An Autoimmune Disease : Sjogren's Syndrome, also known as Sicca Syndrome was described by Dr. Henrik Sjogren. It is a triad of Dry eyes, Dry mouth & Rheumatoid Arthritis. The presentation provides a guide to the students regarding the disease including Types, History, Epidemiology, Etiopathogenesis, Clinical features, Systemic & Oral manifestations, Diagostic criteria, Histopathological features, Serological findings, Radiography & Salivary gland imaging (involving sialography, scintigraphy, sonography & MRI), its Treatment along with the advancements in treatment, Complications & Prognosis. Presentation by - Dr.Harsimran Singh Kapoor

1. SJOGREN’S SYNDROME
- Harsimran Singh Kapoor

2. INTRODUCTION
also known as -

Dacryosialoadenopathia atrophicans,

Keratoconjunctivitis sicca,

Keratoconjunctivitis sicca-xerostomia,

Secretoinhibitor-xerodermostenosis,

Sicca syndrome,

Sjogren-Gougerot syndrome.
The disease was described in 1933 by Henrik Sjogren after whom it is
named.

3. DEFINATION
Sjögren’s syndrome is a chronic autoimmune
disease characterized by symptoms of oral and
ocular dryness, exocrine dysfunction, lymphocytic
infiltration and destruction of the exocrine glands.
It is considered as a triad consisting of -

Keratoconjunctivitis (Dry eyes)

Xerostomia (Dry mouth)

Rheumatoid Arthritis

4. It is a complex disorder characterised by both organ
specific and systemic manifestations, potentially
expanding to lymphoproliferative complications.
In Sjögren syndrome, the immune system primarily
attacks the lacrimal and salivary glands impairing
their ability to secrete the fluids.
It is characterised by lymphocytic infiltration of the
glands, leading to glandular fibrosis and exocrine
failure.

5. TYPES

Primary Sjögren’s Syndrome -
It is a systemic disorder that includes both
lacrimal and salivary gland dysfunctions
without another autoimmune condition.

Secondary Sjögren’s Syndrome -
It includes salivary and lacrimal gland
dysfunction in the setting of another
connective tissue disease
(eg. - SLE, Rheumatoid Arthritis,
Scleroderma, Polymyositis, Primary
Biliary Cirrhosis).

6. EPIDEMIOLOGY
Sjögren syndrome is a relatively common disorder.
Occurance - 0.2 to 3 percent of the population
Female to Male ratio is 9 : 1
primarily affecting peri- and post - menopausal women.
Younger indiviuals and children may also be affected.
Typical age of onset is between 40 and 50 years.

7. ETIOPATHOGENESIS
The etiology of Sjögren’s syndrome is unknown.
Sjögren syndrome is thought to result from a combination of genetic
susceptibility and environmental factors; however, no associations between
specific genetic changes and the development of Sjögren syndrome have
been confirmed.
Genetic studies have identified an association with HLA haplotypes and
susceptibility genes in cytokine genes and genes involved in B-cell
differentiation.
Various causes of this disease have been suggested: genetic, hormonal,
infectious and immunologic, among others. It may be a combination of
factors, both extrinsic and intrinsic, play a role in the etiology of this
condition.
Most authorities consider an altered immunologic response to be the main
intrinsic factor which is responsible for the disease. Laboratory findings
support the autoimmune etiologic role.

8. CLINICAL MANIFESTATIONS
Sicca symptoms -
The typical features of the disease are dryness of
the mouth and eyes as a result of hypofunction of
the salivary and lacrimal glands.

Dry eyes may lead to
itching, burning sensation,
feeling of sand in the eyes,
redness, blurred vision or
intolerance to bright or
fluorescent light.

9. 
Dry mouth can feel chalky or full of cotton and often results in
painful, burning sensations of the oral mucosa, sensitive to
spices and heat, altered taste, difficulty in speaking and
swallowing, halitosis, dental caries, poor retention of denture
and generalised oral discomfort with oral mucosal surfaces
sticking together.

Patients often have dry, cracked lips and
angular cheilitis.

