Treatment Options for Refractory Urticaria

Transcription

1 Treatment Options for Refractory Urticaria David A. Khan, MD Professor of Medicine Allergy & Immunology Program Director Division of Allergy & Immunology University of Texas Southwestern Medical Center - Dallas 1

2 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

3 Objectives To develop a step-wised approach to chronic urticaria To gain an understanding of the use of alternative agents in refractory chronic urticaria 3

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 4

5 Urticaria Parameter Update Revised manuscript submitted to JACI Publication in 2014? 5

6 Management of Chronic Urticaria 6

7 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

8 Step 1 8

9 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: Secondgeneration antihistamines are safe and effective therapies in CU and are considered first-line agents. (A) 9

10 Step 2 10

11 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) 11

12 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 12

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

14 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) 14

15 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 2 nd generation antihistamine monotherapy. 15

16 Step 3 16

17 1 st Generation Antihistamines SUMMARY STATEMENT 79: Firstgeneration 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) Firstgeneration antihistamines may be considered in patients who do not achieve control of their condition with higher dose second-generation antihistamines.(d) 17

18 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 antileukotrienes.(d) 18

19 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 mg qhs as a single dose Increase dose by mg weekly as tolerated Target of mg qhs 19

20 Corticosteroids SUMMARY STATEMENT 83: Systemic corticosteroids are frequently used for refractory CU patients, but no controlled studies have demonstrated efficacy. In some patients, shortterm 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) 20

21 Step 4 21

22 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) 22

23 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) 23

24 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 24

25 J Allergy Clin Immunol: In Practice 2013;1: e1 25

26 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 26

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

28 Alternative Agents with the Highest Level of Evidence Omalizumab Cyclosporine 28

29 Omalizumab Evidence in Literature Dose Onset of Improvement Estimated effectiveness frequency Risks Lab monitoring Ib (3 DBPC studies, incuding 2 large trials, numerous case series and case reports) Optimal dose unknown mg every 4 weeks effective (75 mg isn t) days >75% Anaphylaxis (rare) none Cost $$$$ Remission possible unlikely Metz M, Maurer M. Curr Opin Allergy Clin Immunol 2012, 12:

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

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

32 J Allergy Clin Immunol 2013;132:

33 Omalizumab in CU refractory to H1 plus H2 and/or LTRA therapies 33

34 Dose and Frequency Adjustments of Omalizumab in CU Uysal P et al. J Allergy Clin Immunol 2014 (in press) 34

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

36 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 36

37 Time to Relapse after Stopping Omalizumab Metz M et al. JAMA Dermatol 2014 online. 37

38 Evidence in Literature Dose Onset of Improvement Estimated effectiveness frequency Risks Lab monitoring Cyclosporine Ib (3 DBPC studies, numerous case series and case reports) 2.5-5mg/kg/d (higher dose) 1-2 mg/kg/d (low dose) Days (higher dose) Weeks-months (low dose) >75% GI, headache, HTN, nephrotoxicity, hisrutism, gingival hyperplasia, paresthesias Renal function, CSA levels monthly Lipids, glucose intermittent Cost $$$ Remission possible yes 38

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

40 Trojan T, Khan DA. Curr Opin Allergy Immunol 2012;12:

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

42 Long-term Cyclosporine Therapy Kessel A et al. Allergy 2010 Tolerated well No lab abnormalities 42

43 Alternative Agents with Lower Levels of Evidence 43

44 Dapsone Evidence in Literature Dose Onset of Improvement Estimated effectiveness frequency Risks Lab monitoring IIb (few studies, many small numbers) mg daily (I start at 100 mg usually) 2-6 weeks ~50% Mild anemia expected (Hgb decrease by 10-20%) Methemoglobinemia, hepatitis, neuropathy, DRESS rare G6PD prior to therapy CBC in 2 weeks then monthly CBC with LFT Cost $ Remission possible yes 44

45 Hydroxychloroquine Evidence in Literature Dose Onset of Improvement Estimated effectiveness frequency Risks Lab monitoring Ia (single study, small numbers) 200 mg twice a day 6-12 weeks <25 % GI intolerance Retinopathy (very rare) Consider baseline LFT, renal function Cost $$ Remission possible? 45

46 Baseline examination within 1 st year of use Annual screening after 5 years of use Ophthalmology 2011;118:

47 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:

48 Sulfasalazine Evidence in Literature Dose Onset of Improvement Estimated effectiveness frequency Risks Lab monitoring III (few case series, small numbers) mg bid (I start at 500 mg bid for 7 days then increase as tolerated) 2-6 weeks % GI intolerance, HA Cytopenias, hepatitis, proteinuria (rare) CBC, LFT, renal function, U/A monthly Cost $ Remission possible yes

49 Sulfasalazine in CU 49

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

51 Tacrolimus Evidence in Literature Dose Onset of Improvement Estimated effectiveness frequency Risks Lab monitoring III (1 small case series) I start 1 mg bid Increase to 2 mg bid in 1-2 weeks Max 6 mg/d Days >75% GI, paresthesias, headache, HTN, nephrotoxicity Renal function, tacrolimus levels monthly Lipids, glucose intermittent Cost $$$ Remission possible yes 51

52 Evidence in Literature Dose Onset of Improvement Estimated effectiveness frequency Risks Lab monitoring Mycophenolate IIb (1 small observational study, few case series) mg twice daily (I start at 500 mg bid and go up to 2000 mg bid) 1-9 weeks 30 % GI intolerance (common and dose related) Cytopenias, infection (rare), malignancy (very rare) CBC monthly Cost $$$ Remission possible yes Zimmerman AB et al. J Am Acad Derm 2012 May;66(5):

53 More Alternative Agents for CU Leukotriene Modifiers Colchicine Calcium channel blockers Theophylline Beta-agonists COX-2 inhibitors Anticoagulants Androgens Cyclophosphamide Methotrexate Gold TNF-inhibitors Phototherapy IL-R antagonists Plasmapheresis Rituximab Autohemotherapy sirolimus Immunotherapy IVIG

54 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) 54

55 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 55

56 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 56

57 Why Aren t Alternative Agents Used More? Fear Lack of Training Outside of comfort zone 57

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59 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 59

60 The art of medicine consists in amusing the patient while nature cures the disease. Voltaire ( )