CTDs/ Muscle Disease/ Vasculitis Flashcards
Examples of Connective Tissue Diseases
> SLE
> Sjögren’s syndrome
> Systemic sclerosis
> Dermatomyositis
> Polymyositis
> Mixed Connective Tissue Disease
> Anti-phospholipid syndrome
Connective Tissue Diseases
NOT diseases of connective tissue
Presence of spontaneous over activity of the immune system.
Specific auto-antibodies
Evolve over a number of years —> organ failure –> death
SLE
General definition
Aetiology
Systemic autoimmune disease that can affect any part of the body.
Immune system attacks the body’s cells and tissues, resulting in inflammation and tissue damage
Antibody immune complexes precipitate and cause further immune response.
More females than males
> Genetic factor
- high concordance in monozygotic twins
- increased incidence amongst relatives
> Hormonal
- increased oestrogen exposure. Oestrogen containing contraceptives and HRT
> Environmental factors:
Viruses e.g. Epstein Barr virus
UV light may stimulate skin cells to secrete cytokines stimulation B cells
Silica dust
Asians, afro-americans, afro-caribbeans, Hispanics
SLE Pathogenesis
> Loss of immune regulation
> Increased and defective apoptosis
> Necrotic cells release nuclear material which act as potential auto antigens
> Autoimmnity probably results from extended exposure to nuclear and intracellular auto-antigens
> B & T cells are stimulated.
> Autoantibodies are produced.
SLIC Classification Criteria
Criteria for Systemic Lupus Erythematosus
Clinical Criteria
Immunologic criteria
SLE - constitutional symptoms
> Fever > Malaise > Poor appetite > Weight loss > Fatigue
Mucocutaneous features of SLE
> Photosensitivity
Malar rash
– may or may not be associated with sun exposure
– spares the naso-lablial folds
> Discoid lupus erythematosus (may scar)
> Subacute cutaneous lupus
> Mouth ulcers (painless)
> Alopecia (non-scarring)
Musculoskeletal features of SLE
> Non deforming polyarthritis/polyarthralgia
- RA distribution but no radiological erosion
> Deforming arthropathy
> Erosive arthritis
> Myopathy - weakness, myalgia & myositis
SLE - serositis
> Pericarditis
Pleurisy
Pleural effusion
Pericardial effusion
SLE - renal features
> Proteinuria of >500mg in 24 hours
> Red cell casts
SLE - neurological features
> Depression/psychosis
- not always related to disease activity
> Migranous headache
> Seizures
> Cranial or peripheral neuropathy
> Mononeuritis multiplex
SLE - Haematological features
> Lymphadenopathy
~25% of all patients during their course of illness
> Leucopenia
> Lymphopenia
> Haemolytic anaemia
> Thrombocytopenia
Anti phospholipid antibodysyndrome
> Venous and arterial thrombosis
> Recurrent miscarriage
> Livedo reticular (mottled, reticulated skin pattern)
> Association with other autoimmune conditions especially SLE
> Thrombocytopoenia
> Prolonged APTT (activated partial thromboplastin time)
> Can be primary or secondary
suspect when:
occurrence of one or more otherwise unexplained venous or arterial events, esp. in young patients
Foetal death after 10 weeks, premature birth due to severe pre-eclampsia or placental insufficiency/multiple embryonic losses
Otherwise unexplained thrombocytopenia or prolonged APTT
SLE susceptibility to infection
> Intrinsic factors
- Low complements
- Impaired cell mediated immunity
- Defective phagocytosis
- Poor antibody response to certain antigens
> Extrinsic factors
- steroids
- other immunosuppressive drugs
- nephrotic syndrome
SLE - investigation
> Confirm/establish diagnosis
> Determine degree of organ involvement
> Anti nuclear antibody (positive in titre of 1:160 or greater in almost all SLE patients) — ANA
> If other antinuclear antibodies are positive –> take ANA test seriously.
