Exocrine Gland Involvement
The dominating feature of SS is exocrine gland dysfunction, leading to the classic sicca symptoms of xerostomia (oral dryness) and xerophthalmia or keratoconjunctivitis sicca (dry eyes).
Oral dryness is the principal symptom of SS, caused by decreased saliva secretion, which is persistent and continuous throughout the day and night and can significantly compromise quality of life. Reduced salivation causes difficulty in chewing and swallowing dry foods. Dryness of the tongue and oral mucosa leads to an altered sense of taste and, at times, produces a burning discomfort, especially when eating acidic or spicy foods. Physical examination may reveal a red and fissured tongue with a characteristic atrophy of the filiform papillae or angular cheilitis. Ulcerations can be found, particularly in SS patients with dentures, usually in proximity to the mucosal surface that makes contact with the denture.
Saliva has antimicrobial properties, so lack of saliva can predispose to infections. Oral thrush is common and can be manifested as pseudomembranous or erythematous mucosal lesions. Furthermore, patients with SS have an increased incidence of caries. A characteristic feature of caries in SS is its primary location at the cervical and incisal regions of the teeth.
Bilateral salivary gland enlargement usually occurs in the parotid glands of SS patients. It is frequently nontender, and it can be recurrent or chronic (Box 161-1). Painful, unilateral parotid enlargement should raise the suspicion of an infection (Fig. 161-1) or a salivary gland stone. In cases of persistent unilateral parotid gland enlargement, the presence of lymphoma should be excluded (see Box 161-1).
Box 161-1 Differential Diagnosis of Parotid Gland Swelling ||Download (.pdf)
Box 161-1 Differential Diagnosis of Parotid Gland Swelling
Epstein's–Barr, cytomegalovirus, coxsackie
Human immunodeficiency virus, human T-lymphotropic virus-I
Recurrent parotitis of the childhood
Acute infectious parotitis. Note the asymmetric swelling of the left parotid gland.
Medical causes of oral dryness, such as dehydration, diabetes, viral infections, or drug treatment, should be considered when evaluating a patient for Sjögren's syndrome.
Ocular dryness is the other dominant feature of SS. A burning and itching sensation in the eyes, commonly exacerbated by smoke, is caused by lack of tear production. Patients frequently complain of intolerance to contact lenses. Paradoxically, the quantity of tears produced during crying may not be affected. Physical evaluation shows corneal injection and mucous discharge in the lower fornix. Enlarged lachrymal glands have been described in Sjögren's patients, but occur less commonly than enlarged salivary glands. The constellation of symptoms and signs indicating dry eyes constitutes keratoconjunctivitis sicca.
Other Sicca Manifestations
Cutaneous xerosis, a term used to describe dryness of the skin, is very common in SS, with a frequency varying between 23% to 68%. The most common symptoms of xerosis are nonspecific pruritus, burning sensation and a pin-prick-like feeling. Physical examination reveals roughness, fine scaling, and loss of elasticity of the skin. The pathogenesis of xerosis is unknown. Impairment of the sweat glands is considered an important factor because decreased sweating has been reported in SS patients. A recent study has indicated that xerosis may be related to increased epidermal proliferation with disturbed epidermal differentiation.29
Dryness of the upper respiratory tract can cause epistaxis, hoarseness, and bronchial hyper-responsiveness. Another common complaint in women with SS is vaginal dryness, which may lead to an increased incidence of vaginal infections and dyspareunia.
Nonexocrine Gland Involvement
Cutaneous manifestations are common extraglandular features of SS (Table 161-1).30 They are generally considered either vasculitic or nonvasculitic lesions.
