Multi-System Autoimmune Disease Flashcards
What is the sequence of events in autoimmunity?
Initiating event + genetic susceptibility Breakdown of self-tolerance Auto-reactivity Humoral +/- cellular Autoimmune disease
What is involved in the susceptibility for the development of autoimmune disease?
Multifactorial
Involves interaction of internal factors e.g. genes, hormones, immune dysregulation with exogenous factors e.g. infections, drugs, UV radiation
When combined together, the initiating exogenous factors in an inherently susceptible individual leads to a breakdown of damaging immune response and ultimately tissue or organ damage
- genetic/regulatory/hormonal/environmental/other factors
- breakdown of immunological tolerance
- pathological autorecognition
- inflammation and tissue damage, autoimmunity, hypersensitivity
Autoimmune diseases are conventionally organised into what?
Those which are predominantly organ specific i.e. where the aberrant immune response is directed against self-antigens which are localised or confined to particular tissues
Non-organ specific i.e. where the immune response is directed against self-antigens which have a more widespread, ubiquitous distribution
Some diseases in the middle of the spectrum tend to have a mixture of both organ-specific and non-organ specific immunopathology
The connective tissue disorders are all at the non-organ specific pole of the spectrum
What is involved in immune pathology?
Autoimmunity
Hypersensitivity
Immune deficiency
What are the functions of the complement system?
Phagocyte chemotaxis
Opsonisation
Lysis of micro-organisms
Maintaining solubility of immune complexes
The complement system is a component of what immune system?
Innate
What does the complement system comprise?
Collection of serum proteins organised into a classical pathway, an alternate pathway and a terminal pathway
Control of proteins in the serum and body fluids which prevents inappropriate complement activation, or down regulate and turn off complement activation
Series of cell surface control proteins which control and regulate the activity of the complement pathway
What is the classical pathway activated by?
Immune complexes containing IgG and IgM
Antigen bound IgM is particularly effective at classical pathway activation
The alternate pathway cycles constantly at what rate?
Very low rate of physiological activity
What is the alternate pathway up-regulated by?
A number of factors, including exposure to endotoxin-producing micro-organisms
At what point do the classical and alternate pathways converge?
At the point of breakdown of C3 into its breakdown products C3a and C3b
What happens in the terminal pathway?
C5 is broken down into C5a and C5b and the components C6, C7, C8 and C9 sequentially bind to C5b to form a multi-molecular C5b-C6-C7-C8-C9 complex called the membrane attack complex
In what diseases are the opsonisation function and maintenance of immune complex solubility of focal importance?
Connective tissue disease, particularly those where abnormal production, handling and deposition of immune complexes are involved in disease pathogenesis
Employment of complement measurements has three principle areas of importance in connective tissue disease, what are these?
Diagnosis
Monitoring
Detection of hereditary deficiencies
What do complement components roughly reflect?
The amount of immune complexes being generated, the more immune complexes being produced during disease exacerbation the more complement is consumed and the lower the measured levels
What happens to complement as diseases go into remission?
Immune complex production decreases and complement levels rise
Measuring complement levels can therefore be useful in disease diagnosis and in the monitoring of disease activity
In what disease is complement measurement of little practical value?
In diseases such as RA which are caused mainly by cellular mechanisms with only a small pathogenic component of localised immune complex formation
The use of complement tests for consideration and detection of hereditary complement deficiencies is principally a reflection of what?
The important role of classical pathway components (C1, 2 and 4) and their breakdown products in opsonisation and maintaining the solubility of immune complexes, and in preventing their pathological deposition into tissues
What happens when there are genetic deficiencies of one or more classical pathway component?
Immune complexes being produced in the course of a normal reaction to infection/dietary proteins etc. cannot be dealt with by normal pathological mechanisms and so readily deposit out of solution into tissues e.g. kidneys, joints and skin
Damage is therefore not the result of inappropriate and excessive immune complex formation but rather an inability to handle and dispose of even normal levels of immune complex formation
In classical pathway deficiencies, what is a major clue that the mechanistic problem lies within the complement system rather than ANA autoantibody production?
Patients are ANA negative
What are the features of complement deficiency?
Genetic deficiencies of components in three main parts of the complement system, presenting in characteristic but different ways
Alternate and terminal pathways present with infection
Deficiencies of classical pathway components characteristically present as lupus-like systemic immune complex disease
What are cryoglobulins?
Immunoglobulin molecules which reversibly precipitate out of solution at temperatures under 37 degrees celsius
In what conditions are cryoglobulins seen?
