New frontiers in precision medicine for Sjogren’s syndrome

References

• Fox RI. Sjögren’s syndrome. Lancet. 2005;366(9482):321–331.
   PubMed Web of Science ®Google Scholar
• Brito-Zerón P, Baldini C, Bootsma H, et al. Sjögren syndrome. Nature reviews. Disease Primers. 2016;2(1):16047.
   PubMedGoogle Scholar
• Qin B, Wang J, Yang Z, et al. Epidemiology of primary Sjögren’s syndrome: a systematic review and meta-analysis. Ann Rheum Dis. 2015;74(11):1983–1989. .
   PubMed Web of Science ®Google Scholar
• Narváez J, Sánchez-Fernández S, Seoane-Mato D, et al. Prevalence of Sjögren’s syndrome in the general adult population in Spain: estimating the proportion of undiagnosed cases. Sci Rep. 2020;10(1):10627.
   PubMed Web of Science ®Google Scholar
• Alamanos Y, Tsifetaki N, Voulgari PV, et al. Epidemiology of primary Sjogren’s syndrome in north-west Greece, 1982-2003. Rheumatol. 2006;45(2):187–191.
   PubMed Web of Science ®Google Scholar
• Chatzis L, Pezoulas VC, Ferro F, et al., Sjögren’s syndrome: the clinical spectrum of male patients. J Clin Med. 9(8): 2620. 2020. .
   PubMed Web of Science ®Google Scholar
• Patel R, Shahane A. The epidemiology of Sjögren’s syndrome. Clin Epidemiol. 2014;6:247–255.
   PubMed Web of Science ®Google Scholar
• Mariette X, Criswell LA. Primary Sjögren’s syndrome. N Engl J Med. 2018;378(10):931–939.
   PubMed Web of Science ®Google Scholar
• Skopouli FN, Dafni U, Ioannidis JP, et al. Clinical evolution, and morbidity and mortality of primary Sjögren’s syndrome. Semin Arthritis Rheum. 2000;29(5):296–304.
   PubMed Web of Science ®Google Scholar
• Zintzaras E, Voulgarelis M, Moutsopoulos HM. The risk of lymphoma development in autoimmune diseases: a meta-analysis. Arch Intern Med. 2005;165(20):2337–2344.
   PubMedGoogle Scholar
• Papageorgiou A, Ziogas DC, Mavragani CP, et al. Predicting the outcome of Sjogren’s syndrome-associated non-Hodgkin’s lymphoma patients. PloS One. 2015;10(2):e0116189.
   PubMed Web of Science ®Google Scholar
• Papageorgiou A, Voulgarelis M, Tzioufas AG. Clinical picture, outcome and predictive factors of lymphoma in Sjgren syndrome. Autoimmun Rev. 2015;14(7):641–649.
   PubMed Web of Science ®Google Scholar
• 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 Rheumatism. 2010;62(4):960–968.
   PubMed Web of Science ®Google Scholar
• Verstappen GM, van Nimwegen JF, Vissink A, et al. The value of rituximab treatment in primary Sjögren’s syndrome. Clin Immunol. 2017;182:62–71. [ (Orlando, Fla.)].
   PubMed Web of Science ®Google Scholar
• Norheim KB, Harboe E, Gøransson LG, et al. Interleukin-1 inhibition and fatigue in primary Sjögren’s syndrome–a double blind, randomised clinical trial. PloS One. 2012;7(1):e30123.
   PubMed Web of Science ®Google Scholar
• Sankar V, Brennan MT, Kok MR, et al. Etanercept in Sjögren’s syndrome: a twelve-week randomized, double-blind, placebo-controlled pilot clinical trial. Arthritis Rheumatism. 2004;50(7):2240–2245.
   PubMedGoogle Scholar
• Goules AV, Exarchos TP, Pezoulas VC, et al. Sjögren’s syndrome towards precision medicine: the challenge of harmonisation and integration of cohorts. Clin Exp Rheumatol. 2019;118(3):175–184. 37 Suppl.
   Google Scholar
• Kivity S, Arango MT, Ehrenfeld M, et al. Infection and autoimmunity in Sjogren’s syndrome: a clinical study and comprehensive review. J Autoimmun. 2014;51:17–22.
   PubMed Web of Science ®Google Scholar
• Agmon-Levin N, Dagan A, Peri Y, et al. The interaction between anti-Ro/SSA and anti-La/SSB autoantibodies and anti-infectious antibodies in a wide spectrum of auto-immune diseases: another angle of the autoimmune mosaic. Clin Exp Rheumatol. 2017;35(6):929–935.
   PubMed Web of Science ®Google Scholar
• Goules AV, Kapsogeorgou EK, Tzioufas AG. Insight into pathogenesis of Sjögren’s syndrome: dissection on autoimmune infiltrates and epithelial cells. Clin Immunol. 2017;182:30–40. [ (Orlando, Fla.)].
   PubMed Web of Science ®Google Scholar
• Moutsopoulos HM. Sjögren’s syndrome: autoimmune epithelitis. Clin Immunol Immunopathol. 1994;72(2):162–165.
   PubMedGoogle Scholar
• Mitsias DI, Kapsogeorgou EK, Moutsopoulos HM. Sjögren’s syndrome: why autoimmune epithelitis? Oral Dis. 2006;12(6):523–532.
   PubMed Web of Science ®Google Scholar
• Spachidou MP, Bourazopoulou E, Maratheftis CI, et al. Expression of functional Toll-like receptors by salivary gland epithelial cells: increased mRNA expression in cells derived from patients with primary Sjögren’s syndrome. Clin Exp Immunol. 2007;147(3):497–503.
   PubMed Web of Science ®Google Scholar
• Tsunawaki S, Nakamura S, Ohyama Y, et al. Possible function of salivary gland epithelial cells as nonprofessional antigen-presenting cells in the development of Sjögren’s syndrome. J Rheumatol. 2002;29(9):1884–1896.
   PubMed Web of Science ®Google Scholar
• Kapsogeorgou EK, Moutsopoulos HM, Manoussakis MN. Functional expression of a costimulatory B7.2 (CD86) protein on human salivary gland epithelial cells that interacts with the CD28 receptor, but has reduced binding to CTLA4. J Immunol (Baltimore, Md: 1950). 2001;166(5):3107–3113.
