Fess' Flashcards
Investigations show: ANA+ve Anti-dsDNA+ve Low C3 and C4 High ESR
Negative results for: Ro, La, Sm, RNP SCL70 Centromere Jo-1
What is the most likely diagnosis?
A. CREST syndrome B. Systemic lupus erythematosus C. Polyangitis with granulomatosis D. Dermatomyositis E. Sjogren's syndrome
B. Systemic lupus erythematosus
A positive anti-nuclear antibody (ANA) test is a generic indicator of autoimmune disease, and so is not very helpful in narrowing down the options here. However, anti-double stranded DNA (Anti-dsDNA) antibodies are extremely specific for systemic lupus erythematosus (SLE), and so are the only result you strictly need to get the right answer here. Depletion of C3 and C4 gives an idea of how severe the disease is, as although C4 will be depleted in any active SLE, depleted C3 indicates severe disease. High ESR is a very generic marker of inflammation.
Which option best defines auto-inflammatory disease?
A. Aberrant T cell and B cell responses in primary and secondary lymphoid organs lead to breaking of tolerance with development of immune reactivity towards self-antigens
B. Hypersensitivity of the immune system towards otherwise harmless antigens which results in both chronic inflammation and acute episodes
C. Local factors at sites predisposed to disease lead to activation of innate immune cells such as macrophages and neutrophils, with resulting tissue damage
D. Mutations/polymorphisms in genes encoding proteins involved in innate and adaptive T cell function.
E. IgE-mediated local inflammation as a result of cross-linking and subsequent mast cell degranulation
C. Local factors at sites predisposed to disease lead to activation of innate immune cells such as macrophages and neutrophils, with resulting tissue damage
The difference between auto-inflammatory and auto-immune is essentially that auto-inflammatory involves the innate immune system, and auto-immune involves the adaptive immune system. As a result, auto-immune diseases are often more systemic than auto-inflammatory diseases, and have associated antibodies.
Which of the following mutations is present in Familial Mediterranean Fever?
A. Loss of function in Pyrin-Marenostrin (MEFV gene)
B. Gain of function in Pyrin-Marenostrin (MEFV gene)
C. Loss of function in Cryopyrin (NALP3 gene)
D. Gain of function in Cryopyrin (NALP3 gene)
E. Mutation of TNF receptor
A. Loss of function in Pyrin-Marenostrin (MEFV gene)
The Pyrin-Marenostrin protein acts as a negative regulator within the inflammasome: a complex responsible for activation of inflammatory responses. The inflammasome complex receives input from Pyrin-Manenostrin (negative regulator) and Cryopyrin (positive regulator which reacts to inflamamtory triggers e.g. toxins, pathogens, urate), which then influences activation of apoptosis-associated speck-like proteins (ASC) and Procaspase 1. This then influences expression of IL-1 and NF-kB. It’s worth looking at diagrams for the inflammasome complex.
A loss of function mutation in the Pyrin-Manenostrin gene (MEFV) leads to Mediterranean fever.
Which of the following is not a feature of Familial Mediterranean Fever?
A. Peritonitis and arthritis
B. Periodic fevers lasting 48-96 hours
C. Haemoptysis from alveolar damage
D. Pericarditis or pleuritis causing chest pain
E. Long term dysfunction in the kidneys and liver from Serum Amyloid A deposition
C. Haemoptysis from alveolar damage
Familial Mediterranean Fever is a monogenic disease characterised by ‘attacks’ which feature periodic fevers lasting between 48-96 hours in conjunction with inflammation leading to peritonitis, pericarditis, pleuritis, arthritis, and rash. Features may be present in a variety of combinations, making diagnosis tricky.
During inflammatory attacks, the liver produces various acute-phase proteins including Serum Amyloid A, which then deposits in organs, particularly the kidneys, liver and spleen. Deposition of these proteins leads to formations of oligomers and eventually fibrils, which are toxic to the organs in which they deposit. Management of these patients therefore focuses on limiting the number of attacks they have using Colchicine, which disrupts neutrophil migration and chemokine secretion. If Colchicine doesn’t work, Etanercept (TNF alpha inhibitor) or Anakinra (IL-1 antagonist) may be used.
