Today I have the pleasure of introducing two of the authors of the AAPMNR Practice Guideline Orthobiologic Management of Osteoarthritis of the Knee. Dr. Pratham Jayaram and Jenny Yuan are here and I'm just kind of going to be doing some of an introductory aspect of this and then closing at the very end kind of educating people on where we're going to be going with the next steps in terms of these guidance statements. A little introduction for myself, my name is Dr. David Lee, I'm an interventional pain specialist, AAPMNR trained in New York and I'll practice just up the road here in Orange County about an hour and a half north. I've been, even though despite having done an interventional pains fellowship and majority of my practice being in interventional pain, I still really hold tightly to my PMNR roots. I'm the chair for the Clinical Practice Guidelines Committee for AAPMNR. I'm a committee member for the Evidence Quality Performance Committee and also the Quality and Research Committee that's been recently started. So a big part of that is overseeing a lot of these initiatives to fit in with the BOLD initiative for PMNR. So kind of moving forward here, no disclosures. This is kind of our agenda here today, so I'm going to be turning over the mic to them to really do the discussions of the details of the study. But before we do that I wanted to give a little bit of a history of how this started. So this was 2018 at that time and I know this is a little busy of a slide, but the Evidence Quality Performance Committee kind of looked at this and said, well part of BOLD initiative, like what can we do to develop guidance for our constituents, our members? And part of that was maybe putting out statements or guidance papers on various physiatry based topics, right? And there's a lot of organizations out there, non-physiatry, that do this already, you know. And the Clinical Practice Guidelines Committee, we review these and we give them our endorsement or affirmation for our members to follow. But I think as a large organization as the AAPMNR is, we should also ourselves be putting our own guidance out there, right? Because we're taking them and we're saying, okay well AAOS for instance came out with this OA of the knee guideline statement, but you know a lot of times that statement or that paper may not have everything that is, you know, pertinent to the physiatry community, right? So if we direct our own guidance statements, it's a lot of work you're gonna see here momentarily that these individuals put in. It takes a village, but then we can do so with a physiatry focus. So it was the American Board of Governors that then decided on this topic. You guys saw on the initial slide, it's very specific, right? It's orthobiologics for osteoarthritis of the knee. And that was very, that was done very purposefully because if you just did orthobiologics as a whole, it's just, you know, when you do the literature research, you know, that there's requisite to doing this kind of review, it's just overwhelming, right? So we wanted to be focused for our constituents and for the members of the Academy because we wanted to give them some things germane that they can actually put into practice, right? And it's just not a bunch of, you know, using orthobiologics everywhere. So then the orthobiological group started work on this in 2022. So we're at 2024 now, and it just recently has been submitted for publication in the Maine Purple Journal. This is kind of showing you a little bit more granular detail of the process, you know, just to give everybody an idea of, like, how much methodological rigor was put into this process. We wanted to make sure that the data that we were putting out there was pertinent, but also very accurate. So really quickly, for all these guidance statements, for not just this one, but for those going forward, you know, we wanted to make sure that people understood what this is and what this is not. So I'll start on the right side because it's easier. What it's not, it's not a full review of pathophysiology. We didn't want to do that. You can read textbooks and other publications for those specific type of data or that background. This isn't a one-size-fits-all guide. You know, we want to make sure that people understand that you still need to use clinical judgment. Appropriate history and physical is critical, and then decision-making process should be dynamic, should be one that, you know, really fits your specific patient. And it should not preclude clinical judgment for your patients. What it is is a structured, condensed review of the evidence. This is not a guideline. It's a guidance paper. As many of you already probably understand, to create a guideline, it's even more of a rigorous methodology that's required, and you need to have a certain level of evidence to confidently put out a guideline statement versus a guidance. This is to support payment our clinicians and decisions for caring for their patients, endorse the high-quality evidence, and help identify areas of future research that are absent in terms of what we've found in our evidence review. So after the writing panel was selected, their first meeting, again, was about two years ago. They used PICO criteria to advance the questions that were pertinent to the subject matter of orthobiologics to Neo OA. We use a third party to help us with that search. That third party was really mainly used for conducting literature search based off the PICO criteria that was identified by the working group. Writing panel then reviewed the literature, and then they eventually broke into smaller groups to start developing the paper. So there's a couple different methodological measures that were utilized in the process. One was the sort guideline. This is looking at the strength of recommendation taxonomy. This is looking at actually the evidence in itself, and it's relatively simple. It's a three-tiered recommendation or three-tiered rigor grading system. So type A is good quality patient-oriented evidence, B inconsistent, and then C is the lowest that's just consensus statements and things of that nature. So case reports, case studies, case series. And then additionally looking at the evidence in a different way as well, it was using this methodology level 1, level 2, level 3. Again, a very similar type of strategized criteria with level 1 being the most rigorous. So after recommendations were drafted, each of these was given a sort grade. For the methodological aspect of this, there had to be a consensus, and that consensus was deemed as at least 85% agreement amongst the writing group. And as I previously mentioned, it's been submitted for publication in the PM&R Journal, so please very much keep an eye out for that. And then I'm going to turn this over to the authors. Thanks, Dr. Lee. Thank you all for being here, and really want to acknowledge our group here. This is really, as David had mentioned, a work in the last few years, and really Kavitha, Beth, Meredith, Michael, Sarah have been kind of hand-holding us through this process. This would really not be possible without them getting us on the same calendar, reminding us what we're actually trying to do, what we committed to, and so forth. And it was really a labor of love for a lot of people, so many nights on calls. Thanks, Dr. Wan, for being here. She's been an integral part of the authorship process as well. Dr. Borgstein couldn't be here, and kind of co-chairing this process with her, but everyone's been involved, and it's been an exciting venture so far. I would, you know, take this kind of presentation as very high level, and I think for those of you who know a lot about PRP in the room, and I recognize a lot of you here, that it's not going to be as technical in terms of specific formulations, but I think you should look at this from the perspective of when a learning tool to educate, you know, you're visiting students, medical students that have committed