Sjögren's Syndrome

Synonyms: Gougerot's syndrome, sicca complex

There is lymphocytic infiltration of exocrine glands, producing the main symptoms of xerophthalmia (dry eyes), xerostomia (dry mouth), and enlargement of the parotid glands.

The disease is called primary if it develops in isolation and secondary if it occurs with other autoimmune diseases, usually rheumatoid arthritis, systemic lupus erythematosus (SLE) or scleroderma.

One study in Manchester using the European diagnostic criteria calculated a prevalence of 3-4% of adults.¹ Prevalence rises with age but age of onset is usually in the 30s or 40s. Rarely, it can occur in childhood.¹ There is a preponderance of women. The female to male ratio is 9:1.²

Risk factors

There are as yet no chromosomal regions identified by linkage studies (e.g. twin studies) which yield definitive proof of a genetic component but circumstantial evidence is heavily in favour of a genetic aetiology.³ There is a genetic predisposition for the disease but the HLA association varies among ethnic groups.⁴ In white people it is linked to HLA-B8, HLA-Dw3, and HLA-DR3.⁵ The link is to HLA-DRw53 in Japanese and to HLA-DR5 in Greeks and Israelis.⁶

History

The commonest presenting features are dry eyes and dry mouth. However, this is a common complaint and may affect as many as a third of elderly people.⁹ Hence, whilst dry eyes and dry mouth are common features of Sjögren's syndrome, most people who present with such symptoms do not have the disease. As well as fibrosis and atrophy of glands predisposing to sicca syndrome in the elderly, they may also be taking drugs with antihistamine or anticholinergic effects. Dry mouth may present with a number of related complaints:

• Difficulty eating dry food, typically cracker biscuits
• Habit of having a glass of water by the bed at night
• Altered sense of taste
• Difficulty with dentures
• Complaint of tongue sticking to the roof of mouth
• Speaking for long periods of time causes hoarseness
• Dental and periodontal problems
• Oral candidiasis and angular cheilitis

Dry eyes tend to cause a gritty sensation. There is predisposition to blepharitis and the eyes may be sticky in the morning.

There are a number of other features that can occur with the disease:¹⁰

• There may be recurrent parotitis, usually bilateral. Glands are usually enlarged but this is not often the presenting feature.
• Dryness of the mucosa of the trachea and bronchi may present as a dry cough.
• Dryness of the pharynx and oesophagus may cause difficulty in swallowing and lack of saliva and secretions may predispose to gastro-oesophageal reflux.
• There can be dry skin and vaginal dryness causing dyspareunia.^11,12
• Disease of the pancreas can lead to malabsorption and even acute pancreatitis or chronic pancreatitis but a more likely cause of elevated serum amylase is parotitis.
• About 20% have Raynaud's phenomenon.
• Rare features include polyneuropathy that may be a sensory peripheral neuropathy, cranial neuropathy, usually of the facial or trigeminal nerves or vasculitis can produce a mononeuritis multiplex.

Examination

• Look at the eyes. There may be dilatation of the conjunctival vessels. Look for corneal lesions and gently pull down the lower eyelid to assess the tear pool. There may be blepharitis.
• The mouth may look dry and a wooden tongue depressor may stick to the tongue. There may be evidence of infection including oral candida and dental caries.
• Submandibular glands may be enlarged but more obvious is normally bilateral enlargement of the parotid glands. A unilateral and hard salivary gland tumour should prompt immediate referral. Other salivary gland disorders may need to be considered.
• There may be features of other autoimmune disorders such as rheumatoid arthritis, SLE , scleroderma and even primary biliary cirrhosis or chronic hepatitis.

There may be a number of associated autoimmune conditions, such as the CREST variant of scleroderma (calcinosis, Raynaud's phenomenon, (o)esophageal motility disorder, sclerodactyly, and telangiectasiae).^7,13 There may be joint pain, swelling and fatigue or recurrent miscarriage with antiphospholipid syndrome.¹⁴

• Amyloidosis, immunoglobulin-related
• Bulimia
• Chronic pancreatitis
• Graft versus host disease
• Polymyositis
• Rheumatoid arthritis
• Salivary gland tumours
• Sarcoidosis
• Scleroderma
• Systemic lupus erythematosus
• Tuberculosis

