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A. Definitionnavigator

  1. Autoimmune disease with progressive lymphocytic destruction of exocrine glands
  2. Primary Sjogren's Syndrome (SS) occurs alone
  3. Secondary SS occurs in combination with other autoimmune diseases
  4. Common Manifestations
    1. Glandular efects lead to symptoms within exocrine system most commonly:
    2. Keratoconjuncitivitis sicca (dry eyes)
    3. Xerostomia (dry mouth)
    4. Extraglandular effects involve other tissues such as lung, skin, heart, kidney

B. Characteristicsnavigator

  1. Primary SS
    1. 90% of patients are women
    2. Mean age 52 years, range 17-75 years
    3. Overall, up to 1.0% of population has some symptoms of SS
    4. ~0.5% of the population likely has actual SS
  2. Secondary SS
    1. ~30% Rheumatoid Arthritis
    2. ~10% Systemic Lupus Erythematosus
    3. ~1% Scleroderma
    4. More common in younger women
  3. Major Histocompatibility Loci
    1. HLA-B8 and DRw3 show increased prevalence in primary disease
    2. Heterozygosity for DQ1 and DQ2
    3. HLA-DR4 is increased in prevalence in secondary SS
  4. All patients with ataxia and kinesthetic sensory loss should be evaluated for SS
  5. Laboratory
    1. ANA >1:80 90%
    2. RF+ 60%
    3. Cryoglobulins 30%
    4. ESR >25mm/hr 60%
    5. Cytopenias 10%
    6. Anti-Ro (SSA) ~60%
    7. Anti-La (SSB) ~40%
    8. Thyroid Auto-Abs ~45%
  6. High rates of autoimmune thyroid disease in patients with SS

C. Diagnosis [1] navigator

  1. International Consensus Criteria for SS (Items 2-6)
  2. Ocular Symptoms (at least one present):
    1. Persistent, troublesome dry eyes every day for >3 months
    2. Recent sensation of sand or gravel in the eyes
    3. Use of a tear substitute >3 times per day
  3. Oral Symptoms (at least one present):
    1. Feeling of dry mouth every day for >3 months
    2. Recurrent feeling of swollen salivary glands as an adult
    3. Need to drink liquids to aid in swallowing dry food
  4. Objective Evidence of Dry Eyes (at least one present):
    1. Tear assessment: <9mm wetting on Schirmer's Test is positive (abnormal)
    2. Rose Bengal staining can reveal abnormal tear formation
    3. Lacrimal gland biopsy with focus score >1
  5. Objective Evidence of Salivary-Gland Involvement (at least one present):
    1. Salivary gland scintigraphy
    2. Parotid sialography
    3. unstimulated whole sialometry (<1.6mL per 15 minutes)
  6. Laboratory Abnormality (at least one present)
    1. Anti-SSA (Ro) or anti-SSB autoantibodies are most specific for SS
    2. ANA elevation
    3. IgM Rheumatoid Factor (RF)
  7. Positive Histopathology on Lip Biopsy
    1. Sublabial salivary gland biopsy is most specific test for SS
    2. Finding of lymphocytic infiltration in the gland is positive biopsy
  8. Absence of HIV, Sarcoidosis, GVHD, (Primary Cryoglobulinemia) is absolutely required

