SJOGREN SYNDROME

Introduction
Background

Sjögren syndrome (SS) is a systemic chronic inflammatory disorder characterized by lymphocytic infiltrates in exocrine organs. Most individuals with Sjögren syndrome present with sicca symptoms, such as xerophthalmia (dry eyes), xerostomia (dry mouth), and parotid gland enlargement. In addition, numerous extraglandular features may develop, such as arthralgia, arthritis, Raynaud phenomenon, myalgia, pulmonary disease, gastrointestinal disease, leukopenia, anemia, lymphadenopathy, neuropathy, vasculitis, renal tubular acidosis, and lymphoma.

Primary Sjögren syndrome occurs in the absence of another underlying rheumatic disorder, whereas secondary Sjögren syndrome is associated with another underlying rheumatic disease, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), or scleroderma. Given the overlap of Sjögren syndrome with many other rheumatic disorders, it is sometimes difficult to determine whether a clinical manifestation is solely a consequence of Sjögren syndrome or is due to one of its overlapping disorders.

Importantly, classic clinical features of Sjögren syndrome may also be seen in viral infections with hepatitis C, human immunodeficiency virus (HIV), and human T-cell lymphotrophic virus (HTLV). Treatment for Sjögren syndrome is largely based on symptoms, but patients must be monitored carefully for the potential development of lymphoma.
Pathophysiology

The pathophysiology of Sjögren syndrome is not well understood. The presence of activated salivary gland epithelial cells expressing major histocompatibility complex (MHC) class II molecules and the identification of inherited susceptibility markers suggest that environmental or endogenous antigens trigger a self-perpetuating inflammatory response in susceptible individuals. In addition, the continuing presence of active interferon pathways in Sjögren syndrome suggests ongoing activation of the innate immune system.1,2 Together, these findings suggest an ongoing interaction between the innate and acquired immune systems in Sjögren syndrome.

The genetic associations in Sjögren syndrome vary among ethnic groups. In white persons, for instance, the condition is linked to human leukocyte antigen (HLA)–DR3, HLA-DQ2, and HLA-B8,3 whereas the linkage is to HLA-DRB1*15 in Spanish persons4 and to HLA-DR5 in Greek and Israeli persons.5 Some evidence indicates that the true association of Sjögren syndrome may be with HLA-DQA1, which is in linkage disequilibrium with HLA-DR3 and HLA-DR5.6 These HLA associations appear restricted to individuals with Sjögren syndrome who have antibodies to SSA and SSB rather than to the disease manifestations themselves.7

Viruses are viable candidates as environmental triggers, although proof of causation has remained elusive, and certainly no single virus has been implicated. Sjögren-like syndromes are seen in patients infected with HIV, HTLV-1, and hepatitis C.8,9,10

Damage and/or cell death due to viral infection or other causes may provide triggering antigens to Toll-like receptors in or on dendritic or epithelial cells, which, by recognizing pathogen-associated patterns, are activated and begin producing cytokines, chemokines, and adhesion molecules. As T and B lymphocytes migrate into the gland, they themselves become activated by dendritic and epithelial cells, thereafter acting as antigen-presenting cells.11 Expressed antigens include SSA/Ro, SSB/La, alpha-fodrin and beta-fodrin, or cholinergic muscarinic receptors.7 Dendritic cell triggering by immune complexes formed from SSA-anti-SSA (or other immune complexes) may propagate the ongoing innate and acquired immune activation.

The pathology of a typical involved salivary or lacrimal gland in Sjögren syndrome reveals aggregations of lymphocytes—periductal at first, then panlobular. These cells are primarily CD4 T cells (75%) and memory cells, with 10% B cells and immunoglobulin-secreting plasma cells. Although individual lobules can be destroyed, salivary gland biopsy samples from patients with Sjögren syndrome typically retain 40%-50% of their viable glandular structure. Therefore, inflammatory destruction of salivary and lacrimal glands may not fully account for the symptoms of Sjögren syndrome.

Recent studies suggest that the disease process of Sjögren syndrome has a neuroendocrine component. Proinflammatory cytokines released by epithelial cells and lymphocytes may impair neural release of acetylcholine. In addition, antibodies to acetylcholine (muscarinic) receptors may interfere with the neural stimulation of local glandular secretion12 , perhaps by interfering with aquaporin.13 Moreover, a recent study reports that M3 muscarinic receptor antibodies may cause autonomic dysfunction in patients with Sjögren syndrome.14

Current studies have also focused on the role of apoptotic mechanisms in the pathogenesis of primary Sjögren syndrome. A defect in Fas-mediated apoptosis, which is necessary for down-regulation of the immune response, can result in a chronic inflammatory destruction of the salivary gland, resembling Sjögren syndrome.15

Owing to these structural and functional changes in the lacrimal and salivary glands, their aqueous output is diminished. In the eye, tear hyperosmolarity results and is itself a proinflammatory stimulus, resulting in an inflammatory cascade on the ocular surface,16 with evidence of immune activation of the conjunctival epithelium and local cytokine and metalloproteinase production. Damage to the corneal epithelium, already vulnerable due to inadequate tear film protection, ensues, with resultant epithelial erosions and surface irregularity.

Extraglandular involvement in Sjögren syndrome manifests in part as hypergammaglobulinemia and the production of multiple autoantibodies, especially antinuclear antibody (ANA) and rheumatoid factor (RF). This may be due to polyclonal B-cell activation, but the cause of this expanded activation is not known. Involvement of other organs and tissues may result from effects of these antibodies, immune complexes, or lymphocytic infiltration and occurs in one third of patients with Sjögren syndrome. Prolonged hyperstimulation of B cells may lead to disturbances in their differentiation and maturation and may account for the greatly increased incidence of lymphoma in these patients.17
Frequency
United States

Sjögren syndrome affects 0.1-4% of the population. This wide range, in part, reflects the lack of uniform diagnostic criteria.
International

Sjögren syndrome is observed throughout the world.
Mortality/Morbidity

Morbidity associated with Sjögren syndrome is mainly associated with the gradually decreased function of exocrine organs, which become infiltrated with lymphocytes. The increased mortality rate associated with the condition is primarily related to disorders commonly associated with Sjögren syndrome, such as SLE, RA, and primary biliary cirrhosis. Patients with primary Sjögren syndrome who do not develop a lymphoproliferative disorder have a normal life expectancy.
Race

Sjögren syndrome affects persons of all races.
Sex

The female-to-male ratio of Sjögren syndrome is 9:1.
Age

Sjögren syndrome can affect individuals of any age but is most common in elderly people. Onset typically occurs in the fourth to fifth decade of life. For more information on pediatric Sjögren syndrome, see the article Sjogren Syndrome in eMedicine’s Pediatrics: General Medicine volume.

