Sjogren Syndrome

Background

Sjِgren syndrome is a chronic autoimmune disorder characterized by xerostomia (dry mouth), xerophthalmia (dry eyes), and lymphocytic infiltration of the exocrine glands. This triad is also known as the sicca complex.

Sjِgren syndrome displays a wide spectrum of severity and can go undiagnosed for several months to years. The Swedish physician Henrik Sjِgren first described the syndrome in 1933.

Pathophysiology

Sjِgren syndrome can occur as a primary disease of exocrine gland dysfunction or in association with several other autoimmune diseases (eg, systemic lupus erythematosus [SLE], rheumatoid arthritis, scleroderma, systemic sclerosis, cryoglobulinemia, polyarteritis nodosa). These primary and secondary types occur with similar frequency, but the sicca complex seems to cause more severe symptoms in the primary form.

Virtually all organs may be involved. The disease commonly affects the eyes, mouth, parotid gland, lungs, kidneys, skin, and nervous system.

Frequency

United States

Sjِgren syndrome is estimated to be the second most common rheumatologic disorder, behind only SLE.

International

Comparative studies between different ethnic groups have suggested that Sjِgren syndrome is a homogeneous disease that occurs worldwide with similar prevalence and affects 1-2 million people.

Mortality/Morbidity

Although the disease process rarely shortens a patient's lifespan, morbidity can be devastating. Ocular dryness can lead to chronic keratoconjunctivitis and corneal ulcers. Oral dryness leads to caries, fissures, candidal infections, and difficulty speaking and swallowing food. These patients often are undiagnosed or misdiagnosed for years. They often feel physicians are uneducated or unsympathetic to their disease.
As a result of the lymphocytic infiltration, 10% of patients may develop pseudolymphoma, a lymphoproliferative process. Approximately 10% of these patients can develop non-Hodgkin lymphoma (1% of all patients with Sjögren syndrome).

Sex

The female-to-male ratio is 9:1.

Age

Peak incidence occurs in the fourth and fifth decades of life.

History

Onset is insidious, and symptoms may be mild.

Dry eyes and/or mouth (required for the clinical diagnosis)
Musculoskeletal (60%)

Fatigue (60%)
Arthralgias (60-70%)
Myalgias (20-30%)

Dry skin (40%)
Vaginal dryness (40%)

Physical

The disease may be mild or hard to detect clinically.

Keratoconjunctivitis
Salivary insufficiency
Vasculitis (25%)
Lymphadenopathy (20%)
Polyneuropathies (10-15%)
Renal involvement

Glomerulonephritis
Interstitial nephritis

Parotid gland enlargement

Lab Studies

Schirmer test

The Schirmer test is probably the only test available in the ED to strongly support or refute suspicion of Sjögren syndrome.
A test strip of number 41 Whatman filter paper is placed near the lower conjunctival sac to measure tear formation.
Healthy persons wet 15 mm or more after 5 minutes. A positive test occurs when less than 5 mm is wet after 5 minutes.

Erythrocyte sedimentation rate (ESR) is elevated in 80% of patients.
Rheumatoid factor is present in 52% of cases of primary-type Sjögren syndrome and in 98% of secondary-type cases.
Complete blood count (CBC)

A mild normochromic normocytic anemia is present in 50% of patients.
Leukopenia occurs in up to 42% of patients.

Autoantibodies (outside of ED)

Anti-SS-A and anti-SS-B are present in most cases of primary-type Sjögren syndrome, while antisalivary duct antibodies are present in most cases of the secondary type.
Antinuclear antibodies of the speckled and homogeneous type are present in most cases of primary Sjögren syndrome.

Creatinine clearance may be diminished in up to 50% of patients.

Imaging Studies

No imaging studies are helpful in the initial diagnosis of Sjögren syndrome. However, CT scan could be helpful if progression to lymphoma is suspected. This may not be necessary in the emergent setting.

Other Tests

Rose bengal staining is a test performed on an outpatient basis to confirm ocular involvement.

Procedures

Minor salivary gland or lower lip biopsy

For histopathologic confirmation of exocrine gland infiltration
Outside the scope of the ED

Emergency Department Care

Diagnosis can be made from the ED if the index of suspicion is high.
Patients may present with mild symptoms (eg, eye grittiness, eye dryness or discomfort, dry mouth, recurrent caries). Bilateral parotid gland swelling is also a common presentation.
Patients with known Sjögren syndrome should not be taken lightly for their complaint of dry eyes or dry mouth, as these chronic problems can be very distressing and obtrusive.

