New Trends and Guidelines EAACI\EDF\GA2LEN in Urticaria Treatment: Clinical Studies Review Role of Desloratadine in Urticaria

Lawrence DuBuske MD Consultant in Allergy, Brigham and Womens Hospital, Harvard Medical School, Boston Secretary General, INTERASMA Past President, American Association of Certified Allergists Board of Regents, American College of Allergy, Asthma and Immunology

Urticaria
Perivascular infitration of lymphocytes with rare eosinophils may respond to antihistamines

Interstitial edema

Acute vs Chronic Urticaria

Acute Urticaria lasts 6-8 weeks or less Viral syndromes (especially in young children) Insect bites or stings (fire ants, scabies) Food induced reactions (eat this- get that) Medication related (antibiotics, NSAIDs, narcotics, angioedema due to ACE inhibitors) Chronic Urticaria lasting longer than 8 weeks Physical urticarias (dermographism, cholinergic, cold) Urticarial vasculitis Urticaria/angioedema associated with autoimmunity

Epidemiology of Chronic Idiopathic Urticaria

Prevalence of chronic idiopathic urticaria (CIU) Affects 0.1%3% of the population1 30%50% of cases have an autoimmune component2 50% are likely to remit within 1 year3 Over 50% of patients will experience at least one recurrence of CIU4

1Negro-Alvarez

JM, Miralled-Lopez JC. Allergol Immunopathol (Madr). 2001;29(4):129-132; 2Greaves MW. Curr Opin Allergy Clin Immunol. 2003;3(5):363-368; 3Krishnaswamy G, Youngberg G. Postgrad Med. 2001;109(2):107-108, 111114, 119-123; 4Beltrani VS. In ACP Medicine Online: Immunology/Allergy, 2007.

Pathophysiology of Urticaria
Dilatation of small venules and capillaries in dermis Minimal perivascular lymphocytic infiltrate Swelling of collagen fibers

Greaves MW. N Engl J Med. 1995;332(26): 1767-1772. Copyright 1995 Massachusetts Medical Society. All rights reserved. Baxi S, Dinakar C. Immunol Allergy Clin N Am. 2005;25(2):353-367.

Pathophysiology of Urticaria
Non-Immunological Activation Immunological Activation

TLR CD88

STAT6

Ca++ CD48

Degranulation Cytokines Chemokines Immediate Phase Edema

Hennino A, et al. Clin Rev Allergy Immunol. 2006;30(1):3-11.

Prostaglandins Leukotrienes Late Phase

Leukocyte infiltration

Algorithm for the Diagnosis of Chronic Urticaria

Urticaria
Lesions last >24 hours or systemic features (eg, arthralgia) Associated autoimmune disorder Consistent allergic trigger (eg, latex, animal, food) On a drug known to cause urticaria Exclusion of all known precipitating factors

Consider other tests including skin biopsy as clinically indicated

Confirm with appropriate skin tests

Consider trial off drug

Further appropriate tests negative

No vasculitis

Urticarial vasculitis

Consider delayed-pressure urticaria

Autoimmune urticaria most likely

Allergic urticaria

Drug-induced urticaria

Idiopathic urticaria

Recommendations of the British Society for Allergy and Clinical Immunology

Adapted from Powell RJ, et al. Clin Exp Allergy. 2007;37(5):631-650.

Antibodies Associated with Urticaria

IgG autoantibody to the IgE receptor Antithyroglobulin antibody Antimicrosomal antibody Both antibodies One antibody or both

35% to 40% 8% 5% 14% 27%

Adapted from Ferrer M, et al. Int Arch Allergy Immunol. 2002;129:254-260.

Autologous Serum Skin Test

Serum obtained from patient 0.05 ml injected intradermally Examination of wheal response at 30 minutes Positive test is extension of wheal response by at least 1.5 mm greater than original Patients with positive skin test associated with histamine-releasing FceRI autoantibodies Patients with sera with histamine releasing activity had more severe urticaria compared to those without
Sabroe RA et al. J Allergy Clin Immunol 2002; 110: 494-9

Autologous Intradermal Skin Test

Induration extends beyond original margin by at least 1.5 mm

Autoimmunity is the Most Likely Cause For Chronic Idiopathic Urticaria (CIU)

Many patients with CIU found to have auto antibodies to the FceRI (IgE high affinity receptor) Hide M et al N Engl J Med 1993; 328: 1599-1604 Patients with auto antibodies to the FceRI and/or IgE had higher itch scores and more wheals than those patients without autoantibodies (with CIU) Sabroe RA et al J Am Acad Derm 1999; 40: 443-50

Autoantibodies in CIU
9% 15% 41%
Immunoreactive Histamine-releasing anti-FceRI Immunoreactive antiFceRI without histamine releasing activity Mast-cell relasing factor

