Professional Documents
Culture Documents
Gabor Illei,
Sarfaraz A. Hasni,
Ilias Alevizos
Sjogrens syndrome
Epidemiology
Sjogrens syndrome predominantly effects females (female:male
ratio 9:1) in their fourth and fifth decades of life. However, symptoms can be present for much longer time and there is usually
a 5- to 10-year delay in the diagnosis of SS. The reported prevalence of SS varies widely from 0.1 to 4.8%.3 This variation may be
due to the use of different classification criteria, geographical
and environmental influences, and study size and target population. When a more strict definition is applied to the available
data the true prevalence of SS is estimated to be around 1%,4
making it the second most common systemic rheumatic disease
after rheumatoid arthritis.
Immunopathogenesis
The pathogenesis of SS is still largely unknown. In a genetically
predisposed individual, various environmental factors, such as
viral infections, may lead to epithelial cell activation and a protracted inflammatory response with features of autoimmunity.
Autoreactive lymphocytes and autoantibodies are considered
important in this process, although the pathogenic role of any
particular autoantibody is still undefined.5
Immunogenetic factors
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Environmental factors
The inciting event in the pathogenesis of SS is not known, and it
may not be a single event. The strong predominance of females
suggests gender-specific predisposing factors. Although sex hormones are obvious targets, there is no conclusive proof yet that
the difference in the pathogenesis between males and females is
due to sex hormones alone. Estrogens are considered contributors to autoimmunity, whereas androgens are thought to be protective. But since the peak age of onset in SS occurs around
menopause, characterized by a decrease in estrogens, the increased risk may be due to a change in the androgenestrogen
ratio rather than absolute levels of estrogens. Ovaries produce
low levels of testosterone, which decrease at the time of menopause. The other significant source of androgens is the adrenal
cortex, which produces dehydroepiandrosterone (DHEA), a
weak androgen prohormone that can be converted to either androgens or estrogen locally in target organs. This intracrine conversion of DHEA to active sex steroids accounts for a significant
proportion of all sex steroids produced in humans. Patients with
SS have low systemic DHEA levels as well as a defective intacrine processing of DHEA in salivary glands, suggesting both
a systemic and local androgen deficient state. Women may be
particularly vulnerable to local androgen deficiency in the salivary gland in SS since their local dihydrotestosterone production
is completely dependent on local conversion of DHEA, whereas
in men systemic androgens may satisfy the local requirement.7
Viral infections have also been proposed as inciting events.
This theory is strongly supported by the fact that chronic inflammation of the salivary glands has been observed with chronic
hepatitis C, HTLV-1, and human immunodeficiency virus
infections, and such infections cause a disease with a clinical
spectrum very similar to that of SS. The fact that some viruses,
such as EpsteinBarr virus (EBV), are known to replicate in oropharyngeal and lachrymal glands led to the hypothesis that
Sjogrens syndrome
these viruses may be involved in the pathogenesis of SS. In
fact, genetic material from EBV was detected by DNA hybridization in SS salivary tissue, but it was also found in normal individuals. Other viruses, such as coxsackievirus or endogenous
retroviruses, have also been proposed as causative agents. However, there is no proof, to date, that any of these viruses play a
pathogenic role in SS.
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Autoantibodies
Autoantibodies are the hallmarks of systemic autoimmune
diseases, including SS. The best defined autoantibodies in SS
are the anti-Ro/SSA and anti-La/SSB antibodies.10 Both are targeted against ribonucleoprotein antigens. Anti-Ro/SSA recognizes two RNA binding proteins (the 52- or the 60-kDa
protein), whereas anti-La/SSB antibodies recognize RNA polymerase III. Anti-Ro/SSA antibodies are found in over 70% of patients with SS, but are also frequently found in SLE and other
autoimmune diseases even in the absence of oral or ocular dryness. Anti-La/SSB is more specific; it is present in 50% of patients
with primary SS or SS/SLE but is rarely seen in other diseases.
