The majority of patients with Sjögren’s syndrome have symptoms related to impaired lacrimal and salivary gland function. The disease evolution is slow and in the majority of patients runs a benign course. Studies have shown that prior to disease onset, patients with Sjögren’s syndrome experience major stressful life events with which they cannot cope adequately.
The principal oral symptom of Sjögren’s syndrome is dryness (xerostomia). Patients report difficulty in swallowing dry food, a burning mouth sensation, an increase in dental caries, and problems in wearing complete dentures. Physical examination shows a dry, erythematous, sticky oral mucosa. There is atrophy of the filiform papillae on the dorsum of the tongue, and saliva from the major glands is either not expressible or cloudy. Enlargement of the parotid or other major salivary glands occurs in two-thirds of patients with primary Sjögren’s syndrome but is uncommon in those in association with rheumatoid arthritis. Diagnostic tests include sialometry and newer imaging techniques, including ultrasound, MRI, and magnetic resonance sialography of the major salivary glands. Biopsy of the labial minor salivary gland permits histopathologic confirmation of focal lymphocytic infiltrates.
Ocular involvement is the other major manifestation of Sjögren’s syndrome. Patients usually describe a sandy or gritty feeling under the eyelids. Other ocular symptoms include burning, accumulation of secretions in thick strands at the inner canthi, decreased tearing, redness, itching, eye fatigue, and increased photosensitivity. These symptoms, which define keratoconjunctivitis sicca, are attributed to the destruction of corneal and bulbar conjunctival epithelium. Diagnostic evaluation of keratoconjunctivitis sicca includes measurement of tear flow by Schirmer’s I test and determination of tear composition, with assessment of tear breakup time or tear lysozyme content. Slit-lamp examination of the cornea and conjunctiva after lissamine green or Rose Bengal staining reveals punctuate corneal ulcerations and attached filaments of corneal epithelium.
Involvement of other exocrine glands, which occurs less frequently, includes a decrease in mucous gland secretions of the upper and lower respiratory tree, resulting in dry nose, throat, and trachea (xerotrachea). In addition, diminished secretion of the exocrine glands of the gastrointestinal tract leads to esophageal mucosal atrophy and atrophic gastritis. Dyspareunia due to dryness of the external genitalia and dry skin also may occur.
Extraglandular (systemic) manifestations are seen in one-third of patients with Sjögren’s syndrome (Table 354-2) but are very rare in patients whose Sjögren’s syndrome is associated with rheumatoid arthritis. They can be categorized as follows: Non-specific, involvement of parenchymal organs by lymphocytes (peri-epithelial), immune complex-mediated pathology, and lymphoma development. In the first category easy fatigability, low-grade fever, Raynaud’s phenomenon, myalgias, arthralgias, and arthritis are included. Arthritis in patients with primary Sjögren’s syndrome is non-erosive. Involvement of parenchymal organs such as the lungs, kidneys and the liver is due to peri-epithelial accumulation of lymphocytes. On the basis of this observation the term autoimmune epithelitis has been coined. Lung involvement is usually manifested with dry cough and rarely with dyspnea. The underlying lung pathology includes peribronchial infiltrates and rarely lymphocyte interstitial pneumonitis. Renal involvement includes interstitial nephritis, clinically manifested by hyposthenuria and renal tubular dysfunction with or without acidosis. Untreated acidosis may lead to nephrocalcinosis. Immune complex-mediated disease is expressed with vasculitis affecting primarily small-sized vessels, mainly manifested with purpura and rarely with urticarial rash, skin ulcerations, mononeuritis multiplex, and membranoproliferative glomerulonephritis associated with mixed cryoglobulinemia. Central nervous system involvement is rarely recognized. A few cases of myelitis associated with antibody to aquaporin 4 have been described.
TABLE 354-2Prevalence of Extraglandular Manifestations in Primary Sjögren’s Syndrome ||Download (.pdf) TABLE 354-2 Prevalence of Extraglandular Manifestations in Primary Sjögren’s Syndrome
|Clinical Manifestation ||Percent ||Remarks |
|Fatigability/Myalgias ||25 ||Fibromyalgia |
|Arthralgias/Arthritis ||60 ||Usually non-erosive, leading to Jaccoud’s arthropathy |
|Raynaud’s phenomenon ||37 ||In one-third of patients, precedes sicca manifestations |
|Lung involvement ||14 ||Small airway disease/lymphocyte interstitial pneumonitis |
|Kidney involvement ||9 ||Interstitial kidney disease is usually asymptomatic |
|Liver involvement ||6 ||Primary biliary cirrhosis stage I |
|Immune-Complex mediated |
|Small vessel vasculitis || ||Purpura, urticarial lesions |
|Peripheral neuropathy ||2 ||Polyneuropathy, either sensory or sensorimotor |
|Glomerulonephritis || ||Membranoproliferative |
|Lymphoma ||6 ||Glandular MALTa lymphoma is most common |
Patients with Sjögren’s syndrome associated with rheumatoid arthritis and systemic lupus erythematosus have an increased cardiovascular risk.
Lymphoma in Sjögren’s syndrome usually presents later in the disease course. Persistent parotid gland enlargement, purpura, leukopenia, cryoglobulinemia, low serum C4 complement levels, autoantibodies (anti-Ro/SS-A, anti-La/SS-B), and ectopic germinal center formation in minor salivary glands are manifestations predicting the development of lymphoma. Most lymphomas are extranodal, low-grade marginal-zone B cell lymphomas and are usually detected incidentally during evaluation of the labial minor salivary gland biopsy. The affected lymph nodes are usually peripheral. Survival rates are decreased in patients with B symptoms, lymph node mass >7 cm in diameter, and high or intermediate histologic grade.
