ACUTE DISEASES OF THE SALIVARY GLANDS IN CHILDREN: EPIDEMIC AND NEEPIDEMICHNYY MUMPS, CALCULOUS AND NON-CALCULOUS SUBMAKSYLIT.

CHRONIC DISEASES OF THE SALIVARY GLANDS IN CHILDREN: MUMPS, SUBMAKSYLIT.

 

Sialadenitis is the inflammation of the salivary glands, the glands that produce saliva in our mouths. Saliva is essential for the normal functioning and health of the mouth.  Disorder of salivary glands function can lead to oral disease, for example tooth decay and gum disease. Sialadenitis is usually caused by bacterial or viral infection but the disorder can occasionally be due to other causes, such as trauma, radiation and allergic reactions.

Bacterial sialadenitis

Bacterial sialadenitis can be generally divided into acute and chronic forms.

Acute bacterial sialadenitis

This uncommon disorder mainly involves the parotid gland.

Causes of parotid sialadenitis

The main bacteria involved are Streptococcus pyogenes and Staphyloccus aureus, and they infect the salivary gland by ascending the ductal system due to reduced salivary flow associated with:

• Dehydration, for example following abdominal surgery

• Radiotherapy for oral or salivary gland cancer

• Gland or duct abnormalities or obstruction

• Sjögren syndrome

• Weaken immune system

• Result of aggravation in a previously chronic sialadenitis, usually seen in submandibular sialadenitis

Acute bacterial sialadenitis of left parotid gland © BMJ Publishing Group

Parotid sialadenitis symptoms

Acute parotitis presents with:

• Painful swollen salivary gland

• Redness of the overlying skin

• Pus may exude from the parotid duct

• Difficulty in opening the mouth

• Fever

• Swelling of the lymph nodes in the neck region

• Body discomfort

Acute bacterial sialadenitis treatment

The pus collected from the salivary duct will be taken for laboratory testing and antibiotics will be prescribed to you by your dentist or doctor. Any soft swelling should be surgically drained and supportive therapy, such as adequate fluid intake, painkillers and practice of good oral hygiene, is important. Once the acute condition has resolved, the causative factors, such as duct stones, are to be identified and corrected.

Chronic bacterial sialadenitis

Causes of chronic sialadenitis

Salivary gland stone

Mainly involving the submandibular gland, this disease that reduces the salivary flow is:

• Most often due to obstruction of the salivary duct by duct stones (salivary calculi)

• Low-grade ascending infection

• This may also develop following acute sialadenitis, particularly if the acute condition was not treated adequately or causative factors not removed.

Chronic sialadenitis symptoms

• Swelling on one side of the face

• Can be symptomless or with intermittent pain of the gland

Chronic sialadenitis treatment

Treatment can vary depending on the position of the duct stone. If the stone is within the duct, the stone can be removed with the duct but if the stone is within the gland, the entire gland will have to surgically removed.

Viral sialadenitis

Mumps (acute viral sialadenitis, epidemic parotitis)

A common acute viral disease that mainly affects the parotid glands, mumps is highly infectious and is the most common cause of acute parotid swelling.

Mumps is caused by:

• An paramyxovirus (mumps virus)

• Transmitted by direct contact or by droplets of saliva

• Long dormant period of 2 to 3 weeks

• Followed by immunity to further attacks

Mumps symptoms

Children are mainly affected. Typically:

• Painful swelling (parotitis), usually on both sides of the face

• Difficulty in opening the mouth

• Fever

• Headache

• Body discomfort

Mumps in adults is less common but once infected, it may involve other organs:

• Orchitis (Inflammation of one or both testes)

• Pancreatitis (Inflammation of the pancreas)

• Meningoencephalitis (Inflammation of the brain and spinal cord and their meninges)

• Rarely, oophoritis (Inflammation of one or both ovaries)

Mumps treatment

No specific anti-viral agents are available therefore treatment is symptomatic involving:

• Painkillers

• Adequate hydration

• Reducing fever

• Infected individuals are advised to isolated themselves for 6 to 10 days since virus is in saliva during this time

Mumps will resolve by itself after about 7 days.

Prevention of mumps

Mumps vaccination is provided as the measles-mumps-rubella (MMR) vaccination. The vaccination is given at around 1 to 4 years of age.

Postirradiation sialadenitis

Radiation sialadenitis is a common complication of radiotherapy directly related to the dose of radiation given. Infection in severely damaged salivary glands is often irreversible but with less damage, some degree of salivary gland function may return after several months.

Obstructive sialadenitis (sialolithiasis)

Benign parotid tumor

Salivary duct obstruction is not uncommon and is usually caused by:

• A calculus (stone) (mostly in submandibular glands)

• Spasm or an abnormal passage of the parotid duct

• Mucus plug (mostly in parotid glands)

• Tumor

• Abnormal narrowing of the duct

• Rarely from irritation of the duct by, for example a denture clasp

Sialolithiasis symptoms

Duct obstruction can cause:

• Painful swelling of the gland

• Pain just before or at mealtimes due to disruption of salivary flow

• There may be dull pain over the affected gland in older patients

Sialolithiasis treatment

X-rays, sialography, CT, MRI or ultrasonography are taken to determine the position of the stone. Duct obstructions are usually correctable by removing the cause.

When to see a doctor

Contact your doctor when you develop any of the following symptoms:

• Painful swelling on the face especially over the salivary glands

• Difficulty in opening your mouth

• Dry mouth

There are three pairs of major salivary glands located in and around the mouth and throat: the parotid, submandibular andsublingual glands. The parotid glands are the largest and overlie the angle of the jaw in front of the ear. From the gland a duct drains saliva into the mouth. The submandibular glands lie deep to the horizontal portion of the lower jaw and their ducts enter the mouth under the tongue. The sublingual glands lie close to the submandibular ducts.

·         In addition to the major salivary glands there are thousands of minor salivary glands present throughout the lips, mouth and throat. Approximately 1 to 1.5 litres of saliva is produced per day. Saliva is 90% water, but also contains proteins that both aid digestion, and keep the mouth and teeth healthy.

·         Salivary gland enlargement may occur because of:

·         Obstruction to the duct of one of the glands.

·         This may be due to either a stone or a narrowing of the duct. Gland swelling typically occurs during eating and is painful. The swelling is caused by saliva build up in the obstructed gland and this can become infected. Stones are most common in the submandibular gland, but occasionally occur in the parotid.

·         Salivary Gland Tumours.

·         These are most common in the parotid gland. 80% are benign (not cancers) and typically present as a slowly growing salivary mass. The risk of a salivary lump being malignant is higher for submandibular tumours (50% are cancers), and most tumours occurring in the minor salivary glands are malignant but these are rare.

Factors suggesting that a salivary lesion may be malignant include:

• Rapid growth

• Fixation of tumour to adjacent structures

• Facial nerve involvement (invasion) resulting in facial muscle weakness

• The presence of enlarged neck lymph glands (although this may also be found with inflammatory lesions).

Salivary Gland Tumours

a. Benign Parotid Tumours

The most common benign parotid tumour is a Pleomorphic Adenoma which is solid. The second most common benign lesion is a Warthins Tumour which is cystic (Cyst-adenoma), and most commonly found in the inferior portion of the parotid. They present as a firm but mobile mass but they can become quite large if left untreated. The majority (80-90% of parotid tumours) occur in the superficial aspect of the gland (superficial to the facial nerve) because 80-90% of the gland is superficial to the nerve. In 10-20% of cases, however, tumours occur in the deep part of the gland, and such lesions can even present as a lump in the throat with expansion of an area called the parapharyngeal space at the back of the mouth. In this latter setting the lump may be visible by looking inside the mouth. Benign salivary gland tumours only rarely cause facial weakness, a finding that is virtually diagnostic of malignancy, however pleomorphic adenomas have a risk of malignant change over a long period of time.

b. Malignant Parotid Tumours

Warthin’s tumor

The most common malignant tumour (70+%) of the parotid gland in New Zealand occurs as a result of involvement of the lymph glands present in the parotid by either a Squamous Cell Cancer (SCC) or melanoma (MM) of skin of the face or scalp. There may be a past history of a previous skin cancer (SCC or MM) but in a small percentage of patients there is no known previous skin cancer.
These are highly aggressive tumours that often also spread to lymph nodes in the neck. These tumours can involve the facial nerve causing facial weakness. The mass feels hard and irregular and can be fixed to deep structures and/or invade the overlying skin causing discolouration or ulceration. They may be palpable lymph nodes in the neck most frequently in the upper deep cervical region (level II) immediately below the parotid. See “Neck Dissection” in this website for classification of neck levels
Primary parotid cancers are rare. As with the more common metastatic SCC or Melanoma cancers they are usually hard and irregular, can involve adjacent structures or skin and can result in facial nerve invasion and facial muscle weakness.

c. Submandibular Tumours

50% of these are malignant. The mass is below the jaw. If malignant, they can invade adjacent structures and cause facial weakness and abnormalities in tongue function. If malignant, there again may be associated with enlarged lymph nodes, most commonly at levels I and II .

d. Sublingual Tumours

The commonest tumour here is a mucous cyst called a Ranula (a term derived from the Greek word for the swollen area below the mouth of a frog). These may be confined to the floor of the mouth (simple Ranula), or they may extend down into the neck: a plunging or diving Ranula.

Cancers of the sublingual gland are rare and usually present as a hard mass in the floor of the mouth and can often involve the lingual nerve causing numbness in the floor of the mouth and tongue.

e. Minor Salivary Gland Tumours.

These are rare and virtually all are malignant. They are most common in the palate. The most common type is an adenoid cystic cancer which has a tendency to invade along nerves and has a high incidence of local recurrence irrespective of the treatment employed.

Parotidectomy

Parotidectomy is the removal of the parotid gland, the largest salivary gland. The paratoid is usually removed because of a tumor, a chronic infection, or a blocked saliva gland. Most parotid gland tumors are not cancerous.

The nerve that closes the eyes, wrinkles the nose, and moves the lips grows through the middle of the parotid gland. Small branches of the nerve might need to be trimmed if the gland is large and the surgeon cannot remove it. Decreased motion of facial muscles might occur while the nerve recovers from surgery. If facial movement does not completely return, rehabilitation can help restore facial movements.

Surgeons think of the gland as two separate lobes: a superficial lobe and a deep lobe.
The facial nerve separates the two lobes. The parotid gland can usually be removed without permanent damage to the facial nerve. A facial nerve monitoring machine (facial nerve stimulator) allows the surgeons to monitor the nerve during the operation.

Benign (non-cancerous) tumors usually need only the superficial lobe removed. But if a benign tumor is located deep in the gland, the deep lobe might need to be partially or completely removed.

In most cases, the entire gland is removed if the tumor is cancerous. If the tumor is small and low-grade (does not spread and does not grow quickly), the surgeon might be able to remove only the superficial lobe.

General anesthesia is required for a parotidectomy.

During the operation, the surgeon will determine the amount of tissue that should be removed. After the gland or section is taken, it is sent to a pathologist. The pathologist slices a thin section, freezes it, colors it with special dyes, and examines it under a microscope. This procedure is called a frozen section. The frozen section is used to determine if the tumor is cancerous or benign, and the specific type of tumor. The most common type of cancer tumor in the head and neck is called squamous cell carcinoma.

After surgery

After surgery you might feel

• numbness of the earlobe and incision site from the scar

• weak face muscles

·         Nerves that link to the saliva producing areas in the parotid gland sometimes link with the nerves that control sweating in the skin. This might cause sweating of the skin at meal time (Frey’s syndrome).

·         A rare condition, called a salivary fistula or sialocele, can develop and cause saliva to leak through the skin.

·         Submandibular sialadenectomy (removal of the submandibular gland)

·         Approach for submandibular sialodenectomy

·         The submandibular gland is also called the submaxillary gland.

·         A submandibular sialadenectomy is used for chronic infections, stones, and tumors. The most common reason for removing a submandibular gland is as a result of infection that occurs if the tubes that drain saliva become blocked. Blockages usually arise as a result of stones. The saliva secreted by the submandibular gland is a bit thicker than that produced by othersalivary glands. Due to its thickness, this saliva can sometimes form little stones in the salivary glands and their ducts similar to those that form in the kidneys. Other indications  for surgery include benign “lumps”, such as pleomorphic  adenomas. Submandibular gland tumors are often malignant and the entire gland needs to be removed.

·         The mandibular branches of the facial nerve lies close the gland. The nerve is positioned away from the gland during surgery. A two inch incision is made below the lower jaw.

·         Many other glands in the mouth make saliva, so the mouth will still have enough saliva after the submandibular gland is removed.

·         Excision of the Submandibular Calculi

·         If the stone is palpable in the floor of the mouth a small incision is made into the duct of the submandibular gland inside the mouth and the calculus (stone) is removed. The incision is left open to prevent narrowing of the duct. If the stone is located well back in the duct or in the gland itself often the submandibular gland must be removed.

