perspectives on the impact of inflammation in...

1https://www.medscape.org/viewarticle/901145

Perspectives on the Impact of Inflammation in Osteoarthritis: Current Approaches and Future Options CME

https://www.medscape.org/viewarticle/901145


Supported by an independent educational grant from Flexion Therapeutics Inc.



Target AudienceThis activity is intended for orthopedists, orthopedic surgeons, rheumatologists, neurologists, and nurses.

GoalThe goal of this activity is to educate clinicians regarding the pathophysiology of osteoarthritis (OA), including the involve-ment of inflammation in the disease process, and current and appropriate use of anti-inflammatory therapies in the manage-ment of OA through patient-focused case studies.

Learning ObjectivesUpon completion of this activity, participants will:

• Have increased knowledge regarding the • Pathophysiologic mechanisms that underlie the disease process of OA• Current and emerging anti-inflammatory therapies for the management of OA

• Have greater competence related to • Selecting an appropriate anti-inflammatory therapy for the treatment of OA

Credits AvailablePhysicians - maximum of 0.50 AMA PRA Category 1 Credit(s)™ABIM Diplomates - maximum of 0.50 ABIM MOC pointsNurses - maximum of 0.50 contact hours 0.50 contact hours are in the area of pharmacology)

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Disclosures

Moderator

Jeffrey N. Katz, MDProfessor of Medicine and Orthopedic SurgeryHarvard Medical SchoolVice Chair for ResearchDirectorOrthopedic and Arthritis Center for Outcomes ResearchBrigham and Women’s HospitalBoston, Massachusetts

Disclosure: Jeffrey N. Katz, MD, has disclosed the following relevant financial relationships: Received grants for clinical research from: Samumed

Dr Katz does intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

Dr Katz does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

Panelist

Allan Gibofsky, MD, JDProfessor of Medicine, Health Care Policy and ResearchWeill Cornell MedicineAttending Physician, RheumatologistHospital for Special SurgeryNew York-Presbyterian HospitalMemorial-Sloan Kettering Cancer CenterNew York, New York

Disclosure: Allan Gibofsky, MD, JD, has disclosed the following relevant financial relationships: Served as an advisor or consultant for: AbbVie Inc.; Celgene Corporation; Flexion Therapeutics; Merck & Co., Inc.; Pfizer Inc.; Samumed; SanozServed as a speaker or a member of a speakers bureau for: AbbVie Inc.; Celgene Corporation; Flexion Therapeutics; Merck & Co., Inc.; Pfizer Inc.; Novartis Pharmaceuticals CorporationOwns stock, stock options, or bonds from: AbbVie Inc.; Amgen Inc.; Bristol-Myers Squibb Company; Johnson & Johnson Pharmaceutical Research & Development, L.L.C.; Regeneron Pharmaceuticals, Inc.

Dr Gibofsky does intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

Dr Gibofsky does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.



David S. Jevsevar, MD, MBAChair and Associate ProfessorDepartment of OrthopedicsDartmouth-Hitchcock Medical CenterDartmouth Geisel School of MedicineChairAAOS Council on Research and QualityLebanon, New Hampshire

Disclosure: David S. Jevsevar, MD, MBA, has disclosed the following relevant financial relationships: Served as a speaker or a member of a speakers bureau for: Medacta USAReceived grants for clinical research from: DePuy Synthes; Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Dr Jevsevar does intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

Dr Jevsevar does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

Editors

Karen Badal, MD, MPH Scientific Director, Medscape, LLCDisclosure: Karen Badal, MD, MPH, has disclosed the following relevant financial relationships: Owns stock, stock options, or bonds from: Kallyope, Inc.

Heather Lewin, MATAssociate Scientific Director, Medscape, LLCDisclosure: Heather Lewin, MAT, has disclosed no relevant financial relationships.

CME Reviewer / Nurse Planner

Amy Bernard, MS, BSN, RN-BC, CHCPLead Nurse Planner, Medscape, LLCDisclosure: Amy Bernard, MS, BSN, RN-BC, CHCP, has disclosed no relevant financial relationships.



