urticaria/angioedema - management

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Urticaria/Angioedema - Urticaria/Angioedema - Management Management David M. Lang, MD David M. Lang, MD Head, Allergy/Immunology Section Head, Allergy/Immunology Section Respiratory Institute Respiratory Institute Cleveland Clinic Cleveland Clinic

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Urticaria/Angioedema - Management. David M. Lang, MD Head, Allergy/Immunology Section Respiratory Institute Cleveland Clinic. Disclaimer. - PowerPoint PPT Presentation

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Page 1: Urticaria/Angioedema - Management

Urticaria/Angioedema - ManagementUrticaria/Angioedema - Management

David M. Lang, MDDavid M. Lang, MDHead, Allergy/Immunology SectionHead, Allergy/Immunology Section

Respiratory InstituteRespiratory InstituteCleveland ClinicCleveland Clinic

Page 2: Urticaria/Angioedema - Management

DisclaimerDisclaimer• I have received honoraria from, have carried I have received honoraria from, have carried

out clinical research with, and/or have out clinical research with, and/or have served as a consultant for:, served as a consultant for:, Genentech/Novartis, GlaxoSmithKline, Genentech/Novartis, GlaxoSmithKline, Hycor, Merck, Sanofi-Aventis, Hycor, Merck, Sanofi-Aventis, Schering/Key.Schering/Key.

• My presentation will include discussion of My presentation will include discussion of off-label uses of a number of FDA approved off-label uses of a number of FDA approved products, but not agents that are not FDA-products, but not agents that are not FDA-approved.approved.

Page 3: Urticaria/Angioedema - Management

DisclaimerDisclaimer• Updated Urticaria/Angioedema parameter in preparation.Updated Urticaria/Angioedema parameter in preparation.• WorkgroupWorkgroup

o Chair: Jonathan Bernstein, MDChair: Jonathan Bernstein, MDo Liaison: David Lang, MDLiaison: David Lang, MDo Members:Members:

Timothy Craig, DOTimothy Craig, DO David Dreyfus, MDDavid Dreyfus, MD David Khan, MDDavid Khan, MD Javed Sheikh, MD Javed Sheikh, MD David Weldon, MDDavid Weldon, MD Bruce Zuraw, MDBruce Zuraw, MD

Page 4: Urticaria/Angioedema - Management

Learning ObjectiveLearning Objective

• Describe evidence-based Describe evidence-based management of patients with management of patients with chronic urticaria/angioedemachronic urticaria/angioedema

Page 5: Urticaria/Angioedema - Management

H-1 AntihistaminesH-1 AntihistaminesHigh Quality EvidenceHigh Quality Evidence

• Preferred 1st line therapy for patients with Preferred 1st line therapy for patients with chronic urticaria/angioedema.chronic urticaria/angioedema.

• H1-antihistamines efficacious in numerous H1-antihistamines efficacious in numerous published RCTs since 1950s.published RCTs since 1950s.

• 1st generation agents associated with risk 1st generation agents associated with risk for sedation and anti-cholinergic effectsfor sedation and anti-cholinergic effects

• 2nd generation agents also efficacious and 2nd generation agents also efficacious and in many patients are better toleratedin many patients are better tolerated

Strong RecommendationStrong Recommendation

Page 6: Urticaria/Angioedema - Management

Efficacy of Doxepin Compared Efficacy of Doxepin Compared with Diphenhydraminewith Diphenhydramine

43%

74%

5%

10%

0% 10% 20% 30% 40% 50% 60% 70% 80%

Total clearing ofpruritus and

urticarial lesions

Total or partialcontrol of

pruritus andurticaria

Doxepin 10 mg TID Diphenhydramine 25 mg TID

Green SL, et al. J Am Acad Dermatol 1985 12: 669-75Green SL, et al. J Am Acad Dermatol 1985 12: 669-75* p < .001

*

*

Page 7: Urticaria/Angioedema - Management

Dose Advancement of 2Dose Advancement of 2ndnd Generation Antihistamines Generation Antihistamines

