AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Sjögren syndrome (SS) is characterized by lymphocytic infiltrates in exocrine organs. Typically, most patients present with sicca symptoms, such as xerophthalmia (dry eyes), xerostomia (dry mouth), and parotid gland enlargement. However, numerous extraglandular features may also be present, such as arthralgia, arthritis, Raynaud phenomenon, myalgia, pulmonary disease, gastrointestinal disease, leukopenia, anemia, lymphadenopathy, neuropathy, vasculitis, renal tubular acidosis, and lymphoma.

SS is sometimes called primary SS when no other underlying rheumatic disorder is present, whereas SS is sometimes called secondary SS if it is associated with another underlying rheumatic disease, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), or scleroderma (Scl). Given the overlap of SS with many other rheumatic disorders, determining whether a clinical manifestation is solely a consequence of SS or is due to one of its overlapping disorders is sometimes difficult. Importantly, classic clinical features of SS may also be seen in viral infections with hepatitis C, human immunodeficiency virus (HIV), and human T-cell lymphotrophic virus. Treatment for SS is largely based on symptoms, but patients must be watched carefully for the potential development of lymphoma.

Pathophysiology

The pathophysiology of SS is not well understood. A genetic predisposition exists for the disease, and, interestingly, the genetic association varies among ethnic groups. In white persons, for instance, a linkage exists to human leukocyte antigen (HLA)–B8, HLA-Dw3, and HLA-DR3; whereas the linkage is to HLA-DRw53 in Japanese persons and to HLA-DR5 in Greek and Israeli persons. Some evidence indicates that the true association of SS may be with HLA-DQA1, which is in linkage disequilibrium with HLA-DR3 and HLA-DR5.

Whereas major histocompatibility complex (MHC) class II molecules are normally expressed on activated immune cells, these HLA-DR molecules are also expressed at high levels on salivary gland epithelial cells. What triggers these epithelial cells to express MHC class II molecules remains unclear. Viruses are a viable candidate, and some evidence suggests involvement by retroviruses. Alternatively, this enhanced expression could be triggered by cytokines, such as interferon gamma.

T_H1 cytokines are overexpressed in patients with SS. Therefore, these salivary gland epithelial cells that express MHC class II molecules could conceivably act as nonprofessional antigen-presenting cells to CD4⁺ T cells, which then infiltrate the salivary gland and subsequently interfere with its normal glandular function. Although more information is available about the minor salivary gland because of its accessibility, these events could also occur in other exocrine organs.

Another feature of SS is hypergammaglobulinemia and autoantibody formation, especially antinuclear antibody (ANA) and rheumatoid factor (RF). This may be due to polyclonal B-cell activation, but the cause of this activation is not known.

Recent studies suggest that SS has neuroendocrine component to the disease process. Normal salivary and lacrimal output is maintained in animals and humans until the gland is more than 90% destroyed. However, salivary gland biopsy samples from patients with SS 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 SS. Proinflammatory cytokines released by epithelial cells and lymphocytes may impair neural release of acetylcholine. Moreover, a recent investigation reports that M3 muscarinic receptor antibodies may cause autonomic dysfunction in patients with SS.

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

Frequency

United States

SS affects 0.1-3% of the population. This wide range, in part, reflects the lack of uniform diagnostic criteria.

International

SS is observed throughout the world.

Mortality/Morbidity

Morbidity is mainly associated with the gradually decreased function of exocrine organs, which become infiltrated with lymphocytes. Increased mortality is primarily related to disorders commonly associated with SS, such as SLE, RA, and primary biliary cirrhosis. Patients with primary SS have a normal life expectancy, unless they develop a lymphoproliferative disorder.

Race

Persons of all races are affected.

Sex

The female-to-male ratio is 9:1.

