Arzu Didem Yalcin* and Academia Sinica
Genomics Research Center, Dr. Academia Sinica, 11529, Taipei, Taiwan, And Internal Medicine, Allergy and Clinical Immunology, Near East University, Nicosia, Cyprus
Received: 29 October, 2014; Accepted: 03 December, 2014; Published: 05 December, 2014
Arzu Didem Yalcin MD. Genomics Research Center, Dr.Academia Sinica, 11529, Taipei, Taiwan, And Internal Medicine, Allergy and Clinical Immunology, Near East University, Nicosia, Cyprus, Tel: 8860278977509; Email:
Yalcin AD, Sinica A (2015) A Commentary: Is Context an Important Consideration in Asthma. Glob J Allergy 1(1): 003-012. DOI: 10.17352/2455-8141.000002
© 2014 Yalcin AD, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Asthma; Anti-IgE; Omalizumab; Chronic urticaria; Inflammatory proteins; Side effects; Safety; Genetic factors
Asthma is common chronic inflammatory disease of the airways characterised by variable and attacks of cough and breathlesness, usually precipitated by an enviromental trigger (air pollution, smoke, etc). The prevalence and severity for allergic asthma have increased markedly in the last several decades. Dysregulated expression patterns of pro- and anti inflammatory mechanisms are thought to be responsible for the development of chronic inflammation. The risk of developing asthma has a strong genetic component, with estimated heritability ranging from 35 to 85%. The mechanism of action of Omalizumab in the treatment of asthma is believed to be multifactorial.
Asthma and Genetic Factors
Asthma is common chronic inflammatory disease of the airways characterised by variable and attacks of cough and breathlesness, usually precipitated by an enviromental trigger (air pollution, cold, dry air, smoke, etc). The prevalence and severity for allergic asthma have increased markedly in the last several decades. Dysregulated expression patterns of pro- and anti inflammatory mechanisms are thought to be responsible for the development of chronic inflammation. The sequence of immunopathogenesis is unclear but there is clearly a genetic predisposition. Asthma is caused by multiple interacting genes, some having a protective effect and others contributing to the disease pathogenesis, with each gene having its own tendency to be influenced by the environment. By the end of 2010, 100 genes had been associated with asthma in six or more separate populations, including GSTM1, IL-1 (α,β), IL-1RN, TSLP-R, IL-1R1, IL-8RA, IL-3,4,5,9,10,12,13, NAT2, CTLA-4, SPINK5, V-CAM 1, TNF-α, ARG1, GSTM1, A3AR, CHIA, LELP1, TGFβ1, SOD-1, EGFR, GPRA, CCR2, FcεRIβ, PHF11, ACE, IRAK-3, CD69, IL-18, MUC-2, eNOS; NOS3, CMA1, and ADAM33, among others [1-3]. The risk of developing asthma has a strong genetic component, with estimated heritability ranging from 35 to 85% . Asthma is described as a complex disease arising from the contribution of multiple genetic and environmental factors [4,5]. Some of these genes may also be involved with other phenotypes such as helminthic infections (FcεRIβ and IL-4), COPD, cardiovascular diseases, congenital thrombotic thrombocytopenia, Crohn's disease (ADAM33) renal cell carcinoma, blood malignancies (PHF11), tuberculosis (TB), hyperparathyroidism, prostate cancer, insulin dependent diabetes mellitus, leprosy and chronic hepatitis B infection (vitamin D receptor:VDR) . Thymic stromal lymphopoietin (TSLP) is an epithelial-derived cytokine similar to IL- 7, whose gene is located on chromosome 5q22. 1 and it exerts its biological function through the TSLP-Receptor (TSLP-R). TSLP is expressed primarily by epithelial cells at barrier surfaces such as the skin, gut and lung in response to danger signals. TSLP genetic variants and its dysregulated expression have been linked to atopic diseases such as atopic dermatitis, asthma, allergic rhinitis and eosinophilic esophagitis .
The response to drug treatment in asthma is a complex trait and is markedly variable even in patients with apparently similar clinical features. Pharmacogenomics, which is the study of variations of human genome characteristics as related to drug response, can play a role in asthma therapy. Both a traditional candidate-gene approach to conducting genetic association studies and genome-wide association studies have provided an increasing list of genes and variants associated with the three major classes of asthma medications: β2-agonists, inhaled corticosteroids, and leukotriene modifiers. Moreover, a recent integrative, systems-level approach has offered a promising opportunity to identify important pharmacogenomics loci in asthma treatment .
