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Objective: To directly compare clinical and MRI outcomes of multiple intra-articular injections of adipose-derived stromal cells (ASCs) or platelet-rich plasma (PRP) in patients with knee osteoarthritis (OA)., Design: We retrospectively compared 24-month outcomes in (1) 27 patients receiving 3-monthly intra-articular injections with a total of 43.8 million ASCs and (2) 23 patients receiving 3-monthly injections of 3-ml preparation of PRP. All patients had Kellgren-Lawrence grade 1, 2, or 3 knee OA with failed conservative medical therapy. The Numeric Pain Rating Scale (NPRS) scores; Knee injury and Osteoarthritis Outcome Score (KOOS) at baseline, 6, 12, and 24 months after the first injection; and the MRI Osteoarthritis Knee Score (MOAKS) at 12 and 24 months were considered as outcomes., Results: No major complications occurred in any patient. Both groups significantly improved in pain NPRS score and KOOS at 6 months. At 12- and 24-month evaluations, the ASC group significantly decreased scores to a greater degree ( P < 0.001) than the PRP group. MOAKS scores indicated a decrease in disease progression in the ASC group., Conclusion: Both ASCs and PRP were safe and resulted in clinical improvement in patients with knee OA at 6 months; however, at 12 and 24 months, ASCs outperformed leukocyte-poor PRP in clinical and radiological outcomes., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: To evaluate the safety and efficacy of platelet-rich plasma (PRP) intra-articular injective treatments for ankle osteoarthritis (OA)., Methods: A systematic literature search was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines in PubMed, Scopus, Embase, Google Scholar, and the Cochrane library until May 2022. Both randomized and non-randomized studies were included with the assessment of the risk of bias. We recorded the participant's age, gender, type of PRP, injection volume, the kit used, and activating agent. We subsequently assessed the short-term and long-term efficacy of PRP using the functional scores and visual analog scale (VAS)., Results: We included four studies with a total of 127 patients, with a mean age of 56.1 years. 47.2% were male (60/127), according to eligibility criteria. There were three cohort studies and one randomized controlled trial (RCT) study, and no study reported severe adverse events. All included studies used the Leukocyte-poor PRP. Short-term follow-up results suggested significant improvement of the American Orthopaedic Foot and Ankle Society (AOFAS) score in the PRP injection group compared to the control group (n = 87 patients; MD: 6.94 [95% CI: 3.59, 10.29]; P < 0.01). Consistently, there was a statistical difference in AOFAS score between PRP injection and control groups in the final follow-up (≥ 6 months) (n = 87 patients; MD: 9.63 [95% CI: 6.31, 12.94]; P < 0.01). Furthermore, we found a significant reduction in VAS scores in the PRP groups at both the short-term follow-up (n = 59 patients; MD, - 1.90 [95% CI, - 2.54, - 1.26]; P < 0.01) and the ≥ six months follow-up (n = 79 patients; MD, - 3.07 [95% CI, - 5.08, - 1.05]; P < 0.01). The improvement of AOFAS and VAS scores at ≥ six months follow-up reached the minimal clinically important difference (MCID). Nevertheless, the treatment effect of AOFAS and VAS scores offered by PRP at short-term follow-up did not exceed the MCID. Substantial heterogeneity was reported at the ≥ six months follow-up in VAS scores (I 2 : 93%, P < 0.01)., Conclusion: This meta-analysis supports the safety of PRP intra-articular injection for ankle OA. The improvements of AOFAS and VAS scores in the PRP group at short-term follow-up do not exceed the MCID to be clinically significant. PRP injection provides significant improvement of AOFAS score and reduced pain at ≥ six months follow-up. The efficacy of PRP should be interpreted with caution regarding the high heterogeneity and the scarcity of available literature, which urges large-scale RCTs with longer follow-up to confirm the potential efficacy of PRP injection for ankle OA., (© 2023. The Author(s) under exclusive licence to SICOT aisbl.)

Background: The aim of the study was to investigate the effect of platelet-rich plasma (PRP) on subchondral bone marrow edema (BME) and the level of biomarkers in synovial fluid of the knee osteoarthritis., Methods: Eighty-one patients with symptomatic knee osteoarthritis were randomly divided into two groups according to the number of inpatients. Forty-five cases were treated with intra-articular injection of PRP (PRP group), 36 cases were treated with sodium hyaluronate (SH group), and the clinical effects were evaluated using the Visual Analogue Scale (VAS) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores. The changes of subchondral BME were assessed by magnetic resonance imaging (MRI) before and after treatment. The levels of TNFα, IL-6, MCP-1, MMP-1, MMP-3, and MMP-9 in synovial fluid were also detected., Results: All the patients completed the corresponding treatment and were followed up for 12 months without serious complications. After the treatment, the VAS and WOMAC scores of the two groups were significantly decreased, and the difference was statistically significant at different time points (P < 0.05). The VAS and WOMAC scores of the PRP group were better than those of the SH group (P < 0.05). MRI showed that the subchondral bone edema of the two groups were reduced in varying degrees, and the reduction was more noticeable in the PRP group (P < 0.05). The levels of TNFα, IL-6, MCP-1, MMP-1, MMP-3, and MMP-9 in two groups were decreased, and the difference was statistically significant at different time points (P < 0.05). However, the levels of TNFα, IL-6, MCP-1, MMP-1, MMP-3, and MMP-9 in the PRP group were significantly lower than those in the SH group (P < 0.05)., Conclusions: Intra-articular injection of PRP can significantly reduce the subchondral BME and the level of biomarkers in synovial fluid of the symptomatic knee osteoarthritis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: Knee arthropathy causes pain to people with hemophilia (PWH). One of the current controversies is whether injections of intra-articular platelet-rich plasma (PRP) are effective in relieving the knee pain of PWH., Areas Covered: A narrative literature review was conducted on the efficacy of PRP injections in the knees of PWH., Expert Opinion: Intra-articular PRP knee injections are widely used in patients with knee osteoarthritis to relieve pain and delay total knee arthroplasty. Although numerous publications have supported the use of PRP in knee osteoarthritis, there is still major controversy regarding its true usefulness, given that a number of studies with a high degree of evidence have failed to show the efficacy of PRP. With respect to painful hemophilic arthropathy, the use of PRP injections is even more controversial, as there are only four publications on the subject supporting the use of PRP in hemophilia, all of them with a low degree of evidence. A publication with grade 1 evidence recommended against the use of PRP in hemophilic arthropathy because its efficacy has not been demonstrated. My opinion is that intra-articular PRP injections should not be used in hemophilia until there is more evidence of its benefits.

Background: Knee osteoarthritis (OA) is a common, chronic, progressive and degenerative disease which affects patients' quality of life and may cause disability and social isolation. OA is a huge economic burden for the patient and a large strain for the whole healthcare system. Articular cartilage has a small potential to repair, with progressively more clinicians emphasizing cellular therapy. Subcutaneous fat tissue in human body is a large reservoir of mesenchymal stem cells (MSCs) and is been harvested in minimally invasive, simple procedure. The purpose of this study was to define a specific group of patients with knee osteoarthritis, who are the most likely to benefit from the treatment with intra-articular injection of an autologous adipose tissue (AAT)., Methods: From 2016 to 2018, 59 symptomatic bilateral and unilateral knee OA patients were treated with a single intra-articular (IA) injection of an autologous adipose tissue (AAT). Before the treatment and at the follow-up, the participant was asked to fulfill the Knee Injury and Osteoarthritis Outcome Score (KOOS), the International Knee Documentation Committee 2000 (IKDC 2000), The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), the Health Questionnaire EQ-5D-5L and to quantify the pain in the affected joint with a Numeric Rating Scale (NRS). Moreover, the patients were asked to: (i) assess their satisfaction with the effects of the conducted treatment: from 0 (unsatisfied) to 10 (very satisfied), (ii) describe the rehabilitation, if it was performed (supervised or individual and duration in weeks) and (iii) indicate any additional treatment applied, like IA injections of hyaluronic acid (HA) or platelet-rich plasma (PRP), knee arthroscopy, partial or total knee arthroplasty (TKA) at the follow-up., Results: The mean age of 37 participants (16 males and 21 females) included into statistical analysis was 57.78 ± 7.39 years, the mean BMI was 31.30 ± 7.51. The questionnaires were fulfilled after the average follow-up time of 27 ± 6.5 months. A significant difference (p < 0.05) compared with the baseline, was observed in pain [NRS], WOMAC, KOOS index, pain, symptoms, ADL, Sport and Rec, QoL, EQ-5D-5L index. The satisfaction in the whole group was 6.16 ± 3.07. There was no significant difference between satisfied and unsatisfied patients in BMI and pain [NRS] at the baseline. 6 out of 7 patients with stage IV in K-L were unsatisfied with the effects of the treatment with AAT., Discussion: The main conclusion of this study is that the patients with stage II of the knee OA with normal BMI are were most likely to benefit from IA injection of AAT, in contrast to the patients with stage IV, who will not beware not satisfied with the effectiveness of this kind of treatment. There were no adverse events reported at the donor site as well as in the treated knee joints., (© 2021. The Author(s).)

