(SHOW-grins) syndrome is an autoimmune disease that attacks the exocrine
glands (i.e., moisture-producing glands) of the body, specifically the
lacrimal and salivary glands. It is classified among such diseases as
rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis.
Sjögren's syndrome can affect
any part of the body; however, patients typically present with two hallmark
symptoms--feelings of dryness in the eyes (keratoconjunctivitis sicca) and in
the mouth (xerostomia). Dryness can extend to other areas of the body such as
the nose, skin, lungs, and vaginal tract. No two patients will present in the
exact same way, which contributes to the difficulty in diagnosing this
No cure has been found for
Sjögren's syndrome; however, there are a number of prescription and
nonprescription (OTC) medications/products on the market to help alleviate the
symptoms of dryness. Pharmacists can have a dramatic impact on patients'
quality of life. Providing pharmaceutical services (i.e., medication
counseling, advising OTC product selection and nonpharmacologic treatment
options) can help these patients live happier lives.
A number of studies
have been conducted to determine the prevalence of Sjögren's syndrome, and
among these studies, an estimated 0.04% to 4.8% prevalence has been cited.
1-3 It is believed to afflict approximately one to four million
Americans, 90% of whom are women. The broadness of this prevalence statistic
is due to the lengthy and sometimes difficult process of diagnosis. Typically,
most individuals are older than 40 when affected by this syndrome. However,
the condition can occur in all age groups. This syndrome is diagnosed in
individuals of all races and ethnic backgrounds.
Etiology and Pathophysiology
still unclear about the exact cause of Sjögren's syndrome. However, a number
of genes have been identified that are thought to play a role in the
development of this syndrome; these include various forms of the HLA-DRB
, HLA-DQA, and HLA-DQB genotypes.4,5 Researchers have
hypothesized that a combination of this genetic predisposition and
environmental triggers (i.e., viral or bacterial infection) cause Sjögren's
syndrome to develop.
Two different processes
characterize the pathogenesis of Sjögren's syndrome. The first involves a
T-cell mediated process that leads to direct cell destruction and B-cell
activation, leading to the production of autoantibodies.5 Salivary
and lacrimal glands are infiltrated by the T cells. This infiltration leads to
the release of cytokines and the resultant inflammation and destruction. The B
cells produce autoantibodies, SSA (anti-Ro) and SSB (anti-La), which are
associated with Sjögren's syndrome.
So the hypothesis is as
follows: a person has the genetic predisposition and is subsequently infected
by a virus or bacterium. This infection then causes these dormant genes to be
expressed and the immune system to attack. However, the genes steer the attack
away from the invading organism toward the host.6 The glands, which
are resistant to apoptosis--resistance to apoptosis is believed to be
genetic--are lymphatically infiltrated; this inflammation then causes the
destruction of the glands.6 A debate remains on whether this
lymphatic infiltration causes complete destruction of the lacrimal and
salivary glands or whether the production of saliva and tears is only
The symptoms of
Sjögren's syndrome are caused by the inflammation and destruction of the
exocrine glands and other parts of the body. Some of the characteristic
symptoms that patients present with include dry eye and dry mouth. Patients
with keratoconjunctivitis complain of a dry, gritty feeling in the eyes. They
may also describe "what feels like sand in the eye(s)." Symptoms associated
with dry mouth can range from a dry, cracked tongue to difficulty talking,
swallowing, or chewing dry food.7 Other common complaints include a
dry, sore, or burning throat, a change in sense of taste or smell, dry cough,
or hoarseness.4,6,7 An increase in dental decay and/or mouth sores
is also observed in these patients due to a lack of saliva production and of
the antibacterial substances that saliva naturally contains.
A wide variety of other
symptoms are observed in patients with Sjögren's syndrome. These symptoms are
nonspecific and can mimic those of other disease states (e.g., extreme
fatigue, muscle pain, neuropathy, dry skin, stomach ulcers). A list of
symptoms that patients might display can be found in Table 1. When the
inflammation and dryness extend to other parts of the body, besides the eyes
and mouth, it is termed extraglandular involvement.7 The
areas of the body that can be affected include the skin, nose, liver, kidney,
lungs, vascular system, genital area, nervous system, and digestive system. It
is important to note that not every patient will display the same set of
diagnosing Sjögren's syndrome can be a lengthy and difficult process. The time
frame from the onset of symptoms to diagnosis is more than six years.7
There are a number of reasons for this prolonged timeframe. First and
foremost, symptoms of Sjögren's syndrome are similar to those of other disease
states, such as rheumatoid arthritis and lupus. Another reason is that
Sjögren's syndrome encompasses many clinical specialties, such as
rheumatology, dentistry, and ophthalmology, making the diagnosis difficult.
