Management of Sjögren’s Syndrome

INTRODUCTION

Sjögren’s syndrome (SS) is an autoimmune inflammatory disorder of exocrine glands. It particularly affects the lacrimal and salivary glands. Dry mouth and dry eyes are frequently the presenting symptoms. Extraglandular manifestations, for example, arthritis and polyneuropathy can also be present ( Table 12-1 ). In addition, many SS patients report functionally limiting chronic fatigue.

Table 12-1

Extraglandular Manifestations in Primary Sjögren’s Syndrome

Anatomic System	Findings	Percentage *
Constitutional symptoms	Fatigue Fever Lymphadenopathy	80% 5% 15%
Joints/muscles	Articular involvement Tendomyalgia Myositis	50% 40% 2%
Skin	Raynaud’s phenomenon Cutaneous vasculitis Skin involvement other than cutaneous vasculitis	40% 15% 5%
Endocrine	Autoimmune thyroiditis	10%
Respiratory tract	Pulmonary involvement Serositis	25% 2%
Gastrointestinal tract	Esophageal involvement Autoimmune hepatitis Acute pancreatitis	5% 10% 1%
Nervous system	Peripheral neuropathy CNS involvement	10% 2%
Urogenital tract	Renal involvement Bladder involvement	10% 15%
Hematology	Thrombocytopenia Lymphoproliferative disease	2% 5%

CNS, central nervous system.

* Percentages differ greatly between studies.

SS can be a primary idiopathic condition of unknown etiology (primary Sjögren’s syndrome, pSS). SS may also occur in the presence of another autoimmune disorder such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), scleroderma, or mixed connective tissue disease. In these cases, the condition is designated as secondary Sjögren’s syndrome (sSS). The estimated prevalence of SS in the general population is between 0.5% and 1%, which makes SS, after RA, the most common systemic autoimmune disease. In RA, the prevalence of SS is around 30%, and 20% of patients with SLE fulfill the criteria for sSS. SS is more frequent in women (female-to-male ratio, 9:1). Furthermore, SS is associated with organ-specific autoimmune diseases such as autoimmune thyroid disease, primary biliary cirrhosis, and autoimmune gastritis. This underscores the autoimmune nature of the disease. Like other rheumatologic conditions, SS exerts a major impact on patients’ quality of life. Apart from the symptoms mentioned earlier, patients may be restricted in their activities and their participation in society, resulting in reduced health-related quality of life and impaired socioeconomic status.

Because patients have concomitant oral, ocular, and systemic medical problems, the management of the patient with SS should ideally involve a multidisciplinary team of health care practitioners with good lines of communication between them. In a multidisciplinary team with a specialized rheumatologist, oral and maxillofacial surgeon, ophthalmologist, pathologist, hematologist, dentist and oral hygienist, SS patients can get the care they need. It is important that one physician, usually the rheumatologist, has overall responsibility for the care of the patient. The strategy followed at the University Medical Center Groningen, The Netherlands is given in Figure 12-1 .

Although there is as yet no curative or causal treatment for SS, various supportive and palliative treatment options are available, and targeted approaches (biologics) are in development or currently being tested in phase I or phase II trials. This chapter presents and discusses the management of both glandular and extraglandular manifestations of SS (including mucosa-associated lymphoid tissue [MALT] lymphoma), and discusses prospects focusing on better understanding of the progression and more effective treatment of SS.

CLASSIFICATION AND DIAGNOSIS OF SJÖGREN’S SYNDROME

Many classification criteria for SS have been suggested. Presently, the revised American-European classification criteria for SS, which were proposed in 2002, are the most widely accepted and validated criteria ( Table 12-2 ). These criteria combine subjective symptoms of dry eyes and dry mouth with objective signs of keratoconjunctivitis sicca and xerostomia.

Table 12-2

Revised International Classification Criteria and Revised Rules For Classification of Sjögren’s Syndrome

Ocular symptoms: a positive response to at least one of the following questions:
Have you had daily, persistent, troublesome dry eyes for more than 3 months?
Do you have a recurrent sensation of sand or gravel in the eyes?
Do you use tear substitutes more than three times a day?