This study aimed to evaluate the clinical effects of hyaluronic acid (HA), platelet-rich plasma (PRP), and platelet-rich fibrin (I-PRF) injections in the internal derangement of the temporomandibular joint. Adult patients who had failed to respond to nonsurgical treatment were were included in the study. The patients were divided into three treatment groups according to the given substance: 1) HA administration three times in a row on a weekly basis, 2) a single dose of PRP, or 3) a single dose of I-PRF. Clinical assessment was performed preoperatively and 6 and 12 months after the treatment, including maximal mouth opening (MMO) and pain level (Visual Analog Scale). Low and high molecular weight (HA L , HA H ) hyaluronic acid forms were also compared. 68 adult patients, with a total of 109 joints were included in the study. The mean age was 53 ± 16 years. The statistical analysis showed a significant improvement in MMO in the HA group (p < 0.01). The pain level significantly decreased in all treatment groups (p HA,PRP,I-PRF <0.01). Comparing HA L and HA H forms, no significant difference was found in the evaluation of MMO and VAS values. Within the limitations of the study it seems that due to the similar effects of HA and the autologous blood substances, the platelet concentrates should be preferred in the intra-articular treatment in order to reduce the risk of possible adverse effects., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest and the study received no support from industry or other similar resources., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Platelet-rich plasma (PRP) usage in orthopedics continues to rise, despite guidelines suggesting non-superiority to comparative cohorts. Therefore, we performed a systematic review and meta-analysis on PRP efficacy using two clinical assessments: (1) Visual Analog Scale and (2) Western Ontario and McMaster Universities Osteoarthritis Index. We assessed consistency and clinical relevancy by determining study heterogeneity (eg, sample sizes, ages, body mass index, arthritic severities, etc.). Comparative cohorts were: (A) hyaluronic acid (HA); (B) corticosteroid (CS); (C) normal saline (NS); and (D) exercise therapy. We performed sub-analyses of structural changes assessed on ultrasound, radiograph, or magnetic resonance imaging ., Methods: We utilized PubMed, Cochrane Library, and Embase databases up to December 1, 2021, according to Preferred Reporting Items for Systematic-Reviews and Meta-Analyses guidelines. Twenty-four studies met criteria, with comparisons to: HA (n = 11); CS (n = 6); NS (n = 5); and exercise therapy (n = 3). Seven studies assessed structural changes. Evaluations utilized a methodological scoring system. I 2 statistics and forest plots pooled analyses and delineated study results., Results: PRP led to Visual Analog Scale and Western Ontario and McMaster Universities Osteoarthritis Index improvements in most studies when compared to HA, CS, and NS (P ≤ .05). Comparison to exercise therapy resulted in inconclusive findings (P ≥ .05). However, substantial heterogeneity (I 2 ≥ 76%) was reported due to study variability. No differences were found when assessing structural changes or cartilage thickness by magnetic resonance imaging (standardized mean difference -0.01 [-0.19, 0.18], P = .91)., Conclusions: PRP may be associated with pain and functional improvements but was not clinically relevant (inconsistent study- and patient-metrics). In addition, PRP did not confer superiority when assessing knee-related structural changes., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The osteoarthritis (OA) symptoms cannot be fully remedied by using only a single functional component because of its complex pathogenesis. Herein, a MnO 2 nanozyme-encapsulated hydrogel was fabricated via dispersing bovine serum albumin (BSA)-MnO 2 (BM) nanoparticles (NPs) into a hyaluronic acid (HA)/platelet-rich plasma (PRP) gel network crosslinked by Schiff base reaction. Due to the self-healing and pH-responsive properties of Schiff base bonds, the hydrogel not only functioned as viscosupplementation but also exhibited pH-responsive release of BM NPs and growth factors in PRP. The BM NPs could attenuate the severe oxidative stress, and the PRP could promote chondrocyte proliferation. In a rat OA model, the HA/PRP/BM hydrogel markedly suppressed cartilage matrix degradation. Both the in vitro and in vivo studies showed that this novel hydrogel platform could inhibit the development of osteoarthritis through a synergetic effect of mechanical dissipation, depressing inflammation, facilitating cartilage repair, and thus has essential application prospects in OA treatment., (Copyright © 2021. Published by Elsevier Ltd.)

Objective: Using stringent inclusion criteria, a double-blinded study protocol, and fluoroscopically guided injections, we compare intra-articular sacroiliac joint platelet-rich plasma injections with intra-articular steroids., Design: Double-blind, randomized controlled trial., Setting: Two large university-based interdisciplinary spine centers., Subjects: A total of 26 patients with a positive diagnostic block (>80% relief)., Methods: Subjects who had a positive diagnostic block were randomized to undergo either a fluoroscopically guided intra-articular injection of steroid or a platelet-rich plasma injection. Follow-up was at 1 month, 3 months, and 6 months. Outcomes included level of pain, as indicated on a 0- to 100-mm numeric pain rating scale, and functional disability score, obtained via the Oswestry Disability Index (ODI)., Results: At 1, 3, and 6 months, both groups improved; however, subjects who received steroid injections reported lower pain scores than did subjects who received platelet-rich plasma. Using categorical data, we observed significantly more responders (defined as pain scores that improved by 50% or more from baseline) at 1 and 3 months in the group who received steroids than in the group who received platelet-rich plasma., Conclusion: Although both groups showed improvements in pain and function, the steroid group had significantly greater response and significantly more responders than did the platelet-rich plasma group., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: To compare the effectiveness of intra-articular injection (IAI) of Platelet-Rich Plasma (PRP) with Triamcinolone Hexacetonide (TH) and Saline Solution (SS), in patients with knee osteoarthritis (OA)., Design: A randomized controlled trial, with blinded patients and assessor., Setting: Outpatient rheumatology service., Subjects: Patients with knee osteoarthritis grades II and III., Interventions: Patients received IAI with PRP, 40 mg TH, or SS., Methods: Patients were assessed at baseline and after 4, 8, 12 e 52 weeks with: visual analogue scale (VAS) for pain at rest and movement, WOMAC questionnaire, Timed to Up and Go test, 6-min walk test, percentage of improvement, goniometry, quality of life SF-36 questionnaire, Likert scale and Kelgreen & Lawrence (KL) radiographic scale (only at baseline and 52 weeks)., Results: 100 patients were studied, with a mean age of 67.13(6.56) years. The TH group was superior for: percentage of improvement (versus SS group from 4 to 52 weeks); WOMAC total and pain (versus PRP group at 4 weeks); and WOMAC stiffness (versus SS group at 12 weeks). The SS group was inferior for WOMAC function (from 8 to 52 weeks). The PRP group showed lowest radiographic progression [TH 17 (51.51%) to 24 (72.72%); SS 17 (51.51%) to 30 (90.90%); PRP 20 (58.82%) to 21 (61.76%)]., Conclusion: The Triamcinolone Hexacetonide group was superior for percentage of improvement and WOMAC, pain and stiffness. For the WOMAC function, the Platelet-Rich Plasma group and Triamcinolone Hexacetonide group were superior to the Saline group. The Platelet-Rich Plasma group showed the lowest radiographic progression at 52 weeks of follow-up.

Background: Osteoarthritis of the knee is a chronic inflammatory condition resulting in significant patient disability, with intra-articular platelet rich plasma (PRP) injections having shown potential to improve symptomatic outcomes. This retrospective cohort pilot study aimed to observe whether PRP injections were beneficial in the symptomatic management of knee osteoarthritis in an Australian population, based on patient reported outcomes. An additional aim was to observe for an association between the number of injections and patient characteristics, such as body mass index, age, sex and radiologically determined severity of the disease., Methods: The cohort was drawn from those who attended Ballarat Orthopaedic and Sports Medicine for PRP injections and who had completed the appropriate pre- and post-injection Western Ontario and McMaster Universities Arthritis Index (WOMAC) questionnaire. WOMAC scores were analysed to observe for any difference following a course of PRP injections., Results: The data suggest that the use of PRP improved patient reported WOMAC scores. Additionally, it was shown that two injections had a greater effect than one injection, with a third injection providing no further benefit. Finally, there was an association with lower WOMAC scores post PRP therapy amongst male participants compared to female participants., Conclusion: These results suggest two PRP injections are optimal for the symptomatic management of knee osteoarthritis, identifying a need for further prospective research in this Australian population., (© 2022 Royal Australasian College of Surgeons.)

Osteoarthritis (OA) is a progressive degenerative disease that manifests as pain and inflammation and often results in total joint replacement. There is significant interest in understanding how intra-articular injections made from autologous blood or bone marrow could alleviate symptoms and potentially intervene in the progression of the disease. There is in vitro an in vivo evidence that suggests that these therapies, including platelet-rich plasma (PRP), autologous anti-inflammatories (AAIs), and concentrated bone marrow aspirate (cBMA), can interrupt cartilage matrix degradation driven by pro-inflammatory cytokines. This review analyzes the evidence for and against inclusion of white blood cells, the potential role of platelets, and the less studied potential role of blood plasma when combining these components to create an autologous point-of-care therapy to treat OA. There has been significant focus on the differences between the various autologous therapies. However, evidence suggests that there may be more in common between groups and perhaps we should be thinking of these therapies on a spectrum of the same technology, each providing significant levels of anti-inflammatory cytokines that can be antagonists against the inflammatory cytokines driving OA symptoms and progression. While clinical data have demonstrated symptom alleviation, more studies will need to be conducted to determine whether these preclinical disease-modifying findings translate into clinical practice.

