Primary Sjögren's Syndrome

Essentials

• Primary or essential Sjögren's syndrome is an autoimmune disease characterized by chronic lymphocytic inflammation of exocrine glands and resulting glandular hypofunction and dryness of mucosa.
• Its primary symptoms are dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia).
• Some patients also experience symptoms outside the exocrine glands and general symptoms.
• Presence of autoantibodies (rheumatoid factor, anti-nuclear antibodies, ENAAb) is typical for the disease. Their absence in patients suffering from dry eyes and dry mouth speaks against the diagnosis.
• Topical treatment is used for dryness of mucosa. Extraglandular symptoms and complicated disease may be treated with glucocorticoids, hydroxychloroquine and immunosuppressive medication.
• Secondary Sjögren's syndrome may occur in patients with other autoimmune diseases.

Prevalence

• Applying strict diagnostic criteria, the prevalence of Sjögren's syndrome in the adult population is approximately 0.1%.
• The prevalence of mild or subclinical disease is not known precisely but it is probably many times that of the disease fulfilling the strict criteria.
• In postmenopausal women, the prevalence may be as high as 1-2%.
• The first symptoms usually occur at the age of 30-50 years. The majority of patients (> 90%) are women.
• The average time from the first symptoms (usually dry eyes, dry mouth or recurrent parotitis) to diagnosis is 7 years.
• Various degrees of hypofunction of exocrine glands also occur in patients with other autoimmune diseases. In the secondary form of the disease symptoms of dryness are milder than in primary disease.

Symptoms and findings

Glandular symptoms

• Dryness of the eyes causes stinging, foreign body or gritty sensation in the eyes, redness and itching of the eyes, as well as sensitivity to light. Eyes get tired and reading can be difficult.
• Disturbing daily dryness of the mouth, which complicates eating and speaking and disturbs sleep
• There may be recurrent or constant swelling of salivary glands
• Increased caries rate and rapid dental cavity formation
• Impaired sense of taste and smell. There may be ulceration in the corners of the mouth.
• The nose and airways are dry. There is dry irritative cough.
• Dryness of the vulva and vagina, dyspareunia.

Extraglandular symptoms and signs

• Extraglandular symptoms occur in about 30-70% of patients.
• Of general symptoms, fatigue is common. A mild increase in temperature may be part of the clinical picture.
• Skin symptoms
  • Can be varied, ranging from mild dryness to a purpuric rash primarily on the lower limbs (leukocytoclastic vasculitis, picture ).
  • Other possible skin manifestations include urticarial vasculitis, subacute lupus rash, annular erythema and leg ulcers.
  • Some patients have abnormal skin reactions to sunlight.
  • White finger (Raynaud) phenomenon Raynaud's Phenomenon (RP) or White Finger Disease is mild.
• Lymph nodes may be enlarged.
• Joint and muscle symptoms
  • Muscle and joint pains are common.
  • Arthritis is mild and myositis is rare.
• Gastrointestinal symptoms
  • Dry mouth and oesophageal dysfunction may cause difficulty in swallowing.
  • Acute and chronic pancreatitis Acute Pancreatitis are rare.
  • Other rare gastrointestinal manifestations include atrophic gastritis, autoimmune hepatitis Autoimmune Hepatitis and primary biliary cholangitis Primary Biliary Cholangitis.
  • Coeliac disease Coeliac Disease is common (in up to 10-15% of patients).
• Kidney symptoms
  • The most common renal finding is tubulointerstitial nephritis. Its most common manifestation is distal renal tubular acidosis with high urinary pH despite metabolic acidosis. Proteinuria and possible renal dysfunction are mild.
  • Glomerulonephritis Glomerulonephrites, vasculitis and interstitial cystitis Bladder Pain Syndrome (Interstitial Cystitis) are rare.
• Pulmonary symptoms
  • Dry irritative cough is common.
  • Exertional dyspnoea and asthma-like symptoms are possible.
  • The most characteristic pulmonary finding is interstitial pneumonia on X-ray or high-resolution computed tomography (HRCT).
  • Increased pulmonary hypertension Increased Pulmonary Blood Pressure: Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension and pleuritis Pleural Effusions and Thoracentesis are rare.
• Neurological symptoms
  • Peripheral neurological symptoms occur in about 10-20% of patients.
  • The most common form of the disease is mainly sensory polyneuropathyPolyneuropathies, which may include tingling as well as pins and needles sensation in the distal parts of extremities, and loss of tactile sensation.
  • Mononeuritis multiplex and trigeminal neuropathy are rare.
  • About 5% of patients present with central nervous system symptoms that may cause severe clinical pictures (e.g. acute transverse myelitis, optic neuromyelitis).
• Autoimmune hypothyroidism is a relatively common comorbidity (in about 10% of patients) Chronic Autoimmune Thyroiditis.
• The risk of lymphoma Lymphomas is increased.
  • This may be indicated by low-grade fever, weight loss, persistent swelling of the salivary glands and abnormally large lymph nodes.
• Maternal anti-SS-A and anti-SS-B antibodies are associated with a fetal risk of cardiac conduction disorder; see Pregnancy below.

