Perspectives in Asthma Management: Where Do We Go From Here?

At a symposium held in conjunction with the American College of Allergy, Asthma, & Immunology Annual Meeting in San Antonio, Texas, four leaders in asthma research discussed recent developments in our understanding of asthma and how that may affect how we measure clinical outcomes and how we treat patients with asthma.

This program was supported by unrestricted educational grants from Genentech Inc. and Novartis Pharmaceuticals Corporation.

Comparative Effects of Asthma Pharmacotherapy and Markers of Inflammation and Airway Remodeling

“Asthma is characterized by three key features, obstruction, hyper-responsiveness and inflammation, but I submit that airway remodeling is also a key feature of asthma,” began Nizar Jarjour, MD, Associate Professor of Medicine in the Pulmonary Medicine Section at the University of Wisconsin in Madison, WI.

Allergy is a key factor for the inception, exacerbation, and progression of asthma. When a patient with allergies gets exposed to a relevant allergen, they typically manifest an early acute inflammation involving the release of mediators such as histamine and leukotrienes. The subsequent generation of cytokines such as IL-5 recruits eosinophils that cause tissue injury. This cascade of events can lead to chronic inflammation, resulting in fibrosis or remodeling.

There are several different methods to assess airway inflammation including both direct (bronchoscopy with bronchoalveolar lavage, endobronchial biopsies, and bronchial brushing) and indirect (induced sputum, exhaled gases, peripheral blood) measures. At the University of Wisconsin, Dr. Jarjour and colleagues have used bronchoscopy extensively to access features of airway inflammation and as a research tool for allergen exposure studies. In these latter studies, a bronchoscope is inserted into a given segment and an allergen or sham challenge is introduced. This can be repeated several times in different segments with different antigen dosages, or by treating one segment with an active drug and a matching segment with placebo to evaluate the anti-allergic effects of a given medication. Using this model, Dr. Jarjour showed the audience that a challenge of saline will have little effect on histamine levels whereas 5 minutes following an allergen challenge, histamine is high. If a biopsy is performed on that segment 2 days later you “see a lot of epithelial shedding and significant infiltration of eosinophil in the airway that received the antigen challenge,” said Dr. Jarjour. The increase in eosinophil is associated with an increase in IL-5, a cytokine that is important for maturation and survival of eosinophil.

Chronic inflammation and Remodeling
Patients with asthma have structural airway changes that include sub-epithelial (or sub-basement membrane) fibrosis, increased extracellular matrix protein deposition, angiogenesis, and mucous gland hyperplasia. Collectively, these features are referred to as airway remodeling and that is believed to be important for the severity, lack of reversibility, progression, and morbidity seen in asthma. “It has been proposed that inflammation is the first step to remodeling, but the exact genesis of remodeling is still unclear,” said Dr. Jarjour.

Treatment
“When you treat the patient in your clinic with asthma medication, you need to treat all of these features of asthma if possible,” said Dr. Jarjour. Asthma medications available include:
• Short-acting beta-agonists
• inhaled corticosteroids
• long-acting beta-agonists
• leukotriene-modifying drugs
• theophylline
• cromolyn
• nedocromil
• oral corticosteroids

Corticosteroids are the most potent anti-inflammatory agents available and have an excellent safety profile. Cortico-steroids improve asthma control and bronchial hyper-responsiveness, and reduce exacerbation. Studies have shown the corticosteroid budesonide to be effective in reducing severity of both early and late phase and the associated eosinophilic airway inflammation (Am J Resp Crit Care Med 2000; 162:883-890; Am J Resp Crit Care Med 1996; 154:1267-1271).

In addition, long-acting beta-agonists have been shown to improve lung functions, asthma symptoms, quality of life, and reduce mast cell degranulation, vascular permeability, and cell activation. “They reduce early and late phase response and when added to inhaled corticosteroid, patients do actually do better than after doubling the dose of inhaled corticosteroids which raises the question whether there is some synergistic effect between these two drugs,” said Dr. Jarjour.

Theophylline is “an old drug that’s trying to make a comeback,” said Dr. Jarjour. It has some anti-inflammatory effects at fairly low doses and recent studies indicate it may attenuate the late phase response to allergens, decrease eosinophils, decrease leukotriene B-4 production, and increase histone deacetylase- H-DAC activity. In a study that examined the late phase response in patients, theophylline reduced the severity of the late phase response compared to placebo in patients with mild allergic asthma (Ann Allergy Asthma Immunol 1998; 81:231-236). In one long-term study (2-4 weeks), theophylline treatment reduced sputum eosinophils by 40% (Clin Exp Allergy 2000;30:1151-1160).

In regard to leukotriene modifying drugs, Dr. Jarjour said they may also be effective in late phase reactions and have been shown to improve airway function and quality of life, and reduce steroid and beta-agonist use. One of the problems of these drugs is that some patients do not respond well to them (Am J Resp Crit Care Med 1998;157:1363-1371).

