Sjögren syndrome

Sjögren’s syndrome is a chronic autoimmune disease characterised by reduced lacrimal and salivary gland function.

Sjögren’s syndrome (SS) is characterised by dry eyes and dry mouth due to reduced lacrimal and salivary gland function, respectively. It is a systemic condition associated with extraglandular clinical features and can affect almost any organ.

Terminology

A number of terms are used in SS.

• Sicca syndrome: old term that is synonymous with SS.
• Keratoconjunctivitis sicca: refers to the dry eye symptoms experienced in SS
• Xerostomia: refers to dry mouth

Primary vs. secondary

SS may be classified as primary or secondary:

• Primary: Sjögren’s syndrome in the absence of an underlying rheumatic disease
• Secondary: Sjögren’s syndrome in the presence of another systemic rheumatic disease

The most commonly implicated systemic rheumatic diseases in secondary SS are Rheumatoid arthritis, Systemic lupus erythematosus (SLE) and Systemic sclerosis.

Primary SS is a relatively common condition.

SS is found worldwide but the true incidence and prevalence of the condition varies, but is estimated between 0.1-4% depending on the diagnostic criteria used. Importantly, the majority of patients with dry eyes and mouth (i.e. Sicca symptoms), especially older adults, do not have underlying SS.

Primary SS

Primary SS is most commonly seen in females (9-20:1 female to male ratio) in the 4^th or 5^th decade of life.

Secondary SS

Secondary SS is commonly found in association with SLE, rheumatoid arthritis and systemic sclerosis. The epidemiological data of secondary SS varies widely depending on the underlying condition.

Other autoimmune diseases

SS may also be found in association with other autoimmune diseases. These include:

• Autoimmune hepatitis
• Primary biliary cholangitis
• Autoimmune thyroiditis (hypothyroidism)
• Graves’ disease (hyperthyroidism)
• Antiphospholipid syndrome

The lacrimal glands are exocrine glands needed for the production of tears.

The lacrimal glands are paired exocrine glands located anteriorly within the superolateral aspect of each orbit. The sensory innvervation of the lacrimal glands is via the first sensory branch of the trigeminal nerve (V1) and the autonomic innervation is via of the pterygopalatine ganglion, which is supplied by branches of the facial nerve (VII).

The lacrimal glands are needed for the formation of the normal tear film, which is composed of three structures:

• Surface lipid layer: produced by meibomian gland
• Middle aqueous layer: produced by the lacrimal glands
• Inner mucus layer: produced by goblet cells found in the cornea and conjunctiva

The salivary glands are exocrine glands needed for the production of saliva.

Salivary glands are divided into the three paired major salivary glands and minor salivary glands.

Major salivary glands

The major salivary glands refer to three paired exocrine glands:

• Parotid glands: largest salivary gland. Located inferior to the zygomatic arch in the pre-auricular region. Drains into the oral cavity via the parotid duct of Stensen. Innervated by the IX cranial nerve (glossopharyngeal nerve).
• Submandibular glands: second largest salivary gland. Located in the submandibular triangle of the neck. Drains into the oral cavity via Wharton’s duct. Innervated by the VII cranial nerve (facial nerve).
• Sublingual glands: smallest salivary gland. Located within the sublingual folds that lie directly under the mucous membrane covering the floor of the mouth. Drain into the oral cavity via the minor sublingual ducts (of Rivinus). Innervated by the VII cranial nerve (facial nerve).

Minor salivary glands

There are hundreds of minor salivary glands located throughout the oral cavity. These may have their own secretory duct or form a common duct with another gland. Any of these glands may be affected in SS.

The exact cause of SS remains unknown.

The underlying cause of SS is not completely understood. There appears to be association with certain human leucocyte antigens (HLA), which are involved in antigen processing in the immune system. However, there is significant heterogeneity in risk among different ethnic groups.

Other factors influenced in the development of SS include gender, which is likely to relate to sex hormones, viral infectious triggers (e.g. Epstein-Barr virus) and other non-HLA genetic elements.

The condition is divided into primary and secondary SS.

• Primary: Sjögren’s syndrome in the absence of an underlying rheumatic disease
• Secondary: Sjögren’s syndrome in the presence of another systemic rheumatic disease

In general, the sicca symptoms (dry eyes and dry mouth) are more severe in the primary form.

SS is characterised by the formation of autoantibodies anti-Ro/SSA and anti-La/SSB.

Glandular disease

SS is characterised by autoimmune lymphocytic infiltration (CD4 T cells and B plasma cells) of glandular tissue including lacrimal and salivary glands. This infiltration of immune cells is accompanied by glandular and ductal atrophy. In addition, there is suspected to be glandular dysfunction with altered release of acetylcholine and response to neural stimulation.