The tongue is often smooth (depapillated).
Mucocutaneous candidal infections
particularly of the erythematous form are
common.

10. Patients may experience salivary gland
enlargement and are also susceptible to
salivary gland infections and
obstructions.
Parotid gland enlargement can be
unilateral or bilateral, acute or chronic
and can be due to retrograde salivary
gland infection due to stasis or maybe
secondary to inflammation.
Systemic involvement - Constitutional symptoms
include fatigue, sweats, low-grade fever and anorexia
can seriously impair quality of life.

11. Extraglandular involvement -
In some cases, the immune system may attack and
damage other organs and tissues. It can be categorized
into two major groups :

The peri-epithelial organ involvement, which
includes interstitial nephritis, liver involvement and
obstructive bronchiolitis, is the result of lymphocytic
invasion into the epithelial tissues of organs.

The extra-epithelial manifestations, palpable
purpura, glomerulonephritis and peripheral
neuropathy, result from immune complex deposition.

12. 
Rheumatic conditions -
Affected individuals may develop inflammation in connective
tissues which may result in painful inflammation of the joints and
muscles. Rheumatoid arthritis is commonly associated with
secondary SS.

Pulmonary manifestations -
Tracheobronchial mucosal dryness can manifest as dry cough and
hoarseness of voice. Mild abnormalities in lung function tests can
occur. Pneumonitis or bronchiectasis is a recognized association.

Cardiac involvement -
Although rare, pericarditis, pulmonary arterial hypertension and
left ventricular diastolic dysfunction have been documented.

13. Cutaneous manifestations -
Dry skin is very common as a result of
lymphocytic infiltration into skin glands.
Cutaneous vasculitis is a recognized but
usually self-limiting condition and usually
affects small vessels. It manifests as
palpable purpura, urticarial lesions or
erythematous maculopapules.
Patients with may develop purpuric rash,
often in the lower limbs. Subacute
cutaneous lupus erythematosus and
Raynaud’s phenomenon can also occur.

14. 
Gastrointestinal system and liver -
Dysphagia due to pharyngoesophageal dryness is seen.
Gastroesophageal reflux disease occurs due to reduced saliva
production and lack of acid clearance.
It is associated with coeliac disease, primary biliary cirrhosis and
autoimmune hepatitis.

Neurological manifestations -
Peripheral neuropathy is most commonly reported as excrutiating,
burning pain of extremities. Mononeuritis multiplex and cranial
neuropathies affecting trigeminal, optic and facial nerves can occur.
Autonomic symptoms such as sweating, postural hypotension and
dizziness are common. .
Other CNS manifestations include multiple sclerosis-like syndromes,
myelopathy, encephalopathy, optic neuropathy and seizures.

15. ORAL MANIFESTATIONS

Ulcers and mouth sores - Dry tissue inside the mouth is extra-
sensitive to any injury and more likely to develop ulcers or sores
in response to any injury. Cheeks, lips and the tongue are more
likely to get bitten without the lubrication provided by saliva

Dental Caries - Without saliva neutralizing the oral cavity, the
cariogenic bacteria are able to proliferate and produce more acid,
making caries much more likely.

Periodontal diseases - Saliva contains antibacterial component,
without which the bacteria that cause periodontal diseases thrive.

Bad breath - It is caused by an overgrowth of bacteria. Patients
feel the sensation of waking up with a “cotton mouth” feeling and
extreme bad breath.

16. ●
Candidal infection - Due to lack of antibacterial action of saliva.
●
Burning sensation - The lack of lubrication makes the lining of
the cheeks, lips and tongue hypersensitive to every stimulus,
often creating a burning or tingling sensation to the mouth
●
Difficulty speaking - The cheeks, lips and tongue cannot
function well when the saliva production is impaired. The position
of these tissues is essential to making certain sounds, so some
patients notice changes in their speech when their mouths are
extremely dry.
●
Difficulty swallowing - Saliva is necessary to form bolus that
can be swallowed and to lubricate the throat and esophagus
during the swallowing process.

