B cell therapy in ANCA-associated vasculitis: current and emerging treatment options

A Publisher Correction to this article was published on 02 November 2018

This article has been updated


Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is an organ-threatening and life-threatening multi-system autoimmune disease in which B cell-derived ANCAs cause neutrophil activation and endothelial damage, strongly implicating these autoantibodies in the pathogenesis of AAV. B cell depletion with rituximab combined with glucocorticoids is associated with a reduction in ANCA concentrations and with clinical remission in the majority of patients with AAV. However, the safety profile of rituximab is no better than that of conventional therapy with cyclophosphamide, and long-term glucocorticoid treatment is needed to achieve and maintain disease-free remission. A need for new therapies exists to reduce the time to remission, to spare the use of glucocorticoids and to promote long-lasting remission without the risk of relapse. Over the past 20 years, there has been great interest in therapeutically targeting B cell cytokines, such as B cell-activating factor (BAFF), in many autoimmune disease settings. Dual B cell-targeted immunotherapy that combines B cell depletion and BAFF blockade could potentially be more efficacious than targeting either mechanism alone. In this Review, the theoretical background for use of this combination approach in AAV is presented and discussed.

Key points

  • B cell depletion therapy with rituximab is an effective alternative to cyclophosphamide for the induction of remission in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV).

  • The safety profile of rituximab is not better than that of conventional therapy, suggesting that new therapies are needed to treat patients with AAV.

  • B cell-activating factor (BAFF), an essential cytokine in B cell survival and development, is associated with autoimmune disease, being present at high concentrations in patients with AAV.

  • Autoreactive B cells can be rescued from deletion in the presence of high concentrations of BAFF.

  • BAFF antagonism with belimumab is efficacious in patients with systemic lupus erythematosus and is undergoing evaluation in several other autoimmune diseases, including AAV.

  • Combination therapy with rituximab and belimumab is an attractive therapeutic strategy, as additional BAFF antagonism might enable effective early B cell depletion and reduce the re-emergence of autoreactive B cells.

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Fig. 1: Methods of therapeutically targeting B cells.
Fig. 2: Stages of B cell development and expression of cell surface receptors.
Fig. 3: BAFF in the production of ANCAs.

Change history

  • 02 November 2018

    In the section ‘Combining B cell-targeted therapies’ in the originally published version of this article, the 24-week interim analysis for the CALIBRATE study was incorrectly given as the 2- to 4-week interim analysis. This error has now been corrected in the HTML and PDF versions of the manuscript.


  1. 1.

    Jennette, J. C. et al. 2012 revised international Chapel Hill consensus conference nomenclature of vasculitides. Arthritis Rheum. 65, 1–11 (2013).

  2. 2.

    Christiaan Hagen, E. et al. Diagnostic value of standardized assays for anti-neutrophil cytoplasmic antibodies in idiopathic systemic vasculitis for the EC/BCR project for ANCA assay standardisation. Kidney Int. 53, 743–753 (1998).

    Google Scholar 

  3. 3.

    Sablé-Fourtassou, R. et al. Antineutrophil cytoplasmic antibodies and the Churg–Strauss syndrome. Ann. Intern. Med. 143, 632–638 (2005).

    PubMed  Google Scholar 

  4. 4.

    Jennette, J. C. & Falk, R. J. Pathogenesis of antineutrophil cytoplasmic autoantibody-mediated disease. Nat. Rev. Rheumatol. 10, 463–473 (2014).

    CAS  PubMed  Google Scholar 

  5. 5.

    Voswinkel, J. et al. Single cell analysis of B lymphocytes from Wegener’s granulomatosis: B cell receptors display affinity maturation within the granulomatous lesions. Clin. Exp. Immunol. 154, 339–345 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Popa, E. R., Stegeman, C. A., Bos, N. A., Kallenberg, C. G. & Tervaert, J. W. Differential B- and T-cell activation in Wegener’s granulomatosis. J. Allergy Clin. Immunol. 103, 885–894 (1999).

    CAS  PubMed  Google Scholar 

  7. 7.

    Stone, J. H. et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N. Engl. J. Med. 363, 221–232 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Hoffman, W., Lakkis, F. G. & Chalasani, G. B cells, antibodies, and more. Clin. J. Am. Soc. Nephrol. 11, 137–154 (2016).

    CAS  PubMed  Google Scholar 

  9. 9.

