Connective Tissue Flashcards
What is polymyositis and dermatomyositis both associated with?
Underlying malignancy
What are the clinical features of myositis
- Insidious Weakness: usually over a matter of weeks and it is symmetrical (cannot reach as high to cupboards, getting out of bed etc.)
- Pain is not a predominant feature
- Systemic symptoms: e.g fever, weight loss and fatigue
- Lungs:
respiratory or pharyngeal muscle involvement
(CHECK JO-1 ANTIBODIES- SHOWS WHETHER THEY ARE MORE AT RISK OF DEVELOPING LUNG INVOVLEMENT) - Skin : Gottron’s papules (scaly, violaceous, psoriasiform plaques over PIP AND DIP joints - can be palpated)
- heliotrope rash (violaceous discoloration of the eyelid)
What parts of the body does myositis affect?
Can be upper limb, can be lower limb and it can also be both
Investigations of myositis
- Serum levels of creatine kinase (can be low if the condition had an insidious onset)
- MRI to find abnormal muscle
- Electromyography ( is very useful for highlighting non- autoimmune/non- inflammatory myopathies
- Screening for underlying malignancy e.g history(e.g voice changes), examination, CXR, CT of chest/abdomen/pelvis, PSA mammography)
- Muscle biopsy (best done in surgery under local anaesthesia) - looks for fibre necrosis, regeneration and inflammatory cell infiltrate
Management of myositis
- Oral glucocorticoids (IV if severe
- Maintenance dose (5-7.5 mg)
- Immunosuppressive therapy: methotrexate, MMF. Azathioprine
- Rituximab probably efficacious
- IV immunoglobulin may be effective in refractory cases
Paraneoplastic condition?
- Underlying Malignancy that looks like something else
Define vasculitis
- Inflammation and necrosis of blood vessel walls associated damage to skin, kidney, lung, heart, brain and gastrointestinal tract
- Wide spectrum of symptoms and severity (from mild and transient disease to life- threatening disease0
- Clinical features results from a combination of local tissue ischaemia (due to vessel inflammation and narrowing) and the systemic effects of widespread inflammation
When should you consider vasculitis in anyone?
- could be primary (antibody associated)
- or secondary
Anyone who has a fever, weight loss, fatigue, multisystem involvement, rashes, raised inflammatory markers and abnormal urinalysis
What is giant cell arteritis
Vasculitis `
Why is temporal artery biopsy not preferred?
- can be diagnostic
- skip lesions can occur (some parts of the parts in the biopsy are skipped past)
What is the management of giant cell arteritis
- Steroids e.g prednisolone (15mg as a starting dose)
- dose should be progressively reduced (2-3weeks)
- rate of reduction should then be slowed to 1mg per month
- symptoms might recur and then dose should be increased again
- SAFETYNETTING IS IMPORTANT HERE
- Most patients need glucocorticoids for an average of 12- 24 months
- use bisphosphonates for bones
SEE NOTES FOR COMPARISON BETWEEN POLYMYOSITIS AND POLYMYALGIA RHEUMATICA
!!!!
What conditions can mimic polymyalgia rheumatica?
Calcium pyrophosphate disease
Spondyloarthritis
Hyper-/hypothyroidism
Psoriatic arthritis (enthesopathic)
Systemic vasculitis
Multiple myeloma
Inflammatory myopathy
Lambert–Eaton syndrome
Multiple separate lesions (cervical spondylosis, cervical radiculopathy, bilateral subacromial impingement, facet joint arthritis, osteoarthritis of the acromioclavicular joint)
What is giant cell arteritis? (GCA)
- granulomatous arteritis that affects any large (including aorta) and medium- sized arteries
- it is symmetrical
- included shoulder ,neck and hip girdle pain and stiffness
- often co-exists with polymyalgia rheumatica
- rare under the age of 60 years
- average onset is 70
- more prevalent in females
Clinical features of GCA?`
- headaches localised to temporal or occipital region
- jaw pain when chewing/talking
- scalp tenderness
- visual disturbance
- rarely some neurological involvement e.g brainstem infarcts
- with PMR: stiffness and painful restriction of active shoulder movements on waking but muscles are not tender or weak
What is primary Raynaud’s phenomenon usually triggered by?
- cold temperatures, anxiety and stress
- temporary spasm of blood vessels which blocks the flow blood
What are the clinical features of Raynaud’s phenomenon?
