Intra-articular Agents in Knee OA: Treatment Options and Future Developments

Novel nonsurgical treatments for osteoarthritis are being developed, but the benefits of new treatments must be weighed against their cost and potential risks.

Knee osteoarthritis (OA), the most prevalent joint disorder in the United States, causes symptoms in more than 1 in 10 US adults aged 60 years and older.1 Once believed to originate from the inevitable mechanical wear-and-tear associated with aging, OA is increasingly understood as a complex inflammatory disorder.1 Unfortunately, current available treatments do not reflect that complexity. The mainstays of pharmacotherapy for early to mid-stage knee OA are analgesic and do not affect the disease process. Based on conservative treatment paradigms and practices, more than half of all patients with knee OA will eventually progress to meet the criteria for total knee replacement.2,3

Intra-articular agents represent an attractive treatment option for knee OA due to their fewer adverse effects, increased bioavailability, and ability to target the cartilage, which is non-vascularized and thus inefficiently reached by systemic drug delivery.4 However, professional organizations have come to divergent and sometimes contradictory conclusions on the appropriateness of these agents in knee OA. In its recommendations for the use of non-pharmacologic and pharmacologic therapies for hand, hip, and knee OA, the American College of Rheumatology (ACR) included intra-articular corticosteroid injections as a conditionally recommended option for the initial management of knee OA in patients who fail to achieve adequate pain relief with over-the-counter (OTC) acetaminophen, OTC nonsteroidal anti-inflammatory drugs, or OTC nutritional supplements.5 The ACR made no recommendations regarding the use of intra-articular hyaluronic acid, citing a lack of data from randomized clinical trials. Platelet-rich plasma is not discussed at all in the guidelines.

In contrast, in its evidence-based guidelines, the American Academy of Orthopaedic Surgeons (AAOS) declined to make a recommendation for or against the use of intra-articular corticosteroids, growth factor injections, or platelet-rich plasma in patients with symptomatic knee OA, while strongly recommending against the use of hyaluronic acid.6 Osteoarthritis Research Society International (OARSI) guidelines, which designate treatments  as “appropriate,” “uncertain, “ or “not appropriate,” recommend intra-articular corticosteroids as an “appropriate” treatment modality for knee OA and designate intra-articular hyaluronic acid as “uncertain.” OARSI guidelines did not evaluate the use of platelet-rich plasma therapy and growth factor injections.7

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“Current studies (of intra-articular treatments for knee [OA]) have very high variability in design, patient population, the severity of disease, dosages, follow-up times, measured outcomes, etc. That makes it very difficult to group them to create robust evidence and have solid conclusions,” Juan Mora, MD, assistant professor in the Department of Anesthesiology at the University of Florida College of Medicine in Gainesville commented in an interview with Rheumatology Advisor. “There is still the challenge to be able to determine how much of the improvement is secondary to placebo and also defining which patients would benefit the most.”

Despite the inconsistencies in the evidence and lack of support in clinical guidelines, intra-articular injections of corticosteroids and hyaluronic acid are frequent treatment choices for knee OA. According to a recent analysis of records from the Humana administrative claims database, 405,101 (38.0%) of 1,065,175 patients with knee OA were treated with intra-articular corticosteroid injections and 137,004 (12.9%)  were treated with intra-articular hyaluronic acid injections.8 Another study showed that intra-articular hyaluronic acid was the intervention most often selected by members of the American Association of Hip and Knee Surgeons presented with clinical vignettes describing patients with stage 2 and stage 3 knee OA as defined by the Kellgren and Lawrence system for radiographic classification.9 Intra-articular administration of platelet-rich plasma, autologous blood centrifuged to achieve an elevated concentration of platelets above normal levels, is sometimes used  as a treatment modality for knee OA, although it is not approved for that purpose by the US Food and Drug Administration.10,11

“Most clinicians continue to use hyaluronic acid products because they are [effective in clinical practice] and patient satisfaction with the treatments generally approaches 70%,” noted Jeffrey E. Rosen, MD, associate professor of clinical orthopedic surgery at Weill Medical College of Cornell University in New York, New York, in an interview with Rheumatology Advisor.  “If their patients are happy and get relief and are able to delay a knee replacement if that is what they want, then they will continue to use this as a treatment modality.”

Dr Rosen noted that meta-analyses that pool multiple study data using multiple products may account for some of the conflicting data on the efficacy and safety of hyaluronic acid. “It could be argued that all hyaluronic acid products are not the same and therefore should not be pooled.  An analysis of a subset of hyaluronic products, such as high molecular weight products might — and I believe did — show a different outcome which actually would have led the AAOS to a different conclusion.” In one such analysis, hyaluronic acid therapies with an average molecular weight ≥3000 kDa were found to be more efficacious and to result in fewer discontinuations due to treatment-related adverse events than those of lower molecular weights.12 This effect has been ascribed to the superior ability of high molecular weight hyaluronic acid to block production of pro-inflammatory mediators and increase fluid retention in the joint.13

New intra-articular treatments for knee OA are in clinical development. These include LMWF-5A, an injectable, low molecular weight fraction of 5% human serum albumin containing aspartyl-alanyl diketopiperazine, a substance which may have anti-inflammatory or immunomodulatory effects; SM04690, a novel small-molecule Wnt-β-catenin signaling pathway inhibitor; rhFGF18 (sprifermin), a recombinant form of endogenous human fibroblast growth factor 18 (FGF18); CNTX-4975, a synthetic, ultra-pure preparation of trans-capsaicin; and TissueGene C, a cell therapy containing chondrocytes that have been transduced with a viral vector containing transforming growth factor beta-1 proprotein (TGFB1).10

“Knee [OA] is a particularly challenging medical condition, given the unique characteristics of the knee joint, the very slow progression and the wide variety of internal and external contributing factors,” Dr Moro noted. “These factors have made it markedly difficult to have a clear idea of the specific etiology for each patient. Hence, there is a big need for a better understanding of the etiologies, and then to identify which specific ones are affecting an individual patient. That would help to better direct the treatment and determine the prognosis of the OA. In addition, there is a need for improvement in non-surgical treatments in order to reduce adverse effects, increase efficacy, significantly reduce pain, increase functionality and ideally decrease progression or even better to reverse the damage of the joint components. Patients are adequately served if we take into account the current evidence and resources that we have available. They have a wide variety of options to choose from, but hopefully, advancements in therapeutics would allow us to serve them better.”


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9.         Carlson VR, Ong AC, Orozco FR, Hernandez VH, Lutz RW, Post ZD.  Compliance with the AAOS guidelines for treatment of osteoarthritis of the knee: a survey of the American Association of Hip and Knee Surgeons. J Am Acad Orthop Surg. 2018;26(3):103-107.

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11.       Jones IA, Togashi RC, Thomas Vangsness C.  The economics and regulation of PRP in the evolving field of orthopedic biologics. Curr Rev Musculoskelet Med. 2018;11(4):558-565.

12.       Altman RD, Bedi A, Karlsson J, Sancheti P, Schemitsch E. Product differences in intra-articular hyaluronic acids for osteoarthritis of the knee. Am J Sports Med. 2016;44(8):2158-2165.

13.       Gigis I, Fotiadis E, Nenopoulos A, Tsitas K, Hatzokos I.  Comparison of two different molecular weight intra-articular injections of hyaluronic acid for the treatment of knee osteoarthritis. Hippokratia. 2016;20(1):26-31.