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David A. Khan, MDProfessor of Medicine

Allergy & Immunology Program Director

Division of Allergy & ImmunologyUniversity of Texas Southwestern

Medical Center - Dallas

Updates from the New Urticaria Practice Parameter

Disclosures

Research Grants 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 2

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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

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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

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Urticaria Parameter Update

Manuscript in submission Summary statements and other

recommendations presented may change

Publication in 2014?

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Urticaria Practice Parameter

SectionsI. Executive SummaryII. Acute UrticariaIII. Diagnosis and Management of Chronic

Urticaria IV. Physical Urticaria/AngioedemaV. Differential DiagnosisVI. Treatment for Acute and Chronic Urticaria

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Diagnostic Evaluation in Urticaria

How Many and What Tests Are Required?

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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]

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Chronic Urticaria Etiologies

Idiopathic Physical Autoantibody Associated Urticarial Vasculitis

Systemic diseases (other than perhaps thyroid disease) are very rarely associated with CU

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Tests For Physical Urticaria

Cold Ice cube test

Localized Heat Test tube water 44ºC

Cholinergic Exercise for 15-20 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

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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

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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)

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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)

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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

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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)

Role of H. pylori in CU ?

Shakouri A. et al. Curr Opin Allergy Immunol 2010;10:362-9.

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.

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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)

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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;34:166-70.

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.

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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]

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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]

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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]

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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): 409-16

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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): 409-16

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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.

26Tarbox JA et al. Ann Allergy Asthma Immunol 2011;107:239 –243.

17% of 1,872 ordered tests were abnormal

27Tarbox JA et al. Ann Allergy Asthma Immunol 2011;107:239 –243.

1 patient with hypothyroidism with normal TSH and elevated microsomal AB responded to higher dose thyroxine

1/356 (0.28%) benefitted from testing!

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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.

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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]

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Task Force Labs in CU Consensus

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Differential Diagnosis and Evaluation of Urticaria

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Drug Exanthem vs. Urticaria

Drug ExanthemUrticaria

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Contact Dermatitis

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urticaria

subacute cutaneous lupus

urticaria pigmentosa

fixed drug eruption

angioedema

Multiforme-looking lupus(Rowell syndrome)

Sweet syndrome

Urticarial phase of bullous pemphigoid

Brodell LA, Beck LA. Ann Allergy Asthma Immunol 2008;100:181-8.

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Management of Chronic Urticaria

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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

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Step 1

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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)

 

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Step 2

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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)

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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

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High Dose Antihistamines in CU

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

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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)

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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.

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Step 3

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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)

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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)

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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)

Step 4

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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 100-125mg/day) may be considered to have refractory CU. (E)

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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)

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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

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

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56J Allergy Clin Immunol: In Practice 2013

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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)

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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.

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

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Trojan T, Khan DA. Curr Opin Allergy Immunol 2012;12:412-20.61

Trojan T, Khan DA. Curr Opin Allergy Immunol 2012;12:412-20.62

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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)

64N Engl J Med. 2013 Mar 7;368(10):924-35.

65N Engl J Med. 2013 Mar 7;368(10):924-35.

Treatment period

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

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

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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)

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

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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

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Why Aren’t Alternative Agents Used More?

Fear Lack of Training Outside of comfort zone

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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