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29-11-2018 | Osteoarthritis | Article

Intra-articular treatment options for knee osteoarthritis

Journal: Nature Reviews Rheumatology

Authors: Ian A. Jones, Ryan Togashi, Melissa L. Wilson, Nathanael Heckmann, C. Thomas Vangsness Jr

Publisher: Nature Publishing Group UK

Abstract

Intra-articular drug delivery has a number of advantages over systemic administration; however, for the past 20 years, intra-articular treatment options for the management of knee osteoarthritis (OA) have been limited to analgesics, glucocorticoids, hyaluronic acid (HA) and a small number of unproven alternative therapies. Although HA and glucocorticoids can provide clinically meaningful benefits to an appreciable number of patients, emerging evidence indicates that the apparent effectiveness of these treatments is largely a result of other factors, including the placebo effect. Biologic drugs that target inflammatory processes are used to manage rheumatoid arthritis, but have not translated well into use in OA. A lack of high-level evidence and methodological limitations hinder our understanding of so-called ‘stem’ cell therapies and, although the off-label administration of intra-articular cell therapies (such as platelet-rich plasma and bone marrow aspirate concentrate) is common, high-quality clinical data are needed before these treatments can be recommended. A number of promising intra-articular treatments are currently in clinical development in the United States, including small-molecule and biologic therapies, devices and gene therapies. Although the prospect of new, non-surgical treatments for OA is exciting, the benefits of new treatments must be carefully weighed against their costs and potential risks.

Introduction

Osteoarthritis (OA) is a chronic and debilitating joint disease that causes damage to the articular cartilage and underlying bone1. Although commonly referred to as a ‘wear and tear’ disease, complex interactions between genetic, metabolic, biochemical and biomechanical factors are also thought to be important in disease progression2,3. Indeed, osteoarthritic chondrocytes are not apoptotic, but degenerated and deranged, as evidenced by ultrastructural changes and an uncoordinated gene expression pattern4. Moreover, the whole joint is involved in the progression of the disease5 and the roles of the synovium, muscles and ligaments are likely to be underestimated6. Intra-articular drug delivery, in which a concentrated therapeutic dose is distributed throughout the joint capsule7, might therefore be the ideal mode of drug delivery for OA therapies (Fig. 1).
In this Review, we briefly introduce intra-articular therapies before critically appraising the evidence supporting the use of standard intra-articular treatment options. We also discuss clinical studies that have investigated single-molecule biologic therapies and provide a high-level overview of cell-based therapies. Finally, we deliver an update on and a critical assessment of some of the most anticipated and promising intra-articular OA therapies that are currently in clinical development for the United States market. The surgical treatment of OA and the basic biology of the joint are not discussed in detail, as these topics have been covered extensively elsewhere811, as have other clinically investigated treatments12 and administration routes13.

Intra-articular drug delivery

Intra-articular drug delivery has a number of advantages over systemic delivery, including increased local bioavailability, reduced systemic exposure, fewer adverse events and reduced cost7,8. However, the efficacy of intra-articular therapies remains controversial and clinical guidelines regarding their use are often inconsistent with one another14,15. In addition, factors such as drug residence time16, systemic effects17 and administration technique18 contribute to treatment variability.
Intra-articular therapies are rapidly cleared from the synovial fluid by lymphatic drainage at a rate that largely depends on the size of the molecule. For example, the half-life of albumin in the joint is roughly 1–13 hours, whereas hyaluronic acid (HA) takes approximately 26 hours to clear the joint16. Additionally, the half-life of NSAIDs and soluble steroids in the joint is only 1–4 hours19. Despite the short residence time of intra-articular therapies, studies frequently report effects that last for several months20. The mechanism behind these long-term effects is treatment-specific and is not well understood.

The placebo effect

When considering the evidence for or against an intra-articular therapy, it is important to understand that intra-articular injections elicit a strong placebo effect21. Self-reported parameters such as pain and stiffness are particularly responsive to intra-articular placebo22. In fact, the effect size of intra-articular placebo injections might be greater than that of both topical and oral placebos23. Although intra-articular therapies are widely used in the treatment of OA, conflicting evidence exists as to whether standard intra-articular treatment options (HA and glucocorticoids) are beneficial compared with joint aspiration alone for many patients24.
The strong placebo effect of intra-articular injections might account for the difficulty in detecting differences between treatment groups in clinical trials, especially when the difference between the groups is small. Even in patients who receive mock injections (an injection without therapeutic agent or placebo), the reported benefit is not statistically different to that of those who receive saline, lactic acid, procaine or hydrocortisone25. A 2017 meta-analysis showed the effect of intra-articular saline on pain scores (visual analogue scale (VAS) and Western Ontario and McMaster Universities osteoarthritis index (WOMAC)), revealing statistically significant differences at 6 months for both the VAS and the WOMAC score26.

Interpreting clinical findings

The degree to which a treatment affects the outcome of interest is called the effect size. Effect size is the most important statistic reported — not the P value — because it communicates how effective the treatment is at alleviating OA symptoms27. Any given treatment might or might not have a large effect on the clinical population, irrespective of the statistical significance of the outcomes of the treatment. When an effect size is very large, it suggests possible clinical significance even in the absence of statistical significance, as the latter is heavily dependent on sample size. Even studies that meet standard power parameters (80% statistical power) still might not have sufficient power to detect a clinically significant difference (a type II error), which, by design, occurs 20% of the time. Likewise, a small effect size might be statistically significant but could have little to no clinically meaningful significance.
A tool that can be used to understand the clinical relevance of reported differences is the minimal important difference (MID), also known as the minimal clinically important difference (MCID). The MID was originally defined as the smallest difference in a score that patients perceive as being beneficial28, and is most frequently calculated using the mean change method, which is the average score of patients who report feeling ‘slightly better’ minus the average score of patients who report feeling ‘about the same’29,30. In other words, the MID attempts to capture both the magnitude of the improvement and the value patients place on that improvement31.
A 2017 systematic review revealed plausible MID values for the WOMAC, the knee injury and osteoarthritis outcome score (KOOS) and the European quality of life five-dimension questionnaire (EQ-5D)32. These estimates can be used to provide pretext when clinically appraising a treatment’s effectiveness. However, the MID cannot be used to assess individuals30 and does not take into account the overall risk–benefit ratio or the cost of a treatment33,34. In addition, the MID should not be treated as a universal fixed value35,36, as it tends to vary between populations and contexts, and by the calculation method used33,37,38.

Standard intra-articular treatments

Although not categorically defined as standard-of-care, glucocorticoids and HA are standard intra-articular treatment options for the management of OA-related knee pain in patients who fail to respond to non-pharmacological therapy, NSAIDs or analgesics. However, an emerging body of evidence exists that calls the efficacy of standard intra-articular treatments into question39, and an increasing number of professional organizations are questioning their appropriateness (Table 1).
Table 1
Hyaluronic acid and glucocorticoids to treat osteoarthritisa
 
American Academy of Orthopaedic Surgeons (2013)41
Osteoarthritis Research Society International (2014)48
National Institute for Health and Care Excellence (2014)52
American College of Rheumatology (2012)53
Hyaluronic acid
Not recommended
Inconclusive
Not recommended
Inconclusive
Glucocorticoids
Inconclusive
Recommended
Recommended
Recommended
aSelected clinical guidelines published in the past 10 years.
Rather than putting forward specific treatment recommendations on the basis of existing evidence, the following sections explore several of the most widely cited and clinically used guidelines on the treatment of OA. The evidence supporting each recommendation is discussed to highlight potential strengths and weaknesses. Importantly, what is appropriate for use in the general population of patients with OA might differ for specific subsets of patients, and patients with some phenotypes of OA might respond to standard treatment options differently than others40. Additionally, efficacy should be carefully weighed against both the cost of the treatment and the potential risk of harm, especially when the efficacy of a given treatment is questionable.

Glucocorticoids

In their 2013 guidelines, the American Academy of Orthopaedic Surgeons (AAOS) found a lack of compelling evidence to support the use of glucocorticoids for the treatment of OA, as well as an unclear balance between the benefits and potential harms of this treatment41. This recommendation was formed on the basis of the quality and generalizability of the included studies, which was determined in advance using an automated coding scheme. The final recommendation of the AAOS was made on the basis of six key studies, four of which were placebo-controlled trials that evaluated pain for at least 4 weeks4245. The results of these studies were mixed, and all of these studies included one or more design flaws. Owing to the weak efficacy data of these studies4245, as well as the results of other studies that suggested that glucocorticoid injections might be inferior to HA injections46 or tidal lavage47, the AAOS determined that inconclusive evidence existed to support the use of glucocorticoids for knee OA41.
Guidelines published in 2014 by the Osteoarthritis Research Society International (OARSI)48 issued a more favourable recommendation than the AAOS, concluding that intra-articular glucocorticoid injections were ‘appropriate’ and that the quality of the evidence was ‘good’. These conclusions were supported by the results of two systematic reviews49,50 that were published in 2009 and 2006. However, a close inspection of the data in conjunction with current evidence suggests that the OARSI guidelines48 might have overestimated the therapeutic efficacy of glucocorticoid injections. The authors of the 2009 systematic review49 concluded that glucocorticoids provided benefits over HA at 2 weeks, but not at 4, 8, 12 or 26 weeks. By contrast, the authors of the 2006 systematic review50, which was published in the Cochrane Database, took a more favourable stance concerning the effectiveness of glucocorticoids. However, an updated Cochrane meta-analysis published in 2015 showed that, although glucocorticoids seemed to offer small-to-moderate benefits over placebo for ≤6 weeks (standardized mean difference (SMD) -0.41; 95% CI -0.61 to -0.21), it was unclear whether this difference was clinically important51. The authors also pointed out inconsistent and highly variable treatment effects, imprecise pooled estimates that did not rule out potentially relevant clinical effects, a high or unclear risk of bias, considerable heterogeneity between trials and evidence of small-study effects51.
The guidelines published by the National Institute for Health and Care Excellence (NICE)52 in 2014 and by the ACR53 in 2012 both recommended glucocorticoids for patients with knee OA; however, both groups provided weak support for their recommendations. NICE recommended that glucocorticoid injections be considered as an adjunct to core treatments for the relief of moderate-to-severe pain in patients with OA on the basis of the ability of glucocorticoids to provide short-term (1–4 weeks) pain relief52, but their recommendation relied on the out-of-date 2006 Cochrane Database review50 that was also referenced in the OARSI guidelines48, and failed to consider any literature published between 2006 and 2014. The ACR guidelines ‘strongly’ recommended glucocorticoid injections for patients who do not respond to full-dose paracetamol (acetaminophen), but provided no supporting references to justify this recommendation53.
Since the aforementioned recommendations were published, concern has increased around the detrimental catabolic effects that glucocorticoids have on cartilage54. For example, the results of a 2017 study suggested that administering glucocorticoid injections before total knee arthroplasty might increase the risk of postoperative infection55. Notably, the results of one study showed that patients who had been treated with intra-articular glucocorticoids (40 mg triamcinolone) had significantly greater cartilage volume loss than those who had been given intra-articular saline over a 2 year period (between group difference −0.11 mm; 95% CI −0.20 to −0.03 mm)56. This result is concerning because a 1% increase in the rate of tibial cartilage loss between baseline and 2 years corresponds to an ~20% increase in the risk of undergoing knee replacement surgery at 4 years57, and because high rates of cartilage loss have been directly associated with an increased risk of undergoing arthroplasty58.

