Skip to main content

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

  • Review Article
  • Published:

Current and future therapies for primary Sjögren syndrome

Abstract

Primary Sjögren syndrome (pSS) is a systemic autoimmune disease that is characterized by a triad of symptoms that affect all patients (dryness, pain and fatigue). In addition, systemic involvement can affect between one-third and one-half of patients. The management of patients with pSS has been negatively affected by a lack of effective treatments; however, knowledge of the epidemiology of pSS has increased, and advances in developing classification criteria, systemic disease activity scoring and patient-reported outcomes have been made during the past decade. Progress has also been made in understanding the mechanisms that underlie the pathogenesis of pSS, which has enabled a more targeted therapeutic approach to be taken. At present, therapeutic decisions rely on the evaluation of symptoms and systemic manifestations and are mostly formed on the basis of experience rather than evidence, and on similarities with other autoimmune diseases, although the 2019 management recommendations from EULAR are now being used to inform clinical management of pSS. This Review summarizes the available evidence for systemic treatments for pSS and includes discussions of advances in outcome assessment, the current evidence for DMARD use and an overview of promising future therapeutics.

Key points

  • Currently available classic immunosuppressive drugs might be effective for treating some systemic manifestations of primary Sjögren syndrome (pSS), as is the case for other connective tissue diseases.

  • Following the failure of the first randomized controlled trials (RCTs) in pSS, efforts are ongoing to define new therapeutic targets and new outcome measures.

  • For the first time, two agents have met their primary outcome of improvement in systemic disease activity in RCTs in pSS: anti-B cell-activating factor receptor and anti-CD40 antibodies.

  • Targeting B cells remains the most promising therapeutic approach for pSS.

  • New outcome measures for RCTs aim to combine end points to assess all disease manifestations, including systemic activity, saliva and tears function, patient-reported outcomes and biological features.

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

Access options

Buy this article

Purchase on Springer Link

Instant access to full article PDF

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

Fig. 1: New therapeutic targets in primary Sjögren syndrome.

Similar content being viewed by others

References

  1. Ramos-Casals, M. et al. Primary Sjögren syndrome in Spain: clinical and immunologic expression in 1010 patients. Medicine 87, 210–219 (2008).

    Article  CAS  PubMed  Google Scholar 

  2. Mariette, X. & Criswell, L. A. Primary Sjögren’s syndrome. N. Engl. J. Med. 378, 931–939 (2018).

    Article  PubMed  Google Scholar 

  3. Nocturne, G. & Mariette, X. Advances in understanding the pathogenesis of primary Sjögren’s syndrome. Nat. Rev. Rheumatol. 9, 544–556 (2013).

    Article  CAS  PubMed  Google Scholar 

  4. Ramos-Casals, M. et al. EULAR recommendations for the management of Sjögren’s syndrome with topical and systemic therapies. Ann. Rheum. Dis. 79, 3–18 (2020).

    Article  CAS  PubMed  Google Scholar 

  5. Brito-Zerón, P. et al. Efficacy and safety of topical and systemic medications: a systematic literature review informing the EULAR recommendations for the management of Sjögren’s syndrome. RMD Open 5, e001064 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  6. James, K. et al. A transcriptional signature of fatigue derived from patients with primary Sjögren’s syndrome. PLoS ONE 10, e0143970 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Gottenberg, J.-E. et al. Correlation of serum B lymphocyte stimulator and β2 microglobulin with autoantibody secretion and systemic involvement in primary Sjogren’s syndrome. Ann. Rheum. Dis. 64, 1050–1055 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Nocturne, G. et al. Rheumatoid factor and disease activity are independent predictors of lymphoma in primary Sjögren’s syndrome. Arthritis Rheumatol. 68, 977–985 (2016).

    Article  CAS  PubMed  Google Scholar 

  9. Nocturne, G., Pontarini, E., Bombardieri, M. & Mariette, X. Lymphomas complicating primary Sjögren’s syndrome: from autoimmunity to lymphoma. Rheumatology https://doi.org/10.1093/rheumatology/kez052 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Papageorgiou, A. et al. Predicting the outcome of Sjogren’s syndrome-associated non-Hodgkin’s lymphoma patients. PLoS ONE 10, e0116189 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Nocturne, G. & Mariette, X. Sjögren syndrome-associated lymphomas: an update on pathogenesis and management. Br. J. Haematol. 168, 317–327 (2015).