The polymorphisms within the ADRB2 gene that are potentially associated with obesity and asthma include Arg16Gly and Glu27Gln, and probably to some extent Thr164Ile, as well. The pleiotropic nature of ADRB2 makes it a good candidate for such an association. It also has an established role in the development of both conditions separately. The underlying mechanism seems to depend on both the alternations in lung function and the metabolic effect associated with ADRB2. However, it could also be linked to immunological functions related to ADRB2 expressions on leukocytes .
A genome-wide association study (GWAS) identified a previously unknown asthma-susceptibility locus on chromosome 17q21, harboring the adjacent genes ORMDL3 (ORMDL sphingolipid biosynthesis regulator 3) and GSDMB (Gasdermin B). This genetic association has been confirmed in ethnically diverse populations, and gene–environment interactions have been detected between susceptibility alleles and exposure to cigarette smoke and furred pets. Acevedo et al. showed that, significant differences in the DNA methylation levels of the ORMDL3promoter of asthmatic children, independent of age, gender, genotype and differential leukocyte cell counts, which might partially explain the increased ORMDL3 expression observed in cases. Their results strongly support the role of both genetic and epigenetic factors contributing to asthma susceptibility in the 17q21 locus [9,10].
Omalizumab, a humanized mAb that binds to the CH3 domain, near the binding site for the high-affinity type-I IgE Fc receptors of human IgE, can neutralize free IgE and inhibit the IgE allergic pathway without sensitizing mast cell and basophils. Omalizumab, which has been conceptualized for treating IgE mediated allergic diseases and approved for treating patients with severe persistent allergic asthma in many countries, can neutralize IgE, impede the IgE allergic pathway, and render mast cells and basophils insensitive to activation through IgE/FcεRI. In addition to asthma, Omalizumab has been investigated in various other conditions including chronic urticaria (CU), perennial and seasonal allergic rhinitis (AR), pruritic bullous pemphigoid, latex allergy, peanut allergy, idiopathic anaphylaxis, hyper-IgE syndrome, chronic rhinosinusitis, interstitial cystitis, aspirin sensitivity, mastocytosis, eosinophilic gastroenteritis and atopic dermatitis. Most patients with chronic urticaria have an autoimmune cause: some patients produce IgE autoantibodies against autoantigens, such as thyroperoxidase or doublestranded DNA, whereas other patients make IgG autoantibodies against FcεRI, IgE, or both, which might chronically activate mast cells and basophils. In the remainder of patients with CSU, the nature of the abnormalities has not yet been identified. Accumulating evidence has shown that IgE, by binding to FcεRI on mast cells without FcεRI cross-linking, can promote the proliferation and survival of mast cells and thus maintain and expand the pool of mast cells. IgE and FcεRI engagement can also decrease the release threshold of mast cells and increase their sensitivity to various stimuli through either FcεRI or other receptors for the degranulation process [11,12]. The development of Omalizumab therapy over the past 20 years provides an interesting example of the emergence of a conceptually new, biotechnology-produced pharmaceutical [13-18].
Omalizumab and IgE receptors
In a patient with an allergic disease caused by type I hypersensitivity toward specific external antigens, omalizumab induces multifactorial therapeutic effects. Omalizumab depletes free IgE in the blood and interstitial space and inhibits IgE binding to FcεRI on basophils, mast cells, and dendritic cells. Omalizumab cannot bind to IgE that is already bound to FcεRI and does not have a direct effect on FcεRI levels. However, the depletion of free IgE results in the downregulation of FcεRI on cells bearing the receptor, making those cells insensitive to the stimulation by incoming allergens [16-19].
Most asthmatic individuals respond satisfactorily to inhaled corticosteroids and β-adrenergic agonists; however, 5-10% of them have severe, persistent symptoms that respond poorly to such treatment. The introduction of Omalizumab as an add on therapy for inadequately controlled moderate-to-severe or severe persistent allergic asthma (SPA) provided a valuable new treatment option for patients. Given the importance of anti-inflammatory therapy for control of SPA, it is important to determine the effects of omalizumab on markers of inflammation. The interaction between Omalizumab and free IgE interrupts a key step in the allergic inflammatory cascade, preventing IgE from binding to mast cells, basophils, and dendritic cells, and down-regulating IgE receptor expression on these inflammatory cells thereby inhibiting degranulation and the release of inflammatory mediators [19-22]. Omalizumab has been approved in over 120 countries for treating patients with SPA. These pharmaceutical developments have validated the IgE pathway as an effective therapeutic target for treating IgE-mediated allergic disease [23-25].
