Journal of Autoimmunity xxx (2014) 1e6

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Sjögren’s syndrome: Where do we stand, and where shall we go? Divi Cornec a, b, Christophe Jamin b, Jacques-Olivier Pers b, * a b

Department of Rheumatology, Brest Teaching Hospital, Brest, France EA 2216 Immunology and Pathology, Brest University, SFR ScinBios, Labex ‘Immunotherapy, Graft, Oncology’, Brest, France

a r t i c l e i n f o

a b s t r a c t

Article history: Received 5 February 2014 Accepted 11 February 2014

Primary Sjögren’s syndrome (pSS) is one of the most frequent autoimmune systemic diseases, mainly characterized by ocular and oral dryness due to the progressive destruction of lachrymal and salivary glands by an inflammatory process. A noteworthy proportion of patients also features extraglandular manifestations, sometimes severe and life-threatening. Until now, its management relies mostly on symptomatic interventions, long-term monitoring, and, in patients with severe systemic complications, immunosuppressive drugs can be provided. However, recent years have seen great progresses in the understanding of the pathological processes of the disease. The central role of regulatory lymphocytes, the implication of the type 1 interferon pathway in some patients or the importance of epigenetics have been highlighted. New classification criteria have been recently published and have shed in light an international attempt for a better recognition of the patients, probably thanks to the development of new diagnostic procedures such as salivary gland ultrasonography. To facilitate the detection of treatment efficacy in clinical trials and to help in determining which subgroups of patients would have benefits from intensive therapies, a better definition of activity scores and the availability of new prognostic markers are urgent. Thereby, the development of future therapies should be based on specific molecular signatures that will enable a personalized management of each patient. This review focuses on the most striking advances in the fields of pathophysiology, diagnosis and treatment of pSS, which generate a great hope for pSS patients. Ó 2014 Elsevier Ltd. All rights reserved.

Keywords: Sjögren’s syndrome Pathophysiology Diagnosis Ultrasonography Classification criteria Outcome measures Treatment

1. Introduction Primary Sjögren’s syndrome (pSS) is among the most frequent systemic autoimmune diseases, with an estimated prevalence between 0.01 and 0.1% of the population [1]. Its main clinical features are ocular and oral dryness, along with widespread pain and intense fatigue leading to an altered quality of life. However, a significant proportion of patients develop extraglandular manifestations, which may require intensive immunosuppressive therapy. Important steps have been made in the very recent years towards the understanding of all the facets of this pleomorphic disease. We will focus in this review on the most striking recent advances in the fields of the pathophysiology, diagnosis and treatment of pSS, generating a great hope for the management of these patients.

2. Recent advances and perspectives in the pathophysiology of pSS 2.1. Genetic variants associated with pSS A great step forward the understanding of the genetic determinants of pSS was taken in 2013 with the completion of a large international genome-wide association study (GWAS) [2]. Beside the strong and well-studied association with the HLA genes [3], not only this study confirmed the association of pSS with key genes in the homeostasis of the immune system such as IRF5, STAT4 and various cytokines, but also suggested the importance of several genes that are involved in both innate and adaptive immunity. Whether the combination of such genetic risk factors could constitute a diagnostic tool, or even a predictive instrument, has yet to be evaluated [4].

2.2. Epigenetics aberrations in pSS * Corresponding author. EA2216, Laboratoire d’Immunologie, Hôpital Morvan, BP 824, F 29609 Brest Cedex, France. Tel.: þ33 298223384; fax: þ33 298223847. E-mail address: [email protected] (J.-O. Pers).

However, the weight of genetic determinants is highly variable between autoimmune diseases, and only subgroups of patients 0896-8411/Ó 2014 Elsevier Ltd. All rights reserved.

