History
The clinical presentation of Sjögren syndrome may vary. Most patients are women, and onset is usually at age 40-60 years, but the syndrome also can affect men and children. The onset is insidious. The first symptoms in primary Sjögren syndrome can be easily overlooked or misinterpreted, and diagnosis can be delayed for as long as several years.
Xerophthalmia (dry eyes) and xerostomia (dry mouth) are the main clinical presentations in adults. Bilateral parotid swelling is the most common sign of onset in children.
Extraglandular involvement in Sjögren syndrome falls into two general categories: periepithelial infiltrative processes and extraepithelial extraglandular involvement. Periepithelial infiltrative processes include interstitial nephritis, liver involvement, and bronchiolitis and generally follow a benign course.
Extraepithelial extraglandular involvement in Sjögren syndrome is related to B-cell hyperreactivity, hypergammaglobulinemia, and immune complex formation and includes palpable purpura, glomerulonephritis, and peripheral neuropathy. These latter manifestations occur later in the course of Sjögren syndrome and are associated with a higher risk of transformation to lymphoma. [5]
Symptoms of Sjögren syndrome can decrease the patient's quality of life in terms of its physical, psychological, and social aspects.
Sicca symptoms (dry eyes and dry mouth)
Although dry eyes and dry mouth are the most common symptoms in patients with Sjögren syndrome, most patients who report these symptoms have other underlying causes. The incidence of sicca symptoms increases with age. Indeed, more than one third of elderly persons have sicca symptoms. Whether this is part of the normal aging process (associated with fibrosis and atrophy observed on some lip biopsy studies) or is due to the accumulation of associated illnesses and medications is unclear. [36]
Common medications that can cause sicca symptoms in any age group include antidepressants, anticholinergics, beta blockers, diuretics, and antihistamines. Anxiety can also lead to sicca symptoms. Women who use hormone replacement therapy may be at increased risk of dry eye syndrome. [37]
Patients may describe the effects dry mouth in the following ways:
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Inability to eat dry food (eg, crackers) because it sticks to the roof the mouth
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Tongue sticking to the roof of the mouth
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Putting a glass of water on the bed stand to drink at night (and resulting nocturia)
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Difficulty speaking for long periods of time or the development of hoarseness
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Higher incidence of dental caries and periodontal disease
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Altered sense of taste
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Difficulty wearing dentures
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Development of oral candidiasis with angular cheilitis, which can cause mouth pain
Dry eyes may be described as red, itchy, and painful. However, the most common complaint is that of a gritty or sandy sensation in the eyes. Symptoms typically worsen throughout the day, probably due to evaporation of the already scanty aqueous layer. Some patients awaken with matting in their eyes and, when severe, have difficulty opening their eyes in the morning. Blepharitis can also cause similar morning symptoms.
Parotitis
Patients with Sjögren syndrome may have a history of recurrent parotitis, often bilateral. Although in some patients the parotid glands become so large that the patients report this as a problem, more often the examining physician discovers them.
Cutaneous symptoms
Nonvasculitic cutaneous manifestations in Sjögren syndrome include the following [38] :
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Dryness
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Eyelid dermatitis
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Pruritus
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Erythema annulare
Cutaneous vasculitis, such as palpable purpura, develops in some patients with Sjögren syndrome, especially those with hypergammaglobulinemia or cryoglobulinemia. [38, 39] Raynaud phenomenon is observed in approximately 20% of patients.
Pulmonary symptoms
Patients with Sjögren syndrome can develop dryness of the tracheobronchial mucosa (xerotrachea), which can manifest as a dry cough. [40] Less often, patients develop dyspnea from an interstitial lung disease that is typically mild. [40, 41] Patients may develop recurrent bronchitis or even pneumonitis (infectious or noninfectious).
