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Issue 4, Vol. 3.May-June 2014
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SJOGREN’S SYNDROME – A REVIEW
GAYATHRI DEVI KUMARESAN1 (BDS 2nd YEAR),
KARTHIKEYAN.M2(BDS 3rd YEAR),
JYOTHI.S3( BDS 2nd YEAR),
Saveetha dental college,
162,Poonamalee High Road,
Vellapanchavadi,
Chennai 600077
TAMILNADU
INDIA
Mobile: 9042300454
ABSTRACT:
Sjogren's syndrome is an autoimmune rheumatic disease. The most common symptoms of
Sjogren's syndrome are extreme tiredness, along with dry mouth (xerostomia) and dry eyes
(keratoconjunctivitis sicca). Saliva plays an essential role in numerous functions of the mouth.
Xerostomia can be caused by medical treatments, such as radiation therapy and bone marrow
transplant, medications, chronic diseases like Sjogren's syndrome. Xerostomia finally lead to
difficulty in swallowing, severe and progressive tooth decay, or oralinfections. Despite having
excellent oral hygiene, individuals with Sjogren's syndrome have high levels of dental caries,
along with the loss of many teeth. Sjogren's syndrome brings about change in the composition of
saliva by modifying the protein profile. There is an elevated level of lactoferrin, β2microglobulin, sodium, lysozyme C, and cystatin C, and a decrease in salivary amylase and
carbonic anhydrase. Up to 90% of individuals with Sjogren's syndrome have antibodies targeting
the Ro 60 and La autoantigens. Natural aging, regardless of Sjogren's syndrome, is also another
factor that brings about a significant change in the composition of saliva. The most prevailing
cause of xerostomia in elderly persons is the use of anticholinergic medications. Although
primary Sjogren’s syndrome is often a benign condition, characterized by lymphocytic
infiltration of salivary and lacrimal glands, some patients develop systemic features.Currently,
there is no cure for Sjogren's syndrome, and treatment is mainly palliative..Most of the
population, know little or nothing about Sjogren's syndrome. As the second most common form
of arthritis, greater awareness and understanding is important for patients, their support system,
and the medical profession. The main aim of this article is to deliver a little knowledge about the
common autoimmune diseases – Sjogren's syndrome.
KEY WORDS: Sjogren's syndrome, autoantibodies, dry mouth, dental caries.
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INTRODUCTION:
Sjogren's syndrome is a chronic autoimmune disease in which the body's white cells destroy the
exocrine glands, specifically the salivary and lacrimal glands, that produce saliva and tears,
respectively.[1] The immune-mediated attack on the salivary and lacrimal glands leads to the
development of dry mouth (xerostomia) and dry eyes (keratoconjunctivitis sicca), which takes
place in association with lymphocytic infiltration of the glands[2] That inflammatory process
eventually severely damages or destroys the glands.There are two types of Sjogren's syndrome,
primary &secondary form. Primary Sjogren’s syndrome presents alone, in the absence of other
autoimmune or connective tissue disorders [1][2] and only impacts the salivary and lacrimal
glands. Although often a relativelybenign condition [5], some patients have associatedsystemic
features. There have been numerous reportsdescribing lung [6,7], renal [8] and central
nervoussystem (CNS) [9–11] involvement. There is an increasedincidence of organ-specific
autoimmune conditions suchas primary biliary cirrhosis [12–15]and autoimmunethyroid disease
[16–18]. There is often an overlap withother connective tissue disorders such as systemic lupus
erythematosus (SLE) [19], scleroderma [20] or rheuma-toid arthritis (RA) [21, 22]. In addition,
an increased incidence of lymphoma is well recognized [23–25].Secondary Sjogren’s syndrome
presents along with other autoimmune or connective tissue disorders, such as rheumatoid
arthritis (RA) or systemic lupus erythematosus [1][3][4] People with secondary Sjogren's
frequently continue to develop additional autoimmune disorders, such as Interstitial Cystitis.
HISTORY:
Johann von Mikulicz-Radecki (1850-1905) is generally credited with the first description of
Sjogren’s syndrome. In 1892, he described a 42-year old man with enlargement of the parotid
and lacrimal glands associated with a round-cell infiltrate and acinar atrophy.[26][27] However,
the criteria Mikulicz established for diagnosis, often led to misdiagnosis of Mikulicz’s syndrome.