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share these susceptibility loci. Studies in twins lead to the concept of the partial “heritability” of autoimmune diseases [5]. Thus, other factors participate in the pathogenesis of pSS, and among them, the importance given to epigenetics is growing [6]. Epigenetics refers to the heritable changes in gene expression that do not involve mutations in the DNA itself. Two main mechanisms have been described: DNA methylation, which can repress or increase the expression of various genes, and microRNAs which are able to specifically inhibit various messenger RNA (mRNA). In pSS patients, global DNA methylation is reduced in salivary gland epithelial cells, and this abnormality is associated with a dysregulation of key enzymes regulating DNA methylation such as DNMT1 or Gadd45alpha [7]. An epigenome-wide DNA methylation study identified several genes which were hypo or hypermethylated in peripheral naïve CD4þ T cells from pSS patients compared to healthy controls [8]. Hypomethylated genes were mainly involved in lymphocyte activation and immune response, whereas hypermethylated genes were involved in antigen processing and presentation. MicroRNAs are small RNAs (20e22 nucleotides) which can decrease a specific gene expression through either mRNA degradation or disruption of translation (posttranscriptional regulation). A single microRNA may target several genes involved in a given function. Microarrays have been developed to study the expression of all microRNAs in a cell type or tissue, in order to establish an expression profile [9]. In pSS salivary glands, this microRNA expression profile is altered compared to healthy controls, and could constitute a signature of the disease [10]. 2.3. Regulatory lymphocyte subsets Both T cells [11] and B cells [12] play a major role in the development of pSS. Growing evidence accumulates on the importance of regulatory lymphocytes in the pathogenesis of autoimmune diseases. The common feature of regulatory cells is their ability to decrease the proliferation of T cells in order to maintain a state of tolerance toward self-antigens. If the phenotypic characterization of regulatory T cells (Treg) is widely accepted, i.e. mostly CD3þ CD4þ CD25þ FoxP3þ, no clear phenotype of regulatory B cells (Breg) has been described yet. Several specifications of Breg have been claimed, such as production of IL-10 or TGFb, high expression of CD24 and CD38 (transitional B cell-like phenotype), or expression of CD5 [13]. In the blood of pSS patients, an increase of several potential Breg populations has been described, whereas Treg proportions were not different from healthy control [14]. 2.4. NK cells, macrophages, and the interferon signature Type I IFN is one of the major cytokines of innate immunity. The major sources of type I IFN are plasmacytoid dendritic cells (pDC). Type 1 IFN may act through inhibition of viral replication, activation of natural killer (NK) cells, generation and activation of dendritic cells (DC) and maturation of B cells toward antibody secreting cells [15]. Numerous isoforms of type I IFN exist, so the direct dosage of the protein is not appropriated. Instead, techniques have been developed to measure the consequences of high levels of type 1 IFN, i.e. the level of expression of various type I IFN-inducible genes, which has been referred to as the IFN signature. Around 50% of pSS patients display an IFN signature [16], either in the blood or in the salivary glands [17]. A recent study described a link between an NK-cell specific receptor (NCR3/NKp30) gene promoter polymorphism and pSS, and demonstrated a correlation between the levels of this receptor, the type of IFN production, and the severity of salivary gland inflammation [18]. Furthermore, NK cells accumulate in the lymphocytic