Hyaluronic acid

Clinical recommendations for the use of intra-articular HA for knee OA tend to be less favourable than those for glucocorticoids. The 2013 AAOS guidelines strongly recommend against the use of HA for symptomatic knee OA41. This recommendation was formed on the basis of a meta-analysis of 14 studies that showed an effect that was <0.5 MID units. The reliance of the AAOS guidelines41 on a MID of 0.5 on a five-point scale has prompted debate, with some researchers arguing that a MID should only be used as a supplementary instrument and not as a basis for clinical decision making59. However, the results of a 2017 systematic review32 that aimed to establish credible, anchor-based MID values for patients with OA support the approach taken by the AAOS. Nevertheless, a lack of treatment consensus in the orthopaedic community continues to persist, which has led to an apparent disconnect between the AAOS recommendations and what occurs in clinical practice60.
The OARSI guidelines48 were more favourable towards HA than the AAOS guidelines41 and suggested that the efficacy of HA for knee OA was ‘uncertain’. The recommendation of uncertain by OARSI was formed on the basis of three meta-analyses20,49,61. The first of these meta-analyses showed that the long-term effects of intra-articular HA were superior to intra-articular glucocorticoids49; however, HA was not compared with saline as a placebo in this study, which raises doubt over the validity of the conclusions. The second meta-analysis from 2011 compared HA to placebo and showed that the effect size favoured HA by week 4 (0.31; 95% CI 0.17–0.45), peaked at week 8 (0.46; 95% CI 0.28–0.65) and then trended downwards, with residual effects still present at week 24 (0.21; 95% CI 0.10–0.31)20. By contrast, the results of the third meta-analysis from 2012 revealed that the benefits of HA for patients with symptomatic OA were minimal-to-non-existent and discouraged the use of HA owing to an increased risk of harm61. The apparent disconnect between the conclusions of these two studies20,61 is probably caused by the use of newer data, the exclusion of studies with fewer than 100 patients per treatment group and the inclusion of an additional five unpublished studies that showed that HA was not superior to placebo in the 2012 meta-analysis61.
Similar to the AAOS guidelines41 and the OARSI guidelines48, the NICE guidelines52 and the ACR guidelines53 were both less favourable towards HA injections than they were towards glucocorticoid injections. NICE recommended against the use of HA for the management of knee OA52 — a recommendation that relied on a 2006 Cochrane Database review62 and an additional 20 studies that were published between 2006 and 2014. The NICE guidelines concluded that the evidence to show that HA was clinically effective was uncertain and determined that HA was unlikely to be cost effective. The ACR did not issue broad recommendations either for or against the use of HA in patients with knee OA53.
Systematic reviews published after the AAOS guidelines and OARSI guidelines (2013 and 2014, respectively) have drawn inconsistent conclusions regarding the clinical utility of HA injections. A 2015 meta-analysis of double-blinded, sham-controlled trials that had at least 60 patients found an average treatment effect that was only 29% of the MID compared with placebo and no clinically important improvement in pain or other outcomes, even after subdividing HA preparations by molecular mass (Mr)63. By contrast, a 2018 systematic review in which non-operative treatments for knee OA were compared showed ‘strong evidence’ for clinically important treatment effects when using intra-articular HA formulations with an Mr of between 1,500 kDa and 6,000 kDa64. Continued publication of contradictory recommendations, in conjunction with a lack of treatment consensus among clinicians, indicates that a need still exists for well-designed, pragmatic trials to evaluate the real word effectiveness of intra-articular HA for OA.

Intra-articular delivery of biologics

The idea that the progression of OA could result from an imbalance of catabolic and anabolic factors, as well as the known effectiveness of biologics in the treatment of inflammatory forms of arthritis, has raised hope that biologic agents might be used to treat OA5. Over the past 10 years, several notable studies investigating the use of biologic agents for OA have been published (Table 2), but to date, results from clinical trials have mostly been disappointing. In the following sections, we discuss some of the most notable clinical studies to have used intra-articular biologic agents.
Table 2
Clinical trials using intra-articular biologic therapies to treat osteoarthritis
Study (year)
Therapy
Study size (groups)
Final follow-up
Outcomes
Ref
Chevalier et al. (2009)
Anakinra (rhIL-1RA)
170 (101 anakinra, 69 placebo)
12 weeks
Low-dose anikara was inferior to placebo on pain score; high-dose anikara was superior to placebo on pain score
71
Ohtori et al. (2015)
Etanercept (anti-TNF)
39 (19 etanercept, 20 HA)
4 weeks
Etanercept was inferior to HA for VAS, WOMAC pain score, WOMAC stiffness score, WOMAC physical function score and total WOMAC score
77
Hunter et al. (2010)
Eptotermin alfa (rhBMP7)
33 (25 eptotermin alfa, 8 placebo)
24 weeks
Eptotermin alfa was superior to placebo for achieving WOMAC pain 20%, 50% and 70% reduction scores
79
Lohmander et al. (2014)
Sprifermin (rhFGF18)
192 (126 sprifermin, 42 placebo)
52 weeks
Sprifermin was superior to placebo for WOMAC pain scores and showed a dose-dependent response
80
BMP7, bone morphogenic protein 7; FGF18, fibroblast growth factor 18; HA, hyaluronic acid; IL-1RA, IL-1 receptor antagonist; rh, recombinant human; VAS, visual analogue scale; WOMAC, Western Ontario and McMaster Universities osteoarthritis index.

Targeting IL-1

IL-1β is a key mediator of the inflammatory and catabolic processes that lead to cartilage degradation and the destruction of joint tissues65,66. IL-1β has been used to induce the dedifferentiation of chondrocytes in vitro67, and the results of in vivo experiments suggest that IL-1β might directly mediate the erosive processes that lead to OA6870. A 2009 randomized, multicentre, double-blind, placebo-controlled trial showed the IL-1β antagonist anakinra to be well tolerated, but not associated with improvements in OA symptoms compared with placebo71. A 2012 study, in which the effects of anakinra following anterior cruciate ligament injury were examined, found that patients treated with anakinra had reduced pain and improved knee function compared with the control group72.

Targeting TNF

TNF is a pro-inflammatory cytokine that interacts with chondrocytes73 and is associated with a loss of knee cartilage74,75. Infliximab was one of the first anti-TNF therapies to be clinically investigated as a potential intra-articular treatment for OA. Despite evidence of initial tolerability, the development of infliximab for OA never progressed beyond early exploratory trials76. Another TNF inhibitor, etanercept, was subsequently evaluated for pain relief in patients with moderate-to-severe knee OA77. In this study, 39 patients were treated with a single intra-articular injection of either HA or etanercept and followed for 4 weeks77. For patients treated with etanercept, the VAS at week 1 and week 2 was improved compared with the VAS of those treated with HA, but these differences were diminished by week 4. Intra-articular administration of the TNF inhibitor adalimumab has also been investigated in patients with knee OA in an open-label randomized controlled trial (RCT)78. The authors of this study reported safety and improvements in VAS78; however, major methodological flaws, the most notable being the failure to register the trial and to pre-specify the outcomes, limit the utility of their findings.

Growth factor therapy

Only two clinical trials have been published to date that use intra-articular growth factor therapy to treat knee OA. The first study, published in 2010, was a randomized, double-blind, placebo-controlled, single-dose escalation study in which the safety, tolerability and dose-limiting toxicity of recombinant human bone morphogenetic protein 7 (rhBMP7) was evaluated79. All 33 enrolled participants completed the 24-week study. No dose-limiting toxicity was found and the WOMAC scores suggested an improvement in pain, particularly in the mid-dose cohort. Although the findings of this study79 generally supported continued development of rhBMP7, no further intra-articular clinical investigations have been initiated.
The second study to use an intra-articular growth factor therapy in patients with knee OA was a randomized, double-blind, placebo-controlled, proof-of-concept trial that aimed to evaluate the safety and efficacy of recombinant human fibroblast growth factor 18 (rhFGF18, also known as sprifermin)80. Single-dose and multiple-dose regimens were trialled in 180 patients, 168 of whom were evaluated for the primary endpoint of changes in cartilage thickness at 6 months and 12 months. No significant difference was seen in serious adverse events or acute inflammatory reactions between the treatment and placebo groups, and patients treated with sprifermin had statistically significant dose-dependent improvements in several secondary outcomes80. Post hoc analysis from this trial and the preliminary results of the ongoing phase II trial are discussed in detail in the intra-articular therapy pipeline section of this Review.

Cell therapies

Autologous point-of-care cell therapies

A lack of study comparability, as well as both methodological and intrinsic limitations, makes the efficacy of point-of-care cell therapies difficult to critically appraise. A comprehensive review of these treatments is beyond the scope of this Review; however, a basic understanding of point-of-care cell therapies is crucial given their widespread clinical use in the United States. In the following sections, we provide a general overview of the most commonly administered and/or studied point-of-care cell therapies used to treat knee OA (Fig. 2).

Platelet-rich plasma

Platelet-rich plasma (PRP) is autologous blood that has been centrifuged to concentrate the platelets to a level above that normally found in serum81; however, the term PRP has been used to describe a range of different treatments82. PRP contains a complex and diverse milieu of chemical mediators that interact with endogenous cells within the joint83. This treatment was originally cleared by the FDA for use in enhancing the handling properties of bone graft materials84 or, in the case of PRP gel, to ‘maintain moisture’ in a wound85. Although intra-articular injections of PRP can be legally offered off-label in the United States to patients with OA in the clinic86, they are not approved by the FDA for this indication and are not covered by most health insurance companies8789.
Despite being the most studied point-of-care cell therapy for OA, a lack of well-powered trials and confusion resulting from both the biological complexity and lack of standardization between different PRP protocols90 make it difficult to draw conclusions about the efficacy of PRP. However, several meta-analyses have attempted to broadly shed light on this topic9193. A 2013 quantitative synthesis of data from RCTs showed that patients treated with sequential intra-articular PRP injections had significant improvements in WOMAC scores at 6 months compared with those who had been treated with injections of saline or HA (mean difference 18.0; 95% CI 8.3 to 28.8)92. A 2016 systematic review suggested similar improvements in WOMAC scores up to 1 year post-intervention (mean difference −15.4; 95% CI −28.6 to −2.3)93. The magnitude of these differences is notable9496, but additional standardized, high-quality studies are needed before preliminary conclusions about efficacy can be drawn.

Bone marrow aspirate concentrate

The methods used to prepare bone marrow aspirate concentrate (BMAC) are similar to those used to prepare PRP. As such, BMAC and PRP share many of the same limitations. For example, the methods used to prepare BMAC are highly variable97,98, which limits the comparability of treatments and studies. Intra-articular injections of BMAC for knee OA are not covered by health insurance in the United States. As with PRP, BMAC is a source of potentially beneficial anabolic and anti-inflammatory mediators99; however, extracting bone marrow is more costly and invasive than extracting peripheral blood. Moreover, BMAC injections are frequently marketed as ‘stem cell’ or regenerative treatments100 despite the facts that only 0.001–0.01% of the cellular content of BMAC is stromal cells101 and that no clear regenerative benefits have been demonstrated to date97.