Table 161-1 Cutaneous Manifestations of Sjögren's Syndrome ||Download (.pdf)
Table 161-1 Cutaneous Manifestations of Sjögren's Syndrome
- Raynaud's phenomenon
- Cutaneous vasculitis
- Nonpalpable purpura
- Palpable purpura
- Urticarial vasculitis
- Necrotizing vasculitis
- Annular erythema
- Erythema multiforme
- Erythema perstans
- Erythema nodosum
- Dry mucous membranes
- Papillary atrophy of the tongue
- Angular cheilosis
- Eyelid dermatitis
Raynaud's phenomenon is probably the most common abnormality. It can be seen in 15% to 35% of patients and can precede sicca symptoms by many years. Raynaud's phenomenon in Sjögren's syndrome is not accompanied by telangectasias as seen in systemic sclerosis. Calcifications have been described, but are uncommon. Although Raynaud's is usually mild in SS, it is a marker of a subgroup with increased risk of extraglandular manifestations.31
Purpuric macules are very common in Sjögren's. Flat, nonpalpable, blanching purpura has been associated with an entity called benign hyperglobulinemic purpura, characterized by polyclonal hypergammaglobulinemia and a positive rheumatoid factor. The skin biopsies reveal ruptured blood vessels with complement deposition.32
Cutaneous vasculitis (CV) can present as palpable purpura or urticarial vasculitis.
Palpable purpura, which does not blanch when pressure is applied to the skin is due to dermal vasculitis with extravasation of red blood cells, and typically involves the lower extremities and buttocks (see Chapter 164). It represents an important marker of more severe disease, and is associated with an increased risk of lymphoma development and mortality. Histopathologically, palpable purpurae can be divided into two groups. Neutrophilic inflammatory vascular disease is characterized by a predominantly neutrophilic infiltrate, fibrinoid necrosis, occlusion of the lumen, and extravasation of red blood cells, and is indistinguishable from the classical leukocytoclastic vasculitis (Fig. 161-2) (see Chapter 163). On the other hand, mononuclear inflammatory vascular disease is characterized by a mononuclear inflammatory infiltrate with invasion of the blood vessel walls. Fibrinoid necrosis is present but less prominent. The clinical presentation of these two forms are indistinguishable, but neutrophilic inflammatory vascular disease is associated more strongly with markers of systemic autoimmunity, such as antinuclear antibodies and anti-Ro/SSA and anti-La/SSB antibodies, hypergammaglobulinemia, rheumatoid factor, and hypocomplementemia. Cryoglobulinemic vasculitis can also be seen among Sjögren's patients and has the same cutaneous manifestations (see Chapter 169).
Cutaneous vasculitis in primary Sjögren's syndrome. Biopsy showed leukocytoclastic vasculitis.
Urticarial vasculitis is the second most frequent form of CV in SS and presents as pruritic wheals with erythema (see Chapter 38). In contrast to true urticaria, individual lesions last for more than 24 hours and often resolve with hyperpigmentation. Biopsy of the skin lesions demonstrates a perivascular neutrophilic infiltrate accompanied by leukocytoclasia. Necrotizing vasculitis is not commonly seen in Sjögren's syndrome. It can present as palpable purpuric lesions of the lower extremities, which may ulcerate, finally resolving within 1–4 weeks. They heal with atrophy or scar tissue formation. This form of vasculitis has been observed more frequently among patients with more active disease; it has been associated with arthritis, Raynaud's phenomenon, peripheral neuropathy, fever, and pulmonary or glomerular involvement. Antineutrophil cytoplasmic antibodies with perinuclear fluorescence can be found, but are uncommon in Sjögren's syndrome.
Annular erythema is found primarily among Asian patients who have anti-Ro/SSA antibodies. Characteristic lesions are annular erythematous plaques with elevated borders and central clearing. They are localized on the face, arms, back, trunk, and proximal thighs. Lesions are similar to subacute cutaneous lupus but seem to represent a distinct clinical and histopathologic entity.
A painful nodular eruption of the anterior surface of the lower extremities, suggesting erythema nodosum (see Chapter 70) may occur in patients with sicca manifestations. Because erythema nodosum in SS patients is rare, its presence should raise suspicion for sarcoidosis. Erythema multiforme-like lesions and superficial ill-defined patches (erythema perstans) have also been described in SS.
