Preena Joshi Flashcards
Genetic susceptibility factors for SLE
- More common in people with early complement protein deficiency - (c1q, c2, c4 - results in lack of clearance of immune complexes)
- Histocompatibility genes (6p21.33; 6p21.32). HLA B8, DR2, DR3
Which finding would suggest drug induced SLE?
Anti-histone antibody
What are the major subcategories of SLE pathophysiology
- Type II hypersensitivity reaction (cytotoxic antibody mediated attack) mainly
- Type III hypersensitivity reaction (immune complex mediated) to a lesser degree
Describe the type II pathophysiology in SLE
Type II Hypersensitivity
- Autoantibodies binding directly to surface of blood cells - especially erythrocytes but all leukocytes to lesser extent
- Results in pancytopenia and increase susceptibility to infection
Effect of SLE on the kidneys
- Can be nephrotic (>3.5 g/day protein) or nephritic (bleeding and inflammation) - usually nephritis doe
- IC deposition results in activation of complement (classical) via a type III hypersensitivity reaction
- Most commonly results in diffuse proliferative glomerulonephritis seen as subendothelial,intramembranous and/or mesangial deposition of IgG with C3 deposition
- LM will show wire looping in kidneys and granular immunofluorescence
Effect of SLE on the heart?
- LSE disease (Libman Sacks Endocarditis)
- Verrucous thrombi (nonbacterial vegetations on both sides of the mitral and aortic valves)
- These vegetation may result form immune complex deposition.
- The condition may progress to valve fibrosis resulting in regurgitation or possible stenosis.
Signs and symptoms of SLE with justification
Rash (malar or discoid) - Skin infiltration by leukocytes and other immune cells in response to UV light are crucial to the development of CLE lesions.
Arthritis (inflammatory, migratory, nonerosive - monoarthritis is rare in SLE)
Serositis (pericarditis, pleuritis - manifests as chest pain and SOB
Haematoligcal dysfuction - pancytopenia - manifests as fatigue
Oropharyngeal/mouth ulcers - painless but prolonged and recurrent
Renal impairment - manifests as edema, hematuria, proteinura, oliguria
Photosensitivity
Antinuclear antibodies
Immunoligic disorder
Neuroligcal disroder (seizure, psychosis)
Other:
Alopecia
Cardiovascular: HTN, dysrhytmias, venous/arterial thrombosis
Fibronyalgia
Raynaud’s phenomenin - colour changes of the digits induced by cold or emotion
- Triphasic colour change from white to blue to red in fingers and toies
- Bilateral
- Fever
- Weight loss
- Lymphadenopathy
- peripheral that is regional rather than generalised (cervical and axillar regions)
- Non tender around 3-4 cm
- Abdominal pain and diarrhoea
First line investigations of SLE
1st to order:
- FBC and differential:
anaemia, leukopenia, thrombocytopenia; rarely pancytopenia
- Leukopenia is usually caused by lymphopenia rather than neutropenia. - Activated PTT:
May be prolonged in patients with antiphospholipid - U & E:
Elevated due to renal manifestations - ESR and CRP:
Non specific
ESR due to increase immunoglobulins - ANA, anti dsDNA, Smith antigen
- Anti dsDNA suggestive of renal impairment
- ANA most sensitive
Clinically relevant ANA are IgG
- Positive ANA in itself may also indicate other connective tissue disease such as RA, Sjogren’s, thyroid disease and certain drugs
Ddx of SLE
- RA
Joint X ray would show symmetrical erosive arthrtis in RA but non erosive in SLE - Antiphospholipid syndrome
Recurrent venous or arterial thrombosis
Recurrent miscarriages
Anticardiolipin IgG or IgM present in moderate or high levels on >2 occasions at leat 6 weeks apart
Lupus anticoagulant detected >2 occasiona at least 6 weeks apart
B glycoprotein positive
Veneral disease research labortaty test: flase positive due to cardiolipin (Syphillis) - Systemic sceloris
Raynouds phenomenon that ulcerates (does not ulcerate in SLE)
Patients with systemic sclerosis have characteristic sclerodactyly and calcinosis, not present in SLE.
positive anti-centromere antibodies or anti topoisomerase antibodies - Mixed connective tissue disease
Tend to lack anti-Sm, anti-Ro and anti dsDNA - Adult Still’s disease
Variant of juvenile RA characterised by seronegative chronic polyarthritis with systemic manifestations
Elevated ferritin
Rash is usually only seen in febrile peroids and is usually salmon coloured - Lyme disease
Exposure to ticks
Lyme specific IgM or IgG
Presence of ANA common but dsDNA and Smith are not - HIV
HIV ELISA positive
ANA may be present but dsDNA and Smiths are not
CMV
Serology positive
ANA may be present but dsDNA and Smiths are not
8. Infectious Mononucleosis In patients with EBV Positive agglutination Septic arthritis Positive culture joint aspiration
Genes associated with SLE
HLA B8, DR2, DR3
Which virus may trigger SLE?