Adipose tissue injections

Autologous adipose tissue injections (also known as fat grafts) are obtained and processed at the point-of-care from lipoaspirate by mechanical means without the use of enzymatic digestion102. In accordance with the 2015 FDA guidelines for human cells, tissues, cellular products and tissue-based products103, proponents of these treatments claim that mechanical processing of adipose tissue does not alter the original relevant characteristics of the tissue relating to its utility for reconstruction, repair or replacement, and that the injections merely provide cushioning and support. These 2017 claims104 amount to careful restatements of the 2015 FDA’s criteria for ‘minimal manipulation’ and ‘homologous use’, which must be met for a product to be regulated solely under Section 361 of the Public Health Service Act105. Despite being widely available throughout the United States, few human studies have been conducted to date that have demonstrated the effectiveness of these ‘minimally manipulated’ treatments98.

Stromal vascular fraction

Stromal vascular fraction (SVF) is treated differently than the aforementioned mechanically derived point-of-care cell therapies. The FDA has stated that they consider SVF to be beholden to the provisions for investigational new drugs (INDs) because enzymatic digestion is needed to dissociate and isolate the stromal elements from the surrounding connective tissue104. The final cell product, which is prepared by centrifugation of the enzymatically digested tissue, is a distinct component of lipoaspirate that contains a population of progenitor cells106. However, SVF is highly heterogeneous107 and only ~15–30% of the cellular content is stromal cells108. Moreover, although adipose-derived stromal cells can be purified from SVF106, SVF should not be confused with adipose-derived stromal cells102,108. Few clinical studies have been performed to investigate the use of SVF to treat cartilage pathology109,110, but SVF is not commonly used as an intra-articular agent111 and the few studies that have been published have only provided preliminary safety data112,113.

‘Stem’ or stromal cell therapies

Mesenchymal ‘stem’ (or stromal) cell (MSC)-based therapies are not a homogeneous class of cellular treatments114. Because clinical trials to date have been limited to low-powered safety studies (that often did not include a control), the authors of systematic reviews that have attempted to critically appraise the use of intra-articular MSCs have failed to reach clinically applicable conclusions115118. Nevertheless, given the increase in orthopaedic clinics marketing ‘stem cell’ treatments in the United States100, these therapies cannot be ignored. A comprehensive overview of studies investigating MSC injections for knee OA will not be provided here, as numerous reviews of this topic exist116119. However, certain aspects of the field are often overlooked and require clarification (Box 1).

Stem cells or stromal cells?

The term MSC was first coined in the early 1990s and was taken to mean mesenchymal stem cell120. Since that time a number of different definitions have been associated with the term121. The most pervasive and widely accepted definition (mesenchymal stromal cell) was established in 2006 by the International Society for Cellular Therapy (ISCT)122 1 year after they released a position statement that attempted to retain the ‘MSC’ abbreviation while separating MSCs from the ‘stem cell’ label123. According to the ISCT criteria, MSCs must be plastic-adherent, express or lack specific cell surface markers and be capable of trilineage differentiation in vitro into osteoblasts, adipocytes and chondrocytes122.
The term mesenchymal ‘stem’ cell conveys assumptions that were not included in the original concept120 or supported by direct experimental evidence124. However, with respect to their clinical use as an intra-articular therapy for OA, MSCs are plastic-adherent (or prospectively isolated) populations of stromal cells that can be obtained from any tissue, and that express specific cell surface markers and are capable of trilineage differentiation in vitro108,122. This definition clearly distinguishes MSC treatments from the various cell concentrates discussed previously without overtly conflicting with the original ISCT criteria (Fig. 2).

Mechanism of action

Although the in vivo mechanisms of therapeutically used MSCs are still unclear, the release of chemical mediators is thought to be important125. The conditions currently treated with MSCs fall into two broad categories: immune or inflammatory conditions and tissue repair or regeneration126. However, it is important to stress that besides in a few well-established indications, the assertion that MSCs have an intrinsic capacity to sense and address whatever is needed for the repair and regeneration of cartilaginous tissue in the joint is not based on scientific evidence127.

Are MSC therapies safe to use?

The safety profile of MSC therapies depends on the type of cell that is used, as well as the methods that are used to isolate and process it. For example, autologous cells administered at point-of-care are likely to have a lower risk of tumorigenicity than cells that have been expanded in vitro128, as culture conditions can modulate the mechanisms by which therapeutic cell products operate in vivo67,126. Although no major adverse events have been reported that were attributable to autologous or allogeneic MSCs administered via intra-articular injection115,117, malignant transformation remains a potential risk for any cell therapy. According to the results of a 2017 systematic review, over one third of studies failed to clearly describe their method of assessing safety129. Additionally, the majority of studies have focused on the use of autologous cells; only two studies have been published on intra-articular allogeneic MSC treatments for knee OA or knee cartilage repair130,131. Moreover, even in the absence of serious adverse events, the use of expensive, unproven cell therapies could delay or hinder a patient’s access to well-established surgical treatment options105.

Clinical use of MSCs and progenitor cells

With a few exceptions115,116, literature reviews have tended to take a positive view of MSCs as a promising potential treatment alternative for OA and cartilage repair117119,132,133. However, an apparent disconnect exists between the results of in vitro studies, preclinical studies and human studies134, and the highly heterogeneous nature and poor quality of studies published to date precludes quantitative synthesis118. Moreover, among the RCTs that have been published, intra-group improvements and/or inter-group sub-score differences are often highlighted, whereas intra-group comparisons fail to show improvement or are left unreported135. Overall, the limited availability of strong clinical data suggests that the generally positive efficacy conclusions concerning MSC therapy for knee cartilage pathology are premature and might be overstated. Nevertheless, broad efficacy conclusions are of little practical utility given the complexity and intrinsic lack of comparability between different MSC treatments. Just as each biologic therapy must be evaluated on a case-by-case basis, so too must each MSC therapy.

Box 1 Controversies surrounding mesenchymal stem (or stromal) cell therapies

Terminology
The term MSC can be used to describe two different types of cells: mesenchymal stem cells and mesenchymal stromal cells. Stem cells are multipotent and can self-renew in vivo195. By contrast, stromal cells are loosely defined as plastic-adherent cells that express and/or lack specific cell surface markers and are capable of trilineage differentiation into osteoblasts, adipocytes and chondrocytes in vitro108,122.
Nomenclature
The terms marrow stromal cell, multipotent stromal cell, adipose-derived stromal cell and medicinal signalling cell have all been used to describe passaged, plastic-adherent adult multipotent mesenchymal cells121. This inconsistent nomenclature reflects the assumed, and not yet fully understood, immunomodulatory and/or immunosuppressive properties that are associated with stromal cell populations126, as well as the confusion surrounding the dynamic interactions between cellular niches that help to determine cell fate196.
Regulation for use as a therapy
With respect to their use as an intra-articular therapy in clinical research, true MSCs are classed as drugs that require federal regulatory approval before they can be administered to patients104. Although some treatments containing multipotent stromal cell populations might claim to be exempt from FDA regulation (such as so-called minimally manipulated cell therapies and certain blood-derived products), these treatments should not be confused with true MSC therapies, as they tend to contain more heterogeneous cell populations than those in true MSC therapies and have effects that are not primarily attributed to their medicinal immunomodulatory and/or immunosuppressive capacity or differentiation potential197.
Therapeutic use
Direct-to-consumer marketing of MSC therapies is widespread in the United States100 despite the fact that few high-quality studies have been published118. Moreover, the authors of many of the randomized controlled trials that evaluated the efficacy of MSC therapy for knee cartilage pathology have reported intra-group differences and/or inter-group sub-score differences, but have failed to report the original intended outcomes of the studies135, suggesting a need for prudence moving forward. Although scientific optimism and enthusiasm is warranted, it is important that patients interested in these treatments understand that a lack of robust data exist to support their use.

The intra-articular therapy pipeline

Several intra-articular treatments for OA are currently in clinical development (Fig. 3). In the following section, we discuss some of the most anticipated and promising of these treatments and critically appraise the data that are currently available. Therapies in this section have all had clinical data published or presented and are progressing towards FDA approval. As such, promising therapeutic candidates that are currently in early clinical or preclinical development, such as RCGD 423 (ref.136) and UBX0101 (refs137,138), are not discussed. Treatments for which clinical data have been published, but for which there are no current plans for further development, such as co-injected Tr14 (Traumeel) and Ze14 (Zeel)139, have also been excluded from this Review.
One of the notable intra-articular therapies that is not included in the discussion below is AmnioFix, a mixture containing human amniotic and chorionic membranes that have been dehydrated, micronized and suspended in saline140,141. This treatment deserves mention because, before 2013, a number of clinics in the United States were using AmnioFix to treat knee OA under the assumption that the treatment was ‘minimally manipulated’. However, MiMedx (the company that produces AmnioFix) was forced to recant their claims when the FDA warned that the treatment could not be offered to patients until an IND application was obtained142. In 2017, MiMedx reported that the FDA had allowed their IND-approved, phase IIb study143 to proceed. However, no clinical data have been released and only one animal study investigating the effects of AmnioFix for knee cartilage pathology has been published144.

LMWF-5A (Ampion)

LMWF-5A (Ampion) is an injectable, low molecular weight fraction of 5% human serum albumin that is currently being developed by Ampio Pharmaceuticals (Englewood, FL, USA). The primary constituent of LMWF-5A, artyl-alanyl diketopiperazine, modulates the inflammatory immune response in vitro via a pathway in which T cells are implicated145, and several clinical studies have been published in which the effects of LMWF-5A on knee OA were investigated146148.
To date, the most notable study146 to investigate the use of LMWF-5A to treat knee OA was published in 2014. In this study, 329 patients were randomized at a ratio of 1:1:1:1 to receive a single 4 ml or 10 ml intra-articular injection of either LMWF-5A or saline. The WOMAC pain scores of patients treated with LMWF-5A were significantly better than those treated with placebo at week 12 (estimated difference from control −0.25, P = 0.004)146. However, the effect size was roughly one quarter of what was assumed and such a small difference is not likely to be clinically meaningful to an appreciable number of patients32. Nevertheless, Ampio Pharmaceuticals announced that their phase III clinical trial met its primary endpoint, with 71% of patients in the treatment group meeting the Outcome Measures in Rheumatology (OMERACT)–OARSI responder criteria149. Overall, the available data suggest that the short-term effects of LMWF-5A might be non-inferior (although they are not likely to be superior) to currently used intra-articular treatment modalities. The long-term effects of LMWF-5A have yet to be determined, but the results of in vitro studies145,150 and of a post hoc analysis148 are encouraging. An open label, phase III extension study to evaluate the long-term safety of LMWF-5A is currently underway151.

HA–triamcinolone hexacetonide (Cingal)

Cingal is an HA-triamcinolone hexacetonide combination drug that was developed by Anika Therapeutics, Inc. (Bedford, MA, USA). A 2017 double-blind, saline-controlled trial compared the use of Cingal, HA (the same as that used in Cingal) and saline in 149, 150 and 69 patients with knee OA, respectively152. In this study, Cingal provided better symptomatic relief than placebo, as measured by the WOMAC pain score at 26 weeks. However, Cingal only produced statistically significant benefits at week 1 and week 3 when compared with HA alone. Although the authors of this study152 claim that the rapid response seen in patients demonstrates the ‘clinical significance’ of Cingal, the report does not mention the MID and the short-term improvements compared with HA alone were modest (<10% difference)152. A single-group follow-on study in which the safety of repeated Cingal injections was investigated was completed in 2015, but the results have yet to be announced or published153. Overall, the currently available data do not support the use of Cingal over HA, although the results from an ongoing phase III trial (n = 576) in which Cingal is compared with HA alone and triamcinolone hexacetonide alone154 are needed before firm efficacy conclusions can be drawn.

