US Pharm. 2007;32(3):72-81.

Sjögren's (SHOW-grins) syndrome is an autoimmune disease that attacks the exocrine glands (i.e., moisture-producing glands) of the body, specifically the lacrimal and salivary glands. It is classified among such diseases as rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis.

Sjögren's syndrome can affect any part of the body; however, patients typically present with two hallmark symptoms--feelings of dryness in the eyes (keratoconjunctivitis sicca) and in the mouth (xerostomia). Dryness can extend to other areas of the body such as the nose, skin, lungs, and vaginal tract. No two patients will present in the exact same way, which contributes to the difficulty in diagnosing this syndrome.

No cure has been found for Sjögren's syndrome; however, there are a number of prescription and nonprescription (OTC) medications/products on the market to help alleviate the symptoms of dryness. Pharmacists can have a dramatic impact on patients' quality of life. Providing pharmaceutical services (i.e., medication counseling, advising OTC product selection and nonpharmacologic treatment options) can help these patients live happier lives.

A number of studies have been conducted to determine the prevalence of Sjögren's syndrome, and among these studies, an estimated 0.04% to 4.8% prevalence has been cited. 1-3 It is believed to afflict approximately one to four million Americans, 90% of whom are women. The broadness of this prevalence statistic is due to the lengthy and sometimes difficult process of diagnosis. Typically, most individuals are older than 40 when affected by this syndrome. However, the condition can occur in all age groups. This syndrome is diagnosed in individuals of all races and ethnic backgrounds.

Etiology and Pathophysiology
Researchers are still unclear about the exact cause of Sjögren's syndrome. However, a number of genes have been identified that are thought to play a role in the development of this syndrome; these include various forms of the HLA-DRB , HLA-DQA, and HLA-DQB genotypes.4,5 Researchers have hypothesized that a combination of this genetic predisposition and environmental triggers (i.e., viral or bacterial infection) cause Sjögren's syndrome to develop.

Two different processes characterize the pathogenesis of Sjögren's syndrome. The first involves a T-cell mediated process that leads to direct cell destruction and B-cell activation, leading to the production of autoantibodies.5 Salivary and lacrimal glands are infiltrated by the T cells. This infiltration leads to the release of cytokines and the resultant inflammation and destruction. The B cells produce autoantibodies, SSA (anti-Ro) and SSB (anti-La), which are associated with Sjögren's syndrome.

So the hypothesis is as follows: a person has the genetic predisposition and is subsequently infected by a virus or bacterium. This infection then causes these dormant genes to be expressed and the immune system to attack. However, the genes steer the attack away from the invading organism toward the host.6 The glands, which are resistant to apoptosis--resistance to apoptosis is believed to be genetic--are lymphatically infiltrated; this inflammation then causes the destruction of the glands.6 A debate remains on whether this lymphatic infiltration causes complete destruction of the lacrimal and salivary glands or whether the production of saliva and tears is only diminished.

Clinical Presentation
The symptoms of Sjögren's syndrome are caused by the inflammation and destruction of the exocrine glands and other parts of the body. Some of the characteristic symptoms that patients present with include dry eye and dry mouth. Patients with keratoconjunctivitis complain of a dry, gritty feeling in the eyes. They may also describe "what feels like sand in the eye(s)." Symptoms associated with dry mouth can range from a dry, cracked tongue to difficulty talking, swallowing, or chewing dry food.7 Other common complaints include a dry, sore, or burning throat, a change in sense of taste or smell, dry cough, or hoarseness.4,6,7 An increase in dental decay and/or mouth sores is also observed in these patients due to a lack of saliva production and of the antibacterial substances that saliva naturally contains.

A wide variety of other symptoms are observed in patients with Sjögren's syndrome. These symptoms are nonspecific and can mimic those of other disease states (e.g., extreme fatigue, muscle pain, neuropathy, dry skin, stomach ulcers). A list of symptoms that patients might display can be found in Table 1. When the inflammation and dryness extend to other parts of the body, besides the eyes and mouth, it is termed extraglandular involvement.7 The areas of the body that can be affected include the skin, nose, liver, kidney, lungs, vascular system, genital area, nervous system, and digestive system. It is important to note that not every patient will display the same set of symptoms.

Definitively diagnosing Sjögren's syndrome can be a lengthy and difficult process. The time frame from the onset of symptoms to diagnosis is more than six years.7 There are a number of reasons for this prolonged timeframe. First and foremost, symptoms of Sjögren's syndrome are similar to those of other disease states, such as rheumatoid arthritis and lupus. Another reason is that Sjögren's syndrome encompasses many clinical specialties, such as rheumatology, dentistry, and ophthalmology, making the diagnosis difficult.

