Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Joint-specific memory, resident memory T cells and the rolling window of opportunity in arthritis

Nature Reviews Rheumatology volume 20, pages 258–271 (2024)Cite this article

Subjects

Abstract

In rheumatoid arthritis, juvenile idiopathic arthritis and other forms of inflammatory arthritis, the immune system targets certain joints but not others. The pattern of joints affected varies by disease and by individual, with flares most commonly involving joints that were previously inflamed. This phenomenon, termed joint-specific memory, is difficult to explain by systemic immunity alone. Mechanisms of joint-specific memory include the involvement of synovial resident memory T cells that remain in the joint during remission and initiate localized disease recurrence. In addition, arthritis-induced durable changes in synovial fibroblasts and macrophages can amplify inflammation in a site-specific manner. Together with ongoing systemic processes that promote extension of arthritis to new joints, these local factors set the stage for a stepwise progression in disease severity, a paradigm for arthritis chronicity that we term the joint accumulation model. Although durable drug-free remission through early treatment remains elusive for most forms of arthritis, the joint accumulation paradigm defines new therapeutic targets, emphasizes the importance of sustained treatment to prevent disease extension to new joints, and identifies a rolling window of opportunity for altering the natural history of arthritis that extends well beyond the initiation phase of disease.

Key points

  • In rheumatoid arthritis and juvenile idiopathic arthritis, joints previously affected are more likely to flare than joints previously spared, a phenomenon termed joint-specific memory.

  • One mechanism underlying joint-specific memory is the accumulation of synovial resident memory T (TRM) cells, long-lived resident lymphocytes that remain during remission and promote recurrent disease.

  • Synovial TRM cells are predominantly CD8+ T cells and exhibit a restricted TCR repertoire; in animal models, TRM cells trigged by specific antigens induce arthritis flare by releasing chemokines, including CCL5.

  • Mechanisms that predispose individual joints to greater disease activity include inflammation-induced fibroblast priming and an increase in the abundance of pro-inflammatory macrophages compared with that of regulatory macrophages.

  • Recognition that both systemic factors and local factors drive arthritis suggests a new paradigm of chronicity, the joint accumulation model, implying a ‘rolling window of opportunity’ for therapy, even in established arthritis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Joint-specific memory.
Fig. 2: Multilineage interactions in the joint.
Fig. 3: The joint accumulation model and the rolling window of opportunity.
Fig. 4: Candidate mechanisms through which arthritis extends into new joints.

Similar content being viewed by others

References

  1. Chang, M. H. & Nigrovic, P. A. Antibody-dependent and -independent mechanisms of inflammatory arthritis. JCI Insight 4, https://doi.org/10.1172/jci.insight.125278 (2019).

  2. Gravallese, E. M. & Firestein, G. S. Rheumatoid arthritis — common origins, divergent mechanisms. N. Engl. J. Med. 388, 529–542 (2023).

    CAS  PubMed  Google Scholar 

  3. Roberts, W. N., Daltroy, L. H. & Anderson, R. J. Stability of normal joint findings in persistent classic rheumatoid arthritis. Arthritis Rheum. 31, 267–271 (1988).

    CAS  PubMed  Google Scholar 

  4. Chang, M. H. et al. Joint-specific memory and sustained risk for new joint accumulation in autoimmune arthritis. Arthritis Rheumatol. 74, 1851–1858 (2022).

    PubMed  PubMed Central  Google Scholar 

  5. Chang, M. H. et al. Arthritis flares mediated by tissue-resident memory T cells in the joint. Cell Rep. 37, 109902 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Heckert, S. L. et al. Joint inflammation tends to recur in the same joints during the rheumatoid arthritis disease course. Ann. Rheum. Dis. 81, 169–174 (2022).

    PubMed  Google Scholar 

  7. Heckert, S. L. et al. Patterns of clinical joint inflammation in juvenile idiopathic arthritis. RMD Open 9, e002941 (2023).

    PubMed  PubMed Central  Google Scholar 

  8. Gebhardt, T., Palendira, U., Tscharke, D. C. & Bedoui, S. Tissue-resident memory T cells in tissue homeostasis, persistent infection, and cancer surveillance. Immunol. Rev. 283, 54–76 (2018).

