But it does work (and we know that it does)…
2018; Elsevier BV; Volume: 3; Issue: 5 Linguagem: Inglês
10.1136/jisakos-2018-000254
ISSN2059-7762
Autores Tópico(s)Inflammatory mediators and NSAID effects
ResumoWe generally agree how to manage knee osteoarthritis (OA), and in this issue, Parker et al 1Parker DA Scholes C Neri T Non-operative treatment options for knee osteoarthritis: current concepts.JISAKOS. 2018; 3: 274-281Google Scholar summarise in their current concepts article on the non-operative options. What is our approach? Well, we start by suggesting small changes to lifestyle, such as weight loss and strengthening exercises. If these serve no purpose, we prescribe oral anti-inflammatories. However, anti-inflammatory medication has serious side effects, so we replace them—or follow them—with intra-articular injections. We probably all agree that this is best praxis. Our regulators, however, do not. The current guidelines of the American Society of Orthopaedic Surgeons (AAOS) are ‘inconclusive’ about injections with corticosteroid and PRP, and there is a strong recommendation against hyaluronic acid (HA).2Jevsevar DS Brown GA Jones DL et al.The American Academy of Orthopaedic Surgeons evidence-based guideline on: treatment of osteoarthritis of the knee, 2nd edition.J Bone Joint Surg Am. 2013; 95: 1885-1886Crossref PubMed Google Scholar The previous guideline on HA was ‘inconclusive’, but after changing the criteria of clinical relevance, the guidelines are now ‘strongly against’.2Jevsevar DS Brown GA Jones DL et al.The American Academy of Orthopaedic Surgeons evidence-based guideline on: treatment of osteoarthritis of the knee, 2nd edition.J Bone Joint Surg Am. 2013; 95: 1885-1886Crossref PubMed Google Scholar The UK's National Institute for Health and Care Excellence,3The NICE Clinical Guideline Osteoarthritis: care and management.www.nice.org.ukDate: 2014Google Scholar in their current guideline, is equally definitive: ‘Do not offer intra-articular HA injections for the management of OA’. These strong recommendations against intra-articular HA are not without consequence as they dissuade insurance companies from reimbursing HA. However, if you scratch intra-articular injections, you eliminate an important step between anti-inflammatory drugs and surgery, and we all know these patients which benefit from their annual HA injection. An American journalist recently wrote: ‘The insanity of covering a $50 000 total knee replacement operation, but not a relatively cheap HA injection, is one of the reasons why the US health care system is the most expensive‘.4Lazarus D The insanity of covering a $ 50.000 knee operation but not a relatively cheap injection. Los Angeles Times, Los Angeles2018Google Scholar That journalist was right, and not just about the economics. A recent meta-analysis from the American Medical Society for Sports Medicine (AMSSM) showed a small but clinically significant difference for intra-articular HA versus a placebo.5Trojian TH Concoff AL Joy SM et al.AMSSM scientific statement concerning viscosupplementation injections for knee osteoarthritis: importance for individual patient outcomes.Clin J Sport Med. 2016; 26: 1-1110.1097/JSM.0000000000000274Crossref PubMed Scopus (36) Google Scholar Another recent systematic review found a clinically significant improvement, in pain and function, for HA versus an intra-articular placebo.6Campbell KA Erickson BJ Saltzman BM et al.Is local viscosupplementation injection clinically superior to other therapies in the treatment of osteoarthritis of the knee: a systematic review of overlapping meta-analyses.Arthroscopy. 2015; 31: 2036-204510.1016/j.arthro.2015.03.030Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar But why have previous studies disagreed? There are various reasons. First, the literature has been dominated by company sponsored studies that are very biased—also known as mine is better than yours. As such, the literature showing the effectiveness of HA is weak. Second, it is difficult to demonstrate a significant difference when HA is compared with saline.7Zhang W Robertson J Jones AC et al.The placebo effect and its determinants in osteoarthritis: meta-analysis of randomised controlled trials.Ann Rheum Dis. 2008; 67: 1716-172310.1136/ard.2008.092015Crossref PubMed Scopus (448) Google Scholar, 8Colen S van den Bekerom MP Mulier M et al.Hyaluronic acid in the treatment of knee osteoarthritis: a systematic review and meta-analysis with emphasis on the efficacy of different products.BioDrugs. 2012; 26: 257-26810.2165/11632580-000000000-00000Crossref PubMed Google Scholar Arthrocentesis with or without saline has been recognised as an effective intervention for patients with knee OA.9Schumacher HR Aspiration and injection therapies for joints.Arthritis Rheum. 