CLINICAL ALLERGY

0025-7125/92 $0.00 + .20

ANTI-INFLAMMATORY DRUGS IN THE TREATMENT OF ALLERGIC DISEASE Stanley J. Szefler, MD

PRESENT STATUS OF ASTHMA THERAPY

Anti-inflammatory therapy is utilized to treat a number of allergic diseases, including asthma, atopic dermatitis, rhinitis, and rarely, allergic conjunctivitis. At the present time, the treatment of asthma in the United States is undergoing changes in direction to emphasize anti-inflammatory therapy in patients with persistent symptoms. For this reason, this discussion focuses on the use of anti-inflammatory therapy in the treatment of asthma, with particular attention to glucocorticoid therapy. Certain patients fail to respond adequately, despite optimal bronchodilator and anti-inflammatory therapy. These patients may be candidates for medications with other anti-inflammatory or immunomodulator properties. In order to understand the selection process for the various medications, a model is proposed to overview the pathogenesis of asthma and the role of available interventions. STAGING THE PROGRESSION OF ASTHMA

The development of new information regarding the pathogenesis of asthma and the role of inflammation in the acute symptoms and progression of the chronic disease is moving at a rapid pace. Initially, the rapid deterioration in pulmonary function was attributed solely to airway muscle constriction. Therefore, emphasis was placed on bronchodilator therapy, specifically beta-adrenergic agonist and theophylline therapy. It is now clear that asthma is an inflammatory disease that leads to edema, airway smooth muscle constriction, and obstruction of the airways with secretions. From the Departments of Pediatrics and Pharmacology, University of Colorado Health Sciences Center, and the National Jewish Center for Immunology and Respiratory Medicine, Denver, Colorado THE MEDICAL CLINICS OF NORTH AMERICA VOLUME 76' NUMBER 4' JULY 1992

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The inflammatory cells release mediators that cause significant airway hyperresponsiveness to various stimuli, such as histamine, exercise, and cold air. 3 Initially, the inflammatory response was attributed to mast cells and eosinophils. Recently, the role of other cells identified in the airways, such as macrophages, neutrophils, lymphocytes, and platelets, has been implicated in the inflammatory process. These cells may contribute to the damage of the airway tissue or may be present to promote the healing process. Furthermore, the cells present in normal respiratory tissue, such as epithelial and endothelial lining cells, fibroblasts, muscle cells, and secretory cells, may interact with the inflammatory cells to generate a response to offending allergens or irritants. One would expect that the resultant effect would be resolution of the inflammatory process; however, there is clear evidence of persistent inflammation and chronic, irreversible airway damage with concomitant deterioration in pulmonary function. Based on the concept of inflammation, airway hyperresponsiveness, and obstruction, the recent trend in asthma therapy is to combine a bronchodilator, primarily beta-adrenergic agonists, with a nonbronchodilator antiasthma drug, either cromolyn or a glucocorticoid. 32 , 62, 66 The patient with severe chronic asthma requires a combined therapy of medications. The decision to begin certain treatments is primarily based on the severity of the disease, and asthma is broadly classified as mild, moderate, or severe. While this classification permits a simple categorization for therapeutic intervention, it does not adequately reflect the complexity of the disease. There are certain characteristics that impact on the management of asthma, including the exposure to specific allergens, the degree of airway hyperresponsiveness that may be manifested by bronchospasm induced by exercise, cold air, environmental irritants, and weather changes, and the presence of nocturnal exacerbations. In general, it is important to identify precipitants and develop methods to minimize their impact, alleviate airway hyperresponsiveness, and target therapy to control nocturnal symptoms. With the present emphasis on anti-inflammatory therapy, it is useful to turn to the experience gained from therapeutic intervention with other inflammatory diseases. For example, extensive experience is available with the application of anti-inflammatory and immunomodulator therapy in rheumatoid arthritis, inflammatory bowel disease, and systemic lupus erythematosus. Although the specific inflammatory process and efficacy of the various interventions may differ among these disorders, perhaps there are lessons to be gained from the experience of staging the disease and evaluating the efficacy of treatment interventions. One such model was proposed for the staging and treatment of rheumatoid arthritis.3334 Briefly, this model stages rheumatoid arthritis based on pathology, symptoms, physical signs, and radiographic changes. Treatments are progressive and designed to address joint symptoms and systemic involvement. Initially, management begins with education, physical therapy, and nonsteroidal anti-inflammatory drugs. The concern is that some aspects of the disease may be reversible and other aspects irreversible. It is possible that irreversible destruction can occur even at the stage of early diagnosis. As the disease progresses, other therapeutic modalities, such as methotrexate, gold, hydroxychloroquine, and d-penicillamine, are considered. Interestingly, systemic glucocorticoid therapy is considered "bridge therapy," that is, it provides relief while the other "disease-modifying anti-rheumatic drugs" are becoming effective. If these drugs fail, other alternatives, such as cytotoxics, pulse glucocorticoid combinations, totallymphocyte irradiation, interferon, and cyclosporine,