Oral symptoms: a positive response to at least one of the following questions:
Have you had a daily feeling of dry mouth for more than 3 months?
Have you had recurrently or persistently swollen salivary glands as an adult?
Do you frequently drink liquids to aid in swallowing dry food?

Ocular signs –that is, objective evidence of ocular involvement defined as a positive result for at least one of the following two tests:
Schirmer’s I test, performed without anesthesia (≤5 mm in 5 minutes)
Rose Bengal score or other ocular dye score (≥4 according to Van Bijsterveld’s scoring system)

Histopathology: in minor salivary glands (obtained through normal-appearing mucosa) focal lymphocytic sialoadenitis, evaluated by an expert histopathologist, with a focus score ≥1, defined as a number of lymphocytic foci (which are adjacent to normal-appearing mucous acini and contain more than 50 lymphocytes) per 4 mm ²of glandular tissue

Salivary gland involvement: objective evidence of salivary gland involvement defined by a positive result for at least one of the following diagnostic tests:
Unstimulated whole salivary flow (≤ 1.5 mL in 15 minutes)
Parotid sialography showing delayed uptake, reduced concentration and/or delayed excretion of tracer
Salivary scintigraphy showing delayed uptake, reduced concentration and/or delayed excretion of tracer

Autoantibodies: presence in the serum of the following autoantibodies:
Antibodies to Ro(SSA) or La(SSB) antigens, or both
Revised rules for classification

For Primary SS

In patients without any potentially associated disease, primary SS may be defined as follows:
The presence of any 4 of the 6 items is indicative of primary SS, as long as either item IV (Histopathology) or VI (Serology) is positive
The presence of any 3 of the 4 objective criteria items (that is, items III, IV, VI)
The classification tree procedure represents a valid alternative method for classification, although it should be more properly used in clinical-epidemiological survey

For Secondary SS

In patients with a potentially associated disease (for instance, another well defined connective tissue disease), the presence of item I or item II plus any 2 from among items III, IV, and V may be considered as indicative of secondary SS

Exclusion criteria:

Past head and neck radiation treatment
Hepatitis C infection
Acquired immunodeficienty disease (AIDS)
Pre-existing lymphoma
Sarcoidosis
Graft versus host disease
Use of anticholinergic drugs (since a time shorter than the 4-fold half life of the drug)

The subjective ocular and oral symptoms are obtained by history taking. Two tests are used to objectify reduced tear production. In the Schirmer’s test a piece of filter paper is placed laterally on the lower eyelid, which results in wetting due to tear production. If less than 5 mm of paper is wetted after 5 minutes, the test result is positive ( Fig. 12-2 ). In the Rose Bengal test, dye stains devitalized areas of the cornea and conjunctiva which can be scored using a slit lamp. A Rose Bengal score ≥4 according to the Van Bijsterveld scoring system is considered abnormal. Instead of Rose Bengal stain, lissamin green can be used, which shows comparable results but is less painful. An additional test that is not accepted as a diagnostic technique for SS but provides a global assessment of the function of the tear film is the tear break-up time test. This test is performed by measuring break-up time and tear osmolarity after instillation of fluorescein. An interval of less than 10 seconds is considered abnormal.

To confirm the diagnosis of SS histopathologically, usually a biopsy from a labial salivary gland is taken. This should show focal lymphocytic sialoadenitis with a focus score of ≥ 1 (a focus is defined as an accumulation of 50 or more lymphocytes per 4 mm ²). Recently it has been shown that parotid biopsy might serve as a proper alternative for labial biopsy in the diagnosis of SS ( Fig. 12-3 ). Its morbidity is less than that of labial salivary gland biopsy. In addition, MALT/non-Hodgkin’s lymphoma (NHL) pathology is easier to detect, because the labial glands are less commonly affected by MALT/NHL than the parotid glands. Moreover, in contrast to a labial biopsy, parotid biopsies can be used to monitor various treatment methodologies since the same gland can be biopsied more than once.

