Background: The economic impact of intra-articular hyaluronic acid (IAHA) for the treatment of knee pain associated with osteoarthritis (OA) has been evaluated in the United States, but not systematically summarized. Objective: We reviewed the literature to determine the economic impact of IAHA for pain associated with knee OA in the United States. Methods: A literature review was performed in PubMed (including MEDLINE and MEDLINE In-Process), Embase, the Cochrane Database of Systematic Reviews, and National Health Service Economic Evaluation Database and was limited to English language human studies published from January 2000 to October 2020. Results: The literature search identified 215 unique abstracts; of these, 47 were selected for full-text review and 21 studies met the inclusion criteria. Intra-articular hyaluronic acid injections delayed progression to total knee arthroplasty (TKA), and repeated courses of treatment successfully delayed TKA by more than 5 years. Intra-articular hyaluronic acid was found to reduce the use of pain medications overall and reduce the number of patients receiving opioid prescriptions by 6% ( P < .001). Several studies showed that IAHA is more cost-effective in treating pain associated with knee OA compared with conventional care with nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics, and corticosteroids, and several authors concluded that IAHA should be the dominant treatment strategy. Conclusions: Current studies suggest that IAHA may reduce the use of pain medications, such as NSAIDs and opioids, and impact time to TKA procedures, thus potentially decreasing overall treatment costs of knee OA over time. Furthermore, IAHA was determined to be cost-effective against NSAIDs, corticosteroids, analgesics, and conservative treatment. As the safety and efficacy of IAHA for knee OA have been well established, the findings from our literature review may be used to inform future economic evaluations.

Objective The objective of this systematic review and meta-analysis was to report the safety of intra-articular hyaluronic acid (IAHA) in patients with symptomatic knee osteoarthritis (OA). Methods We identified randomized controlled trials reporting the safety of IAHA versus IA saline in adults with symptomatic knee OA. Main safety outcomes were adverse events (AEs), local AEs, serious adverse events (SAEs), study withdrawals, and AE-related study withdrawals. Results A total of 35 randomized controlled trials with 38 group comparisons comprising 8,078 unique patients (IAHA: 4,295, IA saline: 3,783) were included in the meta-analysis. Comparing IAHA with IA saline over a median of 6 months follow-up, there were no differences in the risk of AEs (42.4% vs. 39.7%, risk ratio [RR] = 1.01, 95% CI = 0.96-1.07, P = 0.61), SAEs (1.8% vs. 1.2%, RR = 1.44, 95% CI = 0.91-2.26, P=0.12), study withdrawals (12.3% vs. 12.7%, RR = 0.99, 95% CI = 0.87-1.12, P = 0.83), or AE-related study withdrawals (2.7% vs. 2.1%, RR = 1.37, 95% CI = 0.97-1.93, P = 0.08). Local AEs, all of which were nonserious, were more common with IAHA vs. IA saline (14.5% vs. 11.7%, RR = 1.21, 95% CI = 1.07-1.36, P = 0.003) and typically resolved within days. Conclusion IAHA was shown to be safe for use in patients with symptomatic knee OA. Compared with IA saline, IAHA is associated with an increased risk of nonserious, transient local reactions. There was no evidence to suggest any additional safety risks of IAHA.

Pain management and injury repair represent areas of significant clinical unmet need in Orthopedics and Sports medicine, especially in the management of chronic and degenerative connective tissue diseases such as osteoarthritis and tendinopathies.