Age

SS can affect patients of any age but is most common in elderly people. Onset typically occurs in the fourth to fifth decade of life.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Sicca symptoms (dry eyes and dry mouth)
• • While dry eyes and dry mouth are the most common symptoms in patients with SS, most patients who report these symptoms have other underlying causes. Indeed, more than a third of elderly persons have sicca symptoms.
  • The incidence of sicca symptoms increases with age; however, whether this is a 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.
  • A common explanation for sicca symptoms in any age group is the use of medications, such as antidepressants, anticholinergics, beta-blockers, diuretics, and antihistamines. Also remember that anxiety can lead to sicca symptoms.
  • Patients may report dry mouth in the following ways:
  • • Inability to eat dry food, such as crackers, because it sticks on 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
    • 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
  • Dry eyes may be red, itchy, and painful. However, the most typical complaint is a gritty or sandy sensation in the eyes. Symptoms typically worsen throughout the day, probably due to evaporation of the aqueous layer. Occasionally, patients may awaken with matting in their eyes and, when severe, have difficulty opening their eyes in the morning. Blepharitis can also cause similar morning symptoms.
  • Patients can also have difficulty with dry skin and a dry vagina that can lead to dyspareunia.
• Parotitis
• • Patients may have a history of recurrent parotitis, often bilateral.
  • Occasionally, the parotid glands are large enough that patients may report this as a problem. More often, the examining physician discovers them.
• Pulmonary symptoms
• • Patients with SS can develop dryness of the tracheobronchial mucosa (xerotrachea), which can manifest as a dry cough.
  • Less often, patients develop dyspnea from an interstitial lung disease that is typically mild.
  • Patients may develop recurrent bronchitis or even pneumonitis (infectious or noninfectious).
• Gastrointestinal symptoms
• • 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.
  • The lack of saliva may lead to impaired clearance of acid and result in gastroesophageal reflux and esophagitis.
  • Abdominal pain and diarrhea can occur. Rarely, patients develop acute or chronic pancreatitis and malabsorption due to pancreatic insufficiency. However, be cautious when interpreting the results from laboratory studies because an elevated amylase level may arise from the parotid gland.
• Skin and related symptoms
• • Palpable purpura develops in some patients with SS, especially those with hypergammaglobulinemia or cryoglobulinemia.
  • Raynaud phenomenon is observed in approximately 20% of patients.
• Neurologic symptoms
• • The occurrence of central nervous system involvement in SS is controversial. While one center reports a high incidence of a variety of central neurological problems associated with SS, including seizures and dementia, this has not been observed in other studies.
  • Symmetric, peripheral, sensory neuropathies are found in up to 10% of patients.
  • Cranial neuropathies can develop, particularly trigeminal neuropathy or facial nerve palsy.
  • Mononeuritis multiplex should prompt a search for a vasculitis.
• Other symptoms
• • SS 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, and primary biliary cirrhosis, among others.
  • Patients with SS may report fatigue, joint pain, and, sometimes, joint swelling.
  • Women with SS may have a history of recurrent miscarriages or stillbirths, and 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
• • While looking for corneal lesions and a decreased tear pool in the lower conjunctiva during physical examination is important, patients should be referred to an ophthalmologist for more formal testing for keratoconjuctivitis sicca.
  • Patients may have dilation of the conjunctival vessels.
  • Pericorneal injection and dullness or irregularity of the corneal image may be present.
  • Blepharitis may be present as an alternate or additional problem, particularly if the lower eyelid is inflamed.
  • 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.
  • In a 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 be useful to help exclude or confirm significant dryness of the eyes, but it is not disease-specific. Furthermore, false-positive results occur. Indeed, in one study of asymptomatic patients, 41% had an abnormal Schirmer test result but had normal findings after minor salivary gland biopsy.
• Mouth examination
• • Look for a decreased sublingual salivary pool.
  • The tongue may stick to the tongue depressor.
  • Patients 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.
  • Patients 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.
• Ear, nose, and throat examination
• • Bilateral parotid gland enlargement is common in persons with SS. Some waxing and waning of size may occur. Exudates from the parotid gland are largely lymphocytes.
  • Submandibular glands can be enlarged.
  • 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 can be due to SS, infection, or obstruction, although the latter two conditions are more often associated with a very tender parotid gland and accompanying fever.
• Joint examination
• • Arthritis may be a component of primary or secondary SS.
  • Symmetric, polyarticular, inflammatory arthritis suggests underlying RA or a connective tissue disease such as SLE or scleroderma.
  • The arthritis in patients with primary SS is typically nonerosive and mild.
  • One third of patients with RA have SS.
• Pulmonary examination: Bibasilar rales can be heard in patients with interstitial lung disease.
• Skin examination
• • Patients 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.
  • Patients can also develop urticarial vasculitis, erythema multiforme–like lesions, digital vasculitis, petechiae, erythema nodosum, and annular erythematous plaques.
• Other
• • Signs of another connective tissue disease (secondary SS) may be present, such as SLE, scleroderma, or polymyositis.
  • 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 SS is not known 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 SS is much more common in women.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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
Therapeutic radiation or surgery to the head and neck
Age

