Intra-articular drug delivery has a number of advantages over systemic administration; however, for the past 20 years, intra-articular treatment options for the management of knee osteoarthritis (OA) have been limited to analgesics, glucocorticoids, hyaluronic acid (HA) and a small number of unproven alternative therapies. Although HA and glucocorticoids can provide clinically meaningful benefits to an appreciable number of patients, emerging evidence indicates that the apparent effectiveness of these treatments is largely a result of other factors, including the placebo effect. Biologic drugs that target inflammatory processes are used to manage rheumatoid arthritis, but have not translated well into use in OA. A lack of high-level evidence and methodological limitations hinder our understanding of so-called ‘stem’ cell therapies and, although the off-label administration of intra-articular cell therapies (such as platelet-rich plasma and bone marrow aspirate concentrate) is common, high-quality clinical data are needed before these treatments can be recommended. A number of promising intra-articular treatments are currently in clinical development in the United States, including small-molecule and biologic therapies, devices and gene therapies. Although the prospect of new, non-surgical treatments for OA is exciting, the benefits of new treatments must be carefully weighed against their costs and potential risks.
The cost and unclear effectiveness of hyaluronic acid and glucocorticoids have raised concerns over their broad use for osteoarthritis (OA)-related knee pain.
Self-reported parameters such as pain and stiffness are particularly responsive to intra-articular placebo, which poses challenges when attempting to ascribe clinical meaning to therapeutic interventions.
Estimates of the minimal (clinically) important difference for patient-reported outcomes can provide useful pretext when appraising the effectiveness of intra-articular therapies.
Lack of data, study heterogeneity and methodological limitations hinder our understanding of point-of-care injectable cell therapies such as platelet-rich plasma, bone marrow aspirate concentrate and adipose tissue-derived treatments.
The generally positive efficacy conclusions concerning mesenchymal ‘stem’ cell therapy for knee cartilage pathology might be overstated owing to selective outcome reporting.
A number of intra-articular therapeutic candidates for OA are currently in clinical development, including small-molecule therapies, biologic therapies, gene therapies and novel devices.
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The work of the authors was supported by grants UL1TR001855 and UL1TR000130 from the National Center for Advancing Translational Science (NCATS) of the US National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Nature Reviews Rheumatology thanks C. Evans, D. Hunter and A. Migliore for their contribution to the peer review of this work.