    CAS  PubMed  Google Scholar 

  9. Szabo, P. A., Miron, M. & Farber, D. L. Location, location, location: tissue resident memory T cells in mice and humans. Sci. Immunol. 4, eaas9673 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Boniface, K. et al. Vitiligo skin is imprinted with resident memory CD8 T cells expressing CXCR3. J. Invest. Dermatol. 138, 355–364 (2018).

    CAS  PubMed  Google Scholar 

  11. Richmond, J. M. et al. Resident memory and recirculating memory T cells cooperate to maintain disease in a mouse model of vitiligo. J. Invest. Dermatol. 139, 769–778 (2019).

    CAS  PubMed  Google Scholar 

  12. Boyman, O. et al. Spontaneous development of psoriasis in a new animal model shows an essential role for resident T cells and tumor necrosis factor-α. J. Exp. Med. 199, 731–736 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Samat, A. A. K., van der Geest, J., Vastert, S. J., van Loosdregt, J. & van Wijk, F. Tissue-resident memory T cells in chronic inflammation-local cells with systemic effects? Cells 10, 409 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Fonseca, R. et al. Developmental plasticity allows outside-in immune responses by resident memory T cells. Nat. Immunol. 21, 412–421 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Wijeyesinghe, S. et al. Expansible residence decentralizes immune homeostasis. Nature 592, 457–462 (2021).

    CAS  PubMed  Google Scholar 

  16. Mueller, S. N. & Mackay, L. K. Tissue-resident memory T cells: local specialists in immune defence. Nat. Rev. Immunol. 16, 79–89 (2016).

    CAS  PubMed  Google Scholar 

  17. Heeg, M. & Goldrath, A. W. Insights into phenotypic and functional CD8+ TRM heterogeneity. Immunol. Rev. 316, 8–22 (2023).

    CAS  PubMed  Google Scholar 

  18. Kumar, B. V. et al. Human tissue-resident memory T cells are defined by core transcriptional and functional signatures in lymphoid and mucosal sites. Cell Rep. 20, 2921–2934 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Crowl, J. T. et al. Tissue-resident memory CD8+ T cells possess unique transcriptional, epigenetic and functional adaptations to different tissue environments. Nat. Immunol. 23, 1121–1131 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Mackay, L. K. et al. Hobit and Blimp1 instruct a universal transcriptional program of tissue residency in lymphocytes. Science 352, 459–463 (2016).

    CAS  PubMed  Google Scholar 

  21. Poon, M. M. L. et al. Tissue adaptation and clonal segregation of human memory T cells in barrier sites. Nat. Immunol. 24, 309–319 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Christo, S. N. et al. Discrete tissue microenvironments instruct diversity in resident memory T cell function and plasticity. Nat. Immunol. 22, 1140–1151 (2021).

    CAS  PubMed  Google Scholar 

  23. Lin, Y. H. et al. Small intestine and colon tissue-resident memory CD8+ T cells exhibit molecular heterogeneity and differential dependence on Eomes. Immunity 56, 207–223.e8 (2023).

    CAS  PubMed  Google Scholar 

  24. Schenkel, J. M. et al. IL-15-independent maintenance of tissue-resident and boosted effector memory CD8 T cells. J. Immunol. 196, 3920–3926 (2016).

    CAS  PubMed  Google Scholar 

  25. FitzPatrick, M. E. B. et al. Human intestinal tissue-resident memory T cells comprise transcriptionally and functionally distinct subsets. Cell Rep. 34, 108661 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Milner, J. J. et al. Heterogenous populations of tissue-resident CD8+ T cells are generated in response to infection and malignancy. Immunity 52, 808–824.e7 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Frizzell, H. et al. Organ-specific isoform selection of fatty acid-binding proteins in tissue-resident lymphocytes. Sci. Immunol. 5, https://doi.org/10.1126/sciimmunol.aay9283 (2020).

  28. Pan, Y. et al. Survival of tissue-resident memory T cells requires exogenous lipid uptake and metabolism. Nature 543, 252–256 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Howie, D., Ten Bokum, A., Necula, A. S., Cobbold, S. P. & Waldmann, H. The role of lipid metabolism in T lymphocyte differentiation and survival. Front. Immunol. 8, 1949 (2017).