- anti dsDNA
- anti Sm
- Anti - Ro
- Anti RNP
> anti dsDNA
– anti double stranded DNA antibody
- highly specific for SLE
- titre correlates with overall disease activity
> Anti-phospholipi antibodies
- anti-cardiolipin antibody
- lupus anticoagulant
- antibeta 2 glycoprotein
– must be positive on 2 occasions 12 weeks apart
Anti phospholipids antibodies should be positive on how many occasions?
2 occasions 12 weeks apart.
IgM or IgG anticardiolipin abs
Lupus anticoagulant
IgM or IgG beta 2 glycoprotein
Serum C3/C4 levels and SLE
These levels NEGATIVELY correlate with disease activity
SLE - management & Drug treatment
> Counselling
Regular monitoring
Avoid excessive sun exposure
Pregnancy issues
Drug Treatment
> NSAIDs and simple analgesia
> Anti malarias, hydroxxychloroquine
- useful for arthritis, cutaneous manifestations and constitutional symptoms
- may reduce systemic complications
> Steroids
- side effects
- variable doses for different manifestations
> Immunosuppressants
- Azathioprine
- Cyclophosphamide
- Methotrexate
- Mycophenolate mofetil
> Biological agents
- anti CD20 (Rituximab)
- anti Blys (belimumab)
SLE - steroid doses
small doses (prednisolone <15 mg/d) for skin rashes, arthritis and serositis
moderate doses (0.5 mg/kg/d) for resistant serositis, haematologic abnormalities and class V GN
high doses (1mg/kg/d or IV) for severe/resistant haematologic changes, diffuse GN and major organ involvement
SLE Spectrum of disease treatmnet
MILD
- Hydroxychloroquine
- topical steroids
- NSAIDs
MODERATE
- oral steroids
- azathioprine
- methotrexate
SEVERE
- IV steroids
- Cyclophosphamide
- Rituximab
Wire loop lesion in the kidneys is indicative of?
Lupus nephritis
Anti-phospholipid antibody syndrome - treatment
Lifelong anticoagulation for thrombosis
Aspirin/heparin to prevent pregnancy complications
Hydroxychloroquine
Sjögren’s Syndrome
> Chronic autoimmune inflammatory disorder
> Diminished lacrimal and salivary gland function resulting in dry eyes, dry mouth
> Primary or secondary
> Women in 50s/60s
> Extra glandular involvement
Sjögren’s syndrome - symptoms
> Dry eyes, gritty feeling
> Dry mouth
> Dry throat
> Vaginal dryness
> Bilateral parotid gland enlargement
> Joint pains
> Fatigue
> Unexplained increase in dental caries
Sjögrens syndrome - antibodies
Anti-Ro
Anti-La
High IgG, ESR and rheumatoid factor
Other tests:
- salivary gland US
- Labial gland biopsy
Sjögren’s syndrome - treatment
> Artificial tear supplements
> Ciclosporin eye drops
> Punctual plugs
> Saliva supplements
> Pilocarpine
> Hydroxychloroquine
> Immunosuppression w/ methotrexate, leflunomide, B cell depleters — if major organ involvement
Diffuse Cutaneous Systemic Sclerosis
Vascular endothelial changes
Fibrosis
Skin involvement proximal to forearms & involving torso
Rapid skin changes
Early organ involvement
Interstitial lung disease more common than pulmonary hypertension
Renal crisis can occur
Anti-topoisomerase or anti SCL-70 or anti RNA III polymerase antibody
Anti-topoisomerase or anti SCL-70 or anti RNA III polymerase antibody are associated with?
Diffuse cutaneous systemic sclerosis
systemic scelrosis
Limited SSc
Skin involvement distal to elbows and NOT involving torso
Used to be called CREST (Calcinosis, Raynaud’s, Esophageal dysmotility, Sclerodactyly, Telangiectasia)
Raynaud’s seen in 90% of patients
Pulmonary hypertension is a common complication
Small intestinal bacterial overgrowth
Anti centromere antibody
Sclerodactyly
Localised thickening and tightening of the skin of the fingers/toes
Systemic sclerosis - treatment
Raynaud’s - Ca channel blockers, phosphodiesterase inhibitors
If digital ulcers-Iloprost infusions.
