Sjögren's syndrome (SS)

see also:

• rheumatology
• blepharitis / dry eyes
• autoimmune disease
• wikipedia

• also known as “Mikulicz disease” and “Sicca syndrome” is an autoimmune disorder in which immune cells attack and destroy the exocrine glands that produce tears and saliva.
• named after Swedish ophthalmologist Henrik Sjögren (1899-1986), who first described it.
• 90% of Sjögren's patients are women and the average age of onset is late 40s, although Sjögren's occurs in all age groups in both women and men.
• the second most common autoimmune rheumatic disease and affects 2% of adults although is undiagnosed in half of these
• it is a common, slowly progressive autoimmune disease that exhibits a wide range of organ-specific and systemic manifestations
• whilst it is generally a benign and non–life-threatening disorder, it can impact quality of life signficantly
• can exist as a disorder in its own right (Primary Sjögren's syndrome) or in 60% of cases may develop years after the onset of an associated rheumatic disorder such as rheumatoid arthritis, systemic lupus erythematosus (SLE), scleroderma, primary biliary cirrhosis etc and histoligic evidence is estimated to occur in 25% of patients with RA or SLE (Secondary Sjögren's syndrome)

• chronic immune system stimulation with B-cell activation is a consistent finding, and B (20% of infiltrate) and T cells (esp. CD4⁺ helper T cell) invade and destroy target organs
  • histology shows focal lymphocytic infiltrates, particularly mainly around the glandular ducts which gradually extends to involve the whole acinar epithelium
• B-cell hyperreactivity is expressed through hypergammaglobulinemia and circulating autoantibodies
  • 60% have non–organ-specific autoantibodies (including rheumatoid factors, antinuclear antibodies, and antibodies to the small RNA-protein complexes Ro/SS-A and La/SS-B) while organ-specific autoantibodies include antibodies to cellular antigens of salivary ducts, the thyroid gland, the gastric mucosa, erythrocytes, the pancreas, the prostate, and nerve cells ¹⁾

• ~2% of adults have SS although half remain undiagnosed
• 90% are women
• endometriosis is a risk factor and appears to have a hazard ratio of 1.4-1.57 ²⁾

• the hallmark symptoms of the disorder are dry mouth and dry eyes (part of what are known as sicca symptoms)
  • one study suggests presence of dry mouth, sore mouth and dry eyes was ~93% specific for SS ³⁾
  • oral dryness may interfere with eating, speaking, and sleeping
    • however 15% of those with primary SS and 26% of those with secondary SS do not complain of dry mouth
    • the salivary glands normally produce 1 to 1.5 L of saliva daily
    • reduction of salivary volume and subsequent loss of the antibacterial properties of saliva may accelerate infection, tooth decay, periodontal disease, and may also cause angular cheilitis associated with candidiasis ⁴⁾
    • salivary gland swelling becomes bilateral and can be episodic or chronic
    • in ambulatory patients, SS is the most common underlying cause of acute bacterial sialadenitis, usually staphylococcal or pneumococcal
  • mucous gland secretions in the respiratory tract may reduce producing dryness of the nose, throat, and trachea (xerotrachea) which may result in a chronic dry cough
  • ocular dryness may cause sensations of itching, grittiness, soreness, and dryness, despite the eyes having a normal appearance
    • occurs in ~2/3rds of patients with SS ⁵⁾
    • may be exacerbated by the low levels of humidity
    • may cause blepharitis, or inflammation of the meibomian glands
    • reduced secretion of tears may lead to chronic irritation and destruction of corneal and bulbar conjunctival epithelium (keratoconjunctivitis sicca)
• may also cause:
  • dry skin
    • occurs in ~half of patients with ~a fifth describing burning skin and 10% develop rashes which are generally vasculitic
    • almost a third with primary SS develop Raynaud's but this is usually mild
  • vaginal dryness (pruritus, irritation, and dyspareunia)
  • may affect other organs of the body, including:
    • the kidneys which may include:
      • type I renal tubular acidosis (RTA)
      • impaired concentrating ability
      • hypercalcinuria
      • proximal tubule defects
      • renal biopsy may show tubulointerstitial nephritis with sparing of the glomeruli
        • in those who have glomeruli involvement, haematuria, proteinuria, and renal insufficiency may occur and some of these develop nephrotic syndrome
      • some develop renal vasculitis with significant hypertension and renal insufficiency.
    • blood vessels
    • lungs
      • usually chronic dry cough due to xerotrachea
      • ~ a third have subclinical pulmonary disease
      • some have small-airway obstruction on lung function tests however β-agonists or corticosteroids produce little significant benefit
      • some may develop other pulmonary complications include lymphocytic alveolitis, lymphocytic interstitial pneumonitis and fibrosis, and pseudolymphoma
    • GIT
      • oesophageal dysmotility has been reported in 36% to 90% of patients ⁶⁾
      • mild biochemical pancreatitis and hepatitis is common
      • 7% have antimitochondrial antibodies and some of these may have abnormal LFTs but liver biopsy histopathologic appearance is similar to that of early (stage 1) primary biliary cirrhosis
    • brain
      • CNS involvement is rare and controversial
      • those with anticardiolipin antibodies may have sensorineural hearing loss
    • peripheral nervous system
      • ~ one fifth develop a peripheral neuropathy, primarily sensory and in ~10% this is the presenting complaint
• 50% of those with primary SS have debilitating fatigue which can be the most troublesome feature
• ~half have arthralgias and a fifth have myalgias
  • some have intermittent polyarticular arthropathy primarily affecting small joints, asymmetrically at times
• a small subgroup with adverse prognostic features such as purpura, low C4 complement levels, and mixed monoclonal cryoglobulinaemia have earlier deaths mainly due to lymphoma ⁷⁾
• causes increased levels of IL-1RA in CSF suggesting increased activity in the Interleukin 1 system and that this is associated with increased fatigue through cytokine induced sickness behavior
• patients with secondary Sjögren's syndrome also have signs and symptoms associated with rheumatic disorder.
• higher rate of non-Hodgkin lymphoma compared to both patients with other autoimmune diseases and healthy people - risk of any lymphoma is said to be 44x greater in those with SS
  • ~5% of patients with Sjögren's syndrome will develop some form of lymphoid malignancy, most are of B-cell lineage and are of low- or intermediate-grade malignancy and are usually localized in extranodal areas such as the salivary glands, gastrointestinal tract, thyroid gland, lung, kidney, or orbit
  • risk factors for progression to lymphoma ⁸⁾:
    • persistent parotid gland enlargement
    • splenomegaly
    • lymphadenopathy
    • palpable purpura
    • leg ulcers
    • low serum C4
    • mixed monoclonal cryoglobulinaemia
    • cross-reactive idiotypes of monoclonal rheumatoid factors
• Sjögren's syndrome in women who become pregnant has been linked to increased incidence of neonatal lupus erythematosus with congenital heart block requiring a pacemaker.
• some have a spondylitis such as ankylosing spondylitis (AS)