    Article  CAS  PubMed  Google Scholar 

  12. Nocturne, G. & Mariette, X. B cells in the pathogenesis of primary Sjögren syndrome. Nat. Rev. Rheumatol. 14, 133–145 (2018).

    Article  CAS  PubMed  Google Scholar 

  13. Devauchelle-Pensec, V. et al. Treatment of primary Sjögren syndrome with rituximab: a randomized trial. Ann. Intern. Med. 160, 233–242 (2014).

    Article  PubMed  Google Scholar 

  14. Bowman, S. J. et al. Randomized controlled trial of rituximab and cost-effectiveness analysis in treating fatigue and oral dryness in primary Sjögren’s syndrome. Arthritis Rheumatol. 69, 1440–1450 (2017).

    Article  CAS  PubMed  Google Scholar 

  15. Manfrè, V. et al. One year in review 2020: comorbidities, diagnosis and treatment of primary Sjögren’s syndrome. Clin. Exp. Rheumatol. 38 (Suppl. 126), 10–22 (2020).

    PubMed  Google Scholar 

  16. Shiboski, C. H. et al. 2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjögren’s syndrome: a consensus and data-driven methodology involving three international patient cohorts. Ann. Rheum. Dis. 76, 9–16 (2017).

    Article  PubMed  Google Scholar 

  17. Seror, R. et al. European League Against Rheumatism Sjögren’s Syndrome Disease Activity Index and European League Against Rheumatism Sjögren’s Syndrome Patient-Reported Index: a complete picture of primary Sjögren’s syndrome patients. Arthritis Care Res. 65, 1358–1364 (2013).

    Article  CAS  Google Scholar 

  18. Seror, R. et al. Defining disease activity states and clinically meaningful improvement in primary Sjögren’s syndrome with EULAR primary Sjögren’s syndrome disease activity (ESSDAI) and patient-reported indexes (ESSPRI). Ann. Rheum. Dis. 75, 382–389 (2016).

    Article  CAS  PubMed  Google Scholar 

  19. Seror, R. et al. Accurate detection of changes in disease activity in primary Sjögren’s syndrome by the European League Against Rheumatism Sjögren’s Syndrome Disease Activity Index. Arthritis Care Res. 62, 551–558 (2010).

    Article  Google Scholar 

  20. Seror, R. et al. Validation of EULAR primary Sjögren’s syndrome disease activity (ESSDAI) and patient indexes (ESSPRI). Ann. Rheum. Dis. 74, 859–866 (2015).

    Article  PubMed  Google Scholar 

  21. Gottenberg, J.-E. et al. Efficacy of rituximab in systemic manifestations of primary Sjogren’s syndrome: results in 78 patients of the AutoImmune and Rituximab registry. Ann. Rheum. Dis. 72, 1026–1031 (2013).

    Article  CAS  PubMed  Google Scholar 

  22. Pertovaara, M. & Korpela, M. Serum β2 microglobulin correlates with the new ESSDAI in patients with Sjögren’s syndrome. Ann. Rheum. Dis. 70, 2236–2237 (2011).

    Article  CAS  PubMed  Google Scholar 

  23. Quartuccio, L. et al. BLyS upregulation in Sjogren’s syndrome associated with lymphoproliferative disorders, higher ESSDAI score and B-cell clonal expansion in the salivary glands. Rheumatology 52, 276–281 (2013).

    Article  CAS  PubMed  Google Scholar 

  24. Tobón, G. J. et al. Role of Fms-like tyrosine kinase 3 ligand as a potential biologic marker of lymphoma in primary Sjögren’s syndrome. Arthritis Rheum. 65, 3218–3227 (2013).

    Article  PubMed  CAS  Google Scholar 

  25. Brito-Zerón, P. et al. Systemic activity and mortality in primary Sjögren syndrome: predicting survival using the EULAR-SS Disease Activity Index (ESSDAI) in 1045 patients. Ann. Rheum. Dis. 75, 348–355 (2016).

    Article  PubMed  CAS  Google Scholar 

  26. Flores-Chávez, A. et al. Severe, life-threatening phenotype of primary Sjögren’s syndrome: clinical characterisation and outcomes in 1580 patients (GEAS-SS Registry). Clin. Exp. Rheumatol. 36 (Suppl. 112), 121–129 (2018).