For the very first time, we used omalizumab in symptomatic therapy of recurren laryngeal oedema attacts in a patient with post operative pulmonary carcinoid tumor for 4 months. During the 3 years of follow-up no reccurrens was noted in tumor.
Omalizumab effects on sApo-2 L and allergen ipecific immunotherapy
Tumor necrosis factor related apoptosis-inducing ligand (TRAIL: Apo-2L) is used as a marker for apoptosis. TRAIL (Apo-2L) is a transmembrane (type II) glycoprotein belonging to the TNF superfamily. The extracellular domain of TRAIL is homologous to that of other family members and shows a homotrimeric subunit structure. Like TNF and FasL, sApo-2L also exists physiologically in a biologically active soluble homotrimeric form. An increase in eosinophil levels has been reported in allergic asthma, and is thought to reflect an increase in peripheral blood eosinophil survival promoted by Apo-2 L.
In our previous study we showed that soluble Apo-2 L levels in patients with severe persistent allergic asthma decreased after anti-IgE treatment using omalizumab. These results suggested that sApo-2L may act as a soluble effector molecule, and that the decrease in levels after omalizumab treatment may allow us to use this marker to monitor clinical improvement. Combination therapy with omalizumab and specific subcutaneous immunotherapy (SCIT) in patients with severe persistent asthma also suggest that omalizumab is an effective therapy in such individuals. Omalizumab reduces serum IgE levels and FceRI receptor expression on key cells in the inflammatory cascade. The consequences of these processes are the inhibition of the release of inflammatory mediators from mast cells, and diminished recruitment of inflammatory cells, especially eosinophils, into the airways [21,26-28].
Allergen Specific Immunotherapy (SIT) has the advantage of being the only causal treatment of allergic controlled asthma and rhinitis but is fraught with the dangers of severe systemic or local side effects and anaphylaxis [29-32]. Omalizumab can possibly overcome these limitations by binding exclusively to circulating IgE molecules and reducing the levels of circulating IgE regardless of allergen specificity by binding to the constant region of circulating IgE molecule. This prevents free IgE from interacting with the high- and low-affinity IgE receptors (Fc”RI and Fc”RII) on mast cells, basophils, macrophages, dendritic cells, B lymphocytes, and subsequently leads to a decrease in the release of the mediators of the IgE mediated allergic response, namely, cytokines, histamines and leukotrienes [33,34].
The first clinical trial looking for the clinical effects of a combined therapy of SIT and Omalizumab was performed in grass- and birch-pollen allergic children and adolescents in Germany. Kuehr and colleagues recruited 221 children and adolescents to evaluate the efficacy and safety of Omalizumab with SIT on birch pollen induced allergic rhinitis (AR) . SIT plus Omalizumab-treated subjects were reported to have a 48% reduction in allergen-induced symptom load over two pollen seasons independent of the allergen. Furthermore, rescue medication use, number of days with symptoms and symptom severity were significantly lower in the SIT plus Omalizumab groups compared with SIT alone. A post hoc sub-analysis of this study to assess the effects of each treatment (SIT or Omalizumab) demonstrated that SIT alone did not significantly reduce either symptoms severity score . Hence, combination therapy may be complimentary, providing the superior effect compared to individual treatments. Recently, there have been trials of Omalizumab and SIT in patients with AR and co-morbid asthma. In the trial by Kopp and colleagues, a significant reduction of 40% in symptom load was observed in favor of SIT plus Omalizumab compared with SIT alone (p = 0.04) . Another study showed that the tolerability of SIT after pretreatment with Omalizumab or placebo in patients with symptomatic asthma was not adequately controlled with inhaled corticosteroids. A total of 13.5% of patients treated with Omalizumab showed systemic allergic reactions to SIT compared to 27% in those receiving placebo (p =0.017). More patients were able to reach the target maintenance SIT dose (p=0.004) in the Omalizumab group compared to placebo [38,39], suggesting that pre-treatment with Omalizumab was associated with fewer systemic allergic reactions to SIT and enabled more patients to achieve the target immunotherapy maintenance dose.
