Robert I. Fox, M.D., Ph.D., Rheumatology, Gene Izuno, M.D., Dermatology, John Willems, M.D., Gynecology, Raymond Stewart, D.D.S., Oral Medicine, Mitchell H. Friedlaender, M.D., Ophthalmology
Scripps Clinic and Research Foundation, 10666 North Torrey Pines Road, La Jolla, CA 92037
Sjögren's syndrome is a chronic disorder of unknown cause characterized by a particular form of dry mouth and dry eyes. This loss of tears and saliva may result in characteristic changes in the eyes (called aqueous tear deficiency or keratoconjunctivitis sicca) and in the mouth with deterioration of the teeth, increased oral infection, difficulty in swallowing, and painful mouth.
There are many different causes for dry eyes and dry mouth. When they occur as a result of an "autoimmune" process, the condition is called Sjögren's syndrome, which usually occurs in middle-aged women and has prevalence in about 1 in 500 persons.
Patients may also have inflammation of the joints (arthritis), muscles (myositis), nerves (neuropathy), thyroid (thyroiditis), kidneys (nephritis), or other areas of the body. Also, patients may have severe fatigue and disruption of their sleep pattern. Also, the blood of Sjögren's patients may contain antibodies directed against normal cellular substances such as nuclear antigens and immunoglobulins. Therefore, this disease is termed an "autoimmune" disorder to denote the apparent reaction of the immune system against the patient's own tissues. The trigger for this process remains unknown but may be a virus.
Diagnosis is based on clinical examination of the eyes and mouth. Specific blood tests and a biopsy of the minor salivary gland (taken from the inside of the lower lip) help confirm the diagnosis. Sjögren's syndrome is not fatal. However, attention must be paid to preventing the complications due to dry mouth (such as rampant caries) and to dry eyes (corneal erosions and infections), as well as treatment of other organ systems involved as a consequence of the disease.
The risk for passing this disease on to family members is extremely low. There is a slightly increased incidence of autoimmune diseases in siblings and children. Pregnant women should notify their obstetricians and pediatricians, since maternal autoantibodies may cross the placenta and cause problems for the infant.
II. THE SYMPTOMS OF SJÖGREN'S SYNDROME
Dry eyes and dry mouth result from lack of secretion by the lacrimal (tear) glands and salivary (parotid, sublingual and submandibular) glands. In the eye, this condition is called "aqueous tear deficiency" since the "water" secretion into the tears is diminished.
Historically, Mikulicz first reported these symptoms in 1898 so this condition was called "Mikulicz syndrome." It is more commonly named for Henrik Sjögren (pronounced sho-gren), a Swedish ophthalmologist, who reported the association of severe dry eyes [keratoconjunctivitis sicca (KCS)], dry mouth and rheumatoid arthritis in 1933. Later, it was recognized that patients might have dry eyes and dry mouth but no rheumatoid arthritis. Thus, the distinction was made as primary Sjögren's syndrome (SS) (1° SS with no associated rheumatoid arthritis) and secondary Sjögren's syndrome (2° SS, where no associated rheumatoid arthritis is present). 1° SS and 2° SS both occur predominantly in middle-aged women, although they may be present in either sex at any age.
There is no "standard" criteria for diagnosis of Sjögren's syndrome at different medical centers. Although the diagnostic tests for dry eyes are well standardized, the definition for the "oral" component of Sjögren's syndrome remains controversial. This has resulted in confusion in the medical literature and in clinical practice. We favor a stringent criteria for diagnosis of Sjögren's syndrome in order to identify a group of patients with objective evidence of keratoconjunctivitis sicca and a systemic autoimmune process. Other groups use less stringent criteria for diagnosis and label many different conditions associated with dryness as Sjögren's syndrome. Therefore, we sometimes disagree with a previous diagnosis of Sjögren's syndrome. This discrepancy reflects an honest difference of opinion among rheumatologists who use different criteria for diagnosis.
Eye symptoms in Sjögren's patients usually include dryness and a "gritty" sensation in the eyes, often associated with pain or sensitivity to light (photophobia). The white part of the eye (conjunctiva) may be red and previous eye infections may have occurred. These symptoms result from a decreased production of tears that normally lubricate and protect the eye.
To determine the amount of tear production, a strip of sterile filter paper is inserted under the lower eyelid and the amount of wetting in 5 minutes is recorded; normal values usually exceed 8 mm per 5 minutes, but even normal levels may decrease with age. This is called the Schirmer I tear test. If this measurement is low, the Schirmer II test is performed by stimulating the "nasolacrimal gland reflex by inserting a Q-tip into the nose.
To assess the effects of diminished tears on the eye, a small drop of fluorescein dye or rose bengal dye are carefully put inside the lower eyelid. Areas that are dry briefly retain this dye. The region between the eyelids, the exposure region, is particularly susceptible to drying since this area is only partially covered by the eyelids and is subject to more rapid evaporation. When the dryness has been prolonged and severe, corneal erosions can develop.
Dry mouth results from decreased salivary gland function. Under normal conditions, a low level of saliva is produced continuously to lubricate the mouth and is called "basal" or "resting" salivary secretion. When stimulation by taste, chewing, or smell occurs, the level of salivary flow is increased and is called "stimulated" secretion. The level of salivary flow is controlled by the brain and the signals are carried to the glands by nerves called "cholinergic" and "sympathetic" fibers. Thus, it is possible to have a normal number of salivary gland cells but to still have a dry mouth because the nerves are not giving the "on" signal to the glands. This is one reason why certain drugs (especially antidepressant medication as well as over-the-counter decongestant remedies) cause dry mouth and dry eyes; this side effect is due to their unwanted ability to inhibit the "cholinergic" nerve fibers that innervate the glands.
In Sjögren's syndrome, it is likely that the mouth and eye dryness results both from destruction of the salivary glands and from interruption of nerve signals that control secretion. In the early stages of Sjögren's syndrome, patients experience maximum dryness between meals and during the night due to a diminished "basal" secretion, but are still able to eat dry food without difficulty. As the "dryness" syndrome progresses, more fluid is required to eat and swallow.
