Abstract

Sjögren syndrome (SjS) is a systemic autoimmune disease that primarily affects the exocrine glands (mainly the salivary and lacrimal glands) and results in the severe dryness of mucosal surfaces, principally in the mouth and eyes. This disease predominantly affects middle-aged women, but can also be observed in children, men and the elderly. The clinical presentation of SjS is heterogeneous and can vary from sicca symptoms to systemic disease (characterized by peri-epithelial lymphocytic infiltration of the affected tissue or the deposition of the immune complex) and lymphoma. The mechanism underlying the development of SjS is the destruction of the epithelium of the exocrine glands, as a consequence of abnormal B cell and T cell responses to the autoantigens Ro/SSA and La/SSB, among others. Diagnostic criteria for SjS include the detection of autoantibodies in patient serum and histological analysis of biopsied salivary gland tissue. Therapeutic approaches for SjS include both topical and systemic treatments to manage the sicca and systemic symptoms of disease. SjS is a serious disease with excess mortality, mainly related to the systemic involvement of disease and the development of lymphomas in some patients. Knowledge of SjS has progressed substantially, but this disease is still characterized by sicca symptoms, the systemic involvement of disease, lymphocytic infiltration to exocrine glands, the presence of anti-Ro/SSA and anti-La/SSB autoantibodies and the increased risk of lymphoma in patients with SjS.

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References

  1. 1.

    , , & Primary Sjögren syndrome. BMJ 344, e3821 (2012).

  2. 2.

    et al. Sjögren's syndrome associated with systemic lupus erythematosus: clinical and laboratory profiles and comparison with primary Sjögren's syndrome. Arthritis Rheum. 50, 882–891 (2004).

  3. 3.

    et al. Preliminary criteria for the classification of Sjögren's syndrome. Results of a prospective concerted action supported by the European Commununity. Arthritis Rheum. 36, 340–347 (1993).

  4. 4.

    et al. Epidemiology of primary Sjögren's syndrome: a systematic review and meta-analysis. Ann. Rheum. Dis. 74, 1983–1989 (2015).

  5. 5.

    , , & Incident cases of primary Sjögren's syndrome during a 5-year period in Stockholm County: a descriptive study of the patients and their characteristics. Scand. J. Rheumatol. 44, 135–142 (2015).

  6. 6.

    , , & Incidence and mortality of treated primary Sjögren's syndrome in Taiwan: a population-based study. J. Rheumatol. 38, 706–708 (2011).

  7. 7.

    et al. Epidemiology of primary Sjögren's syndrome in a French multiracial/multiethnic area. Arthritis Care Res. (Hoboken) 66, 454–463 (2014).

  8. 8.

    et al. The prevalence of Sjögren's syndrome in adult women. Scand. J. Rheumatol. 35, 379–383 (2006).

  9. 9.

    et al. Google-driven search for big data in autoimmune geoepidemiology: analysis of 394,827 patients with systemic autoimmune diseases. Autoimmun. Rev. 14, 670–679 (2015).

  10. 10.

    et al. Ocular complications of primary Sjögren syndrome in men. Am. J. Ophthalmol. 160, 447–452.e1 (2015).

  11. 11.

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

  12. 12.

    et al. A child with primary Sjögren syndrome and a review of the literature. Clin. Pediatr. (Phila.) 46, 738–742 (2007).

  13. 13.

    et al. Comparison of labial minor salivary gland biopsies from childhood Sjögren syndrome and age-matched controls. J. Rheumatol. 41, 1178–1182 (2014).

  14. 14.

    , , , & Secondary Sjögren's syndrome in systemic lupus erythematosus defines a distinct disease subset. J. Rheumatol. 37, 1143–1149 (2010).

  15. 15.

    , & Systemic lupus erythematosus with Sjögren syndrome compared to systemic lupus erythematosus alone: a meta-analysis. J. Clin. Rheumatol. 18, 28–32 (2012).

  16. 16.

    et al. How does functional disability in early rheumatoid arthritis (RA) affect patients and their lives? Results of 5 years of follow-up in 732 patients from the Early RA Study (ERAS). Rheumatology (Oxford) 39, 603–611 (2000).

  17. 17.

    et al. Rheumatoid arthritis in Spain: occurrence of extra-articular manifestations and estimates of disease severity. Ann. Rheum. Dis. 62, 897–900 (2003).

  18. 18.

    et al. Associated autoimmune diseases in systemic sclerosis define a subset of patients with milder disease: results from 2 large cohorts of European Caucasian patients. J. Rheumatol. 37, 608–614 (2010).

  19. 19.

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

  20. 20.

    , & Pathogenesis of Sjögren's syndrome: what we know and what we should learn. J. Autoimmun. 39, 4–8 (2012).

  21. 21.

