Why remission is not enough: underlying disease mechanisms in RA that prevent cure.
Journal
Nature reviews. Rheumatology
ISSN: 1759-4804
Titre abrégé: Nat Rev Rheumatol
Pays: United States
ID NLM: 101500080
Informations de publication
Date de publication:
03 2021
03 2021
Historique:
accepted:
10
11
2020
pubmed:
12
12
2020
medline:
11
5
2021
entrez:
11
12
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33303993
doi: 10.1038/s41584-020-00543-5
pii: 10.1038/s41584-020-00543-5
doi:
Substances chimiques
Antirheumatic Agents
0
Cytokines
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
135-144Subventions
Organisme : Versus Arthritis
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom
Références
Felson, D. T. Defining remission in rheumatoid arthritis. Ann. Rheum. Dis 71 (Suppl. 2), i86–i88 (2012).
pubmed: 22460146
pmcid: 3648878
McInnes, I. B. & Schett, G. Pathogenetic insights from the treatment of rheumatoid arthritis. Lancet 389, 2328–2337 (2017).
pubmed: 28612747
Aga, A. B. et al. Time trends in disease activity, response and remission rates in rheumatoid arthritis during the past decade: results from the NOR-DMARD study 2000-2010. Ann. Rheum. Dis. 74, 381–388 (2015).
pubmed: 24285493
Fransen, J., Creemers, M. & Van Riel, P. Remission in rheumatoid arthritis: agreement of the disease activity score (DAS28) with the ARA preliminary remission criteria. Rheumatology 43, 1252–1255 (2004).
pubmed: 15238643
Smolen, J. S. et al. A simplified disease activity index for rheumatoid arthritis for use in clinical practice. Rheumatology 42, 244–257 (2003).
pubmed: 12595618
Aletaha, D. et al. Remission and active disease in rheumatoid arthritis: defining criteria for disease activity states. Arthritis Rheum. 52, 2625–2636 (2005).
pubmed: 16142705
Felson, D. T. et al. American College of Rheumatology/European League Against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Ann. Rheum. Dis. 70, 404–413 (2011).
pubmed: 21292833
Hughes, C. D. et al. Intensive therapy and remissions in rheumatoid arthritis: a systematic review. BMC Musculoskelet. Disord. 19, 389 (2018).
pubmed: 30376836
pmcid: 6208111
Bijlsma, J. W. J. et al. Early rheumatoid arthritis treated with tocilizumab, methotrexate, or their combination (U-Act-Early): a multicentre, randomised, double-blind, double-dummy, strategy trial. Lancet 388, 343–355 (2016).
pubmed: 27287832
Schett, G. et al. Tapering biologic and conventional DMARD therapy in rheumatoid arthritis: current evidence and future directions. Ann. Rheum. Dis. 75, 1428–1437 (2016).
pubmed: 27261493
Olsen, C. L. et al. Predictors of fatigue in rheumatoid arthritis patients in remission or in a low disease activity state. Arthritis Care Res. 68, 1043–1048 (2016).
Verstappen, M. DMARD-free remission as novel treatment target in rheumatoid arthritis: a systematic literature review of achievability and sustainability. RMD Open 6, e001220 (2020).
pubmed: 32393523
pmcid: 7299506
Ajeganova, S. & Huizinga, T. Sustained remission in rheumatoid arthritis: latest evidence and clinical considerations. Ther. Adv. Musculoskelet. Dis. 9, 249–262 (2017).
pubmed: 28974987
pmcid: 5613855
Akdemir, G. et al. Clinical and radiological outcomes of 5-year drug-free remission-steered treatment in patients with early arthritis: IMPROVED study. Ann. Rheum. Dis. 77, 111–118 (2018).
pubmed: 28970207
van Gaalen, F. A. et al. Autoantibodies to cyclic citrullinated peptides predict progression to rheumatoid arthritis in patients with undifferentiated arthritis: a prospective cohort study. Arthritis Rheum. 50, 709–715 (2004).
pubmed: 15022309
Sokolove, J. et al. Autoantibody epitope spreading in the pre-clinical phase predicts progression to rheumatoid arthritis. PLoS One 7, e35296 (2012).
