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Comparative Effectiveness of Platelet-Rich Plasma Injections for Treating Knee Joint Cartilage Degenerative Pathology: A Systematic Review and Meta-Analysis
Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital, BeiHu Branch, and National Taiwan University College of Medicine, Taipei, TaiwanGraduate Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei, Taiwan
Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital, BeiHu Branch, and National Taiwan University College of Medicine, Taipei, Taiwan
Corresponding author Wen-Shiang Chen, MD, PhD, Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital and National Taiwan University College of Medicine No. 7, Chun-San S. Rd, Taipei, 100, Taiwan ROC.
Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
To explore the effectiveness of platelet-rich plasma (PRP) in treating cartilage degenerative pathology in knee joints.
Data Sources
Electronic databases, including PubMed and Scopus, were searched from the earliest record to September 2013.
Study Selection
We included single-arm prospective studies, quasi-experimental studies, and randomized controlled trials that used PRP to treat knee chondral degenerative lesions. Eight single-arm studies, 3 quasi-experimental studies, and 5 randomized controlled trials were identified, comprising 1543 participants.
Data Extraction
We determined effect sizes for the selected studies by extracting changes in functional scales after the interventions and compared the PRP group pooled values with the pretreatment baseline and the groups receiving placebo or hyaluronic acid (HA) injections.
Data Synthesis
PRP injections in patients with knee degenerative pathology showed continual efficacy for 12 months compared with their pretreatment condition. The effectiveness of PRP was likely better and more prolonged than that of HA. Injection doses ≤2, the use of a single-spinning approach, and lack of additional activators led to an uncertainty in the treatment effects. Patients with lower degrees of cartilage degeneration achieved superior outcomes as opposed to those affected by advanced osteoarthritis.
Conclusions
PRP application improves function from basal evaluations in patients with knee joint cartilage degenerative pathology and tends to be more effective than HA administration. Discrepancy in the degenerative severity modifies the treatment responses, leading to participants with lower degrees of degeneration benefiting more from PRP injections.
The knee is the most common joint in the lower extremity affected by cartilage degeneration, with severity ranging from degenerative chondropathy to advanced osteoarthritis (OA). The progression of articular chondral lesions results in pain, stiffness, swelling, and restricted joint motion, greatly affecting the quality of life and socioeconomic well-being.
A variety of pain-relieving oral medications are available and appear effective in the early disease stages, including acetaminophen, nonsteroidal anti-inflammatory drugs, and weak opioid analogues.
EULAR recommendations 2003: an evidence based approach to the management of knee osteoarthritis: report of a Task Force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT).
Intra-articular corticosteroid injections have been widely used in the management of symptomatic knee OA, but their effectiveness seems to be limited to 1 month.
Synthetic hyaluronic acid (HA), whose natural form is present in healthy joint fluid, has been used to treat knee OA for decades based on the theoretical benefits of viscosupplementation and modulation of inflammatory reactions. Although an antecedent meta-analysis disclosed the superiority of HA over corticosteroids in terms of longer efficacy, a recent large-scaled meta-analysis
discouraged the use of viscosupplementation because of a clinically irrelevant advantage and an increased risk of serious adverse events after HA injections.
Platelet-rich plasma (PRP), a natural concentrate of autologous growth factors from the blood, is an emerging regenerative therapy for tissue injury and degeneration.
Degranulation of platelets causes the release of various growth factors and cytokines, which play a crucial role in joint homeostasis and healing processes. Current evidence synthesized by performing several meta-analyses
Comparative effectiveness of injection therapies in lateral epicondylitis: a systematic review and network meta-analysis of randomized controlled trials.
showed positive effects of PRP on lateral epicondylitis and periodontal and sinus bone grafts, but less favorable outcomes in arthroscopic rotator cuff repair, joint arthroplasty, reconstruction of cruciate ligaments, and chronic tendinopathy.
Accordingly, the efficacy of PRP likely varies in different pathologic conditions and body sites. Research on PRP treatment for articular cartilage lesions has been published since 2010.