Background and objectives : Knee osteoarthritis (KO) is one of the most common joint diseases, determining knee pain and reduction of mobility, with a negative effect on quality of life. Intra-articular injections of different formulations of platelet-rich plasma (PRP) are an increasingly common non-surgical treatment for KO. Recently, in order to combine the anti-inflammatory effect of platelet rich plasma and the viscosupplementation effect of hyaluronic acid, a formulation of PRP combined with hyaluronic acid (PRP + HA) has been proposed. The purpose of this study is to retrospectively compare the effectiveness of plasma with high concentration of platelets and leukocytes (L-PRP) with PRP + HA in patients with mild to moderate (Kellgren-Lawrence scale II-III grade) KO. Materials and Methods : Among the 51 patients included, 28 have been treated with L-PRP, while 23 with PRP + HA. A retrospective evaluation at baseline (T0), after 3 months (T1) and 1 year (T2) has been performed. The outcome analyzed are the Knee Society Score (KSS), the Visuo Analogic Scale (VAS) (at T0, T1, and T2) and the Knee Injury and Osteoarthritis Outcome Score (KOOS) (T0 and T2). We evaluated change in mean scores within and between groups among different time points using repeated measures ANCOVA. Results : Although the two treatments have been both effective in reducing VAS, the group treated with PRP + HA showed a significantly lower KSS. Conclusions : Our results show that the use of both treatments may help to reduce pain in patients with mild to moderate KO. PRP + HA showed better results in improving knee mobility and function. These results should be considered only preliminary: Further research is needed to completely describe the clinical effectiveness of these formulations.

Various systematic reviews have recently shown that intra-articular platelet-rich plasma (IA-PRP) can lead to symptomatic relief of knee osteoarthritis for up to 12 months. There exist limited data on its use in small joints, such as the trapeziometacarpal joint (TMJ) or carpometacarpal joint (CMCJ) of the thumb. A prospective, randomized, blind, controlled, clinical trial of 33 patients with clinical and radiographic osteoarthritis of the TMJ (grades: I-III according to the Eaton and Littler classification) was conducted. Group A patients (16 patients) received 2 ultrasound-guided IA-PRP injections, while group B patients (17 patients) received 2 ultrasound-guided intra-articular methylprednisolone and lidocaine injections at a 2-week interval. Patients were evaluated prior to and at 3 and 12 months after the second injection using the visual analogue scale (VAS) 100/100, shortened Disabilities of the Arm, Shoulder, and Hand Questionnaire (Q-DASH), and patient's subjective satisfaction. No significant differences between the baseline clinical and demographic characteristics of the 2 groups were identified. After 12 months' follow-up, the IA-PRP treatment has yielded significantly better results in comparison with the corticosteroids, in terms of VAS score ( P = 0.015), Q-DASH score ( P = 0.025), and patients' satisfaction ( P = 0.002). Corticosteroids offer short-term relief of symptoms, but IA-PRP might achieve a lasting effect of up to 12 months in the treatment of early to moderate symptomatic TMJ arthritis.

Background: Base of the thumb osteoarthritis (OA) represents a challenge to clinicians due to limited efficient treatment options. Local injection treatment is a good choice for its low systemic side effects and rapid improvement. We conducted our study to compare the effectiveness of Platelet-Rich Plasma (PRP) versus hyaluronic acid injection (HA) versus corticosteroids in thumb carpometacarpal(CMC) joint osteoarthritis based on clinical and functional outcome measures., Material and Methods: 45 patients with thumb CMC OA, assessed by palpation for joint tenderness grading, Provocative tests (Grind test and Lever test), VAS for pain, AUSCAN score for hand function, grip and pinch strength. Patients were randomly divided into three equal groups, Group 1 received an intra-articular PRP injection. Group 2 received an HA injection, and Group 3 a corticosteroid injection. Re-evaluation was done at 4 and 12 weeks., Results: All groups showed a significant improvement after 4 weeks regarding VAS, tenderness grading, AUSCAN score, grip and pinch strength in comparison to before injection. However, these improvements were not sustained for the PRP and steroid groups after 12 weeks, when there was a deterioration in the AUSCAN score, highly statistically increase in VAS and decrease in grip & pinch strength, while the HA group showed a highly statistically significant improvement at 12 weeks on all items evaluated., Conclusion: 1. The 3 types of injection (PRP, HA, steroids) produced good results in thumb base OA with re-gard to improving pain and hand function, but only HA had a long-lasting effect and best results for pain and function. 2. The limitations in our study may be the follow-up period which needs to be longer to show how long the effect will last with HA.

Purpose of Review: Osteoarthritis (OA) is a highly prevalent cause of chronic hip pain, affecting 27% of adults aged over 45 years and 42% of adults aged over 75 years. Though OA has traditionally been described as a disorder of "wear-and-tear," recent studies have expanded on this understanding to include a possible inflammatory etiology as well, damage to articular cartilage produces debris in the joint that is phagocytosed by synovial cells which leads to inflammation., Recent Findings: Patients with OA of the hip frequently have decreased quality of life due to pain and limited mobility though additional comorbidities of diabetes, cardiovascular disease, poor sleep quality, and obesity have been correlated. Initial treatment with conservative medical management can provide effective symptomatic relief. Physical therapy and exercise are important components of a multimodal approach to osteoarthritic hip pain. Patients with persistent pain may benefit from minimally invasive therapeutic approaches prior to consideration of undergoing total hip arthroplasty. The objective of this review is to provide an update of current minimally invasive therapies for the treatment of pain stemming from hip osteoarthritis; these include intra-articular injection of medication, regenerative therapies, and radiofrequency ablation.

Purpose: To compare the clinical and laboratory outcomes of intra-articular injections of culture-expanded bone-derived mesenchymal stem cells (MSCs) with or without platelet-rich plasma (PRP) to intra-articular corticosteroid injections for the treatment of knee osteoarthritis (OA)., Methods: Forty-seven patients with radiographic and symptomatic knee OA were randomized into three groups for intra-articular injections: autologous bone marrow-derived culture-expanded MSCs (n = 16); autologous bone marrow-derived culture-expanded MSCs + PRP (n = 14); and corticosteroid (n = 17). The outcomes were assessed by the Knee Injury and Osteoarthritis Outcome Score (KOOS) and range of motion (ROM) at baseline, 1, 2, 3, 6, 9 and 12 months and intra-articular cytokines analysis at baseline, 6 and 12 months postoperatively., Results: The three groups showed significant improvement in most KOOS domains and global score at 1st month and all domains and global score at 12-month follow-up (p < 0.05). At the 1st month, only the MSCs group showed significant differences in KOOS symptoms domain (p = 0.003). The MSCs and MSCs + PRP groups showed the highest percentage of improvement in most KOOS domains and global score compared to the corticosteroid group. All three groups showed a significant reduction in intra-articular levels of human interleukin-10 cytokine, from baseline to 12 months (p < 0.05)., Conclusion: An intra-articular injection of bone marrow-derived culture-expanded MSCs with or without the addiction of PRP is effective in improving the function and decreasing symptoms caused by knee OA at 12-month follow-up., Level of Evidence: II.

Background: The interest in biological treatments that have the potential to modify cartilage biology has gradually increased in recent years., Objective: The aim of our study was to investigate the effects of intra-articular platelet-rich plasma (IA-PRP) injections on the femoral cartilage thickness, pain, functional status, and quality of life of patients with knee osteoarthritis., Methods: A total of 71 patients (109 knees) with knee osteoarthritis who were administered IA-PRP injections twice with two-week intervals were included in this study. The resting and activity pain values measured using a Visual Analogue Scale (VAS), the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores, the Lequesne index scores, and the quality of life scores measured using Short Form-36 (SF-36) were recorded before treatment and at 1 month, 3 months, and 6 months after treatment. The femoral cartilage thickness was measured via ultrasonography before treatment, and at 3-month and 6-month follow ups. Obtained results were analyzed by the Wilcoxon signed rank test., Results: The mean age of the patients was 47.4 ± 10.4 years old. The resting and activity pain scores were significantly decreased at 1-month, 3-month and 6-month follow ups when compared to the pre-injection values (p< 0.05). Significant reductions were found in the Lequesne index and WOMAC pain, stiffness, and function scores at 1, 3, and 6 months (p< 0.05), while a significant increase was detected in the third month scores when compared to the first month. Significant improvements were determined in the physical functioning, physical role, pain, general health, and emotional role sub-scores during the 6-month period (p< 0.05). However, there was no significant difference with regard to the cartilage thickness at the follow ups (p> 0.05)., Conclusions: The results of our study indicated that the IA-PRP injections improved the pain, stiffness, physical functioning, and quality of life of knee osteoarthritis patients; however, they did not seem to affect the cartilage thickness during the 6-month follow up period.

