HYPERSENSITIVITY

Question 1

drug/ food/ etc allergies

Answer 1

• Immunologically mediated hypersensitive reaction to sub in sensitised person

Response of immune system to antigenic sub leads to host tissue damage (organ specific// generalised systemic reaction)

6-10%

Question 2

what is present in allergy

Answer 2

○ IgE released
○ Type 1 Immediate hypersensitivity
§ TH2 cells, IgE Ab, mast cells, eosinophils
§ Mast cell-derived mediators
§ Cytokine-mediated inflam
§ Eosino, neut

Question 3

Immune response:

Answer 3

• Hives
• Rash
• Hypotension
• Bronchospasm
• Anaphylaxis
• Vasculitis

Question 4

Drug hypersensitivity

Answer 4

• Adverse events that clinically resemble drug allergy
• Not proven to be associated with immune response

Question 5

Drug hypersensitivity what is present

Answer 5

• Drug release mast cell
• Basophil derived mediators
• By pharmacologic or physical effect
•Not IgE

Question 6

eg of drug hypersensitivity

Answer 6

• Vancomycin
• Red man syndrome
• Direct release of histamine when infused too quickly

• ACE/ sacubitril
• Angioedema
• Inhibit breakdown of bradykinin
• Inflammation, vasodilation, permeation

• NSAID
• Induced asthma
• Alter metabolism of prostaglandins
•Vasoconstriction

Question 7

effector of allergic / DH reactions

Answer 7

○ Involve major components of INNATE/ ADAPTIVE immune
§ Cellular elements: macro, T, B lymph, mast cells
§ Ig E
§ Complements
§ Cytokines

○ Release of pharmacologically active chemical mediators
§ histamine
§ Platelet-activating factor – platelet aggregation
§ Prostaglandin
§ Thromboxane
§ Leukotrienes – bronchodilators

Question 8

Clinical manifestation of drug allergies/ hypersensitive rxn

Answer 8

anaphylaxis
serum sickness (drug fever)
drug-induced autoimmunity
vasculitis
respiratory
hematologic
Serious cutaneous ADR

Question 9

Anaphylaxis

Answer 9

Acute, life threatening reaction
Multiple organ systems involved
• Risk of fatality within first few hrs (acute)
○ Skin: hives, itch, flushed skin, swelling of lips, tongue, throat, face
○ Airway: bronchospasm, trouble breathing, chest tightness
○ CNS
○ CVS: low BP, fast HR
○ GIT

• Most reported: penicillin, NSAID, insulin

Question 10

Serum sickness/ drug fever

Answer 10

• Circulating immune complexes (antigen in body, drug/ transplant)
• Systemic symptoms
• Fever, malaise, rash

Antibiotics

Question 11

Drug induced autoimmunity

Answer 11

• Systemic lupus erythematosus (SLE)
• Hemolytic anemia: Methyldopa
•Hepatitis: phenytoin

Question 12

vasculitis

Answer 12

• Inflammation and necrosis of blood vessel walls
• Limited to skin, or may involve multiple organs
• Kidney, liver etc

Allopurinol, thiazide (diuretic)

Question 13

respiratory

Answer 13

• Asthma: NSAID
• acute infiltrative and chronic fibrotic pulmonary reactions: bleomycin (chemo)

• nitrofurantoin

Question 14

Hematologic

Answer 14

• Eosinophilia common manifestation of DH
• Hemolytic anemia(RBC)
• Thrombocytopenia(PLT)
• Agranulocytosis
○ Low neut count
○ Low granulocytes

Question 15

Serious cutaneous AD

Answer 15

• Drug rash with eosinophilia and systemic symptoms (DRESS)
•mucocutaneous disorders
•steven-Johnson syndrome
•toxic epidermal necrolysis

Question 16

• Drug rash with eosinophilia and systemic symptoms (DRESS)

Answer 16

• Triad:
1) Rash
2) Eosinophilia
3) Internal organ involved
i. Hepatitis, carditis, interstitial nephritis, odynophagia

