Q:

4/30/2014
I have a best practice question that I just need another opinion. Now that omaluzimab has been approved for CIU, how many therapies are people using prior to trying this very expensive option that works well?

It seems that trying maximal doses of antihistamines with or without montelukast would make sense as first line, but would you also try dapsone, sulfasalazine, hydroxychloroquine, or cyclosporin before going to Xolair for the next step? There are costs to consider. I recently read an article in February’s Annals about considering sulfasalazine and utilizing this for at least 3 months for effect. I feel there needs to be a practice parameter update on this subject (last one was in 2000 from the Joint Task Force). Is there one coming soon?

A:

Thank you for your inquiry.

The points that you made are well taken, and I believe that, when the new Practice Parameters for Urticaria are available, there will be a section dealing with omalizumab. However, at the present time, to my knowledge, there is no consensus as to the length of time one might try alternative therapies such as the ones mentioned in your letter before trying omalizumab. In addition I am unaware of any well established "pecking order" to employ when one uses these agents. But I can refer you to two excellent review articles that discuss these issues (1,2) I think there may be some help in this regard when omalizumab is on the market. The package insert will clearly give us some indication as to when this drug should be applied. My guess, however, is that each physician will, at least initially, vary significantly in their use of omalizumab, and it will take time to "sort out" its exact role in the management of difficult to treat urticaria patients. For now, however, I cannot give you a definitive answer to your inquiry.

Nonetheless, I am going to refer your inquiry to Dr. David Lang. He may be able to give us some indication as to when the next Parameter on Urticaria will be available.

Thank you again for your inquiry.

Refernces
1. Morgan and Kahn. Therapeutic alternatives for chronic urticaria, an evidence-based review, Part 1. Annals of Allergy, Asthma and Immunology, Volume 100 (Number 5), pages 403-412, May 2008.

2. Morgan and Kahn. Therapeutic alternatives for chronic urticaria, an evidence-based review, Part 2. Annals of Allergy, Asthma and Immunology, Volume 100 (Number 6), pages 517-526, 2008.

Sincerely,
Phil Lieberman, M.D.

Note: Dr David Lang informed us that:
The Urticaria parameter will appear in the May 2014 issue of J Allergy Clin Immunol. As has been the case with several recently published parameters, the majority of the text will be published online. He has also agreed to respond to your question with his thoughts. We will send his response to you when we receive it.

Phil Lieberman, M.D.

We have heard from Dr. Lang about your inquiry. Thank you again and we hope this response is helpful to you.

Sincerely,
Phil Lieberman, M.D.

Response from Dr. David Lang:
 
As you know, despite advances that have been made in our understanding of chronic urticaria/angioedema (CUA), many patients with CUA continue to experience poor control of their disease and severe impairment in their quality of life (1,2). A number of therapeutic agents, including those which you have mentioned, have been reported to be efficacious in patients with refractory CUA in case reports or case series; however, such studies are frequently subject to bias and do not provide high quality evidence. Randomized controlled trials tend to be rated as high quality evidence; however, the quality of evidence may be lowered based on methodological issues and other factors (3). Of the four agents for which randomized controlled trials in patients with refractory CUA have been reported: hydroxychloroquine (4), stanozolol (5), cyclosporine (6,7), and omalizumab (8-11), cyclosporine and omalizumab are the only agents with more than one randomized controlled trial.

In the 2014 update of the Urticaria/Angioedema Practice Parameter (12), which appears in the May 2014 issue of The Journal of Allergy and Clinical Immunology, a critical appraisal of the literature supporting the therapeutic utility of cyclosporine judged this evidence to be of low quality based on a number of methodological shortcomings, leading to a weak recommendation for use of cyclosporine for refractory CUA. The weak recommendation does not imply that cyclosporine may not be of benefit in properly selected patients with refractory CUA, or that it should not be prescribed. The weak recommendation signifies the need for clinicians to carefully consider whether administration of cyclosporine is favorable from the standpoint of balancing the potential for benefit with the potential for harm, and discuss this with patients to determine that the decision to proceed with a trial of cyclosporine is consistent with their values and preferences.

The proper role of omalizumab for treatment of refractory CUA will require further experience and ongoing investigation. The parameter (12) advocates a step care approach for management of patients with CUA, which is illustrated in the figure below. Prior to initiation of therapy with an alternative agent, we recommend antihistamine dose advancement with or without antileukotriene (step 2 and then step 3 therapy), as tolerated, based on best evidence; however, initiation of omalizumab at an earlier point has also been proposed (13).

