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Charoen Choonhakarn, MDDiv ision of Dermatology

Khon Kaen Univ ersity

Classification of Urticaria

Z uberbier et al . Z uberbier et al . A llergy.A l lergy. 2005. In press.2005. In press.

Spontaneous Spontaneous urticariaurticaria

PhysicalPhysicalurticariaurticaria

Other Other urticariaurticariadisordersdisorders

Acute urticariaChronic urticaria

Cold contact urticariaDelayed pressure

urticariaHeat contact urticaria

Solar urticariaUrticaria factitia/

dermographic urticariaVibratory urticaria/

angioedema

Aquagenic urticariaCholinergic urticaria

Contact urticariaExercise-induced

anaphylaxis/urticaria

Dermographism

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Cold urticaria

Cholinergic urticaria

Overview

� Ov erv iew of Chronic Idiopathic Urticaria (CIU)

� How is its importance?� Who needs inv estigation?� Ev olution of Therapy f or CIU � Clinical Ef f icacy of Antihistamines in CIU� Summary and Conclusions

Definition of Chronic Urticaria

�Spontaneous wheals and/or angioedema > 6 weeks; daily or almost daily or at least 2 times/wk1-2

�Pruritus can be severe and debilitating�Significant negative impact on quality of

l i fe3

EAACI = EAACI = European Academ y of Allergology and Clinical Im m unology. EDF = European Derm atology Forum.European Academ y of Allergology and Clinical Im m unology. EDF = European Derm atology Forum.

11. Joint Ini t iat ive of E AACI Dermatology Sect ion and GA. Joint Ini t iat ive of E AACI Dermatology Sect ion and GA22L E N. L E N. 22nd Internat ional Consensus Meet ing on nd Internat ional Consensus Meet ing on Urt icariaUrt icaria. . Urt icariaUrt icaria 20042004; ; 22. . Z uberbierZ uberbier et al . et al . J J InvestigInvestig DermatolDermatol SympSympP rocP roc. . 20012001;;66::123123; ; 33. O'Donnel l et al. O'Donnel l et al . . B r J B r J DermatolDermatol . . 19971997;;136136::197197;;

Definition of Chronic Urticaria� Chronic idiopathic urticaria (CIU):

- 1/3 : circulat ing antoant ibodies to either high af f inity IgE receptor (FcεRI) or to IgE “autoimmune urticaria”

- 2/3 : idiopathic� 2005 EAACI/GA²LEN/EDF guidelines do not

recognize chronic idiopathic urticaria as a separate category within chronic urticaria4

1. Joint Ini t iat ive of E AACI Dermatology Sect ion and GA1. Joint Ini t iat ive of E AACI Dermatology Sect ion and GA22L E N. 2nd Internat ional Consensus L E N. 2nd Internat ional Consensus

Meet ing on Meet ing on Urt icariaUrt icaria. . Urt icariaUrt icaria 2004; 2004; 2. 2. Z uberbierZ uberbier et al . et al . J J InvestigInvestig DermatolDermatol SympSymp P rocP roc. 2001;6:123;. 2001;6:123;

3. O'Donnel l et al3. O'Donnel l et al . . B r J B r J DermatolDermatol . 1997;136:197; 4. . 1997;136:197; 4. Z uberbierZ uberbier et al . et al . A llergy.A l lergy. 2005. In press.2005. In press.

Prevalence of Chronic Urticaria

� Urticaria af f ects 1/4 of populat ion1

� Estimated 25% of cases are chronic (>6 weeks)2

� Chronic spontaneous urticaria prev alence estimates range f rom 0.5%-1% of populat ion3

� Chronic urticaria : all age groups, more common among adults and women than among children and men4,5

11. Cooper. . Cooper. J A m J A m A cadA cad DermatolDermatol .. 19911991;;2525::166166. . 22. Greaves. . Greaves. N N E nglE ngl J MedJ Med. . 19951995;;332332::176 7176 7. . 33. . SabroeSabroe and Greaves. and Greaves. A rch A rch DermatolDermatol . . 19971997;;133133::10031003. .

44. . HernHernáándezndez Garcia. Garcia. JarpioJarpio. . 19991999;;4747. . 55. . KozelKozel and and SabroeSabroe. . DrugsDrugs. . 20042004;;6464::25152515. .

