Sjögren's syndrome

From Wikipedia, the free encyclopedia
  (Redirected from Sjogren's syndrome)
Jump to: navigation, search
Not to be confused with Sjögren–Larsson syndrome, a skin disorder.
"SS-B" redirects here. For further association of the term, see Anti-nuclear antibody.
Sjögren syndrome
Sjogren syndrome (2).jpg
Histopathologic image of focal lymphoid infiltration in the minor salivary gland associated with Sjögren's syndrome, lip biopsy, H & E stain
Classification and external resources
Specialty Rheumatology
ICD-10 M35.0
ICD-9-CM 710.2
OMIM 270150
DiseasesDB 12155
MedlinePlus 000456
eMedicine med/2136 emerg/537 derm/846 ped/2811 oph/477 oph/695
Patient UK Sjögren's syndrome
MeSH D012859

Sjögren's syndrome or Sjögren syndrome (pronounced /ˈʃɡrn/ or /ˈʃɜːrɡrɛn/[1] in English, the latter to approximate the Swedish pronunciation [ˈɧøːɡreːn]) is a chronic autoimmune disease in which the body's white blood cells destroy the exocrine glands, specifically the salivary and lacrimal glands, that produce saliva and tears, respectively.[2] The immune-mediated attack on the salivary and lacrimal glands leads to the development of xerostomia (dry mouth) and keratoconjunctivitis sicca (dry eyes), which takes place in association with lymphocytic infiltration of the glands.[3] That inflammatory process eventually severely damages or destroys the glands.

Sjögren’s syndrome is usually classified as either 'primary' or 'secondary'. Primary Sjögren’s syndrome occurs by itself and secondary Sjögren’s syndrome occurs when another connective tissue disease is present. However, this classification does not always correlate with the severity of symptoms or complications. Primary and secondary Sjögren’s syndrome patients can all experience the same level of discomfort, complications, and seriousness of their disease.

Signs and symptoms[edit]

The hallmark symptom of Sjögren's syndrome is a generalized dryness, typically including xerostomia and keratoconjunctivitis sicca, part of what are known as sicca symptoms. Sicca syndrome also incorporates vaginal dryness and chronic bronchitis. Sjögren's syndrome may cause skin, nose, and vaginal dryness, and may affect other organs of the body, including the muscles (myositis), kidneys, blood vessels, lungs, liver, biliary system, pancreas, peripheral nervous system (distal axonal sensorimotor neuropathy or small fiber peripheral neuropathy) and brain. Many patients have gastric issues such as GERD or gastroparesis.

Skin dryness in some Sjögren's patients 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 the complaints of sicca may be otherwise attributed to medications, a dry environment, aging, or may be regarded as not of severity warranting the level of investigation necessary to establish the presence of the specific underlying autoimmune disorder condition.[4]

Sjögren's syndrome can damage vital organs of the body with symptoms that may plateau or worsen, or go into remission as with other autoimmune diseases.[28] 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 are forced to cope with blurred vision, constant eye discomfort, recurrent mouth infections, swollen parotid glands, hoarseness, and difficulty in swallowing and eating. Debilitating fatigue and joint pain can seriously impair quality of life. Some patients can develop renal involvement (autoimmune tubulointerstitial nephritis) leading to proteinuria, urinary concentrating defect, and distal renal tubular acidosis.


Although the cause of Sjögren’s syndrome is unknown, it is believed to be under the influence of a combination of genetic, environmental, and several other factors, as is the case with many other autoimmune disorders.[2]

Genetic factors[edit]

The observation of high prevalence of autoimmune disorders in families of Sjögren’s syndrome is linked with a genetic predisposition to the syndrome.[5] Studies on the polymorphisms of human leukocyte antigen (HLA)-DR and HLA-DQ gene regions in Sjögren’s syndrome patients show differential susceptibility to the syndrome due to different types of the resulting autoantibody production.[5]

Hormonal factors[edit]

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.[5] Androgens are generally considered to prevent autoimmunity.[6] Studies on mice models suggest estrogen deficiency stimulates presentation of autoantigens, inducing Sjögren’s syndrome-like symptoms.[5]

Microchimerism factors[edit]

Microchimerism of fetal cells (offspring lymphoid cells in maternal circulation) may generate autoimmunity in women who have been previously pregnant.[6][7] 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.[6]

Environmental (exogenous) factors[edit]

Viral proteins, engulfed molecules, or degraded self-structures may initiate autoimmunity by molecular mimicry and increase the chances of Sjögren’s syndrome development.[6] Epstein-Barr virus, hepatitis C, and human T-cell leukemia virus-1 are among the most studied infectious agents in Sjögren’s syndrome.[6] 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.[6]