EBV
Antibodies in SLE and % of times that they wil be positive in people with SLE
- ANA (most sensitive) 95%
- Anti dsDNA (highly specific) - 60%
- Anti Rf - 40%
- Anti ENA - (Anti RO, La, Sm RNP) - 20-30%
- Antiphospholipid Ab’s (lupus anticoag and anticardiolipin) - also assocaited with Shogrens (15-20% ) autoimmune thyroid disease (5-10%)
Best tests for monitoring SLE activity
- Anti dsDNA
- C3 and C4 (denotes consumption of complement, hence C3 and C4 low, and
C3d and C4d high, their degradation products). - ESR
Relationship between ESR and CRP
if ESR high but CRP normal think about SLE whenever someone has a multisystem disorder
If CRP is high think of infection, serositis or arthritis
Which drugs may worsen idiopathic SLE
- Sulphonamides
2. OCP
Tx of SLE acute flares
(eg haemolytic anaemia, nephritis, severe pericarditis
or CNS disease)
- IV Cyclophosphamide
2. High dose prednisolone
Tx of SLE cutaneous symtoms
- Topical steroids
2. High factor sunblock
Maintenance Mx of SLE
- NSAIDs
- Hydrochloroquine (joint and sin)
- Low does steroids for chronicity
- Azathioprine,
methotrexate and mycophenolate are used as steroid sparing treatment
Tx of lupus nephritis
May require more intensive immunosuppression with steroids
and cyclophosphamide or mycophenolate
What is the injury in a”floating shoulder injury”
Fracture of the distal clavicle and neck of the scapula
What is the common mechanism of injury in a floating shoulder injury
Occurs due to high energy trauma such as motor vehicle accidents, fall from height, crush injury, gunshot wound
What is the artery at most risk in a floating shoulder injury
Axillary - see pics in joint anatomy sheet
What are the main componeNts of anasTAmoses around the scapula?
SEE IMAGE IN JOINT ANAT. SHEET
- The Arterial Anastomosis around Scapula is principally created between the branches of the first part of the subclavian and the third part of the axillary arteries.
1. Suprascapular artery (from the thyrocervical trunk)
2. Circumflex scapular artery (subscapular artery, from axillary)
3. Dorsal scapular artery (of the subclavian)
4. Intercostal arteries (thoracic aorta) - SEE IMAGE IN JOINT ANATOMY SHEET
What is the clinical significance of the scapular anatamoses
The Arterial Anastomosis around Scapula is principally created between the branches of the first part of the subclavian and the third part of the axillary arteries.
If the subclavian and axillary arteries are blocked anywhere between 1st part of subclavian artery and 3rd part of axillary artery, the scapular anastomosis acts as a potential pathway (collateral circulation) between the first part of the subclavian artery and the third part of the axillary artery, to ensure the adequate circulation to the upper limb.
Which nerve is most likely to be damage in an anterior dislocation of the shoulder? How would this present?
Axillary nerve damage
Inability to abduct >15 degrees (deltoid)
flattened deltoid
loss of sensation over deltoid muscle and lateral arm
Also might have damage to the radial nerve since it is tightly bound in the radial groove
Which muscles attach to the glenohumeral capsule?
Rotator cuff muscles
Another name for adhesive capsulitis
Frozen shoulder
What is the function of the glenohumeral joint capsule?
a fibrous sheath which encloses the structures of the joint. It extends from the anatomical neck of the humerus to the border of the glenoid fossa. The joint capsule is lax, permitting greater mobility (particularly abduction).
What is the function of the synovial membrane and its associated bursae?
The synovial membrane lines the inner surface of the joint capsule, and produces synovial fluid to reduce friction between the articular surfaces.
To reduce friction in the shoulder joint, several synovial bursae are present. A bursa is a synovial fluid filled sac, which acts as a cushion between tendons and other joint structures.
What changes occur in the joint capsule in adhesive capsulitis/frozen shoulder
Thickening and contraction of the glenohumeral joint capsule and formation of adhesions cause pain and loss of movement
Which muscles attach to the lateral supracondylar ridge
- Brachioradialis
- Extensor carpi radialis longus
- Triceps brachii
Pronators of the forearm
- Brachioradialis
- Pronator teres
- Pronator quadratus
Supinators of the arm
- Supinator
2. Biceps brachi
How are the medial and lateral epicondyles related to the flexors and extensors of the forearm? How might flexor/extensor muscle movement create pain for people suffering from lateral/medial epicondylitis?
flexors on medial epicondylitis = golfers elbow
extensors on lateral epicondyle = tennis elbow
Borders of the cubital fossa
Lateral border – The medial border of the brachioradialis muscle.
Medial border– The lateral border of the pronator teres muscle.
Superior border – An imaginary line between the epicondyles of the humerus.
Contents of the cubital fossa
From lateral to medial
“Really Need Beer To Be At My Nicest.”