No-identifiable factor

26%
Anti-IgE-like autoantibodies

9%

Sabroe RA, et al. J Allergy Clin Immunol 2002; 110: 492-9

Anti-FceRI Auto Antibodies

Associated

with increased symptoms, but not dramatically Increased frequency of thyroid autoimmunity

73% of patients with anti-thyroid Ab have functional Ab to FceRI (p<0.001)

Sabroe RA et al., J. Am. Acad. Dermatol 1990; 40: 443-50 Sabroe RA et al., J Allergy Clin Immunol 2002; 110: 492-9 Kikuchi Y, Fann T, Kaplan AP. J Allergy Clin Immunol 2003;112(1):218 Grattan, CEH. Immunol Allergy Clinics of NA 2004;163-182

Association of Chronic Idiopathic Urticaria with Autoimmunity and IgE levels

A.Chomiciene, L.M. DuBuske, A.Blaziene Vilnius University, Vilnius, LITHUANIA, Immunology Research Institute of New England, Gardner, MA

Rationale

Approximately one-third of patients with chronic idiopathic urticaria (CIU) have circulating functional auto-antibodies directed against either the high affinity IgE receptor FcRI or IgE and an association with autoimmune thyroiditis.

Methods
39 patients with CU were studied including 32 females and 7 males, age range 20-70 years old. Total IgE, thyroid peroxidase antibodies (ATPO) and Autologous Serum Skin Tests (ASST) were performed on all subjects.

Results
Positive ASST were seen in 9(23%) patients. Elevated ATPO were found in 7(18%), 5(71%) of whom had a positive ASST. Increased total IgE was found in 15(38.5%) of patients, 12(80%) having a negative ASST, and 3(20%) having a positive ASST.

Conclusions
Most patients with CIU are middle-aged female. About one-fourth of patients had a positive ASST, most having autoimmune thyroid disease. Increased total IgE , seen in two-fifths of patients, was more often noted in patients without functional auto-antibodies.

Summation

Two distinct subgroups of CIU were identified: -Those with autoimmune etiology featuring functional auto-antibodies -Those with elevated IgE generally without autoantibodies Together these two groups comprise nearly twothirds of CIU patients.

This study suggests there are heterogeneous pathophysiologic etiologies of CIU.

Increased Basophil CD63 and CD203c Expression Versus Autologous Serum Skin Tests in Chronic Urticaria Patients

A. Chomiciene1, A. Blaziene1, L. Jurgauskiene1, L. M. DuBuske2

1Vilnius

University, Vilnus, LITHUANIA, 2Immunology Research Institute of New England, Gardner, MA, USA

ACAAI, Nov 2008

Methods

1) 34 patients with a history of CU, age 22 to 71 years old, including 30 females and 4 males, were evaluated. 2) The autologous serum skin test (ASST) was performed on all patients. 3) Basophil activation tests (BAT) using CD63 and CD203c expression were performed on basophils from selected atopic donors after stimulation with sera from CU patients. 4) Sera from 10 healthy donors were used as normal controls in the BAT.

RESULTS

1) The ASST was positive in 13 (38.2 %) of CU patients (Figure 1). 2) The mean percent of basophil CD63 expression with CU patient sera was 15.84 1.70 versus 4.17 0. 46 with healthy control sera. 3) The mean percent of basophil CD203c expression with CU patient sera was 13.70 1.76 versus 2.46 0.08 with healthy control sera. 4) 29 (85.3 %) CU patients had a positive basophil CD63 expression assay. 5) 26 (76.5%) CU patients had a positive basophil CD203c expression assay. 6) There was a good correlation between basophil CD63 and CD203c expression, but no correlation between results of these Basophil Activation Tests and Autologous Serum Skin Test results.

Basophil Activation Marker Expression Induced by Sera from CU Patients Versus Healthy Controls

Group Basophil Activation Test CD63 Positive Negative CD203c Positive Negative CU Patients Number 29 5 26 8 % 85.3% 14.7% 76.5% 23.5% Healthy Controls Number 0 10 0 10 % 0.0% 100.0% 0.0% 100.0%

Basophil Activation Marker Expression Using Calculated Thresholds Versus Autologous Serum Skin Tests

Group Basophil Activation Test CD63 Positive Negative CD203c Positive Negative CU Patients Number 29 5 26 8 % 85.3% 14.7% 76.5% 23.5% Healthy Controls Number 0 10 0 10 % 0.0% 100.0% 0.0% 100.0%

Correlations Between Autologous Serum Skin Tests and Basophil Activation Tests CD63 and CD203

ASST Spearman's rho ASST Correlation Coefficient Sig. (2-tailed) N CD63PN Correlation Coefficient Sig. (2-tailed) N CD203cPN Correlation Coefficient Sig. (2-tailed) N 34 .156 .379 34 .134 .449 34 1.000

CD63PN 0.156 .379 34 1.000

CD203cP N .134 .449 34 .357(*) .038

34 .357(*) .038 34

34 1.000

34

CONCLUSIONS

1) BAT assessing enhanced expression of either CD63 or CD203c are frequently positive in patients with CU. 2) BAT results do not correlate with ASST results 3) Lack of correlation between ASST and high basophil CD63 and CD203c expression suggests that factors other than anti-FcRI antibodies are present in CU sera leading to up-regulation of basophil CD63 and CD203c expression.

