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  • Review Article
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Emerging cell and cytokine targets in rheumatoid arthritis

Nature Reviews Rheumatology volume 10, pages 77–88 (2014)Cite this article

Subjects

Key Points

  • Rheumatoid arthritis (RA) is caused by an intricate interplay between T cells, macrophages and B cells; these cells or their products are, therefore, important targets of therapy

  • T-cell directed approaches target co-stimulation as well as molecules involved in T-cell activation and regulation (such as CD4 antigen)

  • Novel therapeutic approaches might include harnessing the action of regulatory T cells

  • Compounds targeting GM-CSF and IL-17 are already in an advanced stage of clinical development in RA

  • Cytokines such as IL-20 and IL-21 contribute to the pathogenesis of RA and have promise as potential targets for treatment

  • B-cell directed therapies comprise anti-CD20 therapies, CD19-directed and CD52-directed depletion strategies; alternative approaches include CD22-mediated ligation of inhibitory B-cell receptor and modification of adhesion molecule expression by B cells

Abstract

Despite major progress in the treatment of rheumatoid arthritis (RA), strong unmet medical need remains, as only a minor proportion of patients reach sustained clinical remission. New approaches are therefore necessary, and include manipulation of regulatory T cells, which might be able to restore the disturbed immune system and could even lead to a cure if this restored regulation were to prove sustainable. Logistical and conceptual problems, however, beset this attractive therapeutic approach, including difficulties with ex vivo expansion of cells, specificity of targeting and the optimal time point of administration. Therefore, alternative avenues are being investigated, such as targeting B-cell effector functions and newly identified proinflammatory cytokines. On the basis of success with B-cell depleting therapy using anti-CD20 agents, further treatment modalities are now exploring direct or indirect interference in B-cell-mediated immunity with the use of agents directed against other B-cell surface molecules. Novel approaches target intracellular B-cell signalling and regulatory B cells. New cytokine-directed therapies target important proinflammatory mediators such as GM-CSF, new members of the IL-1 family, IL-6 and its receptor, IL-17, IL-20, IL-21, IL-23 as well as synovium-specific targets. This article reviews these emerging cell and cytokine targets with special focus on biologic agents, some of which might reach the clinic soon whereas others will require considerable time in development. Nevertheless, these exciting new approaches will considerably enhance our repertoire in the battle against this potentially devastating disease.

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Figure 1: Stepwise development of arthritis in RA.
Figure 2: Potential interventions using TREG cells in RA.
Figure 3: Direct and indirect B-cell targeting.

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References

  1. Burmester, G. R., Pratt, A. G., Scherer, H. U. & van Laar, J. M. in EULAR Textbook on Rheumatic Diseases 1st edn, Ch. 9. Rheumatoid arthritis: pathogenesis and clinical features (ed. Bijlsma, J. W.), 206–231 (BMJ Group, London, 2012).

    Google Scholar 

  2. Cope, A. P, Schulze-Koops, H. & Aringer, M. The central role of T cells in rheumatoid arthritis. Clin. Exp. Rheumatol. 25 (Suppl. 46), S4–S11 (2007).

    CAS  PubMed  Google Scholar 

  3. Komatsu, N. & Takayanagi, H. Autoimmune arthritis: the interface between the immune system and joints. Adv. Immunol. 115, 45–71 (2012).

    Article  CAS  PubMed  Google Scholar 

  4. Ornstein, M. H., Kerr, L. D. & Spiera H. A reexamination of the relationship between active rheumatoid arthritis and the acquired immunodeficiency syndrome. Arthritis Rheum. 38, 1701–1706 (1995).

    Article  CAS  PubMed  Google Scholar 

  5. Fiocco, U. et al. Co-stimulatory modulation in rheumatoid arthritis: the role of (CTLA4-Ig) abatacept. Autoimmun. Rev. 8, 76–82 (2008).

