Advertisement

Editorial Commentary: Intra-Articular Injections for Painful Knee Osteoarthritis: What Is the Current Treatment Paradigm?

Published:September 22, 2020DOI:https://doi.org/10.1016/j.arthro.2020.09.031

      Abstract

      Intra-articular corticosteroids are useful for acute and short-term pain relief, whereas hyaluronic acid is useful for a longer-term treatment effect for patients with knee osteoarthritis. More rigorous research using homogeneous preparations and techniques and randomizing larger numbers of knee osteoarthritis patients are warranted before recommending any wider acceptance of platelet-rich plasma and stem cell therapies. This is of utmost importance, especially with several new injectables such as anti–nerve growth factor antibodies, Wnt pathway inhibitors, and capsaicin showing promise to enter the market soon.
      The advancement and adaptation of network meta-analysis techniques to the health care field has prompted a new genre of comparative effectiveness research that focuses on assessing multiple treatments against each other and ranking them based on their efficacy and safety profiles. This is a powerful and very useful technique when used appropriately by researchers with advanced statistical expertise and an understanding of the methodology, in collaboration with clinical experts.
      I read the study 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” by Han, Seo, and Shin with interest.
      • Han S.
      • Seo I.
      • 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.
      The major strength of this study is that it addresses a clinically relevant question. Knee injections are a clinically proven strategy for symptom management in patients with painful osteoarthritis of the knee. However, the study demonstrated several limitations specific to its design, including (1) the inclusion of studies that report potentially implausible results, with insufficient measures taken to adjust for their effects on the analysis
      • Gormeli G.
      • Gormeli C.A.
      • Ataoglu B.
      • Colak C.
      • Aslanturk O.
      • Ertem K.
      Multiple PRP injections are more effective than single injections and hyaluronic acid in knees with early osteoarthritis: A randomized, double-blind, placebo-controlled trial.
      • Uslu Guvendi E.
      • Askin A.
      • Guvendi G.
      • Kocyigit H.
      Comparison of efficiency between corticosteroid and platelet rich plasma injection therapies in patients with knee osteoarthritis.
      • Hong Z.
      • Chen J.
      • Zhang S.
      • et al.
      Intra-articular injection of autologous adipose-derived stromal vascular fractions for knee osteoarthritis: A double-blind randomized self controlled trial.
      • Caborn D.
      • Rush J.
      • Lanzer W.
      • Parenti D.
      • Murray C.
      Synvisc 901 Study Group
      A randomized, single-blind comparison of the efficacy and tolerability of hylan G-F 20 and triamcinolone hexacetonide in patients with osteoarthritis of the knee.
      ; (2) the arbitrary exclusion of certain comparisons performed in included articles, such as Gormeli’s comparisons of hyaluronic acid versus placebo, and of single platelet-rich plasma injection versus placebo
      • Gormeli G.
      • Gormeli C.A.
      • Ataoglu B.
      • Colak C.
      • Aslanturk O.
      • Ertem K.
      Multiple PRP injections are more effective than single injections and hyaluronic acid in knees with early osteoarthritis: A randomized, double-blind, placebo-controlled trial.
      ; and (3) the inclusion of highly heterogeneous studies, including but not limited to extremely wide ranges of time to follow-up (6 to 104 weeks), which stands to undermine the transitivity assumption on which network meta-analysis methods depend.
      Furthermore, the results of the study demonstrated some irregularities that directly threaten their plausibility, including (1) although placebo is reported to rank third among active interventions, every active intervention appears to perform significantly better than placebo for pain; and (2) with regard to steroids, the reported standardized mean difference of 2.13 (95% confidence interval 0.51 to 3.76) (which translates to 42 [10, 75] points on 0-to-100 scale), on top of intra-articular placebo effects, is highly unlikely.
      • Bannuru R.R.
      • McAlindon T.E.
      • Sullivan M.C.
      • Wong J.B.
      • Kent D.M.
      • Schmid C.H.
      Effectiveness and implications of alternative placebo treatments: A systematic review and network meta-analysis of osteoarthritis trials.
      Additionally, to elicit such a huge change from baseline, the expected baseline pain value would range between 60 and 90, when in fact the average baseline pain value across 80 placebo-controlled trials of hyaluronic acid and steroid was 51 ± 10.
      • Bannuru R.R.
      • McAlindon T.E.