Resolution of Urticaria After Treatment of Thyroid Disease

6/46 patients with chronic urticaria and autoimmune thyroid disease improved with thyroid replacement therapy
Leznoff A, Sussman GL. J Allergy Clin Immunol 1989; 84: 66-71

7/10 euthroid patients with chronic urticaria and antibodies elevated anti-thyroid (anti-TMA or anti-thyroglobulin) responded to thyroxine (0.05 0.25 mg/d)
Rumbyrt JS, Katz JL, Schocket AL. J Allergy Clin Immunol 1995; 96: 901-5

Are All FceRI Autoantibodies Functional and Cause Histamine Release?

Some anti- FceRI autoantibodies found in other conditions (pemphigus, lupus, dermatomyositis)

Different subtypes (IgG1 and IgG3) compared to urticaria associated autoantibodies (IgG2 and IgG4)

Autoantibodies against anti- FceRI autoantibodies could neutralize their effect Bi-specific autoantibodies that cross-link FceRI and FcgR11 receptors cause inhibition of histamine release
Tam, et al Allergy 2004; 59: 772-780

Histamine Release in CIU Due to Autoantibodies is Augmented by Complement Activation

30

Histamine Release (%)

25 20 15 10 5 0 Patient Patient Patient Patient Patient Normal A B C D E IgG -C5 +C5

Adapted from Kikuchi Y and Kaplan AP J Allergy Clin Immunol 2002; 109: 114-8

Complement Participation in the Inflammatory Response

As a result of complement activation (IgG or IgM mediated activation via classical cascade) or C3 activation via the alternative cascade (from bacterial infection), C3a and C5a (anaphylatoxins) are released
C3a and C5a both participate in chemotaxis of inflammatory cells as well as mast cell activation

Disease Management

Therapeutic Options

Therapy with antihistamines work best for most patients with acute-types of short-lasting urticaria Combination therapy should be attempted if H1 antagonists do not suffice (30% of cases) Steroids and other immunosuppressants should be reserved for severe urticaria associated with angioedema of oropharnyx or other systemic signs, moderate to severe drug reactions, urticarial vasculitis, and refractory cases of CIU

Step-up Treatment Plan for Chronic Urticaria

Treatment should be stepped down once control is achieved
Education and Avoidance of Triggers

6) Add or substitute other second-line agents (ie, cyclosporin or a low-dose corticosteroid*)

5) Consider adding or substituting with secondline agent (ie, anti-leukotriene)

Identification of Triggers

4) Consider sedating antihistamine at night

3) Add second non-sedating H1 antihistamine (regular or as required) 2) Higher dose of H1 antihistamine 1) Standard dose of non-sedating H1 antihistamine

Recommendations of the British Society for Allergy and Clinical Immunology * Low-dose daily corticosteroid (510 mg/day) or low-dose alternative day corticosteroid (1520 mg alt day) could be considered.
Powell RJ, et al. Clin Exp Allergy. 2007;37(5)631-650.

Classification of Urticaria

EAACI/GA2LEN/EDF guideline. T. Zuberbier et al. Allergy 2006: 61: 316320

Diseases Related to Urticaria

EAACI/GA2LEN/EDF guideline. T. Zuberbier et al. Allergy 2006: 61: 316320

Differential Diagnosis of Urticaria

HAE, hereditary angioedema; AAE, acquired angioedema with C1 esterase inhibitor deficiency; SA, spontaneous angioedema as manifestation of chronic urticaria with only deep swellings but no superficial wheals. *Duration of individual wheals; **duration of urticaria.

