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Immunosuppression Flashcards

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1
Q

What is RA

A

Inflammatory issues round synovium = pannum. Systemic symptoms. erosive damage -> disability
• An autoimmune multi-system disease • Fairly common: UK prevalence 1%
• Initially localized to synovium
• Inflammatory change and proliferation of synovium (pannus) leading to dissolution of cartilage and bone

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2
Q

Describe the pathogenises of RA

A

Hyperactive immune system. Imbalance between pro and anti inflammatory. Get auto rheumatic diseas ehwen pro inflammatory mroe active than anti. Il-6, il-1, tnfa. Over expression of metalloproteinases leds to inflammation of joints

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3
Q

What are the symptoms of RA

A

Clinical criteria
• Morning stiffness >=1 hour
• Arthritis of >= 3 joints
• Arthritis of hand joints
• Symmetrical arthritis
• Rheumatoid nodules
Non-clinical criteria
• Serum rheumatoid factor/Anti-CCP antibodies
• X-ray changes
More joints inflamed = more severe symptoms. Nodules late bc treated early. Acpa
X ray changes typically abt 6mths-1 year into disease.
Regulation can affect children a young as 4.. a

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4
Q

What are the treatment goals for RA

A

 Symptomatic relief

 Prevention of joint destruction

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5
Q

Describe teh treatment strategy for RA

A
  • Early use of disease-modifying drugs
  • Aim to achieve good disease control
  • Use of adequate dosages
  • Use of combinations of drugs
  • Avoidance of long-term corticosteroids
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6
Q

Describe sle

A

Ss, No organ is spared. Can affect any organ - widespread. A disease of women f childbearing age.

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7
Q

Describe asuclitis

A

LFTS - leucocytic infiltrates, fibrinoid nicrocsis , thrombosis

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8
Q

What are he treatment goals in sle ad vasculitis

A
  • Symptomatic relief e.g arthralgia, Raynaud’s phenomenon
  • Reduction in mortality
  • Prevention of organ damage
  • Reduction in long term morbidity caused by disease and by drugs
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9
Q

What are some immunosuppressants

A
  • Corticosteroids • Methotrexate
  • Azathioprine
  • Ciclosporin
  • Tacrolimus
  • Mycophenolate mofetil • Leflunomide
  • Cyclophosphamide
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10
Q

Describe teh moa do corticosteroids

A

• Prevent interleukin IL-1 and IL-6 production by macrophages
• Inhibit all stages of T-cell activation
Heatshcok protein complex - glucocorticoid interacts with this - goes into nucleus - chin of events - not very targeted

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11
Q

What are steroid side effects

A

Teroi side effects - many systems. Side effects - accelerates old age - cataracts, MI, stroke, raised cholesterol, tru cal obesity, buffalo hump, osteoporosis, diabetes

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12
Q

What are demands

A

Non-biologics (cheaper but just as effective)
• Sulphasalazine
• Hydroxychloroquine

Biologics
• Anti-TNF agents
• Rituximab
• IL-6 inhibitors, JAK inhibitors

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13
Q

What is azathioprine

A

• SLE & vasculitis -as maintenance therapy
• RA–veryweakevidence
• Inflammatory bowel disease
• Bullous skin disease
Atopic dermatitis
• Many other uses as ‘steroid sparing’ drug - This allows to cu short the exposure to steroids if used first

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14
Q

Describe the pd of azathioprne

A
  • 6-MP is metabolized by thiopurine - Tpmt converts aaa to 6mp methyltransferase (TPMT)
  • TPMT gene highly polymorphic
  • Individuals vary markedly in TPMT activity
  • Low/absent TPMT levels = Risk of myelosupression
  • Therefore test TPMT activity before prescribing
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15
Q

Describe teh azthiprine moa

A

• Cleaved to 6-mercaptopurine (6-MP)
• anti-metabolite decreases DNA and RNA synthesis
Ss
Suppress immunity. Decreases dna and rna synthesis. If you shut down synthesis , inflammation reduces

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16
Q

What are the side effects of dmards

A 
Bone marrow suppression – Monitor FBC
• Increased risk of malignancy
– Esp transplanted patients -NHL
• Increased risk of infection
• Hepatitis
– Monitor LFT