Livedo reticularis Raynaud's Peripheral cyanosis Purpura/vasculitis Glomerulonephritis Neuropathy Arthralgia Thrombosis Haemorrhage
How are connective tissue diseases diagnosed?
History
Examination
Relevant investigations
Laboratory investigations
What are the performance characteristics?
Accuracy Precision Sensitivity Specificity \+ve/-ve predictive value Purpose for which the test is used
What are the test purposes in relation to disease?
Diagnosis Sub-Classification Prognosis/risk stratification Monitoring/progression Screening Research
What are the test purposes in relation to treatment?
Planning Selection Triage Monitoring Evaluation
What are the things to consider when ordering a test?
Why you are ordering it
What the consequences of doing/not doing the test are
How good the test is for the purpose for which you are using it
How the results are interpreted
How the results will influence patient management and outcome
What are the immunology tests?
Antinuclear antibodies Antineutrophil cytoplasmic antibodies Antiphospholipid antibodies Complement Cryoglobulin Rheumatoid factor Anti-CCP Serum immunoglobulin Autoantibodies against formed elements in the blood Tissue typing Biopsy of skin or kidney s
Why might immunological tests be useful?
Diagnosis
Prognostic assesemnet
Monitoring
of connective tissue diseases
Why might autoantibodies be of use?
Disease diagnosis
Monitoring of disease activity
Sub-classification of disease
What is the sensitivity to antinuclear antibody testing in; SLE Drug-induced LE MCTD RA Sjogren's Scleroderma Dermatomyositis Old age Chronic inflammation Neoplasia CAH PBC Normality
SLE > 95% Drug-induced LE 95% MCTD 95% RA 50% Sjogren's 60% Scleroderma 60% Dermatomyositis 15% Old age > 40% Chronic inflammation > 30% Neoplasia 10% CAH 70% PBC 25% Normality 3-5%
What are the features of SLE?
Systemic autoimmune disorder mediated by widespread deposition of immune complexes (type III hypersensitivity) containing autoantigen and autoantibody throughout the body
Deposits happen throughout body but have a predilection for the skin, joints and kidney
Autoantibodies characteristically produced against a range of nuclear auto antigens but also against a range of other non-organ specific autoantigens e.g. cardiolipin and ribosomes
ANA has a high sensitivity but very low specificity for SLE, what does this mean?
It has high negative predictive value and low positive predictive value
If ANA test -ve, SLE is extremely unlikely
Almost all cases of SLE will have detectable ANA but in the general population, an ANA test done for non-specific symptoms with a positive result is unlikely in itself to be indicative of SLE, why is this?
As SLE is relatively rare and other conditions e.g. cancer, old age and infection can cause a positive ANA and are more common
Why is ANA testing more useful to exclude SLE in a patient with non-specific symptoms?
Because of the high predictive value of a negative result
What are the four different patterns of ANA staining seen using the fluorescent test?
Homogenous pattern staining - present when there are autoantibodies directed against chromosomal autoantigens (double/single stranded or histone proteins)
Speckled pattern staining - where there are autoantibodies directed against non-chromosomal nuclear proteins (which are physically distinct from nucleic acids in the nucleus)
Nucleolar staining - where autoantibodies are directed solely against nucleolar RNA
Peripheral/membranous staining - where staining is confined to the nuclear membrane
What potential autoantigens are contained in the human nucleus?
Double stranded DNA Single stranded DNA Histone proteins Nucleolus Non-histone nuclear proteins
In some conditions, particularly in SLE, autoantibodies can be produced against a range of nuclear autoantigens, what does this result in?
Different staining patterns on testing when visualised down a microscope
In homogeneous staining, in what conditions are dsDNA, ssDNA and histone proteins seen?
dsDNA - SLE, some autoimmune liver disease
ssDNA - non-specific, many inflammatory disorders
Histone proteins - drug-induced lupus, other connective tissue disorders
What does homogenous staining result from?
Autoantibodies being directed against one or more of three nuclear autoantigens - double stranded DNA, single stranded DNA or histone proteins
What does the specificity of nuclear antibodies help with?
Making a specific disease diagnosis, but none of the autoantibodies are precisely disease-specific
Antibodies to dsDNA are frequently regarded as the hallmark of SLE but they also occur in other conditions
In what conditions might Ro speckled staining be seen?
Sjogren's SLE SCLE RA Scleroderma Neonatal lupus
In what conditions might La speckled staining be seen?
Sjogren’s
SLE
In what conditions might Sm speckled staining be seen?
SLE
In what conditions might RNP speckled staining be seen?