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are considered. It is easy to see where the direction for asthma therapy is following this path, and perhaps a similar model can be defined (Fig. 1). In applying this model, the following stages and characteristics are proposed: Stage 1: Stage 1 comprises the early onset of symptoms and could be characterized by sudden, episodic exacerbations often precipitated by allergen exposure or respiratory infections, usually viral in origin. This often begins in early childhood. Treatment is targeted to provide rapid relief of respiratory distress, and beta-adrenergic agonists and short courses of oral glucocorticoids are most effective. Stage 2: Symptoms in stage 2 become more frequent requiring institution of maintenance therapy. Education, compliance, allergen avoidance measures, and prophylactic therapy are very important. The treatment is designed to relieve symptoms and to minimize inflammation, specifically with combination bronchodilator (beta-adrenergic agonist, theophylline) and antiasthma (cromolyn, inhaled glucocorticoid) therapy. Stage 3: Symptoms in stage 3 significantly impact on the quality of life. Systemic glucocorticoid therapy is required for resolving acute exacerbations and may be necessary for maintenance therapy. The patient may be at risk for irreversible damage secondary to inflammation or adverse effects of systemic glucocorticoid therapy. These patients are considered for trials of high-dose inhaled steroid therapy or other forms of antiinflammatory therapy, such as troleandomycin, methotrexate, gold, hydroxychloroquine, or dapsone. Stage 4: Patients in stage 4 have deteriorating pulmonary function, persistent symptoms, and frequent life-threatening episodes of acute exacerbations. They may also be characterized as "recalcitrant" based on their poor response to bronchodilator and glucocorticoid therapy. They require specialty care and consideration for more aggressive forms of immunomodulator therapy since they are at significant risk for adverse effects related to high-dose bronchodilator and glucocorticoid therapy. Carefully controlled clinical trials are needed to define the role of immunomodulators, such as intravenous gamma globulin, interferongamma, and cyclosporine. Questions could easily be raised whether this form of immunomodulator therapy should begin earlier to prevent extensive irreversible damage to the airways. Unfortunately, the ability to characterize asthma and its specific stages is limited by the diagnostic techniques presently available. Characterization is highly dependent on symptom presentation, medication requirement, and pulmonary function tests. Careful analysis of the chronic severity and pathologic changes is in its infancy and includes the application of ongoing documentation of changes in pulmonary function through the use of home monitoring devices (peak flow meter) and sophisticated pulmonary function techniques (body plethysmography, airway challenges to specific and nonspecific stimuli), as well as the incorporation of bronchoalveolar lavage, endobronchial biopsy, and expanded radiographic techniques. This could be further refined by the identification of easily measured markers of inflammation to assess the presence and intensity of ongoing inflammation. When we reach this level of evaluation, we will be able to define the specific contribution of the proposed interventions. This will lead to a refinement in the presently proposed step-care, individualized approach to asthma therapy.

ASTHMA THERAPY - STAGE 1: ONSET OF SYMPTOMS TO THE TIME OF DIAGNOSIS AND FIRST LINE THERAPY Diagnosis of asthma

Symptoms - episodic

Pathologic changes Asthma often begins in early childhood with episodic exacerbations. Pathologic changes may be present at this early stage.

ASTHMA THERAPY - STAGE 2: SYMPTOMS BECOME MORE FREQUENT REQUIRING INSTITUTION OF MAINTENANCE THERAPY Symptoms· frequent

Allergen avoidance Symptom control (~agonists, theophylline) Anti·inllammatory therapy (cromolyn, glucocorticoids)

Pathologic changes Therapy is designed to relieve symptoms and also to minimize airway inflammation. Education, compliance, allergen avoidance measures, and prophylactic therapy are important.

ASTHMA THERAPY - STAGE 3: SYMPTOMS SIGNIFICANTLY IMPACT ON QUALITY OF LIFE

Symptoms· frequent, muHiple exacerbations Hlgh-cloaelnhaled glucocorticoid.

Attornalive antHnllommototy therapy Troteandomycin Methotrexate Gold

Hydroxychloroqulne Dapsone

Time

Pathologic changes. ? Irreversible

Systemic glucocorticoid therapy is required for acute exacerbations or maintenance therapy. Patient is at risk for irreversible damage secondary to inflammatory mediators or adverse: effects of glucocorticoids.

Figure 1. See legend on opposite page

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ASTHMA THERAPY· STAGE 4: DETERIORATING PULMONARY FUNCTION AND FREQUENT LIFE THREATENING EXACERBATIONS

Time

Require specialty care. Carefully controlled clinical trials needed to define appropriate medication and stage of intervention. Beware of potential placebo effsets.

Figure 1. Proposed model for the staging of asthma pathogenesis and treatment. The upper portion of the radian represents symptom presentation, such as episodic bronchospasm, exercise-induced asthma, nocturnal exacerbations, and deteriorating pulmonary function. The lower portion indicates pathologic changes, some of which may be reversible (airway secretions, edema, cellular infiltration, epithelial lining desquamation) but others irreversible (subepithelial fibrosis, smooth muscle hypertrophy). Also indicated is the present strategy for intervention at each stage.

MEDICATION SELECTION

The goal of asthma therapy is multiphasic: (1) to provide a bronchodilator effect to relieve bronchospasm; (2) to protect the airways from irritant stimuli and to prevent the pulmonary and inflammatory responses to an allergen; and (3) to resolve the inflammatory process in the airways, with consequent improvement in pulmonary function and reduced airway hyperresponsiveness. The individual medications may be grouped into those that are primarily bronchodilators (beta-adrenergic agonists, theophylline, anticholinergics) and those that are considered nonbronchodilator antiasthma medications (cromolyn, glucocorticoids). Response can be monitored in the office with pulmonary function tests and in the home with a peak flow meter. In addition, sophisticated testing such as bronchial challenge with methacholine and histamine can detect the degree of airway hyperresponsiveness, and body plethysmography can measure chronic changes such as hyperinflation resulting from persistent bronchospasm. Table 1 summarizes available information regarding the relative clinical effects of each medication class based on ability to bronchodilate, to protect the airways from allergen and irritant stimuli, and to resolve ongoing inflammation. Role of Bronchodilators in the Treatment of Asthma

In some respects, these medications are now viewed as supplementary to the nonbronchodilator antiasthma medications. The frequency of use could be an indication of the need for additional anti-inflammatory therapy.