Diagnosis of Urticaria: History

1) time of onset of disease 2) frequency and duration of wheals 3) diurnal variation 4) shape, size and distribution of wheals 5) associated angioedema 6) associated subjective symptoms of lesion, e.g. itch, pain 7) family history regarding urticaria, atopy 8) previous or current allergies, infections, internal diseases, or other possible causes 9) induction by physical agents or exercise 10) use of drugs [nonsteroidal antiinflammatory drugs (NSAIDs), injections, immunizations, hormones, laxatives, suppositories, ear and eye drops and alternative remedies]

EAACI/GA2LEN/EDF guideline. T. Zuberbier et al. Allergy 2006: 61: 316320

Diagnosis of Urticaria: History

11) food 12) smoking habits 13) type of work 14) hobbies 15) occurrence in relation to weekends, holidays and foreign travel 16) surgical implantations 17) reactions to insect stings 18) relationship to the menstrual cycle 19) response to therapy 20) stress 21) quality of life related to urticaria

EAACI/GA2LEN/EDF guideline. T. Zuberbier et al. Allergy 2006: 61: 316320

Recommended Diagnostic Tests

EAACI/GA2LEN/EDF guideline. T. Zuberbier et al. Allergy 2006: 61: 316320

Assessment of Disease Activity

EAACI/GA2LEN/EDF guideline. T. Zuberbier et al. Allergy 2006: 61: 316320

Negative Drug Studies

EAACI/GA2LEN/EDF guideline: T. Zuberbier et al. Allergy 2006: 61: 321331

Conclusions
The quality of life in urticaria is severely affected and management of the disease should therefore be prompt and in close cooperation between patient and physician. Due to high variability of disease severity, an individual approach is necessary for each patient. As a first line, triggering factors should be avoided as far as possible and any associated diseases should be treated.

In the majority of patients, symptomatic pharmacological treatment is possible with new generation antihistamines, with a very low adverse effect profile and good patient compliance.
In nonresponding patients, higher dosages (up to fourfold) and alternative medication should be tried. Most of these, such as corticosteroids or cyclosporin, should be reserved for severely affected patients because of their unfavorable adverse effect profile.

Effects of Loratadine and Desloratadine

Structures

Loratadine

Desloratadine

Radioligand Binding to H1 Receptors

Effects of loratadine and desloratadine (DL) on radioligand specific binding to H1 receptors Compound
Loratadine Desloratadine

IC50
721 nM 51 nM

No significant serotonergic, adrenergic effects

Functional Characteristics of Desloratadine vs Loratadine

Methods:

Chinese Hamster Ovary (CHO) cell line that express cloned human H1 receptor Primary culture of human bronchial smooth muscle (HBSM) cell which endogenously expresses the H1 receptor Histamine induces Ca2+ flux as an H1-receptor agonist in both cell cultures Histamine EC50 for calcium flux: CHO cells: 98 nM HBSM cells: 164 nM

Relative Potency of Antihistamines to Bind to The Cloned Human H1 Receptor in CHO Cells
100 80
Relative Potency

100

60 40 20 3 0
Antihistamine

Desloratadine Astemizole Terfenadine Cetirizine Loratadine Fexofenadine

Relative Potency of Antihistamines to Block H1 Response on Human Bronchial Cells

100 80 60 40 20 0

100

18

14 6 2 2 1 1

Desloratadine Mizolastine Astemizole Terfenadine Loratadine Fexofenadine Ebastine Cetirizine

Relative Potency

Antihistamine

Ex Vivo Antihistamine Activity Functional Antagonism H1 Receptors

Inhibition of histamine induced contraction of guinea pig ileum
Percent Block
100
75 50 25 0 -25 5 20 35 50 65 80 95 110 125

DL

LOR

Minutes each compound tested at 1x10-9 M

Handley, Ann Allergy Asthma Immunol. 78, 142 1997.

In Vivo Animal Antihistamine Activity

Inhibition of histamine induced wheal and flare in the guinea pig
Average Area (mm2)
300 250 200 150 100 50 0 0.0003 0.0010.003 0.01 0.03 0.1 0.3

Bradykinin vehicle DPH LOR

DL

mmol histamine/site
Handley, Ann Allergy Asthma Immunol. 78, 144 1997.

Occupancy of the H1-Receptor

CHO-H1 membranes (5-10 mg) were incubated with 2 nM [3H]desloratadine (60 min) or [3H]pyrilamine (30 min) with or without 10-5 M chlorpheniramine Dissociation was initiated by the addition of 5 mM desloratadine or 5 mM pyrilamine Dissociation kinetic analysis demonstrated that [3H]pyrilamine had a short H1-receptor binding time with a t1/2 of 3.8 min [3H]desloratadine had a long H1-receptor binding time with 63% of the ligand remaining after 6 hrs

Lippert U. EAACI Poster Presentation. 2001.

Occupancy of the H1-Receptor

120

Antagonist Bound (%)

100 80

60
40 20 0

Desloratadin e
Pyrilamine

50

100

150 200
Time (min)

250

300 350

400

Lippert, Allergy 2001

Effect of Desloratadine on Mediator Release From Human Lung Mast Cells 60

50 40 57 PGD2 40 LTC4 31 Histamine

% Inhibition

30 20 10 0

34 21 16 7 6 19

10 Desloratadine, M

30

Genovese et al. Clin Exp Allergy. 1997;27:559.