pubmed: 22662108
pmcid: 3360701
Simon, D. et al. Micro-structural bone changes are associated with broad-spectrum autoimmunity and predict the onset of rheumatoid arthritis. Arthritis Rheum. https://doi.org/10.1002/art.41229 (2020).
doi: 10.1002/art.41229
Figueiredo, C. P. et al. Anti-modified protein antibody response pattern influences the risk for disease relapse in patients with rheumatoid arthritis tapering disease modifying anti-rheumatic drugs. Ann. Rheum. Dis. 76, 399–407 (2017).
pubmed: 27323772
Stahl, E. A. et al. Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat. Genet. 42, 508–514 (2010).
pubmed: 20453842
pmcid: 4243840
Makrygiannakis, D. et al. Smoking increases peptidylarginine deiminase 2 enzyme expression in human lungs and increases citrullination in BAL cells. Ann. Rheum. Dis. 67, 1488–1492 (2008).
pubmed: 18413445
Van den Broek, M. et al. Discontinuation of infliximab and potential predictors of persistent low disease activity in patients with early rheumatoid arthritis and disease activity score-steered therapy: subanalysis of the BeSt study. Ann. Rheum. Dis. 70, 1389–1394 (2011).
pubmed: 21515916
Tjin, C. C. et al. Synthesis and biological evaluation of an indazole-based selective protein arginine deiminase 4 (PAD4) inhibitor. ACS Med. Chem. Lett. 9, 1013–1018 (2018).
pubmed: 30344909
pmcid: 6187405
Burgoyne, C. H. et al. Abnormal T cell differentiation persists in patients with rheumatoid arthritis in clinical remission and predicts relapse. Ann. Rheum. Dis. 67, 750–757 (2008).
pubmed: 17644540
Lawson, C. A. et al. Early rheumatoid arthritis is associated with a deficit in the CD4
pubmed: 16571607
van Roon, J. A. et al. Numbers of CD25
pubmed: 20693259
Dominguez-Villar, M. & Hafler, D. A. Regulatory T cells in autoimmune disease. Nat. Immunol. 19, 665–673 (2018).
pubmed: 29925983
pmcid: 7882196
Komatsu, N. et al. Pathogenic conversion of Foxp3
pubmed: 24362934
Nguyen, D. X. et al. Regulatory T cells as a biomarker for response to adalimumab in rheumatoid arthritis. J. Allergy Clin. Immunol. 142, 978–980 (2018).
pubmed: 29935955
pmcid: 6127034
Buckner, J. H. Mechanisms of impaired regulation by CD4
pubmed: 21107346
pmcid: 3046807
Van Amelsfort, J. M. R. et al. Proinflammatory mediator-induced reversal of CD4+CD25+regulatory T cell-mediated suppression in rheumatoid arthritis. Arthritis Rheum. 56, 732–742 (2007).
pubmed: 17328044
Flores-Borja, F. et al. Defects in CTLA-4 are associated with abnormal regulatory T cell function in rheumatoid arthritis. Proc. Natl Acad. Sci. USA 105, 19396–19401 (2008).
pubmed: 19036923
Chemin, K., Gerstner, C. & Malmström, V. Effector functions of CD4+T cells at the site of local autoimmune inflammation-lessons from rheumatoid arthritis. Front. Immunol. 10, 353 (2019).
pubmed: 30915067
pmcid: 6422991
Yang, X. Z. et al. Restoring oxidant signaling suppresses proarthritogenic T cell effector functions in rheumatoid arthritis. Sci. Transl Med. 8, 331ra38 (2016).
pubmed: 27009267
pmcid: 5074090
Rosenzwajg, M. et al. Immunological and clinical effects of low-dose interleukin-2 across 11 autoimmune diseases in a single, open clinical trial. Ann. Rheum. Dis. 78, 209–217 (2019).
pubmed: 30472651
Hao, H. et al. Conversion of T follicular helper cells to T follicular regulatory cells through transcriptional regulation in systemic lupus erythematosus. Arthritis Rheumatol. https://doi.org/10.1002/art.41457 (2020).
doi: 10.1002/art.41457
pubmed: 32720470
Crotty, S. T follicular helper cell biology: a decade of discovery and diseases. Immunity 50, 1133–1148 (2019).