Jeffrey Katz, MD, MS: Hi, I am Dr Jeffrey Katz, professor of medicine and orthopedic surgery at Harvard Medical School. I am pleased to welcome you to this program entitled, “Perspectives on the Impact of Inflammation in Osteoarthritis: Current Approaches and Future Options.”

Joining me today are Dr Allan Gibofsky, professor of medicine and healthcare policy and research at Weill Cornell University School of Medicine, and Dr David Jevsevar, chairman and associate professor of orthopedic surgery at the Dartmouth Geisel School of Medicine. Welcome.



Before we begin, I would like to mention that this program will include a discussion of investigational agents that are not approved by the FDA for use in the United States.

I will start by laying out a few ideas about osteoarthritis (OA). OA is a major public health problem, particularly with the aging of the population and with increasing rates of obesity.[1-5] It is the most common form of joint disease, affecting about 31 mil-lion adults in the United States and a leading cause of chronic pain and disability worldwide.[1,3,4]



Our understanding of OA is that it is a total joint disease characterized by a gradual loss in articular cartilage, the formation of osteophytes, remodeling of subchondral bone, and degeneration of the meniscus.[6,7] The sequence of these events is not entirely clear and likely differs from one person to the other, producing different phenotypes. Inflammation plays a key role in the pathogenesis of OA.[6,7] In today’s discussion, we will focus on anti-inflammatory therapies for OA. Let us spend some time talking about the inflammatory aspects of OA.



David S. Jevsevar, MD, MBA: Jeff, I think you did a great job of talking about some of the pathologic anatomy that we see with OA and some of the changes that occur at the articular cartilage and at the joint level. The inflammatory aspect that you mentioned is something that we recognize more and more as being a part of OA. We certainly know that there are in-flammatory mediators like cytokines that are involved with what we see with the inflammation associated with OA.[8] A num-ber of these have been characterized, and more will be characterized in the future, and even some treatments that we have today, and that are being developed in the future, will try to hit some of these inflammatory mediators that we have seen. Things like cytokines, things like leukotriene, things like chemokines, even adipokines, which are associated with obesity, something we are well familiar with when we look at people with knee OA.[9,10]

Allan Gibofsky, MD, JD: We tend to think of OA as mechanical disruption, but it is a true “itis.” We should not underestimate the inflammatory component of the disease. Perhaps, we should focus on how to best treat the mechanical disruption by focusing on the inflammation that it causes.



Dr Katz: I will now present a patient case to guide the rest of our discussion. A 54-year-old man presents to the practice with left knee pain for the last 3 months. He reports that he is having difficulty doing his usual work as a postal worker. His body mass index is 34 kg/m2. He reports no pain at rest, and tells you that the pain does not interfere with household activities; however, he is having difficulty working. He has been icing his knee, and he occasionally takes acetaminophen for the pain. His x-ray shows an osteophyte at the medial-tibial plateau and it shows mild joint space narrowing medially. Our impression is that he has mild OA of the left knee. What should we do first for this patient, at his first visit?



Dr Gibofsky: Before we do anything else, we need to assess the degree of involvement of his left knee, as well as other joints in the body. Not infrequently, we would assess the joints above and below the painful joint, in addition to the joint that is causing the pain. We would try and determine whether there are any modifiable factors to his pain. We would start with conservative therapy, including education, weight loss, perhaps physical therapy, if appropriate.[11-14] Depending upon what he has been doing up until that point, we can start him on an appropriate medication. This can be acetaminophen on a reg-ular schedule or perhaps a nonsteroidal anti-inflammatory drug (NSAID).

Dr Jevsevar: The only thing I would add to that is sometimes we see patients who have suddenly changed their activity pro-file and started doing something that has either added to the discomfort or has created the discomfort that they have. That is also an important factor to consider because sometimes activity modification is one of the easiest initial treatments that we have.



Dr Katz: The patient is put on a regular dose of acetaminophen and he returns in 2 months, continuing to complain of pain. He is also now having difficulty with stairs in his house and with shopping, so his functional limitation is worsening. Let us talk about next steps.



