BTK Overexpression Is Associated with the Risk of Lymphoma in Primary Sjögren’s Syndrome: Data from Whole Blood Transcriptome of 346 Patients Followed-up Prospectively for 10 Years

Pierre-Marie Duret¹, Tao Ye ², Wan-Fai Ng ³, Alain Saraux ⁴, Valérie Devauchelle Pensec ⁵, Raphaele Seror ⁶, Veronique Le-Guern ⁷, Claire Larroche ⁸, Aleth Perdriger ⁹, Jean Sibilia ¹⁰, Jessica Tarn ¹¹, Gaetane Nocturne ¹², Xavier Mariette ¹³ and Jacques-Eric Gottenberg ¹⁴, ¹Hôpitaux civils de Colmar, COLMAR CEDEX, France, ²GenomEAST platform / Institut National de la Santé et de la Recherche Médicale (INSERM), U1258, Institut de Génétique et de Biologie Moléculaire, IGBMC, Strasbourg, France, ³Musculoskeletal Research Group Institute of Cellular Medicine Faculty of Medical Sciences Newcastle University, Newcastle, United Kingdom, ⁴CHU de la Cavale-Blanche Brest, Brest, France, ⁵University Hospital of Brest, Brest, France, ⁶Hopitaux universitaires Paris Sud, Kremlin-Bicetre, France, ⁷Department of Internal Medicine, Referral Center for Rare Autoimmune and Systemic Diseases, Hôpital Cochin, AP-HP, Université Paris Descartes, Paris, France,, Paris, France, ⁸Internal Medicine, Paris, France, Paris, France, ⁹Rheumatology department, Rennes University Hospital, France, Rennes, France, ¹⁰CHU Strasbourg, Strasbourg, France, ¹¹Institute of Cellular Medicine Newcastle University, Newcastle, United Kingdom, ¹²Center for Immunology of Viral Infections and Autoimmune Diseases, Assistance Publique – Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Le Kremlin-Bicêtre, Université Paris Sud, INSERM, Paris, France., Paris, France, ¹³Center for Immunology of Viral Infections and Autoimmune Diseases, Assistance Publique – Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Le Kremlin-Bicêtre, Université Paris Sud, INSERM, Paris, France, ¹⁴Department of Rheumatology, Strasbourg University Hospital, Strasbourg, France

Meeting: 2019 ACR/ARP Annual Meeting

Keywords: biomarkers and BTK, Cancer, Gene Expression, Sjogren's syndrome

Session Information

Date: Monday, November 11, 2019

Title: 4M119: Sjögrenʼs Syndrome – Basic & Clinical Science (1902–1907)

Session Type: ACR Abstract Session

Session Time: 4:30PM-6:00PM

Background/Purpose: To identify a molecular signature associated with lymphomagenesis in primary Sjögren’s Syndrome (pSS).

Methods: Whole peripheral blood samples were collected from 346 well-phenotyped pSS patients enrolled in the ASSESS prospective cohort. A transcriptomic analysis was performed using Clariom S Human Arrays (Affymetrix). Patients with a pSS-related Non-Hodgkin lymphoma (NHL) (historic or incident NHL) were compared with 3 control populations: i) Patients without lymphoma and without any risk factor, among 9 validated predictive factors of developing lymphoma (systemic complications, parotid swelling, purpura, lymphocytopenia, CD4/CD8≤0.8, rheumatoid factors, cryoglobulinemia, monoclonal component and low C4 levels) (this comparator limits the risk of including patients who might develop lymphoma later during follow-up); ii) Patients without lymphoma but with moderate or high systemic disease activity at enrolment (ESSDAI≥5) (this comparator allows to identify relevant predictors in an at-risk population); iii) All patients without lymphoma. We focused on genes that were significantly differentially expressed in patients with lymphomas compared to each of these control populations.

Results: At enrolment, 13 patients had a history of lymphoma. During the 10-year follow-up, 9 patients developed an incident lymphoma. A total of 324 pSS patients had no lymphoma, including 110 patients with an ESSDAI≥5 and 61 patients without any risk factor of lymphoma. Gene Set Enrichment Analysis (GSEA) identified an over-expression of B-cell activation related genes in NHL-pSS, such as BAFF (p=0.007), APRIL (p=0.0009), BCMA (p=0.02) or BTK (p=0.0003) compared to patients without any risk factor of NHL. APRIL and BCMA were significantly up regulated when NHL-pSS patients were compared to all patients without NHL (p=0.002, p=0.04, respectively) but not BAFF (p=0.1). However, the gene expression profile of NHL-pSS patients compared to patients with an ESSDAI ≥ 5 did not show significant over expression of BAFF (p=0.3), APRIL (p=0.2) and BCMA (p=0.2). Conversely, the Bruton Tyrosine Kinase (BTK) gene was over expressed at enrolment, before the occurrence of lymphoma in patients with an incident NHL, in patients with a history of NHL, and in all NHL-pSS patients (either history of or incident) when compared to patients without any risk factor of developing lymphoma (p=0.006, p=0.005 and p=0.0003, respectively), to patients without lymphoma but with an ESSDAI ≥ 5 (p=0.03, p=0.02, p=0.003, respectively) and to all patients without lymphoma (p=0.02, p=0.01, p=0.0008 respectively).

Conclusion: BTK, a pivotal transducer of B-cell receptor, is over expressed in the peripheral blood of pSS patients before the occurrence of lymphoma. Conversely to BAFF, APRIL, and BCMA, BTK over expression is not related to a higher disease activity since BTK is up regulated in patients with lymphoma even when compared to patients with a moderate or high systemic disease activity and no lymphoma. BTK might therefore represent a pivotal pathogenic player in the transition from B-cell polyclonal activation to a monoclonal malignant proliferation. The present results suggest that BTK might represent a therapeutic target of interest in pSS.

Disclosure: P. Duret, None; T. Ye, None; W. Ng, None; A. Saraux, None; V. Devauchelle Pensec, Bristol_myers Squibb, 2, CHUGAI, 2, Chugai Pharma France, 8, Roche, 2; R. Seror, Bristol-Myers Squibb, 5, GlaxoSmithKline, 5, UCB, 5, Lilly, 5, Pfizer, 5; V. Le-Guern, None; C. Larroche, None; A. Perdriger, None; J. Sibilia, None; J. Tarn, None; G. Nocturne, None; X. Mariette, Biogen, 2, Bristol-Myers Squibb, 5, GlaxoSmithKline, 5, Janssen, 5, LFB Pharmaceuticals, 5, OSE Immunotherapeutics, 2, Pfizer, 2, 5, UCB Pharma, 5, 8; J. Gottenberg, Abbvie, 8, BMS, 2, 5, Lilly, 5, 8, Pfizer, 2, 5, Roche, 8, Sanofi-Genzyme, 5, 8, UCB, 5, 8.

To cite this abstract in AMA style:

Duret P, Ye T, Ng W, Saraux A, Devauchelle Pensec V, Seror R, Le-Guern V, Larroche C, Perdriger A, Sibilia J, Tarn J, Nocturne G, Mariette X, Gottenberg J. BTK Overexpression Is Associated with the Risk of Lymphoma in Primary Sjögren’s Syndrome: Data from Whole Blood Transcriptome of 346 Patients Followed-up Prospectively for 10 Years [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/btk-overexpression-is-associated-with-the-risk-of-lymphoma-in-primary-sjogrens-syndrome-data-from-whole-blood-transcriptome-of-346-patients-followed-up-prospectively-for-10-years/. Accessed .

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