D. Pathophysiology navigator

  1. Lymphocytic infiltration into lacrimal and salivary glands and other organs
    1. Interaction with epithelial cells, cytokine release, and organ dysfunction
    2. Increased TCR Vß6.7b and Vß13.2 with IFNg and IL2 cytokine production
    3. Absence of the cytokine TGFß in salivary gland lesions with severe inflammation
    4. 10% have "pseudolymphoma": lymphadenopathy with parotid gland enlargement
  2. Other Considerations
    1. Immune complex deposition may be found
    2. Ro + La autoantibodies are associated with more severe glandular and systemic disease
    3. Deletion of TGFß from the mouse germline leads to SS like disease
    4. Mice infected with retroviruses develop SS like disease
  3. Islet Cell Antigen 69 (ICA69) [4]
    1. ICA69 is expressed on pancreatic islet, lacrimal gland, others
    2. T cells reactive to this antigen found in 8 of 9 SS patients, not in other disorders
    3. ICA69 critical to development of SS in mouse model systems
    4. ICA69 may be an important autoantigen in SS
  4. Aquaporin-5 (AQP5) Anomalies [5]
    1. Defective cellular trafficking of lacrimal gland aquaporin-5 is found in SS
    2. Normal AQP5 is found on the apical side in lacrimal acinar cells
    3. In SS, AQP5 was found in the cytoplasm
    4. Distribution of Na+ channel and Na+/K+ ATPase were normal in SS
    5. Abnormal AQP5 likely contributes to dry eyes in SS
  5. Nervous System Involvement [3]
    1. Ataxic Sensory Neuropathy (Ataxia due to sensory loss)
    2. Dorsal Root Ganglionitis
    3. Due to infiltration of axons with activated T lymphocytes
    4. All sensory modalities affected (pain, temperature, position, vibration)
    5. Sensorineural hearing loss, often subclinical, found in ~45% of tested SS patients [7]

E. Symptomsnavigator

  1. Keratoconjunctivitis sicca: Gritty sensation in eyes
  2. Xerostomia: severe dryness of the mouth
    1. Inflammation of salivary glands
    2. Characteristic changes on sialography
  3. Renal Involvement
    1. Present in ~40% of primary SS
    2. Mild interstitial nephritis
    3. Glomerulonephritis, immune complex mediated
    4. Renal tubular acidosis, distal, Type I, often with hypokalemia [8]
    5. Interstitial nephritis may respond to glucocorticoids
  4. Vasculitis ~25% [3]
    1. Cryoglobulinemia
    2. Cutaneous palpable purpura, episodic
    3. Fever
    4. Skin rash (other than purpura)
    5. Bowel infarction, ischemia
    6. Neuropathy prominent with vasculitic involvement (see below)
    7. Lymphocytoplasmic vasculitis present
  5. CNS Disease
    1. Global Changes: Psychiatric Dysfunction, Cognitive Dysfunction
    2. Focal Disease
    3. Very low incidence of CSF autoantibodies (anti RNP or anti-neuronal) in these patients
    4. This is in contrast with some CNS-lupus patients who have definite CSF changes
    5. Cranial neuropathies including CNS III, IV, VI, VIII [7]
  6. Peripheral Nervous System
    1. Sensory Polyneuropathy
    2. Autonomic Neuropathy
    3. Mononeuritis multiplex
  7. Congenital Heart Block
    1. Associated with anti-Ro and anti-La Abs
    2. More common in patients with SLE
  8. Pulmonary [6]
    1. Upper airway: epistaxis, recurrent sinusitis, dessicated nasal mucosa
    2. Lower airway: tracheobronchial dessication, obstructive lung disease
    3. Follicular lyphocytic bronchitis and bronchiolitis
    4. Bronchiolitis obliterans organizing pneumonia (BOOP)
    5. Interstitial Lung Disease: lymphocytic interstitial pneumnonia and alveolitis
    6. Amyloidosis
    7. Interstitial fibrosis
    8. Pulmonary Cysts
    9. Mass Lesions: pseudolymphoma, lymphoma
    10. Pulmonary hypertension
    11. Pleural Disease: effusion, pleuritis, thickening
    12. Little change in diffusing capacity (DLCO); obstructive pattern most common

