Abstract
Sjögren’s syndrome (SS) is an autoimmune inflammatory disorder of the exocrine glands, particularly affecting lacrimal and salivary glands. Hallmark symptoms are dry mouth and dry eye, often in conjunction with general symptoms, such as malaise and fatigue. Lymphomas could develop in 5–10% of the patients. As SS is a rather complex syndrome with many features, the one patient being diagnosed with SS may suffer from a different complex of complaints than another SS patient and may thus be in need of a different treatment approach. To better classify SS patients and to personalize their treatment, many clinicians and researchers are currently working on efforts (1) to refine classification of SS patients, (2) to ease the diagnostic work-up of SS, and (3) to better understand the etiopathogenesis of SS. Latter knowledge is essential to understand the course of the disease. This way clinicians will be able to identify patients who are at risk of developing SS or lymphomas; can intervene at an early stage of the disease to prevent damage to, e.g., the glands; as well as can personalize treatment with, e.g., biologicals. In this chapter, current major achievements are discussed, and promising new directions are indicated.
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Keywords
- Sjögren’s syndrome
- Classification criteria
- Biomarker
- Histology
- Labial salivary gland
- Parotid gland
- Saliva
- Trial design
- Personalized treatment
- Lymphoma
- B cell
- Germinal center
- Lymphoepithelial lesion
10.1 Introduction
Sjögren’s syndrome (SS) is an autoimmune inflammatory disorder of the exocrine glands, particularly affecting lacrimal and salivary glands. Hallmark symptoms are dry mouth and dry eyes, often in conjunction with general symptoms, such as malaise and fatigue. Lymphomas could develop in 5–10% of the SS patients.
Recent studies indicate that the prevalence of SS in the general population is about 7 per 100,000 person-years [1], which shares SS among the most common systemic autoimmune diseases. SS is nine times more frequent in women than in men. SS is mostly recognized after the age of 40 but can already present in childhood. SS can be a primary condition (dry eyes, dry mouth, recurrent swellings of salivary glands: primary SS (pSS)) or co-occur with another autoimmune disease, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and scleroderma (pSS combined with another autoimmune disease: secondary SS (sSS)).
With regard to SS, there are currently a lot of efforts with a translational character, e.g., (1) to better classify SS patients so that results from studies can be better compared with each other and the outcome can be better generalized, (2) to ease the diagnostic work-up of SS by either applying biomarker assays that are specific for SS or by applying (more) simple diagnostic clinical tools, and (3) to understand the etiopathogenesis of SS. Latter knowledge is essential to understand the course of the disease. This way clinicians will be able to identify patients who are at risk of developing SS or lymphomas; can intervene at an early stage of the disease to prevent damage to, e.g., the glands; as well as can personalize treatment with, e.g., biologicals. For example, Lendrem et al. [2] identified four distinct pSS clinical phenotypes. These phenotypes were defined on the basis of hierarchical cluster analysis of patient-reported pain, fatigue, dryness, anxiety, and depression. Importantly, these four phenotypes exhibited marked differences in a variety of biologic parameters. Presumably, SS patients within these clusters will differently response to a particular treatment, both in terms of subjective and objective parameters. In this chapter, current major achievements are discussed, and promising new directions are indicated.
10.2 Characterizing SS Patients
Over the years, many classification criteria for SS have been developed of which the 2002 revised American-European Consensus Group (AECG) classification criteria are currently the most frequently used. The AECG criteria combine subjective symptoms of dry eyes and dry mouth with the objective signs of keratoconjunctivitis sicca and xerostomia [3]. In 2012, endorsed by the American College of Rheumatology (ACR) , a new preliminary classification criteria set was introduced that purely focused on objective measures [4]. As the ACR criteria were not well received by the international SS community, a joint working group consisting of members from ACR and European League Against Rheumatism (EULAR) developed a new classification criteria set (Table 10.1; [5]). This criteria set was endorsed by both ACR and EULAR and was well received by the international SS community. The ACR-EULAR classification criteria for pSS are a step in the right direction. Further refinement is needed, however, to increase their utility [6].
To increase the utility and to make the criteria even more commonly applicable for clinicians, lots of effort are currently applied to test whether salivary gland ultrasonography (sGUS) is more specific and more sensitive than measuring salivary secretion or other objective tests applied or could replace more invasive tests such as salivary gland biopsies. This to show that sGUS is a good diagnostic tool to add to the ACR-AECG classification criteria and even might have the potential to replace (some of the) current objective tests in future [7, 8]. The focus is on assessing the diagnostic potential of sGUS as sGUS is a well-tolerated, noninvasive, inexpensive, non-irradiating technique that is widely available in rheumatologic outpatient clinics. Recently, it was shown that a combination of positive sGUS and presence of anti-SSA/Ro antibodies highly predicts classification according to the ACR-EULAR classification criteria [8]. When applying the ACR-EULAR criteria for monitoring disease activity and treatment evaluation, it is recommended that the same ultrasonographer follows the same patient as a function of time as the interobserver variation of ultrasonographers is rather large (Fig. 10.1; Delli et al. [10]). Furthermore, it has to be assessed whether sGUS images of SS patients are grossly dissimilar from those of patients with diseases involving the salivary glands that mimic SS, such as sarcoidosis, hepatitis C, and HIV.
10.3 Biomarkers and SS
Although a variety of diagnostic and therapeutic biomarkers has been proposed to classify pSS and its subsets over the years [11, 12], there is still a crucial need for novel specific biomarkers to ease diagnostics, to diagnose SS at an early stage, and to predict which patient might be helped with a tailored, targeted treatment or is at risk of developing specific comorbidity [13, 14].
10.3.1 Serology
A great variety of biomarkers is known to be present in serum of SS patients. The most frequently detected and most widely used are antibodies directed against nuclear components (ANA), antibodies directed against intracellular antigens (Ro52/SSA, Ro60/SSA, La/SSB), and rheumatoid factor (RF). These autoantibodies can already be detected many years before SS has become clinically apparent, which imply their potential use to predict onset of pSS (Fig. 10.2; [15, 16]). It has to be mentioned, however, that it is not yet set which subject that is positive for anti-Ro/SSA and/or anti-LA/SSB will indeed develop SS in future.
Anti-Ro/SSA is found in 70–90% of SS patients and may predict the course of the disease. E.g., positivity for anti-Ro/SSA is linked with a younger age at diagnosis, a longer disease duration, a higher incidence of recurrent parotid gland swelling, a higher focus score, and a higher prevalence of extraglandular manifestations [17, 18]. Sole positivity for anti-La/SSB is rare.