    PubMed  Google Scholar 

  30. Jin, R. et al. Role of FABP5 in T cell lipid metabolism and function in the tumor microenvironment. Cancers 15, https://doi.org/10.3390/cancers15030657 (2023).

  31. Steinert, E. M. et al. Quantifying memory CD8 T cells reveals regionalization of immunosurveillance. Cell 161, 737–749 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Jung, J. et al. Synovial fluid CD69+CD8+ T cells with tissue-resident phenotype mediate perforin-dependent citrullination in rheumatoid arthritis. Clin. Transl. Immunol. 9, e1140 (2020).

    CAS  Google Scholar 

  33. Guggino, G., Rizzo, A., Mauro, D., Macaluso, F. & Ciccia, F. Gut-derived CD8+ tissue-resident memory T cells are expanded in the peripheral blood and synovia of SpA patients. Ann. Rheum. Dis. 80, e174 (2021).

    PubMed  Google Scholar 

  34. Horai, R. et al. Development of chronic inflammatory arthropathy resembling rheumatoid arthritis in interleukin 1 receptor antagonist-deficient mice. J. Exp. Med. 191, 313–320 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Zhang, F. et al. Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry. Nat. Immunol. 20, 928–942 (2019).

    PubMed  PubMed Central  Google Scholar 

  36. Jonsson, A. H. et al. Granzyme K+ CD8 T cells form a core population in inflamed human tissue. Sci. Transl. Med. 14, eabo0686 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Petrelli, A. et al. PD-1+CD8+ T cells are clonally expanding effectors in human chronic inflammation. J. Clin. Invest. 128, 4669–4681 (2018).

    PubMed  PubMed Central  Google Scholar 

  38. Vanni, A. et al. Clonally expanded PD-1-expressing T cells are enriched in synovial fluid of juvenile idiopathic arthritis patients. Eur. J. Immunol. 53, e2250162 (2023).

    PubMed  Google Scholar 

  39. Maschmeyer, P. et al. Antigen-driven PD-1+ TOX+ BHLHE40+ and PD-1+ TOX+ EOMES+ T lymphocytes regulate juvenile idiopathic arthritis in situ. Eur. J. Immunol. 51, 915–929 (2021).

    CAS  PubMed  Google Scholar 

  40. Steel, K. J. A. et al. Polyfunctional, proinflammatory, tissue-resident memory phenotype and function of synovial interleukin-17A+CD8+ T cells in psoriatic arthritis. Arthritis Rheumatol. 72, 435–447 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Povoleri, G. A. M. et al. Psoriatic and rheumatoid arthritis joints differ in the composition of CD8+ tissue-resident memory T cell subsets. Cell Rep. 42, 112514 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Penkava, F. et al. Single-cell sequencing reveals clonal expansions of pro-inflammatory synovial CD8 T cells expressing tissue-homing receptors in psoriatic arthritis. Nat. Commun. 11, 4767 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Qaiyum, Z., Gracey, E., Yao, Y. & Inman, R. D. Integrin and transcriptomic profiles identify a distinctive synovial CD8+ T cell subpopulation in spondyloarthritis. Ann. Rheum. Dis. 78, 1566–1575 (2019).

    CAS  PubMed  Google Scholar 

  44. Sasson, S. C., Gordon, C. L., Christo, S. N., Klenerman, P. & Mackay, L. K. Local heroes or villains: tissue-resident memory T cells in human health and disease. Cell Mol. Immunol. 17, 113–122 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Arazi, A. et al. The immune cell landscape in kidneys of patients with lupus nephritis. Nat. Immunol. 20, 902–914 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Zhou, M. et al. JAK/STAT signaling controls the fate of CD8+CD103+ tissue-resident memory T cell in lupus nephritis. J. Autoimmun. 109, 102424 (2020).

    CAS  PubMed  Google Scholar 

  47. Boothby, I. C. et al. Early-life inflammation primes a T helper 2 cell-fibroblast niche in skin. Nature 599, 667–672 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Nygaard, G. & Firestein, G. S. Restoring synovial homeostasis in rheumatoid arthritis by targeting fibroblast-like synoviocytes. Nat. Rev. Rheumatol. 16, 316–333 (2020).

    PubMed  PubMed Central  Google Scholar 

  49. Bottini, N. & Firestein, G. S. Duality of fibroblast-like synoviocytes in RA: passive responders and imprinted aggressors. Nat. Rev. Rheumatol. 9, 24–33 (2013).