The final treatment option discussed by Dr. Jarjour was omalizumab which is an anti-IgE drug. In a study from the University of California at San Francisco, 19 subjects with mild allergic asthma were randomized to receive either IV omalizumab or placebo. Antigen and methacholine challenges and sputum induction were done after 8 weeks of therapy. Omalizumab-treated patients showed reduced early and late phase responses to allergens, and a significant reduction of eosinophils (Am J Respir Crit Care Med 1997;155:1828-1834). Dr. Jarjour said, “at the end of the treatment with omalizumab they had few or virtually no eosinophil in their sputum and following antigen challenge the percent of eosinophils were still very low.”

Concluding Remarks
Airway remodeling is present in all asthmatic patients, even in mild, asymptomatic asthma patients. Inhaled corticosteroids provide the best anti-inflammatory effect in asthma and may reverse some changes associated with remodeling, but recent developments in our understanding of remodeling indicate that other medications such as theophylline or omalizumab are viable options.

Critical Assessment of Traditional Measures of Treatment Efficacy and Disease Progression

James P. Kemp, MD, Clinical Professor of Pediatrics at the University of California in San Diego, CA, began his presentation by stating there are many ways to measure treatment outcomes in asthma patients. Traditionally, FEV₁ has been the standard outcome used by the FDA but recent developments in our understanding of early and late-phase responses in asthma and involvement of the small airways in asthma make it clear better outcomes need to be employed. “There seems to be also a real disconnect or a lack of correlation between symptoms and other measurements of asthma outcomes compared to FEV₁,” said Dr. Kemp. For example, a study conducted at Stanford University examined outcomes in asthmatic children and found a very poor correlation between FEV₁ and other outcomes measures (wheezing episodes, asthma attacks, in-patient stays in the hospital, urgent care visits, symptom days, patient reported morning peak flows, nightime awakenings and bronchodilator use) (Pediatrics 2002;10:797-804). This is also true in adults. In a study by Drs. Teeter and Bleecker (Chest 1998;113: 272-277), a poor correlation between FEV1 and other outcomes measures (cough, wheeze, chest tightness, shortness of breath, sputum production and evening awakenings) was observed.

Measuring Treatment Efficacy
“Now, what about treatment?” asked Dr. Kemp. In the Optima study (Am J Respir Care Med 2001;164:1392-1398), over 600 steroid-naive patients who had a post-bronchodilator FEV₁> 80% of predicted were given placebo, low dose budesonide (100 mg bid), or budesonide (100 mg) + formoterol (4.5 µg). The
addition of the beta-agonist formaterol dramatically improved FEV₁ but there was no significant differences in the two groups in several other outcome measures including symptom days, rescue albuterol use, nighttime awakenings, or exacerbation rates. “So, if you were doing a study such as this with a long-acting bronchodilator you obviously would want to focus your primary efficacy outcome on pulmonary function testing,” said Dr. Kemp, adding, “but, that may not give you a total picture of how well the patient is doing because the patients may still have the same number of asthma exacerbations, symptom days, and night-time awakenings.”

To further illustrate the importance of multiple outcomes measures, Dr. Kemp mentioned that both the Greening and Wilcox studies (Lancet 1994;344: 219-234; Am J Crit Care Med 1996; 153:1481-1488) involved patients that were initially on inhaled steroids who were either given an increased dose of the corticosteroid or an inhaled long- acting beta- agonist (salmeterol). In both studies, the combination therapy was superior to doubling the dose of the steroid in symptom control and lung function. In the FACT study published in Lancet (Lancet 2001;357:257-261) the combination of inhaled steroid and formoterol had slightly better outcomes especially in pulmonary function but there was poor correlation between peak flow and other symptoms.

In realistic terms, the disconnect between FEV₁ and symptomology is best exemplified by the poor correlation between FEV₁ and pharmaco-economic parameters such as work/school day loss, unscheduled office visits, emergency department visits, and so forth.

Concluding Remarks
“FEV₁ is clearly a very objective measurement of large airway diameter and is very helpful in managing patients with obstructive airway disorders such as asthma. However, relying on changes in this parameter alone may miss a large part of the improvement which is occurring in asthma therapy, especially if the drug being studied is not a bronchodilator,” said Dr. Kemp, adding, “we really need to give a greater emphasis to more global measurements of the disease especially those measurements that reflect a patient’s ability to function normally or those which have a major effects on the total cost of the disease.” An exacerbation of asthma should not only be considered an indication of poorly controlled asthma but also a very expensive means of treatment.

The Patient with Difficult to Treat Asthma

“If one looks at the traditional way of categorizing and stratifying patients with asthma, one can turn to the GINA guidelines for the diagnosis and management of asthma and find that with intermittent disease we have characterized symptoms which are infrequent and lung functions which are normal,” began William Busse, MD, Professor of Medicine at the University of Wisconsin Medical School in Madison, WI, adding, “in patients with persistent disease, we can have mild, moderate and severe, and generally we tend to rank those based upon the level of airflow obstruction (mild AO > 80%; moderate OA > 60%; severe AO < 60%).” However, asthma is more than airflow obstruction and other outcomes should be measured, including symptoms, exacerbations, emergency room visits, hospitalizations, nocturnal symptoms, lung functions, and need for medications. In a recent report from an American Thoracic Society Workshop, the major characteristics of severe or refractory asthma was defined as a patient in need of treatment with continuous use inhaled (high dose) or oral corticosteroids. In addition, at least two minor criteria should be present to be considered having severe or refractory asthma (e.g., requirement for daily treatment with a controller medication in addition with the inhaled corticosteroid, long-acting beta-agonist, leukotriene receptor modifiers; need for short-acting beta-agonists use on a daily or nearly daily basis; evidence of airflow obstruction; 3 or more oral corticosteroid bursts per year; prompt deterioration of health following 25% reduction in medication; history of near fatal asthma event within past year). In summary, the new definition states airflow obstruction is not necessarily a major criteria.

