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connective tissue diseases Flashcards

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1
Q

Define connective tissue diseases

A

A group of overlapping auto-immune diseases
Abnormalities of acquired (& sometimes innate) immune system present,with anti-nuclear antibodies, causing tissue damage usually inflam
Multiple organs involved but connective tissues and blood vessels usually affected
Both genetic and environmental components to aetiology of CTDs

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2
Q

How do you confirm the presence of ANA?

A

indirect immunofluorescence test ;; showing presence of antibodies to cell nuclei
antibodies made to many different components of cell nuclei

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3
Q

Define tolerance

A

Failure of immune system to recognise antigens

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4
Q

Define autoimmunity

A

failure of SELF tolerance. tolerance is ‘‘leaky’’

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5
Q

How is tolerance maintained ?

A 
Central T cell tolerance
•Thymic “education”
Peripheral T cell tolerance
•Absence of Signal 2/danger signal
•Active regulation
B cell tolerance
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6
Q

Explain some known mechanisms of autoimmunity

A

Availability of epitope : macrophages clear DNA, however defective clearance can occur and antigen is now available

Release of sequestered antigens: penetrating eye injury , activates T cells in nodes , T cells attacks both eyes

Altered self: Ex: red blood cell and a drug combine to form new structure: thus immune system attacking drug, in doing so attacks RBC

Tissue develops ability to present antigens

Superantigen : T reg’s inability to stop T cell production

Molecular mimicry- where antigen mimics that of a structure in body; thus immune system not only attacks antigen but also similar structure - immune complex deposition

Defective immune regulation genes

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7
Q

Explain test performance definitions

A

True Positive (Sensitivity) - % with disease who have positive test result
True negative (Specificity) - % without disease who have negative test result
False Positive - % WITHOUT disease who have Positive result
False Negative - % WITH the disease who have NEGATIVE test result

Positive Predictive Value
% of people with a positive test who turn out to have the disease/condition

Negative Predictive Value
% of people with a negative test who do not have the disease
Critically dependent on disease prevalence in the population tested

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8
Q

Impact of indiscriminate testing

A

False positive results create anxiety & risk to patient
-unnecessary tests
- may get inappropriate treatment
- delay getting correct diagnosis
Cost
Delay test results for patients who need them

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9
Q

List connective tissue diseases

A
  • Systemic Lupus erythematosus
  • Scleroderma
  • Polymyositis
  • Mixed connective tissue disease
  • Sjögren’s syndrome
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10
Q

Define SLE

A 
The prototypic connective tissue disease, with excess auto-antibody formation and immune complex deposition in tissues and complement activation causing inflammation
Genetic variation (e.g. in Fcγ receptors) influences antibody binding and pathologic effects
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11
Q

What is some typical pathology a/w SLE

A

hematoxylin bodies, Libman-Sacks endocarditis, vasculitis, thrombotic microangiopathy and glomerulonephritis

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12
Q

Epidemiology a/w SLE

A

more common in females , premenopausal
higher prevalence in african americans, afro caribbeans and asians than white Europeans
RARE disease
a/w C4A null allele

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13
Q

Aetology of SLE

A

-autoimmune a/w multiple auto-antibodies, immune complex deposition and complement activation
-B-Cell hyperactivity, with raised gammaglobulins
-Type 1 interferon hyperactivity
-Multiple genes involved, most immune related
Considerable genetic and racial variation –e.g. Worse in African-Americans, Afro-caribbean and Asian populations

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14
Q

What are the a/ mechanisms of action in SLE (hint - hypersensitivity)

A 
•Type II hypersensitivity
Haemolytic anaemia
Autoimmune neutropenia/thrombocytopenia
•Type III Hypersensitivity
Renal disease
Skin disease
Vasculitis
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15
Q

Clinical features of SLE

A

Inflammation any organ, predominantly
•Skin- malar rash, discoid rash, photosensitivity, painless oral/nasopharyngeal ulcers
•Joints- non erosive arthritis
•Kidneys- persistent proteinuria or cellular casts, GN
•Brain-seizures, psychosis, stroke like syndromes
•Serosal surfaces- pleuritis/pericarditis
•Immune cytopenias are common- haemolytic anemia, leukopenia, lymphopenia, thrombocytopenia

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16
Q

What does the diagnosis of SLE depend on

A

typical multisystem involvement and identifying autoantibodies

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17
Q

What is the screening test for SLE

A

anti nuclear factor (ANF)

+e in 98%

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18
Q

What are some autoantibodies present in SLE?

