sjögren syndrome sjögren syndrome sjögren syndrome or sjögren's syndrome (sjs, ss) is a long-term autoimmune disease that affects the body's moisture-producing (lacrimal and salivary) glands, and often seriously affects other organ systems, such as the lungs, kidneys, and nervous system. primary symptoms are dryness (dry mouth and dry eyes), pain and fatigue. other symptoms can include dry skin, vaginal dryness, a chronic cough, numbness in the arms and legs, feeling tired, muscle and joint pains, and thyroid problems. those affected are also at an increased risk (15%) of lymphoma. not to be confused with sjögren–larsson syndrome and marinesco–sjögren syndrome. sjögren's syndromeother namessjögren's syndrome, sicca syndromeimage with a microscope of focal lymphoid infiltration in the minor salivary gland associated with sjögren's syndrome.pronunciationuk: /ˈʃɜːɡrɛn/, us: /ˈʃoʊɡrɛn/swedish: specialtyimmunology, rheumatology symptomsdry mouth, dry eyes, other areas of drynesscomplicationslymphomausual onsetmiddle agedurationlong termcausesautoimmune disease (unknown cause)diagnostic methodtissue biopsy, blood testsdifferential diagnosismedication side effect, anxiety, sarcoidosis, amyloidosistreatmentartificial tears, medications to reduce inflammation, surgeryprognosisnormal life expectancyfrequency~0.7% while the exact cause is unclear, it is believed to involve a combination of genetics and an environmental trigger such as exposure to a virus or bacterium. it can occur independently of other health problems (primary sjögren's syndrome) or as a result of another connective tissue disorder (secondary sjögren's syndrome). sjögren's syndrome may be associated with other autoimmune diseases, including rheumatoid arthritis (ra), systemic lupus erythematosus (sle) or systemic sclerosis. the inflammation that results progressively damages the glands. diagnosis is by biopsy of moisture-producing glands and blood tests for specific antibodies. on biopsy there are typically lymphocytes within the glands. while sjögren's syndrome is one of the most common auto-immune diseases, it has no specific and non-invasive diagnostic tests and treatment is directed at managing the person's symptoms. for dry eyes, artificial tears, medications to reduce inflammation, punctal plugs, or surgery to shut the tear ducts may be tried. for a dry mouth, chewing gum (preferably sugar-free), sipping water, or a saliva substitute may be used. in those with joint or muscle pain, ibuprofen may be used. medications that can cause dryness, such as antihistamines, may also be stopped. the most specific extant diagnostic test requires lip biopsy. the disease was described in 1933 by henrik sjögren, after whom it is named; however, a number of earlier descriptions of people with the symptoms exist. between 0.2 and 1.2% of the population is affected, with half having the primary form and half the secondary form. it is around 10 times more common in women than in men. though the disease commonly begins in middle age, anyone can be affected. among those without other autoimmune disorders, life expectancy is unchanged. signs and symptoms characteristic dryness appears at multiple locations, such as the tongue, face, and eyes. marked at left are the salivary glands (which may be swollen), not a facial rash. the hallmark symptom of sjögren syndrome is dry mouth and keratoconjunctivitis sicca (dry eyes). vaginal dryness, dry skin, and dry nose may also occur. other organs of the body may also be affected, including the kidneys, blood vessels, lungs, liver, pancreas, and brain. skin dryness in some people with ss may be the result of lymphocytic infiltration into skin glands. the symptoms may develop insidiously, with the diagnosis often not considered for several years because sicca may be attributed to medications, a dry environment, or aging, or may be regarded as not of a severity warranting the level of investigation necessary to establish the presence of the underlying autoimmune disorder. sjögren's syndrome can damage vital organs, with symptoms that may plateau or worsen, or go into remission, as with other autoimmune diseases. some people may experience only the mild symptoms of dry eyes and mouth, while others have symptoms of severe disease. many patients can treat problems symptomatically. others experience blurred vision, constant eye discomfort, recurrent mouth infections, swollen parotid glands, dysphonia (vocal disorders including hoarseness), and difficulty in swallowing and eating. debilitating fatigue and joint pain can seriously impair quality of life. some patients can develop kidney involvement (autoimmune tubulointerstitial nephritis) leading to proteinuria (excess protein in urine), urinary concentrating defect, and distal renal tubular acidosis. hypokalemic paralysis due to primary