eMedicine Specialties > Rheumatology > Systemic Rheumatic Disease

Sjogren Syndrome

Author: Anne V Miller, MD, Assistant Professor of Medicine, Division of Rheumatology, Southern Illinois University School of Medicine
Coauthor(s): Sriya K M Ranatunga, MD, MPH,, Assistant Professor, Department of Clinical Medicine, Southern Illinois University School of Medicine; Mark L Francis, MD, Chief, Associate Professor, Department of Internal Medicine, Division of Rheumatology, Southern Illinois University School of Medicine
Contributor Information and Disclosures

Updated: Mar 13, 2009

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)
  • 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
  • Common medications that can result in sicca symptoms in any age group include antidepressants, anticholinergics, beta-blockers, diuretics, and antihistamines.
  • Anxiety can also lead to sicca symptoms.
  • 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
  • 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.
  • Patients may also have difficulty with dry skin and a dry vagina that can lead to dyspareunia, vaginitis, and pruritus.
  • Nasal dryness can result in discomfort and bleeding
  • Women who use hormone replacement therapy may be at increased risk of dry eye syndrome.¹⁹
• Parotitis
  • Patients with Sjögren syndrome may have a history of recurrent parotitis, often bilateral.
  • Some patients have parotid glands large enough that they report this as a problem. More often, the examining physician discovers them.

• Skin and related symptoms
  • Nonvasculitic cutaneous manifestations in Sjögren syndrome include dryness, eyelid dermatitis, pruritus, and erythema annulare.²¹
  • Cutaneous vasculitis such as palpable purpura develops in some patients with Sjögren syndrome, especially those with hypergammaglobulinemia or cryoglobulinemia.^22,21
  • Raynaud phenomenon is observed in approximately 20% of patients.
  • For more information on cutaneous manifestations of Sjögren syndrome, see the article Sjogren Syndrome in eMedicine’s Dermatology volume.
• Pulmonary symptoms
  • Patients with Sjögren syndrome can develop dryness of the tracheobronchial mucosa (xerotrachea), which can manifest as a dry cough.²³
  • Less often, patients develop dyspnea from an interstitial lung disease that is typically mild.^23,24
  • Patients may develop recurrent bronchitis or even pneumonitis (infectious or noninfectious).
• Gastrointestinal symptoms²³
  • 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.
  • Lack of saliva may lead to impaired clearance of acid and may result in gastroesophageal reflux and esophagitis.
  • 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.
  • In patients with gastritis, Helicobacter pylori infection should be sought because of its association with gastric mucosa-associated lymphoid tissue lymphomas.²⁵
• Cardiac symptoms
  • Pericarditis and pulmonary hypertension, with their attendant symptomatology, can occur in Sjögren syndrome.²⁶
  • Orthostatic symptoms related to dysfunction of autonomic control of blood pressure and heart rate is associated with increased severity of Sjögren syndrome²⁷
• Neurologic symptoms
  • 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.
  • 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.
  • Cranial neuropathies can develop, particularly trigeminal neuropathy or facial nerve palsy.
  • Mononeuritis multiplex should prompt a search for a vasculitis.
  • Progressive weakness and paralysis secondary to hypokalemia due to underlying renal tubular acidosis can occur and is potentially treatable.³¹
• Renal symptoms
  • 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.
  • Interstitial cystitis, with symptoms of dysuria, frequency, urgency, and nocturia, is strongly associated with Sjögren syndrome.^32,33
  • 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
  • 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
  • Patients with Sjögren syndrome may report fatigue, joint pain, and, sometimes, joint swelling.
  • 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
  • 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.
  • Patients with Sjögren syndrome may have dilated conjunctival vessels.
  • Patients may have pericorneal injection, as well as dullness or irregularity of the corneal image.
  • 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 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 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.

    [ CLOSE WINDOW ]

    

    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
  • Look for a decreased sublingual salivary pool.
  • The tongue may stick to the tongue depressor.
  • 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.
  • 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 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.

    [ CLOSE WINDOW ]

    

    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
  • 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 gland enlargement in a patient with primary Sjögren syndrome. Sicca syndrome is a common clinical finding.

    [ CLOSE WINDOW ]

    

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

  • 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 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
  • Arthritis may be a component of primary or secondary Sjögren syndrome.
  • Symmetric, polyarticular, inflammatory arthritis suggests underlying RA or a connective-tissue disease such as SLE or scleroderma.
  • The arthritis in patients with primary Sjögren syndrome is typically nonerosive and mild.
  • One third of patients with RA have Sjögren syndrome.
• Pulmonary examination: Bibasilar rales can be heard in patients with interstitial lung disease.
• Skin examination
  • 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
  • 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 Sjögren syndrome) 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 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.

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