Nausea dn vomiting

17
Q

Describe calcineurin inhiitors in practise

A

• Ciclosporin & tacrolimus widely used in transplantation
• Also for atopic dermatitis & psoriasis
• Not often used in rheumatology -renal toxicity
• Check BP and eGFR regularly
• Multiple drug interactions are possible (Cytochrome P-450)
Tacrolimus in use. Anti rejection. Circle good for skin problems - but can make gums swell. Can elevate k+.
Inhibi cytochromsp450. Get more drug bc not as metabolised /

18
Q

What are the moas of cyclosporine and tacrolimis

A

• Active against helper T-cells, preventing production of IL-2 via calcineurin inhibition
• Ciclosporin binds to cyclophilin protein
• Tacrolimus binds to tacrolimus-binding protein
• Drug/protein complexes bind calcineurin
• Calcineurin exerts phosphatase activity of activated T- cells then nuclear factor migration starts IL-2 transcription
Hot t bone steak. Hot - il1 causes fever. T - interleukin 2 stimulate T cell. Bone - il3 stimulate bone marrow. Steak. EA - 4 and 5 act on ige and igg

19
Q

When is mycophenolate mofetil used

A
  • Primarily in transplantation
  • Good efficacy as induction and maintenance therapy for lupus nephritis/Vasculitis maintenance
  • In transplantation medicine: Mycophenolic acid may be monitored
20
Q

What are the moa of mmf

A

• Is a prodrug derived from fungus Penicillium stoloniferum
• Inhibits inosine monophosphate dehydrogenase (required for guanosine synthesis)
• impairs B- and T-cell proliferation
• spares other rapidly dividing cells
(due to guanosine salvage pathways in other cells)

21
Q

What are the side effects ofmmf

A
  • Most common include nausea, vomiting, diarrhea

* Most serious is myelosuppression

22
Q

What are the effects and indications of cyclophosphamide

A

Cytotoxic Agent :
Alkylating agent -cross links DNA so that it cannot replicate
Many immunological effects:
– suppresses T cell activity
– suppresses B cell activity
Indications:
– Lymphoma, leukaemia, solid cancers
– Lupus nephritis
– Wegener’s granulomatosis (ANCA-vasculitis)
Starts working in abt 10 days. Cancer doses big eg 5g. In rheumatology, big drugs 1.5g. Induce remission. But cant keep giving it - can cause cancer.. once remission induced, pull out, give mm or aza instead (maintenance)

23
Q

Describe the pd of cyclophsphamide

A
  • Is a prodrug
  • Converted in the liver (cytochrome P450) to active forms
  • The main active metabolite is 4-hydroxycyclophosphamide
  • 4-hydroxycyclophosphamide exists in equilibrium with its tautomer, aldophosphamide.
  • Most of the aldophosphamide is oxidised to make carboxyphosphamide. A small proportion of aldophosphamide is converted into phosphoramide mustard (main active metabolite)
24
Q

What needs to me given with cyclophosphamide and why

A

• Cyclophosphamide is excreted by the kidney
• Acrolein, another metabolite is toxic to the bladder epithelium and can lead to hemorrhagic cystitis
• This can be prevented through the use ohydration and/or Mesna.
Mensa mopes up acrol

25
Q

What are important consideration for cycophosphamide

A

• Significant toxicity
– increased risk of bladder cancer, lymphoma and leukaemia – Infertility: Risk relates to cumulative dose and patient age
– monitor FBC
– Adjust dose in renal impairment
• Mycophenolate mofetil safer and as effective in lupus nephritis - Does the same thing BUT takes 6 weeks to kick in. Needed more steroids in the meantime

26
Q

What is methotrexate

A 
• Developed in 1940s (ALL)
• Gold standard treatment for RA
• Other indications – malignancy
– psoriasis
– Crohn’s disease
• Unlicensed roles: Inflammatory myopathies,vasculitis, steroid-sparing agent in asthma
27
Q

