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Immunology, skin cancer, drugs, Rheumatoid Arthritis, Multiple Sclerosis -…

- - - - Autologous/Allogeneic stem cell transplantation
      - Cord blood stem cells
    - - Malignant disease
      - Leukaemia & lymphoma
      - Solid organ tumours, Multiple myeloma
      -  Genetic diseases
      - Immunodeficiency & Haematological
      - Storage disorders
      -  Autoimmune disease (rare; few units)
    - - Non-engraftment
      -  Infection
      -  GvHD
        
        Can occur when
        
        Viable T cells are given to
        
        immunodeficienct / immunosuppressed
        
        recipient
        
         Bone marrow transplantation
        
         Solid organ Tx (very rarely)
        
         Post transfusion in severely
        
        immunocompromised
      -  Recurrence
      -  Toxicity of conditioning regimen
    - - Acute
        
        Skin
        
         GIT
        
         Liver
        
         Bone marrow
        
        Common
         Prophylaxis given
      - chronic
        
        Skin thickening
        
         Sicca syndrome
        
         Pneumonitis
        
         Immunodeficiency
        
        25%-45% of those
        surviving >6 months
  - - - Irreversible organ failure
      - Disease with low risk of recurrence
      - Recipient free of infection
      - Recipient free of malignancy
      - Recipient fit for major surgery
      - Recipient psychologically suitable.
    - - Allocation of scarce resources
      - Living donor programme
    - - Relevant to solid organ and HSCT
      - Better matching decreases the
      - immunological barrier
      - Better outcomes
      - Less sensitisation (anti-HLA antibodies)
    - - Hyperacute <24 hours
      - Acute cellular common <6 mths
      - Acute antibody mediated usually < 6 weeks
      - Chronic rejection years
      - Mechanism of Tissue Damage
        
        Hyperacute & Acute antibody mediated
        
        Antibody & complement
        
        Acute inflammation &
        
        Cellular Rejection: T cell cytotoxic damage
        
        Chronic Rejection: Role of antibodies now prominent
      - Preformed antibodies to graft
        
        Can cause hyperacute rejection
        
        Contraindication (except for liver transplants)
        
        Blood group antibodies (ABO & other)
        
        Anti-HLA antibodies
        
        Post Renal Transplant -
        Immunosuppression
        
        T cell depleting antibody – anti-CD25
        
         Tacrolimus – calcineurin inhibitor
        
         Mycophenylate – anti-proliferative agent
        
         Steroids
  - - - Rare causes – dural patches, heart valves
      - Environmental exposures
      - Infection: HIV, EBV & others
      - Artificial surfaces:
        
        LVADs (Left ventricular assist devices)
        
        AIDs (Artificial Implantable Defibrillators)
  - - - Matching
      - Immunosuppression
- - - - Source of all blood cells
      - Haematopoietic stem cells
    - - Bone marrow
      - Thymus
      - Lymph nodes
      - Spleen
      - Appendix
      - Tonsils
      - Adenoids
      - Peyer’s patches
  - - - Self vs non-self
        
        KEY FEATURE OF IMMUNE DETECTION
        
        we've evolved mechanisms to recognise Pathogenic Antigens
        
        Antigen = substance that activates immune response
        
        Non-Self Molecule: Pathogen-Associated Molecular Pattern [PAMP]: protein, DNA, RNA, lipid & sugars of bacteria, viruses, fungi or parasites
        
        Self Molecules: proteins, RNA, DNA, lipids, carbohydrates that make up our own cells, tissues & organs
        
        Tolerance to Self Molecules:
        
        As immune system matures it learns to recognise our self molecules + not react to them
      - Immune surveillance,
        
        PAMPs are detected by Innate Immune Cell Pathogen Recognition Receptors (PRRs):provide policing of our bodies for infection
        
        PRRs —> PAMPs —> Intracellular Signalling —> Pro Inflammatory & Anti-Pathogenic Mediators —> Act Directly or Enhance other Immune Cells
      - Innate cells (Neutrophils, Eosinophils, Basophils, Mast cells, Natural Killer cells, Monocytes, Macrophages, Dendritic cells)
        
        Respond RAPIDLY to microbes
        
        Monocytes
        
        Physically the largest immune cells (~2-10%)
        
        Originate & develop in Bone Marrow
        
        Circulate in the blood & 50% stored in Spleen
        
        Agranulocytes:
        
        Do not contain large granules like granulocytes
        
        Have lysosome vesicles than contain enzymes
        
        Can perform:
        
        Phagocytosis
        
        Antigen presentation to T cells
        
        Cytokine production (enhance inflammation)
        
        Migrate to tissues (effector cells in their own right & replenish macrophages & DCs)
        
        In tissues they can differentiate into Macrophages or Dendritic Cells
        
        Macrophages
        
        Can be infiltrating or tissue resident
        
        Present in nearly all tissues, where they patrol for foreign entities
        
        Innate Immune functions:
        
        Phagocytose & digest (kill) microbes, debris, cancer cells (anything foreign)
        
        When ingested the pathogen becomes trapped in a phagosome, which then fuses with a lysosome & enzymes and toxic peroxides digest it
        
        Link to Adaptive Immunity:
        
        Antigen presentation to T cells
        
        Secretion of cytokines & chemokines
        
        Take various forms (& names) throughout the body:
        
        Liver - Kupffer cells
        
        Lung - Alveolar macrophages
        
        CNS - Microglial cells
        
        Bone - Osteoclasts
        
        Dendritic cells
        
        Tissue resident & circulating
        
        Present in tissues that are in contact with the external environment:
        
        Present in tissues that are in contact with the external environment:
        
        Skin (called Langerhans cell)
        
        Lining of the nose, lungs, stomach & intestines
        
        Immature DCs found in the blood
        
        DC Functions:
        
        Phagocytose pathogens
        
        then become activated, mature & migrate to the lymph nodes (LNs)
        
        In the LNs DCs present antigens to T & B cells (Antigen Presentation)
        
        Granulocytes (Neutrophils, eosinophils, basophils & mast cells)
        
        Neutrophils (PolyMorphonuclear Neutrophilic Leukocytes PMNs)
        
        Most abundant immune cell in the blood (60-70%)
        
        Multi-lobed nucleus & granules
        
        Mature in bone marrow
        
        Bone marrow releases & replenishes neutrophils upon infection
        
        Patrols blood & rapidly infiltrates tissue during infection
        
        3 key functional processes:
        
        Phagocytosis
        
        Degranulation (release enzymes & anti-microbial proteins)
        
        Neutrophil Extracellular Trap (NET) - release of decondensed chromatin & granule (enzymes) contents – capture, entangle & kill bacteria
        
        Neutrophils die after phagocytosing pathogens & killing them
        Clear bacterial & fungal infections (also viral!!)
        