Match each lettered disease with the appropriate numbered description
A. APECED
B. IPEX
C. ALPS
D. Familial Mediterranean Fever
- Single gene mutation of the MEFV gene and affecting the inflammasome complex, resulting in recurrent episodes of serositis
- Mutation within the Fas pathway associated with lymphocytosis, lymphomas and auto-immune cytopenias
- Single gene mutation involving FOXp3 resulting in abnormality of T reg cells
- A defect in the AIRE gene leading to a lack of expression of self-antigens in the thymus, which results in survival of autoreactive lymphocytes
Each disease is a monogenetic cause of autoimmune or auto-inflammatory (Familial Mediterranean Fever) disease:
APECED - A defect in the AIRE gene leading to a lack of expression of self-antigens in the thymus, which results in survival of autoreactive lymphocytes
IPEX - Single gene mutation involving FOXp3 resulting in abnormality of T reg cells
ALPS - Mutation within the Fas pathway associated with lymphocytosis, lymphomas and auto-immune cytopenias
Familial Mediterranean Fever - Single gene mutation of the MEFV gene and affecting the inflammasome complex, resulting in recurrent episodes of serositis
Auto-immune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome: APECED
APECED is caused by a defect in the auto-immune regulator gene (AIRE). The AIRE gene transcribes a transcription factor which is able to transcribe any other gene. This is crucial in the thymus where AIRE serves to produce self-antigens to identify lymphocytes which would be self-reactive in circulation, which are then apoptosed. IF this fails, self-reactive lymphocytes are released into circulation resulting in widespread autoimmunity.
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome: IPEX
The FOXp3 gene is important for the development of Treg cells, which normally function to negatively regulate autoreactive B-cells. Mutations in FOXp3 lead to dysfunctional Treg cells, and dysregulated B-cell responses.
Auto-immune lymphoproliferative syndrome: ALPS
The FAS pathway usually functions to trigger apoptosis. Mutations in the FAS pathway leads to survival of lymphocytes after infections that have been cleared. The result is chronic lymphocytosis, auto-immunity, and an increased incidence of lymphoma. The manifestation of the disease is fairly heterogenous as it may be caused my multiple mutations within the FAS pathway.
Familial Mediterranean Fever
Familial Mediterranean Fever is a monogenic disease characterised by ‘attacks’ which feature periodic fevers lasting between 48-96 hours in conjunction with inflammation leading to peritonitis, pericarditis, pleuritis, arthritis, and rash. Features may be present in a variety of combinations, making diagnosis tricky.
During inflammatory attacks, the liver produces various acute-phase proteins including Serum Amyloid A, which then deposits in organs, particularly the kidneys, liver and spleen. Deposition of these proteins leads to formations of oligomers and eventually fibrils, which are toxic to the organs they deposit in. Management of these patients therefore focuses on limiting the number of attacks they have using Colchizine, which disrupts neutrophil migration and chemokine secretion. If Colchizine doesn’t work, Etanercept (TNF alpha inhibitor) or Anakinra (IL-1 antagonist) may be used.
A mutation within which gene increases the risk of Crohn’s disease?
A. TNF-alpha B. Cryopyrin C. TGF-beta D. FASL E. NOD 2
E. NOD 2
This gene is only present in ~1/3 of Crohn’s patients but is associated with the disease, especially if there are two copies present.
Match the lettered polymorphisms with the numbered diseases they are associated with
A. HLA DR3 B. HLA B27 C. HLA DR15 D. HLA DR 4 E. Both HLA DR3 and DR4
- Goodpasture’s disease
- Rheumatoid arthritis
- Type I Diabetes Mellitus
- Ankylosing spondylitis
- Graves’ disease, SLE
HLA DR3 - Graves' disease, SLE HLA B27 - Ankylosing spondylitis HLA DR15 - Goodpasture's disease HLA DR 4 - Rheumatoid arthritis Both HLA DR3 and DR4 - Type I Diabetes Mellitus
HLA associations are most common in polygenic autoimmune diseases, which all of the above are (apart from ankylosing spondylitis, which falls under mixed pattern disease).
Where is inflammation mostly enhanced in ankylosing spondylitis?