Clinical
History

Glandular or exocrine manifestations of Sjögren syndrome (SS) result from the periepithelial lymphocytic infiltration of the salivary and lacrimal glands.

* Sicca symptoms (dry eyes and dry mouth)
o Although dry eyes and dry mouth are the most common symptoms in patients with Sjögren syndrome, most patients who report these symptoms have other underlying causes. The incidence of sicca symptoms increases with age. Indeed, more than one third of elderly persons have sicca symptoms. Whether this is part of the normal aging process (associated with fibrosis and atrophy observed on some lip biopsy studies) or due to the accumulation of associated illnesses and medications is unclear.18
o Common medications that can result in sicca symptoms in any age group include antidepressants, anticholinergics, beta-blockers, diuretics, and antihistamines.
o Anxiety can also lead to sicca symptoms.
o Patients may describe dry mouth in various ways, as follows:
+ Inability to eat dry food (eg, crackers) because it sticks to the roof the mouth
+ Tongue sticking to the roof of the mouth
+ Putting a glass of water on their bed stand to drink at night (and resulting nocturia)
+ Difficulty speaking for long periods of time or the development of hoarseness
+ Higher incidence of dental caries and periodontal disease
+ Altered sense of taste
+ Difficulty wearing dentures
+ Development of oral candidiasis with angular cheilitis, which can cause mouth pain
o Dry eyes may be described as red, itchy, and painful. However, the most typical complaint is that of a gritty or sandy sensation in the eyes. Symptoms typically worsen throughout the day, probably due to evaporation of the already scanty aqueous layer. Some patients awaken with matting in their eyes and, when severe, have difficulty opening their eyes in the morning. Blepharitis can also cause similar morning symptoms.
o Patients may also have difficulty with dry skin and a dry vagina that can lead to dyspareunia, vaginitis, and pruritus.
o Nasal dryness can result in discomfort and bleeding
o Women who use hormone replacement therapy may be at increased risk of dry eye syndrome.19
* Parotitis
o Patients with Sjögren syndrome may have a history of recurrent parotitis, often bilateral.
o Some patients have parotid glands large enough that they report this as a problem. More often, the examining physician discovers them.

Extraglandular involvement falls into two general categories. Periepithelial infiltrative processes include interstitial nephritis, liver involvement, and bronchiolitis and generally follow a benign course. Extraepithelial extraglandular involvement in Sjögren syndrome is related to B-cell hyperreactivity, hypergammaglobulinemia, and immune complex formation and includes palpable purpura, glomerulonephritis, and peripheral neuropathy. These latter manifestations occur later in the course of Sjögren syndrome and are associated with a higher risk of transformation to lymphoma.20

* Skin and related symptoms
o Nonvasculitic cutaneous manifestations in Sjögren syndrome include dryness, eyelid dermatitis, pruritus, and erythema annulare.21
o Cutaneous vasculitis such as palpable purpura develops in some patients with Sjögren syndrome, especially those with hypergammaglobulinemia or cryoglobulinemia.22,21
o Raynaud phenomenon is observed in approximately 20% of patients.
o For more information on cutaneous manifestations of Sjögren syndrome, see the article Sjogren Syndrome in eMedicine’s Dermatology volume.
* Pulmonary symptoms
o Patients with Sjögren syndrome can develop dryness of the tracheobronchial mucosa (xerotrachea), which can manifest as a dry cough.23
o Less often, patients develop dyspnea from an interstitial lung disease that is typically mild.23,24
o Patients may develop recurrent bronchitis or even pneumonitis (infectious or noninfectious).
* Gastrointestinal symptoms23
o Dryness of the pharynx and esophagus frequently leads to difficulty with swallowing (deglutition), in which patients usually describe food becoming stuck in the upper throat.
o Lack of saliva may lead to impaired clearance of acid and may result in gastroesophageal reflux and esophagitis.
o Abdominal pain and diarrhea can occur. Rarely, patients develop acute or chronic pancreatitis, as well as malabsorption due to pancreatic insufficiency. However, caution is advised when interpreting laboratory results because an elevated amylase level may arise from the parotid gland.
o In patients with gastritis, Helicobacter pylori infection should be sought because of its association with gastric mucosa-associated lymphoid tissue lymphomas.25
* Cardiac symptoms
o Pericarditis and pulmonary hypertension, with their attendant symptomatology, can occur in Sjögren syndrome.26
o Orthostatic symptoms related to dysfunction of autonomic control of blood pressure and heart rate is associated with increased severity of Sjögren syndrome27
* Neurologic symptoms
o The occurrence of central nervous system and spinal cord involvement in Sjögren syndrome is estimated by various studies at 8-40%, with manifestations including myelopathy, optic neuropathy, seizures, cognitive dysfunction, and encephalopathy.17,28,29 Attempts must be made to distinguish other causes of these symptoms, including concomitant SLE, multiple sclerosis, cerebrovascular disease, and Alzheimer disease.
o Sensory, motor, or sensorimotor peripheral neuropathy, often subclinical, can be detected in up to 55% of unselected patients with Sjögren syndrome.30 Symptoms of distal paresthesias may be present.
o Cranial neuropathies can develop, particularly trigeminal neuropathy or facial nerve palsy.
o Mononeuritis multiplex should prompt a search for a vasculitis.
o Progressive weakness and paralysis secondary to hypokalemia due to underlying renal tubular acidosis can occur and is potentially treatable.31
* Renal symptoms
o Renal calculi, renal tubular acidosis, and osteomalacia can occur secondary to tubular damage caused by interstitial nephritis, the most common form of renal involvement in Sjögren syndrome.
o Interstitial cystitis, with symptoms of dysuria, frequency, urgency, and nocturia, is strongly associated with Sjögren syndrome.32,33
o Glomerulonephritis can be caused by Sjögren syndrome but is uncommon and is usually attributable to another disorder such as SLE or mixed cryoglobulinemia.
* Other symptoms
o Sjögren syndrome is associated with a wide variety of other disorders. Therefore, a careful review of systems is needed to detect problems such as RA, SLE, scleroderma, polymyositis, chronic active hepatitis, idiopathic pulmonary fibrosis, primary biliary cirrhosis,34 and autoimmune thyroid disease.35
o Patients with Sjögren syndrome may report fatigue, joint pain, and, sometimes, joint swelling.
o Women with Sjögren syndrome may have a history of recurrent miscarriages or stillbirths, and both women and men may have a history of venous or arterial thrombosis. These are related to the presence of antiphospholipid antibodies (eg, lupus anticoagulant or anticardiolipin antibodies).

