S8) Rheumatology and Immunosuppressants Flashcards

1
Q

Identify some diseases rheumatologists treat

A
  • Rheumatoid arthritis (RA)
  • Psoriatic Arthritis (PsA)
  • Systemic lupus erythematosus (SLE)
  • Systemic vasculitis
  • Autoimmune myositis
  • Spondyloarthropathy
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2
Q

Briefly illustrate the pathogenesis of rheumatoid arthritis

A

There is an imbalance between pro-inflammatory chemical mediators and anti-inflammatory chemical mediators

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3
Q

State 7 different possible ways of diagnosing RA

A
  • Morning stiffness ≥ 1 hour
  • Arthritis of ≥ 3 joints
  • Arthritis of hand joints
  • Symmetrical arthritis
  • Rheumatoid nodules
  • Serum rheumatoid factor
  • X-ray changes
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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

Outline the 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

What are the treatment goals in SLE & 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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7
Q

Identify five immunosuppressant drugs

A
  • Corticosteroids
  • Azathioprine
  • Ciclosporin
  • Tacrolimus
  • Mycophenolate mofetil
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8
Q

Identify five other disease-modifying anti-rheumatic drugs (DMARDs)

A
  • Methotrexate
  • Sulphasalazine
  • Anti-TNF agents
  • Rituximab
  • Cyclophosphamide
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9
Q

Describe 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

Methotrexate is the gold standard treatment for Rheumatoid Arthritis.

What are its other indications?

A
  • Malignancy
  • Psoriasis/Psoriatic arthritis
  • Crohn’s disease
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11
Q

In three steps, describe the mechanism of action for methotrexate on malignant cells, myeloid cells, GI & oral mucosa

A

⇒ Methotrexate competitively and reversibly inhibits dihydrofolate reductase (DHFR)

⇒ This prevents the conversion of dihydrofolate to active tetrahydrofolate in purine and thymidine synthesis

⇒ Thus, inhibits the synthesis of DNA, RNA and proteins (cytotoxic in S phase)

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12
Q

The mechanism of action of methotrexate in non-malignant disease e.g. RA, psoriasis is not clear. The mechanism is not via anti-folate action.

Suggest three possible mechanisms

A
  • Inhibition of T cell activation
  • Suppression of intercellular adhesion molecule expression by T cells
  • Inhibition of enzymes involved in purine metabolism → accumulation of adenosine
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13
Q

What is adenosine and what does it do?

A
  • Adenosine is a regulatory autocoid that is generated as a result of cellular injury or stress
  • It interacts with specific GPCRs on inflammatory and immune cells to regulate their function
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14
Q

How is methotrexate administered?

A
  • Oral
  • Intramuscular
  • Subcutaneous
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15
Q

How does the oral/intramuscular bioavailability change for methotrexate?

A
  • Mean oral bioavailability = 33% (13-76%)
  • Mean intramuscular bioavailability = 76%
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16
Q

When are doses given for methotrexate?

A

Weekly, not daily dosing – metabolised to polyglutamates with long half lives

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17
Q

Identify five ADRs of methotrexate

A
  • Mucositis
  • Marrow suppression
  • Hepatitis
  • Cirrhosis
  • Pneumonitis
18
Q

How can mucositis and marrow suppression as a result of methotrexate be treated?

A

Folic acid supplementation

19
Q

Why should a female patient on methotrexate not fall pregnant?

A

Methotrexate is highly teratogenic and abortifacient

20
Q

Which conditions are treated by sulphasalazine?

A

Sulphasalazine is used to treat inflammatory arthritis:

  • Rheumatoid arthritis
  • Psoriatic Arthritis
  • Spondyloarthritis
21
Q

What are the immunological effects of sulphazine on T cells?

A

T cell:

  • Inhibition of proliferation
  • Apoptosis (possible)
  • Inhibition of IL-2 production
22
Q

What are the immunological effects of sulphazine on neutrophils?

A

Neutrophil:

  • Reduced chemotaxis
  • Reduced degranulation
23
Q

Where is the site of release for sulphasalazine and what is the significance of this?

A
  • Site of release is the colon (poorly absorbed)
  • Effective in IBD
24
Q

The adverse effects of sulphasalazine are mainly due to sulfapyridine moiety.

What are they?

A
  • Myelosuppression
  • Hepatitis
  • Rash
25
Q

Which clinical conditions are treated by azathioprine in practice?

A
  • SLE
  • Vasculitis
  • Atopic dermatitis
  • Bullous skin disease
26
Q

Describe the mechanism of action of azathioprine

A
  • Cleaved to 6-mercaptopurine (6-MP)
  • Anti-metabolite decreases DNA and RNA synthesis
27
Q

What are the adverse effects of azathioprine?

A
  • Bone marrow suppression (monitor FBC)
  • Increased risk of malignancy
  • Increased risk of infection
  • Hepatitis (onitor LFT)
28
Q

When is mycophenolate mofetil used in practice?

A
  • Transplantation (primariliy)
  • Lupus nephritis (induction and maintenance therapy)
29
Q

What are the adverse effects of mycophenolate mofetil?

A
  • Nausea
  • Vomiting
  • Diarrhoea
  • Myelosuppression
30
Q

Describe the mechanism of action of mycophenolate mofetil

A
  • Inhibits inosine monophosphate dehydrogenase (required for guanosine synthesis)
  • Impairs B- and T-cell proliferation
  • Spares other rapidly dividing cells
31
Q

Cyclophosphamide is a cytotoxic alkylating agent which cross links DNA so that it cannot replicate.

What are its immunological effects?

A
  • Suppresses T cell activity
  • Suppresses B cell activity
32
Q

What are the indications for cyclophosphamide?

A
  • Lymphoma
  • Leukaemia
  • Solid cancers
  • Lupus nephritis
  • Wegener’s granulomatosis (ANCA vasculitis)
33
Q

Cyclophosphamide has significant toxicity and thus, some important considerations should be made.

What are these?

A
  • Increased risk of bladder cancer, lymphoma and leukaemia
  • Infertility
  • Monitor FBC
  • Adjust dose in renal impairment
34
Q

What are biopharmaceuticals / “biologicals”?

A
  • Biologicals are drugs made from substances extracted from living systems e.g. blood components, stem cell therapy
  • It uses recombinant DNA technology to produce substances nearly identical to the body’s own key signalling proteins e.g. GH, EPO
35
Q

What are the three effects of blocking TNF-α?

A
  • ↓ Inflammation
  • ↓ Angiogenesis
  • ↓ Joint destruction
36
Q

What are the risks of Anti-TNF therapy?

A

TB reactivation – TNFα is essential for development + maintenance of granulomata (released from macrophages in reponse to M TB infection)

37
Q

The biological, rituximab is very effective in RA.

Explain why by describing its mechanism of action

A
  • Binds specifically to a cell-surface marker CD20 found on a subset of B cells
  • Causes B cell apoptosis
38
Q

Identify two calcineurin inhibitors

A
  • Ciclosporin
  • Tacrolimus
39
Q

Describe the three uses of ciclosporin and tacrolimus in clinical practice

A
  • Transplantation
  • Atopic dermatitis
  • Psoriasis
40
Q

Why are calcineurin inhibitors not used in rheumatology?

A

Renal toxicity

41
Q

Describe the mechanism of action of calcineurin inhibitors

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