   PubMed Web of Science ®Google Scholar
• Kapsogeorgou EK, Dimitriou ID, Abu-Helu RF, et al. Activation of epithelial and myoepithelial cells in the salivary glands of patients with Sjögren’s syndrome: high expression of intercellular adhesion molecule-1 (ICAM.1) in biopsy specimens and cultured cells. Clin Exp Immunol. 2001;124(1):126–133.
   PubMed Web of Science ®Google Scholar
• Li P, Yang Y, Jin Y, et al. B7-H3 participates in human salivary gland epithelial cells apoptosis through NF-κB pathway in primary Sjögren’s syndrome. J Transl Med. 2019;17(1):268.
   PubMed Web of Science ®Google Scholar
• Ciccia F, Guggino G, Rizzo A, et al. Potential involvement of IL-22 and IL-22-producing cells in the inflamed salivary glands of patients with Sjogren’s syndrome. Ann Rheum Dis. 2012;71(2):295–301.
   PubMed Web of Science ®Google Scholar
• Kawanami T, Sawaki T, Sakai T, et al. Skewed production of IL-6 and TGFβ by cultured salivary gland epithelial cells from patients with Sjögren’s syndrome. PloS One. 2012;7(10):e45689.
   PubMed Web of Science ®Google Scholar
• Fox RI, Kang HI, Ando D, et al. Cytokine mRNA expression in salivary gland biopsies of Sjögren’s syndrome. J Immunol (Baltimore, Md: 1950). 1994;152(11):5532–5539.
   PubMed Web of Science ®Google Scholar
• Jin JO, Shinohara Y, Yu Q. Innate immune signaling induces interleukin-7 production from salivary gland cells and accelerates the development of primary Sjögren’s syndrome in a mouse model. PloS One. 2013;8(10):e77605.
   PubMed Web of Science ®Google Scholar
• Blokland SLM, Flessa CM, van Roon JAG, et al. Emerging roles for chemokines and cytokines as orchestrators of immunopathology in Sjögren’s syndrome. Rheumatol. 2019. 10.1093/rheumatology/key438
   Google Scholar
• Salomonsson S, Larsson P, Tengnér P, et al. Expression of the B cell-attracting chemokine CXCL13 in the target organ and autoantibody production in ectopic lymphoid tissue in the chronic inflammatory disease Sjögren’s syndrome. Scand J Immunol. 2002;55(4):336–342.
   PubMed Web of Science ®Google Scholar
• Barone F, Bombardieri M, Rosado MM, et al. CXCL13, CCL21, and CXCL12 expression in salivary glands of patients with Sjogren’s syndrome and MALT lymphoma: association with reactive and malignant areas of lymphoid organization. J Immunol (Baltimore, Md: 1950). 2008;180(7):5130–5140.
   PubMed Web of Science ®Google Scholar
• Amft N, Curnow SJ, Scheel-Toellner D, 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 Rheumatism. 2001;44(11):2633–2641.
   PubMed Web of Science ®Google Scholar
• Ittah M, Miceli-Richard C, Eric Gottenberg J, et al. B cell-activating factor of the tumor necrosis factor family (BAFF) is expressed under stimulation by interferon in salivary gland epithelial cells in primary Sjögren’s syndrome. Arthritis Res Ther. 2006;8(2):R51. .
   PubMed Web of Science ®Google Scholar
• Jonsson MV, 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.
   PubMed Web of Science ®Google Scholar
• Rivière E, Pascaud J, Tchitchek N, et al., Salivary gland epithelial cells from patients with Sjögren’s syndrome induce B-lymphocyte survival and activation. Ann Rheum Dis. 79(11): 1468–1477. 2020.
   PubMed Web of Science ®Google Scholar
• Carrillo-Ballesteros FJ, Palafox-Sánchez CA, Franco-Topete RA, et al. Expression of BAFF and BAFF receptors in primary Sjögren’s syndrome patients with ectopic germinal center-like structures. Clin Exp Med. 2020;20(4):615–626.
   PubMed Web of Science ®Google Scholar
• Kawakami A, Nakashima K, Tamai M, et al. Toll-like receptor in salivary glands from patients with Sjögren’s syndrome: functional analysis by human salivary gland cell line. J Rheumatol. 2007;34(5):1019–1026.
   PubMed Web of Science ®Google Scholar
• Frank-Bertoncelj M, Pisetsky DS, Kolling C, et al. TLR3 ligand poly(I:C) exerts distinct actions in synovial fibroblasts when delivered by extracellular vesicles. Front Immunol. 2018;9:28.
   PubMed Web of Science ®Google Scholar
• Karikó K, Ni H, Capodici J, et al. mRNA is an endogenous ligand for Toll-like receptor 3. J Biol Chem. 2004;279(13):12542–12550.
   PubMed Web of Science ®Google Scholar
• Manoussakis MN, Spachidou MP, Maratheftis CI. Salivary epithelial cells from Sjogren’s syndrome patients are highly sensitive to anoikis induced by TLR-3 ligation. J Autoimmun. 2010;35(3):212–218.
   PubMed Web of Science ®Google Scholar
• Vakrakou AG, Polyzos A, Kapsogeorgou EK, et al. Impaired anti-inflammatory activity of PPARγ in the salivary epithelia of Sjögren’s syndrome patients imposed by intrinsic NF-κB activation. J Autoimmun. 2018;86:62–74.
   PubMed Web of Science ®Google Scholar
• Deshmukh US, Nandula SR, Thimmalapura PR, et al. Activation of innate immune responses through Toll-like receptor 3 causes a rapid loss of salivary gland function. J Oral Pathol Med. 2009;38(1):42–47.
   PubMed Web of Science ®Google Scholar
• Kyriakidis NC, Kapsogeorgou EK, Gourzi VC, et al. Toll-like receptor 3 stimulation promotes Ro52/TRIM21 synthesis and nuclear redistribution in salivary gland epithelial cells, partially via type I interferon pathway. Clin Exp Immunol. 2014;178(3):548–560.