Diagnosing Sjögren's syndrome is complicated by the range of symptoms a patient may manifest, and the similarity between symptoms of Sjögren's syndrome and those of other conditions. Also, patients who have symptoms of Sjögren's syndrome approach different specialities regarding their symptoms which make the diagnosis difficult. Since the symptoms of this autoimmune disorder such as dry eyes and dry mouth are very common among people, and mostly observed from the age of 40 and above, it is often mistaken as age-related, thus ignored. However, some medications can also cause symptoms that are similar to those of Sjögren's syndrome. The combination of several tests, which can be done in a series, can eventually lead to the diagnosis of Sjögren's syndrome.[8][9]

In 2014, The Sjögren's Syndrome Foundation announced a five-year goal to cut the time to diagnoses in half.[10][full citation needed]

Blood tests can be done to determine if a patient has high levels of antibodies that are indicative of the condition, such as antinuclear antibody (ANA) and rheumatoid factor (because SS frequently occurs secondary to rheumatoid arthritis), which are associated with autoimmune diseases. Typical Sjögren's syndrome ANA patterns are SSA/Ro and SSB/La, of which SSB/La is far more specific; SSA/Ro is associated with numerous other autoimmune conditions, but are often present in Sjögren's. However, SSA and SSB tests are frequently not positive in Sjögren's syndrome.

The rose bengal test measures state and function of the lacrimal glands. This test involves placing the nontoxic dye rose bengal on the eyes. The dye’s distinctive colour helps in determining the state and functioning of tear film and the rate of tear evaporation. Any distinctive colour change observed will be indicative of Sjögren's syndrome, but many related diagnostic tools will be used to confirm the condition of Sjögren's syndrome.[11]

Schirmer's test measures the production of tears: a strip of filter paper is held inside the lower eyelid for five minutes, and its wetness is then measured with a ruler. Producing less than 5 mm (0.20 in) of liquid is usually indicative of Sjögren's syndrome. This measurement analysis varies among patients depending on other eye-related conditions and medications they are on when the test is taken.[11] A slit-lamp examination can reveal dryness on the surface of the eye.

Symptoms of dry mouth and dryness in the oral cavity are caused by the reduced production of saliva from the salivary glands (parotid gland, submandibular gland, and sublingual gland). To check the status of salivary glands and the production of saliva, a salivary flow rate test is performed. Here, the patient is asked to spit as much as he or she can into a cup, and the resulting saliva sample is collected and weighed. This test's results can determine whether the salivary glands are functioning adequately. Not enough saliva produced could mean the patient has Sjögren's syndrome.[11] An alternative test is nonstimulated whole saliva flow collection, in which the patient spits into a test tube every minute for 15 minutes. A resultant collection of less than 1.5 ml (0.053 imp fl oz; 0.051 US fl oz) is considered a positive result.[12]

A lip/salivary gland biopsy can reveal lymphocytes clustered around salivary glands, and damage to these glands due to inflammation. This test involves removing a sample of tissue from the patient’s inner lip/salivary gland and examining it under a microscope. In addition, a sialogram, a special X-ray test, is performed to see if any blockage is present in the salivary gland ducts (i.e. parotid duct) and the amount of saliva that flows into the mouth.[11]

Also, a radiological procedure is available which is a reliable and accurate test for Sjögren's syndrome. A contrast agent is injected into the parotid duct, which opens from the cheek into the vestibule of the mouth opposite the neck of the upper second molar tooth. Histopathology studies should show focal lymphocytic sialadenitis. Objective evidence of salivary gland involvement is tested through ultrasound examinations, the level of unstimulated whole salivary flow, a parotid sialography or salivary scintigraphy. Autoantibodies against Ro (SSA) and/or La (SSB) antigens are also expected.

SS can be excluded from people with past head and neck radiation therapy, acquired immunodeficiency syndrome, pre-existing lymphoma, sarcoidosis, graft-versus-host disease, and use of anticholinergic drugs.