The diminished salivary flow also predisposes to periodontal disease and oral yeast infections such as Candida. This is because saliva contains important substances that combat these infections. Most saliva is normally made by the parotid, sublingual and submandibular glands, but minor salivary glands located inside the lips also contribute. In some patients, the infiltration of lymphocytes into the parotid or submandibular glands causes pain and swelling. The saliva made in the parotid glands enters the mouth by a small opening (called Stensen's duct) adjacent to the upper molars on each side of the cheek. To accurately measure parotid flow rate, a plastic suction cup is placed over the opening of the duct that leads from the gland into the mouth.
These measurements allow us to determine whether the gland can respond to stimulation (i.e., that the secretory response apparatus is intact), and whether there is infection in the gland since pus may exude from this duct.
There are many causes of decreased flow of saliva. To determine the extent of salivary gland destruction associated with oral dryness, a biopsy may be taken from the lower lip. This biopsy is important since it shows how many (if any) salivary glands remain and reveals the type of inflammatory infiltrate present.
Although Sjögren's syndrome characteristically affects the eyes and the mouth, other parts of the body may also be affected. Joint and muscle pain are frequently present. In some cases, this is due to rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) or SLE-like diseases. These diagnoses are confirmed by blood tests and x-rays of the joint. However, in some cases, the muscle and joint pain is due to Sjögren's.
Fatigue is another common symptom. It is important to rule out hypothyroidism (which may develop in up to 20% of Sjögren's syndrome patients), anemia (due to decreased production of blood cells as well as blood loss from taking medicines such as aspirin, Advil or Naproxen for the joint pains), and poor sleeping patterns (especially due to frequent trips to the bathroom at night because of large oral fluid intake during the day). Decrease in memory and concentration sometimes occurs and may be to the release of inflammatory substances by the immune system. They can also occur due to disrupted sleep pattern. Skin rashes, lung inflammation, swollen lymph nodes, and other symptoms also occur.
III. WHAT CAUSES SJÖGREN'S SYNDROME
Salivary glands that produce saliva exist in "grape-like" clusters. There are no or few lymphocytes in the normal salivary gland but are present in Sjogren's syndrome. Lymphocytes are part of the immune system that normally protect us from infection and tumors. When they appear to attack our own tissues (as in Sjögren's syndrome, systemic lupus, or in rheumatoid arthritis), the term "autoimmunity" is used. Lymphocytes originate in the bone marrow.
Two types of lymphocytes, termed "T cells" and "B cells" are responsible for mediating immune reactions. The T cells migrate from the bone marrow to the thymus (thus the term T cell) where they mature and then exit into their peripheral circulation. B cells migrate to particular regions in the lymph nodes where they mature; in birds, where this process was first studied, the site of maturation is the Bursa of Fabricius (thus the term, B cell). B cells make antibodies, while T cells regulate this production. "T-helper" cells promote antibody formation and "T-suppressor" cells inhibit the B cells.
Other T cells can directly kill viral-infected and cancer-transformed cells (the so-called T-cytotoxic cells). The entire lymphoid system is precisely regulated, largely by messenger molecules that instruct cells to "turn on" or "turn off." Autoimmunity, the excessive reaction against one's own tissues, then results from a failure of the normal regulation of T cells and B cells. This may be due either to an excessive production of helper signals or a failure to respond to suppressor signals. As a consequence, lymphocytes infiltrate the tissues and attack normal cellular structures.
The initial trigger that sets off the autoimmune events remains unknown. Circumstantial evidence suggests that a virus is involved. One possible candidate is the Epstein-Barr virus (EBV), which causes infectious mononucleosis, a condition characterized by swollen salivary glands, joint aches and fatigue. Virtually all adults have been infected with EBV by age 20 years. After the initial infection, this virus normally resides in the salivary glands for life but causes no problems. We and others have speculated that this virus (or a closely-related virus) may trigger an autoimmune response in genetically susceptible individuals.
It needs to be emphasized that there is no direct proof that EBV plays a significant role in Sjögren's syndrome. This is simply one hypothesis and experiments are currently in progress to determine its potential role. Also, Sjögren's syndrome is different from the "chronic fatigue syndrome" or the "chronic EBV syndrome." Patients with Sjögren's syndrome have characteristic abnormalities in the blood tests and salivary gland biopsies that are absent in other syndromes.
It is thought that an as yet unknown infectious agent damages the salivary gland and attracts the "immune" lymphocytes into the salivary gland. These lymphocytes release specific autoantibodies such as rheumatoid factor (RF) and antinuclear antibodies; antibodies are directed against proteins termed Sjögren's-associated antigens A and B (or SS-A and SS-B). These antibodies can enter the bloodstream and are measured in the blood tests that we obtain to confirm the diagnosis of Sjögren's syndrome. Additional T cells enter the gland and the damage is perpetuated. Under normal circumstances, a class of cells called "suppressor cells" turn off the inflammatory process. The continued destruction of the gland represents the abnormal balance of excessive action of T-helper cells and deficient action of T-suppressor cells.
There has been a great deal of research to determine hereditary factors associated with Sjögren's syndrome. To summarize these complicated studies, hereditary factors are important. Particular genes (such as human leukocyte antigen or HLA genes) are inherited in the same manner from parents as are genes for hair color or eye color; that is, one gene from each parent. The HLA genes are important in controlling the immune response and many current research studies are trying to determine exactly how they perform this task.
A specific gene named HLA-DR3 is found in high frequency in Caucasian patients with primary Sjögren's syndrome. In different ethnic backgrounds, different HLA genes are associated with Sjögren's. In addition to HLA, at least four other genes are involved. Although the relative frequency of Sjögren's or lupus is slightly increased in family members of Sjögren's syndrome patients, the specific risk that children or siblings will get these diseases remains very low (<10%). In addition to genetic factors, environmental factors also play a role. It has been proposed that viral infection represents the "other factor," and that Sjögren's syndrome disease results when a genetically susceptible individual (possessing HLA-DR3) is exposed to a certain virus or viruses.
IV. OTHER CAUSES OF DRY EYES AND DRY MOUTH
The production of tears and saliva involves a complicated series of steps. A baseline level of salivation and tear production occurs automatically (just as we breathe and our intestines have motility) without conscious thought about these functions. Thus, the nerves that control these functions are termed the "autonomic" (or "automatic") nervous system. However, additional factors may increase or decrease the signals in tear flow and saliva flow.