Historically, the diagnosis of
Sjögren's syndrome has been made on the basis of a patient history and
physical examination. Also, a number of laboratory tests (i.e., blood, dental,
and ophthalmologic tests) have been used to aid in the diagnosis. A number of
classifications systems have been developed to aid the diagnosis of Sjögren's
syndrome.8,9 In 2002, the American-European Consensus
Classification Criteria for Sjögren's syndrome was released (
Table 2).8 In the revised criteria, patients must present with
four of the six criteria, as well as with an abnormal lip biopsy or positive
serum antibodies, to be diagnosed as having primary Sjögren's syndrome.
8 Patients can also be diagnosed with Sjögren's syndrome if three of the
four objective criteria (III, IV, V, or VI) are present.8 Secondary
Sjögren's syndrome is diagnosed when the patient has an associated disease
(e.g., another connective tissue disorder), the presence of criterion I or II,
and any of criteria III, IV, or V.8 A diagnosis of Sjögren's
syndrome should be excluded if patients have had past head and neck radiation
treatment; if they have hepatitis C infection, AIDS, preexisting lymphoma,
sarcoidosis, or graft versus host disease; or if they are maintained on
The consensus classification
criteria begin by questioning the patient about his or her oral and ocular
symptoms. Subjective data are collected about the use of tear substitutes,
feelings of dryness in the eye and the mouth, swollen salivary glands, and the
need for liquids to aid in swallowing food. Objective data are collected
through the use of laboratory and ophthalmologic tests and examinations.
The blood tests performed are
nonspecific and are used to diagnose many disease states. For instance, an
antinuclear antibody (ANA), rheumatoid factor (RF), or erythrocyte
sedimentation rate (ESR) laboratory test can be performed. Each of these
laboratory tests indicates an inflammatory state and is not specific enough to
make a definitive diagnosis. However, the results of these tests can aid in
making a diagnosis. Sixty percent to 70% of patients with Sjögren's syndrome
are RF positive and approximately 70% of patients are ANA positive.10
A more specific blood test is one that measures for the presence of SSA or
SSB antibodies. SSA, known synonymously as anti-Ro, is a specific antinuclear
antibody present in approximately 70% of patients with Sjögren's syndrome.
SSB, known synonymously as anti-La, is also a specific antinuclear antibody
and is present in about 40% of patients.1,2 The Consensus
Classification Criteria rely only on the presence of the SSA and/or SSB
antibodies in the serum to help in the diagnosis.
help confirm the destruction of lacrimal glands and the reduction in tear
production. Dyes used to observe abnormal cells on the surface of the eye
include Rose Bengal and lissamine green.4 A score of greater than 4
is required for a positive test. A Schirmer test may also be performed to
measure the amount of tear production. Healthy patients will produce more than
8 mm of tears over a five-minute period. Patients with Sjögren's syndrome will
produce less than 5 mm of tears in this time frame. Patients must test
positive for either of these two examinations.
Oral examinations help confirm
the destruction of the salivary glands and the reduction in saliva production.
Patients must test positive for one of the following three tests: unstimulated
gland flow, parotid sialography, or salivary scintigraphy. Unstimulated gland
flow tests measure the amount of saliva produced over a certain period of time.
4 In healthy patients, greater than 1.5 mL of saliva will be produced
over a 15-minute period. Parotid sialography is an x-ray of the salivary duct
system by means of the injection of a dye opaque to x-radiation. Salivary
scintigraphy detects a radioactive material injected into the body.4
In a patient with Sjögren's syndrome, the salivary gland will take up little
to no radioactive material. A lip biopsy is also used to confirm lymphocytic
infiltration of the salivary glands. To make a definitive diagnosis, patients
must have either a positive lip biopsy or a positive serum marker.
Sjögren's syndrome can affect nearly
any part of the body including the respiratory tract, ears, nose, kidneys,
liver, gastrointestinal tract, nervous system, muscles and joints, heart,
reproductive system, and immune system. There is no way to forecast which
organs or areas of the body will be affected in a particular patient.
Areas of the respiratory tract
that are involved include the nose, larynx and trachea, bronchial tubes, and
lungs. Patients with lung involvement can develop atelectasis, an absence of
gas from part or all of the lungs; due to build up of mucus in the bronchi and
lung; tracheobronchitis, interstitial lung disease; hoarseness of the voice if
the larynx is involved; pleurisy; or even pulmonary hypertension.
