Limitations of current treatment

Abstract

Asthma is common and cannot be cured, and there is no convincing evidence that it can be prevented except in an occupational setting. It can be treated, however, and good care and optimum drug treatment can convert asthma from a major handicap to a minor inconvenience. Management of asthma has improved enormously over the past 20 to 30 years due to advances in both drug development and in the way that drugs and care are delivered. While recognising the importance of all aspects of management I will focus here on pharmacological approaches to treatment. Modern pharmacological treatment of asthma dates from the turn of the century when adrenal extract was first used to treat asthma. Progress has been dominated by the progeny of two endogenous hormones, adrenaline and cortisol, to the extent that β-agonists and corticosteroids now account for almost 90% of all prescriptions for asthma in the UK. Research on adrenaline led to the introduction of the β1-selective agonist isoprenaline in 1940, the β2-selective agonists in the 1960s, and the long-acting β2-agonists in the early 1990s. Corticosteroids were introduced more recently, in 1950, and led in the early 1970s to the biggest advance in treatment so far—the introduction of lipid-soluble topically active corticosteroids for use by inhalation. Other drugs used to treat asthma include ipratropium bromide and theophylline amongst the bronchodilators and sodium cromoglycate and nedocromil amongst the prophylactic drugs. The leukotriene antagonists and 5-lipoxygenase inhibitors are available in some countries and their place in relation to other drugs is currently being assessed. Although a recent development over the past 10 years, the introduction of large controlled studies of treatment for asthma has enabled the magnitude of benefit from drug interventions to be assessed and compared in reasonably heterogeneous groups of patients with asthma. Such studies have shown clear benefit from inhaled corticosteroids1Haahtela J Järvinen M Kava T et al.Comparison of a β2-agonist, terbutaline, with an inhaled corticosteroid, budesonide, in newly detected asthma.N Engl J Med. 1991; 325: 388-392Crossref PubMed Scopus (689) Google Scholar, 2van Essen-Zandvliet EE Hughes MD Waalkens HJ Duiverman EJ Pocock SJ Kerrebijn KF The Dutch Chronic Non-Specific Lung Disease Study GroupEffects of 22 months of treatment with inhaled corticosteroids and/or β2-agonists on lung function, airway responsiveness, and symptoms in children with asthma.Am Rev Respir Dis. 1992; 146: 547-554Crossref PubMed Scopus (389) Google Scholar, 3Juniper EF Kline PA Vanzieleghem MA Ramsdale EH O'Byrne PM Hargreave FE Effect of long-term treatment with an inhaled corticosteroid (budesonide) on airway hyperresponsiveness and clinical asthma in nonsteroid-dependent asthmatics.Am Rev Respir Dis. 1990; 142: 832-836Crossref PubMed Scopus (519) Google Scholar and long-acting β-agonist4Tattersfield AE Clinical studies of β-agonists in adults.in: Pauwels R O'Byrne P β2-agonists in asthma treatment. Marcel Dekker, New York, Basel, Hong Kong1997Google Scholar, 5Pearlman DS Chervinski P LaForce C et al.A comparison of salmeterol with albuterol in the treatment of mild-to-moderate asthma.N Engl J Med. 1992; 327: 1420-1425Crossref PubMed Scopus (325) Google Scholar, 6D'Alonzo GE Nathan RA Henochowicz S Morris RJ Ratner P Rennard SI Salmeterol xinafoate as maintenance therapy compared with albuterol in patients with asthma.JAMA. 1994; 271: 1412-1416Crossref PubMed Scopus (162) Google Scholar, 7Wilding P Clark M Thompson Coon J et al.Effect of long term treatment with salmeterol on asthma control: a double blind, randomised crossover study.BMJ. 1997; 314: 1441-1446Crossref PubMed Scopus (108) Google Scholar, 8Juniper EF Johnston PR Borkhoff CM Guyatt GH Boulet L-P Haukioja A Quality of life in asthma clinical trials: comparison of salmeterol and salbutamol.Am J Respir Crit Care Med. 1995; 151: 66-70Crossref PubMed Scopus (174) Google Scholar, 9Pauwels RA, Löfdahl C-G, Postma DS, et al. Effect of inhaled formoterol and budesonide on asthma exacerbations. N Engl J Med (in press).Google Scholar not only in terms of lung function but also in clinical endpoints such as symptoms, nocturnal asthma, quality of life measures, and exacerbations in patients with mild and moderate asthma. In contrast it is now clear that in such patients the regular use of short-acting β-agonists three or four times daily causes little or usually no discernible clinical benefit when compared with their use "as needed".4Tattersfield AE Clinical studies of β-agonists in adults.in: Pauwels R O'Byrne P β2-agonists in asthma treatment. Marcel Dekker, New York, Basel, Hong Kong1997Google Scholar, 5Pearlman DS Chervinski P LaForce C et al.A comparison of salmeterol with albuterol in the treatment of mild-to-moderate asthma.N Engl J Med. 1992; 327: 1420-1425Crossref PubMed Scopus (325) Google Scholar, 6D'Alonzo GE Nathan RA Henochowicz S Morris RJ Ratner P Rennard SI Salmeterol xinafoate as maintenance therapy compared with albuterol in patients with asthma.JAMA. 1994; 271: 1412-1416Crossref PubMed Scopus (162) Google Scholar, 8Juniper EF Johnston PR Borkhoff CM Guyatt GH Boulet L-P Haukioja A Quality of life in asthma clinical trials: comparison of salmeterol and salbutamol.Am J Respir Crit Care Med. 1995; 151: 66-70Crossref PubMed Scopus (174) Google Scholar, 10Sears MR Taylor DR Print CG et al.Regular inhaled β-agonist treatment in bronchial asthma.Lancet. 