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  • Review Article
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Progress in intra-articular therapy

Nature Reviews Rheumatology volume 10, pages 11–22 (2014)Cite this article

Subjects

This article has been updated

Key Points

  • Getting therapeutics into joints in a targeted and sustained fashion is difficult

  • Intra-articular injection solves the delivery problem and brings several additional advantages over systemic administration, including increased bioavailability, reduced systemic exposure, fewer off-target effects and lower costs

  • Soluble drugs exit joints rapidly, via the capillaries (in the case of small molecules) and lymphatic system (for macromolecules)

  • Strategies for extending the intra-articular half-lives of therapeutics include the use of small particles, drug modification and gene transfer

  • Delivery of hyaluronate and corticosteroids accounts for the majority of intra-articular injections; additional therapeutics include recombinant proteins, autologous blood products and analgesics

  • Clinical trials involving the intra-articular injection of mesenchymal stem cells have multiplied enormously in recent years

Abstract

Diarthrodial joints are well suited to intra-articular injection, and the local delivery of therapeutics in this fashion brings several potential advantages to the treatment of a wide range of arthropathies. Possible benefits over systemic delivery include increased bioavailability, reduced systemic exposure, fewer adverse events, and lower total drug costs. Nevertheless, intra-articular therapy is challenging because of the rapid egress of injected materials from the joint space; this elimination is true of both small molecules, which exit via synovial capillaries, and of macromolecules, which are cleared by the lymphatic system. In general, soluble materials have an intra-articular dwell time measured only in hours. Corticosteroids and hyaluronate preparations constitute the mainstay of FDA-approved intra-articular therapeutics. Recombinant proteins, autologous blood products and analgesics have also found clinical use via intra-articular delivery. Several alternative approaches, such as local delivery of cell and gene therapy, as well as the use of microparticles, liposomes, and modified drugs, are in various stages of preclinical development.

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Figure 1: How soluble molecules get into and out of joints.
Figure 2: Concentration ratios of proteins between serum and synovial fluid.

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Change history

  • 29 November 2012

    In the version of this article initially published online, reference 46 was listed incorrectly in the reference list and the in-text citation of reference 23 listed an incorrect year. This error has been corrected for the HTML and PDF versions of the article.

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Acknowledgements

The authors would like to acknowledge financial support from NIAMS in the form of the following grants: P01AR050245, R01AR047442, R01AR051085, X01 NS066865.

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Authors and Affiliations

  1. Center for Advanced Orthopedic Studies, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, RN-115, Boston, 02215, MA, USA

    Christopher H. Evans

  2. Department of Medicine, Duke University Medical Center, Box 3416, Durham, 27710, NC, USA

    Virginia B. Kraus

  3. Department of Biomedical Engineering, Duke University, Room 136 Hudson Hall, Box 90281, Durham, 27708, NC, USA

    Lori A. Setton

Authors
  1. Christopher H. Evans
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  2. Virginia B. Kraus
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  3. Lori A. Setton
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All authors made substantial contributions to all aspects of the preparation of this manuscript.

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Correspondence to Christopher H. Evans.

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Competing interests

C. H. Evans declares that he acts as a consultant for TissueGene Inc. and holds stock in Orthogen AG. L. A. Setton declares that she holds stock in PhaseBio. V. B. Kraus declares that she has received royalties from PhaseBio.

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Evans, C., Kraus, V. & Setton, L. Progress in intra-articular therapy. Nat Rev Rheumatol 10, 11–22 (2014). https://doi.org/10.1038/nrrheum.2013.159

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