Historically, the diagnosis of Sjögren's syndrome has been made on the basis of a patient history and physical examination. Also, a number of laboratory tests (i.e., blood, dental, and ophthalmologic tests) have been used to aid in the diagnosis. A number of classifications systems have been developed to aid the diagnosis of Sjögren's syndrome.8,9 In 2002, the American-European Consensus Classification Criteria for Sjögren's syndrome was released ( Table 2).8 In the revised criteria, patients must present with four of the six criteria, as well as with an abnormal lip biopsy or positive serum antibodies, to be diagnosed as having primary Sjögren's syndrome. 8 Patients can also be diagnosed with Sjögren's syndrome if three of the four objective criteria (III, IV, V, or VI) are present.8 Secondary Sjögren's syndrome is diagnosed when the patient has an associated disease (e.g., another connective tissue disorder), the presence of criterion I or II, and any of criteria III, IV, or V.8 A diagnosis of Sjögren's syndrome should be excluded if patients have had past head and neck radiation treatment; if they have hepatitis C infection, AIDS, preexisting lymphoma, sarcoidosis, or graft versus host disease; or if they are maintained on anticholinergic medications.8

The consensus classification criteria begin by questioning the patient about his or her oral and ocular symptoms. Subjective data are collected about the use of tear substitutes, feelings of dryness in the eye and the mouth, swollen salivary glands, and the need for liquids to aid in swallowing food. Objective data are collected through the use of laboratory and ophthalmologic tests and examinations.

The blood tests performed are nonspecific and are used to diagnose many disease states. For instance, an antinuclear antibody (ANA), rheumatoid factor (RF), or erythrocyte sedimentation rate (ESR) laboratory test can be performed. Each of these laboratory tests indicates an inflammatory state and is not specific enough to make a definitive diagnosis. However, the results of these tests can aid in making a diagnosis. Sixty percent to 70% of patients with Sjögren's syndrome are RF positive and approximately 70% of patients are ANA positive.10 A more specific blood test is one that measures for the presence of SSA or SSB antibodies. SSA, known synonymously as anti-Ro, is a specific antinuclear antibody present in approximately 70% of patients with Sjögren's syndrome. SSB, known synonymously as anti-La, is also a specific antinuclear antibody and is present in about 40% of patients.1,2 The Consensus Classification Criteria rely only on the presence of the SSA and/or SSB antibodies in the serum to help in the diagnosis.

Ophthalmologic examinations help confirm the destruction of lacrimal glands and the reduction in tear production. Dyes used to observe abnormal cells on the surface of the eye include Rose Bengal and lissamine green.4 A score of greater than 4 is required for a positive test. A Schirmer test may also be performed to measure the amount of tear production. Healthy patients will produce more than 8 mm of tears over a five-minute period. Patients with Sjögren's syndrome will produce less than 5 mm of tears in this time frame. Patients must test positive for either of these two examinations.

Oral examinations help confirm the destruction of the salivary glands and the reduction in saliva production. Patients must test positive for one of the following three tests: unstimulated gland flow, parotid sialography, or salivary scintigraphy. Unstimulated gland flow tests measure the amount of saliva produced over a certain period of time. 4 In healthy patients, greater than 1.5 mL of saliva will be produced over a 15-minute period. Parotid sialography is an x-ray of the salivary duct system by means of the injection of a dye opaque to x-radiation. Salivary scintigraphy detects a radioactive material injected into the body.4 In a patient with Sjögren's syndrome, the salivary gland will take up little to no radioactive material. A lip biopsy is also used to confirm lymphocytic infiltration of the salivary glands. To make a definitive diagnosis, patients must have either a positive lip biopsy or a positive serum marker.

Extraglandular Involvement

Sjögren's syndrome can affect nearly any part of the body including the respiratory tract, ears, nose, kidneys, liver, gastrointestinal tract, nervous system, muscles and joints, heart, reproductive system, and immune system. There is no way to forecast which organs or areas of the body will be affected in a particular patient.

Areas of the respiratory tract that are involved include the nose, larynx and trachea, bronchial tubes, and lungs. Patients with lung involvement can develop atelectasis, an absence of gas from part or all of the lungs; due to build up of mucus in the bronchi and lung; tracheobronchitis, interstitial lung disease; hoarseness of the voice if the larynx is involved; pleurisy; or even pulmonary hypertension.