The efficacy is of interest to musculoskeletal specialists because of its potential disease-modifying and regenerative capability, compared with conventional injection regimens. However, to our knowledge, no meta-analytic research has quantified the effectiveness of PRP treatment and analyzed the factors that modify the outcomes. Therefore, we undertook a systematic review and meta-analysis to investigate the clinical results in patients with knee chondral degenerative lesions, with regard to functional changes, compared with the pretreatment condition, after PRP injections, placebo controls, and HA administration.
Methods
Study selection
We systematically searched for all relevant articles in 2 online databases, PubMed and Scopus, from the earliest record to September 2013. PubMed is a free database mainly derived from MEDLINE and is considered an optimal tool in biomedical electronic research. Compared with another free access database, Google Scholar, PubMed offers results of better accuracy. We used Scopus, an online database that covers a wider range of journals, to confirm that all relevant trials were retrieved.
The key terms, including cartilage, knee, osteoarthritis, gonarthrosis, platelet, PRP, and platelet-rich plasma, were entered as medical subject headings and text words for searches. Cochrane Collaboration Central Register of Controlled Clinical Trials, Cochrane Systematic Reviews, ClinicalTrials.gov, and bibliographies of included trials and related meta-analyses were manually scrutinized for additional references.
The review included randomized controlled trials, quasi-experimental studies, and prospective follow-up studies without language restriction. Case reports without a well-designed intervention scheme or outcome measurement were excluded. Studies were eligible if they enrolled adult participants with knee cartilage degenerative disorders diagnosed through clinical and image findings. Trials presenting data on people with other causes of knee pain such as sprain, tendinopathy, and meniscus tear were ruled out. The included studies were required to use PRP at least in 1 treatment arm. Research was eliminated if PRP was not applied through injection. All selected trials were required to have serial functional measurements such as the International Knee Documentation Committee (IKDC) Subjective Knee Form, Knee Injury and Osteoarthritis Outcome Score (KOOS), or Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) before and after the administration of PRP.
Data extraction and quality assessment
Two authors (K.-V.C., C.-Y.H.) independently evaluated all articles eligible for inclusion. The data extracted from the selected studies included patient characteristics, information on PRP administration, and details of outcome measurements. The Jadad scale was used to assess the quality of the randomized controlled trials. The aggregate scores ranged from 0 to 5 points. Trials with scores <3 were assumed to have a lower methodological quality.
Comparative effectiveness of focused shock wave therapy of different intensity levels and radial shock wave therapy for treating plantar fasciitis: a systematic review and network meta-analysis.
Prospective follow-up and quasi-experimental studies were evaluated by using the Newcastle-Ottawa Scale to assess the quality of selection, comparability, exposure, and outcome. The maximum scores observed were 9 points, and total scores <4 points were considered low in quality.
Discrepancies between the 2 independent evaluations for potential articles were resolved through discussion and consensus.
Data synthesis and analysis
Data were extracted from 3 points at or closest to the 2nd, 6th, and 12th months after the interventions. Effect sizes were estimated from functional knee joint scales and applied to compare the results across studies or between different therapeutic approaches. If more than 1 functional scale was available for a study, we selected only 1 measurement according to the order of IKDC, KOOS, and then WOMAC. Since some studies had multiple treatment arms, we treated each arm as a separate data set for analysis. To evaluate the effectiveness of PRP treatment, compared with the pretreatment condition, we used the standardized mean difference between the baseline and status after therapy. Data were derived from the ratio of the difference between baseline and posttreatment functional scores to the SD of the pooled results. Positive and negative values of the effect sizes indicated a functional improvement and decline, respectively. For cases in which the functional score SD was deficient, the value was computed from the P value of the corresponding hypothesis testing. The pooled SD resulted from the square root {[(participant numbers in baseline − 1)*(SD of scores in baseline)2 + (participant numbers after treatment − 1)*(SD of scores after treatment)2]/[(participant numbers in baseline − 1) + (participant numbers after treatment − 1)]}.
Because the pooled SD was calculated based on the rule of intention to treat, the dropout rate was not considered, and the participant numbers remained unchanged between the baseline and posttreatment data sets.
