Elsevier

Autoimmunity Reviews

Volume 15, Issue 7, July 2016, Pages 695-703
Autoimmunity Reviews

Review
Primary Sjӧgren's syndrome: Clinical phenotypes, outcome and the development of biomarkers

https://doi.org/10.1016/j.autrev.2016.03.004Get rights and content

Abstract

Primary Sjӧgren's syndrome (pSS) is a complex autoimmune disease with distinct clinical phenotypes and variable outcomes. The systemic form of the disease is characterized by immune complex mediated manifestations and is complicated by lymphoma as a result of a polyclonal B cell hyperactivity that is evolving into B cell malignancy. In the past decades, well-established clinical and serological markers have been described in the literature to identify high-risk patients and to predict lymphoma development. However, specific biologic treatments have proven ineffective to control the disease. Significant research effort has been made to reveal the major underlying biological events in this subgroup and identify biomarkers for early diagnosis, prognosis and response to treatment. In this review, we summarize the current data for the proposed histological, molecular and genetic biomarkers.

Introduction

Sjӧgren's syndrome (SS) is a slowly progressive, systemic autoimmune disease characterized by chronic inflammatory infiltration of the salivary and lacrimal glands. Although pSS is mainly confined to the exocrine glands, almost every organ can be potentially affected, reflecting the systemic nature of the disease [1]. The relatively limited TCR repertoire of the infiltrating T cells and the presence of hyperreactive B memory cells producing plethora of autoantibodies, in the typical periepithelial lesion of the affected tissues, suggest autoimmunity to play an important role in the pathogenesis of the disease [2], [3], [4], [5], [6]. The majority of pSS patients present with glandular symptoms while a subset may develop extraglandular and extraepithelial manifestations. Although sicca symptoms may be quite disabling, extraepithelial complications and especially lymphoma affect morbidity and survival among pSS population [1], [7]. Sjӧgen's syndrome evolves slowly following a rather benign course with the majority of patients to have a stable clinical picture for a long time. However, when disease is usually diagnosed, patients already experience oral and eye dryness for many years, implying that the underlying pathological process has been already established and therefore the disease is considered advanced [1]. The diverse clinical phenotypes and outcomes of pSS, the slowly progressive clinical course and the fact that the disease is already advanced when it becomes clinically apparent raise challenges regarding the therapeutic interventions in pSS.

Based on the experience from other autoimmune diseases, many biologic regimens have been tested to treat pSS patients [8]. However, biologic agents have proven ineffective to control the disease and improve the quality of life among pSS patients. Several reasons should be considered to interpret carefully this therapeutic failure. One important reason is the fact that the scientific community does not have reliable tools to assess the overall response to treatment. While ESSDAI is a useful research tool for patients with the systemic form of the disease, ESSPRI is based on the subjective perception of patients about dryness and is a measure of self-assessment and not an objective marker of hyposalivation [9]. In addition, the estimation of salivary flow is characterized by diurnal and personal variations and is determined by many factors. On the other hand, the unique clinical features of pSS mentioned previously have not been taken into account, and as a result, patients who participated in these studies represent different clinical subsets, masking the potential clinical benefit in some of them. The distinct clinical phenotypes and the diversity of the clinical course point out the necessity to develop biomarkers capable of stratifying pSS patients according to clinical, histological and molecular criteria. Ideally, biomarkers are expected not only to offer an early diagnosis of pSS but also to predict the disease outcome and the possible response to specific biologic treatments. In this review, we summarize the recent advances in the field of clinical and basic research to indentify and introduce useful biomarkers in the clinical practice.

Section snippets

The wide clinical spectrum of Sjӧgren's syndrome

The wide clinical spectrum of pSS extends from a well-tolerated and benign exocrinopathy restricted to the salivary and lacrimal glands to severe life-threatening conditions such as vasculitis and lymphoma [1]. This enriched clinical picture is considered to result from two distinct underlying immunopathologic phenomena: the lymphocytic infiltration around the epithelium of the affected tissues and the B cell hyperactivity. Over the past decades, it has been shown that the epithelium plays a

Mortality and risk factors in Sjӧgren's syndrome

Different groups have shown that pSS patients display increased mortality compared to the general population. In the largest studies, the standardized mortality ratio (SMR) varies from 1.02 (95% CI = 1.03–3.71) to 4.66 (95% CI = 3.85–5.60), suggesting that pSS has at least a minimal impact on patients' survival [1], [7], [29], [30], [31], [32], [33], [34]. In most of these studies, the leading cause of death was lymphoma. Theader et al., after studying a cohort of 265 pSS patients, found that the

Biological significance and clinical utility

The systemic extraepithelial manifestations and the MALT lymphomas originated from the diseased salivary glands of pSS patients share B cell hyperactivity as a common underlying immunopathologic process. Extensive studies of the minor salivary glands (MSG) of pSS patients have shown that this marked B cell hyperactivity is mainly the result of an ongoing antigenic stimulation [48], [49], [50]. However, monoclonal products and cryoglobulins can be detected in the serum of pSS patients early

Conclusions and future directions

The clinical picture of pSS is characterized by heterogeneity, and the disease outcomes differ according to the clinical phenotype. The majority of patients present with glandular manifestations and disabling symptoms but follow a benign course with low morbidity and impaired quality of life. Some of them are expected to develop extraglandular manifestations such as lung, liver and kidney involvement. In this case, the lesions evolve slowly and infrequently may lead to organ impairment. The

Take-home messages

  • Primary Sjögren's syndrome has distinct clinical phenotypes with diverse outcomes.

  • The systemic form is associated with immune complex mediated manifestations and lymphoma.

  • Biology studies have revealed numerous histological, molecular and genetic biomarkers.

  • Biomarkers are useful for early diagnosis, prognosis and patient stratification for biologic treatments.

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    1

    Current address: Johns Hopkins University, Department of Medicine, Baltimore, USA.

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