Objective: The purpose of this study was (1) to perform a summary of meta-analyses comparing platelet-rich plasma (PRP) injection with hyaluronic acid (HA) and placebo injection for KOA patients, (2) to determine which meta-analysis provides the best available evidence to making proposals for the use of PRP in the treatment of KOA patients, and (3) to highlight gaps in the literature that require future investigation., Material and Methods: PubMed, EMBASE, and Cochrane databases search were performed for meta-analyses which compared PRP injection with HA or placebo. Clinical outcomes and adverse events were extracted from these meta-analyses. Meta-analysis quality was assessed using the Quality of Reporting of Meta-analyses (QUOROM) systems and the Oxman-Guyatt quality appraisal tool. The Jadad decision algorithm was also used to determine which meta-analysis provided the best available evidence., Results: Four meta-analyses were included in our study, and all of these articles were Level I evidence. The QUOROM score of each included meta-analysis range from 14 to 17 points (mean score 15, maximum score 18), and the Oxman-Guyatt score range from 4 to 6 points (mean score 5, maximum score 7). Three meta-analyses indicated PRP showed more benefit in pain relief and functional improvement than the control group, and the other one suggested no difference between these groups. All included meta-analyses found no statistical difference in adverse events between these groups. In addition, a meta-analysis conducted by Shen et al. got the highest methodological quality score and suggested that PRP provided better pain relief and function improvement in the treatment of KOA., Conclusions: For short-term follow-up (≤1 year), intra-articular PRP injection is more effective in terms of pain relief and function improvement in the treatment of KOA patients than HA and placebo, and there is no difference in the risk of an adverse event between PRP and HA or placebo., Level of Evidence: Level I evidence, a summary of meta-analyses TRIAL REGISTRATION: PROSPERO ID CRD42018116168.

Introduction: Intra-articular platelet-rich plasma (PRP) injection therapy has been extensively applied in clinical practice to treat musculoskeletal disorders such as osteoarthritis, but the treatment for haemophilic arthropathy is rarely reported., Aims: This study aimed to compare the efficacy of intra-articular PRP vs hyaluronic acid (HA) injections in treating haemophilic arthropathy of knee joints., Patients: Twenty-two haemophilia patients (mean age, 41.1 ± 1.7 [range, 20-50] years) with painful haemophilic arthropathy of the knee were enrolled for this open-label and observer-blind study., Methods: Eleven patients were treated with a single intra-articular injection of PRP and the other 11 received five consecutively weekly intra-articular injections of HA. Outcome assessment included pain by visual analogue scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Chinese Version and synovial change determined by ultrasonography., Results: Platelet-rich plasma and HA intra-articular injection showed statistically significant reduction in VAS, WOMAC total score and hyperaemia score from baseline to 6-month post-treatment. Inter-group comparison showed statistically significant difference in the change in VAS score, WOMAC pain score, physical function score and total score at 6 months, wherein PRP group showed sustained beneficial effect than HA group at 6 months., Conclusion: Our study demonstrates that, in comparison with five weekly injections of HA, a single PRP injection resulted in better improvement in pain relief and knee joint function, and greater reduction in synovial hyperaemia for up to 6 months. Our results suggest that PRP may be practical and effective for haemophilic knee arthropathy, and further investigation is warranted., (© 2019 John Wiley & Sons Ltd.)

Osteoarthritis (OA) is a degenerative disease involving joint damage, an inadequate healing response and progressive deterioration of the joint architecture that commonly affects the knee and/or hip joints. It is a major world public health problem and is predicted to increase rapidly with an ageing population and escalating rate of obesity. Autologous blood-derived products possess much promise in the repair and regeneration of tissue and have important roles in inflammation, angiogenesis, cell migration and metabolism in pathological conditions, including OA. Utilising platelet-rich plasma (PRP) to treat tendon, ligament and skeletal muscle has shown variable results across many studies with the current evidence base for the efficacy of PRP in treating sports injuries remaining inconclusive. More uniformly positive results have been observed by various studies for PRP in OA knee in comparison to hyaluronic acid, other intra-articular injections and placebo than in other musculoskeletal tissue. However, methodological concerns as well as satisfactory PRP product classification prevent the true characterisation of this treatment. Thus, further research is required to investigate how leukocyte inclusion, activation and platelet concentration affect therapeutic efficacy. Furthermore, the optimisation of timing, dosage, volume, frequency and rehabilitation strategies need to be ascertained. For knee OA management, these concerns must be addressed before this promising treatment can be widely implemented.

Osteoarthritis represents an important social economic burden with a high incidence worldwide. Conservative management of knee OA consists in several therapeutic options: pharmacologic therapy such as analgesics, non-steroid and steroid anti-inflammatory drugs, physical therapy, and injective therapy with hyaluronic acid (HA) and platelet-rich plasma injections (PRP). The aim of our study is to evaluate the effect of combined autologous PRP and HHA (Hybrid Hyaluronic Acid) viscosupplementation on clinical outcomes of patients with knee OA, by assessing the subjects before and after injective treatment. The study was conducted on 60 patients with an age between 40 and 70 years old affected by unilateral symptomatic knee osteoarthritis (stage II and III of Kellgren-Lawrence scale) nonresponsive to pharmacologic and rehab treatment. We divided the patients in two groups, and we treated the group A with injection of HHA and group B with HHA+PRP. Each patient received 3 injections at an interval of 1 week for 3 consecutive weeks. The patients were evaluated by the Knee Injury and Osteroartrhitis Outcome Score (KOOS) and Visual Analog Scale (VAS) at 3, 6 and 12 months after treatment. Statistical comparison between groups showed a significantly better result for the group B concerning the KOOS value, at 3 months and at 6 months. This difference, although clinically relevant, lost the statistical significance at 12 months. The VAS trend differently showed a significant difference at 3 and 12 months, while at 6 months the superiority of group B did not achieve statistical significance. Few studies investigated the effects of HA+PRP combined treatment for knee OA. Numerous studies demonstrated the efficacy of HA injection therapy in knee OA for a clinical point of view, reducing the pain and improving the quality of life. PRP preparations also improved functional outcome scores compared to hyaluronic acid and placebo in patients affected by knee OA. Based on our results we can conclude that the combined PRP and HHA treatment is not only a safe and efficacious procedure which can provide functional benefit but is also significantly better than HHA injective therapy alone, as demonstrated by the comparison within our cohort.

Background: Knee osteoarthritis (OA) is a disease with a high prevalence in the adult population. Nonsteroidal anti-inflammatory drugs (NSAID) or intra-articular injections [hyaluronic acid (HA) or platelet-rich plasma (PRP)] can provide clinical benefit. Magnetic resonance imaging (MRI) has proven to be useful for the evaluation of cartilage volume and thickness in knee osteoarthritis. The purpose of this study was to evaluate the benefit provided by PRP injection in comparison with hyaluronic acid and NSAID in knee OA patients and to compare the radiographic evolution at the 52-week follow-up., Methods: One hundred and six patients were enrolled and randomized according to the Spanish Rheumatology Society knee osteoarthritis diagnosis criteria. Ninety-eight patients completed the study (33 received NSAID treatment, 32 a single hyaluronic acid injection and 33 a single PRP injection). Patients were prospectively evaluated at baseline, 26 and 52 weeks using the Western Ontario McMaster Universities osteoarthritis index (WOMAC) and the visual analogue scale (VAS), and at baseline and 52 weeks with X-ray and MRI., Results: A 20% decrease in WOMAC pain and increase in physical function was found in 30 and 24%, respectively, of those patients who received PRP treatment, at the 52-week follow-up. WOMAC pain and VAS improved in the hyaluronic acid and NSAID groups. However, better results were obtained in the PRP group compared to hyaluronic acid and NSAIDs (P < 0.05). No differences in Kellgren-Lawrence or cartilage thickness progression were found., Conclusions: Leukocyte-poor platelet-rich plasma (LP-PRP) injections are better in terms of clinical improvement with respect to HA injections or oral NSAID treatment in knee osteoarthritis patients at the 52-week follow-up. Moreover, a single LP-PRP injection is effective. However, LP-PRP has no influence on cartilage progression., Level of Evidence: Level II.

Background: Knee osteoarthritis (OA) causes substantial pain, physical dysfunction and impaired quality of life. There is no cure for knee OA, and for some people, the disease may involve progressive symptomatic and structural deterioration over time. Platelet-rich plasma (PRP) is a therapeutic agent that aims to address underlying biological processes responsible for OA pathogenesis. As such, it has the potential to improve both symptoms and joint structure. The aim of this clinical trial is to determine whether a series of injections of PRP into the knee joint will lead to a significantly greater reduction in knee pain, and less loss of medial tibial cartilage volume over 12 months when compared to a series of placebo saline injections in people with knee OA., Methods: This will be a two-group, superiority, randomised, participant-, interventionist- and assessor-blinded, placebo-controlled trial. Two hundred and eighty-eight participants aged over 50 years with painful knee OA and mild to moderate structural change on x-ray (Kellgren and Lawrence grade 2 and 3) will be randomly allocated to receive either three PRP injections or three normal saline injections into the knee joint at weekly intervals. The primary outcomes will be 12-month change in average overall knee pain severity (numeric rating scale) and medial tibial cartilage volume (magnetic resonance imaging (MRI)). Secondary outcomes include additional measures of knee pain and other symptoms, function in daily living and sport and recreation, quality of life, participant-perceived global ratings of change, and other MRI structural outcomes including meniscal and cartilage morphology, synovitis, effusion, bone marrow lesions and cartilage defects. A range of additional measures will be recorded, and a separate health economic evaluation will be performed., Discussion: The findings from this study will help determine whether PRP improves both clinical and structural knee OA outcomes over 12 months when compared to a series of placebo saline injections., Trial Registration: Australian New Zealand Clinical Trials Registry reference: ACTRN12617000853347 . Prospectively registered 9th of June 2017.

