Have your patients ever complained of persistent symptoms of dryness in the mouth or lack of adequate tear production? These are characteristic of Sjögren’s syndrome. The onset is due to an inflammation of the parotid glands that make saliva and/or the lacrimal glands that produce tears in the eyes. Sometimes the inflammation causes the glands to become painful and swollen, but often, they just cease to function. An autoimmune disease, Sjögren’s syndrome can occur on its own (primary) or as a complication of other connective tissue diseases (secondary Sjögren’s syndrome).

What causes it?

Sjögren’s is difficult to diagnose and define. Many people have dry eyes or dry mouth, but they don’t have evidence of autoimmune disease. Others may actually have the disease, but aren’t diagnosed. Consequently, there are no good figures on its true prevalence. In Canada, there are an estimated 300,000 people with the disease, half of whom suffer as a complication of another autoimmune illness. It’s 8-9 times more frequent in women than in men. The peak ages are 30-60 years, but children and the elderly can also be affected. All ethnic groups are at risk.

Etiologically, Sjögren’s syndrome is a disease of the epithelial cells that line the ducts of the salivary and lacrimal glands. Although certain viruses can affect the salivary glands, such as mumps, Epstein-Barr and HIV, no single agent has been documented in primary Sjögren’s. Ro is a tripartite ribonucleoprotein complex that acts as a ubiquitin ligase. La is a protein associated with all RNA polymerase 3 transcripts. Why antibodies form against these proteins isn’t clear, but it’s theorized that they become externalized on the surface of the cells during virus-induced apoptosis. The disease becomes entrenched with spreading immunity to other salivary antigens as tissue becomes disrupted and destroyed. Circulating Ro/anti-Ro complexes may play a role in some of the systemic manifestations of the disease.

Mouth, eye and parotid symptoms

A person with Sjögren’s syndrome may appear perfectly normal. The eyes, though, feel to the patient as if they have gravel in them, and bright sunlight is difficult to tolerate. It’s hard to keep the eyes open, because they burn. Sometimes they become red. Crusting can occur around the eyelid margins, and discharge may appear in the corners. Occasionally, the eyelids stick together in the morning. Contact lenses can’t be worn, and in extreme cases, patients may go on to develop corneal abrasions, corneal ulcers, filamentary keratitis and even scarring or perforation.

The mouth feels dry, and this is often misinterpreted as thirst. People carry water bottles around with them. Dry food can’t be swallowed without liquids, and angular cheilitis is not uncommon. Teeth begin to decay, often with the development of caries at the gum line (cervical caries). The front teeth can become ground down and other teeth may fragment. The tongue may become sore and sensitive to spices, it can appear red, enlarged and furrowed due to monilia overgrowth. Talking can become difficult, as the tongue sticks to the roof of the mouth, and clicks.

Some people develop swelling of the parotid glands, giving the appearance of mumps. This is often on one side at a time, but may eventually
become bilateral. The swelling may be without symptoms, can come and go, or eventually just persist. Some of these patients evolve to non-Hodgkin’s B-cell lymphoma. Some people with Sjögren’s syndrome actually develop episodes of “parotitis,” presumably because of disruption of the duct system with sialectasia, strictures and sometimes stones. During such attacks, the parotid gland becomes quite painful and swollen; there can be fever. Antibiotics don’t always work in this situation, and the pain and swelling usually abate spontaneously over 2-3 weeks. If this scenario recurs often, the glands risk becoming chronically infected, necessitating removal.

Systemic manifestations

Although Sjögren’s is primarily a disease of the salivary and lacrimal glands, systemic manifestations can occur. Most patients complain of fatigue, often quite profound and intrusive. This is likely due to chronic persisting systemic inflammation. To further complicate matters, excessive water intake throughout the day can result in nocturia. The patient awakens at night to urinate, compounding the fatigue and exhaustion the following day. Depression, too, can be a factor.