Currently, three diagnostic tests can be used to objectify salivary gland involvement, other than histopathology. The most commonly applied objective salivary gland diagnostic test is measuring the flow rate of unstimulated, whole saliva. Unstimulated whole saliva is a very useful indicator of salivary function and oral wetness. The patient is asked to expectorate once, then to collect all saliva into a graduated container. After 15 minutes, the volume of saliva is measured. These sialometric tests should be routinely performed regardless of whether the patient does or does not complain of oral disease, allowing later comparisons if the patient develops subjective oral dryness or presents with other symptoms or clinical signs of salivary dysfunction. For research purposes, or if more specific functional information is required for a particular gland, individual gland collection techniques can be used. Collection of glandular saliva is not difficult but requires specialized equipment (e.g., a Lashley cup) and takes more time to perform. Other tests to evaluate salivary gland involvement are sialography and salivary gland scintigraphy. Sialography is the radiographic imaging of the salivary duct system through retrograde infusion of an oil- or water-based contrast fluid ( Fig. 12-4 ). Sialography has a low morbidity and is well accepted by patients. The main sialographic characteristic of SS is a diffuse collection of contrast fluid at the terminal acini of the ductal tree, termed sialectasia. Sialography has a high diagnostic accuracy. Finally, patients with SS demonstrate decreased uptake and release of technetium Tc 99m pertechnetate on scintigraphy. At present, efforts are made to improve the diagnostic accuracy of scintigraphy.

Approximately 80% of patients with SS display antinuclear antibodies (ANAs); about 40% to 60% of them have antibodies against anti-SS-A/Ro. This autoantibody is considered to be the most specific serologic marker for SS, even though it is also found in 25% to 35% of patients with SLE or other autoimmune connective tissue disorders, and in about 5% of healthy subjects. Besides the presence of antibodies to Ro/SSA or La/SSB other laboratory blood studies are helpful in patients suspected of SS. The presence of nonspecific markers of autoimmunity, such as ANAs, rheumatoid factors, elevated immunoglobulins (particularly immunoglobulin G [IgG]), and elevated erythrocyte sedimentation rate are important contributors to the definitive diagnosis of SS.

Diagnostic Work-Up

There is a large diversity in the initial clinical manifestation in patients with SS, and these manifestations are not always present at the same time. Therefore, physicians and dentists sometimes treat each symptom individually, unaware of an underlying systemic disease. In addition, patients with SS were frequently misdiagnosed in the past because their symptoms were considered minor or vague or mimicked those of other diseases. Consequently, delayed diagnosis in SS patients is frequent.

An extensive delay in diagnosis can affect the patient’s well-being if for no other reason than because of the anxiety that accompanies an undiagnosed illness. Early, accurate diagnosis of SS (see Fig. 12-1 ) can help prevent or ensure adequate treatment of many of the complications associated with the disease, and may contribute to prompt recognition and treatment of serious systemic complications of SS. Management strategies are provided in Tables 12-3 and 12-4 .

Table 12-3

Management Strategies for Ocular Manifestations of Sjögren’s Syndrome

Strategy	Approach	Description
Preventive measures	Avoidance of exacerbating factors	Avoiding low humidity atmospheres such as air-conditioned stores, centrally heated houses, airplanes, windy locations Avoiding irritants such as dust and cigarette smoke Avoiding activities that provoke tear film instability (e.g., prolonged reading or computer use)
	Avoidance of drugs that may worsen sicca symptoms	Caution when using antidepressants, antihistamines, anticholinergics, antihypertensives, neuroleptics
	Treatment of other medical conditions that result in dry eyes	Eyelid abnormalites (e.g., ectropion), meibomean gland disease
Symptomatic treatment	Tear substitution therapy	Low viscous eye drops (Schirmer ≤ 5 mm/5min) and high mucus secretions in the cul du sac High viscous eye drops (Schirmer >5 mm/5 min) and low mucus secretions in the cul du sac Opthalmic gels and ointments (at night)
	Blepharitis	Daily eyelid rubs with warm water and diluted baby shampoo Topical antibiotics if indicated
	Add mucolytic agents for mucus secretions/sticky eyes/mucus filaments in eye examination	N-acetylcysteine 5% eye drops (2-3 times daily)
	Tear retention measures	Use of air moisturizers Moisture glasses Lacrimal punctum occlusion (moderate to severe dry eyes)
	Topical immunomodulatory agents	Topical non-preserved corticosteroids (e.g., dexamethason 0.1% eyedrops 2 times daily; taper dose or discontinue drops based on clinical findings and eye pressure)
Tear stimulation	Systemic parasympathomimetic secretogogues	Pilocarpine (5–7.5 mg, 3–4 times/day) Cevimeline (30 mg, three times/day)
Treating underlying disorder	Systemic anti-inflammatory or immune-modulating therapies to treat the autoimmune exocrinopathy of Sjögren’s syndrome	Anti-CD20 (rituximab)