AIM:To determine the efficacy of platelet-rich plasma (PRP) injections for symptomatic tendinopathy.DESIGN:Systematic review of randomised, injection-controlled trials with meta-analysis.DATA SOURCES:Systematic searches of MEDLINE and EMBASE, supplemented by manual searches.ELIGIBILITY CRITERIA FOR SELECTING STUDIES:Randomised controlled trials with 3 months minimum follow-up that evaluated pain reduction with PRP versus control (saline, local anaesthetic, corticosteroid) injections in patients with symptomatic tendinopathy.RESULTS:A total of 16 randomised controlled trials (18 groups) of PRP versus control were included. Median sample size was 35 patients, a study size that would require an effect size ≥1.0 to achieve statistical significance. PRP was more efficacious than control in reducing tendinopathy pain, with an effect size of 0.47 (95% CI 0.22 to 0.72, p<0.001), signifying a moderate treatment effect. Heterogeneity among studies was moderate (I2=67%, p<0.001). In subgroup analysis and meta-regression, studies with a higher proportion of female patients were associated with greater treatment benefits with PRP.CONCLUSIONS:Injection of PRP is more efficacious than control injections in patients with symptomatic tendinopathy.

Osteoarthritis (OA) is the most commonly encountered degenerative joint disorder in clinical medicine and the pain and stiffness caused by osteoarthritis represents a leading cause of physical disability in individuals of retirement age. Treatment options for OA patients are limited and largely targeted to pain management. Such is the mechanism behind the most commonly prescribed OA therapies including acetaminophen, NSAIDs, opioids, and steroids. However, these palliative pain management tools do not address the underlying pathophysiology of OA disease. This leaves a significant clinical unmet need for disease modifying OA therapies. Growth factor therapies and regenerative medicine strategies are emerging as promising alternatives to palliative care because these treatments bring significant potential to control chronic inflammation, enhance cartilage repair, and restore other joint tissues to a healthy state. Interestingly, a Clinicaltrials.gov search using the terms “osteoarthritis” and “growth factor” identified 43 relevant studies. Of these, only 26% used growth factor therapies directly, including FGF-18, BMP-2, and transgenic human chondrocytes producing TGF-b1. 23% of the studies were dedicated to inhibitors of NGF. The overwhelming majority of studies (47%) used autologous blood products, especially platelet rich plasma (PRP), which constituted 33% of the total studies. This was interesting because although platelets in PRP do indeed harbor large quantities of different growth factors that can affect the status of the treated tissue, growth factors represent only a single aspect of the bioactivity of platelets. Furthermore, platelets represent only one aspect of the potential bioactivity of PRP. Depending upon the methods used for PRP generation, it may also contain other physiologically important components of the whole blood from which it is derived. Recent studies indicate non-platelet components of whole blood such as red blood cells and leukocytes are essential for normal platelet function, including growth factor release. Therefore, this narrative review discusses PRP from a physiological context that explores beyond platelet growth factors to encompass and illuminate roles of non-platelet cells in the bioactivity of PRP, and how these additional mechanisms lead to the conclusion that PRP can be much more than a growth factor therapy.

BACKGROUND:Therapeutic success of platelet-rich plasma (PRP) may vary based on the composition and preparation method. The objective of this study was to evaluate the cellular components of platelet concentrates produced by a leucocyte-rich (LR-PRP) and a leucocyte-poor PRP systems (LP-PRP).METHODS:Parameters evaluated included platelet recovery, platelet concentration, red blood cell (RBC) and white blood cell (WBC) composition, platelet growth factor release and stimulation of human tendon cell proliferation in vitro.RESULTS:Platelet recoveries were 52% for LP-PRP and 89% for LR-PRP. LR-PRP demonstrated greater reproducibility with a 4.2% coefficient of variation (CV) compared with 19.4% for LP-PRP (p<0.001). LR-PRP demonstrated a greater increase in platelet concentration (7.9-fold) than LP-PRP (2.2-fold; p<0.001). LP-PRP showed 5.0-fold reductions in WBCs, while LR-PRP showed a 4.0-fold increase (p<0.001). LP-PRP reduced RBCs to a haematocrit of 0.25, while LR-PRP reduced haematocrit to 11.8. LP-PRP did not coagulate robustly on reactivation with CaCl2, and released significantly lower levels of epidermal growth factor (EGF) and transforming growth factor β1 (TGF-β1) than whole blood (p<0.03). LP-PRP also did not stimulate tendon cell proliferation greater than whole blood. In contrast, LR-PRP showed increases in each growth factor on activation with CaCl2 (p<0.01) and stimulated greater proliferation (p<0.05) compared with whole blood. Forced activation of LP-PRP with exogenous thrombin rescued the coagulation deficiency and induced greater growth factor release than comparable whole blood (p<0.03).CONCLUSIONS:These data suggest that non-platelet cellular components in platelet concentrates are important for proper platelet function, including thrombin generation, growth factor release and clot retraction.

