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connective tissue diseases Flashcards

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

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

ESR better guide to inflam

24
Q

Treatment of SLE

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
Q

Spectrum of SLE

A 
classical SLE
antiphospholipid syndrome
latent lupus
drug induced lupus
neonatal lupus
end stage lupus
26
Q

What causes mortality and morbidity in SLE

A

organ damage

effects of immunosuppression

27
Q

Define antiphospholipid syndrome
a/ features
a/ complications

A

•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
Q

Define diagnostic criteria for antiphospholipid syndrome

A
  • Lupus anticoagulant, or
  • Anti-Cardiolipin antibodies, or
  • Anti-Beta 2 glycoprotein 1

positive on 2 occasions , 12 weeks apart

29
Q

Tx for antiphospholipid syndrome

A
  • Aspirin

* Anticoagulation

30
Q

Define scleroderma

A

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
Q

Clinical features of scleroderma

A

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
Q

Epidemiology of scleroderma

A

Peak onset age 30-50 yrs: Female:male = 4:1

33
Q

Define Raynaud’s phenomenon

A

marked pallor on 4th and 5th digits of hands. early symptom

34
Q

Define scleroderma

A

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
Q

What are other a/ clinical features of scleroderma

A

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
Q

Explain clinical features a/w scleroderma/systemic sclerosis

A

-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
Q

Tx for scleroderma

A

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
Q

Define idiopathic inflammatory myopathies

A

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
Q

List types of myositis

A

Dermatomyositis
Polymyositis
Myositis associated w other connective tissue diseases
Myositis associated w malignancy (older Pt)
Inclusion body myositis (older pts)
Others

40
Q

Most common myositis specific antibodies

A

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
Q

Describe dermatomyositis signs

A

facial rash heliotrope on eyelids
photosensitivity and V sign
Gottren’s papules, rash on hands , erythema around nailbeds

42
Q

Diagnosis of IIM

A

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
Q

Define myositis a/w malignancy

A

15-30% of older patients (> 50yrs) with DM have an associated cancer, as do a small number with polymyositis

44
Q

Define inclusion body myositis

A

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
Q

Define mixed connective tissue disease

A

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
Q

Define sjogren’s syndrome

A
  • 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
Q

What antibodies are a/w Sjogren’s syndrome

A

+ ANF with anti-Ro or anti-La antibodies

48
Q

Clinical features of sjogren’s syndrome

A

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
Q

Define a common inflam condition of older pts involving muscle

A

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
Q

Lab and clinical features of polymyalgia rheumatica

A

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
Q

Tx of PR

A

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
Q

Define giant cell arteritis

A

subacute granulomatous vasculitis seen in OLDER pts
autoimmune
affects branches of aortic arch – external carotid (temporal arteries esp), subclavian, ascending aorta

53
Q

Clinical features of giant cell arteritis

A 
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
Q

Diagnostic test for giant cell arteritis

A

Temporal artery biopsy is the diagnostic test

Granulomatous inflammation ofarterial wall with Giant cells attacking internal elastic lamina causing occlusion of lumen

55
Q

Ocular features a/w giant cell arteritis

A

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
Q

Management of GCA

A

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
Q

Rel of polymyalgia to GCA

A

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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