foci within the salivary glands when salivary gland epithelial cells express the specific ligand of NKp30. Inflamed salivary glands of pSS patients contain activated lymphocytes, which are able to recruit macrophages on the site. Macrophages then exacerbate the inflammatory response, leading to tissue destruction, notably through the release of proteolytic enzymes such as matrix metalloproteases and plasmin. Interestingly, one of the main determinants of plasmin secretion within the salivary glands is type I IFN [19]. Thus, targeting of type I IFN pathways could be a promising therapeutic possibility in the near future. In this context, therapeutic vaccination is a novel approach that offers several competitive advantages when compared to monoclonal antibodies. Therapeutic vaccination will indeed target all of the 13 type I IFN subtypes and will lead to a polyclonal antibody response. 3. Recent advances and perspectives in the diagnosis of pSS 3.1. Autoantibodies and B-cell phenotyping As a systemic autoimmune disease, several autoantibodies are frequently detected during pSS [20]. The most frequent autoantibodies are antinuclear antibodies (ANA), in up to 80% of the patients, but the most specific are directed to Ro/SSA or La/SSB antigens. Anti-SSA/-SSB antibodies are the only serological item in the American-European Consensus Group (AECG) classification criteria [21], and they could even predict the disease since they have been recently detected in patients several years before the first clinical manifestation of pSS [22]. Rheumatoid factors (RF) are also often detected in these patients, and may be associated with a higher disease activity [20]. In the recently published American College of Rheumatology (ACR) criteria, the association of high titer ANA (1:320) and RF is considered equivalent to anti-SSA/-SSB positivity [23]. However, we did not confirm the clinical benefits of this item, since we demonstrated that the vast majority of pSS patients who display high titer ANA and RF also have anti-SSA/-SSB antibodies [24]. Other autoantibodies have been described in pSS patients such as antibodies to alpha-fodrin, muscarinic receptors [25] or carbonic anhydrase [26]. However, their diagnostic utility has not been demonstrated. Besides autoantibodies, the systemic autoimmune process in pSS drives alterations in the repartition of the different B-cell subpopulations in the peripheral blood, which can be simply studied by flow cytometry using IgD and CD38 stainings. Analyzing these alterations, we determined that the ratio between Bm2 þ Bm20 and eBm5 þ Bm5 subsets had good diagnostic properties in a caseecontrol study comparing pSS to systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and healthy controls [27]. In a prospective cohort, we recently confirmed the good diagnostic performance of this ratio when considered as a single test, but its integration within currently used AECG classification criteria did not modify their properties dramatically [24]. 3.2. Salivary gland ultrasonography (SGUS) Salivary gland functional or morphologic involvement is a major feature of pSS. According to AECG criteria [21], it can be assessed by unstimulated whole salivary flow, parotid sialography or salivary gland scintigraphy, but these procedures have various weaknesses and are considered obsolete by most physicians. Thus, the potential diagnostic utility of SGUS has been studied by several groups. The main feature seen in patients with pSS is a heterogeneity of the parenchyma, due to the apparition of hypoechogenic areas [28]. In a situation of clinical suspicion of pSS, we have shown that SGUS has

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good diagnostic properties with a sensitivity of 63% and a specificity of 95%, and that the adjunction of SGUS to AECG and ACR criteria would improve significantly their diagnostic performance [29e32]. Recently, an international expert group has been created in order to develop a standardized procedure to validate SGUS for diagnosing pSS through the OMERACT filter. 3.3. Ocular tests Several investigations have been developed to evaluate patients complaining of ocular dryness [33]. The break-up time is considered to lack specificity and is not included in any of the classification criteria sets for pSS. The Schirmer’s test measuring the production of tears using filter-paper strips is simple to perform at the point of care and has good specificity for pSS, although sensitivity is around 50% [34]. Vital dye stains are used only by ophthalmologists. They assess the integrity of the lachrymal film and the presence of keratoconjunctivitis sicca via staining with vital dies (lissamine green and fluorescein). Two scores can be used: the van Bijsterveld score [35] and the recently published ocular staining score (OSS) [36], developed during the creation of the ACR classification criteria [23]. Comparisons of these two scores suggest that the OSS cutoff of 3/12 is probably too low and may lead to very low specificity for pSS [34]. 3.4. Classification criteria No single reference standard exists for diagnosing complex systemic diseases such as pSS, RA, SLE, systemic sclerosis, or inflammatory myopathies. In clinical practice, the diagnosis is made by the evaluating physician, based on clinical findings, biological, morphological or histological work-up, and interpreted through his clinical experience. Consequently, this clinical diagnosis may be highly variable between physicians. Thus, classification criteria for systemic diseases are designed to improve the homogeneity of populations enrolled in clinical studies, in order to allow valid comparisons across studies [37e40]. Nevertheless, classification criteria are often used for diagnostic purposes, despite their limitations [41e43]. Several classification criteria have been proposed for pSS, but the most widely used and accepted is the 2002 AECG criteria [21]. New criteria have been proposed in 2012, based on the analysis of the large international SICCA cohort [44] and approved by the ACR [23]. They differ substantially from the currently used AECG criteria in that 1) they do not include subjective ocular and buccal symptoms nor functional or morphological tests for salivary glands, 2) they use a new OSS as the sole evaluation for ocular involvement, and 3) they consider the association of ANA titer 1:320 and RF positivity as equivalent to anti-SSA/-SSB positivity. Their publication has been followed by an international debate on which criteria should be used henceforth [34,45e47], and a new collaborative group, supported by both the European League Against Rheumatism and the ACR, will work on the development of new consensual criteria. The characterization of the patients discordant for the different sets of criteria will be fundamental. 3.5. Prognostic factors If in most cases, pSS is a chronic, slow-evolving disease characterized only by sicca symptoms, widespread pain and fatigue, some patients experience severe and sometimes life-threatening extraglandular manifestations such as peripheral or central neuropathy, interstitial lung disease, polysynovitis, tubular kidney disease, or cryoglobulinemic vasculitis. These manifestations may require steroids and immunosuppressants, and the definition of


