Clinical Commentary Review
The Use of Anti-IgE Therapy Beyond Allergic Asthma Jeffrey R. Stokes, MDa, and Thomas B. Casale, MDb
Omaha, Neb; and Tampa, Fla
Omalizumab is a monoclonal anti-IgE antibody that has been used to treat allergic asthma for over a decade. The use of omalizumab to treat other diseases has largely been limited to case reports until the recently reported large multicenter studies that have established omalizumab as an effective treatment option for chronic spontaneous urticaria. The utility of omalizumab to treat nonallergic asthma and allergic rhinitis and the added safety and therapeutic benefits in combination with allergen immunotherapy have been demonstrated in placebo-controlled trials. Data supporting the clinical efficacy of omalizumab in treating atopic dermatitis, physical urticarias, mast cell disorders, food allergy, and various other allergic disorders have shown promise in small clinical trials and case studies. More carefully designed, large clinical trials of high quality are needed to fully appreciate the potential of omalizumab in treating various allergic and nonallergic diseases. Ó 2015 Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology (J Allergy Clin Immunol Pract 2015;-:---) Key words: Omalizumab; Urticaria; Asthma; Rhinitis; Atopic
Omalizumab is a recombinant humanized monoclonal IgG antibody that binds to the Fcε3 portion of the IgE antibody. Omalizumab forms complexes with the free IgE and reduces total IgE, thereby reducing IgE expression on mast cells, basophils, and antigen-presenting cells. This results in decreased expression of the high-affinity IgE receptor (FcεRI) on these cells. Omalizumab was initially approved by the US Food and Drug Administration for the treatment of moderate to severe perennial allergic asthma. However, omalizumab has been reported to benefit many different patient populations other than those with allergic asthma. This review focuses on the potential therapeutic utility of omalizumab for diseases other than allergic asthma.
URTICARIA Urticaria and/or angioedema that occurs daily or near daily for more than 6 weeks with no identifiable cause has been termed a
Division of Allergy/Immunology, Creighton University, Omaha, Neb Division of Allergy/Immunology, University of South Florida, Tampa, Fla No funding was received for this work. Conflicts of interest: T.B. Casale has received research support and consulting fees from Genentech and Novartis; is employed by the AAAAI; and has received payment for the development of educational presentations from Genentech. J.R. Stokes declares no relevant conflicts of interest. Received for publication September 21, 2014; revised October 8, 2014; accepted for publication October 10, 2014. Available online -Corresponding author: Jeffrey R. Stokes, MD, CUMC Medicine, 601 N 30th St, 3M100, Omaha, NE 68131. E-mail: [email protected]. 2213-2198 Ó 2015 Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaip.2014.10.010 b
chronic idiopathic urticaria or chronic spontaneous urticaria (CSU). H1 antihistamines are effective for 50% to 60% of these patients.1,2 Several small studies have demonstrated the effectiveness of omalizumab in chronic autoimmune urticaria, nonimmune chronic urticaria, and CSU.3-5 A randomized, placebo-controlled study involving 90 patients with antihistamine refractory CSU evaluated a single administration of 3 different doses of omalizumab, 75, 300, or 600 mg, versus placebo. Only the 300- and 600-mg doses demonstrated an improvement in urticaria scores 4 weeks after treatment and there was no significant difference in efficacy between the higher doses.6 This led to 3 large, phase III, randomized, double-blind, placebo-controlled studies: Asteria I, Asteria II, and Glacial. All the 3 studies evaluated 12- to 75- year-old patients with CSU that was refractory to standard of care with oral H1 antihistamines.7-9 Results of the Asteria I trial were published in 2014.7 In this study, 318 patients were randomized to 1 of 3 different doses of omalizumab (300, 150, 75 mg) or placebo every 4 weeks for 24 weeks after failing licensed doses of H1-antihistamine therapy. The 300-mg dose improved urticaria by the first week of treatment compared with placebo. All 3 omalizumb doses significantly reduced patients’ weekly itch score at 12 weeks compared with placebo. By week 12, 52% of the patients on high-dose omalizumab had their urticaria symptoms well controlled and 36% had their symptoms completely controlled. Angioedema symptoms also improved with the 300-mg dose. The Asteria II trial was similar in design with the same 3 doses of omalizumab or placebo and enrolled 323 patients with CSU who remained symptomatic despite licensed doses of H1antihistamine therapy.8 In this study, patients were treated for only 12 weeks. By week 12, the patients on 150- and 300-mg doses of omalizumab demonstrated significant improvements in symptom scores and number of hives compared with those on placebo. By week 12, 53% of the group members receiving 300 mg of omalizumab were hive free, with 44% free from both hives and itching. The Glacial trial had a significant difference compared with Asteria trials. These patients all failed H1 antihistamines up to 4 times the licensed doses plus patients were allowed to have been on an H2-blocker and/or leukotriene antagonist. In this study, 335 patients were randomized to either 300 mg of omalizumab or placebo every 4 weeks for 24 weeks of treatment and 16 weeks follow-up with continuation of their baseline medications.9 This study reaffirmed the effectiveness of 300 mg of omalizumab every 4 weeks in reducing urticarial lesions and symptoms at 12 weeks of therapy, which was sustained for the 24 weeks of therapy. The overall incidence of adverse events and serious adverse events was similar between omalizumab and placebo recipients in all the 3 trials, and no new omalizumab safety issues were identified. In a review of more than 900 patients with CSU, the response rate to omalizumab in patients symptomatic despite conventional 1
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Abbreviations used ABPA- Allergic bronchopulmonary aspergillosis CSU- chronic spontaneous urticaria FcεRI- High-affinity IgE receptor SCIT- Subcutaneous immunotherapy
therapy was 65%, with complete resolution in 40%, and improvement was noted in just a few days in a subset of patients.10 When omalizumab is discontinued in successfully treated patients with CSU or physical uriticarias, relapse may occur within a few weeks. In these patients, retreatment with omalizumab was effective in again treating their symptoms.11 Current urticaria guidelines of the European Academy of Allergy and Clinical Immunology/Global Allergy and Asthma European Network/European Dermatology Forum/World Allergy Organization give a strong recommendation for the use of omalizumab after failing a second-generation antihistamine at 4 times the standard dose.12 The American Academy of Allergy, Asthma & Immunology and the American College of Allergy, Asthma & Immunology have recommended the use of omalizumab after failure with antihistamines and leukotriene receptor antagonists.13 In March 2014, the US Food and Drug Administration approved the use of omalizumab 150 or 300 mg every 4 weeks in chronic idiopathic urticaria for patients 12 years and older who remain symptomatic despite H1 antihistamines.14 The exact mechanisms of how omalizumab works in chronic idiopathic urticaria are unclear. In a subset of patients, IgG autoantibodies against FcεRI, IgE, or both may exist.15 Because omalizumab decreases the free IgE available with subsequent downregulation of FcεRI, it was natural to postulate that omalizumab’s effects might be due to decreasing the targets for these autoantibodies. However, no differences in effectiveness have been found in patients with or without the autoantibodies. Furthermore, analysis of previous data suggests that it takes time to significantly decrease the expression of high-affinity IgE receptors on either basophils (2 weeks) or mast cells (10 weeks), whereas a therapeutic effect within 1 week is noted in some patients.16,17 An alternative postulate is that IgE antibodies against autoallergens are present and omalizumab reduces the level of these autoantibodies.15 Another possibility is that the binding of free IgE to FcεRI, which promotes the proliferation of mast cells and potentiates their ability to store and synthesize cytokines, would be inhibited by omalizumab. This may result in a nonspecific desenstitization. It is likely that omalizumab works in different ways in subsets of patients and the exact mechanisms remain to be elucidated because its effectiveness in urticaria is not dependent on IgE level or weight.