·         Sublingual gland surgery

 

·         Plunging ranula

·         The incision for sublingual gland surgery is through the mouth. No incision is made in the face or neck.

·         Sublingual Gland Tumours

·         The most common problem with the sublingual gland is development of a mucous cyst called a Ranula. Treatment is usually simple excision through the mouth although more extensive Ranulas (Diving or Plunging Ranula) may also require a Neck incision. Sublingual cancers are rare and require wide excision +/- node dissection.

·         Minor Salivary Gland Tumours

·         These occur in various sites including the lips, mouth, nose and throat. The surgery involves local resection of the tumour and whatever surrounding soft tissue or bone is involved in order to get a clear margin.

Sialolithiasis, Causes, Symptoms and Treatment

Treatment for sialolithiasis commonly involves removal of that stone thereby making sure there is adequate drainage of the salivary gland. Sialolithiasis commonly involves pain and salivary gland swelling.

There are three salivary glands all of which functions include saliva secretions, which is what helps to moisten and digest the food that we eat.

Salivary duct stone formations are the accumulation of calcium and phosphate crystals. These stones can be present in any one of the glands including the parotid, the sublingual or the submandibular gland. The parotid glands lie basically in front of the ears or just behind the jawline. The submandibular and sublingual glands sit deep within the floor of the mouth.

Saliva is brought about in response to our smell and taste sensations. Saliva also provides our teeth with a healthy environment. The saliva helps break down starches and when the water of our saliva is decreased, the calcium and phosphate in the saliva can cause formation of a stone.

Stones are much more likely to develop when the water content of saliva is decreased. Thereby a person who is dehydrated is at much higher risk of stone formation. Certain medications also predispose a person’s likelihood of stone formation. These medications include antihistamines, antidepressants and diuretics.

Some disorders can cause thickening of the saliva and therefore increase a person’s risk for stone formation. Sjogren syndrome in a condition in which causes dryness of the mouth and other mucus membranes. Some autoimmune conditions can also cause the body to attack its own salivary glands. These conditions can cause a decrease in saliva or thickening of the saliva and ultimately formation of stones.

Symptoms

In some instances the patient may have difficulty opening the mouth or swallowing, they may also have an unusually dry mouth in some cases.

When an individual has a stone they may have pain and swelling of the affected gland. The pain usually worsens at mealtimes when more saliva is produced. It also becomes agitated when a person eats sour or acidic foods.

Sometimes the saliva may have an unusual gritty feel or taste. The salivary gland swelling and pain may often go away after several hours. However sometimes the stone blocks the duct and causes a bacterial infection. If an infection occurs in the gland it becomes severely swollen, extremely painful and very tender to the touch. The person may even sometimes exhibit a fever.

Diagnosis

Diagnosis of a salivary stone usually begins with a physical examination. Salivary stones can often be palpated, especially in the submandibular gland. Your physician will then most likely order a x-ray to confirm the diagnosis.

Prevention

Salivary duct stones may be prevented by increasing the water content of one’s saliva. Some tips for increasing saliva water content is drinking six to eight glasses of water a day and massaging the salivary gland after eating in order to clear any thickened saliva. Other methods include seeking treatment for any autoimmune disorder, sucking on sour hard candy and using prescription antihistamines.

Sialogogues is an agent or drug that increases the flow of saliva.

If a chronic bacterial infection gets into the gland, there may be scar formation in the area and the stone is likely to be more difficult to remove.

Treatments

The stone may be pushed or encouraged out of the duct if it is small enough by firm massage. However for larger stones that cannot completely pass from the duct opening, a small incision may be made to remove it or the salivary duct may be probed and thereby widening the opening of the duct. Sometimes the gland and the stone may have to be completely excised.

Surgical removal of the stone however may cause scarring of the salivary duct opening. This can then interfere with the glands ability to properly drain. Other problems may happen then such as other stone formations along with infection. If the gland is removed, complications may include damage to one of the nearby facial nerves. This may then result in facial paralysis or loss of sensations in face or tongue.

After successful stone excision, the salivary gland usually returns to normal. In instances of recurrent stones or chronic infection, the gland may need to be excised.

Sialolithiasis

Sialolithiasis refers to formation of concrements (sialoliths) inside the ducts or parenchyma of salivary glands, and most commonly occurs in the submandibular glands and their ducts.

Epidemiology

Sialolithiasis is most common disease of salivary glands, accounting for approximately 50% of all major salivary gland pathology ⁵. The submandibular salivary gland is most commonly affected (80 – 90% of cases) with almost all the remaining cases located in the parotid duct ^1-2,5.

Sialolithiasis is a disease of adults, typically between 30 and 60 years of age. There is a male predilection ⁵.

Clinical presentation

Typically patient presents with a history of recurrent swelling and pain in the involved gland usually associated with eating due to obstructions of the draining duct, e.g. submandibular duct, thus slowing down or disabling flow of saliva. This in turn predisposes infection of the gland proximal to the obstruction, resulting in bacterial sialoadenitis.

In chronic cases of obstruction the gland undergoes fatty atrophy and becomes asymptomatic, unless secondarily infected.

Radiographic features

Radiologic methods used to evaluate these stones include :

Plain film

Not all stones are radiopaque. Plain radiography is able to visualise only 80-90% of submandibular stones and approximately 60% of parotid duct stones, presumably due to differences in the composition of the secretion of the parent glands ^2-3. Oblique views are often required to project the stones away from adjacent bone and teeth.

Sialography

Sialography excels at delineating the exact size and location of stones with in salivary gland ducts. The stone will be visualised as a filling defect within the duct. In some cases contrast will not be able to pass beyond the stone.

If active infection is suspected sialography is however contraindicated due to the risk of exacerbating the extent of infection ².

Ultrasound

Ultrasonography is well-established in cases of clinical suspicion of sialolithiasis, able not only to visualise the stone in many instance but also the gland ^2-3. Stones appear as strongly hyperechoic lines or points with distal acoustic shadowing represent stones. Small stones (< 2 mm) may however not shadow ^2-3. Ultrasound is able to visualise stones that are radiolucent.

In acute obstructive cases the gland appears enlarged and excretory ducts proximal to the stone may be visibly dilated. 

Examination is best performed with small high frequency intra-oral probes ⁵. 

CT

CT is excellent at visualising stones both within the duct and within the gland. The spacial resolution is not as high as plain radiography and as such very small stones may not be evident.

Additionally CT is able to assess the gland, although not as well as MRI (see below). In acute obstructive cases the gland may appear enlarged, hyperdense and associated with stranding and enhancement following contrast administration. 

In chronic cases fatty atrophy will be evident, with the parenchyma reduced in volume and replaced by fat.

MRI

MRI is able not only to visualise larger stones but able in many instances to map the ductal anatomy and to asses the gland.

Stones appear as low signal regions (on all sequences) outlined by high signal saliva on T2 weighted images.

MRI is able to distinguish acute from chronic obstruction as well as glands with only incomplete obstruction.

In the acute setting glands are enlarged and demonstrate inflammatory changes:

• T1 : reduced signal compared to the other side

• T2 : increased signal (best seen on fat suppressed sequences)

In chronic cases, the gland is reduced in size and demonstrates fatty atrophy ¹ :

• T1 : increased signal compared to the other side

• T2 : reduced signal of gland parenchyma which is itself reduced in amount

In cases where a small non-obstructive sialolith is present, the gland may appear entirely normal.

Treatment and prognosis

In many instances conservative medical management suffices. Hydration, moist heat are helpful and NSAIDS may be beneficial. Sucking on something sour, (such as a lemon) may increase salivation and promote spontaneous expulsion of the stone.

If these measures are unsuccessful, surgical removal of the salivary stone from the duct after may be required. In chronic cases or if the stone is positioned within the parenchyma of the submandibular salivary gland, the gland may need to be excised.

Increasingly non-surgical options exist to treat symptomatic stones, including ⁴ :

• extracorporal sialolithotripsy

• endoscopic stone removal

• endoluminal balloon dilatation and stone extraction

Differential diagnosis

The differential diagnosis really depends on the modality however in general there is little confusion as clinical presentation is relatively specific. For plain film and CT the differential is that of other calcific foci, and includes ² :

• haemangioma / phlebolith

• atherosclerotic calcification

Filling defects on sialography may be caused by :

• injected bubble of air

• tumour

• blood clot

·         Sialosis

Definition:  Sialosis is an uncommooeoplastic and non inflammatory disorder causing bilateral non painful enlargement  of the major salivary glands. Age of occurrence:  Starts to arise in the middle age.  Its peak incidence occurs during the 5th and 6th decades. Females tend to predominate. Among the major salivary glands the parotid gland undergoes the maximum enlargement.  The enlargement develops rather slowly with some decrease in the salivary flow. Etiology: Precise etiology not known.  The underlying pathogenesis points towards a neuropathy. Sialosis is commonly associated with: 1. Diabetes mellitus 2. Hypothyroidism 3. Malnutrition 4. Alcoholic / other hepatic cirrhosis 5. Puberty (rare) 6. Menopause 7. Anti hypertensive medications Histopathology: It is characterized by acinar cell hypertrophy, atrophy of striated ducts associated with oedema of interstitial connective tissue. In end stage disease there is widespread replacement of acini with fatty tissue. Management:  Rather difficult.  Should always be directed at the underlying systemic disorder. In patients with huge enlargement of parotid salivary glands, then surgical reduction could be a possibility. Use of pilocarpine has shown varying results.

 

Background

Sialadenitis of the submandibular gland is a relatively commonly encountered yet infrequently discussed topic. Causes range from simple infection to autoimmune etiologies. Although not as frequent as sialadenitis of the parotid gland, it represents an important area of clinical relevance to the otolaryngologist and other specialists. The following discusses the basic science of the submandibular gland, as well as the more common causes of sialadenitis and sialadenosis of the submandibular gland.

Anatomy

The submandibular gland, along with the parotid and sublingual glands, comprise the major salivary glands. The minor salivary glands are scattered along the upper aerodigestive tract, including the lips, mucosa of the oral cavity, pharynx, and hard palate.

The submandibular gland is the second largest (approximate weight, 10 g) of the major salivary glands (the parotid gland is the largest). Anatomically, it is situated in the submandibular triangle of the neck.

The gland itself can be arbitrarily divided into superficial and deep lobes based on its relationship to the mylohyoid muscle, the former lying superficial to the muscle, and the latter wrapping around the posterior aspect of the muscle. The gland itself lies on the hyoglossus muscle, superficial to both the hypoglossal and the lingual nerves, the latter supplying parasympathetic innervation by way of the chorda tympani nerve (from cranial nerve VII) and the submandibular ganglion. The duct of the submandibular gland, also known as the Wharton duct, exits the gland from the deep lobe, passing through the floor of the mouth, and opening in close proximity to the lingual frenulum.

Sialogram with stenosis secondary to chronic sialadenosis.

Pathophysiology

The salivary glands serve numerous functions, including lubrication; enzymatic degradation of food substances; production of hormones, antibodies, and other blood group–reactive substances; mediation of taste; and antimicrobial protection. The regulation of salivary flow is primarily through the autonomic system and, most importantly, the parasympathetic division. In the case of the submandibular gland, this is mediated through the submandibular ganglion. Presynaptic fibers are derived from the superior salivatory nucleus and carried by the chorda tympani nerve, which joins the lingual nerve traveling towards the ganglion. Postsynaptic fibers extend from the ganglion to the gland itself.

Saliva is produced in the glandular subunit. The fluid component of the saliva is derived from the perfusing blood vessels in proximity to the gland, while the macromolecular composition is derived from secretory granules within the acinar cells. The saliva is produced in the acinus. Myoepithelial cells, containing contractile elements, are located along the periphery of the acinus. Upon contraction of these myoepithelial cells, the saliva is secreted into the ductal system.

The exact mechanism of salivary secretion is not completely understood but is believed to be under the influence of a cyclic AMP (adenosine 3,’5′-cyclic monophosphate) and a calcium-activated phosphorylation mechanism. The salivary secretions are then modified by a variety of cell types along a series of ducts, including the striated, intercalated, and excretory ducts, before finally being excreted through the Wharton duct into the oral cavity.

The concentration of mucus is higher in the submandibular gland, accounting for the viscous nature of its secretions relative to the other salivary glands. This increased viscosity, and subsequent relatively slower flow, contributes to the propensity for salivary gland calculi and stasis in certain disease states.

Epidemiology

Frequency

United States

The exact frequency of submandibular sialadenitis is unclear. The incidence of acute suppurative parotitis has been reported at 0.01-0.02% of all hospital admissions. The submandibular gland is suggested to account for approximately 10% of all cases of sialadenitis of the major salivary glands. Extrapolation would suggest an incidence of 0.001-0.002%, but this is unconfirmed.

