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Does platelet-rich plasma deserve a role in the treatment of tendinopathy?
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Does platelet-rich plasma deserve a role in the treatment of tendinopathy?夽 Geoffroy Nourissat a,b , Paul Ornetti c,d,∗ , Francis Berenbaum e , Jérémie Sellam e , Pascal Richette f , Xavier Chevalier g a
Département de chirurgie orthopédique, groupe Maussins, 75019 Paris, France Inserm UMR-S938, université de la Sorbonne, UPMC Paris VI, 75012 Paris, France c CIC-P Inserm 803, plateforme d’investigation technologique, hôpital universitaire de Dijon, 21000 Dijon, France d Département de rhumatologie, hôpital universitaire de Dijon, Bocage central, 14, rue Gaffarel, 21000 Dijon, France e Département de rhumatologie, hôpital Saint-Antoine, 75012 Paris, France f Département de rhumatologie, hôpital Lariboisière, université Paris VII, 75010 Paris, France g Département de rhumatologie, hôpital Henri-Mondor, université Paris XII, 94010 Créteil, France b
a r t i c l e
i n f o
Article history: Accepted 22 July 2014 Available online xxx Keywords: Platelet-rich plasma Tendinopathy Tendinitis Systematic review Treatment
a b s t r a c t Although tendinopathies constitute a heterogeneous group of conditions, they are often treated by similar combinations of local and systemic symptomatic interventions. The vast number of causes, pathophysiological mechanisms, and histological changes that characterizes tendinopathies may explain that the standard treatment fails in some patients. Platelet-rich plasma (PRP), which contains a host of soluble mediators including growth factors, has been suggested as a second-line treatment for refractory tendinopathy, with the goal of expediting tendon healing or remodeling. Here, we report a systematic literature review of basic research data from humans and animals that support the clinical use of PRP in tendinopathies and of clinical studies in the most common tendinopathies (elbow, knee, shoulder, and Achilles tendon). Our objective is to clarify the role for this new injectable treatment, which is garnering increasing attention. The level of evidence remains low, as few well-designed randomized controlled trials have been published. The available scientific evidence does not warrant the use of PRP for the first-line treatment of tendinopathy. PRP therapy may deserve consideration in specific tendinopathy subtypes, after failure of ultrasound-guided corticosteroid injections. Nevertheless, further studies are needed to define these potential indications and the optimal treatment protocols. A key point is that the complexity of the tendon healing process cannot be replicated simply by injecting a subset of growth factors, whose effects may occur in opposite directions over time. Topics not discussed in this review are the regulatory framework for PRP therapy, PRP nomenclature, and precautions for use, which are described in a previous article (Does platelet-rich plasma have a role in the treatment of osteoarthritis, Ornetti P, et al. [1]). © 2015 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
1. Abbreviations
TGF VEGF
HGF IGF MMP PDGF PRP
2. Introduction
hepatocyte growth factor insulin-like growth factor metalloproteases platelet-derived growth factor platelet-rich plasma
夽 Under the aegis of the osteoarthritis section of the French Society for Rheumatology (Société franc¸aise de rhumatologie [SFR]). ∗ Corresponding author. Tel.: ++33 38 02 93 74 5; fax: ++33 38 02 95 23 9. E-mail address: [email protected] (P. Ornetti).
transforming growth factor beta vascular endothelial growth factor
Tendinopathy is a major reason for patient visits to rheumatologists and orthopedic surgeons [2–4]. The treatment rests on symptomatic interventions including physical therapy, analgesics, and antiinflammatory agents. Tendinopathy chiefly affects young individuals and places a considerable financial burden on society via both medication use and sick-leave days [4]. Tendinopathy is a multifactorial condition often related to a combination of microtrauma, excessive loading, and normal aging [4,5]. Among the mechanisms involved in the development of tendinopathy,
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the initial inflammation is the target of the pharmacological treatment. The effects of local and systemic antiinflammatory therapy, however, are mixed [3–5]. Furthermore, recurrences are not uncommon and antiinflammatory drugs have well-documented adverse effects. Given the limited effectiveness of standard treatments and the pathophysiological factors involved in tendinopathy, the introduction of injectable platelet concentrates, known as platelet-rich plasma (PRP), holds considerable theoretical appeal as a means of combating some of the mechanisms responsible for the development or persistence of the tendon lesions [6–8]. The objective of the systematic literature review reported here is to provide an overview of recent data on PRP therapy for tendinopathy, in order to better delineate the potential benefits from adding this intervention to the fairly limited pharmacological armamentarium, as an adjunct to physical and/or surgical treatments.