Extraglandular disease

A variety of disease mechanisms can occur in extraglandular tissue leading to a wide range of clinical features. These may include immune cell infiltration and damage, immune-complex deposition or lymphoproliferation. Immune-complex deposition refers to the formation of multiple antibody-antigen complexes that subsequently get deposited in tissue and promotes a local inflammatory response. This is typical of many autoimmune diseases and can lead vasculitis.

Autoantibodies

SS, like many rheumatological conditions, is characterised by the development of autoantibodies that target self-antigens.

• Anti-nuclear antibody (ANA): 90% of patients with SS.
• Rheumatoid factor: autoantibody directed against Fc portion of IgG. Seen in many rheumatological conditions. In 40-60% of SS patients.
• Anti-Ro/SSA
• Anti-La/SSB

It is estimated that 60-80% of patients with primary SS with have one or both of Anti-Ro and Anti-La autoantibodies. In secondary SS, only 15% will have evidence of these autoantibodies. Anti-Ro may be found in 50% of patients with SLE and some healthy patients, therefore, it cannot be used alone to diagnose SS.

The hallmark clinical features of SS are dry eyes and dry mouth.

SS is characterised by keratoconjunctivitis sicca (dry eyes) and xerostomia (dry mouth). In addition, up to 50% of patients may have salivary gland enlargement.

Keratoconjunctivitis sicca

• Eye irritation, grittiness or foreign body sensation
• Blurry vision
• Eye itching
• Photophobia
• Corneal erosions or ulceration (detected on fluorescein staining)
• Reduced tear production (see Schirmer test)

Xerostomia

• Dry mouth & lips
• Adherence of food to buccal surface
• Difficulty eating dry food
• Difficulty speaking for long periods
• Problems with dentures
• Change in taste
• Absent sublingual salivary pooling
• Increased dental caries
• Oral infections (salivary gland infections, oral candidiasis)

Lymphoma

Lymphoma may develop in 2-5% of patients with SS. This is typically a non-Hodgkin’s lymphoma (NHL). Tumours may arise from exocrine glands, lymph nodes, or mucosa-associated lymphoid tissue (MALT). The following clinical features may suggest a lymphoproliferative disorder.

• B symptoms: fever, night sweats, weight loss
• Persistent unilateral or bilateral gland swelling
• Hard, nodular gland
• New enlarged lymph node

Extraglandular manifestations

This refers to clinical features due to organ involvement outside of the lacrimal and salivary gland. This is discussed further below.

SS is a systemic disease that can affect virtually any organ in the body.

A range of extraglandular manifestations may occur in SS. In some cases, it may be difficult to distinguish extraglandular manifestations from another underlying rheumatic disease or autoimmune condition.

Skin

• Abnormal dryness (xerosis)
• Purpura (suggests cutaneous vasculitis): seen in 10% of primary SS
• Raynaud phenomenon
• Others (e.g. vitiligo, erythema nodosum).

Musculoskeletal

• Arthralgia with or without arthritis
• Myopathy (muscle weakness): may suggest underlying mixed connective tissue disease

Pulmonary

• Interstitial lung disease (ILD): usually manifests are shortness of breath and cough
• Cystic lung disease: usually seen on imaging

Cardiovascular

• Pericarditis
• Myocarditis
• Heart block

NOTE: congenital heart block can occur in neonates of mothers with SS and anti-Ro autoantibodies. These autoantibodies can cross the placenta.

Renal

• Interstitial nephritis
• Renal tubular acidosis
• Interstitial cystitis

Gastrointestinal

• Dysphagia: due to a combination of poor saliva, pharyngeal dysfunction and oesophageal dysmotility
• Coeliac disease: higher prevalence in SS
• Primary biliary cholangitis: increased association with SS
• Autoimmune hepatitis: increased association with SS

Neurological

• Peripheral neuropathy: seen in 10% of patients

Gynaecological

• Vulvovaginal dryness and pruritus
• Dyspareunia: painful sexual intercourse

Psychiatric

• Depression

Haematological

• Cytopaenias (low blood counts): anaemia, leucopaenia and thrombocytopaenia can all occur
• Hypergammaglobulinaemia (high total antibodies): may be polyclonal or monoclonal. Monoclonal increases in immunoglobulins is linked with development of myeloma or lymphoma.
• Hypogammaglobulinaemia (low total antibodies): less common. May also be a sign of lymphoma.
• Cryoglobulins: refers to proteins (e.g. immunoglobulins) that precipitate at low temperatures. This may lead to vessel occlusion, ischaemia and characteristic rashes due to vasculitis (inflammation of blood vessels)
• Lymphoma
• Immune thrombocytopaenic purpura (ITP)

Several classification systems are used for the diagnosis of SS.