    Brouwer, E. et al. Predominance of IgG1 and IgG4 subclasses of anti-neutrophil cytoplasmic autoantibodies (ANCA) in patients with Wegener’s granulomatosis and clinically related disorders. Clin. Exp. Immunol. 83, 379–386 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Abdulahad, W. H., van der Geld, Y. M., Stegeman, C. A. & Kallenberg, C. G. M. Persistent expansion of CD4+ effector memory T cells in Wegener’s granulomatosis. Kidney Int. 70, 938–947 (2006).

    CAS  PubMed  Google Scholar 

  11. 11.

    Morgan, M. D. et al. Patients with Wegener’s granulomatosis demonstrate a relative deficiency and functional impairment of T regulatory cells. Immunology 130, 64–73 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Abdulahad, W. H. et al. Functional defect of circulating regulatory CD4+ T cells in patients with Wegener’s granulomatosis in remission. Arthritis Rheum. 56, 2080–2091 (2007).

    CAS  PubMed  Google Scholar 

  13. 13.

    Nogueira, E. et al. Serum IL-17 and IL-23 levels and autoantigen-specific TH17 cells are elevated in patients with ANCA-associated vasculitis. Nephrol. Dial. Transplant. 25, 2209–2217 (2010).

    CAS  PubMed  Google Scholar 

  14. 14.

    McKinney, E. F. et al. A CD8+ T cell transcription signature predicts prognosis in autoimmune disease. Nat. Med. 16, 586–591 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Yates, M. et al. EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis. Ann. Rheum. Dis. 75, 1583–1594 (2016).

    CAS  PubMed  Google Scholar 

  16. 16.

    Chen, M., Yu, F., Zhang, Y. & Zhao, M. H. Antineutrophil cytoplasmic autoantibody-associated vasculitis in older patients. Medicine 87, 203–209 (2008).

    CAS  PubMed  Google Scholar 

  17. 17.

    Katsumata, Y., Kawaguchi, Y. & Yamanaka, H. Interstitial lung disease with ANCA-associated vasculitis. Clin. Med. Insights Circ. Respir. Pulm. Med. 9, 51–56 (2015).

    PubMed  PubMed Central  Google Scholar 

  18. 18.

    Schönermarck, U., Gross, W. L. & de Groot, K. Treatment of ANCA-associated vasculitis. Nat. Rev. Nephrol. 10, 25–36 (2013).

    PubMed  Google Scholar 

  19. 19.

    de Groot, K. et al. Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 52, 2461–2469 (2005).

    PubMed  Google Scholar 

  20. 20.

    Faurschou, M. et al. Brief report: long-term outcome of a randomized clinical trial comparing methotrexate to cyclophosphamide for remission induction in early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 64, 3472–3477 (2012).

    CAS  PubMed  Google Scholar 

  21. 21.

    Jayne, D. R. W. et al. Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis. J. Am. Soc. Nephrol. 18, 2180–2188 (2007).

    CAS  PubMed  Google Scholar 

  22. 22.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00987389 (2018).

  23. 23.

    Pagnoux, C. et al. Azathioprine or methotrexate maintenance for ANCA-associated vasculitis. N. Engl. J. Med. 359, 2790–2803 (2008).

    CAS  PubMed  Google Scholar 

  24. 24.

    Metzler, C. et al. Elevated relapse rate under oral methotrexate versus leflunomide for maintenance of remission in Wegener’s granulomatosis. Rheumatology 46, 1087–1091 (2007).

    CAS  PubMed  Google Scholar 

  25. 25.

    Hiemstra, T. F. et al. Mycophenolate mofetil versus azathioprine for remission maintenance in antineutrophil cytoplasmic antibody–associated vasculitis. JAMA 304, 2381 (2010).

    CAS  PubMed  Google Scholar 

  26. 26.

    Phillip, R. & Luqmani, R. Mortality in systemic vasculitis: a systematic review. Clin. Exp. Rheumatol. 26, S94–S104 (2008).

    CAS  PubMed  Google Scholar 

  27. 27.

    Tan, J. A. et al. Mortality in ANCA-associated vasculitis: a meta-analysis of observational studies. Ann. Rheum. Dis. 76, 1566–1574 (2017).

    PubMed  Google Scholar 

  28. 28.

    Morgan, M. D. et al. Increased incidence of cardiovascular events in patients with antineutrophil cytoplasmic antibody–associated vasculitides a matched-pair cohort study. Arthritis Rheum. 60, 3493–3500 (2009).

    PubMed  Google Scholar 

  29. 29.

