Background/Purpose: Sjӧgren’s Syndrome (SS) is a chronic autoimmune disease characterized by lymphocytic infiltration of the lacrimal and salivary glands causing dry eyes and dry mouth.  Its most serious complication is the development of non-Hodgkin’s lymphoma with an estimated 5-15% lifetime risk, or 20-fold increased risk compared to the general population.  Some well-established risk factors for SS-related lymphomagenesis include parotid enlargement, lymphadenopathy, and low C3/C4 complement factors.  Recently, Theander et al. reported that 6 out of 7 SS individuals in their Swedish cohort who later developed lymphoma had germinal center (GC) structures in their labial salivary gland biopsies (LSGB) at the time of SS diagnosis.  Therefore, the aim of this study was to identify ectopic GC formation in LSGB of SS individuals and describe its association with other predictors of lymphoma development in SS. 

Methods: Our study population consisted of participants in the Sjӧgren’s International Collaborative Clinical Alliance (SICCA) Registry [NIDCR contract N01 DE32636] of European (n=305) or Asian (n=329) ancestry who met the ACR classification criteria for SS and had LSGBs available for histopathological review.  In this case control study, the association of GC formation with other well-established clinical risk factors of lymphoma development in SS was evaluated within European and Asian subgroups using chi-square statistics.  We also studied 4 single nucleotide polymorphisms (SNPs) in two candidate genes that have been associated with SS-related lymphomagenesis for association with GC formation.   More specifically, we analyzed the association of these SNPs with GC formation within European and Asian subgroups using logistic regression, adjusting for ancestry via intra-European and intra-Asian principal components.  Results for the two ancestry subgroups were formally combined using meta-analytic techniques if the heterogeneity p<0.10. 

Results: At baseline, 20.3% (n=62) of European SS patients and 10.6% (n=35) of Asian SS patients had GC+ structures in their LSGB.  Among the European subgroup, individuals with GC+ formation were significantly more likely to be rheumatoid factor positive (p=0.004), hypergammaglobulinemic (p=0.007), to have low C4 complement levels (p=0.005), and bilateral parotid enlargement (p<0.0001) compared to GC- individuals.  In the Asian subgroup, bilateral parotid enlargement was suggestively associated with GC+ formation (p=0.07).  We identified the rs9514827 variant of the B-cell activating factor/tumor necrosis factor superfamily, member 13b gene (BAFF/TNFSF13B) to be associated with GC formation in a meta-analysis of the European and Asian subgroups (OR: 0.67; p=0.02).  We also found that the rs6922466 variant of tumor necrosis factor, alpha-induced protein 3 gene (TNFAIP3) was significantly associated with GC formation among the Asian subgroup (OR=2.075; 95% CI:1.18, 3.65; p=0.01).

Conclusion: Our findings suggest that GC formation is correlated with other well-established clinical and genetic risk factors of SS-related lymphomagenesis, and may be useful in genetic and other studies investigating risk factors for lymphoma development in SS given its greater prevalence.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/association-between-germinal-center-formation-in-labial-salivary-gland-biopsies-and-predictors-of-lymphoma-among-participants-of-the-sj%d3%a7grens-international-collaborative-clinical-allianc/