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Kat's Pathology > Immune Modulating Therapies 2 > Flashcards

Immune Modulating Therapies 2 Flashcards

1
Q

What is the purpose of immune modulation of the immune system?

A

To suppress the immune response in conditions where it is overactive

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2
Q

What are some ways to suppress the immune system (6)

A 
Steroids. 
Anti-proliferative agents. 
Plasmapheresis. 
Inhibitors of cell signalling. 
Agents directed at cell surface antigens. 
Agents directed at cytokines
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3
Q

What are corticosteroids

A

Synthetic glucocorticoids

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4
Q

What are corticosteroids based on

A

Naturally occurring steroids

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5
Q

What do steroids not act on

A

Minderalocorticoid receptors

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6
Q

What disorders are corticosteroids used in (5)

A 
Allergic disorders 
Auto-immune disease 
Auto-inflammatory diseases 
Transplantation 
Malignant disease
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7
Q

Give some examples of steroids (3)

A

Prednisolone
Dermovate
Hydrocortisone

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8
Q

What prostaglandin do steroids affects

A

Inhibit phospholipase A2

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9
Q

What is the normal action of phospholipase A2

A

Breaks down phospholipids to form arachidonic acid which is converted to eicosanoids (e.g. prostaglandins, leukotrines) by cyclo-oxygenase.

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10
Q

What effect do corticosteroids have on phospholipase A2

A

Blocks arachidonic acid and prostaglandin formation and so reduces inflammation

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11
Q

What effect do steroids have on phagocytes (3)

A

Decrease traffic of phagocytes to inflamed tissue (decreased expression of adhesion molecules on endothelium. Blocks the signals that tell immune cells to move from the bloodstream and into tissues - results in transient increase in neutrophil counts in blood).
Decreased phagocytosis.
Decreased release of proteolytic enzymes.

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12
Q

What effect do steroids have on lymphocyte function (4)

A

Lymphopenia (sequestration of lymphocytes in lymphoid tissue - affects CD4+ T cells > CD8+ T cells > B cells)
Blocks cytokine gene expression
Decreased antibody production
Promotes apoptosis

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13
Q

What broad categories can the side effects of steroids be categorised into (3)

A

Metabolic effects.
Other effects.
Immunosuppression.

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14
Q

What are the metabolic effects of steroids (7)

A 
Diabetes. 
Central obesity. 
Moon face. 
Lipid abnormalities. 
Osteoporosis. 
Hirsuitism. 
Adrenal suppression.
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15
Q

What are the effects of steroids apart from metabolic ones (5)

A 
Cataracts. 
Glaucoma. 
Peptic ulceration. 
Pancreatitis. 
Avascular necrosis.
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16
Q

What systems do steroids act on to suppress the immune system (3)

A

Prostaglandins.
Phagocytes.
Lymphocytes.

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17
Q

What are some anti-proliferative immunosuppressants (4)

A

Cyclophosphamide.
Mycophenolate.
Azathioprine.
Methotrexate.

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18
Q

What is the MOA of anti-proliferative immunosuppressants.

A

Inhibit DNA synthesis.

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19
Q

What cells are most sensitive to the effects of anti-proliferative immunosuppressants

A

Cells with rapid turnover.

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20
Q

What are the toxic effects of anti-proliferative immunosuppressants (4)

A

Bone marrow suppression
Infection
Malignancy
Taratogenic

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21
Q

What is the MOA of cyclophosphamide

A

Alkylates guanine base of DNA - damages DNA and prevents cell replication.

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22
Q

What cells does cyclophosphoamide most affect

A

B cells > T cells, but at high doses affects all cells with high turnover.

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23
Q

What are the major indications for cyclophosphoamide (2)

A

Multisystem connective tissue disease or vasculitis with severe end organ involvement (e.g. GPA (Wegener’s granulomatosis), SLE)
Anti-cancer agent.

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24
Q

What are the side effects of cyclophosphoamide (4)

A

Toxic to proliferating cells (bone marrow suppression, hair loss, sterility M>F)
Haemorrhagic cystitis (toxic metabolite acrolein excreted via urine).
Malignancy (bladder, haematological, non-melanoma skin cancer)
Infection (pneumocystis juroveci)

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25
Q

What is the MOA of azathioprine

A

Metabolised by liver to 6 mercaptopurine

Blocks de novo purine (e.g. adenine, guanine) synthesis - prevents replication of DNA

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26
Q

What cells does azathioprine preferentially affect

A

Inhibits T cells activation and proliferation

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27
Q

What are the indications for the use of azathioprine (3)

A

Transplantation
Auto-immune disease
Auto-inflammatory diseases (e.g. Crohn’s, UC)

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28
Q

What are the side effects of azathioprine (3)

A

Bone marrow suppression (cells with rapid turnover (leucocytes and platelets) are particularly sensitive).
Hepatotoxicity (idiosyncratic and uncommon)
Infection (serious infection less common than with cyclophosphoamide)

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29
Q

How many people are particularly susceptible to the bone marrow suppression effects of azathioprine

A

1/300

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30
Q

What must be checked before starting a patient on azathioprine treatment

A

Thiopurine methyltransferase (TPMT) activity.