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 it difficult to find out the exact origin and cause, 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.[13]

Sjögren's syndrome was originally proposed to be a specific, self-perpetuating immune system-mediated loss of exocrine glands, specifically acinar and ductal cells. Although this explains the more obvious symptoms, i.e. the lack of salivary 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 to be 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.[13]

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 up-regulation 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.[14] Sjögren's syndrome, though, is characterized by decreased levels of IL-1ra in saliva, which could be responsible for mouth inflammation and dryness.[15] 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[edit]

The genetic locus most significantly associated with primary Sjögren's syndrome is the major histocompatibility complex/human leukocyte antigen (MHC/HLA) region, as demonstrated by the preliminary results of the first genome-wide association study (GWAS).[16] This GWAS 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.[17]

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.[18] HLA class II alleles are associated with the presence of specific subsets of autoantibodies, rather than with the disease itself.[19] Autoantibodies refer to the loss of B-cell tolerance leading to production of antibodies directed against diverse organ-specific and organ nonspecific antigens.[13] Association between HLA and Sjögren's syndrome 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 syndrome patients suggests their imperative role in the pathogenesis of Sjögren's syndrome.[20]

Beyond genetics, epigenetic abnormality related to DNA methylation, histone acetylation, or microRNA expression probably have key roles in the pathogenesis of autoimmune diseases, including Sjögren's syndrome, though research in this area is very limited and minimal.[21]

Environmental triggers[edit]

Environmental factors, such as glandular viral infection, could prompt epithelial cells to activate the HLA-independent innate immune system through toll-like receptors.[22] Although a number of infectious, exogenous agents have been implicated in the pathogenesis of Sjögren’s, such as Epstein-Barr virus (EBV), human T-lymphotropic virus 1, and hepatitis C virus, their association with Sjögren's 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, leading to the initiation or perpetuation of an immune response in target organs. Nonetheless, it remains to be clarified exactly how reactivation of EBV is induced in lesions of patients with Sjögren's, and which specific molecular mechanisms are involved in the process of viral reactivation.[23]

Molecular pathway of inflammation[edit]

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, which dysregulates epithelial cells and allows aberrant homing and activation of dendritic cells (DCs), T cells, and B cells.[24] Dendritic cells are antigen-presenting cells which 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 to be 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.[13]


Dysregulated apoptosis 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 Fas and Fas ligand are overexpressed in primary Sjögren's syndrome patients, while expression of bcl-1, which is known to downregulate apoptosis, was found to be significantly reduced in acinar and ductal epithelial cells of Sjögren's patients compared to healthy controls.[25][26] In situ studies did not show increased apoptosis among glandular epithelial cells, but reduced apoptosis among infiltrating mononuclear cells. Reduced apoptosis was also implicated in the accumulation of autoreactive B-cells found in the glands. The relationship of autoantibodies expressed in Sjögren's to apoptosis is still in research.[2]

Hormonal factors[edit]

Sex hormones seem to influence humoral and cell-mediated immune response, with estrogen being considered one of the biggest factors responsible for gender immunologic dimorphism. Various animal models have indicated a role for estrogen deficiency in Sjögren's syndrome; mice that lack aromatase (estrogen deficiency) develop a lymphoproliferative disease that resembles Sjögren's.[27]


Neither a cure for Sjögren's syndrome nor a specific treatment is known to permanently restore gland secretion. Instead, treatment is generally symptomatic and supportive. Moisture replacement therapies such as artificial tears may ease the symptoms of dry eyes. Some patients with more severe problems use goggles to increase local humidity or have punctal plugs inserted to help retain tears on the ocular surface for a longer time.

Additionally, cyclosporine (Restasis) is available by prescription to help treat chronic dry eye by suppressing the inflammation that disrupts tear secretion. Prescription drugs are also available that help to stimulate salivary flow, such as cevimeline (Evoxac) and pilocarpine. Salagen, a man-made form of pilocarpine, can be used to help produce tears, as well as saliva in the mouth and intestines. It is derived from the jaborandi plant. In women with Sjögren's syndrome vaginal dryness is reported often and thus vaginal lubrications are recommended to avoid any irritation or pain that result from dryness in the vaginal area.[8]

Nonsteroidal anti-inflammatory drugs may be used to treat musculoskeletal symptoms. For individuals with severe complications, corticosteroids or immunosuppressive drugs may be prescribed, and sometimes IVIG (intravenous immunoglobulin). Also, disease-modifying antirheumatic drugs (DMARDs) such as methotrexate may be helpful. Hydroxychloroquine (Plaquenil) is another option and is generally considered safer than methotrexate. However, these prescribed drugs have a range of side effects such as nausea, loss of appetite, dizziness, hair loss, stomach aches/cramps, headache, liver toxicity, and increased risk of infections. Also, patients who are on immune suppression drugs are more likely to develop cancer later.[8]

For systemic symptoms, including fatigue, joint pain, myositis and neuropathy, biologic immunosuppressants such as Riutxan and Benlysta that work via B-cell pathology are often used and have less toxic profile than traditional immunosuppressive regimens.

