refractory chronic urticaria: when omalizumab fails · for treatment of chronic urticaria...

$: Refractory Chronic Urticaria: When Omalizumab Fails · for treatment of chronic urticaria Objectives n Gain an understanding of stepwise approach for urticaria and differences in$
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Refractory Chronic Urticaria: When Omalizumab Fails

David A. Khan, MD Professor of Medicine and Pediatrics

Allergy & Immunology Program Director

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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

2 All medications other than antihistamines and omalizumab are considered “off-label” 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.

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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

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5 Bernstein JA et al. J Allergy Clin Immunol 2014;133:1270-7.

Management of Refractory Chronic Urticaria

Joshi S, Khan DA. J Allergy Clin Immunol Pract 2017;5:1489-99.

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7 Allergy 2018 (in press)

8 Br J Derm (2016);175:1153–1165.

Updosing Antihistamines When Standard Doses Fail

9 Br J Derm (2016);175:1153–1165.

38% response rate to standard antihistamine

dose

60% response rate to updosing of

antihistamine; however lots of heterogeneity

and most studies of low quality

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

Multiple High Dose Antihistamines

12 van den Elzen et al. Clin Transl Allergy (2017) 7:4

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van den Elzen et al. Clin Transl Allergy (2017) 7:4

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van den Elzen et al. Clin Transl Allergy (2017) 7:4

Predicting Response to Antihistamines Based on Histamine Wheal Suppression

15 Sanchez J et al. J Investig Allergol Clin Immunol 2016; Vol. 26(3): 177-184

Large suppression of histamine wheal suggests good response to antihistamines 150 CU patients treated in

blinded fashion with 5 different antihistamines or placebo

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Step 3

16 Bernstein JA et al. J Allergy Clin Immunol 2014;133:1270-7.

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 10-25 mg qhs as a single dose n  Increase dose by 10-25 mg weekly as

tolerated n  Target of 50-150 mg qhs

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Other Potential Problems with 1st 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, 1.21-1.96)

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;175:401-7. 18

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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 mod-severe 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

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Take Home: Don’t forget/fear aggressive antihistamines

31 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 20

31 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

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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 2nd and 1st generation antihistamines tried and failed?

n  Has omalizumab failed? n  How much? n  How long? n  How often? 22

23 JEADV 2017, 31, 964–971

Diagnostic Evaluation in Urticaria

How Many and What Tests Are Required?

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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.

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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]

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Task Force Labs in CU Consensus

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Additional Labs in CU

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J Allergy Clin Immunol Pract 2017;5:1314-18.

32 Doong JC et al. J Allergy Clin Immunol Pract 2017;5:1314-18.

Omalizumab in Chronic Urticaria

Efficacy/Dosing Duration

Predicting Response Physical Urticaria

Angioedema Failures

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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?

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35 Kaplan A et al. J Allergy Clin Immunol 2016;137:474-81.

Omalizumab 300 mg faster response than omalizumab 150 mg


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Complete Responders Higher in omalizumab 300 mg vs 150 mg


12-16 weeks of omalizumab 300 mg appears sufficient to determine response

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39 Casale TB et al. J Am Acad Dermatol. 2018;78(4):793-5.

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Open Label Omalizumab

40 Casale TB et al. J Am Acad Dermatol. 2018;78(4):793-5.

41 Maurer M et al. J Allergy Clin Immunol. 2018;141(3):1138-9 e7.

24-48 weeks omalizumab vs placebo


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Probability of Worsening: Omalizumab vs Placebo


Re-Treatment with Omalizumab After 12 weeks of Placebo


Long-term Use of Omalizumab

45 Har D et al. Ann Allergy Asthma Immunol 2015;115:126-9.

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Long-term Use of Omalizumab


Urticaria Recurred in Vast Majority with Tapering

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Many able to Reduce Frequency to > every 4 weeks, some required more frequent dosing


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More frequent Omalizumab Dosing?

n  No controlled studies have evaluated more frequent dosing

n  Anecdotally, rare patients have a “wear-off” effect n  More hives days 21-28 post omalizumab n  Some of these patients may benefit from

more frequent dosing

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n  Retrospective study of 41 pts treated with omalizumab

n  29 responders n  87% absent CD203c activity

n  12 nonresponders n  25% absent CD203c activity

n  Limitations of small sample size and retrospective study

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J Allergy Clin Immunol Pract 2016;4:529-30.