to other fields where there are robust guidelines, and where PRP's application is in orthobiologics, specifically with knee osteoarthritis, I think these guidance statements are helpful in starting those discussions. As we know, there's just a lot of overwhelming data from a lot of other societies, our rheumatology colleagues, our even orthopedic colleagues, where they recommend, or they're a little indifferent for recommending the use of PRP for knee osteoarthritis, with some guidelines recommending against it. And us as physiatrists, I feel like we're uniquely situated and positioned to, to one, stratify patients who truly have, you know, primary knee osteoarthritis, and that's really driving their symptoms, and where PRP should be applied. So this is a very high kind of level discussion as well, but just really quick for the learners in the room, and feel free to take these slides to, as well, the attendings, as well as you're educating your learners that, you know, OA, as we often talk about, we talk about the cartilage, the articular surface, but it's much more than that, right? It's a whole joint disease, which is where PRP has utility, right? It has a combinatorial agents in it that can address a lot of the key components in the disease process of osteoarthritis. And so understanding that there's a subchondral component as well, there's bone cyst, there's sclerosis and osteophytes, as we point to x-rays to teach our learners, and there's also a capsule component, right? So the synovitis, the inflammatory components of OA, don't just exist on the articular surface, but they really do lead to synovial hypertrophy and other disease effects there as well. I think it's helpful to educate the learners also about, well, qualitatively or, you know, pictorially, we just saw those slides, but what's happening mechanistically? And this is still very simple, but in medical school we learn a lot about these pro and anti-inflammatories and different metabolomic factors, right? And so when it comes to our field and pointing into the knee joint, I find it helpful to educate my medical students that are going into other fields that there is a very important balance here as well, leaning more towards this catabolic component, which is really what's driving, what we think is driving, the progressive nature of primary osteoarthritis. So we kind of say it's a wear and tear disease, and there may be some truth to that, but it's really, there is joint instability that's going on on a micro level, and certainly that's outside the scope of this discussion or this talk, but really this leads to a number of upregulated things. Some of the high-level stuff are MMP9s, some of the aggregants and type 10 collagen, with a reduction in things that you really want to be in the joint. Lubricin, aggregant, and type 2 collagen. So I take this slide to my learners and I say, well, you know, the HA injections, the gel injections, which they've often heard about, and some guidance statements and guidelines recommend for them. Lubricin is, it's really what's in that HA and VSCO supplementation, or a key component of it, or proteoglycan 4. And so I tell them, hey, you know what's in PRP? There's a whole lot of PRG4. And so we kind of have a more mechanistic discussion, and I think it buys a little bit more credibility coming from that standpoint, with a mechanism just from some of the unfortunately unpopular data that's out there in PRP with knee osteoarthritis, which brings up later discussions on whether that's really truly the PRP that we as physiatrists are using from a dosing standpoint. Dr. Wan and colleagues yesterday gave a very good technical talk, so I'd really encourage you guys to go back to those slides. This obviously leads to kind of this chronic low-grade inflammation, and then you just get more bad stuff happening. So high levels of IL-1, beta, a lot of interleukin 6, and prostaglandins, right? So this kind of unchecked chronic low-grade inflammation in this soup of pro-inflammatory mediators are sitting in the joint. So to have kind of a single candidate molecule of any injectable, whether it's a gene therapy or a small molecule inhibitor, it's really not going to be a silver bullet to treat osteoarthritis. But PRP, if it is this heterogeneous formulation of things that do have targets to either inhibit these or reduce the expression of it, it seems like it could be a viable candidate to at least reduce symptom burden, but certainly delay progression of disease. And we've shown that in animal models quite extensively. So what exactly is PRP? Very simplistically, it's just whole blood taken down and spun in a centrifuge with various different protocols, and we believe that the key components are platelets and the plasma, which house some of these bioactive ingredients for key mediators. And there's various different protocols to extrapolate different formulations based on the density gradient, but it's really this ratio of platelets to plasma. And it's hypothesized that these key mediators are within these platelets, and a bunch of them are, a majority of them are, but they're also in white blood cells, so we shouldn't discredit them as well. So very early on I tried to tell our learners again that we still don't know exactly the right formulations, but there's key components to all these factors. We do have robust preclinical data, and our group has published this in Osteoarthritis Society, which recommends against the use of PRP. And we published it there, one because it was a good preclinical study, but we replicated clinical formulations. At that time we called it rich versus poor, and we had really two good sham groups and a saline group, but the data was quite convincing in a preclinical animal model that PRP does delay progression of OA. And interestingly in that study, the leukocyte-rich PRP showed better effects with pain, but more progression with disease, and the leukocyte-poor group again showed actually more protection in terms of articular cartilage. So that journal and that society accepted it, despite their guidelines recommending against it. We do have robust evidence clinically as well, at least from a symptom standpoint, which is what we're going to try to present today. So in terms of PRP administration, what you'll see at the top of these slides are kind of the breakdown points that will be in the manuscript. And we make certain recommended action statements, and where there's not really a lot of evidence based on the sort criteria, we discuss kind of best practice statements. So you'll see at the bottom of this slide the recommended versus best practice. So the available evidence is still inconsistent, as Dr. Wan and everyone else yesterday had talked about rich versus poor and exactly what does that mean, with more studies coming out that are showing that leukocytes potentially could be beneficial and are not as harmful as once thought. A recent study came out a few weeks ago showing some early outcomes of leukocyte-rich PRP as compared to leukocyte-poor PRP at six months, with one year end point showing no difference between the two formulations, which is interesting. So could there be something in the white blood cells that are providing short-term benefits, and perhaps should we be switching over to leukocyte-poor PRP for later time points, some kind of combination of the two. But that kind of points to there being key ingredients in both platelets and white blood cells. And that group is Fularda and DiMartino, they've really been at this for a long time, and some of the early studies came from that group showing that leukocyte-rich did have some anecdotal reports of pain early on in the intervention. So our group came together with the evidence that's existing, and we came with a sort grade B, A being the highest, and going down from there. But we really felt that we couldn't make a strong overwhelming statement that one is better than the other, but there