As Pavlov demonstrated about 100 years ago, dogs can be taught to increase salivation in response to a variety of sounds. Humans start to salivate at the thought or smell of food. Thus, the cognitive areas of the brain can send signals to glands through a series of nerves. Certain drugs can act on the brain to decrease tear and saliva flow and leads to increase symptoms of dryness. One example is tricyclic antidepressants (Elavil or Pamelor) or muscle relaxing agents (such as Flexeril) that influence the metabolism of certain specific brain cells as well as salivary and lacrimal glands.
A different class of medications called monoamine oxidase (known as MAO) inhibitors also give severe dryness. Thus, the patient needs to be aware that many drugs, including anti-seizure medications, blood pressure medications, muscle relaxants, and heart medications, lead to increased dryness by affecting different target molecules within the body.
The tear film contains several different components in addition to the "water" part of the tears. Of importance, substances called lipids are made by glands in the eye including the meibomian glands in the eyelids. This lipid stabilizes the tear film and helps retard evaporation. When these lipid-producing glands become inflamed, the corneal surface of the eye becomes inflamed, leading to "blepharitis." The loss of lipid production (that retards the evaporation of the aqueous tears) will further exacerbate the dry eye symptoms and the appearance of the keratoconjunctivitis sicca.
A. Increased Dryness is a Side Effect of Other Disease
Several disease processes other than Sjögren's influence these brain centers for "autonomic" control of tears and saliva. For example, patients with multiple sclerosis and diabetes may have dryness of the eyes and mouth as a result of the disease process within the brain that also may affect other sensory and motor functions.
In addition to problems with the neural activation of the glands, other medical conditions can cause the glands to be dry or to become enlarged (Table 2). The goal of the physical examination and laboratory studies is to determine the precise cause for the dryness and swelling.
Of particular importance, some patients have a poorly understood group of symptoms called fibrositis or fibromyalgia. These patients have fatigue, memory loss, aching muscles and, occasionally, depression. They very frequently have dryness of the eyes and mouth. Since minor salivary gland biopsies of these patients have the glands with an intact appearance, we deduce that the cause of dryness must involve the generation of signals for the gland at the level of the central nervous system (brain) or in the peripheral nerves that carry these signals to the glands. These symptoms may be very disabling, but it is important to distinguish them from Sjögren's syndrome (an autoimmune process that destroys the gland) since the therapeutic approach is different.
V. APPROACHES TO TREATMENT
At the present time, no therapies are available to "cure" the underlying causes of Sjögren's syndrome. Therefore, therapies are directed at improving symptoms, preventing the complications (such as dental caries, oral candida, or corneal damage) and preventing disease progression. In patients with autoimmune attack on the glands (i.e., Sjögren's syndrome), there may also be autoimmune attack on the joints (arthritis), muscles (myositis), thyroid (thyroiditis), lung (pneumonitis), kidney (nephritis), or other tissues that require specific treatment. Also, there is a slightly increased risk of developing lymphoma (a tumor of the lymph nodes), so careful attention is paid to persistent swelling of these structures. Because of the complexity of decisions regarding the evaluation and treatment of extraglandular features of Sjögren's syndrome, this outline will only deal with the glandular (lacrimal/salivary) problems that are frequently encountered).
A. The Dry Mouth
Clinical management of the dry mouth is a very difficult problem. In addition to chronic dryness, the patients have troublesome intraoral soft tissue problems that include rampant dental caries and difficulty with dentures due to dryness. Painful mouth lesions can result from Candida (yeast) infections of the lips (angular cheilitis) that are more frequent in dry mouth patients.
The mouth frequently exhibits macular erythema (redness) on the hard palate and other areas of the oral mucosa. These lesions result from a chronic erythematous form of candidiasis. Before any treatment program is started, it is important to identify contributing factors such as mouth breathing (due to congested nose), heavy smoking, stress, depression, and drugs that have anticholinergic side effects. The most frequently implicated drugs are the phenothiazines, tricyclic antidepressants, antispasmodics, anti-Parkinsonian, and decongestant medications (described in more detail below). Home remedies, some herbal remedies (including Chinese herbs) and nonprescription medications may possess anticholinergic side effects even though the patients may not recognize these agents as "drugs."
Dental prophylaxis by their dentists is supplemented by frequent use of dental floss, toothbrush or "Waterpik" device. Several toothpastes and mouth rinses have been developed for the patient with dry mouth. For example, Biotene, "Dental Care," and Retardent toothpastes are designed for the dry mouth patient. These toothpastes lack detergents (such as lauryl sulfate) that are frequently present in many commercial toothpastes and that can irritate dry mucosal membranes. Biotene contains an enzyme important in preventing oral bacterial infections and gingivitis. This enzyme supplement is also present in an oral gel (Oral Balance) that is used to help provide salivary flow at night.
"Dental Care" toothpaste contains sodium bicarbonate as a cleaning agent, while Retardent toothpaste uses a chlorine dioxide-based agent to decrease harmful mouth bacteria. These oral products do not contain alcohol as their liquid preservative (such as found in Listerine), which can be drying and irritating and do not result in staining of tooth enamel that can accompany the use of Peridex. Sugarless chewing gum and sugarless lemon drops are helpful in some cases. Use dental floss where possible. Special tooth brushes are often helpful in cleaning between the teeth. Use only a small amount of toothpaste and start on the biting surfaces, then work down to the gums.
A variety of saliva substitutes are available. These differ in their flavoring agents and preservatives.
MouthCote contains a substance called "mucins," which are glycoproteins that help lubricate the mouth and thus last a little longer than "water-based" lubricants. Salivart spray has the theoretical advantage of containing no preservatives since these agents may be responsible for topical irritation in some patients. After administration of these sprays, parotid flow rates are increased for 7-8 minutes in Sjögren's patients. However, the patients' sense of "dry mouth" may be decreased for up to several hours.
Treatment with a 0.4% stannous fluoride has been suggested to enhance dental remineralization of damaged tooth surfaces. Neutral fluoride preparations are often better tolerated than acidic fluoride preparations that are often prescribed by dentists. In patients with severe dental demineralization, special dental "trays" are made for direct application of the fluoride.
Recent studies have reported increased salivary flow rates after administration of certain drugs such as pilocarpine or neostigmine as either a mouthwash or as a systemic medication. A commercial preparation of pilocarpine (Salagen) has recently been approved by the Food and Drug Administration (FDA) for dryness of the mouth in patients with prior radiation therapy; however, it is also useful in some patients with dry eyes and mouth due to Sjögren's. Patients with asthma or irregular heart beat should not take pilocarpine since it may provoke a flare of the lung or heart symptoms.
