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Dr. Maria Michailidou



General Considerations

Sjögren syndrome (SS) is an autoimmune exocrinopathy first described fully by Henrik Sjögren in 1933. Although it is a systemic disorder, the primary targets of the inflammatory process are the exocrine glands. SS can occur either as a primary process or in association with other autoimmune disorders, such as rheumatoid arthritis, systemic lupus erythematosus, scleroderma, mixed connective tissue disease, dermatomyositis, or autoimmune thyroiditis. When it occurs in association with other diseases, the process is called "secondary" SS. The decrease in exocrine gland secretions seen in SS results in dryness that can affect virtually every mucocutaneous surface of the body. The set of symptoms associated with this dryness is termed "the sicca complex."

In pathologic terms, the disease is defined by the infiltration of lymphocytes, plasma cells, and macrophages into target tissues. The precise role of autoantibodies (see ) in the pathophysiology of SS is unclear, but anti-SS-A (Ro) and anti-SS-B (La) are a striking feature of many patients with this condition.

There are at least three major factors in the causation of SS. There is clearly a genetic predisposition to the development of the disease. A number of genes within the HLA-DR3 and HLA-DR4 loci have been associated with the development and the severity of SS. Because these genes are relatively common in populations of healthy individuals, however, environmental factors (eg, viral or retroviral infections) may also play a role, triggering the disease in genetically susceptible persons. However, no consistent environmental triggers have been identified. Finally, because the disease is up to 15 times more common in women than in men, hormonal factors must also be important in the development of SS. The precise role of female hormones in the cause of SS remains unclear.  


Adequate saliva production is crucial for the health of the mouth. Patients with SS complain of constant burning and dryness of oral mucosal surfaces. The lips, tongue, and roof of the mouth frequently stick together, making it difficult to talk without constantly sipping water. It is very difficult or impossible to chew or swallow dry foods such as crackers without consuming liquids at the same time. Most patients complain of burning discomfort in the mouth after eating acidic foods. A decrease in the amount of saliva can result in rampant dental caries, periodontitis with gum resorption, and atrophy of lingual papillae. Aggressive treatment of caries is crucial to prevent premature loss of the teeth in patients with SS.

Oral candidiasis is a common complication of the sicca complex. It is associated with angular cheilosis, accentuation of the lingual papillary atrophy already present in SS patients, and erythema of the tongue. Thrush, however, is unusual in adults with SS. Diffuse lymphocytic infiltration of the parotid and submandibular glands () can result in glandular enlargement, pain, and tenderness. Severe bilateral enlargement of the parotids may result in a typical "chipmunk" facies. Because of decreased salivary flow, patients with SS have increased susceptibility to bacterial infections of the major salivary glands. The offending organisms are generally commensal oral flora such as Staphylococcus or Streptococcus species, including pneumococci. Appropriate antibiotic therapy rests upon the results of culture and sensitivity tests of the purulent material draining from Stensen or Wharton ducts.


A normal tear film consists of layers of mucus, water, and oil. The ocular manifestations of SS are due to decreased production of the aqueous tear component. Dryness of the eyes (keratoconjunctivitis sicca) is usually associated with what is described as a "gritty" or "sandy" discomfort and the sensation of a foreign body in the eye. Symptoms are exacerbated by exposure to dry air. Physical examination reveals injection of the bulbar conjunctiva, particularly that surface exposed to the air. Lack of a normal tear film and accumulation of corneal debris can result in painful corneal filaments and blurred vision. Blepharitis secondary to abnormally thickened meibomian gland secretions develops in some patients. The overnight accumulation of tenacious, inspissated secretions may bind the eyelids during sleep, making opening of the eyes difficult upon awakening. Photophobia is the result of corneal irritation caused by disruption of the protective tear film. Corneal denudation also heightens patients' susceptibility to ocular infections.


The most common cutaneous manifestations of SS are due to a deficiency in the aqueous component of sweat. Dry skin with chronic scaling and pruritus is almost universal in well-established SS. The complications of chronic pruritus include lichenification and pigmentary changes of the skin. Leukocytoclastic vasculitis (often with a lymphocytic predominance) presenting with petechiae or palpable purpura can also be seen, usually associated with hypergammaglobulinemia (either polyclonal or monoclonal), cryoglobulinemia, or elevated circulating immune complexes.


Dryness of the nares results in pain, tenderness, erythema, crusting, pruritus, and frequent anterior nose bleeds. Nasal dryness also leads to decreased smell and a consequent attenuation in the ability to taste food. Dryness of the sinuses is associated with an increased incidence of acute and chronic sinusitis.


Vaginal dryness is associated with pain, tenderness, pruritus, dyspareunia, and recurrent vaginal candidiasis. Dryness of the vulva frequently results in chronic vulvodynia and dysuria.