is evidence to support the utility of both for primary knee osteoarthritis. From a dosage standpoint, we talked to the group yesterday, really talked about this in some detail. Our group was really trying to come up with a minimum threshold, so don't take this as we're recommending that this is the dose you should use. But within PRP, and some of the literature that came out from the Australia group and JAMA, showing that there was no effect of PRP as compared to steroid, really it's a dosage question. And so how many platelets are really per mil in your injectable volume? So the total deliverable platelet is really important. And that's how we should probably be speaking about PRP or any of our orthobiologic interventions, is what's our dosage? And platelet count could be a surrogate for that as opposed to platelet concentration. So we're obviously moving away from that. But with the evidence that was currently there from the papers that were published at the time of reviewing the literature, we found like a minimum of about three to five billion platelets seemed to have a positive effect. Not so much from a minimal clinical important difference standpoint, but at least from a responder rate analysis, which could be defined as about 20% above improvement from baseline, from their baseline. We have not finalized this yet, so we're still coming back with edits and figuring out how best to state this with the current literature that's also coming out, especially in light of recent meta-analysis and systematic reviews. And we can talk a little bit in the Q&A about how each individually do our injections. Not saying that that's how you should do it, but that's what we've been doing. So our sort grade here, again, is a B. So the total deliverable platelets, a minimum threshold somewhere around three to five. More to come in the manuscript once we finalize. With respect to red blood cells, you know, we've talked a lot about them not being very beneficial. Some of the hemophilia data is showing that it's chondrotoxic to the joint. Not a lot of studies looking at just whole blood itself and their detrimental effects. There's some preclinical data to show that red blood cells do affect articular cartilage in a negative way. And so we took that into account with some of the in vitro studies as well. And clinical evidence that red blood cells in PRP is extremely detrimental. There just is not a lot of large data sets to suggest that they are. So we had to come up with the best practice statement based on both expert opinion and the available literature. And so at this time the group felt that we should probably minimize red blood cells. There's perhaps not a therapeutic effect of having a whole lot of red blood cells in there. That being said, it's probably really hard to extract every single red blood cell out there. So there's probably some red blood cell component in the injectable. Frequency and number of injections. That's critical, right? And in terms of response rate, how long does PRP work? It's a big question because there's so many different formulations. We're talking about a very heterogeneous therapy within a heterogeneous disease. And so you're gonna get heterogeneous answers. Multiple PRP injections versus a single one. There really is inconsistent evidence. I think there's more consistent evidence in the preclinical literature where you can kind of regulate that a little bit more and control for that. But there really was not robust evidence to support that a series of three injections should be done every other week. So we really do recommend individualized assessments of this. And for me what that means in my clinic is we'll inject a baseline and I'll follow them up every six weeks. At six weeks I typically tell my patients from that single injection, provided there's no subchondral involvement, it'll last... you should expect a responder rate of about 40 to 60 percent improvement at six weeks. And at 12 weeks when they do come back it should be about 60 to 80 percent. And most patients fall on either side of that. In my practice I deliver probably a total of 9 billion platelets total. So about a billion platelets per mil with the higher volume of about 8 to 9 cc's depending on the patient. So a big volume. In terms of image guidance I think this group obviously appreciates that, but keep in mind that a lot of societies, a lot of our orthopedic colleagues may not be using image guidance, a lot of our rheumatology colleagues may not be using image guidance, and I think this is a strength for us because we really understand ultrasound and fluoroscopy very well, and understand really how to accurately inject into a knee, how to aspirate knees completely, not just on palpation alone. And so, believe it or not, there's really not a lot of great data, and certainly no data comparing PRP guided versus unguided, and so for those reasons, we really came up with a best practice statement, which makes sense to everyone here in the room, but as we discuss with people who are not aware of what we do in physiatry, I think this is actually an important slide, using image guidance as opposed to landmark guidance. Combinatorial injection therapy, so really, what's the evidence for PRP in conjunction with other injectables, other orthobiologics, whether that's HA or cell-based therapy, such as microfragmented adipose or BMAC. When we looked at the literature, we found that it is safe, one, it's safe, and it can safely be administered and sequentially within the joint, and there are randomized control trials, a few supporting that, but there really aren't a lot of randomized control trials showing that there is a specific sequence or a specific regimen you should follow in terms of which combinatorial therapies. There are some really good prospective studies, but no large randomized blinded studies, so again, this falls in the category of best practice statements. How about other therapies, non-injectable? Shockwave, obviously becoming a more popular intervention these days, not a lot of studies, again, as you would know, and lipase, low-intensity pulse ultrasound, both have been found to be safe for patients, and so again, we don't have large randomized trials here, but our best practice statement is they can be considered and can be considered sequentially or standalone. You know, there is some early data that's pointing towards the subchondral components, right? We all do our interventions, whether we're doing guided or under x-ray, fluoro, ultrasound, but the subchondral area under articular cartilage is challenging, and there are some studies coming out that show shockwave therapy might be able to get to those areas more so than intraarticular injections. Joint aspiration, it sounds like a no-brainer for our group and may not be a no-brainer for a lot of people outside of our field, and so we really do recommend aspirating all the synovial fluid. There is really good data to show that we can, you know, once you aspirate all these chondrotoxic mediators, going back to the earlier slide, on chronic low-grade inflammation, that alone provides therapeutic relief immediately for a patient, so those of you who do PRP in the room will often hear patients say, wow, I think that PRP's working like right away, and that's not always the case, right? It's really the aspiration, but what you'll notice is the recurrence of that swollen knee is much less with PRP, right? It's combating a lot of those chondrotoxic mediators that we put up in the earlier slide. So we don't have a lot of controlled studies for this, but so for these reasons, our best practice statement is consider aspirating all of it, and oftentimes with our residents in the room, I tell them to just take their time aspirating, like really scan and make sure you're getting all the aspirate, all the synovial fluid. Oftentimes you can miss pockets of fluid, and we're very methodical in making sure we can do that, because the high