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Table 1. COMPARATIVE EFFICACY OF AVAILABLE ANTIASTHMA MEDICATIONS Protection Medication [3-adrenergic Theophylline Cromolyn Anticholinergic Glucocorticoid

Bronchodilator

Allergen'

Histamine

+++ ++

I I,L I,L,AR

+++

+

L,AR

+

ND

Resolutiont

+ ++ +++

+ + +, marked effect; + +, moderate effect; +, some effect; -, no effect; NO, no data available. *Blocks immediate (I) or late (L) pulmonary response to allergen challenge, or consequent airway hyperresponsiveness (AR). tResolution is defined as a reduction in airway hyperresponsiveness with chronic therapy.

Beta-Adrenergic Agonists

Beta-adrenergic agonists as a group have evolved from those that are relatively short acting (epinephrine, metaproterenol) to those that have a longer duration of action (albuterol, terbutaline, pirbuterol) but that still last only 4 to 6 hours. 42 Their greatest advantage is a rapid onset of effect in the relief of acute bronchospasm via smooth muscle relaxation and increased mucociliary clearance. They are also excellent bronchoprotective agents for pretreatment prior to exercise. Prior to allergen exposure, they effectively block the early pulmonary response, but their duration of action is insufficient to prevent the late-phase pulmonary response and they do not block the development of airway hyperresponsiveness. 1Y It is expected that new beta-adrenergic agonists will be introduced that will extend the duration of bronchodilator and bronchoprotective effects. Two new compounds, salmeterol and formoterol, look very promising. 5 . 86 Theophylline

Although a weak bronchodilator when compared to beta-adrenergic agonists, the main advantage of theophylline is its long duration of action (10 to 12 hours), which is especially useful in the management of nocturnal asthma. 42 Theophylline has moderate bronchoprotective effects with regard to exercise and histamine challenge, and it also attenuates the early- and late-phase pulmonary response to an allergen challenge. 64 This may be related to potential anti-inflammatory properties, since it decreases microvascular leakage and macrophage activity. Doses of theophylline must be individualized to account for patient variability in absorption and elimination. There is a tendency for absorption to be slower at night as compared with the day, resulting in lower serum concentrations at night. A once-daily preparation at night or, alternatively, a rapidly absorbed preparation in the evening if a patient is receiving twice daily sustained-release theophylline may be useful in patients with nocturnal symptoms. 20 . 46. 52 Although the beneficial effects of theophylline are a mainstay for the management of chronic asthma, the narrow margin of safety and the risk for significant adverse effects are a continuing concern for patients and their physicians. All attempts to modify the structure to improve the benefit to risk balance have met with failure. The most recent attempt was enprofylline; however, the significant incidence of headache as an intolerable adverse effect prohibits its use at the present time.

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Anticholinergics

Anticholinergic drugs apparently have limited application in the treatment of severe asthma; however, there are ongoing attempts to further define their role in the treatment of asthma. While they would empirically seem to be beneficial, their actual effect is not very impressive. Perhaps newer agents with a longer duration of action when administered in a sufficient bronchodilator dose will result in increased use of this class of medications. Available studies in severe asthmatic patients suggest that anticholinergics provide additive effects to beta-adrenergic agonists, and higher doses, administered through a nebulizer, may extend the duration of effect of beta-adrenergic agonists. 88 Nonbronchodilator Antiasthma Medications

Cromolyn

Cromolyn blocks both the early- and late-phase pulmonary response to allergen challenge and prevents the development of airway hyperresponsiveness. 19 Its primary advantage is the minimal incidence of adverse effects that make it a safe medication for all age groups, including young children. The beneficial effects of cromolyn relate to its prophylactic effect for allergen- and exercise-induced asthma. Several excellent reviews have summarized the clinical efficacy and potential mechanisms of action of cromolyn in the treatment of asthma. 9 , 25, 61 While cromolyn appears to be an effective mode of therapy in the treatment of mild to moderate asthma (specifically early intervention at the early stage 2 level), cromolyn adds very little to the treatment of severe asthmatic patients in the presence of glucocorticoid therapy. Nedocromil

Nedocromil may provide the advantages of greater potency and an extended mechanism of beneficial effect. 6 49,67 Several recent reviews have summarized the clinical efficacy and potential mechanisms of action of nedocromil in the treatment of asthma. 27 29,40 Attempts to develop oral cromolyn-like agents have not been very successful, although one of these, ketotifen, is used extensively in Eastern countries where oral agents are preferred over the inhaled route. Glucocorticoids

Glucocorticoids represent the most potent anti-inflammatory agents available for the treatment of asthma. When administered prior to an allergen challenge in a sensitized patient, they block the late-phase pulmonary response and the development of airway hyperresponsiveness. 19 Continued administration of inhaled glucocorticoid therapy is also effective in reducing the immediate pulmonary response to an allergen challenge. Inhaled glucocorticoids are also more effective than beta-adrenergic agonists, theophylline, and cromolyn in reducing airway hyperresponsiveness during maintenance treatment. 21, 31. 45, 73 Only nedocromil provides a similar significant and sustained decrease in airway hyperresponsiveness. 6 The principles of glucocorticoid therapy are well established and include the use of systemic glucocorticoids to optimize pulmonary function, an assess-