The pathogenic role of these antibodies is not yet defined except
in newborns born to women with anti-Ro/SSA and/or anti-La/
SSB antibodies. These antibodies can cross the placenta and
bind to Ro and La antigens located on the cell surface of fetal
myocardial tissue, leading to fetal heart block. Other autoantibodies, such as anti-nuclear antibodies and rheumatoid factor,
are frequently present in patients with both primary and secondary SS. Although they lack specificity, they are markers of a systemic autoimmune response and thus can help distinguish SS
from other causes of salivary or lachrymal gland dysfunction.
In recent years, research has focused on identifying antibodies
more specific for SS, such as anti-a-fodrin and anti-muscarinic
acetylcholine receptor antibodies, but the results have been controversial. The major stimulus for saliva production is the binding of acetylcholine to muscarinic acetylcholine receptors. The
hypothesis that oral and ocular dryness could result from antibodies antagonizing the muscarinic acetylcholine receptor-3 is
intriguing. These antibodies have been demonstrated to play
an essential role in eliciting glandular dysfunction in the NOD
mouse model of SS, possibly through an inhibitory effect on
the receptor. In humans, however, results are still contradictory
as multiple attempts to detect these antibodies with conventional
immunologic methods have been fruitless. The best evidence
for their existence comes from functional studies, where IgG
from SS patients inhibited acetylcholine-induced bowel or
bladder contraction or acetylcholine-induced Ca2+ influx in
human salivary gland cells.11
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Clinical manifestations
Clinical Pearls
Chronic fatigue is a prominent presenting feature of Sjogren
syndrome.
Autonomic and peripheral nervous system involvement is
often under recognized.
Mimics of Sjogrens syndrome include IgG4-related disease
(Mikuliczs disease), hepatitis C infection, sarcoidosis, and
HTLV infection.
Presence of joint erosions and CCP antibody is indicative of
secondary Sjogren syndrome due to rheumatoid arthritis.
Avoid prolonged use of topical ophthalmic NSAID and
steroid preparation due to increased risk of complications.
Sudden normalization of previously elevated rheumatoid
factor should prompt evaluation for development of
lymphoma.
Identify and treat oral candidiasis. Sjogren syndrome
patients are at a high risk for oral candidiasis, which can
present as oral erythema and/or pain.
Pediatric primary Sjogren syndrome is rare and presents
with variable, atypical features most commonly recurrent
tender parotid gland swelling.
Fig. 53.2 Punctate keratititis due to dry eye. Lissamine green stains dead or
degenerated corneal epithelial cells green.
(Courtesy of Manuel Datiles, MD.)
Oral involvement
Clinical manifestations due to salivary and lachrymal glands
dysfunction are the dominant features of Sjogren syndrome.
Symptoms secondary to other exocrine gland dysfunction such
as skin and vaginal dryness and chronic cough from tracheal
dryness are frequently present. Multiple extraglandular manifestations can also be present, reflecting the systemic nature of
the autoimmune process.5
Constitutional symptoms
One of the most common extraglandular manifestations of
Sjogren syndrome is excessive fatigue. Approximately 70% of
patients with Sjogren syndrome report disabling fatigue leading
to reduced quality of life.13 Attempts to identify a biological basis
for fatigue failed to reveal any correlations with levels of inflammatory markers, cytokines, or autoantibodies. This fatigue is
commonly associated with arthralgia, malaise, and mental
cloudiness (brain fog), resulting in diagnosis of these patients
as having fibromyalgia or chronic fatigue syndrome. Less commonly patients also experience low grade fever and weight loss.
Ocular involvement
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Musculoskeletal involvement
Musculoskeletal complaints are present in the majority of patients with SS. The incidence of arthralgia is between 50 and
75% in various studies and precedes sicca symptoms in up to
Sjogrens syndrome
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symptoms. Anti-cyclic citrullinated peptide (anti-CCP) antibodies can be found in up to 10% of primary SS patients, mainly
in those with articular manifestations. Patients with positive
anti-CCP antibodies did not develop joint erosions and no progression to RA was found in a large cohort.14
Neuropsychiatric manifestations
Primary SS is associated with multiple neurological manifestations involving both central and peripheral nervous systems. Peripheral nervous system (PNS) manifestations are more common
and are present between 5 and 20% of SS patients.15 PNS
involvement in SS can present as sensory neuropathy, small fiber
neuropathy, cranial neuropathy, inflammatory myopathies, and
autonomic neuropathy. Small fiber neuropathy is increasingly
being recognized as the most common PNS manifestation of SS.
