Chapter 161. Sjögren's Syndrome

Sjögren's syndrome (SS) is one of the most common rheumatic autoimmune diseases. SS affects predominantly women with a female to male ratio of 9:1. Women are most commonly diagnosed in their fifth or sixth decade, but it can affect individuals of any age and sex.

SS has a worldwide distribution. In most studies done mainly in Caucasian populations the estimated prevalence rate in the adult general population is between 0.1% and 0.8%. However, one study in the United Kingdom showed a prevalence rate of 3.3%, whereas another study in Japan showed only a 0.02% prevalence rate. The estimated annual incidence rate was consistently approximately 0.005% in several studies.1

The pathogenesis of SS is still largely unknown. In a genetically predisposed individual, various environmental factors, such as viral infections, may lead to epithelial-cell activation and a protracted inflammatory response with features of autoimmunity. Autoreactive lymphocytes and autoantibodies are considered important in this process, although the pathogenic role of any particular autoantibody is still undefined. Abnormal apoptosis may be important in several ways. First, increased apoptosis of epithelial cells may lead to functional defects and provide autoantigens, whereas the prolonged survival of B and T cells through upregulation of antiapoptotic signals may be involved in sustaining a self-perpetuating autoimmune process. Decreased apoptosis of lymphocytes may also contribute to the increased frequency of lymphoma in SS patients.

Immunogenetic Factors

The role of genetic factors in SS was recognized in family studies where first-degree relatives of patients had an increased prevalence of SS.2 Such family clustering was further observed among first-degree relatives of individuals with anti-Ro/SSA antibodies regardless of their clinical diagnoses (SS or systemic lupus erythematosus or even healthy controls).3

There is a well-established association between SS or anti-Ro/SSA and anti-La/SSB antibodies with HLA class II genes.4 Genes other than those of the HLA loci may also be associated with an increased risk of disease. Associations with a number of cytokine gene polymorphisms, such as interleukin (IL) 6, IL-10, tumor necrosis factor-α (TNF-α) and the IL-1 receptor antagonist, have been reported, but none of these have been confirmed to date.4 Several genetic polymorphisms previously linked to systemic lupus erythematosus and other autoimmune diseases are also associated with SS. From these, two transcription factors, (1) signal transducer and activator of transcription 4 (STAT4)5 and (2) interferon regulatory factor 5 (IRF 5),6 which were both independently associated with SS showed an additive effect in increasing the risk of Sjögren's syndrome from around 1.6–1.9 for one risk allele to 6.7 when both risk alleles were present.7

Environmental Factors

The inciting event in the pathogenesis of SS is not known, and it may not be a single event. The strong predominance of females suggests gender-specific predisposing factors. Although sex hormones are obvious targets, there is no conclusive proof yet that the difference in the pathogenesis between males and females is due to sex hormones alone.8,9 Viral infections have also been proposed as inciting events. This theory is strongly supported by the fact that chronic inflammation of the salivary glands has been observed with chronic hepatitis C and human immunodeficiency virus infections, and such infections cause a disease with a clinical spectrum very similar to SS. The fact that some viruses, such as Epstein–Barr virus (EBV), are known to replicate in oropharyngeal and lachrymal glands led to the hypothesis that these viruses may be involved in Sjögren's pathogenesis. In fact, genetic material from EBV was detected by DNA hybridization in SS salivary tissue, but it was also found in normal individuals. Further experiments have identified an unusual strain of EBV containing a deletion in the genome in salivary gland specimens from Chinese SS patients.10 Similarly, in a Japanese cohort, defective human T-lymphotropic virus-I genome was isolated from salivary gland tissue.11 Other viruses, such as coxsackievirus12 or endogenous retroviruses have also been proposed as causative agents. However, there is no proof, to date, that any of these viruses play a pathogenic role in SS.

Epithelial-Cell Activation and Chronic Inflammation

Sections of salivary and lachrymal glands in SS are characterized by periductal mononuclear infiltrates. The majority of the infiltrating cells are CD4+ T lymphocytes, whereas CD8+ cytotoxic T cells are found in smaller numbers. Activated B lymphocytes are also present, including immunoglobulin-secreting cells.