Race

No race predilection per se exists.

Sex

No sex predilection per se exists.

Age

Although no obvious age predilection exists, per se, sialadenitis as a whole tends to occur in the older, debilitated, or dehydrated patient.

History

Submandibular sialadenitis takes several forms. The diagnostic workup of any submandibular enlargement begins with a thorough history. This should include onset, duration of symptoms, recurrence, recent operative history, recent dental work, and thorough drug history, immunization history (specifically measles , mumps , rubella [MMR] vaccine), past medical (specifically autoimmune) history, past surgical history, and history of radiation therapy. Inquire as to associated fever or chills, weight loss, presence of a mass, bilaterality or unilaterality, skin changes, lymphadenopathy, keratitis , shortness of breath, oral discharge, dental pain, or skin discharge.

Physical

Physical examination should begin with the gland itself. The gland should be palpated for the presence of calculi. Examine the ductal opening for purulence. Palpation should extend into the floor of mouth as well as the soft tissue of the tongue, cheek, and neck. Lingual papillary atrophy should be looked for, as well as loss of enamel from the tooth surface (the latter may be associated withbulimia ). All of the major salivary glands should be examined for masses, symmetry, and the presence of discharge. The presence of lymphadenopathy should be noted. The eyes should be examined for any presence of interstitial keratitis. A quick cranial nerve examination should be conducted with particular attention to cranial nerves VII and XII. The lungs should be examined and a chest radiograph ordered if suspected pulmonary involvement exists.

Causes

• Acute sialadenitis: Acute sialadenitis is an acute inflammation of a salivary gland.

• Patients typically present with erythema over the area, pain, tenderness upon palpation, and swelling. Frank cellulitis and induration of adjacent soft tissues may be present. Purulent material may be observed being expressed from the Wharton duct, particularly upon milking the gland. Rarely, a cutaneous fistula may occur, with spontaneous drainage of purulent material. The inflammation is secondary to an infectious process.

• The most common organism is Staphylococcus aureus. Other bacterial organisms include Streptococcus viridans, Haemophilus influenzae, Streptococcus pyogenes, and Escherichia coli. The infection is often the result of dehydration with overgrowth of the oral flora. The most common causes are postoperative dehydration, radiation therapy, and immunosuppression (eg, diabetes mellitus, organ transplant, chemotherapy, human immunodeficiency virus).

• Of note, infection of the submandibular gland is rare in the neonate and prepubescent child. When it does occur, similar pathogens have been identified, including Pseudomonas aeruginosa and group B streptococci. Physical examination, in addition to the symptoms described above, includes failure to thrive and irritability. Progression may occur, involving the contralateral gland. The etiology of this entity is unclear.

• Although less common than bacteria, several viruses have been implicated in submandibular sialadenitis. These include the mumps virus, which typically affects the parotid gland but can affect the submandibular gland as well. Other viruses include HIV, coxsackievirus, parainfluenza types I and II, influenza A, and herpes.

• Infection of the submandibular gland can result in the formation of a submandibular abscess. In this state, the patient may appear toxic, with features similar to acute submandibular sialadenitis. Spiking fevers are not uncommon. This is a serious condition requiring strict attention because of the possibility that the abscess may spread to involve other deep neck spaces of the neck. Trismus may be indicative of parapharyngeal involvement. Progression to Ludwig angina, a life-threatening infection of the submental and sublingual spaces, although rare, can occur.

• Chronic sialadenitis: Chronic sialadenitis, in contrast, is typically less painful and is associated with recurrent enlargement of the gland (often following meals) typically without erythema. The chronic form of the disease is associated with conditions linked to decreased salivary flow, rather than dehydration. These conditions include calculi, salivary stasis, and a change in the fluid and electrolyte composition of the gland.

• Sialolithiasis: Salivary calculi (sialolithiasis) relate to the formation and deposition of concretions within the ductal system of the gland.

• Eighty percent of all salivary calculi occur in the submandibular gland, with approximately 70% of these demonstrable as radio-opacities on routine plain radiography consisting of intraoral occlusal radiographs.

• The calculi vary in size and may be single or multiple. The formation of calculi is associated with chronic sialadenitis, and in particular, the recurrent nature of the problem.

• The exact mechanism of stone formation is unclear, but it appears to be related to the following conditions:

• Salivary stagnation

• Epithelial injury along the duct resulting in sialolith formation, which acts as a nidus for further stone formation

• Precipitation of calcium salts

• The stones themselves are typically composed of calcium phosphate or calcium carbonate in association with other salts and organic material such as glycoproteins, desquamated cellular residue, and mucopolysaccharides.

• Patients most often present with a colicky postprandial swelling of the gland. The course of the disease is typically relapsing and remitting until a final definitive treatment, usually in the form of surgery, is undertaken.

• Autoimmune sialadenitis: Autoimmune diseases, in particular Sjögren syndrome, can be associated with sialadenitis. Although preferentially affecting the parotid gland, the submandibular and minor salivary glands are also affected. The disease, which is associated with keratoconjunctivitis sicca, xerostomia, salivary gland enlargement, and lingual papillary atrophy, is confirmed through biopsy of the minor salivary glands of the lip. Numerous laboratory tests are also used to confirm the diagnosis, such as autoantibodies Sjögren syndrome A (SS-A) and Sjögren syndrome B (SS-B), rheumatoid factor, and antinuclear antibodies.

• Sialadenosis: Sialadenosis refers to nonneoplastic noninflammatory swelling in association with acinar hypertrophy and ductal atrophy.

• Etiologies fall into 5 major categories.

• Nutritional (eg, vitamin deficiency, bulimia)

• Endocrine (eg, diabetes mellitus, hypothyroidism)

• Metabolic (eg, obesity, cirrhosis, malabsorption)

• Inflammatory/autoimmune (eg, Sjögren disease, Heerfordt syndrome)

• Drug induced (eg, thiourea)

• Physical examination shows a nontender swelling that is often bilateral and symmetric but can be unilateral and asymmetric.

Laboratory Studies

• In evaluating the patient with sialadenitis, steps should be taken in the following order: history, physical examination, culture, laboratory investigation, radiography, and if indicated, fine-needle aspiration biopsy (see History and Physical).

• Laboratory investigations should begin with culture of the offending gland (if possible, prior to the administration of antibiotics).

• Blood cultures should be obtained in the patient exhibiting bacteremia or sepsis.

• As a rule, needle aspiration of a suspected abscess is not indicated.

• Routine electrolytes and complete blood cell count with differential should be obtained to assess for any evidence of dehydration or systemic infection.

• If a diagnosis of autoimmunity is entertained, serum analysis for antinuclear antibody, SS-A, SS-B, and erythrocyte sedimentation rate should be conducted.

 

Imaging Studies

• Numerous radiologic techniques are available in submandibular imaging. Deciding which study to obtain first is often difficult. Examination selection should be based in part on the suspected cause of the problem. The authors’ institution tends to begin with plain radiography, followed by the use of computed tomography scanning with combined sialography.

• Of all the radiologic examinations available, one of the simplest is conventional plain radiography.^[1] Anteroposterior, lateral, and oblique intraoral occlusal views are used. This technique is particularly valuable in evaluating the presence of calculi, which are radio-opaque in approximately 70% of cases. These radiographs are limited in that they do not provide any information about the ductal system or soft tissues.

• Sialography can be used to evaluate sialolithiasis or other obstructive entities, as well as inflammatory and neoplastic disease.

• In this technique, a water-soluble medium such as meglumine diatrizoate is injected into the Wharton duct and lateral, oblique, and anteroposterior plain radiographs are obtained in order to assess the ductal arborization.

• Contraindications for this test are iodine allergy and acute sialadenitis.

• Any filling defects (eg, calculi), retained secretions (eg, chronic sialadenitis), stricture formation (eg, inflammation), extravasation (eg, Sjögren disease), or irregularly contoured borders (eg, neoplasm) are noted.

• Ultrasonography can be used to differentiate between solid versus cystic lesions of the gland. It can also be used to differentiate intrinsic from extrinsic disease and can be helpful in identification of abscess formation. A 2009 study by Bozzato et al determined that application of ascorbic acid (vitamin C) as a contrast agent can aid in the ultrasound assessment of obstructive sialadenitis of the parotid and submandibular glands.^[2]

• Computed tomography scanning is an excellent modality in differentiating intrinsic versus extrinsic glandular disease. It is also extremely valuable in defining abscess formation versus phlegmon. It is limited in evaluating the ductal system unless combined with simultaneous sialography.

• Magnetic resonance imaging is of little utility in sialadenitis or sialadenosis. It does not allow evaluation of the ductal system, and it is not helpful in defining calcifications. It is an excellent tool for soft tissue definition and is invaluable in instances of suspected neoplasia.

Procedures

• Fine-needle aspiration and biopsy

• Open biopsy of the lip should be considered when the diagnosis of Sjögren disease is contemplated.

• If suspicion of a solid neoplasm masquerading as sialadenitis is significant, a fine-needle aspiration with biopsy should be undertaken. The management and differential diagnosis of submandibular neoplasms is beyond the scope of the current discussion.

Medical Care

Management of submandibular sialadenitis and sialadenosis involves a wide range of approaches, from conservative medical management to more aggressive surgical intervention.

• One management scheme is as follows:

• Acute sialadenitis

• Medical management – Hydration, antibiotics (oral versus parenteral), warm compresses and massage, sialogogues

• Surgical management – Consideration of incision and drainage versus excision of the gland in cases refractory to antibiotics, incision and drainage with abscess formation, gland excision in cases of recurrent acute sialadenitis

• Salivary calculi

• Medical management – Hydration, compression and massage, antibiotics for the infected gland

• Surgical management – Duct cannulation with stone removal, gland excision in recurrent cases

• Sjögren disease

• Medical management – Hydration, dental hygiene, rheumatology and dental referral

• Surgical management – Gland excisioot usually needed unless recurrent acute sialadenitis

• Sialadenosis

• Medical management – Treatment of underlying cause

• Surgical management – Not indicated

• Medical management centers on eliminating the causative factor.

• Acute sialadenitis

• In cases of acute sialadenitis, adequate hydration should be ensured and electrolyte imbalances corrected.

• Patients are most often treated on an outpatient basis, with the administration of a single dose of parenteral antibiotics in an emergency department, followed by oral antibiotics for a period of 7-10 days. Clindamycin (900 mg IV q8h or 300 mg PO q8h) is an excellent choice and provides good coverage against typical organisms.

• Patients who exhibit significant morbidity, are significantly dehydrated, or are septic should be admitted to hospital. In this latter group of patients, CT scanning of the area should be performed. If a large abscess is noted, incision and drainage should be considered. Small abscesses typically respond to conservative methods.

• In cases refractory to antibiotics, viral and atypical bacterial causes should be considered.

• Sialolithiasis

• Patients with sialolithiasis should be initially treated with hydration, warm compresses, and gland massage.

• Antibiotics are indicated in patients exhibiting infection.

• Sjögren disease

• In those patients with Sjögren disease, hydration and prevention of complications should be undertaken.

• Dental hygiene should be strictly maintained in order to prevent carries, and dental and rheumatology consults should be sought. Gland excision is rarely indicated.

• Sialadenosis: Sialadenosis should be managed expectantly. Treatment should be directed towards managing the underlying problem and achieving homeostasis. Gland excision is not indicated.

Surgical Care

• Acute sialadenitis

• Patients who exhibit significant morbidity, are significantly dehydrated, or are septic should be admitted to hospital. In this latter group of patients, CT scanning of the area should be performed. If a large abscess is noted, incision and drainage should be considered. Small abscesses typically respond to conservative methods.

• In patients with recurrent acute attacks, gland excision during a period of quiescence should be considered. Serial CT scanning is often useful.

• Endoscopic management of sialadenitis frequently obviates the need for gland removal. Results follow a learning curve.^[3]

• Sialolithiasis

• In patients with calculi in proximity of the opening of the Wharton duct, the duct can be cannulated, dilated, and the stone removed via a transoral approach.

• Patients with deep intraparenchymal stones or multiple stones should have their glands excised on an elective basis. Ultrasonic lithotripsy is rarely effective and is not offered at the authors’ institution.

·         Medication Summary

·         The goals of pharmacotherapy are to eradicate the infection, reduce morbidity, and prevent complications.

 

Antibiotics

Class Summary

Therapy must cover all likely pathogens in the context of this clinical setting.

Clindamycin (Cleocin)

 

Lincosamide for treatment of serious skin and soft tissue staphylococcal infections. Also effective against aerobic and anaerobic streptococci (except enterococci). Inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest.

Further Inpatient Care

• Patients requiring inpatient management should be monitored on a daily basis and preferably twice daily.

• In order to ascertain the progression or improvement of acute sialadenitis, serial CT scanning may be warranted.

• Patients with sialolithiasis should be treated conservatively during the acute exacerbation stage and should be monitored after discharge for definitive surgical intervention.