“at-risk” patients is paramount. In a large Italian cohort of pSS patients, severe extraglandular manifestations were detectable in 15% of the patients and low C3/C4, hypergammaglobulinaemia, RF and cryoglobulinaemia were markers of severity for pSS [48]. The worst concern in patients with pSS is the development of lymphoma, in around 10% of the patients [49]. Prognostic markers linked to the development of lymphoma are classically salivary gland swelling, low C4, cryoglobulins, anti-La antibodies, and leukopenia [50]. However, recent studies gave important clues to better understand the mechanisms underpinning lymphomagenesis in pSS and to better recognize at-risk patients. Genetic polymorphisms linked to the development of lymphoma have been highlighted. Such polymorphisms have been detected in the germline and somatic (i.e. within the lymphoma tissue) TNFAIP3 gene, which encodes the A20 protein [51], as well as in the BAFF gene [52]. Besides, the serum levels of a cytokine crucial in lymphocyte ontogeny, FLT3-L, has been shown to be highly elevated in a subset of patients with pSS [53], which are far more likely to develop lymphoma [54]. 4. Recent advances and perspectives in the treatment of pSS 4.1. Outcome measures Until now, the treatment of pSS relies mainly on symptomatic drugs to relief the symptoms: tears and saliva substitutes, sialogogues such as pilocarpine and cevimeline, analgesics. Patients with severe extraglandular complications are usually treated by systemic steroids and immunosuppressants, but the scientific evidence is scarce [55]. Several randomized controlled studies have failed to prove the efficacy of various drugs, such as prednisone, azathioprine, anti-TNF agents. However, to be able to detect a treatment effect, the outcome measures have to be sensitive and validated. In the recent years, several activity scores have been develop in order to catch the evolution of pSS and ultimately to be used in therapeutic studies. Two scores have been created under the auspices of an EULAR task force. The EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) assesses the patient’s symptoms, and is the mean of dryness, limb pain and fatigue 0e100 self-reported scores [56]. The EULAR Sjögren’s syndrome disease activity index (ESSDAI) is meant to catch the systemic activity of pSS, and is composed of 12 weighted domains picturing all potential extraglandular manifestations of the disease [57]. These 2 scores have shown good metrologic properties in several studies of virtual patient vignettes evaluated by a group of experts [58e60], as well as in a prospective international study [61]. A single post-hoc study in patients enrolled in a controlled trial of rituximab suggested that the ESSDAI would be able to detect the treatment efficacy [62]. However, until now no study has been published using the ESSDAI or the ESSPRI as a primary endpoint. 4.2. B-Cell targeted therapies The understanding of the central role of B cells in the pathogeny of pSS in the recent years has led to several clinical trials of B-cell targeted therapies [63]. The most studied therapy to date is rituximab, a monoclonal antibody targeting CD20 and leading to transient blood B-cell depletion. Rituximab has been tested first in several open-label studies in pSS, which showed an improvement in sicca symptoms and extra-glandular manifestations after infusions [64e70]. Two small controlled studies confirmed its efficacy on fatigue and sicca symptoms, even if their primary endpoints were not met [71e73]. Two larger placebo-controlled double blind studies have been undertaken. The TEARS study (Tolerance and EfficAcy of Rituximab in