Gastrointestinal symptoms
Dryness of the pharynx and esophagus frequently leads to difficulty with swallowing (deglutition), in which case patients usually describe food becoming stuck in the upper throat. [40] Lack of saliva may lead to impaired clearance of acid and may result in gastroesophageal reflux and esophagitis.
Abdominal pain and diarrhea can occur. Rarely, patients develop acute or chronic pancreatitis, as well as malabsorption due to pancreatic insufficiency. However, caution is advised when interpreting laboratory results because an elevated amylase level may arise from the parotid gland.
Patients with gastritis should be tested for Helicobacter pylori infection, because of its association with gastric mucosa–associated lymphoid tissue lymphomas. [42]
Patients with Sjögren syndrome are at increased risk for delayed gastric emptying, which can cause early satiety, upper abdominal discomfort, nausea, and vomiting. [43]
Cardiac symptoms
Pericarditis and pulmonary hypertension, with their attendant symptomatology, can occur in Sjögren syndrome. [44] Orthostatic symptoms related to dysfunction of autonomic control of blood pressure and heart rate is associated with increased severity of Sjögren syndrome. [45]
Neurologic symptoms
The occurrence of central nervous system (CNS) and spinal cord involvement in Sjögren syndrome is estimated by various studies to be 8-40%, with manifestations including myelopathy, optic neuropathy, seizures, cognitive dysfunction, and encephalopathy. [35, 46, 47] Attempts must be made to distinguish other causes of these symptoms, including concomitant SLE, multiple sclerosis, cerebrovascular disease, and Alzheimer disease.
Sensory, motor, or sensorimotor peripheral neuropathy, often subclinical, can be detected in up to 55% of unselected patients with Sjögren syndrome. [48] Symptoms of distal paresthesias may be present. Cranial neuropathies can develop, particularly trigeminal neuropathy or facial nerve palsy. Mononeuritis multiplex should prompt a search for a vasculitis.
Progressive weakness and paralysis secondary to hypokalemia due to underlying renal tubular acidosis can occur and is potentially treatable. [49]
Renal symptoms
Renal calculi, renal tubular acidosis, and osteomalacia, nephrogenic diabetes insipidus, and hypokalemia can occur secondary to tubular damage caused by interstitial nephritis, the most common form of kidney involvement in Sjögren syndrome.
Interstitial cystitis, with symptoms of dysuria, frequency, urgency, and nocturia, is strongly associated with Sjögren syndrome. [50, 51]
Glomerulonephritis can be caused by Sjögren syndrome but is uncommon and is usually attributable to another disorder, such as SLE or mixed cryoglobulinemia.
Additional symptoms
Nasal dryness can result in discomfort and bleeding. Women may also have a dry vagina, which can lead to dyspareunia, vaginitis, and pruritus.
Patients with Sjögren syndrome may report fatigue, joint pain, and, sometimes, joint swelling. A careful review of systems must be performed to differentiate these from the manifestations of other disorders (see DDx). Fibromyalgia is common in patients with Sjögren syndrome, with a prevalence of about 31%. [52]
Women with Sjögren syndrome may have a history of recurrent miscarriages or stillbirths, and both women and men may have a history of venous or arterial thrombosis. These are related to the presence of antiphospholipid antibodies (eg, lupus anticoagulant or anticardiolipin antibodies).
Secondary Sjogren syndrome
Secondary Sjögren syndrome appears late in the course of the primary disease. However, in some patients, primary Sjögren syndrome may precede SLE by many years. Secondary Sjögren syndrome is usually mild, and sicca symptoms are the main feature. Unlike patients with primary Sjögren syndrome, persons with the secondary type have significantly fewer systemic manifestations. These manifestations include the following:
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Salivary gland swelling
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Lung involvement
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Nervous system involvement
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Renal involvement
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Raynaud phenomenon
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Lymphoproliferative disorders
In secondary Sjögren syndrome, symptoms of the primary disease predominate. Secondary Sjögren syndrome does not modify the prognosis or outcome of the basic disease. Polyarteritis nodosa and Sjögren syndrome may also coexist, perhaps best viewed as an overlap syndrome. [53]
Physical Examination
The physical signs of primary Sjögren syndrome can be divided into glandular and extraglandular signs.
