1. Updates from the New Urticaria Practice Parameter
David A. Khan, MD
Professor of Medicine
Allergy & Immunology Program Director
Division of Allergy & Immunology
University of Texas Southwestern Medical Center - Dallas

2. Disclosures Research Grants Speaker Honoraria Organizations:
NIH, Vanberg Family Fund
Speaker Honoraria
Merck, Genentech, Viropharma, Baxter
Organizations:
Joint Task Force on Practice Parameters
All medications other than antihistamines are considered “off-label” for treatment of chronic urticaria

3. Objectives
To be able to discuss limitations and recommendations on testing in chronic urticaria
To develop a step-wised approach to chronic urticaria
To gain an understanding of the use of alternative agents in refractory chronic urticaria

4. The Diagnosis and Management of Acute and Chronic Urticaria: 2014 Update   Chief Editors Jonathan Bernstein, MD; David Lang, MD; David Khan, MD   Workgroup Contributors Timothy Craig, DO; David Dreyfus, MD; Fred Hsieh, MD; Javed Sheikh, MD; David Weldon, MD; and Bruce Zuraw, MD  
Task Force Reviewers David I. Bernstein, MD; Joann Blessing-Moore, MD; Linda Cox, MD; Richard A. Nicklas, MD; John Oppenheimer, MD; Jay M. Portnoy, MD; Christopher R. Randolph, MD; Diane E. Schuller, MD; Sheldon L. Spector, MD; Stephen A. Tilles, MD; and Dana Wallace, MD

5. Urticaria Parameter Update
Manuscript in submission
Summary statements and other recommendations presented may change
Publication in 2014?

6. Urticaria Practice Parameter
Sections
Executive Summary
Acute Urticaria
Diagnosis and Management of Chronic Urticaria
Physical Urticaria/Angioedema
Differential Diagnosis
Treatment for Acute and Chronic Urticaria

7. Diagnostic Evaluation in Urticaria
How Many and What Tests Are Required?

8. Most CU is Idiopathic
SUMMARY STATEMENT 13: Evaluation of a patient with CU should involve consideration of various possible causes. Most cases do not have an identifiable cause [C]

9. Chronic Urticaria Etiologies
Idiopathic
Physical
Autoantibody Associated
Urticarial Vasculitis
Systemic diseases (other than perhaps thyroid disease) are very rarely associated with CU

10. Tests For Physical Urticaria
Cold
Ice cube test
Localized Heat
Test tube water 44ºC
Cholinergic
Exercise for min.
Leg immersion in 44ºC bath
Delayed Pressure
Sand bag test: 15 lb weight for 15 minutes
Dermographism
Stroking skin
Solar
Specific wavelength light exposure
Aquagenic
Water compress
Vibratory
Vortex for 5 minutes

11. Tests for Autoantibodies in CU
Skin tests
Autologous serum skin test
Autologous plasma skin test
Commercially Available Tests
CU Index (IBT Labs)
Measures histamine release from donor basophils activated by patient sera
IGERAB (National Jewish Labs)
Measures CD203c by flow cytometry on donor basophils activated by patient sera

12. Autoantibodies in CU
SUMMARY STATEMENT 22: The utility of the autologous serum skin test (ASST) and the autologous plasma skin test (APST) is unclear, as evidence has not clearly demonstrated this testing identifies a distinct subgroup of patients with CU. Current evidence does not support routine performance of ASST or APST in patients with CU. (C)

13. Autoantibody Testing
SUMMARY STATEMENT 30: While commercial assays are now available, the utility of testing for auto-antibodies to the high-affinity IgE receptor or autoantibodies to IgE has not been determined.(C)

14. Autoimmune Tests Usually Not Warranted
SUMMARY STATEMENT 15: Serology to diagnose underlying autoimmune diseases (e.g., connective tissue disease) is not warranted in the initial evaluation of CU. (B)
No need to get ANA routinely in patients with CU

15. Routine Testing for H Pylori and Celiac Not Required
SUMMARY STATEMENT 19: The co-occurrence of CU with a number of conditions, including Helicobacter pylori infection and celiac disease, has been reported. However, evidence does not support testing for these conditions in a CU patient with an otherwise unremarkable history and physical examination. Moreover, there are no convincing data which demonstrate that treatment based on abnormal test results consistent with these conditions being present leads to improvement or change in the course of CU. (C)

16. Role of H. pylori in CU ? Conclusion:
The evidence that H. pylori eradication leads to improvement of chronic urticaria outcomes is weak and conflicting; this leads to a weak recommendation for routine H. pylori eradication for patients with chronic urticaria.
Shakouri A. et al. Curr Opin Allergy Immunol 2010;10:362-9.