Another approach to dryness is to help break up the thick, sticky secretions. Agents that contain iodides include 10% saturated solution of potassium iodide (SSKI) or organidin (both tablets and liquid). Other agents have properties similar to cough syrups (guanephesin) such as Humabid. Bromhexine, a cough syrup available in Europe, is currently under study in the United States (U.S.). It is further discussed below. Varying degrees of success have been noted with these treatments. Our experience and that reported at the National Institutes of Health indicates that medications may help some patients with relatively early or mild dry mouth (xerostomia) but not patients with severe xerostomia.
Research at the University of California in San Francisco found that many of the symptoms of painful mouth and burning tongue were due to a chronic Candida (yeast) infection and could be improved by treatment with Nystatin or chlortrimazole tablets. These tablets (also called troches or pastilles) are sucked like a "life-saver" (once or twice a day) and suppress yeast in the mouth that secrete toxins and cause a painful mouth. The clinical improvement may not be apparent for at least 3-4 weeks, so be patient. Treatment of this problem is particularly difficult in the patient with dentures, since the denture must be concurrently treated with the mucosa.
Perhaps the most effective treatment for the mouth is the use of Nystatin vaginal suppositories slowly dissolved in the mouth with sips of water twice daily for about 1 month. Although the vaginal suppositories have a bitter taste, other oral forms of antifungal therapy contain a high level of sugar to improve taste and contribute to dental decay. Chlortrimazole vaginal tablets are also available and may be used in the same manner.
The dentures must be carefully cleaned with a toothbrush before soaking overnight in benzalkonium chloride (for example, a 1/200 dilution of surgical scrub solution [Zephiran]). Nystatin powder should be applied to the fitting surfaces of the dentures before reinserting.
B. The Dry Eyes
The treatment of dry eyes is not only symptomatic but also designed to prevent infection or scarring of the cornea. Patients with Sjögren's syndrome generally suffer from a deficiency in the "water" component of tears and are referred to as "aqueous tear deficient." However, the tear film also contains lipids and mucins that help maintain the stability of the tear film. If these glands become inflamed (a condition called blepharitis, described above), then the residual aqueous tear film will not spread evenly or will evaporate too quickly. Thus, the status of the lipid-producing glands in the eyelids (called meibomian glands) must be considered and treated in order to obtain maximal efficient use of the residual aqueous tears (or artificial tears).
The administration of artificial tears (designed to replace the diminished aqueous or "water" component of tears in Sjögren's patients) gives considerable relief to most patients, but disabling symptoms may persist in some patients. The choice of artificial tears in an individual patient is based on several variables. First, does the eye drop feel comfortable immediately upon instillation into the eye? In some cases, burning may be due to the preservative, and you may wish to try an artificial tear with a different preservative.
Several types of artificial tears are preservative-free. In patients who require the frequent use of artificial tears, it has been suggested that "preserved" tears not be used more than four times per day to prevent the problems associated with "preservative buildup." In this situation, the use of a "preserved tear" can be alternated with a "preservative-free" tear. It is important to remember that all artificial tears are not the same and that the patient may have to "educate" the local pharmacist who may substitute if sometimes he does not have the requested artificial tear in stock. We ask patients to try several different preparations sequentially in order to identify those that seem most tolerable.
The second point in evaluating an artificial tear preparation is "Do the drops last long enough?" If the artificial tears are beneficial but the symptoms return relatively soon (i.e., in 1-2 hours), then an artificial tear that is thicker or more viscous might be tried. If the tear preparations still do not last long enough, closing the tear drainage ducts (punctal occlusion) should be considered. The "puncta" are small openings at the inner corners of the eyelids. Under normal conditions, the tears use these "drains" to exit the eye. Thus, narrowing these puncta (on a temporary basis by inserting small plugs or on a permanent basis by sealing them with an electric cautery probe on an outpatient basis) will mean that artificial tears will remain for a longer period of time in the eye.
Third, what is the relative expense and convenience of the artificial tear? Unpreserved artificial tears are packaged in very small quantities, so their cost is relatively high. Some companies provide artificial tears to severe dry eye patients at "wholesale" cost. It does not hurt to ask your ophthalmologist if he/she can help you get artificial tears at a lower cost.
Fourth, some patients may benefit from Lacriserts. These are slow-release artificial tears that dissolve slowly and provide a protective tear film. However, some patients may note increased ocular irritation after inserting these pellets or excessive blurring, leading them to discontinue this medication.
Fifth, visual problems may wax and wane, particularly in association with the seasons when dry winds are prevalent. When patients can identify exacerbating problems, increased frequency of artificial tear application should be started before symptoms develop in the hope of preventing objective eye findings. The use of humidifiers at night, wraparound sunglasses, and even goggles (sold at ski shops) are often helpful. Sudden worsening of ocular symptoms should always suggest possible ocular infection. In patients with associated diseases such as rheumatoid arthritis, other causes of eye pain such as "scleral" lesions or vasculitic lesions also must be considered.
Sixth, do the artificial tears that previously worked currently seem inadequate? Failure to achieve adequate results with an artificial tear may be due to several causes. As noted above, the change in environment (i.e., Santa Ana wind conditions or being in a low humidity site such as an airplane or a department store) or medications (such as cold remedies) may cause a previously effective treatment regimen to be inadequate. Also, patients may progress from mild eye dryness or more severe dryness if the Sjögren's syndrome leads to more destruction of lacrimal glands.
Finally, other causes for persistent or increased eye symptoms must be considered. Corneal abrasions (a scratch on the surface of the eye is more common dry eye patients) or infection of the eye (often associated with a new type of pus-like discharge) may cause sudden worsening and must be promptly treated. Also, irritation of the glands in the eyelid may occur and is called "blepharitis." This cause should be suspected when swelling and redness of the eyelid occur. This may be due to a low-grade infection or sometimes due to irritative effects of preservatives in artificial tears or ointments. One part of the treatment for blepharitis is to keep the eyelids clean using "baby shampoo" or a special product called "eyelid scrub." In some patients with blepharitis, infection of the meibomian glands (in the eyelids) may require treatment with a low dose of antibiotic (such as tetracycline or doxycycline) for several weeks.
