Correspondence

Treatment of Allergic Asthma with Monoclonal Anti-IgE Antibody

N Engl J Med 2000; 342:1292-1293April 27, 2000

Article

To the Editor:

Milgrom et al. (Dec. 23 issue)1 report on the treatment of allergic asthma with monoclonal IgE antibody. It has generally been accepted that IgE has a central role in the pathogenesis of anaphylaxis, allergic rhinitis, and asthma. However, several recent studies seem to question this concept.

Although the role of IgE has been best characterized in the pathogenesis of anaphylaxis and allergic rhinitis, acute anaphylaxis after allergen sensitization has been reported in the absence of IgE in laboratory animals.2 Casale et al.3 demonstrated that use of humanized anti-IgE monoclonal antibody in ragweed-sensitive patients with allergic rhinitis, both before and during the pollen season, did not improve symptom scores, even though it greatly reduced circulating concentrations of free IgE.

Furthermore, the exact role of IgE in the pathogenesis of asthma remains uncertain. Recent studies have shown that the mechanisms underlying the experimental asthma phenotype are largely independent of IgE antibody.4,5 Glucocorticoids and β₂-adrenergic–receptor agonists, the most effective drugs for the treatment of asthma, reduce symptoms and improve lung function and inflammatory indexes. However, both these drugs have been shown to increase IgE levels in vivo as well as in vitro in patients with asthma, despite an improvement in symptoms.6,7 These findings suggest that the exact role of IgE in allergic disorders, particularly asthma, is not fully understood, and it seems likely that an increased concentration of IgE is an unrelated epiphenomenon.6

Milgrom et al. report that a recombinant humanized monoclonal antibody against IgE greatly reduces circulating concentrations of IgE in subjects with moderate asthma and also improves the symptoms of asthma. On close scrutiny, however, the effect of the drug on symptom scores appears to be only marginally better than that of placebo. In the absence of any significant changes in objective measures, such as standard tests of lung function (forced expiratory volume in one second and peak expiratory flow) after treatment with anti-IgE antibody, and in view of the findings in the other studies we have cited, we suggest that the results of this study be interpreted with caution.

Sundeep S. Salvi, M.D., Ph.D.
K. Suresh Babu, M.D., D.N.B.
Southampton General Hospital, Southamptom SO16 6YD, United Kingdom

7 References

1. 1

   Milgrom H, Fick RB, Su JQ, et al. Treatment of allergic asthma with monoclonal anti-IgE antibody. N Engl J Med 1999;341:1966-1973
   Full Text | Web of Science | Medline

2. 2

   Oettgen HC, Martin TR, Wynshaw-Boris A, Deng C, Drazen JM, Leder P. Active anaphylaxis in IgE-deficient mice. Nature 1994;370:367-370
   CrossRef | Web of Science | Medline

3. 3

   Casale TB, Bernstein IL, Busse WW, et al. Use of an anti-IgE humanized monoclonal antibody in ragweed-induced allergic rhinitis. J Allergy Clin Immunol 1997;100:110-121
   CrossRef | Web of Science | Medline

4. 4

   Hogan SP, Mould A, Kikutani H, Ramsay AJ, Foster PS. Aeroallergen-induced eosinophilic inflammation, lung damage, and airways hyperreactivity in mice can occur independently of IL-4 and allergen-specific immunoglobulins. J Clin Invest 1997;99:1329-1339
   CrossRef | Web of Science | Medline

5. 5

   Tournoy KG, Kips JC, Schou C, Pauwels RA. Airway eosinophilia is not a requirement for allergen-induced airway hyperresponsiveness. Clin Exp Allergy 2000;30:79-85
   CrossRef | Web of Science | Medline

6. 6

   Zieg G, Lack G, Harbeck RJ, Gelfand EW, Leung DY. In vivo effects of glucocorticoids on IgE production. J Allergy Clin Immunol 1994;94:222-230
   CrossRef | Web of Science | Medline

7. 7

   Coqueret O, Dugas B, Mencia-Huerta JM, Braquet P. Regulation of IgE production from human mononuclear cells by beta 2-adrenoceptor agonists. Clin Exp Allergy 1995;25:304-311
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: We agree with Drs. Salvi and Babu that the exact role of IgE in allergic disease has yet to be fully understood. Yet it is beyond dispute that IgE causes disease, as shown by the classic passive-transfer experiment of Prausnitz and Küstner.1 Although the role of IgE may vary in individual patients, it is critical for the development of bronchial hyperresponsiveness, a risk factor for asthma, in children. This heightened bronchoconstrictor response to a variety of stimuli is closely related to serum IgE levels.2

