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PPE - Pharmacology > Immunosupression and Rheumatoid disease > Flashcards

Immunosupression and Rheumatoid disease Flashcards

1
Q

What is rheumatoid arthritis?

A

An autoimmune multi-system disease
Initially localized to synovium
Inflammatory change and proliferation of synovium (pannus) leading to dissolution of cartilage and bone
So there is an imbalance of more pro-inflammatory factors to anti-inflammatory factors

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2
Q

How do we diagnose RA?

A 
It is diagnosed clinically but these are the major signs
- Morning stiffness > 1 hour
- Arthritis of > 3 joints
- Arthritis of hand joints
- Symmetrical arthritis
- Serum rheumatoid factor
And there are other signs, but if you see these it is far too late and should have been treated ages ago.
- Rheumatoid nodules
- X-ray changes
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3
Q

What are RA treatment goals?

A

Symptomatic relief

Prevention of joint destruction

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4
Q

What is the general RA treatment strategy?

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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5
Q

What are SLE and vasculitis?

A

Both are multi-systemic, needs to be two or more systems involved(Heart and lungs are very connected so need more than these two alone)
Systemic Lupus Erythematosus -SLE
It is a systemic autoimmune disease
Vasculitis
Inflammation of blood vessels caused by an autoimmune response

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6
Q

What are the treatment goals in SLE and vasculitis?

A

Symptomatic relief e.g. arthralgia, Raynaud’s phenomenon in SLE
Reduction in mortality - induction of disease remission then maintenance
Prevention of organ damage e.g. renal failure in SLE
Reduction in long term morbidity caused by disease and by drugs

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7
Q

Name some immunosuppressants.

A 
Corticosteroids
Azathioprine
Ciclosporin
Tacrolimus
Mycophenolate mofetil
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8
Q

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

A 
Methotrexate (Most used)
Sulphasalazine
Anti-TNF agents
Rituximab
Cyclophosphamide (cytotoxic) (Can be dangerous)
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9
Q

What is the mechanism of action of corticosteroids?

A 
Prevent interleukin (IL)-1 and IL-6 production by macrophages
Inhibit all stages of T-cell activation
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10
Q

What are the key 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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11
Q

What is azathioprine used for in practice?

A

SLE & vasculitis - as maintenance therapy
RA - weak evidence for efficacy
Inflammatory bowel disease
Bullous skin disease
Atopic dermatitis
Many other uses as ‘steroid sparing’ drug

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12
Q

What is azathioprine’s mechanism of action?

A

Cleaved to 6-mercaptopurine (6-MP)

Functions as an anti-metabolite to decrease DNA and RNA synthesis

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13
Q

What is the pharmacodynamic significance of azathioprine?

A

6-MP is metabolized by thiopurine methyltransferase
TPMT gene highly polymorphic
Individuals very markedly in TPMT activity
Those with low or absent TPMT levels are likely to develop myelosuppression (Bone marrow suppression)
Therefore test this before prescribing

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14
Q

What are the adverse effects of azathioprine?

A 
Bone marrow suppression
- Monitor FBC
Increased risk of malignancy
- Especially transplanted patients
Increased risk of infection
Hepatitis
- Monitor LFT
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15
Q

Name 2 calcineurin inhibitors.

A

Ciclosporin and Tacrolimus

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16
Q

Name the mechanism of action of calcineurin inhibitors.

A

Active against helper T-cells, preventing the production of IL-2 via calcineurin inhibition

Calcineurin normally exerts phosphatase activity on the nuclear factor of activated T cells. This factor then migrates to the nucleus to start IL-2 transcription

17
Q

How are calcineurin inhibitors used in practice?

A

Widely used in transplant medicine
Also indicated for atopic dermatitis and psoriasis
Not commonly used in rheumatology
- Concerns about toxicity
Ciclosporin useful in RA/SLE patients with cytopenias as it has no clinical effect on bone marrow

(Monitor for toxicity - check BP and eGFR

18
Q

What are some adverse effects of calcineurin inhibitors?

A

Nephrotoxicity
Hypertension
Hyperlipidemia
Nausea, vomiting, diarrhoea
Hypertrichosis (abnormal hair growth)
Gingival hyperplasia (Increased gum growth)
Hyperuricemia (High uric acid in the blood)
Multiple drug interactions are possible, primarily with agents affecting the cytochrome P450 system

19
Q

What is the mechanism of action of Mycophenolate mofetil?

A

It is a prodrug
It inhibits the enzyme inosine monophosphate dehydrogenase (required for guanosine synthesis)
Impairs B and T cell proliferation
Spare other rapidly dividing cells (because of the presence of guanosine salvage pathways in other cells)

20
Q

What are some adverse effects of Mycophenolate acid?