Radial nerve
Biceps tendon
Brachial artery
Median nerve
Boundaries of Guyons canal
Floor: T
ransverse carpal ligament, hypothenar muscles
Roof: Volar carpal ligament
Ulnar border: Pisiform and pisohamate ligament, abductor digiti minimi muscle belly
Radial: border Hook of hamate
What runs through Guyons canal
Ulnar nerve and artery
ulnar nerve bifurcates into the superficial sensory and deep motor branches
What does the deep branch of the ulnar nerve innervate
- Innervates all of the interosseous muscles and the 3rd and 4th lumbricals.
- Innervates the hypothenar muscles, the adductor pollicis, and the medial head (deep) of the flexor pollicis brevis (FPB)
What is the ulnar paradox and why does it occur
Ulnar claw: Distal to the elbow, proximal to the wrist
1. Ulnar nerve innervated the lumbrical which flex at MCP joint and extend at IP joints. Damage to ulnar nerve results in extension at this joint due to unopposed action of extensor digitorium and extensor digiti minimi
2. Loss of extension of IP joints results in flexion of IP of ulnar two fingers due to the lack of opposition of the FDP = claw appearance
Ulnar paradox: closer to the elbow.
- Ulnar nerve lesion closer to the elbow reduces action of FDP = less flexion = less claw like. Seems like the injury is better but its actually worse!
How to test for collateral blood supply in the hand
Allens Test
radial and ulnar are collateral circulation for one another for the hand - if you occlude one the other will take over provided it is in a healthy condition
If color returns as described, Allen’s test is considered to be normal. If color fails to return, the test is considered abnormal and it suggests that the ulnar artery supply to the hand is not sufficient.[2] This indicates that it may not be safe to cannulate or needle the radial artery.
Carpal tunnel structure
Median nerve
4 x FDP
4 x FDS
Cells in the epidermis
Keratinocytes
Also melanocytes and langerhans cells
Cells in the dermis
skin’s next layer, is a thick
layer of fibrous and elastic tissue made
mostly of collagen, elastin, and fibrillin
Contains blood vessels, nerves and
specialized structures such as sweat glands
and hair follicles
Difference between UVA and UVB
UVA - long wave and causes photoageing (wrinkles and ageing) - 320-400nm
UVB - burns and skin cancer 290-320
Skin phenotypes
SPT I
Always burns, never tans – pale white
SPT II
Burns easily, tans minimally - white
SPT III
Burns moderately, tans gradually to light
brown - white
SPT IV
Burns minimally, always tans well to
moderately brown – light brown
SPT V
Rarely burns, tans profusely to dark
brown – brown (e.g. Asian)
SPT VI
Never burns, deeply pigmented – black
(e.g. African)
Describe sunburn and risk factors associated with it
Acute inflammatory response to UV radiation
More frequently seen in individuals with SPT I
and II
Repeated sunburns lead to photoageing and
increased risk of skin cancer
Tx for sunburn
- cool wet dressings
- topical steroids
- systemic steroids / NSAIDs
Features of action/solar keratoses
Marker of chronic sun damage
Back of hands, forearms, forehead, scalp,
temples, nose, cheeks and ears
Pre – Malignant; Increased risk of
developing non-melanoma skin cancer
Poorly defined scaly areas, erythematous
base
Discrete yellow-brown keratotic lesions
Mc of actinic/solar keratoses
- Cryotherapy (light spray of liquid nitrogen)
- Cauterization
- 5-FU cream (Efudix) for multiple lesions
Desribe polymorphous light eruption
Idiopathic & acquired reaction to UV radiation
5% population, female predilection, 23 years
Lesions appear in Spring/Summer
Pruritic erythematous macules, papules, plaques
and vesicles
Prevention of polymorphous light eruption
Sunscreen
Mx of polymorphous skin eruption
Topical/systemic sterioids
Examples of drug induced photo sensitivity
Phototoxicity
Photoallergy
What cuases phototoxicity
psoralen
Features of phototoxicity
More common
Changes noted within hrs
of exposure
UV ‘activates’ the agent
which then destroys cell
membranes or DNA
Limited to sun-exposed
sites
Looks like severe sunburn
Drugs that cause photoallergy
Thiazides, Amiodarone (causes skin to become blue),
Tetracyclines,
Sulfonamides
Features of photoallergy
Less common
Changes noted 1-3 days
after exposure
UV changes the ‘shape’ of
the substance so that it
gets recognized by the
immune system
Looks like contact
dermatitis mainly at
exposed sites
Which conditions are exacerbated by sunlight
SLE
What differentiates a malar rash from other butterfly rashes
Spares the nasolabial folds - LUPUS
Conditions improved by sunlight
- Psoriasis
2. Atopic dermatitis
Treatment for psoriasis
Narrow band UVB (reduces risk of skin cancer)
Describe porphyria cutanea tarda
UROGEN decarboxylase deficiency
Bullae are seen after sun exposure (dorsum of hands and face)
which resolve with scarring. Condition
What is PCT assocaited with ?