    CAS  PubMed  Google Scholar 

  50. Nakano, K., Whitaker, J. W., Boyle, D. L., Wang, W. & Firestein, G. S. DNA methylome signature in rheumatoid arthritis. Ann. Rheum. Dis. 72, 110–117 (2013).

    CAS  PubMed  Google Scholar 

  51. Whitaker, J. W. et al. An imprinted rheumatoid arthritis methylome signature reflects pathogenic phenotype. Genome Med. 5, 40 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Ai, R. et al. DNA methylome signature in synoviocytes from patients with early rheumatoid arthritis compared to synoviocytes from patients with longstanding rheumatoid arthritis. Arthritis Rheumatol. 67, 1978–1980 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Crowley, T. et al. Priming in response to pro-inflammatory cytokines is a feature of adult synovial but not dermal fibroblasts. Arthritis Res. Ther. 19, 35 (2017).

    PubMed  PubMed Central  Google Scholar 

  54. Friscic, J. et al. The complement system drives local inflammatory tissue priming by metabolic reprogramming of synovial fibroblasts. Immunity 54, 1002–1021.e10 (2021).

    CAS  PubMed  Google Scholar 

  55. Friscic, J. et al. Reset of inflammatory priming of joint tissue and reduction of the severity of arthritis flares by bromodomain inhibition. Arthritis Rheumatol. 75, 517–532 (2023).

    CAS  PubMed  Google Scholar 

  56. Lefevre, S. et al. Synovial fibroblasts spread rheumatoid arthritis to unaffected joints. Nat. Med. 15, 1414–1420 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Orange, D. E. et al. RNA identification of PRIME cells predicting rheumatoid arthritis flares. N. Engl. J. Med. 383, 218–228 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Frank-Bertoncelj, M. et al. Epigenetically-driven anatomical diversity of synovial fibroblasts guides joint-specific fibroblast functions. Nat. Commun. 8, 14852 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Ciurea, A. et al. Joint-level responses to tofacitinib and methotrexate: a post hoc analysis of data from ORAL Start. Arthritis Res. Ther. 25, 185 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Kurowska-Stolarska, M. & Alivernini, S. Synovial tissue macrophages in joint homeostasis, rheumatoid arthritis and disease remission. Nat. Rev. Rheumatol. 18, 384–397 (2022).

    CAS  PubMed  Google Scholar 

  61. Alivernini, S. et al. Distinct synovial tissue macrophage subsets regulate inflammation and remission in rheumatoid arthritis. Nat. Med. 26, 1295–1306 (2020).

    CAS  PubMed  Google Scholar 

  62. Misharin, A. V. et al. Nonclassical Ly6C− monocytes drive the development of inflammatory arthritis in mice. Cell Rep. 9, 591–604 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Culemann, S. et al. Locally renewing resident synovial macrophages provide a protective barrier for the joint. Nature 572, 670–675 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Montgomery, A. B. et al. Tissue-resident, extravascular Ly6c− monocytes are critical for inflammation in the synovium. Cell Rep. 42, 112513 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Alivernini, S. et al. Synovial features of patients with rheumatoid arthritis and psoriatic arthritis in clinical and ultrasound remission differ under anti-TNF therapy: a clue to interpret different chances of relapse after clinical remission? Ann. Rheum. Dis. 76, 1228–1236 (2017).

    CAS  PubMed  Google Scholar 

  66. Aegerter, H. et al. Influenza-induced monocyte-derived alveolar macrophages confer prolonged antibacterial protection. Nat. Immunol. 21, 145–157 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Guilliams, M. & Svedberg, F. R. Does tissue imprinting restrict macrophage plasticity? Nat. Immunol. 22, 118–127 (2021).

    CAS  PubMed  Google Scholar 

  68. Hanlon, M. M. et al. Rheumatoid arthritis macrophages are primed for inflammation and display bioenergetic and functional alterations. Rheumatology 62, 2611–2620 (2023).

