Sjögren's syndrome

Synonyms: Gougerot's syndrome, sicca complex

What is Sjögren's syndrome?¹

Primary Sjögren's syndrome is an immune-mediated condition of unknown aetiology characterised by focal lymphocytic infiltration of exocrine glands. Patients characteristically complain of drying of the eyes and mucosal surfaces along with fatigue and arthralgia.

There is an association with autoimmune thyroid disease, coeliac disease and primary biliary cirrhosis. Systemic features include inflammatory arthritis, subacute cutaneous lupus erythematosus, immune thrombocytopenia, vasculitis with purpura, salivary gland inflammation, neuropathies, interstitial lung disease and a 5-10% lifetime risk of B cell lymphoma.

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 or scleroderma.

Sjögren's syndrome epidemiology²

• The global prevalence calculated for primary Sjögren’s syndrome is 61 per 100,000 inhabitants, with the highest prevalence in Europe.

• Women develop Sjögren’s syndrome significantly more frequently than men. The sex difference ranges between 9:1 to 19:1.

• The mean age at time of first diagnosis of primary Sjögren’s syndrome is 56 years, with another peak occurring between 20 and 40 years. However, symptoms may occur years before diagnosis.

Sjögren's syndrome symptoms^{2 3}

Sicca symptoms are the most common manifestation of Sjögren’s syndrome (up to 98% of cases). Patients with keratoconjunctivitis sicca complain about foreign-body sensation, burning or soreness of the eyes and increased sensitivity to light. Marked xerostomia as a sign of stomatitis sicca presents as difficulties when talking for extended periods of time and while chewing or in salivating dry food. There is an increased prevalence of dental caries and early tooth loss, and oral health is significantly reduced. Recurrent oral infections with Candida albicans occur 10 times more frequently than in the general population. However, sicca symptoms are often reported with advancing age and polypharmacy.

Up to 34% of patients with Sjögren’s syndrome report episodic or chronic, typically bilateral, swelling of the parotid glands.

The most common non-glandular manifestations are arthralgia and a usually non-erosive polyarthritis which occur in approximately 50% of patients.

Pulmonary involvement beyond the sicca complex typically manifests as interstitial lung disease or follicular bronchiolitis, normally after many years of disease activity (9-12% of patients).

About 10% of patients have cutaneous lesions, the majority in the form of a vasculitis with involvement of small and medium vessels of the lower limbs. Other less common skin manifestations include annular erythema, urticarial vasculitis, or hypergammaglobulinaemic purpura.

Renal involvement (approximately 5% of patients) is usually associated with tubulointerstitial changes which frequently go along with distal renal tubular acidosis (RTA type 1) with hypokalaemic muscular hypotonia. Glomerulonephritis is rare in primary Sjögren’s syndrome.

Involvement of the peripheral nervous system, especially later in the course of the disease, typically manifests as sensory neuropathy (10-25%). Rarer are CNS manifestations. Multifocal CNS lesions on MRI may be difficult to distinguish from multiple sclerosis lesions.

Nonspecific complaints include fatigue and diffuse pain.

Women who are anti-Ro/SSA- and anti-La/SSB-positive require special counselling. Placental transmission of these antibodies can cause inflammation with subsequent sclerosis of the atrioventricular (AV) node which carries the risk of the fetus developing a congenital heart block. In 80% of cases, complete irreversible heart block occurs and in 20% fetal mortality is significantly increased.

Associated diseases

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

Differential diagnosis

• Amyloidosis (immunoglobulin-related).

• Bulimia.

• Chronic pancreatitis.

• Graft-vs-host disease.

• Polymyositis.

• RA.

• Salivary gland tumours.

• Sarcoidosis.

• Scleroderma.

• SLE.

• Tuberculosis.

• Non-Sjögren's sicca syndrome.⁴

Investigations^{5 6}

• 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 nonspecific.

• Rheumatoid factor is more often positive in Sjögren's syndrome than it is in rheumatoid disease.

• Antinuclear antibodies are often positive - even without SLE - and there may be positive antiphospholipid antibodies.

• The best-described autoantibodies in primary Sjögren's syndrome are the anti-Ro and anti-La antibodies. About two thirds of patients with primary Sjögren's syndrome have anti-Ro antibodies and/or anti-La antibodies.¹

• In the Schirmer test, a bent piece of filter paper is placed into the lower conjunctiva and left there for five minutes. In normal people the paper will be wet to 15 mm or beyond after five minutes, whereas a definitive positive result is less than 5 mm after five 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 - one study found that salivary gland ultrasound performed well compared with more invasive diagnostic procedures.⁷ For more complex cases, sialography or salivary scintigraphy may assist in diagnosis. Scintigraphy may be helpful in identifying non-Sjögren's sicca syndrome.⁴

• In cases of uncertainty, biopsy of a salivary gland may be required. Usually one of the minor glands from the inner lip is preferred to a parotid. Histology will reveal gland infiltration.

• Creatinine clearance may reduce in up to 50% of patients.