3. Tendinopathies: nosological considerations A prerequisite to discussing the potential therapeutic role for PRP is a clear classification of the various types of tendinopathy. The failure of many studies to demonstrate a therapeutic effect of PRP is probably ascribable to both insufficient attention to defining the treatment targets clearly and inclusion of patients with a wide range of tendon lesions. The first essential distinction is between involvement of the tendon body and involvement of the tendon insertion site. The tendon body is composed chiefly of type I collagen, which contributes 60% of the dry weight but also contains proteoglycans such as decorin, versican, and lumican. Glycoproteins, in particular elastin, contribute 5% of the dry weight [4]. The matrix of the tendon body is produced by tenocytes, which are present in only very small numbers [4]. Insertional tendinopathy affects the enthesis [9], which is mainly composed of type II collagen, contains very little elastin, and has a matrix produced by chondrocyte-like cells, which are present in high concentrations [3,4]. Thus, differentiating the tissue targets is a crucial prerequisite to using a single therapeutic approach. In non insertional tendinopathy, whether the matrix alterations are very marked remains unclear [4]. The amount of type I and III collagen increases in chronic tendinopathy. The concentrations of many proteins involved in the inflammatory process increase or decrease depending on the stage in the course of the tendinopathy. During the development of tendinopathy, transforming growth factor  (TGF), insulin-like growth factor 1 (IGF-1), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF) increase, while receptor 1 for TGF (TGF-R1) decreases. At the stage of chronic tendinopathy, the concentrations of these growth factors return to normal. A number of metalloproteases (MMP) such as MMP1, MMP2, MMP23 tend to increase, whereas MMP3, MMP10, and MMP27 decrease. The tendon matrix undergoes active remodeling [4]. These changes vary with patient age, type of tendinopathy, and progression to chronicity. Ideally, the changes in matrix components and the in situ expression of the various inflammation mediators should be analyzed before the use of treatments targeting matrix repair [5]. In practice, however, such an analysis would require a tendon biopsy, which would be unacceptable. In chronic tendinopathy and during aging, the mechanical properties of the tendon are preserved, whereas the capacity for lesion repair is impaired. Given these data, a single treatment, or a single therapeutic strategy incorporating PRP administration, is probably unable to produce benefits across the vast range of tendinopathy types [6]. Imaging studies have established that the anatomic features of the tendon lesions constitute another relevant factor. Tendinopathy affecting the tendon body may be either focal or diffuse,
and hypervascularization may be present or absent. Histological lesions are consistently present in patients with symptomatic tendinopathy and may also be found in tendons that are completely asymptomatic [9]. The histological alterations vary widely and may include hypoxic mucoid, myxoid, lipoid, hyaline, and fibrous degeneration [10]. Calcific tendinopathy is a separate entity. Tendon degeneration and fibrocartilaginous or osseous metaplasia are borderline physiological alterations. In sum, this wide variability in clinical and anatomic characteristics probably explains the variability of the effects of PRP injections.
4. Background information on platelet-rich plasma (PRP) 4.1. PRP effects on cells and tendons in animal studies A systematic review of basic-science studies on the use of PRP to treat tendinopathy was reported in 2013 [11]. The first investigation of growth-factor effects on tendon tissue was published in 2007 and showed that TGF and PDGF expression by explants of equine flexor digitorum superficialis tendon increased when the specimens were cultured in PRP [12]. Similarly, in a 2009 study of equine tendon specimens, changes induced by culturing in PRP included decreased expression of MMP3 and MMP13, two enzymes involved in breaking down type III collagen; increases in PDGF and TGF, which are involved in fibrosis and tissue healing; and increased production of type I collagen [13]. A study of dog tendons reported in 2010 showed that adding PRP to tendon suture resulted in greater mechanical strength and stiffness compared to suture alone [14]. In cell studies, PRP promoted tenocyte differentiation of stem cells from rabbit patellar tendon and increased target-gene expression [15]. Dog patellar tendon cells cultured on PRP-enriched synthetic scaffolds increased their production of PDGF, total collagen, and glycosaminoglycans [16,17]. Finally, rat Achilles tendon tenocytes exhibited increased proliferation when cultured in PRP [18]. Taken in concert, these basic-science studies indicate a chiefly anabolic effect of PRP that might potentially improve the quality of the tendon matrix.
4.2. PRP effects on human cells and tendons The first in-depth investigation of PRP therapy in humans was reported in 2005 and relied on an original method of sample collection, concentration by centrifugation, activation, and re-injection [19]. Human tendon tissue was harvested during anterior cruciate ligament repair and cultured in PRP for 6 days. Increases were noted in the concentrations of PDGF, VEGF, TGF, and hepatocyte growth factor (HGF), four growth factors that promote matrix production. A 2008 report indicated that tenocyte proliferation increased when human hamstring tendon fragments were cultured in PRP [20,21]. In another study of human hamstring tendon, PRP increased fibroblast proliferation and VEGF expression by tenocytes [22]. PRP increased the survival of human hamstring tenocytes, which seemed protected against corticosteroid toxicity [23]. Human hamstring tenocytes showed a significant increase in growth when exposed to PRP [24]. Tenocytes from human rotator cuff tendons removed during repair surgery grew at an increased rate when exposed to PRP compared to unexposed cells, with a statistically significant dose-effect [25]. In another study, in contrast, human biceps tenocytes cultured with PRP exhibited significant decreases in proliferation and viability when exposed to anesthetics or methylprednisolone [26]. Overall, these in vitro studies of human samples suggest a beneficial influence of PRP mediated by the anabolic effects of certain growth factors, which may promote tendon matrix repair.