    Lionaki, S. et al. The clinical course of ANCA small-vessel vasculitis on chronic dialysis. Kidney Int. 76, 644–651 (2009).

    PubMed  PubMed Central  Google Scholar 

  30. 30.

    Sinico, R. A., Di Toma, L. & Radice, A. Renal involvement in anti-neutrophil cytoplasmic autoantibody associated vasculitis. Autoimmun. Rev. 12, 477–482 (2013).

    CAS  PubMed  Google Scholar 

  31. 31.

    Bomback, A. S. et al. ANCA-associated glomerulonephritis in the very elderly. Kidney Int. 79, 757–764 (2011).

    PubMed  Google Scholar 

  32. 32.

    Weiner, M. et al. Outcome and treatment of elderly patients with ANCA-associated vasculitis. Clin. J. Am. Soc. Nephrol. 10, 1128–1135 (2015).

    PubMed  PubMed Central  Google Scholar 

  33. 33.

    Specks, U. et al. Efficacy of remission-induction regimens for ANCA-associated vasculitis. N. Engl. J. Med. 369, 417–427 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Holle, J. U. et al. Rituximab for refractory granulomatosis with polyangiitis (Wegener’s granulomatosis): comparison of efficacy in granulomatous versus vasculitic manifestations. Ann. Rheum. Dis. 71, 327–333 (2012).

    CAS  PubMed  Google Scholar 

  35. 35.

    Stevenson, H. C. & Fauci, A. S. Activation of human B lymphocytes. XII. Differential effects of in vitro cyclophosphamide on human lymphocyte subpopulations involved in B cell activation. Immunology 39, 391–397 (1980).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Xiao, H. et al. Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. J. Clin. Invest. 110, 955–963 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Specks, U., Fervenza, F. C., McDonald, T. J. & Hogan, M. C. Response of Wegener’s granulomatosis to anti-CD20 chimeric monoclonal antibody therapy. Arthritis Rheum. 44, 2836–2840 (2001).

    CAS  PubMed  Google Scholar 

  38. 38.

    Stasi, R. et al. Long-term observation of patients with anti-neutrophil cytoplasmic antibody-associated vasculitis treated with rituximab. Rheumatology 45, 1432–1436 (2006).

    CAS  PubMed  Google Scholar 

  39. 39.

    Keogh, K. A., Wylam, M. E., Stone, J. H. & Specks, U. Induction of remission by B lymphocyte depletion in eleven patients with refractory antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 52, 262–268 (2005).

    PubMed  Google Scholar 

  40. 40.

    Keogh, K. A. et al. Rituximab for refractory Wegener’s granulomatosis. Am. J. Respir. Crit. Care Med. 173, 180–187 (2006).

    CAS  PubMed  Google Scholar 

  41. 41.

    Jones, R. B. et al. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis: 2 year results of a randomised trial. Ann. Rheum. Dis. 74, 1178–1182 (2015).

    CAS  PubMed  Google Scholar 

  42. 42.

    Walsh, M. et al. Risk factors for relapse of antineutrophil cytoplasmic antibody–associated vasculitis. Arthritis Rheum. 64, 542–548 (2012).

    CAS  PubMed  Google Scholar 

  43. 43.

    Smith, R. M. et al. Rituximab for remission maintenance in relapsing antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 64, 3760–3769 (2012).

    CAS  PubMed  Google Scholar 

  44. 44.

    Jones, R. B. et al. A multicenter survey of rituximab therapy for refractory antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 60, 2156–2168 (2009).

    CAS  PubMed  Google Scholar 

  45. 45.

    Cambridge, G. et al. B cell depletion therapy in systemic lupus erythematosus: relationships among serum B lymphocyte stimulator levels, autoantibody profile and clinical response. Ann. Rheum. Dis. 67, 1011–1016 (2008).

    CAS  PubMed  Google Scholar 

  46. 46.

    Bunch, D. O. et al. Decreased CD5+ B cells in active ANCA vasculitis and relapse after rituximab. Clin. J. Am. Soc. Nephrol. 8, 382–391 (2013).

    PubMed  PubMed Central  Google Scholar 

  47. 47.

    Guillevin, L. et al. Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. N. Engl. J. Med. 371, 1771–1780 (2014).

    PubMed  Google Scholar 

  48. 48.

    Terrier, B. et al. Long-term efficacy of remission-maintenance regimens for ANCA-associated vasculitides. Ann. Rheum. Dis. https://doi.org/10.1136/annrheumdis-2017-212768 (2018).