   PubMed Web of Science ®Google Scholar
• Ping L, Ogawa N, Sugai S. Novel role of CD40 in Fas-dependent apoptosis of cultured salivary epithelial cells from patients with Sjögren’s syndrome. Arthritis Rheumatism. 2005;52(2):573–581.
   PubMed Web of Science ®Google Scholar
• Nakamura H, Horai Y, Shimizu T, et al. Modulation of Apoptosis by Cytotoxic Mediators and Cell-Survival Molecules in Sjögren’s Syndrome. Int J Mol Sci. 2018;19(8):8.
   Web of Science ®Google Scholar
• Kapsogeorgou EK, Abu-Helu RF, Moutsopoulos HM, et al. Salivary gland epithelial cell exosomes: A source of autoantigenic ribonucleoproteins. Arthritis Rheumatism. 2005;52(5):1517–1521.
   PubMed Web of Science ®Google Scholar
• Charras A, Konsta OD, Le Dantec C, et al. Cell-specific epigenome-wide DNA methylation profile in long-term cultured minor salivary gland epithelial cells from patients with Sjögren’s syndrome. Ann Rheum Dis. 2017;76(3):625–628. .
   PubMed Web of Science ®Google Scholar
• Imgenberg-Kreuz J, Sandling JK, Nordmark G. Epigenetic alterations in primary Sjögren’s syndrome - an overview. Clin Immunol. 2018;196:12–20. [ (Orlando, Fla.)].
   PubMed Web of Science ®Google Scholar
• Karagianni P, Goules AV, Tzioufas AG. Epigenetic alterations in Sjögren’s syndrome patient saliva. Clin Exp Immunol. 2020;202(2):137–143.
   PubMed Web of Science ®Google Scholar
• 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 Rheumatism. 2004;50(4):1270–1276. .
   PubMed Web of Science ®Google Scholar
• Felten R, Devauchelle-Pensec V, Seror R, et al. Interleukin 6 receptor inhibition in primary Sjögren syndrome: a multicentre double-blind randomised placebo-controlled trial. Ann Rheum Dis. 2020. DOI:10.1136/annrheumdis-2020-218467.
   PubMed Web of Science ®Google Scholar
• Gandolfo S, De Vita S. Double anti-B cell and anti-BAFF targeting for the treatment of primary Sjögren’s syndrome. Clin Exp Rheumatol. 2019;118(3): 199–208. 37 Suppl.
   Google Scholar
• Diekhoff T, Fischer T, Schefer Q, et al. Ianalumab (VAY736) in primary Sjögren’s syndrome: assessing disease activity using multi-modal ultrasound. Clin Exp Rheumatol. 2020;126(4):228–236. 38 Suppl.
   Google Scholar
• Smolen JNP, Tahir H, Schulze-Koops H, et al. 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 [abstract]. Arthritis Rheumatol. 2019;71 ( 2019).
   PubMedGoogle Scholar
• Nguyen CQ, Hu MH, Li Y, et al. Salivary gland tissue expression of interleukin-23 and interleukin-17 in Sjögren’s syndrome: findings in humans and mice. Arthritis Rheumatism. 2008;58(3):734–743.
   PubMed Web of Science ®Google Scholar
• Qi J, Li D, Shi G, et al. Interleukin‑12 exacerbates Sjögren’s syndrome through induction of myeloid‑derived suppressor cells. Mol Med Rep. 2019;20(2):1131–1138.
   PubMed Web of Science ®Google Scholar
• Zhang LW, Zhou PR, Wei P, et al. Expression of interleukin-17 in primary Sjögren’s syndrome and the correlation with disease severity: A systematic review and meta-analysis. Scand J Immunol. 2018;87(4):e12649.
   PubMed Web of Science ®Google Scholar
• Konsta OD, Le Dantec C, Charras A, et al. Defective DNA methylation in salivary gland epithelial acini from patients with Sjögren’s syndrome is associated with SSB gene expression, anti-SSB/LA detection, and lymphocyte infiltration. J Autoimmun. 2016;68:30–38.
   PubMed Web of Science ®Google Scholar
• Gottenberg JE, Cagnard N, Lucchesi C, et al. Activation of IFN pathways and plasmacytoid dendritic cell recruitment in target organs of primary Sjögren’s syndrome. Proc Natl Acad Sci U S A. 2006;103(8):2770–2775.
   PubMed Web of Science ®Google Scholar
• Kimoto O, Sawada J, Shimoyama K, et al. Activation of the interferon pathway in peripheral blood of patients with Sjogren’s syndrome. J Rheumatol. 2011;38(2):310–316.
   PubMed Web of Science ®Google Scholar
• Hall JC, Casciola-Rosen L, Berger AE, et al. Precise probes of type II interferon activity define the origin of interferon signatures in target tissues in rheumatic diseases. Proc Natl Acad Sci U S A. 2012;109(43):17609–17614.
   PubMed Web of Science ®Google Scholar
• Nezos A, Gravani F, Tassidou A, et al. Type I and II interferon signatures in Sjogren’s syndrome pathogenesis: contributions in distinct clinical phenotypes and Sjogren’s related lymphomagenesis. J Autoimmun. 2015;63:47–58.
   PubMed Web of Science ®Google Scholar
• Apostolou E, Kapsogeorgou EK, Konsta OD, et al. Expression of type III interferons (IFNλs) and their receptor in Sjögren’s syndrome. Clin Exp Immunol. 2016;186(3):304–312.
   PubMed Web of Science ®Google Scholar
• Bodewes ILA, Versnel MA. Interferon activation in primary Sjögren’s syndrome: recent insights and future perspective as novel treatment target. Expert Rev Clin Immunol. 2018;14(10):817–829.
   PubMed Web of Science ®Google Scholar
• Manoussakis MN, Boiu S, Korkolopoulou P, et al. Rates of infiltration by macrophages and dendritic cells and expression of interleukin-18 and interleukin-12 in the chronic inflammatory lesions of Sjögren’s syndrome: correlation with certain features of immune hyperactivity and factors associated with high risk of lymphoma development. Arthritis Rheumatism. 2007;56(12):3977–3988.
