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 a chronic systemic disorder characterized by polyglandular tissue destruction that causes keratoconjunctivitis sicca (KCS) and xerostomia. Patients with primary SS have KCS and xerostomia, whereas those with secondary SS have KCS, xerostomia, and an autoimmune disease. Most commonly, this autoimmune disease is rheumatoid arthritis (RA); however, it can also be systemic lupus erythematosus (SLE), systemic sclerosis (SSc), mixed connective tissue disease (MCTD), or subacute cutaneous lupus erythematosus (SCLE). In addition to primary SS and secondary SS, juvenile SS is another subtype. Some patients with lacrimal gland enlargement resulting from lymphocytic infiltration may represent a new subtype of primary SS.¹

The following eMedicine articles may be of interest:

• Lupus Erythematosus, Subacute Cutaneous
• Rheumatoid Arthritis
• Mixed Connective Tissue Disease
• Systemic Lupus Erythematosus
• Systemic Sclerosis

Additionally, the Medscape Sjogren's Syndrome Resource Center and Lupus Resource Center may be of interest.

Pathophysiology

SS is caused by certain factors that lead to autoimmune dysregulation, which results in the destruction of the acinar cells and ductal epithelia with subsequent dry eyes and dry mouth. In patients with autoimmune diseases, activated lymphocytes selectively migrate into the lacrimal and salivary glands, leading to tissue damage.

Antimuscarinic antibodies in primary SS reversibly inhibit the mechanism of fluid secretion by human submandibular salivary acinar cells. A clearly defined pathogenic autoantibody has not been identified, although autoantibodies that bind to the muscarinic M(3) receptors (M(3)R), which regulate fluid secretion in salivary glands, have been proposed. One recent study showed that immunoglobulin G (IgG) antimuscarinic antibodies in primary SS reversibly inhibit the mechanism of fluid secretion by human submandibular salivary acinar cells.²

The etiology and pathophysiology of SS are still unknown. Autoimmunologic factors and a genetic predisposition are associated with SS. The following human leukocyte antigens (HLAs) increase the risk of SS: DRB1, DRB3, DR5, DRw11, DR52, DRw53, DQA1*0501, DQB1*0201, and DQB1*0301. A strong association between SS and HLA-DR3 is observed. The frequency of HLA-DR52 in patients with primary SS is estimated to be 87%, but it is also significantly increased in secondary SS that occurs with RA or SLE. Anti-Ro/SS-A and anti-La/SS-B antibodies are strongly associated with HLA-DR2 and HLA-DR3. (The latter is a correlate of the severity of the disease rather than a predisposing factor.) Polymorphism of the mannose-binding lectin gene seems to be one of the genetic factors that determines an individual's susceptibility to SS.

Viral infection could be involved in the induction of SS. Epstein-Barr virus (EBV), human T-lymphotrophic virus 1 (HTLV-1), human herpesvirus 6 (HHV-6), human immunodeficiency virus 1 (HIV-1), hepatitis C virus (HCV), and cytomegalovirus (CMV) may have a role.

Polyclonal B-lymphocyte hyperreactivity is one of the most important immunologic phenomena. It results in hypergammaglobulinemia and the presence of the following immune complexes and various antibodies: anti-Ro/SS-A, anti-La/SS-B (95%), rheumatoid factor, antithyroglobulin antibodies (25%), antimicrosomal antibodies, histone antibodies (occasionally), anti-U4/U6snRNP-specific antibodies (uniquely), autoantibodies against platelet GPIIb-IIIa complex, anti-ssDNA antibodies, cryoglobulins, both cytoplasmic and perinuclear antineutrophil cytoplasmic antibodies (ANCA), and precipitating antibodies to extracts of lacrimal and salivary glands.

An autoimmune etiology also is proven by the occurrence of a SS-type syndrome after allogenic bone marrow transplantation. A selective defect in aquaporin-5 is suggested to contribute to decreased lacrimation and dry eyes in patients with SS. An anti–120-kd alpha-fodrin immune response plays a critical role in the development of primary SS. Alpha-fodrin proteolysis and tissue destruction are due to apoptosis, activated by EBV infection, among other causes.

Proapoptotic molecules Bax and caspase 3 are overexpressed in the salivary gland epithelial cells. Intense B lymphocyte infiltration (20-25%) and CD4⁺ T-cell infiltration (70-80%) localized in the salivary glands leads to the destruction of epithelial cells. The role of various cytokines, such as tumor necrosis factor-alpha, is also considered in the development of SS. High expression of the intercellular adhesion molecule 1 (ICAM-1) by the salivary epithelium in patients with SS suggests that it has an important role in the pathogenesis of the disease.

Sex may influence the immunologic manifestations of primary SS. The prevalence of serologic markers tends to be lower in male patients than in female patients. The role of sex hormones (eg, estrogens, androgens) in the pathogenesis of primary SS remains unknown, although adrenal and gonadal steroid hormone deficiency probably affects the immune function of the organism.

