Immune Response

Question 1

Which drugs are used in the treatment of IBD? (4)

Answer 1

1. Azathioprine
2. Cyclosporin
3. Mercaptopurine
4. MTX
   (PLUS steroids and aminosalicylic acid derivatives: mesalazine and sulfasalazine)

*folic acid should be given to reduce the possibility of MTX toxicity (usually given weekly on a different day to MTX)

Question 2

What are the applications of immunosuppressant therapy? (3)

Answer 2

1. Suppression of transplant rejection
2. Chronic inflammatory conditions
3. Chronic autoimmune conditions

Question 3

Which immunosuppressant drugs are considered anti-proliferative? (2)

Answer 3

1. Azathioprine (metabolized to mercaptopurine)

2. Mycophenolate mofetil

Question 4

Which immunosuppressant drugs are calcineurin inhibitors? (2)

Answer 4

1. Cyclosporin

2. Taxrolimus

Question 5

Solid organ transplant patients are maintained on drug regimens, which may include which drugs? (6)

Answer 5

1. Azathioprine
2. Mycophenolate mofetil
3. Cyclosporin
4. Tacrolimus
5. Corticosteroids
6. Sirolimus

Choice is dependent on the type of organ, time after transplantation, and clinical condition of the patient

Question 6

Modification of tissue reactions caused by corticosteroids and other immunosuppressants may result in the rapid _______________

Answer 6

spread of infection

Question 7

Corticosteroids may suppress clinical signs of _____________ and allow diseases such as _____________ or ____________ to reach an advanced stage before being recognized

Answer 7

infection

septicaemia

tuberculosis

Question 8

Wherever possible, immunisation or additional booster doses for individuals with immunosuppression should be carried out either before __________________ occurs or deferred until _________________ has been seen

Answer 8

immunosuppression

an improvement in immunity

Question 9

Azathioprine is widely used for _________________ and it is also used to treat a number of auto-immune conditions, usually when _______________ therapy alone provides inadequate control. It is metabolised to mercaptopurine, and doses should be reduced when allopurinol is given concurrently

Answer 9

transplant recipients

corticosteroid

Question 10

Azathioprine is widely used for transplant recipients and it is also used to treat a number of auto-immune conditions, usually when corticosteroid therapy alone provides inadequate control. It is metabolised to ______________, and doses should be reduced when ____________ is given concurrently

Answer 10

mercaptopurine

allopurinol

Question 11

Azathioprine is widely used for transplant recipients and it is also used to treat a number of auto-immune conditions, usually when corticosteroid therapy alone provides inadequate control. It is metabolised to mercaptopurine, and doses should be ________________ (increased/reduced) when allopurinol is given concurrently

Answer 11

Reduced

Question 12

Mycophenolate mofetil is metabolised to mycophenolic acid which has a more selective mode of action than ________________.

Answer 12

azathioprine

Both anti proliferative immunosuppressants

Question 13

Compared to azathioprine, mycophenolate mofetil is associated with an increased rate of ______________ and a lower rate of _______________

Answer 13

Opportunistic infections (particularly due to tissue-invasive CMV)

Acute transplant rejection

Question 14

Prednisolone is widely used in oncology. It has a marked ______________ effect in acute lymphoblastic leukaemia, Hodgkin’s disease, and the non-Hodgkin lymphomas. It also has a role in ______________ when it may enhance ______________ and produce a sense of ______________.

Answer 14

antitumour

the palliation of symptomatic end-stage malignant disease

appetite

well-being

Question 15

The corticosteroids are also powerful _______________. They are used to prevent organ transplant rejection, and in high dose to treat rejection episodes

Answer 15

immunosuppressants

Question 16

Ciclosporin, a calcineurin inhibitor, is a potent immunosuppressant which is virtually non-_______toxic but markedly _______toxic

Answer 16

myelo

nephro

Question 17

Cyclosporin has an important role in organ and tissue transplantation, for prevention of graft rejection following bone marrow, kidney, liver, pancreas, heart, lung, and heart-lung transplantation, and for prophylaxis and treatment of _____________ disease.

Answer 17

graft-versus-host

Question 18

Tacrolimus is also a calcineurin inhibitor. Although not chemically related to ciclosporin it has a similar mode of action and side-effects, but the incidence of _______________ appears to be greater; _______________ has also been reported

Answer 18

neurotoxicity

cardiomyopathy

*Disturbance of glucose metabolism also appears to be significant

Question 19

Sirolimus is a non-calcineurin inhibiting immunosuppressant licensed for ___________ transplantation

Answer 19

renal

Question 20

Basiliximab is used for _______________ of acute rejection in allogeneic renal transplantation. It is given with ciclosporin and corticosteroid immunosuppression regimens; its use should be confined to specialist centres

Answer 20

prophylaxis

Question 21

Belatacept is a fusion protein and co-stimulation blocker that prevents __________ activation; it is licensed for prophylaxis of graft rejection in adults undergoing renal transplantation who are seropositive for the Epstein-Barr virus

Answer 21

T-cell

Question 22

________________ is a fusion protein and co-stimulation blocker that prevents T-cell activation; it is licensed for prophylaxis of graft rejection in adults undergoing renal transplantation who are seropositive for the Epstein-Barr virus

Answer 22

Belatacept

Question 23

What is the mechanism of action of ciclosporin?

