Xerostomia, the subjective feeling of oral dryness, is the key feature in the diagnosis of primary SjS, occurring in more than 95% of patients. Other oral symptoms may include soreness, adherence of food to the mucosa, and dysphagia. Reduced salivary volume interferes with basic functions such as speaking or eating. The lack of salivary antimicrobial functions may accelerate local infection, tooth decay, and periodontal disease. Xerostomia can lead to difficulty with dentures and the need for expensive dental restoration, particularly in elderly patients. Various oral signs may be observed in SjS patients. In the early stages, the mouth may appear moist, but as the disease progresses, the usual pooling of saliva in the floor of the mouth disappears. Typically, the surface of the tongue becomes red and lobulated, with partial or complete depapillation (Figure 26–1). In advanced disease, the oral mucosa appears dry and glazed and tends to form fine wrinkles. Angular cheilitis, erythematous changes of the hard palate, and a red tongue with atrophic papillae strongly suggest Candida infection.
Dry mouth in a patient with primary SjS: red tongue with depapillation.
The subjective feeling of ocular dryness is associated with sensations of itching, grittiness, soreness, and dryness, although the eyes have a normal appearance. Other ocular complaints include photosensitivity, erythema, eye fatigue, or decreased visual acuity. Environmental irritants such as smoke, wind, air conditioning, and low humidity may exacerbate ocular symptoms. Diminished tear secretion may lead to chronic irritation and destruction of corneal and bulbar conjunctival epithelium (keratoconjunctivitis sicca). In severe cases, slit-lamp examination may reveal filamentary keratitis, marked by mucus filaments that adhere to damaged areas of the corneal surface (Figure 26–2). Tears also have inherent antimicrobial activity and SjS patients are more susceptible to ocular infections such as blepharitis, bacterial keratitis, and conjunctivitis. Severe ocular complications may include corneal ulceration, vascularization, and opacification.
Dry eye with filamentary keratitis.
Reduction or absence of respiratory tract glandular secretions can lead to dryness of the nose, throat, and trachea resulting in persistent hoarseness and chronic, nonproductive cough. Likewise, involvement of the exocrine glands of the skin leads to cutaneous dryness. In female patients with SjS, dryness of the vagina and vulva may result in dyspareunia and pruritus, affecting their quality of life.
Chronic or episodic swelling of the major salivary glands (parotid and submandibular glands) is reported in 10–20% of patients and may commence unilaterally, but often becomes bilateral (Figure 26–3).
Patients with primary SjS often have general symptomatology, including fever, polyadenopathies, generalized pain, fatigue, weakness, sleep disturbances, anxiety, and depression, which may have a much greater impact on the quality of life of patients than sicca features. Low-grade fevers may occur in SjS, usually in young patients with positive immunologic markers. Fatigue, generalized pain, and weakness are among the most debilitating clinical features of primary SjS. The coexistence of primary SjS with a defined fibromyalgia is reported often.
Joint and Muscular Involvement
Joint involvement, primarily generalized arthralgias, is seen in 25–75% of patients. Less frequently, joint disease presents as an intermittent symmetric arthritis primarily affecting small joints. Joint deformity and mild erosions are rare, except for those cases associated with rheumatoid arthritis. Clinical myopathy is rare but myalgias are frequently observed, and a recent study reported that subclinical muscular inflammation is often observed.
Although the main cutaneous manifestation of patients with primary SjS is skin dryness, a wide spectrum of cutaneous lesions may be observed, the most frequent of which is a small-vessel vasculitis, overwhelmingly leukocytoclastic. The skin findings include palpable purpura (Figure 26–4), urticaria, and erythematous macules or papules, and are associated with cryoglobulins in 30% of patients. Life-threatening vasculitis is also closely related to cryoglobulinemia.
Cutaneous purpura in the legs in a patient with SjS and cryoglobulinemia.
Primary SjS patients may also have nonvasculitic cutaneous lesions. Some patients with anti-Ro/SS-A antibodies may present with polycyclic, photosensitive cutaneous lesions (Figure 26–5), clinically identical to the so-called annular erythema described in Asian SjS patients and subacute cutaneous lupus.
Polycyclic, photosensitive cutaneous lesions in a 67-year-old woman with primary SjS and anti-Ro/SS-A antibodies.
Two types of pulmonary involvement, bronchial and interstitial, can complicate primary SjS. Bronchial/bronchiolar involvement is more common than pulmonary fibrosis. The typical symptoms of patients with pulmonary involvement are chronic cough, dyspnea, and recurrent respiratory infections. Studies of respiratory tract involvement in primary SjS have demonstrated that the main underlying pathology in these patients is peribronchial infiltrates that lead to small airway disease. High-resolution computed tomography of the lungs reveals ground-glass pattern or thickened bronchial walls or both. Lymphocytic interstitial pneumonitis evolves only rarely. Interstitial lung disease can occur early in the course of SjS but rarely worsens over follow-up, and a conservative therapeutic approach is advised. Pleurisy is an extremely rare manifestation of primary SjS and often signals the presence of an additional autoimmune disease, particularly lupus.
