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Urticaria/Angioedema - Management

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

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Urticaria/Angioedema - Management

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  1. 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. • 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. • Workgroup • Chair: Jonathan Bernstein, MD • Liaison: David Lang, MD • Members: • 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

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

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

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

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

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

  10. Anti-Leukotrienes • Montelukast/Zafirlukast/Zileuton • Substantial safety advantage compared with other “alternative” or “steroid sparing” agents • RCTs • 5: favorable • 1: no advantage • Data suggest salutary effect more likely • ASA-exacerbated urticaria/angioedema • Physical Urticaria/Angioedema • Positive 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. 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. RCT: Hydroxychloroquine * * * * * * p < 0.05 * p = 0.05 – 0.10 Reeves GEM, et al. Intern Med J 2004; 34: 182-6.

  13. Cyclosporine • 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 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 • Fradin MS, et al. J Am Acad Dermatol 1991; 25: 1065-7. • Toubi E, et al. Allergy 1997; 52: 312-16. • Serhat Inaloz H, et al. J Dermatol 2008; 35: 276-82. • Subject to bias, and do not provide high quality evidence.

  15. Therapeutic Utility of Cyclosporine for Refractory Chronic Urticaria/Angioedema • PubMed Search: • “urticaria”, “cyclosporine” • Limit = RCT • 4 RCT’s • Grattan CE, et al. Br J Dermatol 2000; 143: 352-72. • Di Gioacchino M, et al. Allergy Asthma Proc 2003; 24: 285-90. • Baskan EB, et al. J Dermatolog Treat 2004; 15: 164-8. • Vena 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. • DBRPC study with three arms, N=99: • 16 weeks cyclosporine: 5 mg/kg tapering to 4 mg/kg, then 3 mg/kg. • 8 weeks cyclosporine • placebo • Primary outcome • Improvement in severity score

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

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

  19. Autologous Serum Skin Test (ASST) • 3 of 4 studies enrolled only patients with positive ASST. • ASST not performed in the remaining study • Vena 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. • Taskapan, et al. Clin Exp Dermatol 2008; 33: 754-8. • Asero, et al. Clin Exp Allergy 2004; 34: 1111-14. • The role of positive ASST in predicting salutary effect of cyclosporine is unclear.

  20. Cyclosporine • 4 RCTs in patients with chronic urticaria/angioedema • 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. • Implies that patients in different clinical contexts, with different values or preferences, are candidates for different choices. • Encourages 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 ApproachChronic Urticaria/Angioedema Step-wise= Marked by a gradual progression

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

  23. Therapeutic Role For Anti-IgE • Open trial of omalizumab in patients “with hives present most days of the week despite antihistamines”. • 7/12 achieved complete symptom resolution. Kaplan A., et al. J Allergy Clin Immunol 2008; 122: 569-73

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