MCTD SLE DLE Sjogren's Scleroderma
In what conditions might Scl-70 speckled staining be seen?
Scleroderma
In what conditions might Jo-1 speckled staining be seen?
Polymyositis
Dermatomyositis
In what conditions might centromere speckled staining be seen?
CREST
Scleroderma
Some MCTD, SLE, CAH and PBC
What is the commonest circumstance where speckled ANA staining is found?
Where autoantibodies are produced against the antigens Ro and La in patients who have Sjogren’s syndrome or SLE
What are nucleolar pattern ANAs usually directed against?
Nucleolar RNA
Hallmark finding in patients with scleroderma or overlap syndromes where clinical features of scleroderma and other connective tissue diseases are simultaneously present
What are the clinical features of conditions with positive nucleolar staining?
Tight, shiny skin typical of scleroderma, particularly around the mouth
Facial telangiectasia characteristic of scleroderma
Shiny tight skin in hands with or without ulceration over joints
Advanced/aggressive systemic sclerosis with cutaneous vasculitis, digital ulceration and gangrene
Internal complications frequently present in advanced/aggressive cases, particularly in the lungs and GI tract
In what conditions might peripheral/membranous staining be seen?
SLE
Some autoimmune liver disease
Peripheral ANA staining seen where autoantibodies are being produced against dsDNA
Frequently seen as a combined staining pattern with homogenous staining in patients who have SLE
What is cascade testing?
Movement from screening to specific test
What antibodies can be used to predict known sub-classifications/complications?
Anti-dsDNA - nephritis, vasculitis
Anti-Sm - nephritis, cerebral
Anti-RNP - arthritis, myositis, Raynaud’s
Anti-Ro - photosensitivity, Sjogren’s
Patients who produce high levels of anti-dsDNA antibodies tend to present with/develop what?
Renal complications and/or vasculitis
What is the major autoantigen associated with C-ANCA staining?
Proteinase 3
What is the major autoantigen associated with P-ANCA staining?
Myeloperoxidase
ANCA levels only variably correlate with disease activity, but rises should trigger what?
Vigilance and review
Is ANCA specific or non-specific?
Non-specific Can be raised in - infection - inflammation - drugs - connective tissue disorders - inflammatory bowel disease
What are the antiphospholipid syndromes?
Primary
Secondary
- CT disorders e.g. SLE, RA, systemic sclerosis, Sjogren’s
- Chronic infection e.g. HIV, hep C, malaria
- Drugs e.g. phenytoin, phenothiazines, anti-hypertensives
- Lymphoproliferative disease
What are the major features of antiphospholipid syndromes?
Vascular thrombosis - venous/arterial
Recurrent foetal loss
Livedo reticularis
Thrombocytopenia
What are the anti-phospholipid antibodies and where are they seen?
Anti-cardiolipin antibodies
Anti-beta 2 glycoprotein I antibodies
Lupus anticoagulant
Often seen transiently in acute infection
What are the common connective tissue disease?
SLE Scleroderma Sjogren's syndrome Autoimmune myositis Mixed connective tissue disease
What are the common systemic vasculitis conditions?
Giant cell arteritis
Granulomatosis polyangiitis
Microscopic polyangiitis
Eosinophilic granulomatosis polyangiitis
How do you diagnose connective tissue disease or systemic vasculitis?
Cardinal clinical features - history and examination Immunology Imaging Tissue Exclusion of Dx
What are some mimics of connective tissue disease/systemic vasculitis?
Drugs - cocaine, minocycline, PTU Infection - HIV, endocarditis, hepatitis, TB Malignancy - lymphoma Cardiac myxoma Cholesterol emboli Scurvy
What is the UK prevalence of SLE?
28 per 100,000
What is the UK incidence of SLE?
4 per 100,000
What is the female:male incidence of SLE?
Female:male
9:1
What is the age of onset of SLE?
15-50
What is the classification criteria of SLE?
Any 4 of;
Malar rash
Discoid rash - raised, scaly centre with dark rim, scarring, permanent marks, alopecia
Photosensitivity
Oral ulcers
Arthritis - at least 2 joints
Serositis - pleurisy or pericarditis
Renal - significant proteinuria or cellular casts in urine
Neurological - unexplained seizures of psychosis
Haematological - low WCC, platelets, lymphocytes, haemolytic anaemia
Immunological - anti-dsDNA, SM, cardiolipin, lupus anticoagulant, low complement
ANA
What is the UK prevalence of scleroderma?
24 per 100,000
What is the UK incidence of scleroderma?
