Sjögren Syndrome

Sjögren Syndrome (SS) is a chronic systemic autoimmune disease primarily affecting the exocrine glands (salivary and lacrimal) results in dry mouth and/or dry eyes.  It is a common disorder with a prevalence rate of over 1 % of the general population.

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Women of middle age are predominantly affected by Sjögren Syndrome, with a female to male ratio of 9:1 (Fox, 2005) 

Introduction

  • The clinical presentation of SS is heterogeneous and can vary from sicca symptoms to systemic disease which 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 SS 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 (Mavragani, 2010). 

Classification Criteria 

  • Since 1965, several classification criteria sets have been proposed. More recently, two sets of criteria have been published. The first was the 2002 revised American–European Consensus Group (AECG) Classification Criteria. The second set of criteria was published by the Sjögren’s International Collaborative Clinical Alliance (SICCA) and endorsed by the American College of Rheumatology (ACR) in 2012. Despite the differences between the ACR and AECG classification criteria, in 2014 Rasmussen and colleagues compared the performances of the two sets of criteria and found a high level of concordance, but also no clear evidence for the increased value of the new ACR criteria over the old AECG criteria.

  • The lack of an international consensus on SS classification criteria, prompted the international scientific community to develop a novel set of criteria for SS. As consequence, in 2016 the ACR and the European League Against Rheumatism (EULAR) developed and validated a novel set of classification criteria for SS combining items from both the AECG and ACR criteria. It is worth underlining that these criteria have been elaborated for improving patient recruitment in clinical trials, consequently, they are focused on primary SS because patients with secondary SS are generally excluded from experimental protocols.

  • The three classification criteria are schematically summarized in this table (from Negrini 2022) 

Autoantibodies 

 

  • Antinuclear antibodies (ANA) 

    • Immunofluorescence testing for ANA is highly relevant for the diagnosis of connective tissue disorders. Up to 83% of patients with SS test positive for ANA. However, low-titer (<1:160) and unspecific ANA patterns are also found in 5% to 20% of the general healthy population. In patients with positive ANA titers, a fine speckled fluorescence pattern is strongly indicative of anti-Ro/SSA and/or anti-La/SSB antibodies, which is revealed in approximately 40% to 75% and 23% to 52% of SS patients, respectively. With the recent increase in diagnostic value assigned to anti-Ro/SSA antibodies in the current classification system, it can be expected that significantly more newly classified Sjögren’s syndrome patients will have elevated antibody levels compared with historical cohorts. Positive antibody titers correlate with early onset of disease, more intense tissue infiltration, and higher prevalence of extraglandular manifestations (Nardi, 2006).  

  • Ro/SSA and La/SSB

    • The most common antinuclear antibodies in Sjögren’s patients are those directed against the autoantigens Ro/SSA and La/SSB. Anti-Ro/SSA and anti-La/SSB antibodies are detected in 50 to 70% of primary Sjögren’s patients, depending on the methodology. Anti-Ro/SSA is independent of anti-La/SSB antibody but the contrary is rare with a recent analysis of the Sjögren’s Syndrome International Clinical Alliance (SICCA) cohort concluding that individuals (n=74) with anti-La/SSB but no anti-Ro/SSA did not have the disease (Baer, 2015). 

    • Anti-Ro/SSA and anti-La/SSB antibodies are correlated with younger age at diagnosis, longer disease duration, more severe dysfunction of the exocrine glands, recurrent parotid gland enlargement and higher intensity of the lymphocytic infiltrates in the minor salivary glands. 

  • Anti-centromere antibodies (ACA) 

    • The prevalence of ACA in primary Sjögren’s ranges from 3.7 to 27% when detected by indirect immunofluorescence, and from 20 to 25% when detected by other methodologies (Bournia, 2010).  Kitagawa, et al. described the clinical features of ACA-positive primary Sjögren’s patients and suggested including ACA in the classification criteria. In this study, during a 6.5 year period, 64 patients were diagnosed with primary Sjögren’s, and three groups were established based on ACA. In the ACA(+) group, there were high positive rates for both abnormal Schirmer’s test and fluorescein staining of the cornea, similar to those in the Ro/SSA(+) group and Ro/SSA-La/SSB(+) group. Thus, according to this study, ACA is an autoantibody that reflects the degree of impaired salivary and lacrimal gland function.  

  • Rheumatoid factor  

    • Rheumatoid factor is commonly found in the sera of Sjögren’s patients and is associated with serological positivity for anti-Ro/SSA and anti-La/SSB as well as systemic disease. Recent reports continue to support these associations. In a study of 212 Sjögren’s patients, only anti-Ro/SSA, anti-La/SSB, hypergammaglobulinemia and rheumatoid factor were associated with systemic disease and use of corticosteroid. Similarly a large Italian study found rheumatoid factor was one of only a few markers for severe disease. The presence of rheumatoid factor was a marker of more severe exocrine gland manifestations (keratoconjunctivitis sicca) among 121 Sjögren’s patients followed at least one year. Thus, rheumatoid factor is a prognostic finding in Sjögren’s but may not be useful for clinical diagnosis or research classification purposes because this antibody is found commonly in other diseases (Chung, 2012). 

Direct Immunofluorescence Biopsy studies: 

 

In vivo reactions of ANA that occur with epidermal and other cell nuclei can be seen by direct immunofluorescence (IF) as nuclear deposits of IgG in skin.  Patients with antibodies to Ro(SS-A) may have dust-like particles of IgG as seen by direct IF tests of skin biopsies; these appear primarily in the cytoplasm and nuclei of epidermal basal cells. Velthuis et al. reported 8 of 12 Sjogren’s patients (67%) have such dust-like particles by direct IF studies. 

Sjögren Syndrome Tests:

Selected References

  • Baer AN, McAdams DeMarco M, Shiboski SC, Lam MY, Challacombe S, Daniels TE, et al. The SSB-positive/SSA-negative antibody profile is not associated with key phenotypic features of Sjogren's syndrome. Ann Rheum Dis. 2015;74(8):1557–1561.  

  • Bournia VK, Diamanti KD, Vlachoyiannopoulos PG, Moutsopoulos HM. Anticentromere antibody positive Sjogren's Syndrome: a retrospective descriptive analysis. Arthritis Res Ther. 2010;12(2):R47. 

  • Chung JK, Kim MK, Wee WR. Prognostic factors for the clinical severity of keratoconjunctivitis sicca in patients with Sjogren's syndrome. British Journal of Ophthalmology. 2012;96(2):240–245.  

  • Fox, R.I. Sjögren’s syndrome. Lancet 2005, 366, 321–331. 

  • Kitagawa T, Shibasaki K, Toya S. Clinical significance and diagnostic usefulness of anti-centromere antibody in Sjogren's syndrome. Clin Rheumatol. 2012;31(1):105–112. 

  • Mavragani, C.P.; Moutsopoulos, H.M. The geoepidemiology of Sjögren’s syndrome. Autoimmun. Rev. 2010, 9, A305–A310. 

  • Nardi N, Brito-Zeron P, Ramos-Casals M, et al. Circulating auto-antibodies against nuclear and non-nuclear antigens in primary Sjögren’s syndrome: prevalence and clinical significance in 335 patients. Clin Rheumatol. 2006;25:341–346.   

  • Negrini, S., Emmi, G., Greco, M. et al. Sjögren’s syndrome: a systemic autoimmune disease. Clin Exp Med 22, 9–25 (2022). https://doi.org/10.1007/s10238-021-00728-6. 

  • Velthuis PJ, Kater L, van der Tweel I, et al. In vivo ANA of the skin: Its diagnostic significance and association with selected antinuclear antibodies. Ann. Rheum Dis 1990; 49:163-167.