Consultations

Surgical consultation for lip biopsy as an outpatient is needed to histologically confirm the diagnosis.
All patients with known or suspected Sjögren syndrome should be referred to a rheumatologist.

Aids to lubrication are the mainstay of therapy for the ocular and oral complications of Sjِgren syndrome. No cure for this disease exists.

Drug Category: Lubricants

These agents may be needed every 1-3 h. Thicker, longer-acting drops are available, but they may cause blurring of vision due to the film produced on the cornea and are more appropriate for bedtime use.

Drug Name	Artificial tears (Celluvisc, Murine, Refresh)
Description	Contain equivalent of 0.9% NaCl and are used to maintain ocular tonicity. Act to stabilize and thicken precorneal tear film and prolong tear film breakup time, which occurs with dry eye states.
Adult Dose	1-2 gtt tid/qid prn
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	A - Safe in pregnancy
Precautions	Hyperemia, photophobia, stickiness of eyelashes, ocular discomfort, or irritation may occur

Drug Category: Salivary aids

Use of sugarless chewing gums and salivary substitutes assists in management of oral symptoms.

Drug Name	Pilocarpine (Salagen)
Description	This may increase salivary and lacrimal flow rates in some patients but should not be administered in the ED. MD may wish to write prescription for patient to take home.
Adult Dose	5 mg PO qd; improvement evident following 6 wk of treatment
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; acute inflammatory disease of anterior chamber
Interactions	May be ineffective when used concomitantly with nonsteroidal anti-inflammatory agents
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in acute cardiac failure, peptic ulcer, hyperthyroidism, GI spasm, bronchial asthma, Parkinson disease, recent MI, urinary tract obstruction, and hypertension or hypotension

Drug Category: Cholinergic agents

These agents increase activity of exocrine glands, including salivary glands.

Drug Name	Cevimeline (Evoxac)
Description	Binds to cholinergic (muscarinic) receptors, causing increase in secretion of salivary glands.
Adult Dose	30 mg PO tid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; narrow-angle glaucoma; acute iritis; uncontrolled asthma
Interactions	May have additive effects when used with other cholinergic agents; concurrent use with beta-blockers may cause potential for cardiac conduction disturbances; CYP2D6 inhibitors (eg, fluoxetine, amiodarone, quinidine, ritonavir, paroxetine) or CYP3A3/4 (eg, itraconazole, diltiazem, ketoconazole, verapamil) may increase toxicity; anticholinergic agents (eg, phenothiazines, TCAs, atropine) may decrease effects of cevimeline
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in cardiovascular disease, controlled asthma, COPD, or chronic bronchitis; may induce smooth muscle spasms and precipitate cholangitis, biliary obstruction, cholecystitis, or urethral reflux in patients with history of biliary stones or nephrolithiasis

Drug Category: Immunosuppressive agents

These agents are used with varying degrees of success for glomerulonephritis, interstitial pneumonitis, and pseudolymphoma. They do not appear to aid in the oral or ocular manifestations.

Drug Name	Hydroxychloroquine (Plaquenil)
Description	May be useful in treating arthralgias and skin symptoms, but it has not been shown to affect salivary or lacrimal gland function. Patients with evidence of marked immune dysregulation may benefit from prophylactic therapy with hydroxychloroquine to prevent progression to extraglandular sites. Hydroxychloroquine sulfate 200 mg is equivalent to 155 mg hydroxychloroquine base and 250 mg chloroquine phosphate.
Adult Dose	200 mg PO qd
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; psoriasis; retinal and visual field changes attributable to 4-aminoquinolones
Interactions	Serum levels increase with cimetidine; magnesium trisilicate may decrease absorption
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in hepatic disease, G-6-PD deficiency, psoriasis, and porphyria; not recommended for long term in children; perform periodic (6 mo) ophthalmologic examinations; test periodically for muscle weakness

Certain patients may be candidates for punctal occlusion, usually performed by an ophthalmologist.
The Sjögren Syndrome Foundation, Incorporated, was founded in 1983 and is a good resource for patients. Contact the foundation at 6707 Democracy Blvd, Ste 325, Bethesda, MD, 20817; (800) 475-6473, (301) 530-4415 (fax).

Complications

The sicca complex of Sjögren syndrome rarely leads to serious complications, but potential problems with other associated rheumatic diseases must be considered.
A very small risk (1%) of progression to non-Hodgkin lymphoma does exist.

Prognosis

Prognosis of Sjögren syndrome is good from the standpoint of mortality, but it has significant morbidity.
Patients can be reassured that the Sjögren syndrome itself will not shorten their lifespan

Medical/Legal Pitfalls

Medical pitfalls include failure to re