Sjögren's disease (SjD)[8][9] (previously known asSjögren syndrome orSjögren's syndrome (SjS,SS)) is along-termautoimmune disease that primarily affects the body'sexocrine glands, particularly thelacrimal andsalivary glands.[4][10] Common symptoms includedry mouth,dry eyes and often seriously affect other organ systems, such as the lungs, kidneys, and nervous system.[11]
In a 2021 article on Sjogren's patients, a majority of individuals stated that eight Sjogren's symptoms had a major or moderate impact on their life:fatigue (79%); dry eyes (75%); dry mouth (73%); joint pain (65%); trouble sleeping (64%); eye discomfort (60%); muscle pain (56%); and brain fog (54%).[12][13][14]
Characteristic dryness appears at a number of locations, such as the tongue, face, and eyes. Marked at left are the salivary glands (which may be swollen), not a facial rash.
In some people with SS, skin dryness may be the result oflymphocyticinfiltration intoskin glands. The symptoms may develop insidiously, with the diagnosis often not considered for several years because sicca (dryness) 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.[19]
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.[32] Around 20 autoantibodies could be involved.[33]
The observation of high rates of autoimmune disorders in families with a history of Sjögren's syndrome is linked with agenetic predisposition to the syndrome.[34] Studies on thepolymorphisms ofhuman leukocyte antigen(HLA)-DR andHLA-DQgene regions in Sjögren's patients show differential susceptibility to the syndrome as the result of different types of the resultingautoantibody production.[34]
Viral proteins, engulfedmolecules, or degraded self-structures may initiate autoimmunity bymolecular mimicry and increase the chances of Sjögren's syndrome development.[35]Epstein–Barr virus,hepatitis C, andhuman T-cell leukemia virus-1 are among the most studiedinfectious agents in Sjögren's syndrome.[35] To date, no direct cause-and-effect relationship has been identified between these pathogens and the development of Sjögren's syndrome. Damaged self-structures targeted forapoptosis may be mistakenly exposed to the immune system, triggering autoimmunity inexocrine glands, which are often prone to autoimmune responses.[35]
Thepathogenetic mechanisms of Sjögren's syndrome have not been fully elucidated, resulting in the lack ofpathophysiology knowledge of the management of this autoimmuneexocrinopathy. 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 before the diagnosis of Sjögren's syndrome.[34]
Sjögren's syndrome was originally proposed as a specific,self-perpetuating, immune system-mediated loss of exocrine glands, specificallyacinar andductal cells. Although this explains the more obvious symptoms (such as the lack of saliva andlacrimal fluid), it does not explain the more widespread systemic effects seen in the progression of the disease.[citation needed]
Sjögren's syndrome is associated with increased levels incerebrospinal fluid (CSF) ofIL-1RA, aninterleukin 1antagonist. This suggests that the disease begins with increased activity in the interleukin 1 system, followed by an autoregulatoryupregulation of IL-1RA to reduce the successful binding of interleukin 1 to its receptors. Interleukin 1 likely is themarker for fatigue, but increased IL-1RA is observed in the CSF and is associated with increasedfatigue throughcytokine-inducedsickness behavior.[38] However, Sjögren's syndrome is characterized by decreased levels of IL-1ra in saliva, which could be responsible for mouth inflammation and dryness.[39] Patients with secondary Sjögren's syndrome also often exhibit signs and symptoms of their primary rheumatic disorders, such assystemic lupus erythematosus,rheumatoid arthritis, orsystemic sclerosis.[citation needed]