10 per 1,000,000
What is the age of onset of scleroderma?
30-50 years
What is the female:male incidence of scleroderma?
Female:male
3:1
What are the features of scleroderma morphea?
Scarred skin but better prognosis as no internal organ involvement
What are the features of scleroderma limited?
Skin involvement distal to elbows and knees, no trunk or proximal limb involvement
Onset in teens, no trophic changes, more likely to be a primary phenomenon
If onset at an older age (40s) then this should ring alarm bells and patient should be screened for connective tissue disorders
Limited cutaneous systemic sclerosis
What are the features of scleroderma diffuse?
Affects trunk and proximal and distal limbs
Skin creases disappear, small mouth
What are the complications of scleroderma?
Limited - pulmonary hypertension
Diffuse - pulmonary fibrosis, renal crisis, small bowel bacterial overgrowth
Diffuse is particularly high risk in first 5 years post-diagnosis
Renal crisis is worsened by steroid use, only small doses of prednisolone used in modern treatment
Oesophageal dysmotility
What is the prevalence of Sjogren’s syndrome?
1 per 100
What is the incidence of Sjogren’s syndrome?
4 per 100,000
What is the age of onset of Sjogren’s syndrome?
40-50s
What is the female:male incidence of Sjogren’s syndrome?
Female:male
9:1
What are the clinical presentations of Sjogren’s syndrome?
Dry eyes and mouth - patients struggle to swallow food
Parotid gland enlargement
1/3 have systemic upset - fatigue, fever, myalgia, arthralgia
5% develop lymphoma
What are the complications of Sjogren’s syndrome?
Lymphoma Neuropathy Purpura Interstitial lung disease Renal tubular acidosis
What is the incidence of autoimmune myositis?
6 per 1,000,000
What is the clinical presentation of autoimmune myositis?
Muscle weakness - symmetrical, diffuse, proximal
Polymyositis
Dermatomyositis - Gottron’s papules
Heliotrope rash
Difficulty swallowing - indicates poorer prognosis
What are the complications of autoimmune myositis?
Malignancy
Interstitial lung disease
What are the overlap syndromes?
Mixed connective tissue disease (MCTD) - soft tissue swelling - Raynaud's - myositis - arthralgia May present with flu-like illness
What is the prevalence of vasculitis?
1 per 1000
What is vasculitis?
Autoimmune disease causing inflammation of the blood vessels
What does ANCA associated vasculitis predominantly affect?
Small blood vessels
What are the ANCA associated vasculitides?
Granulomatosis with polyangiitis
Microscopic polyangiitis
Eosinophilic granulomatosis with polyangiitis
What is the overall incidence of ANCA associated vasculitis?
15 per 1,000,000
What ist he overall prevalence of ANCA associated vasculitis?
150 per 1,000,000
What are the features of granulomatosis with polyangiitis?
Necrotising granulomatous inflammation
Usually involves upper and lower respiratory tract
Predominantly affects small to medium sized vessels
Necrotising glomerulonephritis common
Will lead to end stage renal failure if untreated
What are the features of microscopic polyangiitis?
Necrotising vasculitis with few or no immune deposits
Predominantly affects small vessels
Necrotising arteritis involving small and medium sized arteries may be present
Necrotising glomerulonephritis is very common
Pulmonary capillaritis often occurs
Granulomatous inflammation absent
May be acute or chronic presentation
What are the features of eosinophilic granulomatosis with polyangiitis?
Eosinophil-rich and necrotising granulomatous inflammation often involving the respiratory tract
Necrotising vasculitis predominantly affecting small to medium vessels
Associated with asthma and eosinophilia
ANCA more frequent when glomerulonephritis is present
Foot drop
Relapsing disease - relapses range from mild to severe
Patients need to be frequently followed up
Treatment generally lifelong
What is the treatment of multi-system autoimmune disease?
Mild organ threat - hydroxychloroquine
Moderate organ threat - azathioprine, methotrexate, mycophenolate
Severe organ threat - cyclophosphamide, rituximab
Steroids often used in combination
Rituximab and cyclophosphamide most often used in severe kidney or neurological involvement
What are the classification criteria for giant cell arteritis?
3 of the following;
- age at onset 50 or older
- new headache
- temporal artery tenderness/reduced pulsation
- ESR 50 or higher
- abnormal temporal biopsy
What is the investigation and treatment of giant cell arteritis?
Temporal artery biopsy ASAP
Treatment with high dose steroids started immediately on clinical suspicion, prolonged course 4-5 years
30% remain permanently on steroids