    , , & Dendritic cells, T-cells and epithelial cells: a crucial interplay in immunopathology of primary Sjögren's syndrome. Expert Rev. Clin. Immunol. 10, 521–531 (2014).

  22. 22.

    Sjögren's syndrome: autoimmune epithelitis. Clin. Immunol. Immunopathol. 72, 162–165 (1994). This article dissects the main mechanisms on which the previously most-accepted hypothesis of SjS aetiopathogenesis was formed.

  23. 23.

    , & Neuroendocrine dysfunction in Sjögren's syndrome. Neuroimmunomodulation 15, 37–45 (2008).

  24. 24.

    & Sjögren's syndrome: mechanisms of pathogenesis involve interaction of immune and neurosecretory systems. Scand. J. Rheumatol. Suppl. 116, 3–13 (2002).

  25. 25.

    & The role of intrinsic epithelial activation in the pathogenesis of Sjögren's syndrome. J. Autoimmun. 35, 219–224 (2010).

  26. 26.

    & Advances in understanding the pathogenesis of primary Sjögren's syndrome. Nat. Rev. Rheumatol. 9, 544–556 (2013).

  27. 27.

    et al. Differentiation of follicular helper T cells by salivary gland epithelial cells in primary Sjögren's syndrome. J. Autoimmun. 51, 57–66 (2014).

  28. 28.

    , & B-lymphocytes govern the pathogenesis of Sjögren's syndrome. Curr. Pharm. Biotechnol. 13, 2071–2077 (2012).

  29. 29.

    et al. Salivary gland epithelial cells (SGECs) promote the differentiation of B cells. Presented at the 12th International Symposium on Sjögren's Syndrome (2013).

  30. 30.

    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. 178, 548–560 (2014).

  31. 31.

    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. USA 109, 17609–17614 (2012).

  32. 32.

    , , , & Salivary gland tissue expression of interleukin-23 and interleukin-17 in Sjögren's syndrome: findings in humans and mice. Arthritis Rheum. 58, 734–743 (2008).

  33. 33.

    et al. Increased expression of interleukin-7 in labial salivary glands of patients with primary Sjögren's syndrome correlates with increased inflammation. Arthritis Rheum. 62, 969–977 (2010).

  34. 34.

    , & 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 8, e77605 (2013).

  35. 35.

    , , & Interleukin-7 enhances the Th1 response to promote the development of Sjögren's syndrome-like autoimmune exocrinopathy in mice. Arthritis Rheum. 65, 2132–2142 (2013).

  36. 36.

    et al. T regulatory and T helper 17 cells in primary Sjögren's syndrome: facts and perspectives. Mediators Inflamm. 2015, 243723 (2015).

  37. 37.

    & Apoptosis and Sjögren syndrome. Semin. Arthritis Rheum. 33, 49–65 (2003).

  38. 38.

    et al. Enhanced apoptosis by disruption of the STAT3–IκB-ζ signaling pathway in epithelial cells induces Sjögren's syndrome-like autoimmune disease. Immunity 38, 450–460 (2013).

  39. 39.

    , & EBV and other viruses as triggers of tertiary lymphoid structures in primary Sjögren's syndrome. Expert Rev. Clin. Immunol. 10, 445–455 (2014).

  40. 40.

    et al. Association of Epstein–Barr virus (EBV) with Sjögren's syndrome: differential EBV expression between epithelial cells and lymphocytes in salivary glands. Am. J. Pathol. 149, 1511–1517 (1996).

  41. 41.

    et al. Infection and autoimmunity in Sjögren's syndrome: a clinical study and comprehensive review. J. Autoimmun. 51, 17–22 (2014).

  42. 42.

    et al. Human herpesvirus-6 (HHV-6, HBLV) in sarcoidosis and lymphoproliferative disorders. J. Virol. Methods 21, 49–59 (1988).

  43. 43.

    , , , & Antibodies to human herpesvirus-6 in Sjögren's syndrome. Arthritis Rheum. 33, 1749–1750 (1990).

  44. 44.

    , & Serological screening for hepatitis B and C and human herpesvirus 6 in Norwegian patients with primary Sjögren's syndrome. J. Rheumatol. 26, 2065–2066 (1999).

  45. 45.

    et al. Prevalence of serum and salivary antibodies to HTLV-1 in Sjögren's syndrome. Lancet 344, 1116–1119 (1994).

  46. 46.

    et al. Direct infection of primary salivary gland epithelial cells by human T lymphotropic virus type I in patients with Sjögren's syndrome. Arthritis Rheumatol. 67, 1096–1106 (2015).

  47. 47.

    et al. Hepatitis C virus infection in primary Sjögren's syndrome: prevalence and clinical significance in a series of 90 patients. Ann. Rheum. Dis. 56, 173–175 (1997).

  48. 48.

    et al. Lymphocytic sialadenitis of Sjögren's syndrome associated with chronic hepatitis C virus liver disease. Lancet 339, 321–323 (1992).