The titers of anti-Ro and anti-La antibodies are correlated with the severity of the disease and the presence of extraglandular manifestations of SS. These autoantibodies are often present in other diseases, especially SCLE. Anti-Ro antibodies are particularly associated with vasculitis, purpura, lymphadenopathy, and hematologic abnormalities (eg, thrombocytopenia, anemia, lymphopenia). Although the clinical relevance of anti-Ro and anti-La antibodies is obvious, their immunopathogenic role is not fully elucidated. The pathogenesis of juvenile SS seems to be the same as that of adult SS.

Frequency

United States

The prevalence is 4 cases per 100,000 population. A 2008 US Centers for Disease Control and Prevention study estimates that SS affects 0.4-3.1 million American adults.³

International

Approximately 1-3% of the general population is affected. SS is often underdiagnosed.

Mortality/Morbidity

• The prognosis with SS is generally better than that of other autoimmune diseases (eg, SLE, RA).
• Death occurs, especially in secondary SS and in cases with myelopathy.
• To the authors' knowledge, no data are available regarding mortality and morbidity rates in persons with SS.

Race

No racial predilection is recognized.

Sex

Women are affected more often than men; the female-to-male ratio is 9:1.

Age

SS may occur in persons of any age, but it usually occurs in persons aged 30-50 years. The disease rarely affects children.

CLINICAL

Section 3 of 10  

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

History

The clinical presentation of SS may vary. The onset is insidious. It usually starts in women aged 40-60 years, but it also can affect men and children. The first symptoms in primary SS can be easily overlooked or misinterpreted, and diagnosis can be delayed for as long as several years.

Xerophthalmia and xerostomia are the main clinical presentations in adults. Bilateral parotid swelling is the most common sign of onset in children. Symptoms of SS can decrease the patient's quality of life in terms of its physical, psychological, and social aspects.

SS is diagnosed on the basis of either European or San Diego classification criteria.

• European classification
• • Ocular symptoms - Positive response to 1 of 3 questions pertaining to dry eyes
  • Ocular signs - Positive Schirmer test (<5 mm in 5 min) or positive rose bengal staining
  • Oral symptoms - Positive response to 1 of 3 questions pertaining to dry mouth
  • Salivary gland involvement - Objective evidence of salivary gland involvement; salivary scintigraphy; parotid sialography; unstimulated salivary flow less than 1.5 mm/min
  • Serologic or autoantibody test results - Presence of autoantibodies to Ro (SS-A), La (SS-B), or both
  • Categories
  • • Primary SS - Presence of any of 4 of the previous 6 categories
    • Secondary SS - Presence of potentially associated connective tissue or autoimmune disease with the first 2 categories (ocular symptoms and ocular signs) plus any 2 of the next 3 categories
• San Diego classification
• • Ocular symptoms - Symptoms of ocular dryness
  • Ocular signs - Positive Schirmer test (<8 mm in 5 min) and positive rose bengal staining of the cornea
  • Oral symptoms - Symptoms of oral dryness
  • Histopathologic findings - Abnormal biopsy findings in a minor salivary gland (focus score >2 in an average of 4 lobules, multiple foci of lymphoid inflammation)
  • Salivary gland involvement - Decreased parotid flow rate (eg, Lashley cups)
  • Serologic or autoantibody test results - Serologic evidence of systemic autoimmunity, rheumatoid factor greater than 1:320 or antinuclear antibody (ANA) level greater than 1:320 or positive result for SS-A (Ro) or SS-B (La) antibodies
  • Categories
  • • Definite - Objective evidence of dry eyes and/or mouth, autoantibody presence, and characteristic results from minor salivary gland biopsy
    • Probable - Same as the above, but results from minor salivary gland biopsy not required
    • Primary SS - Characteristic signs and symptoms (above) without associated autoimmune disease
    • Secondary SS - Same as primary SS plus the presence of rheumatoid factor, SLE, polymyositis, scleroderma, or biliary cirrhosis
• Patients with T-cell (CD3⁺), large, granular lymphocyte leukemia have a high prevalence of autoantibodies and associated autoimmune diseases, including syndromes, which is an important but often underrecognized association.⁴

Physical

Secondary SS appears late in the course of the primary disease. However, in some patients, primary SS may precede SLE by many years. Secondary SS is usually mild, and sicca symptoms are the main feature. Unlike those with primary SS, patients with the secondary type have significantly fewer systemic manifestations. These manifestations include salivary gland swelling, lung involvement, nervous system involvement, renal involvement, Raynaud phenomenon, and lymphoproliferative disorders. In secondary SS, symptoms of the primary disease predominate. Secondary SS does not modify the prognosis or outcome of the basic disease.

The physical symptoms of primary SS can be divided into glandular and extraglandular symptoms.

