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Immune modulating therapies 2 Flashcards

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1
Q

What drugs suppress the immune response?

A 
Steroids
Anti-proliferative agents
Plasmapheresis
Inhibitors of cell signalling
Agents directed at cell surface antigens
Agents directed at cytokines
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2
Q

What are corticosteroids?

A 
Synthetic glucocorticoids 
Based upon naturally occuring steroids
No mineralocorticoid activity
Prednisolone in Europe
Prednisone in USA
metabolised by liver into prednisolone
Endogenous secretion equivalent to 5-7.5 mg prednisolone

Hench, Kendall and Reichstein received Nobel Prize in 1950

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3
Q

What are steroids used for?

A 
Allergic disorders 
Auto-immune disease
Auto-inflammatory diseases 
Transplantation
Malignant disease
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4
Q

What is the action of steroids on prostaglandins?

A

Phospholipase A2
- Breaks down phospholipids to form arachidonic acid which is converted to eicosanoids (eg prostaglandin)s, leukotrienes) by cyclo-oxygenases

Corticosteroids inhibit phospholipase A2
- Blocks arachidonic acid and prostaglandin formation and so reduces inflammation

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5
Q

What is the action of steroids on phagocytes?

A

Decreased traffic of phagocytes to inflamed tissue
Decreased expression of adhesion molecules on endothelium
Blocks the signals that tell immune cells to move from bloodstream and into tissues
Results in transient increase in neutrophil counts

Decreased phagocytosis

Decreased release of proteolytic enzymes

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6
Q

What is the action of steroids on lymphocytes?

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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7
Q

What are the SEs of steroids?

A

Diabetes, central obesity, moon face, lipid abnormalities, osteoporosis, hirsuitism, adrenal suppression

Cataracts, glaucoma, peptic ulceration, pancreatitis, avascular necrosis

Immunosuppression

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8
Q

What are the Cytotoxic agents Anti-proliferative immunosuppressants?

A

Cyclophosphamide

  • Mycophenolate
  • Azathioprine
  • Methotrexate
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9
Q

What is the action anti proliferative immunosuppressants?

A

Inhibit DNA synthesis

Cells with rapid turnover most sensitive

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10
Q

What is the SEs of anti proliferative immunosuppressants?

A

Bone marrow suppression
Infection
- Malignancy
- Teratogenic

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11
Q

What is the MOA of cyclophosphamide?

A

Alkylates guanine base of DNA
Damages DNA and prevents cell replication
Affects B cells > T cells, but at high doses affects all cells with high turnover

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12
Q

What is the indications of cyclophosphamide?

A

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

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13
Q

What are the SEs of cyclophosphamide?

A

Toxic to proliferating cells
Bone marrow depression
Hair loss
Sterility (male»female)

Haemorrhagic cystitis
Toxic metabolite acrolein excreted via urine

Malignancy
Bladder cancer
Haematological malignancies
Non-melanoma skin cancer

Infection
Pneumocystis jiroveci

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14
Q

What is the MOA and indications of azathioprine?

A

Mechanism of action
Metabolised by liver to 6 mercaptopurine
Blocks de novo purine (eg adenine, guanine) synthesis – prevents replication of DNA
Preferentially inhibits T cell activation & proliferation

Indications
Transplantation
Auto-immune disease
Auto-inflammatory diseases, eg Crohn’s, ulcerative colitis

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15
Q

What is the SEs of azathioprine?

A

Bone marrow suppression
Cells with rapid turnover (leucocytes and platelets) are particularly sensitive
1:300 individuals are extremely susceptible to bone marrow suppression s
Thiopurine methyltransferase (TPMT) polymorphisms
Unable to metabolise azathioprine
Check TPMT activity or gene variants before treatment if possible; always check full blood count after starting therapy
Hepatotoxicity
Idiosyncratic and uncommon
Infection
Serious infection less common than with cyclophosphamide

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16
Q

What is the MOA and indications of mycophenolate mofetil?

A

Mechanism of action
Blocks de novo nucleotide synthesis
– prevents replication of DNA
Prevents T>B cell proliferation

Major Indications
Widely used in transplantation as alternative to azathioprine
Also used in auto-immune diseases and vasculitis as alternative to cyclophosphamide

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17
Q

What is the SEs of mycophenolate mofetil?

A

Bone marrow suppression Infection
Cells with rapid turnover (leucocytes and platelets) are particularly sensitive

Infection
Particular risk of herpes virus reactivation
Progressive multifocal leukoencephalopathy (JC virus)

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18
Q

What is plasmapheresis?

A

Aim: removal of pathogenic antibody
Patient’s blood passed through cell separator
Own cellular constituents reinfused
Plasma treated to remove immunoglobulins and then reinfused (or replaced with albumin in ‘plasma exchange’)

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

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19
Q

Indications for plasmapheresis?

A

Severe antibody-mediated disease
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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20
Q

What are Inhibitors of cell signalling (Calcineurin inhibitors)?

