Sjogren Syndrome

1. Sjogren Syndrome
Tengku Ezulia
CME Presentation
30th September 2015
ORL Dept, HKL

2. Sjogren Syndrome
• A chronic autoimmune inflammatory disease which
involves the exocrine glands, significantly decreasing
the quantity and quality of saliva and tears. 1
• The disease was first identified by a Swedish physician,
Henrik Sjögren, in 1933. 3
• The spectrum of presentation of the disorder is very
broad, ranging from the local consequences of exocrine
gland dysfunction to major, life-threatening systemic
complications such as vasculitis, and renal or lung
involvement & a forty times greater risk of developing
lymphoma. 3,4

3. • Primary and secondary forms.
• About half of the time Sjögren’s syndrome occurs
alone, and the other half it occurs in the presence of
another connective tissue disease such as
rheumatoid arthritis, lupus, or scleroderma.
• When Sjögren’s occurs alone, it is referred to as
“Primary Sjögren’s.” When it occurs with another
connective tissue disease, it is referred to as
“Secondary Sjögren’s.”

4. Epidemiology:
• Sjögren’s is one of the most prevalent autoimmune
disorders, striking as many as 4,000,000 Americans.
• Prevalence: 1-10/1000 (about 1%) 4
• Nine out of ten patients are women.
• 40 and 60 years.

5. Etiopathogenesis:
• Not known.
• Multiple factors - inflammation, viral invasion,
hormonal imbalance and genetics.

6. Viral theory 4,5
• Viral invasion of the lacrimal gland could certainly
cause an autoimmune response.
• Both T and B immune cells are present in the healthy
lacrimal gland and react when viruses invade.
• Early viral theories concentrated on the
cytomegalovirus (CMV).
• Current theory, however, has shifted focus to
Epstein-Barr virus (EBV).

7. • Once EBV invades lacrimal acinar cells  acinar cells
begin to produce and display viral proteins  local
lymphocytes initiate a response involving the
production of inflammatory chemicals that will help
to destroy both the virus and the host cell.
• The displayed viral proteins can mimic acinar self-
proteins, and thus the inflammation induced by a
virus can transform into an autoimmune process.

8. Acinar cell theory6
• Mircheff and others have proposed a theory that
suggests that under duress, the acinar cells stimulate
T cells within the gland to initiate an autoimmune
inflammatory cascade by duplicating themselves and
stimulating B cells.
• The change in function of the acinar cells is likely a
result of prolonged low-grade inflammation that
creates a cytokine environment that encourages the
acinar cells to behave like antigen presenting cells
(APC).

9. • This theory is based on the observation that salivary
gland epithelial cells of most SS patients display MHC
class II molecules.

10. Thymus theory4
• Failure of the thymus to eliminate the T cells that have
potential self-reactivity.
• Thymus function is to elimination of such auto -
stimulated T cells through “negative selection.”
• Numerous signals such as fas, fas ligand, bax and bcl-2
determine whether the potentially self-destructive T
cells are released into the periphery or undergo
apoptosis.
• This selection process appears disturbed in
autoimmune diseases.

11. Hormonal influence
• A healthy lacrimal gland requires a balance of
hormonal stimuli to maintain its form and function.
• Female patients present with dry eye symptoms in
certain hormonal states including lactation,
pregnancy, post-menopause, OCP, supplemental
estrogen use and premature ovarian failure.
• One proposed commonality of these altered
hormonal states is low testosterone bioavailability.

12. • Androgen stimulation of acinar cells via specific
receptor activation has a significant influence on
protein synthesis in these cells.
• As such, androgen deficiency may result in the
inability of the acinar cells to produce and secrete
their contents.
• Androgen levels are decreased in both SS and
systemic lupus erythematosus (SLE).