PHYSICAL URTICARIAS Omalizumab has also improved symptoms in patients with different types of physical urticarias, including solar, cold, localized heat, cholinergic, dermatographic, and pressure.18 NONALLERGIC ASTHMA Omalizumab has clearly shown benefit in patients with allergic asthma, but recent data demonstrate that patients with nonallergic asthma may benefit from omalizumab as well. This may be in part due to local IgE production in the absence of systemic measurable allergen-specific IgE either by skin tests or by in vitro
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testing. The presence of respiratory IgE produced in response to Staphylococcal enterotoxins has also been proposed as a possible stimulus for IgE-mediated inflammation. An initial case study reported a steroid-dependent asthmatic patient with elevated total IgE level but negative aeroallergen skin and in vitro test results who was treated with omalizumab. The patient noted improvement in his symptoms after 16 weeks of omalizumab therapy that continued for 4 years.19 A similar case study of a patient with severe asthma with elevated IgE level but negative food and aeroallergen skin prick and in vitro test results was reported. Treatment with omalizumab dramatically improved symptoms and pulmonary functions, allowing the discontinuation of oral corticosteroids.20 A study comparing 29 patients with severe, nonatopic asthma and 266 patients with severe, atopic asthma all treated with omalizumab showed similar improvements in symptoms in both groups.21 A randomized, placebo-controlled, phase 3B, double-blind study evaluated omalizumab treatment in 41 patients with severe refractory nonatopic asthma. All patients were on high-dose inhaled corticosteroid/long-acting b2-agonist medications, with 33% of the patients requiring oral corticosteroids.22 Omalizumab significantly decreased the expression of FcεRI on basophils and plasmacytoid dendritic cells. All patients treated with placebo (20) had a decrease of less than 50% in basophil FcεRI expression, whereas 90% of omalizumab-treated patients had a decrease of more than 50%. Omalizumab-treated patients had an improvement in lung functions despite no significant changes in exacerbations or asthma control symptoms after 16 weeks of therapy. Occupational asthma can have either allergic or nonallergic causes. Ten patients with uncontrollable occupational asthma were treated with omalizumab. After 4 months, 9 of the 10 patients had improvements in their symptoms and 7 patients were able to continue to work in the same environment.23
ALLERGIC RHINITIS Several early studies demonstrated the effectiveness of omalizumab in reducing symptoms and rescue medication use in patients with allergic rhinitis to ragweed, birch, cedar, and perennial allergens.24-31 A recent meta-analysis published in 2014 screened 352 citations, with 78 articles eligible for review.32 Of these studies, 11 qualified for evaluation, with 2870 patients randomized. In the 9 studies that measured daily nasal symptom scores, omalizumab significantly reduced symptoms. Rescue medication use was also decreased in the 9 studies that evaluated that end point. No significant differences in adverse events in 2005 in these patients were reported on comparing omalizumab with placebo. ATOPIC DERMATITIS The use of omalizumb in atopic dermatitis has been limited to case studies and small trials. Conflicting data on the effectiveness may be due to the exceptionally high level of IgE in these patients making it difficult to reduce the levels to below 10 ng/ mL.33 A recent trial in 7 pediatric patients with severe atopic dermatitis found that omalizumab was effective in reducing atopic dermatitis symptoms in a patient with a baseline IgE level as high as 17,190 IU/L.34 The use of omalizumab in atopic dermatitis has been reported to reduce cytokines involved in TH2 polarization.35 Patients with atopic dermatitis without filaggrin
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FIGURE 1. Omalizamab: Clinical benefits in published data.