- triphasic (three phases): white, blue, red (paler if dark skin)
- fingers, toes, ears, nose, lips or nipples can be affected
- symptoms:
- pain
- numbness
- pins and needles
How do you manage Raynaud’s syndrome?
- Keep warm
- Stop smoking
- Calcium channel blockers
- Iloprost (medication used to treat conditions where vessels are constricted)
- Sildenafil (viagra)
Connective tissue disease that are characterized by inflammation of tissues (autoimmune diseases)
- Polymyositis
- Dermatomyositis
- RA
- Scleroderma
- Sjogren’s syndrome
- Systemic lupus erythematosus
- Vasculitis
Connective tissue disease characterise due to single-gene defects:
- Ehlers- Danlos syndrome
- Epidermolysis bullosa
- Marfan syndrome
- Osteogenesis imperfecta
Systemic lupus erythematosus (SLE, lupus) epidemiology?
- Prevalence: 0.03% in Caucasians, 0.2% in afro- Caribbean
- 90% of affected patients are female
- peak age is 20 to 30 years
- fivefold increase in mortality compared to age and gender-matched controls (cardiovascular disease)
Clinical features of systemic lupus erythematosus epidemiology?
- Variable
- Secondary raynauds disease
Systemic features include:
— fever
— weight loss
— mild lymphadenopathy
— fatigue
— arthralgia
Continuing symptoms and flares/ exacerbations ‘
Joint involvement: - Arthralgia in joints
- Tenosynovitis might occur
- Synovitis is rare
- Jaccoud’s arthropathy is rare too
Pathophysiology of SLE?
- Not fully known
- monozygotic twins,
polymorphic variants at the HLA locus.
inherited mutations in complement components C1q, C2 and C4, in the immunoglobulin receptor FcγRIIIb or in the DNA exonuclease TREX1.
polymorphisms of genes that predispose to SLE, most of which are involved in regulating immune cell function
Autoantibody production
Usually directed against antigens present within the cell or within the nucleus.
Secondary Raynaud’s syndrome is a symptoms of Lupus. TRUE OR FALSE
TRUE
Secondary Raynaud’s disease is a symptom of Lupus
How does Lupus affect the skin?
- Classic facial rash (20% of patients)
- Discoid rash (hyperkeratosis and follicular plugging which can cause scarring alopecia if it involves the scalp)
- Diffuse, non- scarring alopecia
- Urticaria (hives, which are red, itchy wells)
- Livedo reticularis
- Vasculitis(inflammation of blood vessels)
What other systems does lupus affect?
- Renal system
(Hallmark of severe disease, regular urinalysis and blood pressure is essential, can present with haematuria, proteinuria and casts on urine microscopy) - Cardiovascular disease
Can cause myocarditis, pericarditis( inflammation of the pericardium)
Can cause atherosclerosis which increases risk of stroke and myocardial infarction(Tissue death)
-Lungs
Increased risk of DVT, PE etc especially if ANTIPHOSPHOTLIPID ANTIBDOY IS PRESENT - Pleuritic pain or pleural effusion
-Neurological involvement
Headaches, poor concentration etc. - Gastrointestinal involvement
Mouth ulcers are common
Hepatitis is rare
Mesenteric (continues set of tissues in abdomen) vasculitis is serious - Can cause haematological abnormalities e.g neutropenia, lymphopenia, thrombocytopenia etc.
What are urine casts?
- tiny tube shaped particles
- made up of white blood cells, red blood cells, kidney cells, or substances such as protein or fat.
What is the pleura?
Thin membranes that line the lungs
What is antiphospholipid antibody syndrome?
ALPS - autoimmune disorder characterized by the presence of abnormal antibodies in the blood associated with abnormal clotting.
Causes migraines, headaches, recurrent miscarriages etc.
- patients that have lupus are more likely to develop APLS aswell
How do you manage ALPS?
- Avoidance of oral contraceptive
- Avoidance of smoking
- Treatment of hypertension, hyperlipidaemia
- Patients that have arterial thrombosis should be treated with anticoagulants (warfarin) - however this medication should be stopped in the event of wanting to conceive
Asymptomatic patients should not be treated
How do you manage lupus>
- Education about SLE is essential
- Use of sun blocks
- Medications
1. NSAIDs
2. Corticosteroids
3. Cytotoxic drugs in combination to corticosteroids
4. Severe lupus - Tacrolimus can be used
Before giving medications for lupus what do you have to assess?