A

Ciclosporin

Tacrolimus

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21
Q

What do Inhibitors of cell signalling (Calcineurin inhibitors) do?

A

Block cytokine transcription, therefore prevent T lymphocyte proliferation and effector functions

Used for Transplant, SLE and psoriatic arthritis

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22
Q

What are the side effects of calcineurin inhibitors?

A 
Nephrotoxicity
HTN
Neurotoxic
Diabetes
(Ciclosporin) Dysmorphic features
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23
Q

What does Tofacitinib/ Jakinibs do?

Study These Flashcards
A

Tofacitinib (JAK1 and JAK3 inhibitor)

Interferes with JAK-STAT signalling
Influences gene transcription
Inhibits production of inflammatory molecules

Effective in Rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis

24
Q

What is apremilast?

Study These Flashcards
A

Inhibits PDE4 leads to increase cAMP
Influences gene transcription
Modulates cytokine production

Effective in psoriasis and
psoriatic arthritis

25
What are Agents directed at cell surface antigens?
``` Drugs T cells: - Rabbit anti-thymocyte globulin - Basiliximab – anti-CD25 - Abatacept – CTLA4-Ig ``` B cells: - Rituximab – anti-CD20 Lymphocyte migration: - Vedolizumab (anti a4b7 integrin) Action Block signalling Cell depletion (Activate signalling)
26
What is the indications, action and toxicityof anti thymocyte globulin?
Indications and dosing - Allograft rejection (renal, heart) - Daily intravenous infusion Action - Lymphocyte depletion - Modulation of T cell activation - Modulation of T cell migration Toxicity - Infusion reactions - Leukopenia - Infection - Malignancy
27
What are the specificities of anti thymocyte globulin?
``` CD2 CD3 CD4 CD8 CD28 CD11a HLA class I and II ```
28
What is Basiliximab?
Antibody directed at CD25 (IL-2Ra chain)
29
What is the indications, action and toxicity of basilikimab?
Indications and dosing: - Prophylaxis of allograft rejection - Intravenous given before and after transplant surgery Action: - Blocks IL2 signalling which Inhibits T cell proliferation Toxicity Infusion reactions - Infection - Concern re long term risk malignancy
30
What is Abatacept?
CTLA4–Ig fusion protein
31
What is the indications, action and toxicity of Abatacept?
Indications and dosing Rheumatoid arthritis Intravenous 4 weekly Subcutaneous weekly Action Reduces T cell activation Toxicity Infusion reactions Infection (TB, HBV, HCV) - Caution wrt malignancy
32
What is Rituximab?
Antibody specific for CD20
33
What is the indications, action and toxicity of Rituximab?
``` Indications and dose Lymphoma Rheumatoid arthritis - SLE - 2 doses intravenous every 6-12 months (RA) ``` Action Depletes mature B cells Toxicity Infusion reactions Infection (PML) - Exacerbation CV disease
34
What is Natalizumab?
Antibody specific for a4 integrin a4 expressed with b1 or b7 integrin Bind to VCAM1 and MadCAM1 to mediate rolling/arrest of leukocytes Bind to non-endothelial VCAM1 in lymphoid tissue
35
What is the indications, action and toxicity of Natalizumab?
Indications and dosing Highly active relapsing-remitting multiple sclerosis - (Crohn’s disease) - Intravenous every 4 weeks Action Inhibits T cell migration ``` Toxicity Infusion reactions Infection (PML) Hepatotoxic - Concern re malignancy ```
36
What is the indications, action and toxicity of Tocilizumab (Antibody directed at IL-6 receptor)?
Indications and dosing Castleman’s disease Rheumatoid arthritis Intravenous every 4 weeks Action Reduces macrophage, T cell, B cell, neutrophil activation ``` Toxicity Infusion reactions Infection Hepatotoxic Elevated lipids - Caution wrt malignancy ```
37
What are Agents directed at cytokines?
``` Drugs Infliximab – anti-TNFa Adalimumab – anti-TNFa Certolizumab – anti-TNFa Golimumab – anti-TNFa Etanercept – TNF receptor p75-IgG fusion protein ``` Ustekinumab – anti-IL-12 and IL-23 Denosumab – anti-RANK ligand Secukinumab – anti-IL-17 Action Block action of cytokines
38
Anti-TNFa Antibodies Infliximab, Adalimumab, Certolizumab, Golimumab
Anti-TNFa Antibodies Infliximab, Adalimumab, Certolizumab, Golimumab
39
What do Anti-TNFa Antibodies do?
``` Indications and dosing - Rheumatoid arthritis - Ankylosing spondylitis - Psoriasis and psoriatic arthritis Inflammatory bowel disease - Subcutaneous or intravenous ``` Action - Inhibit TNFa ``` Toxicity Infusion or injection site reactions - Infection (TB, HBV, HCV) Lupus-like conditions Demyelination - Malignancy ```
40
What is the indications, action and toxicity of Etanercept?
