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Why remission is not enough: underlying disease mechanisms in RA that prevent cure

Nature Reviews Rheumatology volume 17, pages 135–144 (2021)Cite this article

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Abstract

Cure is the aspirational aim for the treatment of all diseases, including chronic inflammatory conditions such as rheumatoid arthritis (RA); however, it has only been during the twenty-first century that remission, let alone cure, has been a regularly achievable target in RA. Little research has been carried out on how to cure RA, and the term ‘cure’ still requires definition for this disease. Even now, achieving a cure seems to be a rare occurrence among individuals with RA. Therefore, this Review is aimed at addressing the obstacles to the achievement of cure in RA. The differences between remission and cure in RA are first defined, followed by a discussion of the underlying factors (referred to as drivers) that prevent the achievement of cure in RA by triggering sustained immune activation and effector cytokine production. Such drivers include adaptive immune system activation, mesenchymal tissue priming and so-called ‘remote’ (non-immune and non-articular) factors. Strategies to target these drivers are also presented, with an emphasis on the development of strategies that could complement currently used cytokine inhibition and thereby improve the likelihood of curing RA.

Key points

  • The term cure indicates the principle absence of disease, whereas remission indicates that disease is still present but is adequately controlled by therapy.

  • Although effector cytokines involved in rheumatoid arthritis (RA) are well-defined and can be effectively neutralized by current treatment modalities, cure is still rare.

  • Underlying disease mechanisms (referred to as drivers) are thought to continuously promote effector cytokine production and thereby prevent cure of RA.

  • Aberrant T cell activation related to autoimmunity, microenvironmental changes associated with local mesenchymal cell priming and so-called ‘remote’ factors such as intestinal barrier function all serve as drivers of RA.

  • To attain cure of RA as an ultimate treatment goal, strategies need to be developed to therapeutically tackle drivers of RA and enable a sustained interruption of the disease process.

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Fig. 1: Modular analysis of rheumatoid arthritis disease states.
Fig. 2: Drivers that affect the transition from remission to cure in rheumatoid arthritis.

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Acknowledgements

The work of G.S. is supported by the German Research Council (DFG: SPP1468-IMMUNOBONE; CRC1181), the German Ministry of Science and Education (project MASCARA), the European Union (ERC Synergy grant 4DnanoSCOPE) and EU/EFPIA Innovative Medicines Initiative 2 (project RTCure). The work of J.D.I. is supported by the Research into Inflammatory Arthritis Centre Versus Arthritis, the National Institute for Health Research Newcastle Biomedical Research Centre, a partnership between Newcastle Hospitals NHS Foundation Trust and Newcastle University, and the EU/EFPIA Innovative Medicines Initiative 2 (project RTCure).

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Authors and Affiliations

  1. Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-University (FAU) Erlangen-Nuremberg and Universitätsklinikum Erlangen, Erlangen, Germany

    Georg Schett

  2. Deutsches Zentrum fur Immuntherapie, FAU Erlangen-Nuremberg and Universitätsklinikum Erlangen, Erlangen, Germany

    Georg Schett

  3. The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan

    Yoshiya Tanaka

  4. Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK

    John D. Isaacs

  5. Musculoskeletal Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK

    John D. Isaacs

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All authors researched data for the article and provided substantial contributions to discussions of content. G.S. and J.D.I. wrote the article. G.S. and Y.T. reviewed or edited the manuscript before submission.

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Schett, G., Tanaka, Y. & Isaacs, J.D. Why remission is not enough: underlying disease mechanisms in RA that prevent cure. Nat Rev Rheumatol 17, 135–144 (2021). https://doi.org/10.1038/s41584-020-00543-5

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