Dental care[edit]

Preventive dental treatment is also necessary (and often overlooked by the patient), as the lack of saliva associated with xerostomia creates an ideal environment for the proliferation of bacteria that cause cavities. Treatments include at-home topical fluoride application to strengthen tooth enamel and frequent teeth cleanings by a dental hygienist. Existing cavities must also be treated, as cavities that extend into the tooth can not be effectively treated through teeth cleaning alone, and are at a high risk of spreading into the pulp of the tooth, leading to the loss of vitality and need for extraction or root canal therapy. This treatment regimen is the same as that used for all xerostomia patients, such as those undergoing head and neck radiation therapy which often damages the salivary glands, as they are more susceptible to radiation than other body tissues.

Unfortunately, many patients, not realizing the need for dental treatment, do not see a dentist until most of their teeth are beyond the point of restoration. It is not uncommon for a dentist to see a xerostomia patient with severe, untreatable cavities in almost every tooth. In severe cases, the only viable treatment may be to extract all of the patient's teeth and treat with prosthetics such as dentures or implants.


Published studies on the survival of Sjögren's syndrome patients are limited in varied respects, perhaps owing to the relatively small sample sizes, and secondary Sjögren’s syndrome is associated with other autoimmune diseases. However, results from a number of studies indicated, compared to other autoimmune diseases, Sjögren’s syndrome is associated with a notably high incidence of malignant non-Hodgkin lymphoma.[13] NHL is the cancer derived from white blood cells. About 5% of patients with Sjögren's syndrome will develop some form of lymphoid malignancy.[28] Patients with severe cases are much more likely to develop lymphomas than patients with mild or moderate cases.[29] The most common lymphomas are salivary extranodal marginal zone B cell lymphomas (MALT lymphomas in the salivary glands)[30] and diffuse large B-cell lymphoma.[29]

Lymphomagenesis in primary Sjögren's syndrome patients is considered as a multistep process, with the first step being chronic stimulation of autoimmune B cells, especially B cells that produce rheumatoid factor at sites targeted by the disease.[31][32] This increases the frequency of oncogenic mutation, leading to any dysfunction at checkpoints of autoimmune B-cell activation to transform into malignancy. A study's finding has concluded the continuous stimulation of autoimmune B cells, leading to subtle germinal abnormalities in genes having specific consequences in B cells, which underlies the susceptibility to lymphoma.[33]

Apart from this notably higher incidence of malignant NHL, Sjögren’s patients show only modest or clinically insignificant deterioration in specific organ-related function, which explains the only slight increases in mortality rates of Sjögren’s syndrome patients in comparison with the remainder of the population.[13]


Among the complications discussed above, Sjögren's syndrome in women who become pregnant has been linked to an increased incidence of neonatal lupus erythematosus with congenital heart block requiring a pacemaker.[34] Type I cryoglobulinemia is a known complication of Sjögren's syndrome.[35]


There is no prevention mechanism for Sjögren's syndrome due to its complexity as an autoimmune disorder. However, lifestyle changes can reduce the risk factors of getting Sjögren's syndrome or reduce the severity of the condition with patients who have already been diagnosed. Diet is strongly associated with inflammation that is mostly seen in many autoimmune related diseases including Sjögren's syndrome. An experimental study show that Sjögren's syndrome patients show high sensitivity to gluten that directly relates to inflammation.[36] Moderate exercise is also found be helpful in Sjögren's syndrome patients mainly reducing the effect of lung inflammation.[37]


Sjögren’s syndrome is the third most common rheumatic autoimmune disorder, behind only rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE).[38] There are no geographical differences in the prevalence of Sjögren’s Syndrome.[39] Sjögren's syndrome has been reported in all areas of the world, although regional epidemiology is not a thoroughly researched area.[39][40] Depending on the criteria for determining prevalence, studies estimate the prevalence of Sjögren’s syndrome at 500,000 to 2 million patients in the United States. Moreover, other broader studies of prevalence of Sjögren's syndrome range widely with some reports of up to a prevalence of 3% of the population.[38] A few studies that have been conducted on the incidence of Sjögren's syndrome report that the incidence of the syndrome varies between 3 and 6 per 100,000 per year.[38][41]

Nine out of ten Sjögren's patients are reported to be women.[2][40] In addition to prevalence in women, having a first-degree relative with an autoimmune disease and previous pregnancies have been identified as epidemiological risk factors.[42] Differences in prevalence due to race and ethnicity are unknown.

