4/12/18. Refractory Chronic Urticaria: When Omalizumab Fails. Objectives. Disclosures

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1 Refractory Chronic Urticaria: When Omalizumab Fails David A. Khan, MD Professor of Medicine and Pediatrics Allergy & Immunology Program Director 1 Disclosures n Research Grants n NIH n Honoraria n UpToDate, Genentech n Consulting n Aimmune (DSMB) n Organizations: n Joint Task Force on Practice Parameters n AAAAI BOD All medications other than antihistamines and omalizumab are considered off-label 2 for treatment of chronic urticaria Objectives n Gain an understanding of stepwise approach for urticaria and differences in guidelines n Be able to discuss updates on omalizumab in urticaria and angioedema n Gain an understanding of the use and risks of anti-inflammatory, immunosuppressant and other alternative therapies in refractory urticaria/angioedema. 3 1

2 70 yo with CIU n 70 yo M with 20 yrs of episodic hives and 18 months of daily urticaria and frequent angioedema. No obvious triggers and prior lab work up negative. n Currently on fexofenadine 180 bid and hydroxyzine 25 at bedtime without side effects or benefit n On exam has scattered blanchable urticaria 4 Bernstein JA et al. J Allergy Clin Immunol 2014;133: Management of Refractory Chronic Urticaria Joshi S, Khan DA. J Allergy Clin Immunol Pract 2017;5:

3 Allergy 2018 (in press) 7 Br J Derm (2016);175: Updosing Antihistamines When Standard Doses Fail 38% response rate to standard antihistamine dose 60% response rate to updosing of antihistamine; however lots of heterogeneity and most studies of low quality Br J Derm (2016);175:

4 Allergy 2018 (in press) 10 n SUMMARY STATEMENT 78: Higher doses of second-generation antihistamines may provide more efficacy but data are limited and conflicting for certain agents. (B) 11 Multiple High Dose Antihistamines van den Elzen et al. Clin Transl Allergy (2017) 7:4 12 4

5 van den Elzen et al. Clin Transl Allergy (2017) 7:4 13 van den Elzen et al. Clin Transl Allergy (2017) 7:4 14 Predicting Response to Antihistamines Based on Histamine Wheal Suppression 150 CU patients treated in blinded fashion with 5 different antihistamines or placebo Large suppression of histamine wheal suggests good response to antihistamines Sanchez J et al. J Investig Allergol Clin Immunol 2016; Vol. 26(3):

6 Step 3 Bernstein JA et al. J Allergy Clin Immunol 2014;133: Hydroxyzine and Doxepin n Not therapeutically equivalent n Which agent to choose? n Usually based on which one they haven t tried n Doxepin associated with weight gain and likely more sedating n Dosing preferences n Usually mg qhs as a single dose n Increase dose by mg weekly as tolerated n Target of mg qhs 17 Other Potential Problems with 1 st Gen Antihistamines n 10-yr prospective study of Group Health data on 3434 subjects > 65 years n Highest quartile of use had increased risk of dementia 1.54 (95%CI, ) n Based on data this would equate to > 3 years of treatment with: n Hydroxyzine 75 mg/d n Doxepin 10 mg/d n Association, not causality JAMA Int Med 2015;175:

7 70 yo with CIU Epilogue n Increased cetirizine to 20 bid and gradual escalation of hydroxyzine to 100 mg at bedtime with reduction from daily modsevere hives to < 1/week nuisance hives and no sedation n Reduced meds to cetirizine 10 bid and hydroxyzine 75 at bedtime and stable n In process of tapering further to maintain control Take Home: Don t forget/fear aggressive antihistamines yo with CIU Refractory to AH and Omalizumab n 31 yo woman with chronic urticaria for 1 year n Prior laboratory work-up including autoantibodies negative, skin biopsy consistent with urticaria n Failed: n cetirizine 40 mg/d n + desloratadine 5 mg bid n + ranitidine 300 mg/d n + montelukast n +hydroxyzine 150 mg/d yo with CIU Refractory to AH and Omalizumab n Treated with omalizumab 300 mg every 4 weeks for 6 months with no improvement n Requires prednisone 20 mg/d to maintain low level of hive activity n Has gained 30 lbs due to prednisone n Frustrated and tearful during exam n Blanchable typical urticarial lesions 21 7

8 Approach to Refractory Urticaria n Is it really urticaria/ae? n Have you seen the lesions? n Skin biopsy may be helpful (not always) n What kind of work up is recommended? n Is it really antihistamine resistant? n Aggressive dosing of 2 nd and 1 st generation antihistamines tried and failed? n Has omalizumab failed? n How much? n How long? n How often? 22 JEADV 2017, 31, Diagnostic Evaluation in Urticaria How Many and What Tests Are Required? 24 8

9 25 Diagnostic Testing in CU n 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. 26 Routine Labs n 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] 27 9