Autologous protein solution

The nSTRIDE APS kit (Zimmer Biomet, Warsaw, IN, USA) is a single-use device that produces a ‘cell concentrate’ from autologous blood (Fig. 2), which the manufacturer refers to as an autologous protein solution (APS). Conceptually, APS and PRP (both of which contain white blood cells) are very similar. However, unlike traditional PRP systems, the nSTRIDE APS kit passes the concentrated plasma though a dried polyacrylamide gel that preferentially concentrates anti-inflammatory cytokines such as IL-1 receptor antagonist and TNF receptor inhibitor155. Zimmer Biomet have also obtained an Investigational Device Exemption for the nSTRIDE APS kit156, which means that, unlike PRP, if approved, the intra-articular administration of APS to patients with OA would not be considered off-label use.
APS has demonstrated preliminary feasibility in preclinical models157,158 and safety in patients with OA156,159. The results of the phase II trial160 showed a statistically significant improvement in WOMAC pain scores at 12 months for those treated with APS compared with those treated with placebo, which the authors claim became apparent between 6 and 12 months. However, in this study160, outcomes were not assessed between 6 and 12 months, the WOMAC was not a pre-specified outcome of interest and no statistically significant differences between the WOMAC pain scores for APS and placebo were found at week 2, month 1, month 3 or month 6. Additionally, the authors of the study failed to report that the primary outcome (VAS at month 6) was not met and that statistically significant differences were not found in the responder rate, VAS, quality-of-life, patient/clinical global impression of change or KOOS at any timepoint161. Nevertheless, the generally positive safety profile of APS supports its continued clinical development, and the results from an ongoing phase III clinical trial (n = 246) in which the nSTRIDE APS kit is compared with saline162 are needed before preliminary efficacy conclusions can be drawn.

SM04690

SM04690 is a novel small-molecule Wnt–β-catenin signalling pathway inhibitor that is currently being developed by Samumed LLC (San Diego, CA, USA)163. Excessive activation of β-catenin-dependent signalling pathways can severely inhibit cartilage formation, as well as growth plate organization and function164. Additionally, inhibition of β-catenin-dependent signalling pathways induces chondrogenesis and inhibits joint destruction in rats165.
The exact mechanism of action of SM04690 is still under investigation163, and previous attempts in mice to inhibit Wnt signalling pathways have failed166,167. Nevertheless, the results from the first-in-human, 24-week, phase I RCT revealed SM04690 to be safe and well-tolerated, and showed no evidence of exposure outside of the injected joint168. Additionally, all three treatment cohorts had reduced joint-space narrowing compared with the placebo group at 24 weeks. A phase IIb study to evaluate the safety and efficacy of SM04690 is still ongoing169, but a phase IIa trial170 in which 0.03 mg, 0.07 mg and 0.23 mg doses of SM04690 were compared with placebo was completed in 2017 (n = 455). Results from this trial170 have yet to be formally published, but preliminary findings have been announced by Samumed171. The improvements in clinical outcomes and joint-space width (JSW) in the intention-to-treat population were not statistically significant, but a subpopulation of unilateral symptomatic patients in the mid-dose cohort demonstrated better improvements in WOMAC and medial JSW than patients in the control group at week 52 (ref.171). This subpopulation was not a pre-specified group of interest for this trial170, but unilateral symptomatic patients are listed as a subgroup of interest in the ongoing phase IIb trial169.

rhFGF18 (sprifermin)

rhFGF18 (sprifermin) is a growth factor therapy being developed by EMD Serono (Darmstadt, Germany and Billerica, MA, USA). As mentioned in the section on growth factor therapy, the largely successful phase I trial showed preliminary safety and efficacy80. Post hoc analyses of the phase I data showed slight improvements in cartilage at the patellofemoral joint172, as well as a minor increase in total cartilage thickness and a small reduction in total cartilage loss173. A 5-year randomized, placebo-controlled, phase II study in which three, weekly, intra-articular injections of placebo or sprifermin administered in cycles of once every 6 months or once every 12 months are compared (n = 549), is currently in its final year174. In the 2-year results, which were reported at the ACR annual meeting in 2017, the primary endpoint of a change in total tibiofemoral joint cartilage thickness from baseline was met175. Patients who were treated with 100 µg of sprifermin every 6 months or every 12 months had a significantly greater increase in total tibiofemoral joint cartilage thickness than patients in the control group (+0.03 mm and +0.02 mm versus -0.02 mm, respectively; P < 0.001)175. Although clinical outcome data showing improvements in pain and function compared with placebo are still needed to validate the utility of the reported structural modifications, the data released to date seem to suggest a disease-modifying benefit.

CNTX-4975

CNTX-4975 is an injectable, high-purity trans-capsaicin that is currently being developed by Centrexion Therapeutics (Boston, MA, USA). This treatment targets the capsaicin receptor (transient receptor potential cation channel subfamily V member 1), which contributes to the detection and integration of pain-producing stimuli176. The analgesic effects of capsaicin-based treatments have been attributed to several different mechanisms (collectively referred to as the ‘defunctionalization’ of nociceptive fibres), including the transient retraction of nerve fibre terminals177,178. Before the technology was acquired by Centrexion Therapeutics, a less-purified version of CNTX-4975 (ALRGX-4975) was clinically investigated by Anesiva Inc. as a treatment for postoperative pain under the name Adlea179. The results of the studies conducted by Anesiva Inc. were never published or released, and it was not until Centrexion Therapeutics acquired the technology that the treatment was first administered via intra-articular injection to treat moderate-to-severe OA-related pain.
The results of the phase IIb study in which CNTX-4975 was compared with placebo were reported at international meetings in 2017 (refs180,181). Patients treated with 1 mg CNTX-4975 (n = 70) had improved WOMAC A1 scores (10-point VAS) at week 12 (least squares mean differences (LSMD) −1.6) and at week 24 (LSMD −1.35) compared with patients who received placebo (n = 69). With respect to intra-articular therapies currently in clinical use, the magnitude of difference and duration of benefits for CNTX-4975 is very encouraging, particularly given the inclusion of morbidly obese patients and patients with severe OA (Kellgren-Lawrence grade II–IV). The most notable limitation of CNTX-4975 is that it does not halt or reverse the course of OA pathogenesis. Clinical data have been presented at a number of scientific congresses, but the preliminary data have yet to be published. Nevertheless, Centrexion Therapeutics has begun recruiting participants for a phase III trial (n = 325)182, and this treatment was granted Fast Track designation by the FDA in 2018.

TissueGene C (Invossa)

TissueGene C is a cell therapy being developed by Kolon Tissue Gene, Inc. (Rockville, MD, USA). The therapy, which is currently available in South Korea under the trade name Invossa, is a mixture containing chondrocytes that have been transduced with a viral vector containing TGFB1. In preclinical studies, the genetically modified chondrocytes demonstrated long-term transforming growth factor-β secretion and constitutive type II collagen expression in vitro, as well as the ability to form cartilage in vivo183. Following the successful completion of a phase I safety study184, a phase II, multicentre, double-blinded, placebo-controlled RCT was conducted in which TissueGene C (n = 67) was compared with saline (n = 35)185. Although no difference was found between TissueGene C and saline in the International Knee Documentation Committee (IKDC) score or VAS of patients at week 4 or week 24, statistically significant differences between the groups were observed at week 12, week 52 and overall185. The magnitude of the overall difference was notable (12-week VAS (LSMD -13.8; CI -25.0 to -2.6), 52-week VAS (LSMD -13.1; CI -25.1 to -1.1)), particularly for a phase II trial. However, the analysis was not intent-to-treat and 16 patients in the treatment group (24.2%) and 6 patients in the control group (18.8%) were lost to follow-up, which could have introduced selection bias. A 2017 publication in which the structural effects of TissueGene C were detailed provided unclear evidence of disease modification186.
Data from a multicentre, double-blind, clinical trial conducted in South Korea revealed that TissueGene C provided long-term clinical benefits compared with placebo187. In this study, 163 patients with Kellgren-Lawrence grade III OA were randomly assigned to receive a single intra-articular injection of TissueGene C or saline. The study met both of its primary outcomes by showing statistically significant improvements in IKDC scores (+15 versus +5; P < 0.001) and VAS (-25 points versus -10 points; P < 0.001) at 52 weeks compared with control187. The IKDC score and VAS were also improved at week 26 and week 39, and statistically significant improvements were seen in secondary clinical outcomes (WOMAC and KOOS) at week 52 compared with control187. Although significant differences on radiographs (changes in JSW) or whole-organ MRI scoring were not observed, post hoc analysis of MRI data suggested possible (albeit small) improvements in cartilage thickness186. Even in the absence of disease modification, the relatively robust and consistent long-term improvements of patients treated with TissueGene C across different clinical outcomes is promising. A follow-up phase III study (n = 510) has been announced188 that is powered to determine if the treatment provides a disease-modifying effect.

FX006 (Zilretta)

FX006 (Zilretta) is an intra-articular microsphere-based formulation of triamcinolone acetonide developed by Flexion Therapeutics (Burlington, MA, USA) that has been approved by the FDA for use in treating OA-related knee pain189. This extended-release glucocorticoid uses a proprietary matrix that is designed to prolong the analgesic benefits of triamcinolone acetonide in patients with knee OA190. A phase IIa trial in which FX006 was compared with triamcinolone acetonide failed to show a statistically significant improvement in pain from baseline at 12 weeks, but did demonstrate significant improvements at 8 weeks and 10 weeks191 (all three timepoints were pre-specified as primary outcomes192). The promising results of this trial prompted a follow-up phase IIb trial to compare 32 mg FX006 (n = 104), 16 mg FX006 (n = 102) and saline (n = 100)193. Similar to the phase IIa trial, the follow-up phase IIb trial failed to show statistically significant improvements in average daily pain (ADP) at 12 weeks compared with saline (primary outcome), but did show a statistically significant difference in ADP between FX006 and saline at weeks 1–11 and at week 13 (secondary outcomes)193.
In a 24-week, phase III, multicentre, double-blinded RCT, patients with knee OA were treated with a single intra-articular injection of FX006 (n = 161), placebo (n = 162) or triamcinolone acetonide (n = 161)194. Although patients treated with FX006 had a greater improvement in the ADP at week 12 than those treated with placebo (-3.12 versus -2.14), an improvement in ADP compared with patients treated with triamcinolone acetonide was not seen194. The failure to find a statistically significant difference between triamcinolone acetonide and FX006 might have resulted from the large assumed effect size, which was considerably larger than can be justified by the results of the phase IIb study193. Moreover, although statistically significant improvements were seen in several exploratory endpoints (such as WOMAC subscales and KOOS quality-of-life) compared with triamcinolone acetonide, the differences were very small and not likely to be clinically significant.
Overall, FX006 seems to provide better pain relief than intra-articular saline; however, the advantages over traditional formulations of triamcinolone acetonide are unclear. Although it is possible that FX006 provides better pain relief than traditional triamcinolone acetonide formulations, particularly in the short-term (<12 weeks), additional appropriately powered studies that compare traditional triamcinolone acetonide formulations and FX006 are still needed, and it seems unlikely that the magnitude of the difference would be large enough to be clinically important to an appreciable number of patients. Given the lack of long-term data, the potentially harmful long-term effects of glucocorticoids and the questionable clinical benefits of FX006 compared with traditional triamcinolone acetonide, clinicians should be particularly careful when prescribing FX006.