Answer 23

Inhibits calcineurin, thereby reducing IL-2 release and inhibiting production of lymphokines and the cell-mediated immune response

Question 24

What are the licensed indications of ciclosporin? (8)

Answer 24

1. Severe UC refractory to CS
2. Severe active RA
3. Severe atopic dermatitis (short term, where conventional therapy has failed)
4. Severe psoriasis (where conventional therapy has failed)
5. Organ and bone-marrow transplantation (used alone)
6. Prevention of graft-versus-host disease
7. Nephrotic syndrome
8. Severe keratitis in dry eye disease that has not responded to treatment with tear substitutes

Question 25

Are ciclosporin brands interchangeable?

Answer 25

No; switching between formulations without close monitoring may lead to clinically important changes in blood cyclosporin concentration

Question 26

What are the contraindications to using ciclosporin? (5)

Answer 26

When used by eye: 1. Active or suspected ocular or peri-ocular infections 2. Ocular or peri-ocular malignancies or pre-malignant conditions When used systemically: 3. Malignancy 4. Uncontrolled HTN 5. Uncontrolled infection

Question 27

What are the adverse effects associated with ciclosporin? (11)

Answer 27

1. Nephrotoxicity 2. Hepatotoxicity 3. Fluid retention 4. HTN 5. Hyperkalemia 6. Hypertrichosis 7. Gingival hyperplasia 8. Tremor 9. Impaired glucose tolerance 10. Hyperlipidemia 11. Increased susceptibility to infection (Interestingly for an immunosuppressant, ciclosporin is noted by the BNF to be 'virtually non-myelotoxic') https://www.passmedicine.com/review/textbook.php?s=Cyclosporin

Question 28

In psoriasis, exclude _________________ before starting ciclosporin

Answer 28

malignancies (including those of skin and cervix); (biopsy any lesions not typical of psoriasis) and treat patients with malignant or pre-malignant conditions of skin only after appropriate treatment (and if no other option). Discontinue if lymphoproliferative disorder develops.

Question 29

Is ciclosporin safe to use during pregnancy and breastfeeding?

Answer 29

Avoid unless potential benefit outweighs the risk

Question 30

Is ciclosporin safe to use in patients with hepatic and/or renal impairment?

Answer 30

Caution in severe hepatic impairment due to risk of increased exposure (consider dose reduction and monitor blood level until stable) Avoid if baseline renal function is impaired (non-renal transplant patients)

Question 31

What are the monitoring requirements for patients taking systemic ciclosporin? (11)

Answer 31

1. Monitor whole blood ciclosporin concentration (trough level dependent on indication) 2. Dermatological and physical examination including BP and renal function at least twice before starting treatment for psoriasis or atopic dermatitis 3. monitor liver function if concomitant NSAIDs given 4. monitor serum K, especially in renal dysfunction (risk of hyperkalemia) 5. monitor serum magnesium 6. measure blood lipids before treatment and after the first month of treatment 7. investigate lymphadenopathy that persists despite improvement in atopic dermatitis 8. monitor kidney function (dose dependent in crease in serum Cr and urea during first few weeks may necessitate dose reduction in transplant patients or discontinuation in non-transplant patients) 9. monitor BP (discontinue if HTN develops) 10. in long-term management of nephrotic syndrome, perform renal biopsies yearly 11. in RA, measure serum Cr at least twice before treatment and every 2 weeks for the first 3 months, then every month for a further 3 months, then every 4-8 weeks

Question 32

What advice should be given to patients and carers regarding ciclosporin? (3)

Answer 32

1. Should be counseled to avoid using different formulations of ciclosporin 2. Avoid excessive exposure to UV light including sunlight (in psoriasis and atopic dermatitis, avoid use of UVB and PUVA) 3. When taking ciclosporin by eye, increased risk of blurred vision may affect ability to drive and perform skilled tasks

Question 33

What are the indications of mycophenolate mofetil?

Answer 33

Prophylaxis of acute rejection in renal, cardiac, and hepatic transplantation (in combination with a CS and ciclosporin)

Question 34

Is mycophenolate mofetil use associated with increased risk of malformations or miscarriage in pregnancies where the father was taking mycophenolate medicines?

Answer 34

No, however they are genotoxic and a risk cannot be fully excluded. Therefore, male patients or their female partner should use effective contraception during treatment and for 90 days after discontinuation

Question 35

Mycophenolate should be used with caution in which patients? (6)

Answer 35

1. Patients with GI disease (due to increased risk of hemorrhage, ulceration and perforation) 2. Children (higher incidence of side effects) 3. Patients with delayed graft function 4. Elderly 5. Patients with increased susceptibility to skin cancer (avoid exposure to strong sunlight) 6. Patients taking other immunosuppressants (increased risk of hypogammaglobulinemia or bronchiectasis)

Question 36

Measure serum immunoglobulin levels if recurrent infections develop in patients taking mycophenolate and consider _______________ or ______________ if persistent respiratory symptoms such as cough and dyspnoea develop

Answer 36

bronchiectasis pulmonary fibrosis

Question 37

What is the mechanism of action of mycophenolate mofetil (MMF)?