    Article  CAS  PubMed  Google Scholar 

  6. Martinez-Gamboa, L., Brezinschek, H. P., Burmester, G. R. & Dörner, T. Immunopathologic role of B lymphocytes in rheumatoid arthritis: rationale of B cell-directed therapy. Autoimmun. Rev. 5, 437–442 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. Burmester, G. R. et al. The tissue architecture of synovial membranes in inflammatory and non-inflammatory joint diseases. I. The localization of the major synovial cell populations as detected by monoclonal reagents directed towards Ia and monocyte-macrophage antigens. Rheumatol. Int. 3, 173–181 (1983).

    Article  CAS  PubMed  Google Scholar 

  8. McInnes, I. B. & Schett, G. The pathogenesis of rheumatoid arthritis. N. Engl. J. Med. 365, 2205–2219 (2011).

    Article  CAS  PubMed  Google Scholar 

  9. Redlich, K. & Smolen, J. S. Inflammatory bone loss: pathogenesis and therapeutic intervention. Nat. Rev. Drug Disc. 11, 234–250 (2012).

    Article  CAS  Google Scholar 

  10. Smolian, H. et al. Secretion of gelatinases and activation of gelatinase A (MMP-2) by human rheumatoid synovial fibroblasts. Biol. Chem. 382, 1491–1499 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Neumann, E., Lefèvre, S., Zimmermann, B., Gay, S. & Müller-Ladner, U. Rheumatoid arthritis progression mediated by activated synovial fibroblasts. Trends Mol. Med. 16, 458–468 (2010).

    Article  CAS  PubMed  Google Scholar 

  12. McInnes, I. B. & Schett, G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat. Rev. Immunol. 7, 429–442 (2007).

    Article  CAS  PubMed  Google Scholar 

  13. Smolen, J. S., Aletaha, D. & Redlich, K. The pathogenesis of rheumatoid arthritis: new insights from old clinical data? Nat. Rev. Rheumatol. 8, 235–243 (2012).

    Article  CAS  PubMed  Google Scholar 

  14. Singh, J. A. et al. A network meta-analysis of randomized controlled trials of biologics for rheumatoid arthritis: a Cochrane overview. CMAJ 181, 787–796 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Salliot, C. et al. Indirect comparisons of the efficacy of biological antirheumatic agents in rheumatoid arthritis in patients with an inadequate response to conventional disease-modifying antirheumatic drugs or to an anti-tumour necrosis factor agent: a meta-analysis. Ann. Rheum. Dis. 70, 266–271 (2011).

    Article  CAS  PubMed  Google Scholar 

  16. Simard, J. F. et al. Ten years with biologics: to whom do data on effectiveness and safety apply? Rheumatology (Oxford) 50, 204–213 (2011).

    Article  Google Scholar 

  17. O'Shea, J. J., Holland, S. M. & Staudt, L. M. JAKs and STATs in immunity, immunodeficiency, and cancer. N. Engl. J. Med. 368, 161–170 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Feist, E. & Burmester, G. R. Small molecules targeting JAKs--a new approach in the treatment of rheumatoid arthritis. Rheumatology (Oxford) 52, 1352–1357 (2013).

    Article  CAS  Google Scholar 

  19. Mauri, C. & Carter, N. Is there a feudal hierarchy amongst regulatory immune cells? More than just TREGs. Arthritis Res. Ther. 11, 237 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Buckner, J. H. Mechanisms of impaired regulation by CD4+CD25+FOXP3+ regulatory T cells in human autoimmune diseases. Nat. Rev. Immunol. 10, 849–859 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ochs, H. D., Gambineri, E. & Torgerson, T. R. IPEX, FOXP3 and regulatory T-cells: a model for autoimmunity. Immunol. Res. 38, 112–121 (2007).

    Article  CAS  PubMed  Google Scholar 

  22. Morgan, M. E. et al. CD25+ cell depletion hastens the onset of severe disease in collagen-induced arthritis. Arthritis Rheum. 48, 1452–1460 (2003).

    Article  PubMed  Google Scholar 

  23. Frey, O. et al. The role of regulatory T cells in antigen-induced arthritis: aggravation of arthritis after depletion and amelioration after transfer of CD4+CD25+ T cells. Arthritis Res. Ther. 7, R291–R301 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Kong, N. et al. Induced T regulatory cells suppress osteoclastogenesis and bone erosion in collagen-induced arthritis better than natural T regulatory cells. Ann. Rheum. Dis. 71, 1567–1572 (2012).

