eMedicine Specialties > Dermatology > Connective Tissue Diseases

Sjogren Syndrome

Author: Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Coauthor(s): Joanna Narbutt, MD, PhD, Senior Registrar, Lecturer, Department of Dermatology and Venereology, Medical University of Lodz, Poland; Anna Zalewska, MD, PhD, Assistant Professor, Adjunct Professor, Department of Dermatology and Venereology, Medical University of Lodz, Poland; Anna Sysa-Jedrzejowska, MD, PhD, Head, Professor, Department of Dermatology and Venereology, Medical University of Lodz, Poland; Jolanta Dorota Torzecka, MD, PhD, Consulting Staff, Department of Dermatology and Venereology, Medical University of Lodz, Poland
Contributor Information and Disclosures

Updated: Aug 31, 2009

Introduction

Background

Sjögren syndrome (SS) is a chronic systemic disorder characterized by polyglandular tissue destruction that causes keratoconjunctivitis sicca (KCS) and xerostomia. Patients with primary Sjögren syndrome have keratoconjunctivitis sicca and xerostomia, whereas those with secondary Sjögren syndrome have keratoconjunctivitis sicca, 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 Sjögren syndrome and secondary Sjögren syndrome, juvenile Sjögren syndrome is another subtype. Some patients with lacrimal gland enlargement resulting from lymphocytic infiltration may represent a new subtype of primary Sjögren syndrome.1

Pathophysiology

Sjögren syndrome 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 Sjögren syndrome 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 Sjögren syndrome reversibly inhibit the mechanism of fluid secretion by human submandibular salivary acinar cells.2

The etiology and pathophysiology of Sjögren syndrome are still unknown. Autoimmunologic factors and a genetic predisposition are associated with Sjögren syndrome. The following human leukocyte antigens (HLAs) increase the risk of Sjögren syndrome: DRB1, DRB3, DR5, DRw11, DR52, DRw53, DQA1*0501, DQB1*0201, and DQB1*0301. A strong association between Sjögren syndrome and HLA-DR3 is observed. The frequency of HLA-DR52 in patients with primary Sjögren syndrome is estimated to be 87%, but it is also significantly increased in secondary Sjögren syndrome that occurs with rheumatoid arthritis or systemic lupus erythematosus. 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 Sjögren syndrome.
Viral infection could be involved in the induction of Sjögren syndrome. 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 Sjögren syndrome-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 Sjögren syndrome. An anti–120-kd alpha-fodrin immune response plays a critical role in the development of primary Sjögren syndrome. 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 Sjögren syndrome. High expression of the intercellular adhesion molecule 1 (ICAM-1) by the salivary epithelium in patients with Sjögren syndrome suggests that it has an important role in the pathogenesis of the disease.

Sex may influence the immunologic manifestations of primary Sjögren syndrome. 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 Sjögren syndrome 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 Sjögren syndrome. These autoantibodies are often present in other diseases, especially subacute cutaneous lupus erythematosus. 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 Sjögren syndrome seems to be the same as that of adult Sjögren syndrome.

Frequency

United States

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

International

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

Mortality/Morbidity

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

Race

No racial predilection is recognized.

Sex

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

Age

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

Clinical

History

The clinical presentation of Sjögren syndrome 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 Sjögren syndrome 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 Sjögren syndrome can decrease the patient's quality of life in terms of its physical, psychological, and social aspects.
Sjögren syndrome 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 Sjögren syndrome - Presence of any of 4 of the previous 6 categories
      • Secondary Sjögren syndrome - 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 Sjögren syndrome - Characteristic signs and symptoms (above) without associated autoimmune disease
      • Secondary Sjögren syndrome - Same as primary Sjögren syndrome plus the presence of rheumatoid factor, systemic lupus erythematosus, 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 Sjögren syndrome appears late in the course of the primary disease. However, in some patients, primary Sjögren syndrome may precede systemic lupus erythematosus by many years. Secondary Sjögren syndrome is usually mild, and sicca symptoms are the main feature. Unlike those with primary Sjögren syndrome, 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 Sjögren syndrome, symptoms of the primary disease predominate. Secondary Sjögren syndrome does not modify the prognosis or outcome of the basic disease.