        Eosinophils
        
        Circulate in the blood (2-4%)
        
        Originate in bone marrow
        
        Mainly found in connective tissue under respiratory, gut and urogenital epithelium (protective in these areas against infection)
        
        Granules contain enzymes & toxic proteins (coloured by acidic stain: eosin)
        
        Chemokine that attracts them = Eotaxin (CCL11)
        
        Effector Functions:
        
        Release highly toxic granules
        
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        Secrete Chemical Mediators (eg cytokines) - amplifies inflammation
        
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        Well known to:
        
        Kill Parasites
        
        Contribute to allergic inflammatory reactions (can be damaging)
        
        Basophils
        
        Least common (0.5-1%) circulating granulocyte
        
        Originate & mature in bone marrow
        
        Recruited out of the blood into a tissue when needed
        
        Stains with basic dyes (hence basophils)
        
        Basophil nucleus is lobated
        
        Contain large cytoplasmic granules
        
        Basophils are activated & degranulate upon binding:
        
        IgE (antibody for parasite defence & allergy) or
        
        Cytokines
        
        Basophils secrete:
        
        Histamine (vasodilator), promotes blood flow to tissues
        
        Heparin (anticoagulant) - prevents blood from clotting too quickly
        
        Proteolytic enzymes
        
        Several cytokines (eg IL-4 & IL-13) enhancing inflammation
        
        Linked to Allergic Disease
        Anaphylaxis, asthma, atopic dermatitis & hay fever
        
        Mast cells
        
        Circulate in an immature form --> mature once in a tissue
        
        Mast cell nucleus is round
        
        Present in most tissues
        
        Prominent at surfaces exposed to pathogens & allergens
        
        Skin, Mucosa of lungs, digestive tract, mouth, conjunctiva & nose
        
        Present in connective tissue surrounding blood vessels
        
        Activated upon binding IgE:
        
        Granules rich in Histamine & Heparin & Enzymes
        
        Mast cells also release cytokines (eg TNF) to enhance inflammation
        
        Roles in:
        
        allergy/asthma & anaphylaxis
        
        wound healing
        
        defence against pathogens
        
        Natural Killer (NK) cells
        
        MHC-1 is an inhibitory ligand for NK cells
        
        Some viruses & tumours reduce MHC-1 cell surface expression
        
        Thereby, avoiding MCH-1 presenting viral/tumour antigens to CTLs
        
        However, NK cells “notice” this!!!
        
        Reduction in the normal levels of surface MHC-I, activates NK cell killing
        
        NKs release toxic granules (granzyme & perforin) to directly kill the cell
        
        Phagocytes (Ingest invaders via phagocytosis)
        
        Destroy threat by:
        
        Engulfing and secreting cytokines
        
        Sending signals for recruitment (Chemokines)
        
        Inducing Inflammation
      - Phagocytosis Process whereby cell engulfs pathogens, digests & expel the waste products:
        
        Phagocytes engulf a pathogen which forms a phagosome
        
        The fusion of lysosomes (green) with the phagsome creates a phagolysosome
        
        The pathogen is broken down by the lysosome’s digestive enzymes
        
        Resulting waste material is discharged from the phagocyte by exocytosis
      - Antigen presentation
      - The Innate Immune System eliminates infection by:
        
        1) Pathogen detection
        
        Innate immune cell receptors recognise:
        
        Pathogen-Associated Molecular Patterns (PAMPs): “Non-self” molecular structures of pathogens [DNA, RNA, protein, sugar, lipids]: including bacterial cell wall component lipopolysaccharide (LPS) or viral ssRNA/dsRNA
        
        Damage-Associated Molecular Patterns (DAMPs): “Self molecules” produced in response to cell damage: including cytoplasmic DNA (not normal for DNA to be outside nucleus), Uric Acid crytsals (often produced by ischemic or dying cells)
        
        Cell surface or intracellular Pattern Recognition Receptors (PRRs) detect PAMPs
        
        Toll-Like Receptors
        
        (TLR4: detects bacterial LPS. TLR5: detects bacterial flagellin)
        
        RIG-I-like receptors
        
        (detect viral dsRNA)
        
        Receptors that induce
        phagocytosis include:
        
        Dectin-1
        (binds fungal & bacterial sugars)
        
        Pathogen bind cell surface receptor
        (eg Dectin-1 binds pathogenic sugars)
        
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        2) Phagocytosis
        
        Microbes killed in phagolysosome by toxic substances including:
        
        Lysosomal proteases - break down microbial proteins
        
        Nitric Oxide (NO) - made by nitric oxide synthase (iNOS)
        
        Reactive Oxygen Species (ROS) (including superoxide anion & hydrogen peroxide) made by NADPH oxidase = process is often called Respiratory Burst
        
        3) Pathogen Recognition Receptor (PRR) signalling
        
        Pathogens (& their products) also bind other PRRs
        
        PRR activation induces intracellular signalling
        
        PRR activation induces expression of cytokines
        
        EXAMPLE: Bacterial LPS:TLR4 SIGNALLING promotes INFLAMMATION VIA CYTOKINES
        
        4) Pro-inflammatory mediators (eg cytokines)
        
        ACTIVATED IMMUNE CELLS SECRETE
        PROINFLAMMATORY CYTOKINES
        
        Interleukin-1β (IL-1β) (Endothelial & lymphocyte activation, ↑IL-6, Fever – via CNS anterior hypothalamus [coordinates thermoregulation])
        
        TNF-α (Endothelial activation, ↑ vascular permeability, increased fluid draining to lymph nodes, fever, septic shock etc)
        
        IL-6 (Lymphocyte activation, antibody production, acute phase protein production, fever)
        
        IL-8 (CXCL8) (Neutrophil chemotaxis)
        
        IL-12 (NK activation, Th1 cell differentiation)
        
        5) Inflammation
        
        DEFINITION: Local accumulation of fluid, plasma proteins & white blood cells in response to infection or injury
        
        5 signs of Inflammation:
        
        Heat - increased temperature can kill pathogens
        
        Pain - draws attention to the infection & may immobilise that part of the body
        
        Redness - an increase in blood vessel diameter (vasodilation) allows increased blood flow to the site of infection facilitating delivery of effector cells & molecules
        
        Swelling – movement of leukocytes into infected tissues
        
        POSITIVE ROLEs OF INFLAMMATION
        
        1) Respond to infection or injury
        
        2) Bring immune cells to site of infection/injury to fight/mend it
        
        3) Localise infection & protect body from further infection or injury
        
        4) Increase production of protective proteins (eg cytokines)
        
        5) Promote tissue repair & resolution of infection or injury
        
        Overall: Maintain or restore homeostatic balance to our bodies
        
        stages of Inflammation OCCURS AFTER INFECTION
        
        First Step: Cell Activation, Release of inflammatory mediators
        
        Second Step: Vasodilation, Permeability, Cell Adhesion
        
        Third Step: Extravasation
        
        migration from blood to tissue: Extravasation
        
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        6) Antigen Presentation
        
        During phagocytosis proteins broken down into peptides = Antigens
        
        Antigens displayed on cell surfaces by Major Histocompatibility Molecules (MHC)
        
        ANTIGEN PRESENTATION:
        Major Histocompatibility Molecules (MHC)
        
        2 types of MHC – class I & II
        
        Function of MHC is to present antigens to naïve T cells
        
        Inside the cell, during processing the antigen is trapped at the MHC surface “groove”
        
        Antigen:MHC complex transported to cell surface & presented to naive T cell
        
        MHC LOADING WITH PEPTIDES
        
        MHC- 1 molecules present peptides derived from intracellular proteins
        
        Normal Cellular Peptide:MHC-1 complexes:
        
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        Intracellular pathogenic Peptide:MHC-1 complexes:
        
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        MHC-I ANTIGEN PRESENTATION
        
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        MHC-II present peptides derived from internalised extracellular proteins
        
        MHC-II ANTIGEN PRESENTATION
        
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        This process informs T cells of pathogenic infection, so they can either:
        
        kill the infected cell (CD8+ cytotoxic) or
        
        help other immune cells (Th1 or Th2)
        
