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).
• 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 strongly 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

• Daily dryness, foreign body or gritty sensation in the eyes with sensitivity to light
• Disturbing daily dryness of the mouth, which complicates eating and speaking and disturbs sleep
• 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 skin is dry.
• Dry irritant cough may be present as a respiratory symptom.
• Dryness of the vulva and vagina, dyspareunia.

Extraglandular symptoms and signs

• There may be purpura on the lower limbs (leukocytoclastic vasculitis, picture 1). Raynaud's phenomenon Raynaud's Phenomenon (RP) or White Finger Disease is mild. Small vessel vasculitis and subacute cutaneous lupus erythematosus are potential skin manifestations. Some patients have abnormal skin reactions to sunlight.
• Fatigue, myalgia and joint pain are common. Arthritis is mild and myositis rare.
• Rarely acute pancreatitis Acute Pancreatitis, interstitial nephritis and renal tubular acidosis, glomerulonephritis Glomerulonephrites and interstitial cystitis Bladder Pain Syndrome (Interstitial Cystitis).
• Dyspnoea on exertion and respiratory tract infections are possible. Interstitial lung disease, elevated pulmonary blood pressure Increased Pulmonary Blood Pressure: Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension and pleuritis Pleural Effusions and Thoracentesis occur rarely.
• Polyneuropathy Polyneuropathies, mononeuropathy and central nervous system symptoms are rare.
• Some patients have organ-specific autoimmune diseases. Autoimmune hypothyroidism (10%) Chronic Autoimmune Thyroiditis and coeliac disease (10%) Coeliac Disease are common. Atrophic gastritis, chronic active hepatitis Autoimmune Hepatitis and primary biliary cirrhosis Primary Biliary Cholangitis occur rarely.
• There is an increased risk of lymphoma Lymphomas. Lymphoma may be suggested by solid enlargement of parotid glands or the appearance of enlarged lymph nodes, which warrant a biopsy. Because the incidence of lymphoma is low on the population level, lymphoma is rarely seen in patients with primary Sjögren's syndrome despite the increased risk (as high as more than 40-fold).
• Maternal anti-SS-A and anti-SS-B antibodies are associated with a fetal risk of cardiac conduction disorder; see Pregnancy below.

Laboratory tests

• 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 (70-90%) and anti-SS-B antibodies (50-70%).
• Polyclonal hypergammaglobulinaemia (S-Prot-Fr)
• Complement C3 and C4 levels may be low. Cryoglobulinaemia is seen in approximately 10% of patients.
• Chemical screening of the urine may show mild proteinuria.
• Autoantibody tests and other laboratory tests show signs of any associated organ-specific autoimmune diseases.
  • All patients should be screened for coeliac disease and have thyroid antibody tests (TPOAb) done. If these are positive, duodenal biopsy 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
  • Renal tubular acidosis (creatinine, potassium, venous blood acid-base balance, urinary pH)

Diagnosis

• The diagnosis should be made in specialized care using classification criteria of year 2017.
• The diagnosis requires at least 1 extraglandular symptom or at least 1 positive answer to the questions listed below, and, additionally, a total score of at least 4 points using the criteria below.
  • 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?
• 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) ≥ 5 or van Bijsterveld score at least 4 in at least 1 eye = 1 point
  • Schirmer's test ≤ 5 mm/5 minutes in at least one eye = 1 point
  • Unstimulated whole saliva flow rate ≤ 0.1 ml/min = 1 point
• The criteria are fulfilled if the total score is at least 4 and none of the following exclusion criteria are present: history of head and neck radiation treatment, active hepatitis C infection, AIDS, sarcoidosis, amyloidosis, graft-versus-host disease, IgG4-related disease.
• Invasive diagnostic examinations (salivary gland biopsy) should be avoided as far as possible.
• 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 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.
• 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
• For the treatment of dry mouth, see Dryness of the Mouth
• Pilocarpine has been used for the treatment of dry mouth. The dosage is 5 mg four times daily. However, the drug has a lot of adverse effects and it is not reimbursable.
• Hydroxychloroquine (usually 300 mg once daily) is used primarily for the treatment of mild systemic symptoms, joint and skin symptoms. Low dose prednisone (5-7.5 mg once daily) can be added to the regimen for a short period of time.
• More severe systemic manifestations outside the endocrine glands can be treated in specialized care with glucocorticoids and immunosuppressive medication (azathioprine, methotrexate, ciclosporine, mycophenolate and cyclophosphamide).
• The use of biological drugs is not established. Rituximab has been used in special cases.

Follow-up

• Mild and uncomplicated primary Sjögren's syndrome: no regular follow-up or follow-up every 1-2 years in primary health care
  • 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, creatinine, 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 ofhydroxychloroquineduring pregnancy apparently decreases the risk of atrioventricular block in the child. Beginning of medication in early pregnancy needs to be considered with the pregnant patient.
• Follow-up at a mother and child welfare clinic and central/university hospital

References

• Ramos-Casals M, Tzioufas AG, Stone JH et al. Treatment of primary Sjögren syndrome: a systematic review. JAMA 2010;304(4):452-60. [PubMed]
• Brito-Zerón P, Izmirly PM, Ramos-Casals M et al. The clinical spectrum of autoimmune congenital heart block. Nat Rev Rheumatol 2015;11(5):301-12. [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]