Dear Editor: We read the article by Dragoo and colleagues titled ‘‘Comparison of the Acute Inflammatory Response of Two Commercial Platelet-Rich Plasma Systems in Healthy Rabbit Tendons’’ with great interest. The authors conducted the work, which was supported by the manufacturer of the leukocyte-poor platelet-rich plasma (LP-PRP) device, under the premise that leukocyte-rich PRP (LRPRP) would incite a greater acute inflammatory response to the detriment of the treated tissue than LP-PRP, based on the results of in vitro studies. However there is an everexpanding body of primary clinical literature that does not support these findings, and to the contrary, indicates an anti-inflammatory and pain relieving therapeutic effect of LR-PRP in tendinopathy (reviewed in Fitzpatrick et al) and in osteoarthritic patients (reviewed in Chang et al, Khoshbin et al, and Laudy et al). Much of the primary literature comprising these systematic reviews was available at the time that this article was published, however those findings were not considered by Dragoo et al when conceiving their study, nor was this body of evidence adequately addressed in their discussion. In fact, the results of more recent studies and systematic reviews clearly indicate that LR-PRP gives a greater patient benefit in tendinopathy as well as in osteoarthritis than does LP-PRP. The objective of the rabbit study by Dragoo and colleagues was to evaluate the inflammatory effect of LRPRP versus LP-PRP after intratendinous patellar tendon injection. The outcome measures employed were based on standard tissue histopathological analysis using only hematoxylin and eosin (H&E) staining at 5 and 14 days after injection. Therefore, the entire study relied on the assumption that leukocyte detection in extravascular tissues 5 days after injection is indicative of an acute inflammatory reaction leading to the recruitment of leukocytes from the circulation into the injected tissue. The 5-day time point was chosen based on a typical rabbit leukocyte lifespan of less than 5 days, supposing that at this time point only recruited leukocytes would be present in the injected tissue. Literature from in vitro studies does indeed support a short lifespan of isolated granulocytes, however it has also been well established that a multitude of plateletand leukocyte-derived growth factors, chemokines, and inflammatory mediators increase the granulocyte lifespan several fold (reviewed in Kolaczkowska and Kubes as well as Mantovani et al), leading to a neutrophil halflife of over 5 days. In addition, the major leukocytes in rabbit blood are mononuclear cells, not granulocytes, representing approximately 70% of the total cells. These mononuclear leukocytes have a lifespan of at least 2 weeks. Therefore, there is an inherent and obvious problem with the assumption that leukocyte detection in extravascular tissues 5 days after injection is indicative of an acute inflammatory reaction. Standard H&E staining cannot distinguish between activated leukocytes that may have been recruited to the injection site from the circulation (properly interpreted as an inflammatory reaction) and the naı̈ve resting leukocytes that were concentrated into the LR-PRP (Table 3 of Dragoo et al) and introduced to the tissue via injection. Because the authors did not validate the disappearance of injected leukocytes 5 days after injection or differentially label cells to distinguish between recruited and injected populations, it was not established that any of the leukocytes observed in the LR-PRP– injected tissue were actually recruited from the circulation to the injection site. This deficiency leaves any conclusions with respect to inflammatory reactions due to LR-PRP factually baseless and invalid. Thus, the only conclusion that can be made from the standard histopathology in this case is that LR-PRP containing concentrated leukocytes was indeed injected into the tissue. To the contrary, because LP-PRP showed a lack of leukocytes in the tissue at 5 days after injection, the finding of a large leukocyte infiltration at day 14 does indeed signify that a robust, albeit not acute, inflammatory reaction occurred. However, since the sterile saline control showed a similar robust inflammatory reaction on day 14, no specific conclusions regarding inflammatory effects of LP-PRP could be valid either. As other authors have not reported similar effects of saline injections into rabbit tendon tissue, it is possible that the particular model and/or injection paradigm used in the Dragoo et al study is inappropriate for studying inflammatory reactions. The lack of leukocytes in the LP-PRP–injected tissue at 5 days after injection is also of great interest because it is well established that acute leukocyte infiltration into damaged tissue is driven primarily by chemokine and cytokine release from activated platelets. This observation would indicate either that platelets in LP-PRP are completely deficient in activation and subsequent degranulation in vivo, as has been shown on in vitro studies, and are therefore incapable of initiating an acute inflammatory reaction required for activating a healing response, or that the tissue samples analyzed for histology were biased against demonstrating leukocyte infiltration that may be perceived as detrimental to the tissue. The authors also biased their statistical analyses by counting white blood cells twice in the tendon scores presented in Tables 4 and 5 of their article; once as individual parameters, and again as the total white blood cell count. It would be of interest to see the statistical analyses once this error is corrected. There is also no specific staining included in the study to determine vascularity, fiber structure, or the degree of fibrosis. Given the apparent pathological state of the tissue as presented in the The American Journal of Sports Medicine, Vol. 44, No. 12 2016 The Author(s)