   PubMed Web of Science ®Google Scholar
• Christodoulou MI, Kapsogeorgou EK, Moutsopoulos HM. Characteristics of the minor salivary gland infiltrates in Sjögren’s syndrome. J Autoimmun. 2010;34(4):400–407.
   PubMed Web of Science ®Google Scholar
• Greenwell-Wild T, Moutsopoulos NM, Gliozzi M, et al. Chitinases in the salivary glands and circulation of patients with Sjögren’s syndrome: macrophage harbingers of disease severity. Arthritis Rheumatism. 2011;63(10):3103–3115.
   PubMedGoogle Scholar
• Maehara T, Moriyama M, Hayashida JN, et al. Selective localization of T helper subsets in labial salivary glands from primary Sjögren’s syndrome patients. Clin Exp Immunol. 2012;169(2):89–99.
   PubMed Web of Science ®Google Scholar
• van Woerkom JM, Kruize AA, Wenting-van Wijk MJ, et al. Salivary gland and peripheral blood T helper 1 and 2 cell activity in Sjögren’s syndrome compared with non-Sjögren’s sicca syndrome. Ann Rheum Dis. 2005;64(10):1474–1479.
   PubMed Web of Science ®Google Scholar
• Ohyama Y, Nakamura S, Matsuzaki G, et al. Cytokine messenger RNA expression in the labial salivary glands of patients with Sjögren’s syndrome. Arthritis Rheumatism. 1996;39(8):1376–1384.
   PubMedGoogle Scholar
• Kang EH, Lee YJ, Hyon JY, et al. Salivary cytokine profiles in primary Sjögren’s syndrome differ from those in non-Sjögren sicca in terms of TNF-α levels and Th-1/Th-2 ratios. Clin Exp Rheumatol. 2011;29(6):970–976.
   PubMed Web of Science ®Google Scholar
• Katsifis GE, Rekka S, Moutsopoulos NM, et al. Systemic and local interleukin-17 and linked cytokines associated with Sjögren’s syndrome immunopathogenesis. Am J Pathol. 2009;175(3):1167–1177.
   PubMed Web of Science ®Google Scholar
• Walsh SV, Hopkins AM, Nusrat A. Modulation of tight junction structure and function by cytokines. Adv Drug Deliv Rev. 2000;41(3):303–313.
   PubMed Web of Science ®Google Scholar
• Lucchesi D, Coleby R, Pontarini E, et al. Impaired Interleukin-27–Mediated Control of CD4+ T cell function impact on ectopic lymphoid structure formation in patients with Sjögren’s syndrome. Arthritis Rheumatol. 2020;72(9):1559–1570.
   Web of Science ®Google Scholar
• Brandt D, Hedrich CM. TCRαβ(+)CD3(+)CD4(-)CD8(-) (double negative) T cells in autoimmunity. Autoimmun Rev. 2018;17(4):422–430.
   PubMed Web of Science ®Google Scholar
• Alunno A, Carubbi F, Bistoni O, et al. CD4(-)CD8(-) T-cells in primary Sjögren’s syndrome: association with the extent of glandular involvement. J Autoimmun. 2014;51:38–43.
   PubMed Web of Science ®Google Scholar
• Bertorello R, Cordone MP, Contini P, et al. Increased levels of interleukin-10 in saliva of Sjögren’s syndrome patients. Correlation with disease activity. Clin Exp Med. 2004;4(3):148–151.
   PubMed Web of Science ®Google Scholar
• Sheldon J. Laboratory testing in autoimmune rheumatic diseases. Best practice & research. Clin Rheumatol. 2004;18(3):249–269.
   Web of Science ®Google Scholar
• Voulgarelis M, Dafni UG, Isenberg DA, et al. Malignant lymphoma in primary Sjögren’s syndrome: a multicenter, retrospective, clinical study by the European concerted action on Sjögren’s syndrome. Arthritis Rheumatism. 1999;42(8):1765–1772.
   PubMed Web of Science ®Google Scholar
• Gottenberg JE, Aucouturier F, Goetz J, et al. Serum immunoglobulin free light chain assessment in rheumatoid arthritis and primary Sjogren’s syndrome. Ann Rheum Dis. 2007;66(1):23–27.
   PubMed Web of Science ®Google Scholar
• Gottenberg JE, Seror R, Miceli-Richard C, 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. 2013;8(5):e59868.
   PubMed Web of Science ®Google Scholar
• Argyropoulou OD, Pezoulas V, Chatzis L, et al. Cryoglobulinemic vasculitis in primary Sjögren’s syndrome: clinical presentation, association with lymphoma and comparison with hepatitis C-related disease. Semin Arthritis Rheum. 2020;50(5):846–853.
   PubMed Web of Science ®Google Scholar
• Shen L, Gao C, Suresh L, et al. Central role for marginal zone B cells in an animal model of Sjogren’s syndrome. Clin Immunol. (Orlando, Fla.) 2016;168: 30–36.
   PubMed Web of Science ®Google Scholar
• Weill JC, Weller S, Reynaud CA. Human marginal zone B cells. Annu Rev Immunol. 2009;27:267–285.
   PubMed Web of Science ®Google Scholar
• Cornec D, Devauchelle-Pensec V, Tobón GJ, et al. B cells in Sjögren’s syndrome: from pathophysiology to diagnosis and treatment. J Autoimmun. 2012;39(3):161–167.
   PubMed Web of Science ®Google Scholar
• Hansen A, Gosemann M, Pruss A, et al. Abnormalities in peripheral B cell memory of patients with primary Sjögren’s syndrome. Arthritis Rheumatism. 2004;50(6):1897–1908.
   PubMed Web of Science ®Google Scholar
• Bohnhorst J, Bjørgan MB, Thoen JE, et al. Abnormal B cell differentiation in primary Sjögren’s syndrome results in a depressed percentage of circulating memory B cells and elevated levels of soluble CD27 that correlate with Serum IgG concentration. Clin Immunol. 2002;103(1):79–88. (Orlando, Fla.).
   PubMed Web of Science ®Google Scholar
• Bombardieri M, Lewis M, Pitzalis C. Ectopic lymphoid neogenesis in rheumatic autoimmune diseases. Nat Rev Rheumatol. 2017;13(3):141–154.
