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World Allergy Organization
WAO's mission: To be a global resource and advocate in the field of allergy, advancing excellence in clinical care through education, research and training as a world-wide alliance of allergy and clinical immunology societies.

The Application of Monoclonal Therapies and Therapeutics to Asthma and Allergy

Adverse Effects in the Application of Biotechnology

Jean Bousquet & Marc Humbert
University Hospital and INSERM, Montpellier
and University Hospital, Clamart
Montpellier, France

Since the 1986 regulatory approval of muromonomab-CD3, a mouse monoclonal antibody (MAb) directed against the T cell CD3ε antigen, MAbs have become an increasingly important class of therapeutic compounds in a variety of disease areas ranging from cancer, autoimmune, infectious and cardiac diseases as well as asthma. The limitation of murine mAbs due to immunogenicity was overcome by replacement of the murine sequences with their human counterpart leading to the development of chimeric, humanized, and human therapeutic MAb (1, 2). Remarkable progress has also been made following the development of the display technologies, enabling engineering of antibodies with modified properties such as molecular size, affinity, specificity, and valency. Moreover, antibody engineering technologies are constantly advancing to enable further tuning of the effector function and serum half life. Optimal delivery to the target tissue still remains to be addressed to avoid unwanted side effects as a result of systemic treatment while achieving meaningful therapeutic effect.

Other biological agents-like cytokines and fusion proteins as treatment modalities for a number of immune mediated and malignant diseases has also yielded great promise, but there are very few trials in asthma.

1- Efficacy of biologics: from concept to asthma

Anti-IgE MAb
Immunoglobulin E (IgE) is increasingly recognized as a key component of asthma pathophysiology and contributes to both the early- and late-phase inflammatory cascade of the airways by inhibiting allergen-induced activation of mast cells. Omalizumab binds free IgE and inhibits mast-cell degranulation. By reducing free IgE, omalizumab also downregulates FcεRI on basophils and mast cells (3-5). These dual effects of omalizumab are important, since without FcεRI downregulation almost complete removal of free IgE would be necessary to elicit functional consequences on mast cells and basophils. Moreover, unexpectedly, omalizumab considerably decreases the overall airways inflammation in asthma (6).

In patients with allergic asthma, omalizumab significantly reduces both the early phase and late phase asthmatic response to allergen challenge (7). A large number of randomized trials demonstrated that omalizumab is effective in reducing asthma symptoms and improving quality-of-life while reducing the need for inhaled corticosteroids (8). In patients with severe uncontrolled allergic asthma, omalizumab reduces severe exacerbations and hospitalizations (9-11), and the biologic is approved by both FDA and EMEA. Moreover, it has been suggested that the effect may persist after treatment (12).

Anti-CD4 MAb
CD4+ T-cells are likely to be involved as a source of pro-inflammatory cytokines in asthma. Keliximab, an anti-CD4 MAb, leads to a transient reduction in the number of CD4+ T-cells and modulation of CD4+ receptor expression in severe asthmatics. The effects of keliximab may be mediated through a decrease in CD4+ surface expression and T-lymphocyte numbers, in addition to a reduction in allergen-induced proliferation (13). However, the clinical effects were modest (14) and the development of the MAb was stopped.

Anti-IL-5 MAb
Eosinophilia in atopic diseases and hypereosinophilic syndrome are often associated with a high expression of interleukin-5 (IL-5). IL-5 plays an important role in regulating the production, differentiation, recruitment, activation, and survival of eosinophils. Therefore, neutralizing IL-5 with an antibody was a promising therapeutic strategy in eosinophilic diseases (15). A very large number of animal studies proposed that anti-IL-5 MAb could be an effective asthma treatment (16). A first study using bronchial challenge did not show any efficacy in the late phase reaction and non-specific bronchial hyperreactivity following challenge (17). Mepolizumab treatment does not appear to add significant clinical benefit in patients with asthma with persistent symptoms despite inhaled corticosteroid therapy (18). These studies may indicate that eosinophil recruitment is not only driven by IL-5 (19) or that eosinophils do not have the major role proposed (20). However, the effects of IL-5 appear to be mainly in the circulation, inducing peripheral mobilization of eosinophils to the circulation without less effect on eosinophil mobilization in the lungs (21).