Glandular signs
Ocular
While it is important to look for corneal lesions and a decreased tear pool in the lower conjunctiva during physical examination, patients with Sjögren syndrome should be referred to an ophthalmologist for more formal testing of keratoconjunctivitis sicca (KCS). This testing applies grading criteria of inflammatory changes that can direct therapy aimed at preventing corneal damage. [54] In addition, conditions that mimic KCS, such as blepharitis, conjunctivitis, and uveitis can be ruled out or treated.
Patients with Sjögren syndrome may have dilated conjunctival vessels, as well as pericorneal injection and dullness or irregularity of the corneal image. Blepharitis may be present as an alternate or additional problem, particularly if the lower eyelid is inflamed.
Mucinous threads and filamentary keratosis can be detected during a slit-lamp examination. The relative lack of the aqueous layer also leads to rapid tear breakup.
In the Schirmer test, a bent piece of Whatman number 41 filter paper is placed in the lower conjunctiva, and the amount of tearing on the filter paper is recorded. Normal wetting is greater than 15 mm after 5 minutes, whereas a definitive positive result is less than 5 mm after 5 minutes. This test can help to exclude or confirm significant dryness of the eyes, but it is not disease-specific. Furthermore, false-positive results occur. An evaluation of the diagnostic performance of the Schirmer test yielded a sensitivity of 42% and a specificity of 76% for Sjögren syndrome. (See the image below.) [55]
Photograph that demonstrates the Schirmer test, which is used to detect deficient tear production in patients with Sjögren syndrome. The filter paper strip is placed at the junction of the eyelid margins. After 5 minutes, 15 mm of paper should be moistened if tear production is normal, as shown here. Persons older than 40 years may moisten between 10 mm and 15 mm. Patients with Sjögren syndrome have less moistening. Sjögren syndrome is most common in patients with rheumatoid arthritis but may also occur without associated disease and in systemic lupus erythematosus, polyarteritis, systemic sclerosis, lymphoma, and sarcoidosis. (C) 1972-2004 American College of Rheumatology Clinical Slide Collection. Used with permission.
Oral
Oral signs include the following:
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Dryness
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Tongue - Red, smooth, and dry (see the image below)
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Dental caries - Severe and progressive
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Parotid duct narrowing
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Lips - Red, dry, and scaly
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Cracks at the corners of the mouth
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Chronic oral candidiasis
Dryness of the mouth and tongue due to lack of salivary secretion is characteristic of xerostomia associated with Sjögren syndrome. Mouth dryness may produce a deep red tongue, as shown here, and dental caries are common. (C) 1972-2004 American College of Rheumatology Clinical Slide Collection. Used with permission.
Look for a decreased sublingual salivary pool. The tongue may stick to the tongue depressor. Patients with Sjögren syndrome may develop frequent caries, sometimes in unusual locations such as the incisor surface and the gum line.
Patients with Sjögren syndrome are prone to develop oral candidiasis. In addition to white patches, watch for petechial lesions, loss of tongue papilla, erythema and fissuring of the tongue, erythema on other mucosal surfaces, and angular cheilosis. Oral candidiasis can be seen under dentures.
Gingival inflammation has been found to be more evident in the individuals with Sjögren syndrome, particularly those with secondary Sjögren syndrome. [56] Periodontal disease can lead to loss of teeth.
Parotid glands
Sjögren syndrome appears to negatively affect the periodontal condition. Recurrent swelling of the parotid glands (22-66% of patients) occurs; submaxillary and sublingual gland swelling also sometimes takes place.
Bilateral parotid gland enlargement is common in persons with Sjögren syndrome (see the image below). Some waxing and waning of size may occur. Exudates from the parotid gland are largely lymphocytes.