Dr Gibofsky: If I had started the patient on acetaminophen at the first visit, I might now put him on an oral NSAID. Of course, there are concerns about any medication, and we have to be aware of the gastrointestinal and cardiovascular adverse ef-fects of NSAIDs.[15,16] We have seen a recent study looking at several NSAIDs, including a cyclooxygenase 2 (COX-2) inhibitor, ibuprofen, and naproxen, in order to determine whether one is better than the other.[17] I think we have come to the realiza-tion that when it comes to using an NSAID, there is not one that is safer than the other and all should be given carefully and sparingly, at the lowest dose for the shortest period of time possible.

Dr Jevsevar: I agree. I think one of the biggest issues that we have with NSAIDs at this time is the reluctance of physicians across the spectrum to prescribe them secondary to the issues that have been raised. It has changed our approach to con-servative therapy in ways that we generally do not think are beneficial to our patients.

Dr Katz: Would you put this individual on an H2 blocker or a proton pump inhibitor to avert gastrointestinal effects?

Dr Gibofsky: Depending upon what else is going on with the patient, I probably would. I think we have learned that gastro protection is particularly important, regardless of whether the NSAID is selective or nonselective, so I probably would give him a gastro protective agent as well.[18] I would say again, that I would like to have him on the lowest effective dose for the shortest period of time.



The one thing that I would not do at this time to relieve his pain, although it seems to be widespread, is give this patient an opioid. Dave, can you share with us your experience with those?

Dr Jevsevar: At least in our practice, and we are largely a referral practice; 38% of our patients with knee and hip OA come to us having already taken opioid medication for the treatment of their OA. As you are aware, the guidelines generally do not recommend the use of opioids for OA.[11,12,14,19] This is something that we try to counteract quickly with our patients. It is difficult to get a patient who has been on an opioid to be happy and successful with an NSAID at that point. There are, if you believe in the ladder concept, many healthcare providers jumping the ladder and not using appropriately prescribed indications and medications for many of these patients.

Dr Katz: Let us go ahead and put this patient on a regular dose of NSAIDs with a gastroprotective agent, and continue to emphasize the importance of strengthening and weight loss.



Now let’s fast-forward 2 years. The patient returns and describes minimal improvement of his knee pain. He continues to have interference with activities around the house, as well as at work. He is now considering quitting his job. We reevaluate him radiographically and now find that his joint space narrowing is advanced and extensive. He continues to have progres-sive osteophyte formation. He is progressing in terms of functional limitation and progressing structurally. What should we do now for this patient?



Dr Jevsevar: This is the time where I start looking at injectable therapy for knee OA. For us, the staple has always been the use of intra-articular (IA) corticosteroid injections. Most of the guidelines that have been published on OA do recommend, at least to the level of evidence that is possible, the use of IA corticosteroid injections.[12,14,19] It is important to understand that these injections provide short-term relief, and are not long-term treatment for knee OA, or any other osteoarthritic problem.[20]



When the American Academy of Orthopedic Surgeons (AAOS) developed their 2013 clinical practice guideline for treatment of knee OA, the evidence regarding the use of IA corticosteroids for the management of symptomatic knee OA was deter-mined to be inconclusive.[11] As a result, Dr Elizabeth Matkin, a member of the AAOS, developed her own study looking at the efficacy of IA corticosteroid injections in patients with symptomatic knee OA.[21] The study showed that IA corticosteroid injections improved pain and function for up to 6 months post-injection, with relatively minimal side effects. Patients with more severe OA experienced a smaller response to treatment than did patients with less severe OA.



Dr Katz: Can you explain the contradictory findings of the Matzkin study and the randomized controlled trial by Dr Timothy McAlindon and colleagues?[21,22] In the latter study, they evaluated patients who had received either a steroid injection or a placebo saline injection and evaluated them 3 months after injection.[22] Over a period of 2 years, the patients received serial injections, but there was no improvement in pain or in function. Do you think what is happening here is evidence of a strong placebo effect, or does it have to do with the period of assessment following an injection?

Dr Jevsevar: I think it has to do with the latter. I think that the difference between the McAlindon study and the Matzkin study was the time that they were measuring the outcome of interest, which was reduction in pain and improvement in function. I think most of us believe that 3 months is a relatively long time to be measuring outcomes for an IA corticosteroid injection. The other criticism that some of us had regarding the McAlindon study, which was a very well done study, was that it mandated injections every 3 months for 2 years. In the United States, usual clinical practice is to use injections only when needed, such as when a patient has an exacerbation.