        7) Engaging ”Complement” mediators
    - - Adaptive cells
        
        T cells
        
        Matures in the Thymus
        
        Kills host cells
        
        Regulate other immune cells
        
        Precursor originate in Bone Marrow
        
        Develop in thymus gland
        
        Differentiation continues after leaving thymus
        
        T cells have a single antigen receptor (TCR)
        
        2 main types of T cell:
        
        T helper cells (CD4+):
        
        help macrophages to enhance phagocytosis (Th1)
        
        help cytotoxic T cell (Th1)
        
        help B cells to produce antibodies (mainly Th2)
        
        Regulatory (Treg)
        
        Enhance neutrophil production & recruitment (Th17)
        
        Cytotoxic T cell (CD8+):
        kill infected or altered cell – killer T cell
        
        Antigen presentation
        
        MHC class II and MHC class I are cell surface receptors specialised in presenting antigens
        
        Present only peptide antigens
        
        MHC-peptide complexes are recognised by T cells
        
        TCR recognises presented peptides, binds and becomes activated
        
        Communicating about the pathogen to the adaptive immune arm
        
        Unique features of T cells:
        
        T cells must interact with other cells
        
        TCR recognises antigen bound to MHC
        
        Each T cell has a unique TCR - hugely diverse repitoire
        
        Once a T cell is activated – clonal expansion
        
        T helper and cytotoxic T cells have different effector functions
        
        Generate memory T cells that live for >20 years
        
        Life cycle of a T cell
        
        1) T cell Maturation
        Thymus
        (primary lymphoid tissue)
        
        TCR rearrangement
        
        Selection process
        
        Differentiation into CD4/CD8 lineage
        
        Now known as Naïve T cells
        
        T cell maturation – takes place in the thymus
        
        Immature T cells migrate from bone marrow to thymus
        
        Under go maturation in thymus
        
        Mature cells exit to the circulation as NAÏVE T cells as either CD4+ or CD8+
        
        The most immature progenitors are called pro-T cells, thymocytes or DN T cell because they do not express CD4 or CD8.
        
        These cells expand under the influence of Il-7 is produced in the thymus, which expands the number of T cell progenitors.
        
        The first step in the maturation process is the developemt of TCR and CD4 and CD8 – then go onto retain TCR and leave as either single positive CD4 T cell or CD8 T cells
        
        Fully mature but are a Naïve T cell because they haven’t come across antigen yet.
        
        T cell maturation – CHECKPOINTS
        
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        2) T cell Activation
        Lymph Nodes
        (secondary lymphoid tissue)
        
        T cell is ACTIVATED
        
        Clonal expansion of antigen specific clone
        
        Differentiation into Effector cell
        
        Naive T cell - Never met antigen
        
        Circulates in secondary lymph organs
        
        Diverse array of T cells each with a single TCR
        
        Once TCR recognises an antigen bound to MHC on DC
        
        T cell is activated
        
        This specific T cell clone proliferates (clonal expansion)
        
        Naïve T cell differentiates into an effector T cell
        
        It leaves the lymph node to carry out its effector functions
        
        Activation of Naïve T cells requires 3 signals
        
        SIGNAL 1 – antigen specific
        
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        Signal 2 – Costimulation
        
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        Signal 3 – instructive cytokines
        
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        However, T cell activation requires more than the simple expression of MHC molecules by antigen-presenting cells (APCs). The activation of a naive T cell requires interaction with an APC that provides multiple signals (see the figure): ‘signal 1’ is delivered through interaction of the TCR with peptide–MHC complexes; ‘signal 2’ involves co-stimulatory molecules; and ‘signal 3’ is mediated by instructive cytokines. The ability to deliver these three signals is the defining characteristic of a professional APC. The T cell receptor (TCR) recognizes MHC-associated peptide antigens. CD4 or CD8 coreceptors on the T cells recognize MHC molecules on the APC and help the TCR complex to deliver activating signals. Adhesion molecules strengthen the binding of T cells to APCs. Eg the T cell intregrin called leukocyte function-associated antigen-1 (LFA-1) which binds to the APC ligand ‘intracellular adhesion molecule’ ICAM1. Molecules called costimulators, which are expressed on APCs after encounter with microbes, bind to costimulatory receptors on the naive T cells thus promoting responses to infectious pathogens.Cytokines amplify the T cell response and direct it along various differentiation pathways.
        
        CLONAL EXPANSION
        
        Activated T cells will rapidly start to produce IL-2, a T cell growth factor
        
        This increases the expression of the high-affinity IL-2 receptor on the T cell
        
        The T cell can respond to IL-2 and proliferates (autocrine signalling)
        
        The antigen specific T cell clone is expanded
        
        Expansion is remarkable, there is a 1,000-10,000 fold increase in a specific T cell clone in response to infection
        
        A fraction of T cells develop into memory T cells which circulate for years ready to response to the same microbe
        
        3) T cell Effector Function
        Peripheral Tissue
        (any tissue)
        
        T cells/lymphocytes
        
        T cells need to interact with another cell to carry out their effector function
        Two different types of T cell with distinct functions. 2 main types of T cell
        
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        B cells
        
        Matures in the Bursa of birds
        
        Originate in Bone marrow of humans
        
        Produces antibody
        
        B cells are involved in the creation of antibodies
        
        Express a unique BCR = a membrane-bound antibody molecule
        
        BCR of 1 B cell clone recognises & binds to only 1 particular antigen.
        
        B cells differentiate into “effector” plasma cells
        
        Secretes antibodies (globulins): recognise & neutralise foreign objects
        
        Antibodies circulate in the bloodstream & mucosal surfaces
        
        Antibodies secreted by Plasma cells fight infection
        
        Antibodies recognises & bind to specific antigen
        
        Antibodies make antigens easier targets for phagocytes
        
        Antibodies trigger the complement cascade
        
        10% of plasma cells survive as antigen-specific memory B cells
      - Antibodies
      - Arm of the immune system composed of:
        
        T & B Lymphocytes
        
        ~2 trillion lymphocytes (20–40% WBCs)
        
        Found in blood, tissues & lymphatics
        
        T & B Cell Receptors: recognise specific antigens & proliferate
        
        Takes 4-7 days to mount a significant adaptive immune response
      - 2 main responses:
        
        Cell-mediated immune responses
        
        Antibody (humoral) responses (B/Plasma cells)
      - Immunological Memory:
        
        Memory cells generated, allowing quick response upon 2nd infection
        
        Provides long-lasting protection (eg person who recovers from measles is protected against the virus for life)
    - - Skin, Resp Tract, Eyes, GI Tract, GU Tract
        
        Eyes
        
        Eyebrows & eyelashes prevent particles & sweat entering the eye
        
        Tears contain lysozyme (anti-bacterial enzyme)
        
        Mechanical processes: blink reflex “wiper action”
        
        Barrier Failure
        
        Infection (eg bacterial, viral or fungal)
        
        Can affect eyeball, cornea or eyelid
        
        Poor antibiotic penetration of the eye
        
        Bacterial eye infection can be difficult to treat
        
        Respiratory tract
        
        Nasal hairs & mucus (lysozyme = anti-microbial enzyme)
        
        Mechanical processes: protective cough & sneeze reflexes
        
        Cilia of epithelial cells “flushes” mucus, particles & pathogens
        
        Respiratory “commensal” microbiota protects
        
        Barrier Failure
        
        Smoking - damages epithelium & triggers inflammation
        
        Viral Infection
        
        Bacterial infection (often secondary to viral infection)
        
