Background

  • Sjögren syndrome is the second most common autoimmune rheumatic disorder characterized by exocrine gland dysfunction and dryness of mucosal surfaces (sicca symptoms)
    • Estimated population-based prevalence of 0.1%-4.8% worldwide
    • More common in women
  • The cause of Sjögren syndrome  is unknown, but likely due to combination of genetic, environmental (viruses such as cytomegalovirus and Epstein-Barr virus), and hormonal factors
  • Usually affects eyes and mouth, but may affect other mucosal surfaces including the nose, pharynx, larynx, and vagina
  • Disease manifestations beyond the salivary and lacrimal glands (extraglandular manifestations) are common; may affect the musculoskeletal, gastrointestinal, pulmonary, neurologic, renal, and cardiovascular systems
  • May occur as a primary disorder (primary Sjögren syndrome) but about one-third of patients have another underlying autoimmune condition (secondary Sjögren syndrome) such as rheumatoid arthritis, systemic lupus erythematosus, scleroderma, or hypothyroidism

Pathogenesis

  • Autoimmune reaction triggered by environmental stimulus (such as viral infection) in genetically susceptible patient may lead to lymphocytic infiltration of exocrine glands with degeneration of acinar gland, necrosis, atrophy, and decreasing lacrimosalivary function
  • Systemic disease considered expression of autoimmune epithelitis
  • Vasculitis and/or immune complex deposition and complement activation may play a part in pathogenesis

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History

  • Present illness
    • May have variable disease course with wide spectrum of clinical manifestations
    • Most patients present with insidious onset of  ≥1 of the following:
      • Glandular sicca symptoms, usually xerophthalmia (dry eyes), xerostomia (dry mouth), and dry skin
      • Nonspecific symptoms, such as fatigue (in about 70%-80%), sleep disturbances, anxiety, and/or depression
      • Organ-specific symptoms due to systemic manifestation, such as musculoskeletal, pulmonary, and/or gastrointestinal symptoms
    • Extraglandular manifestations are common, and may include:
      • Musculoskeletal (myalgia, stiffness, weakness) reported in up to 90%
      • Constitutional (fever, night sweats, and/or involuntary weight loss are reported in 9%)
      • Gastrointestinal (swallowing disorders in over 60%)
      • Pulmonary manifestations such as airway disease, interstitial lung disease (reported in 9%-22%)
      • Neurologic manifestations (peripheral neuropathies reported in 5%-21%)
      • Hematologic manifestations such as anemia and hypogammaglobulinemia (reported to occur in 20%)
      • Cutaneous manifestations such as vasculitis or purpura (reported to occur in 10%)
      • Renal manifestations (reported to occur in up to 5%)
      • Cardiovascular manifestations (uncommon)
      • Lymphoma (reported to occur in 5%-7%)
  • Medical history
    • Ask about personal or family history of autoimmune diseases

Physical

  • Perform thorough physical exam to evaluate for possible extraglandular manifestations
  • Physical exam findings associated with glandular sicca symptoms include:
    • Skin
      • Vasculitis
      • Annular erythema
      • Xerosis
      • Angular cheilitis
      • Chilblain lupus
    • HEENT (Head, Eyes, Ears, Nose, Throat)
      • Eye exam
        • Keratoconjunctivitis
        • Bacterial conjunctivitis or bacterial interstitial keratitis
        • Eyelid infection
        • Corneal melting/ulcers/perforation
        • Vision loss
      • Oral exam
        • Decreased salivary pool
        • Dry mucous membranes
        • Lobulated or depapillated red tongue
        • Multiple dental caries/periodontal disease
      • Tenderness and/or swelling in salivary glands