Of the other antibodies present in SS patients, RF and cryoglobulins are most common, respectively, in 35–70% and 5–10% of the patients [19, 20]. Both antibodies have been linked to the development of lymphomas [21, 22]. When these antibodies are present in SS patients with parotid gland enlargement, palpable purpura, and low C4 levels, these patients are at a rather high risk of developing a lymphoma or have already developed a lymphoma. Therefore, there is currently much research ongoing to detect which biomarkers are the best markers to predict which SS patient has a high lymphoma risk. This in addition to the presumed predictive value of salivary gland biopsies ([23]; see section on histopathology), which is questioned by other authors [24]. It also has to be set which SS patient with a lymphoma needs treatment or just has to be closely monitored [25].
10.3.2 Histopathology
An issue that is currently heavily discussed is whether a biopsy of the labial salivary gland has to be taken to histopathologically confirm the SS diagnosis. Patients can be classified as suffering from SS syndrome when this biopsy shows focal lymphocytic sialadenitis with a focus score ≥1, i.e., the presence of at least one accumulation of 50 or more lymphocytes per 4 mm2 (Fig. 10.3; [26]). Parotid biopsies can serve as a proper alternative to labial biopsies in the SS diagnostic work-up [27]. A major advantage of parotid biopsies is that in parotid biopsies lymphomas, mostly mucosa-associated lymphoid tissue (MALT) lymphomas , are easier to detect as parotid glands are more commonly affected (70–80% of the lymphomas in pSS patients are MALT lymphomas in the parotid glands; Fig. 10.4). Moreover, the same parotid gland can be biopsied more often which is an important asset for treatment evaluation studies (Fig. 10.5; [28]). Theander et al. [23] and Reksten et al. [29] posed that the presences of germinal center (GC)-like structures by light microscopy in SS diagnostic salivary biopsies are also highly predictive for non-Hodgkin lymphoma development, but Haacke et al. [24] recently showed in a more extensive study that the GCs in labial gland biopsies does not differ between patients with pSS that develop parotid MALT lymphoma and patients with pSS who do not develop lymphoma (Fig. 10.6). Thus, the presence of GCs in labial gland biopsies is probably not a predictive factor for SS syndrome-associated parotid MALT lymphomas. From which cells these lymphoma’s originate needs further study (see also section on lymphomas).
Recently, Delli et al. [28, 31, 32] showed that the histopathologic characteristics of parotid gland biopsies may predict which pSS patients are probably responsive to treatment with anti-CD20 therapy (rituximab) and which patient is not (Fig. 10.7). This observation brings targeted treatment within reach. In fact, the possibility of considering the composition of the inflammatory infiltrate as a tool in clinical trials to recruit homogeneous subsets of patients and to get information on the efficacy and mechanisms of action of novel drugs is challenging and very promising but still in childhood and in need of thorough studying and standardization [33]. For example, Tavoni et al. [34] showed a discrepancy among different readers in the interpretation of minor salivary gland biopsies in clinical practice. Currently, efforts are taken by a working group of EULAR to standardize histopathologic evaluation of salivary gland biopsies, including how to detect GCs [35].
10.3.3 Progress in Biomarker Research
Among the many biomarkers that are currently studied, a promising novel biomarker is the interferon (IFN) type I signature [36]. Dysregulated genes of IFN pathways, both in salivary gland tissue and peripheral blood, are considered to be an asset in diagnosing pSS and monitoring its disease activity [37,38,39]. E.g., presence of myxovirus resistance protein A (MxA) in cell may reflect presence of IFN type I and is correlated with EULAR SS disease activity (ESSDAI) score and levels of immunoglobulins and autoantibodies [40]. Also type II IFN seems to be involved in the pathogenesis of pSS as the focus score is higher in type II IFN pSS patients [41]. Furthermore, a higher IFNg/IFNa mRNA ratio in minor salivary gland tissue seems to be a predictor for lymphoma development [42]. However, the IFN type I signature is not specific for SS. It also could be just a biomarker for, e.g., disease activity. So to prove whether the IFN type I signature indeed is of additional value, the identification of different patient categories awaits long-term analysis of a larger cohort of patients [43].
Another key pathogenetic cytokine is B-cell-activating factor (BAFF) . BAFF is present in peripheral blood monocytes and salivary gland tissue of SS patients. BAFF controls B-cell maturation, tolerance, and malignancy. It has been shown that BAFF levels are higher in pSS patients with higher systemic disease activity [44, 45]. It also has been shown that BAFF-driven B-cell activation may negatively affect the clinical response of pSS patients to treatment with anti-CD20 therapy [46]. Adding a BAFF blocker to anti-CD20 therapy might increase its efficacy [47].
-Omics aims at the collective characterization and quantification of pools of biological molecules that translate into the structure, function, and dynamics of an organism or organisms. Currently, much effort is put on how to apply genomics, proteomics, and metabolomics of serum, saliva, tears, and salivary gland tissue for diagnosing and better understanding SS as well as for patient stratification [12]. Particularly, saliva, and to a lesser extent also tears, is a very attractive biofluid for searching candidate biomarkers for pSS. Saliva is probably a more direct agent than serum as it is produced by glandular tissues that are directly affected by the disease process. Moreover, when compared to blood, saliva (as well as tears) can be collected repeatedly and noninvasively. When using glandular-specific saliva, the biomarkers detected even can be directly linked to the underlying autoimmune inflammatory deregulation and thus to mechanisms in the pathogenesis of SS.
Mass spectrometric analysis of saliva has revealed a variety of biomarkers that are preferably involved in the pathogenesis of pSS (Fig. 10.8; [48,49,50]). An increased expression of inflammatory and immune response-related salivary proteins is observed as well as that the secretion of other proteins is reduced, probably related to the destruction of acinar and ductal structures. Further study is needed, but it is becoming within reach that the diagnosis SS can be made on analysis of a drop of saliva. In this respect the results of a trial focusing on the application of salivary biomarkers for SS detection (NCT01807689) are eagerly awaited.
Micro-RNAs (miRNAs) are well-preserved, small non-coding RNAs of 19–25 nucleotides involved in posttranscriptional regulation of gene expression. Alevizos et al. [51] suggested that miRNAs may serve as a set of biomarkers for pSS. Research in this field is ongoing and is presumed to have a high potential. For example, it has been shown that the risk for developing pSS is related to miR-146a expression [52]. As such, miR-146a expression is a potential biomarker to be used in the diagnostic work-up of patients with a SS suspect.
Another promising approach is laser microdissection coupled with RNA-seq analysis. With this technique acini, ducts, and inflammatory foci of pSS subjects can be isolated for RNA-seq analysis. Tandon et al. [53] showed that marked differences in gene expression occur in the ductal and infiltrating cells compared to acinar cells. In particular, two chemokines involved in immune cell trafficking to secondary lymphoid tissue, viz., CCR7 and CCL21, had a markedly increased expression. The authors suggested that these chemokines may contribute to the recruitment of diverse immune cells to the salivary glands, causing inflammation and loss of secretory function that is commonly observed in SS patients.