Lung disease-Immunosuppression.
Pulmonary Hypertension-CCB, Endothelin receptor antagonists,prostacyclin, home O2
Reflux-proton pump inhibitors, H2 receptor antagonists.
Tight control of BP
Antibiotics for small intestinal bacterial overgrowth.
Mixed connective tissue disease
Features of SLE, polymyositis and systemic sclerosis
Pulmonary hypertension is a recognised complication
Anti RNP antibody positivity
Treatment depends on symptoms and whether there is major organ involvement
What disease has features of SLE, polymyositis and systemic sclerosis?
Mixed connective tissue disease
Monitoring for autoimmune diseases
Clinical examination, history.
Bloods-Cell counts, serum complements.
URINALYSIS.
Pulmonary function tests/CXR/Chest CT scan
ECHO .
General treatment: MILD disease
NSAIDs
Short courses of steroids
Hydroxychloroquine
Symptomatic treatment
General treatment: joint inflammation
Methotrexate
DMARDs
Short course of steroids
ORgan invovlement - general treatment
High dose steroids
Immunosuppression
Address CV risk factors.
Renal disease (SLE related?)
Likely due to deposition of immune complexes in mesangium (associated w/capillaries - in glomerulus)
Complexes consist of nuclear antigens and anti-nuclear antibodies
Complexes form in circulation then are deposited
Once present they activate complement which attracts leucocytes which release cytokines
Cytokine release perpetuates inflammation which, over time, causes necrosis and scarring
Major causes of myopathy
> Inflammatory
Endocrine disorders
Electrolyte disorders
> Metabolic myopathies
> Drugs & toxins
Infections
Rhabdomyolysis
How do muscle diseases present?
> Myalgia
Muscle weakness/tiredness
Stiffness
Abnormal blood tests
Polymyositis
- type of myopathy
- clinical features
> Idiopathic inflammatory myopathy
> Fibre necrosis, degeneration, regeneration and inflammatory cell infiltrate on histology
> muscle weakness
– insidious onset, worsening over months
– symmetrical, proximal muscles
– often specific problems (e.g. difficulty brushing hair, climbing stairs
> Myalgia
> Shoulder and hip girdle muscles affected more commonly
> > Lung
- interstitial lung disease
- respiratory muscle weakness
> Oesophageal
– dysphagia
> Cardiac
- myocarditis
> Other
– fever, weight loss, Raynaud’s , non erosive polyarthritis
Dermatomyositis
- type of myopathy
- clinical features
> Idiopathic INFLAMMATORY myopathy
> Involves the skin
> Fibre necrosis, degeneration, regeneration and inflammatory cell infiltrate on histology
> muscle weakness
– insidious onset, worsening over months
– symmetrical, proximal muscles
– often specific problems (e.g. difficulty brushing hair, climbing stairs
> Myalgia
> Shoulder and hip girdle muscles affected more commonly
> Lung
- interstitial lung disease
- respiratory muscle weakness
> Oesophageal
– dysphagia
> Cardiac
- myocarditis
> Other
– fever, weight loss, Raynaud’s , non erosive polyarthritis
—
Cutaneous signs
- purple-pink coloured (violacious) rash
- Gottrons sign (red scaly papule that arise on the joint)
> Heliotrope rash (rash around eye)
> Shawl sign
–> Malignancy in 15% of cases
Gottron’s sign
Dermatomyositis
Red scaly papule that arise on the joint
Heliotrope rash
Rash around the eyes.