Routine laboratory tests in Sjögren’s syndrome reveal mild normochromic, normocytic anemia. An elevated erythrocyte sedimentation rate is found in ~70% of patients. Certain autoantibodies may determine different disease phenotypes. Patients positive for anticentromere autoantibody present with a clinical picture similar to that of limited scleroderma (Chap. 353). Antimitochondrial antibodies may connote liver involvement in the form of primary biliary cirrhosis (Chap. 339). Autoantibodies to 21-hydroxylase are found in almost 20% of patients in association with a blunted adrenal response.
DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS
Primary Sjögren’s syndrome is diagnosed if (1) the patient presents with eye and/or mouth dryness, (2) eye tests disclose keratoconjunctivitis sicca, (3) mouth evaluation reveals dry oral mucosa, and/or (4) the patient’s serum reacts with immunoglobulins (rheumatoid factors), Ro/SS-A, and/or La/SS-B autoantigens. Labial biopsy is needed for diagnostic and prognostic purposes as well as to rule out other conditions that may cause dry mouth or eyes or parotid gland enlargement (Tables 354-3 and 354-4). Enlargement of major salivary glands, particularly in patients without autoantibodies, should raise the suspicion of IgG4-related syndrome. Validated methods of disease activity and classification criteria have been established (Table 354-5).
TABLE 354-3Differential Diagnosis of Sicca Symptoms ||Download (.pdf) TABLE 354-3 Differential Diagnosis of Sicca Symptoms
|Xerostomia ||Dry Eye ||Bilateral Parotid Gland Enlargement |
Viral infections (HCV, HIV)
Impaired lacrimal gland function
Impaired eyelid function
Hyperlipoproteinemias (types IV and V)
TABLE 354-4Differential Diagnosis of Sjögren’s Syndrome ||Download (.pdf) TABLE 354-4 Differential Diagnosis of Sjögren’s Syndrome
|HIV Infection and Sicca Syndrome ||Sjögren’s Syndrome ||Sarcoidosis |
|Predominant in young males ||Predominant in middle-aged women ||No age or sex preference |
|Lack of autoantibodies to Ro/SS-A and/or La/SS-B ||Presence of autoantibodies ||Lack of autoantibodies to Ro/SS-A and/or La/SS-B |
|Lymphoid infiltrates of salivary glands by CD8+ T lymphocytes ||Lymphoid infiltrates of salivary glands by CD4+ T lymphocytes ||Granulomas in salivary glands |
|Association with HLA-DR5 ||Association with HLA-DR3 and DRw52 ||Unknown |
|Positive serologic tests for HIV ||Negative serologic tests for HIV ||Negative serologic tests for HIV |
TABLE 354-5Revised International Classification Criteria for Sjögren’s Syndromea,b,c ||Download (.pdf) TABLE 354-5 Revised International Classification Criteria for Sjögren’s Syndromea,b,c
Ocular symptoms: a positive response to at least one of three validated questions.
Have you had daily, persistent, troublesome dry eyes for >3 months?
Do you have a recurrent sensation of sand or gravel in the eyes?
Do you use tear substitutes more than three times a day?
Oral symptoms: a positive response to at least one of three validated questions.
Have you had a daily feeling of dry mouth for >3 months?
Have you had recurrent or persistently swollen salivary glands as an adult?
Do you frequently drink liquids to aid in swallowing dry foods?
Ocular signs: objective evidence of ocular involvement defined as a positive result to at least one of the following two tests:
Shirmer’s I test, performed without anesthesia (≤5 mm in 5 min)
Rose Bengal score or other ocular dye score (≥4 according to van Bijsterveld’s scoring system)
Histopathology: In minor salivary glands focal lymphocytic sialoadenitis, with a focus score ≥1.
Salivary gland involvement: objective evidence of salivary gland involvement defined by a positive result to at least one of the following diagnostic tests:
Unstimulated whole salivary flow (≤1.5 mL in 15 min)
Antibodies in the serum to Ro/SS-A or La/SS-B antigens, or both.
TREATMENT Sjögren’s Syndrome
Treatment of Sjögren’s syndrome aims to relieve symptoms and limit the damage from chronic xerostomia and keratoconjunctivitis sicca through substitution or stimulation of impaired secretions (Fig. 354-1).
To replace deficient tears, several ophthalmic preparations are readily available (hydroxypropyl methylcellulose; polyvinyl alcohol; 0.5% methylcellulose; Hypo Tears). If corneal ulcerations are present, eye patching and boric acid ointments are recommended. Certain drugs that may decrease lacrimal and salivary secretions, such as diuretics, antihypertensive drugs, anticholinergics, and antidepressants, should be avoided.
For xerostomia, the best replacement is water. Propionic acid gels may be used to treat vaginal dryness. To stimulate secretions, orally administered pilocarpine (5 mg thrice daily) or cevimeline (30 mg thrice daily) appears to improve sicca manifestations, and both are well tolerated. Hydroxychloroquine (200 mg daily) is helpful for arthralgias and mild arthritis.
Patients with renal tubular acidosis should receive sodium bicarbonate by mouth (0.5–2 mmol/kg in four divided doses). Glucocorticoids and monoclonal antibody to CD20 (Rituximab) appear to be effective in patients with systemic disease, particularly in those with purpura, arthritis, and fatigability. Combination of anti-CD-20 with a classic CHOP regimen (cyclosporine, adriamycin [hydroxydaunorubicin], vincristine [oncovin], and prednisone) leads to increased survival rates among patients with high-grade lymphomas.
I would like to thank Dr. Athanasios G. Tzioufas for his contribution in the previous edition of the chapter.