13. • Prolactin has been shown to influence tear function at a
clinical level in that increased levels of prolactin in
women were found to be associated with several
measures of reduced tear fluid production.
• Rabbit studies have shown that increased levels of
prolactin, which occur in pregnancy and lactation, cause
the lacrimal gland to undergo both immunoarchitectural
changes and functional changes.
• There is a critical level of hormonal support required
for the lacrimal gland to remain healthy and free of
autoimmune disease. Androgen support and a
normal level of prolactin appear to be the most
critical hormones for lacrimal gland function.

14. Genetic influence8
• Familial clusterings of different autoimmune diseases have
been reported. It has been noted that 30%-35% of SS patients
have relatives with other autoimmune diseases.
• Genetic studies have suggested that there may be a cluster of
major Histocompatibility complex (MHC) genes that can
influence the propensity for autoimmune disease.
• Thus humans with a particular form of MHC II molecules are
more likely to pick up ribonuclear associated proteins such as
Ro and La because of their configuration and thus more likely
to take these proteins to the surface of the lacrimal cells and
cause SS autoimmune inflammation.

15. • Apoptosis irregularities have been suggested to be a
part of the SS pathophysiology and therefore studies
have undertaken to look at apoptotic genes.
• Mutations in these genes have been implicated in
human disease.
• Of particular interest are the Fas genes, and mutation
in this gene has been identified as a contributor to
autoimmune lymphoproliferative syndrome.

16. • Nakamura et al. found that alleles on the X chromosome over-expressed
antiapoptotic proteins in SS, thus adding to the understanding of the high
prevalence of this disease in women.
• Genes that encode the transporter molecules that move antigens within
the cytoplasm have also been studied. The question of whether a defect in
these molecules might cause antigens such as Ro and La to be more easily
moved to the cell surface has been explored. The transporter molecule
genes have been suggested as possibly being associated with SS
susceptibility.(143) Kaschner et al.(144) looked at immunoglobin genes
and determined that there was a disturbance of B cell maturation and
abnormal editing of immunoglobulin receptors that may contribute to SS.
Mice have demonstrated that chromosomes 1, 4 and 10 hold major
susceptibility loci for autoimmune saladenitis.(145-147) Generally there is
a belief that certain people are more susceptible to autoimmune disease
because of their genetic makeup. Much work is still to be done in this
area.

17. Summary of flow of inflammation
1. A local inflammation is initiated by a virus or other toxin, a slow wearing down of some lacrimal acinar cell function
because of hormonal changes, ocular surface distress and/or neurological compromise or the arrival of inflammatory
cytokines from the inflamed salivary glands.
2. The inflammation causes a release of pro-inflammatory cytokines by distressed acinar cells and a change in
trafficking of self-proteins, leading to their exposure outside the basal membrane. Dendritic cells are likely to pick them
up.
3. Acinar cells, because of exposure to the pro-inflammatory cytokines, become APCs as they create MHCII molecules
and expose self-proteins such as Ro and La that have now relocated in the cytoplasm because of the confusion within
the cell.
4. The formation of HEVs within the lacrimal gland is a response to the cytokine environment. The cytokines,
chemokines and cell-adhesive molecules on the HEVs of the gland cause migration and homing of lymphocytes and
dendritic cells to the affected gland.
5. Because of the inflammatory environment, local dendritic cells now take up selfantigens and take the message to the
lymph nodes to teach Th cells to recognize the self-proteins. The Th cells return to the lacrimal gland to identify Ro and
La and stimulate the local B cells to become Ig secreting plasma cells. 47
6. As time goes on, the lymphocytic infiltrate organizes itself to maintain a constant inflammation. Specific chemokines
and cytokines promote the local reproduction and prolonged life of B and T cells. This organization is present in a
spectrum from mild organization to actual germinal centres.
The pathophysiology of SS salivary and lacrimal gland inflammation and the subsequent systemic pathology is still in
the early stages of understanding. There is, however, a clearer picture of the T, B, acinar and dendritic cell roles in this
inflammation and the extraordinary influence of the cytokine and hormonal environment

18. Clinical presentation
• Xerostomia (Dry mouth)
• Candida infections
• Dental caries & decay
• Swollen salivary glands
• Dysphagia – Difficulty or soreness when eating and/or
speaking and notice that their taste is affected.
• Odynophagia – Swallowing difficult and frequent sips of
water are often required
• Hoarseness
• Keratoconjuctivitis sicca (Dry eyes) – feeling of “irritable” or
“gritty eyes”
• Recurrent eye infections.
• Dry skin
• Dry vaginal dryness - painful or difficult sexual intercourse.