The effect sizes were pooled by using a random-effect model and were represented by a point estimate with a 95% confidence interval (CI). Regarding the comparison with the baseline condition, an advantage of PRP referred to a positive summed effect size with a 95% CI above a zero value. In terms of comparison with HA injection or placebo treatment, a superiority of intervention was determined by a higher summed effect size in the intervention group without an overlap of the 95% CI in the comparative group.
Effectiveness of bisphosphonate analogues and functional electrical stimulation on attenuating post-injury osteoporosis in spinal cord injury patients—a systematic review and meta-analysis.
The heterogeneity across studies was tested by using I-square and Cochran's Q tests. A P value <.10 for chi-square testing of the Q statistic or an I-square >50% was regarded as the existence of significant heterogeneity.
We performed a subgroup analysis according to the different dosages, regimens, and preparations of PRP, as well as the severity of knee degenerative lesions. A sensitivity analysis was conducted by removing some studies with extreme effect size values to observe whether the action caused serious changes in the overall result. We used a funnel plot and the Begg's test to examine the publication bias, which was defined as the tendency for positive trials to be published and the tendency for negative and null trials not to be published.
was removed because of an inability to extract data from box plots. An assessment of the remaining 16 articles revealed that 8 used a single-arm, open-label, and prospective follow-up design.
Platelet-rich plasma intra-articular injection versus hyaluronic acid viscosupplementation as treatments for cartilage pathology: from early degeneration to osteoarthritis.
A randomized clinical trial evaluating plasma rich in growth factors (PRGF-Endoret) versus hyaluronic acid in the short-term treatment of symptomatic knee osteoarthritis.
The 16 included trials comprised 26 treatment arms, of which 18 used PRP treatments, 7 administered HA, and 1 used saline for placebo controls. Regarding knee-specific outcome measures, we extracted data from IKDC in 8, KOOS in 1, and WOMAC in 7 of the 16 studies.
Fig 1Flow diagram of the evaluation process for the inclusion or exclusion of studies.
The 16 included studies had a total enrollment of 1543 patients, 840 of whom (54.4%) were men (tables 1 and 2). The duration from the onset of knee pain to registration in each trial was listed from 3 months to more than 1 year. The follow-up period ranged from 6 to 24 months, and the latest point of assessment for most trials was at 12 months after PRP injections. Most studies recruited patients with knee OA with a severity less than grade III on the Kellgren-Lawrence (KL) scale, and some of them also enrolled participants affected by cartilage degenerative lesions with a grade of 0 on the KL scale.
Table 1Summary of studies using PRP injection to treat chondral degenerative lesions in knee joints
Platelet-rich plasma intra-articular injection versus hyaluronic acid viscosupplementation as treatments for cartilage pathology: from early degeneration to osteoarthritis.
A randomized clinical trial evaluating plasma rich in growth factors (PRGF-Endoret) versus hyaluronic acid in the short-term treatment of symptomatic knee osteoarthritis.
Abbreviations: F, female; HWHA, high–molecular weight HA; LWHA, low–molecular weight HA; M, male; NRS, numeric rating scale; SF-36, Medical Outcomes Study 36-Item Short-Form Health Survey; VAS, visual analog scale.
∗ Quality scores derived from the Newcastle-Ottawa Scale.
A randomized clinical trial evaluating plasma rich in growth factors (PRGF-Endoret) versus hyaluronic acid in the short-term treatment of symptomatic knee osteoarthritis.
Platelet-rich plasma intra-articular injection versus hyaluronic acid viscosupplementation as treatments for cartilage pathology: from early degeneration to osteoarthritis.