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Age Distribution of Acute andChronic Urticaria

30 .0

2 1.2

36 .4

24 .2

0

31 .6

2. 0

1 9.017 .4

18 .22 1 .0

17 .9

3.3

2 9.328 .5

0

10

20

30

40

0-19 20 -3 9 4 0-59 60 -7 9 >8 0

Acute urticariaChronic urticariaAll patients

Preval

ence (%

)Pre

valenc

e (%)

Age group (years)Age group (years)Courtesy of Prof. T . Z uberbier.Courtesy of Prof. T . Z uberbier. Incidence peak in CIU seen between 20-40 yrs

Clinical Impact and Burden � Pruritus, the primary debilitating symptom of

chronic urticaria, is associated with1

� Severe discomfort � Sleep disturbance � Depression

� Productivity losses2

� Adverse effects on work and classroom performance� 25%-30% reduction in work/school productivity

� Wheals and angioedema affect physical appearance

� The detrimental effect on QoL greater than that of other skin diseases and similar to that of coronary artery disease

1. O'Donnel l et al1. O'Donnel l et al . . B r J DermatolB r J Dermatol . 1997;136:197.. 1997;136:197.

2. T hompson et al . 2. T hompson et al . J A m A cad DermatolJ A m A cad Dermatol . 2000;43:24. . 2000;43:24.

Clinical Impact and Burden � The Nottingham Health Profile (NHP)1� Disease-specific questionnaire administered to142 patients

� Chronic urticaria associated with impairment or difficulty in

1. O'Donnel l et al . B r J Dermatol . 1997;136:197.

–– MobilityMobility

–– SleepSleep

–– EnergyEnergy

–– PainPain

–– Social isolationSocial isolation

–– Emotional reactionsEmotional reactions

–– WorkWork

–– Home managementHome management

–– Social lifeSocial life

–– Home relationshipsHome relationships

–– Sex lifeSex life

–– HobbiesHobbies

Duration of chronic spontaneous urticaria

� Studies indicate that most patients suffer for >1 yr� A considerable number of patients seem to be

affected > 5 yrs� The overall duration likely to be longer in pts with 1. High disease severity (all pts with mild; symptom

free after 2 yrs, 60% pts with moderate to severe symptom persist after 2 yrs and 30% symptom persist after 5 yrs)

2. Angioedema (64-70% vs 43-48% suffer after 1 yr)3. Positivity of autologous serum skin test 4. Combination with physical urticaria

(dermographism, delayed pressure urticaria)

Maurer M, et al . Al lergy; 2011.Maurer M, et al . Al lergy; 2011.

Mechanisms of Urticaria: Immune Effector Cells

�Mast cell is the central effector cell1,2

�Mast cells are the major source of mediators (histamine, cytokines, prostaglandins/leukotrienes)�Basophils, monocytes, neutrophils, and

eosinophils participate to a lesser extent3,4

11. . PiconiPiconi et al . et al . IntInt A rch A l lergy A rch A l lergy ImmunolImmunol . . 20022002;;128128::5959. . 22. Greaves and . Greaves and SabroeSabroe. . B MJB MJ. . 19981998;;316316::11471147. . 33. Kaplan. Kaplan. . J A l lergy J A l lergy Cl inClin ImmunolImmunol . . 20042004;;114114::465465..

44. Haas et al . . Haas et al . IntInt A rch A l lergy A rch A l lergy ImmunolImmunol . . 19981998;;115115::210210..

Mast Cells Mediate Allergic Reactions

MCHistamine

FceRIIgE +

Allergic reaction

Courtesy of Prof. M. Maurer.

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Mast Cells Mediate Allergic and Inflammatory Reactions

IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10,

IL-13, TNFa, MIPs, IFNg,

GM-CSF, TGFb, bFGF,

VPF/VEGF, PGD2, LTB4, LTC4, PAF, Serotonin,Heparin,

Chondroitin-sulfate,

Chymase, Tryptase,

Cathepsin G

Recruitment

Extravasation

Vasodilation

Activation

MC

Courtesy of Prof. M. Maurer.

