Primary Sjögren's syndrome is a complex autoimmune rheumatic disease characterized by mononuclear cell infiltration of exocrine tissues and the presence of autoantibodies against the ribonucleoprotein particles SS-A/Ro and SS-B/La. The salivary and lacrimal glands are the principal targets of a proposed T-cell mediated chronic inflammation, with a resulting glandular atrophy and deficient function. The clinical consequences are dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia). Owing to affection of also other organs there is a number of systemic features of Sjögren's syndrome. See also Inflammation: Chronic
One of the enigmas in this directed autoimmune attack has been the mechanisms responsible for the formation of mononuclear cell accumulations in exocrine glands. It has been hypothesized that primary events (e.g. infections) may occur in the glands themselves, followed in a second phase by an autoimmune attack. Whether B-cell activation is a primary cause or a secondary effect in Sjögren's syndrome is not known.
Among the possible aetiologic and triggering factors involved in Sjögren's syndrome, a discussion about viral infections causing development of autoimmune reactions has been ongoing for decades. Viral triggers might include a number of viruses including EpsteinBarr virus, widely studied in relation to Sjögren's syndrome (James et al., 2001). However, the progress in this field has been slow and no clear-cut evidence has been provided. A genetic predisposition to Sjögren's syndrome has also been suggested (Bolstad and Jonsson, 2002) but the combination with a link to an environmental trigger remains to be defined (Figure 1). See also Autoimmune Disease, Autoimmune Disease: Aetiology and Pathogenesis, and EpsteinBarr Virus
|Figure 1. Proposed aetiopathogenic events before diagnosis of Sjögren's syndrome.|
Historic overview and some milestones
The syndrome has its name after Henrik Sjögren, a Swedish ophthalmologist who in his classical doctoral dissertation from 1933, reported detailed clinical and histological findings in 19 women with xerostomia and keratoconjunctivitis sicca, of whom 13 had chronic arthritis. However, before that between 1882 and 1924, a number of case reports described Sjögren's syndrome with various combinations of dry mouth, dry eyes and chronic arthritis. In 1892, Mikulicz reported a man with bilateral parotid and lacrimal gland enlargement associated with massive round cell infiltration. Gourgerot, in 1925, described three patients with salivary and mucous gland atrophy and insufficiency and in 1927 Mulock Houwer reported the association of filamentary keratitis, the major ocular manifestation of the syndrome, with chronic arthritis.
Subsequently, in 1953, Morgan and Castleman established that Sjögren's syndrome and Mikulicz disease were the same entity. The link between Sjögren's syndrome and malignant lymphoma was described in a classic article in 1964 (Talal and Bunim, 1964). The distinction between primary and secondary Sjögren's syndrome was suggested in 1965 (Bloch et al., 1965) and the Sjögren's syndrome-associated autoantibodies (Ro/SSA) in sera were described in 1969 (Clark et al., 1969). From the diagnostic point of view, the first histologic grading assessing the infiltration of labial glands was described in 1968 (Chisholm and Mason, 1968). A set of preliminary classification criteria was identified by a European Concerted Action in 1993, which has been widely accepted and also modified in 2002 (Vitali et al., 2002).
The hallmarks of Sjögren's syndrome are the sicca symptoms from the eyes and mouth. Dryness of the eyes may be experienced as a gritty sensation, soreness or intolerance to contact lenses. Dryness of the mouth may give rise to difficulties in the swallowing of dry foods without fluid, and need for frequent small sips of water, also at night. Loss of the protective and antimicrobial properties of saliva may increase dental caries and predispose for oral candidiasis. In addition, patients may have other symptoms related to dryness of the mucosal membranes or skin, for instance nasal crusts and nose bleeds, hoarseness and speaking problems, difficulties in swallowing, halithosis, reduced sense of smell and taste, dry cough, intermittent parotid or submandibular swelling and dyspareunia. Dry skin and dry hair are common symptoms among Sjögren's syndrome patients.