volume that I put in in my clinic, you know, if I'm putting eight or nine cc's in a joint, that's a lot, and so if someone has a five cc or 10 cc aspirate synovial fluid in their joint, that makes a big difference. Oftentimes they may not notice the exchange of that high volume of PRP if we're able to get all that fluid out. Use of local anesthetics. Again, the group yesterday talked a lot about that and went into detail about the combination of different anesthetics and how that affects PRP. Qualitatively it didn't seem to, and some studies show that mechanistically it may not be affecting it all that much, but because, and that was in the context of ex vivo, but there is data to show that anesthetics are not necessarily great for the joint long term, and so we focused in on that data, and now adding PRP into the mix on that data alone, we really felt that because of those reasons of chondrotoxicity of anesthetics, especially B-pivocaine, we did not recommend, or our best practice here is saying, let's try to avoid interarticular delivery of the anesthetic. Periarticular might be different for patient comfort. That being said, I have colleagues who do use repivocaine in combination with PRP and obtain excellent results, but our data really, we had to follow the data and the criteria, and hence made the statement. How about severe knee osteoarthritis? This is often the case where patients come in and they're very late disease in terms of radiographic severity, which as we all know here is not necessarily driving our clinical decision making, right? There's such a strong discordance between imaging and symptoms, and so what are the indications for severe? A lot of the colleagues in our technical group, Michael Kadavy in particular, does a lot of subchondral injections of PRP and really pointed us to where the evidence was, and I know that's not the standard of care, but I think this is something that could be a game changer in the field, and us as physiatrists going back to targeting whole joint disease, this is gonna be important. And so the intraosseous injection of PRP directly going into the bone where you can correlate where the subchondral cysts are, seen on MRI, but then correlating that on fluoroscopic injections should really be considered, and Mike did a great job in pointing this to the literature, and the sort grade was actually an A, and at that time I was like, whoa, this is way too aggressive, and one, I don't do this, but when we followed the data process, there was really overwhelming evidence to support that, and so it's something we all need to be thinking about. In terms of post-procedural protocols, what post-procedural protocols are recommended to improve outcomes after PRP injections, and that's really a big topic, and we're not gonna go into all the specifics here. We're gonna get into it in the manuscript in terms of the different components here, but I think the takeaway from this is PRP alone, while it does have multiple targets in key mediators that can attenuate the disease process, more the biological environment in the knee joint, we really need to partner that with good physical therapy, the right DME, post-procedure medications. Oftentimes I will have patients on tramadol afterwards, and outside of the knee joint, which I think is tolerated fairly well for PRP, a lot of the shoulder joints and other areas that we inject are quite painful for patients, so I'll oftentimes tell them to bring a tramadol with them, and after we do a blood draw and it's spinning down, I'll have them take that tramadol to reduce pain, and we can talk a little bit more about this in the Q&A. So our best practice statement here was really consider the multifaceted treatment approach here of the above things, from bracing to physical therapy and specific PT protocols and biomechanical deficits that certainly need to be addressed, and that's really the strength of us here, is the precision guidance of PRP that we're able to deliver, but also these other areas as well. I'm gonna turn this over to Dr. Wan here for patient selection. Okay, all right, well, okay. I'm Jenny Yuan, I'm here from the Uniformed Services University, which is in Bethesda, Maryland. I happen to work in a military treatment facility, so some of these topics I'm gonna be covering today are particularly near and dear in terms of access to care. But first, we're gonna transition now to the more patient-focused topics that are related to PRP injections for knee OA. Okay, all right, okay. All right, so patient selection. So regarding patient selection, what our TEP asked is which patients with knee OA are most likely to benefit from intraarticular PRP injections? And our recommended action is to consider the use of intraarticular PRP for mild to moderate knee OA, which was graded as an A based upon evidence from multiple RCTs that have demonstrated the effectiveness of PRP on pain and function for mild to moderate knee OA. And this is in comparison to severe knee OA, which Dr. Jaram has already discussed, for which evidence is more limited on just intraarticular approaches. PRP may be considered for patients with medial and or lateral compartment predominant knee OA who have persistent symptoms despite conservative treatment. And again, this is in contrast to patients with patellofemoral compartment predominant OA for which evidence is also more limited. And as was mentioned by Dr. Jaram earlier in the talk, we did have evidence from early studies that suggested that there was superiority of leukocyte-poor over leukocyte-rich PRP for knee OA. However, more recent studies, even those in the last few years, have demonstrated that there is benefit to both leukocyte-rich and leukocyte-poor formulations in terms of their efficacy for treating knee OA. And it's certainly still an area of active investigation. So now moving on to patient demographics and factors. We asked, which are known to impact the outcomes of PRP injection for knee OA? So our TEP's best practice recommendation is that intervening earlier in knee OA progression may result in better outcomes. We looked and we didn't find any consensus in literature on the impact of age, gender, BMI, family history, or any other patient demographics and factors on outcomes of PRP injections for knee OA. And actually regarding age, patients that are greater than 75 to 80 years of age are often excluded in RCTs of PRP for knee OA. So our outcomes related to patient age, at least from level one data, are really not well understood. So our expert opinion suggests that improved outcomes may occur for those who are at an earlier stage of OA, typically in the mild to moderate range, rather than simply due to age alone. Okay. So next our TEP asked some questions. Are there medical comorbidities or contraindications to PRP injection for knee OA? And we all agreed that infection is the number one contraindication and that's not just for PRP, but relevant for joint injections in general. Additionally, we felt that for any patients with an active malignancy or a history of malignancy in remission, we suggest consultation with a treating oncologist before PRP injection. However, we do note that the current evidence does not suggest that there's an absolute contraindication to PRP injections for patients that are in cancer remission. And this particularly as PRP has been used clinically for other indications with patients with either an active or history of malignancy. And that could include PRP that's been used to enhance grafting after reconstruction for breast cancer, as well as cancer patients who have suffered from a vascular osteonecrosis of the mandible. That's secondary to dysphosphonate use or even to improve wound healing, such as from venous access devices for chemotherapy or at biopsy sites. So for medical comorbidities such as diabetes, thyroid disorders, cardiovascular disease, the current evidence does not suggest an absolute contraindication to PRP