Thegenetic locus most significantly associated with primary SS is themajor histocompatibility complex/human leukocyte antigen (MHC/HLA) region, as demonstrated by the preliminary results of the firstgenome-wide association study.[40] This study included data from a discovery cohort of 395 patients of European ancestry with primary Sjögren's syndrome, and 1,975 healthycontrol individuals, and from a replication study that comprised 1,234 cases and 4,779 healthy controls. Associations withpolymorphisms located at six independent loci were also detected;IRF5,STAT4,BLK,IL12A,TNIP1, andCXCR5. This also suggested the activation of theinnate immune system, notably through the IFN system, B-cell activation throughCXCR5-directed recruitment tolymphoid follicles and B-cell receptor (BCR) activation involving BLK, andT-cell activation owing to HLA susceptibility and the IL-12-IFN-γ-axis.[41]
Patients of different ethnic origins carry different HLA-susceptibilityalleles, 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 North America show a high prevalence ofB8, DRw52, andDR3 genes.[42] HLA class II alleles are associated with the presence of specific subsets ofautoantibodies, rather than with the disease itself.[43] Autoantibodies refer to the loss of B-cell tolerance leading to the production of antibodies directed against diverse organ-specific and organ nonspecific antigens.[34] 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 thesalivary glands of Sjögren's patients suggests their imperative role in the pathogenesis of SS.[44]
Beyond genetics,epigenetic abnormality related toDNA methylation,histone acetylation, ormicroRNA expression probably has a key role in the pathogenesis of autoimmune diseases, including Sjögren's syndrome, though research in this area is very limited.[45]
Environmental factors, such as glandularviral infection, could promptepithelial cells to activate the HLA-independent innate immune system throughtoll-like receptors.[46] Although several infectious,exogenous agents have been implicated in the pathogenesis of Sjögren's syndrome, such asEpstein-Barr virus (EBV),human T-lymphotropic virus 1, andhepatitis 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 EBVDNA. This indicates viral reactivation and the inability of lymphoid infiltrates to control EBVreplication in Sjögren's syndrome, leading to theinitiation or perpetuation of an immune response in target organs. Nonetheless, exactly how reactivation of EBV is induced inlesions of patients with Sjögren's syndrome, and which specific molecular mechanisms are involved in the process of viral reactivation, remain to be clarified.[47]
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, whichdysregulates epithelial cells and allows aberranthoming and activation ofdendritic cells (DCs), T cells, and B cells.[48] Dendritic cells areantigen-presenting cells that processantigen material and present it to other T cells. Following themigration of lymphocytes into the glands in response tochemokines and specificadhesion molecules, T cells interact with epithelial cells. Epithelial cells are further activated byproinflammatory cytokines (IL-1β, IFN-γ, and TNF), which are produced by adjacent T cells. The early accumulation ofplasmacytoid 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 ofB-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 agerminal centre-like structure (GC-like), which is also the location oflymphomagenesis (origin oflymphoma).[34]
Dysregulation ofapoptosis (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 theFas andFas ligand proteins areoverexpressed in primary Sjögren's patients, while expression ofBCL-1, which is known to downregulate apoptosis, was found significantly reduced in acinar and ductalepithelial cells of Sjögren's patients compared to healthy people.[49][50]In situ studies did not show increased apoptosis among glandular epithelial cells but did show 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 syndrome with apoptosis is still being researched.[32]
Sex hormones seem to influence humoral and cell-mediated immune response, withestrogen being considered one of the biggest factors responsible for sex-immunologicdimorphism.[51]Estrogen deficiency appears to play a role in the development of Sjögren's syndrome.[52] It has beenhypothesized that androgen administration to the ocular surface may serve as an effective therapy for dry eyes.[53]
While Sjögren's syndrome[54] is one of the most common auto-immune diseases, it has no specific and non-invasive diagnostic tests.
