Sjögren Syndrome

Chapter: Sjögren Syndrome
McMaster Section Editor(s): Jonathan D. Adachi
Section Editor(s) in Interna Szczeklika: Irena Zimmermann-Górska, Aleksandra Tuchocka-Kaczmarek, Jan Sznajd
McMaster Author(s): Jonathan D. Adachi
Author(s) in Interna Szczeklika: Irena Zimmermann-Górska
Additional Information

Definition, Etiology, PathogenesisTop

Sjögren syndrome is a chronic autoimmune condition of unknown etiology characterized by lymphocytic infiltrates in the exocrine glands, which result in their impaired secretion, and by inflammation of multiple organs and systems. Sjögren syndrome may be either primary (40% of cases) or secondary (in the course of other conditions, most frequently rheumatoid arthritis [RA]). This is the second most common connective tissue disease after RA, with a prevalence of 0.5% to 5%.

Clinical FeaturesTop

Over 90% of the patients are female. The peak age of onset is ~50 years.

1. Signs and symptoms of involvement of the exocrine glands (the sicca syndrome):

1) Lacrimal glands: Corneal and conjunctival dryness (keratoconjunctivitis sicca) perceived as a sandy or gritty feeling under the eyelids, burning, and itching; sensitivity to light, wind, cigarette smoke; conjunctival injection.

2) Salivary glands: Dry mouth (xerostomia), difficulty in chewing and swallowing, speech problems, loss of taste (dysgeusia), rapidly progressive caries, difficulty using dentures; enlargement of the parotid and/or submandibular salivary glands, stomatitis.

2. Extraglandular manifestations: General systemic symptoms such as fatigue, low-grade fever, myalgia, arthralgia, occasionally arthritis; symptoms of mild myopathy that may resemble RA (these may precede the onset of the sicca syndrome); Raynaud phenomenon (in ~40% of patients); lymphadenopathy (in 20% of patients); pulmonary manifestations (up to 20% of patients, usually causing minor symptoms or asymptomatic; rarely, lymphocytic pneumonitis, nodular changes, or lymphoma); renal manifestations (up to 15% of patients; mainly interstitial nephritis, rarely renal tubular acidosis, occasionally nephrolithiasis and chronic kidney disease); pancreatitis, hepatomegaly; primary biliary cirrhosis; vasculitis affecting small vessels of the skin and manifesting as purpura, urticaria, ulcerations; peripheral neuropathies; dry skin with pruritus (up to 55% of patients), autoimmune thyroiditis (frequent, but usually asymptomatic).

DiagnosisTop

Diagnostic Tests

1. Blood tests: Hypergammaglobulinemia (in 80% of patients), cryoglobulins (30%), antinuclear antibodies (ANAs) at a titer >1:80 (90%), anti-Ro/SSA (55%) and anti-La/SSB (40%) antibodies, rheumatoid factor at a titer >1:40 (60%); anemia (25%), leukopenia (10%).

2. Imaging studies: Sialography reveals irregular dilations and strictures of the glandular ducts (a “cherry blossom” appearance). Salivary scintigraphy reveals a delayed uptake, decreased accumulation, and delayed excretion of the radiolabeled marker following stimulation. Ultrasonography (the most useful test) is used to assess the size and structure of the parotid and submandibular salivary glands, as well as to detect cysts or local lymphadenopathy.

3. Ophthalmologic examination: The Schirmer test is helpful in estimating tear production: a strip of filter paper 5 × 30 mm with a rounded edge at one end is placed under the lower eyelid in such a way that it does not touch the cornea. After 5 minutes, more than 5 mm of the filter paper should be moistened by tears. The rose Bengal stain (or a test using another dye) is used to assess the corneal surface.

4. Assessment of saliva production (without stimulation) using the Saxon test: The patient chews a piece of a sterile gauze (5 × 5cm) for 2 minutes; the weight of the gauze should increase by ≥2.75 g.

5. Histologic examination of salivary gland biopsy specimens: Assessment of the number of lymphocytic infiltrates.

Diagnostic Criteria

Classification criteria: Table. Revised international classification criteria for….

Differential Diagnosis

Exclusion criteria: Table. Revised international classification criteria for….

Differential diagnosis should also include viral infections (eg, chronic parotitis, Epstein-Barr virus infection), amyloidosis, fibromyalgia, hyperlipoproteinemia (types IIa, IV, and V), age-related changes, and IgG4-related systemic disease (differentiated by increased levels of IgG4, absence of anti-Ro and anti-La antibodies). Symptoms of dry eye may be caused by blepharitis or conjunctivitis, infrequent blinking in neurologic or endocrine conditions, or lacrimal gland dysfunction. Xerostomia may occur in diabetes mellitus, hypercalcemia, or due to psychogenic factors. Perhaps the most common cause is the use of anticholinergic medications. Arthritis associated with primary Sjögren syndrome should be differentiated from RA, and a combination of organ involvement with the presence of antibodies should be differentiated from systemic lupus erythematosus.