19. Extra glandular manifestations
Systemic manifestations may involve these systems: 4
1. Musculoskeletal – fatigue, arthralgia, myalgia
2. Vascular – Raynaud’s phenomenon (a vascular disorder that is
characterized by episodes of reversible digital ischemia in response to
cold or stress)
3. Cutaneous – Purpura, dry skin
decreased capacity for sebaceous gland secretion
When the blood vessels of the extremities become inflamed, a
hypergammaglobulinemic purpura results and is usually present
symmetrically in the lower extremities.
it is assumed that immune complexes become trapped at the
bifurcation of small blood vessels, leading to complement activation

20. 4. Lungs – Interstitial lung disease, lymphoid interstitial pneumonitis
) Desiccation of the tracheobronchial tree is a common respiratory
manifestation that is also a result of diminished secretions of the local
mucous glands.(419) The dryness of the trachea manifests itself with a
cough that may be mild or strong. Sjogren himself described this
phenomenon and it was labelled “bronchitis sicca” by Alarcon-Segovia
in 1978.(420) AlHashimi et al. in 2001 stated that 9.5% of their SS
patients had a chronic cough and 14.8% reported recurrent bronchitis
5. Neurological – Peripheral neuropathy
6. Lymphoproliferation – Lymphoma
One of the important reasons for identifying SS patients is their
increased risk for lymphoma, which usually presents as marginal-zone
B cell lymphoma of the mucosaassociated lymphoid tissue (MALT), a
form of non-Hodgkin lymphoma (NHL).

21. 7. Renal – Interstitial nephritis
Tubulointerstitial nephritis is a specific tubular epithelitis that is found most
often in younger SS patients and is characterized by an indolent subclinical
course without development of renal failure.(472) In contrast,
glomerulonephritis is a severe manifestation of pSS that is closely associated
with cryoglobulinaemia and hypocomplementaemia that appears late in the
course of SS and is associated with higher morbidity and mortality.(
8. Hematologic –Leukopenia, defined as WBC count less than 4000 cells/ml,
was present in 20% of SS patients in one study.(386) Previous reports have
noted leukopenia in 6%-33% of patients.(457) The mechanism of this
leukopenia is not well understood but could be the result of immune
destruction of leukocytes, splenic sequestration, abnormal bone marrow
maturation or an accumulation of white blood cells in the organs of
inflammation. In a large series of 400 patients, Ramos-Casals et al. in
2002(473) reported cytopenia in 33% of cases, raised erythrocyte
sedimentation rate in 22% and hypergammaglobulinemia in 22%.

22. 9. Gastrointestinal – acid reflux The gastric mucosa of these
symptomatic patients looks atrophic. Biopsies can reveal cellular
infiltrates that consist mainly of T lymphocytes and are thus
reminiscent of salivary and lacrimal gland infiltrates.(432) Al-Hashimi
et al. reported in 2001 that reflux, indigestion, diarrhea and
constipation were present in 20.1%-29.6% of their SS population
10. Maternity
SS patients may report a history of miscarriage. Pregnant SS patients
have a higher frequency of the fetal complication of congenital heart
block that relates to the transplacental passage of autoantibodies to
Ro and La. In some patients recurrent miscarriages or vascular
thrombosis are a result of antiphospholipid antibodies.