Physical

* Eye examination
o While it is important to look for corneal lesions and a decreased tear pool in the lower conjunctiva during physical examination, patients with Sjögren syndrome should be referred to an ophthalmologist for more formal testing of keratoconjunctivitis sicca (KCS). This testing applies grading criteria of inflammatory changes that can direct therapy aimed at preventing corneal damage.36 In addition, conditions that mimic KCS, such as blepharitis, conjunctivitis, and uveitis can be ruled out or treated.
o Patients with Sjögren syndrome may have dilated conjunctival vessels.
o Patients may have pericorneal injection, as well as dullness or irregularity of the corneal image.
o Blepharitis may be present as an alternate or additional problem, particularly if the lower eyelid is inflamed.
o Mucinous threads and filamentary keratosis can be detected during a slit-lamp examination. The relative lack of the aqueous layer also leads to rapid tear breakup.
o In the Schirmer test, a bent piece of Whatman No. 41 filter paper is placed in the lower conjunctiva, and the amount of tearing on the filter paper is recorded. Normal wetting is greater than 15 mm after 5 minutes, whereas a definitive positive result is less than 5 mm after 5 minutes. This test can help to exclude or confirm significant dryness of the eyes, but it is not disease-specific. Furthermore, false-positive results occur. A recent evaluation of the diagnostic performance of the Schirmer test yielded a sensitivity of 42% and specificity of 76% for Sjögren syndrome.37

Sjögren syndrome. Photograph that demonstrat...
Sjögren syndrome. Photograph that demonstrates the Schirmer test, which is used to detect deficient tear production in patients with Sjögren syndrome. The filter paper strip is placed at the junction of the eyelid margins. After 5 minutes, 15 mm of paper should be moistened if tear production is normal, as shown here. Persons older than 40 years may moisten between 10 mm and 15 mm. Patients with Sjögren syndrome have less moistening. Sjögren syndrome is most common in patients with rheumatoid arthritis but may also occur without associated disease and in systemic lupus erythematosus, polyarteritis, systemic sclerosis, lymphoma, and sarcoidosis.

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Sjögren syndrome. Photograph that demonstrat...

Sjögren syndrome. Photograph that demonstrates the Schirmer test, which is used to detect deficient tear production in patients with Sjögren syndrome. The filter paper strip is placed at the junction of the eyelid margins. After 5 minutes, 15 mm of paper should be moistened if tear production is normal, as shown here. Persons older than 40 years may moisten between 10 mm and 15 mm. Patients with Sjögren syndrome have less moistening. Sjögren syndrome is most common in patients with rheumatoid arthritis but may also occur without associated disease and in systemic lupus erythematosus, polyarteritis, systemic sclerosis, lymphoma, and sarcoidosis.
* Mouth examination
o Look for a decreased sublingual salivary pool.
o The tongue may stick to the tongue depressor.
o Patients with Sjögren syndrome may develop frequent caries, sometimes in unusual locations such as the incisor surface and the gum line. Periodontal disease can lead to loss of teeth.
o Patients with Sjögren syndrome are prone to develop oral candidiasis. In addition to white patches, watch for petechial lesions, loss of tongue papilla, erythema and fissuring of the tongue, erythema on other mucosal surfaces, and angular cheilosis. Oral candidiasis can be seen under dentures.

Sjögren syndrome. Dryness of the mouth and t...
Sjögren syndrome. Dryness of the mouth and tongue due to lack of salivary secretion is characteristic of xerostomia associated with Sjögren syndrome. Mouth dryness may produce a deep red tongue, as shown here, and dental caries are common.

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Sjögren syndrome. Dryness of the mouth and t...

Sjögren syndrome. Dryness of the mouth and tongue due to lack of salivary secretion is characteristic of xerostomia associated with Sjögren syndrome. Mouth dryness may produce a deep red tongue, as shown here, and dental caries are common.
* Ear, nose, and throat examination
o Bilateral parotid gland enlargement is common in persons with Sjögren syndrome. Some waxing and waning of size may occur. Exudates from the parotid gland are largely lymphocytes.

Sjögren syndrome. Marked bilateral parotid g...
Sjögren syndrome. Marked bilateral parotid gland enlargement in a patient with primary Sjögren syndrome. Sicca syndrome is a common clinical finding.

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Sjögren syndrome. Marked bilateral parotid g...

Sjögren syndrome. Marked bilateral parotid gland enlargement in a patient with primary Sjögren syndrome. Sicca syndrome is a common clinical finding.
o Submandibular glands can be enlarged.
o Rock-hard or unilateral parotid gland enlargement should prompt a referral to an otolaryngologist for biopsy to exclude a tumor. Other causes of parotid enlargement include diabetes, sarcoidosis, amyloidosis, diffuse infiltrative lymphocytic syndrome (DILS) of HIV disease, hepatitis C, and alcoholism. Acute unilateral parotitis may be caused by Sjögren syndrome, infection, or obstruction, although the latter two conditions are more often associated with a very tender parotid gland and accompanying fever.
* Joint examination
o Arthritis may be a component of primary or secondary Sjögren syndrome.
o Symmetric, polyarticular, inflammatory arthritis suggests underlying RA or a connective-tissue disease such as SLE or scleroderma.
o The arthritis in patients with primary Sjögren syndrome is typically nonerosive and mild.
o One third of patients with RA have Sjögren syndrome.
* Pulmonary examination: Bibasilar rales can be heard in patients with interstitial lung disease.
* Skin examination
o Patients with Sjögren syndrome can develop a nonpalpable or palpable vasculitic purpura with lesions that are typically 2-3 mm in diameter and located on the lower extremities. They occur most often in patients with hypergammaglobulinemia or cryoglobulinemia. The lesions usually develop on the lower extremities and can ulcerate.22,21
o Patients can also develop urticarial vasculitis, erythema multiforme –like lesions, digital vasculitis, petechiae, erythema nodosum, and annular erythematous plaques.
* Other
o Signs of another connective-tissue disease (secondary Sjögren syndrome) may be present, such as SLE, scleroderma, or polymyositis.
o The patient may have signs of autoimmune liver disease such as primary biliary cirrhosis or autoimmune hepatitis.

