Sjögren's Syndrome

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[edit] Sjögren's Syndrome

Ann L. Parke

Sjögren's syndrome (SS) was originally defined as the presence of xerostomia (dry mouth) and xerophthalmia (dry eyes), specifically keratoconjunctivitis sicca.Dry eyes and mouth have many causes, however, which has led to confusion in defining SS (Box 140-1).A precise method of defining SS is to limit the diagnosis of SS to patients who have a specific pathologic disease process, that is, an autoimmune exocrinopathy demonstrated by the infiltration of T helper cells into exocrine glands.This chapter refers to this pathologic disease process as Sjögren's disease(SD).SD may be found in patients who have a well-defined rheumatologic disease, such as rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) (secondary SS/SD), or in patients who do not have an additional rheumatologic disease (primary SS/SD).

The difficulties that arose from the original definition of SS led to the development of several sets of criteria, including the European classification.^[1] All these sets of criteria have limitations because they are based on subjective sicca complaints and objective investigations designed to evaluate glandular function.The criteria that require pathologic changes to demonstrate an autoimmune exocrinopathy (i.e., a positive lip biopsy) are very specific but are not sensitive, and up to 30% of lip biopsies may be falsely negative.

[edit] EPIDEMIOLOGY

The lack of a precise definition makes it difficult to assess the prevalence of true SS/SD.Previous estimates are based on the assumption that at least 50% of patients with RA have SS/SD and that 50% of patients with SS/SD have primary disease vs.secondary; this has led to the conclusion that SS/SD is the most common connective tissue disease, affecting more than 4 million Americans.Other reports suggest a prevalence of 1:250 individuals in the United States, whereas sicca complaints were found in up to 3% of Quebec's population.True SS/SD is more common in women than men (9:1) and is most common in postmenopausal women, for unknown reasons.Patients with earlier onset of disease and those who produce antibodies to extractable nuclear antigen Ro may develop a more aggressive systemic disease.^[2] In a long-term outcome study of SS patients, malignancy was the major cause of death (56%).^[3]

[edit] PATHOPHYSIOLOGY

[edit] Genetic Factors

Although the etiology of SS/SD is unknown, evidence now demonstrates the abnormal expression of autoantigen, activation of infiltrating lymphocytes, and local synthesis of autoantibodies at the primary site of pathology (i.e., the exocrine glands).These findings indicate a local immune response.HLA antigens play a vital role in individualizing the immune response because they present antigen to T cells.The presence of specific HLAs dictates the host's ability to respond to specific environmental triggers.SS/SD has been reported to be associated with DR2, DR3, and DR5 antigens.Also, production of antibodies to the Ro and La nuclear antigens is associated with DR3 and DR2.DR3 is in linkage disequilibrium with DQ2, and DR2 with DQ1.Subsequent studies have demonstrated that SS patients who are heterozygous for both DQ1 and DQ2 alleles are more likely to produce these autoantibodies.

[edit] Environmental Factors

Viruses have been implicated in the pathogenesis of various autoimmune diseases,^[4] but the evidence for this association remains inconclusive.Renewed interest in this area followed the autoimmune complaints associated with human immunodeficiency virus (HIV) infection.Some HIV patients develop a diffuse infiltrative lymphocytic syndrome (DILS) and may complain of xerostomia and xerophthalmia.Biopsies of the salivary glands of these patients demonstrate lymphocytic infiltrates, but these are predominantly T suppressor cells, not the T helper cells found in SD patients.

