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Gabor Illei,
Sarfaraz A. Hasni,
Ilias Alevizos

PART SIX Systemic immune diseases

Sjogrens syndrome

Sjogrens syndrome (SS) is a chronic systemic autoimmune


disease characterized by lachrymal and salivary gland dysfunction.
It was named after the Swedish ophthalmologist Henrik Sjogren
after he reported 19 cases of keratoconjunctivitis in 1933.1 The
hallmark feature of SS is deficient tear and saliva production
due to lymphocytic infiltration of the salivary and lachrymal
glands leading to xerostomia (dry mouth) and xerophthalmia (dry
eyes). In addition, SS can involve any organ system and present
with a wide spectrum of clinical features. The autoimmune process
seems to primarily affect the lining epithelium of various organs; in
fact some experts propose the term autoimmune epithelitis to be
used instead of SS.2

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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There is a well-established association between SS with HLA


class II genes. The first HLA class II associations described with
primary SS were with DR3 and DR2 in European populations.
This genetic association predominantly involves antibodypositive but not antibody-negative Sjogren patients. Several

small studies suggested an association between anti-Ro/SSA


and anti-La/SSB antibodies and molecularly defined HLA-DR
and HLA-DQ alleles, especially DRB1*0301, DRB1*15, and
DQB1*0201. Several genetic polymorphisms previously linked
to other autoimmune diseases are also associated with SS. From
these, two transcription factors, STAT4 (signal transducer and
activator of transcription 4) and IRF5 (interferon regulatory
factor 5), which were both independently associated with SS
showed an additive effect increasing the risk of SS from around
1.61.9 for one risk allele to 6.7 when both risk alleles were
present.6 Ongoing large genome-wide association studies will
soon provide better insight in the genetic basis of SS.

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.

Epithelial cell activation and chronic inflammation


The histologic hallmark of SS is a periductal mononuclear infiltrate in salivary and lachrymal glands (Fig. 53.1). The majority
of the infiltrating cells are CD4 T lymphocytes, whereas CD8
cytotoxic T cells are found in smaller numbers. Activated B lymphocytes are also present, including autoantibody-secreting
plasma cells.
Epithelial cell activation, such as the expression of HLA class II
molecules and various activation markers on the surface of acinar
and ductal salivary epithelial cells, is key in initiating the recruitment of the inflammatory infiltrate. The expression of these molecules along with upregulation of adhesion molecules and
chemokines contributes to the recruitment of inflammatory cells,
such as T and B lymphocytes, macrophages, and dendritic
cells and suggests that epithelial cells act as antigen-presenting
cells and actively participate in lymphocyte activation.8 The ensuing chronic inflammatory process is characterized by a complex
interaction between activated epithelial cells, the innate and acquired immune system. In the most severe forms of inflammation
the characteristic periductal infiltrates can progress to the formation of germinal centers, which is associated with a higher risk of
lymphoma development. Extraglandular manifestations occur as
a result of similar lymphocytic infiltrations at other organs. This
is described by some as autoimmune epithelitis to better reflect
the systemic nature of the disease.8 In most patients, only partial
destruction of the glands is noted. Local production of cytokines,
autoantibodies, metalloproteinases, and other inflammatory mediators may contribute to the dysfunction of the remaining epithelial cells. It is increasingly recognized that the innate immune
system plays a crucial rule in the immunopathogenesis of SS.9
Increased expression of interferon-regulated genes was described
in the salivary glands and peripheral blood of SS patients. One of
the cytokines upregulated by IFN-a is BAFF (B-cell-activating
factor), which promotes B-cell survival and thus contributes to
B-cell hyperactivity seen in SS.

Fig. 53.1 Minor salivary gland biopsy with characteristic periductal


inflammation.