Over the last two decades, there have been a number of classifications used for the diagnosis of SS.

These include:

• American-European Consensus Group’s (AECG) criteria for the classification of Sjögren syndrome (2002)
• Sjögren’s International Collaborative Clinical Alliance (SICCA) investigators criteria (2012)
• American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification (2016)

AECG criteria

A definitive diagnosis requires 4/6 criteria to be met:

1. Dry eye symptoms
2. Dry mouth symptoms
3. Objective ocular dryness: defined as Schirmer’s test ≤5mm in 5 minutes (see below)
4. Objective oral dryness: salivary gland hypofunction is confirmed by sialometry (rate of saliva production) or scintigraphy (low uptake suggesting hypofunction)
5. Positive anti-Ro/La autoantibodies
6. Typical salivary gland biopsy findings: samples taken from minor salivary glands

Within the four chosen criteria, 5 or 6 must be present. For secondary SS, symptoms of dry eyes and mouth associated with an underlying rheumatoid disease must exist in addition to criteria 3, 4 or 5.

ACR/EULAR diagnostic criteria

There are five criteria, which are all weighted to a particular score. Diagnosis is based on the sum of the five items with a score ≥4 confirming the diagnosis. Prior to using this criteria, there are inclusion questions to ask relating to symptoms.

1. Typical labial salivary gland biopsy findings (3 points)
2. Anti-Ro (SSA) positive (3 points)
3. Ocular staining score ≥5 (1 point)
4. Schirmer’s test ≤5mm in 5 minutes (1 point): see below
5. Whole sialometry with unstimulated whole saliva flow rate ≤0.1 mL/min (1 point)

The ocular staining score assess for corneal damage under fluorescein dye and conjunctival damage under lissamine green dye.

Exclusion

Patients with underlying conditions that predispose to dry eyes and dry mouth need to be excluded prior to using the above diagnostic criteria. These conditions include:

• Past head-and-neck irradiation
• Hepatitis C virus infection
• Acquired immunodeficiency syndrome
• Prior lymphoma
• Sarcoidosis
• Graft versus host disease
• Use of anticholinergic drugs

Other diagnostic tests

Salivary gland ultrasound may be used as an alternative to different ocular and salivary functional tests. MRI may also be used as an alternative to look at glandular structure and has good correlation with biopsy.

Schirmer’s test is used to look at tear production.

Schirmer’s test is a simple bedside test used to assess tear production.

Test procedure

• Step 1: Folded sterile filter paper is placed over the margin of the lower eyelid
• Step 2: The patient is asked to gently close their eyes
• Step 3: The filter paper is left for 5 minutes
• Step 4: The extent of paper wetting is assessed after 5 minutes

Wetting of filter paper ≤5mm within 5 minutes is suggestive of aqueous tear deficiency.

Sialometry refers to the measure of saliva production.

The unstimulated whole salivary flow rate is the easiest test to perform at the bedside. It assesses basal saliva production, predominantly from submandibular and sublingual glands.

Test procedure

• Step 1: Patient asked to expectorate at the start of the test
• Step 2: The patient then asked to collect all saliva in a pre-weighed container
• Step 3: Saliva should be collected over 5-15 minutes
• Step 4: The collection container is reweighed at the end of the time period

Collection ≤ 0.1 mL/minute is indicative of abnormal salivary function.

Other tests

Stimulated salivary tests can be performed if necessary. This mainly assess parotid saliva production. In addition, a series of nuclear medicine or imaging investigations can be used to asses salivary gland function.

Patients with SS require a full work-up to look for extraglandular features and any underlying rheumatological condition.

Investigations are important to assess for disease severity and activity, extraglandular involvement and the presence or absence of any underlying rheumatic disease.

Bedside tests

• Urinalysis: assess for evidence of nephritis
• Saliva gland function (see whole sialometry)
• Lacrimal gland function (see Schirmer test)

Blood tests

• Full blood count
• ESR & CRP
• Urea & electrolytes
• Liver function tests

Autoimmune screen

This refers to a series of blood tests completed in patients presenting with a possible autoimmune disease.

• ANA
• Extractable nuclear antigens (ENAs): this will include anti-Ro and anti-La autoantibodies
• Anti-CCP (if rheumatoid arthritis suspected)
• Anti-dsDNA (if SLE suspected): usually requested separately to ENAs
• Rheumatoid factor
• Complement
• Immunoglobulins
• Serum protein electrophoresis
• Creatinine kinase
• Coeliac screen
• Thyroid function tests
• Virology: hepatitis C, hepatitis B, HIV

Additional tests

These tests are important as part of the diagnostic work-up of SS and discussed in the section on diagnosis.

