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Urticaria
Harijono Kariosentono
Itch-scratch cycle
Definition
An eruption of wheals as a result of transient leakage of plasma from the dermal vasculature
Characterized by short-lived, itchy, raised wheals due to dermal edema.
Table 1. Clinical classification of the urticariasOrdinary urticaria
Acute (up to 6 weeks of continuous activity)Chronic (6 weeks or more of continuous activity)Episodic (acute intermittent or recurrent activity)
Physical urticarias (reproducibly induced by the same physical stimulus)Mechanical
Delayed pressure urticaria,Symptomatic dermographism, Vibratory angio-oedema
ThermalCholinergic urticaria,Cold contact urticaria, Localized heat urticaria
OtherAquagenic urticariaSolar urticaria
Contact urticaria (contact with allergens or chemicals)Urticarial vasculitis (defined by vasculitis on skin biopsy)
Aetiology- classification-Idiopathic-Immunological
Autoimmune (autoantibodies against FcɛRI or IgE)Allergic (IgE-mediated type I hypersensitivity rx)Immune complex (urticarial vasculitis)Complement-dependent (C1 esterase inhibitor deficiency)
-NonimmunologicalDirect mast cell-releasing agents (e.g. opiates)Aspirin, nonsteroidal anti-inflammatories and dietary pseudoallergensAngiotensin-converting enzyme(ACE) inhibitors
1. Chronic idiopathic urticaria (CIU) is defined as the occurrence of wheals (hives) of unknown origin for at least 6 weeks. CIU is usually a recurrent chronic condition, with a prevalence in the general population of 0.5-3.5%
Pruritus is a cardinal symptom of CIU, and combined with the unsightly appearance of the associated wheals, active CIU can have a major negative impact on daily activities and sleep.
Quality of life
Quality of life
Quality of life
Quality of life
Angioedema :
> 40% relationship with partner suffers
> 50% don‘t sleep well
> 50% concentration ↓↓↓
> 55% can‘t work normally
> 60% moody and irritable
> 75% stop/reduce doing fun things
n = 362
What chronic urticaria does to your patient…
Non-acute urticaria is a disabling disease.
Treat disease until it is gone!
What do we learn from this?
Recruitment
Extravasation
Vasodilation
Activation PRURITUS
ERYTHEMA
WHEAL
INFILTRATE
FceRIKit
FcgRTLRs
CR1/2, CR3C3aR, C5aR
NK1ETA /ETB
CD48IL-3,4,15RCCR3OTRs
CysLT1RMC-1/MC5
EP1/EP3CB1/CB2
A2b/A3uPAR
VRPIRA/PIRB
IgESCF
IgGLPS
ComplementAnaphylatoxinsNeuropeptidesEndothelin-1
BacteriaInterleukinsChemokines
OxytocineLeukotriene
POMCsProstaglandins
CannabinoidsAdenosine
UrokinaseCapsaicin
?
MC
Mast cells are the key effector cells in the induction of urticaria symptoms.
IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, TNF,
MIPs, IFN-g, GM-CSF, TGF-b, bFGF,
VPF/VEGF, PGD2, LTB4, LTC4, PAF, histamine, serotonine,
heparin,chondroitin-
sulfate,chymase,
tryptase, CPA
Urticaria – Pathogenesis
Mast Cells are the Key Effector Cells
in the induction of urticaria symptoms
Recruitment
Extravasation
Vasodilation
Activation
MC
Courtesy of Prof. M. Maurer.
IL-1, IL-2, IL-3, IL-4, IL-5, IL-6,
IL-8, IL-10, IL-13, TNFa, MIPs, IFN-g,
GM-CSF, TGF-b, bFGF,
VPF/VEGF, PGD2, LTB4,
LTC4, PAF,
histamine, serotonin,heparin,
chondroitin-sulfate,
chymase, tryptase, carboxy-peptidase
Trigger
CauseMast cell-activating
signal
Mast cellactivation
Mast cellmediators
Urticaria reaction
Urticaria - Therapeutic Strategies
Trigger
CauseMast cell-activating
signal
Mast cellactivation
Mast cellmediators
Urticaria reaction
causal symptomatic
Urticaria - Therapeutic Strategies
Trigger
CauseMast cell-activating
signal
Mast cellactivation
Mast cellmediators
Urticaria reaction
causal symptomatic
Urticaria - Therapeutic Strategies
Trigger
CauseMast cell-activating
signal
Mast cellactivation
Mast cellmediators
Urticaria reaction
causal symptomatic
Urticaria - Therapeutic Strategies
Trigger
CauseMast cell-activating
signal
Mast cellactivation
Mast cellmediators
Urticaria reaction
causal symptomatic
Urticaria - Therapeutic Strategies
Classification of Urticaria
Zuberbier, Bindslev-Jensen, Canonica et al. Allergy. 2005. .