In addition to artificial tears during the day, lubricating ointments at night also play an important role in the treatment of dry eyes. Since ointments usually cause significant blurring of vision they are generally used at bedtime. Sometimes the blurring persists in the morning and can be minimized by using only about 1/8-inch of the ointment at bedtime. It is a common mistake to use too much lubricant at bedtime. In some cases, it is useful first to put in the artificial tears at bedtime; then "seal the moisture in" with the application of the ointment. There are several different brands of ocular ointment. As with artificial tears, they differ in their composition and preservatives. Thus, patients may tolerate some brands better than others.
A European study suggested that bromhexine (Bisolvon), a synthetic alkaloid derivative originally used as a mucolytic agent in cough remedies, may have slight beneficial effects in increasing lacrimal and salivary gland function. Doses of at least 48 mg/day were required since no benefit was reported at lower doses. This medication is not commercially available in the U.S. but is available in Mexico (sold as Bisolvon) and in Europe. Multicenter trials are in progress to determine whether the benefits will be significant enough to justify the expense and the large number of tablets per day.
In theory, soft contact lenses might help spread the tear film over the eye or prevent evaporation of tears. Some types of contact lenses absorb tear fluid as a way to maintain their rigidity and thus further diminish the amount of tears available to protect the eye. Also, great care must be taken to avoid infections and prevent damage to the cornea in dry eye patients who wear contact lenses. Rarely, a partial tarsorrhaphy (sewing the lateral portion of the eyelids together) may be required.
C. Nasal Dryness, Sinusitis, and Upper Airway Dryness
Many Sjögren's patients complain of nasal dryness and have symptoms of sinusitis with postnasal drip. In our experience, Sjögren's patients do not get a higher frequency of sinusitis infections than other individuals. However, they tend to last longer and have a higher chance of persisting longer with "postnasal" drip and cough, or developing into a bronchitis or pneumonia. These complications occur because of decreased secretion of glands lining the nasopharynx, leading to crusting of mucous secretions that block the airways and predispose to infection. Our initial approach is to provide increased moisture to this region by use of normal saline sprays (Ocean) and humidifiers at night.
Also, "lavaging" the sinuses (i.e., rinsing them out with a mild solution of salt water) after loosening the secretions with a humidifier is often very useful in breaking the cycle of repeated sinus and upper respiratory tract infections. "Ocean" spray is simply a brand name for a solution of salt water that helps restore humidity to the nose. It is simple to make your own salt water spray by adding one teaspoon salt to one quart of deionized water and boiling to fully dissolve the salt. The Ocean spray container can then be refilled with homemade salt water.
There are many different types of cool mist humidifiers that vary in size and cost. We recommend the small portable units (choose one that is silent and easy to clean/refill), and not the large humidifier units that are built into the house's furnace/air conditioning systems. The large room units may become contaminated with yeast or fungus that can subsequently lead to "allergic"-type reactions. This problem has not been encountered with the small portable units where the water is changed daily. In areas where the water is "hard" (i.e., contains large amounts of calcium and other salts), "distilled" water (similar to that used for irons) may be less irritating than water from the tap.
In patients with persistent or recurrent sinus blockage, it is important to keep the nose open since breathing through the mouth is a frequent cause of increased dry mouth and the problems described above. In addition to the Ocean spray, it may be beneficial to learn to "lavage" the sinuses to remove the dry, crusted secretions. This is easily performed by the patient using an irrigation syringe (similar to the syringe used for basting a turkey) or a Waterpik (set for the lowest pressure delivery level). In patients with persistent sinus symptoms, it is also useful to obtain a "nasal smear" to determine if allergic factors (indicated by presence of eosinophils on the smear) are playing a factor. Topical nasal sprays (such as Beconase Nasal AQ, Nasalide, or Flonase) may be helpful in these patients, especially after lavaging.
In the setting of sinusitis, it is always important to notice if the color of secretions change from clear to dark green; the latter situation may indicate the occurrence of bacterial infection and necessitate treatment with antibiotics. The diagnosis of sinusitis is confirmed by sinus x-ray with air-fluid levels and purulent sinus drainage. When symptoms of sinus infection are persistent despite the above treatment measures, the possibility of an "abscess" within the sinus must be considered and this may require surgical drainage.
In order to determine if the sinus infection requires this treatment, A CAT scan of the sinuses is performed. The radiologist can perform a "limited" CAT scan at a much lower cost than a full CAT scan. If an abscess is detected, it may be necessary for an ENT specialist to establish sinus drainage, obtain definitive cultures and treat with a specific antibiotic.
D. Skin Dryness
Dry skin and lips are common complaints in Sjögren's syndrome. Topical treatments with creams and lotions are often helpful. Creams are distinguished from lotions by being "greasier" than lotions, which often contain oil/water mixtures. Creams and ointments are preferred since they better "seal" in necessary moisture. In general, we suggest applying the creams after a shower or bath while the skin is still moist. Alternatively, the cream can be applied to dry skin directly after moistening with a damp cloth. Cosmetics such as lipstick can be applied 5-10 minutes later.
Cracking at the angles of the cheek (cheilitis) is often due to Candida infection and will not effectively heal until a topical cream (such as Spectazole or Loprox) is applied. For oral yeast (white patches inside cheeks) oral chlortrimazole troches (such as Nystatin Troches or Mycelex Pastilles) are very helpful. Unfortunately, both of these preparations contain a certain amount of sugar that can further exacerbate dental problems. The vaginal suppository (Nystatin vaginal tablets or Gynelotrimen) does not contain any sugar but has a slightly bitter taste. The oral troches or vaginal suppositories (that are used orally and sucked) must be used for at least 4-6 weeks for the oral yeast infection to be obliterated and the normal oral lining to be regenerated.
E. Gynecologic Issues
Vaginal dryness often leads to painful intercourse (dyspareunia). It is important to be reassured that this does not occur in all Sjögren's patients, even those with severe mouth and eye dryness. A gynecologic exam is useful to rule out other causes of painful intercourse and other causes of vaginal dryness. When it does occur as part of Sjögren's syndrome, the spouse needs to be reassured that this is a "physiological" problem and not related to a failure of sexual arousal. Sterile lubricants such as KY jelly or Surgilube are helpful. The Sjögren's patient currently has many more options regarding safe and effective vaginal lubrication than every before. Lubricants such as Maxilube and Astroglide have slightly different characteristics when compared with KY jelly or Surgilube and yet share the common characteristics of being water-soluble and nonirritating.