        SKIN
        
        Physical Barrier to infection
        
        Sweat - high salt & low acidic pH (pH3-5)
        
        Protective Commensal Bacteria (Staphylococcus epidermidis), which outcompetes foreign bacteria for nutrients
        
        Barrier Failure
        
        Cut = opportunity for infection
        
        If commensal bacteria lost, dangerous bacteria,such as Staphylococcus aureus can colonise
        
        Gastrointestinal tract
        
        Physical epithelial barrier
        
        Mechanical peristalsis moves pathogens along
        
        Vomiting & Diarrhoea aim to get rid of pathogens (& toxins)
        
        Stomach (Gastric Acid) Low pH2 - denatures proteins & kills pathogens
        
        Small & large bowel commensal “flora” keep dangerous bacteria at bay
        
        Anti-microbial peptides (defensins, cathelicidins & histatins) are produced by epithelial & immune cells
        
        Genitourinary tract
        
        Mechanical flow of urine “cleanses”
        
        Bladder contains Lysozyme (anti-microbial enzyme)
        
        Vagina lining has a low acidic pH4.4 (difficult for pathogens to survive)
        
        Vagina’s natural (commensal) flora
        
        prevents dangerous microbe attachment
        
        limits availability of resources
        
        produces anti-microbial chemicals
        
        Thus inhibits growth of dangerous pathogens, such as yeast Candida
      - Types of barriers
        
        Physical
        
        Skin
        
        Physical Barrier to infection
        
        Sweat - high salt & low acidic pH (pH3-5)
        
        Protective Commensal Bacteria (Staphylococcus epidermidis), which outcompetes foreign bacteria for nutrients
        
        Barrier Failure
        
        Cut = opportunity for infection
        
        If commensal bacteria lost, dangerous bacteria, such as Staphylococcus aureus can colonise
        
        Commensal Bacteria competes for nutrients
        
        Epithelial lining - gut, lungs, oral cavity & genital tracts
        
        Chemical
        
        Anti-microbial peptides
        
        defensins, cathelicidins & histatins
        
        ancient defense against infection
        
        produced by epithelial cells & phagocytes
        
        disrupt membranes of bacteria, fungi & virus
        
        Anti-microbial enzymes
        
        lysozyme
        
        in tears, saliva, gut & phagocytes
        
        enzyme breaks down bacterial cell walls
        
        Acid
        
        Salt & Low pH of sweat (pH3-5)
        
        Low pH of stomach acid (pH2)
        
        Mechanical
        
        Tears
        
        Mucus traps microbes & prevents adherence
        
        Cilia aids flushing of mucus, cells & microbes
        
        Rapid turnover of epithelial cells
        
        Peristalsis: continuous movement of food & microbes
    - - Innate & Adaptive IMMUNE CELLS
        
        THE IMMUNE RESPONSE
        
        Immune system:
        INNATE: Non-specific: Granulocytes, Monocytes, Macrophages & DCs
        Adaptive: Specific: B cells, T cells, Antibodies
        they work together in close collaboration
        
        Tissue injury can cause inflammation
        Microbes that breach the barrier cause inflammation
        These triggers activate Innate Immune Cells
        
        Cut
        
        Insect bite
        
        Trauma
        
        Splinter
- - - - Clinically manifest as rhinitis, asthma or hayfever
      - Laboratory – high total IgE
      - Measurement of total IgE rarely useful – history rather than lab tests will help
      - determine if symptoms are allergic
      - IgE mediated disease
        
        Rhinitis
        
        Asthma
        
        Urticaria
        
        Dermographism- A common sign in inducible urticaria
        
        Urticaria +/- angioedema
        
        Seen in 80% of allergic reactions
        
        However most urticaria non-allergic
        
        25% of population will have urticaria
        
        1% at least will have chronic urticaria
        
        Children – most commonly viral infection
        
        Adults – most common cause chronic spontaneous urticaria
        
        Causes huge anxiety
        
        Urticaria & Angioedema
        
        Usually due to Histamine release from mast cells
        
        Urticaria – superficial release
        
        Angioedema – histamine release in subcutis
        
        Histamine – vasodilation
        
        increased vasc permeability
        
        Itch
        
        Its all in the history…….
        
        Allergy causes acute (within 1 hour)
        
        urticaria & angioedema
        
        Chronic urticaria +/- angioedema is NOT caused by allergy
        
        Chronic spontaneous urticaria
        
        Chronic inducible urticaria
        
        Other
        
        Angioedema:
        
        most often characterised by an abrupt and short-lived swelling of the skin and mucous membranes.
        
        All parts of the body may be affected but swelling most often occurs around the eyes and lips.
        
        In severe cases, the internal lining of the upper respiratory tract and intestines may also be affected.
        
        skin reaction similar to urticaria.
        
        Angioedema and urticaria are very similar in many ways and can co-exist and overlap. Urticaria occurs more commonly and is less severe than angioedema as it only affects the skin layers whereas angioedema affects the tissues beneath the skin (subcutaneous tissue).
        
        Acute allergic angioedema
        (almost always occurs with urticaria within 1-2 hours of exposure to the allergen)
        
        Food allergy, especially nuts, shellfish, milk, eggs
        
        Drug-induced urticaria, eg, to penicillin, nonsteroidal anti-inflammatory drugs (NSAIDs), sulfa drugs, vaccines
        
        Radiocontrast media
        
        Insect venoms
        
        Natural rubber latex, eg, medicinal gloves, catheters, balloons, contraceptive devices
        
        Non-allergic drug reaction
        (onset may be days to months after first taking the medication)
        
        Angiotensin-converting enzyme (ACE) inhibitors
        Cascade of effects via kinin production, arachidonic acid metabolism and nitric oxide generation
        
        Idiopathic angioedema
        (frequently chronic and relapsing and usually occurs with urticaria)
        
        In most cases the cause of angioedema is unknown
        
        Recent research indicates that 30–50% of this type of angioedema may be associated with some types of autoimmune disorders including systemic lupus erythematosus (SLE)
        
        Hereditary angioedema
        (very rare autosomal dominant inherited disease)
        
        Inherited abnormal gene that causes a deficiency of a normal blood protein
        
        3 types: Type 1 and II mutations of C1NH (SERPING1) gene on chromosome 11, encoding C1 inhibitor protein; Type III mutation in F12 gene on chromosome 12, encoding coagulation factor XII.
        
        Type 1 results in low levels and function of circulating C1 inhibitor; Type II has normal levels of C1 inhibitor protein but a reduction in function
        
        Occurs in 1 in 50,000 males and females; Type III more severe in women.
        
        Decreased C1 inhibitor activity leads to excessive kallikrein, which in turn produces bradykinin, a potent vasodilator
        
        Acquired C1 inhibitor deficiency
        
        Acquired during life rather than inherited
        May be due to B-cell lymphoma or antibodies against C1 inhibitor
        
        symptoms
        
        Patients often experience no symptoms until they reach puberty
        
        Swellings can occur without any provocation or induced by precipitating factors, including local trauma, vigorous exercise, emotional stress, alcohol, and hormonal factors (menstruation, pregnancy, oestrogen)
        
        Some patients may get a transitory prodromal non-itchy rash, headache, visual disturbance or anxiety
        
        Face, hands, arms, legs, genitals, digestive tract and airway may be affected; swellings spread slowly and may last for 3-4 days
        
        Abdominal cramps, nausea, vomiting, difficulty breathing and rarely urinary retention from swelling of internal tracts
        
        Urticaria (wealing) does not occur
        
        The tendency to angioedema is less pronounced in adults
        
        Anaphylaxis
        
        Management of anaphylaxis
        
        A, B, C (D, E) & call for help
        
        Lie patient flat, unless too breathless
        
        High flow oxygen
        
        Adrenaline IM – repeat if required
        
        Antihistamine
        
        Hydrocortisone IV
        
        Prompt adrenaline saves lives
        
        (Eczema)
      - Genetic tendency to make IgE reactions
    - - How common is allergic asthma?
        