10 Task Force Labs in CU Consensus 28 Additional Labs in CU 29 Allergy 2018 (in press) 30 10

11 J Allergy Clin Immunol Pract 2017;5: Doong JC et al. J Allergy Clin Immunol Pract 2017;5: Omalizumab in Chronic Urticaria Efficacy/Dosing Duration Predicting Response Physical Urticaria Angioedema Failures 33 11

12 Omalizumab in CU n Are the responses to omalizumab 150 mg and 300 mg similar? n How long is needed to see an effect with omalizumab? 34 Kaplan A et al. J Allergy Clin Immunol 2016;137: Omalizumab 300 mg faster response than omalizumab 150 mg Kaplan A et al. J Allergy Clin Immunol 2016;137:

13 Complete Responders Higher in omalizumab 300 mg vs 150 mg Kaplan A et al. J Allergy Clin Immunol 2016;137: weeks of omalizumab 300 mg appears sufficient to determine response 38 Casale TB et al. J Am Acad Dermatol. 2018;78(4):

14 Open Label Omalizumab Casale TB et al. J Am Acad Dermatol. 2018;78(4): Maurer M et al. J Allergy Clin Immunol. 2018;141(3): e weeks omalizumab vs placebo Maurer M et al. J Allergy Clin Immunol. 2018;141(3): e

15 Probability of Worsening: Omalizumab vs Placebo Maurer M et al. J Allergy Clin Immunol. 2018;141(3): e7. 43 Re-Treatment with Omalizumab After 12 weeks of Placebo Maurer M et al. J Allergy Clin Immunol. 2018;141(3): e7. 44 Long-term Use of Omalizumab Har D et al. Ann Allergy Asthma Immunol 2015;115:

16 Long-term Use of Omalizumab Har D et al. Ann Allergy Asthma Immunol 2015;115: Urticaria Recurred in Vast Majority with Tapering 47 Many able to Reduce Frequency to > every 4 weeks, some required more frequent dosing Har D et al. Ann Allergy Asthma Immunol 2015;115:

17 More frequent Omalizumab Dosing? n No controlled studies have evaluated more frequent dosing n Anecdotally, rare patients have a wearoff effect n More hives days post omalizumab n Some of these patients may benefit from more frequent dosing 49 J Allergy Clin Immunol Pract 2016;4: n n n n Retrospective study of 41 pts treated with omalizumab 29 responders n 87% absent CD203c activity 12 nonresponders n 25% absent CD203c activity Limitations of small sample size and retrospective study 50 Ertas R et al. Allergy. 2018;73(3):

18 Ertas R et al. Allergy. 2018;73(3): Maurer M et al. J Allergy Clin Immunol. 2018;141(2): Staubach P et al. Allergy. 2016;71(8):

19 4/12/18 Angioedema Urticaria Staubach P et al. Allergy. 2016;71(8): Staubach P et al. Allergy. 2016;71(8): Chang TW et al. J Allergy Clin Immunol. 2015;135(2):

20 Omalizumab Not Successful 34-44% 58 When Omalizumab Fails Other Alternative Agents for Chronic Urticaria 59 What s Wrong with Steroids? Study of a large health care claims database > 13 million patients Allergy Asthma Proc 2016;37:

21 Corticosteroid Toxicity in CU Majority of CU patients used corticosteroids Allergy Asthma Proc 2016;37: Dose Response of Corticosteroid Toxicity in CU For every 100 tabs of 10 mg prednisone, there is a 7% increased risk of adverse effects Allergy Asthma Proc 2016;37: J Allergy Clin Immunol Practice 2013;1: e

22 Evidence for Alternative Therapies in CU n Overall the evidence for most other alternative therapies is weak n Few agents have well designed randomized placebo-controlled studies n Most studies have small number of participants 64 J Allergy Clin Immunol Practice 2013;1: e1 65 Vena GA et al. Curr Opin Allergy Clin Immunol. 2017;17(4):

23 Vena GA et al. Curr Opin Allergy Clin Immunol. 2017;17(4): Vena GA et al. Curr Opin Allergy Clin Immunol. 2017;17(4): Anti-Inflammatory Agents for CIU Dapsone Sulfasalazine Hydroxychloroquine Vitamin D? Methotrexate Colchicine 69 23

24 Dapsone Evidence in Literature Dose Onset of Improvement Estimated effectiveness frequency Risks Lab monitoring Ib (1 small RCT) 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 70 Dapsone Morgan M et al. J Allergy Clin Immunol Pract 2014;2: Dapsone Itch and overall urtcaria severity statistically different dapsone vs placebo 3/10 dapsone patients had complete resolution of hives Most common adverse effect: decrease in Hgb (mean 13%) Morgan M et al. J Allergy Clin Immunol Pract 2014;2:

25 Back to the Case n Tried 4,000 U Vit D for 2 mos, no effect n Dapsone 100 mg/d for 6 weeks no effect n Remains on prednisone 20 mg/d n Remains frustrated and tearful 73 Management of Refractory Chronic Urticaria Joshi S, Khan DA. J Allergy Clin Immunol Pract 2017;5: Immunosuppressants for CIU Cyclosporine Tacrolimus Mycophenolate Sirolimus 75 25

26 n Cyclosporine Calcineurin Inhibitors in CU n Most evidence with high dose (3-5 mg/kg/d) n Rapid effect n Low dose 1-2 mg/kg/d better tolerated n Slow effect n Tacrolimus n My preferred calcineurin inhibitor n 1-2 mg bid (rapid effect) n No hirsutism, gingival hyperplasia 76 Kulthanan K et al. J Allergy Clin Immunol Pract. 2018;6(2): Evidence in Literature Dose Onset of Improvement Estimated effectiveness frequency Risks 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 with monthly dose increases) 1-9 weeks 30 % 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):

27 Back to the Case n Tacrolimus started and titrated up to 5 mg/d over 8 weeks n Trough tacrolimus level 4 mg/dl n No improvement in urticaria 79 2 refractory cases of CU and 1 UV 2 CU patients responded with complete control of urticaria, both developed LE edema Morgan M. Arch Dermatol 2009;145: Case Finale n Started on sirolimus and titrated up to 2 mg/d n Within weeks able to taper prednisone n Developed lower extremity edema n Dose reduced to 1 mg/d with improvement in edema and was able to taper off prednisone with complete control of hives n Able to wean off sirolimus after ~ 1 year of therapy and remains hive free 81 27

28 n Persistence pays off! Take Home Point n Multiple therapies may be required to find the correct one 82 n n n n n 68 studies of prevalence of Abs Anti-TPO more common Thyroid Abs rare in children Hypothyroidism and Hashimoto s more common than hyperthyroidism and Graves Conflicting evidence on efficacy of thyroid drugs n Significant heterogeneity with treatments Kolkhir P et al. Allergy. 2017;72(10): Kolkhir P et al. Allergy. 2017;72(10):

29 Refractory CIU in an 11 yo n 11 yo F with > 1 year of daily hives and intermittent angioedema, multiple ED visits n No clear triggers n Food avoidance based on skin testing no help n Current medications n Prednisone 15 mg/d x 6 months (gained 80 lbs, now home schooled due to bullying from weight gain) n Xolair 300 mg x 4 months n Cetirizine 10 bid, Levocetirizine 5 bid, Hydroxyzine 30 qid, Doxepin 30 qhs n Famotidine 20 bid 85 Refractory CIU in an 11 yo n Labs n negative ANA/ENA, TSH, ESR 30, leukocytosis n Skin biopsy n urticaria without vasculitis n Physical exam n BMI 36.5, cushingoid, + striae, numerous blanchable urticaria 86 Refractory CIU in an 11 yo n Polypharmacy n Stop levocetirizine, cetirizine, taper off hydroxyzine n Increase doxepin (monotherapy) n Tacrolimus 1 mg bid started n Within 2 weeks had complete resolution of hives n Prednisone tapered off over 2 months n Remains hive free on tacrolimus 1mg/d and Xolair 300 mg and losing weight 87 29

30 Take Home Point n Don t be afraid of treating children aggressively with immunosuppressants when appropriate 88 Mast Cell FсεRI Syk Inhibitor (GSK ) Syk IgG autoantibody Antige n IgE Decreases free IgE levels Current & Future Biologics in CU FсεRI Prevents IgE from binding to Anti-IgE monoclonal FсεRI antibody (omalizumab, Downregulates ligelizumab) FсεRI expression TNFα TNF-α inhibitors Inhibits FсεRI Intravenous Immunoglobulin B cell Decreases autoantibody production by B cells CD20 Induces B cells cytotoxicity and decreased antibody production Rituximab Depletion of IgE classswitched B cells Quilizumab Joshi S, Khan DA. J Allergy Clin Immunol Pract 2017;5: How Safe are Alternative Agents? J Allergy Clin Immunol Pract 2017;5:

31 91 92 No permanent complications observed. J Allergy Clin Immunol Pract 2017;5:

32 94 J Allergy Clin Immunol Pract 2017;5: How Long to Treat? n Once successful alternative agent found n Taper off steroids n Taper off other medications n I treat with alternative agent until urticaria free for at least 3 months then taper over ~3 months n Some patients require long term (years) usage n Find lowest dose to control CU 96 32

33 Conclusions n n n n Omalizumab is effective in most patient with refractory CIU, many physical urticarias and angioedema On the whole, the quality of evidence for alternative agents other than omalizumab is weak and limited Nevertheless despite the absence of high quality evidence, even omalizumab 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 97 The art of medicine consists in amusing the patient while nature cures the disease. Voltaire ( ) 33