Diagnosis

  • There are no universally agreed on diagnostic criteria for Sjögren syndrome, but diagnosis should be suspected in patients with sicca symptoms and  ≥1 of the following:
    • Positive blood test for anti-Ro (anti–Sjögren’s-syndrome-related antigen [anti-SS-A]) and anti-La (anti-SS-B) antibodiesPositive salivary gland biopsy with evidence of chronic inflammatory infiltrate in exocrine glands
    • Nonspecific and/or organ-specific symptoms indicative of systemic manifestations
  • Differential diagnosis
    • In older patients, sicca symptoms may be due to age-related atrophy of secreting tissue
    • Other causes of dry eye:
      • Allergic conjunctivitis
      • Aqueous tear-deficient dry eye due to impaired/dysfunctional lacrimal gland
      • Blepharitis
      • Hyperevaporative dry eyes
      • Rosacea
    • Other causes of dry mouth include:
      • Chronic viral infections
      • Decreased salivary flow due to sarcoidosis
      • Dehydration
      • Diabetes
      • Mouth breathing due to obstructed nasal passages
      • Salivary gland irradiation
    • Drugs that may cause sicca symptoms include:
      • Alpha-1 and alpha-2 antagonists
      • Anticholinergic drugs
      • Antihistamines
      • Benzodiazepines
      • Beta blockers
      • Diuretics
      • isotretinoin 
      • Nicotine
      • Opioids
      • Phenothiazines
      • Selective serotonin reuptake inhibitors
      • Sympathomimetic drugs
      • Tricyclic antidepressants
    • Other causes of swollen parotid glands include:
      • Acute suppurative sialadenitis
      • Lymphoma
      • Mumps
      • Sarcoidosis
      • Tuberculosis

Testing 

  • Initial testing may include:
    • Schirmer test (assesses tear function)
      • Place sterile paper strip below lower eyelid for 5 minutes
      • Positive test defined as moistened area ≤5 mm
    • Corneal staining with colorants (rose bengal, fluorescein) to assess damage to tear meniscus from desiccation to conjunctival epithelium
    • Unstimulated whole salivary flow collection to assess oral dryness
  • Blood and serum tests
    • No single test can provide definitive diagnosis but may help determine underlying cause
    • Most patients display elevated erythrocyte sedimentation rate (ESR) and cytopenias
    • Commonly found antibodies in Sjögren syndrome include:
      • Anti-Ro (anti-SS-A) and anti-La (anti-SS-B) antibodies (positive in 50%-70%)
      • Rheumatoid factor (RF) (positive in 32%-90%)
      • Antinuclear antibodies (ANA) (positive in 55%-97%)
      • Polyclonal hypergammaglobulinemia
      • Elevated immunoglobulin g and decreased immunoglobulin A 
  • Imaging
    • Scintigraphy:  may show delayed uptake, reduced concentration, and/or delayed tracer excretion
    • Sialography: may show diffuse sialectasia (punctuate, cavitary, or destructive pattern) without major duct obstruction
    • Ultrasound to distinguish primary Sjögren syndrome from sicca syndrome
  • Biopsy of salivary gland
    • May be indicated in patients with negative anti-RO/LA antibodies
    • Pathologic hallmark is chronic inflammatory infiltrate in exocrine glands
    • Salivary gland epithelial cells may demonstrate alterations in cell adhesion/shape

