Fissured tongue

Abstract

Sjogren's syndrome (SS) is the most common autoimmune disorder among women. Symptoms occur when the infiltration of immune cells into the salivary and lacrimal glands causes a progressive decline in sight, smell, and taste. Although symptoms seriously disrupt quality of life, the disease's vague manifestations usually prevent individuals from seeking immediate help. By the time a diagnosis is rendered, significant systemic organ involvement may have occurred. Although there is no cure, clinician understanding of the epidemiology, etiology, and pathophysiology of SS enhances its symptomatic management in primary care settings.

Sjogren's syndrome (SS) is the most common autoimmune disorder among women.1,2 SS is a debilitating chronic disease that diminishes the acuity of senses, which are vital for physiologic functioning and emotional responsiveness. Although a cure for the disease does not exist, clinician understanding of the epidemiology, etiology, and pathophysiology enhances its management in primary care settings.

Sjogren's syndrome, first described by Henrik Sjogren in 1933, is characterized by the infiltration of lacrimal, parotid, sublingual, and labial salivary glands by immune cells, primarily the T and B lymphocytes.1,2 The infiltration disrupts gland functioning and causes a progressive decrease in the production of saliva and tears.1,2 The reduced saliva and tears, and the eventual tissue dryness, interfere with the acuity of sight, taste, and smell. In time, the ability to chew, talk, shed tears, and sustain a moist cornea becomes impaired. The manifestations of dry mouth and dry eye are collectively referred to as sicca syndrome.

The disease may provoke systemic involvement in the kidneys, blood components, lungs (bronchitis sicca), stomach (atrophic gastritis), and the central nervous system. SS may occur as the primary disease, termed primary SS (PSS), or in association with other rheumatic disorders, termed secondary SS (SSS).1The clinical symptoms of PSS and SSS are the same regardless of the classification. PSS is diagnosed in the absence of another rheumatic disease. SSS is diagnosed when there is a rheumatic disease present, commonly rheumatoid arthritis and systemic lupus erythematosus.1,2

* Epidemiology and Etiology

Approximately 1 to 2 million Americans have SS; however, because of its insidious nature, the disease often remains undiagnosed.1 Some 95% of SS patients are female.1-4 The prevalence of PSS in the general population ranges from 0.5% to 2.7%; it is most common among the elderly.1,5 Approximately 30% of patients with rheumatoid arthritis have SSS. Although SS can occur at any age, it is most common after menopause, particularly during the fifth decade of life.

The etiology of SS consists of genetic, infectious, endocrine, and psychoneuroimmunologic factors. A genetic predisposition to SS is linked to the major histocompatibility complex genes, which are also known as human leukocyte antigens (HLAs). These genes mark the cell-surface antigens and defend the body against pathogens while recognizing and tolerating host tissues (self-antigens). In autoimmune disorders, self-tolerance is lost as immune cells begin to identify self-antigens (selected host tissue HLAs) as foreign and mount an immune response against them. The mechanism responsible for the loss of self-tolerance is unknown; however, it is associated with having specific HLA markers. For example, individuals with discoid lupus tend to have DR4 HLA markers, whereas HLA-27 is associated with the spinal disease ankylosing spondylitis.1,6

Similarly, immunologic research has shown an increased prevalence of HLAB8, DR3, and DRw52 genes in PSS.1,6,7 The presence of these HLA configurations on the cells produces B and T cell reactivity against host tissues, causing antibody production.

Lymphocytes in salivary glands of SS patients are predominantly T cells with fewer B cells, some macrophages, and mast cells. The majority of T cells carries the cluster of differentiation (CD) CD4s, the helper T cells. 1,2,5 The CD4s alert B cells to the presence of pathogens and assist in producing antibodies against foreign substances.