Table 12-4

Management Strategies for Oral Manifestations of Sjögren’s Syndrome

Strategy	Approach	Description
Preventive measures	Regular dental visits and radiographs	Usually every 3–4 months Intraoral photographs every 6–18 months in dentate subjects who frequently develop new and recurrent caries lesions
	Optimal oral hygiene	Guidance of team of oral health professionals (clinical instructions, written instructions)
	Topical fluorides and remineralizing solutions	Fluoride mouth rinse (0.1%, weekly) Neutral sodium fluoride gel (depending on the level of oral hygiene and residual level of salivary flow: from once a week to every second day; the gel is preferably applied with a custom made tray)
	Diet modifications	Noncardiogenic diet Minimize chronic use of alcohol and caffeine Use of nonfermentable dietary sweeteners (xylitol, sorbitol, aspartame or saccharine), whenever possible
	Avoidance of drugs that may worsen sicca symptoms	Caution when using antidepressants, antihistamines, anticholinergics, antihypertensives, neuroleptics
	Treatment of other medical conditions that result in xerostomia	For example, endocrine disorders, metabolic diseases, viral infections
	Avoidance of exacerbating factors	Low humidity atmospheres such as air-conditioned stores, centrally heated houses, airplanes, windy locations Avoiding irritants such as dust and cigarette smoke
Local salivary stimulation	Masticatory stimulatory techniques	Sugar-free gums and mints
Local salivary stimulation	Combined gustatory and masticatory stimulatory	Lozenges, mints, candies Water, with or without a slice of lemon
Systemic salivary stimulation	Parasympathomimetic secretogogues	Pilocarpine (5-7.5 mg, three to four times/day) Cevimeline (30 mg, three times/day)
Symptomatic treatment	Relief of oral dryness (nonresponders on systemic salivary stimulation)	Use of air moisturizers Frequent sips of water Use of oral rinses, gels, and mouthwashes Use of saliva substitutes Increased humidification
	Oral candidiasis	Topical antifungal drugs: Nystatin oral suspension (100,000 U/mL: 400,000-600,000 units four to five times/day) Clotrimazole cream (1%, two times/day) Ketoconazole cream (2%, one to two times/day) Amphotericin B lozenge (10 mg, 4 times/day) Systemic antifungal drugs: Fluconazole tablets (200 mg on day 1, then 100 mg/day for 7–14 days) Itraconazole tablets (200 mg/day for 1–2 weeks) Ketoconazole (200–400 mg/day for 7–14 days) Dentures should be soaked in chlorhexine (2%) at night
	Angular cheilitis	Nystatin cream or ointment (100,000 U/g, four to five times/day) Clotrimazole cream (1%, two times/day) Miconazole cream (2%, one to two times/day)
Treating underlying disorder	Systemic anti-inflammatory or immune modulating therapies to treat the autoimmune exocrinopathy of Sjögren’s syndrome	Anti-CD20 (rituximab)

GLANDULAR MANIFESTATIONS: EXOCRINE DYSFUNCTION

Patients with SS have symptoms related to a diminished function of the exocrine glands, in particular, the lacrimal and salivary glands, although SS may also affect the glands in the upper respiratory tract, skin, and vagina.

Ocular Manifestations

Dryness of the eyes is the most prominent ocular manifestation of SS, and one fourth of SS patients report eye dryness as the first complaint. It results in sensations of itching, burning, dryness, soreness and grittiness. Other ocular symptoms that may arise from ocular dryness are photosensitivity or photophobia, erythema, eye fatigue, decreased visual acuity, discharge in the eyes, and the sensation of a film across the visual field. These symptoms may be exacerbated by low humidity environments, such as air-conditioned or centrally heated buildings or dry climates, or exposure to irritants such as dust and cigarette smoke.