      • Sullivan M.C.
      • Wong J.B.
      • Kent D.M.
      • Schmid C.H.
      Effectiveness and implications of alternative placebo treatments: A systematic review and network meta-analysis of osteoarthritis trials.
      Our team studied the comparative effectiveness of most commonly used treatments for knee osteoarthritis.
      • Bannuru R.R.
      • Schmid C.H.
      • Kent D.M.
      • Vaysbrot E.E.
      • Wong J.B.
      • McAlindon T.E.
      Comparative effectiveness of pharmacological interventions for knee osteoarthritis: A systematic review and network meta-analysis.
      Our hypothesis was that by ignoring differential placebo effects, intra-articular treatments were held to a different standard than oral treatments. We found that intra-articular treatments (corticosteroids and hyaluronic acid) performed better than oral treatments when compared with a common oral placebo. We also demonstrated that intra-articular placebos alone have a substantial effect on pain compared with oral placebo. In contrast to the Han et al. study,
      • Han S.
      • Seo I.
      • 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.
      we did not include platelet-rich plasma and stem cell therapies in our network, as they failed to meet our inclusion criteria.
      Two of the 3 recently published knee osteoarthritis treatment guidelines recommend both corticosteroids and hyaluronic acid, whereas the third conditionally recommended against hyaluronic acid.
      • Bruyere O.
      • Honvo G.
      • Veronese N.
      • Arden N.K.
      • Branco J.
      • Curtis E.M.
      • et al.
      An updated algorithm recommendation for the management of knee osteoarthritis from the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO).
      • Bannuru R.R.
      • Osani M.C.
      • Vaysbrot E.E.
      • Arden N.K.
      • Bennell K.
      • Bierma-Zeinstra S.M.A.
      • et al.
      OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis.
      • Kolasinski S.L.
      • Neogi T.
      • Hochberg M.C.
      • Oatis C.
      • Guyatt G.
      • Block J.
      • et al.
      2019 American College of Rheumatology/Arthritis Foundation guideline for the management of osteoarthritis of the hand, hip, and knee.
      A reason for the differences in recommendations may be due to variations in the guidelines’ structures and study questions. For example, the Osteoarthritis Research Society International (OARSI) guidelines considered various patient profiles, which included 3 different joint location options, as well as multiple possible comorbidity classifications.
      • Bannuru R.R.
      • Osani M.C.
      • Vaysbrot E.E.
      • Arden N.K.
      • Bennell K.
      • Bierma-Zeinstra S.M.A.
      • et al.
      OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis.
      Therefore, recommendations for when to offer injectable treatments differed based on joint location and comorbidity profiles. In clinical practice, for patients who have had an inadequate response to topical and oral nonsteroidal anti-inflammatory drugs and intraarticular steroids, or for patients with cardiovascular or gastrointestinal risk factors, hyaluronic acid injections may be a favorable option. Intra-articular injections are contraindicated in the presence of systemic septic conditions, cutaneous diseases, or infection in the area surrounding the injection site. Hyaluronic acid is not useful if the joint is affected by severe inflammation that is active or has occurred in the previous 3 to 6 months.
      With regard to platelet-rich plasma and stem cell therapies, the heterogeneity and lack of standardization in the composition of available preparations, as well as in the techniques used in their preparation, make it difficult to specify the contents of a given injection. Additionally, the majority of available platelet-rich plasma and stem cell therapy studies are small and are not methodologically rigorous, and their reporting of safety outcomes has been wholly inadequate. These factors have prompted negative recommendations from all recent clinical practice guidelines.
      Based on their efficacy and safety profile, corticosteroids are useful for acute (1- to 2-week) and short-term (4- to 6-week) pain relief, whereas hyaluronic acid is useful for a longer-term treatment effect. More rigorous research using homogeneous preparations and techniques, randomizing larger numbers of knee osteoarthritis patients, and a comprehensive and longer-term safety profile are warranted before recommending any wider acceptance of platelet-rich plasma and stem cell therapies. With several injectables in the treatment pipeline, including anti–nerve growth factor antibodies, Wnt pathway inhibitors, and capsaicin, showing promise, platelet-rich plasma and stem cell therapies need to strengthen their evidence profile to stay in the race.

