IC9 Immune-mediated toxicities Flashcards
types of allergy
immune (allergy)
non-immune (pseudoallergy)
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
immune (allergy): prevalence
~10-15% of all ADR
cause of non-immune (pseudoallergy)
Drugs causing release of mediators: histamine, prostaglandins, bradykinins → often mast cell & basophil derived
By pharmacologic/ physical effect
non-immune (pseudoallergy): prevalence
~77% of hypersensitivity reactions
Effectors of drug hypersensitivity reactions
Involving major components of innate & adaptive immune systems
Involving release of pharmacologically active chemical mediators
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
Effectors of drug hypersensitivity reactions: pharmacologically active chemical mediators
Histamine, platelet-activating factor (PAF), prostaglandins (PG), thromboxanes, leukotrienes
clinical manifestations (main ones)
anaphylaxis
severe cutaneous adverse reactions
others:
serum sickness/ drug fever
drug induced autoimmunity
vasculitis
haematologic
respiratory
clinical manifestations: anaphylaxis definition
Acute & life-threatening, involves multiple organ systems
First few hours ⇒ highest risk of fatal anaphylaxis
clinical manifestations: anaphylaxis organs involved
skin, CNS, GIT
respiratory - bronchoconstriction: difficulty breathing, SOB, chest tightness
CVS: low BP, high HR, chest pain
clinical manifestations: anaphylaxis first line treatment + how does it work
epinephrine
Acts on ⍺ & β receptors
Counteracts bronchoconstriction & vasodilation
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
clinical manifestations: SCAR types
DRESS, TEN, SJS
clinical manifestations: SCAR (DRESS presentation)
Triad of rash, eosinophilia & internal organ involvement
clinical manifestations: SCAR (DRESS mortality)
10%
clinical manifestations: SCAR (SJS & TEN presentation)
Progressive bullous or “blistering” disorders → dermatologic emergencies
Progress to include mucous membrane erosion & epidermal detachment
clinical manifestations: SCAR (SJS & TEN extent of symptoms)
SJS: less than 10% detachment of body surface area
TEN: greater than 30%
clinical manifestations: SCAR (SJS & TEN mortality)
SJS: 1% to 5%
TEN: 10% to 70%
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
SLE
how it is a multisystem disease
Associated with auto-Ab production
immune-mediated complex can be anywhere in the body
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)
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)
- 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 - 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
- Patient selection: match HLA & blood type as closely as possible → reduce risks of rejection
- Use intensive induction therapy to avoid initial rejection
- Multiple maintenance agents used to target different mechanisms
- 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
- Exogenous GC → decreased secretion of CRH & ACTH
- Over time, whole HPA axis becomes inactive ⇒ cannot produce own cortisol
- Unable to recover function quickly if exogenous steroids are stopped
