LAUSR

Background Primary Sjögren’s syndrome (pSS) is an autoimmune disease characterized by an increased risk for non-Hodgkin lymphoma (NHL) development. Ectopic germinal center (GC) formation in the salivary gland (SG) epithelium of pSS patients is thought to be associated with high risk for pSS-associated NHL. The chemokine (C-X-C motif) ligand 13 (CXCL13) is a major chemoattractant for B cell migration into the GC, plays an important role in the organization of B cell follicles, and enhances BCR-triggered B cell activation. The increased B cell activation within ectopic GC may lead to excessive B cell proliferation and along with genetic abnormalities may drive the transition from the early clusters of GC B cells through oligoclonal and later monoclonal B cell expansion to lymphoma. Objectives To investigate the potential of CXCL13 as a biomarker to assess NHL risk in pSS. Methods Serum CXCL13 concentrations were quantified by ELISA in 48 healthy individuals, 165 pSS patients without NHL and 38 pSS patients with NHL from the United Kingdom Primary Sjögren’s Syndrome Registry (UKPSSR). Among these patients, follow-up serum samples from 83 and 11 patients without and with NHL respectively were available and CXCL13 measured. PSS patients without NHL were stratified into low risk (LR), moderate risk (MR) and high risk (HR) groups according to the lymphoma risk assessment tool proposed by Fragkioudaki et al, 2016. Differences in CXCL13 levels among risk groups were analyzed using the Mann-Whitney test and differences in CXCL13 levels between initial (visit 1) and follow-up (visit 2) samples were measured by repeated measures MANOVA. Associations of CXCL13 with B cell markers were determined by Pearson correlation. Logistic regression analyses were performed to model the NHL risk against CXCL13 concentrations. Results At visit 1, there were 24 LR, 58 MR and 1 HR pSS patients. Because of the small sample size of the HR “group”, it was excluded from further analyses. Serum CXCL13 levels were higher in all pSS groups compared to healthy controls (p <0.0001), and the levels in patients with a history of NHL were higher compared to those without (p =0.0311). Visit 1 LR patients had significantly lower CXCL13 levels than MR patients (p =0.0015) and pSS patients with NHL (p =0.0017). Serum CXCL13 levels remained stable between visit 1 and visit 2 (mean time between visits = 4 years) for all pSS groups. CXCL13 was associated with B cell markers, including Immunoglobulin G (IgG) (p = 0.0014), B-cell activating factor (p < 0.0001), beta-2 microglobulin (p < 0.0001), combined free light chains (p < 0.0001), κ light chain (p < 0.0001), λ light chain (p = 0.0002), κ-to-λ ratio (p = 0.0013), and Anti-SSA/Ro autoantibodies (p = 0.0005). Finally, serum CXCL13 levels, age, IgM, IgA, and white blood cell count were independent predictors of NHL risk score in pSS. Conclusion Our findings have demonstrated that serum CXCL13 levels were elevated in pSS patients with NHL and MR pSS patients compared to LR pSS patients and remained stable between visit 1 and visit 2. CXCL13 was an independent determinant of NHL risk score and could potentially be used as an additional NHL risk biomarker in pSS. References [1] Fragkioudaki S, Mavragani C, Moutsopoulos H. Predicting the risk for lymphoma development in Sjogren syndrome. Medicine. 2016;95(25): e3766.Table 1 – NHL risk predictors for pSS patients without lymphoma at Visit 1 NHL Risk predictors Likelihood ratio ChiSquare Value Prob>ChiSq IgA 6.6459 0.0360* IgM 12.065 0.0024* Disease duration 5.4365 0.0660 Age 18.546 <.0001* Log [White blood cell count] 6.1494 0.0462* Log [CXCL13 c(pg/mL)] 8.3463 0.0154* Disclosure of Interests Emmanuella Traianos: None declared, James Locke: None declared, Dennis Lendrem: None declared, Simon J. Bowman Grant/research support from: Previously UCB Pharma (to University of Birmingham) and Roche, Consultant for: 2016-7: Novartis, Mitsubishi Tanabe Pharma 2017-8: AstraZeneca, MedImmune, GFK, Xtlbio, ONO Pharmaceutical 2018-9: Novartis, AstraZeneca, UCB Pharma, Ben Hargreaves: None declared, Victoria Macrae: None declared, Jessica Tarn: None declared, Wan Fai Ng: None declared