    CAS  PubMed  Google Scholar 

  69. Vickovic, S. et al. Three-dimensional spatial transcriptomics uncovers cell type localizations in the human rheumatoid arthritis synovium. Commun. Biol. 5, 129 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Iijima, N. & Iwasaki, A. T cell memory. A local macrophage chemokine network sustains protective tissue-resident memory CD4 T cells. Science 346, 93–98 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Vu, T. T., Koguchi-Yoshioka, H. & Watanabe, R. Skin-resident memory T cells: pathogenesis and implication for the treatment of psoriasis. J. Clin. Med. 10, https://doi.org/10.3390/jcm10173822 (2021).

  72. Puig, L. et al. The biological basis of disease recurrence in psoriasis: a historical perspective and current models. Br. J. Dermatol. 186, 773–781 (2022).

    PubMed  PubMed Central  Google Scholar 

  73. Matos, T. R. et al. Clinically resolved psoriatic lesions contain psoriasis-specific IL-17-producing ɑβ T cell clones. J. Clin. Invest. 127, 4031–4041 (2017).

    PubMed  PubMed Central  Google Scholar 

  74. Li, X., Jiang, M., Chen, X. & Sun, W. Etanercept alleviates psoriasis by reducing the Th17/Treg ratio and promoting M2 polarization of macrophages. Immun. Inflamm. Dis. 10, e734 (2022).

    PubMed  PubMed Central  Google Scholar 

  75. Mehta, H. et al. Differential changes in inflammatory mononuclear phagocyte and T-cell profiles within psoriatic skin during treatment with guselkumab vs. secukinumab. J. Invest. Dermatol. 141, 1707–1718.e9 (2021).

    CAS  PubMed  Google Scholar 

  76. Whitley, S. K. et al. Local IL-23 is required for proliferation and retention of skin-resident memory TH17 cells. Sci. Immunol. 7, eabq3254 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Dong, C., Lin, L. & Du, J. Characteristics and sources of tissue-resident memory T cells in psoriasis relapse. Curr. Res. Immunol. 4, 100067 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Monti, S., Montecucco, C., Bugatti, S. & Caporali, R. Rheumatoid arthritis treatment: the earlier the better to prevent joint damage. RMD Open 1, e000057 (2015).

    PubMed  PubMed Central  Google Scholar 

  79. Fraenkel, L. et al. 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care Res. 73, 924–939 (2021).

    Google Scholar 

  80. Boers, M. Understanding the window of opportunity concept in early rheumatoid arthritis. Arthritis Rheum. 48, 1771–1774 (2003).

    PubMed  Google Scholar 

  81. van Nies, J. A. et al. What is the evidence for the presence of a therapeutic window of opportunity in rheumatoid arthritis? A systematic literature review. Ann. Rheum. Dis. 73, 861–870 (2014).

    PubMed  Google Scholar 

  82. Burgers, L. E., Raza, K. & van der Helm-van Mil, A. H. Window of opportunity in rheumatoid arthritis — definitions and supporting evidence: from old to new perspectives. RMD Open 5, e000870 (2019).

    PubMed  PubMed Central  Google Scholar 

  83. Nigrovic, P. A. Review: Is there a window of opportunity for treatment of systemic juvenile idiopathic arthritis? Arthritis Rheumatol. 66, 1405–1413 (2014).

    CAS  PubMed  Google Scholar 

  84. Nigrovic, P. A. et al. Biological classification of childhood arthritis: roadmap to a molecular nomenclature. Nat. Rev. Rheumatol. 17, 257–269 (2021).

    PubMed  PubMed Central  Google Scholar 

  85. Nigrovic, P. A. et al. Anakinra as first-line disease-modifying therapy in systemic juvenile idiopathic arthritis: report of forty-six patients from an international multicenter series. Arthritis Rheum. 63, 545–555 (2011).

    CAS  PubMed  Google Scholar 

  86. Ter Haar, N. M. et al. Treatment to target using recombinant interleukin-1 receptor antagonist as first-line monotherapy in new-onset systemic juvenile idiopathic arthritis: results from a five-year follow-up study. Arthritis Rheumatol. 71, 1163–1173 (2019).

    PubMed  PubMed Central  Google Scholar 

  87. Pardeo, M. et al. Early treatment and IL1RN single-nucleotide polymorphisms affect response to anakinra in systemic juvenile idiopathic arthritis. Arthritis Rheumatol. 73, 1053–1061 (2021).

