IC9 Immune-mediated toxicities Flashcards by cuminz 11

types of allergy

immune (allergy)
non-immune (pseudoallergy)

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immune (allergy): types of hypersensitivity reactions

Immediate → IgE mediated; atopy
Type I, II, III hypersensitivity reactions → occurs within 24 hours of exposure
Delayed → IgM, IgG, T cell mediated
Type IV hypersensitivity reaction

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immune (allergy): prevalence

~10-15% of all ADR

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cause of non-immune (pseudoallergy)

Drugs causing release of mediators: histamine, prostaglandins, bradykinins → often mast cell & basophil derived
By pharmacologic/ physical effect

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non-immune (pseudoallergy): prevalence

~77% of hypersensitivity reactions

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Effectors of drug hypersensitivity reactions

Involving major components of innate & adaptive immune systems
Involving release of pharmacologically active chemical mediators

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Effectors of drug hypersensitivity reactions: innate & adaptive components

Cellular elements: macrophages T & B lymphocytes, platelets, mast cells
Immunoglobulins: especially IgE (associated to type I AR, immediate reaction)
Complements: activation of mast cells & inflammatory mediators
Cytokines

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Effectors of drug hypersensitivity reactions: pharmacologically active chemical mediators

Histamine, platelet-activating factor (PAF), prostaglandins (PG), thromboxanes, leukotrienes

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clinical manifestations (main ones)

anaphylaxis
severe cutaneous adverse reactions

others:
serum sickness/ drug fever
drug induced autoimmunity
vasculitis
haematologic
respiratory

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clinical manifestations: anaphylaxis definition

Acute & life-threatening, involves multiple organ systems
First few hours ⇒ highest risk of fatal anaphylaxis

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clinical manifestations: anaphylaxis organs involved

skin, CNS, GIT
respiratory - bronchoconstriction: difficulty breathing, SOB, chest tightness
CVS: low BP, high HR, chest pain

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clinical manifestations: anaphylaxis first line treatment + how does it work

epinephrine

Acts on ⍺ & β receptors
Counteracts bronchoconstriction & vasodilation

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clinical manifestations: anaphylaxis hospital treatment

IV fluids → restore volume/ BP
Intubation PRN → to save airway
Norepinephrine (noradrenaline) → if shock

Others:
possible agents:
Steroids → suppresses later reactions
Glucagon (if patient currently on BB) → helps with chronotropic & inotropic effects, for regular heart beat
H1 [diphenhydramine] + H2 [ranitidine] → blocks all histamine receptors, to slow down reactions

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clinical manifestations: SCAR types

DRESS, TEN, SJS

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clinical manifestations: SCAR (DRESS presentation)

Triad of rash, eosinophilia & internal organ involvement

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clinical manifestations: SCAR (DRESS mortality)

10%

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clinical manifestations: SCAR (SJS & TEN presentation)

Progressive bullous or “blistering” disorders → dermatologic emergencies
Progress to include mucous membrane erosion & epidermal detachment

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clinical manifestations: SCAR (SJS & TEN extent of symptoms)

SJS: less than 10% detachment of body surface area
TEN: greater than 30%

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clinical manifestations: SCAR (SJS & TEN mortality)

SJS: 1% to 5%
TEN: 10% to 70%

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clinical manifestations: SCAR treatment guide

No defined cure; important to stop taking causative drug
Supportive care (similar to burn patients): Wound care, nutritional support, fluids, temperature regulation, pain management & prevention of infection
Possible steroid use (not first line)
IV immunoglobulin, cyclosporin

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SLE
how it is a multisystem disease

Associated with auto-Ab production
immune-mediated complex can be anywhere in the body

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SLE
how is it a multifactorial disease

Strong genetic disposition
Present in first degree relatives ⇒ 20x more likely
environmental factors
smoking, infection, drugs, pollution, UV light, Epstein-Barr virus (herpes)

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SLE
clinical presentation

Lupus nephritis
Kidney disease; requires transplant
4 classes (stages of disease)
Neuropsychiatric lupus
Cerebrovascular disease (stroke), anxiety, seizures, cognitive dysfunction, confusion, peripheral neuropathy, psychosis
CVS
Pericarditis, myocarditis
Accelerated atherosclerosis

SLE
labs

Full blood count
Hemolytic anaemia (↓ RBC)
↓ WBC or ↓ lymphocytes
↓ Platelet
Immunologic

SLE treatment: goals

achieve low disease activity & treat complications To prevent flares & other organ involvement, slow disease activity, reduce use of steroids, improve QOL & minimise AE