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ment of severity as the dose is reduced, and an attempt to reduce the severity through the combination of bronchodilator and nonbronchodilator medications. l3 , 32, 62, 83, n Monitoring patients with a peak flow meter can be useful in assessing severity and evaluating the effect of medication adjustments. It is also important to identify and minimize the effect of triggers, to develop a crisis plan for severe episodes of bronchoconstriction, and to review the course frequently, especially if the goals of treatment are not attained. The dosing strategy involves applying higher and more frequent doses as the severity increases with a gradual reduction as control is established. Efficacy can be monitored by clinical symptoms, peak flow, pulmonary function tests, and possibly airway response to histamine or methacholine. Systemic Glucocorticoid Therapy. Severe acute asthma, status asthmaticus, is treated with high-dose systemic glucocorticoids combined with frequent administration of inhaled beta-adrenergic bronchodilator agents. Glucocorticoids can be administered by the parenteral route (methylprednisolone sodium succinate, hydrocortisone sodium succinate) or, alternatively, through the oral route (prednisone, methylprednisolone) which provides a rapid systemic effect. Methylprednisolone sodium succinate may be administered intravenously in a dosage of approximately 1 mg/kg every 6 hours. 32 , 3h, h2 Following resolution of severe obstruction, the steroid dose is reduced and administered by the oral route. The duration of treatment and tapering dose are dependent on the patient's response and past history. Glucocorticoids are also recommended for the treatment of impending episodes of severe asthma when bronchodilator therapy is inadequate. 4, 35 Prednisone, approximately 1 to 2 mg/kg per day, is administered orally in two to three divided doses for 3 to 7 days. Once again, the dose and duration of treatment are based on the patient's response and past history. In patients with poorly controlled chronic asthma, oral glucocorticoids may be administered in a dosing schedule similar to that previously described to maximize pulmonary function. Once this goal is achieved, the prednisone dose is tapered and may be supplemented and eventually replaced by inhaled glucocorticoids.'3, 32, 62, R3, 92 Inhaled Glucocorticoids. Recent emphasiS has been placed on the development of inhaled glucocorticoids and the important property of topical potency. The biological response to these agents is related to modification of the basic structure of the glucocorticoid molecule (Fig. 2). Modifications at the 16 and 17 position significantly increase topical anti-inflammatory potency. It was previously thought that halogenation at the 6 or 9 position would increase topical potency. In fact, this has little effect, as evidenced by the absence of halogenation in budesonide. Halogenation, however, does increase systemic potency. Therefore, budesonide appears to have the highest topical to systemic potency ratio, although this is based on limited comparisons that have been primarily animal studies. 11 The available inhaled glucocorticoids in the United States, beclomethasone dipropionate, triamcinolone acetonide, and flunisolide, appear to have similar topical to systemic potency ratios; however, more clinical studies are needed to clarify issues around comparative efficacy and toxicity.6h 76 All three are administered by a metered dose inhaler. Budesonide is the most carefully characterized inhaled glucocorticoid. It is a nonhalogenated glucocorticoid with high topical anti-inflammatory potency and low systemic bioavailability. An attempt was made to derive prednisone equivalents for the topical administration of budesonide. 64 From these studies, a 1 mg/day dose of budesonide produces an antiasthmatic effect equivalent to approximately 35 mg/day of prednisone in patients who have previously

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CH -OH

I

2

C=O

o HYDROCORTISONE

F

FLUNISOLIDE

CH -OH

I

2

C=O - - - - ·0'C_CH3 --·0/ 'CH3

o BECLOMETHASONE DIPROPIONATE

TRIAMCINOLONE ACETONIDE CH -OH

I

2

C=O - - - - . O'C-- H --·0/ 'CH2CH2CH3

o BUDESONIDE Figure 2. Structural formulas for glucocorticoids used in the treatment of allergic diseases.

received glucocorticoid therapy and 58 mg/day in patients who have not received glucocorticoids. This dose of inhaled budesonide also produces a systemic effect on serum cortisol concentration that is equivalent to 8.7 mg/day of prednisone. Given in high doses (up to 2.0 mg of inhaled budesonide per day), it may eliminate recurrent episodes of severe bronchospasm, even in patients with moderate to severe asthma. Budesonide doses exceeding 1.84 mg/day in adults may produce systemic effects on cortisol levels and eosinophil counts that are equivalent to 15 mg or greater of prednisone per day. The latter dose is associated with steroid complications, such as osteoporosis. More information is needed on prednisone equivalents, comparative efficacy, and toxicity for the inhaled glucocorticoids available in the United States, especially with long-term treatment. Furthermore, the systemic effect of inhaled glucocorticoids on serum cortisol and eosinophils may not represent meaningful

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clinical effects, and further studies are needed regarding their effect on other steroid adverse effects, such as hypertension, osteoporosis, and cataracts, as well as carbohydrate and lipid metabolism. Several recent studies suggest that high-dose inhaled glucocorticoids may affect growth, serum osteocalcin (a protein synthesized by osteoblasts and associated with bone formation), and skin thickness.!. 16,65,91 At the present time, product information is clear regarding maximum dosing guidelines for adults and children with the available inhaled glucocorticoids (Table 2). For triamcinolone and flunisolide, the maximum recommended dose is 1.6 and 2 mg/day for adult asthmatic patients, respectively. For budesonide, the inhaled steroid with the highest topical to systemic ratio, this dose is equivalent to 15 mg or greater of prednisone per day, which carries a risk for systemic effects. Therefore, patients requiring doses of the inhaled glucocorticoids approaching or exceeding 2 mg/day should be monitored for adverse effects. These maximum dosing guidelines are even lower for children. Needless to say, more studies are needed in both adults and children to establish safety guidelines for doses that exceed the product recommendations. Glucocorticoid Pharmacokinetics and Pharmacodynamics. The magnitude and duration of effect of glucocorticoids are dependent upon the structure of the glucocorticoid, binding to the steroid receptor, and the pharmacokinetics of the specific glucocorticoid. 1O The systemic availability and pharmacologic effect are altered by conditions that affect absorption, distribution, and elimination. Glucocorticoids are primarily eliminated via metabolic pathways, and certain inhaled glucocorticoids, such as beclomethasone dipropionate, are metabolized in the lung before they are absorbed, thus reducing their systemic effect. Very little is known regarding individual patient differences in pharmacokinetics that may influence clinical response. Insight has been gained through the application of assay techniques to measure glucocorticoid concentrations in biological fluids. Our own application of monitoring techniques have identified several important principles for glucocorticoids 39 ; 1. Concomitant medications can induce (phenytoin, carbamazepine) or impair (erythromycin, troleandomycin) glucocorticoid elimination. 2. Methylprednisolone is more susceptible to drug interactions than prednisolone, the active metabolite of prednisone. 7S 3. Assay techniques can be used to monitor compliance and identify rapid metabolizers and poor absorbers of glucocorticoids. Table 2. MAXIMUM RECOMMENDED ADULT AND PEDIATRIC DOSES FOR AVAILABLE INHALED GLUCOCORTICOID PREPARATIONS Adults Glucocorticoid Beclomethasone dipropionate Triamcinolone acetonide Flunisolide