injections. However, care should be taken during patient education and informed consent as the impact of these co-occurring conditions on PRP injection are not well understood and that could include their potential impact on platelet function or the patient response and their outcomes to the PRP itself. Along these lines, medications such as antiplatelet, rheumatologic, hematologic, or oncologic medications, they may impact outcomes but are not necessarily contraindications to pursuing PRP. And in summary, our TEP's best practice recommendation is to consider infection as a contraindication for any joint infection... Oh, sorry, joint injection I should say and additionally, before administering PRP injections to any patient with an active malignancy or a history of malignancy and remission, we recommend consultation with the treating oncology team. So regarding patient optimization before a PRP procedure, our TEP asked if there are any pre-procedural patient factors that may affect short or long-term clinical outcomes and we found only limited evidence to support pre-procedural exercise participation, alcohol cessation, smoking cessation, and diet modifications to improve outcomes. So in this case, our best practice recommendation is to consider the integration of these pre-procedure interventions into patient care as these measures may improve outcomes although higher quality evidence is still needed in the PRP literature. Additional pre-procedure considerations include what factors can be optimized by the physician or healthcare team that may affect short and long-term outcomes and this relates directly to medication management. So to our knowledge, there are no high quality clinical trials that examine the effect of NSAIDs and antiplatelet medications on clinical outcomes of PRP injections. However, this TEP's best practice recommendation is for a washout period of at least one week that may potentially result in optimizing PRP injection outcomes and this is largely based on expert opinion as well as results from pre-clinical and human laboratory studies. So regarding patient education and informed consent, our TEP asked, what are the key concepts that should be conveyed to patients as part of the informed consent process for those who are considering a PRP injection for NeoA? And our best practice recommendation is to complete an informed consent and patient education process prior to offering PRP for NeoA, which ideally should detail risks such as adverse effects as well as cost, expectation management including pain, function, and any structural outcomes, awareness of current FDA regulatory status for PRP and to include a comparison to other treatment options with attention to the conservative versus more invasive procedures, their safety and current best evidence for different interventions. So to be specific, here are a couple of bullet points for discussion that we developed and they're detailed on this slide and next. So regarding risks, we found that no major adverse effects have been reported after intraarticular PRP injection for NeoA, but there are mild adverse effects that include pain, swelling, and inflammation, which are reported in upwards of 10 to 75% of patients during the first week post-procedure. And this is in comparison to other treatments such as oral NSAIDs or corticosteroid injections, which have been shown to increase the risk of medical complications and can also have associated radiologic cartilage degeneration respectively. There was one rheumatologic group that reported dose-dependent hypertension and proteinuria after PRP injections. In terms of cost, PRP is typically an out-of-pocket expense that can range from hundreds to thousands of dollars per injection. So patients should be made aware, if at all possible, of any insurances that do cover this procedure, although the options are quite limited to our knowledge to be quite honest. In terms of expected outcomes, PRP is more effective in patients with mild to moderate OA, as we've mentioned, and they're less effective for those with severe OA. Benefits from PRP may include increased function and decreased pain, but structural changes such as cartilage regeneration should not be expected by the patient. There was a single level one double-blind RCT that has shown slowing of cartilage degeneration, but only non-blinded prospective studies have shown cartilage regeneration, while other studies have shown no structural effects or changes. So in terms of the regulatory status, PRP is not currently regulated by the FDA as it is considered a blood product that requires only current good tissue practices related to its procurement and its processing. It's not subject to registration with the FDA in the annual reporting that is otherwise required for section 361 for human cells, tissues, and cellular-based products. Additionally, it's not subject to preclinical trials, pharmacological studies, investigational new drug approval or biologics license applications that would otherwise be required for higher risk section 351 products. And finally, treatment alternatives may include exercise, weight loss, an anti-inflammatory diet, oral NSAIDs, physical therapy, offloading braces, and or other types of injections such as corticosteroids. Surgical arthroplasty could be recommended for patients with severe osteoarthritis who have not benefited from more conservative management. Okay. Alright. So regarding access to care and disparities to access to PRP. So for many reasons which include the prior variability in scientific evidence of clinical efficacy for PRP for NeoA, a lack of an FDA indication for NeoA, and in turn limited insurance coverage, these all present potential barriers to patient access to this therapy. We only have limited demographics data that have been published from claims studies for patients that have received PRP injections. So here's one example from one study where they reported demographic data that represented nearly 8,700 U.S. patients who received at first time PRP injections that targeted pathologies of the knee. And these were submitted as insurance claims between 2010 and 2019. And this revealed that the highest proportion of recipients were between 55 to 64 years of age, representing 27% of the total cohort. Just over half at 53% were female. And nearly 47% of the injections were performed in the South Geographic region. The top three co-occurring conditions that were found within this cohort were hypertension followed by depression and diabetes. Now I should note that key demographics such as race, ethnicity, and socioeconomic status have not been reported. So some of the issues with disparities in care remain unknown across different groups. And moreover, as you can tell, demographics and characteristics of patients that are receiving injections administered through out-of-pocket payments would not have been captured in these insurance claim databases and therefore not in the study. Alright. So in summary, I'll leave this slide up just for a moment. Here are TEP's sort-graded recommendations for the use of PRP for knee OA. I'll just give you a moment for those who might be taking a picture. Just remember, it's still technically draft mode. Okay. Alright. And this is followed by two slides of our guidance's best practices. For here shown are patient selection and patient optimization. Okay. And then the second slide is PRP administration, post-injection protocols, as well as informed consent. Okay. And I'm going to wrap up this section on future consideration for the use of PRP for knee OA and this could include precision medicine approaches to guide formulations of PRP that are specific to different phenotypes of OA, as well as enhanced guidelines regarding post-procedural rehabilitation and finally studies of pre-procedural modifiable factors that could be used to optimize PRP outcomes. So now I'm going to hand it back to Dr. Lee who's going to wrap it up with the next steps