Laboratory examinations

• ESR levels are usually elevated, CRP normal.
• Anaemia in association with chronic disease is mild, and leukocyte (lymphopenia) and platelet levels may be low.
• Anti-nuclear antibodies detected by immunofluorescence occur in more than 80% of patients, and about 70-80% are rheumatoid factor positive.
• Grouping of antinuclear antibodies (ENAAb) shows anti-SS-A (in 70-90%) and anti-SS-B antibodies (in 40-70%).
• Citrulline peptide antibodies can be found in about 5% of patients
• Monoclonal gammopathy (MGUS), increased IgG levels
• Complement C3 and C4 levels may be low, DNA antibodies negative. Cryoglobulinaemia is seen in approximately 10% of patients.
• eGFR(calculator Gfr Calculator) may be slightly reduced.
• Chemical screening of the urine may show mild proteinuria.
• Autoantibody tests and other laboratory tests show signs of any associated organ-specific diseases.
  • All patients should be screened for coeliac disease and have thyroid antibody tests (TPOAb) done. If these are positive, duodenal biopsy, as considered necessary, or TSH and T4V tests should be performed,.
  • If ALT and ALP are permanently elevated, tests for smooth muscle and mitochondrial antibodies (MitoAb) should be performed in addition to other liver tests
  • Distal renal tubular acidosis (plasma creatinine, potassium, venous blood acid-base balance, urinary pH)

Diagnosis

• Classification criteria of year 2016 can be used as a diagnostic aid.
• At least one positive answer to the questions below or at least one extraglandular symptom is required, plus a total of at least 4 points from the criteria listed below. The patient must also not have any of the conditions listed in the exclusion criteria.
• Questions
  • Have you had daily, persistent, troublesome dry eyes formore than 3 months?
  • Do you have a recurrent sensation ofsand or gravel in the eyes?
  • Do you use tear substitutes morethan 3 times a day?
  • Have youhad a daily feeling of dry mouth for more than 3 months?
  • Do you frequently drink liquids to aid in swallowing dry food?
• Extraglandular symptoms (EULAR Sjögren's syndrome disease activity index, ESSDAI HASH(0x2f5d108) 1)
  • The activity index is HASH(0x2f5d108) 1 when the patient has at least one general or visceral symptom related to the disease. The index includes 12 symptoms.
• Criteria
  • Labial salivary gland biopsy with focal lymphosytic sialadenitis and focus score of at least 1 focus/4 mm² = 3 points
  • Anti-SS-A positive = 3 points
  • OSS (Ocular Staining Score) HASH(0x2f5d108) 5 or van Bijsterveld score at least 4 in at least 1 eye = 1 point
  • Schirmer's test HASH(0x2f62220) 5 mm/5 minutes in at least one eye = 1 point
  • Unstimulated whole saliva flow rate HASH(0x2f62220) 0.1 ml/min = 1 point
• Exclusion criteria: history of head and neck radiation treatment, active hepatitis C infection, AIDS, sarcoidosis, amyloidosis, graft-versus-host disease, IgG4-related disease.
• In everyday clinical work, a clinical diagnosis can usually be made based on autoantibodies (SS-A/SS-B, rheumatoid factor and anti-nuclear antibodies) and sicca symptoms and, if so, all required classification criteria need not be fulfilled.
  • Schirmer's test Dry Eye Syndrome and unstimulated salivary flow rate Dryness of the Mouth can be performed also at the doctor's office.
  • Invasive diagnostic examinations (salivary gland biopsy) should be avoided as far as possible.
• Patients with secondary Sjögren's syndrome have some other autoimmune disease, either systemic (e.g. rheumatoid arthritis Rheumatoid Arthritis, SLE Systemic Lupus Erythematosus (Sle)) or organ-specific (e.g. MS Multiple Sclerosis (Ms), type 1 diabetes Diabetes: Definition, Differential Diagnosis and Classification).