A. Areas of high friction between vertebra and cartilage
B. Areas of bone-bone contact
C. Areas where there are high tensile forces
D. Within small joints in the feet and ankles
E. Within small joints in the hands and wrists
C. Areas where there are high tensile forces
Enthesitis is a classic feature of ankylosing spondylitis, and occurs where tendons or ligaments insert into bone, which are points of high tensile stress.
Match the lettered diseases with the numbered Gell and Coombs reaction classification
A. Eczema and anaphylaxis
B. Contact dermatitis and Type I Diabetes Mellitus
C. SLE and Rheumatoid arthritis
D. Goodpasture’s disease and Pemphigus Vulgaris
- Type I
- Type II
- Type III
- Type IV
Eczema and anaphylaxis - Type I
Contact dermatitis and Type I Diabetes Mellitus - Type IV
SLE and Rheumatoid arthritis - Type III
Goodpasture’s disease and Pemphigus Vulgaris - Type II
The Gel and Coombs classification divides all hypersensitivity reactions into four groups:
Type I - IgE mediated (classic allergy)
Type II - antibody reacts with cellular antigen to exert effect
Type III - also antibody-mediated, but the antibody reacts with soluble antigen to form an immune complex which is deposited and leads to further damage
Type IV - delayed-type hypersensitivity (t-cell mediated)
NB: Rheumatoid arthritis may be classified as either type III or IV because it may be immune complex or T-cell mediated
Match the lettered organ-specific disease with the corresponding numbered antibody type
A. Goodpasture's disease B. Myasthenia Gravis C. Graves' disease D. Pernicious anaemia E. Type I Diabetes Mellitus F. Hashimoto's thyroiditis G. Rheumatoid arthritis
- Anti-GAD
- Anti-thyroglobulin
- Anti-basement membrane
- Anti-intrinsic factor
- Anti-acetylcholine receptor
- Anti-cyclic citrullinated peptide
- Anti-TSH receptor
Goodpasture’s disease - Anti-basement membrane
Myasthenia Gravis - Anti-acetylcholine receptor
Graves’ disease - Anti-TSH receptor
Pernicious anaemia - Anti-intrinsic factor
Type I Diabetes Mellitus - Anti-GAD
Hashimoto’s thyroiditis - Anti-thyroglobulin
Rheumatoid arthritis - Anti-cyclic citrullinated peptide
Which marker is specifically associated with autoimmune connective tissue diseases?
A. Perinuclear anti-neutrophil cytoplasmic antibodies
B. Anti-nuclear antibodies
C. Raised CRP and ESR
D. Rheumatoid factor
E. Anti-neutrophil cytoplasmic antibodies
B. Anti-nuclear antibodies
As a rule: ANAs = autoimmune connective tissue disease, and ANCAs = small-vessel vasculitides
Which pattern of antibody deposition seen on indirect immunofluorescence using hep 2 cells (human epithelial cells used to look for autoimmune conditions) is characteristic of SLE?
A. Speckled deposition B. Homogenous pattern C. Smooth deposition along the basement membrane D. Lightning bolt pattern E. A granular 'lumpy bumpy' pattern
B. Homogenous pattern
Homogenous antibody staining almost always indicates the presence of anti-dsDNA antibodies, which are 95% specific for SLE, with a 60-70% sensitivity
Although the granular ‘lumpy bumpy’ pattern does indicate SLE, it is seen on staining of kidney samples with fluorescent conjugated anti human immunoglobulin. Therefore this pattern is not seen on indirect immunofluorescence of Hep 2 cells.
Staining of lupus nephritis classically reveals a granular ‘lumpy bumpy’ pattern which is the result of immune complex deposition (as SLE is a type III hypersensitivity reaction).
Smooth antibody deposition along the basement membrane is indicative of Goodpasture’s disease - the basement membrane is the giveaway.
Speckled staining indicates the presence of antibodies directed against ribonucleoproteins - Ro, La, Sm, or RNP. Ro and La are associated with Sjogren’s syndrome (autoimmune destruction of exocrine glands leading to dry mouth with associated infections, dry eyes, and dyspareunia from lack of vaginal secretions). Sm (Smith) antibodies are extremely specific for SLE.
Which of the following is not a feature of anti-phospholipid syndrome?