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5. Clinical data on platelet-rich plasma (PRP) used to treat tendinopathy
PRP therapy in patients with Achilles tendinopathy who have failed first-line comprehensive nonoperative therapy.
5.1. Use of PRP in lateral epicondylitis (tennis elbow)
5.3. Use of PRP in patellar tendinopathy (jumper’s knee)
Two prospective randomized trials have been published, as well as several open-label studies providing lower levels of evidence. The first clinical investigation of PRP is a cohort study reported in 2006 [27]. The 20 patients had lateral epicondylitis refractory to pharmacological and physical treatment; among them, 15 received a single injection of PRP (platelet concentration of 5-fold the normal value) and 5 a single injection of bupivacaine. The main effect of PRP was an improvement in the visual analog scale (VAS) pain score after 8 weeks, by 60% compared to 16% in the bupivacaine group [27]. In a randomized double-blind trial of PRP versus local corticosteroid injections in 100 patients with chronic lateral epicondylitis, corticosteroid therapy tended to produce greater effects than PRP during the first 6 months, whereas subsequently pain and overall upper limb function (DASH scores) tended to be better in the PRP group, although the differences fell short of statistical significance [28]. In a prospective cohort study of 31 elbows (30 patients) with lateral epicondylitis refractory to nonoperative treatment including corticosteroid injections, a 25% decrease in pain severity was noted 1 month after a single PRP injection in 90% of cases [29]. A randomized double-blind trial compared PRP and autologous blood in 150 patients who had failed physical therapy [30]. The patients in both groups received two injections at a 1-month interval. Similar improvements were recorded in the two groups. A recent multicenter randomized placebo-controlled trial of leukocyte-containing PRP (L-PRP) in 230 patients showed significantly greater pain relief in the PRP group (12 weeks, 55.1% versus 47.4% of patients; and 12 months, 71.1% versus 56.1% of patients; P < 0.05). After 24 weeks, the proportion of satisfied patients was 84% with PRP and 68% with the placebo. Nevertheless, a 2014 meta-analysis found no evidence that PRP was effective in chronic lateral epicondylitis [31], although most of the study patients had refractory symptoms.
An open-label study in 20 athletes evaluated PRP containing 6 times the normal platelet concentration [37]. The evaluation 6 months after three injections under ultrasound guidance showed improvements in 80% of cases in the SF36, VAS pain score, and knee function score. In 2010, the same group reported outcomes in 15 patients with chronic jumper’s knee who received PRP in the same concentration, according to the same injection schedule, comparatively with those in 16 patients managed using physical therapy alone [38]. The proportion of patients with improved SF36 and VAS pain score results after 6 months was 86.7% with and 68.7% without PRP therapy. A randomized controlled trial compared PRP and focused extracorporeal shock wave therapy (ESWT) in 46 athletes performing at various levels, whereas the remaining 23 patients received three sessions of focused ESWT [39]. Improvements were recorded in both groups but were significantly greater in the PRP group (P < 0.05). Another group subsequently confirmed these findings using a similar protocol [40]. In a case-series study, the efficacy of three ultrasound-guided PRP injections at 1-week intervals was assessed in 28 professional and recreational athletes with patellar tendinopathy [41]. Improvements in the clinical outcome measures and magnetic resonance imaging (MRI) findings were apparent as early as 3 months after the injections, and the MRI improvements were sustained in patients who underwent repeat MRI after 2 years. Nevertheless, 25% of patients were classified as treatment failures at study completion, and the study had no control group. These studies seem to support multiple ultrasound-guided PRP injections to treat insertional patellar tendinopathy after failure of first-line conservative treatment. Their results require confirmation by studies producing a higher level of evidence and having longer patient follow-up times. 5.4. Use of PRP in rotator-cuff tendinopathy
5.2. Use of PRP in Achilles tendinopathy Few studies have assessed PRP effects in Achilles tendinopathy in patients who had no surgical treatment. The first study was a randomized controlled trial published in 2010 [32], with additional imaging data reported the following year [33]. The 54 patients with chronic midportion Achilles tendinopathy were allocated at random to either a single PRP injection or a single saline injection. The same physical therapy program was used in both groups. After 6 and 12 months, no significant differences in the clinical or ultrasound outcome measures were found. In contrast, in a prospective open-label study in 14 patients (15 Achilles tendons) with chronic non-insertional Achilles tendinopathy refractory to standard conservative treatment, improvements in clinical outcomes were noted after 3 months and were sustained after 18 months [34]. Imaging studies showed improvements in tendon vascularization and abnormal tendon thickening. Several studies assessed PRP therapy used in combination with surgical repair of Achilles tendon tears. In 12 athletes who underwent open surgery for complete tendon tears, mean time to sports resumption was 14 weeks when PRP was applied during surgery (n = 6) compared to 22 weeks without PRP (n = 6) (P < 0.05) [35]. In another randomized controlled trial, 30 patients were allocated to surgery with or without PRP (with a very high platelet concentration of 17-fold the normal value). After 1 year, the clinical score was lower in the PRP group [36]. In sum, the available data are limited by the small sample sizes and heterogeneity of the treatment protocols. Overall, they do not support