Check TPMT activity or gene variats before treatment if possible - always check FBC after starting therapy.

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31
Q

What is the MOA of mycophenolate mofetil

A

Blocks de novo nucleotide synthesis - prevents replication of DNA

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32
Q

What cells are affected by mycophenolate mofetil

A

Prevents T>B cell proliferation

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33
Q

What are the indications to use mycophenolate mofetil (2)

A

Widely used in transplantation as an alternative to azathioprine
Also used in auto-immune diseases and vasculitis as an alternative to cyclophosphoamide.

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34
Q

What are the side effects of mycophenolate mofetil (2)

A

Bone marrow suppression (cells with rapid turnover (leucocytes and platelets) are particularly sensitive).
Infection (particular risk of herpes virus reactivation, and PML)

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35
Q

What is plasmapheresis

A

Patient’s own blood passes through cell separator with the aim of removal of pathogenic antibodies

Own cellular constituents reinfused. The plasma is treated to remove immunoglobulins and then reinfused (or replaced with albumin in ‘plasma exchange’)

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36
Q

What are the problems with plasmapheresis

A

Rebound antibody production limits efficacy, therefore usually given with anti-proliferative agent

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37
Q

What are the indications for plasmapheresis (3)

A

Severe antibody mediate diseases (type 2 hypersensitivity reactions)

Goodpastures syndrome (anti-glomerular basement membrane antibodies) 
Severe acute myasthenia gravis (anti-acetyl choline receptor antibodies)
Severe vascular rejection (antibodies directed at donor HLA molecules)
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38
Q

How do calceineurin inhibitors suppress the immune system

A

Calcineurin is part of the cascade for the upregulation of IL-2 (cytokine transcription - blockages prevents lymphocyte proliferationa and effector functions)

Part of the T cell signalling pathway

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39
Q

What two drugs inhibit calcineurin

A

Ciclosporin

Tacrolimus

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40
Q

What are the side effects of ciclosporin (5)

A 
Dysmorphic features. 
Nephrotoxicity. 
Hypertension. 
Neurotoxic. 
Diabetogenic.
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41
Q

What are the side effects of tacrolimus (4)

A

Nephrotoxicity.
Hypertension.
Neurotoxic.
Diabetogenic.

42
Q

Give an example of a JAK inhibitor

A

Tofacitinib (JAK 1 and JAK 3 inhibitor)

43
Q

What is the MOA of tofacitinib (3)

A

JAK1 and JAK3 inhibitor.
Interferes with JAK-STAT signalling.
Influences gene transcription.
Inhibits production of inflammatory molecules.

44
Q

What condition is tofacitinib effective in

A

Rheumatoid arthritis

45
Q

What is the MOA of apermilast

A

PDE4 inhibitor

Leads to increase cAMP.
Influences gene transcription.
Modulates cytokine production.

46
Q

What conditions is apermilast effective in (2)

A

Psoriasis.

Psoriatic arthritis.

47
Q

What are some drugs directed at cell surface antigens (immunosuppressive actions) (6)

A 
Rabbit anti-thymocyte globulin
Basiliximab - anti-CD25
Abatacept - CTLA4-Ig
Rituximab - anti-CD20 
Natalizumab - anti-alpha4 integrin 
Tocilizumab - anti IL-6 receptor
48
Q

What is the MOA of agents directed at cell surface antigens (2)

A

Blocks signalling pathways.

Cell depletion occurs.

49
Q

What are the indications for anti-thymocyte globulin

A

Allograft rejection (renal, heart)

50
Q

What is the dosing of anti-thymocyte globulin

A

Daily IV infusion

51
Q

What is the MOA of anti-thymocyte globulin (3)

A

Lymphocyte depletion
Modulation of T cell activation
Modulation of T cell migration

52
Q

What are the side effects of anti-thymocyte globulin (4)

A

Infusion reactions
Leukepenia
Infection
Malignancy

53
Q

What is the MOA of basiliximab

A

Inhibits T cell proliferation

Antibody directed at CD25.

54
Q

What are the side effects of basiliximab (3)

A

Infusion reaction
Infection
Concern RE long term risk of malignancy

55
Q

What are the indications for basiliximab

A

Prophylasis of allograft rejection

56
Q

What is the dosing of basiliximab

A

IV given before and after transplant surgery

57
Q

What is abatacept indicated for

A

Rheumatoid arthritis

58
Q

How is abatacept given (2)

A

IV 4 weekly or subcutaneously weekly.

59
Q

What is the MOA of abatacept

A

Reduces T cell activation

60
Q

What are the side effects of abatacept (3)

A

Infusion reaction
Infection (TB, HBV, HCB)
Caution RE malignancy

61
Q

What are the indications for rituximab (3)

A

Lymphoma
Rheumatoid arthritis
SLE

62
Q

What is the dosing for rituximab

A

2 doses IV every 6-12 months (RA)

63
Q

What is the MOA of rituximab

A

Depletes mature B cells - antibody specific for CD20

64
Q

What are the side effects of rituximab (3)

A

Infusion reactions
Infection (PML)
Exacerbation of CV disease.