- Risk of osteoporosis and hypovitaminosis D
- Address cardiovascular risk factors (hypertension and hyperlipidaemia)
What is systemic sclerosis?
It is a condition that causes fibrosis of the skin, internal organs and vasculature
- it is also characterized by Raynaud’s, sclerodactyly and cardiac, lung and GI and renal disease
Systemic sclerosis epidemiology
- more common in females
- peak age onset is 4ht and 5th decades
- overall prevalence: 10-20% per 100000
Systemic sclerosis divisions;
- Diffuse cutaneous systemic sclerosis (30% of all cases)
2. Limited cutaneous systemic sclerosis (70%)
What is the pathophysiology of systemic sclerosis
Not fully understood
Clinical features of SS?
- non -pitting oedema of fingers and flexor tendon sheaths
- skin becomes shiny and taunt
- there can be capillary loss
- face and neck are often involved with thinning of the lips
- lcSScl: skin involvement restricted to sites distal to the elbow or knee (also affects the face)
dcSScl: involvement proximal to the knee and elbow and on the trunk is classified as ‘diffuse disease’
Other involvements/ features of systemic sclerosis
-Raynaud’s phenomenon
—-May precede other features by many years.
.When severe and progressive, critical tissue ischaemia, with distal skin infarction and necrosis.
-Musculoskeletal features
.Arthralgia and flexor tenosynovitis are common
.Restricted hand function is due to skin rather than joint disease
.Muscle weakness and wasting can result from myositis
-Gastrointestinal involvement
.Erosive oesophagitis
.Dysphagia
.Malabsorption due to bacterial overgrowth
.Dilatation of bowel
-Pulmonary involvement
.pulmonary hypertension more prevalent in lcSScl than in dcSScl.
complain of shortness of breath on exertion
interstitial lung disease is common
.Renal involvement
.Hypertensive renal crisis
.Rapid increasing hypertension and renal failure
Investigations of SS
- Blood tests
e.g FBC, U&E, LFT, Bone group, Urinalysis = essential.
ANA (usually positive)
.Scl70 positive in 30% of patients with dcSScl
.Anticentromere antibodies in 60% of patients with lcSScl syndrome - Imaging
. Chest x-ray and Chest CT
. Echocardiography (looks at how much pressure the heart is pumping blood etc)
. lung function test (using a pipe you blow into to see elasticity of lungs)
. barium swallow test to see oesophageal involvement
SS management
Nil to stop or reverse fibrosis
Try to slow the effects of the disease on target organs.
Raynaud’s phenomenon and digital ulcers:
Avoid cold, thermal gloves/socks, high core temperature (calcium channel blockers, losartan, fluoxetine, sildenafil. intravenous prostacycline, bosentan
Gastrointestinal complications:
proton pump inhibitors
Hypertension:
ACE inhibitors
Joint involvement
NSAIDs, analgesia
Progressive pulmonary hypertension
bosentan or heart–lung transplant
Interstitial lung disease Glucocorticoids and (pulse intravenous) cyclophosphamide
What is Primary Sjogren’s syndrome? (PSS)
- ## lymphocytic infiltration and fibrosis of salivary and lacrimal glands
Epidemiology of PSS
- Between 40 and 50 years
- 9:1 female to male ratio
- can occur with other autoimmune diseases (this causes secondary Sjogren syndrome)
Clinical features of PSS
Eye- dry or gritty eyes with conjunctivitis and blepharitis and damage to cornea
Mouth – (dry xerostomia) with dental caries
Fatigue
Small joint pain
Interstitial lung disease (rare)
Interstitial nephritis (rare)
40-fold increased lifetime risk of lymphoma
Investigations of PSS`
FBC U&E Rheumatoid factor usually positive in PSS Antinuclear antibody (ANA) • SS-A (anti-Ro) • SS-B (anti-La) Schirmers test: whether a person's eye produces enough tears to keep their eye moist and healthy (6mm + after 5 mins)
Management of PSS
IF SYMPTOMATIC:
Eye drops
Artificial saliva sprays, saliva-stimulating tablets, and pastilles and oral gels
Chewing gum
Oral hygiene
Vaginal dryness is treated with lubricants
pilocarpine (5–30 mg daily in divided doses) is worthwhile in early disease to amplify glandular function.
