Given that Sjögren’s syndrome is the second most common autoimmune rheumatic disease and affects nearly four million people in the United States, these authors review key diagnostic symptoms and classifications, and offer a valuable primer on treatments for dry mouth and dry eye symptoms associated with the disease.

Sjögren’s syndrome is a chronic, systemic autoimmune disease characterized by lymphocytic infiltration of the moisture producing (exocrine) glands. The disease primarily affects the salivary and lacrimal glands, resulting in the hallmark symptoms of dry mouth (xerostomia) and dry eyes (keratoconjunctivitis sicca).

These problems occur as a consequence of glandular destruction and dysfunction. Sjögren’s syndrome may affect as many as four million people in the United States and approximately 90 percent of people with this disease are female.

Indeed, the disease represents a major women’s health problem that is frequently overlooked by the medical community. After rheumatoid arthritis, Sjögren’s syndrome is the second most common autoimmune rheumatic disease. When Sjögren’s syndrome goes undiagnosed and untreated, it not only compromises patient quality of life but also causes devastating oral and ocular complications.



About 4 to 5 percent of patients develop non-Hodgkin’s B-cell lymphomas as a consequence of this disorder.

A Closer Look At The Potential Etiology and Pathogenesis

Although the cause of Sjögren’s syndrome remains unknown, concepts regarding the etiology and pathogenesis of the disease continue to evolve. Hormonal, genetic and environmental factors all play a significant role.

Common oral symptoms associated with Sjögren’s syndrome include: mucosal dryness, pain, discomfort and irritation; difficulty chewing or swallowing; caries or problems with dentures; and mouth sores.

Sjögren’s syndrome is most common among perimenopausal women and exhibits a striking female predominance at every age. Recent studies suggest that women who use hormone replacement therapy, particularly estrogens alone, have an increased risk of dry eye syndrome. When it comes to assessing animal models for dry eyes, researchers have found that sex hormones can bind to receptors on ocular tissues and perturbations of hormone levels can exacerbate ocular surface inflammation.

Sjögren’s syndrome has been hereditary in a few families. More commonly, however, close relatives of affected patients exhibit an increased incidence of other autoimmune disorders such as systemic lupus or Hashimoto’s thyroiditis. In Caucasians with 1º Sjögren’s syndrome, the human leukocyte antigens HLA-DR3 and HLA-DQ2 occur with increased frequency.

A number of viruses are sialotropic and can infect the salivary glands. These viruses include Epstein-Barr virus, cytomegalovirus, mumps, human herpes virus types 6 and 8, hepatitis C, human T-cell lymphotrophic virus-1, human immunodeficiency virus (HIV) and human retrovirus 5. Researchers have described a chronic Sjögren’s syndrome-like illness with sicca symptoms among humans infected with HIV or hepatitis C.
The prevailing thinking is that Sjögren’s syndrome may begin when an environmental agent (e.g. one or more viruses) infects a genetically susceptible host and triggers an autoimmune response. Salivary gland acinar epithelial cells are damaged, undergo apoptosis (programmed cell death) and expose internal cellular proteins that become autoantigens. These autoantigens trigger the invasion of lymphocytes (mainly CD4+) and other inflammatory cells into the exocrine glands.

A Guide To Atypical Presentations Of Sjögren’s Syndrome

- • Accelerated caries • Chronic fatigue syndrome • Corneal melt or perforation • Elevated erythrocyte sedimentation rate, positive antinuclear antibodies or positive rheumatoid factor in an asymptomatic patient • Fever of unknown origin • Inflammatory myositis • Leukocytoclastic vasculitis • Multiple sclerosis-like central nervous system disease • Peripheral neuropathy • Polymyalgia rheumatica • Salivary gland swelling • Renal tubular acidosis • Rheumatoid-like arthritis

Over time, HLA-DR antigens (markers of immune activation) are expressed on acinar epithelial cell surfaces, B-cells become activated and the local production of autoantibodies occurs including Anti-SSA (a.k.a. Anti-Ro) and anti-SSB (a.k.a. Anti-La), the marker antibodies for the disease. The infiltrates and epithelial cells produce a variety of lymphokines and cytokines including TNF-a, Il-1b, IFN-y, Il-6, Il-10 and Il-18. This perpetuates the inflammatory cascade and eventually leads to parenchymal damage and replacement of normal acinar tissue by scar tissue and fat.