sjögren syndrome was rarely reported in the literature. complications among the complications discussed above, women with anti-ro/ss-a and anti-la/ss-b antibodies who become pregnant have an increased rate of neonatal lupus erythematosus with congenital heart block requiring a pacemaker. type i cryoglobulinemia is a known complication of sjögren's syndrome. sjögren's syndrome can affect such organs as the liver, pancreas, kidneys, lungs, and central nervous system. associated conditions sjögren's syndrome is associated with a number of other medical conditions, many of which are autoimmune or rheumatic disorders, such as celiac disease, fibromyalgia, sle (lupus), autoimmune thyroiditis, multiple sclerosis and spondyloarthropathy, and several malignancies, principally non-hodgkin lymphoma. causes the cause of sjögren's syndrome is unknown, but it may be the influence of a combination of genetic, environmental, and other factors, as is the case with many other autoimmune disorders. around 20 autoantibodies could be involved. genetics the observation of high rates of autoimmune disorders in families with a history of sjögren's syndrome is linked with a genetic predisposition to the syndrome. studies on the polymorphisms of human leukocyte antigen (hla)-dr and hla-dq gene regions in sjögren's patients show differential susceptibility to the syndrome as the result of different types of the resulting autoantibody production. hormones since sjögren's syndrome is associated with a high prevalence in women, sex hormones, especially estrogen, are believed to affect humoral and cell-mediated immune responses affecting susceptibility to the syndrome. androgens are generally considered to prevent autoimmunity. studies on mice models suggest estrogen deficiency stimulates presentation of autoantigens, inducing sjögren's-like symptoms. microchimerism microchimerism of fetal cells (offspring lymphoid cells in maternal circulation) may generate autoimmunity in women who have previously been pregnant. generation of an autoimmune potential via microchimerism may lead to a switch from a silent form of autoimmunity with age-dependent decrease in self-tolerance. environment viral proteins, engulfed molecules, or degraded self-structures may initiate autoimmunity by molecular mimicry and increase the chances of sjögren's syndrome development. epstein–barr virus, hepatitis c, and human t-cell leukemia virus-1 are among the most studied infectious agents in sjögren's syndrome. to date, no direct causes and effect relationship has been identified between these pathogens and the development of sjögren's syndrome. damaged self-structures targeted for apoptosis may be mistakenly exposed to the immune system, triggering autoimmunity in exocrine glands, which are often prone to autoimmune responses. pathogenesis the pathogenetic mechanisms of sjögren's syndrome have not been fully elucidated, resulting in the lack of pathophysiology knowledge of the management of this autoimmune exocrinopathy. although the numerous factors contributing to the progression of this disease have made discovering the exact origin and cause difficult, major advances over the past decade have contributed to a proposed set of pathogenic events that occur prior to the diagnosis of sjögren's syndrome. sjögren's syndrome was originally proposed as a specific, self-perpetuating, immune system-mediated loss of exocrine glands, specifically acinar and ductal cells. although this explains the more obvious symptoms (such as the lack of saliva and lacrimal fluid), it does not explain the more widespread systemic effects seen in the progression of the disease. in the presence of a susceptible genetic background, both environmental and hormonal factors are thought capable of triggering the infiltration of lymphocytes, specifically cd4+ t cells, b cells, and plasma cells, causing glandular dysfunction in the salivary and lacrimal glands. sjögren's syndrome is associated with increased levels in cerebrospinal fluid (csf) of il-1ra, an interleukin 1 antagonist. this suggests that the disease begins with increased activity in the interleukin 1 system, followed by an autoregulatory upregulation of il-1ra to reduce the successful binding of interleukin 1 to its receptors. interleukin 1 likely is the marker for fatigue, but increased il-1ra is observed in the csf and is associated with increased fatigue through cytokine-induced sickness behavior. however, sjögren's syndrome is characterized by decreased levels of il-1ra in saliva, which could be responsible for mouth inflammation and dryness. patients with secondary sjögren's syndrome also often exhibit signs and symptoms of their primary rheumatic disorders, such as systemic lupus erythematosus, rheumatoid arthritis, or systemic sclerosis. genetic predisposition the genetic locus