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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

Autonomic nervous system


Autonomic nervous system (ANS) abnormalities are common in
SS and may play an etiologic role in its pathogenesis. Xerostomia
and xerophthalmia, the cardinal SS manifestations, are features
of cholinergic parasympathetic ANS dysfunction, whereas sympathetic cholinergic failure results in xerosis and decreased
sweating, which are frequently reported by SS patients.
The complexity of the ANS along with differences in methodology and studied populations has resulted in variable results but
abnormalities in SS have been reported in both sympathetic and
parasympathetic ANS domains. Delayed gastric emptying is common in SS and is consistent with involvement of the enteric ANS.
The underlying cause of these ANS abnormalities has not yet
been defined but they may potentially be mediated through interference with muscarinic receptor signaling. Recently, it was
shown that IgG from SS patients blocks acetlylcholine-mediated
contraction of smooth muscle preparations from various parts
of the gastrointestinal tract and that this effect was specific to
interference with the muscarinic acetylcholine receptor-3.12 Although other mechanisms cannot be excluded, anti-muscarinic

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PART SIX Systemic immune diseases

acetylcholine receptor autoantibodies would provide a link


between autoimmunity and ANS dysfunction in SS.

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.)

epithelial cell death (Fig. 53.2). Initially it may be limited to the


lower quadrants of cornea and later on involves the entire cornea. If left untreated, corneal ulcers can develop with rapid thinning of cornea. In addition to reduced tear production there is
also evidence of inflammation of the ocular surface epithelium
as shown by the presence of inflammatory cell infiltrate and
elevated levels of inflammatory cytokines.

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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Lachrymal gland dysfunction leads to constellation of symptoms


such as dry, sandy eyes with foreign body sensation. Frequently
there is a history of intolerance to contact lenses. Patients often
complain of sticky eyes and accumulation of thickened mucus
as a result of loss of aqueous component of tears.
Enlarged lachrymal glands can be noted at the onset of disease.
In the initial stages injected conjunctivae with strands of thickened mucus at the inner canthus can be found. In more advanced
stages conjunctivae lose their normal luster and become edematous. Corneal involvement results in punctuate keratitis due to

Saliva plays a critical role in maintaining oral health and comfort.


Saliva has antibacterial, lubricating, remineralizing, digestive,
buffering, and cleansing properties. Therefore decreased salivary
production or altered salivary composition can result in numerous conditions affecting oral health, comfort, and quality of life.
Symptoms and signs of salivary gland dysfunction include
oral dryness (xerostomia); oral pain and sensitivity; difficulty
chewing, swallowing, and speaking; diminished taste; inflamed,
morphologically altered, or infected mucosal tissues; and
increased tooth decay.
The oral symptoms associated with SS mainly result from salivary gland hypofunction leading to dryness of the oral cavity,
which necessitates the use of fluids throughout the day and
night. It is not uncommon for SS patients to wake up at night
to drink fluids to relieve dryness and also to use fluids to be able
to speak, chew, and swallow. A burning sensation along with
taste alterations and decreased tolerance to spicy foods is
described by a significant percentage of patients.
Head and neck examination often reveals dry and chapped lips,
angular cheilitis, and swollen major salivary glands (Fig. 53.3),
which may be recurrent or chronic. Acute swelling might occur
due to blockage of the salivary ducts by thick mucus that forms
plugs, and can also lead to infections. Intraoral findings include
decreased salivary pooling under the tongue, and depapillated
tongue often associated with erythematous candidiasis
(Fig. 53.4). Vasculitis can also manifest in the oral cavity. The teeth
often exhibit an increased rate of caries with characteristic decay
affecting the roots and cusp tips (Fig. 53.5).

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

Fig. 53.3 Parotid enlargement.

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.

Skin is involved in about 50% of SS patients.17 Lesions can either be


vasculitic or non-vasculitic. Most common non-vasculitic
involvement is dry, itchy skin (xerosis) and angular cheilitis. Other
less common non-vasculitis lesions include alopecia, vitiligo, eyelid dermatitis, and erythema nodosum-like lesions. Annular erythema, a rash similar to subacute cutaneous lupus, has been
reported in SS. However, the rash is less photosensitive and
histologically has deeper perivascular and periappendageal
lymphocytic infiltration.
Vasculitic lesions include non-palpable purpura due to hypergammaglobinemia, palpable purpura, and uritcarial vasculitis.17
Patients with vasculitis have higher prevalence of positive ANA,
anti-Ro/SSA antibodies, and rheumatoid factors as compared to
non-vasculitic skin involvement. Palpable purpura is histologically characterized by leukocytoclastic vasculitis and may indicate presence of underlying cryoglobulinemia. The presence of
palpable purpura may be associated with central nervous system
and pulmonary involvement requiring more aggressive treatment. Such patients should be tested for hepatitis C infection.
Raynaud phenomenon is also seen in 3050% of SS patients
and frequently precedes the development of sicca symptoms.