    Article  PubMed  Google Scholar 

  25. Alexander, T. et al. FOXP3+ Helios+ regulatory T cells are expanded in active systemic lupus erythematosus. Ann. Rheum. Dis. 72, 1549–1558 (2013).

    Article  CAS  PubMed  Google Scholar 

  26. Zhou, X., Bailey-Bucktrout, S., Jeker, L. T. & Bluestone, J. A. Plasticity of CD4+ FOXP3+ T cells. Curr. Opin. Immunol. 21, 281–285 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Esensten, J. H., Wofsy, D. & Bluestone, J. A. Regulatory T cells as therapeutic targets in rheumatoid arthritis. Nat. Rev. Rheumatol. 5, 560–565 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Cao, D. et al. Isolation and functional characterization of regulatory CD25brightCD4+ T cells from the target organ of patients with rheumatoid arthritis. Eur. J. Immunol. 33, 215–223 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. Möttönen, M. et al. CD4+ CD25+ T cells with the phenotypic and functional characteristics of regulatory T cells are enriched in the synovial fluid of patients with rheumatoid arthritis. Clin. Exp. Immunol. 140, 360–367 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Lawson, C. A. et al. Early rheumatoid arthritis is associated with a deficit in the CD4+CD25high regulatory T cell population in peripheral blood. Rheumatology (Oxford) 45, 1210–1217 (2006).

    Article  CAS  Google Scholar 

  31. Han, G. M. O'Neil-Andersen, N. J., Zurier, R. B. & Lawrence, D. A. CD4+CD25high T cell numbers are enriched in the peripheral blood of patients with rheumatoid arthritis. Cell. Immunol. 253, 92–101 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ehrenstein, M. R. et al. Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFα therapy. J. Exp. Med. 200, 277–285 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Klareskog, L., Rönnelid, J., Lundberg, K., Padyukov, L. & Alfredsson, L. Immunity to citrullinated proteins in rheumatoid arthritis. Annu. Rev. Immunol. 26, 651–675 (2008).

    Article  CAS  PubMed  Google Scholar 

  34. Skriner, K. et al. Anti-A2/RA33 autoantibodies are directed to the RNA binding region of the A2 protein of the heterogeneous nuclear ribonucleoprotein complex. Differential epitope recognition in rheumatoid arthritis, systemic lupus erythematosus, and mixed connective tissue disease. J. Clin. Invest. 100, 127–135 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wright, G. P., Stauss, H. J. & Ehrenstein, M. R. Therapeutic potential of TREGs to treat rheumatoid arthritis. Semin. Immunol. 23, 195–201 (2011).

    Article  CAS  PubMed  Google Scholar 

  36. Nielen, M. M. et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum. 50, 380–386 (2004).

    Article  PubMed  Google Scholar 

  37. Koreth, J. et al. Interleukin-2 and regulatory T cells in graft-versus-host disease. N. Engl. J. Med. 365, 2055–2066 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Saadoun, D. et al. Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis. N. Engl. J. Med. 365, 2067–2077 (2011).

    Article  CAS  PubMed  Google Scholar 

  39. Czeloth, N. et al. Selective activation of naturally occurring regulatory T cells (TREGs) by the monoclonal antibody BT-061 as a novel therapeutic opportunity: pre-clinical and early clinical results [abstract OP0138]. Ann. Rheum. Dis. 69 (Suppl. 3), 99 (2010).

    Google Scholar 

  40. Uherek, C. et al. The novel regulatory T cell (TREG) agonistic monoclonal antibody (mAb) tregalizumab (BT-061): further characterization of mechanism of action, epitope binding, and clinical effects in patients with rheumatoid arthritis. www.biotest.de[online] (2011).