``` Indications and dosing - Rheumatoid arthritis - Ankylosing spondylitis Psoriasis and psoriatic arthritis - Subcutaneous weekly ``` Action - Inhibits TNFa and TNFb ``` Toxicity Injection site reactions Infection (TB, HBV, HCV) Lupus-like conditions Demyelination - Malignancy ```
41
What is the indications, action and toxicity of Ustekinumab?
IL-12 and IL-23 - IL-12 comprises p40+p35 - IL-23 comprises p40+p19 Indications and dosing Psoriasis, psoriatic arthritis Crohns disease - Subcutaneous every 12 weeks Action Inhibits IL-12 and IL-23 Toxicity Injection site reactions - Infection (TB)
42
What is the indications, action and toxicity of Secukinumab?
IL-17A IL17A protype of IL-17 family Dimer of IL-17A or IL-17A/F - Binds to IL-17RA/RC receptor Indications and dosing Psoriasis and psoriatic arthritis Ankylosing spondylitis SC load and then monthly Action Inhibits IL-17A Toxicity - Infection (TB)
43
What is the indications, action and toxicity of Denosumab?
Indications and dosing Osteoporosis Subcutaneous every 6 months Action Inhibits RANK mediated osteoclast differentiation and function Toxicity Injection site reactions Infection – mildly immunosuppressive - Avascular necrosis of jaw
44
What is the target for etanercept, ustekinumab, secukinumab and denosumab?
TNFa antagonist Ustekinumab Secukinumab Denosumab
45
What are the SEs of biological agents?
Reactions Infusion reactions Urticaria, hypotension, tachycardia, wheeze – IgE mediated Headaches, fevers, myalgias – not classical type I hypersensitivity Cytokine storm Injection site reactions 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
46
What are the SEs of immunosuppressants?
Infection ``` Acute infection - Risk often > 2 x background - Avoidance - Vaccination Temporarily stop immunosuppression - Consider atypical organisms - Appropriate antibiotics ``` Chronic infection Tuberculosis - History, Residence, Travel, Contacts, CXR, TBElispot - Prophylaxis or treatment if required HBV and HCV - Check Hep B core antibody and Hep C antibody HIV - Balance benefits against possible risks CMV - Treat reactivation promptly John Cunningham Virus (JCV) Common polyomavirus that can reactivate - Infects and destroys oligodendrocytes - Progressive multifocal leukoencephalopathy
47
What are the malignancy SEs of immunosuppressants?
Malignancy Lymphoma (EBV) Non melanoma skin cancers (Human papilloma virus) Melanoma (increased in cohort treated with anti-TNF alpha) - Risks appear lower with targeted forms of immunosuppression than with regimes used in transplantation
48
What are the AI SEs of immunosuppressants?
``` SLE and lupus-like syndromes - Anti-phospholipid syndromes Vasculitis Interstitial lung disease Sarcoidosis - Uveitis - Autoimmune hepatitis - Demyelination ```
49
What are mTOR inhibitors?
Rapamycin- mechanistic target of rapamycin mTOR inhibitor inhibit T cell proliferation and function Used in transplant
50
What is Vedolizumab?
Used for IBD IV every 8 weeks a4b7 integrin- binds MadCAM1 to mediate leukocyte binding to endothelium and extravasation to tissue Infusion reaction hepatotoxic infection concern re malignancy
51
What do Anti IL6 do (e.g. tocilizumab)?
Used in castlemans disease, RhA as subcut 1-2wks reduces macrophage, T cell, B cell and neutrophil activation Toxicity: infusion reactions, infection, hepatotoxic, elevated lipids and caution wrt malignancy
52
What is guselkumab?
Ab against P19 subunit of IL13
53
What IL are important in asthma and eczema?
IL4 IL5 IL13 - Th2 and eosinophil responses - Il-4/13 block for IL4R may be useful IL13 ab useful for eczema IL 5 ab may be used for eosinophilic asthma
54
Why is RANKL important?
In osteoclasts for differentiation and function Anti RANKL ab for osteoporosis
55
A young woman with SLE is experiencing weight gain, easy bruising, poor sleep, a raised HbA1C and falling bone density. Which drug is she taking? Azathioprine Anti-CD20 antibody (rituximab) Mycophenolate Prednisolone
Prednisolone
56
Rituximab is a monoclonal antibody specific for CD20 on B cells. For which one of the following is it an effective treatment? Ankylosing spondylitis Malignant melanoma Mutliple sclerosis Osteoporosis Rheumatoid arthritis
Rheumatoid arthritis
57
Which of the following are true about psoriasis and psoriatic arthritis? Responds to inhibition of Rank ligand (denosumab) Responds to CAR-T cells Treatment options include IL6 blockade or B cell depletion with Rituximab Treatment options include inhibition of TNF alpha, inhibition of IL12/23 or IL17A, or use of a PD4 blocker or ciclosporin Responds to use of checkpoint inhibitors such as nivolumab
Treatment options include inhibition of TNF alpha, inhibition of IL12/23 or IL17A, or use of a PD4 blocker or ciclosporin

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