Dr Gibofsky: Yes, we do not like to give multiple injections. There may be concerns about chondrotoxicity regardless of the agent being used.[23] There are also concerns about infection and damage to cartilage; therefore, we would like to give injections as infrequently as possible.[23] In addition, if a patient is going for knee surgery in the next 5 to 6 months, you may not want to inject them at all, over concern that you might either set up a nidus for infection or damage to the tissues.[24]

Dr Jevsevar: The other issue that we run into, just as with the oral medications, are contraindications for the use of IA corticosteroid injections. The one that Allan just referred to is an important one for us as surgeons. We also do not use IA corticosteroid injections for those patients with diabetes who have relatively poor blood glucose control, as this can lead to elevated blood glucose levels, sometimes to a very serious level.[25] We also do not use IA corticosteroid injections if some-body has a remote history of infection within that joint. We just think that the risk is too great.

Dr Katz: In addition, many patients who have OA in 1 knee, may have OA in the contralateral knee, or in their carpometacar-pal (CMC) joints. The ability of an injection in 1 joint to manage the entirety of their disease is limited as well. In this context, we do have a new agent that is available now, a longer lasting corticosteroid injection. Allan, can you tell us about this agent?



Dr Gibofsky: Sure, there is a new agent available to us which is a microsphere-based delivery system. Within each mi-crosphere there are small triamcinolone crystals which are embedded in a poly (lactic loco-glycolic acid) (PLGA) matrix.[26] Studies in patients with knee OA have shown a prolonged residency of triamcinolone in the joint of patients who were treated with this agent, as well as a reduced plasma concentration of this agent, relative to an equivalent dose of immedi-ate-release triamcinolone acetate (TA).[26]



The pivotal study was done in adults with Kellgren grade 2 or 3 knee OA, who were randomized to a single IA injection of either this extended-release microsphere TA, saline solution placebo, or standard TA corticosteroid.[27]

I want to point out that this was not designed as a head-to-head study between the microsphere delivery TA and the stan-dard TA, but it was designed to show the superiority of the new agent to placebo. The primary endpoint was change from baseline to week 12 in weekly mean ADP-intensity scores for extended-release microsphere TA compared with saline-solu-tion placebo, and the primary endpoint was met.

The extended-release microsphere delivery triamcinolone provided significant week-12 improvement in ADP intensity compared with that observed for saline solution placebo.[27] Perhaps equally as important was the fact that there were no significant differences in adverse events among the 3 groups.



Dr Katz: Given the availability now of a longer-term steroid injection, are there patients, who previously were not good candidates for steroid injections, who you would now consider to inject. Conversely, are there patients who receive steroid injections, who may not be good candidates for this extended release formulation?

Dr Jevsevar: I think there is 2 aspects to this: one is for the patient we discussed previously that has diabetes with poor blood glucose control. One of the effects seen with the extended-release TA formulation, was that there were not any spikes of blood glucose that are typically seen with the standard triamcinolone injections.[28] I think this does open up the armamentarium for those patients who may not be amenable to other treatments, but now could potentially have this form of therapy.

I think the one thing that we do not know, is where does it fit if you are looking out in the future to have surgery and knee replacement. How do we fit the extended-release TA formulation into this? We do not know if the longer duration of effect also means there is more of a clinical impact on the risk of infection associated with joint replacement. I still do not know where to put that into my armamentarium for those patients who are looking to the future.

The second thing is that at this time, it is only approved for 1 IA injection in the United States.[29] How do we make sure that we get the maximum benefit for our patients and hopefully give them an extended duration of relief and then treat every-thing else that we are doing? We still have to get back to all those conservative treatments that we have been initiating and hopefully be continuing over this period of time.

Dr Gibofsky: We have only been focusing on our patient with OA of the knee. At this time, we do not have evidence about the effect of microsphere-based agents in other joints that are also subject to the osteoarthritic degenerative and inflamma-tory processes and how that may play out in clinical practice. It is not at all unusual to recognize OA as a disease of multiple joints while there may be a focus on one that the patient complains of, we as their treating physician, have to be aware of limitation, damage and functional concerns in other joints as well.