Sjögren's syndrome is also a systemic disease. Many patients have problems with fatigue and joint and muscular pain, and unspecific neurological complaints. Less common extraglandular affections are arthritis which is usually non-erosive, Raynaud phenomenon, skin vasculitis, lymphadenopathy, serositis, pulmonary fibrosis, symptoms from the central nervous system and renal tubular acidosis. Co-morbidity in the form of thyroid diseases may occur in up to one-third of the patients (Brun et al., 2002; Pertovaara et al., 2001; Skopouli et al., 2000; Haldorsen et al., 2007). See also Chronic Fatigue Syndrome, and Immune Vasculitis
A reduced exocrine function or sicca symptoms may be caused by a variety of conditions and may be age related. Evidence of autoimmunity as outlined in the American-European Consensus Group criteria (AECC) (Vitali et al., 2002) helps distinguish Sjögren's syndrome from these other conditions. The AECC is increasingly used as a guidance or help also for the clinical diagnosis of Sjögren's syndrome. In the AECC four of six criteria are needed for a diagnosis. At least one of these four must be autoantibodies or a positive biopsy (Figure 2).
|Figure 2. American-European Concensus Group Criteria. For details see Vitali et al. (2002).|
Reduction of tear flow may be assessed by the Schirmer test, a measurement of the wetting during 5 min of a 30-mm filter strip placed over the brim of the lower eye lid. Less than 5 mm of wetting is considered abnormal. Sicca symptoms of the eye may also be caused by changes of the physicochemical properties or quality of the tears, for which the tear film break up time is indicative. The number of corneal abrasions is yet another measure of dry eyes (Vitali et al., 2002).
Dryness of the mouth may be related to saliva production, which is measured by the unstimulated salivary flow rate. The patient is asked to collect all of the saliva produced during 15 min into a vial. A volume of less than 1.5 mL is considered abnormal (Vitali et al., 2002).
The most definitive test is a biopsy of the minor salivary glands from the inside of the lower lip. If histology shows one or more mononuclear cell aggregates of 50 or more cells per 4 mm
Autoantibodies to the SSA or SSB antigens are also strongly indicative of Sjögren's syndrome, although they may be found in other systemic diseases like systemic lupus erythematosus (SLE). More than 50% of Sjögren's syndrome patients have one or more of these autoantibodies. Laboratory testing may also show that some patients have an increased erythrocyte sedimentation rate, and polyclonal hypergammaglobulinaemia and rheumatoid factors may also be found.
The clinical examination may reveal a dry and lobulated tongue, fissures in the corners of the mouth, dry skin and in some cases parotid or submandibular swelling, lymphadenopathia, palpable purpura especially of the lower extremities and arthritis. See also Autoimmune Disease: Diagnosis
Current therapy includes topical products like tear and saliva substitutes that help alleviate sicca symptoms and preserve the integrity of the cornea, as well as the gums and teeth. Pilocarpine hydrochloride helps stimulate residual salivary secretion in some patients. Local estrogens may be used for genital dryness and skin ointments for dry skin.
Nonsteroidal anti-inflammatory drugs and antimalarials may be used for arthralgias or mild arthritis. The fatigue and myalgia of Sjögren's syndrome is usually not responsive to pharmaceutical treatment. More severe cases with high inflammatory activity, system or organ involvement or erosive arthritis may be treated with immunomodulatory drugs and corticosteroids in analogy with the manner in which patients with SLE or rheumatoid arthritis (RA) are treated. Various biological treatments have been studied in small groups of Sjögren's syndrome patients. The results of anti-tumour necrosis factor (TNF) treatment have been disappointing, whereas results with B-cell depletion with anti-CD20 treatment (rituximab) warrant further investigation (Isaksen et al., 2008). See also Autoimmune Disease: Treatment
Frequency and Clinical Importance
Classification and epidemiology
As with many of the systemic rheumatic diseases, the diagnosis of Sjögren's syndrome cannot be readily made, for instance, on the basis of a single test or symptom. Classification criteria with a list of well-defined clinical and laboratory variables are an alternative method of securing uniform patient populations for research purposes. During the past three decades various national and international groups have developed multiple criteria sets for Sjögren's syndrome, giving rise to differing research results and epidemiological data.
After a thorough process of validation and re-validation the criteria proposed by the European Study Group were further developed and amended by European and American experts. The resulting AECC for Sjögren's syndrome published in 2002 (Vitali et al., 2002) has gained a wide acceptance and they are also increasingly used as a guidance for the clinical diagnosis of the syndrome. In addition to sicca symptoms from the eyes or mouth and measurements of a decreased exocrine function, evidence of autoimmunity is required, either as shown by autoantibodies to SSA or SSB, or by a positive biopsy of the minor salivary glands of the lower lip, with a focus score of one or more (Figure 2 and Figure 3).