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)

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

Acquired immunodeficiency syndrome
Rheumatoid arthritis
Systemic lupus erythematosus
Scleroderma
Polymyositis
Primary biliary cirrhosis
Thyroiditis
Chronic active hepatitis
Mixed cryoglobulinemia

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• CBC count
• • The CBC count is most often within reference ranges, but anemia of chronic disease may be present.
  • Pernicious anemia may possibly be associated with the atrophic gastritis.
  • An abnormal WBC count, especially with an abnormal differential count, should prompt concerns for a lymphoreticular tumor.
  • Low platelet or WBC count can occur in persons with primary SS but should also prompt consideration for coexisting SLE.
• Chemistry
• • A high total protein level or a low albumin level should prompt the clinician to perform serum protein electrophoresis.
  • A high alkaline phosphatase level should prompt consideration for primary biliary cirrhosis.
  • 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 are observed in 5-10% of patients with SS.
  • Consider evaluating patients with a low bicarbonate level for type I (distal) renal tubular acidosis (RTA). Less commonly, patients can also develop proximal RTA with Fanconi syndrome.
  • Hypokalemia, occasionally severe enough to lead to periodic paralysis, can be observed in patients with type I RTA but can also be observed in patients who have SS without RTA.
• Serum protein electrophoresis
• • Patients with SS often have a polyclonal gammopathy.
  • Loss of a previously detected polyclonal gammopathy can be observed in some patients with SS who develop lymphoma.
  • Development of a monoclonal gammopathy can also signal the development of a lymphoma.
• The sedimentation rate is often elevated, but this finding is nonspecific.
• Rheumatoid factor
• • Positive RF findings are typically found in most patients with SS, 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 SS who develop lymphoma.
• ANA: ANAs are typically present in patients with SS. Consider the diagnosis of SLE only if symptoms and signs typical of this disorder are present.
• Antibodies to SS antigen A (SS-A/Ro) and SS antigen B (SS-B/La)
• • Although measuring these autoantibodies can help in the diagnosis of SS, they are not necessary and can sometimes be misleading.
  • Antibodies against SS-A/Ro are found in approximately 50% of patients with the disease (75% of patients with primary SS and 15% of patients with secondary SS). Thus, the absence of anti-SS-A/Ro antibodies does not eliminate the diagnosis of primary or secondary SS.
  • Antibodies against SS-A/Ro are present in 50% of patients with SLE and are sometimes found in healthy individuals. Thus, by itself, the presence of antibody against SS-A/Ro cannot establish a diagnosis of SS.
  • Finding antibodies against SS-B/La in patients without antibodies against SS-A/Ro is unusual, but this combination has occurred in patients with primary biliary cirrhosis and autoimmune hepatitis.
  • Antibodies against SS-B/La are present in 40-50% of patients with primary SS 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 SS-A/Ro and SS-B/La are more sensitive than previous tests. Thus, the specificity is lower.
  • Antibodies against SS-A/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 (ie, rash, congenital heart block), and some of these mothers have or will develop SS.
• Antiphospholipid antibodies: Patients with primary SS 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.
• Cryoglobulins: Type II cryoglobulins are noted, particularly in patients with palpable and nonpalpable vasculitic purpura. Hepatitis C should be sought in these patients.
• Thyroid-stimulating hormone: In some studies, patients with SS have an increased frequency of autoimmune thyroid disease with hypothyroidism (10-15%). Lymphocytic infiltration can be observed in the thyroid gland.

Imaging Studies

• Sialography
• • 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 SS is seen in a variety of other diseases and, therefore, is not specific.
  • Oil-based contrast medium may not be adequately cleared in patients with SS 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 a good measurement of salivary gland dysfunction. However, the finding of low flow rates is not specific to SS.

Other Tests

• Rose bengal staining
• • Rose bengal is an aniline dye that stains devitalized cells and is more sensitive than fluorescein staining.
  • Conjunctival staining can be detected with the naked eye.
  • Slit-lamp examination is performed after rose bengal staining to detect abnormal uptake in the cornea.
• 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 SS has elevated levels of sodium, chloride, lactoferrin, and immunoglobulin A, but these findings are not specific.