Wunderlich, C. et al. Effects of DMARDs on citrullinated peptide autoantibody levels in RA patients — a longitudinal analysis. Semin. Arthritis Rheum. 46, 709–714 (2017).
pubmed: 28109618
Rao, D. A. et al. Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis. Nature 542, 110–114 (2017).
pubmed: 28150777
pmcid: 5349321
Scott, I. C. et al. The protective effect of alcohol on developing rheumatoid arthritis: a systematic review and meta-analysis. Rheumatology 52, 856–867 (2013).
pubmed: 23287363
Azizov, V. et al. Ethanol consumption inhibits the development of autoimmunity by blocking IL-21 secretion in TFH cells. Nat. Commun. 11, 1998 (2020).
pubmed: 32332730
pmcid: 7181688
Iwata, S. et al. Activation of Syk in peripheral blood B cells in patients with rheumatoid arthritis: a potential target for abatacept therapy. Arthritis Rheumatol. 67, 63–73 (2015).
pubmed: 25303149
Bozec, A. et al. Abatacept blocks anti-citrullinated protein antibody and rheumatoid factor mediated cytokine production in human macrophages in IDO-dependent manner. Arthritis Res. Ther. 20, 24 (2018).
pubmed: 29415763
pmcid: 5803926
Jansen, D. et al. Conversion to seronegative status after abatacept treatment in patients with early and poor prognostic rheumatoid arthritis is associated with better radiographic outcomes and sustained remission: post hoc analysis of the AGREE study. RMD Open 4, e000564 (2018).
pubmed: 29657830
pmcid: 5892779
Emery, P. et al. Evaluating drug-free remission with abatacept in early rheumatoid arthritis: results from the phase 3b, multicentre, randomised, active-controlled AVERT study of 24 months, with a 12-month, double-blind treatment period. Ann. Rheum. Dis. 74, 19–26 (2015).
pubmed: 25367713
Gerlag, D. M. et al. Effects of B-cell directed therapy on the preclinical stage of rheumatoid arthritis: the PRAIRI study. Ann. Rheum. Dis. 78, 179–185 (2019).
pubmed: 30504445
Hartkamp, L. M. et al. Btk inhibition suppresses agonist-induced human macrophage activation and inflammatory gene expression in RA synovial tissue explants. Ann. Rheum. Dis. 74, 1603–1611 (2015).
pubmed: 24764451
Clavel, C., Ceccato, L., Anquetil, F., Serre, G. & Sebbag, M. Among human macrophages polarised to different phenotypes, the M-CSF-oriented cells present the highest pro-inflammatory response to the rheumatoid arthritis-specific immune complexes containing ACPA. Ann. Rheum. Dis. 75, 2184–2191 (2016).
pubmed: 27009917
Nimmerjahn, F. & Ravetch, J. V. Fcγ receptors as regulators of immune responses. Nat. Rev. Immunol. 8, 34–47 (2008).
pubmed: 18064051
Pfeifle, R. et al. Regulation of autoantibody activity by the IL-23-T
pubmed: 27820809
Engdahl, C. et al. Estrogen induces St6gal1 expression and increases IgG sialylation in mice and patients with rheumatoid arthritis: a potential explanation for the increased risk of rheumatoid arthritis in postmenopausal women. Arthritis Res. Ther. 20, 84 (2018).
pubmed: 29720252
pmcid: 5932893
De Moel, E. C. et al. Baseline autoantibody profile in rheumatoid arthritis is associated with early treatment response but not long-term outcomes. Arthritis Res. Ther. 20, 33 (2018).
pubmed: 29482627
pmcid: 5828136
Culemann, S. et al. Locally renewing resident synovial macrophages provide a protective barrier for the joint. Nature 572, 670–675 (2019).
pubmed: 31391580
pmcid: 6805223
Filková, M. et al. Association of circulating miR-223 and miR-16 with disease activity in patients with early rheumatoid arthritis. Ann. Rheum. Dis. 73, 1898–1904 (2014).
pubmed: 23897768
Alivernini, S. et al. Distinct synovial tissue macrophage subsets regulate inflammation and remission in rheumatoid arthritis. Nat. Med. 26, 1295–1306 (2020).