  49. 49.

    et al. How hepatitis C virus modifies the immunological profile of Sjögren syndrome: analysis of 783 patients. Arthritis Res. Ther. 17, 250 (2015).

  50. 50.

    et al. Serum antibodies from patients with primary Sjögren's syndrome and systemic lupus erythematosus recognize multiple epitopes on the La(SS-B) autoantigen resembling viral protein sequences. Scand. J. Immunol. 43, 115–121 (1996).

  51. 51.

    et al. Molecular subsetting of interferon pathways in Sjögren's syndrome. Arthritis Rheumatol. 67, 2437–2446 (2015).

  52. 52.

    Autoantibodies present before symptom onset in primary Sjögren syndrome. JAMA 310, 1854–1855 (2013). This study provides the first evidence showing that SjS-related autoantibodies might be detected several years before the diagnosis of the disease.

  53. 53.

    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. 67, 2427–2436 (2015).

  54. 54.

    , & Prevention of autoimmune rheumatic disease: state of the art and future perspectives. Ann. Rheum. Dis. 69, 2062–2066 (2010).

  55. 55.

    et al. Cardiovascular disease risk burden in primary Sjögren's syndrome: results of a population-based multicentre cohort study. J. Intern. Med. 278, 185–192 (2015).

  56. 56.

    et al. Cardiovascular risk factors in primary Sjögren's syndrome: a case–control study in 624 patients. Lupus 19, 941–948 (2010).

  57. 57.

    et al. Cigarette smoking in primary Sjögren's syndrome: positive association only with ANA positivity. Mod. Rheumatol. 21, 602–607 (2011).

  58. 58.

    et al. Lower frequency of focal lip sialadenitis (focus score) in smoking patients. Can tobacco diminish the salivary gland involvement as judged by histological examination and anti-SSA/Ro and anti-SSB/La antibodies in Sjögren's syndrome? Ann. Rheum. Dis. 59, 54–60 (2000).

  59. 59.

    , , , & Primary Sjögren's syndrome and other autoimmune diseases in families. Prevalence and immunogenetic studies in six kindreds. Ann. Intern. Med. 101, 748–756 (1984).

  60. 60.

    et al. Familial risk of Sjögren's syndrome and co-aggregation of autoimmune diseases in affected families: a nationwide population study. Arthritis Rheumatol. 67, 1904–1912 (2015).

  61. 61.

    et al. Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjögren's syndrome. Nat. Genet. 45, 1284–1292 (2013). This is a key study about the complex genetic landscape of SjS.

  62. 62.

    et al. A genome-wide association study in Han Chinese identifies a susceptibility locus for primary Sjögren's syndrome at 7q11.23. Nat. Genet. 45, 1361–1365 (2013).

  63. 63.

    et al. In primary Sjögren's syndrome, HLA class II is associated exclusively with autoantibody production and spreading of the autoimmune response. Arthritis Rheumatol. 48, 2240–2245 (2003).

  64. 64.

    et al. Horizons in Sjögren's syndrome genetics. Clin. Rev. Allergy Immunol. 32, 201–209 (2007).

  65. 65.

    & Sjögren syndrome-associated lymphomas: an update on pathogenesis and management. Br. J. Haematol. 168, 317–327 (2015). This article reviews the aetiopathogenetic mechanisms and clinical management of SjS-related lymphoma.

  66. 66.

    et al. Germline and somatic genetic variations of TNFAIP3 in lymphoma complicating primary Sjögren's syndrome. Blood 122, 4068–4076 (2013).

  67. 67.

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

  68. 68.

    et al. CXCL13 and CCL11 serum levels and lymphoma and disease activity in primary Sjögren's syndrome. Arthritis Rheumatol. 67, 3226–3233 (2015).

  69. 69.

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

  70. 70.

    et al. BLyS upregulation in Sjögren's syndrome associated with lymphoproliferative disorders, higher ESSDAI score and B-cell clonal expansion in the salivary glands. Rheumatology (Oxford) 52, 276–281 (2013). This is an elegant study that supported the efficacy of blocking BAFF in patients with SjS.

  71. 71.

    et al. B-cell activating factor genetic variants in lymphomagenesis associated with primary Sjögren's syndrome. J. Autoimmun. 51, 89–98 (2014).

  72. 72.

    et al. The Fms-like tyrosine kinase 3 ligand, a mediator of B cell survival, is also a marker of lymphoma in primary Sjögren's syndrome. Arthritis Rheum. 62, 3447–3456 (2010).

  73. 73.

    et al. Sjögren's syndrome — an update for dental practitioners. Br. Dent. J. 213, 353–357 (2012).