 

Further Outpatient Care

• For patients with acute sialadenitis not requiring admission, follow-up visit should be 3 days from the first visit and then 1 week later (with improvement).

• Patients with chronic sialadenitis/sialolithiasis and autoimmune sialadenitis or sialadenosis should be seen on a regular basis and if acute exacerbation of the problem occurs.

 

Inpatient & Outpatient Medications

• In addition to the antibiotics, patients may be treated with any form of nonsteroidal anti-inflammatory medications. Narcotics may be needed in severe cases, and increasing pain refractory to medications is often an indication for admission for further evaluation.

• In addition, medications predisposing to xerostomia should be avoided where possible. These include antiparkinsonian, antiemetics, antinauseants, over-the-counter and prescription cold medications, antidepressants, antihypertensive agents, diuretics, anticholinergics, antianxiety agents, and decongestants.

 

Complications

• The most serious complication of acute sialadenitis is the formation of an abscess. Management is described above.

• Complications of chronic sialadenitis and autoimmune sialadenitis are most often dental iature because of the decreased function of the gland and the protective effect provided against caries.

• Chronic inflammation of the gland with or without calculi often renders the gland difficult to excise because of the loss of normal tissue planes.

 

Prognosis

• The prognosis of acute sialadenitis is very good. Most cases are easily treated with conservative medical management, and admission is the exception, not the rule. Acute symptoms resolve within 1 week; however, edema in the area may last several weeks.

• Postsurgery, patients are often already admitted with appropriate intravenous antibiotics. These patients have a similar prognosis.

• Patients with chronic sialadenitis often have a relapsing and remitting course. Prognosis is dependent on the etiology.

• Patients with sialolithiasis require definitive surgical treatment in most cases, which results in an excellent prognosis.

• Patients with Sjögren or other autoimmune diseases are likely to have a protracted course related to systemic involvement.

• Patients with sialadenosis have a good prognosis, if their underlying problem is adequately controlled. Even if control is attained, bilateral swelling may be persistent.

 

Patient Education

• Patients with any form of sialadenitis should be educated as to the value of hydration and excellent oral hygiene. This lessens the severity of the attacks and prevents dental complications. Patients with sialadenosis should be educated regarding the mechanism of their underlying pathology and methods of maintaining control over them.

• For excellent patient education resources, visit eMedicineHealth’s Oral Health Center.

 

Sjogren Syndrome 

 

Background

Sjögren syndrome is a systemic chronic inflammatory disorder characterized by lymphocytic infiltrates in exocrine organs. Most individuals with Sjögren syndrome present with sicca symptoms, such as xerophthalmia (dry eyes), xerostomia (dry mouth), and parotid gland enlargement, which is seen in the image below.

Marked bilateral parotid gland enlargement in a patient with primary Sjögren syndrome. Sicca syndrome is a common clinical finding.

In addition, numerous extraglandular features may develop, such as arthralgia, arthritis, Raynaud phenomenon, myalgia, pulmonary disease, gastrointestinal disease, leukopenia, anemia, lymphadenopathy, neuropathy, vasculitis, renal tubular acidosis, and lymphoma. About 50% of patients with Sjögren syndrome have cutaneous findings, such as dry skin (xeroderma), palpable and nonpalpable purpura, and/or urticaria.^[1] (See Etiology, Presentation, and Workup.)

Primary Sjögren syndrome occurs in the absence of another underlying rheumatic disorder, whereas secondary Sjögren syndrome is associated with another underlying rheumatic disease, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), or scleroderma. Given the overlap of Sjögren syndrome with many other rheumatic disorders, it is sometimes difficult to determine whether a clinical manifestation is solely a consequence of Sjögren syndrome or is due to one of its overlapping disorders.

Importantly, classic clinical features of Sjögren syndrome may also be seen in viral infections with hepatitis C, human immunodeficiency virus (HIV), and human T-cell lymphotrophic virus (HTLV). Treatment for Sjögren syndrome is largely based on symptoms, but patients must be monitored carefully for the potential development of lymphoma. (See DDx.)

Classification criteria

A number of classification criteria for Sjögren syndrome were designed primarily for clinical research studies but are also often used to help guide clinical diagnoses. The American-European Consensus Group’s criteria for the classification of Sjögren syndrome were proposed in 2002 and are the most commonly used criteria for the diagnosis of Sjögren syndrome. A new set of classification criteria has been developed by the Sjögren’s International Collaborative Clinical Alliance (SICCA) investigators and accepted as a provisional criteria set by the American College of Rheumatology (ACR) in 2012.

American-European Consensus Group classification

The American-European Consensus Group (AECG) criteria for the classification of Sjögren syndrome are outlined below.^{[2, 3]}These criteria allow a diagnosis of Sjögren syndrome in patients without sicca symptoms or who have not undergone a biopsy.

According to the American-European classification system (as modified by Tzioufas and Voulgarelis^[4] ), diagnosis of primary Sjögren syndrome requires 4 of 6 of the below criteria; in addition, either criterioumber 5 or criterioumber 6 must be included. Sjögren syndrome can be diagnosed in patients who have no sicca symptoms if 3 of 4 objective criteria are fulfilled. The criteria are as follows:

• Ocular symptoms – Dry eyes for more than 3 months, foreign-body sensation, use of tear substitutes more than 3 times daily

• Oral symptoms – Feeling of dry mouth, recurrently swollen salivary glands, frequent use of liquids to aid swallowing

• Ocular signs – Schirmer test performed without anesthesia (< 5 mm in 5 min), positive vital dye staining results

• Oral signs – Abnormal salivary scintigraphy findings, abnormal parotid sialography findings, abnormal sialometry findings (unstimulated salivary flow < 1.5 mL in 15 min)

• Positive minor salivary gland biopsy findings

• Positive anti–SSA or anti–SSB antibody results

Secondary Sjögren syndrome is diagnosed when, in the presence of a connective-tissue disease, symptoms of oral or ocular dryness exist in addition to criterion 3, 4, or 5, above.

Application of these criteria has yielded a sensitivity of 97.2% and a specificity of 48.6% for the diagnosis of primary Sjögren syndrome. For secondary Sjögren syndrome, the specificity is 97.2% and the sensitivity, 64.7%.^[5]

Exclusion criteria include past head-and-neck irradiation, hepatitis C infection, acquired immunodeficiency syndrome (AIDS), prior lymphoma, sarcoidosis, graft versus host disease, and the use of anticholinergic drugs.

ACR classification criteria for Sjogren syndrome

These classification criteria were developed by SICCA investigators in an effort to improve specificity of criteria used for entry into clinical trials, especially in light of the emergence of biologic agents as potential treatments for Sjögren syndrome and their associated comorbidities. This high specificity makes the ACR criteria more suitable for application in situations in which misclassification may present a health risk. They were accepted by the ACR as a provisional criteria set in 2012.^[6]

According to the ACR criteria, the diagnosis of Sjögren syndrome requires at least 2 of the following 3 findings:

• Positive serum anti-SSA and/or anti-SSB antibodies or positive rheumatoid factor and antinuclear antibody titer of at least 1:320

• Ocular staining score of at least 3

• Presence of focal lymphocytic sialadenitis with a focus score of at least 1 focus/4 mm² in labial salivary gland biopsy samples

In comparison with commonly used AECG criteria, the ACR criteria are based entirely on a combination of objective tests that assess the 3 main components of Sjögren syndrome (serologic, ocular, and salivary) and do not include criteria based on subjective symptoms of ocular and oral dryness.

Application of these criteria has yielded a sensitivity of 93% and a specificity of 95% for the diagnosis of Sjögren syndrome. These criteria do not distinguish between primary and secondary forms of Sjögren syndrome.

Complications

Complications related to Sjögren syndrome include the following (see Prognosis, Treatment, and Medication):

• Emergence of disorders associated with Sjögren syndrome, such as SLE and RA

• Infection of the parotid gland, typically staphylococcal, streptococcal, or pneumococcal – clues include unilateral worsening of symptoms, along with tenderness, warmth, and erythema

• Emergence of parotid tumors – watch for unusually hard or unilateral parotid enlargement

• Pregnant patients with antiRo/SS-A antidodies are at risk for fetal loss, complete heart block in the fetus ,and neonatal lupus syndrome in the newborn

• Emergence of pseudolymphomas (pleomorphic cells that do not meet the criteria for malignancy) and non-Hodgkin B-cell lymphomas (see the image below)

 

 

Clinical photograph and photomicrograph of a 48-year-old man with Sjögren syndrome with a large left parotid mass. On biopsy, B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type was identified. Microscopic section of parotid biopsy, stained with immunoperoxidase for kappa light chains (brown-stained cells), showed monoclonal population of B cells, confirming the diagnosis.

 

Etiology

Sjögren syndrome can occur as a primary disease of exocrine gland dysfunction or in association with several other autoimmune diseases (eg, systemic lupus erythematosus [SLE], rheumatoid arthritis, scleroderma, systemic sclerosis, cryoglobulinemia, polyarteritis nodosa). These primary and secondary types occur with similar frequency, but the sicca complex seems to cause more severe symptoms in the primary form.

Virtually all organs may be involved. The disease commonly affects the eyes, mouth, parotid gland, lungs, kidneys, skin, and nervous system.

The etiology of Sjögren syndrome is not well understood. The presence of activated salivary gland epithelial cells expressing major histocompatibility complex (MHC) class II molecules and the identification of inherited susceptibility markers suggest that environmental or endogenous antigens trigger a self-perpetuating inflammatory response in susceptible individuals. In addition, the continuing presence of active interferon pathways in Sjögren syndrome suggests ongoing activation of the innate immune system.^{[7, 8]} Together, these findings suggest an ongoing interaction between the innate and acquired immune systems in Sjögren syndrome.

Association with the human leukocyte antigen

The frequency of HLA-DR52 in patients with primary Sjögren syndrome is estimated to be 87%, but it is also significantly increased in secondary Sjögren syndrome that occurs with rheumatoid arthritis or systemic lupus erythematosus.

The genetic associations in Sjögren syndrome vary among ethnic groups. In white persons, for instance, the condition is linked to human leukocyte antigen (HLA)–DR3, HLA-DQ2, and HLA-B8,^[9] whereas the linkage is to HLA-DRB1*15 in Spanish persons^[10]and to HLA-DR5 in Greek and Israeli persons.^[11]

Some evidence indicates that the true association of Sjögren syndrome may be with HLA-DQA1, which is in linkage disequilibrium with HLA-DR3 and HLA-DR5.^[12] These HLA associations appear restricted to individuals with Sjögren syndrome who have antibodies to the antigens SSA and SSB rather than to the disease manifestations themselves.^[13]

Possible disease triggers

Viruses are viable candidates as environmental triggers, although proof of causation has remained elusive, and certainly no single virus has been implicated. Epstein-Barr virus (EBV), HTLV-1, human herpesvirus 6 (HHV-6), HIV, hepatitis C virus (HCV), and cytomegalovirus (CMV) may have a role. Sjögrenlike syndromes are seen in patients infected with HIV, HTLV-1, and hepatitis C.^{[14, 15, 16]}

Damage and/or cell death due to viral infection or other causes may provide triggering antigens to Toll-like receptors in or on dendritic or epithelial cells, which, by recognizing pathogen-associated patterns, are activated and begin producing cytokines, chemokines, and adhesion molecules. As T and B lymphocytes migrate into the gland, they themselves become activated by dendritic and epithelial cells, thereafter acting as antigen-presenting cells.^[17]

Expressed antigens include SSA/Ro, SSB/La, alpha-fodrin and beta-fodrin, and cholinergic muscarinic receptors.^[13] Dendritic cell triggering by immune complexes formed from SSA ̶ anti-SSA (or other immune complexes) may propagate the ongoing innate and acquired immune activation.

Glandular pathology

The pathology of a typical involved salivary or lacrimal gland in Sjögren syndrome reveals aggregations of lymphocytes—periductal at first, then panlobular. These cells are primarily CD4 T cells (75%) and memory cells, with 10% B cells and immunoglobulin-secreting plasma cells. Although individual lobules can be destroyed, salivary gland biopsy samples from patients with Sjögren syndrome typically retain 40%-50% of their viable glandular structure. Therefore, inflammatory destruction of salivary and lacrimal glands may not fully account for the symptoms of Sjögren syndrome.^[18]

Studies suggest that the disease process of Sjögren syndrome has a neuroendocrine component. Proinflammatory cytokines released by epithelial cells and lymphocytes may impair neural release of acetylcholine. In addition, antibodies to acetylcholine (muscarinic) receptors may interfere with the neural stimulation of local glandular secretion,^[19] perhaps by interfering with aquaporin.^[20]Moreover, a study reports that M3 muscarinic receptor antibodies may cause autonomic dysfunction in patients with Sjögren syndrome.^{[21, 22]}

Current studies have also focused on the role of apoptotic mechanisms in the pathogenesis of primary Sjögren syndrome. A defect in Fas-mediated apoptosis, which is necessary for down-regulation of the immune response, can result in a chronic inflammatory destruction of the salivary gland, resembling Sjögren syndrome.^[23]

Owing to these structural and functional changes in the lacrimal and salivary glands, their aqueous output is diminished. In the eye, tear hyperosmolarity results and is itself a proinflammatory stimulus, resulting in an inflammatory cascade on the ocular surface,^[24]with evidence of immune activation of the conjunctival epithelium and local cytokine and metalloproteinase production. Damage to the corneal epithelium, already vulnerable due to inadequate tear film protection, ensues, with resultant epithelial erosions and surface irregularity.