In Sjögren’s syndrome, autonomic nerve dysfunction (perhaps cytokine mediated) and acetylcholine M-3 receptor blocking antibodies may also contribute to dryness from exocrine gland hypofunction.

A Review Of Common Oral And Ocular Manifestations
Eighty percent of patients present with the insidious onset of dryness of the eyes, mouth and other body parts (sicca syndrome) that evolves over a period of several months to several years.

When sicca symptoms develop simultaneously, the diagnosis can be timely. In other instances, however, when one symptom precedes another by months to years, the diagnosis is often overlooked. Diagnostic delays also occur when patients and/or health care providers attribute symptoms of Sjögren’s syndrome to aging or menopause.

The oral and ocular manifestations of Sjögren’s syndrome largely reflect the physiologic importance of saliva and tears in maintaining normal oral and ocular health. The most common oral symptoms include:

• mucosal dryness, pain, discomfort and
irritation;
• frequent ingestion of liquids;
• difficulty chewing or swallowing;
• difficulty with phonation;
• nocturnal fluid ingestion;
• caries or problems with dentures;
• altered taste;
• mouth sores; and/or
• parotid gland swelling.

Ocular manifestations sometimes mimic symptoms of allergies and/or bacterial conjunctivitis. These manifestations include:

• foreign body sensation (gritty, sandy);
• dryness, burning and itching;
• redness and excess mucus production;
• eye fatigue;
• photosensitivity;
• glare, blurred vision; and/or
• blepharitis.

Symptoms of dryness are not exclusive to the mouth and eyes. These symptoms may also involve the skin, respiratory tract, gastrointestinal tract and vaginal tissue.

After dry eyes and dry mouth, fatigue was the third most common symptom reported by patients in a 1998 Sjögren’s Syndrome Foundation survey. Seventy-seven percent of those surveyed listed fatigue as one of their most troubling symptoms. Fatigue can be quite profound and fluctuate from day to day.

In a more advanced stage of Sjögren’s syndrome, the normal acini in the minor salivary gland is replaced by fibrosis and fat.

Musculoskeletal pain is another frequent problem with Sjögren’s syndrome. Fifty percent of patients will experience rheumatic symptoms during the course of their illness. These episodes may present as arthralgias, myalgias, morning stiffness or frank synovitis of large and small joints.

Sjögren’s syndrome may also involve the internal organs in up to one-third of individuals (see “A Primer On Extraglandular Manifestations Of Sjögren’s Syndrome”). Patients who develop the extraoral and extraocular manifestations of Sjögren’s syndrome have significantly increased morbidity and, when lymphomas occur, increased mortality as well. However, prompt recognition and proper treatment can significantly improve patient quality of life and prevent complications.

The mean duration from the onset of symptoms to the diagnosis of Sjögren’s syndrome is over six years. Although 80 percent of patients present with the typical sicca symptoms, 20 percent will present in atypical fashion. In these patients, sicca symptoms are often minimal or nonexistent (see “A Guide To Atypical Presentations of Sjögren’s Syndrome”). Accordingly, it is easy to miss the diagnosis of Sjögren’s syndrome without a high index of suspicion.

The differential diagnosis of sicca syndrome is quite extensive and includes amyloidosis, chronic sialadenitis, diabetes mellitus, eosinophilia-myalgia syndrome, graft-versus-host disease, fibromyalgia, hepatitis C, HIV-related diffuse infiltrative lymphocytosis syndrome, medication-related dryness, mouth breathing, multiple sclerosis, radiation injury, sarcoidosis, sialadenosis, silicone breast implant disease, Sjögren’s syndrome (primary or secondary) and type V hyperlipidemia. Therefore, clinicians cannot base the diagnosis of Sjögren’s syndrome on symptoms alone. An accurate diagnosis of Sjögren’s syndrome requires objective evidence of dry eyes and mouth as well as proof of autoimmunity.

After rheumatoid arthritis, Sjögren’s syndrome is the second most common autoimmune rheumatic disease and represents a major women’s health problem that is frequently overlooked by the medical community.