F. Treatment navigator

  1. Symptomatic
    1. Artificial Tears and ophthalmic lubricants
    2. Nasal sprays
    3. Oral fluoride treatment
    4. Cholinergic Agonists: pilocarpine, cevimeline
    5. Ophthalmic cyclosporine
  2. Hydroxychloroquine (Plaquenil®)
    1. 200mg po per day usually enough to improve symptoms (may require several weeks)
    2. Begin 400-600mg po qd load for 1-2 weeks then 200-400mg/day
    3. Ophthalmological examinations recommended q6 months
  3. Glucocorticoids for more serious symptoms
    1. Pseudolymphoma
    2. Renal dysfunction
    3. Pneumonitis and bronchiolitis
    4. Prednisone 0.5-1.0mg/kg qd initially for moderate and severe symptoms
  4. Pilocarpine (Salagen®) [9,10]
    1. Oral cholinergic agonist
    2. Improves dry mouth and dry eye symptoms, and other dry mucous membranes
    3. Salivary flow increased 2-4 fold after first dose, maintained after 12 weeks
    4. Side Effects: Diaphoresis, nausea, rhinitis, chills, flushing, urinary frequency
    5. Do not use in patients with uncontrolled asthma or with significant bradycardia
    6. Dose is 5mg tid-qid or 10mg po tid
  5. Cevimeline (Evoxac®) [11]
    1. Oral cholinergic agonist
    2. Increases salivary flow and reduces dry mouth
    3. Side Effects: sweating, nausea, rhinitis, diarrhea
    4. Metabolized by CYP2D6 (and CYP3A4)
    5. Therefore, people with CYP2D6 mutations should consider reducing dose
    6. Potential for reducing heart rate and for exacerbating asthma
    7. Dose is 30mg tid po
  6. Ophthalmic Cyclosporine (Restasis®) [12]
    1. Effective in generalized dry eye disease as well as Sjogren's syndrome specifically
    2. Normalized Schirmer score in 15% versus 5% with placebo vehicle alone
    3. Dose is one drop bid in both eyes
    4. Remove contact lenses when taking (can replace after 15 minutes)
  7. Azathioprine or cyclophoshamide for resistant disease

G. Prognosisnavigator

  1. Isolated keratoconjunctivitis sicca
    1. Overall excellent prognosis
    2. No increased risk for lymphoma
  2. Primary Sjogren's Syndrome
    1. Stable (usually mild) course of symptoms (both glandular and extraglandular)
    2. Increased risk of lymphoma - ~10% of patients developed lymphoma over 4 years
    3. Patients with SS have ~44X increased risk of developing lymphoma compared to controls
  3. Pseudolymphoma
    1. Lymphadenopathy is common in Sjogren's Syndrome patients
    2. May progress to true lymphoma
  4. Diagnosis of Sjogren's Syndrome should be confirmed to assess risk of lymphoma

References navigator

  1. Fox RI. 2005. Lancet. 366(9482):321 abstract
  2. Fox RI, Stern M, Michelson P. 2000. Curr Opin Rheumatol. 12:391 abstract
  3. Vallat JM, Cros DP, Hedley-Whyte ET. 2007. NEJM. 356(12):1252 (Case Record) abstract
  4. Winer S, Astsaturov I, Cheung R, et al. 2002. Lancet. 360(9339):1063 abstract
  5. Tsubota K, Hirai S, King LS, et al. 2001. Lancet. 357(9257):688 abstract
  6. Harris RS and Mark EJ. 2001. NEJM. 344(22):1701 (Case Record) abstract
  7. Tumiati B, Casoli P, Parmeggiani A. 1997. Ann Intern Med. 126(6):450 abstract
  8. Cukierman T, Gatt ME, Hiller N, Chajek-Shaul T. 2005. NEJM. 353(5):509 (Case Discussion) abstract
  9. Pilocarpine. 1994. Med Let. 36(929):76 abstract
  10. Vivino FB, Al-Hashimi I, Khan Z, et al. 1999. Arch Intern Med. 159(2):174 abstract
  11. Cevimeline. 2000. Med Let. 42(1084):70 abstract
  12. Ophthalmic Cyclosporine. 2003. Med Let. 45(1157):42 abstract