    PubMed  Google Scholar 

  49. 49.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01697267 (2018).

  50. 50.

    Charles, P. et al. Comparison of individually tailored versus fixed-schedule rituximab regimen to maintain ANCA-associated vasculitis remission: results of a multicentre, randomised controlled, phase III trial (MAINRITSAN2). Ann. Rheum. Dis. https://doi.org/10.1136/annrheumdis-2017-212878 (2018).

  51. 51.

    Alberici, F. et al. Long-term follow-up of patients who received repeat-dose rituximab as maintenance therapy for ANCA-associated vasculitis. Rheumatology 54, 1153–1160 (2015).

    CAS  PubMed  Google Scholar 

  52. 52.

    Molloy, E. S. & Calabrese, L. H. Progressive multifocal leukoencephalopathy associated with immunosuppressive therapy in rheumatic diseases: evolving role of biologic therapies. Arthritis Rheum. 64, 3043–3051 (2012).

    CAS  PubMed  Google Scholar 

  53. 53.

    Wang, Y. H. et al. Efficacy of prophylactic lamivudine to prevent hepatitis B virus reactivation in B cell lymphoma treated with rituximab-containing chemotherapy. Support. Care Cancer 21, 1265–1271 (2013).

    PubMed  Google Scholar 

  54. 54.

    Sagnelli, E., Pisaturo, M., Sagnelli, C. & Coppola, N. Rituximab-based treatment, HCV replication, and hepatic flares. Clin. Dev. Immunol. 2012, 1–5 (2012).

    Google Scholar 

  55. 55.

    Roberts, D. M. et al. Rituximab-associated hypogammaglobulinemia: Incidence, predictors and outcomes in patients with multi-system autoimmune disease. J. Autoimmun. 57, 60–65 (2015).

    CAS  PubMed  Google Scholar 

  56. 56.

    Roberts, D. M. et al. Immunoglobulin G replacement for the treatment of infective complications of rituximab-associated hypogammaglobulinemia in autoimmune disease: a case series. J. Autoimmun. 57, 24–29 (2015).

    CAS  PubMed  Google Scholar 

  57. 57.

    Venhoff, N. et al. Impact of rituximab on immunoglobulin concentrations and B cell numbers after cyclophosphamide treatment in patients with ANCA-associated vasculitides. PLoS ONE 7, e37626 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Kaplan, B., Kopyltsova, Y., Khokhar, A., Lam, F. & Bonagura, V. Rituximab and immune deficiency: case series and review of the literature. J. Allergy Clin. Immunol. Pract. 2, 594–600 (2014).

    PubMed  Google Scholar 

  59. 59.

    Warnatz, K. et al. B cell activating factor receptor deficiency is associated with an adult-onset antibody deficiency syndrome in humans. Proc. Natl Acad. Sci. USA 106, 13945–13950 (2009).

    CAS  PubMed  Google Scholar 

  60. 60.

    Kapetanovic, M. C. et al. Impact of anti-rheumatic treatment on immunogenicity of pandemic H1N1 influenza vaccine in patients with arthritis. Arthritis Res. Ther. 16, R2 (2014).

    PubMed  PubMed Central  Google Scholar 

  61. 61.

    Bingham, C. O. et al. Immunization responses in rheumatoid arthritis patients treated with rituximab: results from a controlled clinical trial. Arthritis Rheum. 62, 64–74 (2010).

    CAS  PubMed  Google Scholar 

  62. 62.

    Czuczman, M. S. et al. Ofatumumab monotherapy in rituximab-refractory follicular lymphoma: results from a multicenter study. Blood 119, 3698–3704 (2012).

    CAS  PubMed  Google Scholar 

  63. 63.

    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).

    PubMed  Google Scholar 

  64. 64.

    McAdoo, S. P. et al. Ofatumumab for B cell depletion therapy in ANCA-associated vasculitis: a single-centre case series. Rheumatology 55, 1437–1442 (2016).

    CAS  PubMed  Google Scholar 

  65. 65.

    McAdoo, S. P. et al. Long-term follow-up of a combined rituximab and cyclophosphamide regimen in renal anti-neutrophil cytoplasm antibody-associated vasculitis. Nephrol. Dial. Transplant. 33, 899 (2018).

    PubMed  Google Scholar 

  66. 66.

    Bologna, L. et al. Mechanism of action of type II, glycoengineered, anti-CD20 monoclonal antibody GA101 in B chronic lymphocytic leukemia whole blood assays in comparison with rituximab and alemtuzumab. J. Immunol. 186, 3762–3769 (2011).