• Allopurinol, anticonvulsants
      • 10% mortality

Question 17

Stevens-Johnson syndrome (SJS)

Answer 17

• Bullous or blistering disorders. Dermatologic emergencies
• Can progress to:
○ Mucous mem erosion
○ Epidermal detachment
○ <10% detachment of BSA

• Antibiotics (sulfonamides)
• 1-5% mortality

Question 18

Toxic epidermal necrolysis (TEN)

Answer 18

• Bullous or blistering disorders. Dermatologic emergencies
• Can progress to:
○ Mucous mem erosion
○ Epidermal detachment
○ >30% detachment of BSA

• Antibiotics (sulfonamides)
• 10-70% mortality

Question 19

Genetic disposition for drug A/ HS

Answer 19

1) HLA (human leukocyte antigen) alleles incr susceptibility to several DHS syndrome

2) Metabolic deactivation of drugs affected by genetics
§ Phase 1,2 metabolism

Question 19

Genetic disposition for drug A/ HS

Answer 19

1) HLA (human leukocyte antigen) alleles incr susceptibility to several DHS syndrome

2) Metabolic deactivation of drugs affected by genetics
§ Phase 1,2 metabolism

Question 20

Therapeutic agents for A/ HS rxn: anaphylaxis

Answer 20

• Restore resp and CVS function
1) Epinephrine (adrenaline)
• Hosp
• IV fluids – restore vol, BP
• Intubation – save airway collapse
• Norepinephrine – SHOCK
• Steroids, glucagon
• diphenhydramine, ranitidine
•Antihistamines

Question 21

Therapeutic agents for A/ HS rxn: Serious cutaneous ADR

Answer 21

• Less defined, standardized
• Manage like burn pts
1) Supportive care
a. Wound care
b. Nutritional support
c. Fluids
d. Temp regulation (ice bathe)
e. Pain management
f. Prevent infections
2) Steroids use ?

Question 22

Autoimmune diseases

Answer 22

condition where body attacked by own immune system

Question 23

Autoimmune diseases caused by:

Answer 23

○ Genetic background
○ Environmental stimuli: smoke, infections, drug use
= incr autoimmune disorder developed

Question 24

Autoimmune diseases difficult to treat

Answer 24

§ Do not respond to treatment/ lose response/ do not tolerate/ ADR § Drugs are poorly indicated, off-label □ Not researched sufficiently on □ Greater variability of treatment among centers and specialists § Costly drugs § Stigma, weakness, less likely to seek help/ diagnosis

Question 25

SLE Clinical manifestation

Answer 25

• Disease fluctuates with periods of remission, flares, progression • BUTTERFLY Rash on face • Muscle and joints ○ Joints swollen, tender ○ Arthritisaches ○ Swollen joints • Heart ○ Endocarditis ○ Atheroclerosis • Lung ○ Pneumonitis ○ Pul emboli ○ Pul hemorrhage • Kidney ○ Blood in urine • Blood ○ Anemia ○ High BP ○ Low blood counts: WBC, RBC, PLATELETS

Question 26

SLE assiociations

Answer 26

• Auto-Ab production (multi-system disease) • More prevalent in females • Genetic disposition + environ factors • Smoke, infections, drugs • Mortality 2.6-3x > general pop • CVS, renal, infections

Question 27

Pathophysiology

Answer 27

• Disorder of innate & adaptive • T, B lymph activation and signaling altered • Abnormal CL of apoptotic debris ○ (containing nuclear material) ○ Not cleared fast enough etc • Stimulate immune response ○ Incr n.o. plasma cells inactive SLE ○ Produce autoAb --> tissue damage § Target nucleic acid § Nuclear proteins

Question 28

Clinical presentation (organs)

Answer 28

1) lupus nephritis 2) neuropsychiatric lupus 3) cardiovascular CVS

Question 29

1) lupus nephritis

Answer 29

• Class I - minimal mesangial • Class II - mesangial proliferative • Class III - focal • Class IV - diffuse •Class VI - advanced sclerosing (cancer)

