Current State of Knowledge on Primary Sjögren's Syndrome, an Autoimmune Exocrinopathy

Abstract

Primary Sjögren's syndrome (pSS) is a chronic systemic autoimmune rheumatic disease characterized by lymphoplasmacytic infiltration of the salivary and lacrimal glands, whereby sicca syndrome and/or systemic manifestations are the clinical hallmarks, associated with a particular autoantibody profile. pSS is the most frequent connective tissue disease after rheumatoid arthritis, affecting 0.3-3% of the population. Women are more prone to develop pSS than men, with a sex ratio of 9:1. Considered in the past as innocent collateral passive victims of autoimmunity, the epithelial cells of the salivary glands are now known to play an active role in the pathogenesis of the disease. The aetiology of the "autoimmune epithelitis" still remains unknown, but certainly involves genetic, environmental and hormonal factors. Later during the disease evolution, the subsequent chronic activation of B cells can lead to the development of systemic manifestations or non-Hodgkin's lymphoma. The aim of the present comprehensive review is to provide the current state of knowledge on pSS. The review addresses the clinical manifestations and complications of the disease, the diagnostic workup, the pathogenic mechanisms and the therapeutic approaches.

Keywords: Sjögren’s syndrome; autoimmune disease; diagnosis; physiopathology; review; treatment.

Figure 1

Overview of physiopathological mechanism underlying Sjögren’s syndrome (SS). Environmental triggers, such as viral infections, genetic predispositions, epigenetics and sex hormone deregulation, cause the disruption of salivary gland epithelial cell (SGEC), the production of type I interferon (IFN) and other cytokines such as B cell Activating Factor of the tumour necrosis factor (TNF) Family (BAFF) [11] and the alteration of proteins involved in saliva secretion. Dendritic cells, as well as SGEC acquire the characteristics of antigen-presenting cells capable of processing viral and self-antigens, leading to the activation of autoreactive T and B cells. Autoreactive T cells induce tissue damage through the release of cytotoxic granules and cause the exposure of autoantigens on the surface of SGEC. In addition, activated B cells produce autoantibodies that induce SGEC apoptosis and create an inflammatory microenvironment. This complex mechanism triggers a self-perpetuating cycle of autoimmunity.

Figure 2

Factors involved in SS trigger phase.

Figure 3

Intracrine steroidogenic machinery in healthy acinar cells. The figure shows the conversion of dehydroepiandrosterone (DHEA) to active sex steroids. STS: steroid sulphatase, SULT2B1: sulfotransferase 2B1, HSD: hydroxy steroid dehydrogenase, 5-α-R: 5α-reductase, TEST: testosterone, DHT: dihydrotestosterone. DHEA-S: DHEA-sulphate.

Figure 4

Synoptic view of targeted drugs (being) studied in pSS. Therapeutic classes are in bold. Biotherapies and small molecules are in black if they have been the subject of one or more trials in pSS or in grey if they exist but have not been tested in pSS. Names in strikethrough are drugs whose development has been stopped because of unacceptable side effects or because of portfolio prioritization.