Moreover, the role of anti-IL-5 MAb may not be totally ruled out since it was found that remodeling may be reduced by anti-IL-5 MAb (22). Moreover, in patients with hypereosinophilic syndrome (23) and eosinophilic esophagitis, anti-IL-5 MAb resulted in an improvement of symptoms (15). Some patients with very high eosinophilic inflammation and nasal polyps may also benefit from anti-IL-5 MAb (24, 25). Further studies are needed to investigate the effect of mepolizumab on exacerbation rates, using protocols specifically tailored to patients with asthma with persistent airway eosinophilia.

Anti-IL-4 biologics
Increases in T helper (Th) 2 cytokine concentrations have been seen in atopic asthma, with IL-4 and IL-13 thought to have a role in asthma and studies in animals suggest a role for this target (26). Although initial studies targeting IL-4 were disappointing (27, 28), a new study with a double inhibition may be more promising. Pitrakinra, an IL-4 variant that targets allergic Th2 inflammation by potently inhibiting the binding of IL-4 and IL-13 to IL-4Rα receptor complexes, was found to have some effect in phase 2 trials in asthma (29).

Anti-TNFα biologics
It has been suggested that some of the features of severe asthma might be due to upregulation of the tumor necrosis factor-α (TNF-α) pathway. In support of this, studies have shown that severe asthma is associated with an increased presence of TNF-α within the airway and an increase in TNF-α expression on peripheral blood mononuclear cells. Moreover, TNF-α has the ability to induce several of the pro-inflammatory changes associated with severe asthma, including neutrophilic inflammation (30). Interest in the role of TNF-α in severe asthma has increased following a small cross-over clinical trial (31) and an open study which have suggested that ethanercept is effective in asthma (32). However, a large randomized clinical trial using golumimab in patients with severe asthma did not confirm these optimistic results.

2- Safety of biologics

Biological agents-like cytokines, MAb and fusion proteins can cause a great variety of adverse side-effects. Based on the peculiar features of biological agents a new classification of these adverse side-effects of biological agents was proposed - related but clearly distinct from the classification of side-effects observed with chemicals and drugs. This classification differentiated five distinct types, namely clinical reactions because of high cytokine levels (type α), hypersensitivity because of an immune reaction against the biological agent (β), immune or cytokine imbalance syndromes (γ), symptoms because of cross-reactivity (δ) and symptoms not directly affecting the immune system (ε) (33) (Figure 1). This classification could help to better deal with the clinical features of these side-effects, to identify possible individual and general risk factors and to direct research in this novel area of medicine.

Figure 1
Figure 1: Classification of adverse side effects of biological agents (33)

Hypersensitivity reactions
Monoclonal antibodies can be derived from several sources: murine antibodies (e.g. OKT-3), chimeric (e.g. infliximab), humanized (e.g. omalizumab) or human (e.g. adalimumab). Two forms of reactions have been identified: acute and delayed. They appear to be related to the presence of antibodies to the MAb (against murine (34) or human components), but many reactions do not appear to be anaphylactic (IgE mediated) (33, 35).

TNF-α antagonists (infliximab, etanercept, adalimumab) are widely used in rheumatoid arthritis and several other inflammatory diseases. Both immediate and delayed adverse reactions have been described, suggesting type I and T cell-mediated mechanisms (36 ). These reactions even occur in children (37). Mild to moderate reactions following injection occur in 29 .3% patients with etanercept (38 ) and 15 .3% with adalimumab (39, 40). Some studies describe histological findings of a cell-mediated Th1 reaction, with CD8+ T cells composing the majority of the dermal infiltrate (41). Histological features of eosinophilic cellulitis as a response to etanercept suggest a Th2-mediated phenomenon (42). Immediate positive skin tests against ethanercept have only been demonstrated recently (43 ). Adalimumab, a human mAb against TNF-α, was not found to induce anaphylactic reactions and can be used in patients allergic to infliximab (44). However, delayed type reactions were observed using intra-dermal skin tests (43).

Like nearly all systemic cancer therapies, MAbs are associated with hypersensitivity reactions (45). Severe hypersensitivity reactions are rare, with an incidence of ≤5%. Reactions to taxanes and monoclonal antibodies are generally immediate, occurring during the first few minutes of the first or second infusion. However, 10%-30% of reactions to MAbs are delayed, and may occur in later infusions, indicating the importance of close observation of the patient following administration. Mild-to-moderate reactions can be managed by temporary infusion interruption, reduction of the infusion rate, and symptom management. Rechallenge should be considered after complete resolution of all symptoms. Severe reactions may require treatment discontinuation.

Cetuximab, a chimeric anti-epidermal growth factor receptor MAb currently used to treat metastatic colorectal cancer, is often associated with hypersensitivity reactions (46). Although cutaneous manifestations are the most common toxicities associated with cetuximab, they are rarely life-threatening. In a small controlled study, the reaction rate was 22% and significantly higher than the rate noted in any large published trial. In this study, all reactions occurred during the first dose and there was a strong relationship between prior allergy history and chance of reaction (47).

Risk of anaphylaxis was included in the US and EU prescribing information for omalizumab (anti-IgE MAb), but the nature of these reactions needed further elaboration. A review of spontaneous postmarketing adverse event reports submitted to the US Food and Drug Administration's Adverse Event Reporting System database and to the manufacturers of omalizumab and cases published in the literature was done through December 2006 (48). Diagnostic criteria for anaphylaxis outlined by the National Institute of Allergy and Infectious Diseases and the Food Allergy and Anaphylaxis Network were used to screen cases. 124 cases of anaphylaxis associated with omalizumab administration in 57,300 patients with asthma were identified (0.2%). Many cases had a delayed onset of symptoms beyond 2 hours after dose administration. Many cases were also characterized by a protracted progression, with individual signs and symptoms of anaphylaxis staggered over hours. Review of the case reports did not reveal any predictive risk factors for the delayed onset or protracted progression of anaphylaxis.

The American Academy of Allergy, Asthma & Immunology and the American College of Allergy, Asthma and Immunology Executive Committees formed the Omalizumab Joint Task Force (OJTF) with the purpose of reviewing the omalizumab clinical trials and postmarketing surveillance data on anaphylaxis and anaphylactoid reactions (49 ). Using the definition of anaphylaxis proposed at a 2005 multidisciplinary symposium (50), the Omalizumab Joint Task Force concluded that 35 patients had 41 episodes of anaphylaxis associated with omalizumab administration between June 1, 2003, and December 31, 2005. With 39,510 patients receiving omalizumab during the same period of time, this would correspond to an anaphylaxis-reporting rate of 0.09% of patients. Thus, omalizumab induces very few anaphylactic reactions by comparison to other biologics. Of those 36 events for which the time of reaction was known, 22 (61%) reactions occurred in the first 2 hours after one of the first 3 doses. Five (14%) of the events after the fourth or later doses occurred within 30 minutes. Considering the timing of these 36 events, an observation period of 2 hours for the first 3 injections and 30 minutes for subsequent injections would have captured 75% of the anaphylactic reactions.

These reactions have lead to a proposed modification of the administration of omalizumab (49). The OJTF report provides recommendations for physicians who prescribe Xolair (omalizumab) on the suggested wait periods after administration and patient education regarding anaphylaxis (Table 1).

Serum sickness
Monoclonal antibodies which induce the formation of IgG antibodies can potentially activate complement and lead to serum sickness (51). Omalizumab does not usually activate complement and only one reaction of serum sickness has been described (52).

Immune imbalance
Biologics that suppress the immune system such as TNF-α blocking drugs are associated with immune imbalance and induce minor infections of the urinary tract, respiratory tract and sinuses, and with serious infections such as tuberculosis, sepsis (bacteria in the blood) and fungal infections (Table 2) shown on next page. Individuals with active infections should not be treated with TNF-α blocking biologics. Some patients who used TNF-α blocking biologics developed cancer. In a study in severe asthma, golimumab-treated patients experienced serious adverse events, infections were the most common adverse events. One patient died from sepsis and some malignancies occurred.

Parasitic infections
Although the role of IgE in immunity against helminth parasites is unclear, there is concern that omalizumab may be unsafe in subjects at risk of helminth infection. An exploratory study was conducted in Brazil to investigate the safety of omalizumab in subjects with allergic asthma and/or allergic rhinitis at high risk of intestinal helminth infection (53). 137 subjects (12-30 years) at high risk of geohelminth infection received pre-study anthelmintic treatment, followed by 52 weeks’ treatment with omalizumab or placebo. Of the omalizumab subjects 50% experienced at least one intestinal geohelminth infection compared with 41% of placebo subjects, providing some evidence for a potential increased incidence of geohelminth infection in subjects receiving omalizumab. Omalizumab therapy was well tolerated, and did not appear to be associated with increased morbidity attributable to intestinal helminths as assessed by clinical and laboratory adverse events, maximal helminth infection intensities and additional anthelmintic requirements. Time to first infection was similar between treatment groups. Infection severity and response to anthelmintics appeared to be unaffected by omalizumab therapy.

3- Immune tolerance

Infliximab, a human-murine chimeric monoclonal IgG antibody against TNF-α effective in rheumatoid arthritis and other inflammatory diseases. With repeated infusions, however, the formation of neutralizing anti-infliximab antibodies becomes a problem, necessitating increased doses or more frequent drug administration and sometimes necessitating discontinuation of therapy because of secondary response failure and/or infusionrelated side effects; this has been observed both in rheumatoid arthritis patients and in patients with other immunoinflammatory diseases. In clinical practice, however, patients with RA or any other chronic inflammatory disease treated with infliximab may differ considerably from the average patient in randomized clinical trials (54, 55). Trough serum infliximab levels after the first 2 intravenous infusions of infliximab at 3 mg/kg varied considerably between patients (range 0-22 g/ml). At this stage, only 13% of the patients were anti-infliximab antibody positive. With subsequent infusions, the frequency of antibody positivity rose to 30% and 44% (at 3 months and 6 months, respectively), accompanied by diminished trough levels of infliximab. Indeed, low infliximab levels at 1.5 months predicted antibody development and later treatment failure. There were highly significant correlations between high levels of antibodies and later dose increases, side effects, and cessation of therapy. Adalimumab is well tolerated and appears to be effective in maintaining clinical remission in patients with bowel disease and lost response to infliximab (56, 57).

Certolizumab pegol is a pegylated humanized Fab' fragment with a high binding affinity for TNF-α. Antinuclear antibodies developed in 8% of the patients in the certolizumab group; antibodies against certolizumab pegol developed in 9% of treated patients (58).

Such a tolerance has not been reported yet for omalizumab.

1- Costs
All biologics are very expensive treatments and many are not devoid of side effects. Thus, the patients treated should be perfectly characterized and biologics only administered if they can reduce severe symptoms and reduce hospitalizations. This is the case for omalizumab which is indicated in severe uncontrolled asthmatics despite the use of optimal therapy. However, even in these patients, the costs of treatment need to be scrutinized. It has been shown that omalizumab is cost-effective in some but not all studies (59-61). However, since this treatment can reduce severe exacerbations and improve quality-of-life, it is indicated in patients with severe uncontrolled asthma despite optimal pharmacotherapy.

Table 1
Table 1: Summary of AAAAI/ACAAI OJTF recommendations concerning omalizumab use (49)

Table 2
Table 2: Classification of side effects of anti-TNF-α biologics (33)

References

  1. Lonberg N. Human monoclonal antibodies from transgenic mice. Handb Exp Pharmacol. 2008(181):69-97.

  2. Nissim A, Chernajovsky Y. Historical development of monoclonal antibody therapeutics. Handb Exp Pharmacol. 2008(181):3-18.

  3. MacGlashan D. Loss of receptors and IgE in vivo during treatment with anti-IgE antibody. J Allergy Clin Immunol. 2004 Dec;114(6):1472-4.

  4. Beck LA, Marcotte GV, MacGlashan D, Togias A, Saini S. Omalizumab-induced reductions in mast cell Fce psilon RI expression and function. J Allergy Clin Immunol. 2004 Sep;114(3):527-30.

  5. Holgate S, Casale T, Wenzel S, Bousquet J, Deniz Y, Reisner C. The antiinflammatory effects of omalizumab confirm the central role of IgE in allergic inflammation. J Allergy Clin Immunol. 2005 Mar;115(3):459-65.

  6. Djukanovic R, Wilson SJ, Kraft M, Jarjour NN, Steel M, Chung KF, et al. Effects of treatment with anti-immunoglobulin E antibody omalizumab on airway inflammation in allergic asthma. Am J Respir Crit Care Med. 2004 Sep 15;170(6):583-93.

  7. Fahy JV. Anti-IgE: lessons learned from effects on airway inflammation and asthma exacerbation. J Allergy Clin Immunol. 2006 Jun;117(6):1230-2.

  8. Holgate ST, Djukanovic R, Casale T, Bousquet J. Anti-immunoglobulin E treatment with omalizumab in allergic diseases: an update on anti-inflammatory activity and clinical efficacy. Clin Exp Allergy. 2005 Apr;35(4):408-16.

  9. Bousquet J, Cabrera P, Berkman N, Buhl R, Holgate S, Wenzel S, et al. The effect of treatment with omalizumab, an anti-IgE antibody, on asthma exacerbations and emergency medical visits in patients with severe persistent asthma. Allergy. 2005 Mar;60(3):302-8.

  10. Bousquet J, Rabe K, Humbert M, Chung KF, Berger W, Fox H, et al. Predicting and evaluating response to omalizumab in patients with severe allergic asthma. Respir Med. 2007 Jul;101(7):1483-92.

  11. Humbert M, Beasley R, Ayres J, Slavin R, Hebert J, Bousquet J, et al. Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE. Allergy. 2005 Mar;60(3):309-16.

  12. Nopp A, Johansson SG, Ankerst J, Palmqvist M, Oman H. CD-sens and clinical changes during withdrawal of Xolair after 6 years of treatment. Allergy. 2007 Oct;62(10):1175-81.

  13. Kon OM, Sihra BS, Loh LC, Barkans J, Compton CH, Barnes NC, et al. The effects of an anti-CD4 monoclonal antibody, keliximab, on peripheral blood CD4+ T-cells in asthma. Eur Respir J. 2001 Jul;18(1):45-52.

  14. Kon OM, Sihra BS, Compton CH, Leonard TB, Kay AB, Barnes NC. Randomised, dose-ranging, placebo-controlled study of chimeric antibody to CD4 (keliximab) in chronic severe asthma. Lancet. 198 Oct 3;352(9134):1109-13.

  15. Simon D, Braathen LR, Simon HU. Anti-interleukin-5 antibody therapy in eosinophilic diseases. Pathobiology. 2005;72(6):287-92.

  16. Pauwels RA, Brusselle GJ, Kips JC. Cytokine manipulation in animal models of asthma. Am J Respir Crit Care Med. 197 Oct;156(4 Pt 2):S78-81.

  17. Leckie MJ, ten Brinke A, Khan J, Diamant Z, O’Connor BJ, Walls CM, et al. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet. 2000 Dec 23- 30;356(9248):214-8.

  18. Flood-Page P, Swenson C, Faiferman I, Matthews J, Williams M, Brannick L, et al. A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. Am J Respir Crit Care Med. 2007 Dec 1;176(11):1062-71.

  19. Rosenberg HF, Phipps S, Foster PS. Eosinophil trafficking in allergy and asthma. J Allergy Clin Immunol. 2007 Jun;119(6):1303-10; quiz 11-2.

  20. O’Byrne PM. The demise of anti IL-5 for asthma, or not. Am J Respir Crit Care Med. 2007 Dec 1;176(11):1059-60.

  21. van Rensen EL, Stirling RG, Scheerens J, Staples K, Sterk PJ, Barnes PJ, et al. Evidence for systemic rather than pulmonary effects of interleukin-5 administration in asthma. Thorax. 2001 Dec;56(12):935-40.

  22. Flood-Page P, Menzies-Gow A, Phipps S, Ying S, Wangoo A, Ludwig MS, et al. Anti-IL-5 treatment reduces deposition of ECM proteins in the bronchial subepithelial basement membrane of mild atopic asthmatics. J Clin Invest. 2003 Oct;112(7):1029-36.

  23. Plotz SG, Simon HU, Darsow U, Simon D, Vassina E, Yousefi S, et al. Use of an anti-interleukin-5 antibody in the hypereosinophilic syndrome with eosinophilic dermatitis. N Engl J Med. 2003 Dec 11;349(24):234-9.

  24. Gevaert P, Lang-Loidolt D, Lackner A, Stammberger H, Staudinger H, Van Zele T, et al. Nasal IL-5 levels determine the response to anti-IL-5 treatment in patients with nasal polyps. J Allergy Clin Immunol. 2006 Nov;118(5):113-41.

  25. Rinia AB, Kostamo K, Ebbens FA, van Drunen CM, Fokkens WJ. Nasal polyposis: a cellular-based approach to answering questions. Allergy. 2007 Apr;62(4):348-58.

  26. Ma Y, Hayglass KT, Becker AB, Halayko AJ, Basu S, Simons FE, et al. Novel cytokine peptide-based vaccines: an interleukin-4 vaccine suppresses airway allergic responses in mice. Allergy. 2007 Jun;62(6):675-82.

  27. Borish LC, Nelson HS, Corren J, Bensch G, Busse WW, Whitmore JB, et al. Efficacy of soluble IL-4 receptor for the treatment of adults with asthma. J Allergy Clin Immunol. 2001 Jun;107(6):963-70.

  28. Borish LC, Nelson HS, Lanz MJ, Claussen L, Whitmore JB, Agosti JM, et al. Interleukin-4 receptor in moderate atopic asthma. A phase I/II randomized, placebo-controlled trial. Am J Respir Crit Care Med. 19 Dec;160(6):1816- 23.

  29. Wenzel S, Wilbraham D, Fuller R, Getz EB, Longphre M. Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies. Lancet. 2007 Oct 20;370(9596):142-31.

  30. Heffler E, Berry M, Pavord ID. Tumor necrosis factor-alpha: a promising therapeutic target for asthma? BioDrugs. 2007;21(6):345-9.

  31. Berry MA, Hargadon B, Shelley M, Parker D, Shaw DE, Green RH, et al. Evidence of a role of tumor necrosis factor alpha in refractory asthma. N Engl J Med. 2006 Feb 16;354(7):697-708.

  32. Howarth PH, Babu KS, Arshad HS, Lau L, Buckley M, McConnell W, et al. Tumour necrosis factor (TNFalpha) as a novel therapeutic target in symptomatic corticosteroid dependent asthma. Thorax. 2005 Dec;60(12):1012-8.

  33. Pichler WJ. Adverse side-effects to biological agents. Allergy. 2006 Aug;61(8):912-20.

  34. Georgitis JW, Browning MC, Steiner D, Lorentz WB. Anaphylaxis and desensitization to the murine monoclonal antibody used for renal graft rejection. Ann Allergy. 191 Apr;66(4):343-7.

  35. Cheifetz A, Mayer L. Monoclonal antibodies, immunogenicity, and associated infusion reactions. Mt Sinai J Med. 2005 Jul;72(4):250-6.

  36. Campi P, Benucci M, Manfredi M, Demoly P. Hypersensitivity reactions to biological agents with special emphasis on tumor necrosis factor-alpha antagonists. Curr Opin Allergy Clin Immunol. 2007 Oct;7(5):393-403.

  37. Kolho KL, Ruuska T, Savilahti E. Severe adverse reactions to Infliximab therapy are common in young children with inflammatory bowel disease. Acta Paediatr. 2007 Jan;96(1):128-30.

  38. Dore RK, Mathews S, Schechtman J, Surbeck W, Mandel D, Patel A, et al. The immunogenicity, safety, and efficacy of etanercept liquid administered once weekly in patients with rheumatoid arthritis. Clin Exp Rheumatol. 2007 Jan-Feb;25(1):40-6.

  39. Weinblatt ME, Keystone EC, Furst DE, Kavanaugh AF, Chartash EK, Segurado OG. Long term efficacy and safety of adalimumab plus methotrexate in patients with rheumatoid arthritis: ARMADA 4 year extended study. Ann Rheum Dis. 2006 Jun;65(6):753-9.

  40. Weinblatt ME, Keystone EC, Furst DE, Moreland LW, Weisman MH, Birbara CA, et al. Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum. 2003 Jan;48(1):35-45.

  41. Zeltser R, Valle L, Tanck C, Holyst MM, Ritchlin C, Gaspari AA. Clinical, histological, and immunophenotypic characteristics of injection site reactions associated with etanercept: a recombinant tumor necrosis factor alpha receptor: Fc fusion protein. Arch Dermatol. 2001 Jul;137(7):893-9.

  42. Winfield H, Lain E, Horn T, Hoskyn J. Eosinophilic cellulitislike reaction to subcutaneous etanercept injection. Arch Dermatol. 2006 Feb;142 (2):218 - 20.

  43. Benucci M, Manfredi M, Demoly P, Campi P. Injection site reactions to TNF-alpha blocking agents with positive skin tests. Allergy. 2008 Jan;63(1):138-9.

  44. Youdim A, Vasiliauskas EA, Targan SR, Papadakis KA, Ippoliti A, Dubinsky MC, et al. A pilot study of adalimumab in infliximab-allergic patients. Inflamm Bowel Dis. 2004 Jul;10(4):33-8.

  45. Lenz HJ. Management and preparedness for infusion and hypersensitivity reactions. Oncologist. 2007 May;12(5):601-9.

  46. Patel DD, Goldberg RM. Cetuximab-associated infusion reactions: pathology and management. Oncology (Williston Park). 2006 Oct;20(11):1373-82; discussion 82, 92-4, 97.

  47. O’Neil BH, Allen R, Spigel DR, Stinchcombe TE, Moore DT, Berlin JD, et al. High incidence of cetuximab-related infusion reactions in Tennessee and North Carolina and the association with atopic history. J Clin Oncol. 2007 Aug 20;25(24):364-8.

  48. Limb SL, Starke PR, Lee CE, Chowdhury BA. Delayed onset and protracted progression of anaphylaxis after omalizumab administration in patients with asthma. J Allergy Clin Immunol. 2007 Dec;120(6):1378-81.

  49. Cox L, Platts-Mills TA, Finegold I, Schwartz LB, Simons FE, Wallace DV. American Academy of Allergy, Asthma & Immunology/American College of Allergy, Asthma and Immunology Joint Task Force Report on omalizumab-associated anaphylaxis. J Allergy Clin Immunol. 2007 Dec;120(6):1373-7.

  50. Sampson HA, Munoz-Furlong A, Bock SA, Schmitt C, Bass R, Chowdhury BA, et al. Symposium on the definition and management of anaphylaxis: summary report. J Allergy Clin Immunol. 2005 Mar;115(3):584-91.

  51. Rutgeerts P, Van Assche G, Vermeire S. Review article: Infliximab therapy for inflammatory bowel disease--seven years on. Aliment Pharmacol Ther. 2006 Feb 15;23(4):451-63.

  52. Pilette C, Coppens N, Houssiau FA, Rodenstein DO. Severe serum sickness-like syndrome after omalizumab therapy for asthma. J Allergy Clin Immunol. 2007 Oct;120(4):972-3.

  53. Cruz AA, Lima F, Sarinho E, Ayre G, Martin C, Fox H, et al. Safety of antiimmunoglobulin E therapy with omalizumab in allergic patients at risk of geohelminth infection. Clin Exp Allergy. 2007 Feb;37(2):197-207.

  54. Bendtzen K, Geborek P, Svenson M, Larsson L, Kapetanovic MC, Saxne T. Individualized monitoring of drug bioavailability and immunogenicity in rheumatoid arthritis patients treated with the tumor necrosis factor alpha inhibitor infliximab. Arthritis Rheum. 2006 Dec;54(12):3782-9.

  55. Svenson M, Geborek P, Saxne T, Bendtzen K. Monitoring patients treated with anti-TNF-alpha biopharmaceuticals: assessing serum infliximab and antiinfliximab antibodies. Rheumatology (Oxford). 2007 Dec;46(12):1828-34.

  56. Peyrin-Biroulet L, Laclotte C, Bigard MA. Adalimumab maintenance therapy for Crohn’s disease with intolerance or lost response to infliximab: an open-label study. Aliment Pharmacol Ther. 2007 Mar 15;25(6):675-80.

  57. Peyrin-Biroulet L, Laclotte C, Roblin X, Bigard MA. Adalimumab induction therapy for ulcerative colitis with intolerance or lost response to infliximab: an open-label study. World J Gastroenterol. 2007 Apr 28;13(16):2328-32.

  58. Schreiber S, Khaliq-Kareemi M, Lawrance IC, Thomsen OO, Hanauer SB, McColm J, et al. Maintenance therapy with certolizumab pegol for Crohn’s disease. N Engl J Med. 2007 Jul 19;357(3):239-50.

  59. Brown R, Turk F, Dale P, Bousquet J. Cost-effectiveness of omalizumab in patients with severe persistent allergic asthma. Allergy. 2007 Feb;62(2):149-53.

  60. Krishnan JA, Gould M. Omalizumab for severe allergic asthma: dollars and sense. J Allergy Clin Immunol. 2007 Nov;120(5):1015-7.

  61. Wu AC, Paltiel AD, Kuntz KM, Weiss ST, Fuhlbrigge AL. Cost-effectiveness of omalizumab in adults with severe asthma: results from the Asthma Policy Model. J Allergy Clin Immunol. 2007 Nov;120(5):1146-52.

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