Answer 37

Blocks purine synthesis by inhibition of IMPDH thereby inhibiting proliferation of B and T cells

Question 38

Wha are the common or very common side effects of mycophenolate? (26)

Answer 38

1. Acidosis 2. Alopecia 3. Anemia 4. Decreased appetite 5. Arthralgia, gout 6. Bone marrow disorders 7. Constipation, diarrhea, GI discomfort and hemorrhage, burping 8. Chills, fever 9. Cough, dyspnea 10. Depression, anxiety 11. Neoplasms 12. Drowsiness, headache, malaise, confusion 13. Dyslipidemia 14. Electrolyte imbalance, hyperuricemia, edema 15. Hyperglycemia 16. HTN, hypotension 17. Increased risk of infection, sepsis 18. Insomnia 19. Leukocytosis, leukopenia, thrombocytopenia 20. Oral disorders 21. Pancreatitis 22. Paresthesias 23. Renal impairment 24. Respiratory disorders 25. Seizure, tremor 26. Weight loss

Question 39

Is mycophenolate safe to use in pregnancy and breastfeeding?

Answer 39

No; Women should use at least 1 method of effective contraception before and during treatment, and for 6 weeks after discontinuation—2 methods of effective contraception are preferred. Male patients or their female partner should use effective contraception during treatment and for 90 days after discontinuation *2 pregnancy tests 8-10 days apart are recommended before beginning treatment Congenital malformations and spontaneous abortions reported when used in pregnancy Avoid in breastfeeding

Question 40

What are the monitoring requirements for patients taking mycophenolate?

Answer 40

Monitor full blood count every week for 4 weeks then twice a month for 2 months then every month in the first year *consider interrupting treatment if neutropenia develops

Question 41

What advice should be given to patients and careers regarding mycophenolate? (3)

Answer 41

1. Ensure female patients understand the need to comply with the pregnancy prevention advice AND advise them to seek immediate medical attention if there is a possibility of pregnancy 2. male patients planning to conceive children should be informed of the implications of both immunosuppression and the effect of the prescribed medications on the pregnancy 3. Patients should be warned to report immediately any signs or symptoms of bone marrow suppression e.g. infection or inexplicable bruising or bleeding

Question 42

Compared to ciclosporin, tacrolimus is associated with a lower incidence of ____________, ___________, and ____________, but a higher incidence of ______________ and ______________

Answer 42

Acute rejection HTN Hyperlipidemia Impaired glucose tolerance DM

Question 43

What are the major contraindications to using topical tacrolimus? (7)

Answer 43

1. Application to malignant or potentially malignant skin lesions 2. Application under occlusion 3. Avoid contact with eyes and mucus membranes 4. Congenital epidermal barrier defects 5. Generalized erythroderma 6. Immunodeficiency 7. Infection at treatment site

Question 44

What is the mode of action of tacrolimus?

Answer 44

Inhibits calcineurin to down-regulate T cell activity and cell-mediated immune activity

Question 45

_______________ has been reported to occur primarily in children with tacrolimus blood trough concentrations much higher than the recommended maximum levels.

Answer 45

Cardiomyopathy; Patients should be monitored by echocardiography for hypertrophic changes—consider dose reduction or discontinuation if these occur

Question 46

Tacrolimus is contraindicated in patients with a history of hypersensitivity to _________________

Answer 46

Macrolides

Question 47

Is tacrolimus safe to use in pregnancy and breastfeeding?

Answer 47

Avoid in both unless benefits outweigh risks. Crosses the placenta and increases risk of premature delivery, intra-uterine growth restriction, and hyperkalemia

Question 48

Can tacrolimus be prescribed in patients with hepatic impairment?

Answer 48

Caution in severe impairment; consider dose reduction.

Question 49

After initial dosing, and for maintenance treatment, tacrolimus doses should be adjusted according to ________________

Answer 49

whole-blood concentration

Question 50

What monitoring is required for patients taking tacrolimus? (5)

Answer 50

1. Monitor whole blood-tacrolimus trough concentration (especially during episodes of diarrhea) 2. Monitor BP 3. ECG (for hypertrophic changes, risk of cardiomyopathy) 4. Fasting blood glucose concentration 5. Hematological and neurological (including visual) and coagulation parameters, electrolytes, hepatic and renal function

Question 51

Effective contraception must be used during treatment and for 12 weeks after stopping ________________

Answer 51

Sirolimus

Question 52

Monitor whole blood-sirolimus trough concentration (_______________ patients may require higher doses)

Answer 52

Afro-Caribbean

Question 53

What 3 things need to be monitored when giving tacrolimus with ciclosporin?

Answer 53

1. Kidney function 2. Lipids 3. Urine proteins