17. Urticarial Vasculitis May Look Like CIU
SUMMARY STATEMENT 18: Urticarial vasculitic lesions may sometimes be evanescent lasting less than 24 hours, similar to CU; for this reason, urticarial vasculitis cannot be completely excluded based on the history of lesions spanning less than 24 hours. (B)

18. Cutaneous Features of UV
Urticaria description
Painful, tender, burning or pruritic
Duration of lesions
24-72 hrs (may be only present in ~40%)
Lesions may resolve with purpura or hyperpigmentation
Tosoni C. et al. Clin Exp Derm 2008;34:

19. Laboratories in UV All forms of UV
 ESR
50% ANA +
dsDNA –
HUV/HUVS (hypocomplomentemic UV/ syndrome)
 C3 ,C4, CH50
  C1q
Anti C1q antibodies present in 100% of HUV
Also seen in Felty’s syndrome, SLE, Sjogren’s syndrome, and MPGN
Kallenberg CG. Autoimmun Rev 2008;7:612-5.

20. Thyroid Labs
SUMMARY STATEMENT 29: Screening for thyroid disease is of low yield in patients without specific thyroid-related symptoms or history of thyroid disease. Elevated levels of anti-thyroglobulin or anti-thyroid antibodies in euthyroid (i.e. normal TSH) individuals are commonly detected, although the clinical implications of this finding are unclear. [C]

21. Skin Biopsy
SUMMARY STATEMENT 32: Skin biopsy may be performed when vasculitis is suspected, such as in refractory CU, or when other non-urticarial immunological skin diseases are a consideration. Routine skin biopsies are not required in most cases of CU. [D]

22. Skin Testing
SUMMARY STATEMENT 33: Immediate hypersensitivity skin or serologic testing for food or other allergens is rarely useful, and is not recommended on a routine basis. [D]

23. Diagnostic Labs in CU
Systematic review of 29 studies involving 6462 urticaria patients
Large variability in determining an etiology: 1-84% (median 38%)
Most studies excluding physical urticarias had lowest identifiable diagnoses (1-20%)
Only 1.6% patients thought to have an internal disease responsible
Majority were cutaneous vasculitis
Kozel MM, et al.. J Am Acad Dermatol 2003; 48 (3):

24. Diagnostic Labs in CU Most authors concluded that history is important
Most authors concluded that routine laboratory tests are not required
Laboratories should be guided by the history, which is the most important instrument in finding an etiology
Kozel MM, et al. J Am Acad Dermatol 2003; 48 (3):

25. 356 CU pts seen at Cleveland Clinic
Retrospective study to investigate the proportion of abnormal test results in patients with CU leading to a change in management and in outcomes of care
356 CU pts seen at Cleveland Clinic
Tarbox JA et al. Ann Allergy Asthma Immunol 2011;107:239 –243.

26. 17% of 1,872 ordered tests were abnormal
Tarbox JA et al. Ann Allergy Asthma Immunol 2011;107:239 –243.

27. 1/356 (0.28%) benefitted from testing!
1 patient with hypothyroidism with normal TSH and elevated microsomal AB responded to higher dose thyroxine
Tarbox JA et al. Ann Allergy Asthma Immunol 2011;107:239 –243.

28. Diagnostic Testing in CU
SUMMARY STATEMENT 28: After a thorough history and physical examination, no diagnostic testing may be appropriate for patients with CU; however, limited routine lab testing may be performed to exclude underlying causes. Targeted lab testing based on clinical suspicion is appropriate. Extensive routine testing for exogenous and rare causes of CU, or immediate hypersensitivity skin testing for inhalants or foods, is not warranted.

