B-Cell-Targeted Therapies in Sjögren’s Syndrome

  • Xavier Mariette


B-cell hyperactivity has been recognized for a long time in Sjögren’s syndrome (SS). More than 30 years ago, Talal et al. demonstrated an increased level of beta-2-microglobulin in the serum of patients with SS [1]. More than 20 years ago, Moutsopoulos et al. detected increased levels of immunoglobulin light chains within the sera of patients with SS [2].


Systemic Lupus Erythematosus Progressive Multifocal Leukoencephalopathy Progressive Multifocal Leukoencephalopathy Immunoglobulin Light Chain Rheumatoid Factor Level 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Talal N, Grey HM, Zvaifler N, et al. Elevated salivary and synovial fluid beta2-microglobulin in Sjogren’s syndrome and rheumatoid arthritis. Science. 1975;187:1196–8.PubMedCrossRefGoogle Scholar
  2. 2.
    Moutsopoulos HM, Steinberg AD, Fauci AS, et al. High incidence of free monoclonal lambda light chains in the sera of patients with Sjogren’s syndrome. J Immunol. 1983;130(6):2663–5.PubMedGoogle Scholar
  3. 3.
    Ioannidis JP, Vassiliou VA, Moutsopoulos HM. Long-term risk of mortality and ­lymphoproliferative disease and predictive classification of primary Sjogren’s syndrome. Arthritis Rheum. 2002;46:741–7.PubMedCrossRefGoogle Scholar
  4. 4.
    Kassan SS, Thomas TL, Moutsopoulos H, et al. Increased risk of lymphoma in sicca syndrome. Ann Intern Med. 1978;89:888–92.PubMedGoogle Scholar
  5. 5.
    Theander E, Henriksson G, Ljungberg O, et al. Lymphoma and other malignancies in primary Sjogren’s syndrome: a cohort study on cancer incidence and lymphoma predictors. Ann Rheum Dis. 2006;65:796–803.PubMedCrossRefGoogle Scholar
  6. 6.
    Zinteras E, Voulgarelis M, Moutsopoulos HM. The risk of lymphoma development in autoimmune diseases: a meta-analysis. Arch Intern Med. 2005;165:2337–44.CrossRefGoogle Scholar
  7. 7.
    Royer B, Cazals-Hatem D, Sibilia J, et al. Lymphomas in patients with Sjögren’s syndrome are marginal zone B-cell neoplasms, arise in diverse extranodal and nodal sites and are not associated with viruses. Blood. 1997;90:766–75.PubMedGoogle Scholar
  8. 8.
    Voulgarelis M, Dafni UG, Isenberg DA, et al. Malignant lymphoma in primary Sjogren’s syndrome: a multicenter, retrospective, clinical study by the European Concerted Action on Sjogren’s Syndrome. Arthritis Rheum. 1999;42:1765–72.PubMedCrossRefGoogle Scholar
  9. 9.
    Bende RJ, Aarts WM, Riedl RG, et al. Among B cell non-Hodgkin’s lymphomas, MALT lymphomas express a unique antibody repertoire with frequent rheumatoid factor reactivity. J Exp Med. 2005;201:1229–41.PubMedCrossRefGoogle Scholar
  10. 10.
    Gottenberg JE, Busson M, Cohen-Solal J, et al. Correlation of serum B lymphocyte stimulator and beta2 microglobulin with autoantibody secretion and systemic involvement in primary Sjogren’s syndrome. Ann Rheum Dis. 2005;64(7):1050–5.PubMedCrossRefGoogle Scholar
  11. 11.
    Gottenberg JE, Aucouturier F, Goetz J, et al. Serum immunoglobulin free light chain assessment in rheumatoid arthritis and primary Sjögren’s syndrome. Ann Rheum Dis. 2007;66(1):23–7.PubMedCrossRefGoogle Scholar
  12. 12.
    Schneider P, MacKay F, Steiner V, et al. BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth. J Exp Med. 1999;189:1747–56.PubMedCrossRefGoogle Scholar
  13. 13.
    Moore PA, Belvedere O, Orr A, et al. BLyS: member of the tumor necrosis factor family and B lymphocyte stimulator. Science. 1999;285:260–3.PubMedCrossRefGoogle Scholar
  14. 14.