Procedures

• Minor salivary gland biopsy
• • In this procedure, an incision is made on the inner lip, and some minor salivary glands are removed for examination.
  • Obtaining the biopsy sample from below normal-appearing mucosa is important in order to avoid false-positive results.
  • At least 4 salivary gland lobules should be obtained for analysis.
  • Currently, this is the best single test to establish a diagnosis of SS.
  • While this is the most definitive test, performing it is not absolutely necessary from a clinical standpoint. Patients with SS 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.
  • Biopsy can also help in the differential diagnosis because noncaseating granulomas of sarcoidosis can be found.

Histologic Findings

Although pathologists use different classification systems, the characteristic findings after minor salivary gland biopsy in a person with SS include the following:

• Focal aggregates of at least 50 lymphocytes are seen and, to a lesser extent, plasma cells and macrophages.
• More than 1 focal aggregate is seen per 4 mm².
• T cells are present that are predominantly CD4⁺ cells, unlike the predominately CD8⁺ T cells seen in the salivary gland biopsy samples from patients with DILS associated with HIV disease.
• Lymphocytic replacement of the normal acini occurs.
• 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. The results of 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 and the noncaseating granulomas of sarcoidosis.

Classification criteria

A number of classification criteria for SS were designed primarily for clinical research studies but are also often used to help guide clinicians in the diagnosis of their patients. The American-European Consensus criteria for the classification of SS are outlined below. These criteria allow the classification of SS in patients without sicca symptoms or who have note undergone a biopsy.

According to the American-European Consensus criteria, diagnosis of primary SS requires 4 of 6 of the below criteria; in addition, either criterion number 5 or criterion number 6 must be included. Diagnosis of SS can be made in patients who have no sicca symptoms if 3 of 4 objective criteria are fulfilled. The criteria are as follows:

1. Ocular symptoms

• Dry eyes for more than 3 months
• Foreign-body sensation
• Tear substitutes are used more than 3 times per day

2. Oral symptoms

• Feeling of dry mouth
• Recurrently swollen salivary glands
• Liquids are frequently used to aid swallowing

3. Ocular signs

• Schirmer test performed without anesthesia (£5 mm in 5 min)
• Positive vital dye staining results

4. Oral signs

• Abnormal salivary scintigraphy findings
• Abnormal parotid sialography findings
• Abnormal sialometry findings (unstimulated salivary flow <0.1 mL/min

5. Positive lip biopsy findings

6. Positive anti–SS-A or anti–SS-B antibody results

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Dry eyes
• • Artificial tears should be applied liberally.
  • • Patients may need to apply artificial tears more often if they enter an environment with low humidity (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.
    • If patients wake up in the morning with severe matting in the eyes, then they should use a more viscous preparation, such as 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 can occasionally lead to blepharitis, which can exacerbate sicca symptoms.
  • Temporary plugging of the lacrimal puncta can increase the amount of tears that remain in the eyes. Electrocautery and other techniques can be used for permanent punctal occlusion.
  • Patients should avoid medications with anticholinergic and antihistamine effects.
  • The use of humidifiers may help. If living in an area with hard water, using distilled water is best.
  • Glasses fitted with moisture shields can decrease evaporation.
• Dry mouth
• • Patients 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 is variable. 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 SS. 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 be needed occasionally. 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.
  • Use of humidifiers may help. For patients living in an area with hard water, using distilled water is best.
  • 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 SS. This medication, however, does not relieve sicca symptoms.
  • Patients with RA associated with SS 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 to treat serious manifestations of SS or disorders associated with SS, clinicians should understand that these agents are also associated with the development of lymphomas.
• Anticoagulation: Long-term anticoagulation may be needed in those 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: SS and its associated disorders necessitate a total patient perspective that is often best provided by an internist.
• Rheumatologist: With specific training and experience in this disorder and its associated disorders, a rheumatologist is a key person in the management of patients with SS.
• 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 damage to the eye.
• Otolaryngologist: Consultation 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 may need to be seen by other specialists, including the following:
• • Nephrologist to help manage RTA
  • Pulmonologist to help manage interstitial lung disease
  • Hematologist/oncologist if pseudolymphoma or lymphoma develops

Activity

Encourage patients to be active.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Most patients 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 xerostomia for which systemic therapy is needed or local therapy is not successful.

Drug Category: Cholinergic parasympathomimetic agents

Can increase salivary secretion by salivary glands.

Drug Category: Natural tears

Various OTC preparations of natural tears are available that provide topical therapy for dry eyes. Encourage patients to try different preparations to determine which works best for them.

Drug Category: Artificial saliva agents

Provide topical therapy for dry mouth.