A. Recurrent arterial thromboses B. Serositis C. A history of recurrent miscarriages D. Thrombocytopenia E. Recurrent venous thromboses
B. Serositis
Antiphospholipid syndrome may occur in the absence of background disease, but is often associated with other autoimmune disease - classically SLE. Antiphospholipid syndrome can be difficult to detect as its symptoms can be generic, but it causes complications in pregnancy (pre-eclampsia, intra-uterine growth restriction, pre-term delivery, miscarriage) which, in combination with an increased risk of both venous and arterial clotting, can be used to identify the disease.
Thrombocytopenia is a non-specific finding in antiphospholipid syndrome, but serositis does not occur (though it may occur in concurrent SLE).
Which of the following options would be appropriate to test for antiphospholipid syndrome?
A. Anti-thyroid peroxidase and anti-thyroglobulin
B. Anti-Smith and Anti-dsDNA
C. ESR and platelet count
D. Schirmer’s test
E. Anti-cardiolipin and lupus anticoagulant
E. Anti-cardiolipin and lupus anticoagulant
The presence of which of the following features would indicate a diagnosis of diffuse rather than limited cutaneous systemic sclerosis?
A. Telangectasia B. Primary pulmonary hypertension C. Sclerodactyly D. Skin tightening on the trunk E. Calcinosis
D. Skin tightening on the trunk
Limited cutaneous systemic sclerosis, by definition, only involves skin on the hands and forearms, and around the mouth. If involvement progresses beyond the forearms, it is diffuse systemic sclerosis.
Limited cutaneous systemic sclerosis is the same thing as CREST syndrome, which is an acronym: C - Calcinosis R - Raynaud's phenomenon E - Esophageal dysmotility S - Sclerodactyly T - Telangectasia
One of the most severe manifestations of CREST syndrome, which is not included in the acronym, is primary pulmonary hypertension.
Diffuse cutaneous systemic sclerosis is characterised by the presence of the CREST features, plus extensive GI involvement, renal impairment and/or crisis, and interstitial pulmonary disease. Furthermore, skin is not affected in CREST beyond the hands, forearms, and skin around the mouth; in diffuse cutaneous systemic sclerosis, the skin involvement progresses further than this.
The two diseases can also be distinguished using antibody tests:
CREST syndrome: anti-centromere antibodies
DIffuse cutaneous systemic sclerosis: anti-Scl70 antibodies (directed against topoisomerase enzyme)
NB: Scleroderma refers to both forms of systemic sclerosis
An 45 year-old woman presents with chronic muscle weakness. You notice a red rash over her eyelids and the knuckles of her hands. ANA tests reveal a raised anti-Jo1 titre.
What is the most likely diagnosis?
A. Sjogren's syndrome B. Psoriatic arthritis C. Dermatomyositis D. SLE E. Polymyositis
C. Dermatomyositis
Chronic muscle weakness in this case arises from myositis. This is confirmed by the presence of anti-Jo1 antibodies, which are directed against tRNA synthetase enzymes in the cytoplasm. The presence of anti-Jo1 antibodies doesn’t distinguish between polymyositis and dermatomyositis, but the presence of the skin rash (the rash over the eyelids is classic and is known as a heliotrope rash) indicates dermatomyositis.
The presence of cANCA antibodies would most strongly suggest which disease?
A. Granulomatosis with polyangitis B. Microscopic polyangitis C. Eosinophilic granulomatosis with polyangitis D. Sarcoidosis E. Sjogren's disease
A. Granulomatosis with polyangitis
ANCA is antibodies activating neutrophils
cANCA are associated with GPA (formerly known as Wegener’s). GPA is a small-vessel vasculitis characterised by upper respiratory, lower respiratory, and renal involvement. Questions may ask you to differentiate between GPA and Goodpasture’s as both affect the lungs and kidneys, but only GPA affects the upper respiratory system; a question will often include nosebleeds to point towards GPA.
There are two other small-vessel vasculitides associated with ANCA: microscopic polyangitis, and eosinophillic GPA. However, both of these are associated with perinuclear ANCA (pANCA) rather than cANCA. cANCA are directed against proteinase 3 in neutrophils, and are very sensitive for GPA, whereas pANCA are directed at myeloperoxidase and are less sensitive and specific for eGPA and microscopic polyangitis