Diagnosing Sjögren's syndrome (SS) is complicated by the range of symptoms that a patient may manifest, and the similarity between symptoms of Sjögren's syndrome and those of other conditions. Also, patients with SS symptoms approach differentspecialities for treatment, which can make diagnosis difficult. Since dry eyes and dry mouth are very common symptoms, and frequently occur in people over 40, affected people may believe that the symptoms are age-related, so ignore them. Some medications can cause symptoms similar to those of Sjögren's syndrome.[citation needed]
Blood tests can be done to determine if a patient has high levels of antibodies that are indicative of the condition, such asantinuclear antibody (ANA) andrheumatoid factor (because Sjögren's syndrome frequently occurs secondary to rheumatoid arthritis), which are associated with autoimmune diseases. Typical SS ANA patterns areSSA/Ro andSSB/La, of which anti-SSB/La is far more specific; anti-SSA/Ro is associated with numerous other autoimmune conditions, but is often present in SS. However anti-SSA and anti-SSB tests are frequently not positive in SS.[citation needed]
Therose bengal test uses a stain that measures the state and function of thelacrimal glands. This test involves placing thenontoxic dye rose bengal on the eyes. The dye's distinctive colour helps in determining the state and functioning of the tear film and the rate of tear evaporation. Any distinctive colour change can indicate SS, but confirming the condition requires many relateddiagnostic tools.[55]
Schirmer's test measures the production of tears: a strip offilter 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 SS. This measurement analysis varies among people depending on other eye-related conditions and medications in use when the test is taken.[55] Aslit-lamp examination can reveal dryness on the surface of the eye.[citation needed]
Use of Schirmer strips to test oral dryness is possible.[58][59]
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, andsublingual gland).In unstimulated whole saliva flow collection, the person spits into atest tube every minute for approximately 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.[60][55] In a stimulated saliva flow test the person sucks on a sugar-free sweet, whilst collecting saliva. An unstimulated salivary flow rate of 0.1 to 0.2 ml/min and a stimulated flow rate of 0.7 ml/min or less is considered to be abnormally low flow rates indicative of salivary gland hypofunction.[61]
Unstimulated saliva production reduces by 40 to 70% between the ages of 20 and 80 years, but stimulated saliva production is not affected.[62]
A lip/salivary glandbiopsy takes a tissue sample that can reveallymphocytesclustered around salivary glands, and damage to these glands from inflammation. This test involves removing a sample of tissue from a person's inner lip/salivary gland and examining it under amicroscope. On such biopsies, the single most important test result in the diagnosis of the oral component of Sjögren syndrome is likely thefocus score, which is the number of mononuclear cell infiltrates containing at least 50 inflammatory cells in a 4 mm2 glandular section.[63] The Chisholm-Mason grades are also widely used for salivary gland biopsies (see table).[64]
A radiological procedure is available as a reliable and accurate test for Sjögren's syndrome, in the form of asialogram. Acontrast agent is injected into the parotid duct, which opens from the cheek into thevestibule of the mouth opposite the neck of the upper secondmolar tooth. The test is intended to detect any blockage in the salivary gland ducts (i.e.parotid duct) and the amount of saliva that flows into the mouth.[55]
No prevention mechanism exists for Sjögren's syndrome (SS) because of its complexity as an autoimmune disorder. However,lifestyle changes can reduce therisk factors related to developing SS or reducing the severity of the condition for patients who have already been diagnosed.[citation needed]
Diet is strongly associated with the inflammation seen in many autoimmune-related diseases, including SS. Anexperimental study concluded that SS patients often show highsensitivity to gluten that directly relates to inflammation.[74]
Moderate exercise is also helpful in SS patients, mainly reducing the effect of lung inflammation.[75][citation needed]
Treatment is directed at managing the person'ssymptoms.[4] For dry eyes,artificial tears; medications to reduce inflammation;punctal plugs or other surgery to shut thetear ducts may be tried.[4] For a dry mouth,chewing gum (preferably sugar-free); sipping water; or asaliva substitute may be used.[4] In those with joint or muscle pain,ibuprofen may be used.[4] Medications that can cause dryness, such asantihistamines, may also be stopped.[4] The most specific extant diagnostic test requires lip biopsy.[76]
Neither a cure nor a specific treatment for Sjögren's syndrome is known to permanently restore glandsecretion. Instead, treatment is generally symptomatic and supportive.[77][78]