Marked bilateral parotid gland enlargement in a patient with primary Sjögren syndrome. Sicca syndrome is a common clinical finding. (C) 1972-2004 American College of Rheumatology Clinical Slide Collection. Used with permission.
Rock-hard or unilateral parotid gland enlargement should prompt referral to an otolaryngologist for biopsy to exclude a tumor. Other causes of parotid enlargement include diabetes, sarcoidosis, amyloidosis, diffuse infiltrative lymphocytic syndrome (DILS) of HIV disease, hepatitis C, and alcoholism. Acute, unilateral parotitis may be caused by Sjögren syndrome, infection, or obstruction, although the latter 2 conditions are more often associated with a very tender parotid gland and accompanying fever.
Other mucous membranes
Other mucous membrane signs include the following:
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Atrophic changes in the mucous membranes of the upper respiratory tract, leading to nasal dryness, recurrent infections, hoarseness, and aphonia
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Atrophic rhinitis
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Atrophic changes in the vulva and vagina resulting in pruritus and vaginitis
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Dryness of the anal and rectal mucous membranes (eg, pruritus, inflammation)
Cutaneous
Dryness of the skin occurs in 50% of patients with Sjögren syndrome; scaling occurs in about 25% of patients. The skin may be irritable, with secondary lichenification. Partial or complete loss of sweating may be present.
Hair may be dry, sparse, and brittle; diffuse alopecia may involve the scalp, limbs, axillae, or pubis. Nail folds may show capillaroscopic abnormalities, which are associated with the presence of antiendothelial cell antibodies. [57] Erythema of the nose and cheeks may be present.
Patients with Sjögren syndrome can develop a nonpalpable or palpable, vasculitic purpura, with lesions that are typically 2-3 mm in diameter and located on the lower extremities. The lesions, which can ulcerate, occur most often in patients with hypergammaglobulinemia or cryoglobulinemia. [39, 38]
Annular erythema with scales, localized especially on the face and neck, is recognized as a cutaneous manifestation of Sjögren syndrome. The patches are recurrent and resolve without hyperpigmentation; no photosensitivity is observed. [58] Annular erythema is a common cutaneous manifestation in Japanese and other Asian patients; however, it is rarely seen in white patents. [59]
In Japanese patients with Sjögren syndrome, annular erythema is divided into the following 3 types:
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Sweet disease–like annular erythema with an elevated border
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Subacute cutaneous lupus erythematosus–like, marginally scaled erythema
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Papular erythema
Those lesions bear some clinical similarities to the annular lesions of subacute cutaneous lupus erythematosus, but their histopathologic features are distinct from those of subacute cutaneous lupus erythematosus. Significant mucin depositions are observed.
Extraglandular signs
Gastrointestinal
Gastrointestinal tract signs include the following:
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Esophageal motility abnormalities
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Pancreatic involvement
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Splenomegaly
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Digestive symptoms (due to atrophy of the gastric mucous membrane with achlorhydria)
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Hepatitis (13%)
Pulmonary
Pulmonary abnormalities occur in 9-29% of cases; they are similar in primary and secondary Sjögren syndrome. Lung signs include the following [60] :
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Pulmonary fibrosis
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Pulmonary hypertension
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Recurrent chest infections
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Granulomatous infiltration and fibrosing alveolitis
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Restrictive ventilatory defect
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Impaired gas transfer
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Bibasilar rales – Can be heard in patients with interstitial lung disease
Articular
Articular changes (eg, arthritis) occur in 42% of patients with Sjögren syndrome; arthritis can be a component of either the primary or secondary form of the disease. One third of patients with RA have Sjögren syndrome.
Symmetrical, polyarticular, inflammatory arthritis suggests underlying RA or a connective-tissue disease such as SLE or scleroderma. The arthritis in patients with primary Sjögren syndrome is typically nonerosive and mild.