Dear Editor: We read with interest the network meta-analysis by Riboh and colleagues titled ‘‘Effect of Leukocyte Concentration on the Efficacy of Platelet-Rich Plasma in the Treatment of Knee Osteoarthritis,’’ which compared intra-articular injection of leukocyte-rich platelet-rich plasma (LR-PRP), leukocyte-poor platelet-rich plasma (LP-PRP), and hyaluronic acid (HA) for treatment of knee osteoarthritis (OA). While the authors should be applauded for the considerable effort involved in the conduct of this research, the methodology and conclusions are questionable and warrant further clarification. The primary concern relates to the paucity of available data. The number of studies reporting Western Ontario and McMaster Universities Arthritis Index (WOMAC) outcome scores were 3 for HA, 1 for LR-PRP, 3 for LP-PRP, and 1 for placebo. Similarly, International Knee Documentation Committee (IKDC) scores were provided in 2 HA studies, 3 LR-PRP studies, 2 LP-PRP studies, and 1 placebo study. Lastly, adverse reactions were included for 2 LR-PRP studies, 3 LP-PRP studies, 4 HA studies, and 1 placebo study. Our view is that no valid conclusions can be derived from a network meta-analysis with such limited data. A second concern relates to the method of analyzing WOMAC and IKDC data. For each outcome, the reported statistic was the absolute change from baseline to final follow-up. Yet mean baseline scores in the included studies ranged from 39 to 80 for WOMAC and from 41 to 56 for IKDC. Given these differences in baseline symptom severity among studies, a given absolute WOMAC improvement from a baseline score of 39 has a vastly different interpretation than the same absolute improvement from a baseline of 80. In fact, the likely reason that LP-PRP was deemed most efficacious was because the study with the greatest WOMAC improvement also had an unusually high baseline WOMAC score. A third concern relates to study selection criteria and heterogeneity in patient characteristics. Each of the 3 LR-PRP studies that reported IKDC scores were performed by the same group using the same protocol involving repeat injections with devitalized freeze-thawed PRP, which is not characteristic of clinical practice. Comparing outcomes from studies using freshly isolated LP-PRP comprising living cells with studies that used freezethawed LR-PRP containing dead cells is not appropriate. In addition, the study by Patel et al that compared 1 versus 2 PRP injections in bilateral OA patients and the study by Kon et al that compared lowversus high-molecularweight HA should have been excluded based on the authors’ study selection criteria (exclusion 3). An example of the deleterious synergistic effects of these concerns relative to WOMAC scores is demonstrated in Table 1, which shows extremely limited data and tremendous differences in baseline symptom severity such that reporting absolute improvement as the outcome of interest is flawed and pooling data among studies is questionable. The main findings of this network metaanalysis are dominated by outcomes where no or limited direct evidence is available, which suggests high risk of bias. Inclusion of nonrandomized trials in this systematic review compounds this risk. Finally, since all surface under the cumulative ranking curve (SUCRA) data were derived from the pooled meta-analysis data that suffer from these same data limitations, the SUCRA data should be considered unreliable. In summary, a more appropriate conclusion to this manuscript would have been that conduct of a network metaanalysis is inappropriate and no reasonable conclusions can be drawn regarding the effect of leukocyte concentration on the safety and efficacy of PRP in knee osteoarthritis.

