fortier L.
      • Cole B.J.
      Effect of leukocyte concentration on the efficacy of platelet-rich plasma in the treatment of knee osteoarthritis.
      • Vilchez-Cavazos F.
      • Millan-Alanis J.M.
      • Blazquez-Saldana J.
      • et al.
      Comparison of the clinical effectiveness of single versus multiple injections of platelet-rich plasma in the treatment of knee osteoarthritis: A systematic review and meta-analysis.
      • Phillips M.
      • Vannabouathong C.
      • Devji T.
      • et al.
      Differentiating factors of intra-articular injectables have a meaningful impact on knee osteoarthritis outcomes: A network meta-analysis [published online January 3, 2020]. Knee Surg Sports Traumatol Arthrosc.
      • Vincent P.
      Intra-articular hyaluronic acid in the symptomatic treatment of knee osteoarthritis: A meta-analysis of single-injection products.
      We would like to thank the authors for their efforts in focusing on the issue, and we also commend the authors on performing a network meta-analysis, as we believe this is a very useful tool where multiple treatment options exist. However, we do have some concerns with the methodology that may confound our understanding on the topic, and thus, feel the conclusions may be misleading. Similar network meta-analyses on this topic have come to very different conclusions. We believe the 2 main concerns are due to the pooling of different platelet-rich plasma (PRP), hyaluronic acid (HA), and corticosteroid (CS) subtypes, as well as the mixing of different follow-up times, as both have been shown to have an effect on the clinical outcomes in osteoarthritic knees.
      Our primary concern with the pooling of different PRP and HA subtypes is that these have both been shown to have different biological properties, which may impact the outcomes. Recently, there have been advances in our understanding of PRP and its biological properties. Particular attention has been paid to the leukocyte concentration regarding whether it is a pure plasma preparation or a platelet-rich fibrin matrix (PRFM). Dohan-Ehrenfest et al.
      • Dohan Ehrenfest D.M.
      • Rasmusson L.
      • Albrektsson T.
      Classification of platelet concentrates: from pure platelet- rich plasma (P-PRP) to leucocyte- and platelet-rich fibrin (L-PRF).
      subgrouped PRPs into 4 categories: (1) leukocyte-poor PRP (LP-PRP), (2) leukocyte-rich PRP (LR-PRP), (3) LP-PRFM, and (4) LR-PRFM. The PRFM differs, as an anticoagulant is not added and it forms a gel-like substance, and thus it is not used as an intra-articular injection but primarily used for ligamentous healing.
      In osteoarthritic knees, there are basic science studies that have shown LP-PRP can stimulate endogenous HA production and decrease cartilage catabolism, as well as suppress the inflammatory mediators and expression of their genes in synoviocytes and cartilage.
      • Sundman E.A.
      • Cole B.J.
      • Karas V.
      • et al.
      The anti-inflammatory and matrix restorative mechanisms of platelet-rich plasma in osteoarthritis.
      Cole et al.
      • Cole B.J.
      • Karas V.
      • Hussey K.
      • Pilz K.
      • Fortier L.A.
      Hyaluronic acid versus platelet-rich plasma: A prospective, double-blind randomized controlled trial comparing clinical outcomes and effects on intra-articular biology for the treatment of knee osteoarthritis.
      found in a randomized controlled trial (RCT) that with LP-PRP there was a decrease in the proinflammatory cytokines, as measured by enzyme-linked immunosorbent assay. Although there may be concern with LR-PRP and that it may be proinflammatory based on basic science studies, Mariani et al.
      • Mariani E.
      • Canella V.
      • Cattini L.
      • et al.
      Leukocyte-rich platelet-rich plasma injections do not up-modulate intra-articular pro-inflammatory cytokines in the osteoarthritic knee.
      found that this did not alter the inflammatory cytokines as measured by enzyme-linked immunosorbent assay. A recently published meta-analysis of RCTs by Belk et al.
      • Belk J.W.
      • Kraeutler M.J.
      • Houck D.A.
      • Goodrich J.A.
      • Dragoo J.L.
      • McCarty E.C.
      Platelet-rich plasma versus hyaluronic acid for knee osteoarthritis: A systematic review and meta-analysis of randomized controlled trials.
      found that PRP resulted in significantly improved clinical outcomes and reduced pain levels compared with HA, in contrast to the authors’ findings. In addition, they showed that LP-PRP may be superior to LR-PRP and that a difference exists between the 2 PRP subtypes. Similarly, Riboh et al.
      • Riboh J.C.
      • Saltzman B.M.
      • Yanke A.B.
      • Fortier L.
      • Cole B.J.
      Effect of leukocyte concentration on the efficacy of platelet-rich plasma in the treatment of knee osteoarthritis.
      also determined in their network meta-analysis that LP-PRP improved outcomes compared with LP-PRP. Thus, the differing subtypes of PRP do appear to alter the outcomes, and it is incorrect to pool them, as the authors have done. The authors findings are also in disagreement with the RCTs in the literature comparing single- and multiple-PRP injections, which may stem from its pooling of different PRP subtypes. Vilchez-Cavazos et al.
      • Vilchez-Cavazos F.
      • Millan-Alanis J.M.
      • Blazquez-Saldana J.
      • et al.
      Comparison of the clinical effectiveness of single versus multiple injections of platelet-rich plasma in the treatment of knee osteoarthritis: A systematic review and meta-analysis.