Compared with the preinjection condition, we found a pooled effect size of 2.31 (95% CI, 1.53–3.09) at 2 months, 2.52 (95% CI, 1.94–3.09) at 6 months, and 2.88 (95% CI, .97–4.79) at 12 months, which all favored the status after PRP treatment (fig 2). If we deleted an outlier with an extremely high effect size,
the beneficial effects from PRP injections remained, with an effect size of 1.84 (95% CI, 1.53–3.09) at 2 months, 2.19 (95% CI, 1.73–2.66) at 6 months, and 2.35 (95% CI, .51–4.20) at 12 months. In the HA group, the effect sizes were 1.15 (95% CI, .78–1.52) at 2 months, .75 (95% CI, .62–.88) at 6 months, and .85 (95% CI, .46–1.24) at 12 months (fig 3). A significant superiority of the PRP intervention was demonstrated by a higher summed effect size in the PRP group without an overlap of the 95% CI of the HA group at months 2 and 6. In addition, after excluding the data from quasi-experimental and single-arm longitudinal follow-up studies and only using the data from randomized controlled trials (fig 4, table 3), the PRP group still demonstrated a significantly higher effect size of 1.55 (95% CI, .97–2.12), compared with .75 (95% CI, .62–.88) in the HA group, at 6 months. Only 1 study used normal saline for placebo controls. The effect sizes were −.29 (95% CI, −.68 to .10) at 2 months and −.48 (95% CI, −.89 to −.07) at 6 months, whose point estimates and 95% CI appeared inferior to the PRP and HA group values.
Fig 2Forest plot of the ES of functional changes from baseline at (A) 2 months, (B) 6 months, and (C) 12 months after PRP injections. Abbreviation: ES, effect sizes.
Fig 4Temporal relationships of effect sizes of functional changes after PRP, HA, and placebo injections. We also analyzed the treatment arm only comprising RCT of PRP interventions. Abbreviation: RCT, randomized controlled trials.
Table 3Analysis of the effect sizes of PRP treatment stratified by their study design, dose of injection, cycle of centrifugation, additional activation agent, and severity of degenerative pathology
The participants receiving PRP treatments were stratified according to the study design, cycles of centrifugation, kind of activation agents, administration doses, and severity of cartilage degeneration (see table 3). The point estimates of the pooled effect size in the single-arm prospective studies and quasi-experimental trials seemed to be higher than those in the randomized controlled trials, and a significant difference was identified at 12 months between the quasi-experimental and randomized controlled trials. The stratified analysis failed to demonstrate a dose-responsiveness relationship in the injection numbers, superiority of double-spinning to single-spinning techniques, and additional activation agents to an activator-free preparation. However, an uncertainty in the treatment effectiveness emerged regarding participants who received ≤2 injection doses, a single-spinning approach, or lack of additional activators, since the 95% CI of the summed effect sizes in these subgroups crossed the value of 0 at any of the 3 time points.
Eight of the 16 trials, including 9 arms of PRP treatment, divided their participants into 2 or 3 subgroups based on knee OA severity. In the present meta-analysis, KL grade 0, grades I and II, and grades III and IV were defined as degenerative chondropathy, early OA, and advanced OA, respectively. The degenerative chondropathy group had the highest effect size point estimate at all time points, followed by the early OA group and the advanced OA group. A significantly better treatment effectiveness was identified at 6 months in the degenerative chondropathy group (effect size, 3.90; 95% CI, 2.54–5.26) compared with the advanced OA group (effect size, 1.59; 95% CI, .85–2.32).
Adverse effects
Eight of the 16 trials reported adverse events after injection, most of which were local swelling and transient regional pain, and the overall incidence was 9.59% (95% CI, 7.79%–11.32%) per person undergoing 1 PRP treatment cycle. The pooled relative risk of adverse reactions after PRP treatment was 1.19 (95% CI, .85–1.66) compared with HA administration, indicating no significant difference between the regimens in eliciting postinjection discomfort.
Publication bias
Asymmetry was observed in the funnel plots based on the effect sizes of changes in the functional scales from baseline in the PRP group (fig 5). P values, determined by using a Begg's test, were .028 at 2 months, .017 at 6 months, and .84 at 12 months, which indicated the existence of significant publication bias regarding the measured outcome at 2 and 6 months.
Fig 5Funnel plots of the effective size of functional changes from baseline at (A) 2 months, (B) 6 months, and (C) 12 months after PRP injections.
