Sjogren's Syndrome Flashcards
Henrich Sjogren’s initially described keratoconjunctivitis sicca (KCS) and arthritis
Sjogren’s syndrome is a ____ affecting __ such as __ (3).
Lymphocytes __ of exocrine organs causing __, __ and __
Slow progressive autoimmune disease affecting exocrine organs (lacrimal, salivary, parotid glands)
Lymphocytes infiltration of exocrine organs causing destruction, reduced secretion and reduced neural stimulation
Differentiate between primary and secondary Sjogren’s syndrome (SS)
Primary SS
- KCS without underlying rheumatic disease
- More common extraglandular features: parotid enlargement, lymphadenopathy, lymphoma
- HLA-DRB 1 *0301 and DRB 1 *1501
- Antibodies: Ro/SSA and La/SSB
Secondary SS
- KCS with another rheumatic disease (most frequently RA)
- Less common extraglandular features
- Immunogenetics and serology as per rheumatic disease (eg: HLA DR4 in RA)
ACR Criteria 2012 - does not distinguish primary vs secondary
Whereas ACR/EULAR 2016 defines them clearly
Epidemiology of SS
Prevalence: 0.1 - 4% population
(25-30% with RA, lesser in other rheumatic disease)
Female predominance (female 9:1 male)
Middle age 30-50 years old
Rarely affects children
Pathogenesis of primary SS
- Lymphocytic infiltration of glandular and non-glandular organs, in Th-1 and Th-17 response
- 90%: CD4+ T lymphocytes - memory phenotype (70%); B lymphocytes (20%)
- 10%: plasma cells, CD8+ T lymphocytes, T regulatory cells, NK cells, dendritic cells - Two modalities of pathogenesis:
2A. Autoimmune attack on acinar epithelium
- Cytotoxic cell death and apoptosis
2B. Muscarinic receptor type 3 antibody
- Accelerated breakdown of ACh by cytokines
- Altered expression of aquaporin channels
Clinical manifestations of SS
A. Sicca symptoms
1. Xeropthalmia
2. Xerostomia
3. Dyspareunia
4. Parotid gland enlargement
B. Extraglandular features
1. Fatigue
2. Arthralgia/arthritis
3. Raynaud’s phenomenon
4. Oesophageal dysfunction
5. Autoimmune thyroid disease
6. Lymphadenopathy
7. Lung, kidney, liver involvement
8. Cutaneous vasculitis
9. Lymphoma
10. Peripheral neuropathy
11. CNS disease
12. Myositis
13. AIHA and MAHA
How does a patient with SS describe ocular symptoms
- Foreign body or gritty sensation, dry eyes
- Painful, itchy or red eyes
- Topical analgesias do not eliminate pain (CNS involvement) - Blurred vision +/- photophobia
- Worse as day progresses (due to evaporation of ocular moisture)
- Infection, corneal ulceration
- Vision loss
All of these describe xeropthalmia (KCS)
- Deficient tear film layer
How would you differentiate from blepharitis?
Low grade inflammation of meibomian glands
Crusting and discomfort
Worse in the morning
Ophthalmology investigations of SS
- Schirmer’s test
- Filter paper placed under inferior eyelid without anaesthesia
- Measure amount of wetness
- Normal: > 15mm in 5 minutes
- Abnormal: < 5mm (15% false positive/negative) - Ocular surface staining (OSS)
- Fluorescein dye for cornea disruption, lissamine green dye for conjunctiva damage
- Sum of 0-6 score for cornea, 0-3 score x2 for conjunctiva (over nasal and temporal)
- Abnormal: score 5 or more - Tear break up time (TBUT)
- Measures disruption in tear film and mucous layer
- Abnormal: 10s or less
- Replacement for Rose Bengal stain (toxic to corneal epithelium)
What is the normal salivary production in a day?
How do patients describe symptoms of dry mouth (xerostomia)?
Normal saliva production: 1-1.5L/day
Abnormal when flow rate < 50% of basal production
Symptoms of:
1. Burning sensation
2. Change in taste - metallic, salty, bitter
3. Swallowing difficulty
4. Disturbed sleep (dry mouth, nocturia)
5. GERD - lack of saliva buffer
6. Dental caries, cracked teeth, loose fillings
7. Lipstick sign (lipstick adheres onto front teeth)
8. Oral candidiasis
9. Denture issues
Salivary gland investigations in SS
- Sialometry
- Unstimulated flow rate < 0.1mL/minute - Scintigraphy - injection of Tc-99m to quantitate flow rate
- Sialography
- Outlines anatomy
- Risk of pain, infection, duct rupture - MRI or ultrasound
- Minor salivary gland biopsy (gold standard)
- Incisional biopsy over lower labial mucosa - 5-10 minor glands
- > 50 lymphocytes, focus fcore > 1 foci/4mm2
- Risk of persistent lip numbness
Differential diagnoses of dry eyes and mouth
A. Medications
1. Antihistamines
2. Benzodiazepines
3. Clonidine
4. Diuretics
5. TCA
B. Conditions
1. Amyloidosis
2. Blepharitis
3. Cystic fibrosis
4. Dehydration
5. Uncontrolled DM
6. GVHD
7. Granulomatous (sarcoid, TB, leprosy)
8. Hepatitis C, HIV/ AIDS
9. IgG-4 related disease
10. Mucous membrane pemphigoid
11. Psychogenic - fear, depression
12. Viral infection - mumps
13. Vitamin A deficiency
C. Others
1. Age related sicca syndrome
2. Congenital gland abnormality
3. Contact lens irritation
4. Radiation to head and neck
What are causes of salivary gland enlargement?