This also holds true for the new non-hormonal vaginal moisturizer Replens which may be used unassociated with intercourse. For those patients who do not like the gel-type lubricants, there is now available Lubrin vaginal inserts. Added to this, a new once-a-week vaginal lubricant called Vagikote is currently in clinical trials. Finding the right preparation for a specific individual is often a matter of trial and error inasmuch as satisfaction with each lubricant is a matter of personal preference. The patient needs to be frank with her physician regarding her satisfaction or dissatisfaction with a particular preparation.
The external use of preparations containing petrolatum or oils which "seal in" moisture, such as vaseline or cocoa butter, may lead to maceration of the vaginal lining and are to be avoided.
Vaginal dryness in perimenopausal or postmenopausal women is often related to vaginal atrophy because of declining estrogen levels and therefore responds to vaginal estrogen creams. Cortisone creams are not beneficial in this situation. If vaginal yeast infection occurs, prompt treatment with clotrimazole cream or suppositories (Gynelotrimin) is effective and safe. On the external vulvar surface, dryness may be treated with lubricating creams as you would other skin surfaces (see section on skin dryness). Several patients have reported considerable satisfaction with the use of a thin film of vitamin E oil used on the vulva once or twice a day.
An issue of concern to female Sjögren's patients has been whether or not estrogen replacement therapy at the time of menopause is harmful to their condition. With regards to estrogen replacement in general, the clinical evidence is now fully convincing that blocking osteoporosis and reducing cardiovascular mortality while improving quality of life by eliminating hot flashes and hormone-related vaginal dryness, makes properly monitored estrogen replacement therapy an overwhelmingly attractive management strategy. Earlier investigators were concerned that estrogen might have a negative influence on Sjögren's based on animal studies. At Scripps Clinic, we have not seen any deterioration of Sjögren's syndrome related to either estrogen replacement therapy or low estrogen forms of oral contraceptives. Because of this, we encourage adequate estrogen replacement for the properly screened postmenopausal Sjögren's patient.
Many women with Sjögren's syndrome are interested in the risks of pregnancy and risks to the baby. Obstetrical authorities report slightly higher rates of recurrent fetal death and congenital heart block in those pregnancies complicated by maternal autoimmune disease. In rare patients, fetal loss has been associated with presence of the antibodies called "antiphospholipid antibodies," "lupus anticoagulant" and anticardiolipin antibodies. Congenital heart block is an abnormality of the rate or rhythm of the fetal or infant heart. Certain autoantibodies, such as an antibody called "anti-SS-A," have been associated with congenital heart block in the newborn. These autoantibodies may be present in patients with systemic lupus erythematosus and with Sjögren's syndrome, as well as in patients with no apparent disease.
However, it is important to reassure patients planning families that the vast majority of patients with Sjögren's syndrome have babies with no congenital abnormalities. Thus, we encourage family planning to be conducted without this being a major consideration. Nevertheless, it is important for patients anticipating pregnancy (or those with multiple prior miscarriages) to have screening blood tests and that their pregnancies require supervision by obstetricians experienced in handling patients with autoimmune diseases. A team approach combining both rheumatology and obstetrics can be used to optimize the outcome for both mother and baby.
F. Myalgias and Arthralgias
Physicians frequently use terms like arthralgia and arthritis. The former term means that the joint aches and the latter term means "inflammation" as indicated by the presence of heat, redness and swelling. In a similar sense, myalgia refers to aching of the muscle and myositis to actual muscle inflammation. Finally, neuralgia refers to "nerve pain" while neuritis or neuropathy refers to inflammation of the nerve.
The distinction between arthralgias and arthritis can often be made on clinical examination. However, more sensitive tests including x-rays or bone scans may be required. In the case of muscles, blood tests and, occasionally, electrical stimulation tests [called electromyography (EMG) and nerve conduction velocity] are useful.
In some patients, inflammation of the nerves may produce symptoms of pain. The nerves may be affected at many different sites. If inflammation of the brain is suspected, procedures such as an EEG (brain wave study) or MRI (magnetic resonance imaging) may be required. In our experience, brain inflammation is uncommon but has been reported in higher frequency at another medical center. There may be inflammation of peripheral nerves (those that have exited from the spinal cord). The involvement of the nerves can cause weakness or numbness. The EMG and nerve conduction study may be required for diagnosis in this situation. Also, it is important to remember that many other common problems result in nerve, muscle or joint pain.
For example, a pinched nerve at the level of the spine may cause numbness and weakness in an arm or leg. A torn cartilage in the knee or a degenerated disc in the back may lend to joint pain or muscle spasms. These common problems are not due to Sjögren's syndrome. Too often, patients and their physicians may not look for "the obvious" causes of symptoms and simply blame the problem on Sjögren's syndrome. This delays the institution of the correct therapy for the problem.
Fatigue is probably the most common complaint in patients with Sjögren's syndrome. Fatigue may have many causes, including those related directly and indirectly to the Sjögren's syndrome. Two types of fatigue should be considered. The first type is late morning or early afternoon fatigue. In this case, the patient arises with adequate energy but simply "runs out of gas." This type of fatigue suggests an inflammatory or metabolic process. Patients describe this type of fatigue as "flu-like" symptoms, and it results from an active immune system liberating specific hormones of inflammation called interleukins. To help determine whether fatigue is due to active inflammation, blood tests called "sedimentation rate" or "C-reactive protein" are ordered by your physician, since these tests are usually elevated by the same interleukins that cause fatigue.
A second type of fatigue is "morning fatigue," where the patient arises in the morning and does not feel that he/she has obtained an adequate night's sleep. This is also quite common in Sjögren's syndrome and may exist in addition to "inflammatory" fatigue.
For example, patients may have inadequate sleep due to joint or muscle pain. Also, Sjögren's patients often drink a great deal of liquid during the day because of dry mouth and throat. Then at night, the patient may be awakened three or four times to urinate. This disrupts the sleep pattern and leads to morning fatigue. When this is the case, it is best to treat the symptoms directly and better sleep should follow. For example, humidifiers and oral lubricants (i.e., saliva substitutes) at night might be beneficial. Nonetheless, there may be periods when one doesn't sleep well, and it is important not to allow certain negative sleep habits to become ingrained. All persons, especially those with a tendency to poor sleep or daytime fatigue should adhere to the following general suggestions for good sleep:
• 1. Maintain a regular and consistent wake-up time. Do not oversleep or spend excessive amounts of time in bed.
