Skip to main content
Log in

Targeted Therapy for Primary Sjögren’s Syndrome: Where are We Now?

  • Leading Article
  • Published:
BioDrugs Aims and scope Submit manuscript

Abstract

Primary Sjögren's syndrome (pSS) is an autoimmune exocrinopathy characterized by dryness symptoms. This review briefly describes recent advances in the targeted therapies for pSS. Biologics evaluated for pSS treatment mainly include B cell-depleting agents, inhibitors of B cell activation, and agents that target co-signaling molecules or proinflammatory cytokines. Small molecule inhibitors that target signaling pathways have also been evaluated. However, current evidence for the efficacy of targeted therapies in pSS is still sparse. Although ianalumab (an anti–B cell-activating factor [BAFF]-receptor antibody) and iscalimab (an anti-CD40 antibody) are promising biologics for pSS, their efficacy still needs to be evaluated in larger clinical trials. For other biologics, clinical trials have found no differences versus placebo in the change from baseline in European League Against Rheumatism Sjögren's Syndrome Disease Activity Index (ESSDAI) score and fatigue score. Possible causes of the disappointing outcomes mainly include the inefficacy of those evaluated biologics in treating pSS, the high heterogeneous nature of pSS, irreversible exocrine glandular failure at advanced disease stages, inappropriate recruitment strategy in clinical trials, and outcome measures. Early diagnosis and glandular function-centered outcome measures may help to improve the current situation in the systemic therapy of pSS.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Mariette X, Criswell LA. Primary Sjogren’s syndrome. N Engl J Med. 2018;378(10):931–9. https://doi.org/10.1056/NEJMcp1702514.

    Article  PubMed  Google Scholar 

  2. Parisis D, Chivasso C, Perret J, Soyfoo MS, Delporte C. Current state of knowledge on primary Sjogren’s Syndrome, an autoimmune exocrinopathy. J Clin Med. 2020;9(7):2299. https://doi.org/10.3390/jcm9072299.

    Article  CAS  PubMed Central  Google Scholar 

  3. Maciel G, Crowson CS, Matteson EL, Cornec D. Prevalence of primary Sjogren’s syndrome in a US population-based cohort. Arthritis Care Res (Hoboken). 2017;69(10):1612–6. https://doi.org/10.1002/acr.23173.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Mavragani CP, Moutsopoulos HM. Sjogren’s syndrome. Annu Rev Pathol. 2014;9:273–85. https://doi.org/10.1146/annurev-pathol-012513-104728.

    Article  CAS  PubMed  Google Scholar 

  5. Pego-Reigosa JM, Restrepo-Velez J, Baldini C, Rua-Figueroa Fernandez de Larrinoa I. Comorbidities excluding lymphoma in Sjogren’s syndrome. Rheumatol Oxf. 2021;60(5):2075–84. https://doi.org/10.1093/rheumatology/key329.

    Article  CAS  Google Scholar 

  6. Johnsen SJ, Brun JG, Goransson LG, Smastuen MC, Johannesen TB, Haldorsen K, et al. Risk of non-Hodgkin’s lymphoma in primary Sjogren’s syndrome: a population-based study. Arthritis Care Res (Hoboken). 2013;65(5):816–21. https://doi.org/10.1002/acr.21887.

    Article  PubMed  Google Scholar 

  7. Ramos-Casals M, Brito-Zeron P, Bombardieri S, Bootsma H, De Vita S, Dorner T, et al. EULAR recommendations for the management of Sjogren’s syndrome with topical and systemic therapies. Ann Rheum Dis. 2020;79(1):3–18. https://doi.org/10.1136/annrheumdis-2019-216114.

    Article  CAS  PubMed  Google Scholar 

  8. Chu LL, Cui K, Pope JE. Meta-analysis of treatment for primary sjogren’s syndrome. Arthritis Care Res (Hoboken). 2020;72(7):1011–21. https://doi.org/10.1002/acr.23917.

    Article  PubMed  Google Scholar 

  9. Gottenberg JE, Ravaud P, Puechal X, Le Guern V, Sibilia J, Goeb V, et al. Effects of hydroxychloroquine on symptomatic improvement in primary Sjogren syndrome: the JOQUER randomized clinical trial. JAMA. 2014;312(3):249–58. https://doi.org/10.1001/jama.2014.7682.

    Article  CAS  PubMed  Google Scholar 

  10. Brito-Zeron P, Retamozo S, Kostov B, Baldini C, Bootsma H, De Vita S, et al. Efficacy and safety of topical and systemic medications: a systematic literature review informing the EULAR recommendations for the management of Sjogren’s syndrome. RMD Open. 2019;5(2): e001064. https://doi.org/10.1136/rmdopen-2019-001064.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Xuan J, Ji Z, Wang B, Zeng X, Chen R, He Y, et al. Serological evidence for the association between Epstein-Barr virus infection and Sjogren’s syndrome. Front Immunol. 2020;11: 590444. https://doi.org/10.3389/fimmu.2020.590444.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Taylor KE, Wong Q, Levine DM, McHugh C, Laurie C, Doheny K, et al. Genome-wide association analysis reveals genetic heterogeneity of Sjogren’s syndrome according to ancestry. Arthritis Rheumatol. 2017;69(6):1294–305. https://doi.org/10.1002/art.40040.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Mavragani CP. Mechanisms and new strategies for primary Sjogren’s syndrome. Annu Rev Med. 2017;68:331–43. https://doi.org/10.1146/annurev-med-043015-123313.

    Article  CAS  PubMed  Google Scholar 

  14. Mingueneau M, Boudaoud S, Haskett S, Reynolds TL, Nocturne G, Norton E, et al. Cytometry by time-of-flight immunophenotyping identifies a blood Sjogren’s signature correlating with disease activity and glandular inflammation. J Allergy Clin Immunol. 2016;137(6):1809–21. https://doi.org/10.1016/j.jaci.2016.01.024.

    Article  PubMed  Google Scholar 

  15. Tasaki S, Suzuki K, Nishikawa A, Kassai Y, Takiguchi M, Kurisu R, et al. Multiomic disease signatures converge to cytotoxic CD8 T cells in primary Sjogren’s syndrome. Ann Rheum Dis. 2017;76(8):1458–66. https://doi.org/10.1136/annrheumdis-2016-210788.

    Article  CAS  PubMed  Google Scholar 

  16. Pontarini E, Murray-Brown WJ, Croia C, Lucchesi D, Conway J, Rivellese F, et al. Unique expansion of IL-21+ Tfh and Tph cells under control of ICOS identifies Sjogren’s syndrome with ectopic germinal centres and MALT lymphoma. Ann Rheum Dis. 2020;79(12):1588–99. https://doi.org/10.1136/annrheumdis-2020-217646.

    Article  CAS  PubMed  Google Scholar 

  17. Mielle J, Tison A, Cornec D, Le Pottier L, Daien C, Pers JO. B cells in Sjogren’s syndrome: from pathophysiology to therapeutic target. Rheumatol (Oxf). 2019. https://doi.org/10.1093/rheumatology/key332.

    Article  Google Scholar 

  18. Reed JH, Verstappen GM, Rischmueller M, Bryant VL. When B cells break bad: development of pathogenic B cells in Sjogren’s syndrome. Clin Exp Rheumatol. 2020;126(4):271–82.

    Google Scholar 

  19. Verstappen GM, Ice JA, Bootsma H, Pringle S, Haacke EA, de Lange K, et al. Gene expression profiling of epithelium-associated FcRL4(+) B cells in primary Sjogren’s syndrome reveals a pathogenic signature. J Autoimmun. 2020;109: 102439. https://doi.org/10.1016/j.jaut.2020.102439.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Fonseca VR, Romao VC, Agua-Doce A, Santos M, Lopez-Presa D, Ferreira AC, et al. The ratio of blood T follicular regulatory cells to T Follicular helper cells marks ectopic lymphoid structure formation while activated follicular helper T cells indicate disease activity in primary Sjogren’s syndrome. Arthritis Rheumatol. 2018;70(5):774–84. https://doi.org/10.1002/art.40424.

    Article  CAS  PubMed  Google Scholar 

  21. Bombardieri M, Lewis M, Pitzalis C. Ectopic lymphoid neogenesis in rheumatic autoimmune diseases. Nat Rev Rheumatol. 2017;13(3):141–54. https://doi.org/10.1038/nrrheum.2016.217.