  74. 74.

    et al. Early diagnosis of primary Sjögren's syndrome: EULAR-SS Task Force clinical recommendations. Expert Rev. Clin. Immunol. 12, 137–156 (2016). This study notes that patients with SjS can present with systemic manifestations of disease and are at high risk of developing poor outcomes.

  75. 75.

    , , & Urban legends series: Sjögren's syndrome. Oral Dis. 19, 46–58 (2013).

  76. 76.

    et al. Ocular and systemic morbidity in a longitudinal cohort of Sjögren's syndrome. Ophthalmology 122, 56–61 (2015).

  77. 77.

    et al. Skin involvement and outcome measures in systemic autoimmune diseases. Clin. Exp. Rheumatol. 24, S52–S59 (2006).

  78. 78.

    et al. Primary Sjögren'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. Rheumatology 53, 839–844 (2013).

  79. 79.

    et al. Validation of the classification criteria for cryoglobulinaemic vasculitis. Rheumatology (Oxford) 53, 2209–2213 (2014).

  80. 80.

    et al. Cryoglobulinaemic vasculitis at diagnosis predicts mortality in primary Sjögren syndrome: analysis of 515 patients. Rheumatology (Oxford) (2016).

  81. 81.

    et al. EULAR Sjögren's syndrome disease activity index: development of a consensus systemic disease activity index for primary Sjögren's syndrome. Ann. Rheum. Dis. 69, 1103–1109 (2010). This study has led to a step forwards in the evaluation of systemic complications of SjS.

  82. 82.

    & Lower prevalence of extra-glandular manifestations and anti-SSB antibodies in patients with primary Sjögren's syndrome and widespread pain: evidence for a relatively benign subset. Clin. Exp. Rheumatol. 32, 349–353 (2014).

  83. 83.

    et al. Fatigue in primary Sjögren's syndrome: clinical, laboratory, psychometric, and biologic associations. Arthritis Care Res. (Hoboken) 68, 123–131 (2016).

  84. 84.

    et al. Characterization of systemic disease in primary Sjögren's syndrome: EULAR-SS Task Force recommendations for articular, cutaneous, pulmonary and renal involvements. Rheumatology (Oxford) 54, 2230–2238 (2015).

  85. 85.

    et al. Ultrasound imaging for the rheumatologist. XXIII. Sonographic evaluation of hand joint involvement in primary Sjögren's syndrome. Clin. Exp. Rheumatol. 27, 747–750 (2009).

  86. 86.

    et al. Clinical and biological differences between cryoglobulinaemic and hypergammaglobulinaemic purpura in primary Sjögren's syndrome: results of a large multicentre study. Scand. J. Rheumatol. 44, 36–41 (2015).

  87. 87.

    et al. Lung involvement in primary Sjögren's syndrome: correlation between high-resolution computed tomography score and mortality. J. Chin. Med. Assoc. 77, 75–82 (2014).

  88. 88.

    , , & Clinically significant renal involvement in primary Sjögren's syndrome: clinical presentation and outcome. Arthritis Rheum. 65, 2945–2953 (2013).

  89. 89.

    et al. Systemic involvement in primary Sjögren's syndrome evaluated by the EULAR-SS Disease Activity Index: analysis of 921 Spanish patients (GEAS-SS registry). Rheumatology (Oxford) 53, 321–331 (2014).

  90. 90.

    , & Primary Sjögren's syndrome: new clinical and therapeutic concepts. Ann. Rheum. Dis. 64, 347–354 (2005).

  91. 91.

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

  92. 92.

    et al. The prognostic value of routinely performed minor salivary gland assessments in primary Sjögren's syndrome. Ann. Rheum. Dis. 73, 1537–1540 (2014).

  93. 93.

    , , , & Assessment of salivary gland function in Sjögren's syndrome: the role of salivary gland scintigraphy. Autoimmun. Rev. 8, 672–676 (2009).

  94. 94.

    in Clinical Ocular Pharmacology (eds Barlett, J. D. & Jaanus, S. D.) 283–294 (Butterworth Heinemann, 2007).

  95. 95.

    & Primary Sjögren's syndrome: diagnostic and prognostic value of salivary gland ultrasonography using a simplified scoring system. Arthritis Care Res. (Hoboken) 66, 1102–1107 (2014).

  96. 96.

    , , , & Analysis of the molecular composition of Ro ribonucleoprotein complexes. Identification of novel Y RNA-binding proteins. Eur. J. Biochem. 267, 2778–2789 (2000).

  97. 97.

    , , , & Anti-SSA Ro52/Ro60 antibody testing by immunodot could help the diagnosis of Sjögren's syndrome in the absence of anti-SSA/SSB antibodies by ELISA. Rheumatology (Oxford) 52, 2223–2228 (2013).

  98. 98.

    , & Latest update on the Ro/SS-A autoantibody system. Autoimmun. Rev. 8, 632–637 (2009).