Causes

As with many rheumatic disorders, the etiology of Sjögren syndrome is unknown but appears to derive from interactions between MHC and non-MHC genetic factors with unknown environmental stimuli. Sex hormones may also play a role because Sjögren syndrome is much more common in women.Differential Diagnoses
Amyloidosis, Immunoglobulin-Related
Salivary Gland Tumors, Major, Benign
Bulimia
Salivary Gland Tumors, Minor, Benign
Graft Versus Host Disease
Sarcoidosis
Pancreatitis, Chronic
Scleroderma
Polymyositis
Systemic Lupus Erythematosus
Rheumatoid Arthritis
Tuberculosis
Other Problems to Be Considered

Sicca

Medications (eg, antidepressants, anticholinergics, beta-blockers, diuretics, antihistamines)
Anxiety and depression
Viral infections (eg, mumps)
Complications from contact lenses
Dehydration
Hypervitaminosis A
Neurotropic keratitis
Mucous membrane pemphigoid
Environmental irritants
Mouth breathing
Chronic blepharitis
Chronic conjunctivitis
Rosacea
Therapeutic radiation or surgery to the head and neck
Age
Alzheimer disease
Parkinson disease
Bell palsy
Amyloidosis
Sarcoidosis
Lymphoma

Parotid enlargement

Viral infection (eg, mumps, Epstein-Barr virus, cytomegalovirus, coxsackievirus A, influenza)
DILS associated with HIV disease
Granulomatous diseases (sarcoidosis, tuberculosis, leprosy)
Hyperlipoproteinemia
Hepatic cirrhosis
Hepatitis C
Bulimia
Recurrent parotiditis of childhood
Chronic pancreatitis
Acromegaly
Amyloidosis
Gonadal hypofunction
Diabetes mellitus
Salivary gland tumor (primarily unilateral)
Bacterial infection (primarily unilateral)
Chronic sialadenitis (primarily unilateral)
Lymphoma

Importantly, evaluate the patient for disorders associated with Sjögren syndrome, including the following:

AIDS
RA
SLE
Scleroderma
Polymyositis
Primary biliary cirrhosis
Thyroiditis
Chronic active hepatitis
Mixed cryoglobulinemia
Celiac sprue
Workup
Laboratory Studies