mutations have shown greater response to omalizumab treatment. This may indicate that patients with skin barrier alterations, mutations, may be less likely to respond to treatment than patients with more of an immunodystregulation profile.36
ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS Allergic bronchopulmonary aspergillosis (ABPA) is associated with pediatric cystic fibrosis and adult asthma. One review on children with cystic fibrosis and ABPA analyzed 8 cases in 13 children. Treatment with omalizumab improved lung functions and reduced respiratory symptoms and systemic corticosteroid use.37 A Cochrane meta-analysis attempted to evaluate the effects of omalizumab for ABPA in patients with cystic fibrosis but concluded that there were no studies that met inclusion criteria.38 A retrospective analysis of 4 adult patients with stage IV ABPA (corticosteroid-dependent) treated with omalizumab for 12 months found that it was steroid sparing and reduced inflammatory markers and symptom scores.39 NASAL POLYPS Nasal polyps are frequently associated with eosinophilic inflammation and local production of IgE. In a randomized, double-blind, placebo-controlled study, patients with nasal polyps and comorbid asthma were treated with either omalizumab (15) or placebo (8) for 16 weeks.40 In the omalizumabtreated group, nasal polyp size decreased by both endoscopy and computed tomography scan assessment regardless of allergic status. Only the omalizumab-treated patients had a significant improvement in their nasal and asthma symptom scores. A similar study of patients with nasal polyps who were continued on their medical regimen (nasal corticosteroids, leukotriene modifiers, and as-needed courses of prednisone and antibiotics) found that the addition of omalizumab decreased nasal polyp size but had no significant effect on symptoms compared with the placebo group.41 In a small retrospective analysis in 2 groups of
patients with asthma postpolypectomy, the addition of omalizumab postoperatively was found to reduce the severity of nasal polyp recurrence.42
FOOD ALLERGY An early study of anti-IgE therapy in patients with peanut allergy used another humanized mAb against IgE, TNX-901.43 This double-blind, placebo-controlled, randomized trial in 84 peanut-allergic patients evaluated 3 doses of TNX-901. By the end of treatment, all groups, including the placebo group, had a greater threshold of peanut tolerability but only the high-dose TNX-901 group had a significant improvement from about 1/2 peanut to more than 8 peanuts. Of note, 25% of the high-dose group had no improvement with therapy. A more recent attempt at a phase II, multicenter, randomized, double-blind, placebocontrolled, parallel-group trial was designed to assess the efficacy of omalizumab in peanut-allergic patients.44 Because of concern of severe anaphylactic reactions during the qualifying food challenges before therapy, only 14 patients (9 omalizumab and 5 placebo) completed treatment. Of these, 4 (44.4%) omalizumabtreated subjects compared with 1 (20%) placebo-treated subject could tolerate more than 1000 mg peanut flour after 24 weeks, but this difference was not significant. Both these studies suggest that omalizumab may be beneficial for food allergy, but the findings are not conclusive. IMMUNOTHERAPY Standard subcutaneous immunotherapy (SCIT) for aeroallergens and venom has a risk of anaphylaxis. A recent review of the use of omalizumab with SCIT found that omalizumab therapy improved the safety of SCIT especially with rush therapy.45 Omalizumab therapy also improved the symptom relief seen with SCIT, but this improvement did not continue after the omalizumab was discontinued.45-47 These studies have not addressed the optimal pretreatment time for omalizumab to impart added safety to SCIT. A reasonable pretreatment based
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on the data to date suggests an 8- to 12-week course of omalizumab before allergen immunotherapy. None of these studies has examined whether it is safe to discontinue omalizumab and continue allergen immunotherapy in high-risk patients, for example, moderate to severe asthma. Recently, the use of oral immunotherapy for food allergy has demonstrated benefit in patients with milk, egg, and peanut allergy.48-50 The use of omalizumab to improve efficacy and safety has been evaluated in several studies. The data suggest that omalizumab may facilitate oral desensitization to peanut and milk.48,50 The addition of omalizumab has allowed children to successfully receive oral immunotherapy to multiple foods simultaneously, including milk, egg, peanut, wheat, soy, and tree nuts.51 In this open-label study, only 3 of the 25 children had total serum IgE level greater than 1500 kuA/L and received the maximum dose of omalizumab (600 mg every 2 weeks).
EOSINOPHILIC ESOPHAGITIS Eosinophilic esophagitis is another potential target for antiIgE therapy. In 2 case studies of patients with eosinophilic esophagitis and multiple food allergies, the addition of omalizumab reduced symptoms but did not improve endoscopic and histologic changes.52 A prospective randomized, double-blind, placebo-controlled trial of omalizumab therapy monthly for 16 weeks in patients with eosinophilic esophagitis who were either refractory to or relapsed after topical corticosteroids found no improvements in either eosinophils in the esophagus or symptom scores.53 It is unlikely that omalizumab will have a significant role in treating this disorder. MAST CELL DISORDERS A recent review on the use of omalizumab in mast cell disorders noted case studies of patients with mastocytosis, cutaneous mastocytosis and venom anaphylaxis, and mast cell activation syndrome showing improvement with omalizumab therapy.54 OTHER DISEASES Case reports and small studies have noted the benefit of omalizumab treatment in Churg-Strauss syndrome, bullous pemphigoid, Kimura’s disease, aspirin-exacerbated respiratory disease, recurrent anaphylaxis, laryngeal angioedema, chronic eosinophilic pneumonia, drug allergy, and vernal keratoconjunctivitis.55-63 CONCLUSIONS Omalizumab is the first of many immune response modifiers to be approved for the management of allergic diseases (Figure 1). Because of the critical role of IgE in the pathogenesis of allergic diseases, it is conceivable that approaches targeting other key TH2-driven mechanisms may fall short of the therapeutic utility demonstrated for omalizumab in the diseases discussed above. However, as we learn more about critical pathways involved in specific diseases and the characteristics of patients that predict positive benefits, it is likely that we will make advances in our judicious use of omalizumab and these other agents. Furthermore, the next generation of anti-IgE strategies will have important advantages over omalizumab such as a lack of limitations of dosing restrictions based on IgE levels. The strength of evidence points to omalizumab’s effectiveness in urticaria, and as an adjunct to allergen immunotherapy.