Inflammation seems to target glandular epithelial cells, and recent research has demonstrated the central role of epithelial-cell activation in initiating the recruitment of the inflammatory infiltrate.13 In animal models, changes in epithelial cells occur before the appearance of lymphocytes in the salivary glands. Initial events include the expression of HLA class II molecules and various activation markers, such as the costimulatory molecules CD80 and CD86, on the surface of acinar and ductal14 salivary epithelial cells. These molecules are crucial in regulating the interaction between antigen-presenting cells and lymphocytes. Their expression in acinar and ductal15,16 epithelial cells suggests that epithelial cells in SS act as antigen-presenting cells and actively participate in lymphocyte activation. Another important step is the upregulation of adhesion molecules and chemokines, all of which contribute to the recruitment of inflammatory cells, such as T and B lymphocytes, macrophages, and dendritic cells. The activation of lymphocytes leads to abnormal cytokine and chemokine expression,17 perpetuating the chronic inflammatory process characterized by a complex interaction between activated epithelial cells, the innate and acquired immune system. Extraglandular manifestations occur as a result of similar lymphocytic infiltrations at other organs. This is described by some as autoimmune epithelitis to better reflect the systemic nature of the disease. Some epithelial cells express Fas and Fas ligand18 and, as a consequence, undergo apoptosis; others may be destroyed by perforin, granzymes, and other cytotoxins produced by lymphocytes. However, in most patients, only partial destruction of the glands is noted. Local production of cytokines, autoantibodies, metalloproteinases, and other inflammatory mediators may contribute to the dysfunction of the remaining epithelial cells by various mechanisms. For example, it has been shown that TNF interferes with the intracellular trafficking of aquaporin-5, one of the water channels required for saliva production. Enhanced activity of the type-1 interferon system has been linked to multiple autoimmune diseases, including Sjögren's syndrome. Increased expression of interferon-regulated genes was described both in the salivary glands and peripheral blood.19–21 One of the cytokines upregulated by interferon-α is B-cell activating factor (BAFF), which promotes B-cell survival and has also been found at higher levels in Sjögren's patients.22,23 Interestingly, both of these cytokines can be upregulated by viruses.24

Autoantibodies

Autoantibodies are the hallmarks of systemic autoimmune diseases, including SS. The best-defined autoantibodies in SS are the anti-Ro/SSA and anti-La/SSB antibodies.25 Both are targeted against ribonucleoprotein antigens. Anti-Ro/SSA recognizes two RNA-binding proteins (the 52-kDa or the 60-kDa protein), whereas anti-La/SSB antibodies recognize RNA polymerase III. Anti-Ro/SSA antibodies are found in over 70% of patients with SS, but are not specific for SS and are frequently found in SLE and other autoimmune diseases even when there are no symptoms or signs of oral or ocular dryness. Anti-La/SSB is more specific; it is present in 50% of patients with primary SS or SS/SLE but is rarely seen in other diseases. The pathogenic role of these antibodies is not yet defined, but, because Ro and La are expressed on the surface of apoptotic epithelial cells, it is possible that an immune response against these antigens contributes to inflammation in the gland. The most compelling in-vivo evidence for a pathogenic role of these autoantibodies comes from newborns with fetal heart block born to women with anti-Ro/SSA and/or anti-La/SSB antibodies. These antibodies can cross the placenta and bind to Ro and La antigens located on the cell surface of fetal myocardial tissue, leading to fetal heart block. Other autoantibodies, such as antinuclear antibodies and rheumatoid factor, are frequently present in patients with both primary and secondary SS. Although they lack specificity, they are markers of a systemic autoimmune response and thus can help distinguish SS from other causes of salivary or lachrymal gland dysfunction.

In recent years, research has focused on identifying antibodies more specific for SS, such as anti-α-fodrin and antimuscarinic acetylcholine receptor antibodies, but the results have been controversial. The major stimulus for saliva production is the binding of acetylcholine to muscarinic acetylcholine receptors. The hypothesis that oral and ocular dryness could result from antibodies antagonizing the muscarinic acetylcholine receptor-3 is intriguing. These antibodies have been demonstrated to play an essential role in eliciting glandular dysfunction in the nonobese diabetic (NOD)mouse model of SS, possibly through an inhibitory effect on the receptor.26 In humans, however, results are still contradictory as multiple attempts to detect these antibodies with conventional immunologic methods have been fruitless.27,28

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).

Xerostomia

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).

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.

Keratoconjunctivitis Sicca

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

Skin Involvement

Cutaneous manifestations are common extraglandular features of SS (Table 161-1).30 They are generally considered either vasculitic or nonvasculitic lesions.

Vascular Lesions

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

Hypergammaglobulinemic Purpura

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).

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

Musculoskeletal 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.

Visceral Manifestations

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

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.

Lymphoproliferative Disease

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

Pregnancy

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.

The diagnosis of SS in a patient with complaints of oral and ocular dryness requires evaluation by a dentist or salivary gland specialist (such as a otorhinolaryngologist) and an ophthalmologist for specialized tests to quantify mucosal dryness, as well as laboratory evidence of autoantibodies and salivary gland biopsy for evidence of inflammation within the gland itself.

