Towards inhibition of morbidity and mortality in Sjögren’s syndrome: opportunities and challenges

Abstract

In recent years considerable progress has been made in our understanding of the immunopathology of primary Sjögren’s syndrome. Several genetic and environmental risk factors as well as cellular and molecular pathways have been identified, providing multiple targets for therapeutic strategies. Establishment of disease activity scores allows careful monitoring of therapeutic strategies and has set the stage for definition of clinical response criteria. Early detection of autoimmune symptoms before the onset of primary Sjögren’s syndrome might trigger early intervention strategies to prevent immunopathology. New studies that indicated a strong association between lymphoid neogenesis and development of lymphoma and extra-glandular manifestations indicate that future therapeutic strategies should perhaps be directed at patients at risk for more severe disease. Several challenges remain, such as dissecting the causes and consequences of several types of IFN signatures or elucidating how viral triggering of the immune system is involved and could be targeted. The biggest challenge may be prevention of dryness since the causes of dryness remain elusive and could include non-immunological ones. In the coming years it will become clear to what extent novel drugs can prevent immunopathology and clinical symptoms like dryness and fatigue.

Vast progress has been made in our comprehension of the immunopathology of primary Sjögren’s syndrome (pSS). In patients with pSS, a considerable number of genetic and environmental risk factors as well as cellular and molecular pathways have been identified, providing multiple targets for therapeutic strategies. Technological innovations over the past decade(s) have revolutionized genetics, genomics and epigenetic research, enabling high-throughput characterization and analysis of DNA (including DNA methylation) and RNA (including miRNA) in patient samples on a genome-wide scale. The applications of these techniques to diseases such pSS will define additional risk factors for disease development and outcome. Recently, in a large-scale genome-wide association study, the importance of genes that are involved in both innate and adaptive immunity in SS was underscored [1]. In this issue of Expert Review of Clinical Immunology, Miceli-Richard et al. give a comprehensive overview of genetic and epigenetic factors that contribute to the immunopathology of pSS [2].

Considering environmental factors, a number of viruses have been associated with pSS, although their role in initiation and/or perpetuation of the disease remains a matter of debate. Hallmarks of pSS are the production of autoantibodies and the presence of lymphocytic aggregates in the salivary glands, which in a considerable number of patients (∼25%) exhibit features of tertiary lymphoid structures supporting an ectopic germinal centre response [3]. Novel studies indicated a strong association between lymphoid neogenesis and the risk of development of lymphoma and extraglandular manifestations [4,5]. Lucchesi et al. in this issue review the relevance of tertiary lymphoid structures (TLS) in SS and the evidence in support of a role for viruses in pSS insurgence and/or persistence [6]. They elegantly review recent data which link viral infection with TLS formation in the salivary gland and suggest that viral–host interactions within TLS favor breach of tolerance and development of autoimmunity in SS.

The role of immunization with vaccines in the etiopathogenesis of pSS has not yet been elucidated. Although immunization with vaccines is safe for the majority of subjects, in rare cases it can trigger or exacerbate autoimmune and rheumatic inflammatory conditions. Soriano et al. in this issue investigate the possible links between immunization with vaccines and the pathogenesis of SS [7].

Viruses clearly could provide a link between production of interferons (IFNs) and the IFN signature that is present in responding cell types. As type I IFN consists of many different subtypes, it is not easily measured using conventional ELISAs. Therefore, the expression of type I IFN-inducible genes – the so-called type I IFN signature – is assessed in salivary gland tissue and blood from patients as a readout for type I IFN activity. Brkic et al. highlight the role for IFN type I in the pathogenesis of pSS [8] and how this could serve as a novel biomarker for disease activity, sub-classification of patients, prediction of therapy response and as a target for therapeutic intervention.

In addition to genetic and environmental factors, a number of cellular and molecular pathways have been identified in patients with pSS, providing multiple targets for therapeutic strategies. Considering our lack of understanding of the pathophysiological and clinical progression of the disease and ways to prevent or halt these processes, animal models have been shown to be extremely helpful. Donate et al. [9] highlight suitable animal models that mimic the major phenotypes of human pSS to delineate the underlying biological or molecular mechanisms defining various aspects of the disease.

Data from animal models and many human ex vivo/in vitro assays have revealed the pivotal role of a number of cell types and inflammatory mediators in different immunopathological processes that are detrimental to pSS.