It presents as a subacute to chronic development of excruciating
burning pain. There is selective impairment of pinprick and
temperature sensation with preserved vibratory sense and
proprioception. Diagnosis is made by skin biopsy.15
Symptoms suggestive of autonomic dysfunction such as orthostatic hypotension, temperature intolerance, constipation,
urinary frequency or hesitancy, or delayed gastric emptying
are present in up to half of the SS patients.16 Central nervous system involvement is rare and can present as white matter lesions
suggestive of multiple sclerosis, myelopathy, optic neuritis as
well as cognitive dysfunction, seizures, and encephalopathy.16
Anxiety and depression is commonly seen in SS patients perhaps
due to severe impact of the symptoms on their quality of life.
Dermatological involvement
Fig. 53.4 Papillary atrophy and candidiasis of the tongue. The loss of filiform
papillae results in a smooth surface of the tongue. Oral candidiasis is common in SS
and can present as erythema only with minimal or no exudate (arrow).
Fig. 53.5 Root caries on the anterior teeth is a common finding due to the loss
of the protective functions of saliva. The cusp tips of the posterior teeth are also
commonly affected.
Gastrointestinal involvement
30% of patients. Arthralgia is symmetrical usually without evidence of synovitis or erosions. Large and small joint involvement
is equally reported and 1020 % of patients have recurrent monoarthritis or oligoarthritis.
From a clinical perspective it is often difficult to differentiate
between primary SS patients with symmetrical joint involvement
and those with rheumatoid arthritis presenting with sicca
Dysphagia is common due to dryness of pharynx and esophageal dysmotility. Nausea, epigastric pain, and constipation
are also common. GI tract dysmotility can be seen as a result
of autonomic nervous system involvement by SS. Pancreatic
dysfunction is present in 25% of SS patients. Commonly exocrine
function is affected with reduced production of amylase and
lipase.
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Pulmonary involvement
Cough is a common complaint in SS patients resulting from tracheobroncitis sicca (tracheal and bronchial dryness). Clinically
significant pulmonary involvement is reported in 912% of
SS patients.18 Pulmonary manifestations include large and
small airway disease, bronchial hyper-responsiveness, and
recurrent respiratory infections. Interstitial lung disease, pulmonary hypertension, pleuritis, and pulmonary amyloidosis are
less commonly seen.
Cardiac involvement
Clinically significant cardiac involvement is uncommon in primary
SS. Patients may develop pericarditis, thickened pericardium, or
left ventricle diastolic dysfunction. Rhythm abnormalities due to
autonomic dysfunction may be encountered. Placental transfer
of anti-SSA/Ro and anti-SSB/La antibodies from pregnant SS patients can cause lesions in the cardiac conducting system of the fetus. Pregnant women with positive anti-SSA/Ro and anti-SSB/La
antibodies have a 2.5% risk of delivering a baby with congenital
heart block.
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Systemic manifestations
Hydroxychloroquine most commonly used to alleviate
fatigue and arthralgia.
Other immunosuppressive medications may be considered
in more severe internal organ involvement.
Sjogrens syndrome
Patients are classified as having primary SS in the absence of
any other systemic autoimmune disease, whereas in secondary
SS sicca manifestations are present in conjunction with other underlying autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, polymyositis/dermatomyositis
or systemic sclerosis. SS is excluded if patients use anticholinergic medications or have other conditions that can mimic SS, such
as chronic viral infections, graft versus host disease or irradiation
of the head and neck region.
Patients presenting with sicca symptoms suggestive of SS
should undergo specialized testing to confirm the diagnosis.
Lachrymal function can be assessed by the Schirmers test to
quantify the amount of tear production, whereas corneal and
conjunctival damage due to dryness can be measured by fluorescein and lissamine green staining. Salivary gland evaluation
is done by collection of unstimulated saliva or salivary
scintigraphy. Laboratory workup should include testing for
auto-antibodies to SSA/Ro and SSB/La antigens, which
are detected in sera of 4570 and 2050%, respectively, of SS
patients. Rheumatoid factor is also commonly positive in Sjogren
patients.