Several sets of diagnostic criteria were developed, and used by various groups over time, creating some confusion about how to define SS. Recently, an international consensus group agreed on a set of criteria, and this revised American–European classification system has been widely accepted (Table 161-2).38 Six features are taken into consideration: subjective complaints and objective evidence of dry eyes or dry mouth, objective evidence of salivary gland inflammation, and the presence of specific autoantibodies in the serum. For the diagnosis of primary SS, at least four criteria should be present, and at least one of them should be either evidence of lymphocytic infiltration or the presence of autoantibodies. Patients with a coexisting connective tissue disease are labeled secondary SS. Exclusions include other diseases and medications that may cause sicca symptoms.

To establish subjective symptoms of dry eyes and dry mouth, a validated uniform questionnaire is used. A variety of noninvasive methods can be used to diagnose reduced salivary flow in clinical practice.

Oral Dryness

Sialometry

Sialometry involves measurement of the total saliva produced from all salivary glands in a time period of 15 minutes. The whole unstimulated salivary flow is considered suggestive of SS if it is less than 1.5 mL in 15 minutes. A “stimulated” salivary flow can be measured after administration of lemon juice or citric acid, and low values are also suggestive of SS.

Salivary Gland Scintigraphy

Salivary gland scintigraphy is a functional study to assess saliva production by measuring the secretion of a radioisotope (99mtechnetium-sodium pertechnetate) into the oral cavity. Salivary gland scintigraphy (SGS) provides functional information about individual salivary glands and can potentially distinguish between decreased production and/or decreased excretion of saliva. The past decade has seen a shift towards the quantitative evaluation of SGS based on various parameters generated from time–activity curves.39 Given the high cost and the exposure to radiation, their routine use may not yet be justified but it is a useful diagnostic tool in selected cases. Sialography is an imaging method based on retrograde injection of contrast media into the parotid duct. Dilatations of salivary ducts and sialolithiases are the most common findings.

Ocular Dryness

The diagnosis of keratoconjuctivitis sicca is based on the demonstration of decreased tear production, corneal damage, or both. Tear production is measured by Schirmer's test. This is performed by placing a standardized paper strip in the inferior fornix of each eye and measuring the length of filter paper that becomes wet after 5 minutes. The American–European classification system uses a cut-off value of 5 mm in 5 minutes, below which the diagnosis of dry eyes is made. An alternative method is staining with a dye (rose Bengal or lissamine green) that preferentially stains the devitalized cornea and conjunctiva. This staining is evaluated through the van Bijsterveld scoring system; a score of 4 or more indicates keratoconjunctivitis sicca. These tests have a high sensitivity but low specificity; they identify ocular dryness, but cannot attribute abnormal findings to SS.

Laboratory Tests

High inflammatory markers, such as high sedimentation rates and signs of chronic inflammation (anemia, hypoalbuminemia) are common in SS patients.

Serologies can demonstrate hyperglobulinemia, in as high as 80% of primary SS patients. Autoantibodies include Ro (SSA) and La (SSB) antibodies, as well as rheumatoid factors and ANA.

None of the above diagnostic procedures is specific for SS. The most reliable objective diagnostic feature is seen on biopsy of the minor salivary gland. A small incision is made on the inner surface of the lip, and a minor salivary gland tissue sample is collected. Evidence of a focal, periductal infiltrate composed of T and B lymphocytes and few plasma cells is the histologic hallmark of SS (Fig. 161-3). The degree of lymphocytic infiltration is evaluated semiquantitatively by means of a focus scoring system. Evidence of one or more focus is considered indicative of SS, and a focus is considered a conglomeration of at least 50 lymphocytes per 4 mm2 of glandular tissue. Atrophy and fat tissue are other findings that may be present in SS patients, but are also present among healthy, elderly individuals. Although salivary gland biopsy provides important clues that may lead to definitive diagnosis, some controversy still exists regarding its sensitivity and specificity. Some patients with primary SS diagnosed on the basis of reduced salivary flow and evidence of anti-SSA and anti-SSB antibodies have no lymphocytic infiltration in biopsy specimens of minor salivary glands. In addition, some healthy individuals may demonstrate lymphocytic foci in their salivary glands.

There are two patterns of primary SS that define two distinct disease categories with very different clinical risks. Patients with low complement C4 levels and/or palpable purpura early in their disease course may be classified as a high-risk disease syndrome (type I). This group comprises approximately 20% of the primary SS diagnoses and carries a significantly increased risk of lymphoproliferative disease and also has an increased mortality rate. Most severe extraglandular manifestations also occur in this group. Patients without these two predictors (80% of all primary SS diagnoses) may be reassured that they have a low-risk (type II) form of primary SS that carries no increased risk of death and in general has a more benign course dominated by sicca symptoms.37

Treatment of Dry Mouth

(Table 161-3)

The treatment of oral dryness is largely symptomatic.40

Nonpharmacologic strategies are the mainstay of treatment.

Adequate hydration, and reduction of irritants like coffee, alcohol and nicotine as well as substitution of drugs that can lead to dry mouth when possible (diuretics, tricyclics, antihistamines, β-blockers) is essential.