The current meta-analysis comparing the conditions of patients with knee degenerative pathology before and after treatment with PRP injections showed a continual efficacy for at least 12 months. Compared with patients receiving HA, those in the PRP group exhibited better and prolonged beneficial effects, and the advantages remained after excluding single-arm and quasi-experimental trials. Injection doses ≤2, the use of a single-spinning approach, and lack of activation agents led to an uncertainty of the treatment effectiveness. Furthermore, patients with a lower degree of cartilage degeneration achieved superior results compared with those with advanced OA. Finally, PRP treatment did not elicit a higher risk of adverse reactions relative to HA administration.
Four meta-analytic research articles investigating the efficacy of PRP in the treatment of orthopedic disorders have been recently published. Krogh et al
Comparative effectiveness of injection therapies in lateral epicondylitis: a systematic review and network meta-analysis of randomized controlled trials.
compared a variety of injection therapies for lateral epicondylitis and found that PRP administration was significantly superior to placebo for pain relief. Chahal
and colleagues reviewed studies comprising participants with full-thickness rotator cuff tendon tears who were treated with arthroscopic repair with or without concomitant PRP supplementation, and they failed to demonstrate a benefit of additional PRP in reducing overall retear rates and improving shoulder-specific outcomes. Sheath et al
compared PRP interventions with control interventions in various orthopedic conditions such as anterior cruciate ligament reconstruction, spinal fusion, total knee arthroplasty, humeral epicondylitis, and Achilles' tendinopathy, and they concluded that the available evidence was insufficient to support PRP as a treatment option for orthopedic or soft tissue injuries. To our knowledge, none of these meta-analyses targeted the issue of PRP prescription for knee degenerative lesions. A focused review
of PRP for the treatment of cartilage pathology has recently been published and did not favor PRP as a first-line treatment for moderate to severe knee OA. However, a quantitative analysis in terms of potential symptom-relieving and disease-modifying effects is still deficient. Therefore, we standardized the functional change from baseline at various time points in an effort to obtain more accurate estimates on the effectiveness of intra-articular PRP injection for the treatment of knee degenerative pathology.
Our meta-analysis suggested that PRP injection significantly improved the functional status, relative to basal evaluations, in patients with knee degenerative pathology, and the beneficial effect was maintained for 1 year after treatment. The major concern regarding our pooled effect sizes is the overestimation of true values because of a lack of control treatments. Only 1 of the included trials used saline as a placebo control, whose effect size was −.29 (95% CI, −.68 to .10) at 2 months and −.48 (95% CI, −.89 to −.07) at 6 months. We believed that the estimated effect of saline injection was reliable since it was derived from a double-blind, randomized controlled trial. The result implies a gradual functional decline with a significant deterioration identified at 6 months after placebo treatment. In contrast, the PRP group revealed a continual improvement until 12 months. Therefore, the present meta-analysis suggests that the effectiveness of PRP derived from a biological benefit, which could not simply be explained by a placebo effect.
The HA effect size pooled in the present meta-analysis indicated that the efficacy reached a highest point at 2 months after injection but declined over time. The change in HA efficacy is comparable to that found in previous meta-analytic research despite a greater effect size,
since we used the patients' baseline as the reference point and included more small, uncontrolled trials. Current evidence suggests a modest effect of HA in relieving pain in patients with knee OA probably through the mechanism of viscosupplementation and modulation of the early inflammatory response.
Compared with the HA group, patients treated with PRP demonstrated better effectiveness at 2 time points, and the trend of improvement was sustained until 12 months (see fig 4). The advantage of PRP over HA remained at 6 months, even when only the results from randomized controlled trials were analyzed. In vitro experiments have demonstrated the capability of PRP in the temporary modulation of cytokine levels and stimulation of chondral anabolism, which may lead to short-term pain relief and long-term functional improvement, respectively.
When comparing the temporal changes in clinical outcomes between the 2 regimens, PRP injections provided a more prompt symptomatic relief than HA. Since the main action of HA derives from the restoration of viscoelasticity of synovial fluid, the prolonged efficacy of PRP might imply a regenerating or disease-modifying potential, which has rarely been reported in studies using HA preparations.