Extraglandular involvement

Extraglandular involvement in Sjögren syndrome manifests in part as hypergammaglobulinemia and the production of multiple autoantibodies, especially ANA and RF. This may be due to polyclonal B-cell activation, but the cause of this expanded activation is not known.

Involvement of other organs and tissues may result from effects of these antibodies, immune complexes, or lymphocytic infiltration and occurs in one third of patients with Sjögren syndrome. Prolonged hyperstimulation of B cells may lead to disturbances in their differentiation and maturation and may account for the greatly increased incidence of lymphoma in these patients.^[25]

Sex hormones

Sex hormones may influence the immunologic manifestations of primary Sjögren syndrome, because the disease is much more common in women than in men. The prevalence of serologic markers tends to be lower in male patients than in female patients. Although the role of sex hormones (eg, estrogens, androgens) in the pathogenesis of primary Sjögren syndrome remains unknown, adrenal and gonadal steroid hormone deficiency probably affects immune function.

Epidemiology

Occurrence in the United States

Sjögren syndrome is estimated to be the second most common rheumatologic disorder, behind SLE. Sjögren syndrome affects 0.1-4% of the population. This wide range, in part, reflects the lack of uniform diagnostic criteria.^[26]

International occurrence

Comparative studies between different ethnic groups have suggested that Sjögren syndrome is a homogeneous disease that occurs worldwide with similar prevalence and affects 1-2 million people.

Sex- and age-related demographics

The female-to-male ratio of Sjögren syndrome is 9:1. Sjögren syndrome can affect individuals of any age but is most common in elderly people. Onset typically occurs in the fourth to fifth decade of life.

Prognosis

Sjögren syndrome carries a generally good prognosis. In patients who develop a disorder associated with Sjögren syndrome, the prognosis is more closely related to the associated disorder (eg, SLE, lymphoma).

Although salivary and lacrimal function generally stabilize, the presence of SSA and/or hypocomplementemia may predict a decline in function.^[27]

Morbidity and mortality

Morbidity associated with Sjögren syndrome is mainly associated with the gradually decreased function of exocrine organs, which become infiltrated with lymphocytes. The increased mortality rate associated with the condition is primarily related to disorders commonly associated with Sjögren syndrome, such as SLE, RA, and primary biliary cirrhosis. Patients with primary Sjögren syndrome who do not develop a lymphoproliferative disorder have a normal life expectancy.^[28]

Lymphoma

Among patients with Sjögren syndrome, the incidence of non-Hodgkin lymphoma is 4.3% (18.9 times higher than in the general population), with a median age at diagnosis of 58 years. The mean time to the development of non-Hodgkin lymphoma after the onset of Sjögren syndrome is 7.5 years.

The most common histologic subtype of non-Hodgkin lymphoma in Sjögren syndrome is mucosa-associated lymphoid tissue (MALT) lymphoma, which can develop in any nonlymphoid tissue infiltrated by periepithelial lymphoid tissue—most commonly the salivary glands, but also the stomach, nasopharynx, skin, liver, kidneys, and lungs. The progression of these infiltrates to lymphoma occurs slowly and in a stepwise fashion. Lymphoma is present at more than 1 site in 20% of patients at initial diagnosis.

The results of one study suggest that diagnostic labial salivary gland tissue biopsy can be used to detect germinal center ̶ like lesions, which can be a highly predictive and easily obtained marker for non-Hodgkin lymphoma in primary Sjögren syndrome patients.^[29]

Patients at an increased risk of lymphoma include those with regional or generalized lymphadenopathy, hepatosplenomegaly, palpable purpura, leukopenia, renal insufficiency, loss of a previously positive polyclonal gammopathy or RF, development of a monoclonal gammopathy, or the development of a monoclonal cryoglobulinemia.

Neonatal lupus and congenital heart block

Children born to mothers with antibodies against SSA/Ro are at an increased risk of neonatal lupus and congenital heart block. If one such child develops congenital heart block, the risk for congenital heart block during a subsequent pregnancy is 15%.

Antiphospholipid syndrome

Patients with Sjögren syndrome who have antiphospholipid antibodies can develop the clinical features of antiphospholipid syndrome, which include increased fetal wastage and vascular thromboses.

History

The clinical presentation of Sjögren syndrome may vary. The onset is insidious. It usually starts in women aged 40-60 years, but it also can affect men and children. The first symptoms in primary Sjögren syndrome can be easily overlooked or misinterpreted, and diagnosis can be delayed for as long as several years.

Xerophthalmia (dry eyes) and xerostomia (dry mouth) are the main clinical presentations in adults. Bilateral parotid swelling is the most common sign of onset in children.

Extraglandular involvement in Sjögren syndrome falls into 2 general categories: periepithelial infiltrative processes and extraepithelial extraglandular involvement. Periepithelial infiltrative processes include interstitial nephritis, liver involvement, and bronchiolitis and generally follow a benign course.

Extraepithelial extraglandular involvement in Sjögren syndrome is related to B-cell hyperreactivity, hypergammaglobulinemia, and immune complex formation and includes palpable purpura, glomerulonephritis, and peripheral neuropathy. These latter manifestations occur later in the course of Sjögren syndrome and are associated with a higher risk of transformation to lymphoma.^[4]

Symptoms of Sjögren syndrome can decrease the patient’s quality of life in terms of its physical, psychological, and social aspects.

Sicca symptoms (dry eyes and dry mouth)

Although dry eyes and dry mouth are the most common symptoms in patients with Sjögren syndrome, most patients who report these symptoms have other underlying causes. The incidence of sicca symptoms increases with age. Indeed, more than one third of elderly persons have sicca symptoms. Whether this is part of the normal aging process (associated with fibrosis and atrophy observed on some lip biopsy studies) or is due to the accumulation of associated illnesses and medications is unclear.^[30]

Common medications that can cause sicca symptoms in any age group include antidepressants, anticholinergics, beta blockers, diuretics, and antihistamines. Anxiety can also lead to sicca symptoms. Women who use hormone replacement therapy may be at increased risk of dry eye syndrome.^[31]

Patients may describe the effects dry mouth in the following ways:

• Inability to eat dry food (eg, crackers) because it sticks to the roof the mouth

• Tongue sticking to the roof of the mouth

• Putting a glass of water on the bed stand to drink at night (and resulting nocturia)

• Difficulty speaking for long periods of time or the development of hoarseness

• Higher incidence of dental caries and periodontal disease

• Altered sense of taste

• Difficulty wearing dentures

• Development of oral candidiasis with angular cheilitis, which can cause mouth pain

Dry eyes may be described as red, itchy, and painful. However, the most common complaint is that of a gritty or sandy sensation in the eyes. Symptoms typically worsen throughout the day, probably due to evaporation of the already scanty aqueous layer. Some patients awaken with matting in their eyes and, when severe, have difficulty opening their eyes in the morning. Blepharitis can also cause similar morning symptoms.

Parotitis

Patients with Sjögren syndrome may have a history of recurrent parotitis, often bilateral. Although in some patients the parotid glands become so large that the patients report this as a problem, more often the examining physician discovers them.

Cutaneous symptoms

Nonvasculitic cutaneous manifestations in Sjögren syndrome include dryness, eyelid dermatitis, pruritus, and erythema annulare.^[32]

Cutaneous vasculitis, such as palpable purpura, develops in some patients with Sjögren syndrome, especially those with hypergammaglobulinemia or cryoglobulinemia.^{[32, 33]} Raynaud phenomenon is observed in approximately 20% of patients.

Pulmonary symptoms

Patients with Sjögren syndrome can develop dryness of the tracheobronchial mucosa (xerotrachea), which can manifest as a dry cough.^[34] Less often, patients develop dyspnea from an interstitial lung disease that is typically mild.^{[34, 35]} Patients may develop recurrent bronchitis or even pneumonitis (infectious or noninfectious).

Gastrointestinal symptoms

Dryness of the pharynx and esophagus frequently leads to difficulty with swallowing (deglutition), in which case patients usually describe food becoming stuck in the upper throat.^[34]

Lack of saliva may lead to impaired clearance of acid and may result in gastroesophageal reflux and esophagitis.

Abdominal pain and diarrhea can occur. Rarely, patients develop acute or chronic pancreatitis, as well as malabsorption due to pancreatic insufficiency. However, caution is advised when interpreting laboratory results because an elevated amylase level may arise from the parotid gland.

In patients with gastritis, Helicobacter pylori infection should be sought because of its association with gastric mucosa-associated lymphoid tissue lymphomas.^[36]

Patients with Sjögren syndrome are at increased risk for delayed gastric emptying, which can cause early satiety, upper abdominal discomfort, nausea, and vomiting.^[37]

Cardiac symptoms

Pericarditis and pulmonary hypertension, with their attendant symptomatology, can occur in Sjögren syndrome.^[38] Orthostatic symptoms related to dysfunction of autonomic control of blood pressure and heart rate is associated with increased severity of Sjögren syndrome.^[39]

Neurologic symptoms

The occurrence of central nervous system (CNS) and spinal cord involvement in Sjögren syndrome is estimated by various studies to be 8-40%, with manifestations including myelopathy, optic neuropathy, seizures, cognitive dysfunction, and encephalopathy.^{[25, 40, 41]} Attempts must be made to distinguish other causes of these symptoms, including concomitant SLE, multiple sclerosis, cerebrovascular disease, and Alzheimer disease.

Sensory, motor, or sensorimotor peripheral neuropathy, often subclinical, can be detected in up to 55% of unselected patients with Sjögren syndrome.^[42] Symptoms of distal paresthesias may be present. Cranial neuropathies can develop, particularly trigeminal neuropathy or facial nerve palsy. Mononeuritis multiplex should prompt a search for a vasculitis.

Progressive weakness and paralysis secondary to hypokalemia due to underlying renal tubular acidosis can occur and is potentially treatable.^[43]

Renal symptoms

Renal calculi, renal tubular acidosis, and osteomalacia, nephogenic diabetes insipidus, and hypokalemia can occur secondary to tubular damage caused by interstitial nephritis, the most common form of renal involvement in Sjögren syndrome.

Interstitial cystitis, with symptoms of dysuria, frequency, urgency, and nocturia, is strongly associated with Sjögren syndrome.^{[44, 45]}

Glomerulonephritis can be caused by Sjögren syndrome but is uncommon and is usually attributable to another disorder, such as SLE or mixed cryoglobulinemia.

Additional symptoms

Nasal dryness can result in discomfort and bleeding. Patients may also have a dry vagina, which can lead to dyspareunia, vaginitis, and pruritus.

Sjögren syndrome is associated with a wide variety of other disorders. Therefore, a careful review of systems is needed to detect problems such as RA, SLE, scleroderma, polymyositis, chronic active hepatitis, idiopathic pulmonary fibrosis, primary biliary cirrhosis,^[46] and autoimmune thyroid disease.^[47] Patients with Sjögren syndrome may report fatigue, joint pain, and, sometimes, joint swelling.

Women with Sjögren syndrome may have a history of recurrent miscarriages or stillbirths, and women and men may have a history of venous or arterial thrombosis. These are related to the presence of antiphospholipid antibodies (eg, lupus anticoagulant or anticardiolipin antibodies).

Secondary Sjogren syndrome

Secondary Sjögren syndrome appears late in the course of the primary disease. However, in some patients, primary Sjögren syndrome may precede SLE by many years. Secondary Sjögren syndrome is usually mild, and sicca symptoms are the main feature. Unlike patients with primary Sjögren syndrome, persons with the secondary type have significantly fewer systemic manifestations.These manifestations include the following:

• Salivary gland swelling

• Lung involvement

• Nervous system involvement

• Renal involvement

• Raynaud phenomenon

• Lymphoproliferative disorders

In secondary Sjögren syndrome, symptoms of the primary disease predominate. Secondary Sjögren syndrome does not modify the prognosis or outcome of the basic disease. Polyarteritis nodosa and Sjögren syndrome may also coexist, perhaps best viewed as an overlap syndrome.

Physical Examination

The physical signs of primary Sjögren syndrome can be divided into glandular and extraglandular signs.