    Article  CAS  PubMed  Google Scholar 

  22. Astorri E, Scrivo R, Bombardieri M, Picarelli G, Pecorella I, Porzia A, et al. CX3CL1 and CX3CR1 expression in tertiary lymphoid structures in salivary gland infiltrates: fractalkine contribution to lymphoid neogenesis in Sjogren’s syndrome. Rheumatology. 2014;53(4):611–20. https://doi.org/10.1093/rheumatology/ket401.

    Article  CAS  PubMed  Google Scholar 

  23. Nayar S, Campos J, Smith CG, Iannizzotto V, Gardner DH, Colafrancesco S, et al. Phosphatidylinositol 3-kinase delta pathway: a novel therapeutic target for Sjogren’s syndrome. Ann Rheum Dis. 2019;78(2):249–60. https://doi.org/10.1136/annrheumdis-2017-212619.

    Article  CAS  PubMed  Google Scholar 

  24. Mavragani CP, Moutsopoulos HM. Sjogren's syndrome: old and new therapeutic targets. J Autoimmun. 2020;110:102364. https://doi.org/10.1016/j.jaut.2019.102364.

  25. Szabo K, Jambor I, Szanto A, Horvath IF, Tarr T, Nakken B, et al. The imbalance of circulating follicular T Helper Cell Subsets In Primary Sjogren’s syndrome associates with serological alterations and abnormal B-cell distribution. Front Immunol. 2021;12: 639975. https://doi.org/10.3389/fimmu.2021.639975.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Abe S, Tsuboi H, Kudo H, Asashima H, Ono Y, Honda F, et al. M3 muscarinic acetylcholine receptor reactive Th17 cells in primary Sjogren’s syndrome. JCI Insight. 2020;5(15): e135982. https://doi.org/10.1172/jci.insight.135982.

    Article  PubMed Central  Google Scholar 

  27. Park JS, Kim SM, Choi J, Jung KA, Hwang SH, Yang S, et al. Interleukin-21-mediated suppression of the Pax3-Id3 pathway exacerbates the development of Sjogren’s syndrome via follicular helper T cells. Cytokine. 2020;125: 154834. https://doi.org/10.1016/j.cyto.2019.154834.

    Article  CAS  PubMed  Google Scholar 

  28. Brkic Z, Maria NI, van Helden-Meeuwsen CG, van de Merwe JP, van Daele PL, Dalm VA, et al. Prevalence of interferon type I signature in CD14 monocytes of patients with Sjogren’s syndrome and association with disease activity and BAFF gene expression. Ann Rheum Dis. 2013;72(5):728–35. https://doi.org/10.1136/annrheumdis-2012-201381.

    Article  CAS  PubMed  Google Scholar 

  29. Nicaise C, Weichselbaum L, Schandene L, Gangji V, Dehavay F, Bouchat J, et al. Phagocyte-specific S100A8/A9 is upregulated in primary Sjogren’s syndrome and triggers the secretion of pro-inflammatory cytokines in vitro. Clin Exp Rheumatol. 2017;35(1):129–36.

    PubMed  Google Scholar 

  30. Vakrakou AG, Boiu S, Ziakas PD, Xingi E, Boleti H, Manoussakis MN. Systemic activation of NLRP3 inflammasome in patients with severe primary Sjogren’s syndrome fueled by inflammagenic DNA accumulations. J Autoimmun. 2018;91:23–33. https://doi.org/10.1016/j.jaut.2018.02.010.

    Article  CAS  PubMed  Google Scholar 

  31. Pringle S, Wang X, Verstappen G, Terpstra JH, Zhang CK, He A, et al. Salivary gland stem cells age prematurely in primary Sjogren’s syndrome. Arthritis Rheumatol. 2019;71(1):133–42. https://doi.org/10.1002/art.40659.

    Article  CAS  PubMed  Google Scholar 

  32. Verstappen GM, Pringle S, Bootsma H, Kroese FGM. Epithelial-immune cell interplay in primary Sjogren syndrome salivary gland pathogenesis. Nat Rev Rheumatol. 2021. https://doi.org/10.1038/s41584-021-00605-2.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Bombardieri M, Argyropoulou OD, Ferro F, Coleby R, Pontarini E, Governato G, et al. One year in review 2020: pathogenesis of primary Sjogren’s syndrome. Clin Exp Rheumatol. 2020;38(4):3–9.

    PubMed  Google Scholar 

  34. Shiboski CH, Shiboski SC, Seror R, Criswell LA, Labetoulle M, Lietman TM, et al. 2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjogren’s syndrome: a consensus and data-driven methodology involving three international patient cohorts. Ann Rheum Dis. 2017;76(1):9–16. https://doi.org/10.1136/annrheumdis-2016-210571.

    Article  PubMed  Google Scholar 

  35. Brito-Zeron P, Acar-Denizli N, Zeher M, Rasmussen A, Seror R, Theander E, et al. Influence of geolocation and ethnicity on the phenotypic expression of primary Sjogren’s syndrome at diagnosis in 8310 patients: a cross-sectional study from the Big Data Sjogren Project Consortium. Ann Rheum Dis. 2017;76(6):1042–50. https://doi.org/10.1136/annrheumdis-2016-209952.

    Article  PubMed  Google Scholar 

  36. Mandl T, Jorgensen TS, Skougaard M, Olsson P, Kristensen LE. Work disability in newly diagnosed patients with primary Sjogren syndrome. J Rheumatol. 2017;44(2):209–15. https://doi.org/10.3899/jrheum.160932.

    Article  PubMed  Google Scholar 

  37. Sandhya P, Janardana R, Sudarsanam T, Mahasampath G, Prakash JAJ, Danda D. Determinants of diagnosis and disease course in primary Sjogren’s syndrome: results from datamining of electronic health records. Int J Rheum Dis. 2019;22(9):1768–74. https://doi.org/10.1111/1756-185X.13641.

    Article  CAS  PubMed  Google Scholar 

  38. Wang B, Chen S, Zheng Q, Li Y, Zhang X, Xuan J, et al. Early diagnosis and treatment for Sjogren’s syndrome: current challenges, redefined disease stages and future prospects. J Autoimmun. 2021;117: 102590. https://doi.org/10.1016/j.jaut.2020.102590.

    Article  PubMed  Google Scholar 

  39. Leverenz DL, St Clair EW. Recent advances in the search for a targeted immunomodulatory therapy for primary Sjogren's syndrome. F1000Res. 2019;8:F1000. https://doi.org/10.12688/f1000research.19842.1.

  40. Saraux A, Pers JO, Devauchelle-Pensec V. Treatment of primary Sjogren syndrome. Nat Rev Rheumatol. 2016;12(8):456–71. https://doi.org/10.1038/nrrheum.2016.100.

    Article  CAS  PubMed  Google Scholar 

  41. Hartkamp A, Geenen R, Godaert GL, Bootsma H, Kruize AA, Bijlsma JW, et al. Effect of dehydroepiandrosterone administration on fatigue, well-being, and functioning in women with primary Sjogren syndrome: a randomised controlled trial. Ann Rheum Dis. 2008;67(1):91–7. https://doi.org/10.1136/ard.2007.071563.

    Article  CAS  PubMed  Google Scholar 

  42. Wang SQ, Zhang LW, Wei P, Hua H. Is hydroxychloroquine effective in treating primary Sjogren’s syndrome: a systematic review and meta-analysis. BMC Musculoskelet Disord. 2017;18(1):186. https://doi.org/10.1186/s12891-017-1543-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Felten R, Scher F, Sibilia J, Gottenberg JE, Arnaud L. The pipeline of targeted therapies under clinical development for primary Sjogren’s syndrome: A systematic review of trials. Autoimmun Rev. 2019;18(6):576–82. https://doi.org/10.1016/j.autrev.2018.12.008.

    Article  CAS  PubMed  Google Scholar 

  44. Tobon GJ, Pers JO, Youinou P, Saraux A. B cell-targeted therapies in Sjogren’s syndrome. Autoimmun Rev. 2010;9(4):224–8. https://doi.org/10.1016/j.autrev.2009.08.001.

    Article  CAS  PubMed  Google Scholar 

  45. Basta F, Fasola F, Triantafyllias K, Schwarting A. Systemic lupus erythematosus (SLE) Therapy: the old and the new. Rheumatol Ther. 2020;7(3):433–46. https://doi.org/10.1007/s40744-020-00212-9.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Kaegi C, Steiner UC, Wuest B, Crowley C, Boyman O. Systematic review of safety and efficacy of belimumab in treating immune-mediated disorders. Allergy. 2021;76(9):2673–83. https://doi.org/10.1111/all.14704.