Childrent

II-g per Inhalation

Inhalations per Day

mg per Day

Inhalations per Day

mg per Day

42

20

0,84

10

0.42

100'

16

1,6

12

1.2

250

8

2,0

4

1.0

•Actually 200 fJ,g per actuation, but 100 fJ,g retained in spacer, tPediatric doses are described for children 6 to 12 years of age,

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4. If glucocorticoid concentration in bronchoalveolar lavage fluid adequately reflects distribution to the lung, then methylprednisolone distributes better than prednisolone. 12. 30. 87 5. Although pharmacokinetic information is available for certain inhaled glucocorticoids, it is not sufficient for clinical applications. The available information has been summarized in a recent review. 7h Inadequate Response to Glucocorticoid Therapy. Most patients respond very favorably to either bronchodilator therapy alone or combined bronchodilator and anti-inflammatory medications. A significant number of patients, however, have severe asthma and require continuous glucocorticoid therapy. In this era of questions related to the increased prevalence of asthma, failure to reduce hospital admissions, escalating cost of health care, and possible increase in asthma mortality, it is important to question the natural history of asthma and methods to effectively control its progression. There appear to be a variety of ways that patients respond to a course of oral glucocorticoid therapy. ss The majority of patients improve within 3 to 5 days, while others require 7 to 10 days to recover maximal pulmonary function. Still others are characterized as "brittle asthmatics," those who have variable pulmonary function despite aggressive courses of glucocorticoid therapy. Patients who require systemic high-dose glucocorticoid therapy are at significant risk for adverse effects depending on the dose and duration of treatment. Remarkably, a proportion of these poorly responsive patients demonstrate minimal adverse effects. There is no question that the correct diagnosis, management of precipitants, appropriate use of conventional therapy, and adherence to the treatment regimen are basic tools to successful management. Certain patients, however, remain difficult to manage, raising questions about conditions that may alter the response to glucocorticoid therapy (Table 3). Failure to respond to glucocorticoid therapy could be related to overwhelming inflammation combined with an insufficient dose of medication. However, questions could be raised whether cellular resistance may result from druginduced desensitization,'S a genetic abnormality in the glucocorticoid receptor, 18.50 or as a consequence of the inflammatory process. Certain mediators such as interleukin-l and interferon-gamma can alter glucocorticoid response. 38. 81 Although the mechanism of action for interferon-gamma is unknown, interleukin-l decreases the density of glucocorticoid receptors. Clearly, further work is needed to understand conditions that may influence response to steroid therapy. Table 3. POTENTIAL MECHANISMS FOR POOR RESPONSE TO GLUCOCORTICOID THERAPY

Other respiratory disorder (vocal cord dysfunction, laryngeal abnormality, etc.) Overwhelming allergen exposure Irreversible airway hyperresponsiveness Poor adherence to treatment schedule Inadequate dose Psychosocial or psychological factors affecting care Pharmacokinetics Rapid elimination Poor distribution to the site of action Incomplete absorption Immunologic mechanisms of glucocorticoid resistance Down regulation of the glucocorticoid receptor Abnormal glucocorticoid receptor or postreceptor phenomenon

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New Directions for Glucocorticoid Therapy. Understanding the mechanisms of glucocorticoid action holds the key to insight into the control of the inflammatory response. A recent investigation of patients with nocturnal asthma demonstrated a circadian variation in the degree of inflammation in certain asthmatic patients. 51 Patients with nocturnal asthma have a heightened airway response to methacholine, an increased number of inflammatory cells in bronchoalveolar lavage fluid, and a decreased leukocyte beta-adrenergic receptor density and function during sleep as compared with during the waking hours. 51, 53. 78 This has implications for the timing of anti-inflammatory as well as bronchodilator therapy. There will be continuing attempts to improve the topical potency of glucocorticoids to maximize the anti-inflammatory effect in the lungs and minimize systemic exposure. A nebulized product with appropriate dosing guidelines for young children would also be very useful. In addition, a steroid selective for relevant inflammatory cells is highly desirable. Perhaps the identification of anti-inflammatory cell products resulting from steroid hormone action will lead to the development of new therapeutic agents.

ALTERNATIVE ANTI-INFLAMMATORY THERAPY

The well-known toxicities of chronic systemic glucocorticoid therapy have led to the search for alternative agents. At the present time, there are several alternatives to systemic glucocorticoid therapy, including troleandomycin, methotrexate, gold, and intravenous gamma globulin therapy. Patients with severe chronic asthma, previously described as stages 3 and 4, should be considered for a trial of alternative therapy: for example, those patients requiring systemic glucocorticoid therapy of greater than 10 mg per day of prednisone and especially those with significant adverse effects. All of these treatments are considered investigational, and their present status is summarized in Table 4. A comprehensive review is provided in reference 77. Troleandomycin