Patients with affected kidneys
can develop interstitial nephritis. This can result in renal tubular acidosis,
glomerulonephritis, nephrogenic diabetes insipidus, and, if the urinary
bladder is involved, interstitial cystitis.
The entire length of the
gastrointestinal tract can be involved as well. Symptoms of dryness begin in
the mouth, followed by effects in the stomach and pancreas. Patients may have
difficulty swallowing food and can experience gastric reflux and chronic
atrophic gastritis that can cause dyspepsia.
Patients with liver
involvement can develop primary biliary cirrhosis (PBC), which is immune
mediated and destroys the small bile ducts. Patients with PBC will present
with fatigue and itching. Autoimmune hepatitis is also common among these
The central, as well as the
peripheral, nervous system can be affected in patients with Sjögren's
syndrome. Involvement of the peripheral nervous system can lead to
neuropathies in the legs, feet, hands, arms, and even the facial region.
Carpal tunnel syndrome is common among these patients. The tissue around the
median nerve in the forearm becomes inflamed and thus presses against the
nerves. This pressure causes sensations of tingling, numbness, and muscle
Pericarditis can develop in
patients who have heart involvement, in which the lining of the heart becomes
inflamed. Involvement of the heart is more common in patients who have another
connective tissue disorder or secondary Sjögren's syndrome.
The reproductive system,
particularly the vaginal area, can also be involved, and complication with
pregnancy can also occur. Lack of moisture production in the vaginal area can
cause discomfort, painful sexual intercourse (i.e., dyspareunia), and a
tendency toward infection. Congenital heart block, (i.e., dysfunction of rate
and/or rhythm) can develop in babies born to women who are positive for the
SSA or SSB antibodies. For this reason, it is important for women with
Sjögren's syndrome to speak with their doctor prior to becoming pregnant to
discuss these issues.
with Sjögren's Syndrome
Patients with Sjögren's syndrome are
at an increased risk for the development of lymphoma. It is estimated that
between 2% and 10% of patients will develop lymphoma. One study found that
patients with Sjögren's syndrome have up to a 44-fold increased risk of
developing lymphoma, compared with the general population.7
Treatment of Sjögren's
Sjögren's syndrome focuses on alleviating symptoms of dryness in the eyes and
mouth as well as in extraglandular areas. Although there are only a few
prescription medications available to treat these symptoms, there are a number
of nonprescription medications available to patients to help alleviate
symptoms (see Table 3).
Dry Eyes and Mouth:
Available products for the treatment of dry eye, or keratoconjunctivitis
sicca, are designed to replace or supplement the deficient tears and/or to
minimize tear loss. One prescription medication, Lacrisert
(hydroxypropylcellulose), is designed to decrease the evaporation of tears
from the surface of the eye. The recommended dosage is one pellet inserted
between the lower eyelid and the eye once or twice daily.11 The
pellets slowly dissolve, forming a film over the surface of the eye. This film
slows the evaporation of the natural tears or administered artificial tears.
The most common adverse effects associated with Lacrisert include blurred
vision, matting/stickiness of the eyelash, and ocular discomfort.11
Another product that was
recently approved for clinical use is Restasis (cyclosporine ophthalmic
emulsion). Restasis decreases inflammation in the lacrimal gland. Its intent
is to reduce the amount of damage to the gland and preserve the tear producing
function.12 The recommended dosage is one drop in both eyes twice
daily. The most common adverse effects include a burning sensation with
administration, red eye, epiphora (the overflow of tears due to imperfect
drainage by the tear-conducting passages), a foreign body sensation (similar
to having something in the eye), itching, and blurred vision.12
are a vast number of OTC products that help moisturize the eye. Products
range from artificial tears to ointments, some of which contain preservatives.
Patients may develop sensitivity to or experience irritation from the
preservatives utilized in some of these products. If this occurs, patients can
either switch to another product with an alternative preservative or select a
preservative-free preparation. Instillation technique is especially important
if a preservative-free preparation is selected for use. Every precaution
should be taken by the patient to avoid contamination/eye infection by direct
contact with the eye dropper and the eye itself. The products on the market
are virtually the same in formulation; however, they differ in viscosity
characteristics. Ointments are used, preferably, at bedtime, because these
product cause blurred vision due to their opacity. The choice of which product
to use is based solely on patient preference, and the products can be used as
needed. If the dryness becomes severe, or if the use of artificial tears
becomes cumbersome, punctual occlusion surgery is the treatment of choice.