• Glandular symptoms
• • Ocular
  • • KCS or dry eye syndrome, characterized by chronic dryness of the cornea and conjunctiva
    • Discomfort (eg, irritation, pain, redness, burning, itching, foreign body sensation, photophobia, blurred vision)
  • Mouth
  • • Dryness
    • Tongue - Red, smooth, and dry
    • Dental caries - Severe and progressive
    • Parotid duct narrowing
    • Lips - Red, dry, and scaly
    • Cracks at the corners of the mouth
    • Chronic oral candidiasis
    • Recurrent swelling of the parotid glands (22-66% of patients), sometimes also submaxillary and sublingual glands
  • Other mucous membranes
  • • Atrophic changes in the mucous membranes of the upper respiratory tract leading to nasal dryness, recurrent infections, hoarseness, and aphonia
    • Atrophic rhinitis
    • Atrophic changes in the vulva and vagina resulting in pruritus and vaginitis
    • Dryness of the anal and rectal mucous membranes (eg, pruritus, inflammation)
  • Skin
  • • Dryness of the skin occurs in 50% of patients with SS; scaling occurs in about 25% of patients. The skin may be irritable with secondary lichenification.
    • Partial or complete loss of sweating may be present.
    • Hair may be dry, sparse, and brittle; diffuse alopecia may involve the scalp, limbs, axillae, or pubis.
    • Erythema of the nose and cheeks may be present.
    • Annular erythematous rash with scales, localized especially on the face and neck, is recognized as a cutaneous manifestation of SS. The lesions are recurrent and clear without pigmentation; no photosensitivity is observed.
    • A higher risk of cutaneous vasculitis is noted.
    • In Japanese patients with SS, annular erythema is divided into 3 types: Sweet disease–like annular erythema with an elevated border, SCLE-like marginally scaled erythema, and papular erythema. These lesions bear some clinical similarities to the annular lesions of SCLE, but their histopathologic features are distinct from those of SCLE. Significant mucin depositions are observed.
    • Sjögren vasculitis involves postcapillary venules, typically on the lower legs. These patients were formerly classified as having Waldenström hypergammaglobulinemic purpura.
• Extraglandular symptoms
• • Gastrointestinal tract
  • • Esophageal motility abnormalities
    • Pancreatic involvement
    • Splenomegaly
    • Digestive symptoms (due to atrophy of the gastric mucous membrane with achlorhydria)
    • Hepatitis (13%)
  • Lungs⁵: Pulmonary abnormalities occur in 9-29% of cases; they are similar in both primary and secondary SS.
  • • Pulmonary fibrosis
    • Pulmonary hypertension
    • Recurrent chest infections
    • Granulomatous infiltration and fibrosing alveolitis
    • Restrictive ventilatory defect
    • Impaired gas transfer
  • Articular changes (eg, arthritis): These occur in 42% of patients with SS.
  • Urinary tract: Patients with SS have significantly more urinary problems than those without SS.
  • • Symptoms of an irritated bladder
    • Urinary frequency and suprapubic pain
    • Renal tubular dysfunction: Patients with primary SS commonly are first seen because of renal impairment, usually from renal tubular dysfunction.⁶
    • Renal tubular acidosis: This affects one third of patients with SS. A correlation apparently exists between hypergammaglobulinemia and distal renal tubular acidosis.⁶
    • Interstitial nephritis (This is rare; occurs in 4% of cases; and is often accompanied by cryoglobulinemia, a decreased level of complement, and the presence of circulating immune complexes.)
    • Impaired renal concentrating ability, generalized aminoaciduria
  • Nervous system
  • • A combination of lesions and relapses can suggest multiple sclerosis. Myelopathy rarely occurs in the course of primary SS. It appears as Brown-Séquard syndrome, acute transverse myelitis, or progressive myelopathy. Clinically, cases with nervous system involvement present with paraparesis or paraplegia resulting from lesions at the thoracic or cervicothoracic levels.
    • Peripheral neuropathy occurs in 10-35% patients with primary SS. Peripheral nerve dysfunction may occur; this can include trigeminal sensory neuropathy, mononeuropathy multiplex, distal sensorimotor polyneuropathy, or pure sensory neuropathy. This tends to be a small-fiber peripheral neuropathy.⁷ Painful distal paresthesias in the feet may be evident, as may abnormal sweating. Examination may reveal findings that include decreased pinprick sensation.
    • Isolated cranial nerve involvement rarely occurs in primary SS.
    • Central nervous system involvement is less common (10-25% of patients with SS) than other types of involvement. It ranges from neuropathy, hemiparesis, transverse myelitis, and dystonia to even encephalopathy and dementia.
    • In SS, focal brain lesions can be present in the cerebral white matter.
    • Dysregulation of hypothalamic-pituitary-adrenal and thyroid axes can cause some neurologic disturbances.

Causes

The following are causes of SS.

• Genetic factors
• • The presence of HLA-DRB1, HLA-DRB3, HLA-DR5, HLA-DRw11, HLA-DR52, HLA-DRw53, and other HLAs increase the risk of SS.
  • Polymorphism of the mannose-binding lectin gene is likely to be one of the genetic factors that determines an individual's susceptibility to SS.
• Viral infections
• • Epstein-Barr virus
  • HTLV-1 and HIV-1
  • Human herpesvirus 6
  • Hepatitis C virus
  • Cytomegalovirus
• Autoimmune dysregulation (loss of immune tolerance and production of various autoantibodies, eg, ANA, anti-Ro, anti-La)
• Dysregulation of apoptosis
• Adrenal and gonadal steroid hormone deficiency

DIFFERENTIALS

Section 4 of 10  

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

Other Problems to be Considered

Xerophthalmia, xerostomia, and enlargement of the parotid glands can result from adverse effects of drugs and other diseases.