   PubMed Web of Science ®Google Scholar
• Bombardieri M, Barone F, Humby F, et al. Activation-induced cytidine deaminase expression in follicular dendritic cell networks and interfollicular large B cells supports functionality of ectopic lymphoid neogenesis in autoimmune sialoadenitis and MALT lymphoma in Sjögren’s syndrome. J Immunol (Baltimore, Md: 1950). 2007;179(7):4929–4938.
   PubMed Web of Science ®Google Scholar
• Vinuesa CG, Linterman MA, Yu D, et al. Follicular Helper T Cells. Annu Rev Immunol. 2016;34(1):335–368.
   PubMed Web of Science ®Google Scholar
• Crotty S. T follicular helper cell differentiation, function, and roles in disease. Immunity. 2014;41(4):529–542.
   PubMed Web of Science ®Google Scholar
• Kitano M, Moriyama S, Ando Y, et al. Bcl6 protein expression shapes pre-germinal center B cell dynamics and follicular helper T cell heterogeneity. Immunity. 2011;34(6):961–972.
   PubMed Web of Science ®Google Scholar
• Verstappen GM, Kroese FGM, Bootsma H. T cells in primary Sjögren’s syndrome: targets for early intervention. Rheumatol. 2019. 10.1093/rheumatology/kez004
   Google Scholar
• Moser B. CXCR5, the defining marker for follicular B helper T (TFH) Cells. Front Immunol. 2015;6:296.
   PubMed Web of Science ®Google Scholar
• van Nierop K, de Groot C. Human follicular dendritic cells: function, origin and development. Semin Immunol. 2002;14(4):251–257.
   PubMed Web of Science ®Google Scholar
• Vosters JL, Roescher N, Polling EJ, et al. The expression of APRIL in Sjogren’s syndrome: aberrant expression of APRIL in the salivary gland. Rheumatol. 2012;51(9):1557–1562.
   PubMed Web of Science ®Google Scholar
• Mingueneau M, Boudaoud S, Haskett S, et al. Cytometry by time-of-flight immunophenotyping identifies a blood Sjögren’s signature correlating with disease activity and glandular inflammation. J Allergy Clin Immunol. 2016;137(6):e1812 (2016. 1809-1821.
   PubMed Web of Science ®Google Scholar
• Furuzawa-Carballeda J, Hernández-Molina G, Lima G, et al. Peripheral regulatory cells immunophenotyping in primary Sjögren’s syndrome: a cross-sectional study. Arthritis Res Ther. 2013;15(3):R68.
   PubMed Web of Science ®Google Scholar
• Simon Q, Pers JO, Cornec D, et al. In-depth characterization of CD24(high)CD38(high) transitional human B cells reveals different regulatory profiles. J Allergy Clin Immunol. 2016;137(5):1577–1584.e1510.
   PubMed Web of Science ®Google Scholar
• Goules AV, Tzioufas AG. Lymphomagenesis in Sjögren’s syndrome: predictive biomarkers towards precision medicine. Autoimmun Rev. 2019;18(2):137–143.
   PubMed Web of Science ®Google Scholar
• 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(8):1229–1241.
   PubMed Web of Science ®Google Scholar
• Bende RJ, Janssen J, Beentjes A, et al., Salivary gland mucosa-associated lymphoid tissue-type lymphoma from Sjögren’s syndrome patients in the majority express rheumatoid factors affinity-selected for IgG. Arthritis Rheumatol. 72(8): 1330–1340. 2020.
   PubMed Web of Science ®Google Scholar
• Papageorgiou A, Mavragani CP, Nezos A, et al. A BAFF receptor His159Tyr mutation in Sjögren’s syndrome-related lymphoproliferation. Arthritis Rheumatol. 2015;67(10):2732–2741.
   PubMed Web of Science ®Google Scholar
• Baldini C, Santini E, Rossi C, et al. The P2X7 receptor-NLRP3 inflammasome complex predicts the development of non-Hodgkin’s lymphoma in Sjogren’s syndrome: a prospective, observational, single-centre study. J Intern Med. 2017;282(2):175–186.
   PubMed Web of Science ®Google Scholar
• Nocturne G, Tarn J, Boudaoud S, et al. Germline variation of TNFAIP3 in primary Sjögren’s syndrome-associated lymphoma. Ann Rheum Dis. 2016;75(4):780–783.
   PubMed Web of Science ®Google Scholar
• Brito-Zerón P, Ramos-Casals M, Bove A, et al. Predicting adverse outcomes in primary Sjogren’s syndrome: identification of prognostic factors. Rheumatol. 2007;46(8):1359–1362.
   PubMed Web of Science ®Google Scholar
• Sutcliffe N, Inanc M, Speight P, et al. Predictors of lymphoma development in primary Sjögren’s syndrome. Semin Arthritis Rheum. 1998;28(2):80–87.
   PubMed Web of Science ®Google Scholar
• Quartuccio L, Isola M, Baldini C, et al. Biomarkers of lymphoma in Sjögren’s syndrome and evaluation of the lymphoma risk in prelymphomatous conditions: results of a multicenter study. J Autoimmun. 2014;51:75–80.
   PubMed Web of Science ®Google Scholar
• Retamozo S, Gheitasi H, Quartuccio L, et al. Cryoglobulinaemic vasculitis at diagnosis predicts mortality in primary Sjögren syndrome: analysis of 515 patients. Rheumatol. 2016;55(8):1443–1451.
   PubMed Web of Science ®Google Scholar
• Baimpa E, Dahabreh IJ, Voulgarelis M, et al. Hematologic manifestations and predictors of lymphoma development in primary Sjögren syndrome: clinical and pathophysiologic aspects. Medicine (Baltimore). 2009;88(5):284–293.
   PubMed Web of Science ®Google Scholar
• Goules AV, Argyropoulou OD, Pezoulas VC, et al. Primary Sjögren’s syndrome of early and late onset: distinct clinical phenotypes and lymphoma development. Front Immunol. 2020 Oct 19;11:594096.