  41. US National Library of Medicine. ClinicalTrials.gov [online], (2011).

  42. Cousens, L. P. et al. Tregitope update: Mechanism of action parallels IVIg. Autoimmun. Rev. 12, 436–443 (2013).

    Article  CAS  PubMed  Google Scholar 

  43. Dörner, T., Kinnman, N. & Tak, P. P. Targeting B cells in immune-mediated inflammatory disease: a comprehensive review of mechanisms of action and identification of biomarkers. Pharmacol. Ther. 125, 464–475 (2010).

    Article  PubMed  CAS  Google Scholar 

  44. Dörner, T., Radbruch, A. & Burmester, G. R. B-cell-directed therapies for autoimmune disease. Nat. Rev. Rheumatol. 5, 433–441 (2009).

    Article  PubMed  CAS  Google Scholar 

  45. Klareskog, L., Widhe, M., Hermansson, M. & Rönnelid, J. Antibodies to citrullinated proteins in arthritis: pathology and promise. Curr. Opin. Rheumatol. 20, 300–305 (2008).

    Article  CAS  PubMed  Google Scholar 

  46. Amara, K. et al. Monoclonal IgG antibodies generated from joint-derived B cells of RA patients have a strong bias toward citrullinated autoantigen recognition. J. Exp. Med. 210, 445–455 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Edwards, J. C. et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N. Engl. J. Med. 350, 2572–2581 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Emery, P. et al. The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial. Arthritis Rheum. 54, 1390–1400 (2006).

    Article  CAS  PubMed  Google Scholar 

  49. Cohen, S. B. et al. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum. 54, 2793–2806 (2006).

    Article  CAS  PubMed  Google Scholar 

  50. Jones, R. B. et al. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N. Engl. J. Med. 363, 211–220 (2010).

    Article  CAS  PubMed  Google Scholar 

  51. Glennie, M. J., French, R. R., Cragg, M. S. & Taylor, R. P. Mechanisms of killing by anti-CD20 monoclonal antibodies. Mol. Immunol. 44, 3823–3837 (2007).

    Article  CAS  PubMed  Google Scholar 

  52. Alduaij, W. et al. Novel type II anti-CD20 monoclonal antibody (GA101) evokes homotypic adhesion and actin-dependent, lysosome-mediated cell death in B-cell malignancies. Blood 117, 4519–4529 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Cragg, M. S. & Glennie, M. J. Antibody specificity controls in vivo effector mechanisms of anti-CD20 reagents. Blood 103, 2738–2743 (2004).

    Article  CAS  PubMed  Google Scholar 

  54. Mei, H. E., Schmidt, S. & Dörner T. Rationale of anti-CD19 immunotherapy: an option to target autoreactive plasma cells in autoimmunity. Arthritis Res. Ther. 14 (Suppl. 5), S1 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Roschke, V. et al. BLyS and APRIL form biologically active heterotrimers that are expressed in patients with systemic immune-based rheumatic diseases. J. Immunol. 169, 4314–4321 (2002).

    Article  CAS  PubMed  Google Scholar 

  56. Stashenko, P., Nadler, L. M., Hardy, R. & Schlossman, S. F. Characterization of a human B lymphocyte-specific antigen. J. Immunol. 125, 1678–1685 (1980).

    CAS  PubMed  Google Scholar 

  57. Stashenko, P., Nadler, L. M., Hardy, R. & Schlossman, S. F. Expression of cell surface markers after human B lymphocyte activation. Proc. Natl Acad. Sci. USA 78, 3848–3852 (1981).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Horton, H. M. et al. Potent in vitro and in vivo activity of an Fc-engineered anti-CD19 monoclonal antibody against lymphoma and leukemia. Cancer Res. 68, 8049–8057 (2008).

    Article  CAS  PubMed  Google Scholar 

  59. Bargou, R. et al. Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. Science 321, 974–977 (2008).

    Article  CAS  PubMed  Google Scholar 

  60. Sato, S., Ono, N., Steeber, D. A., Pisetsky, D. S. & Tedder, T. F. CD19 regulates B lymphocyte signaling thresholds critical for the development of B-1 lineage cells and autoimmunity. J. Immunol. 157, 4371–4378 (1996).