Question 30

2) Neuropsychiatric lupus

Answer 30

• Cerebrovascular disease -stroke • Anxiety+ • Seizure • Cognitive dysfunction • Confusion • Peripheral neuropathy • Psychosis

Question 31

Clinical presentation (LABS)

Answer 31

1. Full blood count a. Hemolytic anemia b. WBC, LYMPH, RBC, PLT 2. Immunologic a. Anti(nuclear) Ab --- ANA b. Anti(double stranded DNA) Ab --- dsDNA c. Anti(smith)Ab ---- Anti-Sm d. Anti(nuclear ribonucleoprotein) Ab -- anti-RNP e. Low complement (C3,4, CH50) i. Used to monitor if pt responding to treatment ii. Try to incr back to normal lvls

Question 32

Clinical presentation (LABS)

Answer 32

1. Full blood count a. Hemolytic anemia b. WBC, LYMPH, RBC, PLT 2. Immunologic a. Anti(nuclear) Ab --- ANA b. Anti(double stranded DNA) Ab --- dsDNA c. Anti(smith)Ab ---- Anti-Sm d. Anti(nuclear ribonucleoprotein) Ab -- anti-RNP e. Low complement (C3,4, CH50) i. Used to monitor if pt responding to treatment ii. Try to incr back to normal lvls

Question 33

SLE management OVERALL

Answer 33

• Remission is goal <-- low disease activity • Prevent flares, other organs ○ Slow disease activity ○ Reduce STEROIDS use ○ Improve QOL ○ Minimise ADR • Treat other comorbidities • Lifestyle, support grp • No smoking

Question 34

Pharmacological (General)

Answer 34

• Aspirin (NSAID) • Prednisolone (steroids) • Hydroxychloroquine (1st line SLE) ○ Immunomodulatory • Belimumab (biologics) • Immunosuppressants • Steroid sparing (less reliance) ○ Induction therapy § Mycophenolate: induce + maintain § Azathioprine: maintain

Question 35

Aspirin

Answer 35

• 1st line for acute symptoms Caution: lupus NEPHRITIS, incr cardiac risk, GI bleed

Question 36

Prednisolone (steroids)

Answer 36

• Mono/ adjunct • Control flares, maintain low disease activity • Rapid onset •Concern: high dose, LT effect

Question 37

Hydroxychloroquine (1st line SLE) antimalaria class of drugs

Answer 37

• Even preg • Prevent flare • LT survival ○ Anti-inflamm ○ Immunomodulatory ○ Anti-thrombotic effect ○ Minimal adverse effects • 4-8wks to have effect

Question 38

Belimumab (biologics)

Answer 38

• Target, disrupt function of B cells, plasma cells ○ Belimumab/ rituximab Ongoing trials for other biologics

Question 39

Immunosuppressants

Answer 39

• IV/PO cyclophosphamide • Steroid sparing (less reliance) ○ Several organ involved ○ Induction therapy § Mycophenolate: induce + maintain §Azathioprine: maintain

Question 40

Complications/ types of SLE

Answer 40

1) Antiphospholipid syndrome (SLE-APS) 2) drug-induced SLE

Question 41

1)Antiphospholipid syndrome (SLE-APS)

Answer 41

• Antiphospholipid Ab ○ Lupus anticoagulant, anticardiolipin, anti-b2 glycoprotein (+ve) • High risk of clotting, preg morbidity • Treatment: ○ 1* thromboprophylaxis § Hydroxychloroquine + aspirin ○ 2* thromboprophylaxis (repeated clots) Warfarin

Question 42

2. Drug-induced SLE 10-15% of SLE from drug use

Answer 42

• IDIOSYNCRATIC reactions: due to genetic, environment • MOA: ○ Small mole induce immune resp When bind to larger mole (albumin, proteins)

Question 43

Drug-induced SLE (high risk drugs)