for AAPMNR guidance. Thank you. Dr. Yuan. So before we... just the future kind of advancements in terms of what we're going to be doing next are important, but I did want to take this time. It's very close to lunch. We appreciate you guys hanging out. We did want to open up to Q&A. I mean that's a big part of having these experts on this panel up here. So there's a microphone in the audience here and we'll take any questions from the audience at this time if there is any. Yeah. Thanks for those questions and those insights. I think the... So the first question kind of solving for the discordance between imaging and we obviously reviewed the literature and so literature will describe mild to moderate in definition in terms of radiographic severity, which as physiatrists we don't... That's not our only metric. And so we had to approach the PRP published data based on a lot of the inclusion criteria that met that and there wasn't a specific inclusion criteria for minimum WOMAC or a COOS-12 or any validated patient reported outcomes. So that becomes challenging and so, you know, in the future consideration slide we talked about subtypes of OA, which I think as physiatrists we probably do it in our clinical decision making. We're not just necessarily publishing on it. I know there's post-traumatic OA but even within primary OA we know that it's very different within patients and sex, gender, all of that has a lot to do with it as well. So it would be great in future studies for that to be kind of the benchmark for inclusion criteria and we're starting to do that at Emory a little bit and do more studies and with formulations to try to address that. I think I lost a little bit of the second question in terms of the treatment gap, so to speak, with arthroplasty and just outcomes there. I don't know. Right. Yeah. So I think the technical components, we certainly can do a better job with PRP formulations. Like what in it... So far we've been talking about leukocyte rich and poor. I think when we get to specific formulations, which... And what I mean by that is, you know, we had that earlier slide with all the pro-inflammatory mediators and there's a specific amount of it. Well, what in PRP is actually addressing that and specifically what's the picogram per mil? And so really getting to dosage I think will actually be important, not just qualitatively saying this is a low dose or mid dose, but if your platelet at whole baseline is able to express this amount of anti-inflammatory or things that are lubricant mediated, then I think having a checkpoint system for that. And so better actual classification systems are going to be needed to kind of include patients who would respond better. So I think some of the responder analysis will kind of depend on that. I mean with arthroplasty it's getting better and better with robotics. And so I often don't have the conversation with patients saying, well, you're not a candidate for arthroplasty just yet, so therefore let's do PRP. A lot of those patients I feel do fail. But yeah, we do need to have better systems of intervention. I was just going to say, because I know we have quite a few questions, although we've got some time I suppose. I think it's going to be really exciting in the next coming years. You know, I saw the article, like the mainstream article. I haven't read the actual article yet on the what Govee were with Neo A and obesity. And I think it's really going to be very interesting in the next coming years, because for those who didn't see that, I mean, you know, sort of at a high level. Essentially folks who were treated with Govee who improved their BMI also happened to improve their symptoms related to Neo A. And I mean, I think a lot of us sort of suspected that might be the case and it's great to know that folks have been doing this work all together. And I think, of course, there's maybe there are better ways than having to inject yourself every single week, but certainly if we now know that controlling the metabolic component can improve away symptoms so much, I mean that's just going to be a really big deal moving forward in research. I think it also, you know, opens up an opportunity to work with our orthopedic colleagues, because I think these things are going to change. Everything is very dynamic these days with a lot of the advancements, particularly on the orthobiologic side. So the orthopedic doctors are doing them too, right? So part of, I didn't mention it, but I was going to, but in the closing, but a lot of these guidance statements that we're putting out now from the academy standpoint is, of course, for mainly for our constituents, but also to be utilized by our other subspecialists showing that we're thinking about things critically, you know, that we want to partner with them. So there's an opportunity there. I'm going to take the next question. Just a quick question. Needle gauge, is that something you guys consider, or is that something that... Needle gauge. ...when you inject? Right. So, I mean, I'm only, what am I, four years out of training? No, five years out of training. Five years out of training? Okay. So I was always trained to use a larger gauge, but I have seen the data, I think, what was it, Kentaro Onishi's work, looking at needle gauge and how it impacted like microfragmented adipose tissue. So I'm fully aware that it actually probably does not matter as much as we think, but typically for knees, I think I still mostly use 21 gauge needles, but I do do like at least a little, you know, local wheel, even if I'm trying to avoid putting in the lidocaine into the joint. So I always do that, do the local anesthetic and then the larger needle. We use a 27, one and a half, for just the local 1% lidocaine, the wheel, and then a 20 gauge needle. It's more for a function of ease and you can aspirate very well through a 20 gauge needle and oftentimes I'll use a 23 and a half and my residents are like, you're using a spine needle and it's to get all the, you know, synovial fluid out in various different pockets. We did a small animal study looking at platelets. Platelets are really tiny, so you're not really going to cause a lot of damage. We looked at even 31 gauge kind of mouse needles and ran PRP through that and it didn't have any effect, at least qualitatively, on the counts. So... First off, thanks for that presentation. I really like the way you guys just laid out the evidence in a very objective basis. I appreciate that and I'm sorry if you've covered this, but what's the theoretic basis and the evidence basis for concern about malignancy and previous malignancy and the second question is, what do you guys do when you call the oncologist and they go, I don't know, you're the physiatrist and are there any particular cancers you're concerned about? Yes. So with active malignancies, you know, we always have a conversation. At least we do and I think we have one statement on this as well. Chetty might have covered it, but we always have a conversation with our oncology partners to that... One, the conversation's had, the patient's at ease and oftentimes they don't recommend against it, so they're... Especially in remission. Yeah. Yeah, I mean the concerns are, you know, you have a spread of growth factors. You don't know exactly what the composition would be. Could it theoretically either... If it's a blood-borne cancer, could it potentially seed or could it potentially augment tumor growth in some way? I mean it sounds a little bit crazy to be fair, but I don't... I think most of us would probably be, you know, a little bit more cautious because certainly we wouldn't want to potentially lead to, you know, some sort of untoward consequence for a patient. What I always make the point though is that there are definitely maybe not high-level evidence, but there's at least case series that have demonstrated PRP used for other reasons in surgical studies as well as wound repair. So it's certainly not a