Some retroviruses are trophic for the ductal epithelium ofsalivary and lacrimal glands, and human T-cell lymphotrophic virus (HTLV-1) may be involved in the pathogenesis of SS.Epstein-Barr virus (EBV), a deoxyribonucleic acid (DNA) virus that belongs to the herpesvirus family, is secreted in saliva and is known to be associated with the development of nasopharyngeal carcinoma.EBV infects B cells and promotes B-cell proliferation and may be associated with SS.SS/SD may also be associated with hepatitis C virus (HCV) infection.HCV is secreted in saliva, and some patients with HCV infection develop sicca complaints.Rheumatic and autoimmune manifestations of chronic HCV are numerous, and chronic infection is much more prevalent than previously thought.Patients with chronic HCV liver disease may develop a sialoadenitis, with focal lymphocytic infiltrates found in salivary gland biopsy.This suggests that HCV is one of the few infections capable of producing a false-positive lip biopsy or that HCV may be directly involved in the pathogenesis of autoimmune sialoadenitis.Approximately 4% of SS/SD patients have persistent HCV ribonucleic acid (RNA) detected by polymerase chain reaction (PCR), and up to 47% of primary SS patients with cryoglobulins have antibodies to HCV.^[5]

[edit] Glandular Factors

Histopathologic changes found in the salivary glands of SD patients include a benign lymphoepithelial lesion (BLEL) and focal lymphocytic sialoadenitis.BLELs are found in approximately 40% of major salivary glands from patients with SS, in whom the salivary epithelium is replaced and infiltrated with lymphocytes.Epimyoepithelial islands, remnants of ductal epithelium, are found, which help to distinguish BLEL from overt lymphoma.A pathologic feature found in the minor salivary glands of these patients is a focal lymphocytic infiltrate that consists primarily of T helper cells (Fig.140-1).This pathology, however, is not specific for SD.Other disease entities (e.g., sarcoidosis, chronic HCV infection, graft-vs.-host disease) and HIV-positive patients with DILS may show similar pathologic changes.

Figure 140-1 Salivary gland biopsy findings in Sjögren's syndrome and Sjögren's disease (SS/SD). A, Foci of lymphocytes.(Magnification ×40.)B, Lymphocytic focus.(×250.)C, Loss of glandular tissue and atrophy with no lymphocytic foci.(×40.)

Xerophthalmia and xerostomia may be consequences of senescence.Studies suggest that glandular fibrosis and atrophy are features of aging.Fatty change with some nonspecific inflammatory cell infiltrates may occur in normal salivary glands.Some believe that glandular atrophy and fibrosis are postinflammatory changes that may occur in SS/SD.

[edit] Immune Abnormalities

[edit] Autoantibody Production.

Most often in SS/SD, organ-nonspecific antibodies are produced, including antinuclear antibodies (ANAs) and rheumatoid factor (RF).Many nuclear antigens exist, and therefore a variety of autoantibodies can give positive ANA tests.The ANA pattern can vary and depends somewhat on the antigenic specificity of the antibody.SS/SD patients most frequently produce a speckled ANA pattern, with the major antibody reactivity directed toward the extractable nuclear antigens Ro and La (SSA and SSB).Depending on the assay's sensitivity, approximately 60% to 90% of primary SS/SD patients have the antibody toRo, but this is not specific for SS/SD; patients with SLE (30%) and subacute cutaneous SLE (60%) also produce this antibody.Sjögren's patients and SLE patients may produce antibodies to different fractions of Ro antigen.Antibodies to the 52-kilo dalton (kD) band alone occur more often in SS patients, whereas antibodies to the 60-kD band alone occur more often in SLE patients.Ro antibodies may be associated with the more severe extraglandular complaints of SD (e.g., vasculitis).Antibodies to La rarely occur alone and are typically associated with antibodies to Ro.The finding of La antibodies in saliva suggests local glandular production of antibody that is antigen driven.

The transplacental passage of the maternal antibody to Ro and La is thought to be involved in the pathogenesis of the neonatal lupus syndrome (NLS).The clinical features of NLS are a transient photosensitive rash and a primary congenital complete heart block (CCHB).Some of these Ro-positive mothers are clinically normal during their abnormal pregnancy, but on long-term follow-up, some of these asymptomatic mothers eventually fulfill criteria for a connective tissue disease, usually SS/SD.^[6]

RF is an autoantibody that is much less specific for SS/SD.Immunoglobulin A (IgA) RF may occur more often in both the blood and saliva of patients with SS/SD than in those with other autoimmune diseases.Mixed cryoglobulinemia may also be found in patients with SS/SD and is more often found in those who produce autoantibodies, especially Ro antibodies.Cryoglobulinemia may be associated with the development of vasculitis (as can any disease resulting in the production of autoantibodies).In Sjögren's patients the deposition of immune complexes with the activation of complement has been incriminated in the pathogenesis of leukocytoclastic vasculitis (perivascular infiltrate of polymorphonuclear leukocytes).In another type of vasculitis the predominant infiltrate is mononuclear, and the pathogenesis is unknown.

