Abstract
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” (
RESULTS:
At the end of the 1st month, WOMAC score in PRP
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.
Introduction
Knee osteoarthritis (OA) is one of the most common disorders that can cause functional disability including cartilage damage with an inadequate healing capacity [1]. It has been reported that approximately 25% of adults over 55 years old suffer from knee pain at least one time a year, and nearly half of them are diagnosed as knee OA in years [2, 3].
Current treatment methods for knee OA include non-pharmacological, pharmacological, and surgical interventions. According to recent treatment guidelines, pharmacological treatment is highly recommended for middle-aged and older patients with the diagnosis of knee OA [4]. Intra-articular (IA) injection is a minimally invasive pharmacological treatment method, which consists of administering various agents into the knee joint to decrease pain and increase function when other pharmacological interventions failed [5].
Although IA use of corticosteroids is still controversial in literature, they are commonly used in orthopedic practice to relieve pain and improve function in patients with knee OA [6]. In the literature, there is strong evidence supporting IA corticosteroid injection for significant pain relief and functional improvement in OA [7]. Synovitis and effusion of the knee joint due to the inflammatory process are frequently presented in knee OA and correlate with pain as well as functional outcome [8]. In light of data from studies reporting the association between the inflammatory process and progression of knee OA, corticosteroids may still have a potential role in the pathophysiology of cartilage damage by reducing the inflammatory process in the knee joint [9]. Beneficial effects can be achieved with the application of IA corticosteroids at low doses; however, its negative effects on healthy cartilage have been shown in vitro and in vivo studies at high doses and durations [10].
On the other hand, IA use of autologous platelet-rich plasma (PRP) injections was indicated for chondral lesions of knee to modify inflammatory response, tissue repair, and regeneration in the knee joint [11]. According to recent systematic reviews in literature, IA PRP injection was suggested as a safe and effective option in the treatment of knee OA compared to hyaluronic acid (HA) viscosupplementation [12]. However, no consensus has been established in literature regarding the number of IA injections as well as ideal intervals between repeated applications [13].
Combination of PRP with local anesthetics and/or corticosteroids is another controversial issue in literature [14]. The synergistic and protective effect of PRP on tendon cell viability when added to methlyprednisolone (MP) has been demonstrated via in-vitro studies, however, the anti-inflammatory effect of PRP in combination with or without corticosteroids is still up for debate [15, 16, 17]. Platelet activation is a primary or secondary feature in rheumatic disorders remains to be elucidated; however, emerging data suggest that the release rate of activated platelets applied topically to the inflamed cartilage in arthritis may suppress the inflammation and facilitate tissue repair [18]. To our current knowledge, there is no study found in available literature comparing IA PRP injection with combined corticosteroid and PRP injection and corticosteroid injection alone for knee OA.
It was hypothesized that the IA MP injection prior to PRP injection would lead to improvements in clinical and pain scores due to synergistic effect. Therefore, the aim of this study was to evaluate clinical outcomes of IA MP injection prior to PRP injection in comparison with single-dose MP and PRP injections alone in patients with knee OA.
Materials and methods
Study population
Patients who admitted to our department between January 2016 and August 2016 and underwent IA injection of knee joint with the diagnosis of knee OA were evaluated in this prospective longitudinal study. The study was approved by Erzincan University, Clinical Researches Ethics Committee (ID No:33216249-604.01.02-E.42916) and conducted in compliance with the Helsinki Declaration. Written informed consent was obtained from all patients.
Patients’ age, gender, body mass index (BMI), past medical history, and clinical scores were noted at the first admission. Weight-bearing anteroposterior and lateral radiographs of both knees were evaluated for radiographic classification of the patients. Magnetic resonance imaging (MRI) of the affected knee was also evaluated for all patients to exclude knee pathologies that need surgical intervention.
Patients with a complete medical record, between 40 and 80 years of age, with a body mass index (BMI) lower than 30 kg/m
Flowchart diagram of the study. n: number of patients, IA: intraarticular, OA: osteoarthritis, PRP: platelet-rich plasma, MP: methylprednisolone.
One hundred and thirty-two patients who met the eligibility criteria were divided into three groups according to IA injection treatment method. Seventeen patients were lost to follow-up and 115 patients completed 12 months follow-up (Fig. 1). The treatment groups were “PRP group” (
All injections were performed in the supine position after sterile preparation of skin. Intra-articular injections were performed through standard suprapatellar approach for IA injection of knee. Oral paracetamol was routinely prescribed for all patients.
Firstly, 2 mL of anticoagulant was withdrawn into a 20 mL sterile injector. Then, 18 mL of peripheral venous blood was taken from patient and a total of 20 mL sample was transferred into the tube of the PRP kit. The tube was centrifuged at 1800 rpm for 8 minutes. Approximately 10 mL of plasma was obtained after centrifuging. The lower part of the plasma (3 mL PRP), which has richer platelet content, was transferred into another sterile injector to administrate into the knee joint. Single dose 3 mL of PRP was combined with 3 mL of prilocaine and injected into the knee joint through suprapatellar approach.
PRP plus MP group
One week prior to IA PRP injection, all patients in the PRP
MP group
In the MP group, a single dose of 1 mL of methypre- dnisolone combined with 3 mL prilocaine was administrated into knee joint under sterile conditions through suprapatellar IA injection approach.