The aim of this study was to evaluate the benefit provided by intraosseous infiltration combined with intra-articular injection of platelet-rich plasma to treat mild and moderate stages of knee joint degeneration (Kellgren-Lawrence score II-III) compared with other treatments, specifically intra-articular injection of PRP and of HA. Eighty-six patients with grade II to grade III knee OA according to the Kellgren-Lawrence classification were randomly assigned to intra-articular combined with intraosseous injection of PRP (group A), intra-articular PRP (group B), or intra-articular HA (group C). Patients in group A received intra-articular combined with intraosseous injection of PRP (administered twice, 2 weeks apart). Patients in group B received intra-articular injection of PRP every 14 days. Patients in group C received a series of five intra-articular injections of HA every 7 days. All patients were evaluated using the Visual Analogue Scale (VAS) and Western Ontario and McMaster Universities (WOMAC) score before the treatment and at 1, 3, 6, 12, and 18 months after treatment. There were significant improvements at the end of the 1st month. Notably, group A patients had significantly superior VAS and WOMAC scores than were observed in groups B and C. The VAS scores were similar in groups B and group C after the 6th month. Regarding the WOMAC scores, groups B and C differed at the 1st, 3rd, 6th, and 12th months; however, no significant difference was observed at the 18th month. The combination of intraosseous with intra-articular injections of PRP resulted in a significantly superior clinical outcome, with sustained lower VAS and WOMAC scores and improvement in quality of life within 18 months.

Intra-articular platelet-rich plasma (PRP) injection has been found to be effective for treating osteoarthritis in patients from Western countries; however, the safety and efficacy of PRP have not been sufficiently investigated in Japanese patients. The present study aimed to evaluate the safety and feasibility of intra-articular PRP injection in Japanese patients with knee osteoarthritis. PRP without white blood cells was prepared using a single-spin centrifuge (PRGF-Endoret; BTI Biotechnology Institute, Vitoria, Spain). A 6-mL PRP volume was injected in the knee joint three times at 1 week intervals. All patients were prospectively evaluated before intervention and at 1, 3, and 6 months after the treatment. Adverse events, the Visual Analog Scale (VAS) pain score, Japanese Knee Osteoarthritis Measure (JKOM) score and Japanese Orthopedic Association score were evaluated. Ten patients (all women; average age, 60.6 years) were treated. Only minor adverse events after injection were noted, and symptoms resolved within 48 hours after the injection. The average VAS pain scores were 71.6 mm and 18.4 mm at baseline and the 6-month follow-up, respectively (P < 0.05). At the 6-month follow-up, 80% of patients had a decrease in the VAS pain score of 50% or more. The average JKOM scores were 35.2 and 14.3 at baseline and at the 1-month follow-up, respectively (P < 0.05). Intra-articular PRP injection likely represents a safe treatment option for Japanese patients with mild-to-moderate knee osteoarthritis, and has the potential to relieve pain for up to 6 months, but further study is needed to verify the efficacy.

Background: The synergistic and protective effect of platelet-rich plasma (PRP) added to methlyprednisolone (MP) has been demonstrated via in-vitro studies. However, there is no report in the literature about this issue., Objective: The aim of this study was to evaluate clinical outcomes of intra-articular (IA) MP injection prior to PRP injection in comparison with single-dose MP and PRP injections alone in patients with knee osteoarthritis (OA)., Methods: The treatment groups were "PRP group" (n= 37) who underwent single-dose IA PRP injection, "PRP + MP group" (n= 40) who underwent MP injection one week prior to single-dose PRP injection, and "MP group" (n= 38) who underwent single-dose MP injection. Visual Analog Scale (VAS) and The Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores were applied at first admission and at 1st, 3rd, 6th, and 12th month follow-ups., Results: At the end of the 1st month, WOMAC score in PRP + MP group was significantly lower than PRP group. At the 3rd month, WOMAC score in PRP + MP group was significantly lower than PRP and MP groups. At the 6th month, VAS and WOMAC score in PRP + MP group was significantly lower than MP group. At the end of the 12th month, no significant difference was observed among three groups in VAS and WOMAC scores., Conclusion: According to our results, IA MP injection prior to PRP injection resulted in significantly better clinical outcomes compared to PRP and MP injections alone in patients who had mild to moderate knee OA.

Objectives: To compare the effectiveness and safety between autologous platelet-rich plasma (PRP) and Local Anesthetic (LA)/corticosteroid in intra-articular injection for the treatment of lumbar facet joint syndrome., Methods: Forty-six eligible patients with lumbar facet joint syndrome were randomized into group A (intra-articular injection with PRP) and group B (intra-articular injection with LA/corticosteroid). The following contents were evaluated: pain visual analog scale (VAS) at rest and during flexion, and the Roland-Morris Disability Questionnaire (RMQ), Oswestry Disability Index (ODI), and modified MacNab criteria for pain relief and applications of post-treatment drugs. All outcome assessments were performed immediately after and at 1 week, 1, 2, 3, and 6 months after treatment., Results: No significant difference between groups was observed at baseline. Compared with pretreatment, both group A and group B demonstrated statistical improvements in the pain VAS score at rest or during flexion, the RMQ, and the ODI (P < 0.01). And there were significant differences between the 2 groups on the above-mentioned items (P < 0.05). For group B, subjective satisfaction based on the modified MacNab criteria and objective success rate were highest (80% and 85%) after 1 month, but only 50% and 20% after 6 months. However, for group A, they increased over time. In addition, there were no treatment-related complications in either group during follow-up., Conclusions: Both autologous PRP and LA/corticosteroid for intra-articular injection are effective, easy, and safe enough in the treatment of lumbar facet joint syndrome. However, autologous PRP is a superior treatment option for longer duration efficacy., (© 2016 World Institute of Pain.)

Purpose: To assess the short-term results of repeated intra-articular platelet rich plasma (PRP) injections into the knee in patients with early osteoarthritis (OA) and to determine a better treatment protocol., Methods: This is a retrospective study in 191 knees (127 patients) with minimum of 12 months follow-up. We compared the clinical results of three types of injection method, once a month, twice monthly, and three injections at monthly interval. The outcomes were assessed using Visual Rating Scale (VRS), functional score, knee score, range of motion (ROM), WOMAC Stiffness/Pain/Function score, IKDC score, before the first injection and at 12 months post treatment., Results: There were significant improvements in all scores after treatment as compared to the pre-treatment values (p < 0.05), except Knee score after 1st and 2nd injection and ROM in three groups. The parameters of Visual Rating Scale (VRS), functional score, and WOMAC Stiffness/Pain/Function score showed significant differences among the three groups in favour of the three injections group (p < 0.05). At 12 months, the effects began to decline in one injection and two injections groups, and the data in one injection group showed significant difference compared to two injection group (p < 0.001). Three injections group had higher scores and more improvement at 12 months after treatment when compared to the other two groups., Conclusion: PRP injection appears to be effective in early symptomatic OA knees. The results after treatment are encouraging with significant reduction in pain and improvement in knee function at 12 months after treatment when compared to the pre-treatment status. Three injections per month yielded significantly better results in short-term follow-up., (Copyright © 2017 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.)

A randomized clinical trial was implemented in adult patients with temporomandibular joint osteoarthritis (TMJ OA). The sample comprised 49 osteoarthritic joints in 31 consecutive patients. Patients were divided randomly into two groups according to the treatment technique applied: the platelet-rich plasma (PRP) group patients underwent initial arthrocentesis plus PRP injection and then four consecutive PRP injections; the hyaluronic acid (HA) group patients underwent one session of arthrocentesis plus HA injection. The predictor variable was the treatment technique. The outcome variables included visual analogue scale (VAS) evaluations and maximum inter-incisal opening (MIO) measurements. Outcome variables were recorded preoperatively and at 12 months postoperative. Descriptive and bivariate statistics were computed and significance was set at P<0.05. The PRP group included 32 joints in 18 subjects, and the HA group included 17 joints in 13 subjects. No statistically significant difference was observed between the groups for any of the changes in VAS parameters or MIO measurements. Both treatment techniques resulted in significant clinical improvements in all VAS parameters and painless MIO. These findings suggest that arthrocentesis plus PRP injections is not superior to arthrocentesis plus a single HA injection; thus PRP injection should not be considered as the first line treatment. Arthrocentesis plus HA injection would appear to be more acceptable for patients., (Copyright © 2016 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