• Full blood count (FBC) is usually normal, although anaemia of chronic disease may be a feature. Abnormal white cell count may suggest a lymphoma. ESR may be raised but is non-specific.
• Rheumatoid factor is more often positive in Sjogren's syndrome than it is in rheumatoid disease.
• Antinuclear antibodies are often positive, even without SLE and there may be positive antiphospholipid antibodies.
• In the Schirmer test, a bent piece of filter paper is placed in the lower conjunctiva and left there for 5 minutes. In normal people the paper will be wet to 15mm or beyond after 5 minutes, whereas a definitive positive result is less than 5mm after 5 minutes. This test can be useful to help exclude or confirm significant dryness of the eyes, but it is not specific for the disease.
• Imaging of the salivary glands - either sialography or salivary scintigraphy - may assist in diagnosis, although the abnormalities demonstrated may not be specific to Sjögren's syndrome. Dynamic magnetic resonance sialography is a new technique which is proving helpful.¹⁵
• In cases of uncertainty, biopsy of a salivary gland may be required. Usually one of the minor glands is preferred to a parotid.

Diagnostic criteria

The diagnosis of Sjögren's syndrome is based on the Copenhagen criteria and, more recently, American-European consensus criteria. This is a combination of clinical features and investigations.^16,17 The condition may be suspected when persistent dry mouth or dry eye syndrome develops. Autoimmune screening tests may then reveal a positive rheumatoid factor and/or antinuclear antibodies and the patient is then appropriately referred to a rheumatologist. When presentation is with glandular swelling (commonly parotid glands), referral to a head and neck specialist for consideration of biopsy is appropriate.

There is no specific treatment for the disease but symptoms can be contained. An index of systemic activity - the SCAI - has recently been developed to assess systemic involvement in primary Sjögren's syndrome. Factors analysed to develop the index included fatigue, musculoskeletal involvement, and Raynaud's syndrome.¹⁸ Anticholinergic drugs should be avoided.

Eyes

Artificial tears should be applied liberally. There are various types and some of the more viscous ones need less frequent application. Patients may try several and see which ones they prefer. If application at intervals of less than 4 hours is required then preservative free preparations are preferred to reduce irritation. Overnight a more viscous preparation such as Lacri-lube may be helpful. Oral pilocarpine has been used with some success for ocular as well as oral symptoms.¹⁹

Mouth

Patients should be encouraged to drink plenty to keep the mouth moist. Artificial saliva is available and pilocarpine tablets are licensed for those who have some residual salivary function left.¹⁹ The dose is 5 mg tablets to be taken 4 times daily, before each meal and at night. Saliva contains IgA and other anti-infective agents and so attention to dental hygiene is required and periodic use of antiseptic mouthwash may be beneficial. Topical fluoride and avoidance of sugars is recommended.²⁰

Other features

Vaginal lubricants may be required and infections such as vaginal candidiasis are more likely. Dry skin may benefit from emollients.

• Associated autoimmune diseases may become manifest and need management
• Infections of eyes and mouth are more likely. The parotid gland may be infected with Staphylococcus spp., Streptococcus spp. or Pneumococcus spp..
• Watch out for parotid tumours in a hard, unilateral gland.
• Some, but not all studies, have found an increase in the risk of developing non-Hodgkin's lymphoma, usually around 7 or 8 years after diagnosis,²¹

Prognosis is generally good unless the condition is part of an associated disorder. There is however considerable morbidity.

Henrik Samuel Conrad Sjögren was a Swedish ophthalmologist who was born in 1899 and died in 1976.²² He graduated in medicine from the Karolinska Institutet in 1922. He married the daughter of a prominent ophthalmologist from Stockholm and became interested in the subject. He described his syndrome in 1933 in his doctoral thesis Zur Kenntnis der keratoconjunctivitis sicca but it was not of a sufficient standard for him to be awarded the title of docent, and this denied him a career in academic ophthalmology. The paper was translated into English in 1943 and the eponym became part of the English language. In France the term Gougerot's syndrome was used, as he had described 3 cases of atrophy of the salivary glands with dry eyes, dry mouth and dry vagina in 1925. Sjögren's work was later but much more thorough and this has earned him the eponym.

Do not confuse Sjögren's syndrome with Graefe-Sjögren syndrome of retinitis pigmentosa, spinocerebellar ataxia and deafness or Marinesco-Sjögren syndrome of spinocerebellar ataxia, congenital cataract, hypertension, dysarthria, short stature, abnormal teeth, brittle thin hair, mental retardation and some skeletal deformities. Fatty aldehyde dehydrogenase deficiency, a condition presenting with mental dehydration, ichthyosis, and spastic neurological disorder is known in Sweden as Sjögren-Larssen syndrome. All these conditions are named after a different person called Karl Gustaf Torsten Sjögren, a Swedish physician and psychiatrist.