Outcome assessment
Patients’ demographics such as age, gender, BMI, and grade of knee OA were recorded for all patients at first admission. Visual Analog Scale (VAS) and The Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores were applied for all patients at first admission and at 1
Statistical analysis
Statistical analysis was performed using the SPSS 20 software (SPSS Inc., IBM, NY, USA). Categorical variables were given with frequency and percentage; continuous numerical variables were given with median (minimum; maximum). The Pearson Chi-Square test was used to compare frequencies. Comparison of VAS and WOMAC scores between groups at first admission, as well as at 1
Results
The demographic data and baseline characteristics of the patients at the initial control were shown in Table 1. There was no statistically significant difference between three groups in terms of age, gender, BMI, Kellgren-Lawrence classifications or the initial VAS and WOMAC scores (Table 1).
Demographics and baseline characteristics of the patients with
values
Demographics and baseline characteristics of the patients with
n.s. not significant.
At the 1
Comparison of clinical scores of the groups at 1st, 3rd, 6th and 12th months after intraarticular injection
n.s. not significant.
The line chart of initial and follow-up (a) VAS and (b) WOMAC scores of the three groups.
At the 3
At the 6
At the end of the 12
According to the results of repeated measures one-way ANOVA test, after IA injection VAS and WOMAC scores differed significantly between time points (
During the follow-up, no systemic complication was observed related to IA injections in the three groups. Besides, no septic reaction occurred after IA injections. Minor adverse reactions were defined as local reactions as pain, mild swelling, and warmth. Minor adverse reactions occurred in 5 of 37 patients (13.5%) in PRP group, in 2 of 40 patients (5%) in PRP
The most important finding of this study was PRP injection in combination with MP injection resulted in better improvements in clinical scores compared to both single-dose PRP and MP injections in patients who had mild to moderate knee OA. After combined IA injection of MP and PRP, significant improvements were observed in clinical scores compared to PRP alone within 3 months. Besides, significant differences were also detected in clinical scores compared to MP group at least 6 months.
Intra-articular PRP injection is considered as a viable treatment method for knee OA according to previous studies [20, 21]. In-vivo and in-vitro studies have shown increases in chondrocyte proliferation as well as decreases in inflammatory cascade after administration of PRP [22]. In an animal study comparing the effects of PRP and saline on full-thickness cartilage defect of knee in immature rabbits, Serra et al. reported no difference in tissue repair at 19 weeks of age [23]. Beitzel et al. reported increased tenocyte and chondrocyte proliferation after application of PRP in their in-vivo study; the authors observed that, although corticosteroid application alone decreased cell viability, this effect could reverse when a combination of PRP was applied [24]. Solchaga et al. also observed a decrease in cell proliferation after application of corticosteroid in a rat tendinopathy model, however, authors reported that histology demonstrated similar repair and they found no significant difference between PRP and corticosteroid in terms of biomechanical function and improvements of tendon [25]. In their in-vitro study on human rotator cuff derived cells, Muto et al. mentioned that PRP might be useful in combination with corticosteroid application to protect deleterious effects of corticosteroids [26]. Intra-articular PRP’s short standing effectiveness on pain modulation even in Grade IV knee OA may demonstrate its anti-inflammatory effect. On the other hand, decrease in clinical symptoms after IA PRP application may indicate its regulatory effect on biological tissue repairing mechanism due to rich content of growth factors.
To date, no study can be found in literature evaluating the clinical outcomes of PRP in combination with corticosteroid for knee OA. In literature, only limited number of studies exist about combination of HA and corticosteroid. Campos et al. compared the clinical outcomes of HA plus triamcinolone with HA alone; the authors reported that addition of triamcinolone improved first week VAS and WOMAC scores [27]. From this point of view, we hypothesized that IA PRP injection in combination with MP may provide a mutually beneficial effect. According to our results, IA injection of MP prior to PRP injection revealed superior clinical outcomes in comparison to PRP alone. However, this synergistic effect continued until the end of the 3
In the literature, the efficacy comparison of PRP and corticosteroid is still unclear. In their randomized clinical trial comparing single dose IA PRP and corticosteroid injection for Kellgren-Lawrence grade II or III knee OA, Forogh et al. reported that PRP was significantly superior to corticosteroid in terms of VAS score and knee clinical scores [28]. However, authors found no significant difference between PRP and corticosteroid when patients’ ranges of motions were compared [28]. Kon et al. reported that PRP injection yielded satisfactory clinical outcomes up to 6
When we reviewed complications after IA injection, no systemic complications or septic condition occurred during follow-up in the three groups. Minor complications due to adverse reaction such as pain, mild swelling, and warmth of the indexed knee were not observed in MP group, where as it was highest in PRP group (13.5%) compared to PRP
The main limitation of this study was comparison of non-randomized three groups. However, a relatively homogeneous patient population, with no significant difference in demographics and stages of diseases, was evaluated in this study. Besides, patients were followed up to the end of 12 months to evaluate clinical efficacy of single-dose PRP in comparison with PRP plus MP and MP alone. In the other hand, the main strength of this study was being the first study in literature reporting the clinical outcomes of IA PRP in combination with MP injection. We did not apply a priori calculation for the sample size; however, post hoc analysis was performed for each of the variables and the lowest statistical power was 0.96 with an alpha value of 0.05. This study may guide further prospective randomized well-controlled clinical trials about this issue, which was investigated widely in previous in-vitro studies.
Conclusion
According to our results, the combination therapy with MP and PRP revealed significantly better improvements at least 3 months compared to single PRP and at least 6 months compared to single MP injection in clinical scores of patients who had mild to moderate knee OA. Further clinical trials are needed to evaluate the synergistic effect of MP in addition with PRP for the treatment of knee OA.
Footnotes
Conflict of interest
None to report.