Many conditions, such as tuberculosis, infections, sarcoidosis, and lymphoma present with
similar conditions to those listed under Mikulicz’s syndrome.[27] Nevertheless, the term
Mikulicz’s syndrome is still used occasionally to describe the appearance of lymphocytic
infiltrates on salivary-gland biopsies.[27]In 1930, Henrik Sjogren (1899-1986), an
ophthalmologist in Jonkoping, Sweden, observed a patient with low secretions from the lacrimal
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Issue 4, Vol. 3.May-June 2014
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and salivary glands.[28] Sjogren introduced the term keratoconjunctivitis sicca for the symptom
of dry eyes (Keratoconjunctivitis). In 1933, he published his doctoral thesis, describing 19
females, most of whom were postmenopausal and had arthritis, showing clinical and pathological
manifestations of the syndrome.[26] Sjogren clarifies that keratoconjunctivitis sicca, resulting
from water deficiency, had no relation to xerophthalmia, resulting from vitamin A
deficiency.[26] Sjogren’s thesis was not well received as the Board of Examiners criticized some
clinical aspects.[28]After extensive research and data collection, Sjogren published an essential
paper in 1951, describing 80 patients with keratoconjunctivitis sicca, 50 of whom also had
arthritis.[28] His subsequent follow-up conference trips pertaining to his paper led to an
international interest in Sjogren’s syndrome.[28] The term keratoconjunctivitis sicca coined by
Sjogren himself began to be identified as Sjogren’s syndrome in literature.[28]
SIGNS AND SYMPTOMS:
PRIMARY SYMPTOMS
Dry eyes
gritty, sandy feeling
stinging feeling
Dry mouth
dry, cracked tongue
sore throat
burning throat
difficulty in talking
difficulty in swallowing
difficulty in chewing dry food
change in sensation of taste/smell
increase in cavities
mouth sores
cracked lips
OTHER SYMPTOMS
swallon parotid gland
nausea
dry skin
joint pain
dry nose
reflux
muscle pain
fatigue
muscle weakness
low-grade fever
vaginal dryness
neuropathy
dizziness
The distinctive characteristic symptom of Sjogren's syndrome is a generalized dryness, typically
including xerostomia (dry mouth) and keratoconjunctivitis sicca (dry eyes), part of what are
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known as sicca symptoms. Sicca syndrome also incorporates vaginal dryness, chronic bronchitis
and lacks signs of arthritis. Sjogren's syndrome may cause skin, nose, and vaginal dryness, and
may affect other organs of the body, including the kidneys, blood vessels, lungs, liver, pancreas,
peripheral nervous system (distal axonal sensorimotor neuropathy) and brain. Skin dryness in
some Sjögren's patients may be the result from lymphocytic infiltration into skin glands. The
symptoms develop insidiously, and the diagnosis is not considered for several years because the
complaints of sicca are attributed to medications, a dry environment, aging, or believed to be too
insignificant to pursue.[29]Sjogren's syndrome is associated with increased levels in
cerebrospinal fluid (CSF) of IL-1RA, an interleukin 1 antagonist. This suggests that the disease
begins with increased activity in the interleukin 1 system, followed by an auto-regulatory upregulation of IL-1RA to reduce the successful binding of interleukin 1 to its receptors. It is likely
that interleukin 1 is the marker for fatigue, however, increased IL-1RA is observed in the CSF
and is associated with increased fatigue through cytokine induced sickness behavior.[30] On the
other hand, Sjogren's syndrome is characterized by decreased levels of IL-1ra in saliva, which
could be responsible for mouth inflammation and dryness.[31] Patients with secondary Sjögren's
syndrome also often exhibit signs and symptoms of their primary rheumatic disorders, such as
SLE, Rheumatoid Arthritis or Systemic Sclerosis.