Sjögren's syndrome is found in all parts of the world. Regional differences have not been studied much. There is a large female preponderance with a ratio of female:male of approximately 9:1. The disease is found in all age groups but usually starts between the age 40 and 60 and is rarely seen in children and adolescents. In parallel with the increase of sicca symptoms with age in the background population, the prevalence of Sjögren's syndrome also increases with age (Haugen et al., 2008). Often there is a several-year delay from the start of symptoms to diagnosis.
As a consequence of different criteria Sjögren's syndrome prevalence estimates have varied widely, with some studies reporting up to 3% of the population. Recent studies based on the American-European criteria show prevalences of approximately 0.1% with confidence intervals in the range <0.10.4% (Bowman et al., 2004; Alamanos et al., 2006). There are few studies on the incidence of Sjögren's syndrome but according to the new criteria the incidence rate is probably between 3 and 6 per 100 000 per year.
In addition to female, first grade relatives with an autoimmune disease and previous pregnancies have been identified as epidemiological risk factors for the development of Sjögren's syndrome (Priori et al., 2007).
Secondary Sjögren's syndrome
Secondary Sjögren's syndrome is the occurrence of aspects of Sjögren's syndrome in conjunction with other autoimmune systemic diseases like RA or SLE. Classification criteria have been developed (Figure 2). The most common primary disease is RA, with a prevalence of secondary Sjögren's syndrome of 1030% (Brun et al., 1994; Uhlig et al., 1999). See also Rheumatoid Arthritis, and Systemic Lupus Erythematosus
Malignancy, mortality and prognosis
Non-Hodgkin lymphoma which may be of the mucosa-associated lymphoid tissue (MALT) type occurs at an increased rate in Sjögren's syndrome. Previous estimates of more than 40-fold increase may have been too high, as a recent large linked registry-based study showed a 16-fold increased risk (Theander et al., 2006). Palpable purpura, low levels of C3 and C4, CD4+ lymphopenia, a low CD4+/CD8+ T cell ratio and parotid enlargement at first visit are presently identified as predictive factors for lymphoma in Sjögren's syndrome (Theander et al., 2006; Ioannidis et al., 2002). See also Leukaemias and Lymphomas, and Non-
With the exception of lymphoma, Theander et al., in two large Swedish prospective cohort studies (2004 and 2006) found no increased mortality or cancer incidence in Sjögren's syndrome (Theander et al., 2004).
Regarding the exocrine function, most Sjögren's syndrome patients experience a decreased but rather stable tear and saliva production over the disease course (Kruize et al., 1997; Haldorsen et al., 2007), reflecting that the major loss of exocrine function probably takes place at a very early stage of the disease (Pijpe et al., 2007; Figure 1). However, a high focus score initially may be predictive of progression of functional loss also in established Sjögren's syndrome (Haldorsen et al., 2007).
Pathophysiology of Sjögren's Syndrome
The lymphoepithelial lesion and lymphoid neogenesis
The pathognomic histological finding in glandular biopsies is a progressive focal infiltration of mononuclear lymphoid cells, replacing glandular epithelium (lymphoepithelial lesion) (Figure 3). This correlates largely to the reduced salivary secretion. However, the mechanisms leading to attraction and accumulation and the biological role of the infiltrating cells remain undefined. The infiltrating cells interfere with glandular function at several levels: destruction of glandular structures by cell-mediated mechanisms, secretion of cytokines that activate pathways related to interferons (IFNs), local production of autoantibodies, etc.
The focal infiltration consists not only of T cells, but also macrophages and plasma cells. Ordinarily, lymphocytes circulate in the blood and invade the tissue as a response to infection or injury. This is a complex process regulated by a range of adhesion molecules on the inflammatory cell surface and the tissue endothelium cells. The lymphocytes adhere to the endothelium by means of adhesion molecules and can move from circulation to tissue. Interestingly, serum levels of an adhesion molecule related to epithelial cells, E-cadherin, have been found to be increased in Sjögren's syndrome indicating the close interaction between epithelial cells and lymphocytic organization.