Platelet rich plasma (PRP) is used to treat many musculoskeletal disorders. We used a canine model to determine the effects of multiple intra-articular injections of leukoreduced PRP (ACP) on anterior cruciate ligament healing, meniscal healing, and progression of osteoarthritis (OA). With Animal Care and Use Committee (ACUC) approval, 12 dogs underwent partial ACL transection and meniscal release in one knee. At weeks 1, 2, 3, 6, and 8 after insult, dogs were treated with intra-articular injections (2 ml) of either ACP (n = 6) or saline (n = 6). Dogs were assessed over 6 months to determine comfortable range of motion (CROM), lameness, pain, effusion, kinetics, and radiographic and arthroscopic assessments. At 6-month endpoint, dogs were assessed for ACL material properties and histopathology. Saline-treated dogs had significantly (p < 0.04) more CROM loss, significantly (p < 0.01) more pain, significantly (p < 0.05) more severe lameness, significantly (p < 0.05) lower function, and significantly (p < 0.05) lower %Total Pressure Index in affected hindlimbs compared to ACP-treated dogs. Radiographic OA increased significantly (p < 0.01) over time within each group. Arthroscopically, saline-treated knees showed moderate to severe synovitis, further ACL disruption, and medial compartment cartilage loss, and ACP-treated knees showed evidence of ACL repair and less severe synovitis. ACL material properties in ACP-treated knees were closer to normal than in saline-treated knees, however, the differences were not statistically significant. ACL histopathology was significantly (p< 0.05) less severe in ACP-treated knees compared to saline-treated knees. Five intra-articular injections of leukoreduced PRP had beneficial effects for ACL healing, improved range of motion, decreased pain, and improved limb function for up to 6 months in this model., (© 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Background: The effectiveness of intra-articular platelet-rich plasma (PRP) injections has been evaluated in knee chondroplasty and osteoarthritis (OA); however, little evidence of its efficacy in hip OA exists., Purpose: To compare the therapeutic efficacy of autologous PRP, hyaluronic acid (HA), or a combination of both (PRP+HA) in hip OA., Study Design: Randomized controlled trial; Level of evidence, 1., Methods: Patients aged between 18 and 65 years who were treated with outpatient surgery and who had hip OA and pain intensity at baseline of >20 on a 100-mm visual analog scale (VAS) were recruited for this study. Exclusion criteria were extensive surgery; presence of excessive deformities; or rheumatic, infective, cardiovascular, or immune system disorders. The primary outcome measure was a change in pain intensity as assessed by the VAS at 2, 6, and 12 months after treatment. Secondary outcome measures were the Harris Hip Score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and concentration of growth factors in PRP and their correlation with clinical outcomes. Clinical outcomes were evaluated by assessors and collectors blinded to the type of treatment administered., Results: A total of 111 patients were randomly assigned to 3 groups and received 3 weekly injections of either PRP (44 patients), PRP+HA (31 patients), or HA (36 patients). At all follow-ups, the PRP group had the lowest VAS scores. In particular, at 6-month follow-up, the mean VAS score was 21 (95% CI, 15-28) in the PRP group, 35 (95% CI, 26-45) in the PRP+HA group, and 44 (95% CI, 36-52) in the HA group (P < .0005 [PRP vs HA] and P = .007 [PRP vs PRP+HA]; F = 0.663). The WOMAC score of the PRP group was significantly better at 2-month follow-up (mean, 73; 95% CI, 68-78) and 6-month follow-up (mean, 72; 95% CI, 67-76) but not at 12-month follow-up. A significant, "moderate" correlation was found between interleukin-10 and variations of the VAS score (r = 0.392; P = .040). Significant improvements were achieved in reducing pain and ameliorating quality of life and functional recovery., Conclusion: Results indicated that intra-articular PRP injections offer a significant clinical improvement in patients with hip OA without relevant side effects. The benefit was significantly more stable up to 12 months as compared with the other tested treatments. The addition of PRP+HA did not lead to a significant improvement in pain symptoms., (© 2016 The Author(s).)

Background: Platelet-rich-plasma (PRP) is rapidly spreading as a conservative treatment option for knee osteoarthritis (KOA), however, its therapeutic efficacy is controversial. This study aimed to investigate the factors affecting the therapeutic effect of intra-articular PRP therapy for KOA in patients who received multiple PRP injections (PRP-I). Methods: This is a historical cohort study included 1057 knees of 701 patients who received PRP-I during KOA treatment from 2018 to 2020. The difference in visual analog scale (VAS) scores before and after PRP-I was defined as the amount of change in VAS (ΔVAS). A linear mixed-effects model was employed with ΔVAS as a random effect and age, sex, BMI, KL classification, pre-treatment VAS, treatment duration, and the number of PRP injections as fixed effects. Evaluations using the Kellgren-Lawrence (KL) classification were added. Results: Age, KL grade, and VAS score before treatment and after three, four, and five PRP-I were significantly associated with ΔVAS score. According to KL grade, age was significantly associated with ΔVAS score in the KL grade 4 group. VAS score before treatment was significantly associated with ΔVAS score, regardless of KL grade. Three-time PRP-I were significantly associated with ΔVAS in the KL-grade 1 and 2 groups. For KL grade 4, two or more PRP-I were significantly associated with the high efficacy. Conclusions: Age, pain before treatment, KL grade and number of injections were associated with pain reduction after intra-articular PRP-I for KOA treatment. Pain reduction can be expected after PRP-I when patients are younger or experience severe pain before treatment. Three-time PRP-I are recommended to reduce pain in early-stage KOA and more than three times in advanced-stage KOA. Trial registration: Retrospectively registration.

Background: Knee osteoarthritis (KOA) is the most common cause of chronic knee pain causing functional disability and dependency. Multiple interventions have been used in reducing pain and improving functionality. We intend to compare the efficacy of intra-articular platelet-rich plasma (PRP) and hyaluronic acid (HA) with botulinum toxin type A and HA in bilateral Grade 3 and 4 KOA. Methods: Prospective single-blinded randomized controlled trial conducted for 6 months. Among 54 participants, 27 received intra-articular botulinum toxin type A with HA (Group A), and the other 27 received intra-articular PRP with HA (Group B), single session. Pain (Numerical Rating Scale [NRS]) and functional limitation (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC]) were assessed at 2, 4, 12, and 24 weeks postintervention. Effect of weight and physiotherapy on NRS and WOMAC score were assessed. P <0.05 was considered statistically significant. Data were analyzed by statistical software R version 4.2.3. Results: Fifty-four participants were enrolled. There was no loss to follow-ups. Except for age (P < 0.001) and mean height (P = 0.013), other demographic data were insignificant. Preprocedural NRS was significantly high in Group A (P = 0.04). Overall NRS postprocedure was significantly lesser in Group B, P < 0.001. The mean WOMAC score postprocedure was significantly low in Group B, P < 0.001. Group B had increased heart rate which was statistically significant (P = 0.051). The mean reduction in WOMAC score was observed with regular physiotherapy in Group B (P = 0.023). Reduction in weight was directly proportional to reduction in NRS (P = 0.015). Conclusion: Intra-articular PRP with HA, single session, is effective in improving pain, functionality, and safe in Grade 3 and 4 KOA. [ABSTRACT FROM AUTHOR]

Background: Knee osteoarthritis (KOA) is the most common cause of chronic knee pain causing functional disability and dependency. Multiple interventions have been used in reducing pain and improving functionality. We intend to compare the efficacy of intra-articular platelet-rich plasma (PRP) and hyaluronic acid (HA) with botulinum toxin type A and HA in bilateral Grade 3 and 4 KOA. Methods: Prospective single-blinded randomized controlled trial conducted for 6 months. Among 54 participants, 27 received intra-articular botulinum toxin type A with HA (Group A), and the other 27 received intra-articular PRP with HA (Group B), single session. Pain (Numerical Rating Scale [NRS]) and functional limitation (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC]) were assessed at 2, 4, 12, and 24 weeks postintervention. Effect of weight and physiotherapy on NRS and WOMAC score were assessed. P

Medical ozone is a molecule composed of three oxygen atoms with anti-inflammatory, analgesic, and antioxidant functions. Ozone therapy (O3 or O2– O3) for knee osteoarthritis has gradually received increasing attention from researchers in recent years. Here, we discuss the research hotspots and development trends of ozone therapy for knee osteoarthritis through literature visualization and analysis. (1) From 2012 to the present, the overall trend of publications on ozone treatment for knee osteoarthritis has been increasing annually, and it has received widespread attention, especially in Iran and China. (2) Keyword analysis revealed that the keywords with the greatest number of citations for ozone treatment of knee osteoarthritis are "osteoarthritis," "ozone," "knee osteoarthritis," "ozone therapy," and "hyaluronic acid." (3) The results of the cocitation analysis revealed that the themes of the cocited literature are concentrated in 11 directions: intra-articular injections, intra-articular oxygen ozone, treatment of knee osteoarthritis, rehabilitation studies, time effects, pain function, comprehensive review, growth factors, rheumatic diseases, ultrasound-guided corticosteroid injections, and placebo. (4) The hotspots of the available highly cited literature have focused mainly on the efficacy and safety of ozone or growth factors alone in the treatment of knee osteoarthritis. Most of the literature suggests that intra-articular injections are the most common form of ozone therapy, and the accuracy and safety of ozone injections can be ensured using ultrasound-guided techniques. Ozone therapy has a positive short-term effect on pain control and functional recovery within 6 months after injection, but how to maintain the long-term efficacy of ozone therapy has rarely been described. It is hypothesized that the combination of ozone and growth factors may be beneficial for prolonging the efficacy of ozone therapy. (5) Ozone therapy has no advantages over other therapies in terms of therapeutic efficacy. Compared with ozone therapy, platelet-rich plasma and growth factor-rich plasma have better long-term outcomes in the treatment of knee osteoarthritis, whereas stromal vascular components have the best effects on pain relief and functional improvement. Few studies address the combination of ozone and growth factors for the treatment of knee osteoarthritis, and a few clinical studies registered have explored other treatments (e.g., corticosteroids). (6) Future studies could further explore the specific mechanisms and optimal dosing regimens of ozone combined with different growth factors in the treatment of knee osteoarthritis to compensate for the short-term efficacy of ozone therapy and to validate the long-term efficacy and safety of this combination therapy. It is also imperative to develop international guidelines for ozone therapy for osteoarthritis of the knee as soon as possible. [ABSTRACT FROM AUTHOR]