Troleandomycin (TAO) was first introduced as an antibiotic in the 1950s and was studied as a potential agent for "infectious asthma." A good clinical response based on sputum production and reduced need for medications in asthmatics was recognized, but this did not appear to be related to antibiotic effects.26.44 Further studies noted clinical improvement when TAO was added to the treatment regimen of severe asthmatic patients who did not respond to high-dose daily glucocorticoids. 41 A steroid-sparing effect was recognized when TAO was combined with methylprednisolone in steroid-dependent asthmatics. Based on observations of a relatively better response with a combination of TAO and methylprednisolone (TAO/MPn) as compared with TAO and prednisone, it is recommended that TAO be combined with methylprednisolone. 71 The use of combination TAO/MPn has been limited because of concerns regarding potential hepatotoxicity and exacerbation of steroid-related adverse effects. However, beneficial effects observed include a reduction in steroid dose, improvement in airway hyperresponsiveness, and improved pulmonary function and quality of life (Table 5). Pharmacokinetic studies show that methylprednisolone and theophylline

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Table 4. STATUS OF MEDICATIONS CONSIDERED AS ALTERNATIVE THERAPY IN THE TREATMENT OF SEVERE ASTHMA Troleandomycin Advantages Significant clinical response Multiple studies, years of experience Potential anti-inflammatory properties Disadvantages Potential increase in steroid side effects, especially in patients who require doses exceeding 12 mg methylprednisolone every other day Hepatotoxicity Future studies Specific effects of troleandomycin Refined guidelines to minimize adverse effects Methotrexate Advantages Ease of administration Growing evidence of efficacy Disadvantages Rebound upon discontinuation Careful monitoring for adverse effects Requirement for liver biopsy Risk for tetatogenic effects Future studies Mechanism of action Long-term safety Liver biopsy requirement-maximum time Oral Gold Advantages Steroid reduction and reduced airway hyperresponsiveness in a proportion of patients Disadvantages Limited experience Future studies Multicenter, placebo-controlled, double-blind trial needed Intravenous Gamma Globulin Advantages Good clinical response Minimal adverse effects Disadvantages Cost Inconvenient Rebound upon discontinuation Future studies Placebo-controlled, multicenter study needed Define minimum effective dose Gamma Interferon, Hydroxychloroquine, Dapsone, and, Cyclosporine Very limited experience Needs multicenter, placebo-controlled, double-blind trial

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Table 5. COMPARATIVE EFFICACY OF AVAILABLE ALTERNATIVE THERAPY Protection Medication

Troleandomycin Methotrexate Gold Hydroxychloroquine Dapsone Intravenous gamma globulin Cyclosporine

Bronchodilator

Allergen

Histamine

Resolution-

ND ND ND ND ND ND

ND ND ND ND ND ND

++

ND

ND

ND

++ ND ND

Steroid Dose Reduction

++ +++ ++ +++ +++ +++ ++

+ + +, marked effect; + +, moderate or inconsistent effect; +, some effect; -, no effect; ND, no data available. 'Resolution is defined as a significant reduction in airway hyperresponsiveness with chronic therapy. Modified from Szefler SJ: Alternative therapy: Rationale and guidelines for application. In Middleton E Jr, Reed CE, Ellis EF, et al (eds): Update Series 11: Allergy: Principles and Practice, 3rd ed. SI. Louis, The Mosby-Year Book Company, 1991, pp 1-11; with permission.

elimination is significantly impaired in the presence of troleandomycin. 79. 80 82 90 In contrast, prednisolone elimination is not altered. A recently reported "lower dose" TAO/MPn protocol for adults offered the advantage of fewer short-term steroid adverse effects and less hepatotoxicity, which may lead to increased use of TAO.s9 In addition, the investigators suggested that use of this treatment regimen may be indicated before high-dose steroid therapy is used and, thus, implied that the long-term adverse effects of glucocorticoids might be avoided. A recent review article summarized the available information and guidelines for troleandomycin therapy for severe asthma. 14 There are ongoing studies to determine the relative benefits of TAO/MPn therapy as compared with conventional therapy, the mechanism of action of troleandomycin, the safety of troleandomycin in children, and the long-term benefits versus risk. 2 Methotrexate

A recently proposed treatment for severe steroid-requiring asthmatic patients is methotrexate used in low doses of approximately 7.5 to 15 mg/week. Its potential as a steroid-sparing agent was first recognized in a patient with concomitant psoriatic arthritis and severe asthma. 57 A subsequent, doubleblinded, placebo-controlled clinical trial substantiated its efficacy in facilitating steroid-dose reduction with the consequent reduction in risk of adverse effects. 55 Several other short-term controlled trials showed similar beneficial effects in reducing oral glucocorticoid doses.», 69 Long-term (18-24 months) trials 56 , 70 showed that methotrexate maintained its effectiveness in reducing oral glucocorticoid doses without significant adverse effects. Potential mechanisms of action include anti-inflammatory properties, such as inhibition of neutrophil chemotaxis, reduction of interleukin-l production by mononuclear cells,68 and inhibition of basophil histamine release,15 In applying methotrexate for asthma therapy, the guidelines for the treatment of rheumatoid arthritis are used.37, 47 It is usually administered in dosages of 7.5 mg the first week, followed by 15 mg weekly. This may be given orally in three divided doses at 12-hour intervals or as a single weekly

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intramuscular dose. The parenteral route is preferred since it assures complete absorption. Prior to initiating methotrexate therapy, patients should be carefully evaluated for other forms of pulmonary disease besides asthma since methotrexate carries a risk for interstitial pneumonitis. Methotrexate is contraindicated in patients with significant abnormalities in renal function or liver chemistry, pregnancy, liver disease, alcohol consumption, severe blood dyscrasias, immunodeficiency, or active infectious disease. In addition, patients who are unreliable in compliance with a treatment program should not be included. Beneficial effects are not immediately apparent, and it may take several months to observe significant steroid dose reduction. 69 Some patients may fail to respond. 23 After 2 g of methotrexate have been given, consultation with a hepatologist for possible liver biopsy is recommended. It is also important to monitor laboratory tests, including blood chemistries, complete blood count with differential, and platelet counts every 4 weeks. These tests should be obtained 1 week after each dose increment. In addition, assays of liver function, such as prothrombin time and serum albumin, should be examined every 3 to 6 months. Adverse effects are minimal with the low-dose protocol but must be monitored carefully. The most frequent adverse effects include gastrointestinal complaints (10%), stomatitis (6%), and hematologic effects (3%) with leukopenia. These are usually dose-related and may be alleviated by temporarily reducing or discontinuing the dose. Patients should also be advised against alcohol consumption and pregnancy. Certain medications may increase the risk for methotrexate toxicity by decreasing renal elimination (salicylates, nephrotoxins) and reducing tubular secretion (salicylates, sulfonamides, penicillins).24 Present Application