Clinicians widely use the American-European consensus criteria for diagnosis (see “A Closer Look At The American-European Criteria For Classification Of Sjögren’s Syndrome”). Primary Sjögren’s syndrome occurs when sicca symptoms develop in a previously healthy individual with no prior history of connective tissue disease. Patients may have secondary Sjögren’s syndrome when sicca symptoms develop in association with a preexisting connective disorder such as rheumatoid arthritis, lupus or scleroderma.

What You Can Learn From The Patient History And Physical Exam
When assessing these patients, one should always emphasize a comprehensive history and physical examination. Clinicians should question patients about sicca symptoms, other causes of dryness, salivary gland swelling, Raynaud’s phenomenon and other symptoms suggestive of connective tissue disease. A family health history is also important particularly as it relates to autoimmunity.

The physical exam can provide information on the patient’s general health status. A careful examination of the eyes may reveal conjunctival injection, a decreased tear meniscus or scattering of the normal corneal light reflex suggestive of ocular surface irregularity due to dryness. In regard to examining the patient’s mouth, the major salivary glands may be tender or swollen. Examination of the oral cavity may reveal cheilosis, loss of glistening of the tongue or mucous membranes, or a diminished sublingual salivary pool. One should also pay special attention to assessing the skin, joints and scalp.

Eighty percent of women with Sjögren’s syndrome present with the insidious onset of dryness of the eyes, mouth and other body parts (sicca syndrome) that evolves over a period of several months to several years.

Clinicians should order routine blood work and several immunological tests. Positive tests for rheumatoid factor and antinuclear antibodies (ANA) are present in 70 to 80 percent of patients and are suggestive of Sjögren’s syndrome. However, be aware that these tests are not disease-specific and can lead to an incorrect diagnosis. Anti-SSA (Ro) and anti-SSB (La) antibodies are more disease-specific and can help differentiate a Sjögren’s patient from a patient with another autoimmune disorder. However, these particular antibodies may also be positive in patients with systemic lupus erythematosus as well. The erythrocyte sedimentation rate, C-reactive protein, and acute phase reactants can also be elevated in patients with Sjögren’s syndrome.

Pursuing Additional Diagnostic Tests And Referrals: What You Should Know
Following this comprehensive evaluation, practitioners typically arrange for additional diagnostic tests to look for objective evidence of dry eyes and dry mouth.

A Primer On Extraglandular Manifestations Of Sjögren’s Syndrome

- General: Fatigue, malaise, fevers Ear, nose and throat: epistaxis, otitis media, conduction deafness, recurrent sinusitis Gastrointestinal: esophageal dysmotility, esophageal webs, reflux, atrophic gastritis, autoimmune pancreatitis, liver disease Genitourinary: vaginitis sicca, dyspareunia, vulvovaginitis, interstitial cystitis Hematological: anemia, leukopenia, lymphopenia, cryoglobulinemia, lymphoma Neurological: peripheral neuropathy, cranial neuropathy, trigeminal neuralgia, central nervous system involvement Pulmonary: xerotrachea, recurrent bronchitis/pneumonia, lymphocytic interstitial pneumonitis, pulmonary fibrosis, bronchiectasis, bronchiolitis obliterans with organizing pneumonia (BOOP) Renal: interstitial nephritis, hyposthenuria, renal tubular acidoses (types 1, 2) Rheumatologic: arthralgias, polyarthritis, myalgias, myositis, Raynaud’s phenomenon Skin: xeroderma, purpura, urticaria, vasculitis

An ophthalmologist, preferably a corneal specialist, should assess the patient for dry eyes. The ophthalmologist can perform a detailed eye examination with a slit lamp (biomicroscopy) along with other tests in order to detect the presence of dryness and related findings like excess debris, mucus and filaments.
The Schirmer’s test measures tear production. One would place a strip of filter in the lower conjunctival sac and measure the degree of wetting after a five-minute period.

A value of less than 10 mm per five minutes is considered abnormal and any measurement less than or equal to 5 mm per five minutes is highly suggestive of dry eyes. Staining of the cornea and conjunctiva with vital dyes such as rose bengal, fluorescein or lissamine green will identify areas where the ocular surface is damaged or devitalized due to chronic dryness.