17. DIAGNOSIS
AECG classification involve six criteria:

two dealing with symptoms of ocular and oral dryness,

one measuring lacrimal function (ocular signs),

one quantifying salivary function (salivary signs),

labial minor salivary gland biopsy (Histopathology),

autoantibodies against anti-SS-A (Ro) and anti-SS-B (La).
Four of these six criteria are required for positive case
classification of primary Sjögren’s syndrome.

18. 1. Ocular symptoms (atleast one of following) -

Dry eyes for more than 3 months

Sensation of foreign body in the eye

Use of tear substitutes more than thrice daily
2. Oral symptoms (atleast one of following) -

Dry mouth for more than 3 months

Recurrent or persistant swollen salivary glands

Need liquids to aid swallowing
3. Ocular signs (positive result from atleast one of following)

Schirmer’s test (<5mm in 5 mins)

Rose bengal test
4. Histopathology- in minor salivary gland biopsy, focal lymphocytic sialadenitis
with focus score >1 per 4 mm2

19. 5. Salivary signs (positive result from one of following) -

Unstimulated whole salivary flow (<1.5ml in 15 mins)

Parotid sialography showing diffuse sialectasis

Salivary scintiography showing delayed uptake, reduced concentration
& delayed excretion of tracer.

6. Autoantibodies (presence of following in serum )

Anti Ro (SSA)

Anti La (SSB) or both

Exclusion criteria – Past head or neck radiation therapy, Hepatitis C
infection, AIDS, Pre existing lymphoma or sarcoidosis, Graft vs Host
disease, Use of Anti cholinergic drugs

20. SCHIMER TEAR TEST

Procedure -
A strip of filter paper is held inside the lower eyelid for five
minutes and its wetness is then measured. A topical anesthesia
may be used to prevent tearing due to the irritation from the
paper ensuring that only basal tear secretion is being measured.
A young person normally moistens 15 mm of strip but an elderly person
may wet only 10 mm as hypolacrimation occurs with age.
Producing less than 5mm of liquid within 5 mins
is usually indicative of SS.
1. Normal : ≥ 15mm wetting of the paper
2. Mild : 14 - 9mm wetting of the paper
3. Moderate : 8 - 4mm wetting of the paper
4. Severe : < 4mm wetting of the paper

21. ROSE BENGAL DYE TEST
Rose Bengal stain (sodium salt of 4,5,6,7-
tetrachloro-2',4',5',7'-tetraiodofluorescein) is
commonly used in test drops to stain
damaged conjuctival and corneal cells.
This test involves placing the non-toxic dye
on the eyes that measures state and
function of the lacrimal glands.
The dye’s distinctive colour helps in
determining the state and functioning of tear
film and the rate of tear evaporation. Any
distinctive colour change can indicate SS.

22. To check the status of salivary glands and the production of saliva,
a salivary flow-rate test is performed, in which the person is asked
to spit as much as they can into a cup, and the resulting saliva
sample is collected and weighed. This test's results can determine
whether the salivary glands are functioning adequately. Not enough
saliva produced could mean the person has Sjogren’s syndrome
An alternative test is non-stimulated whole saliva flow collection,
in which the person spits into a test tube every minute for 15
minutes. A resultant collection of less than 1.5ml is considered a
positive result.
If the diagnosis remains in doubt, it can be confirmed by lip biopsy,
which shows focal lymphocytic infiltrate of the minor salivary glands.

23. HISTOPATHOLOGY
Three types of histologic alterations in the major salivary glands
have been described.
1. Intense lymphocytic infiltration of the gland replacing all acinar
structures with the lobular architecture preserved.
2. Proliferation of ductal epithelium and myoepithelium to form
‘epimyoepithelial islands’.
3. Atrophy of the glands sequential to the lymphocytic infiltration.

24. SEROLOGICAL FINDINGS

Although, there is no single definitive laboratory test for the diagnosis,
a combination of abnormal test results is frequently observed :

Elevated ESR

Mild normocytic normochromic anemia

Leukopenia, Thrombocytopenia

Polyclonal hyperglobulinemia

Presence of autoantibodies including
- Anti - SSA (anti-Ro)
- Anti - SSB (anti-La)
- Rheumatoid factor (RF)
- Antinuclear antibodies (ANA)
Monoclonal gammopathy was associated with higher prevalance of parotid
enlargement, extraglandular features, hypergammaglobulinemia, cryoglobulinemia
and related factors with poor prognosis.

