Sjogren syndrome

Sjogren syndrome is a chronic inflammatory autoimmune disease that most commonly occurs in middle-aged women. Primary Sjogren syndrome is idiopathic; Sjogren syndrome that occurs concomitantly with another autoimmune disease (e.g., rheumatoid arthritis, systemic sclerosis) is classified as secondary Sjogren syndrome. Sjogren syndrome most commonly manifests with sicca syndrome but can also manifest with systemic symptoms such as arthritis, Raynaud phenomenon, and GI involvement as a result of lymphocytic infiltration of glandular and nonglandular organs. The diagnosis is confirmed by the detection of autoantibodies (anti-Ro/SSA or anti-La/SSB antibodies) in patients with sicca syndrome. Salivary gland biopsy is the gold standard test but is often only performed in patients with atypical presentations. Management focuses on supportive measures and, in patients with severe systemic disease, immunosuppressive therapy.

• Sex: : ♀ > ♂ (∼ 9:1) ^[1]
• Age of onset: : typically 40–60 years ^[1]

Epidemiological data refers to the US, unless otherwise specified.

• Primary Sjogren syndrome: idiopathic (association with HLA-DR52) ^[2]
• Secondary Sjogren syndrome: associated with another autoimmune disease, e.g., rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, polymyositis, or primary biliary cirrhosis ^[3]

Viral infections, e.g., HCV, HIV, EBV, and HTLV, are thought to be triggering factors for Sjogren syndrome; however, a causative relationship has not been established. ^[3]

Clinical presentation varies widely, from isolated sicca syndrome to systemic involvement. See “Complications” for other clinical presentations.

Sicca syndrome ^[3][4]

• Ocular symptoms
  • Xerophthalmia: dry eyes due to decreased secretion of tears (daily, persistent)
  • Keratoconjunctivitis sicca
    • Conjunctival injection
    • Eye itching or burning sensation
    • Blurred vision
    • Recurrent sensation of sand or a foreign body in the eyes
• Oral symptoms
  • Xerostomia: dry mouth due to decreased secretion of saliva (daily, persistent) which may lead to:
    • Dental caries and oral infections
    • Parotid gland enlargement, often bilateral
    • Tongue fissures
  • Frequent need to drink liquids to aid swallowing and/or speaking
• Other glandular symptoms
  • Vaginal dryness, leading to dyspareunia and an increased risk of infections
  • Nasal dryness, leading to chronic rhinitis and epistaxis
  • Pharyngeal, tracheal, and bronchial dryness, causing persistent dry cough
  • Xerosis: abnormal skin dryness and pruritus (secondary to hypohidrosis or anhidrosis)

Xerostomia and xerophthalmia are the classic symptoms of sicca syndrome and are present in ∼ 95% of patients with Sjogren syndrome. ^[3][5]

Systemic disease ^[3][4]

• Arthralgias and/or arthritis (most common systemic symptom)
• Raynaud phenomenon
• Constitutional symptoms: fever, weight loss, fatigue
• GI involvement, e.g., dysphagia , dyspepsia, reflux esophagitis
• Pulmonary involvement: interstitial lung disease
• Vasculitis
  • Mainly cutaneous: palpable purpura in the legs, recurrent urticaria, skin ulcerations
  • Glomerulonephritis
• Autoimmune thyroiditis
• Neurological involvement, e.g., peripheral neuropathy, myelitis
• In patients with secondary Sjogren syndrome: features of a concomitant autoimmune condition, e.g., malar rash in patients with SLE

Systemic symptoms are present in 50–60% of patients with Sjogren syndrome. ^[3]

General principles ^[4][6]

• Consider Sjogren syndrome in patients with features of sicca syndrome without a known cause.
• The following are needed to confirm the diagnosis:
  • Positive anti-Ro/SSA or anti-La/SSB autoantibodies
  • Objective confirmation of xerostomia and xerophthalmia
• Classification criteria can help support the diagnosis.
• Further studies may be obtained depending on suspected organ involvement.

Laboratory studies ^[3][4]

Obtain routine studies and autoantibodies for all patients. Prognostic markers may be ordered by a specialist.

• Routine studies: may show nonspecific supportive findings
  • CBC: normocytic anemia, leukopenia, eosinophilia
  • ↑ ESR
  • Urinalysis: proteinuria and/or RBC casts may indicate glomerulonephritis or interstitial nephritis
• Autoantibodies
  • Anti-Ro/SSA antibodies ; (positive in ∼ 70% of cases) and anti-La/SSB antibodies; (positive in ∼ 50% of cases): target ribonucleoprotein antigens (Ro/La) in epithelial cells, especially in the salivary glands ^[3]
  • Antinuclear antibodies (positive in up to 80% of cases) ^[3]
  • Rheumatoid factor (positive in 50% of cases of primary Sjogren syndrome) ^[3]
• Prognostic markers: associated with a poor prognosis
  • Cryoglobulinemia
  • Hypergammaglobulinemia
  • ↓ Complement C3 and/or C4

Assessment of xerostomia

Salivary gland function studies ^[5][6][7]

• Unstimulated salivary flow (preferred)
  • Method: Saliva is collected for 5 minutes.
  • Supportive finding: salivary flow ≤ 0.1 mL/minute ^[6]
• Alternative studies
  • Salivary scintigraphy
  • Stimulated salivary flow

Biopsy of minor labial salivary gland ^[3][4]