Desribe the moas of methotrexate in cancer treatment

A

Inhibit folate - causes ectopic forests to die. Competitive y binds to dif stronger than folate. This is how it treats cancer but not or rheumatoid route. Different mechs
Methotrexate competitively and reversibly inhibits dihydrofolate reductase (DHFR)
• The affinity of methotrexate for DHFR is 1000X that of folate for DHFR.
• Dihydrofolate reductase catalyses the conversion of dihydrofolate to the active tetrahydrofolate the key carrier of one-carbon units in purine and thymidine synthesis
• Methotrexate, therefore inhibits the synthesis of DNA, RNA and proteins
• Methotrexate acts during DNA and RNA synthesis hence cytotoxic during S-phase of the cell cycle. Greater toxic effect on rapidly dividing cells which replicate their DNA more frequently

28
Q

What are the moas of methotrexate in RA

A

Mechanism of action in non-malignant disease e.g. RA, psoriasis is not clear
Mechanism is not via anti-folate action
Possible mechanisms include
– Inhibition of accumulation of adenosine
– the inhibition of T cell activation activation
– suppression of intercellular adhesion molecule expression by T cells

29
Q

Describe teh pk of methotrexate

A
  • Mean oral bioavailability is 33% (13-76%)
  • Mean intramuscular bioavailability is 76%
  • Administered PO, IM or S/C
  • In patients taking PO with partial response or with nausea then swap to s/c
  • WEEKLY NOT DAILY DOSING, metabolized to polyglutamates with long half lives
  • 50% protein bound -NSAIDs displace
  • Renal excretion
30
Q

Describemethotrexate in practise

A
  • Well tolerated
  • 50% of patients continue the drug for >5 years, longer than any other DMARD
  • Improved QOL
  • Retardation of joint damage
  • Anchor drug for DMARD combinations
31
Q

What are the adverse effects of methotrexate

A 
• mucositis
• marrow suppression
both respond to folic acid supplementation
• hepatitis, cirrhosis,
• pneumonitis
• infection risk
• Highly teratogenic, abortifacient
32
Q

What is sulfasalazine

A

• A conjugate of a salicylate (5aminosalicylic acid, 5ASA) and a sulfapyridine molecule
• Developed in 1940s
• RA or ‘rheumatic polyarthritis’ believed to be infectious
• Designed to relieve pain & stiffness
(5-ASA = anti-inflammatory)
• And to fight infection
(sulfapyridine = sulfonamide

33
Q

What are the immunological effects of sulfasalazine

A 
• T-cell
– inhibition of proliferation
– possible T-cell apoptosis
– inhibition of IL-2 production
• Neutrophil
–reduced chemotaxis – reduced degranulation
34
Q

What are the side effects of sulfasalazine

A 
Mainly due to sulfapyridine moiety – myelosuppression
– hepatitis
– Rash
• Milder side effects – nausea
– abdo pain/vomiting
35
Q

Descrive sulfasalazine in practise

A
  • Effective
  • Favorable toxicity
  • Long term blood monitoring not always needed
  • Very few drug interactions
  • No carcinogenic potential
  • Safe in pregnancy
36
Q

What are biological

A

• Extracted from living systems e.g. whole blood + blood components, stem cell therapy
• Recombinant DNA technology producing substances that are (nearly) identical to the body’s own key signalling proteins
e.g. growth hormone, erythropoietin
• Monoclonal antibodies “custom-designed“ made specifically to block any given substance in the body, or to target any specific cell type
• Receptor constructs (fusion proteins), usually based on a naturally- occurring receptor, acting to block it

37
Q

What are the effects of blocking tnfa

A

Decrease Inflammation
Cytokine cascade
Recruitment of leukocytes to joint elaboration of adhesion molecules production of chemokines
Decrease Angiogenesis VEGF levels
Descrease Joint destruction
MMPs and other destructive enzymes Bone resorption and erosion Cartilage breakdown

38
Q

Desribe anto tnf therapy

A

Ss

39
Q

Wat is rituximab

A

binds specifically to a unique cell- surface marker CD20, which is found on a subset of B cells but not on stem cells, pro-B cells, plasma cells or any other cell type
B cells:
present antigen to T cells produce cytokines produce antibodies
Rituximab causes B cell apoptosis Very effective in RA. Good safety data

Cpt (24 decks)

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