29. Routine Labs
Summary Statement 28 (cont’d): Routine laboratory testing in patients with CU, whose history and physical examination lack atypical features, rarely yields clinically significant findings.[C]

31. Task Force Labs in CU Consensus

32. Differential Diagnosis and Evaluation of Urticaria32

33. Drug Exanthem vs. Urticaria

34. Contact Dermatitis

35. Multiforme-looking lupus (Rowell syndrome) subacute cutaneous lupus
angioedema
urticaria
Multiforme-looking lupus
(Rowell syndrome)
subacute
cutaneous lupus
urticaria
pigmentosa
Sweet syndrome
Urticarial phase of bullous pemphigoid
fixed drug eruption
Brodell LA, Beck LA. Ann Allergy Asthma Immunol 2008;100:181-8.

37. Management of Chronic Urticaria

38. Principles of Step Therapy
Begin treatment at step appropriate for patient’s level of severity and previous treatment history
At each level of the step-approach, medication(s) should be assessed for patient tolerance and efficacy or discontinuation to avoid unnecessary polypharmacy.
NOTE: “Step-down” in treatment is appropriate at any step described, once consistent control of urticaria/angioedema is achieved

39. Step 1

40. H1 Antihistamines in CU
SUMMARY STATEMENT 76: H1 antagonists are effective in the majority of patients with CU but may not achieve complete control in all patients. (C)
SUMMARY STATEMENT 77: Second-generation antihistamines are safe and effective therapies in CU and are considered first-line agents. (A)

41. Step 2

42. Higher Dose H1 Antihistamines
SUMMARY STATEMENT 78: Higher doses of second-generation antihistamines may provide more efficacy but data are limited and conflicting for certain agents. (B)

43. High Dose Antihistamines in CU
Cetirizine: conflicting studies
Fexofenadine: no difference between 60 mg, 120 mg and 240 mg twice a day
Desloratadine
20 mg > 5 mg in cold urticaria
Levocetirizine and desloratadine
Higher doses better

44. High Dose Antihistamines in CU
Staevska M et al. J Allergy Clin Immunol 2010;125:

45. H2 Antihistamines
SUMMARY STATEMENT 80: H-2 antihistamines, taken in combination with first and second-generation H-1 antihistamines, have been reported to be more efficacious compared to H-1 antihistamines alone for the treatment of CU. (A) However, this added efficacy may be related to pharmacologic interactions and increased blood levels of first-generation antihistamines. (B) As these agents are well tolerated, the addition of H2-antagonists may be considered when CU is not optimally controlled with second-generation antihistamine monotherapy.(D)

46. Leukotriene receptor antagonists
SUMMARY STATEMENT 81: Leukotriene receptor antagonists have been shown in several but not all randomized controlled studies to be efficacious in patients with CU.(A) Leukotriene receptor antagonists are generally well tolerated (A). Leukotriene receptor antagonists may be considered for CU patients with unsatisfactory responses to 2nd generation antihistamine monotherapy.

47. Step 3

48. 1st Generation Antihistamines
SUMMARY STATEMENT 79: First-generation antihistamines have proven efficacy in the treatment of CU. Efficacy of first-generation antihistamines is similar to second-generation antihistamines but sedation and impairment are greater with first-generation antihistamines, especially with short-term use. (A) First-generation antihistamines may be considered in patients who do not achieve control of their condition with higher dose second-generation antihistamines.(D)

49. Hydroxyzine and Doxepin
SUMMARY STATEMENT 82: Treatment with hydroxyzine or doxepin may be considered in patients who remain poorly controlled with dose advancement of second-generation antihistamines, and the addition of H2-antihistamines, first-generation H-1 antihistamine at bedtime, and/or anti-leukotrienes.(D)

50. Corticosteroids
SUMMARY STATEMENT 83: Systemic corticosteroids are frequently used for refractory CU patients, but no controlled studies have demonstrated efficacy. In some patients, short-term use (e.g. 1-3 weeks duration) may be required to gain control of their disease until other therapies can achieve control. Because of the risk of adverse effects with systemic corticosteroids, long-term use for treatment of CU patients should be avoided as much as possible. (D)