Drug Category: Disease-modifying agents

Treat arthritis associated with SS unresponsive to NSAIDs.

Drug Category: Alkylating agents

Consider for patients with SS who develop a major organ manifestation such as interstitial lung disease.

Drug Category: Cholinergic parasympathomimetic agents

Bind to cholinergic (muscarinic) receptors, causing increase in secretion of exocrine glands, including salivary glands.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Most patients can be monitored at follow-up visits every 3 months and, if the patient is stable, up to every 6 months. If patients have active problems or in case of concern about an emerging associated illness, patients can be seen as often as monthly.

Complications

• Emergence of other associated disorders such as SLE and RA
• Infection of the parotid gland, typically due to staphylococci, streptococci, or pneumococci: 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
• • Patients with SS have a 44-fold increased risk of developing lymphoma, with an overall frequency of 5-8%. However, the increased risk has not been found in all studies.
  • The mean time to development of non-Hodgkin lymphoma is 7.5 years.
  • Watch for 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 SS-A/Ro have an increased risk of developing neonatal lupus and congenital heart block. If one child develops congenital heart block, the risk for congenital heart block during a subsequent pregnancy is 15%.
• Antiphospholipid syndrome: Patients with SS who have antiphospholipid antibodies can develop the clinical features of this syndrome. These include increased fetal wastage and vascular thromboses.

Prognosis

• The prognosis is generally good. If patients develop an associated disorder, the prognosis is more closely related to the associated disorder (eg, SLE, lymphoma).

Patient Education

• Educate patients on avoidance strategies and self-care issues noted 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

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to monitor and evaluate for parotid tumor or lymphoma

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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• Constantopoulos SH, Tsianos EV, Moutsopoulos HM. Pulmonary and gastrointestinal manifestations of Sjogren''s syndrome. Rheum Dis Clin North Am. Aug 1992;18(3):617-35. [Medline].
• Daniels TE. Labial salivary gland biopsy in Sjogren''s syndrome. Assessment as a diagnostic criterion in 362 suspected cases. Arthritis Rheum. Feb 1984;27(2):147-56. [Medline].
• Daniels TE, Fox PC. Salivary and oral components of Sjogren''s syndrome. Rheum Dis Clin North Am. Aug 1992;18(3):571-89. [Medline].
• Fox RI, Saito I. Criteria for diagnosis of Sjogren''s syndrome. Rheum Dis Clin North Am. May 1994;20(2):391-407. [Medline].
• Fox RI. Treatment of the patient with Sjogren''s syndrome. Rheum Dis Clin North Am. Aug 1992;18(3):699-709. [Medline].
• Friedlaender MH. Ocular manifestations of Sjogren''s syndrome: keratoconjunctivitis sicca. Rheum Dis Clin North Am. Aug 1992;18(3):591-608. [Medline].
• Haddad J, Deny P, Munz-Gotheil C, et al. Lymphocytic sialadenitis of Sjogren''s syndrome associated with chronic hepatitis C virus liver disease. Lancet. Feb 8 1992;339(8789):321-3. [Medline].
• Itescu S, Winchester R. Diffuse infiltrative lymphocytosis syndrome: a disorder occurring in human immunodeficiency virus-1 infection that may present as a sicca syndrome. Rheum Dis Clin North Am. Aug 1992;18(3):683-97. [Medline].
• Jacobsson LT, Axell TE, Hansen BU, et al. Dry eyes or mouth--an epidemiological study in Swedish adults, with special reference to primary Sjogren''s syndrome. J Autoimmun. Aug 1989;2(4):521-7. [Medline].
• Provost TT, Watson R. Cutaneous manifestations of Sjogren''s syndrome. Rheum Dis Clin North Am. Aug 1992;18(3):609-16. [Medline].
• Ramos-Casals M, Font J. Primary Sjogren's syndrome: current and emergent aetiopathogenic concepts. Rheumatology (Oxford). Nov 2005;44(11):1354-67. [Medline].
• Schein OD, Hochberg MC, Munoz B, et al. Dry eye and dry mouth in the elderly: a population-based assessment. Arch Intern Med. Jun 28 1999;159(12):1359-63. [Medline].
• de Wilde PC, Kater L, Bodeutsch C, et al. Aberrant expression pattern of the SS-B/La antigen in the labial salivary glands of patients with Sjogren''s syndrome. Arthritis Rheum. May 1996;39(5):783-91. [Medline].

Article Last Updated: May 4, 2006