Patients with affected kidneys can develop interstitial nephritis. This can result in renal tubular acidosis, glomerulonephritis, nephrogenic diabetes insipidus, and, if the urinary bladder is involved, interstitial cystitis.

The entire length of the gastrointestinal tract can be involved as well. Symptoms of dryness begin in the mouth, followed by effects in the stomach and pancreas. Patients may have difficulty swallowing food and can experience gastric reflux and chronic atrophic gastritis that can cause dyspepsia.

Patients with liver involvement can develop primary biliary cirrhosis (PBC), which is immune mediated and destroys the small bile ducts. Patients with PBC will present with fatigue and itching. Autoimmune hepatitis is also common among these patients. 

The central, as well as the peripheral, nervous system can be affected in patients with Sjögren's syndrome. Involvement of the peripheral nervous system can lead to neuropathies in the legs, feet, hands, arms, and even the facial region. Carpal tunnel syndrome is common among these patients. The tissue around the median nerve in the forearm becomes inflamed and thus presses against the nerves. This pressure causes sensations of tingling, numbness, and muscle weakness.

Pericarditis can develop in patients who have heart involvement, in which the lining of the heart becomes inflamed. Involvement of the heart is more common in patients who have another connective tissue disorder or secondary Sjögren's syndrome.

The reproductive system, particularly the vaginal area, can also be involved, and complication with pregnancy can also occur. Lack of moisture production in the vaginal area can cause discomfort, painful sexual intercourse (i.e., dyspareunia), and a tendency toward infection. Congenital heart block, (i.e., dysfunction of rate and/or rhythm) can develop in babies born to women who are positive for the SSA or SSB antibodies. For this reason, it is important for women with Sjögren's syndrome to speak with their doctor prior to becoming pregnant to discuss these issues.

Complications Associated with Sjögren's Syndrome

Patients with Sjögren's syndrome are at an increased risk for the development of lymphoma. It is estimated that between 2% and 10% of patients will develop lymphoma. One study found that patients with Sjögren's syndrome have up to a 44-fold increased risk of developing lymphoma, compared with the general population.7

Treatment of Sjögren's Syndrome
Treatment of Sjögren's syndrome focuses on alleviating symptoms of dryness in the eyes and mouth as well as in extraglandular areas. Although there are only a few prescription medications available to treat these symptoms, there are a number of nonprescription medications available to patients to help alleviate symptoms (see Table 3).

Dry Eyes and Mouth: Available products for the treatment of dry eye, or keratoconjunctivitis sicca, are designed to replace or supplement the deficient tears and/or to minimize tear loss. One prescription medication, Lacrisert (hydroxypropylcellulose), is designed to decrease the evaporation of tears from the surface of the eye. The recommended dosage is one pellet inserted between the lower eyelid and the eye once or twice daily.11 The pellets slowly dissolve, forming a film over the surface of the eye. This film slows the evaporation of the natural tears or administered artificial tears. The most common adverse effects associated with Lacrisert include blurred vision, matting/stickiness of the eyelash, and ocular discomfort.11

Another product that was recently approved for clinical use is Restasis (cyclosporine ophthalmic emulsion). Restasis decreases inflammation in the lacrimal gland. Its intent is to reduce the amount of damage to the gland and preserve the tear producing function.12 The recommended dosage is one drop in both eyes twice daily. The most common adverse effects include a burning sensation with administration, red eye, epiphora (the overflow of tears due to imperfect drainage by the tear-conducting passages), a foreign body sensation (similar to having something in the eye), itching, and blurred vision.12

There are a vast number of OTC products that help moisturize the eye. Products range from artificial tears to ointments, some of which contain preservatives. Patients may develop sensitivity to or experience irritation from the preservatives utilized in some of these products. If this occurs, patients can either switch to another product with an alternative preservative or select a preservative-free preparation. Instillation technique is especially important if a preservative-free preparation is selected for use. Every precaution should be taken by the patient to avoid contamination/eye infection by direct contact with the eye dropper and the eye itself. The products on the market are virtually the same in formulation; however, they differ in viscosity characteristics. Ointments are used, preferably, at bedtime, because these product cause blurred vision due to their opacity. The choice of which product to use is based solely on patient preference, and the products can be used as needed. If the dryness becomes severe, or if the use of artificial tears becomes cumbersome, punctual occlusion surgery is the treatment of choice. Punctual occlusion surgery entails placing a silicone or collagen plug in the lacrimal puncta, through which tears normally drain. Closing off this drainage system allows the artificial tears to reside on the surface of the eye for a longer period of time. Patients should be informed that ocular agents might cause blurred and abnormal vision, cataracts, conjunctivitis, edema of the eyelids, and local irritation.

