Immunosuppressives B6

Question 1

List indications for immunosuppression and targets for immunosuppression

Answer 1

Indications for immunosuppression

• Inflammatory conditions
  
  • Eg vasculitis
• Autoimmunity
  
  • Eg Rheumatoid arthritis
• Rejection
  
  • Eg Solid organ transplant,Graft v host disease

There are 4 main targets of immunosuppression (of lymphocytes)

• 1. Remove lymphocytes
• 2. Suppress proliferation
• 3. Suppress activation
• 4. Modulate effector response

Question 2

List the types of immunosuppressives that remove lymphocytes - desribe rituximab

Answer 2

Removes lymphocytes
-Cytotoxic therapy
cyclophosphamide
- Anti-lymphocyte monocolonal antibodies
Rituximab

Rituximab
- class:Chimeric monoclonal antibody
- Uses:- Used to treat lymphoma but is increasingly used for the treatment of autoimmune diseases.
- Rheumatoid Arthritis as 2nd line if inadequate response to TNFi.
- Used when major organ involved eg lungs, nerves, kidneys in RA, SLE.
- Vasculitis: granulomatosis with polyangiitis and other antineutrophil cytoplasmic antibody-associated vasculitises.
- admin: IV
- MOA:

• Binds to the CD20 surface marker expressed on B cells, including precursor B cells (pre-B cells) and mature and memory B cells. - Reducing B cell inflammatory cascade. Not entirely without B cells
• Following antibody binding, B cells die by a number of mechanisms: antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, apoptosis.

AdvEs:
- Infusion-related reactions (two infusions, dosages vary depending on illness) – need Paracetamol, IV steroid and antihistamine as pre-med.
- Infection risks.
- Vaccinations – avoid live vaccines – need to complete required vaccinations.
- Fertility: not affected. Stop 6 months before pregnancy. (teratogenic?)
- Malignancy: used in malignancy eg Lymphoma. - arrhythmias, HF, angina, MI - PROGRESSIVE multifocal leucoencephalopathy

Other considerations:
- Important to know baseline Immunoglobulin status and vaccination status.
- Loss of B cells from the circulation is transient (usually for about six months).
- Monitor for adverse events and safety

Question 3

Describe cyclophosphamide

Answer 3

Alkylating agent

SLE, vasculitis, inflammatory autoimmune conditions especially those threatening major organs (RA), chemotherapy agent (lymphoma and multiple myeloma)

Crosslinking of DNA (and proteins, RNA) results in impaired DNA replication and transcription. This results in cell death and altered function, thus inhibiting immune function. Cyclophosphamide’s activity is not phase restricted.

Administered IV monthly or weekly; oral daily dose. Parent drug or prodrug metabolised to active form by cytochrome P450 complex. Metabolism occurs in the liver. 80% of the administered dose is metabolised. Excretion in urine.

Bone suppression/myelosuppression (WCC drops in 10 to 14 days), infections (PJP prophylaxis), bladder toxicity due to acrolein accumulation, malignancy risk, teratogenicity, gonadal toxicity; GIT (nausea and vomiting)

Contrad in Pregnancy and hypersensitivity.

Monitoring/tox
- metabolite acrolein, risk of haemorrhagic cystitis, minimised by adequate hydration and Mesna in short term–bladder carcinoma in long term - Cumulative dose poses risk of toxicity - IV therapy may be as low as 1/3 the daily oral dose. This helps reduce infection rates and bladder toxicity. Reproductive planning. Urinalysis. Continuous: PJP prophylaxis, regular urinalysis, liver and BM function every two weeks in first 3 months, then monthly

Question 4

lIST THE immunosuppressives suppressing lymphocyte removal

Answer 4

Glucocorticoids
Calcineurin inhibitors
Anti-proliferative agents
azathioprine (purine antagonist)
leflunomide
Mycophenolate (purine synthesis inhibitor)
Sirolimus