Although Sjögren's occurs in all age groups, the average age of onset is between ages 40 and 60, although experts note that up to half of all cases may be left undiagnosed or unreported.[2][38][43][44] The prevalence of Sjögren’s syndrome generally increases with age.[38]

Sjögren’s syndrome has been known to be reported in 30-50% of patient’s with rheumatoid arthritis, as well as 10-25% with systemic lupus erythematosus.[2]


Henrik Samuel Conrad Sjögren

Johann von Mikulicz-Radecki (1850–1905) is generally credited with the first description of Sjögren’s syndrome. In 1892, he described a 42-year-old man with enlargement of the parotid and lacrimal glands associated with a round-cell infiltrate and acinar atrophy.[8][45] However, the criteria Mikulicz established for diagnosis, often led to misdiagnosis of Mikulicz’s syndrome. Many conditions, such as tuberculosis, infections, sarcoidosis, and lymphoma present with similar conditions to those listed under Mikulicz’s syndrome.[8] Nevertheless, the term "Mikulicz’s syndrome" is still used occasionally to describe the appearance of lymphocytic infiltrates on salivary-gland biopsies.[8]

In 1930, Henrik Sjögren (1899–1986), an ophthalmologist in Jönköping, Sweden, observed a patient with low secretions from the lacrimal and salivary glands.[46] Sjögren introduced the term keratoconjunctivitis sicca for the symptom of dry eyes (keratoconjunctivitis). In 1933, he published his doctoral thesis, describing 19 females, most of whom were postmenopausal and had arthritis, showing clinical and pathological manifestations of the syndrome.[45] Sjögren clarifies that keratoconjunctivitis sicca, resulting from water deficiency, had no relation to xerophthalmia, resulting from vitamin A deficiency.[45] Sjögren’s thesis was not well received as the Board of Examiners criticized some clinical aspects.[46]

After extensive research and data collection, Sjögren published an essential paper in 1951, describing 80 patients with keratoconjunctivitis sicca, 50 of whom also had arthritis.[46] His subsequent follow-up conference trips pertaining to his paper led to an international interest in Sjögren’s syndrome.[46] The term keratoconjunctivitis sicca was coined by Sjögren himself began to be identified as Sjögren’s syndrome in literature,[46] although it can now have more general usage.


Research on multifactorial autoimmune diseases such as Sjögren's syndrome focuses on expanding the knowledge surrounding the disorder, improving diagnostic tools and finding ways to prevent, manage, and cure the disorder. The United Kingdom Primary Sjögren's Syndrome Registry, a tissue biobank of samples taken for research, supported by the Medical Research Council, UK was established in 2010.[47]

As an autoimmune disease, susceptibility to Sjögren's syndrome is greatly influenced by the human leukocyte antigen.[48] DQA1*05:01, DQB1*02:01, and DRB1*03:01 alleles were identified as risk factors, while DQA1*02:01, DQA1*03:01 and DQB1*05:01 alleles were found to be protective factors for the disease.[49] The relationship between alleles and specific race was also established.[50] HLA-DQ2 and HLA-B8 are generally found in Caucasian patients, while HLA-DR5 is related to Greek and Israeli patients.[50] Multiple genome-wide association scans may be conducted in the future to identify key risk variants.[48]

Viruses that can trigger the immune response of the syndrome include human T-lymphotropic virus type 1 (HTLV-1), Epstein-Barr virus (EBV), human immunodeficiency virus (HIV) and hepatitis C virus (HCV).[50] The UK Primary Sjögren's Syndrome Registry supports clinical trials and genetic studies of Sjögren's syndrome and is open to patients wishing to participate in research studies and researchers studying the disease.[47]

Some research showed that the lack of vitamin A and vitamin D are associated with this disease.[50] Vitamin D deficiency was found to be related to neurological manifestations and the presence of lymphoma among patients. On the other hand, vitamin A levels were inversely associated with extra-glandular manifestations of the disease.[50]

In 2005, an animal model of Sjögren's syndrome was developed by immunizing mice with peptides from 60 kDa Ro-antigen.[51][52] Days after immunization, the salivary flow decreased.[51][52] Also, lymphocyte infiltrates and salivary dysfunction were observed which were similar to the symptoms seen in human Sjögren's syndrome.[51][52]

Saliva is a potential diagnostic tool of Sjögren's syndrome because the salivary component is changed after onset of the disease.[53] With the new miniaturization technology, called ‘lab on a chip’, the diagnosis can be more convenient.[53]

With regard to therapeutics, multiple monoclonal antibodies were under investigation in 2007.[54] The most promising seemed to be the anti-CD20 rituximab and the anti-CD22 epratuzumab, while the anti-TNF-α and IFN-α seemed less effective.[54]

In 2008, mucosal administration of α-fodrin, an autoantigen in Sjögren's syndrome, was shown to inhibit the progression of the disorder in mice effectively.[55]

Notable cases[edit]

There are well known people who have been diagnosed with this disorder. World champion tennis player Venus Williams has been diagnosed and said she had struggled with fatigue for years.[56] U.S. Olympic soccer player Shannon Boxx suffers from Sjögren's syndrome and lupus.[57]