• 80 patients with refractory urticaria, 72% previously treated with steroids• Randomized to antihistamine, with dose advancement to 4x standard dose• Goal = symptom free (13 at 5 mg vs. 28 at higher dose, p = 0.02, X2)

Staevska M, et al. J Allergy Clin Immunol 2010; 125: 676-82Staevska M, et al. J Allergy Clin Immunol 2010; 125: 676-82

Antihistamine Dose

Page 8: Urticaria/Angioedema - Management

Refractory Urticaria/AngioedemaRefractory Urticaria/Angioedema

• H2 anti-histaminesH2 anti-histamines• Anti-leukotrienesAnti-leukotrienes• ColchicineColchicine• SulfasalazineSulfasalazine• HydroxychloroquineHydroxychloroquine• MethotrexateMethotrexate

• StanozololStanozolol• IVIGIVIG• MethotrexateMethotrexate• OmalizumabOmalizumab• CyclosporineCyclosporine• Others…Others…

Refractory = Obstinately resistant to authority or control, unruly

Page 9: Urticaria/Angioedema - Management

Antihistamines: H1 Combined with H2Antihistamines: H1 Combined with H2• Evidence difficult to interpretEvidence difficult to interpret

o Small numbers of patients studiesSmall numbers of patients studieso Different H1 antihistamines usedDifferent H1 antihistamines usedo Dose of H2 antihistamine variableDose of H2 antihistamine variable

Cimetidine 800-1200 mg/dayCimetidine 800-1200 mg/day One study: cimetidine 400 mg QIDOne study: cimetidine 400 mg QID

• Superior efficacySuperior efficacyo Clin Allergy 8:429, 1978o Br J Dermatol 117: 81; 1987

• No advantageNo advantageo Br J Dermatol 99: 675; 1978

• Drug-Drug interaction: Hydroxyzine & CimetidineDrug-Drug interaction: Hydroxyzine & Cimetidineo Simons EF, et al. Simons EF, et al. J Allergy Clin ImmunolJ Allergy Clin Immunol 1995; 95: 685-93 1995; 95: 685-93

Page 10: Urticaria/Angioedema - Management

Anti-LeukotrienesAnti-Leukotrienes• Montelukast/Zafirlukast/ZileutonMontelukast/Zafirlukast/Zileuton• Substantial safety advantage compared with Substantial safety advantage compared with

other “alternative” or “steroid sparing” agentsother “alternative” or “steroid sparing” agents• RCTsRCTs

o 5: favorable5: favorableo 1: no advantage1: no advantage

• Data suggest salutary effect more likelyData suggest salutary effect more likelyo ASA-exacerbated urticaria/angioedemaASA-exacerbated urticaria/angioedemao Physical Urticaria/Angioedema Physical Urticaria/Angioedema o Positive Autologous Serum Skin Test Positive Autologous Serum Skin Test

Morgan M, Khan D. Ann Allergy Asthma Immunol 2008; 100: 403-11

Page 11: Urticaria/Angioedema - Management

Methotrexate for Refractory Methotrexate for Refractory Chronic Urticaria/AngioedemaChronic Urticaria/Angioedema

• Retrospective report, total = 88 patients, period = 2005-2009• 8 patients receiving high dose anti-HA & oral steroids.• Response: 3 groups based on symptom severity, tx = 4.5 +/- 3 months

• Complete: no symptoms, tx = MTX with/without anti-HA, no steroid• Partial:: decrease in U/A severity and/or frequency with reduction in steroid dose• No response

• No serious AE’s; 1 case of mild increase in LFT, 2 cases of GI discomfort, managed with switch to IM route.