25. SALIVARY GLAND IMAGING
Sialography -
It may be of diagnostic value in Sjögren’s syndrome. Sialogram is
performed to see if any blockage is present in the salivary gland ducts and
the amount of saliva that flows into the mouth.
Sialographs demonstrate the formation of punctate, cavitary defects filled
with radiopaque contrast media or widespread dots of contrast medium
within the gland, producing a ‘cherry blossom’ or ‘branchless fruit-laden
tree’ or snowflakes effect.
Sialectasis (abnormal salivary ductal dilation) is classified as-
Punctate lesion : if it is less than 1mm in size;
Globular lesion : if it is uniform and 1–2 mm in size;
Cavitary lesion : if it is coalescent and > 2 mm in size;
Destructive lesion : if the normal ductal structures are
no longer visible.

26. Scintigraphy
It is minimally invasive diagnostic test to access salivary gland function and to
determine abnormalities in gland uptake and excretion.
In Sjogren syndrome, the uptake and secretion of Tc 99m pertechnetate are reduced.
Sonography -
Ultrasound waves may reveal parenchymal inhomogenity of the salivary glands.
A characteristic alteration ‘pepper-and-salt appearance’ is used to describe
sonographic images of patients with SS.
The hypo-echoic areas in the salivary parenchyma are either considered to represent
local lymphocytic infiltrates or dilated ducts surrounded by dense lymphocytic infiltrates.
MRI characteristically reveal the presence of hypo- and/or hyper intense nodules.
It is mainly used to screen salivary glands for presence of lymphomas.

27. TREATMENT
Currently, there is no single satisfactory treatment that has
proven to be effective in modifying the course of the
disease. Most patients are treated symptomatically.
Keratoconjunctivitis is treated by -

Moisture replacement therapies -instillation of ocular
lubricants such as artificial tears containing 0.5 %
methylcellulose 4-5 times daily should be used.

Soft contact lenses can be useful for corneal protection
in patients with filamentary keratitis.

Occlusion of the lacrimal ducts by tiny punctal plugs
inserted to help retain tears on the ocular surface for
a longer time is occasionally needed.

Additionally, Cyclosporine (Restasis) helps to treat
chronic dry eye by suppressing the inflammation that
disrupts tear secretion.

28. For Dry Mouth -
Management of salivary gland dysfunction revolve around the use of
symptomatic therapies such as secretogogues, oral rinses and gels, mouth
washes, artificial saliva and water sipping.
There are two FDA- approved medications which induce a transient increase in
salivary output.
Pilocarpine (Salagen) – 5 mg four times daily
Cevimeline (Evoxac) – 30 mg three times daily
Salivary substitutes - such as -Artificial saliva and oral gels (containing mucin or
hydroxy -methyl cellulose) can be found in products such as lubricating gels,
mouthwashes, lozenges, toothpastes and oral sprays.
Scrupulous oral hygiene and frequent fluoride application is indicated to reduce
dental problems.
For Candidiasis -
Topical Nystatin thrice daily for a week, Ketoconazole 200-400 mg daily or
Fluconazole 50-100mg daily or Itraconazole 100mg daily for 2 weeks.

29. 
NSAIDs may be used to treat mild symptoms. For individuals with severe
extraglandular and musculoskeletal manifestations, corticosteroids or
immunosuppressive drugs may be prescribed. Methotrexate,
Hydroxychlorquine may be helpful. However, these drugs have a range of
side effects such as nausea, loss of appetite, dizziness, hair loss, stomach
ache, headache, liver toxicity and increased risk of infections.

For systemic symptoms, including fatigue, joint pain, myositis and
neuropathy, biologic immunosuppressant drugs such as Rituximab and
Belimumab that work via B cell pathology are often used and are less toxic
than traditional immuno - suppressive regimens.