Urinary tract
Patients with Sjögren syndrome have significantly more urinary problems than do those without Sjögren syndrome. Patients may have the following:
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Irritated bladder
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Suprapubic pain
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Renal tubular dysfunction - Patients with primary Sjögren syndrome commonly are first seen because of renal impairment, usually from renal tubular dysfunction [61]
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Renal tubular acidosis - This affects one third of patients with Sjögren syndrome; a correlation apparently exists between hypergammaglobulinemia and distal renal tubular acidosis [61]
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Interstitial nephritis - This is rare, occurring in 4% of cases; it is often accompanied by cryoglobulinemia, a decreased level of complement, and the presence of circulating immune complexes
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Impaired renal concentrating ability, generalized aminoaciduria
Neurologic
A combination of lesions and relapses can suggest multiple sclerosis. Myelopathy rarely occurs in the course of primary Sjögren syndrome. It appears as Brown-Séquard syndrome, acute transverse myelitis, or progressive myelopathy. Clinically, cases with nervous system involvement present with paraparesis or paraplegia resulting from lesions at the thoracic or cervicothoracic levels.
Peripheral neuropathy occurs in 10-35% patients with primary Sjögren syndrome. Peripheral nerve dysfunction—such as trigeminal sensory neuropathy, mononeuropathy multiplex, distal sensorimotor polyneuropathy, or pure sensory neuropathy—may occur. This tends to be a small-fiber peripheral neuropathy. [62] Painful, distal paresthesias in the feet may be evident, as may abnormal sweating. Examination may reveal findings that include decreased pinprick sensation.
Isolated cranial nerve involvement rarely occurs in primary Sjögren syndrome. CNS involvement also is less common (10-25% of patients with Sjögren syndrome) than are other types of involvement; CNS pathology ranges from neuropathy, hemiparesis, transverse myelitis, and dystonia to encephalopathy and dementia.
In Sjögren syndrome, focal brain lesions can be present in the cerebral white matter. In addition, dysregulation of hypothalamic-pituitary-adrenal and thyroid axes can cause some neurologic disturbances.
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Marked bilateral parotid gland enlargement in a patient with primary Sjögren syndrome. Sicca syndrome is a common clinical finding. (C) 1972-2004 American College of Rheumatology Clinical Slide Collection. Used with permission.
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Clinical photograph and photomicrograph of a 48-year-old man with Sjögren syndrome with a large left parotid mass. On biopsy, B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type was identified. Microscopic section of parotid biopsy, stained with immunoperoxidase for kappa light chains (brown-stained cells), showed monoclonal population of B cells, confirming the diagnosis. (C) 1972-2004 American College of Rheumatology Clinical Slide Collection. Used with permission.
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Photograph that demonstrates the Schirmer test, which is used to detect deficient tear production in patients with Sjögren syndrome. The filter paper strip is placed at the junction of the eyelid margins. After 5 minutes, 15 mm of paper should be moistened if tear production is normal, as shown here. Persons older than 40 years may moisten between 10 mm and 15 mm. Patients with Sjögren syndrome have less moistening. Sjögren syndrome is most common in patients with rheumatoid arthritis but may also occur without associated disease and in systemic lupus erythematosus, polyarteritis, systemic sclerosis, lymphoma, and sarcoidosis. (C) 1972-2004 American College of Rheumatology Clinical Slide Collection. Used with permission.
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Dryness of the mouth and tongue due to lack of salivary secretion is characteristic of xerostomia associated with Sjögren syndrome. Mouth dryness may produce a deep red tongue, as shown here, and dental caries are common. (C) 1972-2004 American College of Rheumatology Clinical Slide Collection. Used with permission.
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Photomicrograph of a lip biopsy specimen showing two lymphocytic foci adjacent to normal-appearing mucinous acini typical of minor salivary gland abnormalities in Sjögren syndrome. (C) 1972-2004 American College of Rheumatology Clinical Slide Collection. Used with permission.