    CAS  PubMed  Google Scholar 

  67. 67.

    Goede, V. et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N. Engl. J. Med. 370, 1101–1110 (2014).

    CAS  PubMed  Google Scholar 

  68. 68.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02550652 (2018).

  69. 69.

    Ruderman, E. M. & Pope, R. M. The evolving clinical profile of abatacept (CTLA4 Ig): a novel co-stimulatory modulator for the treatment of rheumatoid arthritis. Arthritis Res. Ther. 7, S21–S25 (2005).

    PubMed  PubMed Central  Google Scholar 

  70. 70.

    Langford, C. A. et al. An open-label trial of abatacept (CTLA4 Ig) in non-severe relapsing granulomatosis with polyangiitis (Wegener’s). Ann. Rheum. Dis. 73, 1376–1379 (2014).

    CAS  PubMed  Google Scholar 

  71. 71.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02108860 (2017).

  72. 72.

    Walsh, M., Chaudhry, A. & Jayne, D. Long-term follow-up of relapsing/refractory anti-neutrophil cytoplasm antibody associated vasculitis treated with the lymphocyte depleting antibody alemtuzumab (CAMPATH 1H). Ann. Rheum. Dis. 67, 1322–1327 (2007).

    PubMed  Google Scholar 

  73. 73.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01405807 (2011).

  74. 74.

    Mackay, F., Schneider, P., Rennert, P. & Browning, J. BAFF AND APRIL: a tutorial on B cell survival. Annu. Rev. Immunol. 21, 231–264 (2003).

    CAS  PubMed  Google Scholar 

  75. 75.

    Rauch, M., Tussiwand, R., Bosco, N. & Rolink, A. G. Crucial role for BAFF-BAFF R signaling in the survival and maintenance of mature B cells. PLoS ONE 4, e5456 (2009).

    PubMed  PubMed Central  Google Scholar 

  76. 76.

    Schiemann, B. et al. An essential role for BAFF in the normal development of B cells through a BCMA-independent pathway. Science 293, 2111–2114 (2001).

    CAS  PubMed  Google Scholar 

  77. 77.

    Sasaki, Y., Casola, S., Kutok, J. L., Rajewsky, K. & Schmidt-Supprian, M. TNF family member B cell-activating factor (BAFF) receptor-dependent and -independent roles for BAFF in B cell physiology. J. Immunol. 173, 2245–2252 (2004).

    CAS  PubMed  Google Scholar 

  78. 78.

    Shulga-Morskaya, S. et al. B cell-activating factor belonging to the TNF family acts through separate receptors to support B cell survival and T cell-independent antibody formation. J. Immunol. 173, 2331–2341 (2004).

    CAS  PubMed  Google Scholar 

  79. 79.

    Stadanlick, J. E. et al. Tonic B cell antigen receptor signals supply an NF-κB substrate for prosurvival BLyS signaling. Nat. Immunol. 9, 1379–1387 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    O’Connor, B. P. et al. BCMA is essential for the survival of long-lived bone marrow plasma cells. J. Exp. Med. 199, 91–98 (2004).

    PubMed  PubMed Central  Google Scholar 

  81. 81.

    Xu, S. & Lam, K. P. B cell maturation protein, which binds the tumor necrosis factor family members BAFF and APRIL, is dispensable for humoral immune responses. Mol. Cell. Biol. 21, 4067–4074 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Yan, M. et al. Activation and accumulation of B cells in TACI-deficient mice. Nat. Immunol. 2, 638–643 (2001).

    CAS  PubMed  Google Scholar 

  83. 83.

    Salzer, U. et al. Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. Nat. Genet. 37, 820–828 (2005).

    CAS  PubMed  Google Scholar 

  84. 84.

    Salzer, U., Jennings, S. & Grimbacher, B. To switch or not to switch — the opposing roles of TACI in terminal B cell differentiation. Eur. J. Immunol. 37, 17–20 (2007).

    CAS  PubMed  Google Scholar 

  85. 85.

    Thien, M. et al. Excess BAFF rescues self-reactive B cells from peripheral deletion and allows them to enter forbidden follicular and marginal zone niches. Immunity 20, 785–798 (2004).

    CAS  PubMed  Google Scholar 

  86. 86.

    Lesley, R. et al. Reduced competitiveness of autoantigen-engaged B cells due to increased dependence on BAFF. Immunity 20, 441–453 (2004).

    CAS  PubMed  Google Scholar 

  87. 87.

