Синдром Шегрена: симптомы, причины и осложнения

Autoimmune disease affecting the body's moisture producing glands

In a 2021 poll of Sjogren's patients, a majority of respondents 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%).

Primary symptoms are dryness (dry mouth and dry eyes 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. The hallmark symptom of Sjögren syndrome is dry mouth and keratoconjunctivitis sicca (dry eyes). including the kidneys, blood vessels, lungs, liver, pancreas, and brain. In some people with SS, skin dryness 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.

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.

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, systemic lupus erythematosus (lupus), autoimmune thyroiditis, multiple sclerosis and spondyloarthropathy, and several malignancies, principally non Hodgkin lymphoma. Sjogren's is the second most common cause of dysautonomia.

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. 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. Around 20 autoantibodies could be involved.

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. Studies on mice models suggest estrogen deficiency stimulates presentation of autoantigens, inducing Sjögren's like symptoms. 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. 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.

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. 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 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.

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). 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. Estrogen deficiency appears to play a role in development of Sjögren's syndrome. It has been hypothesized that androgen administration to the ocular surface may serve as an effective therapy for dry eyes.

While Sjögren's syndrome 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 different specialities 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.

The combination of several tests, which can be done in a series, can eventually diagnose Sjögren's syndrome.

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 Sjögren's syndrome frequently occurs secondary to rheumatoid arthritis), which are associated with autoimmune diseases. Typical SS ANA patterns are SSA/Ro and SSB/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.

The rose bengal test uses a stain that 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 can indicate SS, but confirming the condition requires many related diagnostic tools.

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). In unstimulated whole saliva flow collection, the person spits into a test tube every minute for approximately 15 minutes. A resultant collection of less than is considered a positive result. Unstimulated saliva production reduces by 40 to 70% between the age of 20 and 80 years, but stimulated saliva production is not affected.

A lip/salivary gland biopsy takes a tissue sample that can reveal lymphocytes clustered 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 a microscope. On such biopsies, the single most important test result in the diagnosis of the oral component of Sjögren syndrome is likely the focus score, which is the number of mononuclear cell infiltrates containing at least 50 inflammatory cells in a 4 mm2 glandular section. The Chisholm Mason grades are also widely used for salivary gland biopsies (see table).

Salivary gland ultrasonography is not invasive, and may help reduce unnecessary biopsies in anti SSA negative patients.

A radiological procedure is available as a reliable and accurate test for Sjögren's syndrome, in the form of a sialogram. 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. 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.

People with Sjögren's may also have other autoimmune conditions.

Sjögren's syndrome may be excluded in people with past head and neck radiation therapy, acquired immunodeficiency syndrome, pre existing lymphoma, sarcoidosis, graft versus host disease, and use of anticholinergic drugs.

No prevention mechanism exists for Sjögren's syndrome (SS) because of its complexity as an autoimmune disorder. However lifestyle changes can reduce the risk factors related to developing SS or reduce the severity of the condition for patients who have already been diagnosed. Diet is strongly associated with the inflammation seen in many autoimmune related diseases, including SS. An experimental study concluded that SS patients often show high sensitivity to gluten that directly relates to inflammation. Moderate exercise is also helpful in SS patients, mainly reducing the effect of lung inflammation.

Treatment is directed at managing the person's symptoms.

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 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 manufactured 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, vulvodynia and dyspareunia (painful sexual intercourse) are often reported; personal lubricants are recommended to help lessen irritation or pain that may result from dryness in the vaginal and vulval areas. 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 cannot be effectively treated by 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 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 are other body tissues.

A small study showed possible efficacy of vagus nerve stimulation for Sjogren's fatigue reduction.

Results from a number of studies indicate that, compared to other autoimmune diseases, Sjögren's syndrome is associated with a notably high incidence of non Hodgkin lymphoma, a cancer of white blood cells. Patients with severe cases are much more likely to develop lymphomas than patients with mild or moderate cases. and diffuse large B cell lymphoma. 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. 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.

Apart from the notably higher incidence of malignant NHL, Sjögren's patients show only modest or clinically insignificant deterioration in specific organ related function.

Sjögren's syndrome is associated with a high burden of illness, and has been shown to markedly reduce quality of life (QoL), with a significant impact on ability to work resulting from increased rates of disability. The reduction in QoL is similar to that seen in other chronic conditions such as rheumatoid arthritis, lupus and fibromyalgia. 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. Among those without other autoimmune disorders, life expectancy is unchanged.

Sjögren's syndrome (SS) is the third most common rheumatic autoimmune disorder, behind rheumatoid arthritis and systemic lupus erythematosus. There are no geographical differences in the rates of SS. Sjögren's syndrome has been reported in all areas of the world, although regional rates have not been well studied. Between 0.2 and 1.2% of the population is affected, with half having the primary form and half the secondary form. 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. Despite the lower risk for men, primary SS in men tends to represent a more severe form of the disease. The role of race and ethnicity in the prevalence of the disease is unknown. 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. The prevalence of SS generally increases with age. However, the criteria that 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 ascribed to Mikulicz's syndrome. 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. As with other autoimmune diseases, susceptibility to Sjögren's syndrome is greatly influenced by the human leukocyte antigen. 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. The relationship between alleles and specific race was also established. HLA DQ2 and HLA B8 are generally found in Caucasian patients, while HLA DR5 is related to Greek and Israeli patients. Some research has shown that a paucity of vitamin A and vitamin D are associated with the disease. With the new miniaturization technology, called lab on a chip, the diagnosis can be more convenient. 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.