  99. 99.

    et al. Anti-Ro52 antibody testing influences the classification and clinical characterisation of primary Sjögren's syndrome. Clin. Exp. Rheumatol. 30, 686–692 (2012).

  100. 100.

    & Congenital heart block: evidence for a pathogenic role of maternal autoantibodies. Arthritis Res. Ther. 14, 208 (2012).

  101. 101.

    , & Is identification of anti-SSA and/or -SSB antibodies necessary in serum samples referred for antinuclear antibodies testing? J. Clin. Lab. Anal. 26, 447–451 (2012).

  102. 102.

    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. 14, 1019–1022 (2015).

  103. 103.

    et al. The SSB-positive/SSA-negative antibody profile is not associated with key phenotypic features of Sjögren's syndrome. Ann. Rheum. Dis. 74, 1557–1561 (2015).

  104. 104.

    et al. La positive, Ro60 negative subset of primary Sjögren's syndrome is a reality. ACR (2014).

  105. 105.

    , , & The cryoglobulinaemias. Lancet 379, 348–360 (2012).

  106. 106.

    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. 51, 75–80 (2014).

  107. 107.

    et al. Circulating monoclonal immunoglobulins in Sjögren syndrome. Medicine (Baltimore) 84, 90–97 (2005).

  108. 108.

    et al. Monoclonal gammopathy related to Sjögren syndrome: a key marker of disease prognosis and outcomes. J. Autoimmun. 39, 43–48 (2012).

  109. 109.

    et al. Diagnostic value of labial minor salivary gland biopsy for Sjögren's syndrome: a systematic review. Autoimmun. Rev. 12, 416–420 (2013).

  110. 110.

    et al. Associations between salivary gland histopathologic diagnoses and phenotypic features of Sjögren's syndrome among 1,726 registry participants. Arthritis Rheum. 63, 2021–2030 (2011). This is the largest study describing the different histopathological scenarios that are found in the minor salivary glands of patients with SjS.

  111. 111.

    et al. Parotid gland biopsy compared with labial biopsy in the diagnosis of patients with primary Sjögren's syndrome. Rheumatology (Oxford) 46, 335–341 (2007).

  112. 112.

    , , , & Focal lymphocytic infiltration in aging human palatal salivary glands: a comparative study with labial salivary glands. J. Oral Pathol. Med. 30, 7–11 (2001).

  113. 113.

    , , & Prevalence and clinical significance of lymphocytic foci in minor salivary glands of healthy volunteers. Arthritis Rheum. 47, 520–524 (2002).

  114. 114.

    , , , & The role of ectopic germinal centers in the immunopathology of primary Sjögren's syndrome: a systematic review. Semin. Arthritis Rheum. 42, 368–376 (2013).

  115. 115.

    , , , & Relation of autoimmune cytopenia to glandular and systemic manifestations in primary Sjögren syndrome: analysis of 113 Korean patients. J. Rheumatol. 42, 1817–1824 (2015).

  116. 116.

    , , , & CD4+ T-lymphocytopenia — a frequent finding in anti-SSA antibody seropositive patients with primary Sjögren's syndrome. J. Rheumatol. 31, 726–728 (2004).

  117. 117.

    , , & Hematologic manifestations and predictors of lymphoma development in primary Sjögren syndrome: clinical and pathophysiologic aspects. Medicine (Baltimore) 88, 284–293 (2009).

  118. 118.

    et al. Classification criteria for Sjögren's syndrome: a revised version of the European criteria proposed by the American–European Consensus Group. Ann. Rheum. Dis. 61, 554–558 (2002). This is the ‘gold-standard’ criteria used worldwide for the diagnosis of SjS.

  119. 119.

    et al. American College of Rheumatology classification criteria for Sjögren's syndrome: a data-driven, expert consensus approach in the Sjögren's International Collaborative Clinical Alliance cohort. Arthritis Care Res. (Hoboken) 64, 475–487 (2012).

  120. 120.

    , , & Diagnostic approach to the complexity of IgG4-related disease. Mayo Clin. Proc. 90, 927–939 (2015).

  121. 121.

    , , , & Elevated IgG4 serum levels among primary Sjögren's syndrome patients: do they unmask underlying IgG4-related disease? Arthritis Care Res. (Hoboken) 66, 773–777 (2014).

  122. 122.

    et al. IgG4 multiorgan lymphoproliferative syndrome as a differential diagnosis of primary Sjögren's syndrome in men? Ann. Rheum. Dis. 70, 2234–2235 (2011).

  123. 123.

    , , , & The clinical spectrum of autoimmune congenital heart block. Nat. Rev. Rheumatol. 11, 301–312 (2015).

  124. 124.

    et al. [Primary Sjögren's syndrome: clinical and immunologic study of 80 patients]. Med. Clin. (Barc.) 108, 652–657 (in Spanish) (1997).

  125. 125.