    Liu, Z. & Davidson, A. BAFF and selection of autoreactive B cells. Trends Immunol. 32, 388–394 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Schneeweis, C. et al. Increased levels of BLyS and sVCAM 1 in anti-neutrophil cytoplasmatic antibody (ANCA)-associated vasculitides (AAV). Clin. Exp. Rheumatol. 28 (Suppl. 57), 62–66 (2010).

    PubMed  Google Scholar 

  89. 89.

    Xin, G. et al. Serum B cell activating factor in myecloperoxiase-antineutrophil cytoplasmic antibodies-associated vasculitis. Am. J. Med. Sci. 348, 25–29 (2014).

    PubMed  Google Scholar 

  90. 90.

    Nagai, M. et al. Serum levels of BAFF and APRIL in myeloperoxidase anti-neutrophil cytoplasmic autoantibody-associated renal vasculitis: association with disease activity. Nephron. Clin. Pract. 118, c339–c345 (2011).

    CAS  PubMed  Google Scholar 

  91. 91.

    Sanders, J. S. F., Huitma, M. G., Kallenberg, C. G. M. & Stegeman, C. A. Plasma levels of soluble interleukin 2 receptor, soluble CD30, IL-10 and BAFF during follow-up in vasculitis associated with proteinase 3 antineutrophil cytoplasmic antibodies: associations with disease activity and relapse. Ann. Rheum. Dis. 65, 1484–1489 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Bader, L., Koldingsnes, W. & Nossent, J. B lymphocyte activating factor levels are increased in patients with Wegener’s granulomatosis and inversely correlated with ANCA titer. Clin. Rheumatol. 29, 1031–1035 (2010).

    PubMed  Google Scholar 

  93. 93.

    De Silva, N. S. & Klein, U. Dynamics of B cells in germinal centres. Nat. Rev. Immunol. 15, 137–148 (2015).

    PubMed  PubMed Central  Google Scholar 

  94. 94.

    Nutt, S. L., Hodgkin, P. D., Tarlinton, D. M. & Corcoran, L. M. The generation of antibody-secreting plasma cells. Nat. Rev. Immunol. 15, 160–171 (2015).

    CAS  PubMed  Google Scholar 

  95. 95.

    Vinuesa, C. G., Sanz, I. & Cook, M. C. Dysregulation of germinal centres in autoimmune disease. Nat. Rev. Immunol. 9, 845–857 (2009).

    CAS  PubMed  Google Scholar 

  96. 96.

    Balázs, M., Martin, F., Zhou, T. & Kearney, J. Blood dendritic cells interact with splenic marginal zone B cells to initiate T independent immune responses. Immunity 17, 341–352 (2002).

    PubMed  Google Scholar 

  97. 97.

    Rahman, Z. S., Rao, S. P., Kalled, S. L. & Manser, T. Normal induction but attenuated progression of germinal center responses in BAFF and BAFF R signaling–deficient mice. J. Exp. Med. 198, 1157–1169 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Gatto, D. & Brink, R. The germinal center reaction. J. Allergy Clin. Immunol. 126, 898–907 (2010).

    CAS  PubMed  Google Scholar 

  99. 99.

    Kalled, S. L. Impact of the BAFF/BR3 axis on B cell survival, germinal center maintenance and antibody production. Semin. Immunol. 18, 290–296 (2006).

    CAS  PubMed  Google Scholar 

  100. 100.

    Goenka, R. et al. Local BLyS production by T follicular cells mediates retention of high affinity B cells during affinity maturation. J. Exp. Med. 211, 45–56 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Coquery, C. M. et al. BAFF regulates follicular helper T cells and affects their accumulation and interferon γ production in autoimmunity. Arthritis Rheumatol. 67, 773–784 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Pitzalis, C., Jones, G. W., Bombardieri, M. & Jones, S. A. Ectopic lymphoid-like structures in infection, cancer and autoimmunity. Nat. Rev. Immunol. 14, 447–462 (2014).

    CAS  PubMed  Google Scholar 

  103. 103.

    Mueller, A., Holl-Ulrich, K., Lamprecht, P. & Gross, W. L. Germinal centre-like structures in Wegener’s granuloma: the morphological basis for autoimmunity? Rheumatology 47, 1111–1113 (2008).

    CAS  PubMed  Google Scholar 

  104. 104.