10.4 Personalized Treatment: Which Biological Might Be Effective?
Presence of anti-Ro52/SSA and/or anti-La/SSB, elevated plasma levels of gamma globulins and RF, higher expression levels of Bruton’s tyrosine kinase in B cells, and an increased risk of developing lymphomas, particularly mucosa-associated lymphoid tissue (MALT) lymphomas, all point toward a major role for B cells in the pathogenesis of pSS [54]. This B-cell hyperactivity seems to largely be T-cell dependent, and in particular Tfh cells play a role in SS [55].
Because of the role of B cells, anti-CD20 therapy has been considered as a potentially potent biologic disease-modifying antirheumatic drug (DMARD) to reduce disease activity. Anti-CD20 therapy results in significant depletion of CD20+ B cells via several mechanisms. Open label and smaller randomized placebo-controlled trials (for a summary, see Van Nimwegen et al. [56] as well as the larger TEARS trial [57]) revealed that anti-CD20 therapy (rituximab) shows beneficial effects for pSS patients, while in a larger multicenter placebo-controlled trial, the TRACTISS trial [58], anti-CD20 therapy apparently was not effective at all. Thus, the question raises whether anti-CD20 therapy is indeed a failing therapy or whether anti-CD20 therapy is only effective in a selected category of pSS patients [59]. Probably, the same limitations apply to other biologicals that have been tested, are tested, or will be tested in SS. In other words, pSS patients that are treated with anti-CD20 therapy or other biologicals should be better selected to enhance success of a promising treatment modality. E.g., notwithstanding the negative TRACTISS trial [58], anti-CD20 therapy apparently has beneficial effects as has been reported at a clinical, biological, histological, and ultrasonographical level [56, 57, 60]. Post hoc analyses even have identified possible predictors of response, which might serve as a guide to select patients that likely will respond to a treatment with a particular biological (Fig. 10.5; [28, 31, 32]). Targeted patient inclusion will probably make, particularly when studying a disease with many manifestations as SS is, a biological to a failing or successful trial.
The central position of B cells as target for therapy is further illustrated by other recent positive trials with biologicals that are not based on the direct depletion of B cells but that do target, either directly or indirectly, these cells [56]. These biologicals comprise belimumab that binds to BAFF [47], resulting in less survival and less activation of the B cells, and abatacept [61] that blocks the co-stimulation of T cells and as a consequence the T-cell-dependent activation of the B cells [55]. Although several cytokines and chemokines decrease after anti-CD20 therapy, BAFF levels increase, likely as the result of the relative unavailability of B cells, expressing BAFF-binding receptors (Pollard et al. [62, 63]). Since high BAFF levels have been associated with humoral autoimmunity, the effect of adding belimumab to rituximab on the efficacy of rituximab is currently assessed (NCT02631538). First results are promising [47].
10.5 How to Design and Select Patients for Trials
As mentioned by Vissink and Bootsma [6], the new ACR-EULAR classification criteria for pSS do not guarantee that the proper pSS patients are selected for studies. Either these criteria need refinement or specific inclusion and exclusion criteria have to be added to the ACR-EULAR criteria for a particular study. So, when designing a trial to show efficacy of anti-CD20 therapy (rituximab) or other biologicals, the first step should be to define what specific baseline characteristics a pSS subject should have to be included in a particular trial. The information derived from previous studies with anti-CD20 therapy or other biologicals is worthwhile to identify subpopulations of SS patients that likely will respond to a particular biological.
Applying very strict criteria to include SS patients in a particular trial to make it successful also has the hazard that recruiting eligible SS patients will slowly progress. For example, Oni et al. [64] showed that when applying specific measures of outcome, such as an EULAR SS patient-related index (ESSPRI) score ≥5 and an ESSDAI score ≥5, with requirements for unstimulated whole saliva flow >0 and anti-Ro/SSA positivity, the pool of eligible participants will greatly reduce. On the contrary, when making the inclusion to general, the result will be a failing trial unless the biological tested has such a general beneficial action that it is effective in most subcategories of SS patients.
Another critical step in trial design is to identify centers which have the tools to properly select SS patients with the required specific characteristics as well as have the experience to reliably apply the outcome parameters. For many outcome parameters, specifically trained rheumatologists (experienced in scoring ESSDAI), pathologists (targeted histologic evaluation), ophthalmologists (trained in ocular staining score), and oral and maxillofacial surgeons/specialists in oral medicine (experienced in assessing salivary gland function and taking the required type of salivary gland biopsy) are needed. It is recommended to perform trials in those expert SS centers that are able to include reasonable numbers of patients and have the needed expertise in house. This is because, in particular in multicenter trials, the inherent interindividual variety in applying inclusion criteria and assessment tools cannot be tackled by training and calibration of clinicians when participating centers include only a few subjects. Such issues probably underlie the negative outcome of the larger randomized clinical trials performed in SS: patient selection was not sufficiently strict, and too many participating centers recruited too few patients and/or lacked the needed in-house expertise to cover all needed tests.
10.6 Lymphomas: Why Are They a Commonplace in SS Patients
Lymphomas develop in approximately 5–10% of SS patients. SS patients have an 18.8 (CI 9.5–37.3) times increased risk of developing lymphomas over the life span [65]. In most cases, these lymphomas are marginal zone B-cell lymphomas occurring in the salivary glands, in particular the parotid gland, the so-called MALT lymphomas. Lymphomas in SS patients are generally localized and follow an indolent, rather benign, clinical course, and if treatment is needed, they are very responsive to therapy [25]. In a minority of SS patients, aggressive non-Hodgkin lymphoma (NHL) is present. Even Hodgkin’s disease has been described.
As mentioned before, risk factors for the development of lymphoma in SS patients include the presence of systemic activity, cytopenia, cryoglobulins, low complement C4 levels, and palpable purpura [66,66,68]. Whether the presence of GCs in salivary gland biopsies are predictive for the development of lymphoma is a continuing debate, but, as mentioned before, the larger study of Haacke et al. [24] could not confirm the presumption of Theander et al. [23] that GCs are indeed linked to the development of lymphomas in SS patients (see also section on histopathology).