65
Q

What is the MOA of natalizumab

A

Inhibits T cell migration (alpha4 integrin specific)

66
Q

What is the role of alpha4 integrin

A

Alpha4 expressed with beta1 or beta7.
Bind to VCAM1 and MadCAM1 to mediate rolling/arrest of leukocytes.
Bind to non-endothelial VCAM1 in lymphoid tissue.

67
Q

What are the indications for natalizumab (2)

A

Highly active relapsing-remitting MS

Crohns’ disease.

68
Q

How is natalizumab given

A

IV every 4 weeks.

69
Q

What are the side effects of natalizumab (4)

A

Infusion reactions
Infection (PML)
Hepatotoxic
Concern RE malignancy

70
Q

What is the MOA of tocilizumab

A

Reduces macrophage, T cell, B cell, neutrophil activation.

71
Q

What are the side effects of tocilizumab (5)

A 
Infusion reactions. 
Infection. 
Hepatotoxic 
Elevated lipids 
Caution RE malignancy
72
Q

What are the indications for tocilizumab (2)

A

Castleman’s disease.

Rheumatoid arthritis.

73
Q

How is tocilizumab given

A

IV every 4 weeks

74
Q

What are some drugs directed at blocking the action of cytokines (8)

A 
Infliximab - anti-TNFalpha
Adalimumab - anti-TNFalpha 
Certolizumab - anti-TNFalpha 
Golimumab - anti-TNFalpha 
Etanercept - TNF receptor p75-IgG fusion protein 
Ustekinumab - anti IL-12 and IL-23 
Denosuman - anti-RANK ligant 
Secukinumab - anti IL-17
75
Q

What are the side effects of anti-TNFalpha immunosuppressive drugs (5)

A 
Infusion or injection site reactions. 
Infections (TB, HBV, HCV). 
Lupus-like conditions 
Demyelination. 
Malignancy
76
Q

What are the indications for anti-TNFalpha drugs (4)

A

Rheumatoid arthritis
Ankylosing spondylitis
Psoriasis and psoriatic arthritis
Inflammatory bowel disease

77
Q

How are anti-TNFalpha drugs administered

A

Subcutaneous or IV

78
Q

What is the MOA of ustekinumab

A

Inhibits IL-12 and IL-23

79
Q

What are the indications for ustekinumab (2)

A

Psoriasis, psoriatic arthritis

Crohns disease.

80
Q

What comprises IL-12

A

p40+p35

81
Q

What comprises IL-23

A

p40+p19

82
Q

How is ustekinumab administered

A

Subcutaneously every 12 weeks

83
Q

What are the side effects of ustekinumab (3)

A

Injection site reactions
Infection (TB)
Concerns RE malignancy

84
Q

What is the MOA of secukinumab

A

Inhibits IL-17A

85
Q

What are the side effects of secukinumab

A

Infection (TB)

86
Q

What are the indications of secukinumab (2)

A

Psoriasis and psoriatic arthritis.

Ankylosing spondylitis

87
Q

How is secukinumab administered

A

SC load and then monthly

88
Q

What is the MOA of denosumab

A

Inhibits RANK mediated osteoclast differentiation and function

89
Q

What is denosumab used for

A

Osteoporosis

90
Q

How is denosumab administered

A

SC every 6 months

91
Q

What are the side effects of denosumab (3)

A

Injection site reactions
Infection - mildly immunosuppressive
Avascular necrosis of jaw

92
Q

What are the main types of reactions with biologic agents

A

Infusions reactions

Injection site reactions

93
Q

What are some infusion reactions (3)

A

Urticaria, hypotension, tachycardia, wheeze - IgE mediated.
Headaches, fevers, myalgias - not classical type 1 hypersensitivity
Cytokien storm

94
Q

What are injection site reactions

A

Peak reaction at ~48 hours
May also occur at previous injection sites (recall reactions)
Mixed cellular infiltrates, often with CD8 T cells
Not generally IgE or immune complexes

95
Q

What are the risks of acute infection if on immunosuppressive agents

A

Risk often > 2 x background

96
Q

What are the best ways to prevent infection in people on immunosuppressive agents (2)

A

Avoidance

Vaccination

97
Q

How are people on immunosuppressive treatment managed if they have an acute infection

A

Temporarily stop immunosuppression
Consider atypical organisms
Appropriate antibiotics

98
Q

What kind of vaccines cannt be used on immunosuppressed patients

A

Live attenuated

99
Q

What malignancies are associated more with immunosuppression (3)

A

Lymphoma (EBV)
Non-melanoma skin cancers (HPV)
Melanoma (increased risk in patients treated with anti-TNFalpha)

100
Q

What auto-immune disorders are more common in immunosuppressed patients (8)

A 
SLE and lupus-like syndromes 
ANti-phospholipid syndromes 
Vasculitis 
Intestitial lung disease 
Sarcoidosis 
Uveitis 
Autoimmune hepatitis 
Demyelination

Kat's Pathology (105 decks)

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