Platelet-rich plasma (PRP) is a rising therapy treating locomotor system lesions such as knee osteoarthritis. The objective of this study was to evaluate patients' satisfaction 6 to 12 months after a PRP injection for cartilage lesions of their knee under real-life conditions. Patients' satisfaction was assessed by a specific questionnaire named SATMED-Q©, which explores six different dimensions of a given treatment. In addition, pain and function were assessed thanks to VAS pain, WOMAC, and IKDC scores. Responders were identified through the OMERACT-OARSI criteria. We observed excellent satisfaction after a PRP injection with a SATMED-Q© score of 80.81% 6 to 12 months after the procedure. Even when there was no significant improvement in pain and function scores, 52% of the evaluated population fulfilled the OMERACT-OARSI criteria and were considered responders. According to the sub-group analysis, patients with less osteoarthritis damage (i.e., Kellgren–Lawrence grades 1–2) and older study subjects (i.e., >40 years old) with focal chondropathy had benefited most from their PRP injection. Thus, platelet-rich plasma seems to be a well-tolerated and efficient therapy for cartilage lesions of the knee. [ABSTRACT FROM AUTHOR]

Objectives: To assess the effectiveness of two consecutive intraarticular injections of PRP to treat knee osteoarthritis (KOA), discriminating between responders and impaired patients. Methods: This retrospective study included 73 consecutive patients who were referred for two intra-articular PRP injections (one week apart) for treating symptomatic moderate/severe KOA. Biological characterization of the PRP, including platelets, leukocytes and erythrocytes, was evaluated. Patient's subjective symptoms were recorded before the treatment and 1 year after the second injection using pain VAS and WOMAC scores. Responders were defined by an improvement of 10 points on WOMAC. Results: At a 1-year follow up, we found 36 (49.3%) patients who fulfilled the criteria of responders, and 21 (28.8%) patients were impaired. A statistically and clinically significant global improvement of −29.2 ± 14.3 (p < 0.001) points in WOMAC score was observed 1 year after treatment in the responder group, with a higher response rate in patients with KL 2 (57.7%) compared to KL IV (28.6%). The percentage of patients with KL IV was higher in the impaired group (48.0%) compared to the responders (16.6%). As expected, the evaluation of the functionality of the knee in the impaired group indicates that it significantly worsened after one year from treatment (p = 0.027). However, the average pain score remained stable with no significant differences after 1 year (p = 0.843). No clinical complications or severe adverse events after the PRP injections were reported. Conclusion: The present study suggests that two intra-articular injections of 10 mL of very pure PRP provide pain and functional improvement in symptomatic KOA. [ABSTRACT FROM AUTHOR]

Background: Platelet-rich plasma (PRP) and hyaluronic acid (HA) are non-surgical treatments for osteoarthritis (OA), but the comparison of their efficiency is still inconclusive. Objectives: The objectives of this study were to compare the efficacy of PRP and HA in the treatment of OA by meta-analysis and to explore the effects of different injection times and leukocyte concentration on the efficacy of PRP. Design: Meta-analysis and subgroup analysis were conducted. The data were analyzed by Review Manager v5.4.1. Data sources and methods: Articles were retrieved and screened from PubMed, the Cochrane Library, Web of Science, and Embase. The outcome included the total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), the visual analog scale (VAS), adverse events (AEs), the International Knee Documentation Committee (IKDC), and the satisfaction rate. Results: A total of 30 articles involving 2733 patients were included. The total WOMAC score and IKDC score of the PRP group were better than those of the HA group at the last follow-up time, while there was no significant difference in AEs, satisfaction rate, and VAS between the two groups. In our subgroup analysis, there was no significant difference between single-injection PRP and triple-injection PRP. Leukocyte-poor PRP (LP-PRP) was better than leukocyte-rich PRP (LR-PRP) in IKDC, but there was no significant difference between them in the other scores. Conclusions: In the treatment of OA, compared with HA, PRP performed better in the improvement of the patient's function. There was no significant difference in VAS and AEs between the two groups, and the safety was comparable. LP-PRP looked to be superior to LR-PRP in functional recovery, but there appeared to be no significant difference in pain relief between them. There was no significant difference between single PRP and triple PRP in the subgroup analysis. [ABSTRACT FROM AUTHOR]

Background: Platelet-rich plasma (PRP) and hyaluronic acid (HA) are non-surgical treatments for osteoarthritis (OA), but the comparison of their efficiency is still inconclusive. Objectives: The objectives of this study were to compare the efficacy of PRP and HA in the treatment of OA by meta-analysis and to explore the effects of different injection times and leukocyte concentration on the efficacy of PRP. Design: Meta-analysis and subgroup analysis were conducted. The data were analyzed by Review Manager v5.4.1. Data sources and methods: Articles were retrieved and screened from PubMed, the Cochrane Library, Web of Science, and Embase. The outcome included the total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), the visual analog scale (VAS), adverse events (AEs), the International Knee Documentation Committee (IKDC), and the satisfaction rate. Results: A total of 30 articles involving 2733 patients were included. The total WOMAC score and IKDC score of the PRP group were better than those of the HA group at the last follow-up time, while there was no significant difference in AEs, satisfaction rate, and VAS between the two groups. In our subgroup analysis, there was no significant difference between single-injection PRP and triple-injection PRP. Leukocyte-poor PRP (LP-PRP) was better than leukocyte-rich PRP (LR-PRP) in IKDC, but there was no significant difference between them in the other scores. Conclusions: In the treatment of OA, compared with HA, PRP performed better in the improvement of the patient's function. There was no significant difference in VAS and AEs between the two groups, and the safety was comparable. LP-PRP looked to be superior to LR-PRP in functional recovery, but there appeared to be no significant difference in pain relief between them. There was no significant difference between single PRP and triple PRP in the subgroup analysis. [ABSTRACT FROM AUTHOR]

Background: Knee osteoarthritis (OA) is considered the most common disease affecting knee joint. Various strategies are utilized to decrease the symptoms of knee OA, like analgesics, physiotherapy, intra-articular glucocorticoids and hyaluronic acid [HA] injection as well as arthroscopic debridement (AD). New studies have concentrated on new lines of treatment that stimulate damage improving and healing process of the cartilage, including mainly platelet-rich plasma (PRP) injection as growth factors complex. Aim: Because of the high incidence of OA and its complications, this article aimed to study the effect of AD and PRP injection on patients with knee OA. Methods: This controlled randomized clinical trial involved 20 patients with moderate knee OA. In the PRP group (n = 10), three intra-articular injections at 10-days interval were applied and compared to AD group (n = 10). All patients were prospectively evaluated before and after 6 months of the treatment by KOOS score. Results: After at least 6-months follow-up, KOOS score was significantly improved in PRP group compared to the AD group (P < 0.05). All parameters were improved in the PRP group. Conclusion: The study suggested that injection of PRP is more effective toward reducing pain and symptoms, with improvement of the daily living function, quality of life and function in sport and recreation. PRP is a method of choice in patients with mild to moderate knee OA, who not responding to classical treatment options. [ABSTRACT FROM AUTHOR]

Aims: This study investigates the effects of intra-articular injection of adipose-derived mesenchymal stem cells (AdMSCs) and platelet-rich plasma (PRP) on lameness, pain, and quality of life in osteoarthritic canine patients. Methods: With informed owner consent, adipose tissue collected from adult dogs diagnosed with degenerative joint disease was enzymatically digested and cultured to passage 1. A small portion of cells (n = 4) surplus to clinical need were characterized using flow cytometry and tri-lineage differentiation. The impact and degree of osteoarthritis (OA) was assessed using the Liverpool Osteoarthritis in Dogs (LOAD) score, Modified Canine Osteoarthritis Staging Tool (mCOAST), kinetic gait analysis, and diagnostic imaging. Overall, 28 joints (25 dogs) were injected with autologous AdMSCs and PRP. The patients were followed up at two, four, eight, 12, and 24 weeks. Data were analyzed using two related-samples Wilcoxon signed-rank or Mann-Whitney U tests with statistical significance set at p < 0.05. Results: AdMSCs demonstrated stem cell-like characteristics. LOAD scores were significantly lower at week 4 compared with preinjection (p = 0.021). The mCOAST improved significantly after three months (p = 0.001) and six months (p = 0.001). Asymmmetry indices decreased from four weeks post-injection and remained significantly lower at six months (p = 0.025). Conclusion: These improvements in quality of life, reduction in pain on examination, and improved symmetry in dogs injected with AdMSCs and PRP support the effectiveness of this combined treatment for symptom modification in canine OA for six months.