[edit] Hypergammaglobulinemia.

Polyclonal hypergammaglobulinemia is another marker of B-cell hyperactivity.In some patients, B-cell reactivity becomes oligoclonal or even monoclonal, with the production of monoclonal spikes on immune electrophoresis and monoclonal light chains in both urine and serum.This may remain a benign gammopathy or may be associated with a B-cell malignancy.

[edit] B-Cell Malignancy.

Patients with SS/SD are at an increased risk for developing non-Hodgkin's B-cell lymphoma.^[7] It is estimated that fewer than 10% of Sjögren's patients develop overt malignancy.The majority of these lesions are low-grade lymphomas, and some have been noted to regress spontaneously.B-cell hyperactivity may progress from benign reactivity through a phase called pseudolymphoma before becoming overtly malignant.This pseudolymphomatous change must be managed aggressively if progression to true malignant change is to be averted.Some suggest that decreased titers of autoantibodies may indicate progression toward malignancy, but other studies have failed to confirm this finding.

[edit] T-cell Abnormalities.

The cellular infiltrate contributing to the autoimmune exocrinopathy is predominantly an infiltration of T helper cells.This glandular lymphocytic infiltrate is secondary to some primary initiating event, but the nature of this primary event remains obscure.

[edit] PATIENT EVALUATION

[edit] History

Sjögren's syndrome is a systemic disease that requires a full patient history.Xerostomia and xerophthalmia are often late manifestations of SS/SD, and other features may precede the sicca complaints.^[8] Fatigue is often a dominant symptom and is underestimated.To uncover an underlying connective tissue disease, the physician must ask questions about photosensitivity, alopecia, mucosal ulceration, Raynaud's phenomenon, and any family history.A full obstetric history is also important because an abnormal pregnancy may be an early sign of connective tissue disease.^[6]

[edit] Physical Examination

[edit] Oral Component.

Because the clinical manifestations of SS/SD are so diverse, a comprehensive examination must be performed for both glandular and extraglandular disease (Table 140-1).To assess for oral dryness, the tongue is examined for redness, dryness, and loss of papillae (Fig.140-2).Sublingual pooling and overall moistness of the oral cavity should be evaluated (Fig.140-3).Saliva production can be assessed using the Saxon test, which requires chewing on a gauze swab for 2 minutes.The difference in weight of the swab before and after chewing is a measure of the saliva produced in those 2 minutes (normally, more than 2.75 gm).

Figure 140-2 “Crocodile tongue” in SS patient.

Figure 140-3 Poor sublingual pooling and parotid swelling.

Table 140-1 Clinical Manifestations of Glandular and Extraglandular Disease Associated With Sjögren's Syndrome

Patients with dry mouths are at risk for the development of dental caries (Fig.140-4) and oral candidiasis.These patients frequently do not show the usual white plaques typically associated with oral candidiasis.It is therefore very important to culture for Candida even if an oral inspection is not typical for this problem.Gingivitis, extensive dental caries, an abnormal pattern of dental caries, and burning-mouth syndrome are all complications of the dry mouth.Swollen parotids (“chipmunk facies”) and swollen submandibular glands occur in some patients (Fig.140-5).Persistent unilateral swelling is serious, and the patient should be evaluated for lymphoma (Fig.140-6).Acute, painful swelling is a sign of infection, and milking the affected gland may produce a thick, opaque discharge into the mouth, in contrast to the usual colorless glandular secretion.