    PubMed  Google Scholar 

  27. Gottenberg, J.-E. et al. Serum levels of beta2-microglobulin and free light chains of immunoglobulins are associated with systemic disease activity in primary Sjögren’s syndrome. Data at enrollment in the prospective ASSESS cohort. PLoS ONE 8, e59868 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Sacre, K., Criswell, L. A. & McCune, J. M. Hydroxychloroquine is associated with impaired interferon-alpha and tumor necrosis factor-alpha production by plasmacytoid dendritic cells in systemic lupus erythematosus. Arthritis Res. Ther. 14, R155 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Gottenberg, J.-E. et al. Effects of hydroxychloroquine on symptomatic improvement in primary Sjögren syndrome: the JOQUER randomized clinical trial. JAMA 312, 249–258 (2014).

    Article  PubMed  CAS  Google Scholar 

  30. Fox, R. I., Dixon, R., Guarrasi, V. & Krubel, S. Treatment of primary Sjögren’s syndrome with hydroxychloroquine: a retrospective, open-label study. Lupus 5 (Suppl. 1), S31–S36 (1996).

    Article  PubMed  Google Scholar 

  31. Tishler, M., Yaron, I., Shirazi, I. & Yaron, M. Hydroxychloroquine treatment for primary Sjögren’s syndrome: its effect on salivary and serum inflammatory markers. Ann. Rheum. Dis. 58, 253–256 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kruize, A. A. et al. Hydroxychloroquine treatment for primary Sjögren’s syndrome: a two year double blind crossover trial. Ann. Rheum. Dis. 52, 360–364 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bodewes, I. L. A., Gottenberg, J.-E., van Helden-Meeuwsen, C. G., Mariette, X. & Versnel, M. A. Hydroxychloroquine treatment downregulates systemic interferon activation in primary Sjögren’s syndrome in the JOQUER randomized trial. Rheumatology 59, 107–111 (2020).

    Article  CAS  PubMed  Google Scholar 

  34. van der Heijden, E. H. M. et al. Leflunomide–hydroxychloroquine combination therapy in patients with primary Sjögren’s syndrome (RepurpSS-I): a placebo-controlled, double-blinded, randomised clinical trial. Lancet Rheumatol. 2, e260–e269 (2020).

    Article  Google Scholar 

  35. Mariette, X. 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. 50, 1270–1276 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. Sankar, V. et al. Etanercept in Sjögren’s syndrome: a twelve-week randomized, double-blind, placebo-controlled pilot clinical trial. Arthritis Rheum. 50, 2240–2245 (2004).

    Article  CAS  PubMed  Google Scholar 

  37. Palucka, A. K., Blanck, J.-P., Bennett, L., Pascual, V. & Banchereau, J. Cross-regulation of TNF and IFN-α in autoimmune diseases. Proc. Natl Acad. Sci. USA 102, 3372–3377 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Norheim, K. B., Harboe, E., Gøransson, L. G. & Omdal, R. Interleukin-1 inhibition and fatigue in primary Sjögren’s syndrome—a double blind, randomised clinical trial. PLoS ONE 7, e30123 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Howard Tripp, N. et al. Fatigue in primary Sjögren’s syndrome is associated with lower levels of proinflammatory cytokines. RMD Open 2, e000282 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Pijpe, J. et al. Rituximab treatment in patients with primary Sjögren’s syndrome: an open-label phase II study. Arthritis Rheum. 52, 2740–2750 (2005).

    Article  CAS  PubMed  Google Scholar 

  41. Devauchelle-Pensec, V. et al. Improvement of Sjögren’s syndrome after two infusions of rituximab (anti-CD20). Arthritis Rheum. 57, 310–317 (2007).

    Article  CAS  PubMed  Google Scholar 

  42. St Clair, E. W. et al. Rituximab therapy for primary Sjögren’s syndrome: an open-label clinical trial and mechanistic analysis. Arthritis Rheum. 65, 1097–1106 (2013).

    Article  CAS  Google Scholar 

  43. Devauchelle-Pensec, V. et al. Effects of rituximab therapy on quality of life in patients with primary Sjögren’s syndrome. Clin. Exp. Rheumatol. 29, 6–12 (2011).

    PubMed  Google Scholar 

  44. Meijer, J. M. et al. Health-related quality of life, employment and disability in patients with Sjogren’s syndrome. Rheumatology 48, 1077–1082 (2009).

    Article  PubMed  Google Scholar 

  45. Carubbi, F. et al. Efficacy and safety of rituximab treatment in early primary Sjögren’s syndrome: a prospective, multi-center, follow-up study. Arthritis Res. Ther. 15, R172 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Seror, R. et al. Tolerance and efficacy of rituximab and changes in serum B cell biomarkers in patients with systemic complications of primary Sjögren’s syndrome. Ann. Rheum. Dis. 66, 351–357 (2007).