Prevalence of Atopic Comorbidities in Patients With Urticaria

54.4

44.0

22.318.2

22.017.3

6.4 6.1

Urticari aAll patients

Preval

ence (%

)

Any atopicAny atopicdiseasedisease

Hay feverHay fever AllergicAllergicasthmaasthma

AtopicAtopicdermatitisdermatitis

Courtesy of Prof. T . Z uberbier.

T NFT NFαα = tumor necrosis factor alpha; IL = interleukin; RANT E S = regulated upon act ivat ion, normal T cel l expressed and secreted; MI= tumor necrosis factor alpha; IL = interleukin; RANT E S = regulated upon act ivat ion, normal T cel l expressed and secreted; MIPP--11αα = macrophage inflammatory protein = macrophage inflammatory protein

1 1 alpha; ICAM = intercel lular adhesion molecule.alpha; ICAM = intercel lular adhesion molecule.11. . Z uberbierZ uberbier et al . et al . ActaActa DermDermV enereolV enereol . . 19951995;;7575::484484; ; 22. . Ring et al . Ring et al . IntIntJ J DermatolDermatol . . 20012001;;4040::7272; ; 33. Monroe et al . . Monroe et al . J Am J Am AcadAcad DermatolDermatol . . 20032003;;4848::535535; ; 44. Grattan et al . . Grattan et al . J Am J Am AcadAcad DermatolDermatol .. 20022002;;4646::645645; ; 55. .

MastalerzMastalerz et al . et al . J A llergy J A llergy ClinClin ImmunolImmunol .. 20042004;;113113::771771; ; 66. . PiconiPiconi et al . et al . IntInt Arch Al lergy Arch Al lergy ImmunolImmunol .. 20022002;;128128::5959; ; 77. Barlow et al . . Barlow et al . Br J Br J DermatolDermatol . . 19941994;;131131::641641;;88. Haas et al . . Haas et al . J J InvestigInvestig DermatolDermatolSympSymp P roc.P roc. 20012001;;66::137137. .

Urticaria

Mast cellsMast cells Other cellsOther cells

MediatorsMediators

Proinflammatory cytokines(TNFα, IL-4, IL-6, IL-13)Chemokines(RANTES, MIP-1α)Adhesion molecules(ICAM-1, P-selectin)

InflammationInflammation

Prostaglandins (PGD2)Leukotr ienes (LTE4)

AllergyAllergyHistamineHistamine

HN H

CH2CH2NH2

Chronic urticaria is a systemic disease

WHO NEEDS INVESTIGATION?

Clinical Evaluation and Diagnosis

� Rigorous patient history (infection,occupational exposure, medications, foods)

� Phy sical examination� Diagnostic tests may include

-Differential blood count-ESR (to rule out severe

systemic disease)-Autologous serum skin test-Gastroscopy-Specific IgE

Z uberbier et al . A llergy. 2005.

--Test for Test for HelicobacterHelicobacter--Serum iron levelsSerum iron levels--Stool for worm eggs/parasitesStool for worm eggs/parasites--AutoantibodiesAutoantibodies--Test for infectious diseasesTest for infectious diseases

In many patients, causes and/or triggers are not identified (0-43% successful identification)

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Management

� Ident if ication and elimination of underly ing causes

� Av oidance or elimination of the eliciting stimulus

� Inhibit ion of mast cell mediators

Identif ication and elimination of underlying causes

� Removal of infectious agents and treatment of inflammatory processes

� Removal of FcεRI autoantibodies : plasmapheresis, cyclosporin, IVIg, systemic corticosteroids

� Dietary management : - IgE-mediated food allergy - Avoid pseudoallergens in chronic urticaria for at

least 3-6 months : beneficial effects observed after 2-3 wks

Avoidance eliciting stimulus

� Drugs : suspected drugs, pseudoallergic drugs eg. aspirin, NSAIDs, ACEI

� Phy sical stimuli: physical urticaria

� Stress : 50% of pts with chronic urticaria-stress is a trigger

Inhibition of mast cell mediators

�H1 antihistamines�H2 antihistamines

Evolution of H1 Antihistamines: Timeline

<1970 2000+1990s1980s

LoratadineLoratadineAcrivastineAcrivastine

LevocetirizineLevocetirizineDesloratadineDesloratadine

CetirizineCetirizineEbastineEbastineMizolastineMizolastine

FexofenadineFexofenadine

HydroxyzineHydroxyzineDiphenhydramineDiphenhydramineChlorpheniramineChlorpheniramine