* CBC count
o In patients with Sjögren syndrome (SS), the CBC count is most often within the reference range, but anemia of chronic disease may be present.
o Pernicious anemia may be associated with the atrophic gastritis.
o An abnormal WBC count, especially with an abnormal differential count, should prompt concerns for a lymphoreticular malignancy.
o A low platelet or WBC count can occur in persons with primary Sjögren syndrome but should also prompt consideration for coexisting SLE.
* Chemistry
o A high total protein level or a low albumin level should prompt the clinician to perform serum protein electrophoresis.
o A high alkaline phosphatase level should prompt consideration for primary biliary cirrhosis.
o With elevated transaminase levels, consider the possibility of chronic active hepatitis, which can be associated with sicca symptoms, or hepatitis C, which can cause mild salivary gland enlargement. However, mild (<2-fold) increases in transaminase levels have been observed in 22% of patients with Sjögren syndrome.38 o Consider evaluating patients with a low bicarbonate level for type I (distal) renal tubular acidosis. Less commonly, patients can also develop proximal renal tubular acidosis with Fanconi syndrome. o Hypokalemia, occasionally severe enough to lead to periodic paralysis, can be observed in patients with type I renal tubular acidosis but can also be observed in patients who have Sjögren syndrome without renal tubular acidosis.31 * Serum protein electrophoresis o Patients with Sjögren syndrome often have a polyclonal gammopathy. o Loss of a previously detected polyclonal gammopathy can be observed in some patients with Sjögren syndrome who develop lymphoma. o Development of a monoclonal gammopathy can also signal the development of a lymphoma. * Sedimentation rate: The sedimentation rate is often elevated in Sjögren syndrome, but this finding is nonspecific. * Multiple autoantibodies are associated with Sjögren syndrome:39 o Rheumatoid factor + Positive RF findings are typically found in most patients with Sjögren syndrome, even when they do not have RA. Consider a diagnosis of RA if the patient has symmetric polyarticular synovitis. + Loss of a previously positive RF finding can be observed in some patients with Sjögren syndrome who develop lymphoma. o ANA: ANAs are typically present in patients with Sjögren syndrome. Consider the diagnosis of SLE only if symptoms and signs typical of this disorder are present. o Antibodies to Sjögren syndrome antigen A (SSA/Ro) and Sjögren syndrome antigen B (SSB/La) + Antibodies against SSA/Ro are found in approximately 50% of patients with the disease (75% of patients with primary Sjögren syndrome and 15% of patients with secondary Sjögren syndrome). Thus, the absence of anti-SSA/Ro antibodies does not eliminate the diagnosis of primary or secondary Sjögren syndrome. + Antibodies against SSA/Ro are present in 50% of patients with SLE and are sometimes found in healthy individuals. Thus, by itself, the presence of antibody against SSA/Ro cannot establish a diagnosis of Sjögren syndrome. + Finding antibodies against SSB/La in patients without antibodies against SSA/Ro is unusual, but this combination has occurred in patients with primary biliary cirrhosis and autoimmune hepatitis. + Antibodies against SSB/La are present in 40-50% of patients with primary Sjögren syndrome and in 15% of patients with SLE. + Titers of these antibodies do not reflect disease activity. More recent enzyme-linked immunosorbent assay tests for antibodies to SSA/Ro and SSB/La are more sensitive than previous tests. Thus, the specificity is lower. + Antibodies against SSA/Ro are also associated with the annular erythematous lesions of subacute cutaneous lupus. They are also found in the mothers of newborns with neonatal lupus syndromes and congenital heart block, and some of these mothers have or will develop Sjögren syndrome. o Antiphospholipid antibodies: Patients with primary Sjögren syndrome may have positive test results for lupus anticoagulant and/or anticardiolipin antibodies, and some develop clinical events (ie, fetal wastage, arterial and/or venous thrombosis) associated with antiphospholipid syndrome. o Cryoglobulins: Type II cryoglobulins are noted, particularly in patients with palpable and nonpalpable vasculitic purpura. Hepatitis C should be sought in these patients. o Thyroid-stimulating hormone: In some studies, patients with Sjögren syndrome have an increased frequency of autoimmune thyroid disease with hypothyroidism (10-15%). Lymphocytic infiltration can be observed in the thyroid gland. o Elevations of serum immunoglobulin G4 (IgG4), found in IgG4-related plasmacytic disease (which can mimic the glandular infiltrations of Sjögren syndrome), are not seen in Sjögren syndrome.40,41 Imaging Studies * Sialography o In this test, radiopaque material is injected into the salivary glands. Sialography is useful to exclude the presence of obstructions or strictures, but the diffuse sialectasis of Sjögren syndrome is seen in various other diseases and is therefore not specific. o Oil-based contrast medium may not be adequately cleared in patients with Sjögren syndrome and, consequently, may damage adjacent tissues and lead to a chronic granulomatous reaction. Performing this procedure with oil-based contrast should be avoided, especially during episodes of acute swelling. * Salivary scintigraphy: In this technique, the uptake and secretion of sodium pertechnetate technetium Tc 99m is a gauge of the salivary flow rates and can provide an objective measurement of salivary gland dysfunction. However, the finding of low flow rates is not specific to Sjögren syndrome. * Positive findings on either sialography or scintigraphy fulfill a criterion for objective evidence of Sjögren syndrome by the American-European Consensus Group.42 Other Tests * Rose bengal staining o Rose bengal is an aniline dye that stains epithelial surfaces with diminished mucin protection or with exposed epithelial cell membranes. Conjunctival staining can be detected with the naked eye. o Slit-lamp examination is performed after rose bengal staining to detect abnormal uptake in the cornea. * Lissamine green staining works similarly but is less irritating to the eye. Fluorescein staining can be used to detect corneal damage. * Protein profiling (tear proteomics) has revealed reproducible patterns in primary Sjögren syndrome patients and appears to hold promise as a diagnostic test for this disorder.43 * Sialometry: Like the Schirmer test, sialometry is a good measure of the degree of decreased salivary flow and helps establishes xerostomia, but the findings do not narrow the differential diagnoses. * Sialochemistry: Saliva from patients with Sjögren syndrome has elevated levels of sodium, chloride, lactoferrin, and immunoglobulin A, but these findings are not specific. Procedures * Minor salivary gland biopsy44 o Currently, this is the best single test to establish a diagnosis of Sjögren syndrome. o In this procedure, an incision is made on the inner lip, and some minor salivary glands are removed for examination. o Obtaining the biopsy sample from below normal-appearing mucosa is important in order to avoid false-positive results. o At least 4 salivary gland lobules should be obtained for analysis. o While this is the most definitive test, performing it is not absolutely necessary from a clinical standpoint. Patients with Sjögren syndrome are essentially treated symptomatically and observed for the development of other rheumatic disorders or lymphoma. This can be initiated without performing a biopsy. If the diagnosis is in doubt or if a definitive diagnosis is needed, then this is the best test. o Biopsy can also help in the differential diagnoses because noncaseating granulomas of sarcoidosis can be found. Histologic Findings Although pathologists use different classification systems, the characteristic findings of minor salivary gland biopsy in a person with Sjögren syndrome include the following:45 * The biopsy shows focal aggregates of at least 50 lymphocytes, and, to a lesser extent, plasma cells and macrophages. * More than 1 focal aggregate is seen per 4 mm2. * T cells, predominantly CD4+ cells, are present, unlike the predominance of CD8+ T cells seen in the salivary gland biopsy samples from patients with DILS associated with HIV disease. * Normal acini are replaced by lymphocytes. * Focal aggregates are seen in almost all glands. * Ten percent of the lymphocytes are CD5+ B cells that produce immunoglobulin M and immunoglobulin G antibodies, often with a monoclonal or oligoclonal pattern. * Large foci are present, possibly showing germinal centers. * Epimyoepithelial islands are uncommon in the minor salivary gland but can be seen in the major salivary glands. Lymphocytic infiltrates are also seen in other organs. Findings from a gastric mucosal biopsy may show lymphocytic infiltrates with atrophic gastritis. A kidney biopsy may show interstitial lymphocytic infiltration. Lung biopsy can reveal infiltrating CD4+ T cells of a lymphocytic interstitial pneumonitis. Salivary gland biopsy can help detect pseudolymphoma or lymphoma, as well as the noncaseating