Sjögren's disease
Sjögren's disease, previously known as Sjögren syndrome or Sjögren's syndrome, is a long-term autoimmune disease that primarily affects the body's exocrine glands, particularly the lacrimal and salivary glands. Common symptoms include dry mouth and dry eyes, and it often seriously affects other organ systems, such as the lungs, kidneys, and nervous system.
Signs and symptoms
In a 2021 article on Sjögren's patients, a majority of individuals stated that eight symptoms had a major or moderate impact on their life: fatigue ; dry eyes ; dry mouth ; joint pain ; trouble sleeping ; eye discomfort ; muscle pain ; and brain fog.Primary symptoms are dryness, 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 of lymphoma.
The hallmark symptom of Sjögren's disease is dry mouth and keratoconjunctivitis sicca. 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.
In some people with Sjögren's disease, 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.
Sjögren's disease 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 , and difficulty in swallowing and eating. Debilitating fatigue and joint pain can seriously impair quality of life. Some patients can develop kidney involvement leading to proteinuria, urinary concentrating defect, and distal renal tubular acidosis.
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 disease.Sjögren's disease can affect such organs as the liver, pancreas, kidneys, lungs, and central nervous system.
Associated conditions
Sjögren's disease 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, autoimmune thyroiditis, multiple sclerosis and spondyloarthropathy, and several malignancies, principally non-Hodgkin lymphoma.Sjogren's is the second most common cause of dysautonomia.
Causes
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, as is the case with many other autoimmune disorders. Around 20 autoantibodies could be involved. It can occur independently of other health problems or as a result of another connective tissue disorder. Sjögren's disease may be associated with other autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus 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.Genetics
The observation of high rates of autoimmune disorders in families with a history of Sjögren's disease is linked with a genetic predisposition to the disease. Studies on the polymorphisms of human leukocyte antigen -DR and HLA-DQ gene regions in Sjögren's patients show differential susceptibility to the disease as the result of different types of the resulting autoantibody production.Hormones
Since Sjögren's disease 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 disease. Androgens are generally considered to prevent autoimmunity. Studies on mice models suggest estrogen deficiency stimulates presentation of autoantigens, inducing Sjögren's-like symptoms.Microchimerism
of fetal cells 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
, engulfed molecules, or degraded self-structures may initiate autoimmunity by molecular mimicry and increase the chances of Sjögren's disease development. Epstein–Barr virus, hepatitis C, and human T-cell leukemia virus-1 are among the most studied infectious agents in Sjögren's disease. To date, no direct cause-and-effect relationship has been identified between these pathogens and the development of Sjögren's disease. 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 disease 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 before the diagnosis of Sjögren's disease.Sjögren's disease 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, 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 disease is associated with increased levels in cerebrospinal fluid 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 disease is characterized by decreased levels of IL-1ra in saliva, which could be responsible for mouth inflammation and dryness. Patients with secondary Sjögren's disease 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 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 disease, 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 activation involving BLK, and T-cell activation owing to HLA susceptibility and the IL-12-IFN-γ-axis.Patients of different ethnic origins carry different HLA-susceptibility alleles, of which HLA-DR and HLA-DQ are involved in the pathogenesis of Sjögren's disease. For example, patients from Northern and Western Europe and 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 the 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 disease, though research in this area is very limited.