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David A. Khan, MD

Professor of Medicine Allergy & Immunology Program Director

Division of Allergy & Immunology University of Texas Southwestern

Medical Center - Dallas

Treatment Options for Refractory Urticaria

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

Objectives

  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

  Revised manuscript submitted to JACI

  Publication in 2014?

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Management of Chronic Urticaria

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 7

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. 13

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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Hydroxyzine and Doxepin

  Not therapeutically equivalent   Which agent to choose?

  Usually based on which one they haven’t tried   Doxepin associated with weight gain and likely

more sedating

  Dosing preferences   Usually 10-25 mg qhs as a single dose   Increase dose by 10-25 mg weekly as

tolerated   Target of 50-150 mg qhs

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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)

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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

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J Allergy Clin Immunol: In Practice 2013;1:433-40.e1 25

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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27 Khan DA. J Allergy Clin Immunol: In Practice 2013;1:433-40.e1

Alternative Agents with the Highest Level of Evidence

Omalizumab Cyclosporine

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Omalizumab Evidence in Literature Ib (3 DBPC studies, incuding 2 large trials,

numerous case series and case reports)

Dose Optimal dose unknown 150-300 mg every 4 weeks effective

(75 mg isn’t)

Onset of Improvement days

Estimated effectiveness frequency

>75%

Risks Anaphylaxis (rare)

Lab monitoring none

Cost $$$$

Remission possible unlikely

Metz M, Maurer M. Curr Opin Allergy Clin Immunol 2012, 12:406–411. 29

N Engl J Med. 2013 Mar 7;368(10):924-35. 30

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

Treatment period

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J Allergy Clin Immunol 2013;132:101-9. 32

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

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Dose and Frequency Adjustments of Omalizumab in CU

34 Uysal P et al. J Allergy Clin Immunol 2014 (in press)

35 Uysal P et al. J Allergy Clin Immunol 2014 (in press)

Omalizumab Retreatment in CU

  Observational study of 25 patients with various types of CU treated with omalizumab at varying doses and different durations

  100% responded   100% relapsed   With retreatment, 100% responded again

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Time to Relapse after Stopping Omalizumab

37 Metz M et al. JAMA Dermatol 2014 online.

Cyclosporine Evidence in Literature Ib (3 DBPC studies, numerous case series

and case reports)

Dose 2.5-5mg/kg/d (higher dose) 1-2 mg/kg/d (low dose)

Onset of Improvement Days (higher dose) Weeks-months (low dose)

Estimated effectiveness frequency

>75%

Risks GI, headache, HTN, nephrotoxicity, hisrutism, gingival hyperplasia,

paresthesias

Lab monitoring Renal function, CSA levels monthly Lipids, glucose intermittent

Cost $$$

Remission possible yes 38

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. 40

Trojan T, Khan DA. Curr Opin Allergy Immunol 2012;12:412-20. 41

Long-term Cyclosporine Therapy

42 Kessel A et al. Allergy 2010

Tolerated well No lab abnormalities

Alternative Agents with Lower Levels of Evidence

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Dapsone

Evidence in Literature IIb (few studies, many small numbers)

Dose 50-100 mg daily (I start at 100 mg usually)

Onset of Improvement 2-6 weeks

Estimated effectiveness frequency

~50%

Risks Mild anemia expected (Hgb decrease by 10-20%)

Methemoglobinemia, hepatitis, neuropathy, DRESS rare

Lab monitoring G6PD prior to therapy CBC in 2 weeks then monthly CBC with LFT

Cost $

Remission possible yes 44

Hydroxychloroquine

Evidence in Literature Ia (single study, small numbers)

Dose 200 mg twice a day

Onset of Improvement 6-12 weeks

Estimated effectiveness frequency

<25 %

Risks GI intolerance Retinopathy (very rare)

Lab monitoring Consider baseline LFT, renal function

Cost $$

Remission possible ?

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Ophthalmology 2011;118:415–422.

Baseline examination within 1st year of use Annual screening after 5 years of use

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Recommendations for Hydroxychloroquine Retinopathy Screening

Risk Factors for Hydroxychloroquine Retinopathy

Duration of use > 5 yrs

Cumulative dose >1000 gms

Daily dose > 400 mg/d

Age Elderly

Systemic disease Kidney or liver dysfunction

Ocular disease Retinal disease or maculopathy

Annual screening recommended at initiation of drug if above risk factor(s) present

Ophthalmology 2011;118:415–422. 47

Sulfasalazine

Evidence in Literature III (few case series, small numbers)

Dose 500-1000 mg bid (I start at 500 mg bid for 7 days then

increase as tolerated)

Onset of Improvement 2-6 weeks

Estimated effectiveness frequency

25-80 %

Risks GI intolerance, HA Cytopenias, hepatitis, proteinuria (rare)

Lab monitoring CBC, LFT, renal function, U/A monthly

Cost $

Remission possible yes

Sulfasalazine in CU

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Sulfasalazine in CU

  Retrospective study of 39 patients   Dose 500 mg/d increased weekly to

2,000 mg/d   84% improved in 6 months   28% had remission off sulfasalazine

  Still on antihistamines

  16% failure   Serious side effects rare

50 Orden RA et al. Ann Allergy Asthma Immunol 2014;112:64-70.

Tacrolimus Evidence in Literature III (1 small case series)

Dose I start 1 mg bid Increase to 2 mg bid in 1-2 weeks

Max 6 mg/d

Onset of Improvement Days

Estimated effectiveness frequency

>75%

Risks GI, paresthesias, headache, HTN, nephrotoxicity

Lab monitoring Renal function, tacrolimus levels monthly Lipids, glucose intermittent

Cost $$$

Remission possible yes 51

Mycophenolate Evidence in Literature IIb (1 small observational study, few case

series)

Dose 500-3000 mg twice daily (I start at 500 mg bid and go up to 2000

mg bid)

Onset of Improvement 1-9 weeks

Estimated effectiveness frequency

30 %

Risks GI intolerance (common and dose related) Cytopenias, infection (rare), malignancy

(very rare)

Lab monitoring CBC monthly

Cost $$$

Remission possible yes

Zimmerman AB et al. J Am Acad Derm 2012 May;66(5):767-70. 52

More Alternative Agents for CU

  Leukotriene Modifiers   Colchicine   Theophylline   COX-2 inhibitors   Androgens   Methotrexate   TNF-inhibitors   IL-R antagonists   Rituximab   sirolimus   IVIG

  Calcium channel blockers

  Beta-agonists   Anticoagulants   Cyclophosphamide   Gold   Phototherapy   Plasmapheresis   Autohemotherapy   Immunotherapy

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)

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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

  On the whole, the quality of evidence for alternative agents is weak and limited

  Nevertheless despite the absence of high quality evidence, refractory CU patients still merit therapies that can improve their quality of life

  The potential risk of a given alternative agent needs to be weighed against the patient’s current quality of life and any adverse effects from current therapy (e.g. oral corticosteroids) for their CU

  A logical step wised approach can be used in refractory CU patients to control urticaria and eliminate chronic/frequent steroids

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“The art of medicine consists in amusing the patient while

nature cures the disease.”

Voltaire (1694-1778)