PRP used to treat chronic rotator-cuff tendinopathy was assessed in two studies published in 2013. One was a randomized controlled trial in 40 patients who received a single subacromial ultrasound-guided injection of PRP or saline [42]. The inclusion criteria were broad: shoulder pain for more than 3 months, at least 50% decrease in pain severity after a subacromial lidocaine test, and MRI evidence of tendinopathy with or without tearing). Patients in both groups followed the same standardized exercise program. No significant differences were detected between the two groups after 1 year. The other study was a prospective non comparative open-label trial in 18 patients (19 shoulders) with rotator-cuff tendinopathy refractory to physical therapy and corticosteroid injection [43]. A single ultrasound-guided injection of PRP was administered into the lesion and surrounding tendon. After 3 months, improvements were found in pain, strength, resistance, and imaging study findings. These effects were sustained after 1 year. Given the heterogeneity of the patient populations in these studies, together with a number of other methodological weaknesses, the available data are not sufficient to establish that PRP therapy is effective in rotator-cuff tendinopathy. Five studies assessed the effects of PRP therapy combined with rotator cuff repair. A 2011 randomized trial compared 26 patients managed with an intraoperative application of PRP and 27 managed without PRP [44]. Pain scores were significantly lower in the PRP group during the first postoperative month. No significant difference was found in the healing rate of the rotator cuff tears, although there was some evidence of a beneficial effect of PRP in the
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subgroup with early tears. Another randomized controlled trial in 88 patients with rotator cuff tears compared the application of PRP between the bone and tendon at the end of the repair procedure (n = 43) to no PRP (n = 45). After a mean follow-up of 16 months, no clinical or MRI differences were found between the two groups [45]. In a study of 42 patients with full-thickness rotator cuff tears, 19 chose to receive an application of PRP gel at the end of the surgical procedure and 23 declined this treatment [46]. After a mean follow-up of 16 months, the healing rate was higher in the PRP group, but the difference was not statistically significant. A similar study in the same indication with a minimal follow-up of 2 years confirmed these findings [47]. Finally, L-PRP obtained by centrifugation immediately before use had limited effects in patients undergoing arthroscopic repair of large or massive rotator cuff tears [48]. 6. Conclusion The available data do not support the use of PRP as a first-line treatment for chronic tendinopathy, regardless of lesion site and type. The pharmacological rationale for using PRP in tendinopathy remains ill-defined, since platelets release a vast number of factors whose complex effects vary over time, across target tissues, and with the platelet concentration [1]. From a clinical viewpoint, an important consideration is the considerable heterogeneity of tendinopathies. The characteristics of treated tendinopathies are not always described in detail in published work, a fact that limits the validity of study conclusions and hinders comparisons across studies. Useful information could no doubt be obtained by performing studies in narrower indications, probably at an early stage of the tendon disease. In addition to this heterogeneity of the clinical conditions, the composition of PRP varies widely depending on the preparation method and type of activation. Furthermore, a broad array of protocols in terms of number and schedule of PRP injections has been used, and strong interindividual variability is likely but has received very little attention in research studies. In patients with chronic tendinopathy refractory to standard nonoperative treatment including corticosteroid injections, multiple ultrasound-guided injections of PRP prepared using several concentration steps may hold therapeutic potential, most notably in patellar tendinopathy. However, concomitant evaluations of PRP safety are needed, as adverse effects may arise, particularly with excessive platelet concentrations. Serious adverse effects such as infections and allergies seem rare. Injection site pain may be more common and more severe than with corticosteroids. However, there are no grounds at present for discarding PRP as a potential treatment option in patients with refractory tendinopathy, a condition for which few effective treatments are available in clinical practice. Therefore, rheumatologists should direct close attention to developments in the field of PRP therapy, in particular by contributing to large-scale multicenter randomized clinical trials, which are needed to assess the therapeutic potential of PRP in tendinopathies. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References [1] Ornetti P, Nourissat G, Berenbaum F, et al. Does platelet-rich plasma have a role in the treatment of osteoarthritis. Joint Bone Spine in press. [2] Sharma P, Maffulli N. Tendon injury and tendinopathy: healing and repair. J Bone Joint Surg Am 2005;87:187–202.