        ISAAC - questionnaire survey 12-14yo
        
        wheeze 33%
        
        diagnosis of asthma 20.9%
        
        speech limiting wheeze 8.8%
        
        frequent nocturnal wheeze 3.7%
        
        1/3 no diagnosis of asthma
      - How common is Food allergy?
        
        Wycombe study – 30% think they are allergic to foods (adult population)
        
        Approx 2% adults have IgE mediated food
        
        allergy
        
        Over 5% children have food allergy
        
        Milk & egg common in pre-schoolers
        
        Majority resolve
        
        Peanut allergy – now approx 1:50 children
      - So Why is there such confusion:
        
        Doctors and patients equate urticaria and angioedema with allergy
        
        Many doctors don’t understand the difference between allergy and the sensitisation
        
        Doctors and patients confuse allergy and side effects or intolerance
      - Allergy vs Sensitisation
        
        Allergy – history of allergic reactions to the substance.
        
        History substantiated by demonstration of allergen specific IgE (SPT or blood)
        
        Sensitisation – allergen specific IgE present in the absence of clinical symptoms.
        
        Tolerance maintained by regular exposure
        
        Sensitisation
        
        Weakly positive skin tests/specific IgE
        
        blood tests rarely clinically relevant
        
        People with eczema have grossly elevated total IgE – causes false positive specific IgE
        
        Cutting out food to which person is sensitised can cause allergy
        
        Causes huge anxiety
        
        Allergy vs side effects
        
        Particularly important with drug allergy
        
        Leads to inappropriate label of allergy
        
        Using reserve antibiotics because of spurious allergy
        
        Contributing to emergence of resistence
        
        Eg. Diarrhoea with co-amoxiclav.
        
        Diagnosis of allergy
        
        History
        
        Skin Prick Tests
        
        (Allergen specific IgE)
        
        Food/exposure & symptom diary
        
        Food Challenge
        
        Double Blind Placebo Controlled
        
        Challenge
        
        How not to diagnose allergy
        
        IgG testing
        
        Vega testing
        
        Kinesiology
        
        Hair analysis
        
        Broad testing of specific IgE is not advised
      - Why do people die of allergies?
        
        Incomplete information on allergen avoidence
        
        Poorly controlled asthma
        
        No adrenaline available / not given
      - Severity of allergic reactions
        
        Reactions do not inevitably get worse
        
        Reaction severity affected by
        
        Dose of allergen
        
        Asthma/chest status
        
        Exacerbating factors- exercise, NSAIDs, alcohol
        
        ACE inhibitors; b-blockers
        
        Prompt treatment/emergency plan
      - Practical Points
        
        Patients with severe acute allergic symptoms should be referred for immunological assessment
        
        Discontinue
        
        ACE antagonists
        
        b- blockers
        
        NSAIDS
        
        Optimise asthma management
      - Causes of angioedema +/- other
        allergic features
        
        Allergic – usually venom, food or drugs
        
        Spontaneous / Physical
        
        Drugs
        
        C1inh deficiency Hereditary
        
        Angioedema due to elevated bradykinin
        
        Bradykinin metabolised by ACE
        
        Same mechanism in ACEi induced angioedema
        
        Antihistamines and steroids do not work
        
        Adrenaline ineffective
        
        Treat with C1inhibitor or block
        
        bradykinin (icatibant)
        
        Hereditary
        
        Type I - too little protein
        
        Type II- Dysfunctional protein
        
        Acquired
        
        Consumption
        
        Autoantibody
        
        Need to measure C1inh, C1q and C4
        
        Acquired
        
        Vasculitis
        
        Idiopathic
  - - - Type I Immediate hypersensitivity (IgE)
      - Type II Antibody mediated cytotoxicity : Mechanism of Tissue Injury II
        
        Antibody binds to tissue component
        
        Complement is activated
        
        Influx of inflammatory cells lead to tissue damage
        
        Autoimmune cytopenias, anti-GBM disease
        
        Autoantibodies
        
        Found in many autoimmune diseases
        
        Presence does not imply role in pathogenesis
        
        Useful in diagnosis
        
        Hashimoto’s thyroiditis: Tissue injury is T cell mediated, Anti-thyroid antibodies used to diagnose.
        
        Drug/Metabolite adsorbed
        
        • Bypasses self tolerance
        
        • Antibody produced
        
        Lysis (esp RBC/platelets)
        
        Phagocytosis
        
        “Special” Type II hypersensitivity
        
        Antibodies may bind to functionally important receptors.
        
        Can block the receptor – inhibitory effect
        
        Can have an agonist effect
        
        Blocking Antibodies
        
        Myaesthenia gravis
        
        Antibody to the acetylcholine receptor on the motor end plate.
        
        Motor nerve cannot signal to muscle to contract
        
        Type II HS – Agonist effects
        
        Graves Disease
        
        Form of hyperthyroidism
        
        Also non-thyroid effects eg exophthalmos
        
        Antibody binds to TSH-receptor
        
        Constant agonist
        
        Thyroxine overproduced
        
        Novel mechanisms
        
        ANCA – activate neutrophils
        
        Anti-cardiolipin antibodies – contribute to thrombotic effects
        
        Laboratory Tests
        
        Tissue specific antibodies
        
        GBM - 100% sensitive
        
        Pemphigus/pemphigoid - less sensitive
        
        Complement consumption often masked
        
        Immunoglobulin deposition on biopsy
      - Type III Immune complex deposition
        
        Antibody binds to antigen (soluble or in tissue)
        
        Complement is activated
        
        If not cleared, may get lodged in tissue
        
        SLE, Rheumatoid vasculitis.
        
        Lab. Tests
        
        Complement studies
        
        C3 & C4 (get low levels due to consumption)
        
        Complement Degradation Products
        
        CH100 (to rule out complement deficiency)
        
        Common Causes
        
        Connective Tissue Disease
        
        Anti-nuclear antibody
        
        (Anti-dsDNA, anti-ENA)
        
        Rheumatoid disease - Rheumatoid Factor
      - Type IV Delayed hypersensitivty (cellular)
        
        Antigen presented to T cells
        
        T cell activated & secretes chemokines
        
        Macrophages activated by interferon
        
        Rheumatoid arthritis, cellular rejection
    - - Rhinitis
      - Asthma
      - Urticaria
      - Angioedema
      - Anaphylaxis
      - (Eczema)
    - - Sensitisation
        
        precedes allergic reaction
        
        Sensitisation can occur on first or subsequent exposure
        
        Some patients tolerate penicillin for decades, and then develop allergy in old age
        
        You can be sensitised by substance itself, or something which crossreacts with it eg Pholcodine & rocuronium
      - Early/Acute phase of response
      - Late phase of response
    - - Useful classification scheme
      - Not all allergy is IgE mediated!
      - The same immune mechanisms which protect us, can cause tissue injury when inappropriately triggered
  - - - Central T cell tolerance --> Thymic “education”
      - Peripheral T cell tolerance
        
