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

2. Disclaimer I have received honoraria from, have carried out clinical research with, and/or have served as a consultant for:, Genentech/Novartis, GlaxoSmithKline, Hycor, Merck, Sanofi-Aventis, Schering/Key. I have received honoraria from, have carried out clinical research with, and/or have served as a consultant for:, Genentech/Novartis, GlaxoSmithKline, Hycor, Merck, Sanofi-Aventis, Schering/Key. My presentation will include discussion of off-label uses of a number of FDA approved products, but not agents that are not FDA- approved. My presentation will include discussion of off-label uses of a number of FDA approved products, but not agents that are not FDA- approved.

3. Disclaimer Updated Urticaria/Angioedema parameter in preparation. Updated Urticaria/Angioedema parameter in preparation. Workgroup Workgroup oChair: Jonathan Bernstein, MD oLiaison: David Lang, MD oMembers:  Timothy Craig, DO  David Dreyfus, MD  David Khan, MD  Javed Sheikh, MD  David Weldon, MD  Bruce Zuraw, MD

4. Learning Objective Describe evidence-based management of patients with chronic urticaria/angioedema Describe evidence-based management of patients with chronic urticaria/angioedema

5. H-1 Antihistamines High Quality Evidence Preferred 1st line therapy for patients with chronic urticaria/angioedema. Preferred 1st line therapy for patients with chronic urticaria/angioedema. H1-antihistamines efficacious in numerous published RCTs since 1950s. H1-antihistamines efficacious in numerous published RCTs since 1950s. 1st generation agents associated with risk for sedation and anti-cholinergic effects 1st generation agents associated with risk for sedation and anti-cholinergic effects 2nd generation agents also efficacious and in many patients are better tolerated 2nd generation agents also efficacious and in many patients are better tolerated Strong Recommendation

6. Efficacy of Doxepin Compared with Diphenhydramine Green SL, et al. J Am Acad Dermatol 1985 12: 669-75 * p <.001 * *

7. Dose Advancement of 2 nd 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, X 2 ) Staevska M, et al. J Allergy Clin Immunol 2010; 125: 676-82 Number of patients symptom free Antihistamine Dose

8. Refractory Urticaria/Angioedema H2 anti-histamines H2 anti-histamines Anti-leukotrienes Anti-leukotrienes Colchicine Colchicine Sulfasalazine Sulfasalazine Hydroxychloroquine Hydroxychloroquine Methotrexate Methotrexate Stanozolol Stanozolol IVIG IVIG Methotrexate Methotrexate Omalizumab Omalizumab Cyclosporine Cyclosporine Others… Others… Refractory = Obstinately resistant to authority or control, unruly

9. Antihistamines: H1 Combined with H2 Evidence difficult to interpret Evidence difficult to interpret oSmall numbers of patients studies oDifferent H1 antihistamines used oDose of H2 antihistamine variable  Cimetidine 800-1200 mg/day  One study: cimetidine 400 mg QID Superior efficacy Superior efficacy o oClin Allergy 8:429, 1978 o oBr J Dermatol 117: 81; 1987 No advantage No advantage o oBr J Dermatol 99: 675; 1978 Drug-Drug interaction: Hydroxyzine & Cimetidine Drug-Drug interaction: Hydroxyzine & Cimetidine oSimons EF, et al. J Allergy Clin Immunol 1995; 95: 685-93

10. Anti-Leukotrienes Montelukast/Zafirlukast/Zileuton Montelukast/Zafirlukast/Zileuton Substantial safety advantage compared with other “alternative” or “steroid sparing” agents Substantial safety advantage compared with other “alternative” or “steroid sparing” agents RCTs RCTs o5: favorable o1: no advantage Data suggest salutary effect more likely Data suggest salutary effect more likely oASA-exacerbated urticaria/angioedema oPhysical Urticaria/Angioedema oPositive Autologous Serum Skin Test Morgan M, Khan D. Ann Allergy Asthma Immunol 2008; 100: 403-11

11. Methotrexate for Refractory Chronic 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

12. RCT: Hydroxychloroquine 21 patients with chronic urticaria/angioedema, randomized to Hydroxychloroquine (?dose) or Placebo for 12 weeks, in addition to other medications for urticaria (H1 & H2 antihistamines, doxepin, corticosteroids). 21 patients with chronic urticaria/angioedema, randomized to Hydroxychloroquine (?dose) or Placebo for 12 weeks, in addition to other 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 * * *