    CAS  PubMed  Google Scholar 

  61. Daridon, C. et al. Epratuzumab targeting of CD22 affects adhesion molecule expression and migration of B-cells in systemic lupus erythematosus. Arthritis Res. Ther. 12, R204 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Tedder, T. F., Poe, J. C. & Haas, K. M. CD22: a multifunctional receptor that regulates B lymphocyte survival and signal transduction. Adv. Immunol. 88, 1–50 (2005).

    Article  CAS  PubMed  Google Scholar 

  63. Jacobi, A. M. et al. Differential effects of epratuzumab on peripheral blood B cells of patients with systemic lupus erythematosus versus normal controls. Ann. Rheum. Dis. 67, 450–457 (2008).

    Article  CAS  PubMed  Google Scholar 

  64. Sieger, N. et al. CD22 ligation inhibits downstream B-cell receptor signaling and Ca2+ flux upon activation. Arthritis Rheum. 65, 770–779 (2013).

    Article  CAS  PubMed  Google Scholar 

  65. Dörner, T. & Burmester, G. R. The role of B cells in rheumatoid arthritis: mechanisms and therapeutic targets. Curr. Opin. Rheumatol. 15, 246–252 (2003).

    Article  PubMed  Google Scholar 

  66. Buch, M. H. et al. Updated consensus statement on the use of rituximab in patients with rheumatoid arthritis. Ann. Rheum. Dis. 70, 909–920 (2011).

    Article  CAS  PubMed  Google Scholar 

  67. Stohl, W. et al. Safety and efficacy of ocrelizumab in combination with methotrexate in MTX-naive subjects with rheumatoid arthritis: the phase III FILM trial. Ann. Rheum. Dis. 71, 1289–1296 (2012).

    Article  CAS  PubMed  Google Scholar 

  68. Tak, P. P. et al. Safety and efficacy of ocrelizumab in patients with rheumatoid arthritis and an inadequate response to at least one tumor necrosis factor inhibitor: results of a forty-eight-week randomized, double-blind, placebo-controlled, parallel-group phase III trial. Arthritis Rheum. 64, 360–370 (2012).

    Article  CAS  PubMed  Google Scholar 

  69. Østergaard, M. et al. Ofatumumab, a human anti-CD20 monoclonal antibody, for treatment of rheumatoid arthritis with an inadequate response to one or more disease-modifying antirheumatic drugs: results of a randomized, double-blind, placebo-controlled, phase I/II study. Arthritis Rheum. 62, 2227–2238 (2010).

    Article  PubMed  CAS  Google Scholar 

  70. Taylor, P. C. et al. Ofatumumab, a fully human anti-CD20 monoclonal antibody, in biological-naive, rheumatoid arthritis patients with an inadequate response to methotrexate: a randomised, double-blind, placebo-controlled clinical trial. Ann. Rheum. Dis. 70, 2119–2125 (2011).

    Article  CAS  PubMed  Google Scholar 

  71. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  72. Isaacs, J. D. et al. CAMPATH-1H in rheumatoid arthritis--an intravenous dose-ranging study. Br. J. Rheumatol. 35, 231–240 (1996).

    Article  CAS  PubMed  Google Scholar 

  73. Lorenzi, A. R. et al. Morbidity and mortality in rheumatoid arthritis patients with prolonged therapy-induced lymphopenia: twelve-year outcomes. Arthritis Rheum. 58, 370–375 (2008).

    Article  PubMed  Google Scholar 

  74. Brown, J. & Coles, A. J. Alemtuzumab: evidence for its potential in relapsing-remitting multiple sclerosis. Drug Des. Devel. Ther. 7, 131–118 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Groom, J. et al. Association of BAFF/BLyS overexpression and altered B cell differentiation with Sjögren's syndrome. J. Clin. Invest. 109, 59–68 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Ohata, J. et al. Fibroblast-like synoviocytes of mesenchymal origin express functional B cell-activating factor of the TNF family in response to proinflammatory cytokines. J. Immunol. 174, 864–870 (2005).