    Nardelli B, Belvedere O, Roschke V, et al. Synthesis and release of B-lymphocyte stimulator from myeloid cells. Blood. 2001;97:198–204.PubMedCrossRefGoogle Scholar
  15. 15.
    Mackay F, Woodcock SA, Lawton P, et al. Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations. J Exp Med. 1999;190:1697–710.PubMedCrossRefGoogle Scholar
  16. 16.
    Groom J, Kalled SL, Cutler AH, et al. Association of BAFF/BLyS overexpression and altered B cell differentiation with Sjogren’s syndrome. J Clin Invest. 2002;109:59–68.PubMedGoogle Scholar
  17. 17.
    Mariette X, Roux S, Zhang J, et al. The level of BLyS (BAFF) correlates with the titre of autoantibodies in human Sjogren’s syndrome. Ann Rheum Dis. 2003;62:168–71.PubMedCrossRefGoogle Scholar
  18. 18.
    Jonsson M, Szodoray P, Jellestad S, et al. Association between circulating levels of the novel TNF family members APRIL and BAFF and lymphoid organization in primary Sjögren’s syndrome. J Clin Immunol. 2005;25(3):189–201.PubMedCrossRefGoogle Scholar
  19. 19.
    Pers JO, Daridon C, Devauchelle V, et al. BAFF overexpression is associated with autoantibody production in autoimmune diseases. Ann N Y Acad Sci. 2005;1050:34–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Pers JO, d’Arbonneau F, Devauchelle-Pensec V, et al. Is periodontal disease mediated by salivary BAFF in Sjögren’s syndrome? Arthritis Rheum. 2005;52:2411–4.PubMedCrossRefGoogle Scholar
  21. 21.
    Lavie F, Miceli-Richard C, Quillard J, et al. Overexpression of BAFF in T cells infiltrating labial salivary glands from patients with Sjögren’s syndrome. J Pathol. 2004;202:496–502.PubMedCrossRefGoogle Scholar
  22. 22.
    Daridon C, Devauchelle V, Hutin P, et al. Aberrant expression of BAFF by B lymphocytes infiltrating the salivary glands of patients with primary Sjögren’s syndrome. Arthritis Rheum. 2007;56:1134–44.PubMedCrossRefGoogle Scholar
  23. 23.
    Ittah M, Miceli-Richard C, Gottenberg JE, et al. B-cell activating factor of the TNF family (BAFF) is expressed under stimulation by interferon in salivary gland epithelial cells in ­primary Sjögren’s syndrome. Arthritis Res Ther. 2006;8:R51.PubMedCrossRefGoogle Scholar
  24. 24.
    Bave U, Nordmark G, Lofgren T, et al. Activation of the type-I interferon system in primary SS. Arthritis Rheum. 2005;52:1185–95.PubMedCrossRefGoogle Scholar
  25. 25.
    Hjelmervik TO, Petersen K, Jonassen I, et al. Gene expression profiling of minor salivary glands clearly distinguishes primary Sjogren’s syndrome patients from healthy control subjects. Arthritis Rheum. 2005;52:1534–44.PubMedCrossRefGoogle Scholar
  26. 26.
    Gottenberg J, Cagnard N, Lucchesi C, et al. Activation of interferon pathways and plasmacytoid dendritic cell recruitment in target organs of primary Sjögren’s syndrome. Proc Natl Acad Sci USA. 2006;103:2770–5.PubMedCrossRefGoogle Scholar
  27. 27.
    Ittah M, Miceli-Richard C, Gottenberg JE, et al. Viruses induce high expression of B cell-activating factor by salivary gland epithelial cells through Toll-like receptor- and type-I interferon-dependent and -independent pathways. Eur J Immunol. 2008;38(4):1058–64.PubMedCrossRefGoogle Scholar
  28. 28.
    Mariette X, Ravaud P, Steinfeld S, et al. Inefficacy of infliximab in primary Sjögren’s syndrome. Results of the randomized controlled trial of Remicade in primary Sjögren’s syndrome (TRIPSS). Arthritis Rheum. 2004;50:1270–6.PubMedCrossRefGoogle Scholar
  29. 29.