Effect of Desloratadine on Histamine, LTC4, and IL-4 Secretion by Human Basophils

80 70 60

IL-13 IL-4 Histamine LTC4

% Inhibition

50 40 30 20 10 0 10-7

10-6

10-5

DL (M)

Cells were pretreated 15 minutes with desloratadine before activation with anti-IgE antibody. The three products were measured after 4 hours incubation. Values are mean SEM (n=5) using human basophils to 95% purity
Schroeder JT et al. Clin Exp Allergy. 2001 Sep;31(9):1369-77.

Effect of Desloratadine, Dexamethasone and Cetirizine on Mast Cell IL-6 Release

0
Percent inhibition (%)

-5 -10 -15 -20 -25 -30 -35

-8%

-32%
Dexamethasone 10-8 M

-32.6%
Desloratadine 10-9 M Cetirizine 10-9 M

Lippert et al. Exp Dermatol 2000; 9:118-124.

Effect of Desloratadine, Dexamethasone and Cetirizine on Mast Cell IL-8 Release

0
Percent inhibition (%)

-10 -20

-23% -32.6%

-30 -40 -50

Dexamethasone 10-8 M Desloratadine 10-9 M Cetirizine 10-9 M

-46%

Lippert et al. Exp Dermatol 2000; 9:118-124.

Effect of Desloratadine, Dexamethasone and Cetirizine on Mast Cell IL-3 Release

0
Percent inhibition (%)

-5 -10 -15 -20 -25 -30 -35

Dexamethasone 10-8 M Desloratadine 10-9 M Cetirizine 10-9 M

-14.4 -17.8

-32.1

Lippert et al. Exp Dermatol 2000; 9:118-124.

Effect of Desloratadine, Dexamethasone and Cetirizine on Mast Cell GM-CSF Release

0
Percent inhibition (%)

-5 -10 -15 -20 -25 -30 -35

Dexamethasone 10-8 M Desloratadine 10-9 M

-6.2

-27.8 -31
Cetirizine 10-9 M

Lippert et al. Exp Dermatol 2000; 9:118-124.

Effect of Desloratadine, Dexamethasone and Cetirizine on Mast Cell TNF- Release

0
Percent inhibition (%)

-10 -20 -30 -40 -50 -60 -70

Dexamethasone 10-8 M

-29 -54 -64.5

Desloratadine 10-9 M Cetirizine 10-9 M

Lippert et al. Exp Dermatol 2000; 9:118-124.

Anti-Inflammatory Effect of Desloratadine and Cetirizine on Mast Cell Cytokine Release

0
Percentage Inhibition

-10 -20 -30 -40 -50 -60 -70 IL-6 IL-8 TNFalpha IL-3 GMCSF
Desloratadine 10-9M Cetirizine10-9M

Lippert et al. Exp Dermatol 2000; 9:118-124.

Effect of Desloratadine versus Loratadine on Histamine Activation of Endothelial Cells Molar Concentrations to reach 50% Cytokine Inhibition
IL-6 IL-8

10-6 10-9 10-12

106

Desloratadine

Loratadine

Effect of Desloratadine on TNF- Induced Nasal Epithelial RANTES

120
RANTES pg/mL)

100 80 60 40 20 0

109.26

44.44

TNF-a Stimulation

TNF-a + Desloratadine

Lebel B et al. J Allergy Clin Immunol 1997; 99 (Suppl 444): Abs 1802

Effect of Desloratadine on HistamineInduced P-Selectin Expression

Human umbilical vein endothelial cell expression of P-selectin
100

Percent inhibition

90 80 70 60

50

10-8

10-7 10-6 Desloratadine

10-5

Molet et al. Clin Exp Allergy 1997; 27: 1167-1174.

Effect of Desloratadine on Eosinophil Adhesion

P <0.01 35 P >0.05 P <0.05

% Inhibition

30 25 20 15 10 5 0 10-5 10-6 Desloratadine Concentration (M) 10-7

Effect of Desloratadine on Eosinophil Chemotaxis

P < 0.01

50
Percentage Inhibition P > 0.05

40 30 20 10 0
10-5 10-6 Desloratadine (M) 10-7 P < 0.05

Agrawal, 2000

Desloratadine inhibits Calcium ionophoreinduced LTC4 generation by nasal polyp tissue

M.L.Kowalski, A.Lewandowska, J. Woniak, T.Kornatowski, A. Jankowski , L. DuBuske* Department of Clinical Immunology and Allergy Medical University of Lodz, Poland *Immunology Research Institute of New England

Nasal polyp dispersed cells

(cytospine preparations)