29. Diagnostic criteria of SS
American European Combined Criteria (AECC) in 2002
1. Eye symptoms (at least one the following):
a. symptomatic dry eyes for at least 3 months
b. repeated sensation of foreign bodies in the eyes
c. artificial tears are required at least 3 times a day
2. Mouth symptoms (at least one of the following):
a. symptomatic dry mouth for at least 3 months
b. recurrent salivary gland enlargement
c. requirement of frequent drinking while swallowing dry food
3. Positive eye signs: Schirmer’s test ( 5mm/5 min) (or positive
rose bengal test)
4. Positive salivary gland (lower lip) biopsy. In histology at least 1
lymphoid follicle ( 50 cells) / 4 mm2 tissue)

30. 5. Salivary gland involvement (at least one of the following):
a. positive scintigraphy
b. positive parotid sialography
c. unstimulated salivary flow ( 1.5 ml/15 min)
6. Autoantibodies (at least one of the following):
a. SS-A (Ro) or SS-B (La) antibody
b. antinuclear antibody (ANA)
c. rheumatoid factor (RF)
Definite diagnosis requires at least 4 criteria.
In the absence of other (systemic) autoimmune disease, the
diagnosis is primary SS.

31. The exclusion criteria include:
1. past neck and head radiation treatment
2. hepatitis C infection
3. AIDS
4. pre-existing lymphoma or sarcoidosis
5. graft versus host disease
6. use of anticholinergic drugs

32. Schirmer’s test

33. Keratoconjunctivitis sicca (rose bengal test)

34. keratoconjunctivitis sicca (KCS)

35. Severe Xerostomia with dry tongue

36. Sjogren’s Syndrome - Diffuse Submandibular
Salivary Gland Enlargement

37. Sjogren’s Syndrome - Investigations
MRI

38. Histology of salivary gland in Sjögren’s syndrome

40. • ANA (Anti-Nuclear Antibody)
ANAs are a group of antibodies that react against normal components of a cell
nucleus. About 70% of Sjögren’s patients have a positive ANA test result.
• RF (Rheumatoid Factor)
This antibody test is indicative of a most often performed for the diagnosis of
rheumatoid arthritis (RA) but is positive in many rheumatic diseases. In Sjögren’s
patients, 60-70% have a positive RF.
• SS-A (or Ro) and SS-B (or La)
These are the marker antibodies for Sjögren's. Seventy percent of Sjögren’s
patients are positive for SS-A and 40% are positive for SS-B (these may also found
in lupus patients).
• ESR (Erythrocyte Sedimentation Rate)
This test measures inflammation. An elevated ESR indicates the presence of an
inflammatory disorder, including Sjögren’s.
• IGs (Immunoglobulins)
These are normal blood proteins that participate in immune reactions and are
usually elevated in Sjögren’s patients.

42. Eye tests:
• Schirmer Test
Measures tear production.
• Rose Bengal and Lissamine Green
Eyedrops containing dyes that an eye care
specialist uses to examine the surface of the
eye for dry spots.

43. Dental tests:
• Salivary Flow
Measures the amount of saliva produced over a certain period of
time.
• You'll usually be asked to spit as much saliva as you can into a
cup over a five-minute period. The amount of saliva is then weighed
or measured. An unusually low flow rate can indicate Sjögren's
syndrome.
• Salivary scintigraphy
A nuclear medicine test that measures salivary gland function.
• Salivary gland biopsy (usually in the lower lip)
Confirms inflammatory cell (lymphocytic) infiltration of the minor
salivary glands.
• A positive biopsy is defined as at least one focus of dense,
inflammatory infiltrate containing at least 50 lymphocytes per 4
mm

46. Treatment
• No known cure for Sjögren syndrome
• Treatment focuses on relieving symptoms and
preventing complications.
• Treatments can be grouped into regimens for
KCS, xerostomia, and systemic manifestations.