Haacke et al. [30] tried to shed light whether MALT lymphomas preferably develop in parotid salivary glands. They showed that B cells expressing Fc receptor-like protein 4 (FcRL4), a protein that normally is expressed on a small subset of mucosa-associated B cells as well as on MALT lymphoma B cells, were present in salivary gland tissue of pSS patients where they were closely associated with ductal epithelial cells forming lymphoepithelial lesions (LELs). Remarkably, FcRL4+ B cells were far more frequent in parotid gland than in labial gland tissue (Fig. 10.6). As expected, the FcRL4 mRNA expression level in parotid MALT lymphoma was increased compared to parotid gland tissue of pSS patients without lymphoma. On the contrary, numbers of FcRL4+ B cells in labial gland biopsies taken at the time of pSS diagnosis were not predictive for later development of MALT lymphoma. The enrichment of FcRL4+ B cells in parotid gland tissue may explain why MALT lymphomas preferentially develop at this specific location pSS patients.
10.7 Etiopathogenesis
The most prominent histopathological finding in salivary gland tissue is the presence of focal mononuclear infiltrates of T and B cells and other cells, including plasma cells, macrophages, myeloid and plasmacytoid dendritic cells, and follicular dendritic cells. These infiltrates develop progressively in association with the striated ducts within glandular tissue. The result is impaired function of the glands and ultimately irreversible destruction of glandular tissue. It is also mentioned before that B cells play a central role in the immunopathogenesis and exhibit signs of hyperactivity. Hyperactivity of B cells is the consequence of the coordinated and integrated action of stimulation of the B-cell receptor, CD40, and toll-like receptors (TLR) in the presence of appropriate cytokines. The elevated levels of the B-cell receptor signaling molecule Btk, in B cells of pSS patients, illustrate the hyperactive status of B cells [69]. Overexpression of type I IFN and BAFF on one hand and IL-6 and IL-21 on the other hand is critically involved in the enhanced plasma cell formation in pSS patients. Hyperactivity of B cells results in secretion of autoantibodies and production of various cytokines [55].
As also mentioned previously, in many pSS patients, type I IFN and type I IFN-induced genes and proteins are overexpressed, resulting in the so-called type I IFN signature of pSS [70,70,72]. This observation also suggests involvement of viruses in the pathogenesis of SS. A variety of viruses, e.g., Epstein-Barr virus (EBV), coxsackievirus, and cytomegalovirus, are thought to play a role in onset or triggering of pSS [73]. Especially reactivation of latent EBV in genetically and hormonally susceptible individuals is presumed to play a role in the initiation and perpetuation of the chronic inflammatory autoimmune response in exocrine glands. Inoue et al. [74] postulated that binding of the exogenous ligand dioxin to the aryl hydrocarbon receptor causes lytic reactivation of EBV in B cells and salivary gland epithelial cells, resulting in immune responses in the salivary glands and possibly pSS.
10.7.1 B-Cell Hyperactivity and Role of Chemokines
Histopathologically, pSS is characterized by the presence of progressively developing focal lymphoid infiltrates around salivary gland striated ducts (lymphocytic sialadenitis; Fig. 10.3) as well as the development of LELs, in particular in parotid glands (Figs. 10.4 and 10.6). These lesions are formed by hyperplasia of the epithelium in association with lymphocytes. The histopathological features reflect the autoimmune process and manifestations of local B-cell hyperactivity. The occurrence of GCs, which are predominantly seen in the major salivary glands, is a clear sign of local activation of B cells. Another characteristic histopathological feature of pSS and witness of aberrant B-cell activity is the marked increase in the number of IgG (but not IgA)-secreting plasma cells in the exocrine glands [75]. These IgG plasma cells are predominantly present within the infiltrate, whereas IgA plasma cells dominate in the parenchyma. Chemokines are the driving force for the recruitment of lymphoid cells to sites of inflammation. As such these molecules underlie the immunopathological process in exocrine glands and contribute to B-cell hyperactivity, characteristic for pSS.
10.7.2 Germinal Centers
In approximately 25–30% of pSS patients, structures resembling GCs of secondary lymphoid organs are found within the (organized) ectopic lymphoid tissue of minor (labial) and major (parotid) salivary glands (Figs. 10.4 and 10.6) [76,76,77,78,80]. GCs arise after T-cell-dependent antigenic stimulation, and the presence of these structures obviously reflect local activation of B cells. In salivary glands of pSS patients, GCs are more likely to occur with increased focal infiltration and are associated with more severe disease [81].
10.7.3 B-Cell Hyperactivity and Clonal Expansion
Clonal expansions of B cells and plasma cells are increased in the salivary glands of pSS patients. These expansions are composed of IgA and/or IgG expressing cells [81]. Almost all obtained IgG and IgA sequences are somatically hypermutated, suggesting a post-GC origin of the cells. The occurrence of these clonally related cells as well as the intraclonal switching implies local activation and proliferation of B cells within the glandular tissue. Neoplastic transformations of clonally expanded cells may ultimately lead to the development of lymphoma in 5–10% of the pSS patients [82].
10.7.4 Pathogenetic Function of B Cells in pSS
The pathogenic role of autoantibodies in pSS is still largely obscure. As mentioned, the best known are anti-Ro/SSA and anti-La/SSB, both directed against ribonucleoproteins. The glandular epithelium is an important source for these autoantigens [83,84,85].
Besides their classical role as antibody-producing cells, activated B cells also have the ability to produce and secrete cytokines which are able to modulate immune responses [86, 87]. Herewith, B cells also play an antibody-independent role in tolerance and autoimmunity. TLR signaling appears to be critically involved in the signal required for human B cells to produce cytokine-producing cells [87]. Two subsets of cytokine secreting B cells can be identified, regulatory B cells and effector B cells. Regulatory B cells produce mainly IL-10 and TGFβ, and effector B cells produce cytokines such as IL-2, IL-4, IL-6, IL-12, IFNγ, and TNFα [86]. IL-10 producing regulatory B cells is thought to play an important role in dampening immune responses. Furuzawa-Carballeda et al. [88] showed that patients with pSS have an increased frequency of IL-10 producing circulating regulatory B cells, defined as CD19+CD38hiCD24hiIL-10+ cells, compared to controls. Importantly, the proportion of regulatory B cells was higher in clinically inactive pSS patients, compared to clinically active pSS patients suggesting that these cells may downregulate autoimmune inflammation to induce homeostasis.
10.8 Epilogue
The understanding of the pathogenetic mechanisms of pSS in general, and the role of B cells and plasma cells, in particular, is rapidly expanding. As discussed, -omic approaches will be another asset to elucidate further the complexity of the pathogenesis of pSS and to establish known and novel biomarkers for early diagnosis, measurement of disease activity, and definition of subgroups of pSS patients that might be susceptible to a particular treatment.