Condition associated with
chemicals and drugs (alcohol, estrogen, iron), liver disease
(hepatitis C) and diabetes mellitus
Features of PCT
hypertrichosis(hair growth) (sides of face and
between eyebrows), hyperpigmentation of the facial skin
In this condition there is an hepatic
enzyme abnormality with a genetic predisposition. It presents with
bullous eruption which heals with scarring and milia formation
Diagnosis of PCT
Urine test with Wood lamp examination: orange-red
fluorescence due to increased uroporphirin in urine
Features of xeroderma pigmentosa
Rare autosomal recessive disorder
Cellular hypersensitivity to UV radiation
due to defect in DNA repair
Photosensitivity, pigmentary changes,
premature skin aging & malignant tumour
development.
Management of xeroderma pigmentosa
Management: sun-avoidance, surveillance
for early skin cancer detection.
Basal cell carcinoma lesions
Sun-exposed sites
Raised, pearly or translucent papule
Telangiectasia
Central ulceration
Rolled edge
Does BCC metastasise?
rarely
Tx of BCC
Surgical excision ( consider MOHS for difficult sites)
Curettage + Cautery
Radiotherapy
Topical Imiquimod - superficial BCC’s
Topical 5-FU - superficial BCC’s
Cryotherapy – superficial BCC’s
Diagnosis of squamous CC
Presence of thick keratin layer contained within squamous cells
Features of SCC
Second commonest form of skin cancer
Malignant tumour of keratinocytes
Begin as keratotic nodules
Firm indurated base
Ulcerating as enlarge
Invades deeply and may metastasise if untreated (to the LNDs)
Mx of SCC
Excision
Describe Bowen’s disease
Dysplastic changes are confined to the
epidermis i.e. no invasion
They usually occur in sun exposed sites
(especially lower leg)
Usually will be a lesion that has been there or a number of years
Tx of Bowens disease
Monitor the lesion - it will be increasing in size
It can be treated with cryotherapy,
curettage and cautery or radiotherapy.
Topical 5 fluorouracil is helpful in multiple
lesions
Features of lentigo
“Sun spots”
Benign
Flat, pigmented areas
Composed of increased numbers of
melanocytes
Features of lentigo maligna
Melanoma in situ
ie: patch of malignant melanocytes, in
sun-damaged skin, which proliferate along
dermo-epidermal junction.
Malignant transformation may take years!
Lesion flat, irregular outline and pigment
Management: Excision
Skin surveillance steps
A symmetry (in colour and shape)
B order
C olour
D iameter (<6mm benign)
E volution (elevation – enlargement)
- More than two signs you should be monitored or have the lesion excised
Types of malignant melanomas and who/where they present
Various Forms:
Lentigo Maligna = elderly patient
Superficial Spreading = commonest
Nodular = invasive pattern
Acral = on sole or palm
Subungual = beneath the nail
Amelanotic = often late presentation
Melanoma prognosis
Prognosis directly related to tumour
thickness on histology (Breslow thickness)
<1.5mm~ excellent prognosis
> 3.5mm~ normally metastasise despite wide
resection margins - bad prognosis
Mx of malignant melanoma
Surgical excision with wide margin
Plastic surgery consult often required
Types of immunoflouresence
Direct: single Ab linked to a fluorophore
(tissue-bound Abs)
Indirect: primary and secondary (which
carry the fluorophore) Abs (circulating Abs)
Autoimmune iseases of the skin
Pemphigus
Bullous pemphigoid
Dermatitis herpetiformis
Psoriasis
Vitiligo
Alopecia areata
Epidermal necrolysis
Features of pemphigus
Bullous autoimmune disease of skin and mucous membranes
based on acantholysis – loss of the normal cell-to-cell adhesion in
the epidermis
Circulating IgG antibodies that bind to desmosomes
Vescicles – bullae formation, superficial, flaccid → erosions
Who does pemphigus affect
Affects adults 40-60s, more common in Ashkenazi Jews
Investigations of pemphigus
Biopsy shows intraepidermal vesicles with keratinocytes floating
free in the blister cavity (acantholysis)
Immunofluorescence
shows IgG fixed against intercellular desmosomes between
keratinocytes.
Tx of pemphigus
Treatment is initially with high dose systemic steroids and in the
long-term a steroid sparing agent e.g. Methotrexate, Azathioprine
S+S of pemphigus
It usually begins in the oral mucosa and is characterised by flaccid vesicles which are fragile and burst readily producing eroded areas on the face, scalp, neck and chest
Nikolsky sign positive: by applying lateral pressure to normal skin, there is a resulting shearing of the epidermis→ erosion formation
Pathophys of bulous pemphigoid
The most common autoimmune blistering disease
Affects the older patients
Circulating IgG antibodies that bind to hemidesmosomes
Large, tense bullae
Diagnostic features of pemphigus
Histologically there are subepidermal blisters with the defect in the dermo-epidermal junction.
Immunofluorescence shows IgG and C3 binding to the dermo-epidermal junction in a linear fashion.