Spontaneous urticaria
Physicalurticaria
Other urticaria disorders
Acute urticariaChronic urticaria
Cold contact urticariaDelayed pressure
urticariaHeat contact urticaria
Solar urticariaUrticaria factitia/
dermographic urticaria
Aquagenic urticariaCholinergic urticaria
Contact urticariaExercise-induced
anaphylaxis/urticaria
Other Forms of Urticaria
Physical Urticaria
Acute Spontaneous UrticariaChronic Spontaneous Urticaria
Symptomatic DermographismCold Contact UrticariaSolar Urticaria Delayed Pressure UrticariaHeat Contact Urticaria
Contact UrticariaAquagenic UrticariaCholinergic UrticariaExercise-induced Urticaria / Anaphylaxis
SpontaneousUrticaria
Inducible
Not Inducible
Classification of Urticaria
Treatment Options in Chronic Urticaria
Mast Cells Are the Primary Immune Effector Cells in
Urticaria
Kovarova and Rivera. Curr Med Chem. 2004;11:2083.
• Mast cells are the major source of mediators– Histamine– Cytokines– Prostaglandins/leukotrienes
First-Line Management of Chronic Urticaria:
EAACI/GA2LEN/EDF Guidelines’ Recommendations
TreatmentMethodologic
QualityLevel of
EvidenceGrade of
Recommendation
NS 2nd-G H1-AHAzelastineCetirizine*DesloratadineEbastineFexofenadineLevocetirizine*LoratadineMizolastineBepotastine besilate
++++++
++++++++
1++1-1+1+1-1+1+1+1+
A
*Increased sedation vs placebo.NS 2nd-G H1-AH = nonsedating 2nd-generation H1 antihistamine.Zuberbier, Bindslev-Jensen, Canonica et al. Allergy. 2005
Management of Chronic Urticaria: EAACI/GA2LEN/EDF Guidelines
RecommendationsChronic urticaria diagnosis
Increase dose
Choose alternative therapy
Symptoms not controlled
Symptoms not controlled
Symptoms not controlled
Select another alternative treatment
First-line
Zuberbier, Bindslev-Jensen, Canonica et al. Allergy. 2005.
Nonsedating second-generationH1-antihistamine
Non sedating H1-Antihistamine (nsAH)
nsAH updosing (up to 4x)
+Leukotrieneantagonist, change nsAH
Exacerbation: Systemic Steroid (for 3 – 7 days)
+H2-Antihistamine, Cyclosporine A, Dapsone, anti-IgE
Exacerbation: Systemic Steroid (for 3 – 7 days)
If symptoms persistafter 2 weeks
If symptoms persistafter 1-4 weeks
If symptoms persistafter 1-4 weeks
Management strategy1. Explanation of the nature & prognosis of
urticaria
2. Individual respons to different AH are vary and tachyphylaxis is reported changing AH1 and increasing dose are warranted
3. Combining 2 different long acting AH1 12 hours apart or adding a short acting AH for relief the symptoms. Sedative AH can be useful at night
4. + Leukotriene antagonist (monteluklast) to AH1
5. Pseudoallergen–free diets may help
6. A short course of prednisolone 20-30mg/d for 3 days
7. H2 antagonist combination with AH1 the benefit ?
8. Other drugs:
-doxepin, nifedipine, psoralen with UVA (PUVA), sulfasalazine and warfarin.
-stanozolon & tranexamic acid: for non- hereditair angiooedema
-dipyridamole + AH1
-thyroxine variant results
• Immunosupressive:
- cyclosporin, plasmapheresis and IVIG are effective for severe condition the benefit may be short-lived.
-mycophenalate mofetil, tacrolimus and omalizumab for very severe symptoms.
First line therapies
Non-sedating H1 antagonists
No
n s
eda
ting
H1
a
ntih
ista
min
cetirizine
desloratadin
Fexofenadine
Levocetirizine
Loratadin
mizolastine
Onc
e da
ily
sedating antihistamin (chlorphenamine 4-12 mg, hydroxyzine 10-50 mg) at
night
Second-line Therapies
Leukotriene antagonists
Diet
Corticosteroids
H2 antagonists
Eradication of helicobacter
Doxepin
Nifedipine
PUVA
Sulfasalazine
Warfarin
Stanozolol
Tranexamic acid
Dipyridamole
Thyroid hormone
Third-line Therapies
Ciclosporin Plasmapheresis Intravenous immunoglobulin Tacrolimus Omalizumab
SUMMARY
1. Urticaria can be classified on the clinical presentation without extensive investigation.
2. Urticaria often remains idiopathic after allergic, infectious, physical and drug-related causes have been excluded as far as possible.
3. Advice and information on general measures can be helpful for most patients, especially if an avoidable physical or dietary trigger can be identified.
4. It common practice to increase the dose of 2nd-generation AH1 above (4X) the manufacturer’s licensed recommendation for patients when the potential benefits are considered to outweigh any risks.
5. Combinations of nonsedating AH1 with other agents, such as AH2, sedating antihistamines at night or the addition of antileukotrienes, can be useful for resistant cases
6. Oral corticosteroids should be restricted to short courses for severe acute urticaria or angio-oedema affecting the mouth, although more prolonged treatment may be necessary for delayed pressure urticaria or urticarial vasculitis.
7. Immunomodulating therapies for chronic autoimmune urticaria should be restricted to patients with disabling disease who have not responded to optimal conventional treatments.