“I think one of the questions that we all need to ask ourselves is: are we underestimating the severity of asthma in the patients that we are caring for?” asked Dr. Busse. In one study, the clinicians’ assessment of patients was analyzed and it was found that lung functions correlated well with clinicians’ definition of asthma severity but when other parameters were examined, the younger patients tended to be misdiagnosed. “Under-appreciation of asthma severity is noted at all ages, but it is most dramatic in younger people,” said Dr. Busse.

Treatment
Three treatment options are (or will soon be) available for severe asthma patients. The first option is a potent corticosteroid. For example, a high dose of fluticasone (1000 mg bid) can lead to 80% of patients being able to stop their inhaled steroid use compared to only 3% in the placebo group.

Another option is montelukast. In a study by Robinson et al. (Lancet 2001;357:2007-2011) however, severe asthmatics that were given montelukast (10 mg/day) or placebo did not show improved control of their asthma. Dr. Busse cautioned that further studies are needed to determine the efficacy of montelukast in patients with severe asthma.

One treatment that will likely be available soon is the anti-IgE drug, omalizumab. In phase III trials, omalizumab has been shown to reduce the need for inhaled corticlosteroid use in 75% of the patients (J Allergy Clin Immunol 200; 108:184-190). Dr. Busse warned, however, that in the placebo group, 50% of patients also reduced their inhaled corticosteroid use and Dr. Busse said, “I think it indicates that we may be overtreating some patients with inhaled corticosteroids, but in this situation the presence of this monoclonal antibody against IgE also allowed a greater percentage of these individuals to reduce or totally eliminate their dose of inhaled corticosteroids.” In further analysis, omalizumab was superior to placebo in better symptom control and need for rescue medication.

How Will the Role of the Allergist Change with the Availability of Novel Therapies?

Alkis Togias, MD, Associate Professor of Medicine at the Johns Hopkins University School of Medicine in Baltimore, MD, began his presentation by stating that there is a plethora of molecules involved in the early and late phase reactions associated with inflammation and asthma. There are many drugs in
development that attempt to manipulate the inflammatory responses. Of these new drugs, the most promising is omalizumab.

Pharmacology
Omalizumab is a monoclonal antibody that binds to free IgE. Omalizumab attaches at the Fc moiety of IgE to block IgE’s ability to bind to IgE receptors. The reduction in free IgE leads to a internalization of IgE receptors (high affinity). This is an indirect effect based on tight regulation of free IgE with IgE receptors leading to a reduction in high affinity sites (FceRI) on peripheral basophils (J Immunol 1997;158:1438-1445; J Clin Invest 1978;62:176-181). The end result is a reduction in inflammation and inflammation-induced airway obstruction.

Clearance and Dosing
Omalizulab binds with IgE to form complexes that are safely cleared by the liver. Dr. Togias said the safety profile of omalizumab in human trials has not raised any significant problems and theoretical concerns for immune complex disease or immune response to the complex have not been observed. Further-more, evaluation of renal function has not shown any omalizumab-specific effects.

In regard to dosing, Dr. Togias said baseline IgE and body weight must be obtained to deliver a safe and effective omalizumab:serum IgE ratio of 10:1.

Efficacy
Dr. Togias discussed some recent phase III studies involving patients with moderate to severe asthma (J Allergy Clin Immunol 2001;108:184-190; Eur Respir J 2001;18:254-261; Curr Med Res Opin 2001;17:233-240). In each trial, patients with moderate to severe asthma were treated with omalizumab or placebo, and according to Dr. Togias, “one of the characteristics of these studies is that they gave us very consistent data.” These studies demonstrated significant reduction in the rates of exacerbation ( two- to three-fold reduction over placebo), significant reduction in the dose of inhaled glucocorticosteroids required for asthma control, as well as significant reductions in rescue albuterol requirements, and in daytime and nighttime symptoms. Improvements in spirometric outcomes were also present and were statistically significant, albeit of small magnitude.

A post-hoc analysis of the data showed that the high risk patients (i.e., hospitalized for asthma in past year or prior incubation; n = 254) improved more significantly than the overall group. Dr. Togias ended his presentation saying, “I think that one can conclude from this sub-analysis that omalizumab is impressive in reducing asthma exacerbations and probably hospitalizations,” adding, “it seems that its effects are even stronger in patients with more severe forms of the disease and, on the basis of these data, I would say that it will become a powerful tool in the management of difficult allergic asthma.”

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