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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PART SIX Systemic immune diseases

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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Diagnosis and classification criteria


grens
Management of Sjo
syndrome
Ocular manifestations
Symptomatic relief with artificial tear drops and lubricating
ointments.
Topical cyclosporine eyedrops
Blockage of nasolacrimal duct by punctual plug placement
or surgical cautery.
Oral manifestations
Symptomatic relief with water and artificial saliva
preparations.
Physical measures to increase saliva production: sugar-free
candies and gum.
Maintain meticulous oral hygiene, use fluoride toothpaste.
Sialogogues: pilocarpine, or cevimeline.

Systemic manifestations
Hydroxychloroquine most commonly used to alleviate
fatigue and arthralgia.
Other immunosuppressive medications may be considered
in more severe internal organ involvement.

Anti-TNF blocking agents not recommended.


Genitourinary and renal involvement
Management of
Rituximab showed limited efficacy.
Renal involvement is frequently due to tubulointerstitial nephriPatient education
tis often presenting as distal (type1) renal tubular acidosis, renal
Avoid extreme dry environments such as proximity to open
calculi, and hypokalemia. Glomerular disease is rare. Urinary
fire places.
bladder epithelium can be involved in SS. Its inflammation leads
Wear protective eye glasses or goggles.
to interstitial cystitis in SS patients. Vaginal dryness leading to
Use of sugar-free sour candies or gum.
dyspareunia is observed in 40% of women.
Maintain good ocular and oral hygiene.
Avoid use of medications and substances causing sicca
symptoms.
Clinical manifestations in children
Women of child-bearing age with positive anti-SSA or antiSSB antibodies should be counseled about the risk of
Primary SS is rarely diagnosed in children, but many adult SS pacongenital heart block.
tients recall presence of symptoms since childhood. Clinical pre Educate patient about increased risk of lymphoma
sentation in children is more insidious with predominant
associated with Sjogrens syndrome.
recurrent parotitis and less common, sicca symptoms.19
Safety precautions due to smoke and gas leakage in
patients with loss of smell.
Information regarding focus groups such as Sjogrens
Associated autoimmune conditions
Syndrome Foundation (http://www.sjogrens.com/) and the
British Sjogrens Syndrome Association.
Autoimmune thryoiditis is seen in more than one-third of patients with SS. Celiac disease is also increasingly being recognized in SS patients, with a prevalence 10 times higher than
general population.
Patients with SS can present with heterogeneous combinations of
sicca symptoms and extraglandular manifestations. Moreover,
various clinical syndromes and medications can lead to similar
symptoms and mimic SS. The diagnosis of SS is based on the
Lymphoma associated with SS
combination of subjective symptoms of dryness (sicca symptoms),
objective evidence of lachrymal, or salivary gland hypofunction
Sjogrens syndrome is associated with increased risk of lymand evidence of autoimmunity or salivary gland inflammation.
phoma, with about 5% of SS patients developing lymphoma.
The most recent classification criteria were proposed by an
In a meta-analysis of 20 studies the standardized incidence rate
American-European consensus group in 2002,21 primarily for classiof lymphoma was 18.9% (confidence interval, 9.437.9).20 Most
fication of patients for clinical studies. These criteria are widely
of these are low grade marginal zone lymphomas of MALT
accepted and are frequently used as a guide for clinical diagnosis.
(mucosa-associated lymphoid tissue) type. Only 10% of lymphoApplication of these criteria to classify primary SS patients has a
mas in SS patients evolve into a less differentiated cell (more
sensitivity of 89.5% and specificity of 95.2%, whereas for secondary
aggressive) variety. Risk factors for development of lymphoma
SS its sensitivity is 97.2% and specificity is 90.2%.21 The American
include persistent enlargement of parotid glands, palpable
European consensus classification scheme is based on a set of
purpura, and leg ulcers secondary to vasculitis, mixed cryoglotwo subjective and four objective criteria as listed in Fig. 53.6.
bunemia, and low C4 level.

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.