Glandular signs

Ocular

While it is important to look for corneal lesions and a decreased tear pool in the lower conjunctiva during physical examination, patients with Sjögren syndrome should be referred to an ophthalmologist for more formal testing of keratoconjunctivitis sicca (KCS). This testing applies grading criteria of inflammatory changes that can direct therapy aimed at preventing corneal damage.^[49] In addition, conditions that mimic KCS, such as blepharitis, conjunctivitis, and uveitis can be ruled out or treated.

Patients with Sjögren syndrome may have dilated conjunctival vessels, as well as pericorneal injection and dullness or irregularity of the corneal image. Blepharitis may be present as an alternate or additional problem, particularly if the lower eyelid is inflamed.

Mucinous threads and filamentary keratosis can be detected during a slit-lamp examination. The relative lack of the aqueous layer also leads to rapid tear breakup.

In the Schirmer test, a bent piece of Whatmaumber 41 filter paper is placed in the lower conjunctiva, and the amount of tearing on the filter paper is recorded. Normal wetting is greater than 15 mm after 5 minutes, whereas a definitive positive result is less than 5 mm after 5 minutes. This test can help to exclude or confirm significant dryness of the eyes, but it is not disease-specific. Furthermore, false-positive results occur. An evaluation of the diagnostic performance of the Schirmer test yielded a sensitivity of 42% and a specificity of 76% for Sjögren syndrome. (See the image below.)^[50]

 

Photograph that demonstrates the Schirmer test, which is used to detect deficient tear production in patients with Sjögren syndrome.The filter paper strip is placed at the junction of the eyelid margins. After 5 minutes, 15 mm of paper should be moistened if tear production is normal, as shown here. Persons older than 40 years may moisten between 10 mm and 15 mm. Patients with Sjögren syndrome have less moistening. Sjögren syndrome is most common in patients with rheumatoid arthritis but may also occur without associated disease and in systemic lupus erythematosus, polyarteritis, systemic sclerosis, lymphoma, and sarcoidosis.

Oral

Oral signs include the following:

• Dryness

• Tongue – Red, smooth, and dry (see the image below)

• Dental caries – Severe and progressive

• Parotid duct narrowing

• Lips – Red, dry, and scaly

• Cracks at the corners of the mouth

• Chronic oral candidiasis

Dryness of the mouth and tongue due to lack of salivary secretion is characteristic of xerostomia associated with Sjögren syndrome. Mouth dryness may produce a deep red tongue, as shown here, and dental caries are common.

Look for a decreased sublingual salivary pool. The tongue may stick to the tongue depressor. Patients with Sjögren syndrome may develop frequent caries, sometimes in unusual locations such as the incisor surface and the gum line.

Patients with Sjögren syndrome are prone to develop oral candidiasis. In addition to white patches, watch for petechial lesions, loss of tongue papilla, erythema and fissuring of the tongue, erythema on other mucosal surfaces, and angular cheilosis. Oral candidiasis can be seen under dentures.

Gingival inflammation has been found to be more evident in the individuals with Sjögren syndrome, particularly those with secondary Sjögren syndrome.^[51] Periodontal disease can lead to loss of teeth.

Parotid glands

Sjögren syndrome appears to negatively affect the periodontal condition. Recurrent swelling of the parotid glands (22-66% of patients) occurs; submaxillary and sublingual gland swelling also sometimes takes place.

Bilateral parotid gland enlargement is common in persons with Sjögren syndrome (see the image below). Some waxing and waning of size may occur. Exudates from the parotid gland are largely lymphocytes.

Marked bilateral parotid gland enlargement in a patient with primary Sjögren syndrome. Sicca syndrome is a common clinical finding.

Rock-hard or unilateral parotid gland enlargement should prompt referral to an otolaryngologist for biopsy to exclude a tumor. Other causes of parotid enlargement include diabetes, sarcoidosis, amyloidosis, diffuse infiltrative lymphocytic syndrome (DILS) of HIV disease, hepatitis C, and alcoholism. Acute, unilateral parotitis may be caused by Sjögren syndrome, infection, or obstruction, although the latter 2 conditions are more often associated with a very tender parotid gland and accompanying fever.

Other mucous membranes

Other mucous membrane signs include the following:

• Atrophic changes in the mucous membranes of the upper respiratory tract, leading to nasal dryness, recurrent infections, hoarseness, and aphonia

• Atrophic rhinitis

• Atrophic changes in the vulva and vagina resulting in pruritus and vaginitis

• Dryness of the anal and rectal mucous membranes (eg, pruritus, inflammation)

Cutaneous

Dryness of the skin occurs in 50% of patients with Sjögren syndrome; scaling occurs in about 25% of patients. The skin may be irritable, with secondary lichenification. Partial or complete loss of sweating may be present.

Hair may be dry, sparse, and brittle; diffuse alopecia may involve the scalp, limbs, axillae, or pubis. Nail folds may show capillaroscopic abnormalities, which are associated with the presence of antiendothelial cell antibodies.^[52] Erythema of the nose and cheeks may be present.

Patients with Sjögren syndrome can develop a nonpalpable or palpable, vasculitic purpura, with lesions that are typically 2-3 mm in diameter and located on the lower extremities. The lesions, which can ulcerate, occur most often in patients with hypergammaglobulinemia or cryoglobulinemia.

Annular erythema with scales, localized especially on the face and neck, is recognized as a cutaneous manifestation of Sjögren syndrome. The patches are recurrent and resolve without hyperpigmentation; no photosensitivity is observed.

In Japanese patients with Sjögren syndrome, annular erythema is divided into 3 types: Sweet disease–like annular erythema with an elevated border; subacute cutaneous lupus erythematosus–like, marginally scaled erythema; and papular erythema. These lesions bear some clinical similarities to the annular lesions of subacute cutaneous lupus erythematosus, but their histopathologic features are distinct from those of subacute cutaneous lupus erythematosus. Significant mucin depositions are observed. Annular erythema is a common cutaneous manifestation in Japanese and other Asian patients; however, it is rarely seen in white patents.

Extraglandular signs

Gastrointestinal

Gastrointestinal tract signs include the following:

• Esophageal motility abnormalities

• Pancreatic involvement

• Splenomegaly

• Digestive symptoms (due to atrophy of the gastric mucous membrane with achlorhydria)

• Hepatitis (13%)

Pulmonary

Pulmonary abnormalities occur in 9-29% of cases; they are similar in primary and secondary Sjögren syndrome. Lung signs include the following^[55] :

• Pulmonary fibrosis

• Pulmonary hypertension

• Recurrent chest infections

• Granulomatous infiltration and fibrosing alveolitis

• Restrictive ventilatory defect

• Impaired gas transfer

• Bibasilar rales – Can be heard in patients with interstitial lung disease

Articular

Articular changes (eg, arthritis) occur in 42% of patients with Sjögren syndrome; arthritis can be a component of either the primary or secondary form of the disease. One third of patients with RA have Sjögren syndrome.

Symmetrical, polyarticular, inflammatory arthritis suggests underlying RA or a connective-tissue disease such as SLE or scleroderma. The arthritis in patients with primary Sjögren syndrome is typically nonerosive and mild.

Urinary tract

Patients with Sjögren syndrome have significantly more urinary problems than do those without Sjögren syndrome. Patients may have the following:

• Irritated bladder

• Suprapubic pain

• Renal tubular dysfunction – Patients with primary Sjögren syndrome commonly are first seen because of renal impairment, usually from renal tubular dysfunction^[56]

• Renal tubular acidosis – This affects one third of patients with Sjögren syndrome; a correlation apparently exists between hypergammaglobulinemia and distal renal tubular acidosis^[56]

• Interstitial nephritis – This is rare, occurring in 4% of cases; it is often accompanied by cryoglobulinemia, a decreased level of complement, and the presence of circulating immune complexes

• Impaired renal concentrating ability, generalized aminoaciduria

Neurologic

A combination of lesions and relapses can suggest multiple sclerosis. Myelopathy rarely occurs in the course of primary Sjögren syndrome. It appears as Brown-Séquard syndrome, acute transverse myelitis, or progressive myelopathy. Clinically, cases with nervous system involvement present with paraparesis or paraplegia resulting from lesions at the thoracic or cervicothoracic levels.

Peripheral neuropathy occurs in 10-35% patients with primary Sjögren syndrome. Peripheral nerve dysfunction—such as trigeminal sensory neuropathy, mononeuropathy multiplex, distal sensorimotor polyneuropathy, or pure sensory neuropathy—may occur. This tends to be a small-fiber peripheral neuropathy.^[57] Painful, distal paresthesias in the feet may be evident, as may abnormal sweating. Examination may reveal findings that include decreased pinprick sensation.

Isolated cranial nerve involvement rarely occurs in primary Sjögren syndrome. CNS involvement also is less common (10-25% of patients with Sjögren syndrome) than are other types of involvement; CNS pathology ranges from neuropathy, hemiparesis, transverse myelitis, and dystonia to encephalopathy and dementia.

In Sjögren syndrome, focal brain lesions can be present in the cerebral white matter. In addition, dysregulation of hypothalamic-pituitary-adrenal and thyroid axes can cause some neurologic disturbances.

Diagnostic Considerations

Xerophthalmia, xerostomia, and enlargement of the parotid glands can result from adverse effects of drugs and other diseases. HIV infection can result in diffuse infiltrative lymphocytosis syndrome (DILS), which is characterized by parotid enlargement; involvement of the renal, lung, and gastrointestinal systems; and a low frequency of autoantibody presence. Chronic graft versus host disease may mimic symptoms associated with idiopathic Sjögren syndrome.^[58] SLE might be considered, especially at onset of the disease. Autoimmune thyroid dysfunction may be present. Sjögren syndrome can be underdiagnosed or misdiagnosed.

Histology

Histologic findings of the following disorders can be consistent with Sjögren syndrome:

• Sarcoidosis

• Graft versus host disease

• HIV infection

• HTLV-1 infection

• HCV infection

• Keratoconjunctivitis sicca

Sicca

Differential diagnoses to consider in patients with sicca include the following:

• Medications (eg, antidepressants, anticholinergics, beta-blockers, diuretics, antihistamines, some antiarrhythmic and antiepileptic drugs)

• Anxiety and depression

• Viral infections (eg, mumps)

• Complications from contact lenses

• Dehydration

• Hypervitaminosis A

• Neurotropic keratitis

• Mucous membrane pemphigoid

• Environmental irritants

• Mouth breathing

• Chronic blepharitis

• Chronic conjunctivitis

• Rosacea

• Therapeutic radiation or surgery to the head and neck

• Age

• Alzheimer disease

• Parkinson disease

• Bell palsy

• Amyloidosis

• Sarcoidosis

• Lymphoma

Parotid enlargement

Differential diagnoses to consider in patients with parotid enlargement include the following:

• Viral infection (eg, mumps, Epstein-Barr virus, cytomegalovirus, coxsackievirus A, influenza)

• DILS associated with HIV disease

• Granulomatous diseases (sarcoidosis, tuberculosis, leprosy)

• Hyperlipoproteinemia

• Hepatic cirrhosis

• Hepatitis C

• Bulimia

• Recurrent parotiditis of childhood

• Chronic pancreatitis

• Acromegaly

• Amyloidosis

• Gonadal hypofunction

• Diabetes mellitus

• Salivary gland tumor (primarily unilateral)

• Bacterial infection (primarily unilateral)

• Chronic sialadenitis (primarily unilateral)

• Lymphoma

Associated disorders

Importantly, evaluate the patient for disorders associated with Sjögren syndrome, including the following:

• AIDS

• RA

• SLE

• Scleroderma

• Polymyositis

• Primary biliary cirrhosis

• Thyroiditis

• Chronic active hepatitis

• Mixed cryoglobulinemia

• Celiac sprue

Differential Diagnoses

• Amyloidosis, Immunoglobulin-Related

• Bulimia

• IgG4-related systemic disease

• Pancreatitis, Chronic

• Polymyositis

• Rheumatoid Arthritis

• Salivary Gland Tumors, Major, Benign

• Salivary Gland Tumors, Minor, Benign

• Sarcoidosis

• Scleroderma

• Tuberculosis

 

Approach Considerations

Some laboratory tests can be used to assess salivary and lacrimal involvement in Sjögren syndrome. However, no single test is sufficiently sensitive or specific in the diagnosis of Sjögren syndrome. The condition is properly diagnosed only when the results of various tests are simultaneously positive and when subjective symptoms and serologic abnormalities are present.^[59]

Laboratory test results may indicate the following:

• Elevated erythrocyte sedimentation rate (ESR)

• Anemia

• Leukopenia

• Eosinophilia

• Hypergammaglobulinemia

• Presence of antinuclear antibodies, especially anti-Ro and anti-La

• Presence of RF

• Presence of anti–alpha-fodrin antibody (reliable diagnostic marker of juvenile Sjögren syndrome)

• Creatinine clearance may be diminished in up to 50% of patients

Multiple autoantibodies are associated with Sjögren syndrome.^[60] In a study in which atypical autoantibodies were evaluated in 82 patients with primary Sjögren syndrome, an immunologic overlap (defined by the presence of autoantibodies typical of other systemic autoimmune diseases) was evident in 20% of the patients. The clinical significance of these atypical autoantibodies varied widely.^[61]

Patients with primary Sjögren syndrome may have positive test results for lupus anticoagulant and/or anticardiolipin antibodies, and some patients develop clinical events (ie, fetal wastage, arterial and/or venous thrombosis) associated with antiphospholipid syndrome. Anti ̶ salivary duct antibodies are present in most cases of secondary Sjögren syndrome.