   Google Scholar
• Anquetil C, Hachulla E, Machuron F, et al. Is early-onset primary Sjögren’s syndrome a worse prognosis form of the disease? Rheumatol. 2019;58(7):1163–1167.
   PubMed Web of Science ®Google Scholar
• Brito-Zerón P, Acar-Denizli N, Zeher M, et al. Influence of geolocation and ethnicity on the phenotypic expression of primary Sjögren’s syndrome at diagnosis in 8310 patients: a cross-sectional study from the big data sjögren project consortium. Ann Rheum Dis. 2017;76(6):1042–1050.
   PubMed Web of Science ®Google Scholar
• Theander E, Jonsson R, Sjöström B, et al. Prediction of Sjögren’s syndrome years before diagnosis and identification of patients with early onset and severe disease course by autoantibody profiling. Arthritis Rheumatol. 2015;67(9):2427–2436.
   PubMed Web of Science ®Google Scholar
• Shiboski CH, Shiboski SC, Seror R, 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. Arthritis Rheumatol. 2017;69(1):35–45.
   PubMed Web of Science ®Google Scholar
• Ho SY, Esscher E, Anderson RH, et al. Anatomy of congenital complete heart block and relation to maternal anti-Ro antibodies. Am J Cardiol. 1986;58(3):291–294.
   PubMed Web of Science ®Google Scholar
• Izmirly P, Kim M, Friedman DM, et al. Hydroxychloroquine to prevent recurrent congenital heart block in fetuses of anti-SSA/Ro-positive mothers. J Am Coll Cardiol. 2020;76(3):292–302.
   PubMed Web of Science ®Google Scholar
• Tzioufas AG, Tatouli IP, Moutsopoulos HM. Autoantibodies in Sjögren’s syndrome: clinical presentation and regulatory mechanisms. Presse Medicale (Paris, France: 1983. 2012;41(9):e451–460.
   PubMedGoogle Scholar
• Baldini C, Pepe P, Quartuccio L, et al. Primary Sjogren’s syndrome as a multi-organ disease: impact of the serological profile on the clinical presentation of the disease in a large cohort of Italian patients. Rheumatol. 2014;53(5):839–844.
   PubMed Web of Science ®Google Scholar
• Quartuccio L, Baldini C, Bartoloni E, et al. Anti-SSA/SSB-negative Sjögren’s syndrome shows a lower prevalence of lymphoproliferative manifestations, and a lower risk of lymphoma evolution. Autoimmun Rev. 2015;14(11):1019–1022.
   PubMed Web of Science ®Google Scholar
• Baer AN, McAdams DeMarco M, Shiboski SC, et al. The SSB-positive/SSA-negative antibody profile is not associated with key phenotypic features of Sjögren’s syndrome. Ann Rheum Dis. 2015;74(8):1557–1561.
   PubMed Web of Science ®Google Scholar
• Acar-Denizli N, Horváth IF, Mandl T, et al. Systemic phenotype related to primary Sjögren’s syndrome in 279 patients carrying isolated anti-La/SSB antibodies. Clin Exp Rheumatol. 2020;126(4):85–94. 38 Suppl.
   Google Scholar
• Vlachoyiannopoulos PG, Moutsopoulos HM. Anticentromere (ACA)-positive Sjӧgren’s syndrome: a disease entity? Clin Exp Rheumatol. 2013;31(2):163–164.
   PubMed Web of Science ®Google Scholar
• Li Y, Bookman AAM. Comparison of effect on sicca symptoms of anticentromere antibody-positive Sjögren syndrome and primary Sjögren syndrome alone. J Rheumatol. 2020;47(6):876–880.
   PubMed Web of Science ®Google Scholar
• Baldini C, Mosca M, Della Rossa A, et al. Overlap of ACA-positive systemic sclerosis and Sjögren’s syndrome: a distinct clinical entity with mild organ involvement but at high risk of lymphoma. Clin Exp Rheumatol. 2013;31(2):272–280.
   PubMed Web of Science ®Google Scholar
• Abbara S, Seror R, Henry J, et al. Anti-RNP positivity in primary Sjögren’s syndrome is associated with a more active disease and a more frequent muscular and pulmonary involvement. RMD Open. 2019;5(2):e001033.
   PubMed Web of Science ®Google Scholar
• Kim SM, Park E, Lee JH, et al. The clinical significance of anti-cyclic citrullinated peptide antibody in primary Sjögren syndrome. Rheumatol Int. 2012;32(12):3963–3967.
   PubMed Web of Science ®Google Scholar
• Ter Borg EJ, Kelder JC. Polyarthritis in primary Sjögren’s syndrome represents a distinct subset with less pronounced B cell proliferation a Dutch cohort with long-term follow-up. Clin Rheumatol. 2016;35(3):649–655.
   PubMed Web of Science ®Google Scholar
• Ramos-Casals M, Brito-Zerón P, Yagüe J, et al. Hypocomplementaemia as an immunological marker of morbidity and mortality in patients with primary Sjogren’s syndrome. Rheumatol. 2005;44(1):89–94.
   PubMed Web of Science ®Google Scholar
• Tzioufas AG, Boumba DS, Skopouli FN, et al. Mixed monoclonal cryoglobulinemia and monoclonal rheumatoid factor cross-reactive idiotypes as predictive factors for the development of lymphoma in primary Sjögren’s syndrome. Arthritis Rheumatism. 1996;39(5):767–772.
   PubMedGoogle Scholar
• Ioannidis JP, Vassiliou VA, Moutsopoulos HM. Long-term risk of mortality and lymphoproliferative disease and predictive classification of primary Sjögren’s syndrome. Arthritis Rheumatism. 2002;46(3):741–747.
   PubMed Web of Science ®Google Scholar
• Theander E, Henriksson G, Ljungberg O, et al. Lymphoma and other malignancies in primary Sjögren’s syndrome: a cohort study on cancer incidence and lymphoma predictors. Ann Rheum Dis. 2006;65(6):796–803.
   PubMed Web of Science ®Google Scholar
• Theander E, Vasaitis L, Baecklund 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. 2011;70(8):1363–1368.