Punctual occlusion surgery entails placing a silicone or collagen plug in the
lacrimal puncta, through which tears normally drain. Closing off this drainage
system allows the artificial tears to reside on the surface of the eye for a
longer period of time. Patients should be informed that ocular agents might
cause blurred and abnormal vision, cataracts, conjunctivitis, edema of the
eyelids, and local irritation.
The goals of treating dry
mouth are to increase salivary production, replace salivary secretions, and
avoid complications.13 Two prescription medications are currently
available to stimulate salivary production--Salagen and Evoxac. These products
work in a similar fashion. Salagen (pilocarpine hydrochloride) is a
cholinergic agent.14 It stimulates the action of acetylcholine at
the muscarinic receptors in the salivary gland and thus stimulates salivary
production in those glands that retain some residual function. It is commonly
dosed at 5 to 10 mg orally three to four times a day. In a randomized,
double-blind, controlled trial, patients receiving 5 mg three times a day
reported improvement in dry mouth symptoms and had fewer adverse effects
compared with patients taking 10 mg four times a day.15 The most
common adverse effects associated with Salagen include sweating, rhinitis, and
urinary frequency.15 Cholinergic agents can also cause other side
effects such as excessive salivation, increased diaphoresis, headache, nausea,
diarrhea, flushing, chills, and dizziness.
hydrochloride), like pilocarpine, is a cholinergic agent with increased
activity at the M1 and M3 receptors, which are prevalent in the salivary
glands.16 In a randomized, double-blind, placebo-controlled trial
conducted by Fife et al., patients were given either 30 or 60 mg of cevimeline
orally three times a day for six weeks.17 Both medication regimens
provided a significant difference (P <.01 and P <.05,
respectively) in the subjective relief of xerostomia symptoms, compared with
placebo. Patients tolerated 30 mg of cevimeline three times a day better than
those given 60 mg of cevimeline three times a day.17
Gastrointestinal tract symptoms (i.e., nausea, dyspepsia, diarrhea, abdominal
pain) accounted for the most frequently reported adverse effects in patients
taking 60 mg three times a day.17
Another study, conducted by
Petrone et al., demonstrated that 30 mg of cevimeline three times a day
provided a statistically significant improvement in the objective
measure--increased salivary flow rate (P <.01) and lessening of
dry eye (P <.05)--compared with placebo.18
Improvement of the subjective symptom of dry mouth (P <.001 and P
<.01) was statistically significant, compared with placebo and a regimen of
15 mg of cevimeline three times a day.18 The most common adverse
effects reported by patients included headache, increased sweating, abdominal
pain, and nausea.18
OTC products available for the
relief of xerostomia merely replenish the lack of saliva. Salivart, a natural
saliva substitute, can be used as needed. Moisturizing gels also help patients
with dry mouth. Oral-Base Moisturizing Gel (hydrogenated starch hydrolysate,
glyceryl polymethacrylate, xylitol, hydroxy ethylcellulose, beta-d-glucose,
lactoperoxidase, lysozyme, lactoferrin, glucose oxidase, potassium
thiocyanate, aloe vera) is such a product, and it is used as needed.
Interferon-alpha lozenges have
also been studied to relieve the symptoms of dry mouth and dry eyes in
patients with Sjögren's syndrome. In a small study involving 12 patients who
received 150 IU three times a day for 24 weeks, interferon-alpha lozenges
demonstrated a statistically significant improvement in unstimulated salivary
flow rate (P <.05) and subjective improvement in ocular and oral
dryness (P <.05 for both), compared with placebo.19 The
use of interferon-alpha lozenges is not widespread. Additional studies need to
be conducted to determine their efficacy in larger populations.
Inflammation caused by extraglandular involvement can be treated with a number
of different medications. Nonsteroidal anti-inflammatory drugs, COX-2
inhibitors, corticosteroids as well as disease-modifying anti-rheumatic drugs
have been tried to help combat inflammation. Earlier studies have reported a
positive effect, in terms of clinical and laboratory effects, with the use of
hydroxychloroquine; however, subsequent studies have found marginal or no
clinical benefit.20-22 Other anti-inflammatory agents, such as
azathioprine, prednisolone, methotrexate, and D-penicillamine, have been used
as well, but results are mixed.23-26 At best, these agents provide
only a marginal clinical benefit, and the risks need to be considered when
The role of tumor necrosis
factor (TNF)–alpha has not been fully evaluated in the pathogenesis of primary
Sjögren's syndrome, but it is possible that it may have a key role.