Question 5

Describe cyclosporin and tacrolimus

Answer 5

Both calcineurin inhibitors -
Clycosporin used as
2nd line therapy for RA; osteoarthritis and psoriatic arthritis, polymyositis, dermatomyositis, transplants, uveitis., GvHD, transplants

Tacrolimus used as Transplants, rheumatoid arthritis, uveitis, refractory myositis, systemic sclerosis, severe chronic plaque psoriasis, autoimmune chronic hepatitis. GvHD, transplants

Admin and other PH: Oral bioavailability is 20-50%. Narrow therapeutic index. Metabolised by P4503A in the liver.

Cyclosporin Moa -
Cyclosporin binds cyclophilin, preventing it binding calcineurin. This inhibits movement of NFAT complex to nucleus. NFAT required for induction of a number of cytokine genes including that for IL-2 – a T cell growth and differentiation factor. It thus inhibit cell signalling.

Tacrolimus Moa-
Preventing the production of IL-2 and other cytokines in T cells. Largely affect T response and also affects T-cell dependent B cells. Binds immunophilin and forms a receptor complex that blocks calcineurin.

Toxicity
- renal dysfunction, drop in GFR - hypertension/early vasoconstriction - tremor - gum hyperplasia - hirsutism - diabetes mellitus/impaired glucose metabolism

Clyclosporin:
Multiple drug interactions: antibiotics (trimethroprim), furosemide, apixaban, ‘nexium’. Avoid grapefruit juice. Hypersensitivity, malignancy, uncontrolled malignancy and hypertension. Poor renal function
Tacrolimus also has drug interactions, main other issue is hypersensitiy

Also:
Narrow TI – requires monitoring of organ functions, EUCs (esp K), blood pressure. blood glucose concentration, lipids. complete blood count regularly (eg every 2weeks for first few months or until stable, then every 1–3months)

Cyclosporin and tacrolimus are both calcineurin inhibitors. They are structurally unrelated and bind to different, but related, molecular targets

Question 6

Describe azathioprone and leflunomide

Answer 6

See previous decks for Immsupps and DMARDS

Question 7

Describe glucocorticoids

Answer 7

class:
Antiinf Immsupp Metabolic Develomntal.

Uses: Immsupp and anti-inf

MoA:
1. genomic transactivation and transrepression., DIrect and indirect, post-transcriptional 2- Non-genomic, physio chemical activity exerted on cell membranes. Rapid. Observed with high doses, May not correlate with genomic activity

SEs:
HTN, glucose tolerance and insulin resistance, dyslipidaemia, fluid and electrolyte effects e.g. MC actions, osteoporosis, neuropsychiatirc effects, impaired wound healing

Question 8

Describe sirolimus

Answer 8

e.g. rapamycin, mTOR inhibitor
solid organ transplant

Macrolide antibiotics targets a uniqye serine threonine jinase, mTOR. Synergistic with cyclosporin NOT tacrolimus. Bind to the same intracellular protein (FKBP‑12) as tacrolimus; however, the protein-drug complex blocks the activity of mTOR kinase, preventing cell cycle progression and cytokine-induced Tand Bcell proliferation. Blocks endothelial smooth muscle proliferationand angiongensis. May have anti-VEGF effect. Reduces post allograft malignancy.

SES”
Tcytopenia Leukopenia IMPARIED renal function- raised cretinine concentration ^[when in combo with cyclosporin or tacro], proteinuria Hyperlipidaemia Imapired wound healing Mouth ulcers Lymphocytic pneumonitis Infection Anguoedena VTE/graft thrombosis/TTP/HUS/nosebleeds

Question 9

List and briefly describe drugs for downregulating lymphocyte responsiveness

Answer 9

• Suppress activation
  
  • Belatacept: CTLA4-Ig
• Suppress responsiveness to cytokines ANDSuppress proliferation (inhibit T-cell activation and cytokine production by inhibiting CD-25 expressed on activated T cells)
  