    Article  PubMed  Google Scholar 

  47. Vincent FB, Saulep-Easton D, Figgett WA, Fairfax KA, Mackay F. The BAFF/APRIL system: emerging functions beyond B cell biology and autoimmunity. Cytokine Growth Factor Rev. 2013;24(3):203–15. https://doi.org/10.1016/j.cytogfr.2013.04.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Samy E, Wax S, Huard B, Hess H, Schneider P. Targeting BAFF and APRIL in systemic lupus erythematosus and other antibody-associated diseases. Int Rev Immunol. 2017;36(1):3–19. https://doi.org/10.1080/08830185.2016.1276903.

    Article  CAS  PubMed  Google Scholar 

  49. Grigoriadou S, Chowdhury F, Pontarini E, Tappuni A, Bowman SJ, Bombardieri M. B cell depletion with rituximab in the treatment of primary Sjogren’s syndrome: what have we learnt? Clin Exp Rheumatol. 2019;37(3):217–24.

    PubMed  Google Scholar 

  50. Gottenberg JE, Guillevin L, Lambotte O, Combe B, Allanore Y, Cantagrel A, et al. Tolerance and short term efficacy of rituximab in 43 patients with systemic autoimmune diseases. Ann Rheum Dis. 2005;64(6):913–20. https://doi.org/10.1136/ard.2004.029694.

    Article  CAS  PubMed  Google Scholar 

  51. Pijpe J, van Imhoff GW, Spijkervet FK, Roodenburg JL, Wolbink GJ, Mansour K, et al. Rituximab treatment in patients with primary Sjogren’s syndrome: an open-label phase II study. Arthritis Rheum. 2005;52(9):2740–50. https://doi.org/10.1002/art.21260.

    Article  CAS  PubMed  Google Scholar 

  52. Seror R, Sordet C, Guillevin L, Hachulla E, Masson C, Ittah M, 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(3):351–7. https://doi.org/10.1136/ard.2006.057919.

    Article  CAS  PubMed  Google Scholar 

  53. Devauchelle-Pensec V, Pennec Y, Morvan J, Pers JO, Daridon C, Jousse-Joulin S, et al. Improvement of Sjogren’s syndrome after two infusions of rituximab (anti-CD20). Arthritis Rheum. 2007;57(2):310–7. https://doi.org/10.1002/art.22536.

    Article  CAS  PubMed  Google Scholar 

  54. St Clair EW, Levesque MC, Prak ET, Vivino FB, Alappatt CJ, Spychala ME, et al. Rituximab therapy for primary Sjogren’s syndrome: an open-label clinical trial and mechanistic analysis. Arthritis Rheum. 2013;65(4):1097–106. https://doi.org/10.1002/art.37850.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Pijpe J, Meijer JM, Bootsma H, van der Wal JE, Spijkervet FK, Kallenberg CG, et al. Clinical and histologic evidence of salivary gland restoration supports the efficacy of rituximab treatment in Sjogren’s syndrome. Arthritis Rheum. 2009;60(11):3251–6. https://doi.org/10.1002/art.24903.

    Article  CAS  PubMed  Google Scholar 

  56. Dass S, Bowman SJ, Vital EM, Ikeda K, Pease CT, Hamburger J, et al. Reduction of fatigue in Sjogren syndrome with rituximab: results of a randomised, double-blind, placebo-controlled pilot study. Ann Rheum Dis. 2008;67(11):1541–4. https://doi.org/10.1136/ard.2007.083865.

    Article  CAS  PubMed  Google Scholar 

  57. Meijer JM, Meiners PM, Vissink A, Spijkervet FK, Abdulahad W, Kamminga N, et al. Effectiveness of rituximab treatment in primary Sjogren’s syndrome: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2010;62(4):960–8. https://doi.org/10.1002/art.27314.

    Article  CAS  PubMed  Google Scholar 

  58. Devauchelle-Pensec V, Mariette X, Jousse-Joulin S, Berthelot JM, Perdriger A, Puechal X, et al. Treatment of primary Sjogren syndrome with rituximab: a randomized trial. Ann Intern Med. 2014;160(4):233–42. https://doi.org/10.7326/M13-1085.

    Article  PubMed  Google Scholar 

  59. Bowman SJ, Everett CC, O’Dwyer JL, Emery P, Pitzalis C, Ng WF, et al. Randomized controlled trial of rituximab and cost-effectiveness analysis in treating fatigue and oral dryness in primary Sjogren’s syndrome. Arthritis Rheumatol. 2017;69(7):1440–50. https://doi.org/10.1002/art.40093.

    Article  CAS  PubMed  Google Scholar 

  60. Letaief H, Lukas C, Barnetche T, Gaujoux-Viala C, Combe B, Morel J. Efficacy and safety of biological DMARDs modulating B cells in primary Sjogren’s syndrome: systematic review and meta-analysis. Joint Bone Spine. 2018;85(1):15–22. https://doi.org/10.1016/j.jbspin.2017.06.004.

    Article  CAS  PubMed  Google Scholar 

  61. Voulgarelis M, Giannouli S, Tzioufas AG, Moutsopoulos HM. 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. https://doi.org/10.1136/ard.2005.046193.

    Article  CAS  PubMed  Google Scholar 

  62. Rubin SJS, Bloom MS, Robinson WH. B cell checkpoints in autoimmune rheumatic diseases. Nat Rev Rheumatol. 2019;15(5):303–15. https://doi.org/10.1038/s41584-019-0211-0.

    Article  PubMed  Google Scholar 

  63. Varin MM, Le Pottier L, Youinou P, Saulep D, Mackay F, Pers JO. B-cell tolerance breakdown in Sjogren’s syndrome: focus on BAFF. Autoimmun Rev. 2010;9(9):604–8. https://doi.org/10.1016/j.autrev.2010.05.006.

    Article  CAS  PubMed  Google Scholar 

  64. Mariette X, Roux S, Zhang J, Bengoufa D, Lavie F, Zhou T, et al. The level of BLyS (BAFF) correlates with the titre of autoantibodies in human Sjogren’s syndrome. Ann Rheum Dis. 2003;62(2):168–71. https://doi.org/10.1136/ard.62.2.168.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Ding J, Zhang W, Haskett S, Pellerin A, Xu S, Petersen B, et al. BAFF overexpression increases lymphocytic infiltration in Sjogren’s target tissue, but only inefficiently promotes ectopic B-cell differentiation. Clin Immunol. 2016;169:69–79. https://doi.org/10.1016/j.clim.2016.06.007.

    Article  CAS  PubMed  Google Scholar 

  66. Furie R, Rovin BH, Houssiau F, Malvar A, Teng YKO, Contreras G, et al. Two-year, randomized, controlled trial of belimumab in lupus nephritis. N Engl J Med. 2020;383(12):1117–28. https://doi.org/10.1056/NEJMoa2001180.

    Article  CAS  PubMed  Google Scholar 

  67. Furie R, Petri M, Zamani O, Cervera R, Wallace DJ, Tegzova D, 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. 2011;63(12):3918–30. https://doi.org/10.1002/art.30613.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Brunner HI, Abud-Mendoza C, Viola DO, Calvo Penades I, Levy D, Anton J, et al. Safety and efficacy of intravenous belimumab in children with systemic lupus erythematosus: results from a randomised, placebo-controlled trial. Ann Rheum Dis. 2020;79(10):1340–8. https://doi.org/10.1136/annrheumdis-2020-217101.

    Article  CAS  PubMed  Google Scholar 

  69. Quartuccio L, Salvin S, Corazza L, Gandolfo S, Fabris M, De Vita S. Efficacy of belimumab and targeting of rheumatoid factor-positive B-cell expansion in Sjogren’s syndrome: follow-up after the end of the phase II open-label BELISS study. Clin Exp Rheumatol. 2016;34(2):311–4.

    PubMed  Google Scholar 

  70. Mariette X, Seror R, Quartuccio L, Baron G, Salvin S, Fabris M, et al. Efficacy and safety of belimumab in primary Sjogren’s syndrome: results of the BELISS open-label phase II study. Ann Rheum Dis. 2015;74(3):526–31. https://doi.org/10.1136/annrheumdis-2013-203991.

    Article  CAS  PubMed  Google Scholar 

  71. De Vita S, Quartuccio L, Seror R, Salvin S, Ravaud P, Fabris M, et al. Efficacy and safety of belimumab given for 12 months in primary Sjogren’s syndrome: the BELISS open-label phase II study. Rheumatology. 2015;54(12):2249–56. https://doi.org/10.1093/rheumatology/kev257.