The ophthalmologist can also use fluorescein corneal staining with cobalt blue filter biomicroscopy to assess tear film stability. When the fluorescein tear break up time (how long the cornea remains covered with tears) is less than 10 seconds, the patient has dry eyes.

Diagnostic tests for dry mouth include the measurement of salivary flow (sialometry), nuclear medicine salivary scintigraphy (salivary gland scan) and parotid sialography. While these tests are not specific for Sjögren’s syndrome, clinicians can use these tests to demonstrate objective evidence of salivary gland dysfunction. The results can support the diagnosis of Sjögren’s syndrome when one combines these tests with other diagnostic tests.

When it comes to sialometry, one can easily accomplish this by collecting saliva in the office. The simplest technique involves asking the patient to expectorate into a container for 15 minutes then measuring the weight (1G=1 ML) or volume. A flow rate of less than 0.3 ml/minute is abnormal while a value less than or equal to 0.1 ml/minute is highly suggestive for Sjögren’s syndrome.

Scintigraphy is a routine diagnostic procedure that involves the intravenous injection of a radioisotope that localizes in the major salivary glands. This study measure uptake, spontaneous and stimulated salivary secretion of the major salivary glands. Keep in mind that any of these functions may be defective in Sjögren’s syndrome patients.

Sialography involves the intra-oral injection of water-soluble contrast into Stenson’s duct of the parotid glands and following up with X-ray imaging. Findings may include ductal dilatation, irregularity, stenosis or microaneurysm formation.

Pertinent Pointers About Lip Biopsy Results
The labial minor salivary gland biopsy (lip biopsy) is still considered the gold standard when it comes to diagnosing the salivary component of Sjögren’s syndrome and/or obtaining proof of autoimmunity. An oral surgeon or otolaryngologist, under local anesthesia, typically makes a small incision on the inner surface of the lower lip to directly visualize and excise four to five minor salivary glands. A pathologist measures the surface area of the obtained tissue and counts the number of lymphocytic foci (aggregates of 50 or more cells) to determine a focus score.

A report of focal lymphocytic sialadenitis with a focus score greater than or equal to 1 per 4mm2 tissue is considered positive. Keep in mind that the salivary gland biopsy may be positive even when the autoantibodies are not.

Misinterpretation of histologic findings in lip biopsies is a common problem and causes frequent diagnostic errors or delays. Therefore, proper reporting of the focus score by pathologists and adequate tissue sampling are required to minimize this possibility.

How To Clinch The Diagnosis
A summary of the most important signs, symptoms and studies used to diagnose 1° and 2° Sjögren’s syndrome is outlined in “A Closer Look At The American-European Criteria For The Classification Of Sjögren’s Syndrome”. Proper diagnosis of Sjögren’s syndrome in the patient with sicca symptoms is crucial for many reasons. Like lupus, Sjögren’s is a systemic disease with the potential to affect multiple organs.

The unusually high association between Sjögren’s syndrome and non-Hodgkins B-cell lymphomas (a 44 percent higher incidence according to one study) warrants constant vigilance for this potential complication.
Finally, in recent years, it has become apparent that untreated xerostomia and keratoconjunctivitis sicca in this group results in significant and costly morbidity. Complications of dry eye can include bacterial conjunctivitis, corneal melting, ulceration, perforation and loss of vision. Complications of untreated dry mouth may include accelerated caries, loss of dentition, weight loss, malnutrition, sialolithiasis, bacterial sialadenitis, chronic erythematous candidiasis and chronic sleep disruption. Sleep disruption from untreated sicca symptoms may explain the coexistence of fibromyalgia in up to 50 percent of patients with Sjögren’s syndrome.

What Are The Options For Treating Dry Eyes?
The treatment goals in Sjögren’s syndrome are to palliate symptoms, monitor and prevent complications, and improve the patient’s quality of life. Although no cure or “remittive” agent exists, one may utilize a variety of local and systemic therapies depending upon the severity of the disease. Clinicians usually approach treatment in a stepwise fashion, paying special attention to the eyes, mouth and extraglandular manifestations.