Currently, methotrexate therapy is limited to severe steroid-requiring asthmatic patients. Patients must be carefully evaluated for other conditions that may limit the effect of conventional medical therapy. A high proportion of patients considered for alternative therapy are treatment failures for a variety of reasons, such as poor adherence to prescribed medications, poor education or reluctance to follow instructions regarding medication technique and environmental control, other medical conditions masking asthma (e.g., vocal cord dysfunction or structural laryngeal abnormalities), psychosocial features affecting medical care (e.g., depression, anxiety, or deliberate noncompliance), inadequate access to medical care, inability to afford medical care and medications, concomitant medical conditions influencing asthma control (e.g., gastroesophageal reflux or sinusitis), and pharmacokinetic abnormalities in theophylline or glucocorticoid absorption or elimination. Following exclusion of these variables, the number of eligible patients is very limited. Given the limitations of other forms of alternative therapy, the advantages and disadvantages of methotrexate must be considered. The advantages include ease of administration and evidence of potential efficacy (limited to reduction in steroid dose and some improvement in pulmonary function) in less than 100 patients (Tables 4 and 5). Although the frequency and magnitude of adverse effects appear low, the risk for adverse effects has not been sufficiently examined with a large population of asthmatic patients. Furthermore, there is no specific evidence of anti-inflammatory effect in asthmatic patients; for example, available studies show no effect on airway hyperresponsiveness. This suggests that it may be no more effective than inhaled steroids, especially at

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higher doses. There is no evidence of reduction in inflammatory response by bronchoalveolar lavage or biopsy. Of note is that one study failed to show a significant response in reducing steroid dose or improving pulmonary function. It is possible that these patients failed to respond because of irreversible airway damage (stage 4 disease). At the present time, methotrexate therapy must be applied with caution. Since methotrexate is an approved drug used for a nonapproved application, there are no product guidelines for the treatment of asthma, specifically in relation to selection criteria, duration of treatment, dosing guidelines, and criteria for identifying treatment failure. Available evidence indicates that a long-term commitment to treatment is required because symptoms recur following discontinuation of methotrexate. Methotrexate carries the risk for significant adverse reactions, including irreversible hepatotoxicity and potential for teratogenicity. Since there is no reliable noninvasive technique for early signs of hepatotoxicity, a decision must be made regarding the appropriate time for liver biopsy, a procedure that is not without risk. There is also a risk for drug interactions with commonly used medications, including alcohol, penicillin, salicylates, sulfonamides, and nephrotoxins. 24 Conversely, methotrexate may impair theophylline elimination in certain patients."" Needless to say, there is a critical need to conduct additional studies to verify efficacy and obtain clinical experience in a larger base of patients, bearing in mind the high cost and the difficulty in conducting these studies. If it is as effective as suggested by previous publications, perhaps it should be used earlier, such as in late stage 2 or early stage 3, before significant irreversible adverse effects of glucocorticoid therapy are seen. Since it appears that only a proportion of patients respond, additional studies are needed to characterize the patient population most likely to benefit. Experience to date is primarily in adult patients, with limited information available in asthmatic children." Additional issues to be addressed include guidelines for obtaining liver biopsies, the risk for pulmonary toxicity in asthmatic patients, the effect on airway reactivity, and the mechanism of action."' The beneficial effects of methotrexate have also raised the question of whether other modes of chemotherapy may be effective in the treatment of asthma. 4 " In the interim, methotrexate should be used cautiously and selectively. An adequate time trial should be defined, e.g., 6 months, to limit the time of exposure if treatment is ineffective. Physicians and patients should be fully aware of the potential benefits and risks with documentation by written informed consent. Future Application

Theoretically, the need for methotrexate therapy should be eliminated if the following occurs: 1. Treatment changes direction through national and world consensus on the management of asthma providing a greater number of patients with more effective care; 2. Patient awareness increases regarding asthma and the risk for mortality, morbiditv, and medication selection; 3. Patient e"ducation improves to emphasize the need for medications and appropriate technique; 4. Advances are seen in methods to implement environmental control; 5. Treatment technique improves for asthmatic patients who respond

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poorly, for example, application of high-dose inhaled steroids, application of chronopharmacologic techniques to maximize response and minimize adverse effects, early intervention for acute episodes, early intervention with anti-inflammatory therapy in chronic management, and better medications; and 6. Steps are implemented to improve accessibility to medical care and compliance with recommended therapy.

Gold

Similar to methotrexate, gold therapy is used to treat rheumatoid arthritis, and several reports suggest that it may be beneficial in the treatment of severe steroid-requiring asthmatic patients. Early studies utilized parenteral gold and described improvement in asthmatic symptoms and reduction in the mean daily dose of glucocorticoids. 50 Another study demonstrated that after 6 to 12 months of gold sodium thiomalate, approximately 1500 mg total, asthma symptoms improved along with diminished bronchial hyperresponsiveness to methacholine. 60 With the recent availability of auranofin (Ridaura), an oral gold compound, an open clinical trial was conducted to assess its efficacy in severe asthma. R Following a 20-week treatment period of 3 mg of auranofin given twice daily by mouth, spirometry remained the same while the maintenance steroid dose decreased approximately 33%. In addition, bronchial responsiveness to methacholine was significantly decreased in one half of the patients treated. Adverse effects were limited to mild diarrhea, dermatitis, and proteinuria and were resolved with temporary discontinuation or reduction of the dosage. Based on these provocative studies, further controlled clinical trials are in progress to verify its efficacy. Experience regarding gold therapy in asthma is only available in adult patients. Potential mechanisms of action in asthma may include inhibition of antibody production, lysosomal enzyme release from phagocytic leukocytes, and mediator release in immediate hypersensitivity reactions. Other studies suggest that gold may inhibit histamine and leukotriene D4 -induced contraction of airway smooth muscle and possible suppression of leukotriene B4 and C4 production.