    Article  CAS  PubMed  Google Scholar 

  47. Mekinian, A. et al. Efficacy of rituximab in primary Sjogren’s syndrome with peripheral nervous system involvement: results from the AIR registry. Ann. Rheum. Dis. 71, 84–87 (2012).

    Article  CAS  PubMed  Google Scholar 

  48. Dass, S. et al. Reduction of fatigue in Sjögren syndrome with rituximab: results of a randomised, double-blind, placebo-controlled pilot study. Ann. Rheum. Dis. 67, 1541–1544 (2008).

    Article  CAS  PubMed  Google Scholar 

  49. Meijer, J. M. et al. Effectiveness of rituximab treatment in primary Sjögren’s syndrome: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 62, 960–968 (2010).

    Article  CAS  PubMed  Google Scholar 

  50. Mariette, X. et al. Efficacy and safety of belimumab in primary Sjögren’s syndrome: results of the BELISS open-label phase II study. Ann. Rheum. Dis. 74, 526–531 (2015).

    Article  CAS  PubMed  Google Scholar 

  51. Hirano, T. et al. Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature 324, 73–76 (1986).

    Article  CAS  PubMed  Google Scholar 

  52. Halse, A., Tengnér, P., Wahren-Herlenius, M., Haga, H. & Jonsson, R. Increased frequency of cells secreting interleukin-6 and interleukin-10 in peripheral blood of patients with primary Sjögren’s syndrome. Scand. J. Immunol. 49, 533–538 (1999).

    Article  CAS  PubMed  Google Scholar 

  53. Tishler, M. et al. Elevated tear interleukin-6 levels in patients with Sjögren syndrome. Ophthalmology 105, 2327–2329 (1998).

    Article  CAS  PubMed  Google Scholar 

  54. Felten, R. et al. Interleukin 6 receptor inhibition in primary Sjögren syndrome: a multicentre double-blind randomised placebo-controlled trial. Ann. Rheum. Dis. 80, 329–338 (2021).

    Article  CAS  Google Scholar 

  55. Furie, R. et al. Two-year results from a randomized, controlled study of obinutuzumab for proliferative lupus nephritis [abstract]. Arthritis Rheumatol. 72 (Suppl. 10), 988 (2020).

    Google Scholar 

  56. Lavie, F. et al. B-cell activating factor of the tumour necrosis factor family expression in blood monocytes and T cells from patients with primary Sjögren’s syndrome. Scand. J. Immunol. 67, 185–192 (2008).

    Article  CAS  PubMed  Google Scholar 

  57. Pollard, R. P. E. et al. Serum levels of BAFF, but not APRIL, are increased after rituximab treatment in patients with primary Sjogren’s syndrome: data from a placebo-controlled clinical trial. Ann. Rheum. Dis. 72, 146–148 (2013).

    Article  CAS  PubMed  Google Scholar 

  58. Cornec, D. et al. Blood and salivary-gland BAFF-driven B-cell hyperactivity is associated to rituximab inefficacy in primary Sjögren’s syndrome. J. Autoimmun. 67, 102–110 (2016).

    Article  CAS  PubMed  Google Scholar 

  59. Atisha-Fregoso, Y. et al. Phase II randomized trial of rituximab plus cyclophosphamide followed by belimumab for the treatment of lupus nephritis. Arthritis Rheumatol. 73, 121–131 (2021).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  61. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02631538 (2020).

  62. Dörner, T. et al. Treatment of primary Sjögren’s syndrome with ianalumab (VAY736) targeting B cells by BAFF receptor blockade coupled with enhanced, antibody-dependent cellular cytotoxicity. Ann. Rheum. Dis. 78, 641–647 (2019).

    Article  PubMed  CAS  Google Scholar 

  63. Dörner, T. et al. Ianalumab (VAY736), a dual mode of action biologic combining BAFF receptor inhibition with B cell depletion, reaches primary endpoint for treatment of primary Sjogren’s syndrome [abstract OP0302]. Ann. Rheum. Dis. 79 (Suppl. 1), 187–188 (2020).

    Google Scholar 

  64. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04078386 (2021).

  65. Elgueta, R. et al. Molecular mechanism and function of CD40/CD40L engagement in the immune system. Immunol. Rev. 229, 152–172 (2009).