Figure 140-4 Dental decay. (Courtesy Jason Tanzer, DMD, University of Connecticut School of Dental Medicine.)

Figure 140-5 Swollen parotids in SS patient.

Figure 140-6 A, Unilateral swelling caused by lymphoma in SS patient. B, Lymphoma.

[edit] Ocular Component.

Evaluating the ocular component of SS/SD can be done in the clinic with Schirmer's test.This involves placing filter papers inside the lower lid at the junction of the nasal and middle thirds of the lid for 5 minutes and measuring the length of the filter paper that is made wet by tears (normally, greater than 5 mm of wetting per 5 minutes).All other testing should be done by an ophthalmologist and includes the rose bengal test to assess conjunctival pathology (any residual staining is abnormal), examination ofthe tear film and height, examination for cells and cellular debris as well as mucus and mucous debris, fluorescein staining, and a tear breakup time to assess corneal pathology.Some patients react adversely to the preservative used in rose bengal stain, so preservative-free strips should be used.A potential substitute for rose bengal is lisamine green, which does not cause pain when corneal ulcers are present.Other tests, including tear osmolality and tear lactoferrin levels, are available only in specialized centers.

[edit] Other Clinical Features.

SS/SD is a multiorgan disease, and other glandular manifestations include pancreatic, hepatic, thyroid, and renal disease.More than 70% of patients with primary biliary cirrhosis and 40% with chronic active hepatitis complain of dry eyes or dry mouth.The liver is an exocrine gland, and some suggest that all these features can be explained as consequences of damage to the ductal epithelium.The relationship of SD to these autoimmune hepatic diseases, which have a fairly specific autoantibody production, is unclear, but chronic HCV infection may be one cause.Hepatitis C may also be associated with cryoglobulinemia and vasculitis (Fig.140-7).Vasculitis occurs in SS/SD patients who do not have HCV, however, and more frequently in patients who are Ro antibody positive.Renal involvement also occurs more often in Ro antibody–positive patients.Up to 30% of SS/SD patients may develop renal tubular acidosis, most frequently type I.

Figure 140-7 Vasculitis in SS patient.

[edit] LABORATORY STUDIES AND DIAGNOSTIC PROCEDURES

Laboratory tests include blood work every 6 months (Table 140-2) and a chest radiograph annually.Tests are done primarily to screen for occult lymphoma, with a full examination for lymphadenopathy and hepatosplenomegaly.

Table 140-2 Laboratory Evaluation for Sjögren's Syndrome

Patients complaining of xerostomia should have a lip biopsy, which can be done in an outpatient setting using local anesthesia with epinephrine to minimize blood loss.Patients who take nonsteroidal antiinflammatory drugs (NSAIDs) are usually not troubled by excessive bleeding, but patients who take anticoagulants may have additional blood loss and require suturing.Routinely, however, the mouth heals well, and the wound does not require sutures.All patients requiring antibiotic prophylaxis to prevent bacterial endocarditis must receive antibiotics when having a minor salivary gland biopsy.The biopsy involves the removal of 5 to 10 small salivary glands from inside the lower lip.A focal score greater than 1 (more than 50 cells/4 mm²) is considered a positive biopsy, suggesting an autoimmune exocrinopathy.

Scintigraphy is used to evaluate glandular function and inflammation.Glandular uptake is evaluated by scanning the patient for 20 to 25 minutes after technetium injection.The patient is then given a lemon stimulus to promote glandular emptying and is scanned for an additional 20 to 25 minutes to measure uptake and glandular secretion.Gallium scanning is useful for assessing glandular inflammation (Fig.140-8).The “panda sign” may also be found in patients with sarcoidosis, which can cause false-positive biopsies when evaluating patients for SS/SD.Some centers prefer to use sialography, claiming that scintigraphy with either gallium or technetium is too insensitive; however, the long-term effects of instilling contrast into chronically inflamed tissues are a concern.

Figure 140-8 “Panda sign” in SD patient demonstrated by uptake of gallium-67 citrate in parotid and submandibular glands.In this particular patient, uptake by lacrimal glands is not marked.