Type II cryoglobulins are noted, particularly in patients with palpable and nonpalpable vasculitic purpura. Hepatitis C should be sought in these patients.

In some studies, patients with Sjögren syndrome have an increased frequency of autoimmune thyroid disease with hypothyroidism (10-15%). Lymphocytic infiltration can be observed in the thyroid gland.

Elevations of serum immunoglobulin G4 (IgG4), found in IgG4-related plasmacytic disease (which can mimic the glandular infiltrations of Sjögren syndrome), are not seen in Sjögren syndrome.^{[62, 63]}

Antibodies to carbonic anhydrase 11 can be seen in patients with Sjögren syndrome who have primary billiary cirrhosis.^[46]

Schirmer test

The Schirmer test is probably the only test available in the emergency department (ED) that can be used to strongly support or refute suspicion of Sjögren syndrome. A test strip of number 41 Whatman filter paper is placed near the lower conjunctival sac to measure tear formation. Healthy persons wet 15mm or more after 5 minutes. A positive test occurs when less than 5mm are wet after 5 minutes. A Schirmer test is shown in the image below.

Photograph that demonstrates the Schirmer test, which is used to detect deficient tear production in patients with Sjögren syndrome.The filter paper strip is placed at the junction of the eyelid margins. After 5 minutes, 15 mm of paper should be moistened if tear production is normal, as shown here. Persons older than 40 years may moisten between 10 mm and 15 mm. Patients with Sjögren syndrome have less moistening. Sjögren syndrome is most common in patients with rheumatoid arthritis but may also occur without associated disease and in systemic lupus erythematosus, polyarteritis, systemic sclerosis, lymphoma, and sarcoidosis.

Rheumatoid factor

Rheumatoid factor is present in 52% of patients with primary Sjögren syndrome and in 98% of patients with the secondary disease, occurring even when RA is not present. Consider a diagnosis of RA if the patient has symmetrical polyarticular synovitis. Loss of a previously positive RF finding can be observed in some patients with Sjögren syndrome who develop lymphoma.

Antinuclear antibodies

ANAs are typically present in patients with Sjögren syndrome. Consider the diagnosis of SLE only if symptoms and signs typical of this disorder are present.

Serum protein electrophoresis

Patients with Sjögren syndrome often have a polyclonal gammopathy. Loss of a previously detected polyclonal gammopathy can be observed in some patients with Sjögren syndrome who develop lymphoma. Development of a monoclonal gammopathy can also signal the development of a lymphoma.

Staining

Rose bengal is an aniline dye that stains epithelial surfaces with diminished mucin protection or with exposed epithelial cell membranes. Conjunctival staining can be detected with the naked eye. Slit-lamp examination is performed after rose bengal staining to detect abnormal uptake in the cornea.

Lissamine green staining works similarly but is less irritating to the eye. Fluorescein staining can be used to detect corneal damage.

Salivary testing

Sialometry is a good measure of the degree of decreased salivary flow and helps to establish xerostomia, but the findings do not narrow the differential diagnoses.

Saliva from patients with Sjögren syndrome has elevated levels of sodium, chloride, lactoferrin, and IgA, but these findings are not specific.

Sedimentation rate

The erythrocyte sedimentation rate (ESR) is elevated in 80% of patients with Sjögren syndrome, but the finding is nonspecific.

Protein profiling

Protein profiling (tear proteomics) has revealed reproducible patterns in patients with primary Sjögren syndrome and appears to hold promise as a diagnostic test for this disorder.^[64]

Additional test considerations

Other test results to consider are as follows:

• High total protein level or a low albumin level – Should prompt the clinician to perform serum protein electrophoresis

• High alkaline phosphatase level – Should prompt consideration of primary biliary cirrhosis

• Elevated transaminase levels – Consider the possibility of chronic active hepatitis, which can be associated with sicca symptoms, or hepatitis C, which can cause mild salivary gland enlargement; however, mild (< 2-fold) increases in transaminase levels have been observed in 22% of patients with Sjögren syndrome^[65]

• Low bicarbonate level – Consider evaluating patients with a low bicarbonate level for type I (distal) renal tubular acidosis; less commonly, patients can also develop proximal renal tubular acidosis with Fanconi syndrome

• Hypokalemia – This condition, which is occasionally severe enough to lead to periodic paralysis, can be observed in patients with type I renal tubular acidosis; however, it can also be observed in patients who have Sjögren syndrome without renal tubular acidosis

 

SSA and SSB

Antibodies against SSA/Ro are found in approximately 50% of patients with the disease (75% of patients with primary Sjögren syndrome and 15% of patients with secondary Sjögren syndrome). Thus, the absence of anti-SSA/Ro antibodies does not eliminate the diagnosis of primary or secondary Sjögren syndrome.

Antibodies against SSA/Ro are present in 50% of patients with SLE and are sometimes found in healthy individuals. Thus, the presence of antibody against SSA/Ro cannot by itself be used to establish a diagnosis of Sjögren syndrome.

Antibodies against SSB/La are present in 40-50% of patients with primary Sjögren syndrome and in 15% of patients with SLE. Finding antibodies against SSB/La in patients without antibodies against SSA/Ro is unusual, but this combination has occurred in patients with primary biliary cirrhosis and autoimmune hepatitis.

Titers of anti-SSA/Ro and anti-SSB/La antibodies do not reflect disease activity. Current enzyme-linked immunosorbent assay tests for these antibodies are more sensitive than previous tests. Thus, the specificity is lower.

Antibodies against SSA/Ro are also associated with the annular erythematous lesions of subacute cutaneous lupus. They are also found in the mothers of newborns with neonatal lupus syndromes and congenital heart block, and some of these mothers have or will develop Sjögren syndrome.

CBC

In patients with Sjögren syndrome, the complete blood count (CBC) is most often within the reference range, but anemia of chronic disease may be present. Pernicious anemia may be associated with the atrophic gastritis.

An abnormal white blood cell (WBC) count, especially with an abnormal differential count, should prompt concerns for a lymphoreticular malignancy. In addition, although a low platelet or WBC count can occur in persons with primary Sjögren syndrome, the finding should also prompt consideration for coexisting SLE.

A mild, normochromic, normocytic anemia is present in 50% of patients. Leukopenia occurs in up to 42% of patients.

Sialography and Scintigraphy

In sialography, radiopaque material is injected into the salivary glands. Sialography is useful to exclude the presence of obstructions or strictures, but the diffuse sialectasis of Sjögren syndrome is seen in various other diseases and is therefore not specific.

Oil-based contrast medium may not be adequately cleared in patients with Sjögren syndrome and, consequently, may damage adjacent tissues and lead to a chronic granulomatous reaction. Performing this procedure with oil-based contrast should be avoided, especially during episodes of acute swelling.

With salivary scintigraphy, the uptake and secretion of sodium pertechnetate technetium-99m (^99m Tc) is a gauge of the salivary flow rates and can provide an objective measurement of salivary gland dysfunction. However, the finding of low flow rates is not specific to Sjögren syndrome.

Positive findings on either sialography or scintigraphy fulfill a criterion for objective evidence of Sjögren syndrome by the American-European Consensus Group.

Biopsy

Minor salivary gland biopsy^[66] currently is the best single test to establish a diagnosis of Sjögren syndrome. In this procedure, an incision is made on the inner lip, and some minor salivary glands are removed for examination. In patients with a possible diagnosis of this disease but with severe extraglandular symptoms, a lip biopsy is often performed to firmly establish the diagnosis of Sjögren syndrome. Obtaining the biopsy sample from below normal-appearing mucosa is important in order to avoid false-positive results. At least 4 salivary gland lobules should be obtained for analysis.

While this is the most definitive test, performing it is not absolutely necessary from a clinical standpoint. Patients with Sjögren syndrome are essentially treated symptomatically and are observed for the development of other rheumatic disorders or lymphoma. This can be initiated without performing a biopsy. If, however, the diagnosis is in doubt or if a definitive diagnosis is needed, then this is the best test.

Salivary gland biopsy can also help to detect pseudolymphoma or lymphoma, as well as the noncaseating granulomas of sarcoidosis.

One study showed that not all patients undergoing lip biopsy derived diagnostic benefit from this procedure and that clinical symptoms and serology did not predict a positive lip biopsy.^[67]

In another study, however, a significant correlation was found between positive findings in minor salivary gland biopsy and the Schirmer test, the rose bengal test, xerostomia, and parotid swelling. The investigators utilized biopsy specimens from the lower lip of 360 patients.

Histologic Findings

Although pathologists use different classification systems, the characteristic findings of minor salivary gland biopsy in a person with Sjögren syndrome include the following (see the image below)^[69] :

• The biopsy shows focal aggregates of at least 50 lymphocytes, and, to a lesser extent, plasma cells and macrophages

• More than 1 focal aggregate is seen per 4 mm²

• T cells, predominantly CD4⁺ cells, are present, unlike the predominance of CD8⁺ T cells seen in the salivary gland biopsy samples from patients with DILS associated with HIV disease

• Normal acini are replaced by lymphocytes

• Focal aggregates are seen in almost all glands

• Ten percent of the lymphocytes are CD5⁺ B cells that produce IgM and IgG antibodies, often with a monoclonal or oligoclonal pattern

• Large foci are present, possibly showing germinal centers

• Epimyoepithelial islands are uncommon in the minor salivary gland but can be seen in the major salivary glandsPhotomicrograph of a lip biopsy specimen showing two lymphocytic foci adjacent to normal-appearing mucinous acini typical of minor salivary gland abnormalities in Sjögren syndrome.

A score of greater than 1 focus per 4 mm² has a specificity of 83.5-95% and a sensitivity of 63-81.8% in the diagnosis of Sjögren syndrome. The focus score may be associated with keratoconjunctivitis sicca, the presence of autoantibodies, and, less commonly, xerostomia.

Lymphocytic infiltrates are also seen in other organs. Findings from a gastric mucosal biopsy may show lymphocytic infiltrates with atrophic gastritis. A kidney biopsy may show interstitial lymphocytic infiltration. Lung biopsy can reveal infiltrating CD4⁺ T cells of a lymphocytic interstitial pneumonitis. Salivary gland biopsy can help to detect pseudolymphoma or lymphoma, as well as the noncaseating granulomas of sarcoidosis.

Surgical Therapy

Occlusion of the lacrimal puncta can be corrected surgically. Electrocautery and other techniques can be used for permanent punctal occlusion.

During surgery, the anesthesiologist should administer as little anticholinergic medication as possible and use humidified oxygen to help avoid inspissation of pulmonary secretions. Good postoperative respiratory therapy should also be provided. Patients are at higher risk for corneal abrasions, so ocular lubricants should be considered.

Biopsies that may be performed in association with Sjögren syndrome include the following:

• Minor salivary gland biopsy – For diagnostic purposes

• Parotid gland biopsy – If malignancy is suggested

• Biopsy on an enlarged lymph node – To help rule out pseudolymphoma or lymphoma

 

Consultations

Sjögren syndrome and its associated disorders necessitate a total patient perspective that is often best provided by an internist. A rheumatologist with specific training and experience in Sjögren syndrome and its associated disorders is also essential to the management of the condition. In addition, good oral prophylaxis and therapy are necessary.

Involve ophthalmologists early in the care of patients, for rose bengal and fluorescein staining to help to establish the diagnosis and for assessment of the degree of eye damage.

Consultation with an otolaryngologist may be needed early to perform a minor or major salivary gland biopsy if this is deemed necessary to establish a diagnosis. The specialist may also need to perform a parotid biopsy if malignant transformation is suggested.

Depending on the problems, patients with Sjögren syndrome may need to be seen by other specialists, including the following:

• Nephrologist – To help manage renal tubular acidosis

• Pulmonologist – To help manage interstitial lung disease

• Hematologist/oncologist – If pseudolymphoma or lymphoma develops

 

Approach Considerations

No curative agents for Sjögren syndrome exist. The treatment of the disorder is essentially symptomatic. In secondary Sjögren syndrome, treatment is based on the accompanying disease and its clinical features. Sjögren syndrome and associated SLE improve more than primary Sjögren syndrome. In Sjögren syndrome associated with polymyositis, monthly cyclophosphamide pulse therapy has been used successfully.