Circulating IgG is present in the serum
Tx of bullous pemphigoid
Treatment is initially with moderate doses of systemic steroids and sparing agents e.g Azathioprine, Methotrexate, Dapsone, Minocycline
Differene between pemphigous and bullous pemphigous
SEE SLIDE 26 IN AUTOIMMUNE SKIN LECTURE MUSTKNOW THIS
- know the different layers that they affect
What is Dermatitis Herpetiformis assoc with
Gluten sensitive enteropathy
Who is Dermatitis Herpetiformis
seen in
white peeps 20-30
Histological features of Dermatitis Herpetiformiss
Histologically there are subepidermal blisters and immunofluorescence shows fixed IgA (between dermis and epidermis) in dermal papillae
There is no circulating autoantibody
Tx of Dermatitis Herpetiformis
Treatment is lifelong with a gluten free diet
Dapsone can also be given to these patients (side effects include methaemoglobinaemia and haemolytic anaemia)
Features of D.H.
Intensely pruritic, symmetrically distributed, erythematous papules and vesicles over the extensor surfaces of elbows, knees, forearms, buttocks and face/scal
Pathophys and presentation of vitiligo?
This is an autoimmune condition affecting the melanocytes (in basal layer of the skin) which may be associated with other autoimmune and/or endocrine conditions
Common worldwide – 1% of the population
Hypopigmentary macules, sharply marginated that coalesce
Face orifices, digits and sites of pressure (elbows, knees) are the first affected
Hair depigmentation (poliosis)
Features of vitiligo
Areas of pigment loss are symmetrical and are often annular in outline, but can be various shapes
Usually initially affect fingers, hands, face and genitalia
Exhibits the Koebner reaction, with the development of lesions at traumatized sites e.g. soles of feet when you walk a lot
What is vitiligo assoc with
Graves disease
alopecia areata
Features of alopecia areata
There is patchy hair loss over any part of the scalp but often the occipital area extending into the scalp is usually affected Pathognomonic “exclamation-mark” hairs are broken hairs which indicates disease activity
Hair loss can occur anywhere else and there may be associated nail pitting
Pathophys of epidermal necrolysis
Cell-mediated cytotoxic reaction against keratinocytes leading to massive apoptosis
Acute, life-threatening mucocutaneous reaction characterized by extensive necrosis and detachment of the epidermis
Idiopathic or drug induced (anticonvulsants, antibiotics, NSAIDS, allopurinol)
Overall mortality: 20-25%
Difference between Stevens-Johnson Syndrome
Toxic Epidermal Necrolysi
Variants of epidermal necrolysis, differ only in the percentage of body surface involved.
SJS < 10%
SJS/TEN overlap – 10-30%
TEN > 30%
Clinicalfeatures of epidermal necrolysis
Prodromes: fever, malaise, arthralgias
Skin tenderness, burning sensation, conjuctival burning, mouth tenderness
s include conjunctivitis, uveitis and corneal ulceration, so its important to ask for early ophthalmology review
Macular/target-like lesions → flaccid blisters → necrosis and epidermal detachment
Nikolsky sign
Complications of epidermal necrolysis
Infection predisposition
Sepsis
Fluid loss
Impaired thermoregulation
Visceral involvement (GI bleeding, bronchial erosions & ARDS)
Nutritional deficiencies – impaired oral intake
Mx of epidermal necrolysis
Withdraw the offending drug
Supportive care in hospital setting
Fluid replacement
Early nutritional support
Skin, blood, urine cultures→ antibiotics
Pain management
Mouth antiseptics
Ophthalmological evaluation
Features of skin sclerosis
Classically there is beaking of the nose, furrowing of the lips and facial telangiectasia (they are mainly on the cheeks and nose) - sclerodactyly
Other organ sclerosis
Most organs may be affected but most frequently the oesophagus and patients can present with dysphagia
Describe sclerodactyly
The skin of the fingers appear tightened and shiny due to fibrosis. There are telangiectasia also seen here affecting the hands
Features of sclerderma
hickening of the skin which if only confined to the skin is called morphea (localized scleroderma)
This picture shows a smooth, waxy plaque which has a sclerotic feel. In active morphea there is a purplish border (lilac ring) as is seen here
What presents with thickening of collagen throughout the dermis with loss of appendages (hair follicles, sweat glands, sebaceous glands)
Morphea/systemic sclerosis
Skin manifestations of RA
Rheumatoid nodules
Vasculitis
Vasculitic rash (“palpable purpura”) -PAINFUL
Skin ulceration
Describe the features of dermatomyositis
Heliotrope/Violaceous rash- eyelids
Erythema of the face, neck and upper trunk
Knuckles: Gottron’s papules ( seen here as purple streaky lesions affecting the extensor aspect of the fingers)
Fingernail: periungual telangiectasias
Photosensitivity
Polymyositis (if not: amyopathic DM)
Underlying malignancy
- Patients >40y – investigation is recommended
- Breasts, ovary, lungs, GI, prostate Ca
Types of immunochemical tests
Based on Ab-Ag complexed using enzyme flouresence
Immunofluorescence
Nephelometry
ELISA
Electrophoresis
Flow cytometry
Use of immunochemistry
- Aid in clinical diagnosis (thyroid abs)
- Severity of disease (high RF and CCP)
- Prognosis of the condition (high anti DNA)
- Monitor-relation to disease activity
treatment, relapse, remission (ANCA)
Most common detection method
Indirect immunofluorescence
What does immunochemistry measure
- normal and abnormal immunoglobulins
- Acute phase proteins e.g. CRP
- Complement components
- Complement activity
What is ANA present in?
