Immune-related Toxicities

Question 1

Difference between true allergy and pseudoallergy in terms of components involved?

Answer 1

True allergy: mediators, lgE, lgG, lgM and T cells, formation of immune complexes

Pseudoallergy: mediators (histamine, PGs, kinins), does NOT involve immune system or any Ab

Question 2

What are the drugs that can cause pseudoallergy? (3)

Answer 2

• Vancomycin
• ACE/ Sacubitril
• NSAIDs

Question 3

What are the different types of hypersensitivity reactions? (6)

Which type is SLE?

Answer 3

1. Anaphylaxis
2. Serum-sickness/ drug fever
3. Drug-induced autoimmunity (SLE)
4. Vasculitis
5. Respiratory
6. Hematologic

Question 4

Drugs that can cause anaphylaxis? (3)

Answer 4

Penicillins, NSAIDs, insulins

Question 5

Drugs that can cause serum-sickness/ drug fever? (1)

Answer 5

Antibiotics

Question 6

Drugs that cause drug-induced autoimmunity? (2)

Answer 6

Methyldopa → hemolytic anaemia
Phenytoin → hepatitis

Question 7

Drugs that cause vasculitis? (2)

Answer 7

Allopurinol, Thiazide

Question 8

Drugs that cause respiratory hypersensitivity? (3)

Answer 8

NSAIDs, Bleomycin, Nitrofurantoin

Question 9

Drugs that cause SCAR? (3)

Answer 9

Allopurinol, anticonvulsants and sulflonamides

Question 10

First-line Tx for anaphylaxis and MOA?

What should we do if the pt manages to reach the hospital? (4)

Answer 10

Epinephrine (adrenaline)
MOA: counteracts bronchoconstriction and vasodilation

If pt reaches hospital:
- IV fluids (restore volume/ BP)
- Intubation to save airway (if necessary)
- Norepinephrine (noradrenaline) if in shock (severe hypotension)
- Steroids, glucagon, diphenhydramine (H1) + ranitidine (H2)

Question 11

Tx for SCAR?
Non-pharmacological and pharmacological?

Use of which medication is controversial?

Answer 11

Supportive care (similar to burn pts):
- Wound care
- Nutritional support
- Fluids
- Temperature regulation
- Pain management
- Prevention of infections

May use intravenous immunoglobulin (IVIG) or cyclosporine

Steroid use controversial

Question 12

In what type of people are SLE most prevalent?

Answer 12

More prevalent in females, non-white > white (African descent highest)

Question 13

Which drugs have the highest risk of causing SLE? (3) (HPQ)

Other drugs?

Answer 13

Procainamide, hydralazine, quinidine

Others: minocycline, isoniazid, methyldopa, carbamazepine, TNFα inhibitors

Question 14

What are the clinical presentation (labs) of SLE in terms of blood count?

Answer 14

• Haemolytic anaemia: ↓ RBC
• ↓ WBC / ↓ lymphocytes
• ↓ PLT

Question 15

What are the clinical presentation (labs) of SLE in terms of immunologic components?

Answer 15

Non-exhaustive:
- Antinuclear Ab (ANA)
- Antidouble-stranded DNA (dsDNA)
- Anti-Smith Ab (anti-Sm)
- Antinuclear ribonucleoprotein (anti-RNP)
- Low complement (C3, C4, CH50)

Question 16

Name the drugs used for Tx of SLE (5) (BISHN)

Answer 16

1. Hydroxychloroquine
2. NSAIDs
3. Steroids
4. Biologics
5. Immunosuppressants

Question 17

When do we use hydroxychloroquine for SLE? MOA?

How long to achieve effects?

Answer 17

ALL SLE patients

MOA:
- Prevents flare
- Improves long term survival
- Anti-inflammatory, immunomodulatory and anti-thrombotic effects

• 4-8w to achieve effects

Question 18

Impt ADE of hydroxychloroquine?

What must we monitor?

Answer 18

Retinal toxicity > 10% prevalence after 20 years use

Need retinal checks

Question 19

Elaborate on NSAIDs for SLE and its ADEs

Hence what must we check before initiation?

Answer 19

First-line for acute s/sx

ADEs:
- Worsen kidney function
- ↑ cardiac risk
- GI bleed

Caution in worsening lupus nephritis, check kidney function beforehand

Question 20

Elaborate on use of steroids for SLE (what type of steroid used?)

MOA? ADEs (systemic and topical)?