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

  126. 126.

    et al. EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI): development of a consensus patient index for primary Sjögren's syndrome. Ann. Rheum. Dis. 70, 968–972 (2011).

  127. 127.

    et al. Evaluation of germinal center-like structures and B cell clonality in patients with primary Sjögren syndrome with and without lymphoma. J. Rheumatol. 41, 2214–2222 (2014).

  128. 128.

    et al. Treatment of mucosa-associated lymphoid tissue lymphoma in Sjögren's syndrome: a retrospective clinical study. J. Rheumatol. 38, 2198–2208 (2011).

  129. 129.

    et al. Clinical practice guidelines for oral management of Sjögren disease: dental caries prevention. J. Am. Dent. Assoc. 147, 295–305 (2016).

  130. 130.

    , , , & Topical and systemic medications for the treatment of primary Sjögren's syndrome. Nat. Rev. Rheumatol. 8, 399–411 (2012).

  131. 131.

    , , , & Treatment of primary Sjögren syndrome: a systematic review. JAMA 304, 452–460 (2010). This is the first published systematic review that evaluated the use of the main topical and systemic drugs for the treatment of SjS.

  132. 132.

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

  133. 133.

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

  134. 134.

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

  135. 135.

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

  136. 136.

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

  137. 137.

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

  138. 138.

    et al. Efficacy of rituximab in systemic manifestations of primary Sjögren's syndrome: results in 78 patients of the autoimmune and rituximab registry. Ann. Rheum. Dis. 72, 1026–1031 (2013).

  139. 139.

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

  140. 140.

    et al. Clinical and histologic evidence of salivary gland restoration supports the efficacy of rituximab treatment in Sjögren's syndrome. Arthritis Rheum. 60, 3251–3256 (2009).

  141. 141.

    et al. Development of the Sjögren's Syndrome Responder Index, a data-driven composite endpoint for assessing treatment efficacy. Rheumatology (Oxford) 54, 1699–1708 (2015).

  142. 142.

    et al. Epratuzumab (humanised anti-CD22 antibody) in primary Sjögren's syndrome: an open-label phase I/II study. Arthritis Res. Ther. 8, R129 (2006).

  143. 143.

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

  144. 144.

    et al. Evaluation of histological, serological and clinical changes in response to abatacept treatment of primary Sjögren's syndrome: a pilot study. Arthritis Care Res. (Hoboken) 65, 1862–1868 (2013).

  145. 145.

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

  146. 146.

    US National Library of Medicine. Efficacy and safety of abatacept in patients with primary Sjögren's syndrome (ASAPIII). ClinicalTrials.gov. (2016).

  147. 147.

    et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet 381, 1203–1210 (2013).

  148. 148.

    , , & Long term remission of Sjögren'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. 65, 1033–1037 (2006).

  149. 149.

    et al. Measurement of fatigue and discomfort in primary Sjögren's syndrome using a new questionnaire tool. Rheumatology 43, 758–764 (2004).

  150. 150.

    , , , & Evaluation of quality of life in relation to anxiety and depression in primary Sjögren's syndrome. Mod. Rheumatol. 20, 588–597 (2010).

  151. 151.

    , , , & The psychological defensive profile of primary Sjögren's syndrome patients and its relationship to health-related quality of life. Clin. Exp. Rheumatol. 29, 485–493 (2011).

  152. 152.

    , , & Sjögren's syndrome: a community-based study of prevalence and impact. Br. J. Rheumatol. 37, 1069–1076 (1998).

  153. 153.

    et al. Primary Sjögren's syndrome: health experiences and predictors of health quality among patients in the United States. Health Qual. Life Outcomes 7, 46 (2009).

  154. 154.

    et al. Health-related quality of life, employment and disability in patients with Sjögren's syndrome. Rheumatology (Oxford) 48, 1077–1082 (2009).

  155. 155.

    et al. Quality of life and psychological status in patients with primary Sjögren's syndrome and sicca symptoms without autoimmune features. Arthritis Rheum. 55, 451–457 (2006).

  156. 156.

    et al. Do the European League Against Rheumatism Sjögren's syndrome outcome measures correlate with health status in primary Sjögren's syndrome? Rheumatology (Oxford) 54, 655–659 (2015).

  157. 157.

    , , , & Association of antibodies to interferon-inducible protein-16 with markers of more severe disease in primary Sjögren's syndrome. Arthritis Care Res. (Hoboken) 68, 254–260 (2016).

  158. 158.

    et al. Association of IL-21 cytokine with severity of primary Sjögren syndrome dry eye. Cornea 34, 248–252 (2015).

  159. 159.

    et al. Aromatase controls Sjögren syndrome-like lesions through monocyte chemotactic protein-1 in target organ and adipose tissue-associated macrophages. Am. J. Pathol. 185, 151–161 (2015).