   PubMed Web of Science ®Google Scholar
• Mandl T, Bredberg A, Jacobsson LT, et al. CD4+ T-lymphocytopenia–a frequent finding in anti-SSA antibody seropositive patients with primary Sjögren’s syndrome. J Rheumatol. 2004;31(4):726–728.
   PubMed Web of Science ®Google Scholar
• Risselada AP, Kruize AA, Goldschmeding R, et al. The prognostic value of routinely performed minor salivary gland assessments in primary Sjögren’s syndrome. Ann Rheum Dis. 2014;73(8):1537–1540.
   PubMed Web of Science ®Google Scholar
• Sène D, Ismael S, Forien M, et al. Ectopic germinal center-like structures in minor salivary gland biopsy tissue predict lymphoma occurrence in patients with primary Sjögren’s syndrome. Arthritis Rheumatol. 2018;70(9):1481–1488. .
   PubMed Web of Science ®Google Scholar
• Risselada AP, Looije MF, Kruize AA, et al. The role of ectopic germinal centers in the immunopathology of primary Sjögren’s syndrome: a systematic review. Semin Arthritis Rheum. 2013;42(4):368–376.
   PubMed Web of Science ®Google Scholar
• Haacke EA, van der Vegt B, Vissink A, et al. Germinal centres in diagnostic labial gland biopsies of patients with primary Sjögren’s syndrome are not predictive for parotid MALT lymphoma development. Ann Rheum Dis. 2017;76(10):1781–1784.
   PubMed Web of Science ®Google Scholar
• Johnsen SJ, Gudlaugsson E, Skaland I, et al. Low protein a20 in minor salivary glands is associated with lymphoma in primary Sjögren’s syndrome. Scand J Immunol. 2016;83(3):181–187.
   PubMed Web of Science ®Google Scholar
• Martín-Nares E, Hernández-Molina G. Novel autoantibodies in Sjögren’s syndrome: A comprehensive review. Autoimmun Rev. 2019;18(2):192–198.
   PubMed Web of Science ®Google Scholar
• Kovács L, Marczinovits I, György A, et al. Clinical associations of autoantibodies to human muscarinic acetylcholine receptor 3(213-228) in primary Sjogren’s syndrome. Rheumatol. 2005;44(8):1021–1025.
   PubMed Web of Science ®Google Scholar
• Jeon S, Lee J, Park SH, et al. Associations of anti-aquaporin 5 autoantibodies with serologic and histopathological features of Sjögren’s syndrome. J Clin Med. 2019;8(11):1863.
   Web of Science ®Google Scholar
• Takemoto F, Katori H, Sawa N, et al. Induction of anti-carbonic-anhydrase-II antibody causes renal tubular acidosis in a mouse model of Sjogren’s syndrome. Nephron Physiol. 2007;106(4):p63–68.
   Google Scholar
• Takemoto F, Hoshino J, Sawa N, et al. Autoantibodies against carbonic anhydrase II are increased in renal tubular acidosis associated with Sjogren syndrome. Am J Med. 2005;118(2):181–184.
   PubMed Web of Science ®Google Scholar
• Shen L, Suresh L, Lindemann M, et al. Novel autoantibodies in Sjogren’s syndrome. Clin Immunol. 2012;145(3):251–255. (Orlando, Fla.). .
   PubMed Web of Science ®Google Scholar
• Liu Y, Liao X, Wang Y, et al. Autoantibody to MDM2: A potential serological marker of primary Sjogren’s syndrome. Oncotarget. 2017;8(9):14306–14313.
   PubMedGoogle Scholar
• Cui L, Elzakra N, Xu S, et al. Investigation of three potential autoantibodies in Sjogren’s syndrome and associated MALT lymphoma. Oncotarget. 2017;8(18):30039–30049.
   PubMedGoogle Scholar
• Traianos EY, Locke J, Lendrem D, et al. Serum CXCL13 levels are associated with lymphoma risk and lymphoma occurrence in primary Sjögren’s syndrome. Rheumatol Int. 2020;40(4):541–548.
   PubMed Web of Science ®Google Scholar
• Liu Z, Li F, Pan A, et al. Elevated CCL19/CCR7 expression during the disease process of primary Sjögren’s syndrome. Front Immunol. 2019;10:795.
   PubMed Web of Science ®Google Scholar
• Mariette X, Roux S, Zhang J, et al. The level of BLyS (BAFF) correlates with the titre of autoantibodies in human Sjögren’s syndrome. Ann Rheum Dis. 2003;62(2):168–171.
   PubMed Web of Science ®Google Scholar
• Cornec D, Costa S, Devauchelle-Pensec V, et al. Blood and salivary-gland BAFF-driven B-cell hyperactivity is associated to rituximab inefficacy in primary Sjögren’s syndrome. J Autoimmun. 2016;67:102–110.
   PubMed Web of Science ®Google Scholar
• Gandolfo S, Bulfoni M, Fabro C, et al. Thymic stromal lymphopoietin expression from benign lymphoproliferation to malignant B-cell lymphoma in primary Sjögren’s syndrome. Clin Exp Rheumatol. 2019;118(3):55–64. 37 Suppl.
   Google Scholar
• Gandolfo S, Fabro C, Kapsogeorgou E, et al. Validation of thymic stromal lymphopoietin as a biomarker of primary Sjögren’s syndrome and related lymphoproliferation: results in independent cohorts. Clin Exp Rheumatol. 2020;126(4):189–194. 38 Suppl.
   Google Scholar
• Hall JC, Baer AN, Shah AA, et al. Molecular subsetting of interferon pathways in Sjögren’s Syndrome. Arthritis Rheumatol. 2015;67(9):2437–2446.
   PubMed Web of Science ®Google Scholar
• Kapsogeorgou EK, Papageorgiou A, Protogerou AD, et al. Low miR200b-5p levels in minor salivary glands: a novel molecular marker predicting lymphoma development in patients with Sjögren’s syndrome. Ann Rheum Dis. 2018;77(8):1200–1207.
   PubMed Web of Science ®Google Scholar
• Alevizos I, Alexander S, Turner RJ, et al. MicroRNA expression profiles as biomarkers of minor salivary gland inflammation and dysfunction in Sjögren’s syndrome. Arthritis Rheumatism. 2011;63(2):535–544.