    Article  PubMed  Google Scholar 

  72. De Vita S, Quartuccio L, Salvin S, Picco L, Scott CA, Rupolo M, et al. Sequential therapy with belimumab followed by rituximab in Sjogren’s syndrome associated with B-cell lymphoproliferation and overexpression of BAFF: evidence for long-term efficacy. Clin Exp Rheumatol. 2014;32(4):490–4.

    PubMed  Google Scholar 

  73. McWilliams EM, Lucas CR, Chen T, Harrington BK, Wasmuth R, Campbell A, et al. Anti-BAFF-R antibody VAY-736 demonstrates promising preclinical activity in CLL and enhances effectiveness of ibrutinib. Blood Adv. 2019;3(3):447–60. https://doi.org/10.1182/bloodadvances.2018025684.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Dorner T, Posch MG, Li Y, Petricoul O, Cabanski M, Milojevic JM, et al. Treatment of primary Sjogren’s syndrome with ianalumab (VAY736) targeting B cells by BAFF receptor blockade coupled with enhanced, antibody-dependent cellular cytotoxicity. Ann Rheum Dis. 2019;78(5):641–7. https://doi.org/10.1136/annrheumdis-2018-214720.

    Article  CAS  PubMed  Google Scholar 

  75. Smolen JNP, Tahir H, Schulze-Koops H, Li L, Hojnik M, Gellett A, Liu-Leage S, Pillai S, Mease P. Ianalumab (VAY736), a dual mode of action biologic combining BAFF receptor inhibition with B cell depletion, for treatment of primary Sjögren’s syndrome: results of an International Randomized, Placebo Controlled Dose Range Finding Study in 190 Patients. Arthritis Rheumatol. 2019;2019:71.

    Google Scholar 

  76. Clowse ME, Wallace DJ, Furie RA, Petri MA, Pike MC, Leszczynski P, et al. Efficacy and safety of epratuzumab in moderately to severely active systemic lupus erythematosus: results from two phase III randomized, double-blind, Placebo-Controlled Trials. Arthritis Rheumatol. 2017;69(2):362–75. https://doi.org/10.1002/art.39856.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. O’Keefe TL, Williams GT, Batista FD, Neuberger MS. Deficiency in CD22, a B cell-specific inhibitory receptor, is sufficient to predispose to development of high affinity autoantibodies. J Exp Med. 1999;189(8):1307–13. https://doi.org/10.1084/jem.189.8.1307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Ereno-Orbea J, Sicard T, Cui H, Mazhab-Jafari MT, Benlekbir S, Guarne A, et al. Molecular basis of human CD22 function and therapeutic targeting. Nat Commun. 2017;8(1):764. https://doi.org/10.1038/s41467-017-00836-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. O’Keefe TL, Williams GT, Davies SL, Neuberger MS. Hyperresponsive B cells in CD22-deficient mice. Science. 1996;274(5288):798–801. https://doi.org/10.1126/science.274.5288.798.

    Article  CAS  PubMed  Google Scholar 

  80. Dorner T, Shock A, Goldenberg DM, Lipsky PE. The mechanistic impact of CD22 engagement with epratuzumab on B cell function: Implications for the treatment of systemic lupus erythematosus. Autoimmun Rev. 2015;14(12):1079–86. https://doi.org/10.1016/j.autrev.2015.07.013.

    Article  CAS  PubMed  Google Scholar 

  81. Giltiay NV, Shu GL, Shock A, Clark EA. Targeting CD22 with the monoclonal antibody epratuzumab modulates human B-cell maturation and cytokine production in response to Toll-like receptor 7 (TLR7) and B-cell receptor (BCR) signaling. Arthritis Res Ther. 2017;19(1):91. https://doi.org/10.1186/s13075-017-1284-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Ozgor L, Brandl C, Shock A, Nitschke L. Epratuzumab modulates B-cell signaling without affecting B-cell numbers or B-cell functions in a mouse model with humanized CD22. Eur J Immunol. 2016;46(9):2260–72. https://doi.org/10.1002/eji.201646383.

    Article  CAS  PubMed  Google Scholar 

  83. Steinfeld SD, Tant L, Burmester GR, Teoh NK, Wegener WA, Goldenberg DM, et al. Epratuzumab (humanised anti-CD22 antibody) in primary Sjogren’s syndrome: an open-label phase I/II study. Arthritis Res Ther. 2006;8(4):R129. https://doi.org/10.1186/ar2018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Gottenberg JE, Dorner T, Bootsma H, Devauchelle-Pensec V, Bowman SJ, Mariette X, et al. Efficacy of epratuzumab, an Anti-CD22 Monoclonal IgG antibody, in systemic lupus erythematosus patients with associated Sjogren’s syndrome: post hoc analyses from the Embody trials. Arthritis Rheumatol. 2018;70(5):763–73. https://doi.org/10.1002/art.40425.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Wallace DJ. Editorial: epratuzumab: reveille or requiem? teachable moments for lupus and Sjogren’s syndrome clinical trials. Arthritis Rheumatol. 2018;70(5):633–6. https://doi.org/10.1002/art.40427.

    Article  PubMed  Google Scholar 

  86. Marken J, Muralidharan S, Giltiay NV. Anti-CD40 antibody KPL-404 inhibits T cell-mediated activation of B cells from healthy donors and autoimmune patients. Arthritis Res Ther. 2021;23(1):5. https://doi.org/10.1186/s13075-020-02372-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Pontarini E, Verstappen GM, Grigoriadou S, Kroese FGM, Bootsma H, Bombardieri M. Blocking T cell co-stimulation in primary Sjogren’s syndrome: rationale, clinical efficacy and modulation of peripheral and salivary gland biomarkers. Clin Exp Rheumatol. 2020;38(4):222–7.

    PubMed  Google Scholar 

  88. Gauna AE, Park YJ, Nayar G, Onate M, Jin JO, Stewart CM, et al. Dysregulated co-stimulatory molecule expression in a Sjogren's syndrome mouse model with potential implications by microRNA-146a. Mol Immunol. 2015;68(2):606-16. https://doi.org/10.1016/j.molimm.2015.09.027.

  89. Teng GG, Turkiewicz AM, Moreland LW. Abatacept: a costimulatory inhibitor for treatment of rheumatoid arthritis. Expert Opin Biol Ther. 2005;5(9):1245–54. https://doi.org/10.1517/14712598.5.9.1245.

    Article  CAS  PubMed  Google Scholar 

  90. Adler S, Korner M, Forger F, Huscher D, Caversaccio MD, Villiger PM. Evaluation of histologic, serologic, and clinical changes in response to abatacept treatment of primary Sjogren’s syndrome: a pilot study. Arthritis Care Res (Hoboken). 2013;65(11):1862–8. https://doi.org/10.1002/acr.22052.

    Article  CAS  PubMed  Google Scholar 

  91. Meiners PM, Vissink A, Kroese FG, Spijkervet FK, Smitt-Kamminga NS, Abdulahad WH, et al. Abatacept treatment reduces disease activity in early primary Sjogren’s syndrome (open-label proof of concept ASAP study). Ann Rheum Dis. 2014;73(7):1393–6. https://doi.org/10.1136/annrheumdis-2013-204653.

    Article  CAS  PubMed  Google Scholar 

  92. Nimwegen JME, Zuiden G, Wijnsma R, Delli K, Stel A, 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. 2020;2(3):153–63.

    Article  Google Scholar 

  93. Baer AN, Gottenberg JE, St Clair EW, Sumida T, Takeuchi T, Seror R, et al. Efficacy and safety of abatacept in active primary Sjogren’s syndrome: results of a phase III, randomised, placebo-controlled trial. Ann Rheum Dis. 2020;80(3):339–48. https://doi.org/10.1136/annrheumdis-2020-218599.

    Article  CAS  Google Scholar 

  94. Karnell JL, Rieder SA, Ettinger R, Kolbeck R. Targeting the CD40-CD40L pathway in autoimmune diseases: humoral immunity and beyond. Adv Drug Deliv Rev. 2019;141:92–103. https://doi.org/10.1016/j.addr.2018.12.005.

    Article  CAS  PubMed  Google Scholar 

  95. Elgueta R, Benson MJ, de Vries VC, Wasiuk A, Guo Y, Noelle RJ. Molecular mechanism and function of CD40/CD40L engagement in the immune system. Immunol Rev. 2009;229(1):152–72. https://doi.org/10.1111/j.1600-065X.2009.00782.x.