complete no, but it's something that is certainly shared decision-making and certainly welcoming the input from the treating oncologist. We've gotten questions from folks like, what if it was just like a localized skin cancer? You know, I mean I'm still fairly new in my career, so I would certainly veer on the side of being more cautious. I don't think that anyone would be... certainly if you feel that it's completely... would feel that it's inappropriate to ask. Yeah. Okay. Thank you. There's really nothing out there to look for. Because I think... Yeah. A lot of people... Yeah. Yeah. Well, a lot of Chris Centeno's work has also kind of showed the BMAC in particular, but it kind of opens up the, you know, from a patient education standpoint because they're coming into you thinking you're regenerating their cartilage. So it's my tumor getting regenerated, right? And so it helps us educate the patient that we're not regenerating cartilage. I'm very open up front about that. Well, we all kind of wear this hat of regenerative medicine, but there is evidence to show that we're slowing down progression of disease. So it's an educational opportunity, I think, too. Yeah. And just to close the loop on that, I would say the other component is it depends on what the... if it's a hematological cancer, you know, you may need to do more work to make sure that there isn't a concern for thrombocytopenia or, you know, some other component that may affect platelet function, because, you know, if you're thinking about this from a typical practice where it is not covered, you know, does the patient want to take the risk of something and the cost of it without really knowing what the impact might be, positive or negative. So it's definitely a patient education as well as probably a provider education, even learning from colleagues about what the best approach would be. I have a question about multiple PRP injection. When do you guys decide about doing multiple and it's based on patient's response or when you do, what is the time splot between two injections? Did you guys hear that? Yeah. Yeah. So the question was regarding multiple PRP injections. Yeah. So in terms of following the guidance methodology, we couldn't land on a specific recommendation there. So our best practice was it could be... it can be considered and oftentimes for knee osteoarthritis I will tell my patients that, you know, we'll start with one and we'd like to land on two and again at about six weeks from that first injection, you'll land somewhere between 40 to 60 percent. Now that's in the context of a primary OA that's mild to moderate and does have good range of motion, no really comorbidities, not a lot of, you know, valgus varus and malalignment, no subchondral cyst, you know, truly articular that where the needle is going and addressing those areas. But at six weeks most of my patients will land about 40 to 60 percent improved from their baseline and that from that same injection at 12 weeks, they're about 60 to 80 percent. If they start to plateau at 12 weeks, they're still 60 percent from that first injection, then I will recommend a second one. But oftentimes I don't have to. If the patient doesn't have any improvement after four to six weeks, do you still recommend to... So zero percent, I don't. They should have had some uptick and I'm looking for almost anything and that's just my opinion. There should have been at least a 10 to 20 percent. It doesn't happen that often, but oftentimes when I do get a follow-up MRI, there is a lot more subchondral pathology going on that I don't think an intraharticular injection would be addressing. So hence, could intraosseous be a combinatorial strategy there? Okay, thank you. I think it's been pretty rare for a patient to say there's been no effect. A very short duration I've certainly encountered and I've encountered that quite a bit for my patellofemoral patients where they have some very short-term benefit. Those are definitely the most challenging to treat and in those cases, I mean, I work within a military treatments facility so it doesn't cost our patients anything to get this done. So therefore, I think we are a bit more liberal, perhaps too liberal at times, but patellofemoral pain is one of the... It's actually one of the primary reasons that folks get discharged from the military. So it's a big problem that we have. I'm often looking at what other aspects of pain they might have and it could be, I mean, in this case, probably not the subchondral, but if you're looking at the knee itself, it could be looking at periarticular or extraarticular generators of pain as well in addition to see if you can augment the outcomes that you have within the knee. Dr. Yuen, are you using that same timeline? What's your timeline in terms of... Yeah. So actually, I really appreciate what you said and also what Brennan said at yesterday's because I think he gave like really great anecdotes sort of on his own practice and it was very similar to what you said. I usually do not repeat more than... I try to do it at six months at the earliest. There are some folks who if they can get an appointment to seek to come and see me back, that'll be... that's a big caveat because our scheduling is not great. Some folks, the earliest I would consider redoing it again is three months, but I think this is also somewhat dependent on what PRP system you are using and how confident you are that you are getting the number of platelets that you expect. So we use probably one of the... based on the chart that was presented in yesterday's PRP session, one of the machines that's expected to give you the most platelet yield. So typically, we really try to wait as long as possible and if they really aren't having much of a response, then we look to other modalities. Yeah. Yeah, it's great work in pioneering this. I think it's very much needed. The post-procedural recommendations that were made mentioned bracing. Are we, you know, practicing in Canada, we've seen this wide array from a variety of different providers, some even non-physician providers like naturopathic doctors, of offloading, non-weight bearing, completely immobilizing soft tissues. Where does the evidence really stand in any of that? So where's the evidence to support unloading versus loading? Yeah, like just some people have people non-weight bearing for weeks at a time. Yeah, I think early on when people were integrating PRP and some of them are here in the audience, and please feel to chime in. But I think there was, any time an intervention is taken on early on, there's a little bit more caution and I think a lot of people early on, adopters of PRP were offloading it, almost like a post-op protocol, the crutches and so forth. I've now started to really weight bear pretty quickly, actually, so within a few days. I'll often tell patients to get into PT very early, like as early as the following week, you know, three, four days, because I want mobilization to happen early. Mechanistically, I don't have data to support that loading at a certain threshold, you know, improves kind of anabolic function within the joint. But, you know, in terms of getting range of motion soon, that's really quite, I'm quite aggressive with that. And if you kind of look at the way ACL literature is going to, right, like not a lot of bracing going on and really trying to get range of motion and strength back quickly, so. But you still will non-weight bear for a day or two? I don't personally in my practice. Right away, yeah. And then I know this is OA and knee, but soft tissues as well, are you immobilizing? No, I don't use slings and I immobilize very quickly, yeah. Yeah, so I think there has been a great deal of great work in post-procedural, but not so much for OA and not so much for knee OA, or certainly there hasn't been as much consensus there. I typically don't limit their load bearing, but I also work with the population who tend to not follow those types