patients, while expression of bcl-1, which is known to downregulate apoptosis, was found significantly reduced in acinar and ductal epithelial cells of sjögren's patients compared to healthy people. 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. hormonal factors sex hormones seem to influence humoral and cell-mediated immune response, with estrogen being considered one of the biggest factors responsible for sex-immunologic dimorphism. 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. diagnosis speckled immunofluorescence staining pattern of antinuclear antibodies on hep-20-10 cells 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 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, but aanti-ssa and anti-ssb tests are frequently not positive in ss. rose bengal test 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. schirmer test 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 ss. this measurement analysis varies among people depending on other eye-related conditions and medications in use when the test is taken. a slit-lamp examination can reveal dryness on the surface of the eye. use of schirmer strips to test oral dryness are possible. saliva flow tests 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 say 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. 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. unstimulated saliva production reduces by 40 to 70% between the age of 20 and 80 years, but stimulated saliva production is not affected. lip biopsy 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). other tests 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. for sjögren's syndrome, sudomotor function through electrochemical skin conductance may help in the diagnosis process. sjögren's syndrome 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. prevention no prevention mechanism exists for sjögren's syndrome (ss) because of its complexity as an autoimmune disorder, but 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 neither a cure nor a specific treatment for sjögren's syndrome is known to permanently restore gland secretion. instead, treatment is generally symptomatic and supportive. eye care 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. vaginal dryness 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. musculoskeletal nonsteroidal anti-inflammatory drugs (nsaids) may be used to treat musculoskeletal symptoms. for individuals with severe complications, corticosteroids or immunosuppressive drugs may be prescribed, and sometimes intravenous immunoglobulins. also, disease-modifying antirheumatic drugs 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. systemic for systemic symptoms, including fatigue, joint pain, myositis and neuropathy, biologic immunosuppressant drugs such as rituximab and belimumab that work via b-cell pathology are often used and have less toxic profiles than traditional immunosuppressive regimens. dental care 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 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. prognosis non-hodgkin lymphoma 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. about 5% of patients with ss develop some form of lymphoid malignancy. patients with severe cases are much more likely to develop lymphomas than patients with mild or moderate cases. the most common lymphomas are salivary extranodal marginal zone b cell lymphomas (malt lymphomas in the salivary glands) 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. other organs apart from the notably higher incidence of malignant nhl, sjögren's patients show only modest or clinically insignificant deterioration in specific organ-related function. burden of illness 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. mortality 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 in mortality rates of sjögren's patients in comparison with the remainder of the population. a 2016 study found that primary sjorgrens 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. 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. epidemiology sjögren's syndrome (ss) is the second-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. 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. a few studies have reported that the incidence of the syndrome varies between three and six per 100,000 per year. nine out of 10 ss patients are women. 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. sjögren's syndrome is reported in 30-50% of people with rheumatoid arthritis and in 10-25% with systemic lupus erythematosus. history 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 the parotid and lacrimal glands associated with a round-cell infiltrate and acinar atrophy. however, the criteria that mikulicz established for diagnosis often led to misdiagnosis of