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Because of costs or dosing limitations, omalizumab will unlikely be widely used for the management of allergic rhinitis and atopic dermatitis and ABPA, respectively. More carefully designed, large clinical trials of high quality are needed to fully appreciate the potential of omalizumab and other anti-IgE strategies to treat the other allergic diseases discussed above as well as nonallergic asthma. As the utility of anti-IgE strategies is further explored for disorders other than allergic asthma, it is likely that increases in our understanding of the role of IgE in many disorders will be forthcoming. REFERENCES 1. Casale TB. Omalizumab for chronic urticaria. J Allergy Clin Immunol Pract 2014;2:118-9. 2. Khan DA. Alternative agents in refractory chronic urticaria: evidence and considerations on their selection and use. J Allergy Clin Immunol Pract 2013;1: 433-40.e1. 3. Maurer M, Altrichter S, Bieber T, Biedermann T, Bräutigam M, Seyfried S, et al. Efficacy and safety of omalizumab in patients with chronic urticaria who exhibit IgE against thyroperoxidase. J Allergy Clin Immunol 2011;128:202-9.e5. 4. Ferrer M, Gamboa P, Sanz ML, Goikoetxea MJ, Cabrera-Freitag P, Javaloyes G, et al. Omalizumab is effective in nonautoimmune urticaria. J Allergy Clin Immunol 2011;127:1300-2. 5. Groffik A, Mitzel-Kaoukhov H, Magerl M, Maurer M, Staubach P. Omalizumab—an effective and safe treatment of therapy-resistant chronic spontaneous urticaria. Allergy 2011;66:303-5. 6. Saini S, Rosen KE, Hsieh HJ, Wong DA, Conner E, Kaplan A, 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. 7. Saini SS, Bindslev-Jensen C, Maurer M, Grob JJ, Bülbül Baskan E, Bradley MS, et al. Efficacy and safety of omalizumab in patients with chronic idiopathic/spontaneous urticaria who remain symptomatic on H(1) antihistamines: a randomized, placebo-controlled study. J Invest Dermatol 2014.http:// dx.doi.org/10.1038/jid.2014.306. [Epub ahead of print]. 8. Maurer M, Rosén K, Hsieh HJ, Saini S, Grattan C, Gimenéz-Arnau A, et al. Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria. N Engl J Med 2013;368:924-35. 9. Kaplan A, Ledford D, Ashby M, Canvin J, Zazzali JL, Conner E, et al. Omalizumab in patients with symptomatic chronic idiopathic/spontaneous urticaria despite standard combination therapy. J Allergy Clin Immunol 2013;132:101-9. 10. Kaplan AP. Therapy of chronic urticaria: a simple, modern approach. Ann Allergy Asthma Immunol 2014;112:419-25. 11. Metz M, Ohanyan T, Church MK, Maurer M. Retreatment with omalizumab results in rapid remission in chronic spontaneous and inducible urticaria. JAMA Dermatol 2014;150:288-90. 12. Zuberbier T, Aberer W, Asero R, Bindslev-Jensen C, Brzoza Z, Canonica GW, et al. The EAACI/GA(2) LEN/EDF/WAO Guideline for the definition, classification, diagnosis, and management of urticaria: the 2013 revision and update. Allergy 2014;69:868-87. 13. Bernstein JA, Lang DM, Khan DA, Craig T, Dreyfus D, Hsieh F, et al. The diagnosis and management of acute and chronic urticaria: 2014 update. J Allergy Clin Immunol 2014;133:1270-7. 14. Xolair [package insert]. (revision); March 2014. 15. Chang TW, Chen C, Lin CJ, Metz M, Church MK, Maurer M. The potential pharmacologic mechanisms of omalizumab in patients with chronic spontaneous urticaria. J Allergy Clin Immunol 2014.http://dx.doi.org/10.1016/j.jaci.2014.04. 036. [Epub ahead of print]. 16. Lin H, Boesel KM, Griffith DT, Prussin C, Foster B, Romero FA, et al. Omalizumab rapidly decreases nasal allergic response and FcepsilonRI on basophils. J Allergy Clin Immunol 2004;113:297-302. 17. Beck LA, Marcotte GV, MacGlashan D, Togias A, Saini S. Omalizumabinduced reductions in mast cell Fcepsilon RI expression and function. J Allergy Clin Immunol 2004;114:527-30. 18. Metz M, Altrichter S, Ardelean E, Kessler B, Krause K, Magerl M, et al. Antiimmunoglobulin E treatment of patients with recalcitrant physical urticaria. Int Arch Allergy Immunol 2011;154:177-80. 19. Menzella F, Piro R, Facciolongo N, Castagnetti C, Simonazzi A, Zucchi L. Long-term benefits of omalizumab in a patient with severe non-allergic asthma. Allergy Asthma Clin Immunol 2011;7:9. 20. van den Berge M, Pauw RG, de Monchy JG, van Minnen CA, Postma DS, Kerstjens HA. Beneficial effects of treatment with anti-IgE antibodies
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42. Penn R, Mikula S. The role of anti-IgE immunoglobulin therapy in nasal polyposis: a pilot study. Am J Rhinol 2007;4:428-32. 43. Leung DYM, Sampson HA, Yunginger JW, Burks AW, Schneider L, Wortel CH, et al. Effect of anti-IgE therapy in patients with peanut allergy. N Engl J Med 2003;348:986-93. 44. Sampson HA, Leung DY, Burks AW, Lack G, Bahna SL, Jones SM, et al. A phase II, randomized, double-blind, parallel-group, placebo-controlled oral food challenge trial of Xolair (omalizumab) in peanut allergy. J Allergy Clin Immunol 2011;127:1309-10.e1. 45. Larenas-Linnemann D, Wahn U, Kopp M. Use of omalizumab to improve desensitization safety in allergen immunotherapy. J Allergy Clin Immunol 2014; 133:937.e2. 46. Kopp MV, Hamelmann E, Bendiks M, Zielen S, Kamin W, Bergmann KC, et al. Transient impact of omalizumab in pollen allergic patients undergoing specific immunotherapy. Pediatr Allergy Immunol 2013;24:427-33. 