Experimental evidence supports the role of anti-IgE antibody in suppressing allergic disease and asthma. Heusser et al. demonstrated that anti-IgE antibody inhibits antigen-induced bronchoconstriction, bronchial hyperresponsiveness, and the infiltration of eosinophils into the lungs in sensitized mice.3 Fahy et al. reported that the use of anti-IgE monoclonal antibody in subjects with asthma resulted in the attenuation of both early- and late-phase responses to airway challenge with allergen and the reduction of eosinophil counts in induced sputum samples.4 Casale et al. showed that the improvement in symptoms of seasonal allergic rhinitis with the use of anti-IgE monoclonal antibody is related to the reduction in free IgE concentrations.5

Not surprisingly, the results of our study were not uniform; some patients had a striking improvement, and others more modest relief. Still, the entire group of subjects who received anti-IgE monoclonal antibody had significant improvements in asthma symptoms and quality-of-life scores, a reduction in the number of asthma exacerbations, a sustained improvement in the peak expiratory flow rate despite the withdrawal of corticosteroids, and a reduction in the use of inhaled and oral corticosteroids without an increase in the use of rescue medication. The subjects were already receiving daily corticosteroids (oral, inhaled, or both) and β-agonists as needed.

Our data not only support the value of anti-IgE therapy in patients with asthma but also provide indirect evidence of the role of IgE in the pathogenesis of this heterogeneous disease.6

Henry Milgrom, M.D.
National Jewish Medical and Research Center, Denver, CO 80206

Robert B. Fick, Jr., M.D.
Genentech, South San Francisco, CA 94080-2018

W. James Metzger, M.D.
East Carolina University School of Medicine, Greenville, NC 27858

6 References

1. 1

   Prausnitz C, Kustner H. Studien über die Ueberempfindlichkeit. Zentralbl Bakteriol 1921;86:160-169
   

2. 2

   Burrows B, Martinez FD, Halonen M, Barbee RA, Cline MG. Association of asthma with serum IgE levels and skin-test reactivity to allergens. N Engl J Med 1989;320:271-277
   Full Text | Web of Science | Medline

3. 3

   Heusser CH, Wagner K, Bews JP, et al. Demonstration of the therapeutic potential of non-anaphylactogenic anti-IgE antibodies in murine models of skin reaction, lung function and inflammation. Int Arch Allergy Immunol 1997;113:231-235
   CrossRef | Web of Science | Medline

4. 4

   Fahy JV, Fleming HE, Wong HH, et al. The effect of an anti-IgE monoclonal antibody on the early- and late-phase responses to allergen inhalation in asthmatic subjects. Am J Respir Crit Care Med 1997;155:1828-1834
   Web of Science | Medline

5. 5

   Casale T, Racine A, Sallas A, Fowler Taylor A, Gupta N, Rohane P. Relationship between the clinical efficacy of rhuMAb-E25 (E25) and serum free IgE in seasonal allergic rhinitis. J Allergy Clin Immunol 2000;104:S357-S357 abstract.
   CrossRef | Web of Science

6. 6

   Barnes PJ. Anti-IgE antibody therapy for asthma. N Engl J Med 1999;341:2006-2008
   Full Text | Web of Science | Medline

Citing Articles (3)

Citing Articles

1. 1

   Mitchell Berger, Vidya Shankar, Abbas Vafai. (2002) Therapeutic Applications of Monoclonal Antibodies. The American Journal of the Medical Sciences 324:1, 14-30
   CrossRef

2. 2

   K Suresh Babu, Stephen T Holgate, S Hasan Arshad. (2001) Omalizumab, a novel anti-IgE therapy in allergic disorders. Expert Opinion on Biological Therapy 1:6, 1049-1058
   CrossRef

3. 3

   S. S. Salvi, K. S. Babu, S. T. Holgate. (2000) Glucocorticoids enhance IgE synthesis. Are we heading towards new paradigms?. Clinical <html_ent glyph="@amp;" ascii="&"/> Experimental Allergy 30:11, 1499-1505
   CrossRef