• can be difficult as symptoms are not always present at the same time, can often seem minor and can be mimicked by other conditions which results in an average diagnostic delay of around 10 yrs

• presence of 4 criteria (below), one f which must be either a positive biopsy or autoantibody screen
• dry eye symptoms
• signs of dry eye (abn. Schirmer's or rose bengal test)
• dry mouth symptoms
• abnormal salivary gland function test (abn. flow rate, scintigram or sialogram)
• minor salivary gland biopsy (focus score > 1)
• autoantibodies (SS-A or SS-B)

• conditions and medications that can produce keratoconjunctivitis sicca, xerostomia, and parotid gland enlargement:
  • xerostomia may be caused by:
    • amyloidosis, diabetes mellitus, sarcoidosis, SS, viral infections, trauma, or irradiation or may be psychogenic
    • medications such as antihypertensive, parasympatholytic, and psychotherapeutic agents
  • dry eyes may be caused by:
    • amyloidosis, inflammation (chronic blepharitis or conjunctivitis, pemphigoid, or Stevens-Johnson syndrome), SS, neurologic conditions that impair eyelid or lacrimal gland function, sarcoidosis, toxicity (burns or drugs), and a variety of other conditions (corneal anesthesia, blink abnormality, hypovitaminosis A, eyelid scarring, or trauma).
  • bilateral parotid gland enlargement may be caused by:
    • endocrine disorders (acromegaly or gonadal hypofunction), metabolic diseases (chronic pancreatitis, diabetes mellitus, hepatic cirrhosis, or hyperlipoproteinemias), SS, or viral infections (human immunodeficiency virus infection, hepatitis C, or mumps)
• Differentiation of SS from RA, SLE, scleroderma, and other rheumatic disorders can be problematic
  • all of these conditions can start with nonspecific manifestations such as arthralgias, myalgias, low-grade fever, and Raynaud phenomenon.
• systemic disorders that can affect exocrine glands:
  • sarcoidosis, amyloidosis, human immunodeficiency virus infection, and lymphoma

• goal of the workup for SS is to eliminate differential diagnostic possibilities and to document the key features of SS
• U&E, FBE, ESR, LFTs, urinalysis
• CXR
• ANA
  • typical Sjögren's syndrome anti-nuclear antibodies (ANA) patterns are SSA/Ro and SSB/La, of which SSB/La is far more specific; SSA/Ro is associated with numerous other autoimmune conditions but are often present in Sjögren's
• RhF
• total IG, IgM, IgA
• serum protein electrophoresis
• TSH antibodies
• potential new biomarkers:
  • several newly-identified biomarkers for SS include autoantibodies to proteins specific to the salivary and lacrimal glands [SP-1 (salivary gland protein-1), PSP (parotid secretory protein), CA-6 (carbonic anhydrase VI)] - these novel biomarkers may appear earlier in the course of disease and are often identified in cases that test negative to traditional biomarkers ⁹⁾

• ocular:
  • Schirmer's test
  • slitlamp exam with rose bengal
  • tear breakup time
• oral:
  • dental exam
  • estimate of salivary flw
  • salivary scintigram
  • minor salivary gland biopsy
• other systemic as indicated:
  • rheumatalogic
  • organ specific antibodies
  • viral hepatitis serology if abn. LFTs

• primarily symptomatic to limit the damage resulting from chronic xerostomia and keratoconjunctivitis and directed toward recognizing and treating complications of the disease early
  • frequent use of tear substitutes
  • secretagogues can enhance secretion through the stimulation of the muscarinic receptors of the salivary glands and other organs but have side effects and should only be used if there are no C/I
  • long acting oral moisturizing gel may be useful for overnight usage
  • fastidious dental care is required
  • avoid dehumidified rooms
  • use of humidifiers may help
  • non-steroidal anti-inflammatory drugs (NSAIDs) may help arthralgias, salivary gland soreness
  • however, disease-modifying antirheumatic agents are seldom used because erosive disease is uncommon