TerfenadineTerfenadine

Newer agentsNewer agents

SecondSecond--generationgeneration

FirstFirst--generationgeneration

Risk of firs t-generation H1-antihistamines generation

�Marked sedation/performance impairing�Psychomotor and cognitive function�Anticholinergic effects�Drug interactions�Short-acting duration�Affects REM sleep

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First- and Second-Generation Antihistamines: Prodrugs and Metabolites

Cetirizine* Cetirizine* AcrivastineAcrivastineFexofenadine Fexofenadine DesmethylastemizoleDesmethylastemizoleDesloratadineDesloratadine

HydroxyzineTripolidineTerfenadineAstemizoleLoratadine

CYP CYP 33AA44

*Levocetirizine is an R-enantiomer of cetirizine.

Evolution of Antihistamines� Antihistamines are essential treatment for chronic

idiopathic urticaria because of the dominant role of histamine in disease pathophysiology

� Second-generation antihistamines, including newer agents less sedation (cetirizine, levocetirizine)

no sedation (desloratadine, fexofenadine, loratadine) - fewer anticholinergic effects

- potentially less drug interactions vs the first-generation1-5

- anti-allergic and anti-inflammatory effects (chronic urticaria is a systemic disease)

1. Klein and Clark. A rch Dermatol . 1999;135:1522. 2. Simons. N E ngl J Med. 2004;351:2203. 3. Ring et al . Int J Dermatol . 2001;40:72.

4. Monroe et al . J A m A cad Dermatol . 2003;48:535. 5. Affrime et al . A llergy. 2000;55(suppl 63):277.

Management of Chronic Urticaria: EAACI/GA2LEN/EDF /WAO (2008) Guidelines Recommendations

Increase doseIncrease dose

Choose alternative therapyChoose alternative therapy

Symptoms not controlledSymptoms not controlled

Symptoms not controlledSymptoms not controlled

Symptoms not controlledSymptoms not controlled

Select another alternative treatmentSelect another alternative treatment

FirstFirst--lineline

Z uberbier et al . A llergy. 2008.

Nonsedat ing second-generationH1-antihistamine

(Level of evidence 1+, Grade of recommendation A)

EAACI/GA2LEN/EDF/WAO(2008) Guidelines Recommendations� We recommend the use of the treatment algorithm as

described for chronic urticaria

� We recommend against the use of sedating antihistamines

� We recommend against the use of astemizol and terfenadine

� We recommend against the use of corticosteroids (except short term)

� We recommend aiming for complete symptom control

� We suggest the same first-line treatment and updosing as described for children (weight adjusted) and pregnant or lactating women with chronic spontaneous urticaria

New Guidelines EAACI/GA2LEN/EDF/WAO 2008

Costs Side Effects Therapy TreatmentDuration

First Line

Very low (<1 €/d) Very lowNew generation

H1-antihistamine (where available) 2 weeks

Second Line

Low (<5 €/d) Very low Increased dosage up to fourfold 1-4 weeks

Third LineLow Very low Possible alternative nonsedating antihistamine 1-4 weeks

Low Very low Add on: leukotriene receptor antagonist 1-4 weeks

Medium (<10 €/d) Medium Systemic corticosteroid (only 3-7 days short course!) 3-7 days

Fourth LineVery low Very low H2-antihistamine

Medium Medium Cyclosporin AVery low Medium Dapsone

High (>10 €/d) Very low Omalizumab

First-Line Management of Chronic Urticaria: EAACI/GA2LEN/EDF Guidelines’ Recommendations

TreatmentMethodologic

Quality Level of EvidenceGrade of

RecommendationNS 2nd-G H1-AH

AzelastineCetiriz ine*

Desloratadine

Ebastine

Fexofenadine

Levocetiriz ine*Loratadine

Mizolastine

+++

++

+

++

++++

++

1++

1-1+

1+

1-

1+

1+1+

1+

AA

Increase dosage if necessary

3 C

*Increased sedation vs p lacebo.

NS 2nd-G H1-AH = nonsedating 2nd-generation H1 antihistam ine.Z uberbier et al . A llergy. 2005.