    CAS  PubMed  Google Scholar 

  88. Henderson, L. A. et al. Th17 reprogramming of T cells in systemic juvenile idiopathic arthritis. JCI Insight 5, https://doi.org/10.1172/jci.insight.132508 (2020).

  89. Levescot, A. et al. IL-1β-driven osteoclastogenic Tregs accelerate bone erosion in arthritis. J. Clin. Invest. 131, https://doi.org/10.1172/JCI141008 (2021).

  90. Alivernini, S. et al. Inclusion of synovial tissue-derived characteristics in a nomogram for the prediction of treatment response in treatment-naive rheumatoid arthritis patients. Arthritis Rheumatol. 73, 1601–1613 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Bergstra, S. A. et al. Earlier is better when treating rheumatoid arthritis: but can we detect a window of opportunity? RMD Open 6, https://doi.org/10.1136/rmdopen-2020-001242 (2020).

  92. Goekoop-Ruiterman, Y. P. et al. Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. Arthritis Rheum. 52, 3381–3390 (2005).

    CAS  PubMed  Google Scholar 

  93. Wevers-de Boer, K. et al. Remission induction therapy with methotrexate and prednisone in patients with early rheumatoid and undifferentiated arthritis (the IMPROVED study). Ann. Rheum. Dis. 71, 1472–1477 (2012).

    CAS  PubMed  Google Scholar 

  94. Ebrahimian, S. et al. Can treating rheumatoid arthritis with disease-modifying anti-rheumatic drugs at the window of opportunity with tight control strategy lead to long-term remission and medications free remission in real-world clinical practice? A cohort study. Clin. Rheumatol. 40, 4485–4491 (2021).

    PubMed  Google Scholar 

  95. Krijbolder, D. I. et al. Intervention with methotrexate in patients with arthralgia at risk of rheumatoid arthritis to reduce the development of persistent arthritis and its disease burden (TREAT EARLIER): a randomised, double-blind, placebo-controlled, proof-of-concept trial. Lancet 400, 283–294 (2022).

    PubMed  Google Scholar 

  96. Cope, A. P. et al. Abatacept in individuals at high risk of rheumatoid arthritis (APIPPRA): a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial. Lancet 403, 838–849 (2024).

    CAS  PubMed  Google Scholar 

  97. Sugiyama, D. et al. Impact of smoking as a risk factor for developing rheumatoid arthritis: a meta-analysis of observational studies. Ann. Rheum. Dis. 69, 70–81 (2010).

    CAS  PubMed  Google Scholar 

  98. Anderson, J. J., Wells, G., Verhoeven, A. C. & Felson, D. T. Factors predicting response to treatment in rheumatoid arthritis: the importance of disease duration. Arthritis Rheum. 43, 22–29 (2000).

    CAS  PubMed  Google Scholar 

  99. Aletaha, D. et al. Effect of disease duration and prior disease-modifying antirheumatic drug use on treatment outcomes in patients with rheumatoid arthritis. Ann. Rheum. Dis. 78, 1609–1615 (2019).

    CAS  PubMed  Google Scholar 

  100. Kerschbaumer, A. et al. Efficacy of synthetic and biological DMARDs: a systematic literature review informing the 2022 update of the EULAR recommendations for the management of rheumatoid arthritis. Ann. Rheum. Dis. 82, 95–106 (2023).

    CAS  PubMed  Google Scholar 

  101. Chang, C. Y., Meyer, R. M. & Reiff, A. O. Impact of medication withdrawal method on flare-free survival in patients with juvenile idiopathic arthritis on combination therapy. Arthritis Care Res. 67, 658–666 (2015).

    CAS  Google Scholar 

  102. Guzman, J. et al. The risk and nature of flares in juvenile idiopathic arthritis: results from the ReACCh-Out cohort. Ann. Rheum. Dis. 75, 1092–1098 (2016).

    PubMed  Google Scholar 

  103. Simonini, G. et al. Flares after withdrawal of biologic therapies in juvenile idiopathic arthritis: clinical and laboratory correlates of remission duration. Arthritis Care Res. 70, 1046–1051 (2018).