47. Casale TB, Busse WW, Kline JN, Ballas ZK, Moss MH, Townley RG, et al. Omalizumab pretreatment decreases acute reactions after rush immunotherapy for ragweed-induced seasonal allergic rhinitis. J Allergy Clin Immunol 2006; 117:134-40. 48. Nadeau KC, Schneider LC, Hoyte L, Borras I, Umetsu DT. Rapid oral desensitization in combination with omalizumab therapy in patients with cow’s milk allergy. J Allergy Clin Immunol 2011;127:1622-4. 49. Lafuente I, Mazon A, Nieto M, Uixera S, Pina R, Nieto A. Possible recurrence of symptoms after discontinuation of omalizumab in anti-IgE-assisted desensitization to egg. Pediatr Allergy Immunol 2014. http://dx.doi.org/10.1111/pai. 12259 [Epub ahead of print]. 50. Schneider LC, Rachid R, LeBovidge J, Blood E, Mittal M, Umetsu DT. A pilot study of omalizumab to facilitate rapid oral desensitization in high-risk peanutallergic patients. J Allergy Clin Immunol 2013;132:1368-74. 51. Bégin P, Dominguez T, Wilson SP, Bacal L, Mehrotra A, Kausch B, et al. Phase 1 results of safety and tolerability in a rush oral immunotherapy protocol to multiple foods using omalizumab. Allergy Asthma Clin Immunol 2014;10:7. 52. Rocha R, Vitor AB, Trindade E, Lima R, Tavares M, Lopes J, et al. Omalizumab in the treatment of eosinophilic esophagitis and food allergy. Eur J Pediatr 2011;170:1471-4. 53. Fang JC, Hilden K, Gleich GJ, Emerson LL, Ogorman MA, Lowichik A, et al. A pilot study of the treatment of eosinophilic esophagitis with omalizumab. Gastroenterology 2011;140:S-235. 54. Sokol KC, Ghazi A, Kelly BC, Grant JA. Omalizumab as a desensitizing agent and treatment in mastocytosis: a review of the literature and case report. J Allergy Clin Immunol Pract 2014;2:266-70. 55. Iglesias E, Camacho Lovillo M, Delgado Pecellín I, Lirola Cruz MJ, Falcón Neyra MD, Salazar Quero JC, et al. Successful management of Churg-Strauss syndrome using omalizumab as adjuvant immunomodulatory therapy: first documented pediatric case. Pediatr Pulmonol 2014;49:E78-81. 56. Yu KK, Crew AB, Messingham KA, Fairley JA, Woodley DT. Omalizumab therapy for bullous pemphigoid. J Am Acad Dermatol 2014;71:468-74. 57. Nonaka M, Sakitani E, Yoshihara T. Anti-IgE therapy to Kimura’s disease: a pilot study. Auris Nasus Larynx 2014;41:384-8. 58. Bobolea I, Barranco P, Fiandor A, Cabañas R, Quirce S. Omalizumab: a potential new therapeutic approach for aspirin-exacerbated respiratory disease. J Investig Allergol Clin Immunol 2010;20:448-9. 59. Lee J. Successful prevention of recurrent anaphylactic events with antiimmunoglobulin E therapy. Asia Pac Allergy 2014;4:126-8. 60. Kuprys-Lipinska I, Korczynska P, Tworek D, Kuna P. Effectiveness of omalizumab in a patient with a life-threatening episode of bronchospasm and larynx angioedema after exposure to house dust. Postepy Dermatol Alergol 2014;31: 39-44. 61. Ozturk AB, Kocaturk E. Omalizumab in recurring larynx angioedema: a case report. Asia Pac Allergy 2014;4:129-30. 62. Kaya H, Gümüs¸ S, Uçar E, Aydogan M, Mus¸abak U, Tozkoparan E, et al. Omalizumab as a steroid-sparing agent in chronic eosinophilic pneumonia. Chest 2012;142:513-6. 63. de Klerk TA, Sharma V, Arkwright PD, Biswas S. Severe vernal keratoconjunctivitis successfully treated with subcutaneous omalizumab. J AAPOS 2013; 17:305-6.
The Use of Anti-IgE Therapy Beyond Allergic Asthma Jeffrey R. Stokes, MDa, and Thomas B. Casale, MDb
Omaha, Neb; and Tampa, Fla
Omalizumab is a monoclonal anti-IgE antibody that has been used to treat allergic asthma for over a decade. The use of omalizumab to treat other diseases has largely been limited to case reports until the recently reported large multicenter studies that have established omalizumab as an effective treatment option for chronic spontaneous urticaria. The utility of omalizumab to treat nonallergic asthma and allergic rhinitis and the added safety and therapeutic benefits in combination with allergen immunotherapy have been demonstrated in placebo-controlled trials. Data supporting the clinical efficacy of omalizumab in treating atopic dermatitis, physical urticarias, mast cell disorders, food allergy, and various other allergic disorders have shown promise in small clinical trials and case studies. More carefully designed, large clinical trials of high quality are needed to fully appreciate the potential of omalizumab in treating various allergic and nonallergic diseases. Ó 2015 Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology (J Allergy Clin Immunol Pract 2015;-:---) Key words: Omalizumab; Urticaria; Asthma; Rhinitis; Atopic
Omalizumab is a recombinant humanized monoclonal IgG antibody that binds to the Fcε3 portion of the IgE antibody. Omalizumab forms complexes with the free IgE and reduces total IgE, thereby reducing IgE expression on mast cells, basophils, and antigen-presenting cells. This results in decreased expression of the high-affinity IgE receptor (FcεRI) on these cells. Omalizumab was initially approved by the US Food and Drug Administration for the treatment of moderate to severe perennial allergic asthma. However, omalizumab has been reported to benefit many different patient populations other than those with allergic asthma. This review focuses on the potential therapeutic utility of omalizumab for diseases other than allergic asthma.