    Article  CAS  PubMed  Google Scholar 

  77. Gross, J. A. et al. TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease. Nature 404, 995–999 (2000).

    Article  CAS  PubMed  Google Scholar 

  78. Bajpai, M., Chopra, P., Dastidar, S. G. & Ray, A. Spleen tyrosine kinase: a novel target for therapeutic intervention of rheumatoid arthritis. Expert Opin. Investig. Drugs. 17, 641–659 (2008).

    Article  CAS  PubMed  Google Scholar 

  79. Lindstrom, T. M. & Robinson, W. H. A multitude of kinases—which are the best targets in treating rheumatoid arthritis? Rheum. Dis. Clin. North Am. 36, 367–383 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  80. Mauri, C. & Blair, P. A. Regulatory B cells in autoimmunity: developments and controversies. Nat. Rev. Rheumatol. 6, 636–643 (2010).

    Article  CAS  PubMed  Google Scholar 

  81. Iwata, Y. Characterization of a rare IL-10-competent B-cell subset in humans that parallels mouse regulatory B10 cells. Blood 117, 530–541 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Flores-Borja, F. et al. CD19+CD24hiCD38hi B cells maintain regulatory T cells while limiting TH1 and TH17 differentiation. Sci. Transl. Med. 5, 173ra23 (2013).

    Article  PubMed  CAS  Google Scholar 

  83. Hamilton, J. A. Colony-stimulating factors in inflammation and autoimmunity. Nat. Rev. Immunol. 8, 533–544 (2008).

    Article  CAS  PubMed  Google Scholar 

  84. Berenbaum, F., Rajzbaum, G., Amor, B. & Toubert, A. Evidence for GM-CSF receptor expression in synovial tissue. An analysis by semi-quantitative polymerase chain reaction on rheumatoid arthritis and osteoarthritis synovial biopsies. Eur. Cytokine Netw. 5, 43–46 (1994).

    CAS  PubMed  Google Scholar 

  85. Wang, T., Lazar, C. A., Fishbein, M. C. & Lynch, J. P. 3rd. Pulmonary alveolar proteinosis. Semin. Respir. Crit. Care Med. 33, 498–508 (2012).

    Article  PubMed  Google Scholar 

  86. Khan, A. & Agarwal, R. Pulmonary alveolar proteinosis. Respir. Care 56, 1016–1028 (2011).

    Article  PubMed  Google Scholar 

  87. Hansen, G. et al. The structure of the GM-CSF receptor complex reveals a distinct mode of cytokine receptor activation. Cell 134, 496–507 (2008).

    Article  CAS  PubMed  Google Scholar 

  88. Burmester, G. R. et al. Mavrilimumab, a human monoclonal antibody targeting GM-CSF receptor-α, in subjects with rheumatoid arthritis: a randomised, double-blind, placebo-controlled, phase I, first-in-human study. Ann. Rheum. Dis. 70, 1542–1549 (2011).

    Article  CAS  PubMed  Google Scholar 

  89. Burmester, G. R. et al. Efficacy and safety of mavrilimumab in subjects with rheumatoid arthritis. Ann. Rheum. Dis. 72, 1445–1452 (2013).

    Article  CAS  PubMed  Google Scholar 

  90. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  91. Gaffen, S. L. An overview of IL-17 function and signaling. Cytokine 43, 402–407 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Miossec, P., Korn, T. & Kuchroo, V. K. Interleukin-17 and type 17 helper T cells. N. Engl. J. Med. 361, 888–898 (2009).

    Article  CAS  PubMed  Google Scholar 

  93. Yang, J. et al. TH17 and natural TREG cell population dynamics in systemic lupus erythematosus. Arthritis Rheum. 60, 1472–1483 (2009).

    Article  PubMed  Google Scholar 

  94. Kwan, B. C. et al. The gene expression of type 17 T-helper cell-related cytokines in the urinary sediment of patients with systemic lupus erythematosus. Rheumatology (Oxford) 48, 1491–1497 (2009).