Background: Knee osteoarthritis (KOA) can be effectively treated conservatively using platelet-rich plasma (PRP) injections into the affected joints. While the short-term therapeutic clinical benefits were well documented, the mid-term results remain undetermined. To clarify its efficacy, the mid-term clinical outcomes of intra-articular injections of either PRP or hyaluronic acid (HA) in KOA were compared.Methods: One hundred patients who complied with the inclusion criteria were randomized to undergo once a week 3 weeks, intra-articular injections of either PRP or HA. Patients were evaluated before the injection, at 3, 6, and a mean of 78.9 months of follow-up. Eighty-five patients reached the final evaluation. Data on survival, re-intervention, pain, function, imaging, and satisfaction were collected and analyzed.Results: With surgery for any reason as the endpoint, the cumulative survival rate of the PRP group was 90%, while that of the HA group was 74%. There was a significant difference between the two groups in the total re-intervention rate (56.7% vs 16.2%, p < 0.05). The comparative analyses showed significant intergroup differences in the visual analog scale (VAS) and the Western Ontario and McMaster Universities Arthritis Index (WOMAC) (p < 0.01, p < 0.05, respectively) at the final follow-up. And base on the regression analyses, the type of treatment, age, and Kellgren-Lawrence (K-L) grade served as statistically an independent determinants of VAS (p < 0.001, p = 0.034, p < 0.001, respectively). Likewise, those variables independently determined WOMAC in our study. However, no difference was observed in the imaging evaluation, containing the K-L grade and Cartilage Lesion Score, between the two groups (p > 0.05). Besides, the satisfaction treated by the PRP was 78.6%, with a superiority compared with HA (55.8%, p < 0.05), and no complications were noted in the whole treatment process among patients who participated.Conclusion: PRP was more effective than HA in survival and re-intervention rates, VAS, and WOMAC, although there were no significant differences in the imaging evaluation between the two groups. Furthermore, patients treated with PRP were associated with higher satisfaction compared with HA.

Backgroud Knee osteoarthritis is the most common articular disease. Different methods are used to alleviate the symptoms of patients with knee osteoarthritis, including analgesics, physical therapy, exercise prescription, and intra-articular injections (glucocorticoids, hyaluronic acid). New studies have focused on modern therapeutic methods that stimulate the cartilage healing process and improve the damage, including the use of platelet-rich plasma as a complex growth factor. Aim of the work To evaluate the effectiveness of intra articular PRP in mild to moderate degree knee osteoarthritis. Objectives To slow the rate of progression of knee Osteoarthritis by injection of PRP intraarticular. Decrease pain and disability of patients with knee osteoarthritis and postpone knee arthroplasty as possible. Patients and methods Ninety patients in the age range of 40–75 years who visited the Physical Medicine, Rheumatology, and Rehabilitation outpatient clinic with knee pain for a minimum of 6 months' duration were studied. In these patients, OA was diagnosed according to the visual analog scale (VAS) score, the American College of Rheumatology criteria, radiographic criteria proposed by the Kellgren and Lawrence score 1957 classification, and MSKUS. The patients were classified into three groups according to the number of ultrasonic-guided PRP injections. group I (GI) included 30 patients who received a single PRP injection. Group II (GII) included 30 patients who received two PRP injections 2 weeks apart. Group III (GIII) included 30 patients who received triple PRP injections with a 2-week gap between every injection. The patients were evaluated before treatment, and at the first, third, and 6 months after the PRP injection with the VAS for pain, the Western Ontario and Mc Master Universities Arthritis Index (WOMAC) for physical activity of the knee and MSKUS for the diagnosis and improvement of radiological signs of knee arthritis (grades, synovial hypertrophy, Doppler vascular activity, decreased usage of NSAIDs). Results After the first and second intra-articular PRP injections [i.e., GI [Table 1] and GII [Table 2]], the following results were obtained: According to demographic data [Table 3], the VAS score and the WOMAC score improved, and synovial hypertrophy and usage of NSAIDs decreased after the first and second injections (in mild and moderate cases); there was no significant difference as 50% of mild patients showed improvement, while 18.2% of moderate patients improved). Decreased numbers of improved patients at the sixth month after PRP injection.{Table 1}{Table 2}{Table 3} Conclusion In conclusion, from our results, it was found that intra-articular injection of PRP in patients with mild and moderate knee OA is an effective and safe method. The maximum improvement was observed in mild cases with triple PRP injections.

Purpose: To assess the clinical outcomes of intra-articular Platelet-rich plasma (PRP) injection in knee osteoarthritis (OA) at 2 year follow-up. Methods: This was a prospective interventional study. 68 cases (105 knees) with Kellgren-Lawrence (KL) grades I, II and III knee OA received 3 intra-articular injections of PRP 1 month apart. The cases were followed up for 2-years. Outcomes were measured using Western Ontario and McMaster Universities Arthritis Index (WOMAC) score and Visual analog scale (VAS) scores. Results: The mean age was 51.7 years. 18 knees had KL grade I, 55 had grade II and 32 had grade III OA. The mean pre-treatment VAS score decreased significantly at 1 year (mean difference − 5.3, p = 0.003) and 2 year follow-up (mean difference − 6, p = 0.007). The mean pre-treatment WOMAC score decreased significantly at 1 year (mean difference − 45.9, p = 0.011) and at 2 year (mean difference − 52.4, p = 0.009). The WOMAC and VAS scores improved significantly from baseline to final follow-up across all KL grades (p = 0.001 and 0.001, 0.009 and 0.007, 0.021 and 0.017 for WOMAC and VAS across KL grade I, II and III, respectively). There was no significant differences in WOMAC and VAS scores between three KL grades at final follow-up (p = 0.17 and 0.09, respectively), although the baseline scores had significant difference (p = 0.001 for both VAS and WOMAC) with worse scores in higher KL grades. The variables like age, sex, BMI, KL grade, baseline VAS and baseline WOMAC did not predict the final VAS and WOMAC scores. Conclusion: Triple injection of intra-articular PRP given one month apart significantly relieves the symptoms of knee OA till 2 years in KL grade I, II and III. The improvement in symptoms at 2-year follow-up did not differ across different KL grades. [ABSTRACT FROM AUTHOR]

Backgroud Knee osteoarthritis is the most common articular disease. Different methods are used to alleviate the symptoms of patients with knee osteoarthritis, including analgesics, physical therapy, exercise prescription, and intra-articular injections (glucocorticoids, hyaluronic acid). New studies have focused on modern therapeutic methods that stimulate the cartilage healing process and improve the damage, including the use of platelet-rich plasma as a complex growth factor. Aim of the work To evaluate the effectiveness of intra articular PRP in mild to moderate degree knee osteoarthritis. Objectives To slow the rate of progression of knee Osteoarthritis by injection of PRP intraarticular. Decrease pain and disability of patients with knee osteoarthritis and postpone knee arthroplasty as possible. Patients and methods Ninety patients in the age range of 40-75 years who visited the Physical Medicine, Rheumatology, and Rehabilitation outpatient clinic with knee pain for a minimum of 6 months' duration were studied. In these patients, OA was diagnosed according to the visual analog scale (VAS) score, the American College of Rheumatology criteria, radiographic criteria proposed by the Kellgren and Lawrence score 1957 classification, and MSKUS. The patients were classified into three groups according to the number of ultrasonic-guided PRP injections. group I (GI) included 30 patients who received a single PRP injection. Group II (GII) included 30 patients who received two PRP injections 2 weeks apart. Group III (GIII) included 30 patients who received triple PRP injections with a 2-week gap between every injection. The patients were evaluated before treatment, and at the first, third, and 6 months after the PRP injection with the VAS for pain, the Western Ontario and Mc Master Universities Arthritis Index (WOMAC) for physical activity of the knee and MSKUS for the diagnosis and improvement of radiological signs of knee arthritis (grades, synovial hypertrophy, Doppler vascular activity, decreased usage of NSAIDs). Results After the first and second intra-articular PRP injections [i.e., GI (Table 1) and GII (Table 2)], the following results were obtained: According to demographic data (Table 3), the VAS score and the WOMAC score improved, and synovial hypertrophy and usage of NSAIDs decreased after the first and second injections (in mild and moderate cases); there was no significant difference as 50% of mild patients showed improvement, while 18.2% of moderate patients improved). Decreased numbers of improved patients at the sixth month after PRP injection. Conclusion In conclusion, from our results, it was found that intra-articular injection of PRP in patients with mild and moderate knee OA is an effective and safe method. The maximum improvement was observed in mild cases with triple PRP injections. [ABSTRACT FROM AUTHOR]

Background Osteoarthritis (OA) is a degenerative joint disease of multifactorial etiology and affects synovial joints. The risk of developing OA substantially increases with each decade after the age of 45 years. It is characterized by progressive deterioration and loss of articular cartilage with structural and functional changes in the entire joint, including the synovium, periarticular ligaments, and subchondral bone. Objective To assess the clinical effects of intra-articular injection of platelet-rich plasma (PRP) into the knee joint with mild to moderate OA regarding pain, quality of life, and return to activity. Patients and methods The study included 30 patients in the age range of 30–70 years complaining of knee OA grade II and III based on Kellgren and Lawrence classification and confirmed by radiographs. The patients received three intra-articular PRP injections with weekly intervals. Results A statistically significant improvement in the joint function was observed after 6 months according to the Western Ontario and McMaster Universities Osteoarthritis Index scoring index. Conclusion From the results of our study, intra-articular PRP injection is considered as a safe and low-cost line of knee OA treatment with few adverse effects.