Conclusions

For most of the 21st century, HA and glucocorticoids have been the standard intra-articular treatments for the management of knee OA in patients who fail to respond to non-pharmacological therapy, NSAIDs or analgesics. Although the prospect of new, non-surgical treatments for knee OA is likely to cause excitement in both clinicians and their patients, the benefits of new treatments must be carefully weighed against their cost and potential risks. It should be remembered that a strong placebo response exists towards agents administered via intra-articular injection, and that new intra-articular treatments might not be appropriate for every patient.

Acknowledgements

The work of the authors was supported by grants UL1TR001855 and UL1TR000130 from the National Center for Advancing Translational Science (NCATS) of the US National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Reviewer information

Nature Reviews Rheumatology thanks C. Evans, D. Hunter and A. Migliore for their contribution to the peer review of this work.

Competing interests

C.T.V.Jr. declares that he holds shares in CarthroniX Inc. and in Parcus Medical. The other authors declare no competing interests.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Literature
1.
Sinusas, K. Osteoarthritis: diagnosis and treatment. Am. Fam. Physician 85, 49–56 (2012).PubMed
2.
Liu-Bryan, R. Synovium and the innate inflammatory network in osteoarthritis progression. Curr. Rheumatol Rep. 15, 323 (2013).PubMedPubMedCentralCrossRef
3.
Haseeb, A. & Haqqi, T. M. Immunopathogenesis of osteoarthritis. Clin. Immunol. 146, 185–196 (2013).PubMedPubMedCentralCrossRef
4.
Aigner, T., Söder, S., Gebhard, P. M., McAlinden, A. & Haag, J. Mechanisms of disease: role of chondrocytes in the pathogenesis of osteoarthritis — structure, chaos and senescence. Nat. Clin. Pract. Rheumatol. 3, 391–399 (2007).PubMedCrossRef
5.
Chevalier, X., Eymard, F. & Richette, P. Biologic agents in osteoarthritis: hopes and disappointments. Nat. Rev. Rheumatol. 9, 400–410 (2013).PubMedCrossRef
6.
Lories, R. J. & Luyten, F. P. The bone–cartilage unit in osteoarthritis. Nat. Rev. Rheumatol. 7, 43–49 (2011).CrossRefPubMed
7.
Emami, A. et al. Toxicology evaluation of drugs administered via uncommon routes: intranasal, intraocular, intrathecal/intraspinal, and intra-articular. Int. J. Toxicol. 37, 4–27 (2018).PubMedCrossRef
8.
Evans, C. H., Kraus, V. B. & Setton, L. A. Progress in intra-articular therapy. Nat. Rev. Rheumatol. 10, 11–22 (2014).PubMedCrossRef
9.
Rousseau, J.-C. & Delmas, P. D. Biological markers in osteoarthritis. Nat. Clin. Pract. Rheumatol. 3, 346–356 (2007).PubMedCrossRef
10.
Robinson, W. H. et al. Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis. Nat. Rev. Rheumatol. 12, 580–592 (2016).PubMedPubMedCentralCrossRef
11.
Sellam, J. & Berenbaum, F. The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis. Nat. Rev. Rheumatol. 6, 625–635 (2010).PubMedCrossRef
12.
Maudens, P., Jordan, O. & Allémann, E. Recent advances in intra-articular drug delivery systems for osteoarthritis therapy. Drug Discov. Today 23, 1761–1775 (2018).PubMedCrossRef
13.
Miller, R. E., Block, J. A. & Malfait, A.-M. What is new in pain modification in osteoarthritis? Rheumatology 58, 26 (2018).
14.
Nelson, A. E., Allen, K. D., Golightly, Y. M., Goode, A. P. & Jordan, J. M. A systematic review of recommendations and guidelines for the management of osteoarthritis: the chronic osteoarthritis management initiative of the U.S. bone and joint initiative. Semin. Arthritis Rheum. 43, 701–712 (2014).PubMedCrossRef
15.
Nguyen, C., Lefèvre-Colau, M.-M., Poiraudeau, S. & Rannou, F. Evidence and recommendations for use of intra-articular injections for knee osteoarthritis. Ann. Phys. Rehabil. Med. 59, 184–189 (2016).PubMedCrossRef
16.
Gerwin, N., Hops, C. & Lucke, A. Intraarticular drug delivery in osteoarthritis. Adv. Drug Deliv. Rev. 58, 226–242 (2006).PubMedCrossRef
17.
Habib, G. S. Systemic effects of intra-articular corticosteroids. Clin. Rheumatol. 28, 749–756 (2009).PubMedCrossRef
18.
Jackson, D. W., Evans, N. A. & Thomas, B. M. Accuracy of needle placement into the intra-articular space of the knee. J. Bone Joint Surg. Am. 84, 1522–1527 (2002).PubMedCrossRef
19.
Larsen, C. et al. Intra-articular depot formulation principles: role in the management of postoperative pain and arthritic disorders. J. Pharm. Sci. 97, 4622–4654 (2008).PubMedCrossRef
20.
Bannuru, R. R., Natov, N. S., Dasi, U. R., Schmid, C. H. & McAlindon, T. E. Therapeutic trajectory following intra-articular hyaluronic acid injection in knee osteoarthritis — meta-analysis. Osteoarthr. Cartil. 19, 611–619 (2011).CrossRef
21.
Rosseland, L. A., Helgesen, K. G., Breivik, H. & Stubhaug, A. Moderate-to-severe pain after knee arthroscopy is relieved by intraarticular saline: a randomized controlled trial. Anesth. Analg. 98, 1546–1551 (2004).PubMedCrossRef
22.
Abhishek, A. & Doherty, M. Mechanisms of the placebo response in pain in osteoarthritis. Osteoarthr. Cartil. 21, 1229–1235 (2013).CrossRef
23.
Bannuru, R. R. et al. Effectiveness and implications of alternative placebo treatments: a systematic review and network meta-analysis of osteoarthritis trials. Ann. Intern. Med. 163, 365–372 (2015).PubMedCrossRef
24.
Kirwan, J. R. & Rankin, E. Intra-articular therapy in osteoarthritis. Baillieres Clin. Rheumatol 11, 769–794 (1997).PubMedCrossRef
25.
Hameed, F. & Ihm, J. Injectable medications for osteoarthritis. PM R. 4, S75–S81 (2012).PubMedCrossRef
26.
Saltzman, B. M. et al. The therapeutic effect of intra-articular normal saline injections for knee osteoarthritis: a meta-analysis of evidence level 1 studies. Am. J. Sports Med. 45, 2647–2653 (2017).PubMedCrossRef
27.
Sullivan, G. M. & Feinn, R. Using effect size — or why the P value is not enough. J. Grad. Med. Educ. 4, 279–282 (2012).PubMedPubMedCentralCrossRef
28.
Jaeschke, R., Singer, J. & Guyatt, G. H. Measurement of health status: ascertaining the minimal clinically important difference. Control. Clin. Trials 10, 407–415 (1989).PubMedCrossRef
29.
Redelmeier, D. A. & Lorig, K. Assessing the clinical importance of symptomatic improvements. An illustration in rheumatology. Arch. Intern. Med. 153, 1337–1342 (1993).PubMedCrossRef
30.
Angst, F., Aeschlimann, A. & Angst, J. The minimal clinically important difference raised the significance of outcome effects above the statistical level, with methodological implications for future studies. J. Clin. Epidemiol. 82, 128–136 (2017).PubMedCrossRef
31.
McGlothlin, A. E. & Lewis, R. J. Minimal clinically important difference: defining what really matters to patients. JAMA 312, 1342–1343 (2014).PubMedCrossRef
32.
Devji, T. et al. Application of minimal important differences in degenerative knee disease outcomes: a systematic review and case study to inform BMJ Rapid Recommendations. BMJ Open 7, e015587 (2017).PubMedPubMedCentralCrossRef
33.
Dworkin, R. H. et al. Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations. J. Pain 9, 105–121 (2008).PubMedCrossRef
34.
Copay, A. G., Subach, B. R., Glassman, S. D., Polly, D. W. & Schuler, T. C. Understanding the minimum clinically important difference: a review of concepts and methods. Spine J. 7, 541–546 (2007).PubMedCrossRef
35.
King, M. T. A point of minimal important difference (MID): a critique of terminology and methods. Expert Rev. Pharmacoecon Outcomes Res. 11, 171–184 (2011).PubMedCrossRef
36.
Wright, A., Hannon, J., Hegedus, E. J. & Kavchak, A. E. Clinimetrics corner: a closer look at the minimal clinically important difference (MCID). J. Man. Manip. Ther. 20, 160–166 (2012).PubMedPubMedCentralCrossRef
37.
Cook, C. E. Clinimetrics corner: the minimal clinically important change score (MCID): a necessary pretense. J. Man. Manip. Ther. 16, E82–E83 (2008).PubMedPubMedCentralCrossRef
38.
Revicki, D., Hays, R. D., Cella, D. & Sloan, J. Recommended methods for determining responsiveness and minimally important differences for patient-reported outcomes. J. Clin. Epidemiol. 61, 102–109 (2008).PubMedCrossRef
39.
Bedard, N. A. et al. Impact of clinical practice guidelines on use of intra-articular hyaluronic acid and corticosteroid injections for knee osteoarthritis. J. Bone Joint Surg. Am. 100, 827–834 (2018).PubMedCrossRef
40.
Migliore, A. et al. The discrepancy between recommendations and clinical practice for viscosupplementation in osteoarthritis: mind the gap! Eur. Rev. Med. Pharmacol. Sci. 19, 1124–1129 (2015).PubMed
41.
Jevsevar, D. S. et al. The American Academy of Orthopaedic Surgeons evidence-based guideline on: treatment of osteoarthritis of the knee, 2nd edition. J. Bone Joint Surg. Am. 95, 1885–1886 (2013).PubMedCrossRef
42.
Chao, J. et al. Inflammatory characteristics on ultrasound predict poorer longterm response to intraarticular corticosteroid injections in knee osteoarthritis. J. Rheumatol. 37, 650–655 (2010).PubMedCrossRef
43.
Gaffney, K., Ledingham, J. & Perry, J. D. Intra-articular triamcinolone hexacetonide in knee osteoarthritis: factors influencing the clinical response. Ann. Rheum. Dis. 54, 379–381 (1995).PubMedPubMedCentralCrossRef
44.
Raynauld, J.-P. et al. Safety and efficacy of long-term intraarticular steroid injections in osteoarthritis of the knee: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 48, 370–377 (2003).PubMedCrossRef
45.
Jones, A. & Doherty, M. Intra-articular corticosteroids are effective in osteoarthritis but there are no clinical predictors of response. Ann. Rheum. Dis. 55, 829–832 (1996).PubMedPubMedCentralCrossRef
46.
Caborn, D. et al. A randomized, single-blind comparison of the efficacy and tolerability of hylan G-F 20 and triamcinolone hexacetonide in patients with osteoarthritis of the knee. J. Rheumatol. 31, 333–343 (2004).PubMed
47.
Arden, N. K. et al. A randomised controlled trial of tidal irrigation versus corticosteroid injection in knee osteoarthritis: the KIVIS Study. Osteoarthr. Cartil. 16, 733–739 (2008).CrossRef