Many biological DMARDs are currently available and even more are in development to target various molecules involved in the cascade of hyperactive B cells and plasma cells including biologicals that can interfere with a large number of relevant cytokines and chemokines. In addition, non-biological drugs that inhibit B-cell receptor signaling molecules and cytokine receptors have become available. Because B-cell receptor signaling plays an important role in the autoimmune process, targeting important molecules of this pathway, such as Syk and Btk [89], is presumed to be a promising new approach for treatment of pSS too. A major potential disadvantage of all these therapies is that not only harmful autoimmune responses are affected but also beneficial humoral responses.
Besides a better understanding of the pathogenetic process and the availability of biological and synthetic DMARDs, assessment of disease activity in pSS is an essential step to rate efficacy of the treatment. With the development and validation of ESSDAI and ESSPRI, important tools have become available for rating the disease activity and patients’ complaints in pSS. Both indices are complementary and should be used together in addition to objective measurements of dryness and biological markers of disease activity [90]. A change of ESSDAI of at least three points or a change of ESSPRI with at least one point or 15% seems reasonable to show a clinically relevant effect (Seror et al. [91]). The ClinESSDAI , a modification of ESSDAI to score disease activity independent of B-cell biomarkers, should be used (1) in biological/clinical studies to avoid data collinearity, (2) in clinical trials, as secondary endpoint, to detect change independent of biological effect of the drug, and (3) in clinical practice to assess disease activity for visits where immunological tests have not been done [92]. In a real-life cohort, it was shown that ClinESSDAI is indeed a valid tool to assess clinical disease activity in pSS and may be a useful secondary endpoint in clinical trials [93].
The increased knowledge on the way how to assess patients for a particular therapy, along with the emergence of new targeted therapies, will stimulate the conduction of trials and the development of effective treatment option in SS.
References
Quin B, Wang J, Yang Z, Yang M, Ma N, Huang F, et al. Epidemiology of primary Sjögren’s syndrome: a systematic review and meta-analysis. Ann Rheum Dis. 2015;74:1983–9.
Lendrem D, Howard Tripp N, Mariette X, et al. Rethinking primary Sjögren’s Syndrome: stratification by clinical phenotypes to improve understanding of disease pathogenesis, trial design, clinical management and prospective health gains? Arthritis Rheumatol. 2016;68:abstract 3031.
Vitali C, Bombardieri S, Jonsson R, Moutsopoulos HM, Alexander EL, Carsons SE, et al. Classification criteria for Sjögren’s syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis. 2002;61:554–8.
Shiboski SC, Shiboski CH, Criswell L, Baer A, Challacombe S, Lanfranchi H, et al. American College of Rheumatology classification criteria for Sjögren’s syndrome: a data-driven, expert consensus approach in the Sjögren’s International Collaborative Clinical Alliance cohort. Arthritis Care Res (Hoboken). 2012;64:475–87.
Shiboski CH, Shiboski SC, Seror R, Criswell LA, Labetoulle M, Lietman TM, et al. 2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjögren’s syndrome: a consensus and data-driven methodology involving three international patient cohorts. Ann Rheum Dis. 2017;76:9–16.
Vissink A, Bootsma H. Connective tissue diseases: refining the classification criteria for primary Sjögren syndrome. Nat Rev Rheumatol. 2017;13:10–2.
Jousse-Joulin S, Nowak E, Cornec D, Brown J, Carr A, Carotti M, et al. Salivary gland ultrasound abnormalities in primary Sjögren’s syndrome: consensual US-SG core items definition and reliability. RMD Open. 2017;3(1):e000364.
Mossel E, Delli K, van Nimwegen JF, Stel AJ, Kroese FGM, Spijkervet FKL, et al. Ultrasonography of major salivary glands compared with parotid and labial gland biopsy and classification criteria in patients with clinically suspected primary Sjögren’s syndrome. Ann Rheum Dis. 2017. https://doi.org/10.1136/annrheumdis-2017-211250. pii: annrheumdis-2017-211250. [Epub ahead of print]
Hocevar A, Ambrozic A, Rozman B, Kveder T, Tomsic M. Ultrasonographic changes of major salivary glands in primary Sjögren’s syndrome. Diagnostic value of a novel scoring system. Rheumatology (Oxford). 2005;44:768–72.
Delli K, Arends S, van Nimwegen JF, Dijkstra PU, Stel AJ, Spijkervet FKL, et al. Ultrasound of the major salivary glands is a reliable imaging technique in patients with clinically suspected primary Sjögren’s syndrome. Ultraschall Med. 2017;38:1–8.
Goules AV, Tzioufas AG. Primary Sjögren’s syndrome: clinical phenotypes, outcome and the development of biomarkers. Immunol Res. 2017;65:331–4.
Baldini C, Gallo A, Perez P, Mosca M, Alevizos I, Bombardieri S. Saliva as an ideal milieu for emerging diagnostic approaches in primary Sjögren’s syndrome. Clin Exp Rheumatol. 2012;30:785–90.
Kroese FG, Bootsma H. Biomarkers: new biomarker for Sjögren’s syndrome—time to treat patients. Nat Rev Rheumatol. 2013;9:570–2.
Winthrop KL, Strand V, van der Heijde DM, Mease PJ, Crow MK, Weinblatt M, et al. The unmet need in rheumatology: reports from the targeted therapies meeting 2016. Clin Exp Rheumatol. 2016;34(4 Suppl 98):69–76.
Jonsson R, Theander E, Sjostrom B, Brokstad K, Henriksson G. Autoantibodies present before symptom onset in primary Sjögren syndrome. JAMA. 2013;310:1854–5.
Theander E, Jonsson R, Sjostrom B, Brokstad K, Olsson P, Henriksson G. Prediction of Sjögren’s syndrome years before diagnosis and identification of patients with early onset and severe disease course by autoantibody profiling. Arthritis Rheumatol. 2015;67:2427–36.
Baldini C, Cecchettini A, Gallo A, Bombardieri S. Updates on Sjögren’s syndrome: from proteomics to protein biomarkers. Expert Rev Proteomics. 2017;14:491–8.
Ramos-Casals M, Brito-Zeron P, Solans R, Camps MT, Casanovas A, Sopena B, et al. Systemic involvement in primary Sjögren’s syndrome evaluated by the EULAR-SS disease activity index: analysis of 921 Spanish patients (GEAS-SS Registry). Rheumatology (Oxford). 2014;53:321–31.
Tzioufas AG, Costello R, Manoussakis MN, Papadopoulos NM, Moutsopoulos HM. Cryoglobulinemia in primary Sjögren’s syndrome: a monoclonal process. Scand J Rheumatol Suppl. 1986;61:111–3.
Quartuccio L, Isola M, Baldini C, Priori R, Bartoloni E, Carubbi F, et al. Clinical and biological differences between cryoglobulinaemic and hypergammaglobulinaemic purpura in primary Sjögren’s syndrome: results of a large multicentre study. Scand J Rheumatol. 2015;44:36–41.