1990; 336: 1391-1396Summary PubMed Scopus (854) Google Scholar, 11Drazen JM Israel E Boushey HA et al.Comparison of regularly scheduled with as-needed use of albuterol in mild asthma.N Engl J Med. 1996; 335: 841-847Crossref PubMed Scopus (324) Google Scholar These studies have informed current national and international guidelines on management and have led to substantial improvements in asthma management and control. Any discussion of the limitations of current treatment needs to be seen in the light of these achievements. The drugs available to treat asthma are particularly effective for patients with asthma of mild or moderate severity. They also help those with more severe asthma but many of these patients continue to have disabling symptoms and severe exacerbations. When treatment is given appropriately the proportion of patients with asthma who continue to have symptoms that limit their lifestyle is fairly small but because asthma is common the total number is considerable. Some estimate of the numbers can be gauged from two measures of morbidity: the use of regular oral steroids, a clear indication of severe asthma since patients have to contend with the adverse effects of steroids in addition to those of asthma; and the need for a short course of oral steroids. Our community-based studies suggest that some 50 000 patients in the UK currently take oral steroids on a regular basis for asthma (12Walsh LJ Wong CA Pringle M Tattersfield AE Use of oral corticosteroids in the community and the prevention of secondary osteoporosis: a cross sectional study.BMJ. 1996; 313: 344-346Crossref PubMed Scopus (336) Google Scholar and see figure 1 for spectrum of treatment used) and almost half a million patients take at least one course of oral steroids each year (Walsh LJ et al, Division of Respiratory Medicine, Nottingham, UK, unpublished data; see figure 2). These figures suggest that there is still considerable morbidity from asthma despite current treatment.Figure 2Proportion of patients in a community population in Nottinghamshire requiring a course of oral corticosteroids in the past year according to their treatment step of the asthma management guidelines.Show full captionAdapted with permission from unpublished data from L J Walsh.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Adapted with permission from unpublished data from L J Walsh. Although mortality has fallen in the UK and elsewhere over the past few years the fall has been relatively small and less than the perceived reduction in morbidity. Interpretation of changes in mortality is complicated without more accurate data on asthma incidence and severity and because of potential diagnostic confounding in the elderly with chronic obstructive pulmonary disease. It is further complicated by the fact that nearly all the drugs that are effective are themselves capable of causing death on rare occasions whether directly, as with arrhythmias from theophylline or β-agonists, or indirectly, as with corticosteroid-induced hip fractures. Inadequacies of diagnosis and management and poor compliance with treatment can often be found when patients have died of asthma, and psychosocial factors undoubtedly contribute in many instances. This must not obscure the fact, however, that the underlying problem in most patients is severe asthma that has not responded satisfactorily to treatment. Fortunately for patients with asthma most drugs can be given by inhalation, thus increasing their therapeutic selectivity and reducing systemic adverse effects. The two drugs that are given orally, theophylline and prednisolone, cause more problems. Many patients are unable to tolerate theophylline and its narrow therapeutic window limits its place in treatment.13Woodcock AA Johnson MA Geddes DM Theophylline prescribing, serum concentrations, and toxicity.Lancet. 1983; ii: 610-613Summary Scopus (89) Google Scholar Oral steroids clearly cause substantial morbidity. Drugs given by inhalation for asthma have an excellent safety record and patients rarely report adverse effects. It is something of a paradox, therefore, that potential adverse effects from β-agonists and inhaled corticosteroids have caused concern, the main reason being that the adverse effects in question are not detected easily by clinical trials or clinical experience. Whether β-agonists cause rare but serious adverse effects, and whether the marketing of a high-dose preparation of a non-selective β-agonist (isoprenaline) in the 1960s and a less β2-selective β-agonist (fenoterol) in New Zealand were causally associated with the mortality epidemics at these times is still debated.14Inman WHW Adelstein AM Rise and fall of asthma mortality in England and Wales in relation to use of pressurised aerosols.Lancet. 