Sensitive but not specific
SLE,
MCTD,
Sjogren’s,
Scleroderma
ANA can also be positive in juvenile chronic
arthritis, RA and other autoimmune diseases and
infections.
ANA also found in a percentage of healthy
individuals and in the elderly.
Significance of a homogeneous pattern
A uniform diffuse fluorescence of the entire nucleus of interphase cells. Fluorescence intensity more pronounced in the chromosomal region in mitotic cells
Clinical assoc. of homogeneous pattern
- SLE,
- drug induced lupus,
- RA,
- juvenile
chronic arthritis
Confirmatory test for dsDNA abs
Crithidia test (strongly suggestive of SLE)
specificity of 95% , sensitivity
of 70%
antigen: dsDNA
Use of direct IF
Detection of Immune complexes (IC) on
tissue biopsy from patient.
Tissue sections eg skin or kidney are mounted onto slides
Incubated with anti-human IgG-FITC (fluorescein IsoThioCyanate) which binds to the IgG from the IC.
Lumpy bumpy pattern seen on renal biopsy from lupus patient, ICxes on basement membrane
Relationship between anti-dsDNA Ab and renal disease
The presence of anti - dsDNA ab is closely related to renal disease and an increase in levels alerts to a possible flare of disease.
Important to measure C3 / C4 (low in renal
involvement)
Diagnostic criterIa for SLE
ANA (almost always but not specific)
Anti ds DNA (Almost always – specific)
Anti Smith (not always but VERY specific)
Ro, La,RF, Anticardiolipin (non specific)
Features of antiphospholipid syndrome
- lupus anticoagulant and/or
- antibodies to cardiolipin, ( and anti - β2 GPI antibodies)
- Arterial / venous thrombosis
- Recurrent foetal loss (>3months)
- Migraine
- Livedo reticularis -
the things white girls get when they are cold (and rarely other rashes / skin ulceration) - Sometimes ‘catastrophic antiphospholipid syndrome’ with
multi-organ failure
Key features of APL
- ANA
- Anticardiolipin antibodies
- Anti – b2 GPI antibodies
- Lupus anticoagulant
Features of Sjogren syndrome
Autoimmune condition affective mostly women
- Primary – no other underlying disease
- Secondary - RA, SLE, systemic sclerosis, mixed connective tissue disease,
Hashimoto’s thyroiditis, primary biliary cirrhosis, or chronic autoimmune
hepatitis - Sicca symptoms (Lymphocytes infiltrate the glands that secrete fluids,
such as the salivary and tear glands and injure the glands, resulting in a dry
mouth, dry eyes and gynae dryness - the hallmark symptoms of this
syndrome) - ANA (upto 70%), Ro (SSA), La (SSB), RF
- High serum immunoglobulins
- Salivary gland biopsy
- Rarely other features (Arthritis, vasculitis, renal tubular acidosis etc)
Key diagnostic features of Sjogren
- ANA
- Anti –Ro (SSA)
- Anti La (SSB)
- Rheumatoid factor (often fools people)
What is the next thing we look for after finding positive ANA?
ENA - extractable nuclear antigen
What is ENA
soluble nuclear and cytoplasmic components
Over 100 different antigens have been described
On a routine basis, however, the following are screened for:
Sm, U1-sn RNP, SSA (Ro), SSB (La), Scl-70, Jo-1
Types of ENA
Each individual antigen is used to specify the antibody:
- Sm,
- Diagnostic for SLE and indicates severe disease - U1 RNP,
- SSA (Ro),
- Sjogren, lupus and RA
- High titre in pregnancy cause neonatal lupus syndrome and neonatal heart block - SSB (La),
- ssa, ss, LESS IN sle - Anti Histone
- Drug induced lupus - Anti-RNP
- Marker antibody for mixed connective tissue disorders which comprise overlap features fromseveral
rheumatic diseases and tend to be less severethan SLE,
also found in 30-40% of lupus - Scl-70
- (diffuse) systemic sclerosis - Anticentromere : (limited – & ‘old name CREST’) systemic sclerosis
- Jo-1
- Polymyositis, dermatomyositis
Another name for scleroderma
Systemic sclerosis
Types of scleroderma (ss)
- Generalised
- Diffuse (scl-70 Abs but not always)
- Limited morphea including ‘CREST’ (anticentromere Abs) - Localised
- Linear
- No autoAbs usually no organ involvement
Features of scleroderma
- Chronic disorder characterised by degenerative
changes and scarring. - Affects the skin, joints, internal organs and blood vessel
- Thickened skin most striking feature, although confusingly, sometimes there is little or no skin involvement!
Symptoms
- The usual initial symptom of scleroderma is swelling, then thickening and tightening of the skin at the ends of the fingers.