SS can be underdiagnosed or misdiagnosed. Histologic findings of the following can be consistent with SS: sarcoidosis, graft-versus-host disease, HIV infection, HTLV-1 infection, HCV infection, and KCS.

SLE might be considered, especially at onset of the disease.

Autoimmune thyroid dysfunction may be present.

HIV infection can result in diffuse infiltrative lymphocytosis syndrome (DILS), which is characterized by parotid enlargement; involvement of the renal, lung, and gastrointestinal systems; and a low frequency of autoantibody presence.

Chronic graft versus host disease may mimic symptoms associated with idiopathic SS.⁸

WORKUP

Section 5 of 10  

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

Lab Studies

• Some laboratory tests can be used to assess salivary and lacrimal involvement in SS.
• • However, no single test is sufficiently sensitive or specific in diagnosing SS.
  • SS is properly diagnosed only when the results of various tests are simultaneously positive and when subjective symptoms and serologic abnormalities are present.
• Laboratory test results may indicate the following:
• • Elevated erythrocyte sedimentation rate (ESR)
  • Anemia
  • Leukopenia
  • Eosinophilia
  • Hypergammaglobulinemia
  • Presence of antinuclear antibodies, especially anti-Ro and anti-La
  • Presence of rheumatoid factor
  • Presence of anti–alpha-fodrin antibody (reliable diagnostic marker of juvenile SS)
• Atypical autoantibodies in 82 patients with primary SS were evaluated.⁹ An immunological overlap (defined by the presence of autoantibodies typical of other systemic autoimmune diseases) was evident in 20% of patients with primary SS. The clinical significance of these atypical autoantibodies varied widely.

Imaging Studies

• For the assessment of salivary gland involvement, the following imaging studies are used:
• • Parotid sialography
  • Salivary gland scintigraphy¹⁰
  • Ultrasonography of salivary gland¹¹
  • Magnetic resonance (MR) sialography
• Dynamic contrast-enhanced MR imaging may be valuable to quantify microvascular function in persons with SS and to differentiate between patients with and those without SS.¹²

Other Tests

• The diagnosis of SS is difficult because no good diagnostic test is available; excluding an underlying disease is important.
• Tests that may be helpful in the diagnosis include the following:
• • Schirmer test for assessment of eye function (positive when result is <5 mm)
  • Rose bengal scoring for the assessment of the ocular involvement
  • Minor salivary gland biopsy (widely used)
  • Saliva collection from the mouth - Reduced basal and reflex lacrimation (basal lacrimation of 3 mm and stimulated lacrimation of 4 mm)
  • Esophageal manometry for the assessment of esophageal motor function
  • Electrophysiologic examination for the assessment of peripheral neuropathy

Histologic Findings

Histologic evaluation is valuable for diagnosing SS and in ruling out other pathologic conditions (eg, amyloidosis, sarcoidosis, lymphoma, lipoproteinemia) with sicca manifestation. The histopathologic features of the labial salivary glands concerning the presence of focal lymphocytic sialadenitis in all or most of the glands in the specimen are of great importance in the diagnosis of SS.

Focal lymphocytic sialadenitis (FLS) is defined as multiple, dense, aggregates of 50 or more lymphocytes (1 focus) in perivascular or periductal locations in the gland lobules. FLS is graded in terms of a focus score, which equals the number of foci divided by 4 mm². A score of greater than 1 focus per 4 mm² has a specificity of 83.5-95% and a sensitivity of 63-81.8% in the diagnosis of SS. The focus score may be associated with KCS; presence of autoantibodies; and, less commonly, with xerostomia.

Besides these features, histologic examination may reveal dermal mucin deposition that resembles that of lupus erythematosus tumidus, the absence of sebaceous glands, and a decrease in the number of sweat glands. Cellular infiltration may be observed around the sweat glands. Degenerative changes in the apocrine glands and the external root sheath of hair are reported. Clinical symptoms seem to parallel the histologic changes; therefore, the results of sublabial minor salivary gland biopsy may be considered as markers of disease activity in patients with primary SS.

In patients with a possible diagnosis of SS but severe extraglandular symptoms, a lip biopsy is often performed to firmly establish the diagnosis of SS.  A recent study¹³ showed that not all patients undergoing lip biopsy derive diagnostic benefit from this procedure and that clinical symptoms and serology did not predict a positive lip biopsy.

TREATMENT

Section 6 of 10  

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

Medical Care

No curative agents exist. The treatment of SS is essentially symptomatic. In secondary SS, treatment is based on the accompanying disease and its clinical features. SS and associated SLE improve more than primary SS. In SS associated with polymyositis, monthly cyclophosphamide pulse therapy is useful. In annular erythema in Japanese patients, prednisolone (10-20 mg/d) is effective.

New therapeutic strategies designed to facilitate AQP5 trafficking to the apical plasma membrane might prove useful for the management of dry eyes in SS. The inhibition of protease activity in EBV-mediated apoptotic cells may be a potential therapeutic approach in the treatment of SS.