Medications that block the effects of TNF-alpha have been studied but have not
shown benefit. A study conducted by Mariette et al.27 evaluated the
efficacy of Remicade (infliximab) on 103 patients' perception of improvement
in joint pain, fatigue, and dryness. Improvement was defined as a 30%
improvement in symptoms on two of three visual analog scales between weeks 0
and 10. At week 10, 26.5% of patients receiving placebo and 27.8% of patients
receiving infliximab showed improvement in two of three visual analog scales (
P = .89). The primary end point failed to reach significance, and thus the
authors concluded that infliximab was not effective in patient perception of
improvement in joint pain, fatigue, and dryness.
Enbrel (etanercept) has also
shown no benefit in the treatment of Sjögren's syndrome. Sankar et al.
28 conducted a 12-week, randomized, double-blind, placebo-controlled
trial of etanercept in 28 patients. The primary outcome was an improvement
from baseline of at least 20% in at least two of the following three domains:
subjective or objective measures of dry mouth (by visual analog scales or
total stimulated salivary flow) or dry eyes (by visual analog scales, van
Bijsterveld score, or Schirmer I test), immunoglobulin G level, or ESR. At
week 12, five patients in the etanercept group and three patients in the
placebo group showed improvement from baseline in the primary outcome;
however, results were not statistically significant (P = .2).
pharmaceutical care services to patients with Sjögren's syndrome can greatly
impact their quality of life. These education services include a continuum of
counseling on prescription and nonprescription medications, disease state, and
ways that patients can manage the syndrome at home. There are a number of
nonpharmacologic steps that patients can take to live more comfortably with
Sjögren's syndrome. These "tips" can affect the dryness reported in the eyes,
mouth, nose, skin, and vagina. It is important for patients to realize that
pharmacists are available to help advise/counsel them.
Maintaining excellent oral
hygiene is very important for patients with Sjögren's syndrome. Natural saliva
contains antibacterial substances that help fight bacteria in the mouth. Since
patients with Sjögren's syndrome lack saliva, they are at an increased risk of
developing oral infections such as candidiasis. Visiting a dentist at least
three times per year is important. Dry mouth can be combated through a number
of approaches. Pharmacists should advise patients that chewing sugarless gum
or sucking on sugarless candies could stimulate saliva production and decrease
the feeling of xerostomia. Additionally, increasing fluid intake throughout
the day by periodically ingesting small sips of water can also help.
Patients should be advised
that dry eyes could be minimized by protecting one's eyes from drafts, winds,
and breezes by wearing sunglasses when outdoors and by using a humidifier when
indoors. Patients who work at a computer or do an extensive amount of reading
during the day may benefit from consciously reminding themselves to blink,
which will help moisten the eyes. Also, patients should be encouraged to quit
smoking if they are smokers. In addition to many other problems associated
with cigarette smoke, smoke can dry the eyes and the mouth, causing worsened
symptoms. Women should also avoid wearing eye makeup. A stray piece of eye
makeup, such as a clump of mascara, could find its way into the patient's eye
and scrape the surface of the eye, causing damage.
Applying moisturizing products
to affected areas can lessen the dryness in skin, nose, and vagina. Dry skin
can be treated by applying moisturizing creams or ointments (e.g., Eucerin,
Aquaphor, Nivea). Taking short showers or baths, five minutes or less, can
also help. The temperature of the water should not be excessively hot, but
tepid (3° to 5° above body temperature). After showering, it is important not
to dry off the skin completely. Simply pat dry, leaving beads of water on the
skin, and apply an emollient onto damp skin within three minutes after
emerging from the shower. This traps moisture in the skin. The emollient
should be reapplied three times during the day. Dr. Robert Martin, a
dermatologist at the Arnett Clinic in Lafayette, Indiana, advocates his "Rules
of Threes," which are applicable to treating patients with Sjögren's syndrome
(see Table 4).29
Patients should be advised
that saline nasal sprays could help dry noses. These can be used as needed by
the patient. In addition, vaginal dryness can be treated with vaginal
moisturizers, such as Vagisil Intimate Moisturizer or KY Long Lasting Intimate
Moisturizer. These products can be used as needed. It is important to inform
the patient that lubricants will not moisturize the vaginal tract but,
instead, will rid the area of moisture. Thus, these products should not be
Summary and Conclusion
The most important
concept to realize when selecting appropriate treatment for a patient with
Sjögren's syndrome is that therapy must be adapted to the individual patient's
needs and responses. Each patient will present with some similar symptoms but
also with a unique set of symptoms and complaints. Pharmacists can have an
active role in helping patients manage this syndrome. Providing excellent
pharmaceutical care and continuity of care is the first step. Counseling and
teaching patients about the syndrome as well as providing tips for improving
patients' quality of life can have a dramatic impact.
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