Management

  • No known cure for Sjögren syndrome — treatment goal is symptom relief and prevention of complications
  • Treatment for sicca symptoms
    • For ocular dryness (xerophthalmia)
      • Use preservative-free artificial tears or ocular gels/ointments as first line treatment
      • Cyclosporine ophthalmic solution or emulsion may be indicated in patients with severe symptoms
      • Systemic pilocarpine and cevimeline may improve sicca symptoms
      • Punctual occlusion (plugs, cauterization, or surgery)
        • May be indicated in patients with severe dry eye symptoms refractory to medications  
        • Punctal plugging consists of temporary or permanent occlusion of 1 or both puncta in order to retain tears on the ocular surface by blocking their drainage
  • For oral dryness (xerostomia)
    • Mechanical stimulation, gustatory stimulation, and/or saliva substitutes considered first line of treatment
    • Systemic treatment with pilocarpine or cevimeline to improve salivary flow
    • Intraoral electrostimulation device  
    • Frequent dental exams, antimicrobial mouth rinses, and daily fluoride use may help prevent caries
  • Management of extraglandular manifestations
    • Glucocorticoids
      • Should be at minimum dose and time needed to control active systemic disease
      • May downregulate inflammatory processes in salivary and lacrimal glands
      • Long-term use should be avoided due to risk of adverse effects
  • Immunosuppressive and immunomodulatory agents  
    • Consider immunosuppressive use as glucocorticoid-sparing agents
    • Consider rituximab
      • For adults with primary Sjögren syndrome and suboptimal response or toxicity to standard therapy, inability to taper corticosteroids, and any of  the following:
        • Cryoglobulinemia associated with vasculitis
        • Inflammatory arthritis
        • Peripheral neuropathy
        • Pulmonary disease
        • Severe parotid swelling
        • Vasculitis
      • May also be considered (if conventional therapy insufficient) for treatment of
        • Keratoconjunctivitis sicca  
        • Xerostomia if some evidence of residual salivary production 

Follow-up

  • Suggested frequency
    • Annually in patients with stable disease/limited to mucosal surfaces
    • Every 6 months in patients with systemic, extraglandular manifestations
    • Every 3 months in patients with end-organ damage
  • Clinical examination to assess:
    • Mouth and eyes for evidence of complications
    • For presence of lymphadenopathy
    • Enlargement of parotid and submandibular glands, liver, or spleen
  • Annual laboratory tests should include:
    • Complete blood count
    • Erythrocyte sedimentation rate
    • Renal and liver function tests
  • Immunologic tests not usually indicated in routine follow-up

Complications

  • Complications from glandular sicca symptoms may include:
    • Complications of xerophthalmia (severe dry eye) may include
      • Eyelid infection
      • Destruction of conjunctival epithelium
  • Extraglandular disease manifestations may result in a highly variable range of complications due to numerous possible systemic manifestations and serologic abnormalities

Kendra Church MS, PA-C, is a physician assistant at Dana-Farber Cancer Institute/Brigham & Women’s Hospital, and is also a senior clinical editor for DynaMed, an evidence-based, point-of-care database.

References

  1. Tincani A, Andreoli L, Cavazzana I, et al. Novel aspects of Sjögren’s syndrome in 2012. BMC Med. 2013;11:93. doi: 10.1186/1741-7015-11-93
  2. Ramos-Casals M, Brito-Zerón P, Sisó-Almirall A, Bosch X. Primary Sjögren syndrome. BMJ. 2012;344:e3821. doi:10.1136/bmj.e3821
  3. Vivino FB. Sjögren syndrome: clinical aspects. Clin Immunol. 2017;182:48-54. doi:10.1016/j.clim.2017.04.005
  4. Carsons SE, Vivino FB, Parke A, et al. Treatment guidelines for rheumatologic manifestations of Sjögren syndrome: use of biologic agents, management of fatigue, and inflammatory musculoskeletal pain. Arthritis Care Res (Hoboken). 2017;69(4):517-527. doi:10.1002/acr.22968
  5. Leone MC, Alunno A, Cafaro G, et al. The clinical spectrum of primary Sjögren syndrome: beyond exocrine glands. Reumatismo. 2017 Sep 21;69(3):93-100. doi:10.4081/reumatismo.2017.1032
  6. Vivino FB. Sjögren syndrome: clinical aspects. Clin Immunol. 2017;182:48-54. doi:10.1016/j.clim.2017.04.005
  7. Alunno A, Carubbi F, Bartoloni E, Cipriani P, Giacomelli R, Gerli R. The kaleidoscope of neurological manifestations in primary Sjögren syndrome. Clin Exp Rheumatol. 2019;37 Suppl 118(3):192-198.
  8. Mariette X,  Criswell LA. Primary Sjögren syndrome. N Engl J Med. 2018;378(10):931-939. doi:10.1056/NEJMcp1702514

Topics:

Autoimmune Disorders Rheumatoid Arthritis Systemic Lupus Erythematosus