Sjögren Flashcards
DEFINITION
Sjogren syndrome is an autoimmune systemic disease that targets the exocrine organs, mainly the lacrimal and salivary glands, and is associated with reduced saliva and tear production (‘lazy gland syndrome’).
Another way to refer to this disease is ‘autoimmune epitelitis’, since the starting point of the inflammation is a virus infecting epithelial cells and the main target of the disease is the epithelium.
EPIDEMIOLOGY
relatively common syndrome but it’s often undiagnosed
strong family history for Sjogren syndrome: patient’s relatives often have other autoimmune diseases
- Prevalence - 0.3-1/1000 people (varies according to ethnicity, age, classification criteria referred to for diagnosis, and to diagnostic tests used)
- Incidence- 4 /100.000
- Sex - FEMALE
When the disease does appear in males it tends to have less frequent extra-glandular involvement (e.g. neurologic), and a general ‘lower immunologic expression’, meaning less antibodies production and less severe manifestations
AGE
peak of incidences is at 35-45 years. When the onset occurs <35 years the followings apply:
o The more frequent clinical features include fever, lymphadenopathy and parotid swelling (unlike the classic clinical presentation which we will describe shortly- e.g.: dry eyes, dry mouth etc.)
o There is a greater immunologic expression (more antibodies and lower C3 and C4 levels).
o There is a higher risk of developing lymphoma
PRIMARY OR SECONDARY
Sjogren syndrome can be either ‘primary’, where it appears on its own, or ‘secondary’ where it is associated with other rheumatic autoimmune diseases (e.g. SLE, rheumatoid arthritis, scleroderma and others).
SECONDARY»_space; PRIMARY
Main antibodies:
- ANA antibodies (90-100%) - these are very sensitive autoantibodies but very nonspecific as they can be found in many autoimmune and connective tissue diseases (e.g. SLE, Sjogren, Scleroderma etc.).
- Anti-SSA/Ro and Anti-SSB/La - are the antibodies that are more specific for Sjogren. They are ENA antibodies. The SS stands for Sjogren syndrome.
a. 60-90% of patients with Sjogren syndrome are positive for anti-SSA/Ro.
Anti-SSA/Ro are responsible for ‘neonatal lupus’, a disease of the fetus that occurs due the antibodies crossing the placenta.
b. 30-60% of patients with Sjogren syndrome are positive for anti- SSB/La. - Rheumatoid factor (50-90%) - notice that RF is found at a higher percentage in Sjogren than in rheumatoid arthritis. Thus, RF is NOT specific for RA, and can be found in many autoimmune diseases.
- Other autoantibodies - e.g. cryoglobulins which are antibodies (IgM or IgG) that precipitate below 37° and may cause vasculitis or glomerulonephritis.
Other immunologic features, mainly found in patients with ‘higher immunologic expression’, include:
- Hypocomplementemia- Reduced (C3 and) C4 levels
- Hypergammaglobulinemia - Increased gamma globulins, >20% (quite typical of Sjogren syndrome)
- Glandular lymphocytic infiltrations - the infiltration occurs in several glands (e.g. ocular) but we obtain a biopsy and check for infiltration in the minor salivary glands.
- Overlap with other autoimmune diseases (33%) - could be with other connective tissue diseases e.g. lupus, scleroderma or rheumatoid arthritis or even with organ-specific diseases (especially Hashimoto’s thyroiditis).
- Strong family history
PATHOGENESIS
(GENETIC + ENVIRONMENTAL)
- An environmental trigger such as a viral infection (mainly by Herpes, retroviruses and Coxsackievirus) , supported by genetic predisposition and estrogen deficiency, attacks the resting epithelium of exocrine glands, determining persistent endothelial cells activation.
- This causes damage to epithelial cells of the exocrine glands and exposure of self-antigens through the presence of apoptotic bodies or NET products. In genetically predisposed individuals, these self-antigens activate the innate immune system, in particular the dendritic cells, that carry the self-antigens to the lymph nodes where they present them to T-cells, promoting the activation of the adaptive immunity.
- In addition, the self-antigens activate plasmacytoid dendritic cells which produce very large amount of IFN-α. IFN-α promotes the production of other cytokines, which in turn, promote the activation of the adaptive immunity and the production of autoantibodies. Thus, like in lupus, also in Sjogren syndrome IFN-α is one of the key cytokines involved in the pathogenesis and clinical manifestation of the disease. Another key cytokine in Sjogren syndrome is BAFF (or BLISS) which stimulates the proliferation of plasma cells and production of antibodies, as well as the recruitment of T-cells. The result is the increase of lymphocytes and other immune cells in the exocrine glands. All the above lead to an intense lymphocyte-mediated damage and fibrosis of the glands.
PATHOGENESIS 2
- The activation of the adaptive immunity leads to the recruitment of other immune cells, thanks to the production of adhesion molecules and chemokines, that attract T and B lymphocytes to the site of the inflammation.
- Locally released cytokines further activate epithelial cells and dendritic cells, enhancing the whole process and eventually leading to the gland dysfunction.
PATHOGENESIS SUMMARY
there is an abnormal response to the self-antigens, more sensitive plasmacytoid dendritic cells, more sensitive downstream IFN-α pathway, with a higher expression of interferon-related genes and production of proteins that activate T and B cells.