See also[edit]


  1. ^ Elsevier, Dorland's Illustrated Medical Dictionary, Elsevier. 
  2. ^ a b c d e f Borchers, A. T., Naguwa, S. M., Keen, C. L. & Gershwin, M. E. Immunopathogenesis of Sjögren's syndrome. Clin. Rev. Allergy Immunol. 25, 89-104 (2003)
  3. ^ Nocturne, G. & Mariette, X. Advances in understanding the pathogenesis of primary Sjogren's syndrome. Nature Reviews Rheumatology 9, 544-556 (2013)
  4. ^ Fox, R. I., Stern, M. & Michelson, P. Update in Sjögren syndrome. Curr. Opin. Rheumatol. 12, 391-398 (2000).
  5. ^ a b c d Voulgarelis, M. & Tzioufas, A. G. Pathogenetic mechanisms in the initiation and perpetuation of Sjögren's syndrome. Nature reviews.Rheumatology 6, 529-537 (2010)
  6. ^ a b c d e f Delaleu, N., Jonsson, R. & Koller, M. M. Sjögren's syndrome. Eur. J. Oral Sci. 113, 101-113 (2005)
  7. ^ Whitacre, C. C. Sex differences in autoimmune disease. Nat. Immunol. 2, 777-780 (2001)
  8. ^ a b c d e f Fox, R. I. Sjögren's syndrome. Lancet 366, 321-331 (2005)
  9. ^ Whitacre, C. C. Sex differences in autoimmune disease. Nat. Immunol. 2, 777-780 (2001).
  10. ^ Sjogren's Syndrome Foundation website, "Breakthrough Goal"
  11. ^ a b c d Fox, R. I. Sjögren's syndrome. Lancet 366, 321-331 (2005
  12. ^ Dr. J. Parks, Ancaster ON Canada
  13. ^ a b c d e f Voulgarelis, M. & Tzioufas, A. G. Pathogenetic mechanisms in the initiation and perpetuation of SjÖgren's syndrome. Nature Reviews Rheumatology 6, 529-537 (2010).
  14. ^ Harboe, Erna; Tjensvoll, Anne Bolette; Vefring, Hege K.; Gøransson, Lasse G.; Kvaløy, Jan Terje; Omdal, Roald (2009). "Fatigue in primary Sjögren's syndrome – A link to sickness behaviour in animals?". Brain, Behavior, and Immunity 23 (8): 1104–8. doi:10.1016/j.bbi.2009.06.151. PMID 19560535. 
  15. ^ Perrier, S; Coussediere, C; Dubost, JJ; Albuisson, E; Sauvezie, B (1998). "IL-1 receptor antagonist (IL-1RA) gene polymorphism in Sjögren's syndrome and rheumatoid arthritis". Clinical immunology and immunopathology 87 (3): 309–13. doi:10.1006/clin.1998.4520. PMID 9646842. 
  16. ^ Reveille JD: The molecular genetics of systemic lupus erythematosus and Sjögren's syndrome. Curr Opin Rheumatol 1992, 4:644-656.
  17. ^ Lessard, C. J. et al. Identification of multiple Sjögren’s syndrome susceptibility loci [abstract OP0020]. Ann.Rheum. Dis. 72 (Suppl. 3), 54 (2013).
  18. ^ Kang HI, Fei HM, Saito I, Sawada S, Chen SL, Yi D, Chan E, Peebles C, Bugawan TL, Erlich HA, et al.: Comparison of HLA class II genes in Caucasoid, Chinese, and Japanese patients with primary Sjögren's syndrome. J Immunol 1993, 150:3615-3623.
  19. ^ Bolstad AI, Wassmuth R, Haga HJ, Jonsson R: HLA markers and clinical characteristics in Caucasians with primary Sjögren's syndrome. J Rheumatol 2001, 28:1554-1562.
  20. ^ Fei HM, Kang H, Scharf S, Erlich H, Peebles C, Fox R: Specific HLA-DQA and HLA-DRB1 alleles confer susceptibility to Sjögren's syndrome and autoantibody production. J Clin Lab Anal 1991, 5:382-391.
  21. ^ Lu, Q. The critical importance of epigenetics in autoimmunity. J. Autoimmun. 41, 1–5 (2013).
  22. ^ Takeda, K., Kaisho, T. & Akira, S. Toll-like receptors. Annu. Rev. Immunol. 21, 335–376 (2003).
  23. ^ Pflugfelder, S. C. et al. Epstein–Barr virus and the lacrimal gland pathology of Sjögren's syndrome. Am. J. Pathol. 143, 49–64 (1993).
  24. ^ Manoussakis, M. N. et al. Rates of infiltration by macrophages and dendritic cells and expression of interleukin-18 and interleukin-12 in the chronic inflammatory lesions of Sjögren's syndrome: correlation with certain features of immune hyperactivity and factors associated with high risk of lymphoma development. Arthritis Rheum. 56, 3977–3988 (2007).