A

Most common include nausea, vomiting, diarrhoea

Most serious is myelosuppression

21
Q

What is Mycophenolate mofetil used for in practice?

A

Primarily in transplantation

Good efficacy as induction and maintenance therapy for lupus nephritis
In transplantation medicine drug levels of the active metabolite, mycophenolic acid may be monitored
Toxicity may be precipitated by both renal and liver disease

22
Q

Tell me about Cyclophosphamide.

A 
Alkylating agent
- Cross links DNA so that it cannot replicate
Many immunological effects
- Suppresses T cell and B cell activity
Indication:
- Lymphoma, leukaemia
- Lupus nephritis
- Wegener's granulomatosis
- Polyarteritis nodosum
23
Q

What sre the risks of using Cyclophosphamide?

A

Significant toxicity:
- Increased risk of bladder cancer, lymphoma and leukaemia
- Infertility
- Monitor FBC
- Adjust dose in renal impairment
MMF may supersede cyc in lupus nephritis
Trial of MMF versus cyc for vasculitis is underway

24
Q

What is Methotrexate used for in practice?

A 
Gold standard treatment for RA
Other indications:
- Malignancy
- Psoriasis
- Crohn's disease
25
Q

What is the mechanism of action in methotrexate?

A

It competitively and reversibly inhibits dihydrofolate reducate (DHFR)
The affinity of methotrexate for DHFR in 1000X that of folate
DHFR catalyses the conversion of dihydrofolate to the active tetrahydrofolate, the key carrier of on-carbon units in purine and thymidine synthesis
Methotrexate, therefore inhibits the synthesis of DNA, RNA and proteins
Methotrexate acts specifically during DNA and RNA synthesis, and so has greater toxic effect on rapidly dividing cells

BUT this is only works for cancer treatment, the mechanism for RA treatment is unknown

26
Q

What are some of the theories of methotrexates mechanism of action for treatment of non-malignant diseases?

A
  • Inhibition of enzymes involved in purine metabolism,
    leading to accumulation of adenosine. Adenosine is a
    regulatory autocoid that interacts with specific
    G-protein coupled receptors on inflammatory and
    immune cells to regulate their function
  • The inhibition of T cell activation
  • Suppression of intercellular adhesion molecule
    expression by T cells
27
Q

What is special about the dosing of methotrexate?

A

WEEKLY NOT DAILY DOSING.

Metabolized to polyglutamates with long half lives

28
Q

What are some adverse effects of methotrexate?

A

Mucositis
Marrow suppression
(Both respond to folic acid supplementation)

Hepatitis, cirrhosis
Pneumonitis
infection risk

Highly teratogenic, abortifacient

29
Q

How do we monitor methotrexate toxicity?

A

Baseline chest x-ray
Baseline FBC, LFT, U + E + creatinine
Regular, e.g. monthly FBC, LFT etc

30
Q

What are the effects of Sulfalazine?

A

T cell

  • Inhibition of proliferation
  • Possible T cell apoptosis
  • Inhibition of IL-2 production

Neutrophil

  • Reduced chemotaxis
  • Reduced degranulation
31
Q

What are the adverse effects of sulfasalazine?

A 
Myelosuppression
Hepatitis
Rash
Nausea
Abdominal pain/vomiting
32
Q

What are the guidelines about using anti-TNF drugs?

Why are these strict?

A

Only prescribed is they have had a trial of MTX and another DMARD for two months

Only prescribed if there is evidence of clinically active RA

Treatment is withdrawn if patient experiences an adverse event or fails to respond

Anti-TNF drugs are very expensive

33
Q

What are the effects of anti-TNF drugs?

A

Decrease in inflammation

  • Cytokine cascade
  • Recruitment of leukocytes to joint

Decrease in angiogenesis
- VEGF and IL-8 levels

Decrease in joint destruction

34
Q

What are some specific adverse effects of anti-TNF drugs?

A

No increase in malignancy, but an increase in recurrence of malignancy in patients with previous malignancy
Risk of serious infection, in anti-TNF increased risk of skin/soft tissue infections

TB reactivation and other intracellular bacterial infections

35
Q

Name some anti-TNF drugs

A

Adalimumab
Etanercept
Infliximab

36
Q

How does rituximab work?

A

It binds specifically to a unique cell-surface marker CD20 which is found on a subset of B cells, but not stem cells, pro B cells, plasma cells or any other cell type

And so it’s mechanism of action is B cell depletion by:

  • Activation of complement mediated B cell lysis
  • Initiation of cell mediated cytotoxicity via macrophages
  • Induction of apoptosis
37
Q

What are some long term considerations of rituximab?

A

Development of hypogammaglobulinaemia and increased risk of infection
Development of hypersensitivity or blocking immune responses

PPE - Pharmacology (24 decks)

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