A

ANF
ANTI dsDNA (40%) or ANTI Sm or anti phospholipid antibodies or ANTI Ro or LA
antibodies to RBC, WBC, platelets

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19
Q

Define malar rash
discoid rash
photosensitivity

A

Malar rash - butterfly rash across cheeks- sparing of nasolabial folds

Discoid rash - Raised patches, adherent keratotic scaling, follicular plugging; may cause scarring

Photosensitivity- skin rash from sunlight

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20
Q

Describe renal disease a/w SE

A

Glomerulonephritis (gn) is a typical presentation of SLE and usually associated with anti-bodies to ds-DNA
Kidneys may be normal, or only show immune deposits on EM or immunofluorescence (immune complex (IgG-antigen) deposition in glomerulus BM )
Mesangial gn, or focal or diffuse proliferative gn or diffuse membranous gn, sclerosis, focal segmental gn all seen
May present with nephritic or nephrotic syndromes or just with biochemical abnormalities early on.

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21
Q

How do you diagnose renal disease a/w SLE

A

urine microscopy: cellular casts shaped by the tubule- cast surrounded by few RBCs
RBC casts - most definitive marker of glomerulonephritis

kidney biopsy: glomerulonephritis, focal segmental

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22
Q

Diagnosis of SLE

A
  • Clinical history & exam
  • Urinalysis + urine microscopy
  • ANF
  • Anti-dsDNA( levels correlate to disease severity)
  • Anti-ENA (anti-Sm specific; anti-Ro/La) Ro or La- photosensitivity/skin disease
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23
Q

How do you monitor SLE disease activity

Study These Flashcards
A
  • Function of affected organs
  • FBC, ESR
  • Complement (consumption – low C3 & C4)
  • Anti-dsDNA

ESR better guide to inflam

24
Q

Treatment of SLE

Study These Flashcards
A

suppress inflam and abberant immune response

Glucocorticoids - in high doses for nephritis or CNS involvement

immunosupressants - azathioprine, cyclophosphamide ; additional benefit and to spare GC dose ;; renal and CNS need aggressive use w cyclophosphamide

antimalarials - hydroxychloroquine - for skin and joint disease

monoclonal antibodies- rituximab ;; used against B cells
Belimumab- anti Blys antibody