TreatmentTop

1. Eye protection using preservative-free ophthalmic preparations to replace deficient tears (tear substitutes, artificial tears) in a form of solution or gel and soft contact lenses are helpful in mild disease. The addition of ocular 0.05% cyclosporine (INN ciclosporin) in patients with severe refractory disease may be tried. The symptoms of xerostomia are treated using artificial saliva preparations and sugar-free chewing gum; in patients with preserved residual function of the salivary glands, drugs stimulating production of saliva should be considered (eg, pilocarpine 5 mg every 6 hours;Evidence 1Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the short duration of the intervention and the potential of significant side effects. Vivino FB, Al-Hashimi I, Khan Z, et al. Pilocarpine tablets for the treatment of dry mouth and dry eye symptoms in patients with Sjögren syndrome: a randomized, placebo-controlled, fixed-dose, multicenter trial. P92-01 Study Group. Arch Intern Med. 1999 Jan 25;159(2):174-81. PubMed PMID: 9927101. alternatively acetylcysteine in the case of contraindications to or intolerance of pilocarpine). Sips of water may be helpful, however if too frequent, they may increase the symptoms due to a loss of the mucus film and may also lead to nocturia, which increases fatigue due to sleep disruption. The patient should be advised to avoid alcohol and tobacco and instructed about the importance of good oral hygiene.

2. Among the agents modifying the inflammatory process the most frequently used are hydroxychloroquine 200 mg/d and chloroquine 250 mg/d. These have been used empirically, but their effectiveness has been questioned in a recent randomized controlled trial. As a result, we suggest that they not be used routinely.Evidence 2Weak recommendation (downsides likely outweigh benefits, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the lack of data on long-term effects. Gottenberg JE, Ravaud P, Puéchal X, et al. Effects of hydroxychloroquine on symptomatic improvement in primary Sjögren syndrome: the JOQUER randomized clinical trial. JAMA. 2014 Jul 16;312(3):249-58. doi: 10.1001/jama.2014.7682. PubMed PMID: 25027140. Treatment of extraglandular manifestations is based on glucocorticoids and other immunosuppressants, although anti-tumor necrosis factor treatments have not been shown to be clinically efficacious. In particularly resistant cases, rituximab is used; however, a recent study was not able to show alleviation of symptoms or disease activity over 24 weeks of follow-up. In secondary Sjögren syndrome, treat the underlying condition.

Follow-UpTop

There is an increased risk of developing non-Hodgkin lymphomas compared to the general population, with an incidence of ~5%. Regular follow-up should be considered in individuals at high risk for the development of lymphoma. Predictors of lymphoma include purpura (cutaneous vasculitis), persisting or recurrent salivary gland enlargement and lymphadenopathy, monoclonal cryoglobulinemia, decreased serum levels of the C3 and/or C4 complement components, reduced levels of CD4+ cells, and a reduced ratio of CD4+/CD4- cells in the peripheral blood. The presence of structures resembling germinal centers within the lymphocytic infiltrates revealed by a minor salivary gland biopsy may be another predictor for lymphoma development.

TablesTop

Table. Revised international classification criteria for Sjögren syndrome

I. Ocular symptoms

A positive response to ≥1 of the following questions:

1) Have you had daily, persistent, troublesome dry eyes for >3 months?

2) Do you have a recurrent sensation of sand or gravel in the eyes?

3) Do you use tear substitutes >3 times a day?

II. Oral symptoms

A positive response to ≥1 of the following questions:

1) Have you had a daily feeling of a dry mouth for >3 months?

2) Have you had recurrently or persistently swollen salivary glands as an adult?

3) Do you frequently drink liquids to help swallow dry food?

III. Ocular signs

At least one of the following test results must be positive:

1) The Schirmer test performed without anesthesia (≤5 mm in 5 min).

2) A rose Bengal score or other ocular dye score (≥4 according to the van Bijsterveld scoring system).

IV. Histopathology

In minor salivary glands (obtained through a normal-appearing mucosa), focal lymphocytic sialoadenitis, evaluated by an expert pathologist, with a focus score ≥1, defined as the number of lymphocytic foci (which are adjacent to the normal-appearing mucous acini and contain >50 lymphocytes) per 4 mm2 of glandular tissue

V. Salivary gland involvement

Objective evidence of salivary gland involvement defined by a positive result of ≥1 of the following diagnostic tests:

1) Unstimulated whole salivary flow (≤1.5 mL in 15 min)

2) Parotid sialography showing the presence of diffuse sialectasias (a punctate, cavitary, or destructive pattern) without evidence of obstruction in the major ducts

3) Salivary scintigraphy showing delayed uptake, reduced concentration, and/or delayed excretion of the tracer

VI. Autoantibodies

Presence in the serum of anti-Ro and/or anti-La antibodies

Definite diagnosis of primary Sjögren syndrome is made in patients who:

1) Fulfill ≥4 of the 6 above criteria, as long as either the biopsy (IV) or serology (VI) results are positive

2) Fulfill 3 out of 4 objective criteria (ie, III, IV, V, VI)

Diagnosis of secondary Sjögren syndrome: In patients with a potentially associated disease (eg, another connective tissue disease), the presence of item I or item II plus any 2 from among items III, IV, and V may be considered as indicative of secondary Sjögren syndrome

Exclusion criteria:

– Previous head or neck radiation therapy

– Hepatitis C virus infection

– HIV infection or symptoms of AIDS

– Previously diagnosed lymphoma

– Sarcoidosis

– Graft-versus-host disease

– Use of anticholinergic drugs (if the time since their administration is shorter than 4-fold the half-life of the drug)

Sensitivity of the criteria for primary Sjögren syndrome is 84.2%-89.5% and specificity is 95.2%.

Adapted from: Vitali C, Bombardieri S, Jonsson R, et al; European Study Group on Classification Criteria for Sjögren's Syndrome. Classification criteria for Sjögren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis. 2002 Jun;61(6):554-8.

AIDS, acquired immunodeficiency syndrome; HIV, human immunodeficiency virus.

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