    Sankar V, Brennan MT, Kok MR, et al. Etanercept in Sjogren’s syndrome: a twelve-week randomized, double-blind, placebo-controlled pilot clinical trial. Arthritis Rheum. 2004;50:2240–5.PubMedCrossRefGoogle Scholar
  30. 30.
    Mavragani CP, Niewold TB, Moutsopoulos NM, et al. Augmented interferon-alpha pathway activation in patients with Sjögren’s syndrome treated with etanercept. Arthritis Rheum. 2007;56:3995–4004.PubMedCrossRefGoogle Scholar
  31. 31.
    Somer BG, Tsai DE, Downs L, et al. Improvement in Sjogren’s syndrome following therapy with rituximab for marginal zone lymphoma. Arthritis Rheum. 2003;49(3):394–8.PubMedCrossRefGoogle Scholar
  32. 32.
    Voulgarelis M, Giannouli S, Anagnostou D, et al. Combined therapy with rituximab plus cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) for Sjogren’s syndrome-associated B-cell aggressive non-Hodgkin’s lymphomas. Rheumatology (Oxford). 2004;43(8):1050–3.CrossRefGoogle Scholar
  33. 33.
    Harner KC, Jackson LW, Drabick JJ. Normalization of anticardiolipin antibodies following rituximab therapy for marginal zone lymphoma in a patient with Sjogren’s syndrome. Rheumatology (Oxford). 2004;43(10):1309–10.CrossRefGoogle Scholar
  34. 34.
    Ramos-Casals M, Lopez-Guillermo A, Brito-Zeron P, et al. Treatment of B-cell lymphoma with rituximab in two patients with Sjogren’s syndrome associated with hepatitis C virus infection. Lupus. 2004;13(12):969–71.PubMedCrossRefGoogle Scholar
  35. 35.
    Pijpe J, van Imhoff GW, Vissink A, et al. Changes in salivary gland immunohistology and function after rituximab monotherapy in a patient with Sjogren’s syndrome and associated MALT lymphoma. Ann Rheum Dis. 2005;64(6):958–60.PubMedCrossRefGoogle Scholar
  36. 36.
    Ahmadi-Simab K, Lamprecht P, Nolle B, et al. Successful treatment of refractory anterior scleritis in primary Sjogren’s syndrome with rituximab. Ann Rheum Dis. 2005;64(7):1087–8.PubMedCrossRefGoogle Scholar
  37. 37.
    Ring T, Kallenbach M, Praetorius J, et al. Successful treatment of a patient with primary Sjogren’s syndrome with rituximab. Clin Rheumatol. 2006;25(6):891–4.PubMedCrossRefGoogle Scholar
  38. 38.
    Voulgarelis M, Giannouli S, Tzioufas AG, et al. Long term remission of Sjogren’s syndrome associated aggressive B cell non-Hodgkin’s lymphomas following combined B cell depletion therapy and CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). Ann Rheum Dis. 2006;65(8):1033–7.PubMedCrossRefGoogle Scholar
  39. 39.
    Pijpe J, van Imhoff GW, Spijkervet FK, et al. Rituximab treatment in patients with primary Sjogren’s syndrome: an open-label phase II study. Arthritis Rheum. 2005;52:2740–50.PubMedCrossRefGoogle Scholar
  40. 40.
    Seror R, Sordet C, Guillevin L, et al. Tolerance and efficacy of rituximab and changes in serum B cell biomarkers in patients with systemic complications of primary Sjogren’s syndrome. Ann Rheum Dis. 2007;66:351–7.PubMedCrossRefGoogle Scholar
  41. 41.
    Devauchelle-Pensec V, Pennec Y, Morvan J, et al. Improvement of Sjögren’s syndrome after two infusions of rituximab (anti-CD20). Arthritis Rheum. 2007;57:310–7.PubMedCrossRefGoogle Scholar
  42. 42.
    Dass S, Bowman SJ, Vital EM, et al. Reduction of fatigue in Sjogren’s syndrome with rituximab: results of a randomised, double-blind, placebo controlled pilot study. Ann Rheum Dis. 2008;67:1541–4.PubMedCrossRefGoogle Scholar
  43. 43.
    Meijer JM, Meiners PM, Vissink A, et al. Effectiveness of rituximab treatment in primary Sjögren’s syndrome: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2010;62:960–8.PubMedCrossRefGoogle Scholar
  44. 44.
