Immune modulating therapies 2 Flashcards
What drugs suppress the immune response?
Steroids Anti-proliferative agents Plasmapheresis Inhibitors of cell signalling Agents directed at cell surface antigens Agents directed at cytokines
What are corticosteroids?
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
What are steroids used for?
Allergic disorders Auto-immune disease Auto-inflammatory diseases Transplantation Malignant disease
What is the action of steroids on prostaglandins?
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
What is the action of steroids on phagocytes?
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
What is the action of steroids on lymphocytes?
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
What are the SEs of steroids?
Diabetes, central obesity, moon face, lipid abnormalities, osteoporosis, hirsuitism, adrenal suppression
Cataracts, glaucoma, peptic ulceration, pancreatitis, avascular necrosis
Immunosuppression
What are the Cytotoxic agents Anti-proliferative immunosuppressants?
Cyclophosphamide
- Mycophenolate
- Azathioprine
- Methotrexate
What is the action anti proliferative immunosuppressants?
Inhibit DNA synthesis
Cells with rapid turnover most sensitive
What is the SEs of anti proliferative immunosuppressants?
Bone marrow suppression
Infection
- Malignancy
- Teratogenic
What is the MOA of cyclophosphamide?
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
What is the indications of cyclophosphamide?
Multisystem connective tissue disease or vasculitis with severe end-organ involvement
eg GPA (Wegener’s granulomatosis), SLE
Anti-cancer agent
What are the SEs of cyclophosphamide?
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
What is the MOA and indications of azathioprine?
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
What is the SEs of azathioprine?
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
What is the MOA and indications of mycophenolate mofetil?
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
What is the SEs of mycophenolate mofetil?
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)
What is plasmapheresis?
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
Indications for plasmapheresis?
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
What are Inhibitors of cell signalling (Calcineurin inhibitors)?
Ciclosporin
Tacrolimus
What do Inhibitors of cell signalling (Calcineurin inhibitors) do?
Block cytokine transcription, therefore prevent T lymphocyte proliferation and effector functions
Used for Transplant, SLE and psoriatic arthritis
What are the side effects of calcineurin inhibitors?
Nephrotoxicity HTN Neurotoxic Diabetes (Ciclosporin) Dysmorphic features
What does Tofacitinib/ Jakinibs do?
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
What is apremilast?
Inhibits PDE4 leads to increase cAMP
Influences gene transcription
Modulates cytokine production
Effective in psoriasis and
psoriatic arthritis
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)
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
What are the specificities of anti thymocyte globulin?
CD2 CD3 CD4 CD8 CD28 CD11a HLA class I and II
What is Basiliximab?
Antibody directed at CD25 (IL-2Ra chain)
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
What is Abatacept?
CTLA4–Ig fusion protein
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
What is Rituximab?
Antibody specific for CD20
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
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
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
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
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
Anti-TNFa Antibodies Infliximab, Adalimumab, Certolizumab, Golimumab
Anti-TNFa Antibodies Infliximab, Adalimumab, Certolizumab, Golimumab
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
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
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)
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)
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
What is the target for etanercept, ustekinumab, secukinumab and denosumab?
TNFa antagonist
Ustekinumab
Secukinumab
Denosumab
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
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
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
What are the AI SEs of immunosuppressants?
SLE and lupus-like syndromes - Anti-phospholipid syndromes Vasculitis Interstitial lung disease Sarcoidosis - Uveitis - Autoimmune hepatitis - Demyelination
What are mTOR inhibitors?
Rapamycin- mechanistic target of rapamycin
mTOR inhibitor inhibit T cell proliferation and function
Used in transplant
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
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
What is guselkumab?
Ab against P19 subunit of IL13
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
Why is RANKL important?
In osteoclasts for differentiation and function
Anti RANKL ab for osteoporosis
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
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
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