Dermatomyositis
Polymyositis & dermatomyositis - Diagnosis
> History
– tired muscles, functional difficulties, muscle pain
– Diabetes, thyroid disease
– Drugs: steroids, statins
– Fix
– Alcohol illicit drug use
– Weight loss, cough, breathlessness, Raynaud’s
> Blood tests
- Muscle enzymes (CK)
- Inflam markers
- electrolytes, calcium PTH, TSH
- autoantibodies: ANA, Anti-Jo-1
–
EXAMINATION
> muscle wasting
confrontational testing
– direct testing of power (pushing down on patient’s arm)
> Isotonic testing
- 30 second sit to stand test
> Electromyography (EMG)
– increased fibrillation, abnormal motor potentials, complex repetitive discharges.
> Muscle biopsy - gold standard
- perivascular inflammation
- muscle necrosis
> MRI
Effects side effect of statins on muscle
Cause of muscle pain
Anti-Jo-1 - specific to which disease?
Polymyositis
What is the gold standard diagnostic test for polymyositis/dermatomyositis?
MUSCLE BIOPSY
Polymyositis/ Dermatomyositis
> Glucocorticoids > Azathioprine > Methotrexate > Ciclosporin > IV Immunglobulin > Rituximab
What can methotrexate cause in the respiratory system?
Pneumonitis
Inclusion body myositis
> Often misdiagnosed as polymyositis
> Patients >50 years. (men more often)
> Insidious onset
> Distal muscle weakness (vs proximal in polymyositis)
> weakness wrist and finger flexors in upper limbs and quadriceps and anterior tibial muscles in legs
> Symmetrical
> CK levels lower than in PM
> Responds poorly to therapy
> MUSCLE BIOPSY is diagnostic (inclusion bodies present)
Main symptom of inflammatory myositis
Muscle weakness
Polymyalgia Rheumitca
- clinical manifestations
> Inflammatory
> Over 50 years old almost exclusively.
> Incidence higher in northern regions (Sweden, Scotland
> Associated with temporal arteritis/ giant cell arteritis
> ## IMPROVES w/EXERCISEClinical Manifestations
- Muscle stiffness and soreness
- Ache in shoulder and hip girdle
- Morning stiffness
- Usually symmetrical
- Fatigue, anorexia, weight loss and fever
- Reduced movement of shoulders, neck and hips
- no inflammatory infiltrate
- Muscle strength is NORMAL
What is Polymyalgia rheumatic associated with?
Temporal arteritis
Giant cell arteritis
Is muscle strength normal or not in polymyalgia rheumatica
Muscle strength is normal
Temporal arteritis/ giant cell arteritis
> Granulomatous arteritis of large vessels
> Headache - constant dull pain
> Scalp tenderness
> Jaw claudication - aching in jaw muscle as they chew because blood supply to muscle is restricted.
> Visual loss (amaurosis fugax) - “black curtain” coming over their eye.
> Tender, enlarged, NON pulsatile temporal arteries
Appearance/feel of temporal arteritis
Artery is standing out
It is firm but the pulse cannot be palpated.
Scelorosed artery on histology
Diagnosis of temporal/giant cell arteritis
Raised ESR, PV, CRP
Temporal artery biopsy if suspicious
Polymyalgia rheumatica related.
No specific test however.
Polymyalgia Rheumatica - treatment
> Rapid and dramatic response to low dose steroids
> If temporal arteritis present, higher steroid doses required
> Gradual reduction in steroid dose over 18 months
Headache – 40mg of prednisolone
Eye problems – 60mg of prednisolone
Polymyalgia -
Prednisolone Doses in Polymyalgia Rheumatica
Headache – 40mg
Eye problems – 60mg
Polymyalgia - 15mg
Fibromyalgia
> Common MSK pain
> NOT associated with inflammation
> Cause of pain is unknown
> May begin after emotional or physical trauma
> Fibromyalgia cycle
- Pain…muscle tension…stress…limited activity…fatigue…depression…pain…
> Poor sleep pattern can predate the condition more often than not
> Overlap between it and conditions like chronic migraine, chronic fatigue, IBS depression
Fibromyalgia - clinical manifestations & findings
> PAIN in neck, shoulders, lower back, chest wall
> Diffuse and chronic
> Varies in intensity
> Worse on exertion, fatigue and stress
> Swelling sensation
> Fatigue and poor, unrefreshing sleep
> Pins and needles/tingling, headaches, depression, abdo pain, poor concentration and memory
Excessive tenderness on palpation of soft tissues.