most significantly associated with primary ss is the major histocompatibility complex/human leukocyte antigen (mhc/hla) region, as demonstrated by the preliminary results of the first genome-wide association study. this study included data from a discovery cohort of 395 patients of european ancestry with primary sjögren's syndrome, and 1,975 healthy control individuals, and from a replication study that comprised 1,234 cases and 4,779 healthy controls. associations with polymorphisms located at six independent loci were also detected; irf5, stat4, blk, il12a, tnip1, and cxcr5. this also suggested the activation of the innate immune system, notably through the ifn system, b-cell activation through cxcr5-directed recruitment to lymphoid follicles and b-cell receptor (bcr) activation involving blk, and t-cell activation owing to hla susceptibility and the il-12-ifn-γ-axis. patients of different ethnic origin carry different hla-susceptibility alleles, of which hla-dr and hla-dq are involved in the pathogenesis of sjögren's syndrome. for example, patients from northern and western europe and from north america show a high prevalence of b8, drw52, and dr3 genes. hla class ii alleles are associated with the presence of specific subsets of autoantibodies, rather than with the disease itself. autoantibodies refer to the loss of b-cell tolerance leading to production of antibodies directed against diverse organ-specific and organ nonspecific antigens. association between hla and ss is restricted to patients with anti-ssa/ro or anti-ssb/la antibodies. seropositivity for anti-ro and anti-la is associated with greater severity and longer duration of disease, and findings of their high abundance from the salivary glands of sjögren's patients suggests their imperative role in the pathogenesis of ss. beyond genetics, epigenetic abnormality related to dna methylation, histone acetylation, or microrna expression probably has a key role in the pathogenesis of autoimmune diseases, including sjögren's syndrome, though research in this area is very limited. environmental triggers environmental factors, such as glandular viral infection, could prompt epithelial cells to activate the hla-independent innate immune system through toll-like receptors. although a number of infectious, exogenous agents have been implicated in the pathogenesis of sjögren's syndrome, such as epstein-barr virus (ebv), human t-lymphotropic virus 1, and hepatitis c virus, their association with sjögren's syndrome appears weak. while ebv is present in the salivary glands of normal individuals, a high incidence of ebv reactivation in sjögren's patients has been reported with increased levels of ebv dna. this indicates viral reactivation and inability of lymphoid infiltrates to control ebv replication in sjögren's syndrome, leading to the initiation or perpetuation of an immune response in target organs. nonetheless, exactly how reactivation of ebv is induced in lesions of patients with sjögren's syndrome, and which specific molecular mechanisms are involved in the process of viral reactivation, remain to be clarified. inflammation epithelial cells in sjögren's syndrome lesions are active participants in the induction and perpetuation of the inflammatory process. environmental and hormonal factors, in concert with an appropriate genetic background, are believed to trigger sjögren's syndrome, which dysregulates epithelial cells and allows aberrant homing and activation of dendritic cells (dcs), t cells, and b cells. dendritic cells are antigen-presenting cells that process antigen material and present it to other t cells. following the migration of lymphocytes into the glands in response to chemokines and specific adhesion molecules, t cells interact with epithelial cells. epithelial cells are further activated by proinflammatory cytokines (il-1β, ifn-γ, and tnf), which are produced by adjacent t cells. the early accumulation of plasmacytoid dendritic cells in the target tissues, which produce high levels of type 1 ifns, seems important, as these cells can further dysregulate the immune response through abnormal retention of lymphocytes in the tissues and their subsequent activation. ifn-α stimulates the production of b-cell activating factor (baff) by epithelial cells, dcs, and t cells. baff stimulates aberrant b-cell maturation, leading to the emergence of self-reactive b cells, which locally produce autoantibodies, in a germinal centre-like structure (gc-like), which is also the location of lymphomagenesis (origin of lymphoma). programmed cell death dysregulation of apoptosis (programmed cell death) is believed to play a role in the pathogenesis of a variety of autoimmune diseases, though its role in sjögren's syndrome is controversial. both the fas and fas ligand proteins are overexpressed in primary sjögren's