As reviewed recently (14), omalizumab has been shown to be efficacious and safe in patients with refractory CUA, and this has been demonstrated in 4 randomized controlled trials. The quality of evidence supporting the therapeutic utility of omalizumab is superior to any of the other alternative agents, but a number of questions concerning omalizumab as a therapeutic intervention for refractory CUA still remain -- including but not limited to:

- identifying patients with refractory CUA who are most likely to benefit
- appropriate dose and duration of therapy
- strategies for suspending or tapering omalizumab in those who benefit
- establishing the efficacy of omalizumab in patients with physical urticarial/angioedema, who were excluded from the 4 randomized controlled trials.

As you point out, omalizumab is more costly than other alternative agents.  Studies with formal economic models using cost utility (cost per quality year of life gained) and cost-effectiveness (cost per attack prevented) analyses will be helpful to aid Allergy/Immunology providers in clarifying appropriate patient selection for omalizumab in the setting of refractory CUA.
 
STEP 1
Monotherapy with second generation antihistamine Avoidance of triggers (e.g., NSAIDs) and relevant physical factors if physical urticaria/angioedema syndrome is present.
 
STEP 2
One or more of the following:
Dose advancement of 2nd generation antihistamine used in Step 1 Add another second generation antihistamine Add H2- antagonist Add leukotriene receptor antagonist add 1st generation antihistamine to be taken at bedtime
 
STEP 3
Dose advancement of potent antihistamine (e.g., hydroxyzine or doxepin (as tolerated)
 
STEP 4
Add an alternative agent
 Omalizumab or cyclosporine
 Other anti-inflammatory agents, immunosuppressants, or biologics

REFERENCES
1. Kaplan AP.  Treatment of chronic spontaneous urticaria. Allergy Asthma Immunol Res 2012; 4: 326-31.
2. Engin B, Uguz F, Yilmaz E, Ozdemir M, Mevlitoglu I. The levels of depression, anxiety, and quality of life in patients with chronic idiopathic urticaria. J Eur Acad Dermatol Venereol 2008; 22: 36-40.
3. Guyatt, G.H., et al., GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008; 336: 924-6.
4. Reeves, G.E., Boyle MJ, Bonfield J, Dobson P, Loewenthal M. Impact of hydroxychloroquine therapy on chronic urticaria: chronic autoimmune urticaria study and evaluation. Intern Med J 2004; 34: 182-6.
5. Parsad D, Pandhi R. Juneja A. Stanozolol in chronic urticaria: a double blind, placebo controlled trial. J Dermatol 2001; 28: p. 299-302.
6. Grattan C, O'Donnell B, Francis D; et al. Randomized double-blind study of cyclosporin in chronic ''idiopathic'' urticaria. Br J Dermatol 2000; 143: 365-72.
7. Vena GA, Cassano N, Colombo D, Peruzzi E, Pigatto P; Neo-I-30 Study Group. Cyclosporine in chronic idiopathic urticaria: a double-blind, randomized, placebo-controlled trial. J Am Acad Dermatol 2006; 55: 705-9.
8. Saini S, Rosen KE, Hsieh HJ, et al. A randomized, placebo-controlled, dose-ranging study of single-dose omalizumab in patients with H1-antihistamine-refractory chronic idiopathic urticaria. J Allergy Clin Immunol 2011; 128: 567-73.
9. Maurer M, Altrichter S, Bieber T; et al. Efficacy and safety of omalizumab in patients with chronic urticaria who exhibit IgE against thyroperoxidase. J Allergy Clin Immunol 2011; 128: 202-209.
10. Maurer M, Rosen KE, Hsieh HJ; et al. Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria. N Engl J Med 2013; 368: 924-35.
11. Kaplan A, Ledford D, Ashby M; et al. Omalizumab in patients with symptomatic chronic idiopathic/spontaenous urticaria despite standard combination theraepy. J Allergy Clin Immunol 2013; 132:101-9.
12. Bernstein JA, Lang DM, Khan DA, Craig T, Dreyfus D, Hsieh F, Sheikh J, Weldon D, Zuraw B, Bernstein D, Blessing-Moore J, Cox L, Nicklas R, Oppenheimer J, Portnoy JM, Randolph CR, Schuller DE, Spector SL, Tilles SA, Wallace D. The Diagnosis and Management of Acute and Chronic Urticaria: 2014 Update. J Allergy Clin Immunol, 2-14: 133: 1270-1277.
13. Kaplan A.  Therapy of chronic urticarial: a simple, modern approach. Ann Allergy Asthma Immunol 2014; 112: 419-25.
14. Lang DM. A Critical Appraisal of Omalizumab as a Therapeutic Option for Chronic Refractory Urticaria/Angioedema. Ann Allergy Asthma Immunol 2014, 112: 276-279.

AAAAI - American Academy of Allergy Asthma & Immunology