    Salliot C, Dougados M, Gossec L. Risk of serious infections during rituximab, abatacept and anakinra treatments for rheumatoid arthritis: meta-analyses of randomised placebo-controlled trials. Ann Rheum Dis. 2009;68:25–32.PubMedCrossRefGoogle Scholar
  45. 45.
    Gottenberg JE, Ravaud P, Bardin T, et al. Risk factors for severe infections in patients with rheumatoid arthritis treated with rituximab in the autoimmunity and rituximab registry. Arthritis Rheum. 2010 Sep;62(9):2625–32.Google Scholar
  46. 46.
    Carson KR, Evens AM, Richey EA, et al. Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project. Blood. 2009;113:4834–40.PubMedCrossRefGoogle Scholar
  47. 47.
    Cambridge G, Stohl W, Leandro MJ, et al. Circulating levels of B lymphocyte stimulator in patients with rheumatoid arthritis following rituximab treatment: relationships with B cell depletion, circulating antibodies, and clinical relapse. Arthritis Rheum. 2006;54:723–32.PubMedCrossRefGoogle Scholar
  48. 48.
    Toubi E, Kessel A, Slobodin G, et al. Macrophage function changes following rituximab treatment in patients with rheumatoid arthritis. Ann Rheum Dis. 2007;66(6):818–20.PubMedCrossRefGoogle Scholar
  49. 49.
    Lavie F, Miceli-Richard C, Ittah M, et al. Increase of B-cell activating factor of the TNF family (BAFF) after rituximab: insights into a new regulating system of BAFF production. Ann Rheum Dis. 2007;66(5):700–3.PubMedCrossRefGoogle Scholar
  50. 50.
    Pers JO, Devauchelle V, Daridon C, et al. BAFF-modulated repopulation of B lymphocytes in the blood and salivary glands of rituximab-treated patients with Sjögren’s syndrome. Arthritis Rheum. 2007;56:1464–77.PubMedCrossRefGoogle Scholar
  51. 51.
    Steinfeld SD, Tant L, Burmester GR, et al. Epratuzumab (humanised anti-CD22 antibody) in primary Sjögren’s syndrome: an open-label phase I/II study. Arthritis Res Ther. 2006;8(4):R129.PubMedCrossRefGoogle Scholar
  52. 52.
    Stohl W, Chatham W, Weisman M, et al. Belimumab (BmAb), a novel fully human monoclonal antibody to B-lymphocyte stimulator (BLyS), selectively modulates B-cell sub-populations and immunoglobulins in a heterogeneous rheumatoid arthritis subject population. Arthritis Rheum. 2005;52:S444.CrossRefGoogle Scholar
  53. 53.
    Wallace DJ, Stohl W, Furie RA, et al. A phase II, randomized, double-blind, placebo-controlled, dose-ranging study of belimumab in patients with active systemic lupus erythematosus. Arthritis Rheum. 2009;61(9):1168–78.PubMedCrossRefGoogle Scholar
  54. 54.
    Navarra S, Ilianova E, Bae SC, et al. Belimumab, a blys-specific inhibitor, reduced disease activity, flares, and steroid use in patients with seropositive systemic lupus erythematosus (SLE): BLISS-52 study. EULAR 2010 meeting, poster SAT0204, Rome, 2010.Google Scholar
  55. 55.
    van Vollenhoven RF, Zamani O, Wallace DJ, et al. Belimumab, a blys-specific inhibitor, reduces disease activity and severe flares in seropositive sle patients: BLISS-76 study. EULAR 2010 meeting, oral presentation, Rome, 2010.Google Scholar
  56. 56.
    Seror R, Ravaud P, Bowman S, et al. EULAR Sjogren’s Syndrome Disease Activity Index (ESSDAI): development of a consensus systemic disease activity index in primary Sjogren’s syndrome. Ann Rheum Dis. 2010;69(6):1103–9.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag London Limited 2011

Authors and Affiliations

  • Xavier Mariette
    • 1
    • 2
  1. 1.Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris (AP-HP)Université Paris-Sud 11Le Kremlin BicêtreFrance
  2. 2.Institut Pour la Santé et la Recherche Médicale (INSERM)ParisFrance

Personalised recommendations