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Does platelet-rich plasma deserve a role in the treatment of tendinopathy?夽 Geoffroy Nourissat a,b , Paul Ornetti c,d,∗ , Francis Berenbaum e , Jérémie Sellam e , Pascal Richette f , Xavier Chevalier g a
Département de chirurgie orthopédique, groupe Maussins, 75019 Paris, France Inserm UMR-S938, université de la Sorbonne, UPMC Paris VI, 75012 Paris, France c CIC-P Inserm 803, plateforme d’investigation technologique, hôpital universitaire de Dijon, 21000 Dijon, France d Département de rhumatologie, hôpital universitaire de Dijon, Bocage central, 14, rue Gaffarel, 21000 Dijon, France e Département de rhumatologie, hôpital Saint-Antoine, 75012 Paris, France f Département de rhumatologie, hôpital Lariboisière, université Paris VII, 75010 Paris, France g Département de rhumatologie, hôpital Henri-Mondor, université Paris XII, 94010 Créteil, France b
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Article history: Accepted 22 July 2014 Available online xxx Keywords: Platelet-rich plasma Tendinopathy Tendinitis Systematic review Treatment
a b s t r a c t Although tendinopathies constitute a heterogeneous group of conditions, they are often treated by similar combinations of local and systemic symptomatic interventions. The vast number of causes, pathophysiological mechanisms, and histological changes that characterizes tendinopathies may explain that the standard treatment fails in some patients. Platelet-rich plasma (PRP), which contains a host of soluble mediators including growth factors, has been suggested as a second-line treatment for refractory tendinopathy, with the goal of expediting tendon healing or remodeling. Here, we report a systematic literature review of basic research data from humans and animals that support the clinical use of PRP in tendinopathies and of clinical studies in the most common tendinopathies (elbow, knee, shoulder, and Achilles tendon). Our objective is to clarify the role for this new injectable treatment, which is garnering increasing attention. The level of evidence remains low, as few well-designed randomized controlled trials have been published. The available scientific evidence does not warrant the use of PRP for the first-line treatment of tendinopathy. PRP therapy may deserve consideration in specific tendinopathy subtypes, after failure of ultrasound-guided corticosteroid injections. Nevertheless, further studies are needed to define these potential indications and the optimal treatment protocols. A key point is that the complexity of the tendon healing process cannot be replicated simply by injecting a subset of growth factors, whose effects may occur in opposite directions over time. Topics not discussed in this review are the regulatory framework for PRP therapy, PRP nomenclature, and precautions for use, which are described in a previous article (Does platelet-rich plasma have a role in the treatment of osteoarthritis, Ornetti P, et al. [1]). © 2015 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
1. Abbreviations
TGF VEGF
HGF IGF MMP PDGF PRP
2. Introduction
hepatocyte growth factor insulin-like growth factor metalloproteases platelet-derived growth factor platelet-rich plasma
夽 Under the aegis of the osteoarthritis section of the French Society for Rheumatology (Société franc¸aise de rhumatologie [SFR]). ∗ Corresponding author. Tel.: ++33 38 02 93 74 5; fax: ++33 38 02 95 23 9. E-mail address: [email protected] (P. Ornetti).
transforming growth factor beta vascular endothelial growth factor
Tendinopathy is a major reason for patient visits to rheumatologists and orthopedic surgeons [2–4]. The treatment rests on symptomatic interventions including physical therapy, analgesics, and antiinflammatory agents. Tendinopathy chiefly affects young individuals and places a considerable financial burden on society via both medication use and sick-leave days [4]. Tendinopathy is a multifactorial condition often related to a combination of microtrauma, excessive loading, and normal aging [4,5]. Among the mechanisms involved in the development of tendinopathy,
http://dx.doi.org/10.1016/j.jbspin.2015.02.004 1297-319X/© 2015 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
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the initial inflammation is the target of the pharmacological treatment. The effects of local and systemic antiinflammatory therapy, however, are mixed [3–5]. Furthermore, recurrences are not uncommon and antiinflammatory drugs have well-documented adverse effects. Given the limited effectiveness of standard treatments and the pathophysiological factors involved in tendinopathy, the introduction of injectable platelet concentrates, known as platelet-rich plasma (PRP), holds considerable theoretical appeal as a means of combating some of the mechanisms responsible for the development or persistence of the tendon lesions [6–8]. The objective of the systematic literature review reported here is to provide an overview of recent data on PRP therapy for tendinopathy, in order to better delineate the potential benefits from adding this intervention to the fairly limited pharmacological armamentarium, as an adjunct to physical and/or surgical treatments.