Viruses are considered cofactors in the development of SS. Viruses most often implicated include Epstein-Barr virus, cytomegalovirus, hepatitis C virus, and retroviruses.1,6-8

The role of hormones in autoimmune disease has been studied extensively.3,4,9,10 Hormones, such as estrogen and prolactins, have important roles in immune reactivity and in the upkeep of secretory glands.4,11 Estrogens stimulate immune reactivity, and androgens suppress immune reactivity. High levels of estrogen may stimulate T and B cell reactivity; this may make women immunologically stronger than men, but it may also make them more immunoreactive.9,10

* Clinical Features

The primary symptoms of SS initially manifest themselves through two organs, the mouth and the eyes. Symptom manifestation is similar regardless of age or gender.

Oral Manifestations

A dry mouth, termed xerostomia, is the dominant clinical oral symptom of SS. The principal glands of salivation are the parotid, submaxillary, and sublingual glands. The salivary glands produce 1,000 to 1,500 mr of saliva daily11 Saliva produces ptyalin, an enzyme that aids starch digestion and mucus for lubrication. Mucus is necessary for esophageal food passage. When inadequate saliva is produced, chewing, swallowing, and talking become difficult. Inadequate saliva production causes loss of taste and the development of oral bacterial infections.

Subjective oral manifestations include an increased liquid intake; chewing difficulty, particularly with dry foods; sensitivity to acids; and voice alteration.12,13 Patients report burning and tingling sensations in the mouth with frequent voice coarseness or hoarseness and a change in the sense of smell. Frequent upper respiratory infections are also reported. Oral manifestations reduce self-esteem, affect work productivity, and alter quality of life.14

Objective oral manifestations of SS include dry oral mucosa, the inability to produce saliva, and difficulty talking. Approximately 70% of patients exhibit dental caries and 85% manifest oral infections, particularly oral candidiasis.12,13 Patients also exhibit an inability to distinguish between normal, bitter, and sweet tastes. The tongue may be dry, red, and fissured, and oral ulcers may be present.12,13 The lips may be cracked and have a tendency to peel.

Ocular Manifestations

Dry eyes, termed xerophthalmia, is the dominant ocular feature of SS. The lacrimal gland produces lacrimal fluid at the rate of 1 ml per day.6,11 Tears are essential in moistening the eye surface, lubricating eyelids, and flushing foreign objects. Tears also contain the enzyme lysozyme, which kills certain bacteria. When the lacrimal gland fails to produce tears, eye movement is impaired.

Ocular manifestations of SS are associated with deficient mucin production.6 Normal production of mucins promote decreased viscosity, allowing the upper eyelid to smoothly slide over the ocular surface. When mucins are deficient, ocular movements become sluggish, debris is not removed, and eye irritation and infection appear.

Approximately 47% of SS patients report xerophthalmia.1,25 Subjective features of xerophthalmia, also known as keratoconjunctivitis sicca, include a sensation of a foreign body in the eye, particularly under the eyelids; decreased tearing; a sense of soreness and burning in the eye; difficulty tolerating dry air and contact lenses; and eye fatigue during reading and television watching.

Objective manifestations of xerophthalmia include eye redness, accumulation of thick strands at the inner canthus, itching, photophobia, blink abnormality, and decreased visual acuity.1,2,7 A failure to produce tears is determined by the Schirmer test. In untreated cases, corneal scarring, desiccation, ulcerations, and opacification may occur. The destruction of the corneal and bulbar conjunctival epithelium may also be present.1,7 Corneal alterations may be further evidenced by a positive response to a rose bengal test.

Systemic Manifestations

The incidence of systemic manifestations in PSS is provided in Table 1. Patients repeatedly report extraordinary fatigue1,2,5 and have also reported vaginal dryness, skin dryness, and dyspareunia. In about 50% of SS patients, symmetrically enlarged parotid glands may be present and accompanied by fever and tenderness.1,2,5

A well-documented association exists between SS and lymphoma development.1,5,7 The risk of lymphoma development is fortyfold higher in the SS population compared with the healthy population; the individual risk of developing lymphoma is 6% to 10% in the SS population.5 Clinical symptoms of emerging lymphoma include persistent enlargement of parotid glands, the spleen, and lymph nodes.1,2,5 The most common lymphoma in the SS population is low-grade B-cell lymphoma, including small lymphocytic lymphomas and mantle cell and follicular center lymphomas. Lymphoma development is one of the most important complications to rule out and monitor during SS management.