      Supplementary Data

      References

        • Han S.
        • Seo I.
        • 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.
        Arthroscopy. 2021; 37: 292-306
        • Gormeli G.
        • Gormeli C.A.
        • Ataoglu B.
        • Colak C.
        • Aslanturk O.
        • Ertem K.
        Multiple PRP injections are more effective than single injections and hyaluronic acid in knees with early osteoarthritis: A randomized, double-blind, placebo-controlled trial.
        Knee Surg Sports Traumatol Arthrosc. 2017; 25: 958-965
        • Uslu Guvendi E.
        • Askin A.
        • Guvendi G.
        • Kocyigit H.
        Comparison of efficiency between corticosteroid and platelet rich plasma injection therapies in patients with knee osteoarthritis.
        Arch Rheumatol. 2018; 33: 273-281
        • Hong Z.
        • Chen J.
        • Zhang S.
        • et al.
        Intra-articular injection of autologous adipose-derived stromal vascular fractions for knee osteoarthritis: A double-blind randomized self controlled trial.
        Int Orthop. 2019; 43: 1123-1134
        • Caborn D.
        • Rush J.
        • Lanzer W.
        • Parenti D.
        • Murray C.
        • Synvisc 901 Study Group
        A randomized, single-blind comparison of the efficacy and tolerability of hylan G-F 20 and triamcinolone hexacetonide in patients with osteoarthritis of the knee.
        J Rheumatol. 2004; 31: 333-343
        • Bannuru R.R.
        • McAlindon T.E.
        • Sullivan M.C.
        • Wong J.B.
        • Kent D.M.
        • Schmid C.H.
        Effectiveness and implications of alternative placebo treatments: A systematic review and network meta-analysis of osteoarthritis trials.
        Ann Intern Med. 2015; 163: 365-372
        • Bannuru R.R.
        • Schmid C.H.
        • Kent D.M.
        • Vaysbrot E.E.
        • Wong J.B.
        • McAlindon T.E.
        Comparative effectiveness of pharmacological interventions for knee osteoarthritis: A systematic review and network meta-analysis.
        Ann Intern Med. 2015; 162: 46-54
        • Bruyere O.
        • Honvo G.
        • Veronese N.
        • Arden N.K.
        • Branco J.
        • Curtis E.M.
        • et al.
        An updated algorithm recommendation for the management of knee osteoarthritis from the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO).
        Semin Arthritis Rheum. 2019; 49: 337-350
        • Bannuru R.R.
        • Osani M.C.
        • Vaysbrot E.E.
        • Arden N.K.
        • Bennell K.
        • Bierma-Zeinstra S.M.A.
        • et al.
        OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis.
        Osteoarthritis Cartilage. 2019; 27: 1578-1589
        • Kolasinski S.L.
        • Neogi T.
        • Hochberg M.C.
        • Oatis C.
        • Guyatt G.
        • Block J.
        • et al.
        2019 American College of Rheumatology/Arthritis Foundation guideline for the management of osteoarthritis of the hand, hip, and knee.
        Arthritis Care Res (Hoboken). 2020; 72: 220-233