    Google Scholar 

  104. Curtis, J. R. et al. Etanercept or methotrexate withdrawal in rheumatoid arthritis patients in sustained remission. Arthritis Rheumatol. 73, 759–768 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Emery, P. et al. Adalimumab dose tapering in patients with rheumatoid arthritis who are in long-standing clinical remission: results of the phase IV PREDICTRA study. Ann. Rheum. Dis. 79, 1023–1030 (2020).

    CAS  PubMed  Google Scholar 

  106. Ringold, S. et al. Disease recapture rates after medication discontinuation and flare in juvenile idiopathic arthritis: an observational study within the childhood arthritis and rheumatology research alliance registry. Arthritis Care Res. 75, 715–723 (2023).

    Google Scholar 

  107. Richmond, J. M. et al. Antibody blockade of IL-15 signaling has the potential to durably reverse vitiligo. Sci. Transl. Med. 10, https://doi.org/10.1126/scitranslmed.aam7710 (2018).

  108. Hassert, M. et al. Regenerating murine CD8+ lung tissue resident memory T cells after targeted radiation exposure. J. Exp. Med. 221, https://doi.org/10.1084/jem.20231144 (2024).

  109. Schenkel, J. M., Fraser, K. A. & Masopust, D. Cutting edge: resident memory CD8 T cells occupy frontline niches in secondary lymphoid organs. J. Immunol. 192, 2961–2964 (2014).

    CAS  PubMed  Google Scholar 

  110. Beura, L. K. et al. T cells in nonlymphoid tissues give rise to lymph-node-resident memory T cells. Immunity 48, 327–338.e5 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Stolley, J. M. et al. Retrograde migration supplies resident memory T cells to lung-draining LN after influenza infection. J. Exp. Med. 217, https://doi.org/10.1084/jem.20192197 (2020).

  112. Klicznik, M. M. et al. Human CD4+CD103+ cutaneous resident memory T cells are found in the circulation of healthy individuals. Sci. Immunol. 4, https://doi.org/10.1126/sciimmunol.aav8995 (2019).

  113. Mijnheer, G. et al. Compartmentalization and persistence of dominant (regulatory) T cell clones indicates antigen skewing in juvenile idiopathic arthritis. Elife 12, https://doi.org/10.7554/eLife.79016 (2023).

  114. Spreafico, R. et al. A circulating reservoir of pathogenic-like CD4+ T cells shares a genetic and phenotypic signature with the inflamed synovial micro-environment. Ann. Rheum. Dis. 75, 459–465 (2016).

    CAS  PubMed  Google Scholar 

  115. Leijten, E. F. et al. Tissue-resident memory CD8+ T cells from skin differentiate psoriatic arthritis from psoriasis. Arthritis Rheumatol. 73, 1220–1232 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Kunnamo, I., Kallio, P., Pelkonen, P. & Viander, M. Serum-sickness-like disease is a common cause of acute arthritis in children. Acta Paediatr. Scand. 75, 964–969 (1986).

    CAS  PubMed  Google Scholar 

  117. Lawley, T. J. et al. A prospective clinical and immunologic analysis of patients with serum sickness. N. Engl. J. Med. 311, 1407–1413 (1984).

    CAS  PubMed  Google Scholar 

  118. Steere, A. C. et al. Treatment of Lyme arthritis. Arthritis Rheum. 37, 878–888 (1994).

    CAS  PubMed  Google Scholar 

  119. Oen, K. et al. Early predictors of longterm outcome in patients with juvenile rheumatoid arthritis: subset-specific correlations. J. Rheumatol. 30, 585–593 (2003).

    PubMed  Google Scholar 

  120. Selvaag, A. M., Aulie, H. A., Lilleby, V. & Flato, B. Disease progression into adulthood and predictors of long-term active disease in juvenile idiopathic arthritis. Ann. Rheum. Dis. 75, 190–195 (2016).

    PubMed  Google Scholar 

  121. Lengl-Janssen, B., Strauss, A. F., Steere, A. C. & Kamradt, T. The T helper cell response in Lyme arthritis: differential recognition of Borrelia burgdorferi outer surface protein A in patients with treatment-resistant or treatment-responsive Lyme arthritis. J. Exp. Med. 180, 2069–2078 (1994).