Recent studies have identified germinal centre-like structures (Figure 3) that could be identified in up to 1/3 of salivary gland samples (Jonsson et al., 2005) and coincided with elevated titres of rheumatoid factor, other autoantibodies, increased IgG (immunoglobulin G) levels and higher focus score. The results nevertheless suggest that formation of ectopic lymphoid microstructures in nonlymphoid organs participate in the pathogenesis. Involvement of salivary glands as a site of ectopic germinal centre formation and selection of high-affinity autoantibodies (Tengnér et al., 1998) mediating this autoimmune state suggest novel targets for future immunomodulatory therapeutic strategies.
Cytokines and chemokines
Although a number of studies have investigated cytokines that seem to be involved in the pathogenesis of Sjögren's syndrome, reports on cytokine polymorphisms are limited and do not allow any firm conclusion. Despite the interaction between epithelial cells and infiltrating T cells has been characterized in some detail, the cytokines involved in local B-cell activation remain largely unknown.
Patients with primary Sjögren's syndrome have an activated type I IFN system (Båve et al., 2005). Although virus may initiate the production of IFN, the continued IFN synthesis is caused by ribonucleic acid (RNA)-containing immune complexes that activate plasmacytoid dendritic cells to prolong IFN production at the tissue level (Båve et al., 2005). The finding that U1 snRNA (small nuclear RNA) and hY1RNA have IFN-inducing capacity indicates that immune complexes containing such RNA can be at least partly responsible for the ongoing IFN production seen in Sjögren's syndrome (Lövgren et al., 2006). The activation of IFN pathways and presence of plasmacytoid dendritic cells was also verified in a subsequent study (Gottenberg et al., 2006) and supports the notion that interaction between the innate and the adaptive immune systems is central in the pathogenesis of Sjögren's syndrome.
Accordingly, the infiltration of lymphocytes into glandular aggregates has a central role in the tissue pathology of Sjögren's syndrome. This process seems to be tightly regulated at least in part by chemokines and the local expression of their receptors. Studies on chemokine patterns have pointed further to the role of epithelial cells in the pathogenesis of Sjögren's syndrome (Xanthou et al., 2001; Ogawa et al., 2002). This offers new insight into the mechanisms of leukocyte attraction and formation of secondary lymphoid tissue structures. In particular the B-cell attracting chemokine CXCL13, required for normal polarization of germinal centres, has been implicated as a key regulator of lymphoid neogenesis. However, the chemokines CXCL13, CCL21 and CXCL12 do not display any typical pattern for germinal centre formation in situ (Salomonsson et al., 2003).
B-cell activating factor (BAFF) is a member of the TNF superfamily and a crucial factor in B-cell survival and differentiation. In Sjögren's syndrome, disturbances in the B-cell biology and humoral immunity including BAFF-mediated processes have been described (Szodoray and Jonsson, 2005). Locally in the glands, a reduced level of apoptosis among BAFF-expressing cells might lead to longer-existing BAFF production and thereby maintaining signalling for tissue-infiltrating B cells to proliferate and supposedly to become autoantibody-producing plasma cells. Altogether, the activity in the BAFF system together with the IFN pathway activity could be powerful systems escalating the progression and perpetuation of autoimmunity in Sjögren's syndrome.
Another molecule of the same family a proliferation-inducing ligand (APRIL) has been found to be increased in serum and related to serological deviations and lymphoid organization in the salivary glands of Sjögren's syndrome patients (Jonsson et al., 2005).
Recent multiplex cytokine screenings of patients with Sjögren's syndrome have additionally identified interesting cytokine profiles that correlate with organization of the lymphoid aggregates. Germinal centre positive patients had higher serum levels of IL-4, IL-17, IL-1 and the IL-23 subunit IL-12p40 (Reksten et al., 2009). Exploration with discriminant function analysis has revealed that the biomarkers having the strongest discriminatory power were CCL11 (eotaxin), IFN and BAFF (Szodoray et al., 2005).