  160. 160.

    et al. The contribution of epigenetics in Sjögren's syndrome. Front. Genet. 5, 71 (2014).

  161. 161.

    et al. Overlap between differentially methylated DNA regions in blood B lymphocytes and genetic at-risk loci in primary Sjögren's syndrome. Ann. Rheum. Dis. 75, 933–940 (2016).

  162. 162.

    Fio et al. PUF60: a prominent new target of the autoimmune response in dermatomyositis and Sjögren's syndrome. Ann. Rheum. Dis. 75, 1145–1151(2016).

  163. 163.

    et al. Antibodies against carbamylated proteins are present in primary Sjögren's syndrome and are associated with disease severity. Ann. Rheum. Dis. (2015).

  164. 164.

    et al. Low numbers of blood and salivary natural killer cells are associated with a better response to belimumab in primary Sjögren's syndrome: results of the BELISS study. Arthritis Res. Ther. 17, 241 (2015).

  165. 165.

    , , , & TSP-1 deficiency alters ocular microbiota: implications for Sjögren's syndrome pathogenesis. J. Ocul. Pharmacol. Ther. 31, 413–418 (2015).

  166. 166.

    et al. T cell epitope mimicry between Sjögren's syndrome antigen A (SSA)/Ro60 and oral, gut, skin and vaginal bacteria. Clin. Immunol. 152, 1–9 (2014).

  167. 167.

    et al. Primary Sjögren's syndrome and occupational risk factors: a case–control study. J. Autoimmun. 60, 80–85 (2015).

  168. 168.

    et al. Nested case–control study of selected systemic autoimmune diseases in World Trade Center rescue/recovery workers. Arthritis Rheumatol. 67, 1369–1376 (2015).

  169. 169.

    et al. Fine particulate air pollution, nitrogen dioxide, and systemic autoimmune rheumatic disease in Calgary, Alberta. Environ. Res. 140, 474–478 (2015).

  170. 170.

    et al. Inter-grader agreement of the Ocular Staining Score in the Sjögren's International Clinical Collaborative Alliance (SICCA) Registry. Am. J. Ophthalmol. 160, 1150–1153.e3 (2015).

  171. 171.

    et al. Corneal fluorescein staining correlates with visual function in dry eye patients. Invest. Ophthalmol. Vis. Sci. 52, 9516–9522 (2011).

  172. 172.

    et al. Clinical and molecular inflammatory response in Sjögren syndrome-associated dry eye patients under desiccating stress. Am. J. Ophthalmol. 161, 133–141.e2 (2016).

  173. 173.

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

  174. 174.

    et al. Development of clinESSDAI score (clinical EULAR Sjögren's Syndrome Disease Activity Index) without the biological domain: a tool for biological studies. Ann. Rheum. Dis. (2016).

  175. 175.

    et al. Conventional MRI techniques combined with MR sialography on T2-3D-DRIVE in Sjögren syndrome. Int. J. Clin. Exp. Med. 8, 3974–3982 (2015).

  176. 176.

    et al. Use of a novel high-resolution magnetic resonance neurography protocol to detect abnormal dorsal root ganglia in Sjögren patients with neuropathic pain: case series of 10 patients and review of the literature. Medicine (Baltimore) 93, 121–134 (2014).

  177. 177.

    et al. 18F-fluorodeoxyglucose positron emission tomography/computer tomography as an objective tool for assessing disease activity in Sjögren's syndrome. Autoimmun. Rev. 12, 1109–1114 (2013).

  178. 178.

    , , & Diagnostic utility of major salivary gland ultrasonography in primary Sjögren's syndrome. Clin. Exp. Rheumatol. 33, 56–62 (2015).

  179. 179.

    et al. Salivary gland ultrasonography: a highly specific tool for the early diagnosis of primary Sjögren's syndrome. Arthritis Res. Ther. 17, 146 (2015).

  180. 180.

    , & The overlap of Sjögren's syndrome with other systemic autoimmune diseases. Semin. Arthritis Rheum. 36, 246–255 (2007).

  181. 181.

    et al. The prevalence and clinical characteristics of primary Sjögren's syndrome patients with lung cancer: an analysis of ten cases in China and literature review. Thorac Cancer 6, 475–479 (2015).

  182. 182.

    et al. Cardiovascular risk factors in women with primary Sjögren's syndrome: United Kingdom primary Sjögren's syndrome registry results. Arthritis Care Res. (Hoboken) 66, 757–764 (2014).

  183. 183.

    , , & Main causes and risk factors for hospitalisation in patients with primary Sjögren's syndrome. Clin. Exp. Rheumatol. 33, 721–725 (2015).

  184. 184.

    et al. A systematic review of non-pharmacological interventions for primary Sjögren's syndrome. Rheumatology (Oxford) 54, 2025–2032 (2015).

  185. 185.