B cells are indicated to play a central role in the immunopathogenesis of pSS. Kroese et al. describe the triggers that lead to hyperactivity of B cells [10]. They describe how coordinated and integrated action of stimulation of the B-cell receptor, CD40, toll-like receptors and proinflammatory cytokines induces B-cell hyperactivity (including type I IFNs and BAFF, IL-6 and IL-21). Hyperactivity of B cells results in secretion of autoantibodies and production of various cytokines promoting immunopathology. These insights into the role of B cells in the pathogenetic process of pSS offer ample targets for successful therapeutical intervention in pSS. In addition, the gained knowledge could provide means to predict progression to lymphoma development in pSS.

Giannouli and colleagues discuss the clinical and immunological characteristics that have been described as (B-cell) lymphoma predictors [11]. Since considerable differences in both disease severity and prognosis between patients with various types of lymphoma exist, there is a demand to identify risk factors that predict the development of the distinct subtypes. Also the newly discovered range of biological variables appears to influence clinical behavior and lymphoma outcome. In this issue, lymphoma prognostication in pSS, outlining long-established predictors, analyzing currently available prognostic models and exploring the predictive potential of recent biological and molecular advances, is discussed.

Monocytes/macrophages are potent regulators of B-cell activity and tissue destruction, and these cells, although perhaps less abundant, seem to be important players in pSS. Zhou and McNamara review the role of these cells in pSS and tissue destruction and ways to target monocytic activity to slow down disease progression in animal studies and human clinical trials [12]. As an example, they discuss the effectiveness of topical and/or systemic IL-1 receptor antagonist, anakinra, and whether this may prove useful in the treatment of keratoconjunctivitis sicca associated with pSS.

T cells have been shown to play a central role in tissue destruction and regulation of B-cell activity and the production of autoantibodies typifying pSS. Despite the fact that dendritic cells (DCs) are key players in the activation of T and B cells in pSS, their contribution to immunopathology in pSS has been under evaluated. Hillen et al. review the current insights into DC biology and highlight literature describing the pivotal role of DCs (myeloid and plasmacytoid) in the immunopathology of pSS, describing a crucial interplay in immunopathology of pSS between DCs, epithelial cells and T cells [13].

In the complex interconnections between epithelial barrier, innate and adaptive immunity that occurs in pSS IL-22 could play an important role. IL-22 is a pleiotropic cytokine that can be placed at the junction of the adaptive and innate branches of immunity. Ciccia et al. discuss evidence to suggest that IL-22 plays a noticeable pro-inflammatory role driving the early phase of tissue and systemic inflammation and participating in the self-perpetuation of pSS [14]. Recent data also suggest an important contribution of NK cells, a subset of cells of the innate immune system, in the development and perpetuation of inflammation, which seems considerably dependent on IL-22.

The cellular and molecular targets identified in pSS offer multiple possibilities for therapeutic intervention (reviewed by Fazaa et al., [15]). Establishment of disease activity scores allows careful monitoring of therapeutic strategies and has set the stage for definition of clinical response criteria. Symptomatic treatments remain the cornerstone of therapy in pSS, but new biologic treatments are currently evaluated, including those that target B cells (anti-CD20 and CD22) or B-cell activating factors (IFNs, BAFF and IL-6). In addition, therapies aimed at T-cell-driven immune activation including JAK/STAT inhibition by tofacitinib, blockade of cytokines like IL-7, IL-21 and co-stimulatory molecules (achieved by CD80/86 or inducible T-cell costimulator blockade) are underway or initiated. Considering the strong association between lymphoid neogenesis and development of lymphoma and extraglandular manifestations, several therapeutic strategies are specifically directed at factors involved in lymphoid neogenesis (targeting lymphotoxin beta, IL-7, inducible T-cell costimulator) to treat these patients at risk for more severe disease.

Inflammation in the lacrimal functional unit contributes to development of dry eye by causing dysfunction and even death of tear secreting epithelium in the lacrimal gland and conjunctiva that alters tear composition and stability. Inflammatory mediators, like IFNg, IL-17, IL-1, IL-6 and matrix metalloproteinases, have been identified, and therapies targeting these mediators topically are emerging (reviewed by Pflugfelder [16]).

Early detection of autoimmune symptoms before the onset of pSS, as was recently demonstrated [17], could allow early treatment strategies to prevent immunopathology, possibly employing novel drugs. Several challenges remain, like dissecting the causes and consequences of IFN signatures and how these should be targeted. The biggest challenge may be prevention of dryness, since the pathological causes of dryness still remain elusive. Targeting of this might go beyond immunomodulation and might require regenerative medicine. In the coming decade, it will become clear how the currently tested armamentarium will have its place.

Financial & competing interests disclosure

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.

No writing assistance was utilized in the production of this manuscript.