Sagi L. Acta Derm Venereol 2001; 91: 303-306

Page 12: Urticaria/Angioedema - Management

RCT: HydroxychloroquineRCT: Hydroxychloroquine• 21 patients with chronic urticaria/angioedema, randomized to 21 patients with chronic urticaria/angioedema, randomized to

Hydroxychloroquine (?dose) or Placebo for 12 weeks, in addition to other Hydroxychloroquine (?dose) or Placebo for 12 weeks, in addition to other medications for urticaria (H1 & H2 antihistamines, doxepin, corticosteroids).medications for urticaria (H1 & H2 antihistamines, doxepin, corticosteroids).

• Med taper q 2 weeks if well controlled; 18 completed trial, ITT analysis.Med taper q 2 weeks if well controlled; 18 completed trial, ITT analysis.

Reeves GEM, et al. Intern Med J 2004; 34: 182-6.

** * p < 0.05

* p = 0.05 – 0.10

*

**

Page 13: Urticaria/Angioedema - Management

CyclosporineCyclosporine

• Most extensively studied agent for treatment Most extensively studied agent for treatment of refractory chronic urticaria/angioedemaof refractory chronic urticaria/angioedema

• May exert salutary effect via down-regulation May exert salutary effect via down-regulation of Th1 responses and T cell dependent of Th1 responses and T cell dependent antibody generation of B lymphocytes, along antibody generation of B lymphocytes, along with inhibition of release of histamine and with inhibition of release of histamine and other mediators from mast cells and other mediators from mast cells and basophilsbasophils

Madan V, Griffiths CE. Dermatol Ther 2007; 20: 239-50.

Page 14: Urticaria/Angioedema - Management

Therapeutic Utility of Cyclosporine for Therapeutic Utility of Cyclosporine for Refractory Chronic Urticaria/AngioedemaRefractory Chronic Urticaria/Angioedema

• Case Series and Case ReportsCase Series and Case Reportso Fradin MS, et al. J Am Acad Dermatol 1991; 25: Fradin MS, et al. J Am Acad Dermatol 1991; 25:

1065-7. 1065-7. o Toubi E, et al. Allergy 1997; 52: 312-16.Toubi E, et al. Allergy 1997; 52: 312-16.o Serhat Inaloz H, et al. J Dermatol 2008; 35: 276-Serhat Inaloz H, et al. J Dermatol 2008; 35: 276-

82.82.

• Subject to bias, and do not provide high Subject to bias, and do not provide high quality evidence.quality evidence.

Page 15: Urticaria/Angioedema - Management

Therapeutic Utility of Cyclosporine for Therapeutic Utility of Cyclosporine for Refractory Chronic Urticaria/AngioedemaRefractory Chronic Urticaria/Angioedema

• PubMed Search: PubMed Search: o ““urticaria”, “cyclosporine”urticaria”, “cyclosporine”

o Limit = RCTLimit = RCT

• 4 RCT’s4 RCT’so Grattan CE, et al. Br J Dermatol 2000; 143: 352-72.Grattan CE, et al. Br J Dermatol 2000; 143: 352-72.

o Di Gioacchino M, et al. Allergy Asthma Proc 2003; 24: 285-90.Di Gioacchino M, et al. Allergy Asthma Proc 2003; 24: 285-90.

o Baskan EB, et al. J Dermatolog Treat 2004; 15: 164-8. Baskan EB, et al. J Dermatolog Treat 2004; 15: 164-8.

o Vena GA, et al. J Am Acad Dermatol 2006; 55: 705-9.Vena GA, et al. J Am Acad Dermatol 2006; 55: 705-9.

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Therapeutic Utility of Cyclosporine for Therapeutic Utility of Cyclosporine for Chronic Urticaria/AngioedemaChronic Urticaria/Angioedema

Vena GA, et al. J Am Acad Dermatol 2006; 55: Vena GA, et al. J Am Acad Dermatol 2006; 55: 705-9.705-9.