Unilateral
1. Bacterial infection (virus bilateral)
2. Chronic sialdenitis
3. Lymphoma or primary salivary gland malignancy
4. Salivary duct obstruction
Bilateral asymmetric
1. Granulomatous disease
2. HIV/diffuse infiltrative lymphocytosis syndrome
3. IgG-4 related disease
4. Recurrent parotitis
5. Viruses - mumps, CMV, influenza, coxsackie
Bilateral symmetric
1. Acromegaly
2. Alcoholism
3. Anorexia or bulimia
4. Chronic pancreatitis
5. DM
6. Gonadal hypofunction
7. Hepatitis cirrhosis
8. Hyperliproproteinaemia
9. Idiopathic
What other exocrine glands can be involved in primary SS?
- Upper airway dryness - non allergic rhinitis, sinusitis, bleeding
- Larynx - hoarseness
- Trachea - dry cough
- Vagina - dyspareunia
- GI tract - constipation, dysphagia
- Skin - xerosis, pruritus
How does arthritis in primary SS present?
- Distribution similar to RA
- Symmetric arthralgia of wrists, MCPJ, PIPJ
- Morning stiffness and fatigue - Non-erosive, mild arthritis
- Anti-CCP only in 8-10%, however predicts severe progression
Extraglandular complications of primary SS
A. Lungs
- Xerotrachea, xerobronchitis (dryness, dry cough)
- Bronchiolitis (constrictive)
- Bronchial associated lymphoid tissue lymphoma
- ILD: NSIP, LIP, UIP
- Bronchiectasis - thick secretions, recurrent pneumonia
(Consider SS in patient with unexplained lung disease and positive ANA)
B. Renal disease
- Type 1 RTA (distal): hypokalaemia, muscle paralysis
- Tubular interstitial nephritis
- Glomerulonephritis (rarely)
- Nephrogenic DI
C. GI disease
- Coeliac disease (in HLA DRB1, DQB1)
- Primary biliary cholangitis
- Autoimmune hepatitis
- Recurrent pancreatitis
D. Vasculitis
- Cutaneous vasculitis (palpable purpura)
- Necrotising vasculitis, polyarteritis nodosa
- Cryoglobulinaemia
E. Nervous system
- Multiple sclerosis like lesions
- Transverse myelitis (LETM)
- Optic neuritis and NMOSD (positive AQP4 Ab)
- Peripheral neuropathy, mononeuritis multiplex (motor/sensory/both)
Complications of pregnancy in SS
In anti-SSA or anti-SSB positive SS pregnancy
- Neonatal lupus
- Congenital heart block
Laboratory investigations in primary SS
- ANA (85%)
- ESR (80%)
- Hypergammaglobulinaemia (80%)
- Anti-SSA (Ro) (50%)
- Anti-SSB (La) (33%)
- Rheumatoid factor (50%)
- Anaemia of chronic disease (25%)
- Leukopenia, thrombocytopenia (10% - rare)
SS without any positive autoimmunity (seronegative SS) is extremely difficult to diagnose
Recent advances for diagnosis of seronegative SS
- Anti-centromere antibodies
- Novel antibodies (Sjo test)
- Salivary protein-1
- Carbonic anhydrase 6
- Parotid secretory protein
Cancer risk in SS
5 to 44 fold increased risk for lymphoma
(Lifetime frequency 5-10%)
Usually NHL (B cell)
Others: extranodal marginal zone BCL
Transformation to DLBCL
Risk factors for developement:
1. Persistent salivary gland enlargement
2. Lymphadenopathy
3. Raynaud’s phenomenon
4. Splenomegaly
5. Palpable purpura
6. Glomerulonephritis
7. Peripheral neuropathy
8. Disease duration > 10 years
9. Moderate high disease activity > 5
10. Hypergammaglobulinaemia (IgM kappa)
11. Low C3 or C4, loss of positive RF
ACR/EULAR Classification Criteria for primary SS (2016)
Sensitivity 96%, specificity 95%
Mandatory criteria:
- Ocular or oral dryness
Score at least 4 out of 9 from:
- Labial salivary gland biopsy - lymphocytic sialdenitis and FS > 1 foci/4 mm2 (3 points)
- Anti-SSA/Ro (3 points)
- OSS 5 or more (1 point)
- Schirmer’s test < 5mm/5 minutes (1 point)
- Unstimulated whole salivary flow rate < 0.1mL/minute (1 point)
Management of non-occular sicca symptoms in SS
- Vaginal dryness - topical lubricants
- Dry skin - lotion, cream, emollients
- Xerostomia - mouthwashing, regular toothbrushing, flossing
- Sugar free gum or lozenges
- Avoid alcohol, coffee, nicotine, acidic beverages
- Regular water ingestion
- Nasal polypectomy
- Oral candidiasis - nystatin, clotrimazole
- Pilocarpine 5mg QDS - cholinergic secretagogues
(caution in glaucoma, asthma, beta blocker use)
Management of xeropthalmia in SS
A. Non-Pharmacological
1. Limit caffeine intake
2. Smoking cessation
3. Limit screen use
4. Turn off fans, use humidifiers
5. Special eyewear with moisture chamber or scleral contact lenses with moisture reservoir
6. Eliminate offending medications
7. Warm compress
B. Pharmacological
1. Eye drops - TNPF
2. Moderate-severe disease
- Topical corticosteroids
- Cyclosporin 1 drop BD or lifitegrast 1 drop BD
(stings, and takes 4-12 weeks for full effect)
3. Blepharitis
- Topical azithromycin
- Systemic doxycycline
C. Surgical
1. Punctal occlusion and temporary plugs
Management of extraglandular complications of SS
- Arthritis - NSAIDs, low dose prednisolone
- Severe manifestation - steroids, azathioprine, MMF, methotrexae or cyclophosphamide
- Rituximab
- Belimumab and abatacept
