The prognostic value of routinely performed minor salivary gland assessments in primary Sjögren's syndrome.

OBJECTIVES: To investigate the prognostic value of the lymphocytic focus score (LFS) and the percentages of IgA+, IgM+ and IgG+ plasma cells for disease severity of primary Sjögren syndrome (pSS). METHODS: Medical charts of 174 pSS patients were retrospectively analysed, comparing histology results (LFS and percentages of IgA+, IgM+ and IgG+ plasma cells) with disease outcomes as non-Hodgkin lymphoma (NHL) and clinical scores including cumulative EULAR (European League against Rheumatism) Sjögren syndrome disease activity index (ESSDAI) and the total number of extraglandular manifestations. RESULTS: The mean LFS was significantly higher in patients developing NHL (3.0±0.894 vs 2.25±1.086; p=0.021). The threshold of ≥3 foci has a positive predictive value of 16% for lymphoma, and a negative predictive value of 98%. Only LFS ≥3 contributed significantly and independently to NHL development in a standard multiple regression model. Ig class distribution of plasma cells did not help to identify patients developing lymphoma. Patients with LFS ≥3, ≤40% IgA+ or ≥25% IgM+ plasma cells in salivary gland biopsy specimens had significantly enhanced systemic disease. CONCLUSIONS: Routine histopathological minor salivary gland assessment has important prognostic value. The LFS might help to identify patients with an increased risk for lymphoma.

Clinical features distinguishing lymphoma development in primary Sjögren's Syndrome--a retrospective cohort study.

OBJECTIVE: The objective is to determine the relationship between clinical features and non-Hodgkin lymphoma (NHL) development in primary Sjögren's Syndrome (pSS), taking recently designed disease activity/severity scores into account. METHODS: Medical charts of pSS patients were retrospectively analyzed, scoring first and last visits with the (cumulative) EULAR Sjögren's Syndrome Disease Activity Index and counting extraglandular manifestations, comparing patients with and without NHL. RESULTS: One hundred ninety-five patients were analyzed with a median follow-up of 92 months (range 12-256). Twenty-one patients (11%) had NHL. Associations of parotid gland enlargement (OR 2.84) and low C4 (OR 7.71) with NHL were confirmed. In NHL patients, development of purpura, peripheral neuropathy (PNP), and glomerulonephritis (GN) concurred with lymphoma in 3/3, 5/7, and 2/2 of cases, respectively. Otherwise, purpura and PNP were not associated with NHL later on. This suggests that these symptoms might represent paraneoplastic events (in 16%, 24%, and 100% of our cases, respectively). Presence of IgM-kappa clonal components was associated with lymphoma in 64% of cases. Disease activity/severity scores at first visit could not predict lymphoma development, nor was the pSS disease course significantly worse in patients with NHL. CONCLUSIONS: In our cohort, no clinical manifestation or disease score could clearly select patients with subsequent lymphoma development. Presence of IgM-kappa clonal components and development of purpura, PNP, and GN should alert the clinician for the presence of lymphoma.

The role of ectopic germinal centers in the immunopathology of primary Sjögren's syndrome: a systematic review.

OBJECTIVES: To determine whether the presence of germinal centers (GCs) in salivary glands of patients with primary Sjögren's syndrome (pSS) is related to the severity of disease course and distinct immunopathology features. METHODS: A systematic search was performed in September 2011 for terms and synonyms of Sjögren's syndrome and germinal centers. A total of 80 articles were retrieved, of which 16 were included for (meta-) analysis. RESULTS: GC morphology was present in a mean ± SD 25.1 ± 5.0% of pSS patients. Mean lymphocyte focus scores were 1.25 points higher in patients with GCs as compared to those without GCs. Saliva production was reduced in patients with GCs, although this did not reach statistical significance. Percentages of patients positive for rheumatoid factor, anti-Sjögren's syndrome A (SSA), and anti-Sjögren's syndrome B (SSB) antibodies were significantly higher in patients with GCs (mean increase, 15%, 18%, and 18%, respectively). Additionally, patients with GCs were characterized by enhanced levels of local and systemic proinflammatory mediators. Importantly, these patients have a higher risk of lymphoma development (14% versus 1%). CONCLUSIONS: Patients with GCs are characterized by more severe disease, although the small number of studies and their design hamper generalizability of results. The precise mechanisms that contribute to the development and persistence of germinal centers in pSS are largely unknown. This and the strongly increased risk of lymphoma development warrant intensive studies for the role of germinal centers in the immunopathology of pSS.

Relation of systemic autoantibodies to the number of extraglandular manifestations in primary Sjögren's Syndrome: a retrospective analysis of 65 patients in the Netherlands.

OBJECTIVES: Extraglandular manifestations (EGM) are often seen in patients with primary Sjögren's syndrome and are probably due to a (more) disturbed immune system. Their relation to systemic autoantibodies remains controversial. We hypothesized that positive serology as reflected by the presence of 1 of more systemic autoantibodies is related to the number of EGM. METHODS: To this purpose, all patients, visiting a large nonacademic teaching hospital, with primary Sjögren's syndrome, according to the revised American-European classification criteria of 2002, were retrospectively analyzed. RESULTS: In this group of 65 patients, systemic autoantibodies were abundant: anti-Sjögren syndrome A antigen (SSA) and/or anti-Sjögren syndrome B antigen (SSB) (80%), immunoglobulinM-Rheumatoid factor (IgM-RF) (68%), and anti-nuclear antibodies (ANA) (77%). Their presence was often found together and correlated to the presence of hypergammaglobulinemia. There was a statistically significant correlation between the number of systemic autoantibodies and the total number of EGM (P = 0.025). Anti-SSA was the strongest predictor of the presence of EGM (OR = 4.67, P = 0.024). CONCLUSIONS: These findings indicate that a more disturbed immune system, as reflected by B-cell hyperactivity, with autoantibody formation and hypergammaglobulinemia, is associated with more systemic manifestations in patients with primary Sjögren's syndrome.