Sjogrens Syndrome (SS)

At a Glance

Sjogren’s syndrome (SS) is a systemic autoimmune disease that initially affects lacrimal and salivary glands, resulting in keratoconjunctivitis sicca (dry eye disease) and/or stomatitis sicca (dry mouth disease), and that can later involve a variety of systemic manifestations. The disease may be isolated (primary SS) or it may occur in association with other rheumatic diseases (secondary SS), such as rheumatoid arthritis (RA), systemic sclerosis (SSc), polymyositis(PM), and systemic lupus erythematosus (SLE). Other diseases that are occasionally associated with SS are autoimmune thyroiditus (Hashimoto’s thyroiditis), primary bilary cirrhosis, sclerosing cholangitis, pancreatitis, interstitial nephritis, interstitial lymphocytic pneumonitis, and peripheral vasculitis.

Primary SS is characterized by lymphocytic infiltration and progressive destruction of exocrine glands. Almost all patients have benign but disabling manifestations, such as dryness, pain, and fatigue. In 20-40% of affected individuals, the inflammatory process expands to other organs, causing severe systemic manifestations, such as joint pain and inflammation (arthritis), fibromyalgia-like syndrome, Raynaud’s phenomenon, lung inflammation, lymph node enlargement, and kidney, liver, nerve, and muscle disease. Rare serious complications include vasculitis and non-Hodgkin’s B-cell lymphomas.

Although patients can develop SS at any age, most individuals are older than 40 years of age at diagnosis. As with many autoimmmune connective tissue diseases, women are affected 10-20 times more frequently than men. The symptoms can vary from person to person, change over time, be non-specific (chronic fatigue and fever), and involve other organs besides lacrimal and salivary glands. Therefore, recognizing and diagnosing SS can be challenging, so it is not surprising that the average time to diagnose a symptomatic person can be more than 6 years.

The main symptoms of SS are dry eyes and dry mouth. Patients report sensations of burning and itching in their eyes: the eyes feel gritty, as if there is sand in them, and vision is sometimes blurry. The mouth feels like it is full of cotton, making it difficult to chew, swallow, or speak. The saliva is thick or stringy, and there is pain in the mouth and changes in the sense of taste or smell. Patients complain of dry nose, dry or peeling lips, hoarseness, sore tongue, and/or dry or burning throat. Presence of eye infections, corneal abrasion, mouth sores, cracked tongue, halitosis, increased dental decay, gum disease/swelling, swollen salivary glands, stones, and/or infection of the parotid gland can be found on examination.

It is important to note that dry eyes are not a finding limited to SS. It can be found as part of the normal aging process or climate changes, in many ophthalmic disorders (e.g., blepharitis, corneal ulcers and infections, eye infections), laser vision correction, previous eyelid or facial surgery, in other rheumatic disorders, or in vitamin A deficiency.

Additional symptoms include joint pain, swelling, and stiffness; skin rashes or dry skin; vaginal dryness leading to painful intercourse; persistent dry cough; prolonged fatigue; fever; change in the color of hands or feet; esophageal dysphagia, epigastric pain, and dyspepsia; and tingling and numbness in the limbs.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Useful tests that should be ordered as part of SS work-up include laboratory tests, ocular and oral functional tests, and chest X-rays (Table 1) (Table 2) (Table 3).

Table 1.

Test	Comments
Eythrocyte Sedimentation Rate (ESR)	This test measures inflammation. An elevated ESR indicates the presence of an inflammatory disorder, including SS.
Complete Blood Count (CBC)	This can show signs of anemia in SS.
Immunoglobulins	Immunoglobulins are usually elevated in SS patients.
Rheumatoid Factor (RF)	Anti-IgG antibody. RF is present in RA, SS, and occasionally SSc and PM. RF is also seen in the overlap syndromes, such as RA/SLE overlap and SSc/RA overlap. 60-70% of SS patients have a positive RF.
Anti-nuclear Antibodies (ANA)	These are a group of antibodies that react against normal components of a cell nucleus. They are found in more than 2/3 of primary SS patients, but they are not specific to this disease, as they are found in a variety of autoimmune diseases.
Anti-SSA/Ro	These are found in 30-60% of primary SS patients, 30% of SLE patients, and 5-10% of patients with progressive SSc. The sensitivity of the anti-SSA/Ro assay for SS is about 8-70%, and the specificity is 87%.They seem to be associated with primary SS forms with vasculitis and leucopenia. In SLE, these antibodies have been closely associated with the development of nephritis, vasculitis, lymphadenopathy, leucopenia, photosensitivity, thrombocytopenia, ANA-negative SLE, an subacute cutaneous SLE. Pregnant SLE patients should be screened for anti-SSA/Ro antibodies, as their presence increases the risk of neonatal lupus and heart block. Anti-SSA/Ro-positive patients with SLE/SS-overlap syndromes have a more progressive disease course. Antibodies to SSA/Ro alone occur in patients who have a homozygous deficiency of the C2 complement fraction and in primary biliary cirrhosis who develop SS. The anti-SSA autoantibodies can bind to several antigenic epitopes expressed by two proteins of molecular masses of 52 and 60 kDa associated with RNA. Only the anti-SSA autoantibodies that recognize the 60-kDa protein are tested routinely. It seems that the reactivity profile can differ for patients who are afflicted with primary SS (isolated anti-52-kDa SSA reactivity) or SLE (anti-60-kDa reactivity).
Anti-SSB/La	These are also characteristic of primary SS. They are detected in 5-50% of SS patients and coexist with anti-SSA autoantibodies in more than 50% of the patients; their coexistence is highly suggestive of primary SS. Fifteen to 25% of patients with SLE and 5-10% of patients with SSc also have this antibody. The sensitivity of the anti-SS/La assay for SS is about 16-40%, and the specificity is 94%. SSA/Ro and SSB/La are found in up to 62% of pateints with subacute cutaneous lupus and in 85% of patients with SS who develop vasculitis. High titers of anti-SSB/La are also associated with fetal atrioventricular block.
Kidney function testing	Urine testing (urinalysis ad microscopy) is helpful in assessing kidney involvement. The presence of red cells and protein indicates active kidney inflammation in the absence of bladder and kidney infection. In the case of kidney involvement and reduction of kidney function, blood urea nitrogen (BUN) and creatinine will be elevated.
Liver function testing	Liver enzymes ALT and AST can be elevated

Table 2.

