Biomarkers of lymphoma in Sjögren’s syndrome: what’s the latest?

ABSTRACT

Introduction

Primary Sjögren’s syndrome (pSS) is a chronic autoimmune disease standing in the crossroads of autoimmunity and lymphomagenesis, characterized by chronic B-cell hyperactivity and ectopic lymphoid tissue neoformation, potentially driving lymphoid malignant transformation. Lymphoma development is considered the most serious complication of pSS.

Areas covered

‘Old-classical’ biomarkers (clinical, serological, hematological, and histological) validated in the past are analyzed under the perspective of recently published research. Biomarkers that have emerged during the last decade are subdivided to ‘old-new’ and ‘newly proposed-novel’ ones, including biomarkers pathophysiologically related to B-cell differentiation, lymphoid organization, and immune responses, identified in serum and tissue, both at genetic and protein level. Upcoming new imaging biomarkers, promising for further patient stratification, are also analyzed.

Expert opinion

Salivary gland enlargement and cryoglobulinemia still remain the best validated ‘classical-old’ biomarkers for lymphoma development. Though new biomarkers still need to be validated, some can be used for the identification of high-risk patients long before lymphoma diagnosis, and some might be more relevant in distinct age subgroups, while others have an added value in the assessment of lymphoma remission or relapse. Future development of composite indices, integrating old and recently proposed biomarkers, could contribute to a more precise lymphoma prediction model.

KEYWORDS:

• Sjögren’s syndrome
• lymphoma
• biomarkers
• salivary gland MALT lymphoma
• autoimmunity
• lymphomagenesis

Article highlights

• Salivary gland (SG) enlargement and cryoglobulinemia still remain the best validated ‘classical-old’ biomarkers for lymphoma development in primary Sjögren’s syndrome (pSS) patients.

• Focus score at pSS diagnosis can be a useful biomarker for the discrimination of the subset of pSS patients at high risk for lymphoma development and lead to the decision to perform a second minor SG biopsy.

• Composite indexes/scores, combining multiple classical biomarkers, are a useful tool for lymphoma prediction in pSS patients.

• FLT-3 ligand (Flt-3L) serum levels and miR200p-5b SG levels have been shown to increase long before lymphoma development, allowing early detection and closer follow-up of high-risk patients

• Tumor necrosis factor alpha-induced protein 3 (TNFAIP3) rs2230926 variant, the functional leukocyte immunoglobulin-like receptor A3 (LILRA3) gene variant and B-cell activating factor receptor (BAFF-R) His159Tyr mutation could be useful lymphoma biomarkers for patients with pSS onset at a young age

• Serum thymic stromal lymphopoietin (TSLP) levels and miR200p-5b SG levels could be used to assess therapeutic response and to monitor relapse in pSS-lymphoma patients

• The inclusion of imaging biomarkers could lead to the selection of patients that are candidates for targeted histologic examination of suspicious SG lesions.

• Development of algorithms integrating clinical, serological, and molecular data to predict the risk of lymphoma in pSS could offer a useful up-to-date patient stratification tool for clinicians

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.