Sjögren's syndrome

Sjögren’s syndrome is a chronic autoimmune condition that is characterised by lymphocyte infiltration of exocrine glands. This leads to impaired secretions but can also manifest with extraglandular features. It is classified as a connective tissue disorder. It is commonly associated with other autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus (SLE).

🏘️ Epidemiology

Sjögren’s syndrome has a global prevalence of 61 per 100,000 with it more commonly being seen in Europe and significantly more prevalent in women.

Women are affected more than men at a ratio of 9:1. It more common in middle-aged women

Pathophysiology

Although not well understood, the aetiology of Sjögren’s syndrome is multifactorial. It involves genetic, environmental, hormonal and immunological factors.

Genetic predisposition is seen in individuals with specific HLA alleles, especially those with the HLA-DR and HLA-DQ alleles. Seeing as it is associated with other autoimmune diseases, it also highlights the potential genetic predisposition.

Environmental triggers such as infections like Epstein-Barr virus (EBV) and cytomegalovirus (CMV) have also been implicated. They are believed to trigger an autoimmune response through molecular mimicry in genetically susceptible individuals.

Hormonal influences seem to be significant too as it predominantly affects women - particularly those who are middle-aged. This may implicate oestrogen in modulating the immune response. Theories suggest that lower levels of oestrogen post-menopause might exacerbate the condition. Oestrogen receptors are present on immune cells and fluctuations in oestrogen levels could affect the balance between pro-inflammatory and anti-inflammatory responses.

Activated dendritic cells present self-antigens, such as Ro (also known as SSA) and La (SSB), to auto-reactive T cells. Ro and La are ribonucleoproteins that are involved in RNA processing. Ro consists of Ro52 and Ro60 and La is separate altogether. These proteins are released from apoptotic cells and stimulate an immune response when presented to T cells. Auto-reactive T cells infiltrate the exocrine gland and produce an inflammatory response with the release of pro-inflammatory cytokines that perpetuate the inflammatory response. B cells produce autoantibodies such as anti-Ro and anti-La antibodies that form immune complexes that contribute to glandular inflammation and damage. The antibodies interfere with muscarinic receptors and secretion of matrix metalloproteinases (MMPs) results in destruction of the extracellular matrix of surrounding glandular cells. Lymphocytic infiltration and destruction of glandular tissue is the hallmark of the disease. Due to the destruction of such glands (such as salivary and lacrimal glands) we see the manifestations of dry eyes and dry mouth that comes with Sjögren’s syndrome.

Antibodies implicated or associated with Sjögren’s syndrome, other than anti-Ro and anti-La, include:

• Anti-nuclear antibodies (ANA) - present in 90% of patients.
• Rheumatoid factor (RF) - present in 50% of patients.
• Anti-thyroglobulin antibodies (Anti-TG) - present ion 25% of patients.

⚠️ Risk factors

• Female
• Middle-age
• SLE
• Rheumatoid arthritis
• Systemic sclerosis

😷 Presentation

Sjogren’s is typically a disease that is known to affect the lacrimal and salivary glands the most but it has extraglandular manifestations too.

The 3 main symptoms of Sjogren’s are:

1. Fatigue
2. Dry eyes (xerophthalmia)
3. Dry mouth (xerostomia)

💡 The 2 symptoms of dry eyes and dry mouth are referred to as sicca and form part of a syndrome known as Sicca syndrome (dryness of the mucous membranes). Sjögren’s is not synonymous with Sicca but may include the manifestations of it. Most patients with Sjögren’s experience Sicca symptoms but not all patients with Sicca have Sjögren’s. Other causes may be medications, radiotherapy or other systemic diseases, for example.

Ocular manifestations

• Dry eyes (xerophthalmia) - this will present with a gritty sensation in the eyes, with itch or burning too. It persists >3 months with multiple episodes per week.
• Keratoconjunctivitis sicca - this is keratoconjunctivitis that is caused due to dryness and an inadequate tear film. It may lead to superimposed bacterial conjunctivitis infection.

Oral manifestations

• Dry mouth (xerostomia) - this may come with associated difficulties in chewing and swallowing, speaking or altered taste.
• Dental caries (cavities)
• Oral candidiasis
• Intermittent parotid swelling
• Tongue fissures

Other glandular symptoms include:

• Vagnial dryness which may cause dyspareunia
• Nasal dryness leading to chronic rhinitis and epistaxis (due to crusting)
• Pharyngeal and tracheal dryness leading to a dry cough
• Xerosis (severely dry skin) due to hypohidrosis/anhidrosis

Systemic symptoms are present in 50-60% of patients:

• Arthralgia is the most common systemic symptom.
• Raynaud phenomenon
• Dysphagia, oesophagitis and gastritis
• Constitutional symptoms such as fever, weight loss and fatigue
• Small vessel vasculitis and purpura

🔍 Investigations

Bloods

• ESR/CRP - raised.
• Autoantibodies
• Anti-Ro and anti-La autoantibodies - present in 70% of patients.
• ANA - positive (but not specific for Sjogren’s).
• RF - positive in 50% of cases of
• U&Es - creatinine clearance may be low in 50% of patients.

Special tests:

• Schirmer’s test - this is a test used to assess the tear production of an individual. It is done using a strip of litmus paper that is placed on the lower eyelid for five minutes. . In normal individuals there is wetting of ≥15mm after 5 minutes. It is positive if there is <5mm wetting after 5 minutes. However, this is not specific for Sjogren’s but rather for sicca symptoms.
• Rose-Bengal staining of the cornea - may show keratitis by staining dead and degenerating cells as well as mucus. Once again it indicates sicca.
• Salivary flow rate monitoring - this demonstrates xerostomia by using a radio-labelled dye.
• Salivary gland biopsy - usually one of the labial salivary (sublingual, for example) glands is biopsies from the inner lip. It is the gold-standard but not necessary to make the diagnosis. Histological analysis may show destruction of the minor salivary glands, sialadenitis with dense focal lymphocytic infiltrations.

🔢 Criteria

The American College of Rheumatology/European League Against Rheumatism (ACR-EULAR) criteria for primary Sjögren’s syndrome is as follows:

• Labial salivary gland with focal lymphocytic sialadenitis with ≥1 foci - 3 points.
• Anti-Ro (Anti-SSA) positive - 3 points.
• Ocular staining score ≥5 in at least 1 eye - 1 point.
• Schirmer test ≤5mm in 5 min in at least 1 eye - 1 point.
• Unstimulated saliva flow rate ≤0.1ml/min - 1 point.

The patient must have a score of ≥4 + at least 1 symptom of xerostomia or xerophthalmia as well as no exclusion criteria for it to be classified as primary Sjögren’s syndrome.

Exclusion criteria include:

• History of radiotherapy to head and neck
• Active hepatitis C infection
• AIDS
• Sarcoidosis
• Amyloidosis
• Graft-versus-host disease
• IgG4-related disease

🧰 Management

🚨 Complications

• Bacterial conjunctivitis
• Bacterial sialadenitis
• B-cell lymphoma (Non-Hodgkin lymphomas)