ETIOLOGY:
Although the cause of Sjögren’s syndrome is unknown, it is believed to be under the influence of
a combination of genetic, environmental and several other factors, as is the case with many other
autoimmune disorders.[1]
Genetic factors
The observation of high prevalence of autoimmune disorders in families of Sjögren’s syndrome
is linked with a genetic predisposition to the syndrome.[32] Studies on the polymorphisms of
Human Leukocyte Antigen (HLA)-DR and HLA-DQ gene regions in Sjögren’s syndrome
patients show differential susceptibility to the syndrome due to different types of the resulting
autoantibody production.[32]
Hormonal factors
Since Sjögren’s syndrome is associated with a high prevalence in women, sex hormones,
especially estrogen, are believed to affect humoral and cell-mediated immune responses affecting
susceptibility to the syndrome.[32] Androgens are generally considered to prevent
autoimmunity.[33] Studies on mice models suggest that estrogen deficiency stimulates
presentation of autoantigens, inducing Sjogren’s syndrome-like symptoms.[32]
Microchimerism factors
Microchimerism of fetal cells (offspring lymphoid cells in maternal circulation) may generate
autoimmunity in women who have been previously pregnant.[33][26] Generation of an
autoimmune potential via microchimerism may lead to a switch from a silent form of
autoimmunity with age-dependent decrease in self-tolerance.[33]
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Environmental (exogenous) factors
Viral proteins, engulfed molecules, or degraded self-structures may initiate autoimmunity by
molecular mimicry and increase the chances of Sjögren’s syndrome development.[33] EpsteinBarr virus (EBV), Hepatitis C (HCV), and human T-cell leukemia virus-1 (HTLV-1) are among
the most studied infectious agents in Sjögren’s syndrome.[33] Damaged self-structures targeted
for apoptosis may be mistakenly exposed to the immune system, triggering autoimmunity in
exocrine glands which are often prone to autoimmune responses.[33]
DIAGNOSIS:
Diagnosing Sjogren's syndrome is complicated by the range of symptoms a patient may
manifest, and the similarity between symptoms of Sjogren's syndrome and those of other
conditions. Also, patients who have symptoms of Sjogren's syndrome approach different
specialities regarding their symptoms which make the diagnosis difficult. Since the symptoms of
this autoimmune disorder such as dry eyes and dry mouth are very common among people, and
mostly observed from the age of 40 and above, it is often mistaken as age related, thus ignored.
On the other hand, some medications can also cause symptoms that are similar to those of
Sjogren's syndrome. However, the combination of several tests, which can be done in a series,
can eventually lead to the diagnosis of Sjogren's syndrome[33][34].Blood tests can be done to
determine if a patient has high levels of antibodies that are indicative of the condition, such as
anti-nuclear antibody (ANA) and rheumatoid factor (because SS frequently occurs secondary to
rheumatoid arthritis), which are associated with autoimmune diseases. Typical Sjogren's
syndrome ANA patterns are SSA/Ro and SSB/La, of which SSB/La is far more specific; SSA/Ro
is associated with numerous other autoimmune conditions but are often present in Sjogren's
[35][26] . Rose Bengal test measures state and function of the lacrimal glands. This test includes
a nontoxic dye call Rose Bengal which is placed on to the surface of the eyes. The dye’s
distinctive colour help in determining the state and functioning of tear film and the rate of tear
evaporation. If any distinctive colour change is observed will point towards the condition of
Sjogren's syndrome, but man related diagnostic tools will be used to confirm the condition of
Sjogren's syndrome.[36]Schirmer's test measures the production of tears: a strip of filter paper is
held inside the lower eyelid for five minutes, and its wetness is then measured with a ruler.
Producing less than five millilitres of liquid is usually indicative of Sjogren's syndrome. This
measurement analysis vary among patients depending on other eye related conditions and
medications that they are on when the test is taken.[36] A slit-lamp examination can reveal
dryness on the surface of the eye.In case of dry mouth and dryness in oral cavity, these
symptoms are caused by the reduced production of saliva from salivary glands which composed
of parotid gland, submandibular gland and sublingual gland. To check the status of salivary
glands and the production of saliva, salivary flow rate is performed. Here, the patient is asked to
spit as much as he/she can in to a cup and the resulting saliva sample is collected and weighed.
This test results can determine whether the salivary glands are functioning adequately. If not
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enough saliva is produced it could mean that the patient has Sjogren's syndrome.[36] An
alternative test is nonstimulated whole saliva flow collection, in which the patient spits into a test
tube every minute for 15 minutes. A resultant collection of less than 1.5 mL is considered a
positive result [31]A lip/salivary gland biopsy can reveal lymphocytes clustered around salivary
glands, and damage to these glands due to inflammation. This test involves removing a sample of
tissue from the patient’s inner lip /salivary gland and examining under microscope. In addition a
sialogram, a special X-ray test is performed to see if there is any blockage in the salivary gland
ducts (i.e. parotid duct) and the amount of saliva that flows in to the mouth.[36]There is also a
radiological procedure which is a reliable and accurate test for Sjogren's syndrome. A contrast
agent is injected into the parotid duct, which opens from the cheek into the vestibule of the
mouth opposite the neck of the upper second molar tooth. Widespread puddling of the injected
contrast scattered throughout the gland indicates Sjogren's syndrome. The Revised Classification
Criteria for Sjogren's Syndrome[34] requires the presence of signs, symptoms, and lab findings.