Joint and muscle pain may be minor, but occasionally, there’s severe inflammation. Sjögren’s can also cause dryness of the nose, skin, sinuses, airways and vagina. It can be associated with interstitial pneumonitis, and can lead to renal tubular acidosis as a consequence of interstitial nephritis.

With this type of kidney disease, serum creatinine can rise, bicarbonate falls, the potassium value rises and urinary pH remains neutral while the urine concentration is poor. Liver disease is seen in about 10% of Sjögren’s patients, particularly a rare form known as primary biliary cirrhosis. Cutaneous vasculitis can occur, presenting as crops of petechiae on the lower legs, sometimes associated with peripheral sensory neuropathy. Raynaud’s phenomenon is not rare.

Although most women with this disease are beyond their prime childbearing years, the existence of the anti-Ro antibody during pregnancy could result in congenital heart block in the newborn. The baby is born with a very slow pulse, and may need a pacemaker. Neonatal lupus, a syndrome with skin rash that usually subsides after 3 months, can be seen in children of mothers with Sjögren’s. The incidence of these complications appears to be less than 6% of births among patients.

Non-Hodgkin’s B-cell lymphoma occurs in 5–10% of patients with Sjögren’s syndrome. Usually, this is a slow growing, low-grade malignancy, that can be cured if discovered. It occurs perhaps with greater frequency in patients who have chronic swelling in the parotid glands. The glands develop a new lump, or lymph nodes in the neck are felt to be swollen. The diagnosis isn’t easy, and requires a biopsy with special studies on the specimen (immunoperoxidase stains for cell surface antigens and polymerase chain reaction analysis of DNA for immunoglobulin gene transformation).

Lab findings

Antibodies against particles within the nucleus of normal cells are often seen. About 85% of patients have anti-Ro and about 50% have anti-La antibodies. These sometimes go by another set of names, anti-SSA and anti-SSB, respectively. Patients with Sjögren’s also quite frequently have antinuclear antibodies, but not always. Though this is a screening test for autoimmune disease, and is quite sensitive, it can still actually be negative even when anti-Ro or anti-La are positive. Rheumatoid factor is frequently abnormal in patients with Sjögren’s syndrome as well. Most of the other blood test abnormalities seen with this condition reflect the fact that the body is in a state of chronic inflammation. These include a low hemoglobin level, a low lymphocyte count, a high sedimentation rate and elevated gammaglobulins.

Making the diagnosis

It takes the average patient 30 months and three specialists to achieve a diagnosis of Sjögren’s syndrome.

Like many autoimmune diseases, Sjögren’s can’t be diagnosed from one test alone. Since 2002, European and American Rheumatologists specializing in this disease have agreed upon a set of classification criteria (Table 1). The purpose in creating these criteria was to assure that research was being conducted on a uniform group of patients, but many specialists use the criteria to assure that they have the correct diagnosis.

Four of six categories must be found abnormal. One of these four must be either the presence of anti-Ro and/or anti-La antibodies (VI) or an abnormal minor salivary gland biopsy (IV). Sjögren’s can also be diagnosed if the patient has three of these objective criteria: biopsy, anti-Ro/La, Schirmers test and unstimulated salivary flow (III, IV, V, VI).

The minor salivary gland biopsy, done using local anesthetic, is a small incision on the inside of the lower lip. The glands are the bumps you feel when you run your tongue behind your lip. The pathologist should be familiar with the 2002 American-European Consensus Criteria, because the biopsy must be interpreted in a specified manner, looking for at least one lymphocyte focus (a clump of about 50 lymphocytes or more). The specimen must have a surface area of at least 4mm². If the biopsy is performed in a centre unfamiliar with Sjögren’s, the interpretation will be of no assistance. A biopsy is, furthermore, of limited value unless the patient has at least three other features of the disease, because false positive biopsies are seen in 10-15% of people without Sjögren’s.

A diagnosis of Secondary Sjögren’s Syndrome requires the prior diagnosis of another autoimmune disease, the complaint of either (I) dry eyes or (II) dry mouth, and the objective evidence of two of (III) dry eye, (IV) abnormal minor salivary gland biopsy or (V) abnormal salivary gland (Table 1).