Similar to other autoimmune disorders, SS symptoms develop insidiously. The symptoms begin to appear between ages 35 and 45. The disorder's slow progress typically causes a 10-year gap between symptom onset and disease diagnosis. The definitive diagnosis usually occurs at or around menopause.1,2,5 may evolve from organ-specific SS (exocrine glands) to systemic SS (extraglandular). Xerophthalmia and xerostomia, however, remain the most common clinical manifestations in adults.

A comprehensive conceptual model that classifies SS manifestations is provided in Figure 1.2 This clinically useful model illustrates that the disorder can involve exocrine and nonexocrine tissues and that few organs are exempt from being affected by SS.

* Diagnosis

SS diagnosis criteria remain controversial. The European Community Study group proposes less stringent diagnostic criteria than some American investigators, and the European criteria is gaining increasing acceptance. 1,2,7 According to the European criteria, the presence of four of six items may establish a definitive diagnosis (see Table 2).

Laboratory Studies

The most common PSS laboratory abnormalities are shown in Table 3. Autoantibodies are found in peripheral blood and the salivary glands. About 90% of patients have a positive antinuclear antibodies test whereas rheumatoid factor is present in 60% of cases.1'2'5 Accelerated erythrocyte sedimentation rate and polycloncal hypergammaglobulinemia are present in 80% of SS patients! Mild normocytic anemia and leukopenia are not uncommon.

Sicca Syndrome Testing

In the primary care setting, three procedures are used to aid in diagnosing SS: Schirmer test, rose bengal staining of the cornea, and positive unstimulated whole salivary flow (USWSF). The Schirmer test measures the amount of tearing, rose bengal staining measures damaged conjunctival epithelium, and USWSF measures dry mouth.

Dry Eyes

Eye dryness is measured with the Schirmer test. The clinician places a strip of Whatman No. 41 filter under the conjunctival sac. After 5 minutes, the moistened portion of the paper is measured; the test is positive if less than 5 mm of the paper is wet.

Rose bengal staining is performed by installing 25 ml of rose bengal solution in the inferior fornix of the eye. The patient blinks twice to disperse the solution. Injured epithelial cells absorb the red stain. The result is evaluated by counting the number of red spots: one or more sparsely scattered, two or more densely scattered, or three or more confluent at the cornea, lateral, and nasal conjunctiva. If the sum of scores from these three sites is greater than 4 in at least one eye, the test is considered positive.1

Dry Mouth

Dry mouth assessment via the USWSF test is performed under basal conditions: the patient should not eat or drink after midnight prior to the test and should not engage in smoking, tooth brushing, or mouth rinsing at least 1 hour before the test.1,15 Saliva is collected in calibrated tubes for 15 minutes. If the amount of saliva is less than 1.5 ml, the test is considered positive.1 The salivary gland involvement may also be tested by scintigraphy, which measures the uptake of ^sup 99m^-Tc pertechnetate during the 60-minute period after the intravenous injection.1,5 If SS is present, the gland uptake and secretion of labeled saliva are delayed or absent.

Differential Diagnosis

Clinical features of SS are similar to that of several diseases and to anticholinergic effects of certain drugs (see Table 4).1,7 SS patients have bilateral asymmetric salivary gland enlargement as opposed to unilateral nontender enlargement, which is commonly seen in other diseases.

Differential diagnosis of SS is definitively rendered via minor salivary gland biopsy. The lip gland biopsy reveals focal lymphocytic infiltrates, mostly CD4 cells.

In Figure 2, the top figure shows normal salivary glandular architecture with normal epithelium. The lower figure, a biopsy from a SS patient, reveals marked lymphocytic infiltrate with the destruction of salivary glandular epithelium. These epithelial structures with lymphocytic infiltrate are also referred to as lymphoepithelial lesion.