Treatments and therapeutic agents for specific conditions may include the following:

• Dry eyes
• • Artificial tears (eg, methylcellulose, 1% hyaluronic acid solution, alcohol solutions) applied 4-6 times daily
  • Punctual occlusion with silicone plugs
  • Bromhexine 16 mg 3 times a day
  • Topical cyclosporine A 0.05-0.1% (reduces the lymphocyte infiltration of lacrimal glands)¹⁴
  • The use of ointments and oil-based drugs are contraindicated.
  • A novel device for dry eye patients with and without SS can be used to reduce symptoms.¹⁵
• Dry mouth
• • Frequent small drinks and mouthwashes
  • Artificial saliva
  • Saliva stimulation (eg, by sweets, lemon drops)
  • Use of detergent-free toothpaste and topical use of fluoride
  • Potassium iodine and parasympathetic agents (eg, pilocarpine, neostigmine), bromhexine, trithioparamethoxyphenylpropene
  • Although not widely used, natural human interferon-alfa improves salivary output and decreases the incidence of xerostomia.
• Parotid enlargement
• • Nonsteroid anti-inflammatory drugs (NSAIDs), eg, naproxen
  • Low-dose corticosteroids, eg, prednisone
• Arthritis
• • NSAID, eg, naproxen
  • Low-dose corticosteroids, eg, prednisone
  • Chloroquine and hydroxychloroquine sulphate (not recommended by all the authors)
• Peripheral nerve dysfunction
• • No treatment is known.
  • Plasmapheresis is useful in patients with secondary neuropathy.
• Central nervous system involvement
• • Intravenous corticosteroids plus an immunosuppressive agent (eg, methylprednisolone and cyclophosphamide)
  • Plasmapheresis (Consider this in patients with sensory neuropathy associated with SS.)
• Vasculitis - Immunosuppressive agents, if necessary
• Raynaud phenomenon - Pentoxifylline and nifedipine

Consultations

Consultations with the following specialists may be helpful:

• Rheumatologist
• Ophthalmologist
• Dentist
• Dermatologist
• Neurologist

Activity

Activity should be limited in patients with arthralgia.

MEDICATION

Section 7 of 10  

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

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Corticosteroids

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

Drug Category: Immunosuppressant agents

These agents inhibit cell growth and proliferation, decreasing immune activity.

Drug Category: Nonsteroidal anti-inflammatory agents

These agents have analgesic, anti-inflammatory, and antipyretic activities. Their mechanism of action is not known, but they may inhibit cyclo-oxygenase activity and prostaglandin synthesis. Other mechanisms may exist as well; these include inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, and various cell membrane functions.

Drug Category: Antimalarial agents

Certain types of agents in this class have anti-inflammatory activity.

Drug Category: Immune globulin intravenous

These agents are used to improve the clinical and immunologic aspects of the disease. They may decrease autoantibody production and increase the solubilization and removal of immune complexes.

Drug Category: Lubricants

Lubricants are used to keep as much moisture in the eye as possible and to reduce irritation.

FOLLOW-UP

Section 8 of 10  

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

Further Outpatient Care

• Patients should receive follow-up care by the specialists.

Complications

• Most complications result from concomitant connective tissue diseases.
• The occurrence of B-cell non-Hodgkin lymphoma (NHL) is the major complication in the course of disease in patients with SS.
• • The risk of B-cell NHL is 44 times greater in patients with SS than in a healthy population; NHL affects about 5% patients with SS.
  • NHL occurs preferentially in the salivary glands and in other mucosa-associated lymphoid tissue. However, it can also occur in the lymph nodes or bone marrow.
• Corneal ulceration is a rare complication of SS. It usually occurs secondary to RA.

Prognosis

• SS is a chronic disease that usually has a mild course, but it may be complicated by NHL or severe systemic symptoms.
• Early diagnostic and therapeutic treatment of patients with primary SS, together with close follow-up, may contribute to a significant improvement in their quality of life.¹⁶

Patient Education

• Patients with SS must be informed about the chronic nature of the illness and the goals of therapy.
• Patients with SS should be aware of the possible coexistence of other potentially severe diseases, such as SLE, RA, and SSc.
• 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

• A negative biopsy result in the labial salivary glands or nasal mucosa does not exclude SS.
• Potential effects of corticosteroid and cyclosporine A use should be taken into account when sublabial minor salivary gland biopsy results are interpreted.
• The risk of dental caries is increased in SS; therefore, regular dental assessment is strongly advised.
• Chronic swelling and enlargement of the parotid glands may indicate the development of lymphoma. This possibility should be considered.
• Patients with severe lymphocytic infiltration in the minor salivary gland tissue rarely have kidney involvement. Often, they have lymphadenopathy and circulating rheumatoid factor, cryoglobulins, and anti-Ro/SS-A and anti-La/SS-B antibodies.
• Every patient requires a detailed examination to determine the extent and nature of the associated abnormalities.

Special Concerns

• Juvenile SS should be considered in the differential diagnosis in children with recurrent parotitis, KCS, and pronounced and early tooth decay associated with xerostomia.
• Pregnancies in women with autoantibodies against Ro/SS-A and/or La/SS-B may be associated with a fetal atrioventricular (AV) block.
• • In high-risk pregnancies, the fetal heart rate must be monitored closely, especially from 16 weeks' gestation onward.
  • Dexamethasone treatment should be immediately started when a heart block is detected.