    CAS  PubMed  Google Scholar 

  122. Steere, A. C. et al. Antibiotic-refractory Lyme arthritis is associated with HLA−DR molecules that bind a Borrelia burgdorferi peptide. J. Exp. Med. 203, 961–971 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. James, E. A. et al. Citrulline-specific Th1 cells are increased in rheumatoid arthritis and their frequency is influenced by disease duration and therapy. Arthritis Rheumatol. 66, 1712–1722 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Nigrovic, P. A. & White, P. H. Care of the adult with juvenile rheumatoid arthritis. Arthritis Rheum. 55, 208–216 (2006).

    PubMed  Google Scholar 

Download references

Acknowledgements

M.H.C. acknowledges related grant support from K08AR080992, the Rheumatology Research Foundation, the Arthritis National Research Foundation, Boston Children’s Hospital and the Arbuckle Family Foundation. R.C.F. acknowledges related grant support from R01AR075906 and P30AR079369. P.A.N. acknowledges related grant support from NIH/NIAMS grants R01AR073201, R01AR075906 and P30AR070253, the Rheumatology Research Foundation and the Arbuckle Family Foundation.

Author information

Authors and Affiliations

  1. Division of Immunology, Boston Children’s Hospital, Boston, MA, USA

    Margaret H. Chang & Peter A. Nigrovic

  2. Department of Paediatrics, University of Colorado School of Medicine, Aurora, CO, USA

    Robert C. Fuhlbrigge

  3. Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital, Boston, MA, USA

    Peter A. Nigrovic

Authors
  1. Margaret H. Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert C. Fuhlbrigge
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peter A. Nigrovic
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Peter A. Nigrovic.

Ethics declarations

Competing interests

P.A.N. declares consulting relationships with Alkermes, Apollo, BMS, Exo Therapeutics, Fresh Tracks Therapeutics, Merck, Novartis, Pfizer, Qiagen and Sobi; equity in Edelweiss Immune Inc.; investigator-initiated research grants from BMS and Pfizer; and authorship and editorial income from UpToDate, the American Academy of Paediatrics and Arthritis & Rheumatology. M.H.C. and R.C.F. declare no competing interests.

Peer review

Peer review information

Nature Reviews Rheumatology thanks Femke Van Wijk, Stefano Alivernini and Sytske Anne Bergstra for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Cell spread model

New joints become inflamed when cells originating from an arthritic joint (such as resident memory T cells or fibroblasts) enter the circulation and deposit in previously unaffected joints.

Founder model

New joints become inflamed when pathogenic cells seeded during an index event expand past a threshold that renders the joint symptomatic; joints cross this threshold at different times, depending on local factors that include the size of the initial inoculum.

Irreversible steps

Durable changes that occur in tissues exposed to inflammation; such changes could include, for example, the accumulation of tissue-resident memory T cells, fibroblast priming and changes in synovial tissue macrophage populations.

Joint accumulation model

A conceptual paradigm in which the course of inflammatory arthritis reflects two distinct forces: systemic drivers of arthritis, through which disease begins and extends to new joints, and durable local factors that promote disease recurrence and severity within an individual joint, mediating joint-specific memory.

Joint-specific memory

The phenomenon that inflammatory arthritis is more likely to recur in joints that were previously affected by disease than in comparable joints that were previously spared.

Parabiotic mice

A pair of mice in which the circulatory systems have been surgically connected, typically at the level of the skin, such that cells in the circulation equilibrate between the two animals whereas cells resident in tissue do not.

Priming

The process through which activation of a cell, such as a synovial fibroblast, renders the cell hyper-responsive to subsequent stimuli.

Systemic driver model

New joints become inflamed through the same processes that originally initiated arthritis, for example, the deposition of arthritogenic T cells from the circulation.

Systemic drivers of arthritis

Processes outside of joints that have the potential to ignite synovitis; examples include autoantibodies and arthritogenic effector T cells.

Trained immunity

The acquisition of enhanced responsiveness to previously encountered stimuli, typically through changes in the epigenome, conferring durable immune ‘memory’ in innate immune cells.

Window of opportunity

A period during which intervention can induce a durable change in the natural history of a disease.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chang, M.H., Fuhlbrigge, R.C. & Nigrovic, P.A. Joint-specific memory, resident memory T cells and the rolling window of opportunity in arthritis. Nat Rev Rheumatol 20, 258–271 (2024). https://doi.org/10.1038/s41584-024-01107-7

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41584-024-01107-7

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing