Genetic Variant and High Levels of CCL11 in Serum Are Associated with the Occurrence of Lymphoma and Disease Activity in Primary Sjögren’s Syndrome Patients (pSS)

Gaetane Nocturne¹, Olivier Fogel², Joanne Nititham³, Kimberly E. Taylor⁴, Philippe Dieude⁵, Jean Jacques Dubost⁶, Anne-Laure Fauchais⁷, Vincent Goëb⁸, Eric Hachulla⁹, Claire Larroche¹⁰, Véronique Le Guern¹¹, Jacques Morel¹², Aleth Perdriger¹³, Xavier Puéchal¹⁴, Stephanie Rist Bouillon¹⁵, Alain Saraux¹⁶, Damien Sène¹⁷, Olivier Vittecoq¹⁸, Lindsey A. Criswell¹⁹, Corinne Miceli-Richard²⁰, Jacques Gottenberg²¹ and Xavier Mariette²², ¹INSERM U1012, Paris sud university, Le Kremlin Bicetre, France, ²INSERM U1012, Paris sud university, Le Kremlin Bicêtre, France, ³University of California San Francisco, 374 Parnassus Avenue, San Francisco, CA, ⁴Department of Medicine, University of California, San Francisco, Rosalind Russell / Ephraim P. Engleman Rheumatology Research Center, San Francisco, CA, ⁵Rhumatologie, Hopital Bichat Claude Bernard, Paris, France, ⁶Rheumatology, CHU G.-Montpied, Clermont-Ferrand, France, ⁷Department of Internal Medicine A, Dupuytren Hospital, Limoges University Hospital, Limoges, France, ⁸Rheumatology, Amiens University Hospital, Amiens, France, ⁹Faculté de Médecine Henri Warembourg, Université Lille Nord de France, Lille, France, ¹⁰Internal Medicine, Avicenne Hospital,, Assistance Publique des Hôpitaux de Paris,, Bobigny, France, ¹¹Internal Medicine, National Referral Center for Rare Systemic Autoimmune Diseases, Hôpital Cochin, AP–HP, Université Paris Descartes, Paris, Paris, France, ¹²Department of Rheumatology, Hôpital Lapeyronie, Montpellier, France, ¹³Rhumatologie, Rennes, France, ¹⁴National Referral Center for Rare Systemic Autoimmune Diseases, Hôpital Cochin, AP–HP, Université Paris Descartes, Paris, Paris, France, ¹⁵Rhumatologie, Hopital La Source, La Source, France, ¹⁶CHU Brest and EA 2216, UBO, Brest, France, ¹⁷Hopital Lariboisière, service de Médecine Interne, Paris, France, ¹⁸Rheumatology, Department of Rheumatology, Rouen University Hospital & Inserm 905, Institute for Biomedical Research, University of Rouen, Rouen, France, ¹⁹Medicine, University of California, San Francisco, Rosalind Russell / Ephraim P. Engleman Rheumatology Research Center, San Francisco, CA, ²⁰Rheumatology Department, Université Paris-Sud 11, Bicêtre Hospital,, Kremlin Bicêtre, France, ²¹Rheumatology, Strasbourg University Hospital, Strasbourg, France, ²²rheumatology, Université Paris-Sud, Le Kremlin Bicêtre, France

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: chemokines and pathogenesis, Sjogren's syndrome

Session Information

Title: Sjogren's Syndrome: Pathophysiology

Session Type: Abstract Submissions (ACR)

Background/Purpose: Development of non-Hodgkin lymphoma (NHL) is one of the most severe complications of pSS. It occurs in 5-10% of the patients. A more accurate detection of the high risk patients is mandatory to enable a more individualized approach. Presence of ectopic germinal center (GC) in salivary glands biopsy has been shown to be a predictor of NHL occurrence in pSS patients[1]. Interestingly, 2 single nucleotide polymorphisms (SNPs) located within CCL11 (Eotaxin)gene are associated with GC structures in pSS patients[2]. CCL11 is a chemokine that plays a role in chemotaxis of eosinophils and in allergy. In this study, we decided to assess the role of CCL11 both at the genetic and proteic level in the occurrence of pSS-associated NHL.

Methods:

Genotyping of the 2 SNPs (rs3091328 and rs1860184, located on chromosome 17) known to be associated with GC structures was performed in 562 pSS cases (ASSESS cohort and Paris-Sud teaching hospital cohort) and 435 healthy controls, both of them of European ancestry as assessed by 47 ancestry informative markers. Among patients, 25 had a history of NHL. CCL11 serum levels at inclusion in the ASSESS cohort were evaluated in 385 pSS patients by multiplex assay. Among them, 21 patients had a NHL (history or future). Case-only associations (i.e., pSS patients with vs. without lymphoma) were tested with logistic regression adjusting for the top two Immunochip principal components. Association between CCL11 levels and genotype was assessed with the Kruskal-Wallis test. Levels of CCL11 were compared in the different subsets of patients with a Mann-Whitney test.

Results:

The 2 CCL11 SNPs were not significantly associated with risk of pSS. However, we found a significant association between the rs1860184A located within the first intron of CCL11and pSS complicated by NHL: OR 1.87 CI95% [1.07-3.27], p= 0.03 compared to pSS patients without NHL and OR 1.84 CI95% [1.02-3.31], p= 0.04 compared to healthy controls. The median [range] serum level of CCL11 was 106.5 [13.2-283.5]pg/ml in the 385 pSS patients from the ASSESS cohort. We did not find any association between the CCL11 levels and the rs1860184 genotype (p=0.36). We found a trend for an association between CCL11 levels and the occurrence of NHL: (median [range]): 105 [13.23-283.5] in patients without NHL vs 141.3 [46.76-211] in patients with NHL (p=0.053). Interestingly we found a significant increased serum level of CCL11 in patients with an active disease defined by an ESSDAI ≥ 5 vs patients with inactive disease (112.2 pg/ml [13.23 – 283.5] vs 103.1 pg/ml [14.13 – 281.5] respectively, p=0.01). Last, we found significant correlations between CCL11 serum levels and B cells biomarkers (RF titer: p=0.01; free light chain kappa/lambda ratio: p=0.02 and β2-microglobulin level: p=0.0003).

Conclusion: This study highlights the potential implication of CCL11 in the occurrence of NHL in pSS patients. We show that the rs1840186 SNP is associated with NHL occurrence. An increased serum level of CCL11 tends to be associated with NHL occurrence and is associated with increased disease activity and B cells bio-markers. Further studies will be mandatory to determine the functional role of CCL11 in this phenomenon.

1.Theander et al ARD, 2011 2.Reksten, ARD 2014

Disclosure:

G. Nocturne,
None;

O. Fogel,
None;

J. Nititham,
None;

K. E. Taylor,
None;

P. Dieude,
None;

J. J. Dubost,
None;

A. L. Fauchais,
None;

V. Goëb,
None;

E. Hachulla,
None;

C. Larroche,
None;

V. Le Guern,
None;

J. Morel,
None;

A. Perdriger,
None;

X. Puéchal,
None;

S. Rist Bouillon,
None;

A. Saraux,
None;

D. Sène,
None;

O. Vittecoq,
None;

L. A. Criswell,
None;

C. Miceli-Richard,
None;

J. Gottenberg,
None;

X. Mariette,
None.

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