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Treatment
Symptomatic treatment of sicca symptoms
The mainstay of treatment in SS is providing symptomatic relief.
Use of artificial tears is often helpful. In patients with sticky
mucus or strands over the eyes use of mucolytic agents is indicated. Blockage of lachrymal ducts with punctual plugs or
surgically can be beneficial.
Artificial saliva available as spray or lozenges provides only
limited relief. Local activation of salivary glands (in patients with
preserved function) with sugar-free sour candies or gums
provides relief of symptoms.
Cholinergic agonists such as pilocarpine and cevimeline provide good symptomatic relief in selected patients. Cevimeline
is a more selective muscarinic agonist predominantly affecting
M1 and M3 receptors; hence it is associated with fewer side
effects than pilocarpine.4
1. Have you had daily, persistant, troublesome dry eyes for more than 3 months?
1. Have you had a daily feeling of dry mouth for more than 3 months?
III. Ocular signs: Positive results for at least one of the following two tests:
IV. Histopathology:
VI. Autoantibodies:
Presence in the serum of the following autoantibodies:
1. Antibodies to Ro(SSA) or La(SSB) antigens or both.
Exclusion criteria:
To avoid incorrectly diagnosing such patients with Sjgren syndrome, the
presence of the following are considered as exclusion criteria: past head and
neck radiation treatment, hepatitis C infection, acquired immunodeficiency
disease (AIDS), pre-existing lymphoma, sarcoidosis, graft versus host disease
and the use of anticholinergic drugs (within 4 half-lives of the drug).
Fig. 53.6 AmericanEuropean Consensus Group classification criteria for Sjogrens syndrome.
(Modified from Vitali C, Bombardieri S, Jonsson R, et al. Classification criteria for Sjogrens syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann
Rheum Dis 2002; 61(6): 554-558.)
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Future direction
As no effective treatment is currently available to treat SS patients, several medications and other non-drug-based modalities
are being studied. B-cell-depleting agents (rituximab, epratuzumab) and anti-B cell-activating factor (belimumab) therapy are
currently in clinical trials. Use of steroids locally in the salivary
glands showed some promising initial results, which should be
confirmed in independent studies.
Patient education
Due to its significant impact on quality of life, educating patients
and their families is of utmost importance. Excellent resources
for patient education are available through focus groups such
as the Sjogrens Syndrome Foundation (http://www.sjogrens.
com/) and the British Sjogrens Syndrome Association.
In general patients are advised to avoid dry environments, protect eyes from bright sunlight, maintain good dental hygiene, and
be aware of symptoms suggestive of lymphoma. They should
avoid medications and substances that may worsen sicca symptoms. Women of child-bearing age with positive anti-SSA/Ro
and anti-SSB/La antibodies should be counseled regarding the
risk of congenital heart block in fetuses. Patients with loss of smell
associated with SS are at an increased risk of injury in the event
of gas leakage. Alternate methods to detect gas leakage in the
patients environment should be employed.
Translational research
On the Horizon
Genome-wide association studies will lead to better
understanding of genetic risk factors.
Further studies are needed to better understand the
interaction between immune and non-immune
abnormalities leading to Sjogrens syndrome.
Pilot clinical studies are needed to identify candidates for
larger efficacy trials.
There is a pressing need to identify and to validate clinically
relevant biomarkers.
Sjogrens syndrome is the clinical manifestation of a complex interplay between genetic factors, environmental and stochastic events
that involve innate and adaptive immunity, hormonal mechanisms, and the autonomic nervous system. A better understanding
of these elements is necessary to develop more effective treatments.
Two large genome-wide association studies are currently underway to better delineate the genetic risk factors of SS. Pilot treatment
trials targeting key cells (B and T lymphocytes) and mediators
(Blyss, lymphotoxin, interferon) of autoimmune/inflammatory
pathways are expected to identify the most promising molecule(s)
that can be tested in larger efficacy studies. There is a clear and
present need to identify and validate biomarkers that can be used
in clinical trials as well as everyday clinical practice to improve
the management of Sjogren patients.
Sjogrens syndrome
References
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