URTICARIA Urticaria and/or angioedema that occurs daily or near daily for more than 6 weeks with no identifiable cause has been termed a
Division of Allergy/Immunology, Creighton University, Omaha, Neb Division of Allergy/Immunology, University of South Florida, Tampa, Fla No funding was received for this work. Conflicts of interest: T.B. Casale has received research support and consulting fees from Genentech and Novartis; is employed by the AAAAI; and has received payment for the development of educational presentations from Genentech. J.R. Stokes declares no relevant conflicts of interest. Received for publication September 21, 2014; revised October 8, 2014; accepted for publication October 10, 2014. Available online -Corresponding author: Jeffrey R. Stokes, MD, CUMC Medicine, 601 N 30th St, 3M100, Omaha, NE 68131. E-mail: [email protected]. 2213-2198 Ó 2015 Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaip.2014.10.010 b
chronic idiopathic urticaria or chronic spontaneous urticaria (CSU). H1 antihistamines are effective for 50% to 60% of these patients.1,2 Several small studies have demonstrated the effectiveness of omalizumab in chronic autoimmune urticaria, nonimmune chronic urticaria, and CSU.3-5 A randomized, placebo-controlled study involving 90 patients with antihistamine refractory CSU evaluated a single administration of 3 different doses of omalizumab, 75, 300, or 600 mg, versus placebo. Only the 300- and 600-mg doses demonstrated an improvement in urticaria scores 4 weeks after treatment and there was no significant difference in efficacy between the higher doses.6 This led to 3 large, phase III, randomized, double-blind, placebo-controlled studies: Asteria I, Asteria II, and Glacial. All the 3 studies evaluated 12- to 75- year-old patients with CSU that was refractory to standard of care with oral H1 antihistamines.7-9 Results of the Asteria I trial were published in 2014.7 In this study, 318 patients were randomized to 1 of 3 different doses of omalizumab (300, 150, 75 mg) or placebo every 4 weeks for 24 weeks after failing licensed doses of H1-antihistamine therapy. The 300-mg dose improved urticaria by the first week of treatment compared with placebo. All 3 omalizumb doses significantly reduced patients’ weekly itch score at 12 weeks compared with placebo. By week 12, 52% of the patients on high-dose omalizumab had their urticaria symptoms well controlled and 36% had their symptoms completely controlled. Angioedema symptoms also improved with the 300-mg dose. The Asteria II trial was similar in design with the same 3 doses of omalizumab or placebo and enrolled 323 patients with CSU who remained symptomatic despite licensed doses of H1antihistamine therapy.8 In this study, patients were treated for only 12 weeks. By week 12, the patients on 150- and 300-mg doses of omalizumab demonstrated significant improvements in symptom scores and number of hives compared with those on placebo. By week 12, 53% of the group members receiving 300 mg of omalizumab were hive free, with 44% free from both hives and itching. The Glacial trial had a significant difference compared with Asteria trials. These patients all failed H1 antihistamines up to 4 times the licensed doses plus patients were allowed to have been on an H2-blocker and/or leukotriene antagonist. In this study, 335 patients were randomized to either 300 mg of omalizumab or placebo every 4 weeks for 24 weeks of treatment and 16 weeks follow-up with continuation of their baseline medications.9 This study reaffirmed the effectiveness of 300 mg of omalizumab every 4 weeks in reducing urticarial lesions and symptoms at 12 weeks of therapy, which was sustained for the 24 weeks of therapy. The overall incidence of adverse events and serious adverse events was similar between omalizumab and placebo recipients in all the 3 trials, and no new omalizumab safety issues were identified. In a review of more than 900 patients with CSU, the response rate to omalizumab in patients symptomatic despite conventional 1
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Abbreviations used ABPA- Allergic bronchopulmonary aspergillosis CSU- chronic spontaneous urticaria FcεRI- High-affinity IgE receptor SCIT- Subcutaneous immunotherapy
therapy was 65%, with complete resolution in 40%, and improvement was noted in just a few days in a subset of patients.10 When omalizumab is discontinued in successfully treated patients with CSU or physical uriticarias, relapse may occur within a few weeks. In these patients, retreatment with omalizumab was effective in again treating their symptoms.11 Current urticaria guidelines of the European Academy of Allergy and Clinical Immunology/Global Allergy and Asthma European Network/European Dermatology Forum/World Allergy Organization give a strong recommendation for the use of omalizumab after failing a second-generation antihistamine at 4 times the standard dose.12 The American Academy of Allergy, Asthma & Immunology and the American College of Allergy, Asthma & Immunology have recommended the use of omalizumab after failure with antihistamines and leukotriene receptor antagonists.13 In March 2014, the US Food and Drug Administration approved the use of omalizumab 150 or 300 mg every 4 weeks in chronic idiopathic urticaria for patients 12 years and older who remain symptomatic despite H1 antihistamines.14 The exact mechanisms of how omalizumab works in chronic idiopathic urticaria are unclear. In a subset of patients, IgG autoantibodies against FcεRI, IgE, or both may exist.15 Because omalizumab decreases the free IgE available with subsequent downregulation of FcεRI, it was natural to postulate that omalizumab’s effects might be due to decreasing the targets for these autoantibodies. However, no differences in effectiveness have been found in patients with or without the autoantibodies. Furthermore, analysis of previous data suggests that it takes time to significantly decrease the expression of high-affinity IgE receptors on either basophils (2 weeks) or mast cells (10 weeks), whereas a therapeutic effect within 1 week is noted in some patients.16,17 An alternative postulate is that IgE antibodies against autoallergens are present and omalizumab reduces the level of these autoantibodies.15 Another possibility is that the binding of free IgE to FcεRI, which promotes the proliferation of mast cells and potentiates their ability to store and synthesize cytokines, would be inhibited by omalizumab. This may result in a nonspecific desenstitization. It is likely that omalizumab works in different ways in subsets of patients and the exact mechanisms remain to be elucidated because its effectiveness in urticaria is not dependent on IgE level or weight.
PHYSICAL URTICARIAS Omalizumab has also improved symptoms in patients with different types of physical urticarias, including solar, cold, localized heat, cholinergic, dermatographic, and pressure.18 NONALLERGIC ASTHMA Omalizumab has clearly shown benefit in patients with allergic asthma, but recent data demonstrate that patients with nonallergic asthma may benefit from omalizumab as well. This may be in part due to local IgE production in the absence of systemic measurable allergen-specific IgE either by skin tests or by in vitro
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testing. The presence of respiratory IgE produced in response to Staphylococcal enterotoxins has also been proposed as a possible stimulus for IgE-mediated inflammation. An initial case study reported a steroid-dependent asthmatic patient with elevated total IgE level but negative aeroallergen skin and in vitro test results who was treated with omalizumab. The patient noted improvement in his symptoms after 16 weeks of omalizumab therapy that continued for 4 years.19 A similar case study of a patient with severe asthma with elevated IgE level but negative food and aeroallergen skin prick and in vitro test results was reported. Treatment with omalizumab dramatically improved symptoms and pulmonary functions, allowing the discontinuation of oral corticosteroids.20 A study comparing 29 patients with severe, nonatopic asthma and 266 patients with severe, atopic asthma all treated with omalizumab showed similar improvements in symptoms in both groups.21 A randomized, placebo-controlled, phase 3B, double-blind study evaluated omalizumab treatment in 41 patients with severe refractory nonatopic asthma. All patients were on high-dose inhaled corticosteroid/long-acting b2-agonist medications, with 33% of the patients requiring oral corticosteroids.22 Omalizumab significantly decreased the expression of FcεRI on basophils and plasmacytoid dendritic cells. All patients treated with placebo (20) had a decrease of less than 50% in basophil FcεRI expression, whereas 90% of omalizumab-treated patients had a decrease of more than 50%. Omalizumab-treated patients had an improvement in lung functions despite no significant changes in exacerbations or asthma control symptoms after 16 weeks of therapy. Occupational asthma can have either allergic or nonallergic causes. Ten patients with uncontrollable occupational asthma were treated with omalizumab. After 4 months, 9 of the 10 patients had improvements in their symptoms and 7 patients were able to continue to work in the same environment.23
ALLERGIC RHINITIS Several early studies demonstrated the effectiveness of omalizumab in reducing symptoms and rescue medication use in patients with allergic rhinitis to ragweed, birch, cedar, and perennial allergens.24-31 A recent meta-analysis published in 2014 screened 352 citations, with 78 articles eligible for review.32 Of these studies, 11 qualified for evaluation, with 2870 patients randomized. In the 9 studies that measured daily nasal symptom scores, omalizumab significantly reduced symptoms. Rescue medication use was also decreased in the 9 studies that evaluated that end point. No significant differences in adverse events in 2005 in these patients were reported on comparing omalizumab with placebo. ATOPIC DERMATITIS The use of omalizumb in atopic dermatitis has been limited to case studies and small trials. Conflicting data on the effectiveness may be due to the exceptionally high level of IgE in these patients making it difficult to reduce the levels to below 10 ng/ mL.33 A recent trial in 7 pediatric patients with severe atopic dermatitis found that omalizumab was effective in reducing atopic dermatitis symptoms in a patient with a baseline IgE level as high as 17,190 IU/L.34 The use of omalizumab in atopic dermatitis has been reported to reduce cytokines involved in TH2 polarization.35 Patients with atopic dermatitis without filaggrin
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FIGURE 1. Omalizamab: Clinical benefits in published data.