    Article  CAS  PubMed  Google Scholar 

  66. Belkhir, R. et al. Upregulation of membrane-bound CD40L on CD4+ T cells in women with primary Sjögren’s syndrome. Scand. J. Immunol. 79, 37–42 (2014).

    Article  CAS  PubMed  Google Scholar 

  67. Fisher, B. A. et al. Assessment of the anti-CD40 antibody iscalimab in patients with primary Sjögren’s syndrome: a multicentre, randomised, double-blind, placebo-controlled, proof-of-concept study. Lancet Rheumatol. 2, e142–e152 (2020).

    Article  Google Scholar 

  68. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04572841 (2021).

  69. Petro, J. B., Rahman, S. M., Ballard, D. W. & Khan, W. N. Bruton’s tyrosine kinase is required for activation of IκB kinase and nuclear factor κB in response to B cell receptor engagement. J. Exp. Med. 191, 1745–1754 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Wang, M. L. et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N. Engl. J. Med. 369, 507–516 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Wilson, W. H. et al. Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma. Nat. Med. 21, 922–926 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Kil, L. P. et al. Btk levels set the threshold for B-cell activation and negative selection of autoreactive B cells in mice. Blood 119, 3744–3756 (2012).

    Article  CAS  PubMed  Google Scholar 

  73. Rivière, E. et al. Salivary gland epithelial cells from patients with Sjögren’s syndrome induce B-lymphocyte survival and activation. Ann. Rheum. Dis. 79, 1468–1477 (2020).

    Article  PubMed  CAS  Google Scholar 

  74. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04035668 (2021).

  75. Fruman, D. A. et al. The PI3K pathway in human disease. Cell 170, 605–635 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Furman, R. R. et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N. Engl. J. Med. 370, 997–1007 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Gopal, A. K. et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N. Engl. J. Med. 370, 1008–1018 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Juarez, M. et al. A phase 2 randomized, double-blind, placebo-controlled, proof-of-concept study of oral seletalisib in primary Sjögren’s syndrome. Rheumatology 60, 1364–1375 (2021).

    Article  CAS  PubMed  Google Scholar 

  79. Amft, N. et al. Ectopic expression of the B cell-attracting chemokine BCA-1 (CXCL13) on endothelial cells and within lymphoid follicles contributes to the establishment of germinal center-like structures in Sjögren’s syndrome. Arthritis Rheum. 44, 2633–2641 (2001).

    Article  CAS  PubMed  Google Scholar 

  80. Salomonsson, S. et al. Cellular basis of ectopic germinal center formation and autoantibody production in the target organ of patients with Sjögren’s syndrome. Arthritis Rheum. 48, 3187–3201 (2003).

    Article  CAS  PubMed  Google Scholar 

  81. Halse, A. K., Marthinussen, M. C., Wahren-Herlenius, M. & Jonsson, R. Isotype distribution of anti-Ro/SS-A and anti-La/SS-B antibodies in plasma and saliva of patients with Sjögren’s syndrome. Scand. J. Rheumatol. 29, 13–19 (2000).

    Article  CAS  PubMed  Google Scholar 

  82. Theander, E. et al. Lymphoid organisation in labial salivary gland biopsies is a possible predictor for the development of malignant lymphoma in primary Sjögren’s syndrome. Ann. Rheum. Dis. 70, 1363–1368 (2011).

    Article  PubMed  Google Scholar 

  83. 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).

    Article  CAS  PubMed  Google Scholar 

  84. St Clair, E. W. et al. Clinical efficacy and safety of baminercept, a lymphotoxin β receptor fusion protein, in primary Sjögren’s syndrome: results from a phase II randomized, double-blind, placebo-controlled trial. Arthritis Rheumatol. 70, 1470–1480 (2018).

    Article  CAS  Google Scholar 

  85. Crotty, S. Follicular helper CD4 T cells (TFH). Annu. Rev. Immunol. 29, 621–663 (2011).

    Article  CAS  PubMed  Google Scholar 

  86. Verstappen, G. M., Kroese, F. G. M. & Bootsma, H. T cells in primary Sjögren’s syndrome: targets for early intervention. Rheumatology https://doi.org/10.1093/rheumatology/kez004 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Mariette, X. et al. A phase 2a study of MEDI5872 (AMG557), a fully human anti-ICOS ligand monoclonal antibody in patients with primary Sjögren’s syndrome [abstract]. Arthritis Rheumatol. 71 (Suppl. 10), 2417 (2019).