granulomas of sarcoidosis. Classification criteria A number of classification criteria for Sjögren syndrome were designed primarily for clinical research studies but are also often used to help guide clinical diagnoses. The American-European Consensus criteria for the classification of Sjögren syndrome are outlined below.42,46 These criteria allow a diagnosis of Sjögren syndrome in patients without sicca symptoms or who have not undergone a biopsy. According to the American-European Consensus criteria (as modified by Tzioufas and Voulgarelis47 ), diagnosis of primary Sjögren syndrome requires 4 of 6 of the below criteria; in addition, either criterion number 5 or criterion number 6 must be included. Sjögren syndrome can be diagnosed in patients who have no sicca symptoms if 3 of 4 objective criteria are fulfilled. The criteria are as follows: * 1. Ocular symptoms o Dry eyes for more than 3 months o Foreign-body sensation o Use of tear substitutes more than 3 times per day * 2. Oral symptoms o Feeling of dry mouth o Recurrently swollen salivary glands o Frequent use of liquids to aid swallowing * 3. Ocular signs o Schirmer test performed without anesthesia (<5 mm in 5 min) o Positive vital dye staining results * 4. Oral signs o Abnormal salivary scintigraphy findings o Abnormal parotid sialography findings o Abnormal sialometry findings (unstimulated salivary flow <1.5 mL in 15 minutes) * 5. Positive minor salivary gland biopsy findings * 6. Positive anti–SSA or anti–SSB antibody results Secondary Sjögren syndrome is diagnosed when, in the presence of a connective-tissue disease, symptoms of oral or ocular dryness are present in addition to criterion 3, 4, or 5 above. Application of these criteria has yielded a sensitivity of 97.2% and a specificity of 48.6% for the diagnosis of primary Sjögren syndrome; for secondary Sjögren syndrome, the specificity was 97.2% and the sensitivity 64.7%.48 Exclusion criteria include past head and neck irradiation, hepatitis C infection, AIDS, prior lymphoma, sarcoidosis, graft versus host disease, and use of anticholinergic drugs. More on Sjogren SyndromeTreatment Medical Care Dry eyes The treatment of dry eyes depends on the severity of eye dryness, which is best determined by an ophthalmologist and which is graded according to degree of symptoms, conjunctival injection and staining, corneal damage, tear quality, and lid involvement.49,50 * Level 1 - Mild symptoms, no corneal signs o Artificial tears should be applied liberally. + Patients may need to apply artificial tears more often if they enter a low-humidity environment (ie, air conditioning, airplanes). + Artificial tears with hydroxymethylcellulose or dextran are more viscous and can last longer before reapplication is needed. Encourage patients to try various preparations to determine what works best for them. + If artificial tears burn when they are instilled, the preservative in the artificial tears is likely irritating the eye. If artificial tears are used more often than every 4 hours, patients should use a preservative-free preparation to avoid eye irritation from the preservatives. o Environmental controls: the use of humidifiers may help. If living in an area with hard water, the patient should use distilled water. o Patients should avoid medications with anticholinergic and antihistamine effects. * Level 2 - Moderate or severe symptoms with tear film signs or visual signs, or mild corneal/conjunctival staining o Unpreserved tears or gels or nighttime ointments + Patients who wake up in the morning with severe matting in the eyes should use a more viscous preparation (eg, Lacri-Lube) at night. While the more viscous preparations can be applied less often, they can make patients' vision filmy. Therefore, they are best used at night. + The more viscous preparations occasionally lead to blepharitis, which can exacerbate sicca symptoms. o Topical steroids o Secretagogues o Cyclosporine A51 o Nutritional supplements * Level 3 - Severe symptoms with marked corneal changes or filamentary keratitis o Tetracyclines o Autologous serum tears o Temporary plugging of the lacrimal puncta: This can increase the amount of tears that remain in the eyes. * Level 4 - Extremely severe symptoms with altered lifestyle, or severe corneal staining, erosions, or conjunctival scarring o Systemic anti-inflammatory therapy including acetylcysteine o Topical Vitamin A o Electrocautery and other techniques: These can be used for permanent punctal occlusion. o Glasses fitted with moisture shields: These can decrease evaporation. * Data on novel secretagogues and androgen therapies are promising.52 Dry mouth53 * Patients with dry mouth can liberally drink sips of water and take bottled water with them on trips. They can also place a glass of water at their bedside for nighttime use, as needed. * Sugar-free lemon drops can also be used as needed to stimulate salivary secretion. * Artificial saliva can be used as needed, although patient tolerance varies. Preparations include Salivart, Saliment, Saliva Substitute, MouthKote, and Xero-Lube. * Patients should be seen regularly by a dentist, who might advise fluoride treatments. Toothpaste without detergents can reduce mouth irritation in patients with Sjögren syndrome. Brands include Biotene toothpaste, Biotene mouth rinse, Dental Care toothpaste, and Oral Balance gel. * Patients should avoid medications with anticholinergic and antihistamine effects. * Watch for and treat oral candidiasis and angular cheilitis with topical antifungal agents, such as nystatin troches. Oral fluconazole may occasionally be needed. Patients also need to be sure to disinfect their dentures. * Sinusitis and sinus blockade should be treated because these problems may contribute to mouth breathing. Emphasize the use of isotonic sodium chloride solution nasal sprays to avoid using antihistamines. * The use of humidifiers may help. Distilled water is best in patients living in an area with hard water. * Pilocarpine or cevimeline (see Medication) tablets are options. Some small studies suggest that interferon alfa may be a useful therapy in the future. Skin and vaginal dryness * Patients should use skin creams, such as Eucerin, or skin lotions, such as Lubriderm, to help with dry skin. * Patients should use vaginal lubricants, such as Replens, for vaginal dryness. Vaginal estrogen creams can be considered in postmenopausal women. Watch for and treat vaginal yeast infections. Arthralgias and arthritis * Acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs) can be taken for arthralgias. * Consider hydroxychloroquine if NSAIDs are not sufficient for the synovitis occasionally associated with primary Sjögren syndrome. However, hydroxychloroquine does not relieve sicca symptoms. * Patients with RA associated with Sjögren syndrome likely require other disease-modifying agents. Other * In patients with major organ involvement, such as lymphocytic interstitial lung disease, consider therapy with steroids and immunosuppressive agents, such as cyclophosphamide. * While cyclophosphamide and similar agents may be helpful for treating serious manifestations of Sjögren syndrome or disorders associated with Sjögren syndrome, clinicians should understand that these agents are also associated with the development of lymphomas. * Of the biologic therapies, etanercept has failed to demonstrate benefit in Sjögren syndrome, while rituximab appears promising in the treatment of vasculitis and intravenous immunoglobulin (IVIG)–dependent ataxic neuropathy.52,54 * In a double-blind, randomized, placebo-controlled trial, Meijer et al (2010) found that rituximab significantly improved saliva flow rate, lacrimal gland function, and other variables in patients with primary Sjögren syndrome.55 * In a small group of patients with primary Sjögren syndrome, mycophenolate sodium reduced subjective but not objective ocular dryness and significantly reduced hypergammaglobulinemia and RF.56 Anticoagulation Long-term anticoagulation may be needed in patients with vascular thrombosis related to antiphospholipid antibody syndrome. Surgical Care * Perform a minor salivary gland biopsy for diagnostic purposes. * Perform a biopsy on the parotid gland if malignancy is suggested. * Perform a biopsy on an enlarged lymph node to help rule out pseudolymphoma or lymphoma. * Occlusion of the lacrimal puncta can be corrected surgically. Electrocautery and other techniques can be used for permanent punctal occlusion. * During surgery, the anesthesiologist should use as little anticholinergic medications as possible and use humidified oxygen to help avoid inspissation of pulmonary secretions. Good postoperative respiratory therapy should also be provided. Patients are at higher risk for corneal abrasions, so ocular lubricants should be considered. Consultations * Internal medicine specialist: Sjögren syndrome and its associated disorders necessitate a total patient perspective that is often best provided by an internist. * Rheumatologist: With specific training and experience in Sjögren syndrome and its associated disorders, a rheumatologist is key in the management of patients with Sjögren syndrome. * Ophthalmologist: Involve ophthalmologists