1969; ii: 279-285Summary Google Scholar, 15Jackson RT Beaglehole R Rea HH Sutherland DC Mortality from asthma: a new epidemic in New Zealand.BMJ. 1982; 285: 771-774Crossref PubMed Scopus (175) Google Scholar A serious but rare adverse effect will be detected when it is unusual, such as aplastic anaemia following chloramphenicol treatment, but is much more difficult to detect if it is an arrhythmia or worsening asthma as has been suggested for β-agonists, particularly when death occurs outside hospital. Yet a very rare event can still be important. If, for example, one in 8000 patients had a fatal outcome from a widely used drug it could in fact account for 50% of deaths from asthma in the under 50s in the UK. The question of inhaled steroids is different and relates to the difficulty in detecting long-term systemic effects. The adverse effects of oral steroids are obvious because they appear in some patients after short periods of treatment. Inhaled corticosteroids have detectable systemic activity and are therefore likely to have some systemic adverse effects but after a longer period of time. Osteoporosis is the long-term adverse effect of most concern16Wong CA Walsh LJ Tattersfield AE Perceived systemic effects of inhaled and oral corticosteroids.Am J Respir Crit Care Med. 1996; 153: A341Google Scholar and the relevant question therefore is how much does a given dose of a given inhaled corticosteroid increase the risk of osteoporotic fracture if taken for 30 or 40 years. The question is almost impossible to answer prospectively since cross-sectional studies suggest that the effect of 1000 μg a day of an inhaled corticosteroid on bone mineral density over 1 year is very small.17Wisniewski AF, Lewis SA, Green DJ, Maslanka W, Burrell H, Tattersfield AE. A cross-sectional investigation of the effects of inhaled corticosteroids on bone density and bone metabolism in patients with asthma. Thorax (in press).Google Scholar The cumulative effect over 30 or 40 years could nevertheless be appreciable. The question is important since 3% of the total population in the UK is currently taking an inhaled steroid and a fifth of these, roughly 330 000 people, are taking 1000 μg a day or more (Walsh LJ, personal communication). These two examples illustrate the difficulty in getting hard information on some adverse effects which nevertheless are potentially very important and where concerns undoubtedly influence prescribing and compliance with drug treatment. Cost is an important consideration for chronic conditions such as asthma and inhalers unfortunately cost more than tablets. Studies of the health economics of treating asthma and the cost implications of introducing new treatments have shown that some treatments such as inhaled steroids can be cost effective, at least in patients with moderately severe asthma in whom the additional cost of treatment is offset by a reduction in hospital costs.18Weiss KB The health economics of treating mild asthma.Eur Respir Dis. 1996; 33: 45-49Google Scholar, 19Sullivan S Elixhauser A Buist AS Luce BR Eisenberg J Weiss KB National Asthma Education and Prevention Program Working Group Report on the Cost Effectiveness of Asthma Care.Am J Respir Crit Care Med. 1996; 154: S84-S95Crossref PubMed Google Scholar These studies do not look at the financial consequences of drug costs for individual patients, however, and indeed there is little information on the extent to which reduced compliance or increased mortality is related to the expense incurred by patients in obtaining drugs or visiting a doctor. There are few countries in which patients do not have to find some money for treatment or consultations. Problems of cost and availability of drugs in western countries are trivial compared with those in many developing countries where even the cheapest drugs, theophylline and prednisolone, may not be available to some patients. Improving the diagnosis and delivery of health care to patients with asthma must continue to be a high priority. We also need new therapeutic approaches. Although less exciting than finding new types of drug it is worth restating that most of the major developments in the drugs available for asthma over the past 50 years have been due to modifications to the formula and/or formulations of β-agonists and corticosteroids. Are further improvements possible? Perhaps the main challenges are to increase the therapeutic index for inhaled corticosteroids by reducing their systemic activity and to determine why patients with more severe asthma do not get more benefit from higher doses. It may be possible, for example, to reduce