      performed a meta-analysis of these trials and determined that although there was no difference in pain at 6 months, multiple injections of PRP resulted in improved functional outcomes at 6 months.
      HA and its subtypes also have differing effects in osteoarthritic joints. HA has 2 main subgroups based on its molecular weight, high-molecular weight HA (HMW-HA), and low-molecular weight HA (LMW-HA). HMW-HA has been suggested to be more efficacious, as it more closely resembles the natural HA in the knee, which is lost in an osteoarthritic joint.
      • Balazs E.A.
      • Watson D.
      • Duff I.F.
      • Roseman S.
      Hyaluronic acid in synovial fluid. I. Molecular parameters of hyaluronic acid in normal and arthritis human fluids.
      • Moreland L.W.
      Intra-articular hyaluronan (hyaluronic acid) and hylans for the treatment of osteoarthritis: Mechanisms of action.
      • Goldberg V.M.
      • Buckwalter J.A.
      Hyaluronans in the treatment of osteoarthritis of the knee: Evidence for disease-modifying activity.
      • Pelletier J.P.
      • Martel-Pelletier J.
      The pathophysiology of osteoarthritis and the implication of the use of hyaluronan and hylan as therapeutic agents in viscosupplementation.
      Another recent network meta-analysis by Phillips et al.
      • Phillips M.
      • Vannabouathong C.
      • Devji T.
      • et al.
      Differentiating factors of intra-articular injectables have a meaningful impact on knee osteoarthritis outcomes: A network meta-analysis [published online January 3, 2020]. Knee Surg Sports Traumatol Arthrosc.
      found that HMW-HA was the most efficacious treatment for knee osteoarthritis in terms of reducing pain and improving functional outcomes. This is supported by the basic science evidence, as Elmorsy et al.
      • Elmorsy S.
      • Funakoshi T.
      • Sasazawa F.
      • Todoh M.
      • Tadano S.
      • Iwasaki N.
      Chondroprotective effects of high-molecular-weight cross-linked hyaluronic acid in a rabbit knee osteoarthritis model.
      found in a rabbit osteoarthritis model, that HMW-HA has greater chondroprotective effects than LMW-HA.
      The authors used differing time points for their analysis, pooling outcomes at 6- and 12-month follow-up. As the authors note, CS may be most efficacious in the short term, and that this effect may not be seen beyond 6 months’ follow-up, and thus may have led to their earlier follow-up success.
      • Han S.B.
      • Seo I.W.
      • Shin Y.S.
      Intra-articular injections of hyaluronic acid or steroid associated with better outcomes than platelet-rich plasma, adipose mesenchymal stromal cell, or placebo in knee osteoarthritis: A network meta-analysis.
      ,
      • Arden N.K.
      • Reading I.C.
      • Jordan K.M.
      • et al.
      A randomised controlled trial of tidal irrigation vs corticosteroid injection in knee osteoarthritis: The KIVIS Study.
      ,
      • de Campos G.C.
      • Rezende M.U.
      • Pailo A.F.
      • Frucchi R.
      • Camargo O.P.
      Adding triamcinolone improves viscosupplementation: A randomized clinical trial.
      However, this does not take into account the differences between standard- and extended-release CS, which may also affect the outcomes.
      • Phillips M.
      • Vannabouathong C.
      • Devji T.
      • et al.
      Differentiating factors of intra-articular injectables have a meaningful impact on knee osteoarthritis outcomes: A network meta-analysis [published online January 3, 2020]. Knee Surg Sports Traumatol Arthrosc.
      ,
      • Kraus V.B.
      • Conaghan P.G.
      • Aazami H.A.
      • et al.
      Synovial and systemic pharmacokinetics (PK) of triamcinolone acetonide (TA) following intra-articular (IA) injection of an extended-release microsphere-based formulation (FX006) or standard crystalline suspension in patients with knee osteoarthritis (OA).
      Many of the included RCTs not only report their outcomes at final follow-up but also at their mid-term follow-up time points, which is a strength of these trials. Therefore, it may be more appropriate for future meta-analysis and network meta-analysis to compare the outcomes at different time points and not pool for final follow-up alone. Although CS may be most efficacious in the short term, it is unclear if they lead to long-term success, and further analyses may better determine the efficacy of these treatments over time.
      While we appreciate the authors’ work on this study, we believe the methodologic concerns of pooling different PRP and HA subtypes, as well different follow-up time points, may lead to incorrect conclusions being drawn from this study. We would like to echo our previous calls for greater reporting on the cytology of PRP, as it is poorly reported on and thus limits our true understanding of the area; until then, it is still unclear what we are using.
      • Davey M.S.
      • Hurley E.T.
      • Withers D.
      • Moran R.
      • Moran C.J.
      Anterior cruciate ligament reconstruction with platelet-rich plasma: A systematic review of randomized control trials.
      • Hurley E.T.
      • Lim Fat D.
      • Moran C.J.
      • Mullett H.
      The efficacy of platelet-rich plasma and platelet-rich fibrin in arthroscopic rotator cuff repair: A meta-analysis of randomized controlled trials.
      • Hurley E.T.
      • Hannon C.P.
      • Pauzenberger L.
      • Fat D.L.
      • Moran C.J.
      • Mullett H.
      Nonoperative treatment of rotator cuff disease with platelet-rich plasma: A systematic review of randomized controlled trials.

      Supplementary Data

      References

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