Sjögren’s syndrome (SS) has a prevalence of 0.4% to 1% and the incidence is estimated to be between three to six new cases per 100,000 people per year.¹ It affects up to four million people in the US, however prevalence in Ireland is unknown.²

It is under-recognised in the general population. Incidence peaks between the ages of 40-60 years with 90% of patients being female.³ It is more common in those with a family history of autoimmune disease.

Epidemiology, pathogenesis and risk factors

SS is a systemic autoimmune disorder characterised by diminished lacrimal and salivary gland function. It is characterised by dry eyes and dry mouth. Other organ systems can be affected in many patients, with lymphoma being a well-recognised complication. 

SS can be classified as either primary or secondary. SS can occur in a primary form not associated with other diseases, and in a secondary form that complicates other autoimmune diseases such as rheumatoid arthritis (RA), lupus and scleroderma. 

The pathogenesis of SS is unknown.⁴ It is postulated that SS is a result of an environmental or viral trigger that promotes an autoimmune reaction in genetically susceptible people. 

Although no single virus has been proven to cause SS, those which have been implicated include Epstein-Barr virus (EBV), hepatitis C, human herpesvirus 6 (HHV-6) and human immunodeficiency virus (HIV).⁵ 

In both primary and secondary SS the hallmark is lymphocytic infiltration of the exocrine glands leading to decreased exocrine gland function. This causes the ‘sicca complex’, a combination of dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia).

Clinical features

Over 90% of patients with SS typically present with glandular dryness, although occasionally patients may present with extraglandular features.³

Ocular dryness (keratoconjunctivitis) is due to reduced tear formation. It usually presents over years and patients may report worsening of their symptoms in the evening. Symptoms include grittiness, dryness, itchiness and the sensation that a foreign body such as sand is present. 

Despite profound ocular dryness, the ability to cry is usually not affected. 

On physical examination of the eyes, there may be conjunctival injection or, in more severe cases, corneal ulceration.⁶

The oral effects of SS are due to reduced saliva formation. Xerostomia is the most common oral symptom reported. However, patients may also complain of difficulty eating, swallowing and speaking. 

Patients may report waking up at night to drink water as a result of a dry mouth. Complications of xerostomia include multiple dental caries due to decreased salivary flow, recurrent oral infections and oesophagitis.⁶ Examination may reveal dry mucous membranes and ulceration. Parotid glands may be swollen and tender.

Extraglandular features of SS include: 

• Arthralgia or arthritis. Arthritis in primary SS is usually symmetrical, non-deforming, non-erosive and most commonly affects the hands and knees

• Gastrointestinal symptoms most commonly include dysphagia due to decreased saliva, but can also include oesophageal dysmotility similar to that seen in scleroderma.⁸ Coeliac disease may be more prevalent in patients with SS than in the general population⁹

• Cardiopulmonary disease including chronic cough, pleural and pericardial effusions, pulmonary hypertension and fibrosis

• Autoimmune thyroiditis including both hyper and hypothyroidism

• Raynaud’s phenomenon and cutaneous vasculitis

• Renal involvement can include renal tubular acidosis, glomerulonephritis and interstitial nephritis¹⁰

• Neurological features can include peripheral neuropathy, mononeuritis multiplex and cranial neuropathies.¹¹

A major long-term risk factor for patients with primary SS is a 20-to-40-fold increased risk of lymphoma. They are at a particular increased risk of mucosa-associated lymphoid tissue (MALT) and non-Hodgkin lymphoma.¹² Although there is no evidence to suggest screening for lymphoma, the following features should raise suspicion: regional or general lymphadenopathy, parotid gland enlargement, hepatosplenomegaly or hypergammaglobulinaemia.

Diagnosis

The diagnosis of SS is established by a characteristic history, clinical examination and a combination of blood-work, biopsies and objective tests which can help aid diagnosis. SS often has a sub-acute onset, thus diagnosis can often be delayed and difficult.¹³ 

A wide range of blood-work can be performed as an initial investigation. Inflammatory markers such as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and immunoglobulins can frequently be raised in SS, as in other connective tissue diseases. 

Antinuclear antibodies and rheumatoid factor may be positive/raised, as SS may often complicate RA. More specifically, anti-SSA autoantibodies (anti-Ro) or (anti-La) antinuclear antibodies may be positive.¹⁴ However, anti-Ro may occur in other disease such as SLE and primary biliary cirrhosis.

Schirmer’s test measures tear production. A small piece of filter paper is placed on the lateral aspect of the lower eyelid and the degree of wetness is measured with a ruler after five minutes. It is positive if less than 5mm of wetness is produced.¹⁴ Rose-Bengal staining of the conjunctiva and cornea is a relatively inexpensive and non-invasive test to detect corneal abrasions and ulcers. The Rose-Bengal dye will stain devitalised tissue and can identify keratoconjunctivitis when minimal ocular symptoms are present.¹⁵

When oral symptoms are present, a variety of investigations may be performed. Salivary gland scintigraphy visualises the salivary glands and ducts, as contrast is instilled into the parotid duct. The finding of low uptake of contrast is highly specific for SS. 

