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IMMUNOMODULATORS SHOULD STILL BE CONSIDERED EXPERIMENTAL DRUGS FOR THE TREATMENT OF SYSTEMIC GLUCOCORTICOID DEPENDENT SEVERE PERSISTENT ASTHMA? Methotrexate Gaetano Caramori and Leonardo Fabbri Address for correspondence: Leonardo M. Fabbri, MD, Dipartimento di Medicina Clinica e Sperimentale, Sezione di Malattie dell’Apparato Respiratorio, Università degli Studi di Ferrara, Via Savonarola 9, 44100 Ferrara, Italy. Tel: x-39-532-210532, Fax x-39-532-210297.
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In this article we will briefly review the definitions of glucocorticoid-dependent and glucocorticoid-resistant asthma, and the role of immunomodulators as systemic glucocorticoids sparing drugs in their treatment. We anticipate the conclusion that, considering the cost-benefit of this treatment modality, immunomodulators should be used only in asthmatic patients in whom all current available treatments have been tried unsuccessfully and in whom systemic glucocorticoid dependance (not resistance) has been carefully demonstrated. We also believe that even in these patients, treatment should be instituted and carefully monitored only in specialised centres, by investigators with specific experience (1,2). Immunomodulators by definition have an effect (immunosuppression or immunostimulation) on the immune response (3). Asthma is actually considered an airways inflammatory disease immune mediated and in this article we will review the immunomodulators drugs which have proven to have a systemic glucocorticoids sparing effect in systemic glucocorticoids dependent asthmatics using for the whole group the term of systemic glucocorticoids sparing drugs. This first section includes definitions of glucocorticoid-dependent and glucocorticoid-resistant asthma and on the role of methotrexate. Further sections will be dedicated to cyclosporin A, gold salts, high-dose intravenous immune globulin and future immunomodulators.
PHARMACOLOGICAL TREATMENT OF ASTHMA
The current international guidelines on treatment of asthma recommend that whenever asthma is persistent, in addition to a major effort to prevent asthma by instructing the patients to avoid triggers, pharmacological treatment should include regular anti-inflammatory agents (inhaled glucocorticoids or sodium cromoglycate or nedocromil sodium) plus short acting bronchodilators only when needed (2). Regular treatment with long-lasting bronchodilators (inhaled salmeterol or formoterol; oral bambuterol, slow release terbutaline, sustained-release theophylline) is recommended only when regular anti-inflammatory agents do not put and maintain asthma under control (2). Administration of systemic, usually oral, glucocorticoids is limited to severe persistent asthma.
DEFINITION OF GLUCOCORTICOID DEPENDENT AND RESISTANT ASTHMA
Most patients with asthma respond to anti-inflammatory agents, and particularly to glucocorticoids, and in most of asthmatic patients adequate doses of inhaled glucocorticoids, combined with long-acting bronchodilators (e.g. long-acting ß 2 agonists and/or sustained-release theophylline) allow systemic glucocorticoids to be reduced or withdrawn completely (4-31). In fact, the current guidelines recommend to carefully monitor asthmatic patients not controlled by high doses inhaled glucocorticoids, and to check carefully the technique of inhalation and to add full doses of long-acting bronchodilators before considering systemic glucocorticoids (2). However, few patients with severe persistent asthma regularly treated with high doses inhaled glucocorticoids and full doses of short- and long-acting bronchodilators may still require high doses of systemic glucocorticoids to control their asthma, and in these patients long-term side-effects of systemic glucocorticoids, and particularly osteoporosis with bone fractures (32-35) become a serious problem. These patients are defined systemic glucocorticoid dependent asthmatics (SGDA). In a small minority of asthmatic patients inhaled and systemic glucocorticoids, even at very high doses, do not decrease symptoms nor increase significantly forced expiratory volume in 1 second (FEV1). These patients are defined glucocorticoid resistant asthmatics (GRA).
Glucocorticoid responsiveness in asthma (glucocorticoid sensitive asthma, GSA) has been defined in most studies as an increase in FEV1 of greater than 30% during a 7-14 day course of 20-40 mg prednisone (or prednisolone) per Os. At the present time, there is no universally accepted definition of glucocorticoid resistant asthma. Usually glucocorticoid resistance in asthmatics patients is defined by an improvement of less than 15% in FEV1 after a similar course of prednisone, despite a >= 15% increase in FEV1 in response to bronchodilator therapy (36-38). Thus, glucocorticoid resistant asthmatics are the patients who do not respond clinically to glucocorticoids, whereas systemic glucocorticoid dependent asthmatics are the patients who are controlled clinically only by high doses of systemic glucocorticoids.
DIAGNOSIS OF GLUCOCORTICOID DEPENDENT AND RESISTANT ASTHMA
The prevalence and incidence of glucocorticoid dependent and glucocorticoid resistant asthma are unknown. There are no epidemiological surveys of true glucocorticoid resistant asthma, but only gross estimate of 1:100-1:10,000 asthmatic patients (37,39). The great variability depends of the criteria of definition of glucocorticoid dependent and glucocorticoid resistant asthma, and most investigators working in this field strongly recommend to take full advantage of all available treatments before defining a patient glucocorticoid dependent. This recommendation is supported by the marked effect of placebo observed in systemic glucocorticoid dependent asthmatics treated with systemic glucocorticoid sparing drugs , which suggest that many of the patients defined as systemic glucocorticoid dependent are actually not properly treated.