  25. ^ Ohlsson, M. et al. (2002) CD40, CD154, Bax and Bcl-2 expression in Sjögren’s syndrome salivary glands: a putative anti-apoptotic role during its effector phases. Scand. J. Immunol. 56, 561–571
  26. ^ Ohlsson, M. et al. (2001) Fas-induced apoptosis is a rare event in Sjo ̈ gren’s syndrome. Lab. Invest. 81, 95–105
  27. ^ Nocturne, G. & Mariette, X. Advances in understanding the pathogenesis of primary Sjögren's syndrome. Nature Reviews Rheumatology 9, 544-556 (2013).
  28. ^ Tzioufas, Athanasios G.; Voulgarelis, Michael (2007). "Update on Sjögren's syndrome autoimmune epithelitis: from classification to increased neoplasias". Best Pract Res Clin Rheumatol 21 (6): 989–1010. doi:10.1016/j.berh.2007.09.001. PMID 18068857. 
  29. ^ a b Smedby, K. E.; Baecklund, E.; Askling, J. (2006). "Malignant lymphomas in autoimmunity and inflammation: a review of risks, risk factors, and lymphoma characteristics". Cancer Epidemiol. Biomarkers Prev. 15 (11): 2069–77. doi:10.1158/1055-9965.EPI-06-0300. PMID 17119030. 
  30. ^ Voulgarelis, Michael; Skopouli, Fotini N. (2007). "Clinical, immunologic, and molecular factors predicting lymphoma development in Sjogren's syndrome patients". Clin Rev Allergy Immunol 32 (3): 265–74. doi:10.1007/s12016-007-8001-x. PMID 17992593. 
  31. ^ Martin, T. et al., Salivaryglandlymphomasin patients with Sjögren’s syndrome may frequently develop from rheumatoid factor B cells. Arthritis Rheum. 43, 908–916 (2000).
  32. ^ Bende, R. J. et al. Among B cell non-Hodgkin’s lymphomas, MALT lymphomas express a unique antibody repertoire with frequent rheumatoid factor reactivity. J. Exp. Med. 201, 1229–1241 (2005).
  33. ^ Nocturne, G. et al. Germinal and somatic genetic variants of TNFAIP3 promote lymphomagenesis process complicating primary Sjögren’s syndrome [abstract OP0023]. Ann. Rheum. Dis. 72 (Suppl. 3), 55 (2013).
  34. ^ Manthorpe, R; Svensson, A; Wirestrand, LE (November 2004). "Late neonatal lupus erythematosus onset in a child born of a mother with primary Sjögren's syndrome". Ann. Rheum. Dis. 63 (11): 1496–7. doi:10.1136/ard.2003.014944. PMC 1754813. PMID 15479901. 
  35. ^ Ramos-Casals, Manel; Cervera, Ricard; Yagüe, Jordi; García-Carrasco, Mario; Trejo, Olga; Jiménez, Sonia; Morlà, Rosa M; Font, Josep; Ingelmo, Miguel (Dec 1998). "Cryoglobulinemia in primary Sjögren's syndrome: prevalence and clinical characteristics in a series of 115 patients". Semin Arthritis Rheum. 28 (3): 200–5. doi:10.1016/S0049-0172(98)80037-1. PMID 9872481. 
  36. ^ Liden, M. et al. Gluten sensitivity in patients with primary Sjogren's syndrome. Scand. J. Gastroenterol. 42, 962-962 (2007).
  37. ^ Strombeck, B.E. et al. Effects of exercise on aerobic capacity and fatigue in women with primary Sjögren's syndrome. Rheumatology 46, 868-871 (2007)
  38. ^ a b c d e Fox, R. I., Stern, M. & Michelson, P. Update in Sjögren syndrome. Curr. Opin. Rheumatol. 12, 391-398 (2000)
  39. ^ a b Mavragani, C. P. & Moutsopoulos, H. M. The geoepidemiology of Sjogren's syndrome. Autoimmunity Reviews 9, A305-A310 (2010)
  40. ^ a b Jonsson, R., Vogelsang, P., Volchenkov, R. & Espinosa, A. The complexity of Sjogren's syndrome: Novel aspects on pathogenesis. Immunol. Lett. 141, 1; 1-9; 9 (2011)
  41. ^ Alamanos, Y. et al. Epidemiology of primary Sjögren's syndrome in north-west Greece, 1982-2003. Rheumatology (Oxford) 45, 187-191 (2006)