3. Tendinopathies: nosological considerations A prerequisite to discussing the potential therapeutic role for PRP is a clear classification of the various types of tendinopathy. The failure of many studies to demonstrate a therapeutic effect of PRP is probably ascribable to both insufficient attention to defining the treatment targets clearly and inclusion of patients with a wide range of tendon lesions. The first essential distinction is between involvement of the tendon body and involvement of the tendon insertion site. The tendon body is composed chiefly of type I collagen, which contributes 60% of the dry weight but also contains proteoglycans such as decorin, versican, and lumican. Glycoproteins, in particular elastin, contribute 5% of the dry weight [4]. The matrix of the tendon body is produced by tenocytes, which are present in only very small numbers [4]. Insertional tendinopathy affects the enthesis [9], which is mainly composed of type II collagen, contains very little elastin, and has a matrix produced by chondrocyte-like cells, which are present in high concentrations [3,4]. Thus, differentiating the tissue targets is a crucial prerequisite to using a single therapeutic approach. In non insertional tendinopathy, whether the matrix alterations are very marked remains unclear [4]. The amount of type I and III collagen increases in chronic tendinopathy. The concentrations of many proteins involved in the inflammatory process increase or decrease depending on the stage in the course of the tendinopathy. During the development of tendinopathy, transforming growth factor  (TGF), insulin-like growth factor 1 (IGF-1), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF) increase, while receptor 1 for TGF (TGF-R1) decreases. At the stage of chronic tendinopathy, the concentrations of these growth factors return to normal. A number of metalloproteases (MMP) such as MMP1, MMP2, MMP23 tend to increase, whereas MMP3, MMP10, and MMP27 decrease. The tendon matrix undergoes active remodeling [4]. These changes vary with patient age, type of tendinopathy, and progression to chronicity. Ideally, the changes in matrix components and the in situ expression of the various inflammation mediators should be analyzed before the use of treatments targeting matrix repair [5]. In practice, however, such an analysis would require a tendon biopsy, which would be unacceptable. In chronic tendinopathy and during aging, the mechanical properties of the tendon are preserved, whereas the capacity for lesion repair is impaired. Given these data, a single treatment, or a single therapeutic strategy incorporating PRP administration, is probably unable to produce benefits across the vast range of tendinopathy types [6]. Imaging studies have established that the anatomic features of the tendon lesions constitute another relevant factor. Tendinopathy affecting the tendon body may be either focal or diffuse,
and hypervascularization may be present or absent. Histological lesions are consistently present in patients with symptomatic tendinopathy and may also be found in tendons that are completely asymptomatic [9]. The histological alterations vary widely and may include hypoxic mucoid, myxoid, lipoid, hyaline, and fibrous degeneration [10]. Calcific tendinopathy is a separate entity. Tendon degeneration and fibrocartilaginous or osseous metaplasia are borderline physiological alterations. In sum, this wide variability in clinical and anatomic characteristics probably explains the variability of the effects of PRP injections.
4. Background information on platelet-rich plasma (PRP) 4.1. PRP effects on cells and tendons in animal studies A systematic review of basic-science studies on the use of PRP to treat tendinopathy was reported in 2013 [11]. The first investigation of growth-factor effects on tendon tissue was published in 2007 and showed that TGF and PDGF expression by explants of equine flexor digitorum superficialis tendon increased when the specimens were cultured in PRP [12]. Similarly, in a 2009 study of equine tendon specimens, changes induced by culturing in PRP included decreased expression of MMP3 and MMP13, two enzymes involved in breaking down type III collagen; increases in PDGF and TGF, which are involved in fibrosis and tissue healing; and increased production of type I collagen [13]. A study of dog tendons reported in 2010 showed that adding PRP to tendon suture resulted in greater mechanical strength and stiffness compared to suture alone [14]. In cell studies, PRP promoted tenocyte differentiation of stem cells from rabbit patellar tendon and increased target-gene expression [15]. Dog patellar tendon cells cultured on PRP-enriched synthetic scaffolds increased their production of PDGF, total collagen, and glycosaminoglycans [16,17]. Finally, rat Achilles tendon tenocytes exhibited increased proliferation when cultured in PRP [18]. Taken in concert, these basic-science studies indicate a chiefly anabolic effect of PRP that might potentially improve the quality of the tendon matrix.
4.2. PRP effects on human cells and tendons The first in-depth investigation of PRP therapy in humans was reported in 2005 and relied on an original method of sample collection, concentration by centrifugation, activation, and re-injection [19]. Human tendon tissue was harvested during anterior cruciate ligament repair and cultured in PRP for 6 days. Increases were noted in the concentrations of PDGF, VEGF, TGF, and hepatocyte growth factor (HGF), four growth factors that promote matrix production. A 2008 report indicated that tenocyte proliferation increased when human hamstring tendon fragments were cultured in PRP [20,21]. In another study of human hamstring tendon, PRP increased fibroblast proliferation and VEGF expression by tenocytes [22]. PRP increased the survival of human hamstring tenocytes, which seemed protected against corticosteroid toxicity [23]. Human hamstring tenocytes showed a significant increase in growth when exposed to PRP [24]. Tenocytes from human rotator cuff tendons removed during repair surgery grew at an increased rate when exposed to PRP compared to unexposed cells, with a statistically significant dose-effect [25]. In another study, in contrast, human biceps tenocytes cultured with PRP exhibited significant decreases in proliferation and viability when exposed to anesthetics or methylprednisolone [26]. Overall, these in vitro studies of human samples suggest a beneficial influence of PRP mediated by the anabolic effects of certain growth factors, which may promote tendon matrix repair.