    , , & The origins, function, and regulation of T follicular helper cells. J. Exp. Med. 209, 1241–1253 (2012).

  186. 186.

    US National Library of Medicine. Efficacy of tocilizumab in primary Sjögren's syndrome. (ETAP). ClinicalTrials.gov (2014).

  187. 187.

    et al. Engineering of a novel anti-CD40L domain antibody for treatment of autoimmune diseases. J. Immunol. 192, 4083–4092 (2014).

  188. 188.

    , , & Fingolimod efficacy in multiple sclerosis associated with Sjögren syndrome. Acta Neurol. Scand. 131, 140–143 (2015).

  189. 189.

    , & Refractory primary Sjögren syndrome successfully treated with bortezomib. J. Clin. Rheumatol. 21, 31–32 (2015).

  190. 190.

    et al. Eligibility for clinical trials in primary Sjögren's syndrome: lessons from the UK Primary Sjögren's Syndrome Registry. Rheumatology (Oxford) 55, 544–552 (2016).

  191. 191.

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

  192. 192.

    , , , & Advances in salivary gland gene therapy — oral and systemic implications. Expert Opin. Biol. Ther. 15, 1443–1454 (2015).

  193. 193.

    et al. Generation of bioartificial salivary gland using whole-organ decellularized bioscaffold. Cells Tissues Organs 200, 171–180 (2014).

  194. 194.

    & Biomarkers. Saliva proteomics is a promising tool to study Sjögren syndrome. Nat. Rev. Rheumatol. 11, 202–203 (2015).

  195. 195.

    et al. High fidelity between saliva proteomics and the biologic state of salivary glands defines biomarker signatures for primary Sjögren's syndrome. Arthritis Rheumatol. 67, 1084–1095 (2015).

  196. 196.

    et al. A prospective evaluation of dental and periodontal status in patients with suspected Sjögren's syndrome. Joint Bone Spine 83, 235–236 (2016).

  197. 197.

    et al. Quality of sexual life in women with primary Sjögren syndrome. J. Rheumatol. 42, 1427–1431 (2015).

  198. 198.

    et al. The impact of primary Sjögren's syndrome on female sexual function. Rheumatology 54, 1286–1293 (2015).

  199. 199.

    et al. The quality of life burden associated with voice disorders in Sjögren's syndrome. Ann. Otol. Rhinol. Laryngol. 124, 721–727 (2015).

  200. 200.

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

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Acknowledgements

The authors thank L. Alós, Pathology Department, Hospital Clínic, IDIBAPS, Barcelona, Spain, for her assistance in preparing the histopathological images.

Author information

Affiliations

  1. Autoimmune Diseases Unit, Department of Medicine, Hospital CIMA-Sanitas, Barcelona, Spain.

    • Pilar Brito-Zerón
  2. Sjögren Syndrome Research Group (AGAUR), Laboratory of Autoimmune Diseases Josep Font, IDIBAPS-CELLEX, Barcelona, Spain.

    • Pilar Brito-Zerón
    •  & Manuel Ramos-Casals
  3. Department of Autoimmune Diseases, ICMiD, Hospital Clínic, C/Villarroel, 170, 08036 Barcelona, Spain.

    • Pilar Brito-Zerón
    •  & Manuel Ramos-Casals
  4. Rheumatology Unit, University of Pisa, Pisa, Italy.

    • Chiara Baldini
  5. Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

    • Hendrika Bootsma
  6. Rheumatology Department, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.

    • Simon J. Bowman
  7. Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway.

    • Roland Jonsson
  8. Department of Rheumatology, Haukeland University Hospital, Bergen, Norway.

    • Roland Jonsson
  9. Université Paris Sud, INSERM, Paris, France.

    • Xavier Mariette
  10. Center for Immunology of Viral Infections and Autoimmune Diseases, Assistance Publique — Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Le Kremlin-Bicêtre, Paris, France.

    • Xavier Mariette
  11. Oklahoma Sjögren's syndrome Center of Research Translation, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.

    • Kathy Sivils
  12. Department of Rheumatology, Malmö University Hospital, Lund University, Lund, Sweden.

    • Elke Theander
  13. Department of Pathophysiology, School of Medicine, National University of Athens, Athens, Greece.

    • Athanasios Tzioufas
  14. Department of Medicine, University of Barcelona, Barcelona, Spain.

    • Manuel Ramos-Casals

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Contributions

Introduction (P.B.-Z.); Epidemiology (M.R.-C.); Mechanisms/pathophysiology (A.T., K.S. and R.J.); Diagnosis, screening and prevention (C.B. and P.B.-Z.); Management (E.T., H.B. and X.M.); Quality of life (S.J.B.); Outlook (M.R.-C.); Overview of Primer (M.R.-C.).

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Manuel Ramos-Casals.

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DOI

https://doi.org/10.1038/nrdp.2016.47

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