13. Cyclosporine Most extensively studied agent for treatment of refractory chronic urticaria/angioedema Most extensively studied agent for treatment of refractory chronic urticaria/angioedema May exert salutary effect via down-regulation of Th1 responses and T cell dependent antibody generation of B lymphocytes, along with inhibition of release of histamine and other mediators from mast cells and basophils May exert salutary effect via down-regulation of Th1 responses and T cell dependent antibody generation of B lymphocytes, along with inhibition of release of histamine and other mediators from mast cells and basophils Madan V, Griffiths CE. Dermatol Ther 2007; 20: 239-50.

14. Therapeutic Utility of Cyclosporine for Refractory Chronic Urticaria/Angioedema Case Series and Case Reports Case Series and Case Reports oFradin MS, et al. J Am Acad Dermatol 1991; 25: 1065-7. oToubi E, et al. Allergy 1997; 52: 312-16. oSerhat Inaloz H, et al. J Dermatol 2008; 35: 276- 82. Subject to bias, and do not provide high quality evidence. Subject to bias, and do not provide high quality evidence.

15. Therapeutic Utility of Cyclosporine for Refractory Chronic Urticaria/Angioedema PubMed Search: PubMed Search: o“urticaria”, “cyclosporine” oLimit = RCT 4 RCT’s 4 RCT’s oGrattan CE, et al. Br J Dermatol 2000; 143: 352-72. oDi Gioacchino M, et al. Allergy Asthma Proc 2003; 24: 285-90. oBaskan EB, et al. J Dermatolog Treat 2004; 15: 164-8. oVena GA, et al. J Am Acad Dermatol 2006; 55: 705-9.

16. Therapeutic Utility of Cyclosporine for Chronic Urticaria/Angioedema Vena GA, et al. J Am Acad Dermatol 2006; 55: 705-9. Vena GA, et al. J Am Acad Dermatol 2006; 55: 705-9. DBRPC study with three arms, N=99: DBRPC study with three arms, N=99: o16 weeks cyclosporine: 5 mg/kg tapering to 4 mg/kg, then 3 mg/kg. o8 weeks cyclosporine oplacebo Primary outcome Primary outcome oImprovement in severity score

17. Therapeutic Utility of Cyclosporine for Chronic Urticaria/Angioedema n Vena GA, et al. J Am Acad Dermatol 2006; 55: 705-9. Mean Improvement in Severity Score * p<.05 * p<.01 * ** * * * *

18. Kaplan A., N Engl J Med 2002; 346: 175-9. Evidence of Autoimmunity in Patients with Chronic Urticaria

19. 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 study ASST not performed in the remaining study oVena GA, et al. J Am Acad Dermatol 2006; 55: 705-9. In other published studies, results of ASST has not consistently correlated with in vitro assays and positive ASST has been observed in patients without urticaria. In other published studies, results of ASST has not consistently correlated with in vitro assays and positive ASST has been observed in patients without urticaria. oTaskapan, et al. Clin Exp Dermatol 2008; 33: 754-8. oAsero, et al. Clin Exp Allergy 2004; 34: 1111-14. The role of positive ASST in predicting salutary effect of cyclosporine is unclear. The role of positive ASST in predicting salutary effect of cyclosporine is unclear.

20. Cyclosporine 4 RCTs in patients with chronic urticaria/angioedema 4 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 costs, the quality of evidence supporting cyclosporine administration is LOW -- leading to a WEAK RECOMMENDATION, based on current evidence. In the context of study limitations, potential harms and costs, the quality of evidence supporting cyclosporine administration is LOW -- leading to a WEAK RECOMMENDATION, based on current evidence. oImplies that patients in different clinical contexts, with different values or preferences, are candidates for different choices. oEncourages clinicians to be more deliberate and judicious in incorporating evidence regarding risks/benefits in the context of patient circumstances, values, and preferences to make the best management decision.

21. Step Wise Approach Chronic Urticaria/Angioedema Step-wise = Marked by a gradual progression

22. Step Care Approach Refractory Chronic Urticaria/Angioedema Step-wise = Marked by a gradual progression

23. Therapeutic 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.