TEST NAME	COMMENTS
Schirmer Test	Measures tear production by testing the eye’s ability to wet a small testing paper strip placed under the eyelid. More than 10 mm of moisture on the filter paper after 5 minutes is a sign of normal tear production. Both eyes normally release the same amount of tears.
Ocular surface staining using vital dyes rose bengal and lissamine green	This uses eyedrops/strips containing these dyes to examine the eye for dry spots and corneal damage and visualize devitalized cells and strands of devitalized surface tissue. A scoring system has been developed to rate the severity of these changes and is useful for monitoring dry eye treatment over time. The two dyes can be used interchangeably, but lissamine is better tolerated.
Slit-lamp test	This is an examination of the surface of the eye with the help of a fluorescin dye and a biomicroscope (slit lamp) to provide a magnified image of the tear film, the ocular surface and the eyelids, and to allow careful examination of the anterior portions of the eye, including the anterior chamber and iris. Fluorscein allows evaluation of the quality of the tear film and detection of small areas of the cornea where the lining cells have been lost because of dryness or other forms of damage.

Table 3.

TEST NAME	COMMENTS
Sialometry/Salivary flow testing/Spit test	This measures the amount of saliva produced over a certain period of time. It is decreased in SS.
Salivary scintigraphy/Salivary gland function scan	Salivary gland function is assessed by the pattern of uptake and secretion of a radioactive tracer technetium 99. It measures salivary gland function and is used for evaluation of patients with persistent symptoms of dry mouth or to evaluate salivary gland swelling that is due to either infection, inflammation, or obstruction. In SS, it shows signs of decreased saliva formation and inflammation.
Sialogram	This is a special X-ray that detects dye injected into the parotid glands and shows abnormalities in the size or shape of the parotid ducts.
Salivary gland biopsy (usually in the lower lip)	This reveals a lymphocytic infiltrate of the minor salivary glands, called a benign lymphoepithelial lesion. The degree of lymphocytic infiltrate is assessed. Occasionally, SS may progress to a B-cell lymphoma. In these cases, the salivary tissue is obliterated by the lymphocytic infiltrate and contains scattered lymphoepithelial islands.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Sera exhibiting a high degree of hemolysis, icterus, lipemia, or microbial growth should not be used because these conditions may cause aberrant results. Repeated freeze/thawing cycles of patient specimens should be avoided, as this can lead to false-positive or false-negative results.

It is important to note that false-positive and false-negative screening ELISA tests for anti-SSA/Ro and anti-SSB/La are possible. False-negative tests can occur when the titers of autoantibodies are low or because of the limitation of the assay. False-positive tests have been observed using heat-inactivated serum samples and in HIV-infected individuals as a result of polyclonal activation of B-cells or because of the presence of “sticky” serum. In addition, anti-SSA/Ro antibodies can be found in low tiers in about 15% of the normal population.

Different assays do not show equivalent performance in anti-SSA/Ro and anti-SSB/La autoantibody detection because the Ro/LA system is a heterogeneous antigenic complex constituted of three proteins (52 kDa Ro, 60 kDa Ro, and La) and four small RNAs particles. The differences in the detection of 52 kDa, 60kDa Ro, and La could explain the inconsistencies noted between individual assays.

What Lab Results Are Absolutely Confirmatory?

There is no single laboratory test that will confirm the diagnosis of SS. To help physicians diagnose SS, six classification criteria have been established (revised European-American Consensus Group criteria). They consider the patient’s subjective description of ocular and oral symptoms, objective signs of ocular and oral dryness, detection of infiltrating lymphocytes within minor salivary glands (quantified by histopathological evaluation), and the presence in serum of antinucleolar autoantibodies, specifically anti-SSA/Ro and anti-SSB/La.

Ocular symptoms include dry eyes for more than 3 months, foreign body sensation in the eyes, and use of artificial tears more than three times per day.

Oral symptoms include dry mouth for more than 3 months, recurrent or persistently swollen salivary glands, and need for liquids to swallow dry foods.

Ocular signs include Schirmer’s test (without anesthesia) less than or equal to 5 mm/5 min and positive vital dye staining (van Bijsterveld ≥4).

Histopathology includes lip biopsy showing focal lymphocytic sialoadenitis (focus score ≥1 per 4 mm²).

Oral signs include unstimulated whole salivary flow (≤1.5 mL in 15 minutes), abnormal parotid sialography, and abnormal salivary scentigraphy.

Autoantibodies include anti-SSA/Ro and/or anti-SSB/La.

Exclusion criteria include past head and neck radiation treatment, hepatitis C infection, acquired immunodeficiency syndrome (AIDS), pre-existing lymphoma, sarcoidosis, graft versus host disease, and current use of anticholinergic drugs.

Patients are classified as primary SS if four of the six criteria are present, as long as histopathology or serology is positive, or if three or any four objective criteria are present.

In patients with another well-defined major connective tissue disease, the presence of one symptom plus two of the three objective criteria is indicative of secondary SS.

In the rare instances in which the cause of patient symptoms remains obscure, repeat testing and sometimes even additional salivary gland biopsies may be required.

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