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Antihistamine Indications and Formulations:

Agent

Chronic Idiopathic Urticaria Tablet

Syrup/Drops

DesloratadineDesloratadine ≥6 month (≥1y)≥6 month (≥1y) √√ √√LoratadineLoratadine ≥2 y≥2 y √√ √√

CetirizineCetirizine ≥6 y≥6 y √√ √√

LevocetirizineLevocetirizine ≥6 y≥6 y √√ √√FexofenadineFexofenadine ≥ 6 month (≥6y)≥ 6 month (≥6y) √√ √√MizolastineMizolastine ≥12 y≥12 y √√ ——

EbastineEbastine NANA NANA NANA

NA = not available.

Clari tyn® Summary of Product Characterist ics. At : ht tp: //emc. medicines.org. uk/ . Mizol len® Summary of Product Informat ion. At : ht tp: //emc. medicines.org. uk/ .Neoclari tyn® Summary of Product Characterist ics. At: http: / /emc. medicines.org.uk/ . Telfast® Summary of Product Informat ion. At: ht tp: / /emc. medicines.org.uk/ .

Xyzal ® Summary of Product Characterist ics. At : ht tp: / /emc.medicines.org. uk/emc/ industry/defaul t . asp?page=displaydoc. asp&document id=7739.Z irtek® Summary of Product Characterist ics. At : ht tp: //emc. medicines.org. uk/ .

Antihistamine Recommended Doses:

AgentRecommended Dose

(mg)

Adjustment for Impaired

Renal Function

Adjustment for Impaired Liver Function

DesloratadineDesloratadine 1.251.25--55 +/+/–– +/+/––

LoratadineLoratadine 55--1010 +/+/–– √√CetirizineCetirizine 55--1010 √√ √√

LevocetirizineLevocetirizine 55 √ (elderly)√ (elderly) √√FexofenadineFexofenadine 120120--180180 +/+/–– (elderly)(elderly) ––

MizolastineMizolastine 1010 ––** NANAEbastineEbastine NANA NANA NANA

*Mizolastine is contraindicated in patients with significantly impaired liver function. NA = not available.Clari tyn® Summary of Product Characterist ics. At : ht tp: //emc. medicines.org. uk/ . Mizol len® Summary of Product Informat ion. At : ht tp: //emc. medicines.org. uk/ .Neoclari tyn® Summary of Product Characterist ics. At: http: / /emc. medicines.org.uk/ . Telfast® Summary of Product Informat ion. At: ht tp: / /emc. medicines.org.uk/ .Xyzal ® Summary of Product Characterist ics. At : ht tp: / /emc.medicines.org. uk/emc/ industry/defaul t . asp?page=displaydoc. asp&document id=7739.Z irtek® Summary of Product Characterist ics. At : ht tp: //emc. medicines.org. uk/ .

Anti-H1 Ki (nM) Relative AffinityDesloratadine 0.9 194.4Carebastine 10 17.5Mizolastine 22 8.0Terfenadine 40 4.4Cetirizine 47 3.7Ebastine 52 3.4Loratadine 138 1.2Fexofenadine 175 1.0

Desloratadine: Highest H1-Receptor Affinity

Receptor-binding affinity of histamine antagonists on recombinant human H1 receptor

Courtesy of Prof. P. Devi l l ier.Anthes et al . E ur J Pharmacol . 2002;449:229.

Human H1-Receptor in CHO Cells:Kinetic of Dissociation [3H] pyrilamine vs [3H] desloratadine

Pyr ilamine dis sociation50% in 3.8 min

Des loratadine dis sociation37% in 6 hours

è Long Duration of ActionCourtesy of Prof. P. Devillier.Anthes et al . E ur J Pharmacol . 2002;449:229.

Desloratadine: Slow Dissociation from H1-Receptor

Blood and tissue concentrations variability

Antihistamine Pharmacokinetics: Role of Cytochrome and Efflux/Influx Transporter Families

Anti-H1

Absorption+ metabolism

Livermetabolis m

ExcretionBile Kidney

Distribution

RhinitisUrticariaEczema

Variability:age, smoking and alcohol habits, genetic, inducers or inhibitors…

CYP 3A4CYP 2D6

P-GpOATP

CYP3A(4-5)P-Gp P-Gp

P-GpOATP

Courtesy of Prof. P. Devi l l ier.

