Sjogren Syndrome

Tengku EzuliaCME Presentation

30th September 2015ORL Dept, HKL

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

• 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.”

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.

Etiopathogenesis:

• Not known.

• Multiple factors - inflammation, viral invasion, hormonal imbalance and genetics.

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).

• 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.

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).

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

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.

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.

• 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).

• 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.

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.

• 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.

• 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.

Summary of flow of inflammation1. 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

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.

Extra glandular manifestationsSystemic 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 skindecreased capacity for sebaceous gland secretionWhen 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

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 bronchitis5. Neurological – Peripheral neuropathy6. Lymphoproliferation – LymphomaOne 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).

7. Renal – Interstitial nephritisTubulointerstitial 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%.

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. MaternitySS 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.

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 monthsb. repeated sensation of foreign bodies in the eyesc. 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 monthsb. recurrent salivary gland enlargementc. 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)

5. Salivary gland involvement (at least one of the following):a. positive scintigraphyb. positive parotid sialographyc. unstimulated salivary flow ( 1.5 ml/15 min)

6. Autoantibodies (at least one of the following):a. SS-A (Ro) or SS-B (La) antibodyb. 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.

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

Schirmer’s test

Keratoconjunctivitis sicca (rose bengal test)

keratoconjunctivitis sicca (KCS)

Severe Xerostomia with dry tongue

Sjogren’s Syndrome - Diffuse Submandibular Salivary Gland Enlargement

Sjogren’s Syndrome - Investigations

MRI

Histology of salivary gland in Sjögren’s syndrome

• 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.

Eye tests:

• Schirmer TestMeasures tear production.

• Rose Bengal and Lissamine GreenEyedrops containing dyes that an eye care specialist uses to examine the surface of the eye for dry spots.

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 scintigraphyA 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

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.

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.

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.

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.

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.

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

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.

• 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

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

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] 164.12 (Jun 28, 2004): 1275-84

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):465-470

.

8. Cobb BL, Lessard CJ, Harley JB, et al. Genes and Sjogren’s syndrome. Rheum Dis Clin North Am . 2008;34:847–68. vii.