51. Step 4

52. Refractory Chronic Urticaria
SUMMARY STATEMENT 84: CU patients who are not adequately controlled on maximally tolerated antihistamine therapy (e.g., doxepin at a dose of mg/day) may be considered to have refractory CU. (E)

53. Alternative Agents
SUMMARY STATEMENT 85: A number of alternative therapies have been studied for the treatment of CU; these therapies merit consideration for patients with refractory CU. (D)

54. Rationale for Alternative Agents in Chronic Urticaria
While most urticaria is antihistamine responsive, not all patients have adequate control with antihistamine therapy at any dose
Glucocorticoids while typically effective, have predictable and nearly universal toxicity for treatment of chronic urticaria
Alternative Agents
Immunomodulatory
Immunosuppressant
Other

55. Evidence for Alternative Therapies in CU
Overall the evidence for most alternative therapies is weak
Few agents have well designed randomized placebo-controlled studies
Most studies have small number of participants

56. J Allergy Clin Immunol: In Practice 2013

58. Anti-inflammatory Agents
SUMMARY STATEMENT 86: Anti-inflammatory agents including dapsone, sulfasalazine, hydroxychloroquine, and colchicine have limited evidence for efficacy in CU and some require laboratory monitoring for adverse effects.(C) These agents are generally well tolerated, may be efficacious in properly selected patients, and may be considered for treatment of antihistamine refractory CU patients.(D)

59. Immunosuppressants
SUMMARY STATEMENT 87: Several immunosuppressant agents have been used in patients with refractory CU. Cyclosporine has been studied in several randomized controlled trials. (A) For this reason, cyclosporine was selected for closer examination as to the quality of evidence supporting its administration in patients with refractory chronic urticaria/angioedema.

60. Khan DA. In: Maibach HI, Gorouhi F ed
Khan DA. In: Maibach HI, Gorouhi F ed. Evidence Based Dermatology 2nd ed. 2011

61. Trojan T, Khan DA. Curr Opin Allergy Immunol 2012;12:412-20.

62. Trojan T, Khan DA. Curr Opin Allergy Immunol 2012;12:412-20.

63. Omalizumab
SUMMARY STATEMENT 88:  In contrast to other alternative agents for refractory CU, the therapeutic utility of omalizumab has been supported by findings from large double-blind randomized controlled trials and is associated with a relatively low rate of clinically significant adverse effects. On the basis of this evidence, omalizumab should be considered for refractory CU if from an individualized standpoint a therapeutic trial of omalizumab is favorable from the standpoint of balancing the potential for benefit with the potential for harm/burden, and the decision to proceed is consistent with patient values and preferences. (A)

64. N Engl J Med Mar 7;368(10):

65. Treatment period
N Engl J Med Mar 7;368(10):

66. J Allergy Clin Immunol 2013;132:101-9.

67. Omalizumab in CU refractory to H1 plus H2 and/or LTRA therapies

68. Selecting an Alternative Agent
SUMMARY STATEMENT 93: Multiple factors are involved in selecting an alternative agent in refractory CU patients including but not limited to the presence of comorbid factors, frequency of treatment-related visits, cost, rapidity of response, adverse effects and patient values and preferences. The potential for harm and burden association with a given alternative agent is extremely important and needs to be weighed against the patient’s potential for benefit, current quality of life, and any adverse effects from current therapy for their CU. (D)

69. Personal Preferences in Alternative Therapies
I typically start with dapsone
Hydroxychloroquine, sulfasalazine other similar alternatives
In patients demonstrating steroid toxicity, I start with tacrolimus
better tolerated than cyclosporine in my experience
Omalizumab or mycophenolate used after these agents

70. How Long to Treat? Once successful alternative agent found
Taper off steroids
Taper off other medications
I treat with alternative agent until urticaria free for at least 3 months then taper over ~3 months
Some patients require long term (years) usage
Find lowest dose to control CU

71. Why Aren’t Alternative Agents Used More?
Fear
Lack of Training
Outside of comfort zone

73. Conclusions
In the absence of history, diagnostic tests have a low yield in evaluation of CU
The presence of autoantibodies may not aid in management of CU patients
Upcoming urticaria guidelines will provide a very comprehensive resource to aid in management of urticaria patients
Step-wised approach to chronic urticaria should aid allergists in managing patients