Physical examination reveals chronic irritation and destruction of both corneal and bulbar conjunctival epithelium (keratoconjunctivitis sicca) due to insufficient tear secretion. Accumulation of thick rope-like secretions along the inner canthus may be the result of decreased tear film and an abnormal mucus component. At times, desiccation causes small superficial erosions of the corneal epithelium; in severe cases, slitlamp examination reveals filamentary keratitis, marked by mucus filaments that adhere to damaged areas of the corneal surface. Progressive keratitis can result in loss of vision. Blepharitis, which is the inflammation and infection of the meibomian glands of the eyelid, is a common problem in patients with dry eye, and conjunctivitis as a result of secondary infection with Staphylococcus aureus may also occur. Enlargement of the lacrimal glands is rare and should prompt a work-up for MALT. Ocular complications that may arise from SS include corneal ulceration, vascularization, opacification, and rarely perforation.

Oral Manifestations

Autoimmune destruction of the salivary glands results in oral symptoms that accrue primarily as a result of salivary gland hypofunction and are due to the long-term effects of a decrease in oral fluids on mucosal hydration and oral function.

Loss of salivary gland function is already prominent in early onset SS. The submandibular and sublingual salivary glands, which are the most active glands under resting condition, are among the first glands to be involved in SS, whereas the parotid gland, the most active gland when stimulated, appears to be the last salivary gland to be affected. Patients with SS with long disease duration are characterized by severely reduced secretions of the parotid, submandibular, and sublingual glands. This results in a typical symptom pattern: in early SS, the sensation of dry mouth (xerostomia) is often present predominantly at rest and during the night. Over time, as the disease develops, the dryness is also present during the day and finally it gives rise to difficulties in chewing and swallowing food.

Reduction in saliva production ( Fig. 12-5 ) may also lead to difficulties in speaking and be related to burning sensations in the mouth. A diminished ability to taste foods and having problems with smell or a mucosa that is sensitive to spicy or coarse foods, are frequently mentioned symptoms. This limits the patient’s enjoyment of meals and may compromise his or her nutrition. Most patients carry bottles of water or other fluids with them at all times to aid speaking and swallowing and for their overall oral comfort, and many patients report about the decrease in their quality of life since the advent of oral dryness.

Patients with advanced salivary gland hypofunction as a result of SS have obvious signs of mucosal dryness ( Fig. 12-6 ). The lips often appear cracked, peeling and atrophic. They may even appear furrowed or pebbled, like dry soil in an arid climate. The buccal mucosa may be pale and corrugated in appearance, and the tongue may be smooth and reddened, with loss of some of the dorsal papillae or may have a fissured appearance. There is often a marked increase in erosion and dental caries. The decay may be progressive, even in the presence of vigilant oral hygiene. With diminished salivary output, there is a tendency for greater accumulations of food debris at the so-called smooth surfaces and cervical regions, especially where recession has occurred ( Fig. 12-7 ). Patients with a dry mouth as a result of SS also experience an increase in oral infections, particularly mucosal candidiasis ( Fig. 12-8 ). The patient may present with red, erythematous patches on the oral mucosa, for example, beneath dentures, or it may appear as white, curd-like mucocutaneous lesions on any surface (thrush), or the patient may complain of a burning sensation of the tongue or other intraoral soft tissues. Fungal lesions of the corners of the mouth (angular cheilitis) may also occur more frequently in patients with SS (see Fig. 12-6C ).

Enlargement of the Salivary Glands

Enlargement of the salivary glands is seen frequently, in particular of the parotid and submandibular glands. Enlargement is generally due to the presence of an autoimmune inflammatory process in these glands. In the parotid glands this inflammation process can be seen unilaterally but is most often present on both sides. Furthermore, salivary gland enlargement can be chronic or episodic. Stasis of saliva, which may occur due to distortion and narrowing of ducts, can result in secondary infection in cystic areas, leading to further swelling of the glands. Thirdly, glandular enlargement may be due to lymphoma development within, in most cases, the parotid gland. Most often these are MALT lymphomas but other NHLs may also develop.

Normally, palpation of the salivary glands is painless. Saliva can be “milked” from each major gland by compressing the glands, with bimanual palpation, and by pushing the fluid contained within them to the gland orifices. The expressed saliva should be clear, watery, and copious.