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5. Clinical data on platelet-rich plasma (PRP) used to treat tendinopathy
PRP therapy in patients with Achilles tendinopathy who have failed first-line comprehensive nonoperative therapy.
5.1. Use of PRP in lateral epicondylitis (tennis elbow)
5.3. Use of PRP in patellar tendinopathy (jumper’s knee)
Two prospective randomized trials have been published, as well as several open-label studies providing lower levels of evidence. The first clinical investigation of PRP is a cohort study reported in 2006 [27]. The 20 patients had lateral epicondylitis refractory to pharmacological and physical treatment; among them, 15 received a single injection of PRP (platelet concentration of 5-fold the normal value) and 5 a single injection of bupivacaine. The main effect of PRP was an improvement in the visual analog scale (VAS) pain score after 8 weeks, by 60% compared to 16% in the bupivacaine group [27]. In a randomized double-blind trial of PRP versus local corticosteroid injections in 100 patients with chronic lateral epicondylitis, corticosteroid therapy tended to produce greater effects than PRP during the first 6 months, whereas subsequently pain and overall upper limb function (DASH scores) tended to be better in the PRP group, although the differences fell short of statistical significance [28]. In a prospective cohort study of 31 elbows (30 patients) with lateral epicondylitis refractory to nonoperative treatment including corticosteroid injections, a 25% decrease in pain severity was noted 1 month after a single PRP injection in 90% of cases [29]. A randomized double-blind trial compared PRP and autologous blood in 150 patients who had failed physical therapy [30]. The patients in both groups received two injections at a 1-month interval. Similar improvements were recorded in the two groups. A recent multicenter randomized placebo-controlled trial of leukocyte-containing PRP (L-PRP) in 230 patients showed significantly greater pain relief in the PRP group (12 weeks, 55.1% versus 47.4% of patients; and 12 months, 71.1% versus 56.1% of patients; P < 0.05). After 24 weeks, the proportion of satisfied patients was 84% with PRP and 68% with the placebo. Nevertheless, a 2014 meta-analysis found no evidence that PRP was effective in chronic lateral epicondylitis [31], although most of the study patients had refractory symptoms.
An open-label study in 20 athletes evaluated PRP containing 6 times the normal platelet concentration [37]. The evaluation 6 months after three injections under ultrasound guidance showed improvements in 80% of cases in the SF36, VAS pain score, and knee function score. In 2010, the same group reported outcomes in 15 patients with chronic jumper’s knee who received PRP in the same concentration, according to the same injection schedule, comparatively with those in 16 patients managed using physical therapy alone [38]. The proportion of patients with improved SF36 and VAS pain score results after 6 months was 86.7% with and 68.7% without PRP therapy. A randomized controlled trial compared PRP and focused extracorporeal shock wave therapy (ESWT) in 46 athletes performing at various levels, whereas the remaining 23 patients received three sessions of focused ESWT [39]. Improvements were recorded in both groups but were significantly greater in the PRP group (P < 0.05). Another group subsequently confirmed these findings using a similar protocol [40]. In a case-series study, the efficacy of three ultrasound-guided PRP injections at 1-week intervals was assessed in 28 professional and recreational athletes with patellar tendinopathy [41]. Improvements in the clinical outcome measures and magnetic resonance imaging (MRI) findings were apparent as early as 3 months after the injections, and the MRI improvements were sustained in patients who underwent repeat MRI after 2 years. Nevertheless, 25% of patients were classified as treatment failures at study completion, and the study had no control group. These studies seem to support multiple ultrasound-guided PRP injections to treat insertional patellar tendinopathy after failure of first-line conservative treatment. Their results require confirmation by studies producing a higher level of evidence and having longer patient follow-up times. 5.4. Use of PRP in rotator-cuff tendinopathy
5.2. Use of PRP in Achilles tendinopathy Few studies have assessed PRP effects in Achilles tendinopathy in patients who had no surgical treatment. The first study was a randomized controlled trial published in 2010 [32], with additional imaging data reported the following year [33]. The 54 patients with chronic midportion Achilles tendinopathy were allocated at random to either a single PRP injection or a single saline injection. The same physical therapy program was used in both groups. After 6 and 12 months, no significant differences in the clinical or ultrasound outcome measures were found. In contrast, in a prospective open-label study in 14 patients (15 Achilles tendons) with chronic non-insertional Achilles tendinopathy refractory to standard conservative treatment, improvements in clinical outcomes were noted after 3 months and were sustained after 18 months [34]. Imaging studies showed improvements in tendon vascularization and abnormal tendon thickening. Several studies assessed PRP therapy used in combination with surgical repair of Achilles tendon tears. In 12 athletes who underwent open surgery for complete tendon tears, mean time to sports resumption was 14 weeks when PRP was applied during surgery (n = 6) compared to 22 weeks without PRP (n = 6) (P < 0.05) [35]. In another randomized controlled trial, 30 patients were allocated to surgery with or without PRP (with a very high platelet concentration of 17-fold the normal value). After 1 year, the clinical score was lower in the PRP group [36]. In sum, the available data are limited by the small sample sizes and heterogeneity of the treatment protocols. Overall, they do not support