        Absence of Signal 2/danger signal
        
        Active regulation
      - B cell tolerance
    - - Common – tolerance is “leaky”
      - Autoimmune reactivity
      - Autoimmune disease
      - Presence of autoantibodies does NOT mean that disease is caused by antibody
    - - To rule in a diagnosis
      - To rule out a diagnosis
      - To monitor disease activity
      - Remember false positive and false negative results are common
    - - Group of multisystem diseases
      - Pathological changes in blood vessels and connective tissue
      - Usually inflammatory
      - Common clinical features
      - Immunological abnormalities
      - Many differences.
    - - Inflammatory multisystem disease
      - Unknown aetiology
      - Diverse clinical & lab abnormalities
      - Variable course & prognosis
      - Multiple autoantibodies
        
        Cytotoxic function
        
        Immune complex deposition
        
        common autoantibodies
        
        ANF
        
        Anti-dsDNA
        
        Anti-Extractable Nuclear Antibodies
        
        Anti-Sm (Specific; only 30% sensitive)
        
        Anti-Ro (Also seen in Sjögren's Syndrome)
        
        Anti-La (Also seen in Sjögren's Syndrome)
        
        Antibodies to RBC, WBC & Platelets
      - Type II hypersensitivity
        
        Haemolytic anaemia
        
        Autoimmune neutropenia/thrombocytopenia
      - Type III Hypersensitivity
        
        Renal disease
        
        Skin disease
        
        Vasculitis
      - Sex ratio: 9F:1M
      - Peak age: 2nd and 3rd decade
      - Incidence:
        
        Rochester 1.8/100,000/yr
        
        San Francisco 7.6/100,000/yr
        
        Scandinavia 4.8/100,000/yr
      - Prevalence: US 15-50/100,000
      - Racial: African Americans > Caucasian
      - Genetic Associations: C4A null alleles
      - clinical Features
        
        Inflammation any organ, predominantly
        
        Skin
        
        Joints
        
        Kidneys
        
        SLE – Renal Pathology
        
        Focal segmental glomerulonephritis
        
        Focal proliferative glomerulonephritis
        
        Diffuse proliferative glomerulonephritis
        
        Membranous glomerulonephritis
        
        Sclerosis
        
        Brain
        
        Serosal surfaces
        
        Immune cytopenias are common
      - Morbidity & Mortality
        
        Organ damage
        
        Effects of immunosuppression
      - Making the Diagnosis
        
        Clinical history & exam
        
        Urinalysis & urine microscopy
        
        ANF – CTD screen
        
        Anti-dsDNA
        
        Anti-ENA
        
        anti-Sm specific;
        
        anti-Ro/La seen in lupus or Sjogren’s syndrome
        
        Assess function of potentially involved organs
      - Monitoring Disease Activity
        
        Function of affected organs
        
        FBC, ESR
        
        Complement (consumption – low C3 & C4)
        
        Anti-dsDNA. Antibody level varies with disease activity
        
        CRP may be a poor guide to inflammation
        
        Check ESR
      - Baby R is 5 day old girl has : Rash, Enlarged Liver & Spleen, Severe hepatitis + Normal heart rate. Mother had mild SLE diagnosed 1999. Baby R Infection screen negative, Anti-Ro positive, Anti-DNA negative, Rapidly worsening liver failure, Working diagnosis - Neonatal lupus BUT did not explain liver failure. Mum (26yo F) had been well during pregnancy, Never had systemic therapy for SLE, Generally unwell, Fatigue – anaemia, Joint pains and her serology shows ANF >1/400 S & H, Anti-DNA 297iu/ml (Ref <50), , Anti-Ro Strong Positive, Low complement (C3 & C4) and is advised urgent rheumatological review. Baby R Transferred to Kings, Underwent Liver transplant, Explant - congenital Haemochromatosis and had Excellent recovery. Her mum became sicker in London, advised to return home, investigated locally in Donegal, Renal disease detected -referred to BH, 10 weeks post delivery - Cr 222, Lymphopenia, Low platelets. Mum has Renal Biopsy - Diffuse proliferative GN, Treated with IV cyclophosphamide & steroids, Dialysis dependent within 2 weeks. Responded to treatment, and came off dialysis. Mum - Features of lupus: Skin rash & photosensitivity, Arthritis, Leucopenia & thrombocytopenia, Renal disease and she didn’t have Oral ulcers, cerebral disease, Serositis. Points to remember from case: Poor outlook without treatment, Hormonal influence, Transplacental passage of antibody.
      - Antiphospholipid syndrome (APS)
        
        Acquired thrombophilia
        
        Due to antibodies against phospholipids
        
        Clinical and laboratory criteria must both be filled to establish diagnosis
        
        May be primary or secondary
        
        Autoimmune disease, characterised by acquired thrombophilia
        
        Clinicopathological diagnosis
        
        Need to fulfil clinical and laboratory criteria
        
        Novel mechanism of autoantibody action
        
        Documented venous thrombosis
        
        Documented arterial thrombosis
        
        Pregnancy associated morbidity
        
        Mid or 3rd term pregnancy loss
        
        Recurrent first trimester loss
        
        Severe pre-eclampsia
        
        Severe intrauterine growth retardation
        
        Case 2, 39 yo female- DVT 5 years ago – long haul flight. First pregnancy – severe PET. Required delivery at 32 weeks. Anti-phospholipid antibodies. DVT 5 years ago – long haul flight. First pregnancy – severe PET. Required delivery at 32 weeks. Anti-phospholipid antibodies. Decided against further pregnancy. Lifelong aspirin
        
        other features
        
        Thrombocytopenia
        
        Livedo reticularis- a skin symptom. It refers to a netlike pattern of reddish-blue skin discoloration. The legs are often affected. The condition is linked to swollen blood vessels. It may get worse when the temperature is cold.
        
        Transverse myelitis- a disorder caused by inflammation of the spinal cord. It is characterized by symptoms and signs of neurologic dysfunction in motor and sensory tracts on both sides of the spinal cord.
        
        Migraine
        
        Associated but not diagnostic
        
        Laboratory Criteria
        
        Lupus anticoagulant, or
        
        Anti-Cardiolipin antibodies, or
        
        Anti-Beta 2 glycoprotein 1
        
        Positive on 2 occasions, 12 weeks apart
        
        Anti-phospholipid syndrome -Rx
        
        Varies with manifestation
        
        Aspirin
        
        Anticoagulation
    - - Autoimmune disease with prominent scarring
      - Affects skin, blood vessels, muscles and internal organs
      - CREST – Limited, scleroderma
    - - Inflammatory disease of muscles
      - Immune mediated – T cell mediated
      - Pain, weakness, loss of muscle mass
      - Acute phase response
      - Several autoantibodies useful in diagnosis – but epiphenomena
      - Can be paraneoplastic – underlying tumour
    - - Features of SLE, Polymyositis and Scleroderma
      - Serious renal or cerebral disease rare
      - Very variable presentations
      - Associated with anti-RNP antibodies
    - - Can be Primary or Secondary
      - Primary = Sjogrne’s syn alone
      - Secondary + Sjogren’s syn assoc with another connective tissue disease, of rheumatoid disease
      - Sicca Syndrome – dry eyes and dry mouth
      - Due to lymphocytic infiltration (Type IV hypersensitivity)
      - Can be associated with inflammation of blood vessels in any tissue
      - Associated with anti-Ro and anti-La antibodie
    - - Presentation of CTDs varies.
      - Diagnosis relies on clinical awareness
      - Appropriate lab tests help with diagnosis & management
      - Inappropriate tests may be misleading
- - - - Rashes, pigmented & other lesions, “lumps and bumps”
    - - Dermatologists (some ‘dermatological surgeons’)
      - Plastic surgeons, general surgeons
      - Some GPs dermatology interest/minor surgery training
    - - Skin neoplasms/tumours rarely pose threat to patient’s life, Exception is melanoma
      - Pigmented skin lesions common, not all necessarily melanocytic & most melanocytic lesions are naevi
      - Distinguish which is/might be melanoma
      - Some lesions that form a tumour, lesion, lump or bump are not true neoplasms
        