B cells and autoantibodies
Despite the dominance of T cells in the glandular lesions, Sjögren's syndrome is considered to be a humoral (B-cell) driven autoimmune disease (Jonsson et al., 2007). The cells of the immune system work in concert with other immune competent cells and the surrounding epithelial cells may be involved in the disease mechanism, but still the B cells have a prominent role in this disease (Figure 4). This view is based on serum hypergammaglobulinaemia, autoantibodies, rheumatoid factor, focal B-cell infiltrations and, in some cases, the development of B-cell lymphoma (non-Hodgkin lymphoma). See also B Lymphocytes
|Figure 4. Microscopical view of local production of antigen-specific autoantibodies in minor salivary glands in Sjögren's syndrome. For further details see Tengnér et al. (1998).|
A characteristic feature in both primary and secondary Sjögren's syndrome patients is the presence of circulating autoantibodies against the nonorgan-specific Roribonucleoprotein (RNP) complex. The RoRNP complexes consist of both cytoplasmic RNA (hYn), Ro and La, and other polypeptides (Pruijn et al., 1997; Fabini et al., 2000). The cellular function of these RoRNP complexes is most likely to be involved in posttranslational modification and regulation. Consequently, anti-Ro and anti-La autoantibodies have become important markers in the classification criteria for SS (Vitali et al., 2002).
Depending on the method used for detection and the referral bias of the centre performing the study, the detected frequencies of anti-Ro and anti-La vary greatly. A frequency of approximately 70% of anti-Ro and 40% of anti-La is within the commonly accepted range.
Whether these antibodies have a direct pathological effect is not known, but they have been found to be associated with specific symptoms such as sicca complaints, hypergammaglobulinaemia, lymphopenia, congenital heart block and severe salivary gland disease. There exists some evidence that strongly supports a direct pathological role of anti-Ro autoantibodies. In neonatal lupus, maternal anti-Ro IgG crosses the placenta and deposit in the fetal myocardium, causing congenital heart block and skin lesions as the major symptoms (Buyon et al., 1997; Salomonsson et al., 2005). There is no direct connection between these autoantibodies and Sjögren's syndrome, but anti-Ro52, anti-Ro60 and anti-La48 producing plasma cells have been identified in the salivary glands (Halse et al., 1999) and an increased concentration of autoantibodies is detected in SS patients (Halse et al., 2000). Other reports suggest that anti-Ro RNP may form complexes causing an ongoing IFN production in Sjögren's syndrome and SLE (Rönnblom et al., 2006).
However, there are differences in anti-Ro and anti-La antibodies in primary Sjögren's syndrome and healthy subjects. The autoantibody concentrations were generally higher in sera from Sjögren's syndrome patients and posses a more heterogeneous autoantibody repertoire then healthy subjects with regard to the number of autoantigens and antibody isotypes (Garberg et al., 2005).
In some patients even a correlation between the disease activity and the autoantibody titre has been detected (Wahren et al., 1998). The specific immunoglobulin level was higher under exacerbation than under remission, and the specific anti-Ro and anti-La48 immunoglobulin may contribute to a larger fraction of the total serum immunoglobulin level. Hypergammaglobulinaemia (>15.3 g L
Molecular findings gene expression profiling
Recently, microarray has been introduced as a tool in Sjögren's syndrome research. Patient's salivary gland biopsies (Hjelmervik et al., 2005; Gottenberg et al., 2006) have been subjected to microarray analysis. This approach has given us a broader and a more complete picture of the repertoire of molecules that are in action simultaneously during autoimmune inflammation. As already alluded to, IFN and IFN inducible genes are of major interest in studies of Sjögren's syndrome disease mechanisms whose importance has been underscored by microarray studies (Båve et al., 2005; Hjelmervik et al., 2005; Gottenberg et al., 2006; Nordmark et al., 2006). Of particular interest are also the chemokines involved in B- and T-cell activation, responsible for attracting the cells of defence to the inflammatory battle field. Findings were related to the lymph node homing chemotactic receptor CCR7 and its ligands CCL19 and CCL21, as well as CXCL10 that binds to the CXCR3 receptor expressed on activated T cells, to be upregulated in salivary glands of Sjögren's syndrome (Hjelmervik et al., 2005).