• DBRPC study with three arms, N=99:DBRPC study with three arms, N=99:

o 16 weeks cyclosporine: 5 mg/kg tapering to 4 16 weeks cyclosporine: 5 mg/kg tapering to 4 mg/kg, then 3 mg/kg.mg/kg, then 3 mg/kg.

o 8 weeks cyclosporine8 weeks cyclosporine

o placeboplacebo• Primary outcomePrimary outcome

o Improvement in severity scoreImprovement in severity score

Page 17: Urticaria/Angioedema - Management

Therapeutic Utility of Cyclosporine for Therapeutic Utility of Cyclosporine for Chronic Urticaria/AngioedemaChronic Urticaria/Angioedema

Vena GA, et al. J Am Acad Dermatol 2006; 55: 705-9.

Mean Improvement in Severity Score

* p< .05 * p< .01

*

**

*

**

*

Page 18: Urticaria/Angioedema - Management

Kaplan A., N Engl J Med 2002; 346: 175-9.

Evidence of Autoimmunity in Patients with Chronic Urticaria

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Autologous Serum Skin Test (ASST)Autologous Serum Skin Test (ASST)• 3 of 4 studies enrolled only patients with positive ASST.3 of 4 studies enrolled only patients with positive ASST.• ASST not performed in the remaining studyASST not performed in the remaining study

o Vena GA, et al. J Am Acad Dermatol 2006; 55: 705-9.Vena GA, et al. J Am Acad Dermatol 2006; 55: 705-9.• In other published studies, results of ASST has not In other published studies, results of ASST has not

consistently correlated with in vitro assays and positive consistently correlated with in vitro assays and positive ASST has been observed in patients without urticaria.ASST has been observed in patients without urticaria.o Taskapan, et al. Clin Exp Dermatol 2008; 33: 754-8.Taskapan, et al. Clin Exp Dermatol 2008; 33: 754-8.o Asero, et al. Clin Exp Allergy 2004; 34: 1111-14.Asero, et al. Clin Exp Allergy 2004; 34: 1111-14.

• The role of positive ASST in predicting salutary effect of The role of positive ASST in predicting salutary effect of cyclosporine is unclear.cyclosporine is unclear.

Page 20: Urticaria/Angioedema - Management

CyclosporineCyclosporine• 4 RCTs in patients with chronic urticaria/angioedema4 RCTs in patients with chronic urticaria/angioedema• Methodologic shortcomings recognized in each study.Methodologic shortcomings recognized in each study.• In the context of study limitations, potential harms and In the context of study limitations, potential harms and

costs, the quality of evidence supporting cyclosporine costs, the quality of evidence supporting cyclosporine administration is LOW -- leading to a WEAK administration is LOW -- leading to a WEAK RECOMMENDATION, based on current evidence.RECOMMENDATION, based on current evidence.o Implies that patients in different clinical contexts, with Implies that patients in different clinical contexts, with

different values or preferences, are candidates for different different values or preferences, are candidates for different choices.choices.

o Encourages clinicians to be more deliberate and judicious in Encourages clinicians to be more deliberate and judicious in incorporating evidence regarding risks/benefits in the context incorporating evidence regarding risks/benefits in the context of patient circumstances, values, and preferences to make of patient circumstances, values, and preferences to make the best management decision. the best management decision.

Page 21: Urticaria/Angioedema - Management

Step Wise ApproachStep Wise ApproachChronic Urticaria/AngioedemaChronic Urticaria/Angioedema

Advance dose ofAnti-histamine(1st +/or 2ndGeneration)

AddH2-Antihistamine

AddAnti-Leukotriene

2nd GenerationAntihistamine

Step-wise = Marked by a gradual progression

Page 22: Urticaria/Angioedema - Management

Step Care ApproachStep Care ApproachRefractory Chronic Urticaria/AngioedemaRefractory Chronic Urticaria/Angioedema

Step-wise = Marked by a gradual progression

Page 23: Urticaria/Angioedema - Management

Therapeutic Role For Anti-IgETherapeutic Role For Anti-IgE

Kaplan A., et al. J Allergy Clin Immunol 2008; 122: 569-73

• Open trial of omalizumab in patients “with hives present most days of the week despite antihistamines”.• 7/12 achieved complete symptom resolution.