REFERENCES

Section 10 of 10

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

1. Parkin B, Chew JB, White VA, Garcia-Briones G, Chhanabhai M, Rootman J. Lymphocytic infiltration and enlargement of the lacrimal glands: a new subtype of primary Sjögren's syndrome?. Ophthalmology. Nov 2005;112(11):2040-7. [Medline].
2. Dawson LJ, Stanbury J, Venn N, Hasdimir B, Rogers SN, Smith PM. Antimuscarinic antibodies in primary Sjögren's syndrome reversibly inhibit the mechanism of fluid secretion by human submandibular salivary acinar cells. Arthritis Rheum. Apr 2006;54(4):1165-73. [Medline].
3. Helmick CG, Felson DT, Lawrence RC, Gabriel S, Hirsch R, Kwoh CK, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum. Jan 2008;58(1):15-25. [Medline].
4. Friedman J, Schattner A, Shvidel L, Berrebi A. Characterization of T-cell large granular lymphocyte leukemia associated with Sjogren's syndrome-an important but under-recognized association. Semin Arthritis Rheum. Apr 2006;35(5):306-11. [Medline].
5. Crestani B, Schneider S, Adle-Biassette H, Debray MP, Bonay M, Aubier M. [Respiratory manifestations during the course of Sjogren's syndrome.]. Rev Mal Respir. Apr 2007;24(4):535-51. [Medline].
6. Ren H, Wang WM, Chen XN, Zhang W, Pan XX, Wang XL, et al. Renal involvement and followup of 130 patients with primary Sjögren's syndrome. J Rheumatol. Feb 2008;35(2):278-84. [Medline].
7. Lopate G, Pestronk A, Al-Lozi M, Lynch T, Florence J, Miller T, et al. Peripheral neuropathy in an outpatient cohort of patients with Sjogren's syndrome. Muscle Nerve. May 2006;33(5):672-6. [Medline].
8. Tuchocka-Piotrowska A, Puszczewicz M, Kolczewska A, Majewski D. [Graft-versus-host disease as the cause of symptoms mimicking Sjögren's syndrome]. Ann Acad Med Stetin. 2006;52 Suppl 2:89-93. [Medline].
9. Ramos-Casals M, Nardi N, Brito-Zeron P, Aguilo S, Gil V, Delgado G, et al. Atypical autoantibodies in patients with primary Sjogren syndrome: clinical characteristics and follow-up of 82 cases. Semin Arthritis Rheum. Apr 2006;35(5):312-21. [Medline].
10. Martinez-Lazaro R, Cortes-Blanco A, Velilla J. A pilot study of the salivary scintigraphy diagnostic performance in a Spanish population with Sjogren's syndrome diagnosed by the European criteria. Ann Rheum Dis. Mar 2001;60(3):302-3. [Medline].
11. Carotti M, Salaffi F, Manganelli P, Argalia G. Ultrasonography and colour doppler sonography of salivary glands in primary Sjögren's syndrome. Clin Rheumatol. 2001;20(3):213-9. [Medline].
12. Roberts C, Parker GJ, Rose CJ, Watson Y, O'Connor JP, Stivaros SM, et al. Glandular function in Sjögren syndrome: assessment with dynamic contrast-enhanced MR imaging and tracer kinetic modeling--initial experience. Radiology. Mar 2008;246(3):845-53. [Medline].
13. Langerman AJ, Blair EA, Sweiss NJ, Taxy JB. Utility of Lip Biopsy in the Diagnosis and Treatment of Sjogren's Syndrome. Laryngoscope. Jun 2007;117(6):1004-1008. [Medline].
14. Kunert KS, Tisdale AS, Stern ME, Smith JA, Gipson IK. Analysis of topical cyclosporine treatment of patients with dry eye syndrome: effect on conjunctival lymphocytes. Arch Ophthalmol. Nov 2000;118(11):1489-96. [Medline].
15. Spiteri A, Mitra M, Menon G, Casini A, Adams D, Ricketts C, et al. Tear lipid layer thickness and ocular comfort with a novel device in dry eye patients with and without Sjögren's syndrome. J Fr Ophtalmol. Apr 2007;30(4):357-64. [Medline].
16. Belenguer R, Ramos-Casals M, Brito-Zeron P, del Pino J, Sentis J, Aguilo S. Influence of clinical and immunological parameters on the health-related quality of life of patients with primary Sjögren's syndrome. Clin Exp Rheumatol. May-Jun 2005;23(3):351-6. [Medline].
17. Andres E, Federici L, Sibilia J. Myelopathy in Sjogren's syndrome: a causative role for cobalamin (vitamin B12) deficiency. Drugs. 2006;66(5):729. [Medline].
18. Bolstad AI, Wassmuth R, Haga HJ, Jonsson R. HLA markers and clinical characteristics in Caucasians with primary Sjögren's syndrome. J Rheumatol. Jul 2001;28(7):1554-62. [Medline].