Nocturne G, Virone A, Ng WF, Le Guern V, Hachulla E, Cornec D, et al. Rheumatoid factor and disease activity are independent predictors of lymphoma in primary Sjögren’s syndrome. Arthritis Rheumatol. 2016;68:977–85.
Quartuccio L, Baldini C, Bombardieri S, Priori R, Valesini G, Bartoloni E, et al. The need to target mucosa-associated lymphoid tissue for preventing lymphoma in rheumatoid factor-positive patients with Sjögren’s syndrome: comment on the article by nocturne et al. Arthritis Rheumatol. 2016;68:1318–9.
Theander E, Vasaitis L, Baecklund E, Nordmark G, Warfvinge G, Liedholm R, et al. Lymphoid organisation in labial salivary gland biopsies is a possible predictor for the development of malignant lymphoma in primary Sjögren’s syndrome. Ann Rheum Dis. 2011;70:1363–8.
Haacke EA, van der Vegt B, Vissink A, Spijkervet FKL, Bootsma H, Kroese FGM. Germinal centres in diagnostic labial gland biopsies of patients with primary Sjögren’s syndrome are not predictive for parotid MALT lymphoma development. Ann Rheum Dis. 2017. https://doi.org/10.1136/annrheumdis-2017-211290. pii: annrheumdis-2017-211290. [Epub ahead of print]
Pollard RP, Pijpe J, Bootsma H, Spijkervet FK, Kluin PM, Roodenburg JL, et al. Treatment of mucosa-associated lymphoid tissue lymphoma in Sjögren’s syndrome: a retrospective clinical study. J Rheumatol. 2011;38:2198–208.
Daniels TE. Labial salivary gland biopsy in Sjögren’s syndrome. Assessment as a diagnostic criterion in 362 suspected cases. Arthritis Rheum. 1984;27:147–56.
Pijpe J, Kalk WW, van der Wal JE, Vissink A, Kluin PM, Roodenburg JL, et al. Parotid gland biopsy compared with labial biopsy in the diagnosis of patients with primary Sjögren’s syndrome. Rheumatology (Oxford). 2007;46:335–41.
Delli K, Haacke EA, Ihrler S, van der Vegt B, Vissink A, Bootsma H, et al. Need for consensus guidelines to standardise the assessment of germinal centres and other histopathological parameters in salivary gland tissue of patients with primary Sjögren’s syndrome. Ann Rheum Dis. 2016;75:e32.
Reksten TR, Johnsen SJ, Jonsson MV, Omdal R, Brun JG, Theander E, et al. Genetic associations to germinal centre formation in primary Sjögren’s syndrome. Ann Rheum Dis. 2014;73:1253–8.
Haacke EA, Bootsma H, Spijkervet FKL, Visser A, Vissink A, Kluin PM, Kroese FGM. FcRL4+ B-cells in salivary glands of primary Sjögren’s syndrome patients. J Autoimmun. 2017;81:90–8.
Delli K, Haacke EA, Kroese FG, Pollard RP, Ihrler S, van der Vegt B, et al. In primary Sjögren’s syndrome high absolute numbers and proportions of B cells in parotid glands predict responsiveness to rituximab as defined by ESSDAI, but not by SSRI. Ann Rheum Dis. 2016;e34:75.
Delli K, Haacke EA, Kroese FG, Pollard RP, Ihrler S, van der Vegt B, Vissink A, et al. Towards personalised treatment in primary Sjögren’s syndrome: baseline parotid histopathology predicts responsiveness to rituximab treatment. Ann Rheum Dis. 2016;75:1933–8.
Fisher BA, Jonsson R, Daniels T, Bombardieri M, Brown RM, Morgan P, et al. Standardisation of labial salivary gland histopathology in clinical trials in primary Sjögren’s syndrome. Ann Rheum Dis. 2017;76:1161–8.
Tavoni AG, Baldini C, Bencivelli W, Cavazzini L, Covelli M, De Vita S, et al. Minor salivary gland biopsy and Sjögren’s syndrome: comparative analysis of biopsies among different Italian rheumatologic centers. Clin Exp Rheumatol. 2012;30:929–33.
Haacke EA, van der Vegt B, Vissink A, Spijkervet FKL, Bootsma H, FGM K. Standardisation of the detection of germinal centres in salivary gland biopsies of patients with primary Sjögren’s syndrome is needed to assess their clinical relevance. Ann Rheum Dis. 2017. https://doi.org/10.1136/annrheumdis-2017-212164. pii: annrheumdis-2017-212164. [Epub ahead of print]
Mavragani CP, Crow MK. Mechanisms and new strategies for primary Sjögren’s syndrome. Annu Rev Med. 2017;68:331–43.
Mavragani CP, Crow MK. Activation of the type I interferon pathway in primary Sjögren’s syndrome. J Autoimmun. 2010;35:225–31.
Kimoto O, Sawada J, Shimoyama K, Suzuki D, Nakamura S, Hayashi H, et al. Activation of the interferon pathway in peripheral blood of patients with Sjögren’s syndrome. J Rheumatol. 2011;38:310–6.
Nguyen CQ, Peck AB. The interferon-signature of Sjögren’s syndrome: how unique biomarkers can identify underlying inflammatory and immunopathological mechanisms of specific diseases. Front Immunol. 2013;4:142.
Maria NI, Brkic Z, Waris M, van Helden-Meeuwsen CG, Heezen K, van de Merwe JP, et al. MxA as a clinically applicable biomarker for identifying systemic interferon type I in primary Sjögren’s syndrome. Ann Rheum Dis. 2014;73:1052–9.
Hall JC, Baer AN, Shah AA, Criswell LA, Shiboski CH, Rosen A, et al. Molecular subsetting of interferon pathways in Sjögren’s syndrome. Arthritis Rheumatol. 2015;67:2437–46.
Kroese FG, Verstappen GM, de Leeuw K, Bootsma H. Sjögren’s syndrome, should we sign? Expert Rev Clin Immunol. 2016;12:365–7.
Mariette X, Roux S, Zhang J, Bengoufa D, Lavie F, Zhou T, et al. The level of BLyS (BAFF) correlates with the titre of autoantibodies in human Sjögren’s syndrome. Ann Rheum Dis. 2003;62:168–71.
Pers JO, Lahiri A, Tobon GJ, Youinou P. Pathophysiological cytokine network in primary Sjögren’s syndrome. Presse Med. 2012;41(9 Pt 2):e467–74.