[edit] DIFFERENTIAL DIAGNOSIS

The differential diagnosis of xerostomia and xerophthalmia includes many diseases (see Box 140-1).In patients with extraglandular disease and other features of an autoimmunedisease, it is sometimes difficult to differentiate between primary and secondary SS/SD, especially patients with SLE.The diagnosis of SLE requires the presence of 4 of 11 revised criteria, although some patients may have SLE even though they do not meet criteria at a particular time.

Sicca complaints are the end stage of SS/SD.These patients probably have had their autoimmune exocrinopathy for many years before they developed symptoms of dryness.Patients therefore may not complain of dryness but may present with other symptoms (see Table 140-1).

Diseases that can give a false-positive lip biopsy include sarcoidosis and DILS.HIV-positive patients are more likely to be young males than elderly, postmenopausal women.Patients with DILS frequently have massive glandular swelling with numerous extraglandular manifestations.The autoantibody production in classic SD occurs infrequently in these patients.HLA associations also are different, with DR5 and DR6 occurring in black DILS patients and DR6 in white patients.The usual pathology of sarcoidosis is noncaseating granulomas.Sarcoid patients may also produce RFs and have elevated immunoglobulin levels (IgG).Chest radiographs are usually abnormal in these patients, however, revealing either bilateral hilar adenopathy or diffuse parenchymal disease.Gallium scanning is positive in approximately 65% to 70% of sarcoid patients, with a positive panda sign detected as the gallium is taken up by the parotid, lacrimal, and submandibular glands.

[edit] MANAGEMENT

Although considered to be a rare disease, SS/SD is quite common.An estimated 4 million or more Americans have SS/SD, and it can take up to 10 years for patients to be diagnosed appropriately even when the sicca complaints are obvious.^[8] Education of primary care physicians, nurse practitioners, and dentists is therefore a vital component in the management of this disease.Education is also probablythe most important component of patient management.Patients must understand that their complaints are real and the result of a systemic inflammatory disease.Treatment is available, but not a cure.

Long-term studies of SS/SD patients suggest that up to 25% of patients will develop new clinical features, especially those with Ro antibodies.^[9] Malignancy is the most common cause of death,^[10] and the risk for developing a B-cell lymphoma is increased in SS/SD patients.The constant fatigue and difficulty in eating and talking are severely debilitating for SS/SD patients.This sicca complex can lead to major psychosocial and family problems.These patients should have access to support groups through the Arthritis Foundation, the Sjögren's Syndrome Foundation, or the National Sjögren's Syndrome Association (Box 140-2).

[edit] Pharmacologic Treatment

The pharmacologic approach to managing SS/SD patients can be divided into two groups: agents promoting secretion (sialogogues and mucolytic agents) and antiinflammatory agents.Agents that promote the production of natural secretions have been reported to be useful.^[11] Recently approved for SD/SS patients, oral pilocarpine is a positive step in management.Side effects from pilocarpine include sweating, abdominal cramping, diarrhea, bradycardia, hypotension, and bronchospasm.Pilocarpine is generally well tolerated, however, but must not be given to asthmatic patients.Sweating can be minimized if pilocarpine is taken after eating.

Mucolytic agents, such as bromhexine and acetylcysteine, have been reported to be useful, but some controlled studies have not found a benefit.Many patients report relief with bromhexine, and even though this agent is not available in the United States, some patients go to extreme lengths to obtain it.

Hydroxychloroquine (Plaquenil) is an effective agent for treating arthritis and skin disease in patients with RA and SLE.This is an extremely useful drug for patients with SS/SD, although this has not been confirmed by all studies.Some patients report that hydroxychloroquine not only improves their arthralgias and arthritis, but also reduces their overwhelming fatigue.