There is no specific treatment for enlargement of the salivary glands.
Biopsy should be performed to exclude malignancy. Surgery has been
employed but is generally recommended only in patients with discomfort.

30. ADVANCEMENTS IN TREATMENT
There have been substantial efforts to improve salivary function and
oral symptoms with systemic therapies directed at the underlying
disease process which include hormone modulation, general and
targeted anti-inflammatory approaches, blunting of the B-cell
response, and treatment of potential viral etiologies.
- Hormone Modulation - Sex hormones dehydroepiandrosterone
(DHEA), demonstrated no benefit compared with placebo.
- Anti – Malarial Agents - reduce sicca and constitutional symptoms
such as fatigue and Arthralgia.
- Immunosuppresant agents - such as Cyclosporine A, Azathioprine,
Methotrexate, Mycophenolic acid and Leflunomide

31. ●
Anti retroviral agents - Lamivudine, a reverse transcriptase inhibitor.
●
Anti – TNF alpha Antagonists - such as etanercept, infliximab and
thalidomide have shown no significant efficacy for dry mouth
symptoms or salivary function.
●
Low-dose natural (non-recombinant) interferon-a.
●
Direct B – Cell Targated Therapy -
a) Anti CD 20 Monoclonal Antibodies - Rituximab, a humanized
monoclonal antibody
b) Anti CD 22 Monoclonal Antibodies - Epratuzumab is a
humanised anti- CD 22 mAb
●
Indirect B – Cell Targated Therapies - Belimumab, a mAb targeting
soluble BAFF.

32. COMPLICATIONS
A major complicating factor in patients with Sjögren’s
Syndrome is the development of pseudolymphoma
and malignant lymphoma. Most lymphomas are non-
Hodgkin’s types and are B-cell in origin.

Lymphoma -
The most common lymphomas are mucosa
associated B cell lymphomas (MALT lymphomas
involving the salivary glands) and diffuse large B cell
lymphoma (DLBCL). Studies have found that 10% of
MALT lymphomas transfer into more aggresive
DLBCL .

33. Lymphomagenesis is a multistep process, with the first
step being chronic stimulation of autoimmune B cells,
especially B cells that produce rheumatoid factor at sites
targeted by the disease. This increases the frequency of
oncogenic mutation, leading to dysfunction at checkpoints
of autoimmune B-cell activation to transform into
malignancy.
Important predictors in the development of non-Hodgkin’s
lymphoma include hypocomplementaemia (C3 or C4),
mixed cryoglobulinaemia, lymphopenia, low CD4 + T-cell
counts, persistent unilateral / bilateral salivary gland
enlargement, palpable purpura, splenomegaly,
lymphadenopathy, positive RF and cutaneous vasculitis.

34. PROGNOSIS
Studies on the survival of patients are limited in varied respects owing
to the relatively small sample sizes and secondary SS is associated
with other autoimmune diseases. Among those without other
autoimmune disorders, life expectancy is unchanged.
Sjogren's is said to be a "lifestyle-threatening" but not life-threatening
disease. In fact, although the symptoms of Sjogren's syndrome can
negatively impact quality of life and are long lasting, this disorder
rarely completely incapacitates or shortens life span.
Complications from primary Sjogren's syndrome can occur at various
levels, depending on the organs involved. Most of the patients with
Sjogren's syndrome will have a mild, although sometimes debilitating,
clinical course with no significant impact on their general health.

35. REFERENCES

Shafer’s Textbook of Oral Pathology 8th edition

Burket’s Oral Medicine 12th edition

Davidson’s Principles and Practice of Medicine 22nd edition

Oral Radiology : Principles and Interpretation 7th edition – Stuart C. White and
Michael J. Pharoah

https://ghr.nlm.nih.gov/condition/sjogren-syndrome

https://medlineplus.gov/ency/article/000456

Sjögren’s Syndrome - Diagnosis and Therapeutics Manuel Ramos – Casals,
John H. Stone, Haralampos

The Sjogren’s syndrome handbook, Sjogren’s syndrome foundation Daniel J.
Wallace

Sjögren’s Syndrome - Oxford Rheumatology Library, Wan-Fai Ng

36. THANK YOU !