The goals of treating dry mouth are to increase salivary production, replace salivary secretions, and avoid complications.13 Two prescription medications are currently available to stimulate salivary production--Salagen and Evoxac. These products work in a similar fashion. Salagen (pilocarpine hydrochloride) is a cholinergic agent.14 It stimulates the action of acetylcholine at the muscarinic receptors in the salivary gland and thus stimulates salivary production in those glands that retain some residual function. It is commonly dosed at 5 to 10 mg orally three to four times a day. In a randomized, double-blind, controlled trial, patients receiving 5 mg three times a day reported improvement in dry mouth symptoms and had fewer adverse effects compared with patients taking 10 mg four times a day.15 The most common adverse effects associated with Salagen include sweating, rhinitis, and urinary frequency.15 Cholinergic agents can also cause other side effects such as excessive salivation, increased diaphoresis, headache, nausea, diarrhea, flushing, chills, and dizziness.

Evoxac (cevimeline hydrochloride), like pilocarpine, is a cholinergic agent with increased activity at the M1 and M3 receptors, which are prevalent in the salivary glands.16 In a randomized, double-blind, placebo-controlled trial conducted by Fife et al., patients were given either 30 or 60 mg of cevimeline orally three times a day for six weeks.17 Both medication regimens provided a significant difference (P <.01 and P <.05, respectively) in the subjective relief of xerostomia symptoms, compared with placebo. Patients tolerated 30 mg of cevimeline three times a day better than those given 60 mg of cevimeline three times a day.17 Gastrointestinal tract symptoms (i.e., nausea, dyspepsia, diarrhea, abdominal pain) accounted for the most frequently reported adverse effects in patients taking 60 mg three times a day.17

Another study, conducted by Petrone et al., demonstrated that 30 mg of cevimeline three times a day provided a statistically significant improvement in the objective measure--increased salivary flow rate (P <.01) and lessening of dry eye (P <.05)--compared with placebo.18 Improvement of the subjective symptom of dry mouth (P <.001 and P <.01) was statistically significant, compared with placebo and a regimen of 15 mg of cevimeline three times a day.18 The most common adverse effects reported by patients included headache, increased sweating, abdominal pain, and nausea.18

OTC products available for the relief of xerostomia merely replenish the lack of saliva. Salivart, a natural saliva substitute, can be used as needed. Moisturizing gels also help patients with dry mouth. Oral-Base Moisturizing Gel (hydrogenated starch hydrolysate, glyceryl polymethacrylate, xylitol, hydroxy­ ethylcellulose, beta-d-glucose, lactoperoxidase, lysozyme, lactoferrin, glucose oxidase, potassium thiocyanate, aloe vera) is such a product, and it is used as needed.

Interferon-alpha lozenges have also been studied to relieve the symptoms of dry mouth and dry eyes in patients with Sjögren's syndrome. In a small study involving 12 patients who received 150 IU three times a day for 24 weeks, interferon-alpha lozenges demonstrated a statistically significant improvement in unstimulated salivary flow rate (P <.05) and subjective improvement in ocular and oral dryness (P <.05 for both), compared with placebo.19 The use of interferon-alpha lozenges is not widespread. Additional studies need to be conducted to determine their efficacy in larger populations.

Extraglandular Involvement: Inflammation caused by extraglandular involvement can be treated with a number of different medications. Nonsteroidal anti-inflammatory drugs, COX-2 inhibitors, corticosteroids as well as disease-modifying anti-rheumatic drugs have been tried to help combat inflammation. Earlier studies have reported a positive effect, in terms of clinical and laboratory effects, with the use of hydroxychloroquine; however, subsequent studies have found marginal or no clinical benefit.20-22 Other anti-inflammatory agents, such as azathioprine, prednisolone, methotrexate, and D-penicillamine, have been used as well, but results are mixed.23-26 At best, these agents provide only a marginal clinical benefit, and the risks need to be considered when prescribing them.