For mild dry eyes, clinicians may use preservative containing artificial tears (i.e. in bottles) prn up to tid and have patients discontinue the use of all anticholinergic medications. Also instruct these patients to avoid cigarette smoke, dust and low humidity conditions. Patients may use extra tears for activities that dry out the eyes like reading or computer use.

A Closer Look At The American-European Criteria For Classification Of Sjögren’s Syndrome

- 1) Ocular symptoms (any one of three symptoms) Dry eyes > 3 months Tear use > 3 times daily Foreign body sensation 2) Oral symptoms (any one of three symptoms) Dry mouth > 3 months Swollen salivary glands Need liquids to swallow 3) Ocular signs (one of two signs) Unanesthetized Schirmer’s < 5 mm/5 min in both eyes Positive vital dye staining 4 Oral signs (one of three signs) Abnormal salivary scintigraphy Abnormal parotid sialography Abnormal sialometry (unstimulated salivary flow rate < 0.1 ml/min) 5) Positive lip biopsy Focal lymphocytic sialadenitis (focus score > 1 / 4mm2) 6) Positive anti-SSA and/or anti-SSB antibodies The above table has been modified from Vitali C et al. Ann Rheum Dis, 2002. The diagnosis of 1° Sjögren’s syndrome requires four of six criteria including a positive lip biopsy or a positive anti-SSA and/or anti-SSB antibodies. The diagnosis of 2° Sjögren’s syndrome requires established connective tissue disease, one sicca symptom (ocular or oral symptom) plus two of three objective tests for dry mouth and dry eyes. One may also diagnose Sjögren’s syndrome in patients who have no sicca symptoms if three of four objective criteria are fulfilled (ocular signs, oral signs, positive lip biopsy and/or positive anti-SSA and/or anti-SSB antibodies.

Treatment of moderately severe keratoconjunctivitis sicca requires regular follow-up by an ophthalmologist every six to 12 months. The ophthalmologist will usually switch to preservative-free tears in single use applicators qid up to hourly.

Ocular lubricants qhs provide better nighttime relief. One may prescribe topical 0.05% cyclosporine (Restasis™) drops (1 gtt ou bid) to treat persistent symptoms due to ocular surface inflammation. Studies suggest treatment of ocular surface inflammation over a three- to six-month period may not only improve symptoms but aid in tear production and reverse ocular surface damage as well. The most common side effect, ocular burning, is usually transient and patients can usually alleviate this by refrigerating the drops or using them five minutes after using a drop of artificial tears.

In regard to blepharitis, clinicians may treat this with warm compresses, lid scrubs and topical or systemic antibiotics.

In patients with severe dry eyes, “tear preservation” with punctal plugs or punctal cautery to close off the inferior lacrimal canaliculi will provide additional relief. Secretagogues, which are used to treat dry mouth, may also improve symptoms of dry eyes. Clinicians may also have patients wear moisture chamber glasses or glasses with windshields to protect eyes from the elements and retain moisture.

In this biomicroscopic view with fluorescein staining, one can see a corneal ulcer due to untreated dry eye.

In order to treat the aforementioned inflammation, one may use steroid eye drops for up to one month at a time and/or topical 0.05% cyclosporine. Taking nutritional supplements (eg. Thera Tears Nutrition™ 2 po bid, Hydroeye™ 1 po bid) orally may also help.

How To Manage Dry Mouth Symptoms
Secretagogues (oral medications that stimulate saliva flow) comprise the mainstay of treatment for dry mouth associated with Sjögren’s syndrome. Dry mouth animal studies suggest that simulation of saliva flow with secretagogues may help prevent caries in people as well.

Cevimeline (Evoxac™) and pilocarpine (Salagen™) are both FDA approved for the treatment of Sjögren’s syndrome dry mouth. Successful treatment depends on residual glandular function, which one can estimate via salivary scintigraphy or sialometry.

Excessive sweating is the most common side effect with these medications and patients may avoid this by taking the medications with food and starting with low doses. Both pilocarpine and cevimeline are contraindicated in patients with uncontrolled asthma, narrow-angle glaucoma and acute iritis.

Although muscarinic agents are not approved for other uses, clinical studies suggest that they may improve other symptoms of dryness. Failure to respond to one agent does not predict failure to respond to the other.
There are other key steps that patients can take to manage dry mouth symptoms.