systemic effects of corticosteroids by altering their pharmacokinetics or, more speculatively, by tissue-specific modification of intracellular transcription factors that alter the response to corticosteroids. The fact that the leukotriene antagonists are the only new category of drug to reach the market in the past 20 years is disappointing considering the great investment of time and effort that many scientists and pharmaceutical companies have devoted to asthma pharmacology. Perhaps we need to stand back and ask why progress is slow. It undoubtedly reflects our limited understanding of the mechanisms underlying asthma and in particular of the factors that initiate the inflammatory process. Inflammation once established involves a large number of cells, mediators, cytokines, transcription factors, and adhesion molecules and hitting one part of this pathway or some secondary phenomenon to the primary inflammatory pathway is unlikely to have much impact. We need to be able to separate the crucial and pivotal events in the development of inflammation from those that are secondary and relatively inconsequential. Whether there are crucial steps in the inflammatory cascade which, if blocked, would prevent airway inflammation is as yet unclear. Various approaches have or could be tried to develop new drugs for asthma (see panel).PanelApproaches to new drud development for asthmaInhibit or suppress inflammatory responseNeurokinin antagonistsPhosphodiesterase inhibitorsMonoclonal antibodies to interleukins, IgE receptors, adhesion moleculesIdentify genes for asthmaSegregation analysis or genome screening to find new genesDetermine which candidate genes are most important for initiation and maintenance of asthmaImmunological interventionAim to ↑Thl cells and ↓Th2 cells in early life?Exposure or avoidance strategies to environmental allergens?Parenteral immunisation with Th1-selective adjuvantIdentify environmental factors contributing to host susceptibility Inhibit or suppress inflammatory response Neurokinin antagonists Phosphodiesterase inhibitors Monoclonal antibodies to interleukins, IgE receptors, adhesion molecules Identify genes for asthma Segregation analysis or genome screening to find new genes Determine which candidate genes are most important for initiation and maintenance of asthma Immunological intervention Aim to ↑Thl cells and ↓Th2 cells in early life ?Exposure or avoidance strategies to environmental allergens ?Parenteral immunisation with Th1-selective adjuvant Identify environmental factors contributing to host susceptibility Inhibit or suppress inflammatory response—Much effort has been invested in documenting the features of the inflammatory response in asthma in the hope that this will lead to new classes of drugs that might be relatively specific for asthma such as leukotriene antagonists and 5-lipoxygenase inhibitors. Indeed several classes of drugs are under development including neurokinin antagonists, phosphodiesterase inhibitors, and monoclonal antibodies to interleukins, IgE receptors, and adhesion molecules. Whether and to what extent these drugs will be effective depends on how crucial their target is in initiating or maintaining airway inflammation. Perhaps the only way to find out is to look at the effect of antagonists or antibodies to each of these in patients but this approach is cumbersome and expensive. The leukotriene antagonist programme must have cost at least a thousand million pounds and similar investments will be required for any drug that reaches the stage of clinical trials. If this approach is to be repeated for antagonists and antibodies to all the potentially pro-inflammatory neurokinins, interleukins, or adhesion molecules, the cost will be exorbitant. Identify genes for asthma—Asthma requires a genetic predisposition and an appropriate environment. A better understanding of the genetic basis of asthma could help drug development.20Hall IP The future of asthma.BMJ. 1997; 314: 45-49Crossref PubMed Scopus (14) Google Scholar Two main approaches are currently used to try to identify relevant genes. The first, segregation analysis or genome screening, looks at the relation of highly variable sequences of the genome to features of atopy or asthma. This approach could identify new genes and hence new gene products that are important in asthma. The second approach is to look for potential candidate genes in patients with asthma such as those for cytokines, the high affinity IgE receptor, and the β2-adrenoceptor. This approach will not identify new genes but should help determine which genes are most important in the initiation and maintenance of asthma. Finding one or two genes that are particularly important would provide a focus for drug development. So far it is early days in the search for the genetic basis for asthma. Many studies have been small and the findings have varied considerably. One problem is in defining the phenotype as most measures of atopy and