Pharmacology: Immunosuppression and disease modifying therapy in rehaumatology

Question 1

Give some examples of diseases managed by rheumatology

Answer 1

• Rheumatoid arthritis
• Systemic lupus erythematosus (severe joint pain, malar rash on face, headaches, raynauds)
• Systemic vasculitis
• Systemic sclerosis (excess production of collagen in the CT, affects skin, blood vessels, joints, etc)

Question 2

What is the pathology of rheumatoid arthritis?

Answer 2

Initially localised to the synovium which thickens (then called a pannus). The pannus releases lots of cytokines causing inflammation and damage to the cartilage and bone.

Question 3

What is the target for dugs treating rheumatoid arthritis?

Answer 3

The pro-inflammatory cytokines eg IL-1 inhibitors, TNF inhibitors

Question 4

How is rheumatoid arthritis diagnosed?

Answer 4

• morning stiffness lasting more than 30mins (the longer the stiffness the more significant)
• arthritis of 3 or more joints (small joints)
• symmetrical arthritis
• rheumatoid nodules (late stage and shouldnt be left that long)
• xray changes (shouldnt be left til that stage but may see some)

Question 5

Whats the difference between arthritis and arthralgia?

Answer 5

Arthritis is joint pain with swelling

Arthralgia is joint pain without swelling

Question 6

What is the mechanism of action of corticosteroids?

Answer 6

They inhibit all stages of T cell activation across all systems - therefore they have lots of side effects
Prevent IL-1 and IL6 production by macrophages

Question 7

List some common side effects of steroids

Answer 7

• cataracts
• hypertension
• immunocompromised
• peptic ulcers
• osteoporosis
• weight gain
• increased body hair
• easy bruising
• thinning of the skin

Question 8

What is azathioprine used for in practice?

Answer 8

An immunosuppressant used to treat:

• lupus and vasculitis (v effectice)
• RA but weak evidence
• IBD in severe cases
• atopic dermatitis

Question 9

What is a ‘steroid sparing drug’? Give some examples

Answer 9

A medication that allows the stopping of steroids early to avoid side effects
eg Azathioprine, methotrexate

Question 10

What is the mechanism of action of azathioprine?

Answer 10

It is broken down by the TPMT enzyme, the action of the metabolites is to inhibit purine and therefore DNA and RNA synthesis
(Individuals low in TMPT are at risk of myelosupression so need to test TMPT levels before prescribing)

Question 11

What are side effects of immunosuppressants?

Answer 11

• Myelosuppression is the main concern (need regular blood tests to monitor)
• Increased risk of malignancy
• Increased risk of infection
• Hepatitis

Question 12

Name some calcineurin inhibitors

Answer 12

Ciclosporin and tacrolimus

Question 13

What are some uses for calcineurin inhibitors?

Answer 13

• widely used in transplantation
• atopic dermatitis
• severe psoriasis

Question 14

What are the risks of ciclosporin?

Answer 14

Can cause renal toxicity
Raised potassium
Hypertension
Lots of drug interaction (CYP P450)

Question 15

What is the mechanism of action of calcineurin inhibitors?

Answer 15

Inhibit T helper cells (needed to communicate with B cells) which prevents production of IL2

Question 16

What is mycophenolate used to treat?

Answer 16

• primarily transplantation (but needs to be well monitored for risk of myelosuppression)
• good efficacy for treating new onset lupus

Question 17

What is the mechanism of action of mycophenolate?

Answer 17

Inhibits B cell and T cell proliferations selectively

Spares other rapidly dividing cells - more accurate rather than steroids

Question 18

What is cyclophosphamide used for?

Answer 18

• initially chemotherapy for solid cancers, lymphomas and leukaemias
• found to also treat lupus
• vasculitis
  (quickest acting drug - starts to work in 10 days vs 4-6weeks)

Question 19

How does cyclophosphamide work?

Answer 19

Cross links DNA to prevent replication

Suppresses both B and T cell activity

Question 20

What are the side effects of cyclophosphamide?