Moisture replacement therapies such asartificial tears may ease the symptoms of dry eyes. Some patients with more severe problems usegoggles to increase localhumidity or havepunctal plugs inserted to help retain tears on theocular surface for a longer time.[79]
Additionally,cyclosporine (Restasis) is available by prescription to treat chronic dry eye by suppressing the inflammation that disrupts tear secretion.Prescription drugs are also available that help to stimulate salivary flow, such ascevimeline (Evoxac) and pilocarpine.Salagen, a manufactured form ofpilocarpine, can be used to help produce tears, as well as saliva in the mouth and intestines.[80] It is derived from thejaborandi plant.[81]
For systemic symptoms, including fatigue, joint pain, myositis, andneuropathy, biologicimmunosuppressant drugs such asrituximab andbelimumab that work viaB-cell pathology are often used and have less toxic profiles than traditional immunosuppressive regimens.[citation needed]
Preventivedental treatment is also necessary (and often overlooked by the patient), as the lack of saliva associated with xerostomia creates an ideal environment for theproliferation of bacteria that causecavities.[82] Treatments include at-hometopicalfluoride 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 cannot be effectively treated by teeth cleaning alone, and are at a high risk of spreading into thepulp of the tooth, leading to the loss of vitality and need for extraction orroot canal therapy. This treatment regimen is the same as for all xerostomia patients, such as for those undergoing head and neck radiation therapy, which often damages the salivary glands; these glands are more susceptible to radiation than other body tissues.[citation needed]
Fatigue, depression, and aerobic capacity all showed a significant difference after a 12-week exercise program compared with controls, in favor of the exercise intervention.[83] A small study showed possible efficacy ofvagus nerve stimulation for Sjogren'sfatigue reduction.[84]
Results from a number of studies indicate that, compared to other autoimmune diseases, Sjögren's syndrome is associated with a notably high incidence ofnon-Hodgkin lymphoma, a cancer of white blood cells.[34] About 5% of patients with SS develop some form oflymphoid malignancy.[85] Patients with severe cases are much more likely to develop lymphomas than patients with mild or moderate cases.[86] The most common lymphomas are salivary extranodal marginal zone B cell lymphomas (MALT lymphomas in the salivary glands)[87] anddiffuse large B-cell lymphoma.[86]
Lymphomagenesis in primary Sjögren's syndrome patients is considered a multistep process, with the first step being chronic stimulation of autoimmune B cells, especially B cells that producerheumatoid factor at sites targeted by the disease.[88][89] This increases the frequency ofoncogenicmutation, 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, leads to subtle germinal abnormalities in genes having specific consequences in B cells, which underlies the susceptibility to lymphoma.[90]
Apart from the notably higher incidence of malignant NHL, Sjögren's patients show only modest or clinically insignificant deterioration in specific organ-related function.[citation needed]
Sjögren's syndrome is associated with a high burden of illness,[91] and has been shown to markedly reducequality of life (QoL),[92] with a significant impact on ability to work resulting from increased rates of disability.[93][94][95] The reduction in QoL is similar to that seen in other chronic conditions such asrheumatoid arthritis,lupus andfibromyalgia.[94]
Published studies on the survival of Sjögren's syndrome patients have been limited in varied respects, perhaps owing to the relatively small sample sizes and the fact that secondary Sjögren's syndrome is associated with other autoimmune diseases.A 2010 study found a slight increase inmortality rates of Sjögren's patients in comparison with the remainder of the population.[34] A 2016 study found that primary Sjögren's was not associated with an increase in all-cause mortality as compared with the general population, but that a subset of patients with extraglandular involvement, vasculitis, hypocomplementaemia, and cryoglobulinaemia may be at increased risk of mortality.[96] A 2021 metaanalysis showed a 46% increase in mortality, with significantly greater mortality risk in patients with older age, male gender, vasculitis, interstitial lung disease, low complements, positive anti-La/SSB and cryoglobulinaemia.[97]
Among those without other autoimmune disorders,life expectancy is unchanged.[6]
Sjögren's syndrome (SS) is the third-most common rheumatic autoimmune disorder, behind rheumatoid arthritis andsystemic lupus erythematosus.[19]
There are no geographical differences in the rates of SS.[98] Sjögren's syndrome has been reported in all areas of the world, although regional rates have not been well studied.[98][99]