of rules anyway. So for me, I mean, it really depends on the patient age and other things too. So I see a younger population. They're usually quite active. You know, for tendons and things like that, I mean, if they're having severe post-procedural pain, then I will make sure that they have something just in case. Often they will not use it anyway, but at least from a patient safety perspective, I feel better giving them something just so that they're able to get out of the clinic safely. But for knee OA, it's been a very long time and I think I haven't done it since I was training with like an attending who was maybe a bit more conservative. I've definitely read papers where they had people like lie down for like 30 minutes after the procedure so that the PRP wouldn't go all over the place. I did have one attending during fellowship who put them in a knee sleeve for like I think 24 hours afterwards, but I've never done that myself. Yeah, I know there's a big line. My follow-up was just going to be like, is it a mechanical... Is that the thought process or is it like a chemical thought process? Is it because, oh, we don't want the PRP squared away from where we put it or is it more of a... Honestly, I'm sure that was probably the way he was trained. I didn't really ask because I thought it was kind of silly. I kind of... Yeah. And oftentimes I will try to address the underlying meniscus if I can... if I feel it's part of it and I can see it on ultrasound, some of those horizontal tears. For those patients that is a painful injection and oftentimes, as you know, I don't strictly weight bear them, but they're kind of self-weight, non-weight bearing. Yeah. Yeah. We'll take these two last questions here. The lunch is calling us. Okay. Okay. I would just like to ask what the current recommendation is for how long to wait to do a knee PRP injection after a patient has received a knee steroid injection? After they've received a steroid injection? Yeah. The question was, when do you do PRP after a steroid injection? How long to wait? Yeah. I usually have a washout period of about 6 to 12 weeks or somewhere in that range. Steroids can typically last, you know, 3 months or so for... on average when you kind of sample them. So, is it going to counter the effects of PRP after a few weeks? Probably not, but I'd rather have them be somewhat symptomatic again before we introduce PRP. So, I mean, I think most people here agree that steroids are probably the best thing we could put in a knee to get them out of pain that same day. And so, oftentimes I will, you know, a patient comes in with 8, 9, type of 10 pain, PRP is not what I'm offering them first. So, that steroid injection and then I'll have them come back in 6 weeks and see where they're at and then we'll talk about doing PRP in about 6 weeks, plus or minus a week from there. Yeah. I tend to wait on the order of 3 months as well. I know Allison Schroeder presented yesterday and I think she recommended at least 1 month. I do have colleagues who do a great deal of dextrose prolotherapy and usually their minimum is 1 month after steroid to do prolotherapy, which I think would have some similarities because of the, you know, anti-inflammatory concerns. So, somewhere between 1 and 3 months is probably reasonable. Great. Last question. Yeah. Thanks for prolonging your lunch for this last question. But I work with a surgical group with two sports surgical partners. And to your point earlier, understanding the science as well as our limitations has really facilitated trust. So, they send all of their patients to me for non-surgical management and oftentimes referring them to me for biologics. My question to you, what I found in my clinic is it's not so much the severity of OA when affecting medial and lateral joint lines, but rather patellofemoral joint OA is what has affected variability the most for me. And I know it's not part of your guidance, but if personally you've found something similar. So, for patellofemoral OA in particular? Yeah. Yeah. I'll often, you know, patients will come in and say, where exactly is your knee pain, right? And we'll kind of point everywhere. And then we'll try to break it down. Do you feel like it's underneath this kneecap? Is it bothering you with stairs? A lot of the PFA kind of symptoms. And then in my practice, and I know there's literature to support that it works well with some PFA, especially some of the European stuff that's coming out now. But in my experience, that's just not a great area for PRP. And I'll say, if that's where your pain is, I don't think PRP is going to work all that well. And then we'll get to joint line. If your symptoms are there, it will help that area. But my experience has been for patellofemoral, the biomechanical approach has typically been more successful. Yeah. I have a lot of patients who have dealt with patellofemoral symptoms for years and years and years, and it's basically, you know, you know, I can't dead weight like this entire ridiculous amount of weight unless, you know, something is done. So I started off with doing more injections, PRP injections for patellofemoral symptoms than I think I ever would have liked. I did not find that it worked. Anecdotally, I have found, and I think I mentioned this, if you think about it as a whole joint and you look at, you know, extra articular manifestations, if you try to address those things concurrently or after the PRP or before the PRP and just make sure you address any painful areas around the patella in addition to what's going on inside the joint, I do feel it can help. I'm usually very straightforward when I counsel my patients who have this, and, you know, I had one patient who did really well despite the fact that I was basically like, okay, we can do this, I don't know how it's going to work. You know, female marine who has to run miles in her boots, like that's how they do their fitness test. So I would, I no longer say no, but, you know, I always asterisk and I always look and exam carefully and have them follow up to see if there are other things that we need to do besides just the interarticular PRP. I treat MPFL at the same time. I include the attendant to affect that gait very better, and I think that's more effective. Yeah. Well, we're just going to finish up here by just kind of giving a little bit of direction. So for those who don't know, there are other guidance statements out there that the academy has put out there. One was on spasticity not too long ago, and the other was long COVID. So we welcome all of you guys, in addition to going and looking at this research that these authors have put so much work into, but look at all the other guidance statements that are out there. And the next one that is going to be under ways here shortly, under the guidance of Beth, who's in the front row here, is going to be adult treatment of cerebral palsy. And it's very specific, again, for that purpose, hopefully across, you know, referencing a lot of our other subspecialists in the fields of neurology and geriatrics, and also, you know, primary care even. So we're looking forward to that. And just really kind of how to get involved with that. So if you want to get involved, these are opportunities where you can be up here talking about it, you know, in the upcoming years, the research. So if you're having a particular enthusiasm for writing these papers and contributing to the academy and its membership, or just cerebral palsy specifically, please feel free to email guidance at AAPMNR.org. And finally, we want to just thank all the contributors here. And yeah, for all their hard work the past two years. And again, everybody, just look out for the final publication in the Purple Journal. Thank you.

orthobiologic management

knee osteoarthritis

platelet-rich plasma

PRP treatment

physiatry guidance

leukocyte-rich PRP

synovial fluid aspiration

image-guided injections

personalized treatment

chondrotoxic effects