Raynaud phenomenon, with a prevalence of 10–20%, is probably the most common vascular feature observed in primary SjS. The clinical course of Raynaud phenomenon in primary SjS is milder than in other systemic autoimmune diseases such as systemic sclerosis. Vascular complications (eg, digital loss, digital pulp pitting, or fingertip infarctions) are uncommon, and pharmacologic interventions are required in only 40% of cases. Cardiac involvement is rarely observed, with pericardial effusions (usually mild and asymptomatic) being the most frequent feature. Recent studies have described autonomic cardiovascular disturbances.
Gastrointestinal involvement may include altered esophageal motility, chronic gastritis, and less frequently, malabsorption. Helicobacter pylori infection should be excluded in patients with gastritis because of the close association with gastric mucosa-associated lymphoid tissue lymphoma. Pancreatic involvement, usually asymptomatic, is demonstrated by altered pancreatic function tests. Some patients may have chronic pancreatitis. Liver function tests may be elevated in 10–20% of patients with primary SjS. After exclusion of potentially hepatotoxic drugs, the main causes are chronic hepatitis C viral infection (especially in geographic areas with a high prevalence) and primary biliary cirrhosis. Less frequently, SjS patients may present with type 1 autoimmune hepatitis, and even more rarely, autoimmune or sclerosing cholangitis.
Overt renal involvement was only found in 5% of the nearly 2000 patients included in the largest reported series. The main types of renal involvement described are interstitial renal disease and glomerulonephritis. Interstitial nephritis can be an early manifestation of SjS. This condition is usually subclinical, and manifested by a low urine specific gravity (hyposthenuria) and an alkaline urine pH (type I distal tubular acidosis). Nephrocalcinosis that presents with renal colic is a common clinical feature in these patients. Finally, interstitial cystitis, sometimes with severe symptoms, has recently identified as a frequent extraglandular SjS feature.
Peripheral neuropathy is the most common neurologic involvement. A joint analysis of 1025 patients with primary SjS showed peripheral neuropathy in 18%. The most frequent types of neuropathy were mixed polyneuropathy, pure sensory neuronopathy, and mononeuritis multiplex. Of these, pure sensory neuronopathy is recognized as a characteristic neurologic complication of primary SjS, caused by damage to the sensory neurons of the dorsal root and gasserian ganglia. Dorsal root and gasserian ganglionopathies are associated with potentially devastating deficits in proprioception. Mixed polyneuropathy and multiplex mononeuritis are usually associated with vasculitis and often with concomitant cryoglobulinemia. Some patients with primary SjS present with small-fiber neuropathy. SjS patients may present cranial nerve involvement, mainly of the trigeminal (V), vestibulocochlear (VIII), and facial (VII) cranial pairs.
Although earlier studies described central nervous system involvement as a frequent extraglandular manifestation of primary SjS, clinically significant central nervous system involvement is actually very rare. The most frequently detected central nervous system feature in primary SjS is probably asymptomatic white matter lesions in magnetic resonance examinations. A recent study found that these lesions are overwhelmingly associated with concomitant cardiovascular risk factors, although isolated cases of SjS patients presenting with a multiple sclerosis–like disease have been reported. Some patients may present with myelopathy and optic neuritis, similar to neuromyelitis optica (NMO).
Nearly one third of patients with primary SjS have thyroid disease. Subclinical hypothyroidism is the most frequent finding, especially in patients with antithyroid autoantibodies (suggesting previous Hashimoto thyroiditis). Although ear, nose, and throat involvement has been little studied in patients with primary SjS, some studies have described sensorineural hearing loss in nearly 25% of SjS patients. Psychiatric disorders, including depression and anxiety, have been described in many patients with SjS.
The results of routine laboratory tests and immunologic markers in primary SjS are summarized in Table 26–3. The most frequent analytic features are cytopenia, elevated erythrocyte sedimentation rate, and hypergammaglobulinemia (20–30%). The most frequent cytopenias detected are normocytic anemia, leukopenia, and thrombocytopenia. The differential leukocyte count has been studied in large series of patients with primary SjS; the most frequent abnormality was lymphopenia, closely followed by neutropenia. Cytopenias are found more commonly in patients with positive immunologic markers and are usually asymptomatic, but may be clinically overt in some cases. Erythrocyte sedimentation rate levels correlate closely with the percentage of circulating gamma globulins (hypergammaglobulinemia), while serum C-reactive protein levels are usually normal. Highly elevated serum C-reactive protein levels in a patient with primary SjS should raise the suspicion of an infection. Finally, circulating monoclonal immunoglobulins may be detected in nearly 20% of patients with primary SjS, with monoclonal IgG being detected most frequently.