    Article  CAS  Google Scholar 

  95. Wang, Y. et al. Laser microdissection-based analysis of cytokine balance in the kidneys of patients with lupus nephritis. Clin. Exp. Immunol. 159, 1–10 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Nistala, K. et al. TH17 plasticity in human autoimmune arthritis is driven by the inflammatory environment. Proc. Natl Acad. Sci. USA 107, 14751–14756 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Redlich, K. & Smolen, J. S. Inflammatory bone loss: pathogenesis and therapeutic intervention. Nat. Rev. Drug Discov. 11, 234–250 (2012).

    Article  CAS  PubMed  Google Scholar 

  98. Hueber, W. et al. Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Sci. Transl. Med. 2, 52ra72 (2010).

    Article  PubMed  CAS  Google Scholar 

  99. Genovese, M. C. et al. Efficacy and safety of secukinumab in patients with rheumatoid arthritis: a phase II, dose-finding, double-blind, randomised, placebo controlled study. Ann. Rheum. Dis. 72, 863–869 (2013).

    Article  CAS  PubMed  Google Scholar 

  100. Rich, P. et al. Secukinumab induction and maintenance therapy in moderate-to-severe plaque psoriasis: a randomized, double-blind, placebo-controlled, phase II regimen-finding study. Br. J. Dermatol. 168, 402–411 (2013).

    Article  CAS  PubMed  Google Scholar 

  101. Hueber, W. et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut 61, 1693–1700 (2012).

    Article  CAS  PubMed  Google Scholar 

  102. Leonardi, C. et al. Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. N. Engl. J. Med. 366, 1190–1199 (2012).

    Article  CAS  PubMed  Google Scholar 

  103. Genovese, M. C. et al. LY2439821, a humanized anti-interleukin-17 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: a phase I randomized, double-blind, placebo-controlled, proof-of-concept study. Arthritis Rheum. 62, 929–939 (2010).

    Article  CAS  PubMed  Google Scholar 

  104. Genovese, M. et al. A phase 2 study of multiple subcutaneous doses of LY2439821, an anti-IL-17 monoclonal antibody, in patients with rheumatoid arthritis in two populations: naïve to biologic therapy or inadequate responders to tumor necrosis factor α inhibitors [abstract]. Arthritis Rheum. 63 (Suppl. 10) 2591 (2011).

    Google Scholar 

  105. Hsu, Y. H. et al. Function of interleukin-20 as a proinflammatory molecule in rheumatoid and experimental arthritis. Arthritis Rheum. 54, 2722–2733 (2006).

    Article  CAS  PubMed  Google Scholar 

  106. Kragstrup, T. W. et al. The expression of IL-20 and IL-24 and their shared receptors are increased in rheumatoid arthritis and spondyloarthropathy. Cytokine 41, 16–23 (2008).

    Article  CAS  PubMed  Google Scholar 

  107. Hsu, Y. H. Anti-IL-20 monoclonal antibody inhibits the differentiation of osteoclasts and protects against osteoporotic bone loss. J. Exp. Med. 208, 1849–1861 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Hsu, Y. H. et al. Anti-IL-20 monoclonal antibody inhibits the differentiation of osteoclasts and protects against osteoporotic bone loss. J. Exp. Med. 208, 1849–1861 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Al Kotbi, N., Jensen, L. & Graff, L. B. NNC0109–0012 (anti-IL-20 mAb), well tolerated in healthy subjects and patients with rheumatoid arthritis [abstract FRI0196]. Ann. Rheum. Dis. 71 (Suppl. 3), 379 (2012).

    Google Scholar 

  110. Leszczynski, P., Eshof, M. K., Stegmann, H. V. B., Hundahl Møller, N. P. & Graff, L. B. NNC0109–0012 (anti-IL-20 mAb), well tolerated in patients with rheumatoid arthritis [abstract FRI0197]. Ann. Rheum. Dis. 71 (Suppl. 3), 379 (2012).