early in the care of patients for rose bengal and fluorescein staining to help establish the diagnosis and to assess the degree of eye damage. * Otolaryngologist: Consultation with an otolaryngologist may be needed early to perform a minor or major salivary gland biopsy if this is deemed necessary to establish a diagnosis. The specialist may also need to perform a parotid biopsy if malignant transformation is suggested. * Dentist: Good oral prophylaxis and therapy is necessary. * Other subspecialists: Depending on the problems, patients with Sjögren syndrome may need to be seen by other specialists, including the following: o Nephrologist to help manage renal tubular acidosis o Pulmonologist to help manage interstitial lung disease o Hematologist/oncologist if pseudolymphoma or lymphoma develops Activity Encourage patients with Sjögren syndrome to be active. Medication Most patients with Sjögren syndrome can be cared for adequately with topical therapy and with avoidance of medications that exacerbate their symptoms. Pilocarpine or cevimeline can be used in cases of xerostomia for which systemic therapy is needed or local therapy is not successful. Cholinergic parasympathomimetic agents These agents bind to cholinergic (muscarinic) receptors, increasing the secretion of exocrine glands, including salivary glands. Pilocarpine (Salagen) Cholinergic parasympathomimetic agent that can be used to enhance secretion by exocrine glands when systemic therapy is needed or local therapy fails. * Dosing * Interactions * Contraindications * Precautions Adult 5 mg PO tid/qid Pediatric Not established * Dosing * Interactions * Contraindications * Precautions Increases risk for conduction abnormalities with beta-blockers; antagonizes effect of atropine or inhaled ipratropium * Dosing * Interactions * Contraindications * Precautions Documented hypersensitivity; uncontrolled asthma; acute iritis; narrow-angle glaucoma * Dosing * Interactions * Contraindications * Precautions Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus Precautions Most common adverse effect is increased sweating (up to 29%); also associated with headache, visual disturbances, lacrimation, respiratory distress, AV block, tachycardia, bradycardia, hypotension, shock, mental confusion, cardiac arrhythmias, tremors, gastrointestinal spasm, nausea, vomiting, and diarrhea; avoid in patients with cholelithiasis, biliary tract disease, nephrolithiasis, and cognitive or psychiatric disturbances Cevimeline (Evoxac) Indicated for xerostomia in Sjögren syndrome * Dosing * Interactions * Contraindications * Precautions Adult 30 mg PO tid Pediatric Not established * Dosing * Interactions * Contraindications * Precautions May have additive effects when used with other cholinergic agents; concurrent use with beta-blockers may cause potential for cardiac conduction disturbances; CYP2D6 inhibitors (eg, fluoxetine, amiodarone, quinidine, ritonavir, paroxetine) or CYP3A3/4 (eg, itraconazole, diltiazem, ketoconazole, verapamil) may increase toxicity; anticholinergic agents (eg, phenothiazines, TCAs, atropine) may decrease effects * Dosing * Interactions * Contraindications * Precautions Documented hypersensitivity; narrow-angle glaucoma, acute iritis, uncontrolled asthma * Dosing * Interactions * Contraindications * Precautions Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus Precautions Caution in cardiovascular disease, controlled asthma, COPD, or chronic bronchitis; may induce smooth muscle spasms and precipitate cholangitis, biliary obstruction, cholecystitis, or urethral reflux in patients with history of biliary stones or nephrolithiasis Natural tears Various OTC preparations of natural tears that provide topical therapy for dry eyes are available. Encourage patients to try different preparations to determine which works best for them. Artificial tears (Celluvisc, Murine, Refresh, Tears Naturale) Preparations that contain the equivalent of 0.9% sodium chloride and are used to maintain ocular tonicity. They replace the aqueous layer of tears that is lost in patients with Sjögren syndrome. Preparations that have hydroxymethylcellulose or dextran are more viscous and therefore can last longer before reapplication is needed. * Dosing * Interactions * Contraindications * Precautions Adult 1-2 gtt into eye(s) tid/qid prn Pediatric Administer as in adults * Dosing * Interactions * Contraindications * Precautions None reported * Dosing * Interactions * Contraindications * Precautions Documented hypersensitivity * Dosing * Interactions * Contraindications * Precautions Pregnancy A - Fetal risk not revealed in controlled studies in humans Precautions Patients reporting discomfort during application are likely sensitive to preservative and should switch to preservative-free preparations; patients needing to apply artificial tears more frequently than q4h should consider more viscous preparation(s) or preparations without preservatives; caution patients who use more viscous preparations about visual acuity after application because of potential film on the eye; more viscous preparations also have the potential to cause blepharitis Artificial saliva agents These agents provide topical therapy for dry mouth. Artificial saliva Preparations typically contain methylcellulose, sorbitol, and salts to moisten and lubricate the mouth. * Dosing * Interactions * Contraindications * Precautions Adult Spray directly into mouth for 1-2 s prn For nasal crusting, spray on to cotton swab and apply to nose Pediatric Administer as in adults * Dosing * Interactions * Contraindications * Precautions None reported * Dosing * Interactions * Contraindications * Precautions Documented hypersensitivity * Dosing * Interactions * Contraindications * Precautions Pregnancy A - Fetal risk not revealed in controlled studies in humans Precautions Avoid spraying into eyes Disease-modifying agents These agents are used to treat arthritis associated with Sjögren syndrome unresponsive to NSAIDs. Hydroxychloroquine (Plaquenil) Antimalarial agent. Many hypotheses exist regarding its mechanism of action, but mechanism of action in inflammatory arthritis is unknown. * Dosing * Interactions * Contraindications * Precautions Adult 200 mg PO bid Pediatric Not established * Dosing * Interactions * Contraindications * Precautions Serum levels increase with cimetidine; magnesium trisilicate may decrease absorption * Dosing * Interactions * Contraindications * Precautions Documented hypersensitivity; retinal and visual-field changes attributable to 4-aminoquinolones * Dosing * Interactions * Contraindications * Precautions Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus Precautions Caution in hepatic disease, G-6-PD deficiency, psoriasis, and porphyria; not recommended for long-term use in children; perform periodic (every 6 mo) ophthalmologic examinations; test periodically for muscle weakness; associated with nausea, vomiting, diarrhea, tinnitus, headache, dizziness, rash, and stomatitis; transient blurred vision and accommodation problem may occur at initiation of therapy but resolves with continued use Alkylating agents Consider these agents in patients with Sjögren syndrome who develop a major organ manifestation such as interstitial lung disease. Cyclophosphamide (Cytoxan) Alkylating agent with potent immunosuppressant properties. Dosage adjustments based on monitoring clinical response and CBC count or nadir CBC count. * Dosing * Interactions * Contraindications * Precautions Adult 1-3 mg/kg/d PO Alternatively, 0.75 g/m2 IV monthly pulse therapy; range is 0.5-1 g/m2 Pediatric Not established * Dosing * Interactions * Contraindications * Precautions Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones; chloramphenicol may increase half-life while decreasing metabolite concentrations; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase rate of metabolism and leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity * Dosing * Interactions * Contraindications * Precautions Documented hypersensitivity; severely depressed bone marrow function * Dosing * Interactions * Contraindications * Precautions Pregnancy D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus Precautions Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; PO therapy mandates weekly CBC count initially and eventually adjusted to q2-4wk; with IV therapy check nadir CBC count, first at approximately 7, 10, and 14 d after infusion; regularly examine urine for RBCs, which may precede hemorrhagic cystitis; associated with increased risk for infections and malignancies (ie, lymphoproliferative, myeloproliferative, and bladder cancer); GI distress, infertility, and transient/permanent hair loss also reported Immunomodulators These agents may regulate key immune factors responsible for inflammation. Cyclosporine (Restasis) Used to relieve dry eyes caused by suppressed tear production secondary to ocular inflammation. Thought to act as partial immunomodulator. Exact mechanism of action is not known. * Dosing * Interactions * Contraindications * Precautions Adult Instill 1 gtt in each eye q12h Pediatric <16 years: Not established >16 years: Administer as in adultsFollow-up
Further Outpatient Care