Table 26–3. The Laboratory Evaluation in Sjögren Syndrome. ||Download (.pdf)
Table 26–3. The Laboratory Evaluation in Sjögren Syndrome.
|Complete blood cell count|
- Normochromic, normocytic anemia. Isolated cases of hemolytic anemia
- Mild leukopenia (3–4 × 109/L); lymphopenia, neutropenia
- Mild thrombocytopenia (80–150 × 109/L)
|Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)|
- Elevated ESR (>50 mm/h) in 20–30% of cases, especially in patients with hypergammaglobulinemia
- Normal values of CRP
- Monoclonal band
|Liver function tests|
- Raised transaminases (associated with hepatitis C virus or autoimmune hepatitis)
- Raised alkaline phosphatase and/or bilirubin (associated with primary biliary cirrhosis)
|Electrolytes and urinalysis|
- Proteinuria (glomerulonephritis)
- Hyposthenuria, low plasma bicarbonate, and low blood pH (renal tubular acidosis)
|Antinuclear antibody test|
- Positive in more than 80%
- Positive in 40–50% of patients, often leading to diagnostic confusion with rheumatoid arthritis
- Anti-extractable nuclear antigens antibodies
- Complement (C3, C4, and CH50)
- Other autoantibodies
- Positive anti-Ro/SS-A (30–70%) and anti-La/SS-B (25–40%)
- Complement levels are decreased in 10–20% of patients
- Present in 10–20% of patients
- Antimitochondrial antibodies (associated with primary biliary cirrhosis)
- Antithyroid antibodies (associated with thyroiditis)
- Anti-dsDNA (associated with systemic lupus erythematosus)
- Anticentromere (associated with a limited form of systemic sclerosis)
Minor salivary gland biopsy remains a highly specific test for the diagnosis of SjS, although it is an invasive technique that may be accompanied by local side effects when performed incorrectly. Focal lymphocytic sialadenitis, defined as multiple, dense aggregates of 50 or more lymphocytes in perivascular or periductal areas in the majority of sampled glands, is the characteristic histopathologic feature of SjS. The key requirements for a correct histologic evaluation are an adequate number of informative lobules (at least four) and the determination of an average focus score (a focus is a cluster of at least 50 lymphocytes). However, nonspecific sialadenitis is quite common in biopsy samples of minor salivary glands in healthy control populations. Although sialoadenitis is the key histopathologic feature of SjS, this finding in the absence of symptoms and markers suggestive of SjS should be interpreted with caution. Minor salivary gland biopsy is often essential in parsing the differential diagnosis in patients who present with sicca symptoms (eg, sarcoidosis, amyloidosis).
Assessment of Oral Involvement
Several methods to assess oral involvement have been proposed, such as measurement of the salivary flow rate, sialochemistry, sialography, or scintigraphy. Measurement of the salivary flow, with or without stimulation, is the simplest method in evaluating xerostomia, and is acceptable to patients and needs no special equipment, while the study of the degree of salivary gland dysfunction by parotid scintigraphy offers valuable clinical information on the prognosis and outcome of primary SjS. The other tests, though useful for the purposes of research, rarely have clinical applications. Ultrasonography is a noninvasive method that may provide useful information about the etiology of parotid enlargements.
Assessment of Ocular Involvement
The main ocular tests are the Schirmer test and rose bengal staining. The Schirmer test for the eye quantitatively measures tear formation via placement of filter paper in the lower conjunctival sac. The test can be performed with or without the instillation of anesthetic drops to prevent reflex tearing. The test result is positive when less than 5 mm of paper is wetted after 5 minutes. Rose bengal scoring involves the placement of 25 mL of rose bengal solution in the inferior fornix of each eye and having the patient blink twice. Slit-lamp examination detects destroyed conjunctival epithelium due to desiccation.
The main immunologic markers found in primary SjS are antinuclear antibodies, anti-Ro/SS-A or anti-La/SS-B antibodies, rheumatoid factor, hypocomplementemia, and cryoglobulins (see Table 26–3). Antinuclear antibodies are the most frequently detected antibodies in primary SjS (in more than 80% of cases), and titers ≥1:80 play a central role in differentiating SjS from non-autoimmune causes of sicca syndrome. Anti-Ro/SS-A and La/SS-B antibodies, detected in 30–70% of patients, are closely associated with most extraglandular features, especially with cutaneous lesions, neurologic features, congenital heart block, and cytopenias. In nearly 50% of cases, patients with primary SjS also present with positive rheumatoid factor.
Hypocomplementemia and cryoglobulinemia (see Chapter 36) are two closely-related immunologic markers that have been linked with more severe SjS. Recent studies have associated low complement levels and cryoglobulins (usually type II, which are found in 10–20% of patients) with chronic hepatitis C viral infection, lymphoma development, and mortality. Serum monoclonal gammopathy often indicates the presence of an underlying type II mixed cryoglobulinemia.