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

  • Glandular symptoms
    • Ocular
      • Keratoconjunctivitis sicca 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
      • Periodontal conditions: These were evaluated in Sjögren syndrome patients, and Sjögren syndrome appears to negatively affect the periodontal condition. Gingival inflammation was more evident in the individuals with Sjögren syndrome, particularly those with secondary Sjögren syndrome.5
      • 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 Sjögren syndrome; 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.
      • Nail folds may show capillaroscopic abnormalities, which are associated with the presence of antiendothelial cell antibodies.6
      • 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 Sjögren syndrome. The lesions are recurrent and clear without pigmentation; no photosensitivity is observed.
      • A higher risk of cutaneous vasculitis is noted.
      • In Japanese patients with Sjögren syndrome, annular erythema is divided into 3 types: Sweet disease–like annular erythema with an elevated border, subacute cutaneous lupus erythematosus–like marginally scaled erythema, and papular erythema. These lesions bear some clinical similarities to the annular lesions of subacute cutaneous lupus erythematosus, but their histopathologic features are distinct from those of subacute cutaneous lupus erythematosus. 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%)
    • Lungs7 : Pulmonary abnormalities occur in 9-29% of cases; they are similar in both primary and secondary Sjögren syndrome.
      • 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 Sjögren syndrome.
    • Urinary tract: Patients with Sjögren syndrome have significantly more urinary problems than those without Sjögren syndrome.
      • Symptoms of an irritated bladder
      • Urinary frequency and suprapubic pain
      • Renal tubular dysfunction: Patients with primary Sjögren syndrome commonly are first seen because of renal impairment, usually from renal tubular dysfunction.8
      • Renal tubular acidosis: This affects one third of patients with Sjögren syndrome. A correlation apparently exists between hypergammaglobulinemia and distal renal tubular acidosis.8
      • 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 Sjögren syndrome. 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 Sjögren syndrome. 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.9 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 Sjögren syndrome.
      • Central nervous system involvement is less common (10-25% of patients with Sjögren syndrome) than other types of involvement. It ranges from neuropathy, hemiparesis, transverse myelitis, and dystonia to even encephalopathy and dementia.
      • In Sjögren syndrome, 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 Sjögren syndrome.

  • Genetic factors
    • The presence of HLA-DRB1, HLA-DRB3, HLA-DR5, HLA-DRw11, HLA-DR52, HLA-DRw53, and other HLAs increase the risk of Sjögren syndrome.
    • Polymorphism of the mannose-binding lectin gene is likely to be one of the genetic factors that determines an individual's susceptibility to Sjögren syndrome.
  • 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

More on Sjogren Syndrome

Overview: Sjogren Syndrome
Differential Diagnoses & Workup: Sjogren Syndrome
Treatment & Medication: Sjogren Syndrome
Follow-up: Sjogren Syndrome
References
[ CLOSE WINDOW ]

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Further Reading

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Keywords

Sjögren syndrome, Sjogren syndrome, Gougerot-Houwer-Sjögren syndrome, sicca syndrome, SS, keratoconjunctivitis sicca, KCS, xerostomia, rheumatoid arthritis, RA, systemic lupus erythematosus, SLE, systemic sclerosis, SSc, mixed connective tissue disease, MCTD, subacute cutaneous lupus erythematosus, SCLE, juvenile SS

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Contributor Information and Disclosures

Author

Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi
Disclosure: Nothing to disclose.

Coauthor(s)

Joanna Narbutt, MD, PhD, Senior Registrar, Lecturer, Department of Dermatology and Venereology, Medical University of Lodz, Poland
Disclosure: Nothing to disclose.

Anna Zalewska, MD, PhD, Assistant Professor, Adjunct Professor, Department of Dermatology and Venereology, Medical University of Lodz, Poland
Disclosure: Nothing to disclose.

Anna Sysa-Jedrzejowska, MD, PhD, Head, Professor, Department of Dermatology and Venereology, Medical University of Lodz, Poland
Disclosure: Nothing to disclose.

Jolanta Dorota Torzecka, MD, PhD, Consulting Staff, Department of Dermatology and Venereology, Medical University of Lodz, Poland
Disclosure: Nothing to disclose.

Medical Editor

Terry L Barrett, MD, Clinical Professor of Dermatology and Pathology, University of Texas Southwestern School of Medicine; Director, ProPath Dermatopathology, Dallas, Texas
Terry L Barrett, MD is a member of the following medical societies: American Academy of Dermatology, American Dermatological Association, American Medical Association, American Society of Dermatopathology, College of American Pathologists, and United States and Canadian Academy of Pathology
Disclosure: Nothing to disclose.

Pharmacy Editor

David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic, Northside Clinic
David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Managing Editor

Jeffrey J Miller, MD, Associate Professor of Dermatology, Penn State University College of Medicine; Staff Dermatologist, Penn State Milton S Hershey Medical Center
Jeffrey J Miller, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, Association of Professors of Dermatology, North American Hair Research Society, and Society for Investigative Dermatology
Disclosure: Nothing to disclose.

CME Editor

Glen H Crawford, MD, Assistant Clinical Professor, Department of Dermatology, University of Pennsylvania School of Medicine; Chief, Division of Dermatology, The Pennsylvania Hospital
Glen H Crawford, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, Phi Beta Kappa, and Society of USAF Flight Surgeons
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

 
 
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