In annular erythema associated with Sjögren syndrome in Japanese patients, prednisolone (10-20 mg/d) is effective. No evidence-based strategies are available for the management of anular erythema in Western populations because it is rare. However, case reports have demonstrated that hydroxycloroquine can be effective in whites.^[70]

The inhibition of protease activity in EBV-mediated apoptotic cells may be a potential therapeutic approach in the treatment of Sjögren syndrome.

Skin and vaginal dryness

Patients should use skin creams, such as Eucerin, or skin lotions, such as Lubriderm, to help with dry skin. Vaginal lubricants, such as Replens, can be used for vaginal dryness. Vaginal estrogen creams can be considered in postmenopausal women. Watch for and treat vaginal yeast infections.

Arthralgias and arthritis

Acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs) can be taken for arthralgias. Consider hydroxychloroquine if NSAIDs are not sufficient for the synovitis occasionally associated with primary Sjögren syndrome. However, hydroxychloroquine does not relieve sicca symptoms. Patients with RA associated with Sjögren syndrome likely require other disease-modifying agents.

Additional treatment considerations

In patients with major organ involvement, such as lymphocytic interstitial lung disease, consider therapy with steroids and immunosuppressive agents, such as cyclophosphamide.

While cyclophosphamide and similar agents may be helpful for treating serious manifestations of Sjögren syndrome or disorders associated with Sjögren syndrome, clinicians should understand that these agents are also associated with the development of lymphomas.

Long-term anticoagulation may be needed in patients with vascular thrombosis related to antiphospholipid antibody syndrome.

In a small group of patients with primary Sjögren syndrome, mycophenolate sodium reduced subjective, but not objective, ocular dryness and significantly reduced hypergammaglobulinemia and RF.^[71]

Among the biologic therapies, the greatest experience in primary Sjögren syndrome is with rituximab, an anti-CD20 (which is expressed on B-cell precursors) monoclonal antibody. Anti-B–cell strategies, particularly rituximab, have a promising effect in the treatment of patients with severe extraglandular manifestations of Sjögren syndrome.

In a double-blind, randomized, placebo-controlled trial, Meijer et al (2010) found that rituximab significantly improved salivary flow rate, lacrimal gland function, and other variables in patients with primary Sjögren syndrome.^[72] In an recent open-label clinical trial, modest improvements were noted in patient-reported symptoms of fatigue and oral dryness, with no significant improvement in the objective measures of lacrimal and salivary gland function despite effective depletion of blood B cells.^[73]

Rituximab appears promising in the treatment of vasculitis and intravenous immunoglobulin (IVIG)–dependent ataxic neuropathy.^{[74, 75]} Results from the AIR registry (French) indicated that rituximab appears to be effective in cryoglobulinemia or vasculitis-related peripheral nervous system involvement in primary Sjögren syndrome.^[76]

In a prospective study of 78 patients with primary Sjögren syndrome treated with rituximab, significant improvement in extraglandular manifestations was reported, as measured by EULAR [European League Against Rheumatism] Sjögren Syndrome Disease Activity Index (ESSDAI) (disease activity score) and overall good tolerance reported.^[77] Several smaller studies of rituximab revealed improvement of arthralgias, regression of parotid gland swelling,^[78] and improvement of immune-related thrombocytopenia.^[79]

Of the TNF inhibitors, both etanercept and infliximab have failed to demonstrate significant benefit in Sjögren syndrome.

Less data are available with regard to the role of anti-CD22, anti-BAFF, anti-IL-1, type 1 interferon, and anti-T–cell agents in treatment of primary Sjögren syndrome, with further investigations ongoing. The overall paucity of evidence in therapeutic studies in primary Sjögren syndromesuggests that much larger trials of the most promising therapies are necessary.

Emergency department care

The diagnosis of Sjögren syndrome can be made from the ED if the index of suspicion is high. Patients may present with mild symptoms (eg, eye grittiness, eye dryness or discomfort, dry mouth, recurrent caries). Bilateral parotid gland swelling is also a common presentation.

Patients with known Sjögren syndrome should not be taken lightly for their complaint of dry eyes or dry mouth, as these chronic problems can be very distressing and obtrusive.

Inpatient care

Give attention to artificial lubricants and humidified oxygen for intubated and/or sedated patients with Sjögren syndrome.

Outpatient care

Encourage patients with Sjögren syndrome to be active. In addition, patients should be encouraged to avoid exacerbation of dryness symptoms (eg, through smoking or exposure to low-humidity environments). All patients with Sjögren syndrome should be monitored by an ophthalmologist and dentist, in addition to their rheumatologist. Certain patients may be candidates for punctal occlusion, which is usually performed by an ophthalmologist.

Monitoring

Most patients with Sjögren syndrome can be monitored at follow-up visits every 3 months and, if the patient is stable, up to every 6 months. Patients with active problems or in whom an emerging associated illness is a concern can be seen as often as monthly.

Dry Eyes

The treatment of dry eyes depends on the severity of the dryness, which is best determined by an ophthalmologist and is graded according to the degree of symptoms, conjunctival injection and staining, corneal damage, tear quality, and lid involvement.^{[80, 81, 82, 83, 84, 85]}

New therapeutic strategies designed to facilitate AQP5 trafficking to the apical plasma membrane may prove useful in the management of dry eyes in Sjögren syndrome. In addition, data oovel secretagogues and androgen therapies for dry eyes are promising.^[74]

Level 1 – Mild symptoms, no corneal signs

Artificial tears should be applied liberally. Patients may need to apply artificial tears more often if they enter a low-humidity environment (ie, air conditioning, airplanes). Artificial tears with hydroxymethylcellulose or dextran are more viscous and can last longer before reapplication is needed. Encourage patients to try various preparations to determine what works best for them.

If artificial tears burn when they are instilled, the preservative in the artificial tears is likely irritating the eye. If artificial tears are used more often than every 4 hours, patients should use a preservative-free preparation to avoid eye irritation from the preservatives.

The use of humidifiers may help. If the patient is living in an area with hard water, he or she should use distilled water. Patients should avoid medications with anticholinergic and antihistamine effects.

Level 2 – Moderate or severe symptoms with tear film signs or visual signs, or mild corneal/conjunctival staining

Patients should use unpreserved tears or gels or nighttime ointments. Patients who wake up in the morning with severe matting in the eyes should use a more viscous preparation (eg, Lacri-Lube) at night. While the more viscous preparations can be applied less often, they can make patients’ vision filmy. Therefore, they are best used at night. The more viscous preparations occasionally lead to blepharitis, which can exacerbate sicca symptoms.

The following agents may also be indicated:

• Topical steroids

• Secretagogues

• Cyclosporine A^[86]

• Nutritional supplements

Level 3 – Severe symptoms with marked corneal changes or filamentary keratitis

The following treatments may be indicated:

• Tetracyclines

• Autologous serum tears

• Temporary plugging of the lacrimal puncta to increase the amount of tears that remain in the eyes

Level 4 – Extremely severe symptoms with altered lifestyle, or severe corneal staining, erosions, or conjunctival scarring

The following therapies may be indicated:

• Systemic anti-inflammatory therapy, including acetylcysteine

• Topical vitamin A

• Electrocautery and other techniques for permanent punctal occlusion

• Glasses fitted with moisture shields to decrease evaporation

 

Dry Mouth

Patients with dry mouth can liberally drink sips of water and take bottled water with them on trips. They can also place a glass of water at their bedside for nighttime use, as needed.^[87] Sugar-free lemon drops can also be used as needed to stimulate salivary secretion. Artificial saliva can be used as needed, although patient tolerance varies. Preparations include Salivart, Saliment, Saliva Substitute, MouthKote, and Xero-Lube. Patients should avoid medications with anticholinergic and antihistamine effects.

The use of humidifiers may help. Distilled water is best in patients living in an area with hard water.

Patients should be seen regularly by a dentist, who may advise fluoride treatments. Toothpaste without detergents can reduce mouth irritation in patients with Sjögren syndrome. Brands include Biotene toothpaste, Biotene mouth rinse, Dental Care toothpaste, and Oral Balance gel.

Watch for oral candidiasis and angular cheilitis and treat them with topical antifungal agents, such as nystatin troches. Oral fluconazole may occasionally be needed. Patients also need to be sure to disinfect their dentures.

Sinusitis and sinus blockade should be treated because these problems may contribute to mouth breathing. Emphasize the use of isotonic sodium chloride solutioasal sprays to avoid antihistamine use.

Pilocarpine or cevimeline tablets are options. Some small studies suggest that interferon alfa may be a useful therapy in the future.

Medication Summary

Most patients with Sjögren syndrome can be cared for adequately with topical therapy and with avoidance of medications that exacerbate their symptoms. Pilocarpine or cevimeline can be used in cases of xerostomia for which systemic therapy is needed or local therapy is not successful.

Reports on the use of rituximab in patients with primary Sjögren syndrome have emerged in the literature.^{[88, 89, 90]} In a double-blind, randomized, placebo-controlled trial, Meijer et al found rituximab significantly improved saliva flow rate, lacrimal gland function, and other variables in patients with primary Sjögren syndrome.^[72]

Rituximab has a promising effect in the treatment of patients with severe extraglandular manifestations of Sjögren syndrome, such as vasculitis, cryoglobulinemia, and peripheral neuropathy.^{[76, 77]} Although some data support its efficacy for glandular involvement, it is not currently used for treatment of sicca symptoms alone.

Gastrointestinal Agents, Other

Class Summary

These agents bind to cholinergic (muscarinic) receptors, increasing the secretion of exocrine glands, including salivary glands.

Pilocarpine (Salagen)

Pilocarpine is a cholinergic parasympathomimetic agent that can be used to enhance secretion by exocrine glands when systemic therapy is needed or local therapy fails.

Artificial saliva

These preparations typically contain methylcellulose, sorbitol, and salts to moisten and lubricate the mouth.

Cevimeline (Evoxac)

Cevimeline is indicated for xerostomia in Sjögren syndrome.

Ophthalmic Lubricants

Class Summary

Various over-the-counter (OTC) preparations of natural tears that provide topical therapy for dry eyes are available. Encourage patients to try different preparations to determine which works best for them.

Artificial tears (Nu-Tears, Murine Tears, Refresh, Tears Naturale) 

These preparations contain the equivalent of 0.9% sodium chloride and are used to maintain ocular tonicity. They replace the aqueous layer of tears that is lost in patients with Sjögren syndrome. Preparations that have hydroxymethylcellulose or dextran are more viscous and therefore can last longer before reapplication is needed.

Antimalarials

Class Summary

These agents are used to treat Sjögren syndrome ̶ associated arthritis that is unresponsive to NSAIDs.

Hydroxychloroquine (Plaquenil)

Hydroxychloroquine is an antimalarial agent. Its mechanism of action in inflammatory arthritis is unknown.

Antineoplastics, Alkylating

Class Summary

Consider these agents in patients with Sjögren syndrome who develop a major organ manifestation such as interstitial lung disease.

Cyclophosphamide (Cytoxan)

Cyclophosphamide is an alkylating agent with potent immunosuppressant properties. Dosage adjustments should be based on monitoring clinical response and the CBC or nadir CBC.

Immunomodulators

Class Summary

These agents may regulate key immune factors responsible for inflammation.

Cyclosporine ophthalmic (Restasis)

Cyclosporine ophthalmic is used to relieve dry eyes caused by suppressed tear production secondary to ocular inflammation. It is thought to act as a partial immunomodulator, but the exact mechanism of action is not known.

Corticosteroids

Class Summary

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body’s immune response to diverse stimuli.

Prednisone

Prednisone is an immunosuppressant used in the treatment of autoimmune disorders. It may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear cell activity. Prednisone stabilizes lysosomal membranes and also suppresses lymphocytes and antibody production and activity.

Methylprednisolone (A-Methapred, Solu-Medrol, Depo-Medrol)

Methylprednisolone is available in intravenous (IV)/intramuscular (IM) or oral (PO) form. Methylprednisolone may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear (PMN) leukocyte activity.

Prednisolone (Pediapred, Prelone, Orapred)

Prednisolone may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear (PMN) leukocyte activity. It is a commonly used oral agent.

Antineoplastics, Monoclonal Antibody

Class Summary

Rituximab has a promising effect in the treatment of patients with severe extraglandular manifestations of Sjögren syndrome. Although some data support its efficacy for glandular involvement, it is not currently used for the treatment of sicca symptoms alone. Rituximab has an off-label indication for Sjögren syndrome.

Rituximab (Rituxan)

Rituximab is a monoclonal antibody directed against the CD20 antigen on maturing B-lymphocytes, leading to the depletion of mature circulating B-cells, which are believed to play an important role in the pathophysiology of primary Sjögren syndrome.