Hydroxychloroquine (200 mg twice daily) is often used to address skin and musculoskeletal features and may help fatigue
Immunosuppression for progressive interstitial lung disease (e.g. glucocorticoids and cyclophosphamide) and for interstitial nephritis
If lymphadenopathy or salivary gland enlargement develops, exclude malignancy.
What is a skin graft?
Piece of skin moved from one part of the body to another part of the body > it is reliant upon the recipient site for its nutrition
What are the two types of skin grafts used?
- Full thickness graft
- whole epidermis and whole dermis is harvested
- quicker healing of donor site
- only small areas can be cropped
- less contraction of the skin graft - Split thickness skin graft
- only epidermis is harvested
- large areas can be cropped
How do skin grafts take up their blood supply?
- Fibrin adherence (skin graft sticks via fibrins)
- Plasma imbibition (fluid transfers across)
- Inosculation (blood vessels join together)
- Revascularisation (new vessels grow inside the graft)
- Remodelling
What is a flap?
A block of tissue moved from one part of a body to another part of the body where it incorporates its own blood supply for its own nutrition
Describe a local random pattern flap
Border of the flap is shared between the border of the defect
Describe a pedicled flap
Flap is taken for an area distal to the defect
What is a free flap
Movement of tissue from one site to another on the body
What are common connective tissue diseases?
- sarcomas (kaposi’s sarcoma)
- autoimmune disorders (sle)
- congenital disease (osteogenesis imperfecta)
- acquired diseases
- scurvy
- osteoarthritis
- tendinitis
How can you analyse the role and function of proteins in patients?
By the genes
Why is it important to know what genes are affected in which conditions?
Modulate how you treat the disease
Name some examples of connective tissues
Anything that is not bone: Skin Tendon Cartilage Loose connective tissue (in between fibres)
What are the main features of connective tissue?
- Mechanical support and movement
- arena for fighting infection
- regulating cell behaviour
- contains blood vessels and nerves (expect from cartilage)
What are the components of connective tissue
Main fibres
- collagen
- elastic fibres
Proteoglycans
Matricellular proteins
Cells
- Fibroblasts
- Chondrocytes - cartilage
- Osteocytes (osteoblasts, osteoclasts)
What make up elastic fibres (what are the components)?
- Elastin
- Fibrillins
- Fibulins
- Matrix associated glycoproteins
What are the two roles of elastic fibres
- Structure
- Regulatory role (growth factor signalling)
What are some conditions associated with elastic fibres
Cutis laxa (stretchy skin) -caused by genetic defect in elastin
Marfan syndrome
- caused by defect in fibrillin -1
- stiff skin syndrome
What is aggrecan
Large proteoglycans
- it has large proteins
- has sugar side chains
What is the similarity and difference between versican and aggrecan
Similarity:
- both are proteoglycans
Difference:
Versican has less sugars
(see lecture week - connective tissue for pictures of this)
What are the common attachments of proteoglycans
- sulphates (so4 2-)
- ## carboxyl group
What holds water in, in connective tissues
Negative charge on sugar
Versican holds more water in than aggrecan. TRUE or FALSE
FALSE
Aggrecan has larger and more sugars and therefore holds in more water
What tissue has a lot of aggrecan?
Cartilage
Do proteoglycans confer viscoelasticity? Yes or No
What is viscoelasticity?
YES
- It means that if it is being stretched slowly, it will elongated slowly
- If it is stretched quickly, it tends to be inelastic
Speed of loading - changes to how fast you load something
What complex is aggrecan usually attached to?
Hyluronan (HA)
What are the features of the aggrecan and hyluronan complex?
- Highly hydrophilic
- High turgor pressure in tissue (resists compression)
Why does cartilage resits compression
Because it has a lot of aggrecan which binds to HA
That complex has a high turgor pressure and therefore resists compression
What is molecule is lost in osteoarthritis, that causes a lack of resisted compression?
Aggrecan
What is the most abundant protein in the body?
Collagen fibres (30%)
What molecules allows the triple helix formation in collagen fibres?
Glycine
-hydrogen bonds between glycine and oh- proline provide rigidity and stability
What is glycine
The smallest amino acid
What happens when collagen is synthesised
Describe the steps
- Hydroxylation as it enters the endoplasmic reticulum
- Enzymes act on it as proteins are made in the E.R
- It is assembled into the triple helix
- Triple helix is excreted
- Then it is stabilised outside the cells
What causes scurvy?
Caused by lack of Vitamin C
Why does lack of vitamin C cause scurvy?