Most CD4 cells bear memory helper/inducer phenotype and are considered specific to the salivary components of SS. 1,7 Approximately 50% of SS patients exhibit antibodies to Ro/SSA and La/SS-B that are uncommon in nonrheumatoid diseases (see Table 2). The lip gland biopsy in conjunction with an autoantibody profile is used to distinguish SS from other diseases. A rheumatologist consultation is valuable in confirming the diagnosis and when major organ involvement is suspected. After an SS diagnosis is determined, the patient should receive a thorough evaluation from an ophthalmologist and a dentist.

* Management and Treatment

Because SS is incurable, symptom management and prevention or limitation of organ involvement are the goals of treatment. Symptom management is accomplished through substitution of missing secretions.1,2,16 Sicca syndrome is treated with fluid replacement and artificial tears. Artificial tears, devoid of any adverse effects, can be used as often as needed and are available without a prescription. Although more viscous artificial tears have longer effects, patients usually prefer thinner drops that do not leave a residue. Some tear products have a duration of action of about 90 minutes.17 For most of these products, the usual dosage is I to 3 drops instilled 3 to 4 times a day as needed. Boric acid ointment, an antiseptic agent that prevents bacterial growth, may be applied to the eye. If corneal ulceration is present, eye-patching is recommended to provide rest to the cornea. In severe cases, punctal occlusion may be considered to conserve tear production.1

The treatment of xerostomia is challenging because agents that replicate natural saliva are not available. Although pilocarpine, a parasympathomimetic agent, has been reported to increase salivary and lacrimal flow, the results have been inconclusive.1 Oral manifestations are best controlled by avoiding dry, external environments and practices that decrease saliva, such as cigarette smoking and alcohol ingestion. The need for drugs, such as anticholinergics, antihypertensives, diuretics, and antidepressants, should be carefully evaluated because they can cause increased urinary output or mouth dryness. Most important, dental health should be maintained, including regular dental examinations.

Vaginal dryness, which is often reported by SS patients, should be promptly treated because it can cause painful urination, vaginal itching, difficult intercourse, and urinary tract infections. Vaginal estrogen creams can provide immediate relief from most local symptoms.

Systemic treatment of SS is based on involved systems. In recent years, antimalarial drugs have been used to treat SS with increasing acceptance. Patients with evidence of active inflammatory manifestations (elevated erythrocyte sedimentation rate and C-reactive protein) can benefit from prolonged hydroxychloroquine sulfate (Plaquenil Sulfate) treatment.18 Hydroxycholoroquine, also effective in treating rheumatoid arthritis and systemic lupus erythematosus, can be prescribed 200 mg a day (daily dose should not exceed 6.4 mg/kg) for 2 to 3 years. It reduces fatigue, arthralgias, myalgias, and impedes joint degeneration. The drug has a delayed onset of action; full therapeutic effect may take 3 to 6 months. Hydroxycholoroquine, however, has a toxic effect on the retina; initial and semiannual eye examinations are essential.

Musculoskeletal symptoms are treated with nonsteroidal anti-inflammatory drugs. Corticosteroids and other immunosuppressive drugs may be needed to treat renal or severe lung complications. Well-defined nutritional programs that avoid sugar, alcohol, caffeine, but include foods low in acid but rich in water and minerals, should be offered. Sugarless gums and mints may stimulate salivary flow. Humidifiers, both at home and work, are highly recommended.

* Sjogren's Syndrome in Practice

Sjogren's Syndrome is a disease that is often undetected. Although symptoms seriously disrupt patient quality of life, symptom vagueness usually prevents individuals from seeking immediate help. Consequently, by the time a diagnosis is made, significant organ involvement has occurred.

Sjogren's Syndrome patients should receive education on the goals of treatment and be able to monitor SS signs and symptoms. Clinicians can provide patients and their families with resources that enhance self-care (see Table 5).5 Sleep disturbances and fatigue may require ongoing lifestyle adjustments and family understanding and cooperation.14,19,20 SS support groups can provide reliable information, social support, and emotional support.