25
Spectrum of SLE
``` classical SLE antiphospholipid syndrome latent lupus drug induced lupus neonatal lupus end stage lupus ```
26
What causes mortality and morbidity in SLE
organ damage | effects of immunosuppression
27
Define antiphospholipid syndrome a/ features a/ complications
•Documented venous thrombosis- pulmonary, IVC, hepatic and portal vein, renal, superficial and deep veins •Documented arterial thrombosis- retinal brachial,cerebral,coronary,mesenteric,arteries to extremities Pregnancy associated morbidity •Mid or 3rd term pregnancy loss •Recurrent first trimester loss •Severe pre-eclampsia •Severe intrauterine growth retardation characterised by antiphospholipid antibodies ``` Other features : •Thrombocytopenia •Livedo reticularis •Transverse myelitis •Migraine ```
28
Define diagnostic criteria for antiphospholipid syndrome
* Lupus anticoagulant, or * Anti-Cardiolipin antibodies, or * Anti-Beta 2 glycoprotein 1 positive on 2 occasions , 12 weeks apart
29
Tx for antiphospholipid syndrome
* Aspirin | * Anticoagulation
30
Define scleroderma
A generalised autoimmune disorder of connective tissue affecting skin & internal organs Characterised by fibrotic angiopathy of peripheral and visceral vasculature Accumulation of extracellular matrix & collagen in skin and viscera Associated with typical autoantibodies, esp anti-centromere, anti-SCL-70, U3RNP Several subsets with different clinical features
31
Clinical features of scleroderma
Reynaud’s phenomenon; esp adult onset Scleroderma: tightening & thickening of skin Involvement of internal organs, GI tract, lungs, heart, kidneys causes most morbidity & mortality Risk of internal organ involvement strongly correlates with extent of skin disease
32
Epidemiology of scleroderma
Peak onset age 30-50 yrs: Female:male = 4:1
33
Define Raynaud's phenomenon
marked pallor on 4th and 5th digits of hands. early symptom
34
Define scleroderma
characterised by sclerodactyl /acrosclerosis and poor hand function Flexion contractures of the fingers are secondary to a tightened indurated skin- acrosclerosis. skin changes closer to MCP are more specific to system sclerosis/scleroderma than only changes in fingers as described above
35
What are other a/ clinical features of scleroderma
CREST syndrome- CREST variant of systemic sclerosis - features as follows - calcinosis appears as hard irregular nodules on fingers -- overlying skin is thin and underlying calcific material appears small yellowish patches;; surrounding erythema and tenderness. Ulcer can form from which calcific material is extruded;; distal pulp atrophy may occur - Esophageal dysmotility & heartburn - limited cutaneous scleroderma aka sclerodactyly; no prox or trunk involvement &Reynauds & telangiectasia - Anti-centromere antibodies typical - Pulmonary hypertension a late complication - Tends to progress slowly over decades Mauskopf / mouseface-- pinched facial features, tight skin, microstomia telangiectasia - widened blood vessels causing red threadlike marks on skin
36
Explain clinical features a/w scleroderma/systemic sclerosis
-Proximal arms and trunk skin involved -More rapid progression & worse prognosis -Tight skin causes hand dysfunction etc., -GI involvement leads to dysmotility, heartburn, malabsorption, bacterial overgrowth -Progressive fibrotic interstitial lung disease -Scleroderma renal crisis is: Renal vascular disease leads to severe ischaemia of kidneys, activation of the renin-angiotensin system and severe (malignant) hypertension with renal failure etc. Pathology shows “onionskin” intimal thickening of arteriololes Treatment is aggressive use of ACE inhibitors which corrects the pathophysiology
37
Tx for scleroderma
Symptomatic Vasodilators (e.g. nifedipine) for Reynaud’s PPIs for reflux and prokinetic drugs for dysmotility ACE inhibitors for renal crisis Definitive Steroids of little value Immunosuppressive agentsof some benefit - Cyclophosphamide, mycophenylate mofetil, B-cell agents –rituximab Anti-fibrotic drugs Drug of pulmonary hypertension (sildenafil, Bosentan)
38
Define idiopathic inflammatory myopathies
A group of systemic autoimmune diseases with myositis (muscle inflammation) as a major feature Frequently myositis associated auto-antibodies are present and they can determine clinical features Extremely rare
39
List types of myositis
Dermatomyositis Polymyositis Myositis associated w other connective tissue diseases Myositis associated w malignancy (older Pt) Inclusion body myositis (older pts) Others
40
Most common myositis specific antibodies