Fibromyalgia - diagnosis
No diagnostic tests
Inflammatory markers are normal
Absence of other explanation of symptoms
Fibromyalgia - treatment
> Patient education > Multi-disciplinary response > Graded exercise programme > Cognitive behavioural therapy > Complementary medicine eg. acupuncture
> Anti-depressants eg. Tricyclics, SSRIs
> Analgesia
> Gabapentin and pregabalin (atypical analgesics)
Vasculitis
> Presence of leukocytes/immune complexes present in the vessel wall with reactive damage to mural structures.
> Loss of integrity and bleeding
> Ischaemia sometimes associated.
Large vessel Vasculitis
> Takayasu arteritis (granulomatous arteritis)
> Giant cell arteritis
Medium vessel vasculitis
> Polyarteritis nodosa (PAN)
> Kawasaki’s
> Isolated CNS vasculitis
Small vessel vasculitis
> Eosinophilic granulomatosis with polyangiitis (Churg Strauss syndrome)
> Granulomatosis with polyangiitis (Wegener’s)
> Microscopic polyangiitis
> HSP (Henoch–Schönlein purpura)
> Essential cryoglobulinaemia
> Hypersensitiev vasculitis
ANCA positive Vasculitis
- Clinical features
> Wegener’s/ granulomatosis with polyangiitis
> Microscopic polyangiitis
> Churg Strauss - asthma like symptoms sometumes
> Drug induced
Clinical Features
> General
– myalgia, arthralgia/arthritis, fever >38°, weight loss, mucosa
> Skin - infarct, purport, ulcer, gangrene
> ENT - bloody nasal discharge, ulcers, crusts, granulomata; paranasal sinus involvement, can go deaf. Subglottic stenosis, conductive deafness, sensorineural hearing loss, saddle nose deformity (bridge of nose collapses)
> Chest - wheeze, cough
> CVS - loss of pulses, valvular heart disease, pericarditis
> Abdominal - peritonitis, bloody diarrhoea, ischaemic abdo pain
> Renal: hypertension, proteinuria >1+; haematuria >10 abc/hpf, elevated creatinine
> Neurological
– headache, meningitis, organic confusion, seizures, stroke, cord lesions, cranial nerve palsy, sensory peripheral neuropathy, motor mononeuritis multiplex
ANCA negative Vasculitis
HSP (hence Schönlein purpura)
Cryoglobulinaemia
Paranasal involvement in vasculitis can lead to…
Deafness.
Diagnostic test - Vasculitis
ANCA//
IIF (indirect immunofluorescence)
ELISA (enzyme-linked immunosorbent assay)
BIOPSY
- skin, renal, muscle or nerve biopsy
Inflammation of vessel wall
Any neutrophils or immune complexes embedded in vessel wall.
Vasculitis Treatment
Refractory is really aggressive and outcome is poor
Methotrexate or azathioprinee + steroids for localised/early systemic often for life
Renal involvement - plasma exchange
Under control - step down to azathioprine
Refractory (refractory or unmanageable) - IV Ig & retuximab
Localised Vasculitis
Definition
Treatment
Upper and/or lower respiratory tract disease without any other systemic involvement or constitutional symptoms
Methotrexate _+ steroids
Azathioprine + steroids
Generalised vasculitis
Systemic vasculitis
Defintion
Treatment
Renal (creatinine <500) or other organ threatening
Cyclophosphamide + steroids (1st line)
Retuximab + steroids (alt.)
Plasma exchange if creatinine >500
Renal creatinine > 500 = SYSTEMIC
Refractory vasculitis
definition
treatment
Progressive disease unresponsive steroids + cycle
Treatment
- IV Immunoglobulin
- Rituximab