48.
McAlindon, T. E. et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthr. Cartil. 22, 363–388 (2014).CrossRef
49.
Bannuru, R. R. et al. Therapeutic trajectory of hyaluronic acid versus corticosteroids in the treatment of knee osteoarthritis: a systematic review and meta-analysis. Arthritis Rheum. 61, 1704–1711 (2009).PubMedCrossRef
50.
Bellamy, N. et al. Intraarticular corticosteroid for treatment of osteoarthritis of the knee. Cochrane Database Syst. Rev. 2, CD005328 (2006).
51.
Jüni, P. et al. Intra-articular corticosteroid for knee osteoarthritis. Cochrane Database Syst. Rev. 10, CD005328 (2015).
52.
National Institute for Health and Care Excellence. Osteoarthritis: Care and Management in Adults (NICE, 2014).
53.
Hochberg, M. C. et al. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res. 64, 465–474 (2012).CrossRef
54.
Wernecke, C., Braun, H. J. & Dragoo, J. L. The effect of intra-articular corticosteroids on articular cartilage: a systematic review. Orthop. J. Sports Med. 3, 2325967115581163 (2015).PubMedPubMedCentralCrossRef
55.
Bedard, N. A. et al. The John N. Insall Award: do intraarticular injections increase the risk of infection after TKA? Clin. Orthop. Relat. Res. 475, 45–52 (2017).PubMedCrossRef
56.
McAlindon, T. E. et al. Effect of intra-articular triamcinolone versus saline on knee cartilage volume and pain in patients with knee osteoarthritis: a randomized clinical trial. JAMA 317, 1967–1975 (2017).PubMedPubMedCentralCrossRef
57.
Cicuttini, F. M., Jones, G., Forbes, A. & Wluka, A. E. Rate of cartilage loss at two years predicts subsequent total knee arthroplasty: a prospective study. Ann. Rheum. Dis. 63, 1124–1127 (2004).PubMedPubMedCentralCrossRef
58.
Hitzl, W. et al. Greater lateral femorotibial cartilage loss in osteoarthritis initiative participants with incident total knee arthroplasty: a prospective cohort study. Arthritis Care Res. 67, 1481–1486 (2015).CrossRef
59.
Bannuru, R. R., Vaysbrot, E. E. & McIntyre, L. F. Did the American Academy of Orthopaedic Surgeons osteoarthritis guidelines miss the mark? Arthroscopy 30, 86–89 (2014).PubMedCrossRef
60.
Carlson, V. R. et al. Compliance with the AAOS guidelines for treatment of osteoarthritis of the knee: a survey of the American Association of Hip and Knee Surgeons. J. Am. Acad. Orthop. Surg. 26, 103–107 (2018).PubMedCrossRef
61.
Rutjes, A. W. S. et al. Viscosupplementation for osteoarthritis of the knee: a systematic review and meta-analysis. Ann. Intern. Med. 157, 180–191 (2012).PubMedCrossRef
62.
Bellamy, N. et al. Viscosupplementation for the treatment of osteoarthritis of the knee. Cochrane Database Syst. Rev. 3, CD005321 (2006).
63.
Jevsevar, D., Donnelly, P., Brown, G. A. & Cummins, D. S. Viscosupplementation for osteoarthritis of the knee: a systematic review of the evidence. J. Bone Joint Surg. Am. 97, 2047–2060 (2015).PubMedCrossRef
64.
Vannabouathong, C. et al. Nonoperative treatments for knee osteoarthritis: an evaluation of treatment characteristics and the intra-articular placebo effect: a systematic review. JBJS Rev. 6, e5 (2018).PubMedCrossRef
65.
Kapoor, M., Martel-Pelletier, J., Lajeunesse, D., Pelletier, J.-P. & Fahmi, H. Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Nat. Rev. Rheumatol. 7, 33–42 (2011).PubMedCrossRef
66.
Martel-Pelletier, J. Pathophysiology of osteoarthritis. Osteoarthr. Cartil. 6, 374–376 (1998).CrossRef
67.
Ashraf, S. et al. Regulation of senescence associated signaling mechanisms in chondrocytes for cartilage tissue regeneration. Osteoarthr. Cartil. 24, 196–205 (2016).CrossRef
68.
Pettipher, E. R., Higgs, G. A. & Henderson, B. Interleukin 1 induces leukocyte infiltration and cartilage proteoglycan degradation in the synovial joint. Proc. Natl Acad. Sci. USA 83, 8749–8753 (1986).PubMedCrossRefPubMedCentral
69.
Kato, T. et al. Exosomes from IL-1β stimulated synovial fibroblasts induce osteoarthritic changes in articular chondrocytes. Arthritis Res. Ther. 16, R163 (2014).PubMedPubMedCentralCrossRef
70.
Jacques, C., Gosset, M., Berenbaum, F. & Gabay, C. The role of IL-1 and IL-1Ra in joint inflammation and cartilage degradation. Vitam. Horm. 74, 371–403 (2006).PubMedCrossRef
71.
Chevalier, X. et al. Intraarticular injection of anakinra in osteoarthritis of the knee: a multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum. 61, 344–352 (2009).PubMedCrossRef
72.
Kraus, V. B. et al. Effects of intraarticular IL1-Ra for acute anterior cruciate ligament knee injury: a randomized controlled pilot trial (NCT00332254). Osteoarthr. Cartil. 20, 271–278 (2012).CrossRef
73.
Goldring, S. R. & Goldring, M. B. The role of cytokines in cartilage matrix degeneration in osteoarthritis. Clin. Orthop. Relat. Res. 427, S27–S36 (2004).CrossRef
74.
Stannus, O. et al. Circulating levels of IL-6 and TNF-α are associated with knee radiographic osteoarthritis and knee cartilage loss in older adults. Osteoarthr. Cartil. 18, 1441–1447 (2010).CrossRef
75.
Malfait, A. M. et al. Intra-articular injection of tumor necrosis factor-α in the rat: an acute and reversible in vivo model of cartilage proteoglycan degradation. Osteoarthr. Cartil. 17, 627–635 (2009).CrossRef
76.
Lindsley, H. B. et al. Treatment of knee osteoarthritis with intra-articular infliximab improves total WOMAC score. High baseline levels of synovial cellularity predict improvement [abstract FRI0304]. Ann. Rheum. Dis. 71 (Suppl. 3), 417 (2014).
77.
Ohtori, S. et al. Efficacy of direct injection of etanercept into knee joints for pain in moderate and severe knee osteoarthritis. Yonsei Med. J. 56, 1379 (2015).PubMedPubMedCentralCrossRef
78.
Wang, J. Efficacy and safety of adalimumab by intra-articular injection for moderate to severe knee osteoarthritis: an open-label randomized controlled trial. J. Int. Med. Res. 46, 326–334 (2018).PubMedCrossRef
79.
Hunter, D. J. et al. Phase 1 safety and tolerability study of BMP-7 in symptomatic knee osteoarthritis. BMC Musculoskelet. Disord. 11, 232 (2010).PubMedPubMedCentralCrossRef
80.
Lohmander, L. S. et al. Intraarticular sprifermin (recombinant human fibroblast growth factor 18) in knee osteoarthritis: a randomized, double-blind, placebo-controlled trial. Arthritis Rheumatol. 66, 1820–1831 (2014).PubMedCrossRef
81.
Hall, M. P., Band, P. A., Meislin, R. J., Jazrawi, L. M. & Cardone, D. A. Platelet-rich plasma: current concepts and application in sports medicine. J. Am. Acad. Orthop. Surg. 17, 602–608 (2009).PubMedCrossRef
82.
Hsu, W. K. et al. Platelet-rich plasma in orthopaedic applications: evidence-based recommendations for treatment. J. Am. Acad. Orthop. Surg. 21, 739–471 (2013).PubMedCrossRef
83.
Andia, I. & Maffulli, N. Platelet-rich plasma for managing pain and inflammation in osteoarthritis. Nat. Rev. Rheumatol. 9, 721–730 (2013).PubMedCrossRef
84.
Gutman, S. I. 510(k) summary: 3i CelSep centrifuge system. FDA https://​www.​accessdata.​fda.​gov/​cdrh_​docs/​pdf/​K994148.​pdf (2000).
86.
Vaught, M. S. & Cole, B. J. Coding and reimbursement issues for platelet-rich plasma. Oper. Tech. Sports Med. 19, 185–189 (2011).CrossRef
87.
Jones, I. A., Togashi, R. C. & Vangsness, C. T. The economics and regulation of PRP in the evolving field of orthopedic biologics. Curr. Rev. Musculoskelet. Med. 17, 602–608 (2018).
88.
Dhillon, R. S., Schwarz, E. M. & Maloney, M. D. Platelet-rich plasma therapy - future or trend? Arthritis Res. Ther. 14, 219 (2012).PubMedPubMedCentralCrossRef
89.
Beitzel, K. et al. US definitions, current use, and FDA stance on use of platelet-rich plasma in sports medicine. J. Knee Surg. 28, 29–34 (2015).PubMedCrossRef
90.
Chahla, J. et al. A call for standardization in platelet-rich plasma preparation protocols and composition reporting: a systematic review of the clinical orthopaedic literature. J. Bone Joint Surg. Am. 99, 1769–1779 (2017).PubMedCrossRef
91.
Chen, X., Jones, I. A., Park, C. & Vangsness, C. T. The efficacy of platelet-rich plasma on tendon and ligament healing: a systematic review and meta-analysis with bias assessment. Am. J. Sports Med. 2016, 363546517743746 (2017).
92.
Khoshbin, A. et al. The efficacy of platelet-rich plasma in the treatment of symptomatic knee osteoarthritis: a systematic review with quantitative synthesis. Arthroscopy 29, 2037–2048 (2013).PubMedCrossRef
93.
Kanchanatawan, W. et al. Short-term outcomes of platelet-rich plasma injection for treatment of osteoarthritis of the knee. Knee Surg. Sports Traumatol. Arthrosc. 24, 1665–1677 (2016).PubMedCrossRef
94.
Tubach, F. et al. Evaluation of clinically relevant changes in patient reported outcomes in knee and hip osteoarthritis: the minimal clinically important improvement. Ann. Rheum. Dis. 64, 29–33 (2005).PubMedCrossRef
95.
Escobar, A. et al. Responsiveness and clinically important differences for the WOMAC and SF-36 after total knee replacement. Osteoarthr. Cartil. 15, 273–280 (2007).CrossRef
96.
Angst, F., Aeschlimann, A., Michel, B. A. & Stucki, G. Minimal clinically important rehabilitation effects in patients with osteoarthritis of the lower extremities. J. Rheumatol. 29, 131–138 (2002).PubMed
97.
Chahla, J. et al. Concentrated bone marrow aspirate for the treatment of chondral injuries and osteoarthritis of the knee: a systematic review of outcomes. Orthop. J. Sports Med. 4, 2325967115625481 (2016).PubMedPubMedCentral
98.
Bowen, J. E. Technical issues in harvesting and concentrating stem cells (bone marrow and adipose). PM R. 7, S8–S18 (2015).PubMedCrossRef
99.
McCarrel, T. & Fortier, L. Temporal growth factor release from platelet-rich plasma, trehalose lyophilized platelets, and bone marrow aspirate and their effect on tendon and ligament gene expression. J. Orthop. Res. 27, 1033–1042 (2009).PubMedCrossRef
100.
Turner, L. & Knoepfler, P. Selling stem cells in the USA: assessing the direct-to-consumer industry. Cell Stem Cell 19, 154–157 (2016).PubMedCrossRef