Lack of Vit C causes less hydroxylation of collagen
- therefore the collagen is less stable
What are the symptoms of scurvy?
- Bleeding gums
- Loss of teeth
- Skin lesions
- Poor wound healing
- Joint pain and weakness
Which diseases are genetic mutations of hydroxylase enzymes are associated with?
- Osteogenesis imperfecta
- Ehlers Danlos Syndrome
- Bruck syndrome
Why are there multiple chances for various collagens to be affected by genetic mutations?
Because there are 28 different collagens but 43 genes
What type of collagen has common genetic defects?
Type 4 Collagen
- gives rise to ALPORT syndrome
- cause progressive scarring of the kidneys, leading to renal failure in many people with the disease
What are the different collagen compositions and organisation of skin
60% Type I collagen
30% type III collagen
Meshwork of fibres – allows for elasticity
What are the different collagen compositions and organisation of tendons/ligaments
90+% Type I collagen
5% type III collagen
Parallel fibres
What are the different collagen compositions and organisation of cartilages
90% Type 2 collagen
Meshwork
What are the different collagen compositions and organisation of bones
90% Type I collagen
3% type V collagen
Sheets (lamella)
What is the tendon tensile strength determined by?
Parallel type 1 collagen fibril bundles
What are the main 6 different types of Ehlers Danlos Syndrome (EDS)?
- classic (EDS type 1/2)
- Benign Hypermobility (EDS type 3)
- Vascular (EDS type 4)
- Kyphoscoliosis (EDS Type 6)
- Arthrochalasia (EDS type VIIa/VIIb)
- Dermatosperaxis (EDS type VIIc)
What are the autosomal dominant form of EDS(these are also the most common forms of EDS)
- Hypermobility Type 3 > gene defect not known
- Classic Type 1/2 > COL5A/COL5A2
- Vascular Type 4 > COL3A1
What are the features of classic EDS
- easy bruising and scaring
- joint and cardiac defects
- soft extensible skin
- 1/20,000 births
What are the features of vascular EDS
- hypermobility
- bruises
varicose veins
arterial rupture
bowel rupture - 1/200000
What are the features of hypermobility EDS type 3
- benign hypermobility
Type ….(1)…. controls the initiation of type 1 collagen fibril assembly
- Type V (5)
Skin and Blood vessels are rich in type 3 collagen. TRUE OR FALSE
TRUE
What affects fibril formation in type IV EDS?
Deficiency in type III collagen which can lead to fragility of skin and blood vessels
How do you diagnoses EDS?
- Detailed clinical and family history
- Physical examination
- Skin biopsy and histology (can show altered collagen fibril architecture)
- Biochemical analysis (Culture cells with radio-labelled 3H proline SDS-PAGE
Urine analysis of collagen cross-links)
-Molecular analysis of specific gene(s)
eg COL3A1 mutation in 95% of vascular type EDS
How do you treat EDS and other connective tissue disorders
- Control of risk factors
- Healthy lifestyle,
- Protection (bandages, splints etc)
- Vit C supplements
- Avoidance of contact sports and heavy exercise
DRUGS
- avoid NSAIDS and Aspirin (can affect platelet function and clotting)
- beta blockers might reduce aortic dilation
What do type 2 collagen defects lead to?
Abnormalities with development
Name some developmental abnormalities caused by TYPE 2 collagen
- Short stature
Enlarged joints
Spinal curvature
Vision and hearing defects
Cleft palate
Where is type 2 collagen mainly found
In cartilage
What is Sticklers Syndrome
genetic disorder that can cause serious vision, hearing and joint problems. Also known as hereditary progressive arthro-ophthalmopathy, Stickler syndrome is usually diagnosed during infancy or childhood
Investigations for polymyalgia rheumatica
FBC Urea and electrolytes LFTs Bone profile Protein electrophoresis Thyroid function tests Creatinine kinase Rheumatoid factor Urinalysis
What is the laboratory criteria to confirm antiphospholipid syndrome?
At least one of the antiphospholipid antibodies (Lupus anticoagulant, anticardiolipin antibody, anti-B2- glycoprotein I antibody) are present in the woman’s serum/ plasma, on two or more occasions at least 12 weeks apart.
What medication should be started if a patient that has antiphospholip syndrome comes in?
- First line - Warfarin INR 2-3 doses
2. If it is recurrent initate Warfarin INR 3-4 doses