    Article  CAS  PubMed  Google Scholar 

  96. Mahmoud TI, Wang J, Karnell JL, Wang Q, Wang S, Naiman B, et al. Autoimmune manifestations in aged mice arise from early-life immune dysregulation. Sci Transl Med 2016;8(361):361. https://doi.org/10.1126/scitranslmed.aag0367.

  97. Wieczorek G, Bigaud M, Pfister S, Ceci M, McMichael K, Afatsawo C, et al. Blockade of CD40-CD154 pathway interactions suppresses ectopic lymphoid structures and inhibits pathology in the NOD/ShiLtJ mouse model of Sjogren’s syndrome. Ann Rheum Dis. 2019;78(7):974–8. https://doi.org/10.1136/annrheumdis-2018-213929.

    Article  CAS  PubMed  Google Scholar 

  98. Ristov J, Espie P, Ulrich P, Sickert D, Flandre T, Dimitrova M, et al. Characterization of the in vitro and in vivo properties of CFZ533, a blocking and non-depleting anti-CD40 monoclonal antibody. Am J Transplant. 2018;18(12):2895–904. https://doi.org/10.1111/ajt.14872.

    Article  CAS  PubMed  Google Scholar 

  99. Fisher BSA, Ng W, Bombardieri M, Posch M, Papas 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. 2020;2(3):142–52.

    Article  Google Scholar 

  100. Karnell JL, Albulescu M, Drabic S, Wang L, Moate R, Baca M, et al. A CD40L-targeting protein reduces autoantibodies and improves disease activity in patients with autoimmunity. Sci Transl Med. 2019;11(489):eaar6584. https://doi.org/10.1126/scitranslmed.aar6584.

    Article  CAS  PubMed  Google Scholar 

  101. Rujas E, Cui H, Sicard T, Semesi A, Julien JP. Structural characterization of the ICOS/ICOS-L immune complex reveals high molecular mimicry by therapeutic antibodies. Nat Commun. 2020;11(1):5066. https://doi.org/10.1038/s41467-020-18828-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Sullivan BA, Tsuji W, Kivitz A, Peng J, Arnold GE, Boedigheimer MJ, et al. Inducible T-cell co-stimulator ligand (ICOSL) blockade leads to selective inhibition of anti-KLH IgG responses in subjects with systemic lupus erythematosus. Lupus Sci Med. 2016;3(1): e000146. https://doi.org/10.1136/lupus-2016-000146.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Cheng LE, Amoura Z, Cheah B, Hiepe F, Sullivan BA, Zhou L, et al. Brief report: a randomized, double-blind, parallel-group, placebo-controlled, multiple-dose study to evaluate AMG 557 in patients with systemic lupus erythematosus and active lupus arthritis. Arthritis Rheumatol. 2018;70(7):1071–6. https://doi.org/10.1002/art.40479.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Mariette X, Bombardieri M, Alevizos I, Moate R, Sullivan B, Noaiseh G, et al. A phase 2a study of MEDI5872 (AMG557), a fully human anti-ICOS ligandmonoclonal antibody in patients with primary Sjögren’s syndrome [Abstract]. Arthritis Rheumatol. 2019;71(Suppl 10):2417.

    Google Scholar 

  105. Shen L, Suresh L, Malyavantham K, Kowal P, Xuan J, Lindemann MJ, et al. Different stages of primary Sjogren’s syndrome involving lymphotoxin and type 1 IFN. J Immunol. 2013;191(2):608–13. https://doi.org/10.4049/jimmunol.1203440.

    Article  CAS  PubMed  Google Scholar 

  106. Fava RA, Kennedy SM, Wood SG, Bolstad AI, Bienkowska J, Papandile A, et al. Lymphotoxin-beta receptor blockade reduces CXCL13 in lacrimal glands and improves corneal integrity in the NOD model of Sjogren’s syndrome. Arthritis Res Ther. 2011;13(6):R182. https://doi.org/10.1186/ar3507.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Gatumu MK, Skarstein K, Papandile A, Browning JL, Fava RA, Bolstad AI. Blockade of lymphotoxin-beta receptor signaling reduces aspects of Sjogren’s syndrome in salivary glands of non-obese diabetic mice. Arthritis Res Ther. 2009;11(1):R24. https://doi.org/10.1186/ar2617.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Shen L, Suresh L, Wu J, Xuan J, Li H, Zhang C, et al. A role for lymphotoxin in primary Sjogren’s disease. J Immunol. 2010;185(10):6355–63. https://doi.org/10.4049/jimmunol.1001520.

    Article  CAS  PubMed  Google Scholar 

  109. Bienkowska J, Allaire N, Thai A, Goyal J, Plavina T, Nirula A, et al. Lymphotoxin-LIGHT pathway regulates the interferon signature in rheumatoid arthritis. PLoS ONE. 2014;9(11): e112545. https://doi.org/10.1371/journal.pone.0112545.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. St Clair EW, Baer AN, Wei C, Noaiseh G, Parke A, Coca A, et al. Clinical efficacy and safety of Baminercept, a lymphotoxin beta receptor fusion protein, in primary Sjogren’s syndrome: results from a phase II randomized, double-blind placebo-controlled trial. Arthritis Rheumatol. 2018;70(9):1470–80. https://doi.org/10.1002/art.40513.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Odusanwo O, Chinthamani S, McCall A, Duffey ME, Baker OJ. Resolvin D1 prevents TNF-alpha-mediated disruption of salivary epithelial formation. Am J Physiol Cell Physiol. 2012;302(9):C1331–45. https://doi.org/10.1152/ajpcell.00207.2011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Yamamura Y, Motegi K, Kani K, Takano H, Momota Y, Aota K, et al. TNF-alpha inhibits aquaporin 5 expression in human salivary gland acinar cells via suppression of histone H4 acetylation. J Cell Mol Med. 2012;16(8):1766–75. https://doi.org/10.1111/j.1582-4934.2011.01456.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Youinou P, Jamin C. The weight of interleukin-6 in B cell-related autoimmune disorders. J Autoimmun. 2009;32(3–4):206–10. https://doi.org/10.1016/j.jaut.2009.02.013.

    Article  CAS  PubMed  Google Scholar 

  114. Grisius MM, Bermudez DK, Fox PC. Salivary and serum interleukin 6 in primary Sjogren’s syndrome. J Rheumatol. 1997;24(6):1089–91.

    CAS  PubMed  Google Scholar 

  115. Norheim KB, Harboe E, Goransson LG, Omdal R. Interleukin-1 inhibition and fatigue in primary Sjogren’s syndrome—a double blind, randomised clinical trial. PLoS ONE. 2012;7(1): e30123. https://doi.org/10.1371/journal.pone.0030123.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Sankar V, Brennan MT, Kok MR, Leakan RA, Smith JA, Manny J, et al. Etanercept in Sjogren’s syndrome: a twelve-week randomized, double-blind, placebo-controlled pilot clinical trial. Arthritis Rheum. 2004;50(7):2240–5. https://doi.org/10.1002/art.20299.

    Article  CAS  PubMed  Google Scholar 

  117. Mariette X, Ravaud P, Steinfeld S, Baron G, Goetz J, Hachulla E, et al. Inefficacy of infliximab in primary Sjogren’s syndrome: results of the randomized, controlled Trial of Remicade in Primary Sjogren’s Syndrome (TRIPSS). Arthritis Rheum. 2004;50(4):1270–6. https://doi.org/10.1002/art.20146.

    Article  CAS  PubMed  Google Scholar 

  118. Felten R, Devauchelle-Pensec V, Seror R, Duffau P, Saadoun D, Hachulla E, et al. Interleukin 6 receptor inhibition in primary Sjogren syndrome: a multicentre double-blind randomised placebo-controlled trial. Ann Rheum Dis. 2020. https://doi.org/10.1136/annrheumdis-2020-218467.

    Article  PubMed  Google Scholar 

  119. Marketos N, Cinoku I, Rapti A, Mavragani CP. Type I interferon signature in Sjogren’s syndrome: pathophysiological and clinical implications. Clin Exp Rheumatol. 2019;37(3):185–91.

    PubMed  Google Scholar 

  120. Hong SM, Lee J, Jang SG, Cho ML, Kwok SK, Park SH. Type I interferon increases inflammasomes associated pyroptosis in the salivary glands of patients with primary Sjogren’s syndrome. Immune Netw. 2020;20(5): e39. https://doi.org/10.4110/in.2020.20.e39.