Except for the T-cell receptor locus beta, the lymphotoxin (LT) was the highest upregulated gene in salivary glands of Sjögren's syndrome in the study by Hjelmervik et al. (2005). Its receptor, LTR, plays an important role in regulating lymphoid microenvironments. LT and LT form a ligand complex that is tethered to the membrane through the LT transmembrane domain, forming LT
By microarray analysis of salivary glands of SS patients it was also demonstrated that an upregulation of CXCL13 which is associated with B-cell recruitment (Hjelmervik et al., 2005), and of the inflammatory chemokine CCL5 (RANTES), associated with lymphoid homing. CXCL13 is expressed both on ductal and acinar epithelia and binds to CXCR5 on B cells. CXCL13 was found almost exclusively in patients, and also the CXCL13CXCR5 interaction to be absent in salivary glands from normal individuals.
Gene expression analysed by microarray is based on mRNA (messenger RNA) expression levels, and is a reflection of what a cell can do, and not what it has done, with respect to the protein level. The final product is the protein. The post-genomic era time has come for retrieving the function of the expressed proteins, the proteome. Proteomics can be defined as the systematic analysis of proteins for their identity, quantity and function. Technology for large-scale protein analysis has been developed. Proteome analysis is most commonly accomplished by the combination of two-dimensional gel electrophoresis (2DE) and mass spectrometry (MS).
Until now, reports where proteomics in Sjögren's syndrome have been applied are scarce. However, SELDI-TOF-MS has been used to identify biomarkers in parotid saliva (Ryu et al., 2006) and MS/MS for proteome analysis of parotid glandular tissue (Stea et al., 2007) and minor glands (Hjelmervik et al., 2009). The proteomic profile of saliva from Sjögren's syndrome patients was a mixture of increased inflammatory proteins and decreased acinar proteins, and proteomics of saliva has to be further refined (Ryu et al., 2006). Tear proteomic patterns have also been suggested as a potential noninvasive diagnostic tool for the disease, but this approach is so far only of experimental nature.
The genetic component of Sjögren's syndrome
Sjögren's syndrome is a disease with complex genetic background, where multiple genes are responsible for the genetic influence on disease development. The strongest association is with HLA-DR3. The immune response genes are more strongly linked to autoantibody specificity than to disease itself. See also Autoimmune Disease: Genetics, Major Histocompatibility Complex: Disease Associations, and Major Histocompatibility Complex: Human
Genetic studies of Sjögren's syndrome suffer from lack of twin studies, which could confirm the hereditability of the disease. Although valuable, most studies on candidate genes have been performed on small cohorts, and have not been successfully reproduced in patients with different ethnic background (Bolstad and Jonsson, 2002). There are reports of polymorphisms associated with Sjögren's syndrome for instance in the genes encoding IL-1Ra, IL-6, IL-10 that could not be confirmed by others. Similarly, associations between Sjögren's syndrome and polymorphisms in genes encoding TGF, TAP-2, SSA1 and CCR5 have been found by some, but could not be confirmed by others. In conclusion, regarding genetic studies there is a need for research groups to come together, enabling collection of larger and ethnic homogenous patient cohorts.
Many aspects regarding the aetiology and pathogenesis of Sjögren's syndrome are still a matter of speculation although several hypotheses have been tested (Figure 5). A possible scenario is that an initial viral infection induces type I IFN production in exocrine glands with a subsequent activation of the adaptive immune system. A number of autoantibodies forming nucleic acid-containing immune complexes can trigger prolonged type I IFN production with a self-perpuating autoimmune reaction. Accordingly, B-cell activation is a consistent immunoregulatory abnormality in Sjögren's syndrome occasionally culminating in malignant lymphoproliferation.
|Figure 5. Schematic representation of current views of the aetiopathogenesis of Sjögren's syndrome. Adapted from Price and Venables (1995), with permission from Elsevier.|
A challenge in Sjögren's syndrome will be to stratify the disease process including genetic and environmental triggers (Figure 1). A similar challenge will be to sort all molecular data to be generated through array technology. Identification of molecular markers and characterization of novel autoantibodies may lead to the development of targeted molecular therapy in Sjögren's syndrome including its extra-glandular and systemic complications. The application of recent breakthroughs in high-throughput molecular profiling technologies (e.g. microarray) has been the basis for a revolution in molecular medicine. We can envision such approaches for improved diagnosis and therapy also in Sjögren's syndrome.