mutations have shown greater response to omalizumab treatment. This may indicate that patients with skin barrier alterations, mutations, may be less likely to respond to treatment than patients with more of an immunodystregulation profile.36
ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS Allergic bronchopulmonary aspergillosis (ABPA) is associated with pediatric cystic fibrosis and adult asthma. One review on children with cystic fibrosis and ABPA analyzed 8 cases in 13 children. Treatment with omalizumab improved lung functions and reduced respiratory symptoms and systemic corticosteroid use.37 A Cochrane meta-analysis attempted to evaluate the effects of omalizumab for ABPA in patients with cystic fibrosis but concluded that there were no studies that met inclusion criteria.38 A retrospective analysis of 4 adult patients with stage IV ABPA (corticosteroid-dependent) treated with omalizumab for 12 months found that it was steroid sparing and reduced inflammatory markers and symptom scores.39 NASAL POLYPS Nasal polyps are frequently associated with eosinophilic inflammation and local production of IgE. In a randomized, double-blind, placebo-controlled study, patients with nasal polyps and comorbid asthma were treated with either omalizumab (15) or placebo (8) for 16 weeks.40 In the omalizumabtreated group, nasal polyp size decreased by both endoscopy and computed tomography scan assessment regardless of allergic status. Only the omalizumab-treated patients had a significant improvement in their nasal and asthma symptom scores. A similar study of patients with nasal polyps who were continued on their medical regimen (nasal corticosteroids, leukotriene modifiers, and as-needed courses of prednisone and antibiotics) found that the addition of omalizumab decreased nasal polyp size but had no significant effect on symptoms compared with the placebo group.41 In a small retrospective analysis in 2 groups of
patients with asthma postpolypectomy, the addition of omalizumab postoperatively was found to reduce the severity of nasal polyp recurrence.42
FOOD ALLERGY An early study of anti-IgE therapy in patients with peanut allergy used another humanized mAb against IgE, TNX-901.43 This double-blind, placebo-controlled, randomized trial in 84 peanut-allergic patients evaluated 3 doses of TNX-901. By the end of treatment, all groups, including the placebo group, had a greater threshold of peanut tolerability but only the high-dose TNX-901 group had a significant improvement from about 1/2 peanut to more than 8 peanuts. Of note, 25% of the high-dose group had no improvement with therapy. A more recent attempt at a phase II, multicenter, randomized, double-blind, placebocontrolled, parallel-group trial was designed to assess the efficacy of omalizumab in peanut-allergic patients.44 Because of concern of severe anaphylactic reactions during the qualifying food challenges before therapy, only 14 patients (9 omalizumab and 5 placebo) completed treatment. Of these, 4 (44.4%) omalizumabtreated subjects compared with 1 (20%) placebo-treated subject could tolerate more than 1000 mg peanut flour after 24 weeks, but this difference was not significant. Both these studies suggest that omalizumab may be beneficial for food allergy, but the findings are not conclusive. IMMUNOTHERAPY Standard subcutaneous immunotherapy (SCIT) for aeroallergens and venom has a risk of anaphylaxis. A recent review of the use of omalizumab with SCIT found that omalizumab therapy improved the safety of SCIT especially with rush therapy.45 Omalizumab therapy also improved the symptom relief seen with SCIT, but this improvement did not continue after the omalizumab was discontinued.45-47 These studies have not addressed the optimal pretreatment time for omalizumab to impart added safety to SCIT. A reasonable pretreatment based
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on the data to date suggests an 8- to 12-week course of omalizumab before allergen immunotherapy. None of these studies has examined whether it is safe to discontinue omalizumab and continue allergen immunotherapy in high-risk patients, for example, moderate to severe asthma. Recently, the use of oral immunotherapy for food allergy has demonstrated benefit in patients with milk, egg, and peanut allergy.48-50 The use of omalizumab to improve efficacy and safety has been evaluated in several studies. The data suggest that omalizumab may facilitate oral desensitization to peanut and milk.48,50 The addition of omalizumab has allowed children to successfully receive oral immunotherapy to multiple foods simultaneously, including milk, egg, peanut, wheat, soy, and tree nuts.51 In this open-label study, only 3 of the 25 children had total serum IgE level greater than 1500 kuA/L and received the maximum dose of omalizumab (600 mg every 2 weeks).