pubmed: 32601335
Croft, A. P. et al. Distinct fibroblast subsets drive inflammation and damage in arthritis. Nature 570, 246–251 (2019).
pubmed: 31142839
pmcid: 6690841
Ai, R. et al. Comprehensive epigenetic landscape of rheumatoid arthritis fibroblast-like synoviocytes. Nat. Commun. 9, 1921 (2018).
pubmed: 29765031
pmcid: 5953939
Karouzakis, E. et al. Epigenome analysis reveals TBX5 as a novel transcription factor involved in the activation of rheumatoid arthritis synovial fibroblasts. J. Immunol. 193, 4945–4951 (2014).
pubmed: 25320281
Kurowska-Stolarska, M. et al. MicroRNA-155 as a proinflammatory regulator in clinical and experimental arthritis. Proc. Natl Acad. Sci. USA 108, 11193–11198 (2011).
pubmed: 21690378
Karouzakis, E. et al. Analysis of early changes in DNA methylation in synovial fibroblasts of RA patients before diagnosis. Sci. Rep. 8, 7370 (2018).
pubmed: 29743579
pmcid: 5943364
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).
pubmed: 25808728
pmcid: 4485541
Whitaker, J. W. et al. Integrative omics analysis of rheumatoid arthritis identifies non-obvious therapeutic targets. PLoS One 10, e0124254 (2015).
pubmed: 25901943
pmcid: 4406750
Suraweera, A., O’Byrne, K. J. & Richard, D. J. Combination therapy with histone deacetylase inhibitors (HDACi) for the treatment of cancer: achieving the full therapeutic potential of HDACi. Front. Oncol. 8, 92 (2018).
pubmed: 29651407
pmcid: 5884928
Frank-Bertoncelj, M. et al. Epigenetically-driven anatomical diversity of synovial fibroblasts guides joint-specific fibroblast functions. Nat. Commun. 8, 14852 (2017).
pubmed: 28332497
pmcid: 5376654
Zhang, H. J. et al. LncRNA HOTAIR alleviates rheumatoid arthritis by targeting miR-138 and inactivating NF-κB pathway. Int. Immunopharmacol. 50, 283–290 (2017).
pubmed: 28732288
Hu, X. et al. Silencing of long non-coding RNA HOTTIP reduces inflammation in rheumatoid arthritis by demethylation of SFRP1. Mol. Ther. Nucleic Acids 19, 468–481 (2020).
pubmed: 31902746
Scher, J. U. et al. Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. eLife 2, e01202 (2013).
pubmed: 24192039
pmcid: 3816614
Alpizar-Rodriguez, D. et al. Prevotella copri in individuals at risk for rheumatoid arthritis. Ann. Rheum. Dis. 78, 590–593 (2019).
pubmed: 30760471
Tajik, N. et al. Targeting zonulin and intestinal epithelial barrier function to prevent onset of arthritis. Nat. Commun. 11, 1995 (2020).
pubmed: 32332732
pmcid: 7181728
Edwards, R. R. et al. Enhanced reactivity to pain in patients with rheumatoid arthritis. Arthritis Res. Ther. 11, R61 (2009).
pubmed: 19413909
pmcid: 2714104
Yılmaz, V., Umay, E., Gündoğdu, İ., Karaahmet, Z. Ö. & Öztürk, A. E. Rheumatoid arthritis: are psychological factors effective in disease flare? Eur. J. Rheumatol. 4, 127–132 (2017).
pubmed: 28638686
pmcid: 5473448
Evers, A. W. et al. Does stress affect the joints? Daily stressors stress vulnerability, immune and HPA axis activity, and short-term disease and symptom fluctuations in rheumatoid arthritis. Ann. Rheum. Dis. 73, 1683–1688 (2014).
pubmed: 23838082
Kolmus, K., Tavernier, J. & Gerlo, S. β2-Adrenergic receptors in immunity and inflammation: stressing NF-κB. Brain Behav. Immun. 4, 297–310 (2015).
del Rey, A. et al. Disrupted brain-immune system-joint communication during experimental arthritis. Arthritis Rheum. 58, 3090–3099 (2008).
pubmed: 18821705
Harre, U. et al. Glycosylation of immunoglobulin G determines osteoclast differentiation and bone loss. Nat. Commun. 6, 6651 (2015).
pubmed: 25825024
pmcid: 4389255
Radbruch, A. et al. Competence and competition: the challenge of becoming a long-lived plasma cell. Nat. Rev. Immunol. 6, 741–750 (2006).
pubmed: 16977339
Stanway, J. A. & Isaacs, J. D. Tolerance-inducing medicines in autoimmunity: rheumatology and beyond. Lancet Rheumatol. 9, 565–575 (2020).