• Salivary gland biopsy
• Salivary gland imaging

Disease severity and activity

The symptom severity of SS can be assessed using the EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI). Additionally, disease activity can be assessed using the EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI).

Treatment is primarily aimed at Sicca symptoms, but systemic immunosuppression may be needed in severe cases.

EULAR provides recommendations for the management of SS. Treatment can be difficult and has not changed in many years. In general, treatment should be aimed at Sicca symptoms (i.e. dry eyes and dry mouth). However, in severe cases, particularly those with extraglandular involvement, systemic immunosuppression may be needed.

The evidence for therapy is best in primary SS. Recommendations are generally extended to secondary SS, but treatment in theses cases should also focus on the underlying rheumatological condition.

Treatment of dry eyes

There are no treatments that can cure dry eyes. Treatment is available to alleviate symptoms of dryness. In patients with severe or refractory disease, referral to an ophthalmologist is essential.

Primary treatment is with artificial tears and ointments

• Hypromellose eye drops
• Carmellose eye drops 0.5-1.0%
• Sodium hyaluronate eye drops 0.1–0.18%

Recommended twice daily, but can be used as often as hourly to alleviate symptoms. Ointments are thicker and useful for symptom control overnight

Secondary treatment options are usually prescribed by an ophthalmologist and include:

• Topical NSAIDs or Corticosteroids: usually short-term use. Associated with corneal complications long-term.
• Topical cyclosporin: reserved for patients needing recurrent courses of topical steroid.
• Serum tear drops: application of autologous or allogenic serum. Variable efficacy.

Treatment of dry mouth

Baseline assessment of salivary gland function is important prior to initiation of therapy.

Treatment options depend on the severity of salivary gland function:

• Severe dysfunction: treatment with artificial saliva. There are many different preparations that can be used. For example, lozenges, gels or sprays.
• Non-severe dysfunction: treatment with non-pharmacological stimulation. This may include sugar-free sweets, lozenges or sugar-free chewing gum. Patients may also be considered for pharmacological stimulants including muscarinic agonists like pilocarpine.

Dental hygiene is critical in patients with poor salivary function. All patients should be advised to use a neutral pH sodium fluoride gel to prevent caries.

Treatment of systemic disease

SS with extraglandular involvement is seen in around 70% of patients and may be severe in 15%. Systemic therapies are generally restricted to patients with severe active disease as measured by the ESSDAI. There are certain criteria, based on the ESSDAI, for initiating therapy.

Systemic therapy options include:

• Corticosteroids (First line): may be given as a ‘pulse’ of methyprednisolone followed by maintenance. A pulse refers to a short course of high dose steroids (often 1-3 days). Higher doses of maintenance may be needed for more severe disease. The aim is to withdraw steroids completely or get to a maintenance dose of 5 mg/day or less.
• Immunosuppressive agents (second line): these may be considered in patients with severe, or uncontrolled, disease that would otherwise need long-term steroids. There is no evidence to support one immunosuppressive agent over another. Options include Leflunomide (pyrimidine synthesis inhibitor), Methotrexate (Dihydrofolate reductase inhibitor), Azathioprine and Mycophenolate (Purine synthesis inhibitors) and Cyclophosphamide (alkylating chemotherapy agent that crosslinks DNA and RNA)
• Monoclonal antibodies (third line): Patient with severe SS that is refractory to treatment may be treated with immunosuppressive agents that target B lymphocytes. For example, rituximab (monoclonal antibody to CD-20).

The major complication of SS is lymphoma.

Complications of SS may be divided into ocular, oral and extraglandular. The major extraglandular complication is lymphoma, which occurs in 2-5%.

Ocular

• Corneal ulcer
• Corneal perforation
• Ocular infections

Oral cavity

• Ulcers
• Candidiasis
• Caries/dental complications

Extraglandular

• Lymphoma (NHL)
• Severe leucopaenia
• Vasculitis
• Peripheral neuropathy
• ILD
• Perimyocarditis
• Other

Patients with extraglandular involvement may have a reduced quality of life.

Overall, SS is associated with a good prognosis. However, extraglandular involvement is associated with reduced quality of life, which may manifest as lower social functioning, reduced general health and increase bodily pain.

In the absence of developing lymphoma, patients with primary SS have a normal life-expectancy. Those with secondary SS have a life-expectancy and prognosis in keeping with the underlying disorder. Patients with severe exocrine gland involvement have an increased risk of lymphoma. In addition, low levels of complement have been linked with an increased risk of death.