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Immunosuppression Flashcards

1
Q

Physiologically, what do rheumatoid factors do?

A

Clear old IgGs

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2
Q

What does RA cause?

A

Chronic inflammatory synovitis
Progressive erosion of articular cartilage leading to exposure of bone
Pannus - an inflamed synovium

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3
Q

What’s the problem with an inflamed synovium/pannus?

A

Damages the cartilage by restricting normal nutrient flow and released inflammatory factors

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4
Q

What signs/symptoms are used to diagnose RA?

A 
Morning stiffness for less than 1 hour
Arthritis in 3 or more joints
Symmetrical arthritis
Rheumatoid nodules
Serum rheumatoid factor 
X-ray changes
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5
Q

What are the goals of treatment in RA?

A

Symptomatic relief

Prevent joint destruction

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6
Q

What is the strategy in treatment of RA?

A 
Early use of disease-modifying drugs 
Achieve good disease control
Use adequate dosages 
Use a combination of drugs
Avoid long-term corticosteroids
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7
Q

What is SLE (in one sentence)?

A

An autoimmune connective tissue disease

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8
Q

Symptoms of SLE

A 
Fatigue, malaise, fever, weight loss
Splenomegaly, hepatomegaly, lymphadenopathy
Arthralgia
Oral ulcers
Raynaud's phenomenon
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9
Q

What are symptoms/signs specific to SLE?

A

Erythematous, photosensitive rash seen on the face aka malar rash

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10
Q

What are the aims of treatment in lupus?

A

Symptomatic relief of eg arthralgia, Raynaud’s phenomenon
Reduce mortality - induce remission
Prevent organ damage
Reduce long-term morbidity caused by disease/drugs

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11
Q

What is vasculitis?

A

Inflammation of blood vessels

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12
Q

Symptoms of vasculitis?

A

Arthralgia and lethargy

Skin lesions such as purpura

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13
Q

Treatment goals of vasculitis?

A

Symptom relief
Reduce mortality - induce remission
Prevent organ damage
Reduce long-term morbidity caused by disease/drugs

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14
Q

List some types of immunosuppressants

A 
Corticosteroids
Azathioprine
Ciclosporin
Tacrolimus
Mycophenolate mofetil (MMF)
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15
Q

Name some disease-modifying anti-rheumatic drugs (DMARDs)

A

Methotrexate (first line in RA)
Sulphasalazine (not as strong as MTX)
Anti-TNF agents
Rituximab

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16
Q

Mechanism of action of corticosteroids?

A

Prevent IL-1 and IL-6 production

Inhibit all stages of T-cell activation

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17
Q

Adverse effects of corticosteroids?

A 
Weight gain
Fat redistribution
Striae
Growth retardation 
Osteoporosis
Avascular necrosis
Glucose intolerance
Adverse lipid profile
Infection risk
Cataract formation
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18
Q

What is azathioprine used for?

A

An immunosupressant
Used as maintenance therapy in SLE and vasculitis

Also IBD, bullous skin disease, atopic dermatitis

Steroid-sparing

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19
Q

Mechanism of action of azathioprine?

A

Cleaved to 6 mecaptopurine (6-MP)
Functions as an anti-metabolite to decrease DNA and RNA synthesis by inhibiting purine synthesis
Selectively acts on cells that are highly mitotic

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20
Q

How is azathioprine eliminated?

A

Its active form (6-MP) is eliminated by TPMT

Individuals vary in the level of TPMT activity

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21
Q

What can happen to those who take azathioprine with low TPMT activity? What about high TPMT?

A

Likely to develop myelosuppression and increased risk of infection

High - under-treatment

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22
Q

Adverse effects of azathioprine?

A

Bone marrow suppression
Increased risk of malignancy, especially in transplant patients (as with all immunosuppressants)
Increased risk of infection
Hepatitis

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23
Q

Name the calcineurin inhibitors?

A

Tacrolimus

Cyclosporin

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24
Q

Mechanism of action of calcineurin inhibitors?

A

Prevent the production of IL-2 so active against T-helper cells

  • ciclosporin binds to cyclophilin protein
  • tacrolimus binds to tacrolimus-binding protein