PM&RVolume 7, Issue 7 p. 792-793 Letter to the Editor Re: Use of Platelet-Rich Plasma in Intra-Articular Knee Injections for Osteoarthritis William R. Parrish PhD, William R. Parrish PhD DePuy Synthes, Inc., Mitek Sports Medicine, Raynham, MA Disclosure: employed by DePuy Synthes Mitek Sports Medicine, a Johnson & Johnson CompanySearch for more papers by this authorMichael Mafilios BA, Michael Mafilios BA Health Economics Associates LLC, San Diego, CA Disclosure: nothing to discloseSearch for more papers by this authorSamir Bhattacharyya PhD, Samir Bhattacharyya PhD DePuy Synthes, Inc., Mitek Sports Medicine, Raynham, MA Disclosure: employed by DePuy Synthes Mitek Sports Medicine, a Johnson & Johnson CompanySearch for more papers by this author William R. Parrish PhD, William R. Parrish PhD DePuy Synthes, Inc., Mitek Sports Medicine, Raynham, MA Disclosure: employed by DePuy Synthes Mitek Sports Medicine, a Johnson & Johnson CompanySearch for more papers by this authorMichael Mafilios BA, Michael Mafilios BA Health Economics Associates LLC, San Diego, CA Disclosure: nothing to discloseSearch for more papers by this authorSamir Bhattacharyya PhD, Samir Bhattacharyya PhD DePuy Synthes, Inc., Mitek Sports Medicine, Raynham, MA Disclosure: employed by DePuy Synthes Mitek Sports Medicine, a Johnson & Johnson CompanySearch for more papers by this author First published: 18 June 2015 https://doi.org/10.1016/j.pmrj.2015.05.025 Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. Volume7, Issue7July 2015Pages 792-793 RelatedInformation

Objective: Investigation of osteoarthritis (OA) risk alleles suggests that reduced levels of growth and differentiation factor-5 (GDF5) may be a precipitating factor in OA. We hypothesized that intra-articular recombinant human GDF5 (rhGDF5) supplementation to the OA joint may alter disease progression.Methods: A rat medial meniscus transection (MMT) joint instability OA model was used. Animals received either one intra-articular injection, or two or three bi-weekly intra-articular injections of either 30 mu g or 100 mu g of rhGDF5 beginning on day 21 post surgery after structural pathology had been established. Nine weeks after MMT surgery, joints were processed for histological analysis following staining with toluidine blue. Control groups received intra-articular vehicle injections, comprising a glycine-buffered trehalose solution. OA changes in the joint were evaluated using histopathological end points that were collected by a pathologist who was blinded to treatment.Results: Intra-articular rhGDF5 supplementation reduced cartilage lesions on the medial tibial plateau in a dose-dependent manner when administered therapeutically to intercept OA disease progression. A single 100 mu g rhGDF5 injection on day 21 slowed disease progression at day 63. A similar effect was achieved with two bi-weekly injections of 30 mu g. Two bi-weekly injections of 100 mu g or three bi-weekly injections of 30 mu g stopped progression of cartilage lesions. Importantly, three biweekly injections of 100 mu g rhGDF5 stimulated significant cartilage repair.Conclusions: Intra-articular rhGDF5 supplementation can prevent and even reverse OA disease progression in the rat MMT OA model. Collectively, these results support rhGDF5 supplementation as an intra-articular disease modifying OA therapy. (C) 2016 The Author(s). Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International.