47. Eye care
• Artificial tears
• Mild to moderate cases of dry eye can usually be successfully treated with eye drops containing "artificial tears" –
a liquid that mimics tears. These eye drops are available from a pharmacist, without a prescription.
• There are many different types of eye drops, so you can try different brands to find the one that works best for
you. If you're using eye drops regularly (more than three times a day), you should use one that doesn't
contain preservatives. This is because there's evidence that over-exposure to preservatives can damage the
surface of the eye.
• A short-term dose of eye drops containing corticosteroids may be recommended if your eyes become irritated.
However, long-term corticosteroid use isn't recommended because they can cause serious side effects.
• To minimise the chance of experiencing side effects from corticosteroids, you'll be prescribed the lowest effective
dose for the shortest possible time.
• Moisture chamber spectacles
• Wearing glasses reduces tear evaporation by up to 30%, and this effect can be maximised by wearing specially-
made glasses called moisture chamber spectacles. These wrap around your eyes like goggles and help retain
moisture and protect the eyes from irritants.
• Some people used to be embarrassed to wear them, but modern designs look like sports glasses.
• Punctal plugs
• Punctual occlusion is a widely-used technique that seals the tear ducts (into which the tears drain) with small
plugs. This should help keep the eye better protected by tears.
• Temporary plugs made of silicone are usually used first to see if they help. If it does, more permanent plugs can be
used.

48. Mouth care
• Looking after your mouth
• A number of techniques can be used to keep your mouth lubricated, including:
• maintaining good oral hygiene to prevent tooth decay and gum disease
• increasing your fluid intake
• using sugar-free chewing gum to stimulate saliva production
• sucking ice cubes to help lubricate your mouth and reduce dryness
• regularly using mouth rinses to soothe your mouth and protect it against infection
• If you smoke, you should try to quit. Smoking irritates the mouth and increases the
rate at which saliva evaporates.
• Read more about how to stop smoking.
• Saliva substitutes
• There are a number of saliva substitute products that can help lubricate your
mouth. However, they don't replicate the role of saliva in preventing infection, so
you'll still need to maintain excellent oral hygiene.
• Saliva substitutes are available as a spray, lozenge (medicated sweet), gel, or gum.
Your GP or pharmacist can tell you which product is most suitable for you.

49. Medication for Sjögren's syndrome
• Pilocarpine
• The medicine pilocarpine is often used to treat the symptoms of dry eyes and dry mouth. Pilocarpine stimulates the glands to produce more saliva
and tears.
• Side effects of pilocarpine include:
• hyperhidrosis (excessive sweating)
• nausea
• diarrhoea
• heartburn
• abdominal (stomach) pain
• an increased need to go to the toilet
• For some people, the side effects of pilocarpine are mild. Others find that the side effects outweigh the benefits.
• Don't take pilocarpine if you have asthma or chronic obstructive pulmonary disease (COPD), or if you're pregnant or breastfeeding.
• Hydroxychloroquine
• Hydroxychloroquine has been shown to slow down the immune system's attack on the tear and saliva glands. It can also help reduce any associated
symptoms of muscle pain, joint pain and stiffness.
• You'll need to take hydroxychloroquine for several weeks before you notice any improvements, and it could be six months before you experience the
full benefit of the treatment.
• Side effects are uncommon and usually mild. They include:
• nausea
• skin rash
• loss of appetite
• stomach cramps
• vomiting
• In very rare cases, hydroxychloroquine can damage the retina, affecting vision. You'll probably be asked to attend an eye examination so that your
retina can be checked before you start treatment. Regular eye examinations (usually at least once a year) are also recommended after you begin
treatment.
• Hydroxychloroquine shouldn't be used by breastfeeding women.

50. Treating other symptoms of Sjögren's
syndrome
• Dry skin
• Several soaps and creams are specifically designed for people with dry skin. Your
pharmacist or GP can advise you.
• Vaginal dryness
• The symptoms of vaginal dryness can be treated using a lubricant. Some women
also use oestrogen creams or hormone replacement therapy (HRT).
• Muscle and joint pains
• Muscle and joint pains can be treated with an over-the-counter non-steroidal anti-
inflammatory drug (NSAID), such as ibuprofen. If this doesn't work, see your GP, as
stronger NSAIDs are available on prescription.
• NSAIDs can increase your risk of developing stomach ulcers and internal bleeding,
particularly if they're taken on a long-term basis.
• If you find swallowing NSAIDs difficult because of your dry mouth, you can try an
NSAID cream that's rubbed into affected joints.
• NSAIDs aren't recommended for pregnant or breastfeeding women, or for people
with pre-existing risk factors for cardiovascular or kidney conditions.