Drug-protein complexes bind to calcineurin, inhibiting it

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25
What does calcineurin normally do?
Exerts phosphatase activity on the nuclear factor of activated T-cells This factor then migrates to the nucleus to start IL-2 transcription
26
How is ciclosporin produced?
By fungus
27
What are calcineurin inhibitors used for?
Transplant medicine Atopic dermatitis and psoriasis In RA/SLE patients with cytopenias as has no clinical effects on bone marrow
28
How is toxicity monitored with calcineurin-inhibitors?
Blood pressure | eGFR
29
Adverse effects of calcineurin inhibitors?
Nephrotoxicity leading to hyperkalaemia and hyperuraemia Hypertension Hyperlipidaemia Nausea, vomiting (hyperemesis), diarrhoea Hypertrichosis Hyperuricaemia All the H's Has drug interactions due to CYP
30
Mechanism of action of mycophenolate mofetil?
Metabolised to mycophenolic acid Inhibits the enzyme inosine monophosphate dehydrogenase required for guanosine synthesis Impairs B and T proliferation
31
Why are other rapidly dividing cells spared with MMF?
They have guanosine salvage pathways
32
Adverse effects of MMF?
Nausea, vomiting, diarrhoea | Myelosuppression
33
What is MMF used for?
Transplants Induction and maintenance therapy for lupus nephritis Toxicity can be precipitated by both renal and liver disease
34
What causes rheumatoid arthritis?
An antibody against IgG called rheumatoid factor mediates it They bind to form an immune complex This activates complements and sets of the inflammatory process Due to an imbalance of pro and anti-inflammatory factors
35
Mechanism of action of cyclophosphamide?
It is an alkylating agent - cross-links DNA so that it cannot replicate Has immunological effects including suppressing B and T cell activity
36
Indications for cyclophosphamide?
Lymphoma and leukaemia Lupus nephritis Wegener's granulomatosis (can lead to vasculitis) Polyarteritis nodosum
37
Absorption and metabolism of cyclophosphamide?
Prodrug - converted in the liver by CYP450 to active form | Active metabolite is 4-hydroxycyclophosphamide
38
How is cyclophosphamide excreted?
By the kidney
39
What can acrolein, a metabolite of cyclophosphamide do?
Toxic to bladder epithelium, can lead to haemorrhage cystitis Prevented through aggressive hydration/mesna
40
ADRs of cyclophosphamide?
Bladder cancer risk Lymphoma and leukaemia Infertility - risk relates to cumulative dose and patient age
41
How is cyclophosphamide monitored?
FBC | Adjust dose in renal impairment
42
Indications for methotrexate?
RA - first line treatment Malignancy Psoriasis Crohn's
43
Mechanism of action of methotrexate in malignancy?
Competitively and irreversible inhibits dihydrofolate reductase Acts as an antifolate - stops purine and thymidine synthesis so stops DNA, RNA and protein synthesis Greater effect on rapidly dividing cells
44
Mechanism of action of methotrexate in non-malignant disease?
Unknown - suggestions: - inhibit enzymes in purine metabolism, causing accumulation of adenosine which is a regulatory autocoid generated in cellular injury/stress, interacts with GPCRs on inflammatory and immune cells to regulate function - inhibit T cell activation - suppress intercellular adhesin molecule expression by T cells
45
Bioavailability of methotrexate?
Oral - 33% | IM - 76%
46
How can MTX be administered?
Orally IM SC
47
When is methotrexate given? Why?
Weekly - has a very long half-life of weeks to months
48
Important DDI with methotrexate?
It is 50% protein bound so can be displaced by NSAIDs
49
How is MTX excreted?
Renally
50
Adverse effects of MTX?
Mucositis Marrow suppression -these two respond to folic acid Hepatitis and cirrhosis Pneumonitis (hypersensitivity reaction) Infection risk Teratogenic and abortifacient
51
How is MTX monitored for toxicity?
Baseline CXR | FBC, LFT, U&Es, creatinine (baseline and monthly)
52
Indications for sulfasalazine?
RA and IBD
53
What is sulfasalazine made up of?
5-aminosalicyclate (5-ASA) and sulfapyridine
54
What is the absorption of sulfasalazine?
Travels the length of the upper GI tract where it is poorly absorbed until the colon In the colon, bacterial action causes the breakdown of sulfasalazine into 5-ASA and sulfapyridine (5-ASA is the active component)
55
How is sulfasalazine thought to treat RA?
Inhibit T-cell proliferation and IL-2 production, may cause T-cell apoptosis Reduce degranulation and chemotaxis of neutrophils
56
ADRs of sulfasalazine?
Nashua, fatigue, headache most common Myelosuppression, hepatitis, allergic rash Safe in pregnancy
57
Why does sulfasalazine contain the sulphapyridine moiety if this is what is responsible for most ADRs?
Allows 5-ASA to get to the colon
58
When is anti-TNF prescribed in RA?
After they have trialled methotrexate and one other DMARD
59
Why would anti-TNFs be stopped?
If there are any adverse events If there is failure to respond after 6 months (Very expensive and bad ADR profile)
60
Name some anti-TNF drugs
Infliximab Etanercept Adlimumab
61
Mechanism of action of anti-TNF?
Blocks TNF-α leading to -reduced inflammation - affects cytokine cascade, recruits leukocytes to joints leading to elaboration of adhesion molecules and production of chemokines - reduced angiogenesis - due to reduced VEGF and IL-8 levels - reduced joint destruction - due to less bone resorption and erosion, less MMPs and other destructive enzymes, less cartilage breakdown
62
ADRs of anti-TNF agents?
Increased risk of new malignancy in those with prior malignancy Risk of infection similar to other DMARDs Increased risk of skin/soft tissue infections TB reactivation and other intracellular bacterial infections Rituximab - development of hypogammaglobulinaemia
63
What does rituximab do?
Binds specifically to CD20 found on a subset of B cells - leads to activation of complement-mediated B cell lysis - initiation of cell-mediated cytotoxicity via macrophages - induction of apoptosis

Pharmacology (23 decks)

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