Second-Generation Antihistamines: Potential Drug/Food Interactions

Potential interaction Desloratadine Levocetirizine FexofenadineP-gp – NR +++

Erythromycin + NR ++

Ketoconazole + NR ++

QTc interval – – –

Alcohol – + –

Food – – +*

P-gp = P-glycoprotein; NR = not reported.

*Antacid adminis tration reduces fexofenadine bioavailability.

Neoclari tyn® Summary of Product Characterist ics. Avai lable at : ht tp:/ /emc.medicines.org. uk/ . Xyzal ® Summary of Product Characterist ics. Avai lable at : ht tp: //emc. medicines.org. uk/emc/ industry/defaul t. asp?page=displaydoc. asp&document id=7739.T elfast® Summary of Product Informat ion. Avai lable at : ht tp: / /raleigh. avent ishosting. com/avent is_fi le_archive/docs/59/doc0000026602. pdf.

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Pharmacologic Properties of Second-Generation Antihistamines*

Agent SedationDrug/Food Interaction

PotentialDesloratadine – –Levocetirizine + –Fexofenadine – +Loratadine – +

Cetirizine + –Ebastine + +Mizolastine + +

*At clin ically recom m ended doses.

Cl ar i t yn® Sum m ar y of Pr oduct Char act er is t ics . At : htt p: // em c.m edi cines . or g.uk/ . Ebas t el® Sum m ar y of Pr oduct Char act er is t ics . At : www. ebas t el f or t efl as .com .

Mi zol l en® Sum m ar y of Pr oduct I nf or m ati on. At : htt p: // em c.m edi cines . or g.uk/ . Neocl ar it yn® Sum mar y of Pr oduct Char act eri s ti cs . At : ht t p: // emc. m edici nes . org. uk/ .

Tel f as t ® Sum m ar y of Pr oduct I nf or m ati on. At : htt p: // emc. m edici nes . org. uk/ . Xyzal ® Sum m ar y of Pr oduct Char act er i st i cs . At :

ht t p: / / em c. m edi ci nes .or g. uk/em c/ indus t r y/ defaul t .asp?page=di spl aydoc. asp& docum enti d=7739. Zi r tek® Sum m ar y of Pr oduct Char act er is t ics . At : ht tp: // em c.m edi cines . or g.uk/ .

How to prescribe antihistamines ?

Daily Treatment With Desloratadine is Superior to Treatment As-Needed

Grob et al . A llergy. 2009 Apr;64(4):605-12.

Improvement in VQ-Dermato Global Index Score*

*In the intent ion-to-t reat populat ion.

Continuous

PRN

50

40

30

20

10

0

VQ-D

erm

ato

Inde

x Sc

ore

Visi t 1 Visi t 2 Visi t 3 Visi t 4

P = 0. 001 P = 0. 016

Daily Treatment With Desloratadine is Superior to Treatment As-Needed

Grob et al . A llergy. 2009 Apr;64(4):605-12.

50

40

30

20

10

0

VQ-De

rmato

Dime

nsion

Score P RN

Continuous

P = 0. 091

P = 0. 007

P = 0. 005

P = 0. 044

P = NS

P = NS

P = 0. 077

P = 0. 016

Sel f-perception

Dai ly l i feactivi ties

M ood Social l i fe Leisureactivi ties

Limitationdue to

treatment

P hysicalpains

Global VQ-Dermato

index

How to prescribe antihistamines?

�Once control of CIU symptoms is obtained with daily treatment, continuous therapy(whether or not the patient is showing symptoms) preserves patient QoL better over the longterm as compared with than PRN treatment only given only at symptom flare-up.

Nonsedating, second generation H1-antihistamine

If not controlled

Increase dosage

EAACI/GA2LEN/EDF/WAO Guidelines for Treatment

Where Are The Data?

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AUDACU

Aerius updosing in acquired cold urticaria

The AUDACU trial

� Acquired cold urticaria (ACU)� Randomized, Double-blind, Placebo controlled� Triple Crossov er study� 5mg v s. 20mg Desloratadine� n = 30

The AUDACU trial

Parameters assessed� Critical Temperature Threshold

(TempTest 2.0)� Hy perthermic skin area (Thermography )� Wheal v olume (Volumetry )

******

***30

25

20

15

10

5

0

Critic

al Tem

peratu

re Th

reshol

d (°C)

20mg5mgPlaceboBaseline

Critical Temperature Threshold (CTT)

DesloratadineSiebenhaar et al . J A l lergy Clin Immunol . 2009;123:672.