Diffuse swollen glands that are painful on palpation are indicative of infection or acute inflammation. Viscous saliva or scant secretions suggest chronically reduced function. A cloudy exudate may be a sign of bacterial infection. In these cases, there may be mucoid accretions and clumped epithelial cells, which account for the cloudy appearance of saliva. The exudate should be cultured if it does not appear clear, particularly in the case of an enlarged gland. Occasionally, a purulent secretion is observed, which makes the diagnosis of bacterial sialadenitis obvious.

Because the incidence of NHL lymphomas, including MALT lymphomas of the salivary glands, is about 40 times increased in SS patients, physicians should be alert for painless nodular masses, in particular in the parotid gland. Especially SS patients with risk factors for progression to lymphoma, namely those with persistent salivary gland enlargement, low levels of C4, and monoclonal cryoglobulinemia, should be monitored closely.

Additional Dry Surfaces

Dryness is not restricted to the eyes and mouth but also occurs at mucosal surfaces in the upper and lower airways, frequently leading to dryness of the nose, throat, and trachea resulting in persistent hoarseness and a chronic, nonproductive cough. Patients may also experience dermal dryness, and in female SS patients, desiccation of the vagina and vulva may result in dyspareunia and pruritus.

MANAGEMENT OF GLANDULAR MANIFESTATIONS

In general, adequate explanation of the condition, including use of patient information brochures, will help in empowering patients to participate in their own care. Furthermore, various preventive measures and symptomatic treatments can be given in SS. It is possible that a single treatment modality may help; it is also possible that a combination of them may be necessary.

Management of Ocular Manifestations

Dry eye disease might be a sight threatening problem in SS patients, and many patients suffer from eye complaints all day. Treatment of ocular manifestations in these patients is difficult and often does not lead to satisfactory results.

The most widely used therapy for dry eye disease is tear substitution by topical artificial tears, to increase humidity at the ocular surface and to improve lubrication. However, the use of artificial tears has obvious limitations. Natural tears have a complex composition of water, salts, hydrocarbons, proteins, and lipids, which artificial tears cannot completely substitute. In addition, the integrity of the three-layered lipid, aqueous, and mucin structure, which is vital to the effective functioning of the tear film, cannot be reproduced by these artificial components. The majority of tear substitutions is not preservative free. Because many preservatives contain chemical substances that may damage the tear film stability and the corneal epithelium, use of preservative-free artificial tears is strongly recommended. Patients are advised not to use these tear substitutes as frequently as they want, because the substitutes dilute the small amount of natural tears that are still present, and because of the potential harmful effects of preservatives as mentioned earlier (see Table 12-3 ).

Preventive Measures

First of all, factors that can cause exacerbation of ocular symptoms should be avoided whenever possible. This includes windy or low-humidity environments and exposure to irritants such as dust and cigarette smoke. Patients can be instructed how to increase humidity in their own surroundings by installing room humidifiers. Activities that provoke tear film instability, such as prolonged reading or computer use should also be avoided or modified (e.g., taking regular breaks from reading or computer use, and lowering the computer monitor in a way that the gaze is directed downward).

This case describes a 35-year-old female with a 3-year history of pSS. The diagnosis had initially been confirmed by the absence of saliva secretion (unstimulated and stimulated), an abnormal sialography result, low Schirmer test values, an abnormal lissamin green test, anti-SS-A and anti-SS-B antibodies, and a positive labial biopsy. During follow-up she developed progressive, bilateral swelling of the parotid glands ( Fig. 12-9 ) and the submandibular lymph nodes. Other signs were buccal petechiae and bilateral lower limb purpura. Laboratory examination revealed low complement C4 levels (0.05 g/L, normal range 0.1–0.4 g/L), a worsening of her pre-existent hypergammaglobulinemia (IgG 19.6 g/L, normal range 7.0–16.0 g/L) and an elevated rheumatoid factor (153 KIU/L, normal <11 KIU/L). These results raised the suspicion that she had developed a malignant lymphoma. Magnetic resonance imaging showed pronounced enlargement of the parotid glands with multiple cystic lesions. In addition, there were several enlarged cervical lymph nodes. To confirm the diagnosis, an excision biopsy of an enlarged lymph node and a parotid gland biopsy were performed.