Corticosteroids and immunosuppressive agents should be reserved for patients with severe extraglandular disease when vasculitis and end-organ failure are potential problems.Such patients may need high-dose corticosteroids and additional immunosuppression.Methotrexate is not a well-recognized agent for managing SS/SD; however, some patients with SS/SD secondary to RA also experience an improvement in their sicca complaints as well as in their underlying arthritis when treated with methotrexate.The use of azathioprine (Imuran) should be discouraged, since these patients are already at risk for developing lymphoma.Cyclophosphamide should be used only as intermittent boluses because of the bladder toxicity (hemorrhagic cystitis and malignancy) that has been reported with daily oral therapy.Cyclosporine eye drops should soon be available.

[edit] Nonpharmacologic Treatment

Other approaches currently being developed include the use of polyunsaturated fatty acids, such as linoleic acid (the major constituent of oil of evening primrose).Ingesting these fatty acids results in the synthesis of fewer inflammatory prostanoids, and studies have demonstrated that these agents may be useful in the management of RA.Similar studies are currently being carried out in Sjögren's patients.

[edit] Complications

Glandular failure has numerous consequences.Pulmonary infections, sinusitis, glandular infections (particularly of the parotids), and eyelid infections occur frequently and require prompt treatment.Oral candidiasis results in a sore, painful mouth that further hinders eating.The usual oral preparations for treating candidiasis frequently contain sugar; therefore clotrimazole (Mycelex) troches should be prescribed for patients who are not edentulous.Patients should be treated for at least 1 month and should eat live-culture yogurt daily.Studies have demonstrated that yogurt containing lactobacilli can prevent recurrent vaginal candidiasis, which may also help to prevent yeast colonizing the mouth and esophagus.

Artificial tears and artificial saliva are important local treatments for SS to reduce the symptoms of dryness.Artificial eye drops appear to be more effective than artificial saliva.Various preparations are available, and some patients are sensitive to the preservatives used to make artificial tears.Patients frequently need to experiment to find the product best suited for them.Eye drops produced without preservatives are more expensive.

Other measures to protect the dry eye include the use of moisture chamber glasses, with a protective screen extending down the arms of the glasses.This minimizes the effects of wind and automobile heating and cooling systems blowing onto the dry eye surface.Patients who have continuing sicca problems with the cornea and who are at risk for ulceration may benefit from the use of soft contact lenses.Such patients should consider punctal occlusion in an attempt to preserve more of a tear film on the eye surface.Stents can be inserted as a temporary measure to determine if there is a benefit to the patient before surgical ablation of the punctum is performed.

Saliva substitutes do not last long enough and thus are less effective at maintaining moisture in the mouth than artificial tears are for maintaining moisture in the eyes.Patientsfrequently carry water bottles, and some find that mixing water and glycerin (1 L of water to 20 ml of glycerin), with lemon to taste, and using a spray bottle to apply the solution is better than simply sipping water.Constant chewing or sucking helps to stimulate salivary secretion, but a major problem is rampant dental caries if sugarless products are not used.Fluoride-containing gel used twice a day is essential.

Skin dryness may respond to moisturizers, whereas vaginal dryness may be improved with KY jelly or Replens.

[edit] Follow-up and Consultation

Patients with SS/SD must have regular follow-up with an ophthalmologist who specializes in the dry eye, a dentist who has expertise in dry mouth, and either a rheumatologist or an internist.Preventing the major medical problems associated with SS/SD is an essential aspect of care.Other exocrine glandular involvement must be identified because some patients require pancreatic supplementation and others become thyrotoxic or diabetic.Autoimmune thyroid disease may precede the sicca complaints, and therefore the physician must consider this diagnosis in all patients with any exocrine or endocrine glandular disease, chronic fatigue, or fibromyalgia syndromes.

Patients with extraglandular diseases pose additional problems.These patients generally have more severe disease and require aggressive therapy with corticosteroids or immunosuppressive agents.The development of major organ damage and associated vasculitis are of particular concern and require consultation with a rheumatologist.

The increasing awareness of SS/SD will confirm that it is a very common debilitating disease.Treatment is available, and with appropriate referrals to dentists, ophthalmologists, and rheumatologists, this disease and its complications are manageable.

[edit] REFERENCES