• Minimize aggravating factors. Clinicians may recommend medication substitution and/or the elimination of drying drugs. It is also important to educate these patients about the importance of avoiding alcohol, including alcohol containing mouthwash and fluoride rinses. They should also avoid smoking and low humidity conditions. When it comes to patients with tongue and mouth burning, clinicians should treat them for chronic erythematous candidiasis.

• Optimize dental hygiene. Encourage dental checkups every three to six months. Prescribe fluoride for home use (e.g. 1.1% neutral sodium fluoride) to brush on teeth (instead of toothpaste qhs) and have patients retain this for 30 minutes. Encourage patients to floss fluoride between teeth before rinsing off the fluoride. Encourage use of an electric toothbrush and have patient rinse teeth with water after each meal.

• Emphasize adjunctive measures. There are a variety of things patients can do to improve oral comfort. These measures include taking small sips of water or sugar-free fluids liberally, utilizing a room air humidifier to curb nighttime dryness, using sugar-free candies, chewing gum (containing xylitol) or fruit pits to stimulate flow, and paying heed to dietary modifications (e.g. no spicy foods, more gravies, etc.) in order to improve intake and nutrition. Artificial salivas (Mouth Kote™, Salivart™, Numoisyn™) provide short-term relief and may be preferable to water in certain situations (nocturnal dryness, air travel, etc.). Patients should use 2mls po qhr prn while awake. These preparations are safe to swallow.

For patients with no salivary flow, clinicians may prescribe vitamin E oil, mineral oil or moisturizing gels (Oral Balance™, Orajel™) bid pc and qhs to help coat the tongue and mucous membranes. One may add long-acting guaifenesin 600 mg po bid for dry nose and throat.

Other Key Considerations In Managing Sjögren’s Syndrome
When it comes to other dryness symptoms associated with Sjögren’s syndrome, patients may utilize: heavy skin moisturizers, mild/moisturizing soaps and/or sunscreen; nasal saline sprays and gels (AYR™); and vaginal moisturizers (Astroglide™, Replens™) and lubricants for intercourse.

Immunosupressives are required to manage the extraglandular morbidities of Sjögren’s syndrome but they do not help dry eyes or dry mouth. In regard to extraglandular morbidities of this disease, clinicians widely use hydroxychloroquine and it may alleviate fatigue, adenopathy, parotid swelling, arthralgias, myalgias, hypergammaglobulinemic purpura and leukocytoclastic vasculitis. One may employ corticosteroids or methotrexate as a second-line agents.

There are other serious and/or life threatening manifestations with Sjögren’s syndrome. For polyarthritis, one should follow the treatment algorithm for rheumatoid arthritis. When it comes to interstitial pneumonitis/fibrosis or central nervous system disease, experts recommend treatment options such as steroids, azathioprine and cyclophosphamide. Symptomatic treatment such as gabapentin is recommended for mild peripheral neuropathy whereas azathioprine or IV immunoglobulin is recommended for treating severe peripheral neuropathy in these patients. When these patients have severe parotid swelling, IV rituximab is recommended for treatment.

Patients empowered with information are best prepared to deal with the effects of a chronic, devastating illness like Sjögren’s syndrome and actively participate in their own care.

Recent studies suggest that women who use hormone replacement therapy, particularly estrogens alone, have an increased risk of dry eye syndrome.

One may contact the Sjögren’s Syndrome Foundation at 8120 Woodmont Ave., Suite 520, Bethesda, MD, or contact 20814, a non-profit organization dedicated to patient support, educating the public and healthcare community, and working to find a cure. The Foundation can provide a wealth of information to patients and professionals including information on local chapters or support groups. One may contact the foundation at (800) 475-6473 or by accessing www.sjogrens.org.

In Conclusion
Patients with Sjögren’s syndrome present a variety of complex diagnostic and therapeutic challenges. Proper and timely diagnosis is essential as morbidity may result not only from untreated sicca symptoms but also internal organ involvement and associated disorders. Early diagnosis and aggressive treatment, provided by a multidisciplinary team, ensures the best chance for a successful outcome.