Sjögren's syndrome

Sjögren's syndrome, also known as "Mikulicz disease" and "Sicca syndrome", is a systemic autoimmune disease in which immune cells attack and destroy the exocrine glands that produce tears and saliva.

It is named after Swedish ophthalmologist Henrik Sjögren (1899–1986), who first described it.

Nine out of ten Sjögren's patients are women and the average age of onset is late 40s, although Sjögren's occurs in all age groups in both women and men. It is estimated to strike as many as 4 million people in the United States alone, making it the second most common autoimmune rheumatic disease.

Sjögren's syndrome can exist as a disorder in its own right (primary Sjögren's syndrome) or may develop years after the onset of an associated rheumatic disorder, such as rheumatoid arthritis, systemic lupus erythematosus, scleroderma, primary biliary cirrhosis etc. (secondary Sjögren's syndrome).

The disorder should not be confused with the Sjögren–Larsson syndrome, which was also denoted T. Sjögren syndrome in early studies.

Signs and symptoms
The hallmark symptom of Sjögren's syndrome is a generalized dryness, typically including xerostomia (dry mouth) and xerophthalmia (dry eyes), part of what are known as sicca symptoms. In addition, Sjögren's syndrome may cause skin, nose, and vaginal dryness, and may affect other organs of the body, including the kidneys, blood vessels, lungs, liver, pancreas, peripheral nervous system (distal axonal sensorimotor neuropathy) and brain.

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 auto-regulatory up-regulation of IL-IRA to reduce the successful binding of interleukin 1 to its receptors. It is likely that interleukin 1 is the marker for fatigue, however, increased IL-1RA is observed in the CSF and is associated with increased fatigue through cytokine induced sickness behavior. On the other hand, 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 SLE, Rheumatoid Arthritis or Systemic Sclerosis.

Diagnosis
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. Nevertheless, the combination of several tests can lead to a diagnosis of 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 anti-nuclear 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.

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 five millimeters of liquid is usually indicative of Sjögren's syndrome. However, lacrimal function declines with age or may be impaired from other medical conditions. 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 is considered a positive result. It takes longer to perform than Schirmer's test, but does not require special equipment.

A slit-lamp examination can reveal dryness on the surface of the eye. Salivary gland function can be tested by collecting saliva and determining the amount produced in a five minute period. A lip biopsy can reveal lymphocytes clustered around salivary glands, and damage to these glands due to inflammation.

Ultrasound examination of the salivary glands is the simplest confirmatory test and has the added advantage of being non-invasive with no complications. The parenchyma of the gland demonstrates multiple, small-2-6 mm hypoechoic lesions which are representations of the lymphocytic infiltrates. Often sialectasis with calculi are demonstrated if the disease is advanced. The sonographic findings have excellent symptom correlation. The other advantage of ultrasound is that complications of the disease such as extra-nodal lymphomas can often be detected as larger 1–4 cm hypoechoic intra-parenchymal masses.

There is also a radiological procedure 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. Widespread puddling of the injected contrast scattered throughout the gland indicates Sjögren's syndrome.

The Revised Classification Criteria for Sjögren's Syndrome requires the presence of signs, symptoms, and lab findings.

Patient-reported symptoms must include both ocular symptoms, such as daily, persistent, troublesome dry eyes for more than three months, and oral symptoms, such as needing to drink water to swallow food.

Objective evidence of eye involvement relies on Schirmer's test and the Rose bengal score (or similar). 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, hepatitis C infection, Acquired immunodeficiency syndrome (AIDS), pre-existing lymphoma, sarcoidosis, graft-versus-host disease, and use of anticholinergic drugs (since a time shorter than four times the life of the drug).

Pathogenesis
Cell mediated auto-immunity causes the apoptosis of the ductal and acinar epithelial cells which is responsible for the glandular tissue damage.

Treatment
There is neither a known cure for Sjögren's syndrome nor a specific treatment 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. Nonsteroidal anti-inflammatory drugs may be used to treat musculoskeletal symptoms. For individuals with severe complications, corticosteroids or immunosuppressive drugs may be prescribed. Also, disease-modifying antirheumatic drugs (DMARDs) such as methotrexate may be helpful. Hydroxychloroquine (Plaquenil) is another option and is generally considered safer than methotrexate. 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.

Dry eyes
Punctal plugs

In the advanced stage, despite the use of tear replacement drops, the eyes always feel burning, scratchy, sore. The sufferer is always aware of some discomfort, the eyes feel worse in the morning and late evening. The use of tear replacement drops becomes tedious and ineffective. At this point it may be appropriate to consider punctal plugs.

Each eye has two sites at the inner corner of each eyelid where tears drain from the eye. The upper eyelid 'puncta' drains approximately 40% of the tears away and the lower puncta drains away the remaining 60% of the tears. If there is a problem with the quantity of tears, as there is in Sjögren's disease, plugging the lower puncta can result in the tears that the patient has remaining on the eye longer.

Punctal plugs can be inserted into the lower or upper tear drainage canals of the eyes. The procedure takes only a few minutes and is painless. It can be done in the optometrist or ophthalmologist's office. Generally, collagen plugs are inserted first. These plugs will dissolve within a few days, so it gives the patient a chance to see if there is any improvement in comfort. Generally, the improvement is immediate. The patient may proceed to use of permanent plugs, although these too can be removed if necessary.

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 dental caries (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.

Prognosis
Sjögren's can damage vital organs of the body with symptoms that may plateau or worsen, but the disease does not 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 are able to 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.

Patients with Sjögren's syndrome have a higher rate of non-Hodgkin lymphoma compared to both patients with other autoimmune diseases and healthy people. About 5% of patients with Sjögren's syndrome will 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.

Complications
Among the complications discussed above, Sjögren's syndrome in women who become pregnant has been linked to increased incidence of neonatal lupus erythematosus with congenital heart block requiring a pacemaker.

Epidemiology
Sjögren's syndrome affects 1 million–4 million people in the United States. Most people are more than 40 years old at the time of diagnosis. Women are nine times more likely than men to have Sjögren's syndrome.

On September 1, 2011, tennis player Venus Williams announced that she had been diagnosed with Sjögren's syndrome, and that because of the disease, she was withdrawing from the 2011 US Open.

Research
Multiple monoclonal antibodies were under investigation in 2007. The most promising seemed to be the anti-CD20 rituximab and the anti-CD22 epratuzumab; the anti-TNF-α and IFN-α drugs seemed less effective.

α-fodrin functions as an autoantigen in Sjögren's syndrome. Mucosal administration of α-fodrin has been shown to inhibit the progress of the disorder in mice.

Research on diseases such as Sjögren's syndrome focuses on increasing knowledge and understanding of the disorder, improving diagnostic techniques, and finding ways to treat, prevent, and cure the disorder. The Primary Sjögren's Syndrome Registry in the UK is a tissue biobank of samples taken for research supported by the Medical Research Council. The 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.

An animal model of Sjögren's syndrome has been developed by immunizing mice with peptides from 60 kDa Ro-antigen. Days after immunization, salivary flow was decreased, and lymphocyte infiltrates as well as salivary dysfunction were observed which are highly reminiscent of human Sjögren's syndrome.