SLE treatment: drugs involved

hydroxychloroquine steroids NSAIDs biologics immunosuppresants

treatment of SLE: hydroxychloroquine dose

5mg/ kg/ day

treatment of SLE: hydroxychloroquine effect

Prevents flare & improve long term survival ⇒ have anti-inflammatory, immunomodulatory & anti-thrombotic effects - ↓ activation of T & B cells ⇒ no production of auto Ab - ↓ APC & receptors on T cell ⇒ suppression of T cell activation

treatment of SLE: hydroxychloroquine indication

ALL patients to receive (including pregnant women)

treatment of SLE: hydroxychloroquine AE

Minimal AE but retinal toxicity > 10% prevalence after 20 years Important to conduct eye exams

treatment of SLE: hydroxychloroquine time for effects

4-8 weeks

treatment of SLE: NSAIDs indication

1st line for acute symptoms

treatment of SLE: NSAIDs cautionary

worsening lupus nephritis, increase cardiac risk & GI bleed

treatment of SLE: Steroids dose

Low-dose monotherapy/ adjunctive therapy

treatment of SLE: Steroids purpose

controlling flares & maintain low disease activity Rapid onset

treatment of SLE: Steroids concerns

high dose and/ or long term use

treatment of SLE: Steroids AE (PO)

hyperglycemia, HTN, pre-eclampsia (for pregnancy), gestational diabetes & osteoporosis, weight gain, dyslipidemia

treatment of SLE: Steroids AE (topical)

skin atrophy

treatment of SLE: biologics (agents)

Belimumab & Rituximab (for severe disease)

treatment of SLE: biologics MOA

Targets & disrupts functioning B cells

treatment of SLE: immunosuppresants (agents & therapy type)

IV/ PO cyclophosphamide (severe disease) → severe organ involvement; induction therapy Mycophenolate → induction & maintenance therapy Azathioprine → alternative to mycophenolate (maintenance)

treatment of SLE: immunosuppresants cyclophosphamide - AE

cystitis, bladder malignancy, infertility

treatment of SLE: immunosuppresants Mycophenolate - AE

GI SE might limit use & compliance

treatment of SLE: immunosuppresants Azathioprine - requirement before use

Test for thiopurine methyltransferase (TPMT) before initiation → should be able to work & metabolise drug

treatment of SLE: guide (according to severity)

ALL: hydroxychloroquine steroids (PO/IM - mild & PO/IV - moderate and severe) MILD: methotrexate/ azathioprine MODERATE: benlimumab/ mycophenolate SEVERE: cyclophosphamide/ rituximab

SLE Evaluation of therapeutic outcomes

ADR Development of comorbidities Measure disease activity Regular labs every 1-3 months with active disease; 6-12 months if stable - urinalysis/ renal function, anti-dsDNA Ab, Complement C3, C4 levels, CRP, FBC, LFT - other tests dont need repeat --> does not fluctuate with disease state

Immunosuppression: reasons

Autoimmune conditions Solid organ transplants Stem cell/ bone marrow transplants - Involves development of new cell lines → impt to suppress existing immune cells to produce new cells

Immunosuppression: cell targets

T cells, B cells, mediators (cytokines), APC

Immunosuppression: Purpose in autoimmune diseases (induction)

To stop immune system from exerting effects High potency, short-course therapy ASAP → reduce existing damage & prevent worsening of condition To suppress/ lyse/ prevent activation & proliferation of T cells

Immunosuppression: agents used for induction (autoimmune diseases)

1. Lymphocyte-depleting agents causing cell lysis * **Antithymocyte globulin** → targets T cells * **Alemtuzumab** → longer duration of action; binds to CD52 surface Ag on T cells ⇒ triggers apoptosis & destroys T cells 2. Immune modulators preventing activation & proliferation of T cells: Basiliximab

Immunosuppression: Purpose in autoimmune diseases (maintainence)

To keep immune system from functioning

Immunosuppression: use in transplant

1. Patient selection: match HLA & blood type as closely as possible → reduce risks of rejection 2. Use intensive induction therapy to avoid initial rejection 3. Multiple maintenance agents used to target different mechanisms 4. Reduce dosage/ withdraw if toxicity > benefits

Immunosuppression: autoimmune diseases (importance of TDM)

to prevent toxicity, depending on type of transplant & when transplant

Use of steroids

Essential for chronic conditions due to powerful anti-inflammatory & immunosuppressive effects

Dose of HPA-axis suppression

Generally supraphysiologic doses of >5mg prednisone daily for more than 3 weeks Also possible in <5mg prednisone daily after <4 weeks of exposure and tapered withdrawal

Effects of steroid use

reduce pain, swelling, stiffness & physical disability

HPA-axis suppression process of occurrence

1. Exogenous GC → decreased secretion of CRH & ACTH 2. Over time, whole HPA axis becomes inactive ⇒ cannot produce own cortisol 3. Unable to recover function quickly if exogenous steroids are stopped