    Article  PubMed  PubMed Central  Google Scholar 

  121. Bodewes ILA, Versnel MA. Interferon activation in primary Sjogren’s syndrome: recent insights and future perspective as novel treatment target. Expert Rev Clin Immunol. 2018;14(10):817–29. https://doi.org/10.1080/1744666X.2018.1519396.

    Article  CAS  PubMed  Google Scholar 

  122. Duguet F, Ortega-Ferreira C, Fould B, Darville H, Berger S, Chomel A, et al. S95021, a novel selective and pan-neutralizing anti interferon alpha (IFN-alpha) monoclonal antibody as a candidate treatment for selected autoimmune rheumatic diseases. J Transl Autoimmun. 2021;4:100093. https://doi.org/10.1016/j.jtauto.2021.100093.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Khamashta M, Merrill JT, Werth VP, Furie R, Kalunian K, Illei GG, et al. Sifalimumab, an anti-interferon-alpha monoclonal antibody, in moderate to severe systemic lupus erythematosus: a randomised, double-blind, placebo-controlled study. Ann Rheum Dis. 2016;75(11):1909–16. https://doi.org/10.1136/annrheumdis-2015-208562.

    Article  CAS  PubMed  Google Scholar 

  124. Xiao F, Du W, Zhu X, Tang Y, Liu L, Huang E, et al. IL-17 drives salivary gland dysfunction via inhibiting TRPC1-mediated calcium movement in Sjogren’s syndrome. Clin Transl Immunology. 2021;10(4): e1277. https://doi.org/10.1002/cti2.1277.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Sisto M, Lorusso L, Tamma R, Ingravallo G, Ribatti D, Lisi S. Interleukin-17 and -22 synergy linking inflammation and EMT-dependent fibrosis in Sjogren’s syndrome. Clin Exp Immunol. 2019. https://doi.org/10.1111/cei.13337.

    Article  PubMed  PubMed Central  Google Scholar 

  126. Juarez M, Diaz N, Johnston GI, Nayar S, Payne A, Helmer E, et al. A phase 2 randomized, double-blind, placebo-controlled, proof-of-concept study of oral seletalisib in primary Sjogren’s syndrome. Rheumatology. 2021;60(3):1364–75. https://doi.org/10.1093/rheumatology/keaa410.

    Article  CAS  PubMed  Google Scholar 

  127. Favoino E, Prete M, Catacchio G, Ruscitti P, Navarini L, Giacomelli R, et al. Working and safety profiles of JAK/STAT signaling inhibitors. Are these small molecules also smart? Autoimmun Rev. 2021;20(3):102750. https://doi.org/10.1016/j.autrev.2021.102750.

    Article  CAS  PubMed  Google Scholar 

  128. Keeling S, Maksymowych WP. JAK inhibitors, psoriatic arthritis, and axial spondyloarthritis: a critical review of clinical trials. Expert Rev Clin Immunol. 2021;2021:1–15. https://doi.org/10.1080/1744666X.2021.1925541.

    Article  Google Scholar 

  129. Voyer TL, Gitiaux C, Authier FJ, Bodemer C, Melki I, Quartier P, et al. JAK inhibitors are effective in a subset of patients with juvenile dermatomyositis: a monocentric retrospective study. Rheumatology. 2021. https://doi.org/10.1093/rheumatology/keab116.

    Article  PubMed  Google Scholar 

  130. Aqrawi LA, Jensen JL, Oijordsbakken G, Ruus AK, Nygard S, Holden M, et al. Signalling pathways identified in salivary glands from primary Sjogren’s syndrome patients reveal enhanced adipose tissue development. Autoimmunity. 2018;51(3):135–46. https://doi.org/10.1080/08916934.2018.1446525.

    Article  CAS  PubMed  Google Scholar 

  131. Fujimura T, Fujimoto T, Itaya-Hironaka A, Miyaoka T, Yoshimoto K, Sakuramoto-Tsuchida S, et al. Significance of Interleukin-6/STAT pathway for the gene expression of REG Ialpha, a new autoantigen in Sjogren’s syndrome patients, in salivary duct epithelial cells. Clin Rev Allergy Immunol. 2017;52(3):351–63. https://doi.org/10.1007/s12016-016-8570-7.

    Article  CAS  PubMed  Google Scholar 

  132. Lee J, Kwok SK, Baek S, Jang SG, Hong SM, Min JW, et al. JAK-1 inhibition suppresses interferon-induced BAFF production in human salivary gland: potential therapeutic strategy for primary Sjogren’s syndrome. Arthritis Rheumatol. 2018;70(12):2057–66. https://doi.org/10.1002/art.40589.

    Article  CAS  PubMed  Google Scholar 

  133. Charras A, Arvaniti P, Le Dantec C, Arleevskaya MI, Zachou K, Dalekos GN, et al. JAK inhibitors suppress innate epigenetic reprogramming: a promise for patients with Sjogren’s syndrome. Clin Rev Allergy Immunol. 2020;58(2):182–93. https://doi.org/10.1007/s12016-019-08743-y.

    Article  CAS  PubMed  Google Scholar 

  134. Aota K, Yamanoi T, Kani K, Ono S, Momota Y, Azuma M. Inhibition of JAK-STAT signaling by baricitinib reduces interferon-gamma-induced CXCL10 production in human salivary gland ductal cells. Inflammation. 2021;44(1):206–16. https://doi.org/10.1007/s10753-020-01322-w.

    Article  CAS  PubMed  Google Scholar 

  135. Barrera MJ, Aguilera S, Castro I, Matus S, Carvajal P, Molina C, et al. Tofacitinib counteracts IL-6 overexpression induced by deficient autophagy: implications in Sjogren’s syndrome. Rheumatology. 2021;60(4):1951–62. https://doi.org/10.1093/rheumatology/keaa670.

    Article  CAS  PubMed  Google Scholar 

  136. Forero-Torres A, Ramchandren R, Yacoub A, Wertheim MS, Edenfield WJ, Caimi P, et al. Parsaclisib, a potent and highly selective PI3Kdelta inhibitor, in patients with relapsed or refractory B-cell malignancies. Blood. 2019;133(16):1742–52. https://doi.org/10.1182/blood-2018-08-867499.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Lau A, Avery DT, Jackson K, Lenthall H, Volpi S, Brigden H, et al. Activated PI3Kdelta breaches multiple B cell tolerance checkpoints and causes autoantibody production. J Exp Med. 2020;217:2. https://doi.org/10.1084/jem.20191336.

    Article  CAS  Google Scholar 

  138. Durandy A, Kracker S. Increased activation of PI3 kinase-delta predisposes to B-cell lymphoma. Blood. 2020;135(9):638–43. https://doi.org/10.1182/blood.2019002072.

    Article  PubMed  Google Scholar 

  139. Rip J, Van Der Ploeg EK, Hendriks RW, Corneth OBJ. The role of Bruton’s tyrosine kinase in immune cell signaling and systemic autoimmunity. Crit Rev Immunol. 2018;38(1):17–62. https://doi.org/10.1615/CritRevImmunol.2018025184.

    Article  PubMed  Google Scholar 

  140. Langrish CL, Bradshaw JM, Francesco MR, Owens TD, Xing Y, Shu J, et al. Preclinical efficacy and anti-inflammatory mechanisms of action of the Bruton tyrosine kinase inhibitor rilzabrutinib for immune-mediated disease. J Immunol. 2021;206(7):1454–68. https://doi.org/10.4049/jimmunol.2001130.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Nadeem A, Ahmad SF, Al-Harbi NO, Ibrahim KE, Alqahtani F, Alanazi WA, et al. Bruton’s tyrosine kinase inhibition attenuates oxidative stress in systemic immune cells and renal compartment during sepsis-induced acute kidney injury in mice. Int Immunopharmacol. 2021;90:107123. https://doi.org/10.1016/j.intimp.2020.107123.

    Article  CAS  PubMed  Google Scholar 

  142. Liu D, Mamorska-Dyga A. Syk inhibitors in clinical development for hematological malignancies. J Hematol Oncol. 2017;10(1):145. https://doi.org/10.1186/s13045-017-0512-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Walker A, Erwig L, Foster K, Nevin K, Wenzel J, Worm M, et al. Safety, pharmacokinetics and pharmacodynamics of a topical SYK inhibitor in cutaneous lupus erythematosus: a double-blind Phase Ib study. Exp Dermatol. 2020. https://doi.org/10.1111/exd.14253.