  42. ^ Priori, R. et al. Risk factors for Sjögren's syndrome: a case-control study. Clin. Exp. Rheumatol. 25, 378 (2007)
  43. ^ Haugen, A. J. et al. Estimation of the prevalence of primary Sjögren's syndrome in two age-different community-based populations using two sets of classification criteria: the Hordaland Health Study. Scand. J. Rheumatol. 37, 30-34 (2008)
  44. ^ García-Carrasco, M. et al. Primary Sjögren syndrome: clinical and immunologic disease patterns in a cohort of 400 patients. Medicine 81, 270-280 (2002)
  45. ^ a b c Parke, A. L. & Buchanan, W. W. Sjögren’s syndrome: History, clinical and pathological features. Inflammopharmacology 6, 271-287 (1998)
  46. ^ a b c d e Murube, J. Henrik Sjögren, 1899-1986. The ocular surface 8, 2-2 (2010)
  47. ^ a b Ng, W.-F.; Bowman, S. J.; Griffiths, B.; Ukpssr Study, Group (January 2011). "United Kingdom Primary Sjogren's Syndrome Registry--a united effort to tackle an orphan rheumatic disease". Rheumatology (Oxford) 50 (1): 32–9. doi:10.1093/rheumatology/keq240. PMID 20693261. 
  48. ^ a b Ice, John A.; Li, He; Adrianto, Indra; Lin, Paul Chee; Kelly, Jennifer A.; Montgomery, Courtney G.; Lessard, Christopher J.; Moser, Kathy L. (August 2012). "Genetics of Sjögren's syndrome in the genome-wide association era". J. Autoimmun. 39 (1–2): 57–63. doi:10.1016/j.jaut.2012.01.008. PMC 3518871. PMID 22289719. 
  49. ^ Cruz-Tapias, Paola; Rojas-Villarraga, Adriana; Maier-Moore, Shannon; Anaya, Juan-Manuel (February 2012). "HLA and Sjögren's syndrome susceptibility. A meta-analysis of worldwide studies". Autoimmun Rev 11 (4): 281–7. doi:10.1016/j.autrev.2011.10.002. PMID 22001416. 
  50. ^ a b c d e Peri, Yogev; Agmon-Levin, Nancy; Theodor, Emanuel; Shoenfeld, Yehuda (February 2012). "Sjögren's syndrome, the old and the new". Best Pract Res Clin Rheumatol 26 (1): 105–17. doi:10.1016/j.berh.2012.01.012. PMID 22424197. 
  51. ^ a b c Scofield, RH; Asfa, S; Obeso, D; Jonsson, R; Kurien, BT (December 2005). "Immunization with short peptides from the 60-kDa Ro antigen recapitulates the serological and pathological findings as well as the salivary gland dysfunction of Sjogren's syndrome". J. Immunol. 175 (12): 8409–14. PMID 16339583. 
  52. ^ a b c Kurien, B. T.; Asfa, S.; Li, C.; Dorri, Y.; Jonsson, R.; Scofield, R. H. (May 2005). "Induction of oral tolerance in experimental Sjogren's syndrome autoimmunity". Scand. J. Immunol. 61 (5): 418–25. doi:10.1111/j.1365-3083.2005.01593.x. PMID 15882433. 
  53. ^ a b Liu, Jingyi; Duan, Yixiang (July 2012). "Saliva: a potential media for disease diagnostics and monitoring". Oral Oncol. 48 (7): 569–77. doi:10.1016/j.oraloncology.2012.01.021. PMID 22349278. 
  54. ^ a b Meijer, Jiska M.; Pijpe, Justin; Bootsma, Hendrika; Vissink, Arjan; Kallenberg, Cees G. M. (June 2007). "The future of biologic agents in the treatment of Sjögren's syndrome". Clin Rev Allergy Immunol 32 (3): 292–7. doi:10.1007/s12016-007-8005-6. PMC 2071970. PMID 17992596. 
  55. ^ He, Jing; Zhao, Jinxia; Li, Zhanguo (2008). "Mucosal administration of alpha-fodrin inhibits experimental Sjögren's syndrome autoimmunity". Arthritis Research & Therapy 10 (2): R44. doi:10.1186/ar2403. PMC 2453764. PMID 18419828. 
  56. ^ "Williams Says She Struggled With Fatigue for Years". NY Times. 2011. Retrieved 18 February 2014. 
  57. ^ "Olympic soccer player Shannon Boxx's battle with lupus". CNN. 2012. Retrieved 18 February 2014. 

External links[edit]