Dr Katz: Let’s look at some of the other approaches to OA that are currently available or emerging, including orthobiologics. Would you like to comment on this class of drugs?

Dr Jevsevar: I think that the 2 at least that I am most familiar with are platelet rich plasma (PRP) and stem cell injections, which many of our patients ask for.[30-34] Certainly, this is probably facilitated by the fact that we see many professional ath-letes going to other countries to get some of these injections done, and now they are getting them done here in the United States. I think that at least for PRP, there are 2 well done studies with relatively small numbers of patients, that have shown benefit for patients with mild to moderate knee OA, and treatment effect of improved pain and improved function.[30,31]

The problem I guess that I have with use of PRP and stem cells at this time is that it is hard to quantify and identify exactly what you are re-injecting into a patient when you use these technologies.[32] There is not a generated dose-response curve. You are taking a patient’s plasma, spinning it down to reinject it, and you do not know if you are injecting the correct compo-nents into the knee. It is hard to know whether these effects are real across the spectrum. Larger and well-designed studies are still needed.

Dr Gibofsky: Yes, I think that is fair. I think that when one does studies with the orthobiologics, there are so many cohort and individual variables, as you point out, that I think we can best say that more work needs to be done in this area, to tease out the effect of those multiple variables on the outcome, both in the cohort and in individual patients.

Dr Jevsevar: In addition, one thing that we have not talked about is, part of what makes research in knee OA really chal-lenging, is that our patients do not have the same amount of pain every day. We know that it can go all over the place. That makes it very difficult to do research because we are not with the patient every day as they are going through these processes, so that makes some of the investigational agents we are looking at very difficult to study.

We also know the placebo effect for these types of treatments is huge, because patients generally want to try and avoid surgery, so they want to feel better by the other approaches we take. That complicates research, especially in the field of OA.



Dr Katz: Let us return to our patient and what makes this particular patient especially challenging. One is that although corticosteroid injections appear to be effective, their effect is short-term, and we have some concerns about multiple infec-tions.[23] With regards to oral treatments, we are always concerned about the potential toxicity of NSAIDs and are also very wary of initiating opioids in such patients.[16] Here we have a 56-year-old who is beginning to have difficulty maintaining his routine at work, and may lose his job if his pain persists. We can only imagine that he is having difficulty fulfilling different roles in his family and community as well. David, what are some concerns you would have when such a patient comes to an orthopedic practice to discuss joint replacement.

Dr Jevsevar: Part of the reason we do not just say everybody should have a knee replacement is, that we know that the outcomes for knee replacements are not uniformly excellent.[35] We know that about 1 out of 5 of our patients that have knee replacement may not be as satisfied as we would like them to be with the arthroplasty knee replacement that they have had done.[35,36] That makes it challenging.

We also know that in this particular patient, there are a couple of factors to take into consideration. This patient is 56-years-old and still is working. Depending on the level of activity needed for his job, it is sometimes difficult for a patient to return to work doing any type of manual labor or construction type labor, if they have a knee replacement. We all have situations where that has occurred, but we know that the risk of them not returning to work is significant, so that something we need to consider.

Secondarily, we also know that this patient is relatively still on the young side for knee replacement. Although, the curve in the United States for the last 10 to 15 years has been that knee replacement is occurring more and more in people under the age of 65.[37] We know that there is a lifespan, especially for the polyethylene component of a knee replacement, that it will wear out with time. We know with a 56-year-old person who has a normal lifespan, he is looking at more than 1 opera-tion to his knee, he is likely looking at least 2, if not 3 operations, in his lifetime. Every time we do those operations, the risks increase significantly, and this is something that I really like to try to impart on the patient as they go through this deci-sion-making process. I think every patient sees that neighbor down the street who has had a great result, but what they do not see are the neighbors who have not had such a great result and are not able to do the things that they want to do.



Dr Gibofsky: Exactly right. I think, from my perspective, the patient is going to largely make the decision of when it is going to be done for them, based on their functional capacity as well as their pain. A famous maxim from the emeritus chief of or-thopedic surgery at my institution was, when asked when should patients go for joint surgery, his response was “too soon, too soon, too soon, too late.” Suggesting that there is a sweet spot and the patients do not always recognize it, but they tend to, more often than we do.