Frequent sips of water are recommended initially to maintain moisture. Patients should also be encouraged to use sugar-free candies and chewing gums to increase saliva production. Saliva substitutes are available in the form of gels, oils or sprays, but the need for frequent application is inconvenient for many patients.

Sugar-containing foods should be avoided because they contribute to the increased risk of dental caries and oral candidiasis. Meticulous dental hygiene is essential for SS patients to prevent or treat dental caries.

Caries prevention with fluoride applications including prescription-strength toothpaste, fluoride gels, and oral rinses is further recommended.

Oral candidiasis is treated with oral and systemic antifungal therapy. To prevent candidiasis, patients should not wear dentures at night, and the dentures should be soaked in 2% chlorhexidine. Nystatin or clotrimazole cream can be used to treat angular cheilitis.

If dry mouth is not adequately controlled with replacement methods, pharmacologic therapy with secretagogue drugs is an option. Two drugs are approved for this indication: (1) pilocarpine (5 mg four times a day)41 and (2) cevimeline (30 three times/day).42 Both act on muscarinic receptors and increase exocrine gland secretion. They are contraindicated in narrow-angle glaucoma and uncontrolled asthma. Cholinergic side effects, such as excessive sweating, urinary frequency, flushing, and headaches, are common for both agents. Tolerability can be increased if treatment is started at a lower dose, which is then gradually increased (see Table 161-3).

Treatment of Dry Eyes

(See Table 161-3)

Non pharmacologic measures are very important therapeutic interventions; avoidance of dry, smoky and windy environments, avoiding contact lenses or opting for those higher in water content, and minimizing medications that inhibit tear production (diuretics, β-blockers, tricyclic antidepressants, antihistamines) are first-line measures.

Many tear substitutes are available and are commonly used by patients to alleviate ocular dryness. Preservative-free preparations are preferred, especially if used more than four times a day. Methylcellulose-containing ointments may provide longer relief, but their use is limited to nighttime use by the risk for blurred vision.

A frequently used surgical option is the occlusion of the puncta to block tear drainage and consequently increase moisture. The occlusion can be transient by the insertion of collagen or silicone plugs, or permanent by electrocautery.

Cyclosporine A 0.05% ophthalmic solution has been approved by the FDA for the treatment of keratoconjunctivitis sicca.43 Topical corticosteroids are rarely needed and should probably only be prescribed after ophthalmic examination. Infections may present with aggravation of symptoms or increased mucus secretion, and should be promptly treated with topical antibiotics.

Pilocarpine and cevimeline can be effective for dry eyes, too, especially in patients with the most severe dryness.42

Treatment of Extraglandular Manifestations

The treatment of musculoskeletal manifestations of SS is similar to those of other systemic rheumatologic diseases.44 Because of reduced saliva production and esophageal dysmotility, these patients have reduced tolerance to nonsteroidal anti-inflammatory drugs. Antimalarial drugs, such as hydroxychloroquine, are effective for arthralgia/arthritis, myalgia, and fatigue.45 Dryness of eyes and mouth may also improve slightly in some cases.46 Visceral manifestations such as vasculitis, pneumonitis, glomerulonephritis, and neurologic manifestations are treated with corticosteroids and immunosuppressive drugs, in doses similar to those used in systemic lupus erythematosus.

Treatment of lymphoma in SS is the same as in the general population. Most SS-associated lymphomas are low-grade B-cell lymphomas localized to the exocrine glands. For these, watchful waiting may be the most appropriate approach. Higher grade lymphomas require more aggressive treatment with a rituximab, cytotoxic regimen, and/or radiation therapy.

Targeted Therapy

Several randomized case-control studies have focused on therapy for SS using biologic agents, such as the TNF-blocking agents infliximab47 and etanercept,48 but none of the studies showed clinical benefit. There is increasing interest in therapies targeting B cells, such as monoclonal antibodies against CD20 (rituximab) or CD22 (epratuzumab). A recent randomized placebo-controlled study demonstrated efficacy of rituximab over placebo in patients with active primary SS.49 Rituximab improved stimulated salivary flows, laboratory parameters of inflammation and subjective symptoms. This clinical efficacy was supported by reduced glandular infiltration and morphologic improvements of epithelial cells on salivary gland biopsies.50 Other potential targets for biologic therapy include cytokines such as IL-6 and BlyS (BAFF), interferons, adhesion molecules, and chemokines. However, even if effective, systemic immunomodulatory therapy may be associated with unwanted side effects and may not be justified in patients with primary SS whose disease is limited to exocrine glands. An alternative approach is to develop a localized form of immunotherapy by using gene therapy restricted to the salivary and lachrymal glands. This approach would most likely alter the abnormal immune response locally but may avoid the systemic side effects.51