• CT scan should be carried out if it is suspected that lymphoma is developing.

• MRI scan of the salivary glands may help to identify changes associated with chronic sialadenitis.

Diagnostic criteria⁸

The American College of Rheumatology/European League Against Rheumatism (ACR‐EULAR) classification criteria for primary Sjögren's syndrome:

• Labial salivary gland with focal lymphocytic sialadenitis and focus score of ≥1 foci/4 mm² (score 3).

• Anti‐SSA/anti‐Ro positive (score 3).

• Ocular staining score ≥5 (or van Bijsterveld score ≥ 4) in at least one eye (score 1).

• Schirmer's test ≤5 mm/5 min in at least one eye (score 1).

• Unstimulated whole saliva flow rate ≤0.1 ml min⁻¹ (score 1).

The classification of primary Sjögren's syndrome applies to any individual who meets the inclusion criteria, does not have any of the conditions listed as exclusion criteria, and has a score of ≥4 from the five criteria in the table are added.

The inclusion criteria are applicable either to any patient with at least one symptom of ocular or oral dryness, defined as a positive response to at least one of the following:(i) Have you had daily, persistent, troublesome dry eyes for more than three months? (ii) Do you have a recurrent sensation of sand or gravel in the eyes? (iii) Do you use tear substitutes more than three times a day? (iv) Have you had a daily feeling of dry mouth for more than three months? (iv) Do you frequently drink liquids to aid in swallowing dry food?, or in whom there is suspicion of Sjögren's syndrome from the European League Against Rheumatism SS Disease Activity Index questionnaire (at least one domain with a positive item).

Exclusion criteria include prior diagnosis of any of the following conditions: (i) History of head and neck radiation treatment, (ii) Active hepatitis C infection (with confirmation by PCR), (iii) AIDS, (iv) Sarcoidosis, (v) Amyloidosis, (vi) Graft‐vs.‐host disease, (vii) IgG4‐related disease.

Sjögren's syndrome treatment and management

Sjogren's syndrome is a chronic, debilitating condition that warrants effective management. All patients should be counselled and offered topical management for sicca symptoms. Systemic treatment should be considered early in those with constitutional symptoms.

Symptomatic treatments such as artificial tears and saliva are well tolerated and help to relieve the most obvious symptoms.

Disease-modifying drugs have been used to treat some of the systemic manifestations of the disease but the level of evidence is low and larger-scale trials of the most promising treatments are needed.⁹ Rituximab has been recommended for specialist use in patients with significant systemic manifestations refractory to treatment with steroids and other immunosuppressives. It has a role in those with lymphoma, immune thrombocytopenia, vasculitic neuropathy and cryoglobulinaemias.¹

Scoring systems are used to evaluate the severity of the condition. There are several scoring systems developed by the European League Against Rheumatism (EULAR) to assess the severity of symptoms and also of systemic involvement. The EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) is useful to evaluate the day-to-day effects of symptoms such as xerostomia as well as fatigue and musculoskeletal pain. The EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) assesses the systemic effects of the disease such as vasculitis and glomerulonephritis. The two facets of Sjögren's syndrome do not always overlap and it is important to establish which aspect of the disease is most concerning.^{10 11 12}

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 four 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.¹³ Humidifiers may be helpful.

Severe dryness may require special glasses to improve the humidification of the eyes or temporary or permanent blockage of the puncta (thus preventing tear drainage) by electrocautery or other means.¹⁴

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.¹³

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 are recommended.

A possible role for immunosuppressant agents (eg, cyclophosphamide) in the relief of ocular and oral symptoms has been identified. Trials involving anti-tumour necrosis factor (anti-TNF) alpha inhibitors have been disappointing but those involving the use of B-cell depleting agents (eg, rituximab) have been more encouraging.^{15 16}

Other features

Vaginal lubricants may be required and infections such as vaginal candidiasis are more likely. Dry skin may benefit from emollients. Hydroxychloroquine may be useful in suppressing arthralgia and skin symptoms.

Complications of Sjögren's syndrome¹

• Associated autoimmune diseases may become manifest and need management.

• Approximately 50% of patients develop disease in sites other than glands. This could be either lymphocytic invasion of the epithelial cells in lung, liver, or kidney, or as skin vasculitis, peripheral neuropathy, glomerulonephritis and low C4 levels - conditions which represent an immune complex-mediated disease.¹⁷

• Infections of the eyes and mouth are more likely. The parotid gland may be infected with Staphylococcus spp., Streptococcus spp. or pneumococcus.

• Watch out for parotid tumours in a hard, unilateral gland.

• There is an increased risk of developing non-Hodgkin's lymphoma.

Prognosis²

The prognosis of Sjögren’s syndrome is overall favourable. The life expectancy of people with primary Sjögren’s syndrome is comparable with that of the general population. However quality of life is reduced by the diverse manifestations of the disease. Cardiovascular disease, infections, solid tumours, and lymphoma are the main causes of death.

In patients with secondary Sjögren’s syndrome, life expectancy is determined by the primary disease.