ACKNOWLEDGMENT

The author thanks Marilyn Frank-Stromborg, ANP, JD, EdD, FAAN, and Ron Leifheit. Appreciation is extended to Serhan Alkan, MD, for providing biopsy slides.

REFERENCES

1. Anaya IM, Talal N: Sjogren's syndrome and connective tissue diseases associated with other immunological disorders. In: Koopman WJ. Arthritis and allied conditions, 13th edition. Philadelphia Pa.: Williams & Wilkins, 1997;1561-80.

2. Manthorpe R, Asmussen K, Oxholm P: Primary Sjogren's syndrome: Diagnostic criteria, clinical features, and disease activity. J Rheumatol 1997;24(suppl 50);8-11.

3. Beeson PB: Age and sex associations of 40 autoimmune diseases. Am J Med 1994;96:457-462.

4. Sullivan DA: Sex hormones and Sjogren's syndrome. J Rheumatol 1997;24 (suppl 50):17-31.

5. Creamer P, Hochberg CM: Classification and diagnosis of Sjogren's syndrome. Wellesley, Mass.: UpToDate Inc. 1999;7:1 -11.

6. Fox RI, Maruyama T: Pathogenesis and treatment of Sjogren's syndrome. Curr Opin Rheumatol 1997;9(5):393-99.

7. Moutsopoulos HS: Sjogren's syndrome. In: Schumacker RH, Klipperl JH, Koopman WJ, eds. Primer on the rheumatic diseases, loth edition. Atlanta, Ga.: Arthritis Foundation, 1993;131-35.

8. Venables PJW, Rigby SP:Viruses in the etiopathogenesis of Sjogren's syndrome. J Rheumatol 1997;24(supp 50):3-5.

9. Lahita RG: Sex hormones and the immune system-part 1. Baillieres Clin Rheumatol 1990;4:1-12.

10. Grossman JC, Roselle GA, Mendenhall CL: Sex steroid regulation of autoimmunity. J Steroid Biochem Mol Biol 1991;40:649-59.

11. Guyton AC: Textbook of medical physiology. Philadelphia, Pa.: W.B. Saunders, 1991;534-712.

12. Soto-Rojas AE, Villa AF, Sifendo-Osornio J, et al.: Oral manifestations in patients with Sjogren's syndrome. J Rheumatol 1998;25:906-10.

13. Soto-Rojas AE, Villa AF, Sifendo-Osornio J, et al.: Oral candidiasis and Sjogren's syndrome. J Rheumatol 1998;25:911-15.

14. Hollister MC, Weintraub JA. The association of oral status with systemic health, quality of life, and economic productivity. J Dent Educ 1993;57:901-12.

15. Hay EM, Thomas E, Pal B, et al.: Weak association between subjectivesymptoms of and objective testing for dry eyes and dry mouth: Results form a population based study. Ann Rheum Dis 1998;24:20-24.

16. Plugfelder SC: Differential diagnosis of dry eye conditions. Adv Dent Res 1996;10:9-12.

17. Moutsopoulos HM: Sjogren's syndrome therapy: Future directions. J Rheumatol 1997;24(supp 50):33-34.

18. Hahn AN, Oestreich SJK, Barkin RL: Mosby's pharmacology in nursing. St. Louis, Mo.: Mosby, 1986;641-42.

19. Fox RI, Krubel S, Guarassi V: Treatment of primary Sjogren's syndrome with antimalarial drugs. Lupus 1996;5:31-36.

20. Tishler M, Barak Y, Paran M, et al.: Sleep disturbances, fibromyalgia and primary Sjogren's syndrome. Clin Exp Rheumatol 1997; 15:71-74.

Ayhan Aytekin Lash, RN, PhD, FAN

ABOUT THE AUTHOR

Ayhan Aytekin Lash, RN, PhD, FAAN, is associate professor, Northern Illinois University School of Nursing, Dekalb

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