    Article  PubMed  PubMed Central  Google Scholar 

  144. Katewa A, Wang Y, Hackney JA, Huang T, Suto E, Ramamoorthi N, et al. Btk-specific inhibition blocks pathogenic plasma cell signatures and myeloid cell-associated damage in IFNalpha-driven lupus nephritis. JCI Insight. 2017;2(7): e90111. https://doi.org/10.1172/jci.insight.90111.

    Article  PubMed  PubMed Central  Google Scholar 

  145. Tanaka Y, Millson D, Iwata S, Nakayamada S. Safety and efficacy of fostamatinib in rheumatoid arthritis patients with an inadequate response to methotrexate in phase II OSKIRA-ASIA-1 and OSKIRA-ASIA-1X study. Rheumatology. 2021;60(6):2884–95. https://doi.org/10.1093/rheumatology/keaa732.

    Article  CAS  PubMed  Google Scholar 

  146. Kunwar S, Devkota AR, Ghimire DK. Fostamatinib, an oral spleen tyrosine kinase inhibitor, in the treatment of rheumatoid arthritis: a meta-analysis of randomized controlled trials. Rheumatol Int. 2016;36(8):1077–87. https://doi.org/10.1007/s00296-016-3482-7.

    Article  CAS  PubMed  Google Scholar 

  147. Posada J, Valadkhan S, Burge D, Davies K, Tarn J, Casement J, et al. Improvement of severe fatigue following nuclease therapy in patients with primary Sjogren’s syndrome: a randomized clinical trial. Arthritis Rheumatol. 2021;73(1):143–50. https://doi.org/10.1002/art.41489.

    Article  CAS  PubMed  Google Scholar 

  148. Burge DJ, Eisenman J, Byrnes-Blake K, Smolak P, Lau K, Cohen SB, et al. Safety, pharmacokinetics, and pharmacodynamics of RSLV-132, an RNase-Fc fusion protein in systemic lupus erythematosus: a randomized, double-blind, placebo-controlled study. Lupus. 2017;26(8):825–34. https://doi.org/10.1177/0961203316678675.

    Article  CAS  PubMed  Google Scholar 

  149. Hamm-Alvarez SF, Janga SR, Edman MC, Madrigal S, Shah M, Frousiakis SE, et al. Tear cathepsin S as a candidate biomarker for Sjogren’s syndrome. Arthritis Rheumatol. 2014;66(7):1872–81. https://doi.org/10.1002/art.38633.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Fu R, Guo H, Janga S, Choi M, Klinngam W, Edman MC, et al. Cathepsin S activation contributes to elevated CX3CL1 (fractalkine) levels in tears of a Sjogren’s syndrome murine model. Sci Rep. 2020;10(1):1455. https://doi.org/10.1038/s41598-020-58337-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Hargreaves P, Daoudlarian D, Theron M, Kolb FA, Manchester Young M, Reis B, et al. Differential effects of specific cathepsin S inhibition in biocompartments from patients with primary Sjogren syndrome. Arthritis Res Ther. 2019;21(1):175. https://doi.org/10.1186/s13075-019-1955-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Miao M, Hao Z, Guo Y, Zhang X, Zhang S, Luo J, et al. Short-term and low-dose IL-2 therapy restores the Th17/Treg balance in the peripheral blood of patients with primary Sjogren’s syndrome. Ann Rheum Dis. 2018;77(12):1838–40. https://doi.org/10.1136/annrheumdis-2018-213036.

    Article  CAS  PubMed  Google Scholar 

  153. Jensen SB, Vissink A. Salivary gland dysfunction and xerostomia in Sjogren’s syndrome. Oral Maxillofac Surg Clin North Am. 2014;26(1):35–53. https://doi.org/10.1016/j.coms.2013.09.003.

    Article  PubMed  Google Scholar 

  154. Komori K, Komori M, Horino T, Nishiyama S, Takei M, Suganuma N. Factors associated with delayed diagnosis of Sjogren's syndrome among members of the Japanese Sjogren's Association for Patients. Clin Exp Rheumatol. 2021.

  155. Huang YT, Lu TH, Chou PL, Weng MY. Diagnostic delay in patients with primary Sjogren’s syndrome: a population-based cohort study in Taiwan. Healthcare (Basel). 2021;9:3. https://doi.org/10.3390/healthcare9030363.

    Article  Google Scholar 

  156. Seror R, Ravaud P, Bowman SJ, Baron G, Tzioufas A, Theander E, et al. EULAR Sjogren’s syndrome disease activity index: development of a consensus systemic disease activity index for primary Sjogren’s syndrome. Ann Rheum Dis. 2010;69(6):1103–9. https://doi.org/10.1136/ard.2009.110619.

    Article  PubMed  Google Scholar 

  157. de Wolff L, Arends S, van Nimwegen JF, Bootsma H. Ten years of the ESSDAI: is it fit for purpose? Clin Exp Rheumatol. 2020;126(4):283–90.

    Google Scholar 

  158. Wang B, Chen S, Xuan J, Li Y, Zheng Q, Zhang X, et al. Correspondence on “Interleukin 6 receptor inhibition in primary Sjogren syndrome: a multicentre double-blind randomised placebo-controlled trial.” Ann Rheum Dis. 2021. https://doi.org/10.1136/annrheumdis-2020-219666.

    Article  PubMed  Google Scholar 

  159. Del Papa N, Vitali C. Management of primary Sjogren’s syndrome: recent developments and new classification criteria. Ther Adv Musculoskelet Dis. 2018;10(2):39–54. https://doi.org/10.1177/1759720X17746319.

    Article  PubMed  PubMed Central  Google Scholar 

  160. Noaiseh G, Baer AN. Toward better outcomes in Sjogren’s syndrome: The promise of a stratified medicine approach. Best Pract Res Clin Rheumatol. 2020;2020:101475. https://doi.org/10.1016/j.berh.2019.101475.

    Article  Google Scholar 

  161. James JA, Guthridge JM, Chen H, Lu R, Bourn RL, Bean K, et al. Unique Sjogren’s syndrome patient subsets defined by molecular features. Rheumatology. 2020;59(4):860–8. https://doi.org/10.1093/rheumatology/kez335.

    Article  CAS  PubMed  Google Scholar 

  162. Armagan B, Robinson SA, Bazoberry A, Perin J, Grader-Beck T, Akpek EK, et al. Antibodies to both Ro52 and Ro60 may identify Sjogren’s syndrome patients best suited for clinical trials of disease-modifying therapies. Arthritis Care Res (Hoboken). 2021. https://doi.org/10.1002/acr.24597.

    Article  PubMed  Google Scholar 

  163. Jordan-Gonzalez P, Gago-Pinero R, Varela-Rosario N, Perez-Rios N, Vila LM. Characterization of a subset of patients with primary Sjogren’s syndrome initially presenting with C3 or C4 hypocomplementemia. Eur J Rheumatol. 2020;7(3):112–7. https://doi.org/10.5152/eurjrheum.2020.19132.

    Article  PubMed  PubMed Central  Google Scholar 

  164. Jin W, Luo Z, Yang H. Peripheral B cell subsets in autoimmune diseases: clinical implications and effects of B cell-targeted therapies. J Immunol Res. 2020;2020:9518137. https://doi.org/10.1155/2020/9518137.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Ray A, Wang L, Dittel BN. IL-10-independent regulatory B-cell subsets and mechanisms of action. Int Immunol. 2015;27(10):531–6. https://doi.org/10.1093/intimm/dxv033.

    Article  CAS  PubMed  Google Scholar 

  166. Glauzy S, Boccitto M, Bannock JM, Delmotte FR, Saadoun D, Cacoub P, et al. Accumulation of antigen-driven lymphoproliferations in complement receptor 2/CD21(-/low) B cells from patients with Sjogren’s syndrome. Arthritis Rheumatol. 2018;70(2):298–307. https://doi.org/10.1002/art.40352.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Saadoun D, Terrier B, Bannock J, Vazquez T, Massad C, Kang I, et al. Expansion of autoreactive unresponsive CD21-/low B cells in Sjogren’s syndrome-associated lymphoproliferation. Arthritis Rheum. 2013;65(4):1085–96. https://doi.org/10.1002/art.37828.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Manfre V, Cafaro G, Riccucci I, Zabotti A, Perricone C, Bootsma H, et al. One year in review 2020: comorbidities, diagnosis and treatment of primary Sjogren’s syndrome. Clin Exp Rheumatol. 2020;38(4):10–22.