101.
Pittenger, M. F. et al. Multilineage potential of adult human mesenchymal stem cells. Science 284, 143–147 (1999).PubMedCrossRef
102.
Aronowitz, J. A., Lockhart, R. A. & Hakakian, C. S. Mechanical versus enzymatic isolation of stromal vascular fraction cells from adipose tissue. Springerplus 4, 713 (2015).PubMedPubMedCentralCrossRef
103.
Chirba, M. A., Sweetapple, B., Hannon, C. P. & Anderson, J. A. FDA regulation of adult stem cell therapies as used in sports medicine. J. Knee Surg. 28, 55–62 (2015).PubMedCrossRef
104.
Food and Drug Administration. Regulatory considerations for human cells, tissues, and cellular and tissue-based products: minimal manipulation and homologous use. FDA https://​www.​fda.​gov/​downloads/​biologicsbloodva​ccines/​guidancecomplian​ceregulatoryinfo​rmation/​guidances/​cellularandgenet​herapy/​ucm585403.​pdf (2017).
105.
Marks, P. & Gottlieb, S. Balancing safety and innovation for cell-based regenerative medicine. N. Engl. J. Med. 378, 954–959 (2018).PubMedCrossRef
106.
Kokai, L. E., Marra, K. & Rubin, J. P. Adipose stem cells: biology and clinical applications for tissue repair and regeneration. Transl Res. 163, 399–408 (2014).PubMedCrossRef
107.
Oberbauer, E. et al. Enzymatic and non-enzymatic isolation systems for adipose tissue-derived cells: current state of the art. Cell Regen (Lond.) 4, 7 (2015).
108.
Bourin, P. et al. Stromal cells from the adipose tissue-derived stromal vascular fraction and culture expanded adipose tissue-derived stromal/stem cells: a joint statement of the International Federation for Adipose Therapeutics and Science (IFATS) and the International Society for Cellular Therapy (ISCT). Cytotherapy 15, 641–648 (2013).PubMedPubMedCentralCrossRef
109.
Koh, Y.-G., Choi, Y.-J., Kwon, O.-R. & Kim, Y.-S. Second-look arthroscopic evaluation of cartilage lesions after mesenchymal stem cell implantation in osteoarthritic knees. Am. J. Sports Med. 42, 1628–1637 (2014).PubMedCrossRef
110.
Koh, Y.-G., Kwon, O.-R., Kim, Y. S., Choi, Y.-J. & Tak, D.-H. Adipose-derived mesenchymal stem cells with microfracture versus microfracture alone: 2-year follow-up of a prospective randomized trial. Arthroscopy 32, 97–109 (2016).PubMedCrossRef
111.
Pak, J. et al. Current use of autologous adipose tissue-derived stromal vascular fraction cells for orthopedic applications. J. Biomed. Sci. 24, 9 (2017).PubMedPubMedCentralCrossRef
112.
Pers, Y.-M. et al. Adipose mesenchymal stromal cell-based therapy for severe osteoarthritis of the knee: a phase I dose-escalation trial. Stem Cells Transl Med. 5, 847–856 (2016).PubMedPubMedCentralCrossRef
113.
Fodor, P. B. & Paulseth, S. G. Adipose derived stromal cell (ADSC) injections for pain management of osteoarthritis in the human knee joint. Aesthet. Surg. J. 36, 229–236 (2016).PubMedCrossRef
114.
Mendicino, M., Bailey, A. M., Wonnacott, K., Puri, R. K. & Bauer, S. R. MSC-based product characterization for clinical trials: an FDA perspective. Cell Stem Cell 14, 141–145 (2014).PubMedCrossRef
115.
Freitag, J. et al. Mesenchymal stem cell therapy in the treatment of osteoarthritis: reparative pathways, safety and efficacy - a review. BMC Musculoskelet. Disord. 17, 230 (2016).PubMedPubMedCentralCrossRef
116.
Pas, H. I. et al. Stem cell injections in knee osteoarthritis: a systematic review of the literature. Br. J. Sports Med. 51, 1125–1133 (2017).PubMedCrossRef
117.
McIntyre, J. A., Jones, I. A., Han, B. & Vangsness, C. T. Intra-articular mesenchymal stem cell therapy for the human joint: a systematic review. Am. J. Sports Med. 11, 036354651773584 (2017).
118.
Chahla, J. et al. Intra-articular cellular therapy for osteoarthritis and focal cartilage defects of the knee: a systematic review of the literature and study quality analysis. J. Bone Joint Surg. Am. 98, 1511–1521 (2016).PubMedCrossRef
119.
Pak, J., Lee, J. H., Park, K. S., Jeon, J. H. & Lee, S. H. Potential use of mesenchymal stem cells in human meniscal repair: current insights. Open Access J. Sports Med. 8, 33–38 (2017).PubMedPubMedCentralCrossRef
120.
Caplan, A. I. Mesenchymal stem cells. J. Orthop. Res. 9, 641–650 (1991).PubMedCrossRef
121.
Caplan, A. I. Mesenchymal stem cells: time to change the name! Stem Cells Transl Med. 6, 1445–1451 (2017).PubMedPubMedCentralCrossRef
122.
Dominici, M. et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8, 315–317 (2006).PubMedCrossRef
123.
Horwitz, E. M. et al. Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement. Cytotherapy 7, 393–395 (2005).PubMedCrossRef
124.
Bianco, P., Robey, P. G. & Simmons, P. J. Mesenchymal stem cells: revisiting history, concepts, and assays. Cell Stem Cell 2, 313–319 (2008).PubMedPubMedCentralCrossRef
125.
Stappenbeck, T. S. & Miyoshi, H. The role of stromal stem cells in tissue regeneration and wound repair. Science 324, 1666–1669 (2009).PubMedCrossRef
126.
Galipeau, J. & Krampera, M. The challenge of defining mesenchymal stromal cell potency assays and their potential use as release criteria. Cytotherapy 17, 125–127 (2015).PubMedCrossRef
127.
Marks, P. W., Witten, C. M. & Califf, R. M. Clarifying stem-cell therapy’s benefits and risks. N. Engl. J. Med. 376, 1007–1009 (2017).PubMedCrossRef
128.
Prockop, D. J. et al. Defining the risks of mesenchymal stromal cell therapy. Cytotherapy 12, 576–578 (2010).PubMedCrossRef
129.
Toyserkani, N. M. et al. Concise review: a safety assessment of adipose-derived cell therapy in clinical trials: a systematic review of reported adverse events. Stem Cells Transl Med. 6, 1786–1794 (2017).PubMedPubMedCentralCrossRef
130.
Vega, A. et al. Treatment of knee osteoarthritis with allogeneic bone marrow mesenchymal stem cells: a randomized controlled trial. Transplantation 99, 1681–1690 (2015).PubMedCrossRef
131.
Vangsness, C. T. J. et al. Adult human mesenchymal stem cells delivered via intra-articular injection to the knee following partial medial meniscectomy: a randomized, double-blind, controlled study. J. Bone Joint Surg. Am. 96, 90–98 (2014).PubMedCrossRef
132.
Trounson, A. & McDonald, C. Stem cell therapies in clinical trials: progress and challenges. Cell Stem Cell 17, 11–22 (2015).PubMedCrossRef
133.
McIntyre, J. A., Jones, I. A., Danilkovich, A. & Vangsness, C. T. The placenta: applications in orthopaedic sports medicine. Am. J. Sports Med. 122, 363546517697682 (2017).
134.
Goldberg, A., Mitchell, K., Soans, J., Kim, L. & Zaidi, R. The use of mesenchymal stem cells for cartilage repair and regeneration: a systematic review. J. Orthop. Surg. Res. 12, 39 (2017).PubMedPubMedCentralCrossRef
135.
Jones, I. A., Chen, X., Evseenko, D. & Vangsness, C. T. Nomenclature inconsistency and selective outcome reporting hinders our understanding of stem cell therapy for the knee. J. Bone Joint Surg. Am. (in the press).
136.
Shkhyan, R. et al. Drug-induced modulation of gp130 signalling prevents articular cartilage degeneration and promotes repair. Ann. Rheum. Dis. 77, 760–769 (2018).PubMedCrossRef
137.
US National Library of Medicine. ClinicalTrials.gov https://​clinicaltrials.​gov/​ct2/​show/​NCT03513016 (2018).
138.
Jeon, O. H. et al. Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat. Med. 23, 775–781 (2017).PubMedPubMedCentralCrossRef
139.
Lozada, C. J. et al. A double-blind, randomized, saline-controlled study of the efficacy and safety of co-administered intra-articular injections of Tr14 and Ze14 for treatment of painful osteoarthritis of the knee: the MOZArT trial. Eur. J. Integ. Med. 13, 54–63 (2017).CrossRef
140.
Lei, J., Priddy, L. B., Lim, J. J. & Koob, T. J. Dehydrated human amnion/chorion membrane (dHACM) allografts as a therapy for orthopedic tissue repair. Tech. Orthop. 32, 149–157 (2017).CrossRef
141.
Lei, J., Priddy, L. B., Lim, J. J., Massee, M. & Koob, T. J. Identification of extracellular matrix components and biological factors in micronized dehydrated human amnion/chorion membrane. Adv. Wound Care (New Rochelle) 6, 43–53 (2017).CrossRef
143.
US National Library of Medicine. ClinicalTrials.gov https://​clinicaltrials.​gov/​ct2/​show/​NCT03485157 (2018).
144.
Willett, N. J. et al. Intra-articular injection of micronized dehydrated human amnion/chorion membrane attenuates osteoarthritis development. Arthritis Res. Ther. 16, R47 (2014).PubMedPubMedCentralCrossRef
145.
Shimonkevitz, R. et al. A diketopiperazine fragment of human serum albumin modulates T-lymphocyte cytokine production through RAP1. J. Trauma 64, 35–41 (2008).PubMed
146.
Bar-Or, D. et al. A randomized clinical trial to evaluate two doses of an intra-articular injection of LMWF-5A in adults with pain due to osteoarthritis of the knee. PLoS ONE 9, e87910 (2014).PubMedPubMedCentralCrossRef
147.
Schwappach, J., Dryden, S. M. & Salottolo, K. M. Preliminary trial of intra-articular LMWF-5A for osteoarthritis of the knee. Orthopedics 40, e49–e53 (2017).PubMedCrossRef
148.
Cole, B., McGrath, B., Salottolo, K. & Bar-Or, D. LMWF-5A for the treatment of severe osteoarthritis of the knee: integrated analysis of safety and efficacy. Orthopedics 41, e77–e83 (2018).PubMedCrossRef
149.
Ampio Pharmaceuticals. Ampio pharmaceuticals reports positive results for both primary and secondary endpoints of pivotal phase 3 trial of Ampion™ in severe osteoarthritis-of-the knee (OAK). Ampiopharma https://​ampiopharma.​com/​news/​ampio-pharmaceuticals-reports-positive-results-primary-secondary-endpoints-pivotal-phase-3-trial-ampion-severe-osteoarthritis-knee-oak/​ (2017).
150.
Bar-Or, D. et al. Low molecular weight fraction of commercial human serum albumin induces morphologic and transcriptional changes of bone marrow-derived mesenchymal stem cells. Stem Cells Transl Med. 4, 945–955 (2015).PubMedPubMedCentralCrossRef
151.
US National Library of Medicine. ClinicalTrials.gov https://​clinicaltrials.​gov/​ct2/​show/​NCT03349645 (2017).
152.