The measurement of salivary production (sialometry) may also be performed. It is a simple test that requires the patient to collect all saliva produced in 15 minutes in a container. A collection less than 1.5ml is considered positive.¹⁶

A minor salivary gland biopsy taken from the patient’s lip was once considered the gold standard; however, it may not always be necessary.¹³ It can be used to diagnose a suspected case of SS, or to exclude other causes of xerostomia and bilateral gland enlargement such as sarcoidosis. 

Classification

The American-European Consensus Criteria for SS was not designed to make a diagnosis, but is a useful framework.¹⁷ For the diagnosis of primary SS, either (a) any four of the six criteria (must include either iv or vi); or (b) any three of the four objective criteria (iii, iv, v, vi) can be used. In a patient with another well-defined major connective tissue disease, secondary SS can be diagnosed by the presence of one symptom (i or ii) plus two of the three objective criteria (iii, iv and v).

Objective criteria

(i) Ocular symptoms (≥ 1present)

• Symptoms of dry eyes for ≥ 3 months

• Foreign body sensation in the eyes

• Use of artificial tears ≥ 3 per day

(ii) Oral symptoms (≥ 1 present)

• Symptoms of dry mouth for at least three months

• Recurrent or persistently swollen salivary glands

• Need for liquids to swallow dry foods

(iii) Ocular signs (≥ 1 present)

• Abnormal Schirmer’s test (without anaesthesia; ≤ 5 mm/5 minutes)

• Positive vital dye staining of the eye surface

(iv) Histopathology

• Lip biopsy showing focal lymphocytic sialadenitis (focus score ≥ 1 per 4mm²)

(v) Oral signs (at least one present)

• Unstimulated whole salivary flow (≤ 1.5ml/15 minutes)

• Abnormal parotid sialography

• Abnormal salivary scintigraphy

(vi) Autoantibodies (at least one present)

• Anti-SSA (Ro) or anti-SSB (La).

Treatment

Similar to other autoimmune disorders, there is no known cure for SS and thus treatment is focused primarily on relieving symptoms and preventing complications. 

Management of patients with SS is similar whether it is primary or secondary. Many patients benefit from a multidisciplinary approach including general practitioners, rheumatologists, ophthalmologists, dentists and speech and language specialists. Treatments can be grouped according to symptoms: xerostomia, keratoconjunctivitis and systemic features.

Xerostomia

Preventative measures against dry mouth can include regular rinsing of the oral cavity with water, and sugar-free drinks to maintain good hydration which is both convenient and cost-effective. 

Patients should be educated to avoid anticholinergic and over-the-counter (OTC) cold medications which could exacerbate oral dryness.¹⁸ Basic dental care and topical stimulation with sugar-free gum should be encouraged. 

If there is an insufficient response to the above basic measures, artificial saliva, muscarinic agonists such as pilocarpine (Salagen), or systemic medications such as hydroxychloroquine (Plaquenil) can be prescribed.¹⁹

Keratoconjunctivitis

Patients should be encouraged to limit exposure to environments which can exacerbate dry eyes such as dry or windy outdoors, or dry indoors such as airplanes and hospitals. Other measures which can be employed include artificial tear replacement.²⁰

Artificial tears can be prescribed in most patients with SS, including all degrees of disease severity, and can provide both symptomatic relief and an improvement in corneal abrasions, however they can worsen blepharitis.

Systemic features

Hydroxychloroquine (Plaquenil) may be used as an initial treatment for arthralgia and myalgia.²¹ It is usually well tolerated but there is a very low risk of ocular complications such as corneal deposits. If there is an inadequate response then methotrexate can be prescribed. 

Patients with cardiopulmonary manifestations may be treated with glucocorticoids, or other immunosuppressive medications such as azathioprine (Imuran). 

Renal involvement may necessitate the use of mycophenolate (Cellcept) or pulsed cyclophosphamide depending on the clinical urgency.

New emerging therapies include rituximab, a monoclonal antibody against CD20 for the treatment of extraglandular manifestations, however further larger randomised controlled trials are needed to determine the long-term effects of treatment and which patients would benefit most.²²

Conclusion

SS is the second most common autoimmune disorder, however it is relatively underdiagnosed. If there is a clinical suspicion, then there are simple, bedside, non-invasive diagnostic tests which can be performed such as Schirmer’s test and the salivary flow test. Treatment is primarily focused on relieving symptoms and preventing complications.  

References

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