        May be malformations, hamartomas, infection (warts), cysts
        
        Many of the rest benign (seborrhoeic keratosis, dermatofibroma, haemangioma, melanocytic naevi)
  - - - Stratified squamous epithelium
        
        Layered
        
        Orderly maturation from base to surface
        
        Basal layer of small dark round cells
        
        Superficial layers: cells flatten, acquire more abundant (pink) cytoplasm & produce keratin
        
        Dysplasia = showing disorderly maturation and abnormal cytological features
        
        UV light (esp. UV-B) causes DNA damage
      - Specialised for keratin production, barrier
      - Exposed to external damage (UV light)
      - Contains melanocytes
        
        Neural crest origin
        
        Migrate at 6-10/52 in utero to skin
        
        1 melanocyte/10 basal epithelial cells
        
        Produce melanin pigment
        
        Melanin transferred to adjacent squamous cells
        
        Melanin pigment protects nucleus of squamous cells against UV damage to DNA
        
        Melanocytes can form lesions known as melanocytic naevi, cells arranged as nests within these lesions
      - Contains Langerhan’s cells (specialised antigen-presenting cells)
      - Epidermis: note keratin on surface, sharp junction of epidermis with underlying dermis; melanocytes are scattered single cells with surrounding clear space in basal layer of epidermis (H&E stain)
    - - Fibrous and adipose connective tissue
      - Blood and lymphatic vessels
      - Nerves
      - Smooth muscle (blood vessels, arrector pili)
      - Inflammatory cells (lymphocytes, macrophages and mast cells)
      - Skin appendages (epithelial structures: hair follicles, sebaceous glands, apocrine & eccrine sweat glands)
      - Skin from scalp: numerous skin appendages (hair follicles and attached sebaceous glands = pilo-sebaceous units) (H&E stain)
  - - - Epidermis (squamous epithelium)
      - Melanocytes
      - Appendages
      - Dermis (from any of its constituent elements)
    - - May be locally aggressive
      - Only rarely have the potential to metastasise
      - Typical exception can be melanoma
      - Malignant skin tumours
        
        Usually primary
        
        Secondary malignant tumours (i.e. metastases to skin) a late event associated with disseminated malignancy
    - - Squamous epithelium - commonest origin
        
        Basal cell carcinoma (BCC)
        
        Derived from squamous epithelium of epidermis
        
        “Basal cell” because:
        
        Tumour composed of small, dark cells resembling basal cells of epidermis
        
        At edge of groups of tumour cells, cells and nuclei arranged in parallel - ‘palisading’ (palisade is a type of fence)
        
        Local invasion with risk of local destruction - especially nose, mouth and near eye or ear = “rodent ulcer”
        
        Metastasis exceptionally rare
        
        Different histological types more/less destructive, more/less prone to recurrence, more/less easy to define
        
        Site and type guides treatment, stratify low vs. high risk
        
        Squamous cell carcinoma (SCC)
        
        = BCC + SCC = non-melanoma skin cancer (NMSC)
        
        NMSC may be locally invasive but rare cause of metastasis or death
        
        Incidence strongly linked to age
        
        70% >65 years old
        
        Often multiple, often (not always) sun-exposed sites
        
        60% face, women legs, men ears and scalp
        
        2-4% lip, 4-6% eyelid, also neck, back of hand/forearm
        
        75% BCC, rest SCC
        
        BCC exceptionally rare cause of metastasis
        
        SCC uncommon cause of metastasis/death
      - Melanocytes – much less common origin for malignancy: Malignant melanoma
        
        Melanoma potentially more aggressive, outcome depends on stage at diagnosis
      - Other types of primary skin malignancy (e.g. sarcoma from dermal elements, malignant skin appendage tumours or cutaneous lymphoma) rare
      - Skin malignancy related to UV-B light exposure
        
        Light skin, fair/red hair, pale eyes, tendency to freckling
        
        Outdoor work, geographical location relative to Equator, age
        
        SCC related to cumulative exposure
        
        Most melanoma likely related to intense/intermittent exposures
        
        BCC appears to be intermediate
        
        UV-A also important (sunbeds, phototherapy treated psoriasis)
- - - - Pre-malignant conditions:
        
        Actinic Keratosis
        
        Also known as senile keratosis or solar keratosis
        
        Red scaly patch on exposed skin
        
        Common in Elderly & Caucasian patients
        
        Excision is the most effective treatment
        
        Lesions are removed when they ulcerate or bleed
        
        Bowen’s Disease
        
        This is Carcinoma in situ
        
        Similar to actinic keratosis
        
        Presents as a rough, reddened patch of skin
        
        Should be excised because of risk of malignancy
        
        Cornu cutaneum.
        
        Often benign but they may be pre-malignant.
        
        Conical projection above the level of the skin.
        
        Benign in the majority of cases.
        
        Malignancy may be found at the base, most commonly squamous cell carcinoma.
      - Malignant tumour arising from the keratinocytes of epidermis
      - Destructive
      - Metastasizes mainly via lymphatics (2-6%)
      - Cutaneous SCC Vs Head & Neck SCC
      - Metastatic potential
        
        Site (e.g. lip - lymphatic spread)
        
        Size > 2cm
        
        Depth > 4 mm
        
        Histology (poorly differentiated)
        
        Host immunity
        
        Perineural or perivascular spread
      - SCC- Management Options
        
        Surgical excision
        
        Primary site
        
        Regional control
        
        Radiotherapy
        
        Primary site
        
        Regional control
    - - Arises from basal cells in epidermis
      - Rarely Metastasize
      - Can invade into bone and cartilage
      - Clinically small nodules→ ulcerate→ raised “pearl” edges
      - Sites of predilection: 90% found on forehead, face or hair margin
      - Types of BCC
        
        Nodular
        
        Cystic
        
        Nodulo-cystic
        
        Ulcerative
        
        Superficial
        
        Pigmented
        
        Morphoeic
      - Treatment
        
        Shave, Cautery, Curettage
        
        Photodynamic Therapy
        
        Imiquimod Therapy (Immune response modofier /5% Aldara)
        
        Cryotherapy
        
        Radiotherapy
        
        Moh Surgery
        
        Surgical Excision
  - - - Superficial spreading
      - Nodular
      - Lentigo maligna melanoma (Hutchison’s freckle)
      - Acral lentiginous melanoma
      - Subungual melanoma represents approximately 3% of cases of melanoma in white population
    - - Major Signs
        
        Is getting larger or a new one is growing
        
        Has an irregular outline
        
        Colours are mixed shades of brown or black
      - Minor Signs
        
        Bigger than the blunt end of a pencil
        
        Inflamed or has a reddish edge
        
        Bleeding, oozing or crusting
        
        Starts to feel different – itching / painful
    - - Excisional biopsy: 2mm margin
      - Incisional biopsy
        