51 Ertas R et al. Allergy. 2018;73(3):705-12.

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52 Ertas R et al. Allergy. 2018;73(3):705-12.

53 Maurer M et al. J Allergy Clin Immunol. 2018;141(2):638-49.

54 Staubach P et al. Allergy. 2016;71(8):1135-44.

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Angioedema

Urticaria


57 Chang TW et al. J Allergy Clin Immunol. 2015;135(2):337-42.

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Omalizumab Not Successful 34-44%

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When Omalizumab Fails

Other Alternative Agents for Chronic Urticaria

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What’s Wrong with Steroids?

60 Allergy Asthma Proc 2016;37:458-65.

Study of a large health care claims database > 13 million patients

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Corticosteroid Toxicity in CU


Majority of CU patients used corticosteroids

Dose Response of Corticosteroid Toxicity in CU


For every 100 tabs of 10 mg prednisone, there is a 7% increased risk of adverse effects

J Allergy Clin Immunol Practice 2013;1:433-40.e1 63

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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

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

66 Vena GA et al. Curr Opin Allergy Clin Immunol. 2017;17(4):278-85.

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Anti-Inflammatory Agents for CIU

Dapsone Sulfasalazine

Hydroxychloroquine Vitamin D?

Methotrexate Colchicine 69

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Dapsone Evidence in Literature Ib (1 small RCT) 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

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Dapsone

71 Morgan M et al. J Allergy Clin Immunol Pract 2014;2:601-6.

Dapsone

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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;2:601-6

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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

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Management of Refractory Chronic Urticaria


Immunosuppressants for CIU

Cyclosporine Tacrolimus

Mycophenolate Sirolimus

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Calcineurin Inhibitors in CU

n  Cyclosporine 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

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77 Kulthanan K et al. J Allergy Clin Immunol Pract. 2018;6(2):586-99.

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 with monthly dose increases)

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. 78

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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

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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;145:637-9.

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

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Take Home Point

n  Persistence pays off! n  Multiple therapies may be required to

find the correct one

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n  68 studies of prevalence of Abs

n  Anti-TPO more common n  Thyroid Abs rare in children n  Hypothyroidism and

Hashimoto’s more common than hyperthyroidism and Graves

n  Conflicting evidence on efficacy of thyroid drugs

n  Significant heterogeneity with treatments

83 Kolkhir P et al. Allergy. 2017;72(10):1440-60.

84 Kolkhir P et al. Allergy. 2017;72(10):1440-60.

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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

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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

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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

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Take Home Point

n  Don’t be afraid of treating children aggressively with immunosuppressants when appropriate

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Anti-IgE monoclonal antibody (omalizumab, ligelizumab)

Decreases free IgE levels

Downregulates FсεRI expression

Prevents IgE from binding to FсεRI

FсεRI

IgE

Antigen

IgG autoantibody

Mast Cell

B cell

Rituximab

CD20

Induces B cells cytotoxicity and decreased antibody production

Intravenous Immunoglobulin

Inhibits FсεRI

Decreases autoantibody production by B cells

TNF-α

TNF-α inhibitors

Quilizumab

Depletion of IgE class-switched B cells

Syk

Syk Inhibitor (GSK2646264)

FсεRI


Current & Future Biologics

in CU

How Safe are Alternative Agents?

90 J Allergy Clin Immunol Pract 2017;5:165-70..

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No permanent complications observed.

J Allergy Clin Immunol Pract 2017;5:165-70..

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95 J Allergy Clin Immunol Pract 2017;5:165-70..

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

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Conclusions

n  Omalizumab is effective in most patient with refractory CIU, many physical urticarias and angioedema

n  On the whole, the quality of evidence for alternative agents other than omalizumab is weak and limited

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

n  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

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“The art of medicine consists in amusing the patient while

nature cures the disease.”

Voltaire (1694-1778)

refractory chronic urticaria: when omalizumab fails · for treatment of chronic urticaria...

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