Raynaud’s is a must!
The fingertips are taut, shiny, and thickened
Features of systemic sclerosis
1 .Common symptoms include Raynaud’s phenomenon,
polyarthralgia, dysphagia, heartburn, and swelling and
eventually skin tightening and contractures of the fingers.
- GI disturbances (eg, heartburn, dysphagia) or respiratory
complaints (eg, dyspnea) are occasionally the first
manifestations. - Lung, heart, and kidney involvement.
- Diagnosis is clinical, but laboratory tests help with
confirmation.
Features of the two types of generalised systemic sclerosis
- Limited systemic sclerosis, tends to stay restricted to the skin
of the hands and feet / face with occasional other skin /organ features, old
acronym → CREST (calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia.) syndrome
- anti-centromere antibodies (present in 60%).
- Could result in Pulmonary hypertension or less commonly other organ
involvement.
- Diffuse systemic sclerosis
the disorder progresses
- extensive skin disease
- scl-70 abs
- could involve lungs (fibrosis), kidney (renal crisis), heart (pulm hypertension,
etc)
Most important point for scleroderma
No Raynaud’s NO GENERALISED
SCLERODERMA!
Diagnostic features of scleroderma
1 .ANA
- Scl 70 antibodies
- Anti centromere antibodies
We are suspicious of ANA –ve
scleroderma (malignancy)
Features of Polymyositis / Dermatomyositis
Limb weakness in general may be due to
neuropathy or myopathy
- In myositis → proximal weakness (can’t
stand from sitting or walk up stairs) and
upper limbs (lift arms / brush hair) - Characteristic rash (Heliotrope or Gottron’s
papules)
Types of dermatomyositis
- Primary idiopathic polymyositis can occur at any age and does
not involve the skin. - Primary idiopathic dermatomyositis is similar to primary
idiopathic polymyositis but also involves the skin. - Polymyositis or dermatomyositis associated with cancer can occur
at any age but is most common among older adults; the cancer can
develop up to 2 yr before or after the myositis. - Childhood dermatomyositis can be associated with systemic
vasculitis. - Polymyositis or dermatomyositis can occur with an associated
disorder such as progressive systemic sclerosis, mixed connective
tissue disease, RA, SLE, or sarcoidosis.
Features of dermatomyositis
Skin –various rashes / vasculitis /
calcinosis
Lung – muscle weakness / interstitial lung
disease
Heart – Heart block / Arrhythmias /
Cardiomyopathy
Gut – Dysphagia / intestinal hypomobility
Musculoskeletal – Proximal weakness /
arthritis
Diagnostic criteria of polymyositis/dermatomyositis
Diagnostic criteria
- Progressive, symmetrical, proximal muscle weakness
- Muscle biopsy showing typical features (necrosis, phagocytosis,
regeneration, inflammation) - Elevated Creatine Kinase or Aldolase
4.Electromyography typical findings (myopathic potentials,
fibrillations and complex repetitive discharges) (MRI…)
- Rash of Dermatomyositis (blue –red to violet papules on dorsum
of hands, elbows, ankles, neck and trunk Gottron’s papules)
All of 1-4 = Polymyositis
All of 1-5 = Dermatomyositis
Key diagnostic features of poly/dermatomyositis
ANA (often but not always)
From ENA- Jo-1 or other anti-synthetase
antibodies
‘myositis specific antibodies’ (rare –don’t
need to know)
Features of MCTD
Often Raynaud’s before other symptoms
Early, often like SLE, scleroderma, myositis or
even RA.
Often the limited disease and the whole picture
change with time.
Diagnosis of MCTD
- MCTD should be suspected when additional
overlapping features are present in patients
appearing to have SLE, systemic sclerosis,
polymyositis, or RA. - ANA positive
- Anti - RNP antibodies
- Rheumatoid factor frequently positive, and titers are
often high. - Occasionally others e.g scleroderma ones etc
- The ESR is frequently elevated.