The role of tumor necrosis factor (TNF)–alpha has not been fully evaluated in the pathogenesis of primary Sjögren's syndrome, but it is possible that it may have a key role. Medications that block the effects of TNF-alpha have been studied but have not shown benefit. A study conducted by Mariette et al.27 evaluated the efficacy of Remicade (infliximab) on 103 patients' perception of improvement in joint pain, fatigue, and dryness. Improvement was defined as a 30% improvement in symptoms on two of three visual analog scales between weeks 0 and 10. At week 10, 26.5% of patients receiving placebo and 27.8% of patients receiving infliximab showed improvement in two of three visual analog scales ( P = .89). The primary end point failed to reach significance, and thus the authors concluded that infliximab was not effective in patient perception of improvement in joint pain, fatigue, and dryness.

Enbrel (etanercept) has also shown no benefit in the treatment of Sjögren's syndrome. Sankar et al. 28 conducted a 12-week, randomized, double-blind, placebo-controlled trial of etanercept in 28 patients. The primary outcome was an improvement from baseline of at least 20% in at least two of the following three domains: subjective or objective measures of dry mouth (by visual analog scales or total stimulated salivary flow) or dry eyes (by visual analog scales, van Bijsterveld score, or Schirmer I test), immunoglobulin G level, or ESR. At week 12, five patients in the etanercept group and three patients in the placebo group showed improvement from baseline in the primary outcome; however, results were not statistically significant (P = .2).

Patient Education
Providing pharmaceutical care services to patients with Sjögren's syndrome can greatly impact their quality of life. These education services include a continuum of counseling on prescription and nonprescription medications, disease state, and ways that patients can manage the syndrome at home. There are a number of nonpharmacologic steps that patients can take to live more comfortably with Sjögren's syndrome. These "tips" can affect the dryness reported in the eyes, mouth, nose, skin, and vagina. It is important for patients to realize that pharmacists are available to help advise/counsel them.

Maintaining excellent oral hygiene is very important for patients with Sjögren's syndrome. Natural saliva contains antibacterial substances that help fight bacteria in the mouth. Since patients with Sjögren's syndrome lack saliva, they are at an increased risk of developing oral infections such as candidiasis. Visiting a dentist at least three times per year is important. Dry mouth can be combated through a number of approaches. Pharmacists should advise patients that chewing sugarless gum or sucking on sugarless candies could stimulate saliva production and decrease the feeling of xerostomia. Additionally, increasing fluid intake throughout the day by periodically ingesting small sips of water can also help.

Patients should be advised that dry eyes could be minimized by protecting one's eyes from drafts, winds, and breezes by wearing sunglasses when outdoors and by using a humidifier when indoors. Patients who work at a computer or do an extensive amount of reading during the day may benefit from consciously reminding themselves to blink, which will help moisten the eyes. Also, patients should be encouraged to quit smoking if they are smokers. In addition to many other problems associated with cigarette smoke, smoke can dry the eyes and the mouth, causing worsened symptoms. Women should also avoid wearing eye makeup. A stray piece of eye makeup, such as a clump of mascara, could find its way into the patient's eye and scrape the surface of the eye, causing damage.

Applying moisturizing products to affected areas can lessen the dryness in skin, nose, and vagina. Dry skin can be treated by applying moisturizing creams or ointments (e.g., Eucerin, Aquaphor, Nivea). Taking short showers or baths, five minutes or less, can also help. The temperature of the water should not be excessively hot, but tepid (3° to 5° above body temperature). After showering, it is important not to dry off the skin completely. Simply pat dry, leaving beads of water on the skin, and apply an emollient onto damp skin within three minutes after emerging from the shower. This traps moisture in the skin. The emollient should be reapplied three times during the day. Dr. Robert Martin, a dermatologist at the Arnett Clinic in Lafayette, Indiana, advocates his "Rules of Threes," which are applicable to treating patients with Sjögren's syndrome (see Table 4).29

Patients should be advised that saline nasal sprays could help dry noses. These can be used as needed by the patient. In addition, vaginal dryness can be treated with vaginal moisturizers, such as Vagisil Intimate Moisturizer or KY Long Lasting Intimate Moisturizer. These products can be used as needed. It is important to inform the patient that lubricants will not moisturize the vaginal tract but, instead, will rid the area of moisture. Thus, these products should not be recommended.

Summary and Conclusion
The most important concept to realize when selecting appropriate treatment for a patient with Sjögren's syndrome is that therapy must be adapted to the individual patient's needs and responses. Each patient will present with some similar symptoms but also with a unique set of symptoms and complaints. Pharmacists can have an active role in helping patients manage this syndrome. Providing excellent pharmaceutical care and continuity of care is the first step. Counseling and teaching patients about the syndrome as well as providing tips for improving patients' quality of life can have a dramatic impact.

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