Herold, K. C. et al. An anti-CD3 antibody, teplizumab, in relatives at risk for type 1 diabetes. N. Engl. J. Med. 381, 603–613 (2019).
pubmed: 31180194
pmcid: 6776880
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02778906 (2020).
Bio Med Central. ISRCTN Registry https://doi.org/10.1186/ISRCTN46017566 (2020).
Iqbal, K. & Isaacs, J. Potential pharmacologic targets for the prevention of rheumatoid arthritis. Clin. Ther. 41, 1312–1322 (2019).
pubmed: 31196649
Mrsny, R. J. et al. A key claudin extracellular loop domain is critical for epithelial barrier integrity. Am. J. Pathol. 172, 905–915 (2008).
pubmed: 18349130
pmcid: 2276422
Pastori, C. et al. The Bromodomain protein BRD4 controls HOTAIR, a long noncoding RNA essential for glioblastoma proliferation. Proc. Natl Acad. Sci. USA 112, 8326–8331 (2015).
pubmed: 26111795
Cochran, A. G. et al. Bromodomains: a new target class for drug development. Nat. Rev. Drug Discov. 18, 609–628 (2019).
pubmed: 31273347
Lindner, T. et al. Targeting of activated fibroblasts for imaging and therapy. EJNMMI Radiopharm. Chem. 4, 16 (2019).
pubmed: 31659499
pmcid: 6658625
Jia, W. et al. Histone demethylase JMJD3 regulates fibroblast-like synoviocyte-mediated proliferation and joint destruction in rheumatoid arthritis. FASEB J. 32, 4031–4042 (2018).
pubmed: 29481307
Zhou, S. et al. In vivo therapeutic success of microRNA‐155 antagomir in a mouse model of lupus alveolar hemorrhage. Arthritis Rheumatol. 68, 953–964 (2016).
pubmed: 26556607
Häger, J. et al. The role of dietary fiber in rheumatoid arthritis patients: a feasibility study. Nutrients 11, E2392 (2019).
pubmed: 31591345
Bosmann, M. et al. Anti-inflammatory effects of β2 adrenergic receptor agonists in experimental acute lung injury. FASEB J. 26, 2137–2144 (2012).
pubmed: 22318967
pmcid: 3336792
Hadi, T. et al. Beta3 adrenergic receptor stimulation in human macrophages inhibits NADPHoxidase activity and induces catalase expression via PPARγ activation. BBA Mol. Cell Res. 1864, 1769–1784 (2017).
Koopman, F. A. et al. Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. Proc. Natl Acad. Sci. USA 113, 8284–8289 (2016).
pubmed: 27382171
Van der Woude, D., Young, A. & Jayakumar, K. Prevalence of and predictive factors for sustained disease-modifying antirheumatic drug-free remission in rheumatoid arthritis: results from two large early arthritis cohorts. Arthritis Rheum. 60, 2262–2271 (2009).
pubmed: 19644846
Baker, K. F. et al. Predicting drug-free remission in rheumatoid arthritis: a prospective interventional cohort study. J. Autoimmun. 105, 102298 (2019).
pubmed: 31280933
pmcid: 6891251
Jones, G. W. et al. Interleukin-27 inhibits ectopic lymphoid-like structure development in early inflammatory arthritis. J. Exp. Med. 212, 1793–1802 (2015).
pubmed: 26417004
pmcid: 4612100
Teitsma, X. M. et al. Baseline metabolic profiles of early rheumatoid arthritis patients achieving sustained drug-free remission after initiating treat-to-target tocilizumab, methotrexate, or the combination: insights from systems biology. Arthritis Res. Ther. 20, 230 (2018).
pubmed: 30322408
pmcid: 6235217