Depending on the criteria for determining prevalence, studies estimate the prevalence of SS at between 500,000 and two million people in the United States. Broader studies of SS prevalence range widely, with some reports of up to a prevalence of 3% of the population.[19] A few studies have reported that the incidence of the syndrome varies between three and six per 100,000 per year.[19][100]Between 0.2 and 1.2% of the population is affected, with half having the primary form and half the secondary form.[7] It is around 10 times more common in women than in men.[3] Though the disease commonly begins inmiddle age, people of any age can be affected.[2][3]
Nine out of 10 SS patients are women.[32][99] In addition to prevalence in women, having afirst-degree relative with an autoimmune disease and previous pregnancies have been identified as epidemiological risk factors.[101] Despite the lower risk for men, primary SS in men tends to represent a more severe form of the disease.[102] The role of race and ethnicity in the prevalence of the disease is unknown.[citation needed]
Although Sjögren's syndrome occurs in all age groups, the average age of onset is between ages 40 and 60, although as many as half of all cases may be left undiagnosed or unreported.[32][19][103][104] The prevalence of SS generally increases with age.[19]
Sjögren's syndrome is reported in 30-50% of people with rheumatoid arthritis and in 10-25% with systemic lupus erythematosus.[32]
The disease was described in 1933 byHenrik Sjögren, after whom it is named, but a number of earlier descriptions of people with the symptoms exist.[3]
Jan Mikulicz-Radecki (1850–1905) is generally credited with the first description of SS. In 1892, he described a 42-year-old man with enlargement of theparotid andlacrimal glands associated with a round-cell infiltrate andacinaratrophy.[55][105] However, the criteria that Mikulicz established for diagnosis often led tomisdiagnosis ofMikulicz's syndrome. Many conditions, such astuberculosis, infections,sarcoidosis, andlymphoma present with similar conditions to those ascribed to Mikulicz's syndrome.[55] Nevertheless, the term "Mikulicz's syndrome" is still used occasionally to describe the appearance of lymphocytic infiltrates on salivary-gland biopsies.[55]
In 1930,Henrik Sjögren (1899–1986), an ophthalmologist inJönköping,Sweden, observed a patient with low secretions from the lacrimal and salivary glands.[106] Sjögren introduced the term keratoconjunctivitis sicca for the symptom of dry eyes (keratoconjunctivitis). In 1933, he published hisdoctoral thesis describing 19 females, most of whom were postmenopausal and had arthritis, showing clinical and pathological manifestations of the syndrome.[105] Sjögren clarified that keratoconjunctivitis sicca, resulting from water deficiency, had no relation toxerophthalmia, resulting from vitamin A deficiency.[105] Sjögren's thesis was not well received as the Board of Examiners criticized some clinical aspects.[106]
After extensive research and data collection, Sjögren published an essential paper in 1951, describing 80 patients withkeratoconjunctivitis sicca, 50 of whom also had arthritis.[106] His subsequent follow-up conference trips pertaining to his paper led to an international interest in Sjögren's syndrome.[106] The term "keratoconjunctivitis sicca" was coined by Sjögren himself and began to be identified as Sjögren's syndrome in literature,[106] although it can now have more general usage.
Singer-actressCarrie Ann Inaba is the national awareness ambassador and spokesperson for the Sjögren's Syndrome Foundation.
Research into multifactorial autoimmune diseases such as SS focuses on expanding the knowledge surrounding the disorder, improving diagnostic tools and finding ways to prevent, manage and cure the disorder. TheUnited Kingdom Primary Sjögren's Syndrome Registry, a tissuebiobank of samples taken for research, supported by theMedical Research Council, UK, was established in 2010. It supportsclinical trials and genetic studies of Sjögren's syndrome and is open to those wishing to participate in research studies and to researchers studying the disease.[107]
As with other autoimmune diseases, susceptibility to Sjögren's syndrome is greatly influenced by the human leukocyte antigen.[108] DQA1*05:01, DQB1*02:01, and DRB1*03:01 alleles were identified asrisk factors, while DQA1*02:01, DQA1*03:01 and DQB1*05:01 alleles were found to be protective factors for the disease.[109] The relationship between alleles and specific race was also established.[110]HLA-DQ2 andHLA-B8 are generally found inCaucasian patients, whileHLA-DR5 is related toGreek andIsraeli patients.[110] Multiplegenome-wide association scans may be conducted in the future to identify key risk variants.[108]
Some research has shown that a paucity ofvitamin A andvitamin D are associated with the disease.[110]Vitamin D deficiency was found to be related to neurological manifestations and the presence oflymphoma among patients, but vitamin A levels wereinversely associated with extraglandular manifestations of the disease.[110]
Saliva is a potential diagnostic tool for Sjögren's syndrome because the salivary component is changed after the onset of the disease.[113] With the newminiaturization technology, calledlab on a chip, the diagnosis can be more convenient.[113]
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