Treatment

• For the treatment of dry eyes, see Dry Eye Syndrome
  • Moisturising eye drops, eye gels and creams, as well as ocular inserts can be used to moisten the eyes. Viscous ointments are usually used at night.
  • In severe cases, an ophthalmologist can be consulted. Treatment options include cyclosporine eye drops, insertion of silicone plugs or surgical closure of the lacrimal points.
• For the treatment of dry mouth, see Dryness of the Mouth
  • Frequent wetting with water and the use of artificial saliva products helps to relieve dry mouth symptoms. Xylitol gum can be used to stimulate saliva secretion.
  • Regular visits to the dentist and oral hygienist are recommended. Fluoride and chlorhexidine preparations can be used as needed.
  • Pilocarpine has been used to treat dry mouth. The dose is 5 mg 3 times daily. However, the drug has side effects and, depending on the country, may not be reimbursable.
• Dry nose can be treated with vitamin A drops. For dry vaginal mucous membranes, lubricating creams and topical oestrogen therapy can be used.
• For active disease and extraglandular symptoms, systemic medication is needed.
• Joint and muscle pain is treated with NSAIDs. Hydroxychloroquine is used to treat mild arthritis and skin symptoms and may be combined, at least for short periods, with a low dose of a glucocorticoid (prednisone 5-7.5 mg once daily). In myositis, higher doses of glucocorticoids and cytostatic drugs may be needed.
• For dry irritative cough, bronchodilator sprays containing glucocorticoids may be tried. Progressive interstitial lung disease is treated with glucocorticoids and cytostatic drugs.
• In distal renal tubular acidosis, the development of kidney stones Urinary Calculi, hypokalemia and renal failure can be prevented with sodium bicarbonate or potassium citrate.
• In severe neurological manifestations, high doses of glucocorticoids combined with azathioprine, mycophenolate and, in life-threatening situations, also cyclophosphamide may be required.
• The use of biological drugs is not established.
• Primary Sjögren's syndrome is more often associated with other organ-specific autoimmune diseases that need to be treated in addition to the underlying disease. These include coeliac disease Coeliac Disease, autoimmune hypothyroidism Hypothyroidism, primary biliary cholangitis Primary Biliary Cholangitis, chronic active hepatitis Autoimmune Hepatitis, atrophic gastritis and interstitial cystitis Bladder Pain Syndrome (Interstitial Cystitis).

Prognosis and follow-up

• Primary Sjögren's syndrome usually has a mild clinical picture, slow progression of symptoms and a good life expectancy. However, dry mucous membranes can reduce quality of life and the most severe extraglandular complications may be associated with premature mortality.
• The risk of lymphoma is increased, especially if the disease is associated with persistent immunological activity.
• Mild and uncomplicated disease can be followed up in primary health care at infrequent intervals.
  • Primary symptoms and targeted clinical examination, home monitoring of blood pressure
  • Visits to a dentist and oral hygienist
  • ESR, CRP, basic blood count with platelet count, plasma creatinine, potassium, ALT, ALP, chemical screening of urine, TSH and T4V (thyroid tests every 2-3 years if TPOAb is positive)
• Disease with severe symptoms or complications: follow-up in specialized care

Pregnancy

• The risk of pregnancy complications (miscarriage, premature childbirth, low foetal weight, preeclampsia) is not increased; antiphospholipid antibodies are very rare.
• The risk of congenital atrioventricular heart block is 1-2% if anti-SS-A antibodies are positive and 2-4% if both anti-SS-A and anti-SS-B antibody levels are high.
• If a previous child has had atrioventricular block, the risk of recurrence in following children is 16-20%.
• Mother's use of hydroxychloroquine during pregnancy appears to halve the child's risk of cardiac atrioventricular block. The drug is recommended to be started at the 10^th week of pregnancy at a dose of 300-400 mg once daily when the risk of complications is considered high (previous sick child).
• Follow-up at a mother and child welfare clinic and central/university hospital

References

• Ramos-Casals M, Brito-Zerón P, Bombardieri S, et al. EULAR recommendations for the management of Sjögren's syndrome with topical and systemic therapies. Ann Rheum Dis 2020;79(1):3-18 [PubMed]
• De Carolis S, Garufi C, Garufi E, et al. Autoimmune Congenital Heart Block: A Review of Biomarkers and Management of Pregnancy. Front Pediatr 2020;(8):607515 [PubMed]
• Shiboski CH, Shiboski SC, Seror R ym. 2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjögren's syndrome: A consensus and data-driven methodology involving three international patient cohorts. Ann Rheum Dis 2017;76(1):9-16. [PubMed]
• Seror R, Ravaud P, Bowman SJ, ym. EULAR Sjogren's syndrome disease activity index: development of a consensus systemic disease activity index for primary Sjogren's syndrome. Ann Rheum Dis 2010;69(6):1103-9 [PubMed]