Elsevier

Journal of Autoimmunity

Volume 51, June 2014, Pages 75-80
Journal of Autoimmunity

Biomarkers of lymphoma in Sjögren’s syndrome and evaluation of the lymphoma risk in prelymphomatous conditions: Results of a multicenter study

https://doi.org/10.1016/j.jaut.2013.10.002Get rights and content

Highlights

  • Lymphoma risk was studied in different subsets of pSS.

  • Cryoglobulinemia, low C4, anti-SSB/La antibodies and leukopenia were significantly associated with lymphoma in pSS.

  • Presence of ≤1 biomarker provided a high negative predictive value for lymphoma.

  • Patients with salivary swelling and with positive biomarkers may be at higher risk for lymphoma.

Abstract

Objectives

To define the biomarkers associated with lymphoproliferation in primary Sjögren’s syndrome (pSS) by distinguishing in separate groups the two best-recognized non-malignant prelymphomatous conditions in pSS, i.e., salivary gland swelling and cryoglobulinemic vasculitis (CV).

Methods

A multicenter study was conducted in 5 centres. Patients fulfilled the following criteria: (1) positive AECG criteria for pSS, (2) serum cryoglobulins evaluated, and (3) lack of hepatitis C virus infection. Four groups were distinguished and analysed by multinomial analyses: (1) B-cell non-Hodgkin's lymphoma (NHL), (2) CV without lymphoma, (3) salivary swelling without NHL (SW), and (4) pSS patients without NHL or prelymphomatous conditions.

Results

Six hundred and sixty-one patients were studied. Group 1/NHL comprised 40/661 (6.1%) patients, Group 2/CV 17/661 (2.6%), Group 3/SW 180/661 (27.2%), and Group 4/pSS controls 424/661 (64.1%).

Low C4 [relative-risk ratio (RRR) 8.3], cryoglobulins (RRR 6.8), anti-La antibodies (RRR 5.2), and leukopenia (RRR 3.3) were the variables distinguishing Group 1/NHL from Group 4/Controls. As concerns the subset of patients with prelymphomatous conditions, the absence of these biomarkers provided a negative predictive value for lymphoma of 98% in patients with salivary swelling (Group 3/SW). Additional follow-up studies in patients with SW confirmed the high risk of lymphoma when at least 2/4 biomarkers were positive.

Conclusions

Lymphoma-associated biomarkers were defined in a multicentre series of well-characterized patients with pSS, by dissecting the cohort in the pSS-associated prelymphomatous conditions. Notably, it was demonstrated for the first time that among the pSS patients with salivary swelling, only those with positive biomarkers present an increased risk of lymphoma evolution.

Introduction

Primary Sjögren's syndrome (pSS) is an autoimmune and lymphoproliferative disorder primarily involving the salivary and lachrymal glands, leading to glandular damage, dysfunction and sicca syndrome [1], [2]. Lymphoma occurs in about 5% cases, and it is the main cause of a decreased survival in pSS [3], [4].

Different risk factors for lymphoma evolution have been described in pSS [4], [5], [6]. Cryoglobulinemic vasculitis and salivary gland/parotid swelling, in particular, have been repeatedly reported to predispose to lymphoma [4], [7], [8], [9], [10], [11], although specifically designed follow-up studies are lacking. In previous studies dealing with lymphoma risk in pSS, however, the patients had been distinguished into two main groups, i.e., with or without lymphoma. Patients with lymphoma present a cryoglobulinemic vasculitis and/or a salivary a gland/parotid swelling more frequently than pSS patients lacking lymphoma [12]. However, since it is now well-recognized that pSS patients without lymphoma but with cryoglobulinemic vasculitis and/or salivary gland/parotid swelling may evolve into lymphoma with greater frequency, and since biologic studies also indicate these pictures as more advanced stages of lymphoproliferation [10], [13], cryoglobulinemic vasculitis and salivary gland/parotid swelling in the lack of lymphoma can be well considered as prelymphomatous conditions in pSS [11].

These prelymphomatous conditions should be, however, analysed separately, when evaluating lymphoma risk in pSS, to more properly define the risk of lymphoma evolution in different subsets of the disease. The study of a large number of patients, possibly coming from different Centres, would be important to this end. Of note, while cryoglobulinemic vasculitis is rare but more strictly associated with lymphoma in pSS, glandular swelling is more common, though fewer patients develop lymphoma [14]. On the other hand, pSS is primarily a disorder of mucosa-associated lymphoid tissue (MALT), and pSS-associated cryoglobulinemia appears related to MALT lymphoproliferation [15]. Furthermore, among the subset of pSS patients with parotid swelling, integrated clinicopathological and molecular follow-up studies showed that the lymphoma risk is higher when myoepithelial sialadenitis (MESA) presents more aggressive pathologic features and the persistence of tissue monoclonal B-cell expansion in metachronous biopsies [10], [11].

Finally, besides the distinction of pSS with prelymphomatous lymphoproliferation as a separate group, the concomitant presence of infection by the hepatitis C virus (HCV) should also be assessed. Data interpretation would be more difficult if HCV-positive subjects are not separated.

The aim of this study was then to investigate the laboratory biomarkers associated with lymphoproliferation in pSS in a large multicentre study by clearly differentiating patients with prelymphomatous conditions (i.e., cryoglobulinemic vasculitis and salivary gland/parotid swelling) as separate groups, to better evaluate the risk of lymphoma progression in different pSS subsets. A cohort of 1170 Italian pSS patients was considered, studying all the patients who satisfied the American European Consensus Group pSS criteria [16], who had been repeatedly evaluated for cryoglobulins in the serum, and who had all been tested for HCV, being negative for it.

Secondly, the selected biomarkers were investigated in the subset of pSS with prelymphomatous conditions. Of note, it was demonstrated for the first time that among the pSS patients with salivary swelling, only those with positive biomarkers presented an increased risk of lymphoma evolution, while cryoglobulinemic vasculitis in SS cannot be differentiated from lymphoma in pSS by using the biomarkers.

Section snippets

Study design and enrolment criteria

An observational, retrospective, cross-sectional multicentre database involving five Italian reference centres for pSS was considered. A database of 1170 patients pSS from four Rheumatology centres [17] was reviewed.

In this database, all patients fulfilled four or more of the preliminary diagnostic criteria for SS proposed by the European Community Study Group in 1993 [18]. Database data collected have been published, and, briefly, include age at diagnosis, age at inclusion, cumulative clinical

Characteristics of the patients

Six hundred and sixty-one patients with pSS were selected from the original database. Demographic, clinical and laboratory features are reported in Table 1.

Group 1/NHL comprised 40/661 (6.1%), group 2/CV comprised 17/661 (2.6%), group 3/SW comprised 180/661 (27.2%), and group 4/pSS controls comprised 424 (64.1%).

Univariate analyses

The frequencies (with p values related) of the variables considered in the univariate analyses were reported in Table 2. Of note, the majority of variables distinguishing Group 1/NHL

Discussion

Sjögren's syndrome is a systemic autoimmune disease with multi-organ involvement [2]. The majority of patients show a low disease activity characterized by the predominance of sicca symptoms, but lymphoma can develop in about 5% of cases, usually arising in the parotid glands or in other MALT sites [3].

Major salivary gland swelling commonly involves the parotid glands, and is a recognized condition implying a higher risk of lymphoma evolution in pSS [4], [5], [6], [7], [8], [9], [10], [11], [12]

Conflict of interest

No conflicts of interest are disclosed.

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