Lymphoproliferative disorders in Sjögren's syndrome

doi:10.1016/S1568-9972(03)00102-2

Autoimmunity Reviews

Volume 3, Issue 3, March 2004, Pages 175-182

https://doi.org/10.1016/S1568-9972(03)00102-2 Get rights and content

Abstract

Sjögren's syndrome (SS) is a chronic organ-specific autoimmune disease characterized by lymphocytic infiltration into the salivary and lacrimal glands. About half of primary SS patients develop systemic disorders. Primary SS can be divided into three stages according to the extent of organ damage and the course of the disease. In stage I, (approx. 45% of cases), patients have only sicca syndrome and do not experience any systemic involvement, even after 10 years. In stage II (approx. 50% of cases), patients experience lymphocytic organ damage, which may involve the pulmonary, renal, hepatic, hematologic, and/or dermatologic systems, among others. Finally, in stage III (approx. 5% of cases), patients develop malignant lymphomas. Lymphomas in salivary glands are thought to arise from lymphoepithelial lesions in which there are close interactions among epithelial cells, T cells, and B cells. The B cells in the lesions become activated through the interaction between CD40L and CD40. The progression from polyclonal lymphoproliferation to monoclonal lymphoproliferation, to mucosa-associated lymphoid tissue (MALT) lymphoma, and finally to high-grade malignant lymphoma is regarded as a multi-step process. Antigenic activation of B cells, together with oncogenic events, including p53 inactivation and bcl-2 activation, may play important roles in B cell monoclonal proliferation and malignant transformation. The rheumatoid factor clone is regarded as a candidate B cell clone that undergoes transformation.

Introduction

It is well recognized that a number of autoimmune conditions predispose to the development of lymphomas [1], [2], [3], [4], [5], [6]. Most striking among these are organ-specific autoimmune diseases, including Sjögren's syndrome (SS) [5] and Hashimoto's thyroiditis [6]. However, autoimmune phenomena are often observed in patients with cancer and lymphoma [7], [8].

SS is a chronic organ-specific autoimmune disease characterized by lymphocytic infiltration into the salivary and lacrimal glands, resulting in keratoconjunctivitis sicca and xerostomia [9], [10]. Moreover, about half of SS patients develop systemic disorders. During disease progression from focal to systemic involvement, many organs develop lesions with lymphocytic infiltration. It has been reported that approximately 5% of SS patients develop malignant lymphomas [11]. In this review, we explore the associations between SS and lymphoproliferative disorders.

Section snippets

Three stages of SS

In a long-term (over 10 year) follow up of 31 patients with primary SS, we found that they could be divided into two groups based on changes in laboratory parameters or the development of new clinical disorders. The first group (15 patients or 48%) did not experience any change in their symptoms or laboratory data during the course of their disease. In contrast, the second group (16 patients, or 52%) showed changes in laboratory parameters or sustained further lymphocytic organ damage,

Monoclonal gammopathy and monoclonal rheumatoid factor

Although a small number of monoclonal serum proteins can be detected by immunofixation, these proteins are usually detected by routine serum electrophoresis. In our examination of sera from 23 SS patients with distinct monoclonal serum proteins, we found that five contained proteins of the IgG class, nine contained IgA, seven contained IgM, and two contained both IgG and IgM. It is notable that eight of these 23 monoclonal proteins had rheumatoid factor activity. Using monoclonal anti-idiotypic

Benign lymphoproliferative disorder and malignant lymphoma

We found three types of lymphoproliferative disorders in our SS patients: (1) polyclonal lymphoproliferation, (2) monoclonal lymphoproliferation and (3) MALT lymphoma or high-grade malignant lymphoma.

We treated 13 patients who had gross enlargement of bilateral lacrimal, parotid or submandibular glands, a disorder usually called Mikulicz's disease. While eight of these patients had features typical of SS, the other five did not have sicca complex even according to detailed examination. When we

Progression of the disease in SS

The transition from polyclonal lymphoproliferation to monoclonal lymphoproliferation, to MALT lymphoma and finally to high-grade malignant lymphoma is considered to be a multi-step process, such as that shown in colon cancer [36]. Antigenic stimulation of B cells and oncogenic events may be important factors in the progression of the disease. One of the candidate antigens may be IgG, which stimulates rheumatoid factor clones [17], [37]. In addition, the p53 gene may play an important role in

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For decades, Sjögren's syndrome (SS) and Sjögren's syndrome-like (SS-like) disease in patients and mouse models, respectively, have been intensely investigated in attempts to identify the underlying etiologies, the pathophysiological changes defining disease phenotypes, the nature of the autoimmune responses, and the propensity for developing B cell lymphomas. An emerging question is whether the generation of a multitude of mouse models and the data obtained from their studies is actually important to the understanding of the human disease and potential interventional therapies. In this brief report, we comment on how and why mouse models can stimulate interest in specific lines of research that apparently parallel aspects of human SS. Focusing on two mouse models, NOD and B6·Il14α, we present the possible relevance of mouse models to human SS, highlighting a few selected disease-associated biological processes that have baffled both SS and SS-like investigations for decades.
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Lymphoproliferative disorders in Sjögren's syndrome

Abstract

Introduction

Section snippets

Three stages of SS

Monoclonal gammopathy and monoclonal rheumatoid factor

Benign lymphoproliferative disorder and malignant lymphoma

Progression of the disease in SS

Am J Med

Semin Arthritis Rheum

Clin Immunol Immunopathol

J Autoimmun

Lancet

Blood

Blood

Lancet

Cell

Blood

Blood

Am J Pathol

Frequency of neoplasia in systemic lupus erythematosus and rheumatoid arthritis

Arthritis Rheum

Increased risk of cancer in patients with systemic lupus erythematosus

Ann Rheum Dis

Risk of cancer in patients with dermatomyositis or polymyositis and follow-up implications: a Scottish population-based cohort study

Br J Cancer

Increased risk of lymphoma in sicca syndrome

Ann Intern Med

Cancer risks in patients with chronic lymphocytic thyroiditis

N Engl J Med

Non-Hodgkin's lymphoma and Sjogren's syndrome. An immunopathological study of 113 patients

Clin Exp Rheumatol

Cancer and autoimmunity: autoimmune and rheumatic features in patients with malignancies

Ann Rheum Dis

Sjögren's syndrome (sicca syndrome): current issues

Ann Intern Med