I. Ocular symptoms: Positive response to at least one question:

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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

II. Oral symptoms: Positive response to at least one question:

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?

2. Do you have a recurrent sensation of sand or gravel in the eyes?


3. Do you use tear subsitutes more than three times a day?

2. Have you had recurrently or persistant swollen salivary glands as an adult?


3. Do you frequently drink liquids to aid in swallowing dry food?

III. Ocular signs: Positive results for at least one of the following two tests:

IV. Histopathology:

1. Schirmers I test, performed without anesthetsia (5 mm in 5 minutes )


2. Rose bengal score or other ocular dye score (4 according to van Bijstervelds
scoring system).

In minor salivary glands (obtained through normal-appearing mucosa) focal


lymphocytic sialadentis, evaluated by an expert histopathologist with focus score
of 1 defined as a number of lymphocytic foci (which are adjacent to
normal-appearing mucous acini and contain more than 50 lymphocytes)
per 4mm 2 of glandular tissue.

V. Salivary gland involvement:


Objective evidence of salivary gland involvement defined by a positive result for
at least one of the following diagnostic tests:
1. Unstimulated whole salivary flow (1,5 ml in 15 minutes)
2. Parotid sialography revealing diffuse sialectasias (punctate, cavitary or
destructive pattern) without evidence of obstruction in the major ducts
3. Salivary scintigraphy showing delayed uptake, reduced concentration and/or
delayed excretion of tracer.

VI. Autoantibodies:
Presence in the serum of the following autoantibodies:
1. Antibodies to Ro(SSA) or La(SSB) antigens or both.

Primary Sjgren syndrome:

Secondary Sjgren syndrome:

Patients fulfilling 4 out of 6 items are classified as having primary Sjgren


syndrome with compulsory presence of a positive biopsy (item IV) or
anti-SSA or anti-SSB autoantibodies (item VI). Alternatively patients with three
of the four objective items (III, IV, V or VI) may also be classified
with Sjgrens syndrome.

Patients diagnosed with another systemic autoimmune disease are classified as


having secondary Sjgren syndrome if they have either subjective dry eye
(item I ) or dry mouth (item II) and any two from items III, IV and VI.

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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PART SIX Systemic immune diseases

Immune modulating medications


Cyclosporine eye drops are frequently prescribed to reduce a
local immune response involving conjunctiva and cornea. Use
of topical non-steroidal anti-inflammatory and steroid-based
eyedrops provide short-term benefits and should be used
cautiously.
Hydroxychloroquine is commonly prescribed for patients
with SS even though trials showed significant laboratory improvement with no beneficial effects on symptoms.
Other immune modulating agents such as azathioprine, cyclosporine, methotrexate, and mycophenolate mofetil showed only
limited benefits in treating sicca symptoms and are used primarily for extraglandular manifestations.22
Trials using biologic agents such as infliximab and etanercept
failed to show any significant improvement in the primary
outcomes of oral and ocular dryness.22
The data on rituximab are controversial with some studies
showing some benefit.22

Treatment for lymphoma associated with SS


gren
Lymphoma in Sjo
syndrome
Risk factors
Risk increases with time. Cumulative risk 3.4% at
5 years and 9.8% at 15 years after diagnosis of Sjogrens
syndrome.
Persistent enlargement of parotid glands.
Splenomegaly and lymhpadenopathy.
Palpable purpura.
Leg ulcers secondary to vasculitis.
Mixed cryoglobunemia.
Low complement levels.
CD4 lymphocytopenia.
Staging and management (in collaboration with
an oncologist)
CT scan of neck, thorax, and abdomen.
Laboratory tests: LDH, serum and urine electrophoresis and
immunofixation, HIV, and hepatitis C serology.
Bone marrow biopsy.
Localized low grade MALT lymphoma (most common):
careful monitoring.
Multiple extra-nodal site involvement: single agent
chemotherapy.
High grade transformation or aggressive lymphoma at
presentation: rituximab and CHOP.

As discussed above lymphoma associated with SS is usually low


grade with 5-year survival rates of 86100%. In a study of SS
patients overall survival rates of patients with MALT lymphoma
was similar in both treated and untreated groups.23 However,
patients with disseminated and more aggressive lymphoma
showed reduced overall survival.

654

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

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