Patient-reported symptoms must include both ocular symptoms, such as daily, persistent,
troublesome dry eyes for more than three months, and oral symptoms, such as needing to drink
water to swallow food. Objective evidence of eye involvement relies on Schirmer's test and the
Rose bengal score (or similar). Histopathology studies should show focal lymphocytic
sialadenitis. Objective evidence of salivary gland involvement is tested through ultrasound
examinations, the level of unstimulated whole salivary flow, a parotid sialography or salivary
scintigraphy. Autoantibodies against Ro (SSA) and/or La (SSB) antigens are also expected. SS
can be excluded from people with past head and neck radiation therapy, Acquired
immunodeficiency syndrome (AIDS), pre-existing lymphoma, sarcoidosis, graft-versus-host
disease, and use of anticholinergic drugs (since a time shorter than four times the life of the
drug).
TREATMENT:
There is no specific treatment to permanently restore gland secretion. Instead, treatment is
generally symptomatic and supportive. , cyclosporine (Restasis) is available by prescription to
help treat chronic dry eye by suppressing the inflammation that disrupts tear secretion.
Prescription drugs are also available that help to stimulate salivary flow, such as cevimeline
(Evoxac) and pilocarpine. Salagen, a man-made form of pilocarpine, can be used to help produce
tears as well as saliva in the mouth and intestines. It is derived from the Jaborandi plant.[26]
[35][36]For individuals with severe complications, corticosteroids or immunosuppressive drugs
may be prescribed, and sometimes IVIG (intravenous immunoglobulin). Also, disease-modifying
antirheumatic drugs (DMARDs) such as methotrexate may be helpful. Hydroxychloroquine
(Plaquenil) is another option and is generally considered safer than methotrexate.[34] However,
these prescribed drugs have a range of side effects such as nausea, loss of appetite, dizziness,
hair loss, stomach aches/cramps, headache, liver toxicity and increased risk of infections. Also
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studies have shown that patients who are on immune suppression drugs are likely to develop
cancer later on.[33]
DENTAL CARE:
Preventive dental treatment is also necessary (and often overlooked by the patient), as the lack of
saliva associated with xerostomia creates an ideal environment for the proliferation of bacteria
that cause dental caries (cavities). Treatments include at-home topical fluoride application to
strengthen tooth enamel and frequent teeth cleanings by a dental hygienist. Existing cavities must
also be treated, as cavities that extend into the tooth can not be effectively treated through teeth
cleaning alone, and are at a high risk of spreading into the pulp of the tooth, leading to the loss of
vitality and need for extraction or root canal therapy. This treatment regimen is the same as that
used for all xerostomia patients, such as those undergoing head and neck radiation therapy which
often damages the salivary glands, as they are more susceptible to radiation than other body
tissues.Unfortunately, many patients, not realizing the need for dental treatment, do not see a
dentist until most of their teeth are beyond the point of restoration. It is not uncommon for a
dentist to see a xerostomia patient with severe, untreatable cavities in almost every tooth. In
severe cases, the only viable treatment may be to extract all of the patient's teeth and treat with
prosthetics such as dentures or implants.
PROGNOSIS:
Sjögren's can damage vital organs of the body with symptoms that may plateau or worsen, or go
into remission as with other autoimmune diseases.[37] Some people may experience only the
mild symptoms of dry eyes and mouth, while others have symptoms of severe disease. Many
patients can treat problems symptomatically. Others are forced to cope with blurred vision,
constant eye discomfort, recurrent mouth infections, swollen parotid glands, hoarseness, and
difficulty in swallowing and eating. Debilitating fatigue and joint pain can seriously impair
quality of life. Some patients can develop renal involvement (autoimmune tubulointerstitial
nephritis) leading to proteinuria, urinary concentrating defect and distal renal tubular acidosis.
COMPLICATION
Among the complications discussed above, Sjögren's syndrome in women who become pregnant
has been linked to increased incidence of neonatal lupus erythematosus with congenital heart
block requiring a pacemaker.[38] Type I cryoglobulinemia is a known complication of Sjogren's
syndrome.[39]
PREVENTION:
There is no prevention mechanism for Sjogren's syndrome due to its complexity as an
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autoimmune disorder. However, lifestyle changes can reduce the risk factors of getting Sjogren's
syndrome or reduce the severity of the condition with patients who have already been diagnosed.
Diet is strongly associated with inflammation that is mostly seen in many autoimmune related
diseases including Sjogren's syndrome. An experimental study show that Sjogren's syndrome
patients show high sensitivity to gluten which directly relates to inflammation.[40]
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