Studies in allergic rhinitis and asthmatics have shown that pre-treatment with Omalizumab may be an effective option to reduce systemic anaphylactic reactions and achieve a higher dose of allergen immunotherapy in a safe way. This can be of specific relevance to hymenoptera venom immunotherapy. Although there are no controlled trials, there are case reports of anti-IgE therapy with Omalizumab reducing the risk of systemic reaction during induction of venom immunotherapy in patients who have either failed treatment or in those with mastocytosis [40-42].
Omalizumab effects on oxidative stress markers, vitamin-D and homocysteine
An imbalance between oxidative stress and anti-oxidative capacity may play an important role in the development and progression of bronchial asthma (BA) and chronic obstructive pulmonary disease (COPD). The systemic oxidant-antioxidant status changes during exacerbation versus stable periods in patients with BA and COPD. During an exacerbation period of BA, despite the decreases in glutathione peroxidase (GSH-Px), glutathione reductase (GRd) and melatonin levels, malondialdehyde (MDA) and catalase (CAT) levels, and the white blood cell count, the percentage of eosinophils is significantly higher than in the stable period. MDA and superoxide dismutase (SOD) values are higher in the exacerbation period than in the stable period although GSH-Px, GRd, melatonin, pH, and pO2 values are lower in the exacerbation period than in the stable period. Blood counts and respiratory function tests were reported not to change between exacerbation and stable periods in patients with COPD. Thus episodes of BA or COPD might be associated with elevated levels of oxidative stress.
A decrease in NO during omalizumab therapy was also previously described by Silkoff et al. . Down regulation of ET-1 in EBC significantly correlates with a decrease in the markers of allergic (and eosinophilic) inflammation, such as NO, ECP or blood eosinophil counts, as well as increase in spirometric indices. These changes were observed after 16 weeks of therapy. A follow-up observation performed after 52 weeks of treatment revealed a further significant fall in ET-1 concentrations in EBC; however, the improvement of other markers of allergic inflammation was less pronounced. This could indicate that anti-IgE therapy has its greatest influence on eosinophilic inflammation during the first 16 weeks of therapy. Nevertheless the effects of many other immunological mechanisms related to remodeling, as well the known action and interactions of ET-1 observed in the first period of treatment, are thought to continue over time. This suggests that longer-term anti-IgE therapy with omalizumab in asthmatic patients could significantly limit the development of inflammation and bronchial structural changes. In our previous study we investigated changes in total antioxidant capacity in asthmatic patients treated with Omalizumab. Our data suggested that ongoing therapy with Omalizumab, already proven to be clinically effective in treatment of severe allergic asthma. Anti-IgE therapy is an innovative and promising treatment modality that mediates its effects in part at least through decreased inflammation following improved anti-oxidant capability. In turn, our study was suggesting that measuring of the latter may prove to be useful surrogate markers to monitor efficacy of treatment in patients suffering from this disease .
Alternatively, the development of atopy may also be a direct effect of elevated homocysteine or some of its metabolites, which appears to exert a number of diverse effects on immune function. In addition, total homocysteine (Hcy) has been shown to increase in response to immune activation and cell proliferation during a non-allergic Th1-type immune response. Although much less is known about the health effects of sustained post load homocysteine concentrations, there is evidence that it has negative effects on platelet aggregation and endothelial function. A number of studies have indicated that homocysteine may contribute to the development and progression of atherosclerosis, a risk factor for cardiovascular diseases. However, the mechanisms by which Hcy can induce vascular dysfunction are not fully understood [48-53].
Vitamin-D (25(OH)D) has effects on the innate and adaptive immune system. 25(OH)D levels are associated with poor asthma control, reduced pulmonary function, increased medication intake and exacerbations. Little is known about 25(OH)D in adult asthma patients or its association with asthma severity [54,55]. More than that, 25(OH)D triggers a Hcy metabolizing enzyme and data from the Longitudinal Aging Study Amsterdam suggested a correlation between 25(OH)D status and Hcy levels . The decrease in Hcy concentrations and increase in 25(OH)D also supports the possible vascular endothelial protection mechanism.
Omalizumab effects on pruritic bullous pemphigoid
Bullous pemphigoid (BP) is an acquired, autoimmune, bullous disease that is characterized by autoantibodies against the 230-kDa bullous pemphigoid antigen within basal keratinocytes and the 180-kDa type XVII collagen within the basement membrane zone lying between the epidermis and dermis. In addition to skin blisters, patients with BP often experience pruritus and erythematous urticaria-like skin lesions.