19. Brito-Zerón P, Ramos-Casals M. [Prognosis of patients with primary Sjögren's syndrome.]. Med Clin (Barc). Feb 2 2008;130(3):109-15. [Medline].
20. Dass S, Bowman SJ, Vital EM, Ikeda K, Pease CT, Hamburger J, et al. Reduction of fatigue in Sjogren's syndrome with rituximab: results of a randomised, double-blind, placebo controlled pilot study. Ann Rheum Dis. Feb 14 2008;[Medline].
21. de Seze J, Delalande S, Fauchais AL, Hachulla E, Stojkovic T, Ferriby D, et al. Myelopathies secondary to Sjögren's syndrome: treatment with monthly intravenous cyclophosphamide associated with corticosteroids. J Rheumatol. Apr 2006;33(4):709-11. [Medline].
22. Esch TR. Pathogenetic factors in Sjogren's syndrome: recent developments. Crit Rev Oral Biol Med. 2001;12(3):244-51. [Medline].
23. Fox RI, Michelson P, Casiano CA, Hayashi J, Stern M. Sjogren's syndrome. Clin Dermatol. Sep-Oct 2000;18(5):589-600. [Medline].
24. Fujimura T, Aiba S, Suetake T, Tagami H. Erythematous swelling of the lip associated with Sjogren's syndrome and mimicking cheilitis granulomatosa. J Dermatol. Jan 2001;28(1):47-9. [Medline].
25. Gasparotto D, De Vita S, De Re V, Marzotto A, De Marchi G, Scott CA, et al. Extrasalivary lymphoma development in Sjogren's syndrome: clonal evolution from parotid gland lymphoproliferation and role of local triggering. Arthritis Rheum. Nov 2003;48(11):3181-6. [Medline].
26. Haimowitz JE, McCauliffe DP, Seykora J, Werth VP. Annular erythema of Sjogren's syndrome in a white woman. J Am Acad Dermatol. Jun 2000;42(6):1069-72. [Medline].
27. Hammi AR, Al-Hashimi IH, Nunn ME, Zipp M. Assessment of SS-A and SS-B in parotid saliva of patients with Sjogren's syndrome. J Oral Pathol Med. Apr 2005;34(4):198-203. [Medline].
28. Hansen A, Lipsky PE, Dorner T. Immunopathogenesis of primary Sjogren's syndrome: implications for disease management and therapy. Curr Opin Rheumatol. Sep 2005;17(5):558-65. [Medline].
29. Hayashi N, Koshiba M, Nishimura K, Sugiyama D, Nakamura T, Morinobu, et al. Prevalence of disease-specific antinuclear antibodies in general population: estimates from annual physical examinations of residents of a small town over a 5-year period. Mod Rheumatol. 2008;18(2):153-60. [Medline].
30. Heimbacher C, Hansen A, Pruss A, Jacobi A, Reiter K, Lipsky PE. Immunoglobulin Vkappa light chain gene analysis in patients with Sjogren's syndrome. Arthritis Rheum. Mar 2001;44(3):626-37. [Medline].
31. Hulkkonen J, Pertovaara M, Antonen J, Lahdenpohja N, Pasternack A, Hurme M. Genetic association between interleukin-10 promoter region polymorphisms and primary Sjogren's syndrome. Arthritis Rheum. Jan 2001;44(1):176-9. [Medline].
32. Iniguez C, Mauri J, Medrano M, Larrode P, Santos S, Pina J, et al. [Sjogren's syndrome and multiple sclerosis]. Neurologia. May 2001;16(5):232-5. [Medline].
33. Inoue H, Tsubota K, Ono M, Kizu Y, Mizuno F, Takada K, et al. Possible involvement of EBV-mediated alpha-fodrin cleavage for organ-specific autoantigen in Sjogren's syndrome. J Immunol. May 1 2001;166(9):5801-9. [Medline].
34. Ishimaru N, Saegusa K, Yanagi K, Haneji N, Saito I, Hayashi Y. Estrogen deficiency accelerates autoimmune exocrinopathy in murine Sjogren's syndrome through fas-mediated apoptosis. Am J Pathol. Jul 1999;155(1):173-81. [Medline].
35. Jadvar H, Bonyadlou S, Iagaru A, Colletti PM. FDG PET-CT demonstration of Sjogren's sialoadenitis. Clin Nucl Med. Oct 2005;30(10):698-9. [Medline].
36. Johnson EO, Moutsopoulos HM. Neuroendocrine manifestations in Sjögren's syndrome. Relation to the neurobiology of stress. Ann N Y Acad Sci. 2000;917:797-808. [Medline].
37. Karaiskos D, Mavragani CP, Makaroni S, Zinzaras E, Voulgarelis M, Rabavilas A, et al. Stress, coping strategies and social support in patients with primary Sjogren's syndrome prior to disease onset: a retrospective case control study. Ann Rheum Dis. Feb 14 2008;[Medline].
38. Kuhn A, Richter-Hintz D, Schuppe HC, Ruzicka T, Lehmann P. [Annular erythema in Sjögren syndrome. A variant of cutaneous lupus erythematosus?]. Hautarzt. Apr 2000;51(4):270-5. [Medline].