• 2. If unable to sleep, it is better to get up and do something else that is quiet, restful, and enjoyable, such as reading, knitting, or doing a puzzle. Do not lay in bed and try too hard to sleep.
• 3. A steady daily amount of exercise probably deepens sleep.
• 4. Stress reduction techniques such as meditation, biofeedback, or progressive relaxation are encouraged.
• 5. Caffeine should be avoided after lunch, and alcohol should be avoided after dinner. In some people, even one cup of coffee or one alcoholic beverage is enough to disturb sleep.
• 6. The bedroom should be quiet, dark, and comfortable. During the daytime, exposure to sunlight for even one hour at a regular time can strengthen circadian rhythms and improve the quality of sleep. Especially in San Diego, get outside for your lunch hour or take a walk after dinner.
Sometimes following good sleep habits is not enough to improve the sense of daytime fatigue and poor sleep. If this is the case, a specific evaluation for sleep disorders can be done. Certain people may have a higher risk of physiologic sleep disorders. In our experience, patients with Sjögren's frequently have sleep disturbance due to nocturnal myoclonus (a spontaneous muscle cramping) that occurs at night and disrupts the amount of time spent in "restful" sleep.
Some patients respond to quinine and vitamin E at bedtime. Other patients require a medication such as Klonopin (clonazepam), a member of a drug family called benzodiazepams (that includes Valium and Ativan). These drugs have the ability to prevent muscle spasms and were first developed to prevent muscle rigidity associated with seizures. Thus, patients who look up Klonopin are surprised to see that it was first approved for children with seizures. This is because Klonopin reduces severe muscle spasms, a life-threatening part of seizures in children.
However, Klonopin is used in much lower doses to reduce the muscle spasms associated with nocturnal myoclonus. Like its parent compound Valium, Klonopin also has "anti-anxiety" activity and has other uses in addition to nocturnal myoclonus. Other medications such as Elavil (amitriptyline) or Pamelor (nortriptyline) are commonly prescribed for sleep disorders but are generally not well tolerated by Sjögren's patients due to their side effect of increased dryness.
Finally, sleep disruption can occur due to sleep apnea. Sleep apnea is suspected in patients who snore loudly or awake at night gasping for breath. Patients with recent weight gain (often due to corticosteroids) may develop sleep apnea. This problem requires the expertise of a sleep center for evaluation and treatment.
H. Depression in Sjögren's Syndrome
Depression can present in many forms, including difficulty concentrating, poor appetite, or a sleep disorder. The precise role of inflammation and hormone imbalances associated with Sjögren's syndrome as a contributing factor to depression remains unclear, but certainly depression is caused in part by chemical alterations in the brain. Stress, poor sleep, and chronic illness can all contribute to depression. When antidepressant medications are used to help regulate sleep patterns and treat fatigue, drugs lacking anticholinergic side effects are preferred.
As mentioned earlier, certain antidepressants such as tricyclics (Elavil and Pamelor) and monoamine oxidase (MAO) inhibitors may greatly increase dryness and should be avoided. A second class of antidepressants with less dryness include trazodone (Desyrel); newer members of this family include Serzone. A third class of antidepressant drugs are called serotonin re-uptake inhibitors (SSRI). These include Prozac, Paxil, Zoloft, Luvox and Effexor. The incidence of increased dryness (and other side effects including sleep disruption) appears variable among different patients and a careful diary by the patient may help the physician in the selection of the correct drug.
VI. PATIENT SUPPORT GROUPS
The increasing recognition of Sjögren's syndrome has led to the recent formation of patient support groups. One group, called the Sjögren's Syndrome Foundation, puts out a monthly newsletter, "The Moisture Seekers," and has local chapters in many cities including San Diego (local contact persons are listed in each issue of "The Moisture Seekers"). Another group, the National Sjögren's Syndrome Association, publishes a different newsletter, the "Sjögren's Digest," and has chapters including the Los Angeles area, Arizona, Minnesota and Florida. Both newsletters contain informative articles and therapeutic hints for patients. Although we recommend these newsletters as a source of patient information, we wish to caution you that some of the material may be controversial and may conflict with our opinions.
Nevertheless, we strongly believe that patients should have access to all points of view (including those opposed to ours) and we are happy to discuss our reasons for/against any specific suggestions. Just do not take everything that is in a newsletter (or that we say) as "gospel." Similarly, the periodic meetings of patient support groups are a potential source of helpful information and emotional support. However, they also may be a source of misinformation. So approach patient support groups with an open mind as if you were competitively shopping for an important item. Whether you belong to a support group or not, it is important to surround yourself with people who believe in "wellness" behavior rather than with individuals who are chronic complainers.
VII. ROLE OF THE DIET AND NUTRITION
Patients frequently ask about the role of diet either in causing their disease or in their treatment. No definite answers are known, but environmental agents (perhaps even food antigens) may play a role.
One of the best examples of diet-related autoimmune disease is celiac sprue, where autoimmune reaction against gliadin (a wheat-derived product) plays an important role. At a molecular level, the gliadin resembles a viral-encoded protein and thus the body mounts an "antiviral" response every time it encounters this food antigen. It is possible that other foods may provoke and adversely activate the immune system by mechanisms that we do not understand.
It would be helpful if we had reliable methods to detect specific "food allergies" in patients. Despite two decades of trying to develop such tests, there are still no reliable methods. However, some unscrupulous individuals advertise special blood tests for "food allergy." These tests have not been shown to have merit and circulating antibodies against specific food antigens have not been demonstrated in Sjögren's syndrome. We do recommend that patients avoid candy and products containing sugar, which may cause dental cavities and increased gingival disease.
Recent interest has centered around the possible role of fatty acids that are precursors of prostaglandins and/or leukotrienes, which play an important role in the inflammatory response. One preliminary report suggests a deficiency of prostaglandin E1 (a derivative of fatty acids) in Sjögren's patients that were treated with dietary supplements of fatty acids. Recent studies in rheumatoid arthritis have shown that mild subjective improvement and minor degrees of improvement in joint swelling could be achieved by taking fish oil tablets containing particular fatty acids known as omega-3 polyunsaturated fatty acids. It is too early to give these fatty acids any recommendation in Sjögren's syndrome since this "medication" actually increased arthritis when fed to rats.