Key diagnostic features of MCTD
- ANA
- Anti RNP (most specific)
- Occasionally various others
Anticardiolipin diseases
primary and secondary antiphospholipid sy. SLE, RA
and other conditions
Antiparital cell diseases
(Pernicious anaemia , but also autoimmune hepatitis and
chronic liver disease)
Tissue transglutaminase, Gliadin and Endomysial diseases
coeliac disease
Anitmitochondrial diseases
(PBC but chronic infections, chronic liver disease and other
conditions)
AntiACh resecptor disase
Myesthenia gravis
ANCA disease
vasculitis (p and c – VS
myeloperoxidase or proteinase 3
respectively)
Anti GBM disease
good pastures
Examples of NSAIDs
(ibuprofen, naproxen, etoricoxib)
Indications of NSAIDs
- Mild to moderate pain
- Alternative or in addition to paracetamol
2. Regular treatment for pain related inflammatio #
MOA of NSAIDs
- Non selective COX inhibitor
- Role of COX 1:
Mediated platelet aggregation
Produces cytoprotective prostaglandins - protect gastric mucosa - Role of COX 2:
Inhibits platelet aggregation - Recruits inflammatory mediators which induce pain
- Sensitive skin pain receptors
- Regulate hypothalamic temperature control
- Therefore aspirin mainly mediates its effects through
COX 2
Inhibiton of which COX is the cause of the adverse affects of NSAIDs
- Adverse effects of aspirin are due to the inhibition of COX 1
- Selective COX 2 inhibitors e.g. etoricoxib have less adverse effects but COX -2 more associated with CV complications since their normal role is to inhibit platelet aggregation
Adverse affects of NSAIDs
- GI toxicity
- Renal impairment
- Increased risk of MI and stroke
- Hypersensitivity reactions (bronchospasm, angioedema)
- Fluid retention (worsening HTN and heart failure)
NSAID CI
. Severe renal impairment
- Heart failure
- Liver failure
- NSAID hypersensitivity
- Peptic ulcer disease
- GI bleed
- CV disease
- Renal impairmen
NSAID important intereractions
Low dose aspirin Corticosteroids Anticoagulants SSRIs Venflaxine ACE inhibits Diuretics Warfarin - NSAIDs increase the risk of bleeding and reduce effects of antihypertensice and diuerti
Antimalarial (hydroxychloroquine)
- SLE
- Skin, arthralgias, arthritis flares - Malria
- Rheumatoid arthritis
MOA of antimalarials
- Exact mechanism unknown
- Immunomodulator - inhibits rheumatoid factor and acute phase reactiants
- Binds and alters DNA via alkylation
- Accumulated in WBCs to stabilise lysosomal membranes, preventing activity of enzymes like collagenase and protease
Adverse affects of antimalarials
GI disturbance
Headache
Skin reactions
Pruritis
CI of antimalarials
- May exacerbate myasthenia gravis and psoriasis
- Severe GI disorders
- Can use in pregnancy but avoid in breastfeeding
Examples of DMARDs
Methotrexate and cyclophosphamide
MOA of cyclophosphamide
- Alkylation of DNA - prevents DNA synthesis and RNA transcription
- Induction of mispairing of nucleotides
- Cross linking of DNA
Indications for cyclophosphamide
- RA
2. SLE (renal and CNS manifestations)
CI to cyclophosphamide
- Haemorrhagic cysticits
- Avoid in acute prophyrias
- Diabetes mellitu
Adverse affected of cyclophosphamide
- Anorexia
- Cardiotoxicity (high doses)
- Carbohydrate metabolism dysfunction
- Interstitial pulmonary fibrosis
- Pigmentation of palms
Indications for corticosteroids
- Allergic or inflammatory disorder
- Suppression of AI disease
- Cancer chemotherapy
- Hormone replacement in adrenal insufficiency or hypopituitarism
MOA of corticosteroids
- Bind to glucocorticoid receptors which translocate to the nucleus and bind glucocorticoid response elements which regulate gene expression
- Modify immune response
- Upregulate anti inflammatory gene
- Down regulate proinflammatory genes
- Directly suppress monocytes and eosinophils
- Increased gluconeogenesis
mineralocorticoid effects - stimulate na and water retention and k excretion
Adverse effects of corticosteroids
- Infection - immunosuppression
- DM and OP
- Proximal muscle weakness, skin thinning, easy bruising gastritis
- Insomnia, confusion, psychosis, suicidality
- HTN
- Hypokalemia
- Edema
- Adrenal atrophy - idf withdrawn suddenly = addisonian crisi
CI of infection
- Infection
2. Children (Suppress growth)
Important corticosteroid interactions
- Increased risk of peptic ulceration and GI bleed when used with NSAIDS
- Enhance hypokalemia when used with beta blockers, theophylline, loop/thiazide diuretics
DDx of swollen joints
See table in Preena Joshi LOB sheet
Processes involved in immunologial tolerance
- Clonal deletion
- Clonal anergy
Clonal deletion predominates in the elimination of T lymphocytes whilst clonal anergy (or clonal inactivation) predominates for B cells. There are additional mechanisms which can suppress T cell help.
Locations of tolerance
Tolerance can be induced centrally (for the T cell, in the thymus; for the B cell in the bone marrow) or peripherally.
Pathways of tolerance
Central selection: occurs in the thymic cortex
Peripheral selection: continuously in the tissue
T regulatory cells
Describe central selection
Positive selection: occurs in the thymic cortex. cells that don’t bind to MHC are apoptosed
Negative selection: cloncal deletion mainly in the cortex but also in the medulla of cells that bind STRONGLY to self antigen
Describe immunological ignornace
T cells cannot be activated by self antigens which are either sequestered in immuno-privileged sites (eg lens proteins in the eye), or present in too small a concentration to stimulate a response.
Alternatively, though B cells may recognise an antigen they require T cell help and, if that is missing because there are no T cells capable of recognising the presented peptide, then the B cell will become unresponsive.
Key Topic created and reviewed by Terry Poult
Read St Geroges Key topics on AI and immune tolerance
Read St Geroges Key topics on AI and immune tolerance
