Potential Pharmacologic Targets for the Prevention of Rheumatoid Arthritis

  • John D. Isaacs
    Address correspondence to: Prof. John D. Isaacs, Institute of Cellular Medicine, Faculty of Medical Sciences, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
    Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, United Kingdom

    Musculoskeletal Unit, Newcastle Upon Tyne Hospitals National Health Service (NHS) Foundation Trust, Newcastle Upon Tyne, United Kingdom
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  • Kundan Iqbal
    Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, United Kingdom

    Musculoskeletal Unit, Newcastle Upon Tyne Hospitals National Health Service (NHS) Foundation Trust, Newcastle Upon Tyne, United Kingdom
    Search for articles by this author


      Rheumatoid arthritis (RA) immunopathology starts many years before clinical disease manifests. An early event is the breakdown in B-cell tolerance and the emergence of autoantibodies. Some years later, the autoantibody response matures, with epitope spreading and isotype switching suggesting more focused T-cell involvement. Circulating proinflammatory cytokines and chemokines appear concurrently, marking a phase of preclinical inflammation. Eventually individuals develop musculoskeletal symptoms and fatigue, heralding the imminent onset of synovitis. The prevention of RA can be aligned to these disease stages, which may simplistically be viewed as breach of tolerance, maturation of autoimmunity, and subclinical inflammation. At each stage, an "ethical" balance must be struck between the potential for benefit versus harm, in large part determined by the likelihood of progression to RA. In particular, tolerogenic interventions should be favored during asymptomatic disease, providing long-lasting, possibly lifelong, benefit from a short-term intervention. During the breach-of-tolerance phase, tolerogenic interventions might involve the administration of autoantigenic peptides in an attempt to shut down autoreactive B cells. The peptides may be "naked," encapsulated in nanoparticles or loaded into autologous tolerogenic dendritic cells. It may also be possible to interfere with antigen generation and presentation, such as via peptidyl arginine deiminase inhibition. Attempts to interfere with B cells via depletion, differentiation, or intracellular signaling are also logical at this stage, if deemed sufficiently well tolerated. These interventions remain relevant during maturation of autoimmunity, but targeted T-cell interventions also become relevant, such as co-stimulation blockade and, potentially, interventions that target intracellular signaling pathways within T cells. Targeting of interleukin 23 during this phase may interfere with maturation of the autoantibody response by modulating autoantibody glycosylation, as well as by inhibiting T-helper 17 differentiation. During the phase of subclinical inflammation, targeting cytokines and chemokines could conceivably prevent progression to RA. Furthermore, tolerance induction is opposed by systemic inflammation and, during this phase, it may be necessary to consider therapeutic combinations of tolerogenic and antiinflammatory interventions.

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