Many patients with primary SS have an inflammatory, symmetric, nonerosive, arthralgic syndrome that affects small proximal joints. The proliferative synovitis typical of rheumatoid arthritis or systemic lupus erythematosus is not observed in SS. Arthritis typical of the underlying associated disorder can develop in patients with secondary SS. Fibromyalgia is very common in SS. Proximal muscle weakness caused by an inflammatory myopathy that is indistinguishable histologically from idiopathic polymyositis develops in some patients with SS. Most of these patients probably have secondary SS in association with a primary inflammatory myopathy (ie, polymyositis or dermatomyositis), mixed connective tissue disease, systemic lupus erythematosus, or another autoimmune process.


Tracheobronchial dryness can lead to a chronic dry cough, typically worse on cool nights (when the air holds less moisture than during the warmth of daylight hours). The lymphocytic infiltration of tracheobronchial mucous membranes seen in SS can result in the signs and symptoms of acute and chronic obstructive pulmonary disease. Restrictive lung disease is due to aggressive lymphocytic infiltration into the pulmonary interstitium. Pulmonary manifestations include follicular bronchiolitis, lymphocytic interstitial pneumonitis, fibrosing alveolitis, interstitial fibrosis with restriction, pulmonary vasculitis, and pleuritis (with or without pleural effusions). Although rare, respiratory failure due to interstitial lung disease is a potentially fatal complication of SS.


Oral discomfort as well as pharyngeal and upper esophageal dysphagia are frequent complaints in patients with SS, who cannot moisten their food adequately while chewing. Patients with SS are susceptible to reflux esophagitis, perhaps because of a decrease in the protective effects offered to the esophagus by continuous salivary flow. Acute and chronic pancreatitis may result from lymphocytic infiltration into the pancreas, the largest single exocrine gland in the body. Hepatic manifestations of SS include both chronic active hepatitis and primary biliary cirrhosis. Lymphocytic infiltration of the gastric mucosa is associated with chronic atrophic gastritis, while pernicious anemia, lymphocytic colitis, and even the malabsorption syndrome are seen in patients with intestinal mucosal infiltration.


Chronic lymphocytic interstitial nephritis is a well-described and common extraglandular complication of SS. Manifestations include decreased urinary concentrating ability, glycosuria, potassium wasting, renal tubular acidosis, and in patients with dense peritubular lymphocytic infiltration, light chain proteinuria. Renal tubular acidosis can lead to mobilization of calcium from bone with resultant hypercalciuria and nephrolithiasis. Membranous glomerulonephritis, perhaps related to the accumulation of immune complexes in the glomerulus, has also been described. Proliferative glomerulonephritis is unusual in SS and when present is generally associated with cryoglobulinemia.


Considerable controversy has existed in the past about the nature and extent of neurologic manifestations in SS. Reported central nervous system symptoms include decreased cognition, emotional lability, decreased memory, personality changes, and depression. However, confirmation of these many reports has been difficult. The true frequency of central nervous system disease in SS is believed now to be very low. On the other hand, symmetric stocking/glove peripheral neuropathies are clearly associated with hypergammaglobulinemic purpura and the mononuclear cell–mediated vasculitis of SS. Mononeuritis multiplex also has been described in SS patients with leukocytoclastic vasculitis. Much more debilitating is the demyelinating myelopathy reminiscent of multiple sclerosis (so-called "lupus sclerosis") that has been observed— albeit rarely—in patients with SS.


The precise relationship of SS and thyroid disease is controversial, although most investigators believe the incidence of autoimmune thyroiditis, with or without resultant hypothyroidism, is increased in SS. "Pseudolymphoma" is a systemic disorder characterized by fever, diffuse lymphadenopathy, and prominent extraglandular internal organ involvement. As its name implies, this syndrome can mimic lymphoma in the nature of its systemic presentation, except that it is not malignant. Moreover, there is an increased incidence of true generalized histiocytic lymphoma in long-standing SS. (Lymphoma develops in 5% of patients with SS.) Serial biopsy studies have documented the progression from a benign polyclonal lymphocyte aggressive disorder into a lymphoma in some patients.

Laboratory Findings

Autoantibodies develop in most patients with SS at some time during the course of the disease. Rheumatoid factors develop in 90% of patients, over 80% have a positive antinuclear antibody assay (usually with a speckled pattern), and approximately 60% have anti-SS-A (Ro) or SS-B (La) antibodies. Anti-SS-A (Ro) antibodies are more likely to be seen in patients with primary SS or in those with SS and systemic lupus erythematosus. Anti-SS-B (La) antibodies are more specific for primary SS. A polyclonal hypergammaglobulinemia, detectable by immunoelectrophoresis and quantitative immunoglobulin assays, can be seen in up to 50% of patients; a benign monoclonal gammopathy, generally of the IgM kappa type, will develop in many of these patients. The erythrocyte sedimentation rate is commonly elevated due to the inflammation and hypergammaglobulinemia characteristic of the disease. Anemia, leukopenia, thrombocytopenia, hypocomplementemia, elevated circulating immune complexes, and cryoglobulinemia can all be seen in patients with extraglandular internal organ involvement. The cryoglobulinemia associated with SS is generally of the mixed type II variety, with a monoclonal IgM kappa rheumatoid factor.