Hydroxychloroquine

Because of its value in the treatment of connective tissue diseases, hydroxychloroquine has been recognized as a potential alternative for severe asthma. An open-label trial conducted in 11 adult asthmatic patients showed a 50% reduction in patients taking oral glucocorticoids. 17 A reduction in the total serum IgE level was also noted. Hydroxychloroquine may act through inhibition of phospholipase A2 activity, an important enzyme in the synthesis of prostaglandins and leukotrienes. Toxicity to hydroxychloroquine includes retinal damage that can be monitored by ophthalmologic examination and color vision testing. Larger scale controlled studies will be needed to confirm the findings of this pilot study.

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Dapsone

The anti-inflammatory effects of dapsone, including its ability to decrease neutrophil reactive oxygen species, chemiluminescence, and chemotaxis and its effectiveness in several rheumatoid diseases, suggest a potential beneficial role in asthma. An open-label trial demonstrated a reduction in oral glucocorticoid doses over the course of 6 to 13 months in steroid-requiring asthmatics. 7 Adverse effects noted during the study included malaise, rash, thrombocytopenia, and one psychotic episode. Nine of ten subjects had a significant decline in hemoglobin (mean decrease of 3.6 g/dL). Four subjects had transient increases in serum theophylline concentrations. Individuals with glucose-6-phosphate dehydrogenase deficiency are not suitable candidates for dapsone because of the risk of severe hemolytic anemia. Further investigations will be needed to establish the efficacy of dapsone in asthma.

IMMUNOMODULATOR THERAPY

In patients with severe recalcitrant asthma (stage 4 disease), conventional medications have limited efficacy. These patients have persistent symptoms despite aggressive bronchodilator and glucocorticoid therapy. They also have failed trials with one or more of the alternative anti-inflammatory therapies mentioned previously. These patients are at risk for severe exacerbations, as well as the adverse effects from high-dose systemic glucocorticoid therapy. Several treatments hold promise for these patients, specifically intravenous gamma globulin and cyclosporine, which are probably related to their effect on altering the immune response.

Intravenous Gamma Globulin

It is well known that active immunotherapy with specific allergens diminishes symptoms of allergic diseases and results in a decrease in specific IgE. Immunotherapy may also reduce airway hyperresponsiveness and may be effective in some cases of asthma. "Passive" immunotherapy with intravenous immunoglobulin (IVIG) may also provide several favorable effects in the treatment of asthma. In low doses, it increases serum antibody levels and protects individuals with impaired immunity to viral infections. This could diminish the number of episodes of viral-induced wheezing illness. 63 In high doses, IVle may act as an immunomodulator, providing passive protection and potentially assisting the immune system in regulating itself to produce less IgE. In vitro immunoglobulin synthesiS is diminished in patients receiving high-dose IVle in the treatment of immune thrombocytopenic purpura. In a limited open-trial using high-dose IVle in severe steroid-requiring asthmatic patients, reduction of steroid dose, improvement of pulmonary function, and diminution of skin test response to specific allergen were observed. 54 It is also possible that IVle improves asthma by affecting chronic bacterial sinusitis or a persistent infection in the airways. The experience with this mode of therapy is still limited and requires further controlled studies, especially in view of the significant cost for IVle administration.

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Cyclosporine

Cyclosporine inhibits T-lymphocyte immune responses by interfering with cytokine synthesis and release; moreover, it inhibits histamine and leukotriene C4 release from human basophils and pulmonary mast cells challenged with anti-IgE. A 9-month open-label trial using a group of steroid-dependent asthmatic patients led to a 66% reduction in prednisone dose in half the subjects while pulmonary function improved significantly.?4 The remaining half failed to respond. Toxic effects noted during the study included a transient ischemic attack and septic cholangitis in one individual and peripheral venopathy in another. Mild elevation of serum creatinine was common, and some individuals experienced worsening of pre-existing hypertension. While promising, the potential toxicity and the lack of response in half the subjects may limit the use of cyclosporine in asthma.

PROSPECTUS

The treatment of asthma has changed dramatically over the past several years with the development of new medications and delivery systems and the refined use of old medications. There are still a significant number of patients who respond poorly despite appropriate therapy. Alternative treatments are available, but continued research is needed to define the mechanisms of action and the patient population most likely to respond to each treatment. Doubleblind, placebo-controlled trials are needed to verify efficacy. It is also promising that new medications, such as potassium channel activators, platelet activating factor and leukotriene antagonists, leukotriene synthesis inhibitors, thromboxane synthetase inhibitors, and neurokinin antagonists, to name a few, will be available as alternatives to systemic glucocorticoid therapy. Because of the risk for significant morbidity due to the disease and its treatment, ongoing research is essential to improve the life-style of these patients. ACKNOWLEDGMENTS Supported in part by FD-R-000278 from the Food and Drug Administration Program for Orphan Drugs and 2-P01-HL-36577 from the National Institutes of Health, Heart, Lung and Blood Institute.

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Address reprint requests to Stanley J. SzefIer, MD Department of Pediatrics National Jewish Center for Immunology and Respiratory Medicine 1400 Jackson Street Coodman Building, Room 926 Denver, CO 80206