PRP used to treat chronic rotator-cuff tendinopathy was assessed in two studies published in 2013. One was a randomized controlled trial in 40 patients who received a single subacromial ultrasound-guided injection of PRP or saline [42]. The inclusion criteria were broad: shoulder pain for more than 3 months, at least 50% decrease in pain severity after a subacromial lidocaine test, and MRI evidence of tendinopathy with or without tearing). Patients in both groups followed the same standardized exercise program. No significant differences were detected between the two groups after 1 year. The other study was a prospective non comparative open-label trial in 18 patients (19 shoulders) with rotator-cuff tendinopathy refractory to physical therapy and corticosteroid injection [43]. A single ultrasound-guided injection of PRP was administered into the lesion and surrounding tendon. After 3 months, improvements were found in pain, strength, resistance, and imaging study findings. These effects were sustained after 1 year. Given the heterogeneity of the patient populations in these studies, together with a number of other methodological weaknesses, the available data are not sufficient to establish that PRP therapy is effective in rotator-cuff tendinopathy. Five studies assessed the effects of PRP therapy combined with rotator cuff repair. A 2011 randomized trial compared 26 patients managed with an intraoperative application of PRP and 27 managed without PRP [44]. Pain scores were significantly lower in the PRP group during the first postoperative month. No significant difference was found in the healing rate of the rotator cuff tears, although there was some evidence of a beneficial effect of PRP in the
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subgroup with early tears. Another randomized controlled trial in 88 patients with rotator cuff tears compared the application of PRP between the bone and tendon at the end of the repair procedure (n = 43) to no PRP (n = 45). After a mean follow-up of 16 months, no clinical or MRI differences were found between the two groups [45]. In a study of 42 patients with full-thickness rotator cuff tears, 19 chose to receive an application of PRP gel at the end of the surgical procedure and 23 declined this treatment [46]. After a mean follow-up of 16 months, the healing rate was higher in the PRP group, but the difference was not statistically significant. A similar study in the same indication with a minimal follow-up of 2 years confirmed these findings [47]. Finally, L-PRP obtained by centrifugation immediately before use had limited effects in patients undergoing arthroscopic repair of large or massive rotator cuff tears [48]. 6. Conclusion The available data do not support the use of PRP as a first-line treatment for chronic tendinopathy, regardless of lesion site and type. The pharmacological rationale for using PRP in tendinopathy remains ill-defined, since platelets release a vast number of factors whose complex effects vary over time, across target tissues, and with the platelet concentration [1]. From a clinical viewpoint, an important consideration is the considerable heterogeneity of tendinopathies. The characteristics of treated tendinopathies are not always described in detail in published work, a fact that limits the validity of study conclusions and hinders comparisons across studies. Useful information could no doubt be obtained by performing studies in narrower indications, probably at an early stage of the tendon disease. In addition to this heterogeneity of the clinical conditions, the composition of PRP varies widely depending on the preparation method and type of activation. Furthermore, a broad array of protocols in terms of number and schedule of PRP injections has been used, and strong interindividual variability is likely but has received very little attention in research studies. In patients with chronic tendinopathy refractory to standard nonoperative treatment including corticosteroid injections, multiple ultrasound-guided injections of PRP prepared using several concentration steps may hold therapeutic potential, most notably in patellar tendinopathy. However, concomitant evaluations of PRP safety are needed, as adverse effects may arise, particularly with excessive platelet concentrations. Serious adverse effects such as infections and allergies seem rare. Injection site pain may be more common and more severe than with corticosteroids. However, there are no grounds at present for discarding PRP as a potential treatment option in patients with refractory tendinopathy, a condition for which few effective treatments are available in clinical practice. Therefore, rheumatologists should direct close attention to developments in the field of PRP therapy, in particular by contributing to large-scale multicenter randomized clinical trials, which are needed to assess the therapeutic potential of PRP in tendinopathies. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References [1] Ornetti P, Nourissat G, Berenbaum F, et al. Does platelet-rich plasma have a role in the treatment of osteoarthritis. Joint Bone Spine in press. [2] Sharma P, Maffulli N. Tendon injury and tendinopathy: healing and repair. J Bone Joint Surg Am 2005;87:187–202.
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