    Google Scholar 

  88. 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 (Suppl. 2), S21–S25 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Adler, S. et al. Evaluation of histologic, serologic, and clinical changes in response to abatacept treatment of primary Sjögren’s syndrome: a pilot study. Arthritis Care Res. 65, 1862–1868 (2013).

    Article  CAS  Google Scholar 

  90. Meiners, P. M. et al. Abatacept treatment reduces disease activity in early primary Sjögren’s syndrome (open-label proof of concept ASAP study). Ann. Rheum. Dis. 73, 1393–1396 (2014).

    Article  CAS  PubMed  Google Scholar 

  91. van Nimwegen, J. F. et al. Abatacept treatment for patients with early active primary Sjögren’s syndrome: a single-centre, randomised, double-blind, placebo-controlled, phase 3 trial (ASAP-III study). Lancet Rheumatol. 2, e153–e163 (2020).

    Article  Google Scholar 

  92. Baer, A. N. et al. Efficacy and safety of abatacept in active primary Sjögren’s syndrome: results of a phase III, randomised, placebo-controlled trial. Ann. Rheum. Dis. 80, 339–348 (2020).

    Article  CAS  Google Scholar 

  93. Hall, J. C. et al. Molecular subsetting of interferon pathways in Sjögren’s syndrome. Arthritis Rheumatol. 67, 2437–2446 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Werth, V. et al. BIIB059, a humanized monoclonal antibody targeting BDCA2 on plasmacytoid dendritic cells (pDC), shows dose-related efficacy in the phase 2 LILAC study in patients (pts) with active cutaneous lupus erythematosus (CLE) [abstract OP0193]. Ann. Rheum. Dis. 79 (Suppl. 1), 120–121 (2020).

    Article  Google Scholar 

  95. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04496960 (2021).

  96. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04093531 (2021).

  97. Oni, C. et al. Eligibility for clinical trials in primary Sjögren’s syndrome: lessons from the UK primary Sjögren’s syndrome registry. Rheumatology 55, 544–552 (2016).

    CAS  PubMed  Google Scholar 

  98. Devauchelle-Pensec, V. et al. Which and how many patients should be included in randomised controlled trials to demonstrate the efficacy of biologics in primary Sjögren’s syndrome? PLoS ONE 10, e0133907 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Arends, S. et al. Composite of relevant endpoints for Sjögren’s syndrome (CRESS) [abstract]. Arthritis Rheumatol. 72 (Suppl. 10), 1502 (2020).

    Google Scholar 

  100. European Medicines Agency. EU Clinical Trials Register https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-003140-12/NL (2015).

  101. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01782235 (2019).

  102. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02149420 (2019).

  103. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02291029 (2021).

  104. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03905525 (2021).

  105. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02610543 (2020).

  106. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02334306 (2019).

  107. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02067910 (2019).

  108. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02915159 (2020).

Download references

Acknowledgements

The work of the authors is supported by the Innovative Medicines Initiative 2 Joint Undertaking (NECESSITY grant agreement 806975).

Author information

Authors and Affiliations

Authors

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Xavier Mariette.

Ethics declarations

Competing interests

R.S. declares that she has received honorarium from BMS, Pfizer and UCB. G.N. declares that she has received honorarium from Lilly, Novartis and UCB. X.M. declares that he has received honorarium from BMS, Galapagos, Gilead, GSK, Novartis, Pfizer, Servier and UCB. X.M. has also received an unrelated research grant from OSE Immunotherapeutics.

Additional information

Peer review information

Nature Reviews Rheumatology thanks V. Trevisani and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

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

Related links

NECESSITY project: https://www.imi.europa.eu/projects-results/project-factsheets/necessity

Glossary

Xerostomia

Oral dryness.

Xerophthalmia

Ocular dryness.

Light zone

An area of the germinal centre in which B cells depend on T cell help and are selected by competing for antigens presented by follicular dendritic cells.

Dark zone

An area of the germinal centre that contains large centroblasts that are rapidly proliferating and undergoing somatic mutation.

Focus score

The number of foci (dense aggregates of ≥50 mononuclear cells) per 4 mm2 over the whole glandular area of a salivary gland.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Seror, R., Nocturne, G. & Mariette, X. Current and future therapies for primary Sjögren syndrome. Nat Rev Rheumatol 17, 475–486 (2021). https://doi.org/10.1038/s41584-021-00634-x

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41584-021-00634-x

This article is cited by

Search

Quick links

Nature Briefing

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

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