51. General advice
• These simple tips can help prevent many of the
problems associated with Sjögren's syndrome:
• have a dental check-up every six months
• practise good dental hygiene – brushing, flossing and
using mouthwash regularly
• avoid eating too many sweet foods
• avoid strong and perfumed soaps – use special creams
and soaps from your pharmacist
• avoid dry environments, such as air-conditioned
offices, whenever possible
• avoid drinking too much alcohol

52. Prognosis
• The most serious complication associated with primary Sjögren syndrome
is the development of a lymphoproliferative disease, primarily non-
Hodgkin lymphoma. Multiple studies have shown an increase in the risk of
lymphoproliferative disease, but no increase in all-cause mortality.29–31 In
contrast with primary Sjögren syndrome, other rheumatologic diseases,
including lupus, rheumatoid arthritis, and scleroderma, have been
associated with increased mortality rates.29 The risk of lymphoma in
patients with primary Sjögren syndrome is 40 times that of the general
population.1 A prospective study of 484 Swedish patients showed that
lymphoproliferative diseases caused six of 34 deaths (18 percent) in the
seven years of follow-up, with an average age of 75 years at the time of
death.29 However, this study did not show an increase in rates of all-cause
mortality in persons with primary Sjögren syndrome compared with the
general population.29 A larger cohort study of 723 Greek patients with
4,384 person-years of follow-up found that seven of 39 deaths (18
percent) were caused by lymphoma.31 A total of 30 cases of lymphoma
were recorded, with an average follow-up of six years.

53. • Multiple studies have shown that low levels of complement
protein C3 or C4 at the time of diagnosis are associated
with a higher rate of lymphoproliferative disease and a
higher mortality rate.29,31–34 In addition to
hypocomplementemia, vasculitis and severe involvement in
parotid scintigraphy have been linked to lower survival
rates.34
• Although there is no definitive evidence to support
screening guidelines for lymphoproliferative diseases in
patients with Sjögren syndrome, the following features
should raise the physician’s index of suspicion: enlarged
parotid glands, regional or general lymphadenopathy,
hepatosplenomegaly, pulmonary infiltrates, vasculitis, and
hypergammaglobulinemia.1

54. Reference:
1. Sjögren’s Syndrome Foundation. url: http://
www.sjogrens.org
2. Manoussakis M.N. Sjogren Syndrome’s .
Orphanet encyclopedia, 2001.
http://www.orpha.net/data/patho/GB/uk-
sjogren.pdf
3. Muhammad S. Soyfoo and Elie Cogan (2012).
Diagnostic and Prognostic Features of Sjögren’s
Syndrome, Insights and Perspectives in
Rheumatology, ISBN: 978-953-307-846-5

55. 4. Sjogren's syndrome: A clinical and biochemical analysis.
Caffery, Barbara Elaine. University of Waterloo (Canada),
ProQuest Dissertations Publishing, 2009. NR55486.
5. Clinical Manifestations and Early Diagnosis of Sjogren
Syndrome. Kassan, Stuart S; Moutsopoulos, Haralampos
M. Archives of Internal Medicine [H.W. Wilson - GS]
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6. Sjogrens Syndrome as Failed Local Immunohomeostasis:
Prospects for Cell-Based Therapy. Austin K. Mircheff et all.
American Journal of ophthalmology. October 2003 Volume
1, Issue 4, Pages 160–179
7. Diagnosis and Management of Sjögren Syndrome. Paul Kruszka,
Robert J. O Brien. Am Fam Physician.2009 Mar 15;79(6):465-
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