Hangody, L. et al. Intraarticular injection of a cross-linked sodium hyaluronate combined with triamcinolone hexacetonide (Cingal) to provide symptomatic relief of osteoarthritis of the knee: a randomized, double-blind, placebo-controlled multicenter clinical trial. Cartilage 89, 1947603517703732 (2017).
153.
US National Library of Medicine. ClinicalTrials.gov https://​clinicaltrials.​gov/​ct2/​show/​NCT02381652 (2015).
154.
US National Library of Medicine. ClinicalTrials.gov https://​clinicaltrials.​gov/​ct2/​show/​NCT03390036 (2018).
155.
O’Shaughnessey, K. et al. Autologous protein solution prepared from the blood of osteoarthritic patients contains an enhanced profile of anti-inflammatory cytokines and anabolic growth factors. J. Orthopaed. Res. 32, 1349–1355 (2014).CrossRef
156.
Hix, J. et al. An autologous anti-inflammatory protein solution yielded a favorable safety profile and significant pain relief in an open-label pilot study of patients with osteoarthritis. Biores Open Access 6, 151–158 (2017).PubMedPubMedCentralCrossRef
157.
King, W., Bendele, A., Marohl, T. & Woodell-May, J. Human blood-based anti-inflammatory solution inhibits osteoarthritis progression in a meniscal-tear rat study. J. Orthopaed. Res. 35, 2260–2268 (2017).CrossRef
158.
Wanstrath, A. W. et al. Evaluation of a single intra-articular injection of autologous protein solution for treatment of osteoarthritis in a canine population. Vet. Surg. 45, 764–774 (2016).PubMedCrossRef
159.
van Drumpt, R. A. M., van der Weegen, W., King, W., Toler, K. & Macenski, M. M. Safety and treatment effectiveness of a single autologous protein solution injection in patients with knee osteoarthritis. Biores Open Access 5, 261–268 (2016).PubMedPubMedCentralCrossRef
160.
Kon, E., Engebretsen, L., Verdonk, P., Nehrer, S. & Filardo, G. Clinical outcomes of knee osteoarthritis treated with an autologous protein solution injection: a 1-year pilot double-blinded randomized controlled trial. Am. J. Sports Med. 46, 171–180 (2018).PubMedCrossRef
161.
US National Library of Medicine. ClinicalTrials.gov https://​clinicaltrials.​gov/​ct2/​show/​NCT02138890 (2016).
162.
US National Library of Medicine. ClinicalTrials.gov https://​clinicaltrials.​gov/​ct2/​show/​NCT02905240 (2018).
163.
Dell’accio, F. & Cailotto, F. Pharmacological blockade of the WNT-beta-catenin signaling: a possible first-in-kind DMOAD. Osteoarthr. Cartil. 26, 4–6 (2018).CrossRef
164.
Usami, Y., Gunawardena, A. T., Iwamoto, M. & Enomoto-Iwamoto, M. Wnt signaling in cartilage development and diseases: lessons from animal studies. Lab. Invest. 96, 186–196 (2016).PubMedCrossRef
165.
Deshmukh, V. et al. A small-molecule inhibitor of the Wnt pathway (SM04690) as a potential disease modifying agent for the treatment of osteoarthritis of the knee. Osteoarthr. Cartil. 26, 18–27 (2018).CrossRef
166.
Yasuhara, R. et al. Roles of β-catenin signaling in phenotypic expression and proliferation of articular cartilage superficial zone cells. Lab. Invest. 91, 1739–1752 (2011).PubMedPubMedCentralCrossRef
167.
Zhu, M. et al. Inhibition of β-catenin signaling in articular chondrocytes results in articular cartilage destruction. Arthritis Rheum. 58, 2053–2064 (2008).PubMedPubMedCentralCrossRef
168.
Yazici, Y. et al. A novel Wnt pathway inhibitor, SM04690, for the treatment of moderate to severe osteoarthritis of the knee: results of a 24-week, randomized, controlled, phase 1 study. Osteoarthr. Cartil. 25, 1598–1606 (2017).CrossRef
169.
US National Library of Medicine. ClinicalTrials.gov https://​clinicaltrials.​gov/​ct2/​show/​NCT03122860 (2018).
170.
US National Library of Medicine. ClinicalTrials.gov https://​clinicaltrials.​gov/​ct2/​show/​NCT02536833 (2018).
171.
Jeyanesh, R. S. et al. Results from a 52-week, phase 2a study of an intra-articular, Wnt pathway inhibitor, SM04690, for knee osteoarthritis. Samumed https://​www.​samumed.​com/​medium/​image/​the-orthobiologic-institute-tobi-annual-symposium-06072018_​318/​view.​aspx (2018).
172.
Roemer, F. W. et al. Structural effects of sprifermin in knee osteoarthritis: a post-hoc analysis on cartilage and non-cartilaginous tissue alterations in a randomized controlled trial. BMC Musculoskelet. Disord. 17, 267 (2016).PubMedPubMedCentralCrossRef
173.
Eckstein, F., Wirth, W., Guermazi, A., Maschek, S. & Aydemir, A. Brief report: intraarticular sprifermin not only increases cartilage thickness, but also reduces cartilage loss: location-independent post hoc analysis using magnetic resonance imaging. Arthritis Rheumatol. 67, 2916–2922 (2015).PubMedPubMedCentralCrossRef
174.
US National Library of Medicine. ClinicalTrials.gov https://​clinicaltrials.​gov/​ct2/​show/​NCT01919164 (2018).
175.
Hochberg, M. et al. Efficacy and safety of intra-articular sprifermin in symptomatic radiographic knee osteoarthritis: results of the 2-year primary analysis from a 5-year randomised, placebo-controlled, phase II study [abstract]. Arthritis Rheumatol. 69 (Suppl. 10), 1L (2017).
176.
Caterina, M. J. & Julius, D. The vanilloid receptor: a molecular gateway to the pain pathway. Annu. Rev. Neurosci. 24, 487–517 (2001).CrossRefPubMed
177.
Simone, D. A., Nolano, M., Johnson, T., Wendelschafer-Crabb, G. & Kennedy, W. R. Intradermal injection of capsaicin in humans produces degeneration and subsequent reinnervation of epidermal nerve fibers: correlation with sensory function. J. Neurosci. 18, 8947–8959 (1998).PubMedCrossRefPubMedCentral
178.
Anand, P. & Bley, K. Topical capsaicin for pain management: therapeutic potential and mechanisms of action of the new high-concentration capsaicin 8% patch. Br. J. Anaesth. 107, 490–502 (2011).PubMedPubMedCentralCrossRef
179.
Remadevi, R. & Szallisi, A. Adlea (ALGRX-4975), an injectable capsaicin (TRPV1 receptor agonist) formulation for longlasting pain relief. IDrugs 11, 120–132 (2008).PubMed
180.
Stevens, R. et al. Efficacy and safety of CNTX-4975 in subjects with moderate to severe osteoarthritis knee pain: 24-week, randomized, double-blind, placebo-controlled, dose-ranging study. Ann. Rheum. Dis. 76 (Suppl. 2), 121–121 (2017).
181.
Hanson, P. D. CNTX-4975 administration in subjects with knee pain associated with osteoarthritis: results of the randomized, double-blind, placebo-controlled, phase 2b TRIUMPH study. availclinical https://​www.​availclinical.​com/​wp-content/​uploads/​2012/​02/​OA-Double-Blind-Study-Results.​pdf (2017).
182.
US National Library of Medicine. ClinicalTrials.gov https://​clinicaltrials.​gov/​ct2/​show/​NCT03429049 (2018).
183.
Lee, D. K. et al. Continuous transforming growth factor beta1 secretion by cell-mediated gene therapy maintains chondrocyte redifferentiation. Tissue Eng. 11, 310–318 (2005).PubMedCrossRef
184.
Ha, C.-W., Noh, M. J., Choi, K. B. & Lee, K. H. Initial phase I safety of retrovirally transduced human chondrocytes expressing transforming growth factor-beta-1 in degenerative arthritis patients. Cytotherapy 14, 247–256 (2012).PubMedPubMedCentralCrossRef
185.
Cherian, J. J. et al. Preliminary results of a phase II randomized study to determine the efficacy and safety of genetically engineered allogeneic human chondrocytes expressing TGF-β1 in patients with grade 3 chronic degenerative joint disease of the knee. Osteoarthr. Cartil. 23, 2109–2118 (2015).CrossRef
186.
Guermazi, A. et al. Structural effects of intra-articular TGF-β1 in moderate to advanced knee osteoarthritis: MRI-based assessment in a randomized controlled trial. BMC Musculoskelet. Disord. 18, 461 (2017).PubMedPubMedCentralCrossRef
187.
Kim, M.-K. et al. A multicenter, double-blind, phase III clinical trial to evaluate the efficacy and safety of a cell and gene therapy in knee osteoarthritis patients. Hum. Gene Ther. Clin. Dev. 29, 48–59 (2018).PubMedCrossRef
188.
US National Library of Medicine. ClinicalTrials.gov https://​clinicaltrials.​gov/​ct2/​show/​NCT03203330 (2018).
189.
Food and Drug Administration. Drug approval package: ZILRETTA (triamcinolone acetonide). FDA https://​www.​accessdata.​fda.​gov/​drugsatfda_​docs/​nda/​2017/​208845Orig1s000T​OC.​cfm (2017).
190.
Kraus, V. B. et al. Synovial and systemic pharmacokinetics (PK) of triamcinolone acetonide (TA) following intra-articular (IA) injection of an extended-release microsphere-based formulation (FX006) or standard crystalline suspension in patients with knee osteoarthritis (OA). Osteoarthr. Cartil. 26, 34–42 (2018).CrossRef
191.
Bodick, N. et al. An intra-articular, extended-release formulation of triamcinolone acetonide prolongs and amplifies analgesic effect in patients with osteoarthritis of the knee: a randomized clinical trial. J. Bone Joint Surg. Am. 97, 877–888 (2015).PubMedCrossRef
192.
US National Library of Medicine. ClinicalTrials.gov https://​clinicaltrials.​gov/​ct2/​show/​NCT01487161 (2018).
193.
Conaghan, P. G. et al. Brief report: a phase IIb trial of a novel extended-release microsphere formulation of triamcinolone acetonide for intraarticular injection in knee osteoarthritis. Arthritis Rheumatol. 70, 204–211 (2018).PubMedCrossRef
194.
Conaghan, P. G. et al. Effects of a single intra-articular injection of a microsphere formulation of triamcinolone acetonide on knee osteoarthritis pain: a double-blinded, randomized, placebo-controlled, multinational study. J. Bone Joint Surg. Am. 100, 666–677 (2018).PubMedCrossRef
195.
Bianco, P. et al. The meaning, the sense and the significance: translating the science of mesenchymal stem cells into medicine. Nat. Med. 19, 35–42 (2013).PubMedPubMedCentralCrossRef
196.
Prockop, D. J. Repair of tissues by adult stem/progenitor cells (MSCs): controversies, myths, and changing paradigms. Mol. Ther. 17, 939–946 (2009).PubMedPubMedCentralCrossRef
197.
Bravery, C. A. et al. Potency assay development for cellular therapy products: an ISCT review of the requirements and experiences in the industry. Cytotherapy 15, 9–19 (2013).PubMedCrossRef