  • Basiliximab: chimeric mouse-human mAb
  • Daclizumab: humanised
• Suppress activation AND suppress secretion of cytokines/ growth factors AND suppress responsiveness to cytokines
  
  • Inhibits JAK1/JAK 3 (Tofacitinib)
• Suppress migration
  
  • Sphingosine 1 phosphate inhibitor: Fingolimod

Note: belatacept
- MOA: IgG vs EC CTLA4, binds CD80/86 and prevents activation
- adv es: post-transplant lymphoproliferative disorder and progressive multifocal leukoencephalopathy.
- infection, infusion related reactions, malignancy and autoimmune conditions
Basilix, daciliz: mAb vs IL-2 esp CD25 on activated T lymphs, blocks IL-2

Tofacitinib:
- Aims to suppress activation and secretion of cytokines and GFs and suppress response to cytokines
- increased risk of GI perf eg diverticular disease, beware of NSAIDs, drug interactions with CYP3A4 inducers and inhibitors.
Adve: diarrhoea, nausea, rash, headache

Fingolimod:
Adverse effects:

• bradycardia, first-degree (or second) atrioventricular block (transient, when treatment starts),hypertension
• headache, dizziness, diarrhoea, back pain, weakness, cough, dyspnoea
• infection including CNS infections
• eye pain, blurred vision,macular oedema (reversible on stopping treatment)
• leucopenia, lymphopenia,thrombocytopenia
• basal cell carcinoma (note that other skin cancers, eg melanoma, have also been reported)
• posterior reversible encephalopathy syndrome, CNS infection, progressive multifocal leucoencephalopathy (PML),lymphoma.

Question 10

List the drugs that modulate effector response

Answer 10

AntiTNF
etanercept
Infliximab
adalimumab
Anti-cytokine (anti IL)
anakinra
toclizumab
secukinumab
ustekinumab

Question 11

Describe the antiTNFs

Answer 11

Question 12

Describe the anti-cytokines

Answer 12

Anti IL-1: Anakinra (RA, JIA)

• Recombinant form of the IL-1 receptor antagonist
• RA, CAP, other autoimmune conditions, juvenile arthritis
• Competitively blocks binding of IL-1 to IL-1 receptors
• Adverse Effects:
  
  • Injection site reactions,Headache,Serious infections,Neutropenia,Thrombocytopenia,Raised total cholesterol concentration

Anti IL-6:Tocilizumab (Psoriatic arthritis, RA)

• Recombinant humanised monoclonal IgG1 antibody
• Binds to IL-6 receptors, inhibiting binding of IL-6 -> ↓inflammation and immunological responses
• Adverse effects:
  
  • Infections,neutropenia,Increased liver enzymes,Gastritis, mouth ulcers,Increased lipids (largely LDL, responds to standard lipid-lowering treatment), injection site reactions

Anti-IL-17:Secukinumab (psoriasis)

• Recombinant human monoclonal antibody that inhibits the activity of the cytokine interleukin‑17A that is involved in inflammatory and immune responses.
• Adverse effects:
  
  • menstrual disorders (eg dysmenorrhoea, menstrual irregularity), infections,, diarrhoea,hypersensitivity reactions, anti-secukinumab antibodies (below), neutropenia,inflammatory bowel disease (Crohn’s disease, ulcerative colitis), injection site reactions

Anti IL-23 (IL-17):Ustenkinumab (IBD)

• Recombinant human monoclonal antibody that inhibits the activity of the cytokines, interleukin -23 (and 12), which are involved in inflammatory and immune responses.
• Adverse effects:
  
  • infections, dizziness, headache, fatigue, diarrhoea, itch, arthralgia, myalgia, injection site reactions,malignancies, pustular psoriasis, hypersensitivity reactions, exfoliative dermatitis, eosinophilic pneumonia, interstitial pneumonia