Mononuclear cells
(lymphocytes and macrophages)

50 11% 37 10% 10 7% 3 3% 2 2%

Epithelial cells Eosinophils Mast cells Neutrophils

Effect of single concentration desloratadine (10-5M) on calcium ionophore-induced LTC4 generation by NP cells

p<0,001

p<0,004

400 300 200 100 0

Non-stimulated Calcium ionophore

Medium Desloratadine

Desloratadine: Activity/Tolerability in Chronic Idiopathic Urticaria (CIU)

Desloratadine in CIU
Once-daily desloratadine improves the signs and symptoms of chronic idiopathic urticaria: a randomized, double-blind, placebocontrolled study. Ring J, Hein R, Gauger A, Bronsky E, Miller B. Int J Dermatol. 2001 Jan;40(1):72-6.

Desloratadine: Activity/Tolerability in Chronic Idiopathic Urticaria

Objective To evaluate the activity of desloratadine (DL) 5 mg with placebo in patients with chronic idiopathic urticaria Methods and Study Design Randomized, parallel-group, double-blind, placebo-controlled, multicenter trial; N=190
18. Study No. P00221.

Desloratadine in CIU

METHODS: This was a multicenter, randomized, double-blind, placebocontrolled study designed to determine the efficacy and safety of desloratadine in the treatment of moderate-to-severe CIU. A total of 190 patients, aged 12-79 years, with at least a 6-week history of CIU and who were currently experiencing a flare of at least moderate severity, were randomly assigned to therapy with desloratadine 5 mg or placebo once daily for 6 weeks. Twice daily, patients rated the severity of CIU symptoms (pruritus, number of hives, and size of largest hive), as well as the impact of CIU symptoms on sleep and daily activity. Patients and investigators jointly evaluated therapeutic response and overall condition. Safety evaluations included the incidence of treatment-emergent adverse events, discontinuations due to adverse events, and changes from baseline in vital signs, laboratory parameters, and ECG intervals.

Desloratadine: Activity/Tolerability in Chronic Idiopathic Urticaria

Diagnosis and Criteria for Inclusion > 12 years of age Documented signs and symptoms of CIU for >6 weeks CIU flare for >3 weeks before screening, with urticarial lesions visible >3 days per week Overall condition and pruritusmoderate at screening and baseline (score >2) Hives apparent Total pruritus score of >14 for 3 consecutive days prior to baseline

18. Study No. P00221.

Desloratadine: Activity/Tolerability in Chronic Idiopathic Urticaria

Severity of signs and symptoms of CIU were scored 2x/day using diary cards Patients evaluated the following variables:

Pruritus Number of hives Size of largest hive Interference with sleep Interference with activities

7. Study No. P00221.

Desloratadine: Activity/Tolerability in Chronic Idiopathic Urticaria

Total Symptom Score Reflective AverageAfter 1 No. of Size of Dose
Pruritus Hives Largest Hive

0
Mean % change from baseline

Placebo (N=95) -10 DL 5 mg (N=95) -20 -30 -40 -50

* *

*P<0.001

7. Study No. P00221.

Desloratadine: Activity/Tolerability in Chronic Idiopathic Urticaria

Pruritus Analysis Results Full 24 Hour Coverage/ Instantaneous Days 1-8
% Change from Baseline

0 -10 -20 -30 -40 -50 -60

P<.001

Desloratadine Placebo

Desloratadine: Activity/Tolerability in Chronic Idiopathic Urticaria

Pruritus Analyses Reflective Average
0

Mean % change from baseline

-10 -20 -30 -40 -50 -60 -70

Placebo (N=95) DL 5 mg (N=95)

*
* *
3

* * *
4 5

-80
1

*
6

*P<0.001
Endpoint

Last available weeks average. 7. Study No. P00221.

Weeks

Efficacy of Desloratadine in Chronic Urticaria Results of hive number/size

size
0 -10 -20 -30

number

size

number p < 0.04 * p# < 0.02

mean change -40 [%]

-50 -60 -70 -80

p < 0.001
desloratadine placebo

after 1 dose

6 weeks

Desloratadine: Activity/Tolerability in Chronic Idiopathic Urticaria

Improvement in Sleep
80

Mean % change from baseline

70 60 50 40 30 20 10 0
After 1 dose Days 1-8 Days 37-42 Endpoint

Placebo DL

*P<0.05 P<0.001

7. Study No. P00221.

Desloratadine: Activity/Tolerability in Chronic Idiopathic Urticaria

Improvement in Activities
80

Mean % change from baseline

70 60 50 40 30 20 10 0
After 1 dose Days 1-8 Days 37-42

Placebo DL

*P<0.05 P<0.001
Endpoint

7. Study No. P00221.

Desloratadine in CIU

RESULTS: Desloratadine was superior to placebo in controlling pruritus and total symptoms after the first dose and maintained this superiority to the end of the study. Measures of sleep, daily activity, therapeutic response, and global CIU status were also significantly better with desloratadine after the first dose; these clinical benefits were also maintained throughout the 6-week study. No significant adverse events occured.