Little information is available on the beneficial role of vitamin or mineral supplements in Sjögren's syndrome. Certainly, a daily multi-vitamin seems justified, particularly since dietary food intake is often altered due to tooth loss/gingival disease. The beneficial value of neutral fluoride for tooth enamel was described above. Although severe vitamin A deficiency can cause dry eyes, the clinical features of this dry eye syndrome are different from those in Sjögren's syndrome. Further, serum vitamin A levels are normal in Sjögren's patients and excessive intake of this vitamin can cause fatal liver damage. Based on reports that zinc was helpful in reducing stomatitis in patients after head and neck irradiation, we tried zinc sulfate (220 mg/day) without significant improvement in most cases.
However, double-blind studies on large numbers of patients will be required before the role of vitamins and dietary factors can be adequately assessed. We have suggested daily yogurt (especially low fat) since this has had a beneficial response in decreasing oral Candida infections and thus decreasing mouth discomfort.
VIII. HEARTBURN AND ESOPHAGEAL MOTILITY IN SJÖGREN'S SYNDROME
Saliva normally plays a major role in neutralizing gastric acidity. Thus, symptoms of "heartburn" or "hiatal hernia" are common in Sjögren's syndrome. Gastric hyperacidity can be partly overcome by the use of antacids (such as Mylanta II or Maalox II) after meals and at bedtime. Also, elevation of the head of the bed on 1- to 2-inch wood blocks provides a way to reduce the gastric acid from washing back into the esophagus at night. In some patients with severe problems of "heartburn," the medicine sucralfate (Carafate slurry) has been helpful. This medicine was designed to "coat" the esophagus and stomach of patients with ulcer disease.
However, sucralfate coating of the stomach might interfere with the absorption of certain other medications so be certain to check this possible drug interaction with your physician and pharmacist. For heartburn, two types of medications decrease the gastric production of acid. The first type are called "H2 blockers" and include Tagamet, Pepcid, and Zantac; several of these have recently become available over the counter. A second type of medication is Prilosec, which inhibits the secretion of acid, still requires a prescription. Finally, some patients have decreased motility of the esophagus and may benefit from a medicine called cisapride (Propulsid). However, these medications are relatively expensive and may cause other side effects.
Since saliva normally helps during swallowing pills, it is important to recognize that pills can become stuck to "dry" walls of the esophagus and cause painful erosions. For example, iron supplement pills are large in size and uncoated tablets may get stuck in the esophagus, leading to pain and a choking sensation. Also, certain time release preparations tend to adhere to the esophagus in the absence of sufficient saliva. To minimize these problems, coated tablets are preferred (when available) and medication should be taken with lots of water while sitting in the upright position (rather than lying down just after taking the pills).
IX. MEDICATIONS IN TREATMENT OF SJÖGREN'S SYNDROME
The key question for the physician is whether there is evidence of an active inflammatory process. Again, the history, exam and blood tests help provide the physician with objective evidence to guide therapy. The simplest anti-inflammatory agent is aspirin. To minimize stomach upset, enteric-coated forms are preferable. Other forms of aspirin-like drugs (Disalcid or Trilisate) have fewer gastric side effects but require prescriptions. The most common anti-inflammatory drugs are called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) have become very popular during the last decade for treatment of headache, joint and muscle pains. Although these medicines are considered as a single group (i.e., Clinoril, Naproxen, Indocin, Voltaren, Ansaid, Daypro, Relafen and others), individual patients may have good response to one drug and no response (or even toxicity) to another drug.
Ibuprofen (Advil, Nuprin) is available over the counter and thus less expensive, while others such as Indocin, Clinoril and Voltaren have generic equivalents. Indocin is available as a suppository, which may be an advantage in patients where oral medicines lead to stomach upset. Voltaren is enteric-coated, and Naproxen will soon also be available in this form. Ansaid has been shown in one dental study to decrease periodontal disease by decreasing the inflammatory response in the gums.
Steroids (prednisone or Medrol) are stronger drugs that work very effective to decrease the inflammatory response. Unfortunately, these drugs have many side effects when taken for prolonged periods, including diabetes, hypertension, osteoporosis, cataracts and increased risk of infections. However, steroids work rapidly and must be used in certain situations. Attempts to taper the dose of steroids should be pursued to avoid the side effects.
Disease-Modifying Anti-Rheumatic Drugs called (DMARDs) were first developed for rheumatoid arthritis and systemic lupus erythematosus, but are also frequently used in Sjögren's syndrome. One class are called "antimalarial" drugs since chloroquine was first developed for malaria and later found to have benefit in patients with autoimmune diseases. Since chloroquine at high doses was associated with side effects involving the eye, Plaquenil (hydroxychloroquine) was subsequently developed. When taken at the proper dose, Plaquenil has an extremely good safety record, although there remains a remote possibility (probably less than 1/1000) of significant build-up in the eye.
At present, we recommend eye checks (generally every 6 months) so that the medicine can be discontinued if there is any significant ocular side effect. We have found Plaquenil to be beneficial in selected patients with evidence of an active, persistent inflammation. Other disease-modifying agents (imuran, methotrexate, and cyclosporin A) are much stronger drugs and require careful monitoring of their side effects. Our overall approach to medications is that it is best to avoid them if possible since all medications have risks. However, in certain situations, the damage to the body by the immune system is sufficiently great that the relative risks of these medications is justified.
Similarly, it is important to recognize that certain medications may cause increased dryness as a side effect (Table 8). If you are receiving these medications, you might discuss the possibility of changing to a less drying drug.
X. PARTICULAR NEEDS OF THE SJÖGREN'S PATIENT AT THE TIME OF SURGERY
We recommend that patients bring their own medicines (including artificial tears, lubricants, and saliva substitutes) to the hospital. The patient may use their own medicines (if approved by their physician) and this saves not only money but time in dispensing the same medications from the pharmacy.
Certain medications (especially aspirin or NSAIDs) may alter the normal blood clotting mechanisms and need to be stopped prior to surgery. In general, aspirin needs to be stopped approximately 6 days prior to major surgery, while nonsteroidal anti-inflammatory drugs (including Motrin and other over-the-counter analgesics such as Advil) approximately 48 hours prior to surgery.
Even if you are not undergoing surgery, it is always a good idea to carry a written list of your current medicines, their doses, and any drug allergies you might have. Nothing is more annoying for the physician (and dangerous to the patient) than trying to identify the name of "some small white pill" that the patient can't quite remember in the stress of medical evaluation.
In summary, Sjögren's syndrome is