Nonvascular Cutaneous Manifestations
Xerostomia predisposes to angular cheilitis, which presents as recurrent, symmetric, itching fissures. Eyelid dermatitis is defined by the presence of erythematous, infiltrated and lichenificated lesions of the eyelids associated with itching and foreign body sensation. Alopecia and vitiligo can also be seen in SS, albeit infrequently. Despite multiple case reports describing cutaneous B- and T-cell lymphomas in SS patients, they are, in fact, rare.
Noncutaneous Extraglandular Manifestations
A symmetric nonerosive polyarthritis can frequently be seen in primary SS. The distinction from rheumatoid arthritis may be difficult; the absence of rheumatoid factor and anti-CCP antibodies and the absence of erosions on X-rays would favor SS over RA. Arthralgias and myalgias are common complaints but true myositis is rare in primary SS.
Dry cough due to dryness of the tracheal mucosa is common (tracheobronchitis sicca). Rarely, patients can develop interstitial pneumonitis. Patients may also develop mucosa-associated lymphoid tissue (MALT) lymphoma in the lungs.
Genitourinary manifestations include interstitial cystitis, renal tubular acidosis, interstitial nephritis, and, rarely, glomerulonephritis.
Dysphagia due to xerostomia and esophageal dysmotility is common. Helicobacter pylori is associated with an increased risk of MALT lymphomas, therefore, SS patient with gastritis should be checked for H. pylori and treated if found positive. An asymptomatic, chemical pancreatitis with high-serum amylase concentrations has been reported in 25% of patients.
SS is associated with various other diseases, such as celiac disease, primary biliary cirrhosis, and hypothyroidism. Because of these associations, a high index of diagnostic suspicion is warranted to identify and treat these conditions.
Neurologic manifestations can be divided into those that involve the central nervous system, and those that involve the peripheral nervous system and autonomic dysfunction.
The peripheral nervous system is involved in approximately 20% of patients with SS.33 The most common manifestations are peripheral axonal polyneuropathies, which are mostly sensory. Another entity that has been described is a ganglionopathy involving the sensory ganglia of the posterior column. This starts with unilateral peripheral paresthesias evolving over months to years to deep sensory impairment, positive Romberg sign, generalized areflexia, and ataxia.34 Cranial neuropathies are also frequent among SS patients. The most common form is unilateral trigeminal neuropathy; it usually spares the ophthalmic division, thus preserving the corneal reflex. Other cranial neuropathies may lead to Bell's palsy (facial nerve), neural deafness and vestibular dysfunction (vestibule-cochlear), and diplopia (oculomotor, trochlear, abducent nerve).
The central nervous system can be involved, although the prevalence and the spectrum of manifestations are still controversial. Manifestations similar to multiple sclerosis as well as transverse myelitis have been described. The latter is frequently associated with antiaquaporin-4 autoantibodies.
The incidence of lymphoma in Sjögren's patients is increased 15- to 44-fold, according to various studies,35 and 4% to 8% of SS patients develop lymphoma. Most of these are indolent, extranodal, marginal-zone B-cell lymphomas of MALT, but higher grade lymphomas are also seen.
A variety of clinical and laboratory features have been correlated to an increased risk of lymphoma development. Recurrent or persistent salivary gland swelling, palpable purpura, low complement levels, low CD4 counts, and persistently elevated inflammatory markers indicate an increased disease activity and increased risk for lymphoma development.36,37
In Sjögren's syndrome, pregnancy outcomes are similar to those in healthy women. Carriers of the SSA antibody, however, can transmit it through the placental circulation to the fetus. These antibodies can cause congenital heart block or neonatal lupus, characterized by an annular rash with central scarring in the scalp and around the eyes, as well as, liver inflammation and transaminitis. This syndrome develops around the sixth week postpartum. Although the rash spontaneously resolves around the sixth to eighth months of age, the heart block is permanent and requires placement of a pacemaker. Expectant mothers with anti-SSA antibodies should be counseled about this risk and their fetuses should be followed closely for the development of fetal heart block.