Classification criteria:
if they are affected by at least 4 of the following (with at least one of them being a non-clinical criterion
- Clinical criteria:
Ocular symptoms- (at least one the followings):
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
Mouth symptoms- (at least one of the followings):
a. Symptomatic dry mouth for at least 3 months
b. Recurrent salivary gland enlargement (mainly the parotid)
c. Requirement of frequent drinking while swallowing dry food
Ocular signs- Positive Schirmer’s test (<5mm/5 min), or positive rose bengal test
Salivary gland involvement- (at least one of the followings):
a. Positive scintigraphy
b. Positive parotid sialography
c. Unstimulated salivary flow- this is done by collecting all the saliva that is produced in 15 minutes into a tube. Patients with Sjogren collect <1.5 ml.
- Non-clinical criteria:
Positive salivary gland biopsy (lower lip)- In histology at least 1 lymphoid follicle (at least 50 cells) / 4 mm2 tissue)
Positivity of autoantibodies- (at least one of the followings):
a. SS-A (Ro) or SS-B (La) antibody
b. Antinuclear antibody (ANA)
c. Rheumatoid factor (RF)
The Sicca cohort used other classification criteria for Sjogren syndrome according to which at least 2 of the following must occur:
- Positive serum autoantibodies - anti-SSA/Ro and/or anti-SSB/La OR positive rheumatoid factor and antinuclear antibody titer ≥ 1:320
- Labial salivary gland biopsy - exhibiting focal lymphocytic sialadenitis
- Keratoconjunctivitis sicca - dryness of the eyes.
SICCA SYNDROME
refers to the clinical presentation of a dry mouth, dry eyes and dry mucosa, even in the absence of the last 2 immunologic criteria. Therefore, while sicca symptoms occur in the vast majority of Sjögren’s patients, not everyone with these symptoms has Sjögren’s.
According to prof. Spinelli one of the most common causes of having dry eyes and dry mouth is post-menopausal age, the reason is unknown. Other causes can include, parasympathetic disorders, certain drugs or infections, past radiation exposure.
CLINICS
1. Glandular manifestations
- Xerostomia (98%) - dry mouth
- Xerophtalmia (93%) - dry eyes
- Dry skin (31%)
- Genital dryness (19%)
- Parotid enlargment (18%)
Glandular manifestations (i.e. Sicca syndrome) alone occurs in about 35% (1/3) of the patients. However, in the majority of patients (the remaining 65%) we can find Sicca syndrome + extra - glandular manifestations.
Therefore, the exclusion criteria for Sjogren trials include:
® Previous irradiation of head/neck
® HCV infection
® HIV infection
® Pre-existing lymphoma
® Sarcoidosis - in case of involvement of the exocrine glands.
® GVHD
® Anti-cholinergic drugs- that will reduce the salivary drug production
® IgG4-related disease
Dry mouth (xerostomia)
burning sensation, problems during swallowing, speaking and chewing, and taste abnormalities. It can present as dry oral mucosa, lack of saliva, or dense saliva.
Upon physical examination we can find: atrophic papillae, dental caries and oral candidiasis that result from the lack of saliva, and salivary gland swelling.
Keep in mind that xerostomia has a high prevalence in the population (14-46%) we should consider other causes of a dry mouth:
* GLANDULAR- irradiation, surgery, neoplasia, sarcoidosis, HCV, HIV, amyloidosis, GVHD.
* NEUROLOGIC
o Drugs (anti-depressant, neuroleptic, parasympathetic inhibitors, clonidine, beta-blockers, diuretics)
o Autonomic dysfunction
o Alzheimer
o Peripheral neuropathies
* ENDODRINE DYSFUNCTIONS: diabetes mellitus – xerostomia is quite a frequent feature of these patients (and with a much higher prevalence than that of Sjogren) the sensation of dryness is the reason that these patients tend to drink a lot of water.
* DE-HYDRATATION
* ACUTE VIRAL INFECTIONS- e.g. mumps
This means that in the absence of autoantibodies or positive biopsy a diagnosis of Sjogren cannot be confirmed.
Imaging of salivary glands:
- Scintigraphy of the salivary gland - using Tc99m: in Sjogren syndrome we can observe an absence of the signal from the salivary gland due to the reduced production.
- Sialography - an iodinated contrast medium is injected into the salivary glands and an X-ray is performed. The black arrow indicates the reduced density- indicating a reduced amount of iodinated saliva in the duct. This is the main imaging instrument used in the diagnosis process.
- MRI - quite expensive and not used often.
- Ultrasound - where an heterogenous gland is observed - suggesting an inflammatory process. The main US characteristics of the disease are multiple hypoechoic or anechoic areas (<10 in this scan, red arrow), hyperechogenic reflections at the border of these anechoic areas (blue arrow), and sometimes hypervascularization (white arrow). This is not so specific for Sjogren, but along with other specific factors (autoantibodies and positive biopsy) can suggest SS.
Lip biopsy:
In the presence of antibodies positivity, we should perform a biopsy of the minor salivary glands (taken from the lip) showing lymphocytic sialadenitis. This includes a ‘focus’ of lymphocytic infiltration that includes AT LEAST 50 LYMPHOCYTES/ 4mm2 tissue.
The number of foci in the biopsy are then counted- giving rise to a grading:
