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. Author manuscript; available in PMC: 2012 Aug 1.
Published in final edited form as: Curr Opin Allergy Clin Immunol. 2011 Aug;11(4):355–360. doi: 10.1097/ACI.0b013e328348a882

Biologic Modulators in Allergic and Autoinflammatory Diseases

Lori Broderick 1, Louanne M Tourangeau 1, Arthur Kavanaugh 1, Stephen I Wasserman 1
PMCID: PMC3154953  NIHMSID: NIHMS313363  PMID: 21659854

Abstract

Purpose of review

The advent of molecular techniques has resulted in the ability to tailor medications to specific protein targets. This review will emphasize several biological therapies, specifically directed toward cytokine receptors and inhibitors, and their role in the treatment of atopic and autoinflammatory diseases.

Recent findings

Translational research and the identification of the molecular pathophysiology of diseases have led to more targeted treatment approaches. The biologic modulators, encompassing monoclonal antibodies as cytokine inhibitors, receptor blocking antibodies and new fusion receptors are now being applied to diseases beyond their original application.

Summary

The expanded use of biological therapies has experienced success in the treatment of numerous disorders, especially in subsets of patients with disease that has been refractory to conventional therapies.

Keywords: monoclonal antibodies, biologics, autoinflammatory, allergy

Introduction

The advent of molecular techniques has resulted in the ability to tailor medications to specific protein targets. Such therapies are known as biologic immunomodulators, or more commonly, biologics. Since their introduction, these therapies have been designed to specifically target the molecular pathways involved in the pathogenesis of various autoimmune and inflammatory disorders, as well as cancer. More recently, the use of monoclonal antibodies has been expanded to additional diseases, notably in patients with disease that has been unresponsive to conventional therapies. Several recent reviews have focused on the use of such agents in asthma [1] and other inflammatory conditions such as inflammatory bowel disease, lupus and rheumatoid arthritis [2, 3]. These disorders will not be discussed further here. In this review, we focus on the use of these novel therapies to treat diseases encountered by the allergist including allergic diseases, such as urticaria, allergic rhinitis, food allergy, hypereosinophilia syndromes, idiopathic anaphylaxis, and the autoinflammatory syndromes.

Receptor Blocking Agents

Anakinra, is a recombinant form of the naturally occurring IL-1 receptor antagonist. It functions as a competitive inhibitor of IL-1α and IL-1β binding to the IL-1 receptor (IL-1R), by binding to the same receptors without transducing signals. Initially approved for the treatment of rheumatoid arthritis, significant literature establishes the use of anakinra in a multitude of autoinflammatory syndromes which are driven by IL-1 [4**].

In autoinflammatory disorders, anakinra has been most extensively studied in cyropyrin-associated periodic syndromes (CAPS), a continuum of rare autoinflammatory disorders, specifically familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and neonatal onset multi-system inflammatory disorder (NOMID) [5**]. While these syndromes are of varying severity, the basis for their inflammatory pathology lies in IL-1β, and the blockade of IL-1 by anakinra has met with dramatic success in patients with CAPS, with reduction of symptoms, reduction of inflammatory markers and improvement in quality of life [4**]. Additional studies with anakinra have demonstrated improvement or resolution in patients with more progressive and long-term complications of CAPS, including hearing loss and renal disease due to amyloidosis [6, 7]. These benefits have led to the use of anakinra as standard of care in severe cases, namely NOMID, although the FDA approval remains restricted to rheumatoid arthritis.

More recently, a number of case reports and two small series have demonstrated the efficacy and safety of anakinra in patients with tumor necrosis factor receptor-associated periodic syndrome (TRAPS), a rare, autosomal dominant autoinflammatory disease, characterized by recurrent episodes of fever, myalgia, arthralgia, migrating rash and serositis [8]. The goals of treatment are prevention of acute attacks, limiting corticosteroid use, and controlling chronic inflammation to prevent amyloidosis. Despite its name, the use of TNF-blockers has not been met with the success initially anticipated, and other biological modifiers are under investigation. Obici et al. recently reported a series of 7 patients with TRAPS with persistent symptoms despite treatment with either daily prednisone or treatment with etanercept. In all patients, initiation of therapy with daily subcutaneous anakinra led to resolution of symptoms and normalization of CRP and serum amyloid A within the first month of treatment. Only one patient experienced breakthrough attacks requiring low dose prednisone. With an average of 22 months of follow-up, the remaining patients continued to maintain complete clinical response, with resolution of proteinuria and stabilization of renal function. All patients tolerated the daily injections well [9**].

Tocilizumab is a humanized monoclonal antibody against the IL-6 receptor, initially approved for the treatment of rheumatoid arthritis. As IL-6 is implicated in multiple immunologic disorders, the applicability of tocilizumab to other diseases has been under investigation. In a preliminary report of one patient with TRAPS, tocilizumab aborted an evolving attack and prevented further attacks of TRAPS during the 6-month treatment period. During anti-IL-6 therapy, the patient did not require corticosteroids and showed significant clinical improvement in symptoms and quality of life scores. Acute phase response reduced significantly with treatment [10]. Thrombocytopenia and neutropenia, along with elevations in lipoproteins and liver function tests are currently the most recognized side effects of tocilizumab.

Lumiliximab is a primatized macaque/human anti-CD23 monoclonal antibody. CD23, the low-affinity IgE receptor (FcεRII), is expressed on a wide variety of cells and has been implicated in IgE-mediated immune responses, the regulation of IgE synthesis, and stimulation of production of pro-inflammatory mediators from multiple cell types. Existing in both membrane and soluble forms, CD23 is believed to play an important role in allergic reactions. In vitro studies of peripheral blood mononuclear cells from patients with allergic rhinitis, and sensitization to cat and timothy grass, revealed a significant decrease in allergen mediated IL-5 secretion following treatment with lumiliximab [11]. An initial trial in allergic asthmatics demonstrated that lumiliximab had a favorable safety profile. Phase II trials in patients with allergic rhinitis are currently underway [12].

Cytokine Blocking Antibodies

Canakinumab is a human monoclonal antibody to IL-1β with a half-life that permits dosing frequency to be spaced to every 8 weeks. In a nearly year-long, three-phase trial of 35 CAPS patients, Lachmann et al. demonstrated that administration of canakinumab resulted in reduction of symptoms within the first 24 hours of treatment and complete response within the first month. Patients receiving canakinumab during the double-blind withdrawal period remained in remission, compared to 81% of patients in the placebo group who flared during the withdrawal period. One patient did have an infection, leading the authors to caution that vigilance in monitoring for infections remains an important consideration during immunomodulatory therapy [13].

Mepolizumab is a humanized murine IgG1 monoclonal antibody which binds to and inactivates IL-5, a cytokine involved in development and maintenance of eosinophil populations, and thus implicated in the pathogenesis of asthma, eosinophilic esophagitis, hyper-IgE syndrome (HIES) and hypereosinophilia syndromes (HES) [14**]. Mepolizumab has been shown to effectively reduce eosinophils in the peripheral blood for several weeks after infusion and reduce their recruitment into the airways after allergen challenge [14**]. Initial clinical trials in eosinophilic esophagitis have further demonstrated tolerability of mepolizumab, with a significant decrease in peripheral and esophageal tissue eosinophils, but limited improvement in symptoms has been observed, with one study demonstrating only 2/5 patients reporting improvement in swallowing after 2 months of therapy, compared to 1 of 6 controls [15*]. Experience with this agent in asthma suggests that a prolonged course of therapy is necessary to substantially deplete tissue eosinophils.

Mepolizumab has been investigated in hypereosinophilia-related diseases other than eosinophilic esophagitis, specifically HIES and HES. Published data, including one randomized, double-blind, placebo-controlled trial of 85 patients with HES, describing the use of mepolizumab in HIES have shown a similar decrease in peripheral eosinophilia, despite concomitant corticosteroid therapy and a positive response in quality of life measurements, and studies are ongoing [16].

Additional monoclonal antibodies targeting IL-5 (Reslizumab) or the primary producer of IL-5, eosinophils (alemtuzumab) are also under investigation in HES [17]. Reslizumab is a humanized rat IgG4 monoclonal antibody to IL-5 that is currently in trials for the treatment of pediatric eosinophilic esophagitis, asthma and nasal polyps, although reports of rebound eosinophilia may limit its use [18]. Alemtuzumab is a monoclonal antibody targeting the CD52 receptor present on eosinophils and, in case reports, has shown success in the treatment of refractory HES [17, 19], although its approval at this time remains limited to therapy for chronic lymphocytic leukemia. While these studies show promise for the use of anti-IL-5 therapy in these syndromes, further trials are indicated to elucidate the full beneficial effects and adverse events profile.

Fusion receptors

Improved understanding of cytokine signaling, has led to the development of biologic modifiers which competitively inhibit the binding of cytokines to their specific receptor, leading to inhibition of downstream signaling. This class of therapeutics is known as fusion receptors. Fusion receptors consist of two subsets of biologic modulators: protein-based cytokine inhibitors consisting of the cytokine receptor, and cytokine traps which consist of fusions between the Fc region of human IgG linked to the high affinity extracellular domains of two different cytokine receptor components involved in binding the cytokine [20].

Etanercept is a fusion protein between the type II TNF receptor and the Fc portion of human IgG which binds to and inhibits the action of TNF-α. Etanercept also binds TNF-β [21*]. It is the most widely studied anti-TNF therapy for TRAPS, but the results have been mixed [22]. Publications of multiple case reports and one small case series report some benefits in reducing steroid use in TRAPS patients but this response is highly variable and may not be sustained, as evidenced by a patient with progressive amyloidosis while on therapy [23]. Clearly the targeted therapies noted above appear to be more promising in this disorder.

Rilonacept is a fusion protein consisting of the extracellular portions of IL-1R and IL-1R accessory protein linked to the Fc portion of human IgG1, resulting in inhibition of IL-1β signaling. Additionally, rilonacept acts as a soluble decoy receptor that binds IL-1β, thereby preventing its interaction with cell surface receptors. Rilonacept also binds IL-1α and IL-1 receptor antagonist with reduced affinity [4**, 24]. Rilonacept was initially approved in 2008 for the treatment of CAPS, and notably, its pharmacologic profile permits reduction of the frequency of administration to weekly, in comparison to the daily dosing necessary for anakinra. In two Phase III, randomized, double-blind, placebo-controlled trials, Hoffman et al. demonstrated that weekly subcutaneous injections of rilonacept led to dramatic improvements in symptom scores and serum inflammatory markers in 44 patients with FCAS or MWS [25]. Rilonacept is currently under investigation for FMF.

Anti-Immunoglobulin-E

Omalizumab is a humanized, recombinant IgG1 antibody which binds to the Fc portion of circulating IgE. Treatment with omalizumab reduces cell surface levels of IgE and reduces the number of high affinity IgE receptors or FcεRI on the cell surface [26]. It was initially tested and approved for the treatment of allergic asthma, but it has subsequently been applied to the treatment of multiple atopic disorders.

Allergic rhinitis is clearly a target for anti-IgE therapy, and the efficacy of omalizumab has been investigated in several large clinical trials for both seasonal and perennial allergic rhinitis. These trials have demonstrated an improvement in daily symptoms, antihistamine use and in quality of life scores compared to placebo [27, 28]. Notably in one trial of 289 patients with long-standing symptoms of perennial allergic rhinitis, treatment with omalizumab led to improvement following the first dose, resulting in a two-fold improvement in quality of life scores over placebo. Over a 16-week trial, omalizumab was found to be well tolerated without serious adverse events [27]. It was also found to be safe in trials with patients simultaneously receiving subcutaneous immunotherapy [29] and some have advocated its use during the buildup phase of immunotherapy to diminish the risk of allergen-mediated anaphylaxis.

The ability of omalizumab to reduce the number of FcεR1 surface receptors has been exploited to expand its use to patients with urticaria. Several small studies have demonstrated a significant reduction in scores of pruritus, the number of hives and hive size, and reduction in antihistamine use by four weeks of therapy [30]. The successful use of omalizumab has been reported in other cases of urticaria on an individual basis including pressure urticaria [31], heat urticaria [32], cold urticaria and solar urticaria [33], but results in cholinergic urticaria have been variable [34]. This latter failure is to be expected as, in contrast to the other urticarial disorders, is not IgE mediated.

The use of omalizumab has also been investigated in steroid-dependent idiopathic anaphylaxis and systemic mastocytosis, each of which is characterized by recurrent episodes of anaphylaxis. Although the mechanism is unclear, it is postulated that the down regulation of FcεRI by omalizumab may prevent IgE cross-linking on mast cells and basophils, as well as binding free IgE. Several case reports have now demonstrated efficacy in reducing the number of anaphylactic episodes and minimizing steroid use in idiopathic anaphylaxis [28, 35]. In systemic mastocytosis, omalizumab has been shown to reduce the frequency of anaphylactic events [36]. Caution must be used, however, as there is a risk of anaphylaxis associated with the use of omalizumab itself which has led to a black-box warning from the FDA regarding its use [37]. The effect of omalizumab on food allergy symptoms has been observed in patients under treatment for moderate to severe persistent asthma [38]. On average in one study, by the sixth dose of omalizumab, all 22 patients reported an improvement in food-induced urticaria, food-induced rhinitis or food-induced angioedema. It must be emphasized, however, that these observations were made during an open label study during which the amount of allergic food intake was not strictly controlled. Double-blind, placebo-controlled trials are necessary before specific use of omalizumab can be recommended for treatment of food allergy.

Leung et al., investigated the utility of a second anti-IgE antibody, TNX-901, in patients with peanut allergy [39]. TNX-901 is a humanized monoclonal, IgG1 antibody which binds the C3 domain of IgE as well as circulating IgE [40]. In a double blind, placebo-controlled randomized, dose-based trial of 82 patients with confirmed immediate hypersensitivity to peanut, they demonstrated that the high level dose of TNX-901 significantly increased threshold sensitivity to peanut protein as determined by oral food challenge. They concluded that this increase, from approximately 0.5 to nearly 9 peanuts, would lead to partial protection against accidental ingestion. At the current time, TNX-901 remains experimental and future studies are needed to determine the role and feasibility of anti-IgE monoclonal antibody treatment of food allergies.

Limitations in the use of biologics

The increased and expanded use of monoclonal antibodies has met with new observations of adverse reactions that would not be unexpected from modulation of the immune system. The most commonly described adverse effects range from mild, such as infusion reactions for which prophylactic management is available and effective, to the more severe, including reactivation of latent tuberculosis, increased frequency of infection, blood dyscrasias and development of autoantibodies (Table 1). Given the difficulty in predicting these reactions, any use of immune system modulators should be performed with appropriate prudence. While this review exemplifies the breadth of possibilities for biologics in the treatment of human disease, many of the described uses are in preliminary stages and require additional evaluation. Larger studies are necessary to further elucidate the benefit versus risk ratio before recommending the use of monoclonal antibodies in more generalized treatment of allergic disease. Unfortunately, this field has been littered with agents demonstrating initial efficacy that have failed on further testing, further underscoring caution in this rapidly emerging area.

Table 1.

Summary of biologic immunomodulators under investigation for allergic diseases and autoinflammatory syndromes

Therapeutic agent Approved indications Under investigation Serious adverse effects
Anakinra (necombinant IL-1 Ra) Rheumatoid arthritis CAPS, TRAPS Injection site reactions, increased risk of infection [4,9**]
Tocilizumab (anti-IL-6R) Rheumatoid arthritis TRAPS, systemic onset JIA Thrombocytopenia, elevations in LFTs and lipoproteins [10]
Lumiliximab (anti-CD23/FcεRII) Not FDA approved Allergic rhinitis, asthma No serious adverse effects reported to date [11,12]
Canakinumab (anti-IL-1β) CAPS Gout Increased risk of infection, one reported episode of vertigo with acute glaucoma (complication of CAPS) [13]
Mepolizumab (anti-IL-5) Not FDA approved Eosinophilic esophagitis, HIES, HES No serious adverse effects reported to date [17]
Reslizumab (anti-IL-5) Not FDA approved Eosinophilic esophagitis, asthma, nasal polyps Rebound eosinophilia [18]
Alemtuzumab (anti-CD52) B-cell chronic lymphocyte leukemia HES Infusion reactions, cytopenias, cytomegalovirus reactivation and lymphoma have been reported in treatment of leukemia [19]
Etanercept (anti-TNF-α) Rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis TRAPS Infection, active tuberculosis, malignancy [21*]
Rilonacept (IL-1 trap) CAPS FMF Injection site reactions [25]
Omalizumab (anti-IgE) Moderate to severe persistent asthma Allergic rhinitis, urticaria, food allergy, mastocytosis idiopathic anaphylaxis Anaphylaxis, injection site reaction, viral/upper respiratory tract infection, Churg–Strauss syndrome [37]
TNX-901 (anti-IgE) Not FDA approved Food allergy Gastrointestinal symptoms, food allergy (to any food, patient-reported, not related to oral food challenges) [39]
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CAPS, cyropyrin-associated periodic syndromes; FMF, familial Mediterranean fever; HES, hypereosinophilia syndrome; HIES, hyper IgE syndrome; JIA, juvenile idiopathic arthritis; LFTs, liver function tests; TNF, tumor necrosis factor; TRAPS, tumor necrosis factor receptor-associated periodic syndrome.

Conclusions

The ability to screen for mutations in inflammatory syndromes has led to a greater understanding of the pathophysiology behind symptoms and offered opportunities for new therapeutics. Treatment of the CAPS family of diseases is a primary example of progression from phenotypic description of patients to identification of genetic mutations and protein products which were amenable to drug targeting. Further advances in genetic engineering and the modification to humanize antibodies has led to increased serum half-lives of the agents and thus reduced frequency of injections, in addition to decreasing their potential immunogenicity by decreasing the content of foreign material [41]. One would anticipate that continued expansion of our understanding of the human genome and the desire for individualized treatments will lead to the development of additional immunomodulatory therapies, and to novel uses for currently available agents. Ultimately, although the use of monoclonal antibodies has experienced success in the treatment of numerous disorders, especially in patients with disease that has been refractory to conventional therapies, one must remain cautious due to the potential adverse effects from modulation of the immune system.

Key Points

  • The ability to screen for mutations in inflammatory syndromes has led to a greater understanding of the pathophysiology behind symptoms and offered opportunities for new therapeutics which specifically target the mediators of disease.

  • The use of existing biologic modulators has been successfully expanded to the treatment of other allergic and inflammatory diseases.

  • More widespread and prolonged use of immunomodulatory treatments may raise new safety concerns, and caution should be used when employing these therapeutic agents.

Acknowledgements

The authors acknowledge NIH training grant, T32 A107469, for supporting Lori Broderick, MD, PhD and Louanne M. Tourangeau, MD during their fellowship training. Dr. Wasserman has received grant support from Merck.

Financial Disclosures: NIH Training Grant T32 A107469 supports Dr. Broderick and Dr. Tourangeau during their fellowship training. Dr. Wasserman has received grant support from Merck.

Abbreviations

CAPS

cyropyrin-associated periodic syndromes

CRP

C-reactive protein

FCAS

familial cold autoinflammatory syndrome

FMF

Familial Mediterranean Fever

HES

hypereosinophilia syndrome

HIES

hyper IgE syndrome

IL

interleukin

JIA

juvenile idiopathic arthritis

LFTs

liver function tests

MWS

Muckle-Wells syndrome

NOMID

neonatal onset multi-system inflammatory disorder

TNF

tumor necrosis factor

TRAPS

tumor necrosis factor receptor-associated periodic syndrome

Footnotes

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References and Recommended Reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

* of special interest

** of outstanding interest

  • *1.Tourangeau LM, Kavanaugh A, Wasserman SI. Ther Adv Respir Dis. 2011. The Role of Monoclonal Antibodies in the Treatment of Severe Asthma. In press. [DOI] [PubMed] [Google Scholar]; This review highlights many of the current and developing therapies for asthmatics.
  • 2.Lee S, Ballow M. Monoclonal antibodies and fusion proteins and their complications: targeting B cells in autoimmune diseases. J Allergy Clin Immunol. 2010;125(4):814–20. doi: 10.1016/j.jaci.2010.02.025. [DOI] [PubMed] [Google Scholar]
  • 3.Hashkes PJ, Uziel Y, Laxer RM. The safety profile of biologic therapies for juvenile idiopathic arthritis. Nat Rev Rheumatol. 2010;6(10):561–71. doi: 10.1038/nrrheum.2010.142. [DOI] [PubMed] [Google Scholar]
  • **4.Hoffman HM. Therapy of autoinflammatory syndromes. J Allergy Clin Immunol. 2009;124(6):1129–38. doi: 10.1016/j.jaci.2009.11.001. [DOI] [PMC free article] [PubMed] [Google Scholar]; An excellent review of immunomodulatory therapy for autoinflammatory syndromes with a focus on anti-IL-1 treatments.
  • **5.Masters SL, Simon A, Aksentijevich I, Kastner DL. Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease. Annu Rev Immunol. 2009;27:621–68. doi: 10.1146/annurev.immunol.25.022106.141627. [DOI] [PMC free article] [PubMed] [Google Scholar]; A thorough review of autoinflammation inclusive of genetics and molecular pathophysiology.
  • 6.Lepore L, Paloni G, Caorsi R, et al. Follow-up and quality of life of patients with cryopyrin-associated periodic syndromes treated with Anakinra. J Pediatr. 2010;157(2):310–5. doi: 10.1016/j.jpeds.2010.02.040. [DOI] [PubMed] [Google Scholar]
  • 7.Neven B, Marvillet I, Terrada C, et al. Long-term efficacy of the interleukin-1 receptor antagonist anakinra in ten patients with neonatal-onset multisystem inflammatory disease/chronic infantile neurologic, cutaneous, articular syndrome. Arthritis Rheum. 2010;62(1):258–67. doi: 10.1002/art.25057. [DOI] [PubMed] [Google Scholar]
  • 8.Hoffman HM, Simon A. Recurrent febrile syndromes: what a rheumatologist needs to know. Nat Rev Rheumatol. 2009;5(5):249–56. doi: 10.1038/nrrheum.2009.40. [DOI] [PubMed] [Google Scholar]
  • **9.Obici L, Meini A, Cattalini M, et al. Ann Rheum Dis. 2010. Favourable and sustained response to anakinra in tumour necrosis factor receptor-associated periodic syndrome (TRAPS) with or without AA amyloidosis. doi:10.1136/ard.2010.143438. [DOI] [PubMed] [Google Scholar]; The first large series of TRAPS patients treated with anakinra.
  • 10.Vaitla PM, Radford PM, Tighe PJ, et al. Arthritis Rheum. Jan 10, 2011. Role of interleukin-6 (IL-6) in a patient with TRAPS revealed by treatment with tocilizumab (anti-IL-6 receptor monoclonal antibody) doi.org/10.1002/art.30215. [DOI] [PubMed] [Google Scholar]
  • 11.Poole JA, Meng J, Reff M, et al. Anti-CD23 monoclonal antibody, lumiliximab, inhibited allergen-induced responses in antigen-presenting cells and T cells from atopic subjects. J Allergy Clin Immunol. 2005;116(4):780–8. doi: 10.1016/j.jaci.2005.07.007. [DOI] [PubMed] [Google Scholar]
  • 12.Rosenwasser LJ, Meng J. Anti-CD23. Clin Rev Allergy Immunol. 2005;29(1):61–72. doi: 10.1385/CRIAI:29:1:061. [DOI] [PubMed] [Google Scholar]
  • 13.Lachmann HJ, Kone-Paut I, Kuemmerle-Deschner JB, Leslie KS, Hachulla E, Quartier P, et al. Use of canakinumab in the cryopyrin-associated periodic syndrome. N Engl J Med. 2009;360(23):2416–25. doi: 10.1056/NEJMoa0810787. [DOI] [PubMed] [Google Scholar]
  • **14.Busse WW, Ring J, Huss-Marp J, Kahn JE. A review of treatment with mepolizumab, an anti-IL-5 mAb, in hypereosinophilic syndromes and asthma. J Allergy Clin Immunol. 2010;125(4):803–13. doi: 10.1016/j.jaci.2009.11.048. [DOI] [PubMed] [Google Scholar]; Review of the role of IL-5 and potential for therapy of hypereosinophilia and asthma with mepolizumab.
  • *15.Straumann A, Conus S, Grzonka P, et al. Anti-interleukin-5 antibody treatment (mepolizumab) in active eosinophilic oesophagitis: a randomised, placebo-controlled, double-blind trial. Gut. 2010;59(1):21–30. doi: 10.1136/gut.2009.178558. [DOI] [PubMed] [Google Scholar]; A well designed study demonstrating that anti-IL-5 treatment leads to significant decrease in peripheral and esophageal tissue eosinophils, but with limited symptomatic improvement.
  • 16.Rothenberg ME, Klion AD, Roufosse FE, et al. Treatment of patients with the hypereosinophilic syndrome with mepolizumab. N Engl J Med. 2008;358(12):1215–28. doi: 10.1056/NEJMoa070812. [DOI] [PubMed] [Google Scholar]
  • 17.Schwartz LB, Sheikh J, Singh A. Current strategies in the management of hypereosinophilic syndrome, including mepolizumab. Curr Med Res Opin. 2010;26(8):1933–46. doi: 10.1185/03007995.2010.493132. [DOI] [PubMed] [Google Scholar]
  • 18.Rosenwasser LJ, Rothenberg ME. IL-5 pathway inhibition in the treatment of asthma and Churg-Strauss syndrome. J Allergy Clin Immunol. 2010;125(6):1245–6. doi: 10.1016/j.jaci.2010.04.022. [DOI] [PubMed] [Google Scholar]
  • 19.Verstovsek S, Tefferi A, Kantarjian H, et al. Alemtuzumab therapy for hypereosinophilic syndrome and chronic eosinophilic leukemia. Clin Cancer Res. 2009;15(1):368–73. doi: 10.1158/1078-0432.CCR-08-1302. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Economides AN, Carpenter LR, Rudge JS, et al. Cytokine traps: multi-component, high-affinity blockers of cytokine action. Nat Med. 2003;9(1):47–52. doi: 10.1038/nm811. [DOI] [PubMed] [Google Scholar]
  • *21.Lee SJ, Chinen J, Kavanaugh A. Immunomodulator therapy: monoclonal antibodies, fusion proteins, cytokines, and immunoglobulins. J Allergy Clin Immunol. 2010;125(2 Suppl 2):S314–23. doi: 10.1016/j.jaci.2009.08.018. [DOI] [PubMed] [Google Scholar]; Review of additional immunomodulator therapies with thorough discussion on their nomenclature, development and structure.
  • 22.Church LD, Churchman SM, Hawkins PN, McDermott MF. Hereditary auto-inflammatory disorders and biologics. Springer Semin Immunopathol. 2006;27(4):494–508. doi: 10.1007/s00281-006-0015-6. [DOI] [PubMed] [Google Scholar]
  • 23.Simsek I, Kaya A, Erdem H, et al. No regression of renal amyloid mass despite remission of nephrotic syndrome in a patient with TRAPS following etanercept therapy. J Nephrol. 2010;23(1):119–23. [PubMed] [Google Scholar]
  • 24.Hoffman HM. Rilonacept for the treatment of cryopyrin-associated periodic syndromes (CAPS) Expert Opin Biol Ther. 2009;9(4):519–31. doi: 10.1517/14712590902875518. [DOI] [PubMed] [Google Scholar]
  • 25.Hoffman HM, Throne ML, Amar NJ, et al. Efficacy and safety of rilonacept (interleukin-1 Trap) in patients with cryopyrin-associated periodic syndromes: results from two sequential placebo-controlled studies. Arthritis Rheum. 2008;58(8):2443–52. doi: 10.1002/art.23687. [DOI] [PubMed] [Google Scholar]
  • 26.Milgrom H, Fick RB, Jr., Su JQ, et al. Treatment of allergic asthma with monoclonal anti-IgE antibody. rhuMAb-E25 Study Group. N Engl J Med. 1999;341(26):1966–73. doi: 10.1056/NEJM199912233412603. [DOI] [PubMed] [Google Scholar]
  • 27.Chervinsky P, Casale T, Townley R, et al. Omalizumab, an anti-IgE antibody, in the treatment of adults and adolescents with perennial allergic rhinitis. Ann Allergy Asthma Immunol. 2003;91(2):160–7. doi: 10.1016/S1081-1206(10)62171-0. [DOI] [PubMed] [Google Scholar]
  • 28.Casale TB, Stokes J. Anti-IgE therapy: clinical utility beyond asthma. J Allergy Clin Immunol. 2009;123(4):770–1. e1. doi: 10.1016/j.jaci.2009.02.016. [DOI] [PubMed] [Google Scholar]
  • 29.Kamin W, Kopp MV, Erdnuess F, et al. Safety of anti-IgE treatment with omalizumab in children with seasonal allergic rhinitis undergoing specific immunotherapy simultaneously. Pediatr Allergy Immunol. 2010;21(1 Pt 2):e160–5. doi: 10.1111/j.1399-3038.2009.00900.x. [DOI] [PubMed] [Google Scholar]
  • 30.Magerl M, Staubach P, Altrichter S, et al. Effective treatment of therapy-resistant chronic spontaneous urticaria with omalizumab. J Allergy Clin Immunol. 2010;126(3):665–6. doi: 10.1016/j.jaci.2010.05.047. [DOI] [PubMed] [Google Scholar]
  • 31.Bindslev-Jensen C, Skov PS. Efficacy of omalizumab in delayed pressure urticaria: a case report. Allergy. 2010;65(1):138–9. doi: 10.1111/j.1398-9995.2009.02188.x. [DOI] [PubMed] [Google Scholar]
  • 32.Bullerkotte U, Wieczorek D, Kapp A, Wedi B. Effective treatment of refractory severe heat urticaria with omalizumab. Allergy. 2010;65(7):931–2. doi: 10.1111/j.1398-9995.2009.02268.x. [DOI] [PubMed] [Google Scholar]
  • 33.Metz M, Altrichter S, Ardelean E, et al. Anti-immunoglobulin E treatment of patients with recalcitrant physical urticaria. Int Arch Allergy Immunol. 2011;154(2):177–80. doi: 10.1159/000320233. [DOI] [PubMed] [Google Scholar]
  • 34.Sabroe RA. Failure of omalizumab in cholinergic urticaria. Clin Exp Dermatol. 2010;35(4):e127–9. doi: 10.1111/j.1365-2230.2009.03748.x. [DOI] [PubMed] [Google Scholar]
  • 35.Pitt TJ, Cisneros N, Kalicinsky C, Becker AB. Successful treatment of idiopathic anaphylaxis in an adolescent. J Allergy Clin Immunol. 2010;126(2):415–6. doi: 10.1016/j.jaci.2010.05.043. [DOI] [PubMed] [Google Scholar]
  • 36.Kontou-Fili K, Filis CI, Voulgari C, Panayiotidis PG. Omalizumab monotherapy for bee sting and unprovoked “anaphylaxis” in a patient with systemic mastocytosis and undetectable specific IgE. Ann Allergy Asthma Immunol. 2010;104(6):537–9. doi: 10.1016/j.anai.2010.04.011. [DOI] [PubMed] [Google Scholar]
  • 37.Dreyfus DH, Randolph CC. Characterization of an anaphylactoid reaction to omalizumab. Ann Allergy Asthma Immunol. 2006;96(4):624–7. doi: 10.1016/S1081-1206(10)63560-0. [DOI] [PubMed] [Google Scholar]
  • 38.Rafi A, Do LT, Katz R, et al. Effects of omalizumab in patients with food allergy. Allergy Asthma Proc. 2010;31(1):76–83. doi: 10.2500/aap.2010.31.3304. [DOI] [PubMed] [Google Scholar]
  • 39.Leung DYM, Sampson HA, Yunginger JW, et al. Effect of anti-IgE therapy in patients with peanut allergy. 2003;348:986–993. doi: 10.1056/NEJMoa022613. [DOI] [PubMed] [Google Scholar]
  • 40.Brownell J, Casale TB. Anti-IgE therapy. Immunol Allergy Clin North Am. 2004;24(4):551–68. doi: 10.1016/j.iac.2004.06.002. [DOI] [PubMed] [Google Scholar]
  • 41.Weiner LM, Surana R, Wang S. Monoclonal antibodies: versatile platforms for cancer immunotherapy. Nat Rev Immunol. 2010 May;10(5):317–27. doi: 10.1038/nri2744. [DOI] [PMC free article] [PubMed] [Google Scholar]

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