Why is early diagnosis important?

Prevention of complications

Dry eyes can lead to filamentary abrasion of the cornea, and eventual ulceration and scarring. Topical treatment remains most effective at this time. Artificial tears 3-6 times daily in a regular routine provide useful protection, and a gel preparation should be used at night. If the drops are irritating, preservative-free preparations are required. It’s also important to soak the eyelids with hot compresses once or twice daily, followed by a gentle scrub of the eyelashes using baby shampoo. Plugging of the meibomian glands at the eyelid margins decreases the oil content of the tears, preventing them from coating the eyes properly. Glasses can be constructed to prevent evaporation of tears, and artificial plugs can be placed into the drainage ducts in the eyelids to make the tears remain in place over the eyes for a longer period of time.

Topical cyclosporine, an immune suppressant drug, is marketed in the United States as Restasis®. It's been shown to be beneficial in some patients, but isn’t yet available in Canada. When ulceration or damage to the cornea is threatened, artificial tears can be made out of the patient’s own serum, and protective contact lens bandages may be applied.

Dry mouth is best managed with gustatory stimulation. Sugar-free candy or gum, a cherry pit or even a small button in the mouth will provoke secretion of saliva. At bedtime, a vitamin E capsule broken over the fingers and swabbed on the inside of the mouth can give relief. The Biotene® products for mouth cream, rinse and toothpaste can be soothing. Some people benefit from artificial salivary sprays at night such as Moi-Stir® and Salivert®.

Dental decay can be most problematic with this disease. Patients must see the dentist at least every three months for maintenance. Water bottles should be filled with fluoridated tap water where available, rather than non-fluoridated commercial water. Fluoride rinses daily or even fluoride trays supplied from the dentist promote even better protection. Some patients find that dental caps, when indicated, actually protect teeth from further decay, and amalgam fillings in the molars offer better strength against fragmentation than composite fillings. Implants may actually survive much better than initially expected, but time and more experience is required in this area. Ketoconazole cream eases angular cheilitis, and nystatin rinses will alleviate burning tongue.

Systemic medications

Certain drugs impair salivary function, and should be used advisedly. These include muscle relaxants such as cyclobenzaprine, mood-altering drugs, e.g. amitriptyline and nortriptyline, antidepressants, atropine and decongestants.

At this time, no drugs have been proven to alter the course of Sjögren’s syndrome. Medication to modify the intensity of the autoimmune disease could be used in patients suffering with complications that affect vital organs or joints. None of these drugs such as hydroxychloroquine, azathioprine and methotrexate have been shown to improve tear or saliva production, or shrink swollen parotid glands. Such medication may be of benefit to alleviate systemic complications that affect vital organs or joints. Newer biologics such as rituxamab, which targets B cells, are showing some promise in uncontrolled trials and one recent unpublished controlled trial, but this isn’t an easy medication to take, nor is it innocuous. More study is required.

Salagen® (pilocarpine tablets) and Evoxac® (cevimeline tablets, U.S. only) stimulate the parasympathetic nerves that supply the salivary and lacrimal glands. Since these inflamed glands are often not destroyed, such medication can provoke residual function enough to increase tears and saliva. The major side effects include sweating and aggravation of asthma or narrow angle glaucoma.

What the future holds

The scope of this article and the space available preclude a discussion on the research into Sjögren’s syndrome. An understanding of this and other autoimmune diseases is leading to strategies that selectively dampen down an overactive immune system.

Many new drugs have the potential for significant systemic side effects, and the challenge is to find a medication that would be safe enough to use in patients with localized disease affecting mainly the salivary and lacrimal glands. Many biologics have been tried, but don’t seem to improve glandular function. Nonetheless, new targets are being discovered, especially the cytokines for B-cell stimulation: B-cell activating factor (BAFF) and B-lymphocyte stimulator (BLyS). Inhibitors being used in clinical trials for rheumatoid arthritis may ultimately have applications for Sjögren’s syndrome as well.