Cornec D, Jousse-Joulin S, Costa S, Marhadour T, Marcorelles P, Berthelot JM, et al. High-grade salivary-gland involvement, assessed by histology or ultrasonography, is associated with a poor response to a single rituximab course in primary Sjögren’s syndrome: data from the TEARS randomized trial. PLoS One. 2016;11:e0162787.
Corneth OBJ, Verstappen GMP, Paulissen SMJ, de Bruijn MJW, Rip J, Lukkes M, et al. Enhanced Bruton’s tyrosine kinase activity in peripheral blood B lymphocytes from patients with autoimmune disease. Arthritis Rheumatol. 2017;69:1313–24.
De Vita S, Quartuccio L, Seror R, Salvin S, Ravaud P, Fabris M, et al. Efficacy and safety of belimumab given for 12 months in primary Sjögren’s syndrome: the BELISS open-label phase II study. Rheumatology (Oxford). 2015;54:2249–56.
Delaleu N, Mydel P, Kwee I, Brun JG, Jonsson MV, Jonsson R. High fidelity between saliva proteomics and the biologic state of salivary glands defines biomarker signatures for primary Sjögren’s syndrome. Arthritis Rheumatol. 2015;67:1084–95.
Ryu OH, Atkinson JC, Hoehn GT, Illei GG, Hart TC. Identification of parotid salivary biomarkers in Sjögren’s syndrome by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry and two-dimensional difference gel electrophoresis. Rheumatology (Oxford). 2006;45:1077–86.
Hu S, Gao K, Pollard R, Arellano-Garcia M, Zhou H, Zhang L, et al. Preclinical validation of salivary biomarkers for primary Sjögren’s syndrome. Arthritis Care Res (Hoboken). 2010;62:1633–8.
Alevizos I, Alexander S, Turner RJ, Illei GG. MicroRNA expression profiles as biomarkers of minor salivary gland inflammation and dysfunction in Sjögren’s syndrome. Arthritis Rheum. 2011;63:535–44.
Delaleu N, Mydel P, Brun JG, Jonsson MV, Alimonti A, Jonsson R. Sjögren’s syndrome patients with ectopic germinal centers present with a distinct salivary proteome. Rheumatology (Oxford). 2016;55:1127–37.
Sun HY, Lv AK, Yao H. Relationship of miRNA-146a to primary Sjögren’s syndrome and to systemic lupus erythematosus: a meta-analysis. Rheumatol Int. 2017;37:1311–6.
Tandon M, Perez P, Burbelo PD, Calkins C, Alevizos I. Laser microdissection coupled with RNA-seq reveal cell-type and disease-specific markers in the salivary gland of Sjögren’s syndrome patients. Clin Exp Rheumatol. 2017;35:777–85.
Kroese FG, Abdulahad WH, Haacke E, Bos NA, Vissink A, Bootsma H. B-cell hyperactivity in primary Sjögren’s syndrome. Expert Rev Clin Immunol. 2014;10:483–99.
Verstappen GM, Meiners PM, Corneth OBJ, Visser A, Arends S, Abdulahad WH, et al. Attenuation of follicular helper T cell-dependent B cell hyperactivity by abatacept treatment in primary Sjögren’s syndrome. Arthritis Rheumatol. 2017;69:1850–61.
Van Nimwegen JF, Moerman RV, Sillevis Smitt N, Brouwer E, Bootsma H, Vissink A. Safety of treatments for primary Sjögren’s syndrome. Expert Opin Drug Saf. 2016;15:513–24.
Devauchelle-Pensec V, Mariette X, Jousse-Joulin S, Berthelot JM, Perdriger A, Puéchal X, et al. Treatment of primary Sjögren syndrome with rituximab: a randomized trial. Ann Intern Med. 2014;160:233–42.
Bowman S, Everett CC, O’Dweyer JL, Emery P, Pitzalis C, Ng WF, et al. Randomized controlled trial and cost-effectiveness analysis in treating fatigue and oral dryness in primary Sjögren’s syndrome. Arthritis Rheumatol. 2017;69:1440–50.
Bootsma H, Kroese FGM, Vissink A. Editorial: rituximab in the treatment of Sjögren’s syndrome: is it the right or wrong drug? Arthritis Rheumatol. 2017;69:1346–9.
Cornec D, Devauchelle-Pensec V, Mariette X, Jousse-Joulin S, Berthelot JM, Perdriger A, et al. Development of the Sjögren’s syndrome responder index, a data-driven composite endpoint for assessing treatment efficacy. Rheumatology. 2015;54:1699–708.
Meiners PM, Vissink A, Kroese FG, Spijkervet FK, Smitt-Kamminga NS, Abdulahad WH, et al. Abatacept treatment reduces disease activity in early primary Sjögren’s syndrome (open-label proof of concept ASAP study). Ann Rheum Dis. 2014;73:1393–6.
Pollard RP, Abdulahad WH, Vissink A, Hamza N, Burgerhof JG, Meijer JM, et al. Serum levels of BAFF, but not APRIL, are increased after rituximab treatment in patients with primary Sjogren’s syndrome: data from a placebo-controlled clinical trial. Ann Rheum Dis. 2013;72:146–8.
Oni C, Mitchell S, James K, Ng WF, Griffiths B, Hindmarsh V, Price E, Pease CT, Emery P, Lanyon P, Jones A, Bombardieri M, Sutcliffe N, Pitzalis C, Hunter J, Gupta M, McLaren J, Cooper A, Regan M, Giles I, Isenberg D, Saravanan V, Coady D, Dasgupta B, McHugh N, Young-Min S, Moots R, Gendi N, Akil M, Barone F, Fisher B, Rauz S, Richards A, Bowman SJ. Eligibility for clinical trials in primary Sjögren’s syndrome: lessons from the UK Primary Sjögren’s Syndrome Registry. Rheumatology (Oxford). 2017;56(12):2255.
Pollard RP, Abdulahad WH, Bootsma H, Meiners PM, Spijkervet FK, Huitema MG, et al. Predominantly proinflammatory cytokines decrease after B cell depletion therapy in patients with primary Sjogren’s syndrome. Ann Rheum Dis. 2013;72:2048–50.
Zintzaras E, Voulgarelis M, Moutsopoulos HM. The risk of lymphoma development in autoimmune diseases: a meta-analysis. Arch Intern Med. 2005;165:2337–44.
Theander E, Henriksson G, Ljungberg O, Mandl T, Manthorpe R, Jacobsson LT. Lymphoma and other malignancies in primary Sjögren’s syndrome: a cohort study on cancer incidence and lymphoma predictors. Ann Rheum Dis. 2006;65:796–803.
Voulgarelis M, Skopouli FN. Clinical, immunologic, and molecular factors predicting lymphoma development in Sjögren’s syndrome patients. Clin Rev Allergy Immunol. 2007;32:265–74.