CD200 (OX-2) is a novel immune-effective molecule, both cell membrane-bound and also existing in a soluble form in serum (sCD200, sOX-2), which acts both as a pro-inflammatory through its receptor [11,14,47]. In our previous study, we reported a patient who had a pruritic bullous pemphigoid and very high levels of total IgE (5000 kU/L) who was refractory to the aggressive immunosuppressive regimens for bullous pemphigoid but responded rapidly to systemic anti-IgE. The circulating level of sOX-2 was 48.45 pg/mL in serum and 243 pg/mL in blister fluid. Soluble OX-2 levels were higher in blister fluid than in serum. During the second month of follow-up, the patient's sOX-2 level decreased to 26.7 pg/mL. Clinical improvement was demonstrated as histologically re-epithelialization. Optimal treatment modalities need to be clarified in such situations. After the second round of omalizumab (300 mg), frequency of exacerbations decreased and after 13th round it was completely disappeared . Reduction in serum levels sOX-2 with anti- IgE treatment suggests that sOX-2 could be pro-inflammatory [21,24,47,57,58]. Soluble OX-2 might also play a role in immune response in the pathogenesis of autoimmune and inflammatory skin disorders [60,61].
Omalizumab effects on coagulation pathway
More interestingly, as in some of our cases we have observed, one with severe persistent asthma (SPA) patient who had protein C/S deficiency history, multiple massive pulmonary embolus and systemic subacute thrombosis determined in vena saphena parva and in left vena perforantes cruris, underwent Omalizumab treatment. After a long term (20 month) treatment with Omalizumab, he had a decreased fractional exhaled nitric oxide concentrations (FENO), d-dimer (DD), sTRAIL, pro-inflammatory IL-1β and OX-2 and had an increased CXCL8, activated pC (APC), antithrombin III (AIII), protein S (pS), protein C (pC) levels . In this patient's blood levels of APC, AIII, pS, pC were found to be increased (74, 128%, 102%, 86% respectively), and DD level (412 U/L) be decreased at the 30th month under Omalizumab therapy and this results were significant .
Severe Persistent Asthma is associated with a procoagulant state in the bronchoalveolar space, is further aggravated by impaired local activities of the anticoagulant pC/S, AIII system and fibrinolysis, as demonstrated by massive fibrin depositions in the alveoli of a SPA who died from a SPA attack who did not respond to treatment. Recent reports revealed that patients with CU also show signs of thrombin generation and activation of the TF pathway of the coagulation system. DD, a fibrin degradation product formed during the lysis of a thrombus is also detected in high levels in patients with active CU [62-66]. After Omalizumab therapy, significant decrease of the levels of DD shows the importance of procoagulant state in allergic patients. We also believe that DD may also have an important role for the relationship between IgE and extrinsic coagulation pathway in the endothelial cells . The biologic effects of APC and pC can be divided into anticoagulant and cytoprotective effects . In patients with SPA bronchoalveolar levels of APC decreased after a bronchial allergen challenge and were significantly lower than healthy controls and APC/pC ratios were decreased in induced sputum of patients with SPA, pointing to an imbalance between coagulation and the pC system [64,65]. We think that Omalizumab inhibited activation of extrinsic coagulation pathway and lowered d-dimer level by blocking free IgE. Because of this, we think that Omalizumab has a similar effect with heparin. After the injection of heparin, an increase in the percentage of protein C/S has been observed. Anticoagulant treatment with heparin and warfarin had been attempted to reduce the symptoms of CU and SPA; however inhaled heparin is no longer used in clinical practice as adjunctive therapy for SPA attacks because of equivocal results [65-68].
The function of platelets is well known in haemostasis but also platelets are fully functional cells concurrently with haemostasis. Previous studies suggested that platelets have a role in asthma pathogenesis in development of bronchoconstruction, airway inflammation, airway remodelling and bronchial hyperresponsiveness. Lifestyle modification, antihypertensive, lipid lowering and diet therapies can affect MPV values, but these effects need to be investigated with thrombotic endpoints. It was previously suggested that increased MPV values are predictors of early atherosclerosis. However, there were conflicting results in the association of asthma and atherosclerosis. And if MPV value is an indicator of inflammation and atherosclerosis, increased MPV values may be associated with asthma. However, we could not find any difference in MPV values of patients both in pre- and post-omalizumab period. Thrombocytopenia developed in one male patient (no: 11) after the 22nd dose of the drug was given. When the platelet count fell down to 55,000/mm3, the omalizumab treatment was suspended for 4 weeks until the platelet count rose up to 100,000/mm3 , (Figures 1 and 2).
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