* Most patients with Sjögren syndrome can be monitored at follow-up visits every 3 months and, if the patient is stable, up to every 6 months. Patients with active problems or in whom an emerging associated illness is a concern can be seen as often as monthly.

Complications

* Emergence of other disorders associated with Sjögren syndrome, such as SLE and RA
* Infection of the parotid gland, typically staphylococcal, streptococcal, or pneumococcal: Clues include unilateral worsening of symptoms, along with tenderness, warmth, and erythema.
* Emergence of parotid tumors: Watch for unusually hard or unilateral parotid enlargement.
* Emergence of pseudolymphomas (pleomorphic cells that do not meet the criteria for malignancy) and non-Hodgkin B-cell lymphomas (NHL)47
o Among patients with Sjögren syndrome, the incidence of non-Hodgkin lymphoma is 4.3% (18.9 times higher than in the general population), with a median age at diagnosis of 58 years.
o The mean time to the development of non-Hodgkin lymphoma after the onset of Sjögren syndrome is 7.5 years.
o The most common histologic subtype of non-Hodgkin lymphoma in Sjögren syndrome is mucosa-associated lymphoid tissue (MALT) lymphoma, which can develop in any nonlymphoid tissue infiltrated by periepithelial lymphoid tissue—most commonly salivary glands, but also stomach, nasopharynx, skin, liver, kidney, and lung. The progression of these infiltrates to lymphoma occurs slowly and in a stepwise fashion. Lymphoma is present in more than one site in 20% of patients at initial diagnosis.

Sjögren syndrome. Clinical photograph and ph...
Sjögren syndrome. Clinical photograph and photomicrograph of a 48-year-old man with Sjögren syndrome with a large left parotid mass. On biopsy, B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type was identified. Microscopic section of parotid biopsy, stained with immunoperoxidase for kappa light chains (brown-stained cells), showed monoclonal population of B cells, confirming the diagnosis.

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Sjögren syndrome. Clinical photograph and ph...

Sjögren syndrome. Clinical photograph and photomicrograph of a 48-year-old man with Sjögren syndrome with a large left parotid mass. On biopsy, B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type was identified. Microscopic section of parotid biopsy, stained with immunoperoxidase for kappa light chains (brown-stained cells), showed monoclonal population of B cells, confirming the diagnosis.
o Patients at an increased risk of lymphoma include those with regional or generalized lymphadenopathy, hepatosplenomegaly, palpable purpura, leukopenia, renal insufficiency, loss of a previously positive polyclonal gammopathy or RF, development of a monoclonal gammopathy, or the development of a monoclonal cryoglobulinemia.
* Neonatal lupus and congenital heart block: Children born to mothers with antibodies against SSA/Ro are at an increased risk of neonatal lupus and congenital heart block. If one such child develops congenital heart block, the risk for congenital heart block during a subsequent pregnancy is 15%.
* Antiphospholipid syndrome: patients with Sjögren syndrome who have antiphospholipid antibodies can develop the clinical features of this syndrome. These include increased fetal wastage and vascular thromboses.

Prognosis

* Sjögren syndrome carries a generally good prognosis. In patients who develop a disorder associated with Sjögren syndrome, the prognosis is more closely related to the associated disorder (eg, SLE, lymphoma).
* Although salivary and lacrimal function generally stabilize, the presence of SSa and/or hypocomplementemia may predict a decline in function.57

Patient Education

* Educate patients with Sjögren syndrome on avoidance strategies and self-care issues for the treatment of dry mouth, eyes, skin, and vagina (see Medical Care).
* Patient education pamphlets are available through the Arthritis Foundation.
* Patients may find the newsletter Moisture Seekers, published by the Sjögren's Syndrome Foundation, useful.
* For excellent patient education resources, visit eMedicine's Arthritis Center. Also, see eMedicine's patient education article Sjögren Syndrome.

Miscellaneous
Medicolegal Pitfalls

* Failure to monitor and evaluate for parotid tumor or lymphoma