    PubMed  Google Scholar 

  169. Brito-Zeron P, Retamozo S, Ramos-Casals M. Phenotyping Sjogren’s syndrome: towards a personalised management of the disease. Clin Exp Rheumatol. 2018;112(3):198–209.

    Google Scholar 

  170. Carubbi F, Cipriani P, Di Benedetto P, Ruscitti P, Alunno A, Gerli R, et al. Persistence of focal lymphocytic sialadenitis in patients with primary Sjogren’s syndrome treated with rituximab: a possible role for glandular BAFF. Clin Exp Rheumatol. 2016;34(6):1123–4.

    PubMed  Google Scholar 

  171. Cornec D, Costa S, Devauchelle-Pensec V, Jousse-Joulin S, Marcorelles P, Berthelot JM, et al. Blood and salivary-gland BAFF-driven B-cell hyperactivity is associated to rituximab inefficacy in primary Sjogren’s syndrome. J Autoimmun. 2016;67:102–10. https://doi.org/10.1016/j.jaut.2015.11.002.

    Article  CAS  PubMed  Google Scholar 

  172. Cornec D, Jousse-Joulin S, Costa S, Marhadour T, Marcorelles P, Berthelot JM, et al. High-grade salivary-gland involvement, assessed by histology or ultrasonography, is associated with a poor response to a single rituximab course in primary Sjogren’s syndrome: data from the TEARS randomized trial. PLoS ONE. 2016;11(9): e0162787. https://doi.org/10.1371/journal.pone.0162787.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Delli K, Haacke EA, Kroese FG, Pollard RP, Ihrler S, van der Vegt B, et al. Towards personalised treatment in primary Sjogren’s syndrome: baseline parotid histopathology predicts responsiveness to rituximab treatment. Ann Rheum Dis. 2016;75(11):1933–8. https://doi.org/10.1136/annrheumdis-2015-208304.

    Article  CAS  PubMed  Google Scholar 

  174. Seror R, Nocturne G, Lazure T, Hendel-Chavez H, Desmoulins F, Belkhir R, et al. Low numbers of blood and salivary natural killer cells are associated with a better response to belimumab in primary Sjogren’s syndrome: results of the BELISS study. Arthritis Res Ther. 2015;17:241. https://doi.org/10.1186/s13075-015-0750-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Cornec D, Devauchelle-Pensec V, Mariette X, Jousse-Joulin S, Berthelot JM, Perdriger A, et al. Development of the Sjogren’s Syndrome Responder Index, a data-driven composite endpoint for assessing treatment efficacy. Rheumatology. 2015;54(9):1699–708. https://doi.org/10.1093/rheumatology/kev114.

    Article  CAS  PubMed  Google Scholar 

  176. Fisher BA, Everett CC, Rout J, O’Dwyer JL, Emery P, Pitzalis C, et al. Effect of rituximab on a salivary gland ultrasound score in primary Sjogren’s syndrome: results of the TRACTISS randomised double-blind multicentre substudy. Ann Rheum Dis. 2018;77(3):412–6. https://doi.org/10.1136/annrheumdis-2017-212268.

    Article  CAS  PubMed  Google Scholar 

  177. Alunno A, Bartoloni E, Valentini V, La-Paglia GMC, Valentini E, Leone MC, et al. Discrepancy between subjective symptoms, objective measures and disease activity indexes: the lesson of primary Sjogren’s syndrome. Clin Exp Rheumatol. 2018;112(3):210–4.

    Google Scholar 

  178. Kapsogeorgou EK, Voulgarelis M, Tzioufas AG. Predictive markers of lymphomagenesis in Sjogren’s syndrome: from clinical data to molecular stratification. J Autoimmun. 2019;104: 102316. https://doi.org/10.1016/j.jaut.2019.102316.

    Article  CAS  PubMed  Google Scholar 

  179. Goules AV, Tzioufas AG. Lymphomagenesis in Sjogren’s syndrome: predictive biomarkers towards precision medicine. Autoimmun Rev. 2019;18(2):137–43. https://doi.org/10.1016/j.autrev.2018.08.007.

    Article  PubMed  Google Scholar 

  180. Chatzis L, Goules AV, Pezoulas V, Baldini C, Gandolfo S, Skopouli FN, et al. A biomarker for lymphoma development in Sjogren’s syndrome: salivary gland focus score. J Autoimmun. 2021;121: 102648. https://doi.org/10.1016/j.jaut.2021.102648.

    Article  CAS  PubMed  Google Scholar 

  181. Ferro F, Izzetti R, Vitali S, Aringhieri G, Fonzetti S, Donati V, et al. Ultra-high frequency ultrasonography of labial glands is a highly sensitive tool for the diagnosis of Sjogren’s syndrome: a preliminary study. Clin Exp Rheumatol. 2020;126(4):210–5.

    Google Scholar 

  182. Xue L, Sun P, Ou D, Chen P, Chen M, Yan B. Diagnosis of pathological minor salivary glands in primary Sjogren’s syndrome by using Raman spectroscopy. Lasers Med Sci. 2014;29(2):723–8. https://doi.org/10.1007/s10103-013-1398-y.

    Article  PubMed  Google Scholar 

  183. Diekhoff T, Fischer T, Schefer Q, Posch MG, Dorner T, Laurent D, et al. Ianalumab (VAY736) in primary Sjogren’s syndrome: assessing disease activity using multi-modal ultrasound. Clin Exp Rheumatol. 2020;38(4):228–36.

    PubMed  Google Scholar 

  184. Jousse-Joulin S, Devauchelle-Pensec V, Cornec D, Marhadour T, Bressollette L, Gestin S, et al. Brief report: ultrasonographic assessment of salivary gland response to rituximab in primary Sjogren’s syndrome. Arthritis Rheumatol. 2015;67(6):1623–8. https://doi.org/10.1002/art.39088.

    Article  CAS  PubMed  Google Scholar 

  185. Riviere E, Pascaud J, Tchitchek N, Boudaoud S, Paoletti A, Ly B, et al. Salivary gland epithelial cells from patients with Sjogren’s syndrome induce B-lymphocyte survival and activation. Ann Rheum Dis. 2020;79(11):1468–77. https://doi.org/10.1136/annrheumdis-2019-216588.

    Article  CAS  PubMed  Google Scholar 

  186. Wang X, Bootsma H, Terpstra J, Vissink A, van der Vegt B, Spijkervet FKL, et al. Progenitor cell niche senescence reflects pathology of the parotid salivary gland in primary Sjogren’s syndrome. Rheumatology. 2020;59(10):3003–13. https://doi.org/10.1093/rheumatology/keaa012.

    Article  PubMed  PubMed Central  Google Scholar 

  187. Wang X, Shaalan A, Liefers S, Coudenys J, Elewaut D, Proctor GB, et al. Dysregulation of NF-kB in glandular epithelial cells results in Sjogren’s-like features. PLoS ONE. 2018;13(8): e0200212. https://doi.org/10.1371/journal.pone.0200212.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Jeong SY, Choi WH, Jeon SG, Lee S, Park JM, Park M, et al. Establishment of functional epithelial organoids from human lacrimal glands. Stem Cell Res Ther. 2021;12(1):247. https://doi.org/10.1186/s13287-021-02133-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Ackermann P, Hetz S, Dieckow J, Schicht M, Richter A, Kruse C, et al. Isolation and investigation of presumptive murine lacrimal gland stem cells. Invest Ophthalmol Vis Sci. 2015;56(8):4350–63. https://doi.org/10.1167/iovs.15-16475.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Yuan Liu or Guixiu Shi.

Ethics declarations

Funding

This work was supported by grants from the National Natural Science Foundation of China (No. U1605223, No. 81971536 and No. 81971496) and China Postdoctoral Science Foundation (No. 2020M671950).

Conflict of interest

The authors declare no conflict of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and materials

Not applicable.

Code availability

Not applicable.

Authors' contributions

GS was invited to provide the review. YL and GS formulated the content of the review. BW, SC, and GS performed the literature search and wrote the manuscript. All authors reviewed and approved the final manuscript.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, B., Chen, S., Li, Y. et al. Targeted Therapy for Primary Sjögren’s Syndrome: Where are We Now?. BioDrugs 35, 593–610 (2021). https://doi.org/10.1007/s40259-021-00505-7

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40259-021-00505-7

Navigation