        Large lesions
        
        Subungal MM
      - Shave excision or currettage: Not recommended
      - Breslow and Clark Staging
    - - Most important prognostic factor
      - Vertical distance between granular layer epidermis and deepest part of MM
      - Directly related to survival
    - - Males
      - Elderly, >50yrs
      - Ulceration
      - Neurovascular invasion
      - Microscopic satellites
      - MM in pre-existing naevus … better Px
    - - Basic principle: Wide local excision +/- skin graft
        
        Wider Excision Margins: Thickness + recommended margins
        
        In-situ 0.5 – 1 cm
        
        <1 mm 1 cm
        
        1 – 2 mm 1 – 2 cm
        
        2 mm 2 – 3 cm
      - All trials have failed to demonstrate statistically significant differences in overall survival and disease-free survival when comparing wide vs. narrow excision
- - - - Melphalan
      - Achieve locoregional control but no survival benefit
    - - Interferon-alpha, IL-2 in stage III & IV dz
      - Ipilimumab (CTLA-4 inhibitor) or PD-1 inhibitors
      - talimogene laherparepvec (T-VEC)
      - BRAF inhibitors Vemurafenib (Zelboraf) and Dabrafenib (Tafinlar)
  - - - w/in 5cm original lesion
      - 3 – 5 yrs after primary excision
    - - Skin
      - Subcutaneous tissue
      - Distant lymph nodes
      - Lung, liver, brain, bone, GIT
    - - 3 monthly x 3 yrs
      - < 1mm ~ discharge
      - 1mm ~ 6 monthly x 2 yrs
      - Further imaging … if clinically indicated
- - - - Diphenhydramine
      - Can have anti-muscarinic activity
      - More side-effects
        
        Drowsiness
        
        Dry mouth
    - - Cetirizine
      - Loratidine
      - Fewer side-effects
      - Some members withdrawn from the market due to arrhythmias
    - - Most effective in allergic rhinitis and conjunctivitis
      - In other allergic conditions such asthma and anaphylaxis used as adjunct therapy
      - 1st generation are old drugs with lack of good quality clinical studies
      - Only first generation antagonists can be used for motion sickness
- - - - Monotherapy: Methotrexate
      - Double Therapy:
        
        Methotrexate & Sulfasalazine
        
        Methotrexate & Hydroxychloroquine
        
        Sulfasalazine & Plaquenil
      - Triple Therapy: Methotrexate + Sulfasalazine + Hydroxychloroquine
      - If all else fails - Biologic Therapy
  - - - CTLA-4 fusion protein
      - Binds to B7-1 (CD80) & 2 (CD86) preventing their interaction with CD28
      - Reduces TNFa, IFNg and IL-2 secretion
      - Approved for use in RA
    - - Monoclonal antibody to CD20
      - Specific for B-cells
        
        B-Cell Depletion Therapy in RA, How does B-Cell Depletion work?
        
        B-cells cannot act as antigen presenting cells to activate T-cells
        
        B-cells cannot produce rheumatoid factor
        
        B-cells cannot release cytokines
      - Triggers complement formation and cell lysis
      - Used to treat
        
        B-cell lymphoma
        
        RA resistant to anti-TNF therapy
      - Patients can develop fatal SIRS & PML
      - Approved for RA (with MTX)
  - - - Combinations of Conventional DMARDs
      - Combinations of DMARD plus Biologic agents (anti-TNF)
      - Switch to non-TNF agent
  - - - Symptomatic relief, improved function
      - No change in disease progression
    - - May substitute for NSAID
      - Used as ‘bridge therapy’
      - If used long-term, add Ca, Vit D, or bisphosphonates for osteoporosis risk
      - Possible disease modifying effect
- - - - Migraine-cause
        
        Vascular theory: due to vasoconstriction followed by vasodilation. Evidence for vasoconstriction but may be neuronal.
        
        Neuronal theory: similar to cortical spreading depression of concussion. Wave of inhibition in cortex.
        
        Peptidergic theory: Stimulation of trigeminal nerve releases vasodilatory peptides such as calcitonin gene-related peptide (CGRP) from neurones innervating the cranial circulation
        
        Evidence for genetic susceptibility
        
        Triggering events
        
        Lack of food
        
        Stress
        
        Hormonal
        
        Sleep disturbance
    - - 5-HT, CGRP and migrainea | Amino acid structure of human α-type calcitonin gene-related peptide (CGRP). b | The CGRP receptor complex, which consists of the two integral membrane proteins calcitonin receptor-like receptor (CALCRL) and receptor activity-modifying protein 1 (RAMP1) and two cytoplasmic proteins, receptor coupling protein (RCP) and the α-subunit of the GS protein (GαS). c | The targets for CGRP-related migraine therapies illustrated in a CGRP-containing trigeminal nerve varicosity that innervates a cerebrovascular smooth muscle cell. 5-HT, 5-hydroxytryptamine receptor.
    - - 5-HT1 agonists
        
        Frovatriptan – long acting
        
        Zolmitriptan
        
        Sumatriptan – 5-HT1D
      - Ergotamine (ergot alkaloid)
        
        5-HT1 agonist
        
        Adverse effects due to activity on other 5-HT receptors, noradrenergic and dopaminergic receptors
        
        Cannot be used in patients with coronary artery disease
- - - - Anti-inflammatory
      - Interferes with neutrophil function (binds to tubulin leading to microtubular depolymerisation)
      - reduces inflammatory response to deposited crystals
      - diminishes PMN phagocytosis of crystals
      - blocks cellular response to deposited crystals
      - Used in both acute and chronic gout
      - toxicity
        
        Gastrointestinal (nausea, vomiting, cramping, diarrhea, abdominal pain)
        
        Haematologic (agranulocytosis, aplastic anaemia, thrombocytopenia, neutropenia )
        
        Hair loss (due to inhibition of mitosis)
        
        Muscular weakness
        
        Adverse effects are dose-related & more common when patient has renal or hepatic disease
  - - - Xanthine oxidase inhibitor which is administered orally
      - to treat hyperuricemia (excess uric acid in blood plasma) and its complications, including chronic gout
      - It does not alleviate acute attacks of gout
      - is useful in chronic gout to prevent future attacks
- - - - 5-HT1 agonists
        
        Frovatriptan – long acting
        
        Zolmitriptan
        
        Sumatriptan – 5-HT1D
    - - 5-HT1 agonist
      - Adverse effects due to activity on other 5-HT receptors, noradrenergic and dopaminergic receptors
      - Cannot be used in patients with coronary artery disease
  - - - Erenumab (anti-CGRP receptor antibody)
      - Fremanezumab (anti-CGRP antibody)
- - - - Main cause - Heart Attacks and Strokes
      - 60% higher
- - - - MTX is poly-glutamated (long half-life)
      - Inhibits Aminoimidazole carboxamidoribonucleotide (AICAR) transformylase
      - Leads to increased adenosine production
      - Anti-inflammatory via adenosine receptors
    - - Folic acid supplementation to prevent side effects
      - Hepatotoxicity
      - Pulmonary damage – pulmonary fibrosis/pneumonitis
      - Myelosuppression/blood dyscrasias
      - Gastrointestinal problems such as nausea, stomach upset, and loose stools
      - Stomatitis or soreness of the mouth
      - Infection
      - Alopecia
      - Teratogen – not recommended for women of childbearing potential
- - - - Neutropenia
      - Anemia
      - Thrombocytopenia