Answer 20

Glucocorticoids

MOA:
- Control flares
- Maintain low disease activity

ADEs (systemic):
- Osteoporosis
- Cataracts
- Glaucoma
- Hyperglycemia/ diabetes
- HTN
- Dyslipidemia
- Skin thinning
- Weight gain
- Fat redistribution
- Sleep/ mood disturbances

Topical:
- Skin atrophy

Question 21

How do corticosteroids cause HPA axis suppression?

Answer 21

1. Exogenous corticosteroids → ↓ secretion of Corticotropin-Releasing Hormone (CRH) from hypothalamus and Adrenocorticotropic Hormone (ACTH) from pituitary gland
2. Overtime, HPA axis inactive (pts cannot produce own cortisols)
3. End result: adrenal suppression

Question 22

How much steroid use before adrenal suppression occurs?

Answer 22

• Doses > 5mg prednisone daily for > 3w (but actually IRL no clear “cut off”)
• Maintain suspicion as long as pts have taken corticosteroids before/ are taking it currently

Question 23

Type of biologics used for SLE? (2)

MOA? What should we note about live vaccines?

Answer 23

Belimumab, Rituximab

MOA:
- Targets and disrupts functioning of B cells

DO NOT administer live vaccines in pts taking biologics

Question 24

Name the immunosuppressants used for SLE (6)

Note: immunosuppressants are steroid sparing :)

Answer 24

1. Cyclophosphamide (PO, IV)
2. Mycophenolate
3. Azathioprine
4. Methotrexate
5. Mycophenolate Mofetil
6. Cyclosporine
7. Tacrolimus

Question 25

ADEs of cyclophosphamide? Who should avoid?

Answer 25

- Hemorrhagic cystitis - Bladder malignancy - INFERTILITY* Avoid if pt has Hx of cystitis/ bladder problems

Question 26

How often do you monitor labs for SLE? What labs do you monitor?

Answer 26

Regular labs every 1-3 mths with active disease, 6-12 mths if stable Monitor urinalysis, anti-dsDNA Ab, complement C3, C4 levels, C-reactive protein, full blood counts, liver function

Question 27

What is a complication of SLE? What happens during SLE?

Answer 27

Antiphospholipid syndrome (APS) - High risk of clotting - High risk of pregnancy morbidity (no. of miscarriages can also be a diagnostic criteria)

Question 28

Tx of APS SLE? 1. Primary thromboprophylaxis 2. Secondary thromboprophylaxis 3. Protective

Answer 28

1. Primary thromboprophylaxis: aspirin 2. Secondary thromboprophylaxis: thrombophylaxis 3. Protective: hydroxychloroquine

Question 29

Drugs used for induction of immunosuppression? 1. Lymphocyte-depleting agents 2. Immune modulators which prevent activation & proliferation of T cells

Answer 29

Lymphocyte-depleting agents: - Antithymocyte globulin - Alemtuzumab (off-label) Prevent activation & proliferation of T cells: - Basiliximab

Question 30

Drug classes and drugs under each class that are used for maintenance Tx of immunosuppression? Note: ALL need TDM!

Answer 30

*Calcineurin inhibitors: cyclosporin*, tacrolimus* Anti-metabolites: mycophenolate*, azathioprine Corticosteroids mTOR inhibitors: sirolimus*, everolimus* Biologics: adalimumab, belatacept

Question 31

What complications can azathioprine and mycophenolate cause? (2)

Answer 31

- Bone marrow suppression - Hepatotoxicity

Question 32

What complications can steroids and CNI cause? (3)

Answer 32

- HTN - Hyperlipidemia - Hyperglycemia

Question 33

What do we give pts for induction therapy for immunosuppression? Why?

Answer 33

Give biologic Tx to delay use of CNI (CNI is nephrotoxic)

Question 34

What is a common combination of maintenance agents for immunosuppression?

Answer 34

Calcineurin inhibitor + glucocorticoids + mycophenolate

Question 35

What is a combination we should avoid for maintenance agents for immunosuppression and why?

Answer 35

Calcineurin inhibitor + mTOR due to ↑ nephrotoxicity

Question 36

How should we treat CNI-induced renal toxicity? What should we AVOID?

Answer 36

First-line: DHP CCB Avoid ACEi or diuretics

Question 37

DDIs to take note of for drugs under immunosuppression maintenance Tx?

Answer 37

CNI (tacrolimus, cyclosporine) and mTORi → CYP3A4 and P-glycoprotein substrates