    Google Scholar 

  111. Šenolt, L., Göthberg, M., Valencia, X. & Dokoupilová, E. Efficacy and safety of NNC0109–0012 (anti-IL-20 mAb) in patients with rheumatoid arthritis: results from a phase 2a trial [abstract LB0004]. Ann. Rheum. Dis. 71 (Suppl. 3), 152 (2012).

    Google Scholar 

  112. Kwok, S. K. et al. Interleukin-21 promotes osteoclastogenesis in humans with rheumatoid arthritis and in mice with collagen-induced arthritis. Arthritis Rheum. 64, 740–751 (2012).

    Article  CAS  PubMed  Google Scholar 

  113. Rasmussen, T. K. et al. Increased interleukin 21 (IL-21) and IL-23 are associated with increased disease activity and with radiographic status in patients with early rheumatoid arthritis. J. Rheumatol. 37, 2014–2020 (2010).

    Article  CAS  PubMed  Google Scholar 

  114. Raveney, B. J., Oki, S. & Yamamura, T. Nuclear receptor NR4A2 orchestrates TH17 cell-mediated autoimmune inflammation via IL-21 signalling. PLoS ONE 8, e56595 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Niu, X. et al. IL-21 regulates TH17 cells in rheumatoid arthritis. Hum. Immunol. 71, 334–341 (2010).

    Article  CAS  PubMed  Google Scholar 

  116. Gottenberg, J. E. et al. Serum IL-6 and IL-21 are associated with markers of B cell activation and structural progression in early rheumatoid arthritis: results from the ESPOIR cohort. Ann. Rheum. Dis. 71, 1243–1248 (2012).

    Article  CAS  PubMed  Google Scholar 

  117. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  118. Tak, P. P. et al. Chemokine receptor CCR1 antagonist CCX354-C treatment for rheumatoid arthritis: CARAT-2, a randomised, placebo controlled clinical trial. Ann. Rheum. Dis. 72, 337–344 (2013).

    Article  CAS  PubMed  Google Scholar 

  119. Filková, M., Jüngel, A., Gay, R. E. & Gay, S. MicroRNAs in rheumatoid arthritis: potential role in diagnosis and therapy. BioDrugs 26, 131–141 (2012).

    Article  PubMed  Google Scholar 

  120. Gregersen, J. W. & Jayne, D. R. B-cell depletion in the treatment of lupus nephritis Nat. Rev. Nephrol. 8, 505–514 (2012).

    Article  CAS  PubMed  Google Scholar 

  121. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  122. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  123. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  124. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  125. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  126. Wallace, D.J. et al. Efficacy and safety of epratuzumab in patients with moderate/severe active systemic lupus erythematosus: results from EMBLEM, a phase IIb, randomised, double-blind, placebo-controlled, multicentre study. Ann. Rheum. Dis. 10.1136/annrheumdis-2012-202760.

  127. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  128. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  129. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  130. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  131. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  132. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  133. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  134. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

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Authors and Affiliations

  1. Department of Rheumatology and Clinical Immunology, Charité–Universitätsmedizin Berlin, Charitéplatz 1, Berlin, 10117, Germany

    Gerd R. Burmester, Eugen Feist & Thomas Dörner

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  1. Gerd R. Burmester
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  2. Eugen Feist
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All author contributed substantially to each stage of the preparation of this manuscript for submission.

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Correspondence to Gerd R. Burmester.

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Competing interests

G. R. Burmester declares that he has received speakers' honoraria and has acted as a consultant for AbbVie, BMS, MedImmune, MSD, Pfizer, Roche/Chugai and UCB. E. Feist declares that he has received speakers' honoraria and has acted as a consultant for BMS, Pfizer, Novartis and Roche/Chugai. T. Dörner declares that he has received speakers' honoraria and has acted as a consultant for Elli Lilly, NovoNordisk, Roche/Chugai, Takeda and UCB, and has received research/grant support from Roche/Chugai, UCB, Takeda, Janssen/J&J and Sanofi.

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Burmester, G., Feist, E. & Dörner, T. Emerging cell and cytokine targets in rheumatoid arthritis. Nat Rev Rheumatol 10, 77–88 (2014). https://doi.org/10.1038/nrrheum.2013.168

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