• Gold standard test, but not routinely required
• Consider if clinical presentation is atypical.
• Supportive findings
  • Destruction of minor salivary glands (fibrosis, parenchymal atrophy)
  • Sialadenitis with dense focal lymphocytic infiltrations

Assessment of xerophthalmia ^[3]

• Schirmer test: shows decreased tear production
• Slit lamp examination
  • Tear film break-up time: reduced (< 10 seconds)
  • Ocular staining
    • Corneal fluorescein stain: punctate epithelial erosions
    • Conjunctival lissamine green stain: conjunctival erosions

Salivary gland imaging studies ^[3]

May help determine salivary gland involvement and assess for complications (e.g., infections, lymphoma)

• Ultrasound of the parotid gland
  • May appear normal in early stages
  • Alternating hypoechoic areas and band-like hyperechoic septa and cysts may be present in late stages.
• MRI of the parotid gland: The glandular parenchyma may have a honeycomb or cloud-like structure.

• Iatrogenic
  • Chronic use of drugs, e.g., antihistamines, antidepressants, anticholinergics
  • Head and neck radiation
  • Corneal surgery, e.g., LASIK
• Systemic autoimmune diseases
  • Sarcoidosis
  • IgG4-related disease
  • Amyloidosis
• Chronic viral infections
  • Hepatitis C
  • HIV
• Atopic disease: e.g., allergic conjunctivitis
• Other
  • Age-related sicca syndrome ^[8]
    • Definition: xerophthalmia and xerostomia in older patients without evidence of Sjogren syndrome
    • Etiology
      • Decreased tear and saliva production (due to age-related interstitial fibrosis, acinar atrophy with fat replacement, ductal dilation, and nonspecific chronic inflammation)
      • Decreased blinking rate
      • Toxicity from topical drugs
    • Risk factors: older age, female sex, medication use (e.g., anticholinergics)
    • Clinical features: See “Sicca syndrome” above.
    • Diagnostics: Consider in older patients with sicca syndrome and no evidence of underlying Sjogren syndrome. (See “Diagnostics” above.)
  • Dehydration
  • Uncontrolled diabetes mellitus
  • Graft-versus-host disease

The differential diagnoses listed here are not exhaustive.

General principles ^[4][5][9]

• Management should be guided by a rheumatologist and other specialists as required.
• Symptomatic management of sicca syndrome is the mainstay of treatment.
• For patients with active systemic disease, immunosuppressants may be considered.
• Monitor patients for the development of complications, e.g., lymphoma, and associated autoimmune diseases.

Patients with Sjogren syndrome have an increased risk of developing MALT lymphoma.

Management of sicca syndrome ^[5][9]

Xerostomia

• All patients
  • Frequent water intake
  • Caries prophylaxis, e.g., regular dental hygienist visits, topical fluoride or chlorhexidine
  • Avoidance of irritants (e.g., coffee, alcohol) and acidic beverages (e.g., herbal tea, cola) ^[10]
  • Artificial saliva
    • Preferred treatment for patients without residual glandular function
    • May be considered for all patients
• Patient with residual glandular function: stimulation of salivary flow
  • First line: nonpharmacological stimulants, e.g., sugar-free lozenges or gum, acidic candy, xylitol
  • Second line: oral muscarinic agonists
    • Usually reserved for moderate or severe salivary dysfunction because of their potential adverse effects and the lack of strong evidence supporting their benefit
    • Options: pilocarpine, cevimeline

Muscarinic agonists are contraindicated in patients with asthma, multiple sclerosis, and/or glaucoma. ^[11]

Xerophthalmia ^[5][9]

Advise all patients to maintain adequate eye lubrication and avoid dry environments (e.g., shield eyes from wind, increase indoor humidity).

• First line: artificial tears for volume replacement and lubrication
• Second-line therapies: usually reserved for refractory or severe disease because of their potential adverse effects
  • Stimulation of lacrimal gland function with oral muscarinic agonists, i.e., pilocarpine or cevimeline
  • Topical immunosuppressive agents, e.g., topical cyclosporine, short-term (2–4 weeks) topical glucocorticoids
  • Serum eye drops

Management of systemic disease ^[5][9]

Management depends on the specific manifestation and should always be guided by a specialist.

• Inflammatory musculoskeletal pain
  • NSAIDs or acetaminophen
  • Low-dose glucocorticoids
  • DMARDS (e.g., hydroxychloroquine, methotrexate)
• Fatigue
  • Regular exercise
  • Hydroxychloroquine may be considered. ^[9]
• Other manifestations of systemic disease : Systemic immunosuppressants (e.g., glucocorticoids, cyclosporine, rituximab) may be considered for severe symptoms.

TNF-α inhibitors can cause serious adverse effects (e.g., serious infections, cytopenias) and increase the risk of developing non-Hodgkin lymphoma, and therefore should be avoided in patients with Sjogren syndrome. ^[9]

• Development of associated conditions
  • Autoimmune diseases, e.g., systemic lupus erythematosus, rheumatoid arthritis
  • B-cell lymphomas, e.g., MALT lymphoma
    • Prevalence ∼ 5% ^[3]
    • Frequently manifests as unilateral, persistent parotid enlargement
    • Predictors of lymphoma include lymphadenopathy, palpable purpura, and cryoglobulinemia.
  • Renal tubular acidosis type 1 ^[12]
• Corneal scarring, ulcer, rupture, and infection
• Pregnancy: fetal loss, infant with neonatal lupus syndrome and associated complete heart block

References:^[1]

We list the most important complications. The selection is not exhaustive.