39. Lester S, Danda D, Cavill D, Pile K, Downie-Doyle S, Rischmueller M. Humoral immunity to Ro52 is not associated with the Ro52 9571 C/T polymorphism in Australian patients with primary Sjögren's syndrome. Arthritis Rheum. Nov 2003;48(11):3293-4. [Medline].
40. Leung KC, McMillan AS, Cheung BP, Leung WK. Sjögren's syndrome sufferers have increased oral yeast levels despite regular dental care. Oral Dis. Mar 2008;14(2):163-73. [Medline].
41. Maeda M. Dermoscopic patterns of the filiform papillae of the tongue in patients with Sjogren's syndrome. J Dermatol. Feb 2006;33(2):96-102. [Medline].
42. Moody M, Zipp M, Al-Hashimi I. Salivary anti-spectrin autoantibodies in Sjogren's syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. Mar 2001;91(3):322-7. [Medline].
43. Nakken B, Jonsson R, Bolstad AI. Polymorphisms of the Ro52 gene associated with anti-Ro 52-kd autoantibodies in patients with primary Sjogren's syndrome. Arthritis Rheum. Mar 2001;44(3):638-46. [Medline].
44. Ng KP, Isenberg DA. Sjögren's Syndrome: Diagnosis and Therapeutic Challenges in the Elderly. Drugs Aging. 2008;25(1):19-33. [Medline].
45. Okubo H, Maekawa H, Ogawa K, Wada R, Sekigawa I, Iida N, et al. Pseudolymphoma of the liver associated with Sjögren's syndrome. Scand J Rheumatol. 2001;30(2):117-9. [Medline].
46. Ostuni P, Botsios C, Sfriso P, De Sandre P, Semerano L, Todesco S. [Diagnosis and classification of primary Sjogren syndrome. Comparison of 3 criteria sets in 219 cases]. Recenti Prog Med. Jan 2001;92(1):32-6. [Medline].
47. Ozaki Y, Amakawa R, Ito T, Iwai H, Tajima K, Uehira K, et al. Alteration of peripheral blood dendritic cells in patients with primary Sjogren's syndrome. Arthritis Rheum. Feb 2001;44(2):419-31. [Medline].
48. Pertovaara M, Antonen J, Hurme M. Th2 cytokine genotypes are associated with a milder form of primary Sjogren's syndrome. Ann Rheum Dis. May 2006;65(5):666-70. [Medline].
49. Pijpe J, van Imhoff GW, Spijkervet FK, Roodenburg JL, Wolbink GJ, Mansour K, et al. Rituximab treatment in patients with primary Sjogren's syndrome: an open-label phase II study. Arthritis Rheum. Sep 2005;52(9):2740-50. [Medline].
50. Pokrzywnicka-Gajek I. Sjogren's syndrome. Przegl Dermatol. 2001;88:207-213.
51. Sauvezie B, Tournadre A, Chamard C, Dubost JJ. [Secondary Gougerot-Sjogren syndrome]. Rev Prat. Jan 31 2001;51(2):171-6. [Medline].
52. Schoofs N. Caring for women living with Sjogren's syndrome. J Obstet Gynecol Neonatal Nurs. Sep-Oct 2003;32(5):589-93. [Medline].
53. Selva O'Callaghan A, Bosch Gil JA, Solans Laque R, Segura Garcia A, Armadans Gil L, Mijares Boeckh-Behrens T, et al. [Primary Sjogren's syndrome: clinical and immunological characteristics of 114 patients]. Med Clin (Barc). May 26 2001;116(19):721-5. [Medline].
54. Strimlan CV. Pulmonary function in patients with primary Sjögren's syndrome. Ann Rheum Dis. Apr 2001;60(4):429. [Medline].
55. Sutcliffe N, Isenberg D. Sjogren's syndrome: a critical review of clinical management. J Rheumatol. Nov 2000;27(11):2723. [Medline].
56. Tabbara KF, Vera-Cristo CL. Sjogren syndrome. Curr Opin Ophthalmol. Dec 2000;11(6):449-54. [Medline].
57. Tsubota K, Hirai S, King LS, Agre P, Ishida N. Defective cellular trafficking of lacrimal gland aquaporin-5 in Sjögren's syndrome. Lancet. Mar 3 2001;357(9257):688-9. [Medline].
58. Williams CS, Butler E, Roman GC. Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide. Arch Neurol. May 2001;58(5):815-9. [Medline].
59. Witte T, Matthias T, Arnett FC, Peter HH, Hartung K, Sachse C, et al. IgA and IgG autoantibodies against alpha-fodrin as markers for Sjogren's syndrome. Systemic lupus erythematosus. J Rheumatol. Nov 2000;27(11):2617-20. [Medline].
60. Xanthou G, Polihronis M, Tzioufas AG, Paikos S, Sideras P, Moutsopoulos HM. "Lymphoid" chemokine messenger RNA expression by epithelial cells in the chronic inflammatory lesion of the salivary glands of Sjögren's syndrome patients: possible participation in lymphoid structure formation. Arthritis Rheum. Feb 2001;44(2):408-18. [Medline].
61. Youinou P, Mariette X. [Immunopathology of Gougerot-Sjogren syndrome]. Rev Prat. Jan 31 2001;51(2):165-70. [Medline].

Article Last Updated: Apr 22, 2008