20%- anti tRNA synthetases - a/w dermatomyositis, interstitial lung disease, mechanic's hands, fever rare- PM/SCL - polymyositis/scleroderma overlap antiMi2 - older women - classic dermatomyositis, V sign rash, shawl sign rash, cuticular overgrowth anti SRP- african american women - poor prognosis - acute severe muscle weakness, cardiac involvement , myalgia
41
Describe dermatomyositis signs
facial rash heliotrope on eyelids photosensitivity and V sign Gottren's papules, rash on hands , erythema around nailbeds
42
Diagnosis of IIM
Presence of proximal muscle weakness on manual muscle testing and examination Raised muscle enzymes (CPK, LDH,AST, Aldolase) indicating muscle damage Evidence on EMG of typical myopathic findings Positive muscle biopsy showing evidence of inflammatory myopathy Positive ANF +/- myositis associated antibodies
43
Define myositis a/w malignancy
15-30% of older patients (> 50yrs) with DM have an associated cancer, as do a small number with polymyositis
44
Define inclusion body myositis
Inclusion body myositis is a slowly progressive myositis of older men (> women) w proximal and distal weakness, poor response to treatment. Pathology shows typical inclusion bodies on EM
45
Define mixed connective tissue disease
overlap features of scleroderma, SLE, myositis or arthritis They also have a typical auto-antibody profile with + ANF and + anti-RNP antibodies Usually milder course than SLE or Scleroderma
46
Define sjogren's syndrome
- Immune mediated inflammation of salivary glands with Sicca - B-Cell hyperactivity is also seen with hypergammaglobulinaemia - may co exist w/ RA or SLE - Rare features include vasculitis and CNS disease, and B-Cell lymphoma
47
What antibodies are a/w Sjogren's syndrome
+ ANF with anti-Ro or anti-La antibodies
48
Clinical features of sjogren's syndrome
Parotid and salivary gland enlargement, & inflammation Sicca syndrome, dry eyes and mouth + Schirmers test (Whether the eye produces enough water for moisture Keratoconjunctivitis sicca
49
Define a common inflam condition of older pts involving muscle
polymyalgia rheumatica Presents with sub-acute onset of proximal muscle (hip and shoulder girdle) pain and stiffness with loss of movement and function Marked morning stiffness and disability Muscle strength is preserved (myalgias only) Hands and feet not involved Systemic features such as weight loss and fatigue
50
Lab and clinical features of polymyalgia rheumatica
Pelvic and shoulder girdle aching Morning stiffness is prominent Difficulty dressing and with rising from chair Anemia, elevated ESR and C-reactive protein Rapid response to low doses of corticosteroids, e.g. 20mg/day prednisone is very typical
51
Tx of PR
Rapid response to medium dose prednisolone (20 mg daily) Usual time on steroid is 2 years Don’t forget bone protection with calcium and vitamin D and bisphosphonates Aspirin reduces stroke risk
52
Define giant cell arteritis
subacute granulomatous vasculitis seen in OLDER pts autoimmune affects branches of aortic arch – external carotid (temporal arteries esp), subclavian, ascending aorta
53
Clinical features of giant cell arteritis
``` Clinical Temporal (or occipital) headache (thickened and tender temporal arteries w reduced pulsation) Jaw pain or claudication Sudden monocular blindness Tongue or upper limb claudication Malaise, fever etc. Polymyalgia rheumatica ``` Lab Raised ESR (>50mm/Hr) Raised CRP and other acute phase proteins Anaemia & thrombocytosis
54
Diagnostic test for giant cell arteritis
Temporal artery biopsy is the diagnostic test | Granulomatous inflammation ofarterial wall with Giant cells attacking internal elastic lamina causing occlusion of lumen
55
Ocular features a/w giant cell arteritis
Amaurosis fugax 14%- anterior ischaemic optic neuropathy (ciliary arteries supply optic nerve) Sudden monocular blindness 16%- central retinal artery occlusion Diplopia 10%- arteries of extraocular muscles
56
Management of GCA
High dose steroids if diagnosis strongly suspected (40-60 mg prednisolone daily) Temporal artery biopsy diagnostic, do not with hold steroids while awaiting biopsy Unfortunately, biopsy can be negative – may need to treat anyway if high suspicion Bone protection and aspirin needed – average time on steroids 2-3 years
57
Rel of polymyalgia to GCA
40-60% of patients with GCA have PMR symptoms; in about half of these individuals, PMR is their first manifestation of GCA 10-15% of patients with PMR have GCA PMR symptoms can occur before, with, or after GCA symptoms in patients with GCA GCA can develop long after onset and treatment of PMR Treatment of GCA requires larger doses of corticosteroids than does treatment of PMR

connective tissue (1 decks)

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