EOSINOPHILIC ESOPHAGITIS Eosinophilic esophagitis is another potential target for antiIgE therapy. In 2 case studies of patients with eosinophilic esophagitis and multiple food allergies, the addition of omalizumab reduced symptoms but did not improve endoscopic and histologic changes.52 A prospective randomized, double-blind, placebo-controlled trial of omalizumab therapy monthly for 16 weeks in patients with eosinophilic esophagitis who were either refractory to or relapsed after topical corticosteroids found no improvements in either eosinophils in the esophagus or symptom scores.53 It is unlikely that omalizumab will have a significant role in treating this disorder. MAST CELL DISORDERS A recent review on the use of omalizumab in mast cell disorders noted case studies of patients with mastocytosis, cutaneous mastocytosis and venom anaphylaxis, and mast cell activation syndrome showing improvement with omalizumab therapy.54 OTHER DISEASES Case reports and small studies have noted the benefit of omalizumab treatment in Churg-Strauss syndrome, bullous pemphigoid, Kimura’s disease, aspirin-exacerbated respiratory disease, recurrent anaphylaxis, laryngeal angioedema, chronic eosinophilic pneumonia, drug allergy, and vernal keratoconjunctivitis.55-63 CONCLUSIONS Omalizumab is the first of many immune response modifiers to be approved for the management of allergic diseases (Figure 1). Because of the critical role of IgE in the pathogenesis of allergic diseases, it is conceivable that approaches targeting other key TH2-driven mechanisms may fall short of the therapeutic utility demonstrated for omalizumab in the diseases discussed above. However, as we learn more about critical pathways involved in specific diseases and the characteristics of patients that predict positive benefits, it is likely that we will make advances in our judicious use of omalizumab and these other agents. Furthermore, the next generation of anti-IgE strategies will have important advantages over omalizumab such as a lack of limitations of dosing restrictions based on IgE levels. The strength of evidence points to omalizumab’s effectiveness in urticaria, and as an adjunct to allergen immunotherapy.
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Because of costs or dosing limitations, omalizumab will unlikely be widely used for the management of allergic rhinitis and atopic dermatitis and ABPA, respectively. More carefully designed, large clinical trials of high quality are needed to fully appreciate the potential of omalizumab and other anti-IgE strategies to treat the other allergic diseases discussed above as well as nonallergic asthma. As the utility of anti-IgE strategies is further explored for disorders other than allergic asthma, it is likely that increases in our understanding of the role of IgE in many disorders will be forthcoming. REFERENCES 1. Casale TB. Omalizumab for chronic urticaria. J Allergy Clin Immunol Pract 2014;2:118-9. 2. Khan DA. Alternative agents in refractory chronic urticaria: evidence and considerations on their selection and use. J Allergy Clin Immunol Pract 2013;1: 433-40.e1. 3. Maurer M, Altrichter S, Bieber T, Biedermann T, Bräutigam M, Seyfried S, et al. Efficacy and safety of omalizumab in patients with chronic urticaria who exhibit IgE against thyroperoxidase. J Allergy Clin Immunol 2011;128:202-9.e5. 4. Ferrer M, Gamboa P, Sanz ML, Goikoetxea MJ, Cabrera-Freitag P, Javaloyes G, et al. Omalizumab is effective in nonautoimmune urticaria. J Allergy Clin Immunol 2011;127:1300-2. 5. Groffik A, Mitzel-Kaoukhov H, Magerl M, Maurer M, Staubach P. Omalizumab—an effective and safe treatment of therapy-resistant chronic spontaneous urticaria. Allergy 2011;66:303-5. 6. Saini S, Rosen KE, Hsieh HJ, Wong DA, Conner E, Kaplan A, 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. 7. Saini SS, Bindslev-Jensen C, Maurer M, Grob JJ, Bülbül Baskan E, Bradley MS, et al. Efficacy and safety of omalizumab in patients with chronic idiopathic/spontaneous urticaria who remain symptomatic on H(1) antihistamines: a randomized, placebo-controlled study. J Invest Dermatol 2014.http:// dx.doi.org/10.1038/jid.2014.306. [Epub ahead of print]. 8. Maurer M, Rosén K, Hsieh HJ, Saini S, Grattan C, Gimenéz-Arnau A, et al. Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria. N Engl J Med 2013;368:924-35. 9. Kaplan A, Ledford D, Ashby M, Canvin J, Zazzali JL, Conner E, et al. Omalizumab in patients with symptomatic chronic idiopathic/spontaneous urticaria despite standard combination therapy. J Allergy Clin Immunol 2013;132:101-9. 10. Kaplan AP. Therapy of chronic urticaria: a simple, modern approach. Ann Allergy Asthma Immunol 2014;112:419-25. 11. Metz M, Ohanyan T, Church MK, Maurer M. Retreatment with omalizumab results in rapid remission in chronic spontaneous and inducible urticaria. JAMA Dermatol 2014;150:288-90. 12. Zuberbier T, Aberer W, Asero R, Bindslev-Jensen C, Brzoza Z, Canonica GW, et al. The EAACI/GA(2) LEN/EDF/WAO Guideline for the definition, classification, diagnosis, and management of urticaria: the 2013 revision and update. Allergy 2014;69:868-87. 13. Bernstein JA, Lang DM, Khan DA, Craig T, Dreyfus D, Hsieh F, et al. The diagnosis and management of acute and chronic urticaria: 2014 update. J Allergy Clin Immunol 2014;133:1270-7. 14. Xolair [package insert]. (revision); March 2014. 15. Chang TW, Chen C, Lin CJ, Metz M, Church MK, Maurer M. The potential pharmacologic mechanisms of omalizumab in patients with chronic spontaneous urticaria. J Allergy Clin Immunol 2014.http://dx.doi.org/10.1016/j.jaci.2014.04. 036. [Epub ahead of print]. 16. Lin H, Boesel KM, Griffith DT, Prussin C, Foster B, Romero FA, et al. Omalizumab rapidly decreases nasal allergic response and FcepsilonRI on basophils. J Allergy Clin Immunol 2004;113:297-302. 17. Beck LA, Marcotte GV, MacGlashan D, Togias A, Saini S. Omalizumabinduced reductions in mast cell Fcepsilon RI expression and function. J Allergy Clin Immunol 2004;114:527-30. 18. Metz M, Altrichter S, Ardelean E, Kessler B, Krause K, Magerl M, et al. Antiimmunoglobulin E treatment of patients with recalcitrant physical urticaria. Int Arch Allergy Immunol 2011;154:177-80. 19. Menzella F, Piro R, Facciolongo N, Castagnetti C, Simonazzi A, Zucchi L. Long-term benefits of omalizumab in a patient with severe non-allergic asthma. Allergy Asthma Clin Immunol 2011;7:9. 20. van den Berge M, Pauw RG, de Monchy JG, van Minnen CA, Postma DS, Kerstjens HA. Beneficial effects of treatment with anti-IgE antibodies
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