2003; 49: 413-42010.1002/art.11056Crossref PubMed Scopus (55) Google Scholar So intra-articular saline injections should really be categorised as ‘treatment’ (as an 'active-control') rather than a mere 'placebo'. But why inject only saline, when HA is also available? HA is a major component of synovial fluid, which facilitates lubrication and shock absorption. HA suppresses inflammatory mediators like cytokines, prostaglandins and nitric oxide.10Moreland LW Intra-articular hyaluronan (hyaluronic acid) and hylans for the treatment of osteoarthritis: mechanisms of action.Arthritis Res Ther. 2003; 5: 54-6710.1186/ar623Crossref PubMed Google Scholar, 11Nicholls M Manjoo A Shaw P et al.Rheological properties of commercially available hyaluronic acid products in the United States for the treatment of osteoarthritis knee pain.Clin Med Insights Arthritis Musculoskelet Disord. 2018; 11: 5162-516510.1177/1179544117751622Crossref Scopus (14) Google Scholar It is significant that OA is accompanied by changes to the HA: its decreasing molecular weight (MW) and its decreasing concentration in the synovial fluid. Quite simply, ‘topping-up’ the HA restores joint homeostasis, and its anti-inflammatory properties act as a local pain killer. There are many HA products on the market, however. In Italy alone, there are 57.12Migliore A Bizzi E De Lucia O et al.Differences among branded hyaluronic acids in italy, part 1: data from in vitro and animal studies and instructions for use.Clin Med Insights Arthritis Musculoskelet Disord. 2016; 9 (CMAMD.S38857-101)10.4137/CMAMD.S38857Crossref Scopus (5) Google Scholar These versions differ by MW, by molecular structure (whether they are cross-linked), by concentration and by means of production (whether or not they are derived from animals). However, when hospitals lack the relevant knowledge, they can only select by price. Although AAOS is aware that different HA versions give different results, they do not—unfortunately—draw the obvious conclusions. Let's consider the figures. As regards safety: bio-HA (non-animal) has a better safety profile than animal-derived HA.13Altman RD Bedi A Karlsson J et al.Product differences in intra-articular hyaluronic acids for osteoarthritis of the knee.Am J Sports Med. 2016; 44: 2158-216510.1177/0363546515609599Crossref PubMed Scopus (98) Google Scholar As regards rheology and density: HA versions with a high molecular weight (HMW) are consistently more efficient than versions with lower molecular weight (LMW).13Altman RD Bedi A Karlsson J et al.Product differences in intra-articular hyaluronic acids for osteoarthritis of the knee.Am J Sports Med. 2016; 44: 2158-216510.1177/0363546515609599Crossref PubMed Scopus (98) Google Scholar For example, HMW intra-articular HA produces results which, by its own criteria, AAOS should classify as ‘significant’. The value of the Altman paper is that the pooled results for HMW analysis were derived from 11 randomised controlled trials, which included 2094 patients. LMW analysis was derived from 15 trials of 2639 patients. The numbers take out product bias. Why has HMW better results then HMW? Among others, HMW means a higher concentration of active HA molecules per injected volume. A normal knee joint contains on average 2 mL synovial fluid, containing HA with a MW of 800 kDaltons.14Agerup B Berg P Akermark C Non-animal stabilized hyaluronic acid: a new formulation for the treatment of osteoarthritis.BioDrugs. 2005; 19: 23-30Crossref PubMed Scopus (43) Google Scholar Such HA is produced by chondrocytes and synovial cells and has a half-life of about 8 days. The half-life of unmodified commercial hyaluronan, however, is less than 24 hours.15Boettger MK Kümmel D Harrison A et al.Evaluation of long-term antinociceptive properties of stabilized hyaluronic acid preparation (NASHA) in an animal model of repetitive joint pain.Arthritis Res Ther. 2011; 13: R11010.1186/ar3394Crossref PubMed Scopus (24) Google Scholar Manufacturers have tried to increase the half-life time of their injectables, therefore making it more difficult to leave the joint. They achieved this by cross-linking. Cross-linking increases the HA half-life time to 28–32 days. Cross-linking thus has greatly increased the residence time in the joint. What does all this mean? It means that a single injection (of cross-linked HMW) HA can produce a lasting result, compared with 5 weekly injections of a shorter half-life version. It is easier for the patients, cheaper and less of a burden for the system. Do all patients benefit from intra-articular HA? It seems that some respond more robustly than others, and these ‘good responders’ continue to respond to subsequent injections. Good clinical practice, therefore, requires common sense and a careful patient assessment.16Bruyère O Cooper C Pelletier JP et al.A consensus statement on the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) algorithm for the management of knee osteoarthritis-From evidence-based medicine to the real-life setting.Semin Arthritis Rheum. 2016; 45: S3-1110.1016/j.semarthrit.2015.11.010Crossref PubMed Scopus (173) Google Scholar However, intra-articular HA should definitely be included in the treatment algorithm for patients with Kellgren Grade II and III, before surgical interventions are recommended. We strongly recommend that AAOS revises its position about HA for patients with Kellgren Grade II and Grade III. If not for all HA, then at least for the second generation HMW cross-linked versions.
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