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primary Sjögren syndrome) in France, including 122 patients, has been recently completed, and its results are in press in Annals of Internal Medicine. Its primary endpoint (improvement of at least 30 mm on 2 of 4 visual analogic scales exploring global activity, fatigue, pain and dryness, between weeks 0 and 24) was not met, but several secondary evaluation criteria (single dryness or fatigue scores, salivary flow rate) were significantly improved in patients who received rituximab. The data suggest that, despite moderate improvement in both subjective and objective signs, the efficacy of rituximab in pSS is not sufficient to allow its prescription in a large population of patients. The ‘TRACTISS’ Study (Anti-B-Cell Therapy In Patients With Primary Sjögren’s Syndrome, ISRCTN65360827), in UK, is still recruiting [73]. A combined meta-analysis of the two studies is planned in order to determinate which subgroups of pSS patients are more likely to benefit from the treatment. Several other therapeutic ways are under the scope of clinical trials, targeting other B-cell surface proteins: the anti-CD22 epratuzumab [74], or major cytokines of B-cell homeostasis: BAFF [75], IL-6 (the ETAP study in France, NCT01782235), Lymphotoxin-beta (trial NCT01552681).

pathways, demographic features, responses to various therapies and prognosis. The development of “treat-to-target” strategies in pSS probably requires that the molecular mechanisms involved in the disease manifestations of individual patients are identified and adequately targeted. Thus, the development of a molecular taxonomy of pSS patients through the use of high-throughput molecular methods would be particularly interesting. A great effort has to be made in clinical research in order to define practical tools to recognize these different subsets of patients, to be able to propose the best treatments in each individual situation.

4.3. Co-stimulation inhibition

Competing interests

To become activated, CD4þ T cells not only need to recognize their specific antigen by their TCR, but also to receive complementary activating messages involving soluble factors (such as IL2) and membrane-bound protein interactions (notably CD28/ CD80-86 interaction). Abatacept, or CTLA4-Ig, is a fusion protein including the regulatory T-cell receptor CTLA4 and an IgG Fc fragment. CTLA4 has a strong affinity for CD80-86 and disrupts CD28/ CD80-86 interaction. Abatacept has been proven effective and is labeled for the treatment of RA [76]. An open-labeled study of abatacept in 11 pSS patients has been recently published [77]. This pilot study indicates that abatacept therapy may induce changes in lymphocyte subset balance in the blood and in the salivary glands, and suggest some clinical benefits. Another small open-labeled study is currently recruiting patients with either pSS associated with inflammatory arthritis or SS associated with RA, with a primary endpoint concerning joint evaluation (NCT02027298). 4.4. Mesenchymal stem cell therapy Mesenchymal stem cells (MSCs) are multipotent stem cells characterized by their capacity to differentiate into several cell lineages (osteoblasts, chondrocytes, adipocytes, neural cells.). They are numerous in the umbilical cord, and in adults they may be detected in the bone marrow, in fat tissue, and in dental pulp [78]. MSCs express low levels of MHC class I and lack expression of MHC class II surface molecules, and it is postulated that they could escape to allogenic immune system. Although the precise molecular mechanism remains unclear, several reports suggested a therapeutic potential of allogenic MSCs transplantation in inflammatory and autoimmune diseases such as Crohn’s disease [79], systemic sclerosis [80], and SLE [81]. Only one open-labeled study has been published in 24 patients with pSS and displayed spectacular clinical and biological results, including negativation of anti-SSA antibodies in a substantial number of patients [82]. However, no conclusions can be drawn about the efficacy of this therapy in the absence of controlled trials. 4.5. Personalized therapy pSS is a syndrome, which encompasses probably several subsets of patients with different genetic backgrounds, pathophysiological

5. Conclusions Recent years have seen striking progresses in the understanding and management of pSS. A great number of physicians and researchers worldwide challenge the difficulties encountered in this multifaceted disease, towards the ultimate goal of improving patients care and quality of life. We are at the eve of the development of efficient treatments, which will allow proposing to each patient a real personalized therapy.

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Sjögren's syndrome: where do we stand, and where shall we go?

Primary Sjögren's syndrome (pSS) is one of the most frequent autoimmune systemic diseases, mainly characterized by ocular and oral dryness due to the ...
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