Desloratadine in Urticaria

Efficacy demonstrated after first dosage Efficacy sustained for 24 hours after dosing Efficacy sustained during 6 weeks of usage

Desloratadine in CIU: Monroe

Efficacy and safety of desloratadine 5 mg once daily in the treatment of chronic idiopathic urticaria: a double-blind, randomized, placebo-controlled trial Monroe E, Finn A, Patel P, Guerrero R, Ratner P, Bernstein D; Desloratadine Uritcaria Study Group. J Am Acad Dermatol. 2003 Apr;48(4):535-41.

Desloratadine in CIU: Monroe

METHODS: This study was a randomized, double-blind, placebo-controlled, parallelgroup, multicenter trial of 6 weeks' duration. RESULTS: Compared with placebo, desloratadine significantly improved the total CIU symptom score as well as pruritus, the number of hives, and the size of the largest hive.

Desloratadine in CIU: Monroe

Overall therapeutic response and global CIU status improved significantly with desloratadine; interference with sleep was reduced and the performance of daily activities improved. Statistically and clinically significant improvements were seen within the first 24 hours of treatment and were sustained throughout the full duration of the study. The incidence of adverse events, including somnolence, was similar in the desloratadine and placebo groups.

Desloratadine in CIU
Efficacy and safety of desloratadine in adults with chronic idiopathic urticaria: a randomized, double-blind, placebocontrolled, multicenter trial. Ortonne JP, Grob JJ, Auquier P, Dreyfus I. Am J Clin Dermatol. 2007;8(1):37-42

Desloratadine in CIU

METHODS: This was a randomized, placebocontrolled, multicenter trial of 137 adult patients with active CIU who received oral once-daily desloratadine 5mg or placebo for 6 weeks. Outcome measures included pruritus severity, number of wheals, and the size of the largest wheal. Patients assessed signs and symptoms on a four-point scale twice daily. The overall therapeutic response at the end of the 6-week treatment period was also rated.

Desloratadine in CIU

RESULTS: Desloratadine treatment was associated with significant improvements compared with placebo in pruritus scores and in the size of the largest wheals as early as day 1. These improvements continued through to the end of the trial. The mean score for the number of wheals was significantly lower in the desloratadine group than in the placebo group on days 14 and 42 (p < or = 0.016).

Desloratadine in CIU
Overall improvement in CIU (complete, marked, or moderate therapeutic response) was also greater at the end of the study in the desloratadine group compared with placebo (p < 0.001). Adverse events occurred with similar frequency among desloratadine- and placebo-treated patients.

Desloratadine and QOL in CIU

Desloratadine 5 mg once daily improves the quality of life of patients with chronic idiopathic urticaria Lachapelle JM, Decroix J, Henrijean A, Roquet-Gravy PP, De Swerdt A, Boonen H, Lecuyer M, Suys E, Speelman G, Vastesaeger N. J Eur Acad Dermatol Venereol. 2006 Mar;20(3):288-92

Desloratadine and QOL in CIU

OBJECTIVE: Assess the effect of desloratadine 5 mg once daily on the quality of life of patients suffering of chronic idiopathic urticaria (CIU). Study population One-hundred twenty-one consecutive patients with CIU present for at least 6 weeks prior to inclusion and with a current flare of at least 3 weeks, were included in the study in 24 Belgian centres.

Desloratadine and QOL in CIU

RESULTS: The mean dermatology life quality index (DLQI) significantly decreased from baseline to day 7 and further to day 42. Sixty per cent and 77% of patients had a clinically significant change (i.e. a decrease of at least 2 points) at day 7 or day 42, respectively, as compared with that of day 0. Change in pruritus and size of the hives significantly correlated with the change in the score of the quality of life. One-third of patients experienced complete relief whereas in 1 of 10 patients no effect was experienced.

Desloratadine Impact on QOL in CIU

Quality of life in adults with chronic idiopathic urticaria receiving desloratadine: a randomized, double-blind, multicentre, placebo-controlled study. Grob JJ, Auquier P, Dreyfus I, Ortonne JP. Eur Acad Dermatol Venereol. 2008 Jan;22(1):87-93.

Desloratadine Impact on QOL in CIU

MAIN OUTCOME MEASURES: Variation of the scores of two QoL dermatology-specific tools between baseline and day 42, the French translation version of the Dermatology Life Quality Index (DLQI) and the VQ-Dermato (a French-language scoring instrument).