Answer 43

○ Procainamide (anti arrhythmia) ○ Hydralazine ○ Quinidine ○ Minocycline, isoniazid, methyldopa, carbamazepine, others

Question 44

Drug-induced SLE 1st treatment

Answer 44

1* treatment: ○ STOP risk drug ○ SYMPTOMATIC TREATMENT Maybe reversible, but SLE condition may also just start

Question 45

Evaluation and monitoring of SLE

Answer 45

• ADR • Development of comorbidities • Measure disease acitvity • SELENA-SLEDAI • BILAG • Regular labs: (look at trend) • ACTIVE = (1-3mnths) • STABLE = 6-12mnths

Question 46

labs to monitor

Answer 46

○ Don’t need ANA, anti Sm, anti-RNP Ab to repeat at each visit § Do not fluctuate with disease activity 1) Urinalysis/ renal function 2) Anti-dsDNA Ab a. More uncontrolled condition = higher b. Aim for near 0 (normal) 3) Complement C3, 4 levels a. Responding to treatment? Try icnr lvls 4) C-reactive protein a. Inflammatory market 5) Full blood count (WBC, RBC, PLT) 6) Liver function test

Question 47

Immunosuppression in practice

Answer 47

○ Rest of life § Autoimmune conditions § Solid organ transplant § Stem cell/ bone marrow transplants § Blood disorders/ cancer

Question 48

INDUCTION of immunosuppression

Answer 48

§ High potency, short course therapy § Initiate asap to: □ Reduce existing damage □ Prevent worsening of autoimmune condition § Initiate to prevent: □ Acute rejection with lymph depleting therapy - Basiliximab, alemtuzumab

Question 49

MAINTENANCE of imunosuppression

Answer 49

§ Calcineurin inhibitors □ Cyclosporin, tacrolimus § Antimetabolites □ Mycophenolate, azathioprine § Corticosteroids § mtor inhibitors -- transplants □ Sirolimus, everolimus § Biologics □ Adalimumab

Question 50

Complications with immunosuppression

Answer 50

§ Risk opportunistic infections § Risk cancers § Blood disorders □ Leukopenia, thrombocytopenia, pancytopenia § Hepatotoxicity □ Mycophenolate, aza (Antimetabolites) § Renal toxicity □ Cyclo, tacro (Calcineurin inhibitors) § Hypertension, hyperlipemia, hyperglycemia □ (Calcineurin inhibitors & mTOR inhibitors)

Question 51

opportunistic infections

Answer 51

□ Bacterial: Mycobacterium TB, listeria (meningitis), legionella □ Viral: Cytomegalovirus, Epstein Barr, HV □ Fungal: Cryptococcus (soil), Aspergillus, pneumocystis jiroveci □ Parasites: Toxoplasma gondii (cat)

Question 52

Corticosteroids

Answer 52

○ Long term use: anti-inflammatory, immunosuppressive effects ○ Conditions: § Asthma, COPD, autoimmune disease, transplant, IBD - CD/ UC, eczema, cancer, pain

Question 53

ADR with steroids

Answer 53

1) CVS risk 2) cataract, glaucoma 3) skin thinning, hirsutism (hair) 4) gastric ulcer 5) weight gain, fluid retention, CUSHING, b-cell dysfunciton/ insulin resistance 6) neuro-psychiatric symptoms, HPA insuff 7) osteoporosis 8) myopathy 9) infections

Question 54

HPA Axis suppression (reliant on corticosteroids) § Hypothalamic pituitary adrenal axis suppression □ Common in pt on chronic CS therapy

Answer 54

1) Excess exogenous CS/ glucocorticoids 2) Decr secretion of CR, ACTH 3) HPA axis less active a) Unable to recover function to produce endogenous steroids b) Adrenal cortex atrophy (smaller)

Question 55

how to reduce Adrenal suppression

Answer 55

□ Supraphysiologic dose > 5mg pred daily (>3wks) -May occur at lower dose/ lower duration too □ Tapered withdrawal □ Maintain suspicion of adrenal suppression when pt take CS