   PubMedGoogle Scholar
• Cortes-Troncoso J, Jang SI, Perez P, et al. T cell exosome-derived miR-142-3p impairs glandular cell function in Sjögren’s syndrome. JCI Insight. 2020;5(9). 10.1172/jci.insight.133497.
   PubMed Web of Science ®Google Scholar
• Li F, Liu Z, Zhang B, et al. Circular RNA sequencing indicates circ-IQGAP2 and circ-ZC3H6 as noninvasive biomarkers of primary Sjögren’s syndrome. Rheumatol. 2020;59(9):2603–2615.
   PubMed Web of Science ®Google Scholar
• Moreno-Quispe LA, Serrano J, Virto L, et al. Association of salivary inflammatory biomarkers with primary Sjögren’s syndrome. J Oral Pathol Med. 2020;49(9):940–947.
   PubMed Web of Science ®Google Scholar
• Aqrawi LA, Galtung HK, Vestad B, et al. Identification of potential saliva and tear biomarkers in primary Sjögren’s syndrome, utilising the extraction of extracellular vesicles and proteomics analysis. Arthritis Res Ther. 2017;19(1):14.
   PubMed Web of Science ®Google Scholar
• Cecchettini A, Finamore F, Puxeddu I, et al. Salivary extracellular vesicles versus whole saliva: new perspectives for the identification of proteomic biomarkers in Sjögren’s syndrome. Clin Exp Rheumatol. 2019;118(3): 240–248. 37 Suppl.
   Google Scholar
• Cecchettini A, Finamore F, Ucciferri N, et al. Phenotyping multiple subsets in Sjögren’s syndrome: a salivary proteomic SWATH-MS approach towards precision medicine. Clin Proteomics. 2019;16(1):26.
   PubMedGoogle Scholar
• Hu S, Wang J, Meijer J, et al. Salivary proteomic and genomic biomarkers for primary Sjögren’s syndrome. Arthritis Rheumatism. 2007;56(11):3588–3600.
   PubMedGoogle Scholar
• Gallo A, Jang SI, Ong HL, et al. Targeting the Ca(2+) sensor STIM1 by exosomal transfer of Ebv-miR-BART13-3p is associated with Sjögren’s syndrome. EBioMedicine. 2016;10:216–226.
   PubMed Web of Science ®Google Scholar
• Aqrawi LA, Galtung HK, Guerreiro EM, et al. Proteomic and histopathological characterisation of sicca subjects and primary Sjögren’s syndrome patients reveals promising tear, saliva and extracellular vesicle disease biomarkers. Arthritis Res Ther. 2019;21(1):181.
   PubMedGoogle Scholar
• Li M, Zou Y, Jiang Q, et al. A preliminary study of the oral microbiota in Chinese patients with Sjögren’s syndrome. Arch Oral Biol. 2016;70:143–148.
   PubMed Web of Science ®Google Scholar
• van der Meulen TA, Harmsen HJM, Bootsma H, et al. Reduced salivary secretion contributes more to changes in the oral microbiome of patients with primary Sjögren’s syndrome than underlying disease. Ann Rheum Dis. 2018;77(10):1542–1544.
   PubMed Web of Science ®Google Scholar
• Rusthen S, Kristoffersen AK, Young A, et al. Dysbiotic salivary microbiota in dry mouth and primary Sjögren’s syndrome patients. PloS One. 2019;14(6):e0218319.
   PubMed Web of Science ®Google Scholar
• Alam J, Lee A, Lee J, et al. Dysbiotic oral microbiota and infected salivary glands in Sjögren’s syndrome. PloS One. 2020;15(3):e0230667.
   PubMed Web of Science ®Google Scholar
• Moon J, Choi SH, Yoon CH, et al. Gut dysbiosis is prevailing in Sjögren’s syndrome and is related to dry eye severity. PloS One. 2020;15(2):e0229029.
   PubMed Web of Science ®Google Scholar
• Mendez R, Watane A, Farhangi M, et al. Gut microbial dysbiosis in individuals with Sjögren’s syndrome. Microb Cell Fact. 2020;19(1):90.
   PubMed Web of Science ®Google Scholar
• Greiling TM, Dehner C, Chen X, et al. Commensal orthologs of the human autoantigen Ro60 as triggers of autoimmunity in lupus. Sci Transl Med. 2018;10(434):434.
   Web of Science ®Google Scholar
• Jousse-Joulin S, D’Agostino MA, Nicolas C, et al. Video clip assessment of a salivary gland ultrasound scoring system in Sjögren’s syndrome using consensual definitions: an OMERACT ultrasound working group reliability exercise. Ann Rheum Dis. 2019;78(7):967–973.
   PubMed Web of Science ®Google Scholar
• Milic V, Colic J, Cirkovic A, et al. Disease activity and damage in patients with primary Sjogren’s syndrome: prognostic value of salivary gland ultrasonography. PloS One. 2019;14(12):e0226498.
   PubMed Web of Science ®Google Scholar
• Jousse-Joulin S, Gatineau F, Baldini C, et al. OP0040 Integration of salivary-gland ultrasonography in classification criteria for primary sjÖgren’s syndrome: an international vignette-based study. Ann Rheum Dis. 2017;76(Suppl 2):67–68.
   Google Scholar
• van Nimwegen JF, Mossel E, Delli K, et al. Incorporation of salivary gland ultrasonography into the American college of rheumatology/European league against rheumatism criteria for primary Sjögren’s syndrome. Arthritis Care Res (Hoboken). 2020;72(4):583–590.
   PubMed Web of Science ®Google Scholar
• Satış H, Cindil E, Salman RB, et al. Parotid elastography: a potential alternative to replace labial biopsy in classification of patients with primary Sjögren’s syndrome? Clin Rheumatol. 2020;39(12):3707–3713.
   Web of Science ®Google Scholar
• Tarn JR, Howard-Tripp N, Lendrem DW, et al. Symptom-based stratification of patients with primary Sjögren’s syndrome: multi-dimensional characterisation of international observational cohorts and reanalyses of randomised clinical trials. Lancet Rheumatol. 2019;1(2):e85–e94.
   Google Scholar