Desloratadine in and QOL in CIU

Desloratadine and QOL in CIU

Desloratadine and QOL in CIU

Desloratadine and QOL in CIU

Desloratadine and QOL in CIU

Desloratadine and QOL in CIU

Desloratadine Impact on QOL in CIU

RESULTS: The intent-to-treat population comprised 137 patients [desloratadine (n = 65) or placebo (n = 72)]. Desloratadine treatment was associated with significantly greater improvements from baseline to day 42 compared with placebo in DLQI overall score (-6 vs. -2.2 points; P < 0.002) and VQDermato score (18.5 vs. 29.1 points; P = 0.009).

Desloratadine and Oxidative Stress in CIU

Influence of desloratadine on oxidative stress markers in patients with chronic idiopathic urticaria. Cassano N, Raho G, Filieri M, D'Argento V, Amoruso A, Filotico R, Vena GA. Int J Dermatol. 2006 Apr;45(4):394-6.

Desloratadine and Oxidative Stress in CIU

METHODS: Blood samples were obtained from 10 patients with CIU before and after 4 weeks of treatment with desloratadine. Blood samples from 10 healthy volunteers were used as controls. In platelets from both patients and controls, radical oxygen species (ROS) production was measured using spectrofluorimetric detection of dichlorofluorescein oxidation, and superoxide dismutase (SOD) activity was determined by means of the xanthine-xanthine oxidase system.

Desloratadine and Oxidative Stress in CIU

RESULTS: Radical oxygen species concentrations and SOD activity were significantly elevated in patients with CIU at baseline as compared with control subjects. Treatment with desloratadine caused a relevant reduction of ROS levels and SOD activity (P<0.005).

Desloratadine in Cold Urticaria

JACI. 2008; 121 (3) : 794

Desloratadine in Cold Urticaria

JACI. 2008; 121 (3) : 794

Desloratadine in Cold Urticaria

JACI. 2008; 121 (3) : 794

Desloratadine in Cold Urticaria

JACI. 2008; 121 (3) : 794

Desloratadine in Cold Urticaria

JACI. 2008; 121 (3) : 794

Desloratadine in Delayed Pressure Urticaria

Desloratadine in combination with montelukast suppresses the dermographometer challenge test papule, and is effective in the treatment of delayed pressure urticaria: a randomized, double-blind, placebo-controlled study. Nettis E, Colanardi MC, Soccio AL, Ferrannini A, Vacca A. Br J Dermatol. 2006 Dec;155(6):1279-82

Desloratadine in Delayed Pressure Urticaria

METHODS: The study was conducted in 36 subjects affected by DPU. A challenge test with a dermographometer was administered to confirm the diagnosis. After diagnosis, patients were randomized to receive the following treatment once daily for 2 weeks: (i) oral desloratadine 5 mg plus oral placebo; (ii) oral desloratadine 5 mg plus montelukast 10 mg; and (iii) oral placebo alone.

Desloratadine in Delayed Pressure Urticaria

RESULTS: At rechallenge, patients from the treatment groups (desloratadine plus montelukast group and desloratadine alone group) demonstrated a significant reduction in mean diameter of papules after 70 s of pressure compared with the placebo group (P < 0.05). Moreover, patients treated with desloratadine plus montelukast showed a significant reduction in mean diameter of papules at 70 s of pressure compared with those treated with desloratadine alone (P < 0.05). In addition, the combination was effective in improving clinical parameters (erythema, oedema and pruritus, and number of separate urticarial episodes).

Desloratadine in Delayed Pressure Urticaria

CONCLUSIONS: This study has demonstrated that both desloratadine alone and desloratadine plus montelukast administered once daily yield improvements with respect to the baseline assessment, regarding the suppression of the dermographometer challenge test papule and clinical improvement of urticaria. However, the combination of desloratadine and montelukast was shown to be more efficacious and may therefore be proposed in patients with DPU, in order to avoid corticosteroid therapy.

Desloratadine in Urticaria

Consistent improvement in CIU symptoms ranging from 50 to 80% symptom reduction Improvement in symptoms of cold urticaria Improvement in symptoms of deep pressure urticaria QOL improvement Reduction in Oxidative Stress Anti-inflammatory effects At least comparable improvement compared to levocetirizine (50 80% reduction in symptoms and improved QOL) in clinical parameters of CIU in studies versus placebo despite less reduction in histamine induced wheal and flare than levocetirizine

Desloratadine in Urticaria
Greater efficacy than seen in allergic rhinitis where symptom reduction ranges from 20% to 40% improvement from baseline Typical symptom reduction 50-70% for pruritus / hive size and hive number Clinical antihistamine data suggests that histamine plays a relatively greater role in urticaria than in allergic rhinitis