Dr Jevsevar: Many of us also fail to look at the original tenants that you described for this patient, which are physical activity and weight loss. We want to make sure that the patient is engaged and involved and is doing the things that we have asked them to do. Even if they get to the point of having surgery, we know that that makes the outcome of surgery much better.[38]

Dr Katz: In people like this who are dealing with chronic pain and whom you would like to hold them back from knee re-placement for at least several more years, how do you use IA injections? What are the occasions in which you encourage patients to call and ask to have one?

Dr Gibofsky: By and large, as I said before, when we go this route, we are setting the patient closer to a knee replacement, often, this is a stalling or buying time aspect. Not infrequently, I have a patient who says, “look, I know I need to have knee surgery done sooner rather than later, but I have my granddaughter’s graduation coming up, or I have my daughter’s wed-ding coming up, can we buy some time.”

We will begin with the IA injection, with the clear recognition, discussing the risks and benefits, that yes, you will get some short-term relief, yes, you may even get more than some short-term relief, but we are doing this so that we can go down the road and prepare you for the joint surgery that we know has to take place within the next several months.

Dr Katz: It certainly sounds like there still is an opportunity to introduce new agents in this field. I wonder if we might just briefly discuss what some of the new agents are on the horizon or in the pipeline.



Dr Jevsevar: We do have articular cartilage that we can grow and replant into a patient. Interestingly, it works well in patients with articular cartilage defects, but it does not work so well in knee OA.[39] I think it is technology that continues to move forward. I think there are many technologies addressing the cytokines that we talked about previously. You can actually look to the veterinary medicine world, because in animals like horses that race, they use many of these types of treatments, such as interleukin-6 inhibitors and other types of cytokine inhibitors.[40]

Dr Gibofsky: There are also studies in progress looking at inhibitors of the Wnt pathway.[41] Wnt is a signaling mechanism that regulates cartilage remodeling and formation. There are some data suggesting that by inhibiting the Wnt pathway, you can interfere with the cartilage degradation that occurs.[41]

There are studies underway with an agent that is an anti-nerve growth factor, a monoclonal antibody which binds nerve growth factor. Studies have shown efficacy in pain relief and inhibition of structural damage of cartilage.[42] Finally, there are some experiments on the IA injection of capsaicin, or trans-capsaicins, which are interestingly, the active ingredient in hot pepper substances.[43] I think that there are a number of promising investigational agents that we can bring to bear in patients like this in the future.



Dr Katz: I think we will wrap up the case. I think this was an illustrative case because it was a person with initially milder, but ultimately fairly advanced disease at an age at which we would rather not offer joint replacement. I think it was a useful case for which to discuss some of the available agents, and agents that are coming down the pathway. Allan, do you have any closing remarks?

Dr Gibofsky: I would just reiterate and summarize by saying that we have discussed non-pharmacologic and pharmacologic treatment, as well as surgical therapy. These are not so much a continuum as they may be adjunctive for different joints at different points in the lifespan of their disease.

Dr Katz: Dr Gibofsky, Dr Jevsevar, thank you very much for joining this panel. I very much enjoyed the discussion. I would like to thank the audience as well for participating in this CME activity.



Abbreviations

AAOS = American Academy of Orthopaedic SurgeonsACR = American College of RheumatologyADP = average daily painBMI = body-mass indexCOX2 = cyclooxygenase-2 CV = cardiovascularEULAR = European League Against RheumatismGI = gastrointestinalIA-CS = intra-articular corticosteroidIL = interleukinKL = Kellgren-Lawrence MCII = minimal clinically important improvementMMP = matrix metalloproteinaseNSAID = nonsteroidal anti-inflammatory drugs OA = osteoarthritisOARSI = Osteoarthritis Research Society InternationalPPI = proton pump inhibitorPRN = as neededPRP = platelet-rich plasmaTA = triamcinolone acetonideTh = T-helperTKA = total knee arthroplastyTNF = tumor necrosis factorWOMAC = Western Ontario and McMaster Universities Osteoarthritis Index

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