asthma are continuously distributed rather than categorical variables and different groups have used different endpoints. The lack of consistent findings between studies shows that asthma is polygenic, but how polygenic? Most of the genes for pro-inflammatory cytokines, enzymes, relevant receptors, and so on, are potential candidate genes but it is unclear how many genes or their promoters have polymorphisms or the extent to which they could contribute to determining the severity and persistence of asthma if not its initiation. Many studies are trying to determine which genes are important for asthma. Whether their findings can be exploited in the development of drugs should become clearer over the next few years. Immunological intervention—Asthma in western societies usually presents in the first few years of life as does the T cell response to environmental antigens. Having a stable memory population that consists predominantly of Th1 cells secreting interferon-γ and interleukin-2 rather than Th2 cells appears to protect against allergic disease. Interventions in early life might favour the emergence of Th1 cells but how this might be done is less certain. Animal studies suggest that exposure to high concentrations of antigen or derived peptides early in life can produce tolerance and a reduced IgE response whereas some studies in infants suggest that exposure to high concentrations of allergen in early life may have detrimental effects. Parenteral immunisation with a Th1-selective adjuvant might be used to induce Th1 responses21Holt PG A potential vaccine strategy for asthma and allied atopic diseases during early childhood.Lancet. 1994; 344: 456-458Abstract PubMed Scopus (161) Google Scholar though the difficulties in carrying out controlled studies in early life are formidable. identify environmental factors contributing to host Susceptibility—Evidence from a large number of sources shows that environmental factors are hugely important in determining whether patients develop asthma. Asthma is rare in rural communities in the developing world and becomes more common as societies become more westernised and more urbanised. Which factors associated with urbanisaton are relevant to the development of asthma are not as yet clear. The factors that have been considered include pollution, diet, food additives, childhood infections, allergen exposure, and immunisation. There are a lot of clues—associations established beyond hypothesis such as the importance of birth order—but is it host susceptibility that has increased or the level of a pollutant, allergen, or sensitising agent? Seaton has argued that it is much more likely to be host susceptibility, 22Seaton A Godden DJ Brown K Increase in asthma: a more toxic environment or a more susceptible population?.Thorax. 1994; 49: 171-174Crossref PubMed Scopus (415) Google Scholar but which aspect of host susceptibility has changed and which environmental factors are responsible? Determining the environmental factor(s) that are responsible for asthma would be very relevant to drug development. Changing the environmental factor might be possible but may not be feasible or acceptable. It is also possible that an environmental factor has adverse effects in asthma but beneficial effects elsewhere, as would be the case if the increased prevalence of asthma were related to increased consumption of less saturated and more polyunsaturated fats.23Black PN Sharpe S Dietary fat and asthma: is there a connection?.Eur Respir J. 1997; 10: 6-12Crossref PubMed Scopus (428) Google Scholar In this situation it may not be advisable to alter the environmental factor even if possible but knowing the mechanism underlying host susceptibility would provide a logical basis for drug development. Pharmacological treatment for asthma relies heavily on β-agonists and corticosteroids. The development of both classes of drug combined with a general improvement in management means that most patients with mild or moderate asthma can now enjoy a relatively symptom-free life. Many patients continue to have considerable morbidity nevertheless and these patients require a new addition to current treatment. How might this happen? Further substantial improvements to existing drugs are unlikely and whether any antibodies or antagonists to single elements of the inflammatory cascade will produce drugs that are more effective than corticosteroids is uncertain. Further understanding of the genetic determinants of asthma may help, depending on how polygenic asthma turns out to be in the final analysis. Immunological approaches seem to be sensible though the ethical considerations involved in carrying out prospective intervention studies in babies are enormous. The last approach, trying to identify the environmental factors responsible for asthma, could well be the most cost-effective way of finding new developments for treatment—and the best chance of finding therapeutic approaches other than drug treatment.