    Voswinkel, J., Muller, A. & Lamprecht, P. Is PR3 ANCA formation initiated in Wegener’s granulomatosis lesions? Granulomas as potential lymphoid tissue maintaining autoantibody production. Ann. NY Acad. Sci. 1051, 12–19 (2005).

    CAS  PubMed  Google Scholar 

  105. 105.

    Zhao, Y. et al. Granulomatosis with polyangiitis involves sustained mucosal inflammation that is rich in B cell survival factors and autoantigen. Rheumatology 51, 1580–1586 (2012).

    CAS  PubMed  Google Scholar 

  106. 106.

    Parsa, R. et al. BAFF-secreting neutrophils drive plasma cell responses during emergency granulopoiesis. J. Exp. Med. 213, 1537–1553 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Holden, N. J. et al. ANCA-stimulated neutrophils release BLyS and promote B cell survival: a clinically relevant cellular process. Ann. Rheum. Dis. 70, 2229–2233 (2011).

    CAS  PubMed  Google Scholar 

  108. 108.

    Bertram, A. et al. Circulating ADAM17 level reflects disease activity in proteinase 3 ANCA-associated vasculitis. J. Am. Soc. Nephrol. 26, 2860–2870 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Smulski, C. R. et al. BAFF- and TACI-dependent processing of BAFFR by ADAM proteases regulates the survival of B cells. Cell Rep. 18, 2189–2202 (2017).

    CAS  PubMed  Google Scholar 

  110. 110.

    Kreuzaler, M. et al. Soluble BAFF levels inversely correlate with peripheral B cell numbers and the expression of BAFF receptors. J. Immunol. 188, 497–503 (2012).

    CAS  PubMed  Google Scholar 

  111. 111.

    Carter, L. M., Isenberg, D. A. & Ehrenstein, M. R. Elevated serum BAFF levels are associated with rising anti–double-stranded DNA antibody levels and disease flare following B cell depletion therapy in systemic lupus erythematosus. Arthritis Rheum. 65, 2672–2679 (2013).

    CAS  PubMed  Google Scholar 

  112. 112.

    Silverman, G. J. Therapeutic B cell depletion and regeneration in rheumatoid arthritis emerging patterns and paradigms. Arthritis Rheum. 54, 2356–2367 (2006).

    CAS  PubMed  Google Scholar 

  113. 113.

    Baker, K. P. et al. Generation and characterization of LymphoStat B, a human monoclonal antibody that antagonizes the bioactivities of B lymphocyte stimulator. Arthritis Rheum. 48, 3253–3265 (2003).

    CAS  PubMed  Google Scholar 

  114. 114.

    Navarra, S. V. et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet 377, 721–731 (2011).

    CAS  PubMed  Google Scholar 

  115. 115.

    Furie, R. et al. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum. 63, 3918–3930 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116.

    Ginzler, E. M. et al. Disease control and safety of belimumab plus standard therapy over 7 years in patients with systemic lupus erythematosus. J. Rheumatol. 41, 300–309 (2014).

    CAS  PubMed  Google Scholar 

  117. 117.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01639339 (2018).

  118. 118.

    Stohl, W. et al. Belimumab reduces autoantibodies, normalizes low complement levels, and reduces select B cell populations in patients with systemic lupus erythematosus. Arthritis Rheum. 64, 2328–2337 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119.

    Halpern, W. G. et al. Chronic administration of belimumab, a BLyS antagonist, decreases tissue and peripheral blood B lymphocyte populations in cynomolgus monkeys: pharmacokinetic, pharmacodynamic, and toxicologic effects. Toxicol. Sci. 91, 586–599 (2006).

    CAS  PubMed  Google Scholar 

  120. 120.

    Lech, M. & Anders, H. J. The pathogenesis of lupus nephritis. J. Am. Soc. Nephrol. 24, 1357–1366 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Thiel, J. et al. B cell repopulation kinetics after rituximab treatment in ANCA-associated vasculitides compared to rheumatoid arthritis, and connective tissue diseases: a longitudinal observational study on 120 patients. Arthritis Res. Ther. 19, 101 (2017).

    PubMed  PubMed Central  Google Scholar 

  122. 122.

    Jayne, D. et al. Efficacy and safety of belimumab in combination with azathioprine for remission maintenance in granulomatosis with polyangiitis and microscopic polyangiitis: a multicenter randomized, placebo-controlled study [abstract]. Arthritis Rheumatol. 69 (Suppl. 10), 207AD (2017).

    Google Scholar 

  123. 123.