Brito-Zerón P, Kostov B, Fraile G, Caravia-Durán D, Maure B, Rascón FJ, et al. SS Study Group GEAS-SEMI. Characterization and risk estimate of cancer in patients with primary Sjögren syndrome. J Hematol Oncol. 2017;10:90.
Hjelmervik TO, Petersen K, Jonassen I, Jonsson R, Bolstad AI. Gene expression profiling of minor salivary glands clearly distinguishes primary Sjögren’s syndrome patients from healthy control subjects. Arthritis Rheum. 2005;52:1534–44.
Gottenberg JE, Cagnard N, Lucchesi C, Letourneur F, Mistou S, Lazure T, et al. Activation of IFN pathways and plasmacytoid dendritic cell recruitment in target organs of primary Sjögren’s syndrome. Proc Natl Acad Sci U S A. 2006;103:2770–5.
Wildenberg ME, van Helden-Meeuwsen CG, van de Merwe JP, Drexhage HA, Versnel MA. Systemic increase in type I interferon activity in Sjögren’s syndrome: a putative role for plasmacytoid dendritic cells. Eur J Immunol. 2008;38:2024–33.
Igoe A, Scofield RH. Autoimmunity and infection in Sjögren’s syndrome. Curr Opin Rheumatol. 2013;25:480–7.
Inoue H, Mishima K, Yamamoto-Yoshida S, Ushikoshi-Nakayama R, Nakagawa Y, Yamamoto K, et al. Aryl hydrocarbon receptor-mediated induction of EBV reactivation as a risk factor for Sjögren’s syndrome. J Immunol. 2012;188:4654–62.
Szyszko EA, Brokstad KA, Oijordsbakken G, Jonsson MV, Jonsson R, Skarstein K. Salivary glands of primary Sjögren’s syndrome patients express factors vital for plasma cell survival. Arthritis Res Ther. 2011;13(1):R2.
Amft N, Curnow SJ, Scheel-Toellner D, Devadas A, Oates J, Crocker J, et al. Ectopic expression of the B cell-attracting chemokine BCA-1 (CXCL13) on endothelial cells and within lymphoid follicles contributes to the establishment of germinal center-like structures in Sjögren’s syndrome. Arthritis Rheum. 2001;44:2633–41.
Barone F, Bombardieri M, Manzo A, Blades MC, Morgan PR, Challacombe SJ, et al. Association of CXCL13 and CCL21 expression with the progressive organization of lymphoid-like structures in Sjögren’s syndrome. Arthritis Rheum. 2005;52:1773–84.
Barone F, Bombardieri M, Rosado MM, Morgan PR, Challacombe SJ, De Vita S, et al. CXCL13, CCL21, and CXCL12 expression in salivary glands of patients with Sjögren’s syndrome and MALT lymphoma: association with reactive and malignant areas of lymphoid organization. J Immunol. 2008;180:5130–40.
Jonsson MV, Skarstein K, Jonsson R, Brun JG. Serological implications of germinal center-like structures in primary Sjögren’s syndrome. J Rheumatol. 2007;34:2044–9.
Risselada AP, Kruize AA, Goldschmeding R, Lafeber FP, Bijlsma JW, van Roon JA. The prognostic value of routinely performed minor salivary gland assessments in primary Sjögren’s syndrome. Ann Rheum Dis. 2014;73:1537–40.
Risselada AP, Looije MF, Kruize AA, Bijlsma JW, van Roon JA. The role of ectopic germinal centers in the immunopathology of primary Sjögren’s syndrome: a systematic review. Semin Arthritis Rheum. 2013;42:368–76.
Routsias JG, Goules JD, Charalampakis G, Tzima S, Papageorgiou A, Voulgarelis M. Malignant lymphoma in primary Sjögren’s syndrome: an update on the pathogenesis and treatment. Semin Arthritis Rheum. 2013;43:178–86.
Routsias JG, Tzioufas AG. Autoimmune response and target autoantigens in Sjögren’s syndrome. Eur J Clin Investig. 2010;40:1026–36.
Routsias JG, Tzioufas AG. B-cell epitopes of the intracellular autoantigens Ro/SSA and La/SSB: tools to study the regulation of the autoimmune response. J Autoimmun. 2010;35:256–64.
Tzioufas AG, Kapsogeorgou EK, Moutsopoulos HM. Pathogenesis of Sjögren’s syndrome: what we know and what we should learn. J Autoimmun. 2012;39:4–8.
Lund FE. Cytokine-producing B lymphocytes-key regulators of immunity. Curr Opin Immunol. 2008;20:332–8.
Fillatreau S. Cytokine-producing B cells as regulators of pathogenic and protective immune responses. Ann Rheum Dis. 2013;72(Suppl 2):ii80–4.
Furuzawa-Carballeda J, Hernandez-Molina G, Lima G, Rivera-Vicencio Y, Ferez-Blando K, Llorente L. Peripheral regulatory cells immunophenotyping in primary Sjögren’s syndrome: a cross-sectional study. Arthritis Res Ther. 2013;15:R68.
Puri KD, Di Paolo JA, Gold MR. B-cell receptor signaling inhibitors for treatment of autoimmune inflammatory diseases and B-cell malignancies. Int Rev Immunol. 2013;32:397–427.
Moerman RV, Arends S, Meiners PM, Brouwer E, Spijkervet FK, Kroese FG, et al. EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) is sensitive to show efficacy of rituximab treatment in a randomised controlled trial. Ann Rheum Dis. 2014;73:472–4.
Seror R, Bootsma H, Saraux A, Bowman SJ, Theander E, Brun JG, et al. Defining disease activity states and clinically meaningful improvement in primary Sjögren’s syndrome with EULAR primary Sjögren’s syndrome disease activity (ESSDAI) and patient-reported indexes (ESSPRI). Ann Rheum Dis. 2016;75:382–9.
Seror R, Meiners P, Baron G, Bootsma H, Bowman SJ, Vitali C, et al. Development of the ClinESSDAI: a clinical score without biological domain. A tool for biological studies. Ann Rheum Dis. 2016;75:1945–50.
Quartuccio L, Baldini C, Bartoloni E, Priori R, Carubbi F, Alunno A, et al. Correlation between ESSDAI and ClinESSDAI in a real-life cohort of patients with Sjögren’s syndrome. Clin Exp Rheumatol. 2017;35:546–7.
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Vissink, A., Spijkervet, F.K.L., Kroese, F.G.M., Bootsma, H. (2018). Translational Research in Sjögren’s Syndrome. In: Meurman, J. (eds) Translational Oral Health Research. Springer, Cham. https://doi.org/10.1007/978-3-319-78205-8_10
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