Answer 20

• one of the metabolites causes haemorrhagic cystitis of the bladder therefore need to give with mesna to bind up the metabolite and encourage drinking lots of water
• increases risk of bladder cancers long term
• infertility (doses changing so becoming less of an issue, but still 10-25%) may offer to freeze the eggs to have IVF

Question 21

What is methotrexate used to treat?

Answer 21

• v high doses for malignancy
• gold standard for RA
• psoriasis
• crohns disease
  Unlicensed: myopathies, steroid sparing in asthma

Question 22

What is the mechanism of action of methotrexate in malignancy?

Answer 22

Inhibits dihydrofolate reductase (competes against folate)

Inhibits the s phase of the cell cycle - cytotoxic to rapidly dividing cells such as malignany, GI mucosa

Question 23

What is the mechanism of action of methotrexate in non malignant diseases?

Answer 23

Mechanism not clear, but it is NOT via anti-folate action like it is in malignancy.

Question 24

What are the methods of administering methotrexate?

Answer 24

Orally - oral bioavailability is 35%
IM - bioavailability is 75%
Sub cutaneous - used if they cannot tolerate oral eg nausea aside effects

Question 25

What is the frequency of dose of methotrexate?

Answer 25

Weekly
SHOULD NEVER BE GIVEN DAILY - this is because the drug undergoes extensive metabolism and the metabolites have a long half life. Daily dosing would result in toxicitiy

Question 26

What are the adverse effects of methotrexate?

Answer 26

• mucositis
• marrow suppression
  (above only need folic acid to avoid so prescribe alongside)
• hepatitis, cirrhosis
• pneumonitis
• infection
• HIGHLY TERATOGENIC AND ABORTIFACIENT (because it is a folic acid antagonist)

Question 27

What is sulfasalazine used to treat?

Answer 27

Rheumatoid arthritis

Question 28

What are the immunological effects of sulfasalazine?

Answer 28

T cells: inhibits proliferation, possible apoptosis, inhibits IL2 synthesis
Neutrophils: reduced chemotaxis, reduced degranulation

Question 29

What are the side effects of sulfasalazine?

Answer 29

Usually only in the first few weeks then resolve

• myelosuppression
• hepatitis
• rash
• nausea and vomiting

Question 30

What RA drugs can be used in pregnancy?

Answer 30

Sulfasalazine

Question 31

What are biological therapies (generally)?

Answer 31

Therapies that have been synthesised using some human DNA eg recombinant DNA technology producing substances nearly identical to bodys own key signalling therapies
Most are mono-clonal antibodies which are made to specifically block any given substance in the body

Question 32

How does anti-TNF therapy work?

Give an example

Answer 32

Biological therapy:
Reduce inflammation by inhibiting cytokine release
Decrease joint destruction - less bone erosion, less cartilage breakdown
eg Humira

Question 33

What are the contraindications to anti-TNF therapy?

Answer 33

TNFa is needed to resolve TB so TB status must be tested and latent TB treated.
Even after treatment there is a risk of getting TB so patients screened for their TB risk status

Question 34

How does rituximab work?

Answer 34

Biological therapy:
Binds to a surface marker on CD20 which is found on a specific subset of B cells, causing apoptosis
Very effective in treating RA by preventing antibody production

Question 35

What is giant cell arteritis?

What are the symptoms?

Answer 35

A type of vasculitis where the arteries of the head become inflamed. Patients present with sudden onset severe peri-orbital headache, jaw claudication, malaise.

Question 36

How is giant cell arteritis diagnosed?

Answer 36

Temporal artery biopsy

Question 37

What are the complications of giant cell arteritis?

Answer 37

Clinical emergency - can get blockage of the opthalmic artery resulting in irreversible blindness.

Question 38

What is the treatment for giant cell arteritis?

Answer 38

High dose oral steroids eg 60mg prednisolone
Treatment should be started asap - dont wait for diagnosis. The steroids should be tapered off across 2 years, if they are suddenly stopped there can be adrenal insufficiency.