    Merrill, J. T. et al. Phase III trial results with blisibimod, a selective inhibitor of B cell activating factor, in subjects with systemic lupus erythematosus (SLE): results from a randomised, double-blind, placebo-controlled trial. Ann. Rheum. Dis. 77, 883–889 (2018).

    PubMed  Google Scholar 

  124. 124.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02514967 (2017).

  125. 125.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01598857 (2015).

  126. 126.

    Isenberg, D. A. et al. Efficacy and safety of subcutaneous tabalumab in patients with systemic lupus erythematosus: results from ILLUMINATE 1, a 52 week, phase III, multicentre, randomised, double-blind, placebo-controlled study. Ann. Rheum. Dis. 75, 323–331 (2016).

    CAS  PubMed  Google Scholar 

  127. 127.

    Schiff, M. et al. Efficacy and safety of tabalumab, an anti-BAFF monoclonal antibody, in patients with moderate-to-severe rheumatoid arthritis and inadequate response to TNF inhibitors: results of a randomised, double-blind, placebo-controlled, phase 3 study. RMD Open 1, e000037 (2015).

    PubMed  PubMed Central  Google Scholar 

  128. 128.

    Vincent, F. B., Saulep-Easton, D., Figgett, W. A., Fairfax, K. A. & Mackay, F. The BAFF/APRIL system: Emerging functions beyond B cell biology and autoimmunity. Cytokine Growth Factor Rev. 24, 203–215 (2013).

    CAS  PubMed  Google Scholar 

  129. 129.

    Ginzler, E. M. et al. Atacicept in combination with MMF and corticosteroids in lupus nephritis: results of a prematurely terminated trial. Arthritis Res. Ther. 14, R33 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130.

    Merrill, J. T. et al. Efficacy and safety of atacicept in patients with systemic lupus erythematosus. Arthritis Rheumatol. 70, 266–276 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131.

    Gong, Q. et al. Importance of cellular microenvironment and circulatory dynamics in B cell immunotherapy. J. Immunol. 174, 817–826 (2005).

    CAS  PubMed  Google Scholar 

  132. 132.

    Bekar, K. W. et al. Prolonged effects of short-term anti-CD20 B cell depletion therapy in murine systemic lupus erythematosus. Arthritis Rheum. 62, 2443–2457 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133.

    Lin, W. et al. Dual B cell immunotherapy is superior to individual anti-CD20 depletion or BAFF blockade in murine models of spontaneous or accelerated lupus. Arthritis Rheumatol. 67, 215–224 (2015).

    CAS  PubMed  Google Scholar 

  134. 134.

    Kraaij, T. et al. The NET-effect of combining rituximab with belimumab in severe systemic lupus erythematosus. J. Autoimmun. 91, 45–54 (2018).

    CAS  PubMed  Google Scholar 

  135. 135.

    Aranow, C. et al. Phase 2 trial of induction therapy with anti-CD20 (rituximab) followed by maintenance therapy with anti-BAFF (belimumab) in patients with active lupus nephritis [abstract]. Ann. Rheum. Dis. 77, A690 (2018).

    Google Scholar 

  136. 136.

    BEAT Lupus. BEAT Lupus. BEAT Lupus https://beatlupus.uk/ (2017).

  137. 137.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03312907 (2018).

  138. 138.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02631538 (2018).

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The work of the authors is funded by a grant from GlaxoSmithKline (GSK) and the Medical Research Council (MRC) (grant number MR/R502145/1 to D.J. and R.J.). M.M. is in receipt of an MRC–GSK Experimental Medicine Initiative to Explore New Therapies (EMINENT) fellowship and S.G. is funded through the Experimental Medicine Training Initiative.

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Nature Reviews Rheumatology thanks D. Cornec and J. Thiel for their contribution to the peer review of this work.

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M.M. researched data for this article and wrote the manuscript. D.J., M.M. and R.J. made substantial contributions to discussion of content. All authors reviewed and/or edited the manuscript before submission.

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Correspondence to David Jayne.

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R.J. and D.J. declare that they have received financial support in the form of a grant from GlaxoSmithKline and the Medical Research Council towards an experimental medicine study evaluating the biological effects of combination therapy with rituximab and belimumab in anti-neutrophil cytoplasmic antibody-associated vasculitis. The other authors declare no competing interests.

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McClure, M., Gopaluni, S., Jayne, D. et al. B cell therapy in ANCA-associated vasculitis: current and emerging treatment options. Nat Rev Rheumatol 14, 580–591 (2018). https://doi.org/10.1038/s41584-018-0065-x

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