Updosing of Desloratadine Improves Urticaria Skin Symptoms

DL 20mgDL 5mgPlaceboBaseline

Whe

al v

olum

e (m

m³)

1200

1000

800

600

400

200

0

***

******

Siebenhaar et al . J A l lergy Clin Immunol . 2009;123:672.

The AUDACU Trial

� Standard dose of AERIUS works in ACU

� UPDOSING (using 4x the standard dose) results in ev en better total symptom control in patients with ACU

� UPDOSING is saf e

04/10/54

10

0

20

40

60

80

100

0

20

40

60

80

100***

***

Pruritu

s redu

ction (

in %)

Pruritu

s redu

ction (

in %)

Patients with dermatological disease Patients with pruritus of unknown origin

Levocetiriz ineFexofenadineAzelastine

Levocetiriz ineFexofenadine Desloratadine 4 x 1

1-0-11-0-11-0-1

1-0-11-0-1

Combination

3 x 2 4 x 1

Updosing

2 x 2

Combination

3 x 2 4 x 1

Updosing

2 x 2

***

Combination vs. Updosing

Schulz et al . , Hautarzt. 2009;60:564.

Other treatments for chronic urticaria ?

Nonresponsive Chronic Urticaria: EAACI/GA2LEN/EDF Guidelines’ Recommendations

TreatmentMethodologic

QualityLevel of Evidence

Grade of Recommendation

Combination

NS 2nd-G H1-AH

+ Cyclospor in A

+ Montelukast

+ H2-AH

Monotherapy

Tr icyclic (doxepin)

Ketotifen

Hydroxychloroqui ne

Dapsone

Sulfasalasine

Methotrexate

Corticosteroids

++

+

+

+

++

-

No RCT

No RCT

No RCT

No RCT

2++

2-

2-

2+

2++

2-

3

3

3

4

C

D

D

D

C

D

D

D

D

D

NS 2nd-G H1-AH = nonsedat ing 2nd-generat ion H1-ant ihistamine; RCT = randomised control led t rial .

Z uberbier et al . A llergy. 2005. In press.

Chronic Urticaria : Conclusions� Common systemic disease with a significant

impact on work productivity and quality of life� Idiopathic nature, mostly� Nonsedat ing 2nd -generation AH (newer agents)

: recommended first-line therapy� Continuous treatment is recommended � Regular dose nonsedating 2nd –generation AH:

absence of symptoms<50% of pts� Updosing to 4X if no response: 1/3-1/4 pts

remain symptomatic

Maurer M, et al. Allergy; 2011.

Desloratadine � Highest H1-receptor affinity among second-generation1

� Slow dissociation from H1-receptor1

� Greater in vitro2 and in vivo3 antihistaminic potency than loratadine

� No anticholinergic effects at clinical doses4-5

� Unlike loratadine, not metabolized by liver cytochrome P450 3A4 pathway8-9

� Unlike fexofenadine, no interaction with intestinal P-gp and OATP 9-11*

� No interaction with food6-7

� Unlike levocetirizine, no sedation4-5

1. Anthes et al . Eur J P harmacol . 2002;449:229; 2. Kreutner et al. A rzneimit telforschung. 2000;50:345; 3. Anthes et al . A llergy. 2000;55:277; 4. Ring et al. Int J Dermatol . 2001;40:72; 5. Monroe et al . J A m A cad Dermatol . 2003;48:535; 6. Neoclarityn® Summary of Product Characterist ics. At : ht tp: / /emc. medicines.org. uk/ ; 7. Gupta et al . Clin Pharmacokinet . 2002;41(suppl 1):7; 8. Affrime et al .

A llergy. 2000;55(suppl 63):277; 9. Banfield et al . Clin Pharmacokinet . 2002;41(suppl 1):29; 10. Cayen et al . Allergy. 2000;55(suppl 63):1009; 11. Dresser et al . Clin Pharmacol Ther. 2002;71:11.

04/10/54

11

THANK YOU

Maurer M, et al. Allergy; 2011.