Several factors mentioned by antecedent research might modify the effect of PRP injections. In terms of the study design, the pooled effect sizes in single-arm and quasi-experimental studies were likely to be higher than that in randomized controlled trials. As a result, to prevent overestimation of PRP effectiveness, the present meta-analysis also interpreted the comparisons between PRP and HA based on the outcomes from randomized controlled trials. One potential modifier is the centrifugation method. Some authors advocate a double-spinning technique instead of a single-spinning method because the former might generate a higher platelet concentration and thus result in better efficacy.
Our stratified analysis did not identify a significant discrepancy in effectiveness between groups by using different centrifugation methods or activation agents. However, the use of a single spinning method and a lack of activation agents tended to generate an effect size covering the zone of ineffective treatment (see table 3). Regarding the number of PRP injections, a dose-responsiveness relationship was unclear. Likewise, uncertainty of effectiveness existed with doses ≤2, suggesting a minimal requirement of 3 doses during clinical practice. Finally, our subgroup analysis showed that the efficacy varied according to the degenerative severity, which was related to the regenerative potential of damaged cartilage. Our results are compatible with those of most trials, favoring discriminative usage of PRP in cases with degenerative chondropathy and mild OA.
Study limitations
Several limitations should be considered in the interpretation of the present meta-analysis. First, most trials retrieved from the electronic database used a single-arm, prospective follow-up design without controls and randomization of the participants. These fundamental flaws rendered the studies low in research quality and level of evidence. Second, there was marked heterogeneity across the included studies regarding the PRP preparation and dosage, follow-up duration, and functional outcome assessment scales. Although we tried to compensate for methodological deficiencies by performing a stratified analysis, some results remained inconclusive since several reports lacked the documentation of the key factors mandatory for stratification. Finally, many trials recruited patients with degenerative chondropathy defined as a grade 0 on the KL scale. Without the use of magnetic resonance, the diagnosis of a chondral lesion is difficult, leading these studies to possibly enroll some subjects with knee pain without degenerative pathology. In addition, physicians seldom prescribed an injection therapy as the first line of treatment in patients with such an early lesion. Although the degenerative chondropathy group had the most benefit from PRP injections in our subgroup analysis, we suggest that future trials should be conducted to focus on patients with mild to moderate knee OA based on the consideration of clinical utility.
Conclusions
The present meta-analysis demonstrates a significant functional improvement after PRP intervention in patients with knee cartilage degenerative pathology, compared with their pretreatment baseline, although this finding should be interpreted with caution because of the low methodological quality of the included trials. The effectiveness of PRP is likely superior to that of HA, with a longer effective duration. Discrepancy in the degenerative severity modified the treatment response, leading the participants with a lower degree of knee degenerative lesions to benefit more from PRP injections. We suggest that future studies target the population with mild to moderate knee OA based on the consideration of clinical utility.
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StataCorp LP, 4905 Lakeway Dr, College Station, TX 77845-4512.
EULAR recommendations 2003: an evidence based approach to the management of knee osteoarthritis: report of a Task Force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT).
Comparative effectiveness of injection therapies in lateral epicondylitis: a systematic review and network meta-analysis of randomized controlled trials.
Comparative effectiveness of focused shock wave therapy of different intensity levels and radial shock wave therapy for treating plantar fasciitis: a systematic review and network meta-analysis.
Effectiveness of bisphosphonate analogues and functional electrical stimulation on attenuating post-injury osteoporosis in spinal cord injury patients—a systematic review and meta-analysis.
Platelet-rich plasma intra-articular injection versus hyaluronic acid viscosupplementation as treatments for cartilage pathology: from early degeneration to osteoarthritis.
A randomized clinical trial evaluating plasma rich in growth factors (PRGF-Endoret) versus hyaluronic acid in the short-term treatment of symptomatic knee osteoarthritis.
Supported by the National Science Council , Taiwan (grant no. 100-2314-B-002-012-MY3 ).
No commercial party having a direct financial interest in the results of the research supporting this article has conferred or will confer a benefit on the authors or on any organization with which the authors are associated.
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