The presence of systemic glucocorticoid dependent asthma may be an indication for the use of systemic glucocorticoid sparing drugs. Any drug that is effective in asthma, whatever its mechanism of action, will, by definition, have a systemic glucocorticoid sparing effect in that less systemic glucocorticoid will be required to achieve a given improvement in asthma control. Because of the toxicity of many of these drugs, and particularly of cytotoxic drugs, it is important, before diagnosing systemic glucocorticoid dependent asthma, to ensure that SGDA is in fact present (39,40).
The questions to be answered before establishing a diagnosis of systemic glucocorticoid dependent asthma are (40): 1) does the patients have asthma? Sometimes the poor response to glucocorticoids results from the fact that the patient has been misdiagnosed, and have another disease, often chronic obstructive pulmonary disease, which will not improve with glucocorticoid treatment (40-43); 2) are adequate doses of glucocorticoids reaching the airways? It is necessary to check the actual device and drug being used by the patient, as well as the inhalation technique of the patient (40); 3) have all provoking stimuli, especially domestic allergens or occupational sensitizers, been removed from the daily environment of the patient? Careful avoidance of allergens or chemical sensitizers has been proven to be quite effective in some asthmatic (40); 4) have all the potential aggravating factors such as drugs or gastroesophageal reflux been removed? (44, 45); 5) has the patient stopped taking regular doses of inhaled short-acting ß 2 agonists? (40); 6) has the patient followed a strict management plan, aimed at reducing the severity of the disease, for at least 6 months? (40).
Failure to control asthma on doses of 2 mg inhaled glucocorticoids per day (particularly if combined with regular full doses of long-acting bronchodilators) after all these factors have been addressed indicates systemic glucocorticoid dependent asthma. It is relatively unusual for patients with asthma who are taking these high doses of inhaled glucocorticoids correctly to require more than 5-7.5 mg prednisolone per day for asthma. Patients taking more than this should be investigated very carefully (46).
TREATMENT OF SYSTEMIC GLUCOCORTICOID DEPENDENT SEVERE PERSISTENT ASTHMA WITH SYSTEMIC GLUCOCORTICOID SPARING DRUGS
Systemic glucocorticoid sparing drug is any drug that is effective in asthma because by definition, it have a systemic glucocorticoid sparing effect in that less systemic glucocorticoids will be required to achieve a given improvement in asthma control (46). Systemic glucocorticoid sparing drugs are indicated only for systemic glucocorticoid dependent asthmatics (46).
In contrast to systemic glucocorticoid dependent asthmatics, truly glucocorticoid resistant asthmatics showing a response to bronchodilators and not to glucocorticoids should not be prescribed glucocorticoids nor systemic glucocorticoids sparing drugs (46). Systemic glucocorticoid dependent asthmatics should take advantage of all antiasthma treatments available, e.g. long-acting inhaled ß 2 agonists, sustained-release theophylline (28-31).
Whether in systemic glucocorticoid dependent asthmatics systemic glucocorticoids can be successfully replaced by experimental drugs depends on the extent to which the new drugs can replace systemic glucocorticoids maintaining control of asthma (systemic glucocorticoids sparing effect), and on the extent to which the side effects of the new drug are less than those of the dose of systemic glucocorticoids that it replaces (46).
There is apparently no significantly systemic glucocorticoid sparing effect from azathioprine (47), dapsone (48), hydroxychloroquine (49-52), pyridoxine (53), throleandomycin (54-64).
There is more convincing evidence of a systemic glucocorticoid sparing effect from methotrexate, gold salts (65-74) and cyclosporin A (45, 75-80). Other drugs (e.g. colchicine, 81-84; erithromycin, 85; supplemental estrogens in women, 86; 5-lipoxygenase inhibitors and cysteinil leukotriene receptors antagonists, 87 ;inhaled lysine acetylsalicylate and furosemide, 88; high dose intravenous immune globulin, 89-91) have been shown to have a systemic glucocorticoid sparing effect in some studies, but should be further investigated. In this first editorial we will concentrate on the systemic glucocorticoids sparing effects of methotrexate. Other immunomodulators, e.g., cyclosporin A, gold salts, and high dose intravenous immune globulin will be discussed in future notes.
TREATMENT OF SYSTEMIC GLUCOCORTICOIDS DEPENDENT SEVERE PERSISTENT ASTHMA WITH METHOTREXATE
Between the double blind, placebo controlled, studies on the treatment of systemic glucocorticoid dependent asthmatics with methotrexate (all studies used low-dose methotrexate: 15-30 mg/week oral or 15 mg/week intramuscolar), there are four positive studies with oral methotrexate (92-95), and five negative studies, three with oral and one with intramuscolar methotrexate (96-100). The positive studies reported a reduction of systemic glucocorticoid daily dose (92-95), and except one (94), reduced symptom scores. The negative studies reported no significantly benefits of methotrexate treatment at the end of the study respect to placebo (96-100).
All the placebo-controlled studies on methotrexate in systemic glucocorticoid dependent asthmatics show a reduction in systemic glucocorticoids requirement also in the placebo group , which emphasizes that there is a large overtreatment tendency or placebo effect in this disease, and that treatment on enrollment may be suboptimal. This suspicion is reinforced by the careful analysis of the patients characteristics. We were surprised to see that asthmatic patients with near normal lung function were included in some studies, and that in some of the studies there was not a careful attempt to reduce systemic glucocorticoids by properly treating the patients with full doses of inhaled glucocorticoids and long-lasting bronchodilators (e.g. sustained-release theophylline and/or long-lasting ß 2 agonists). Some of the studies on methotrexate have been performed before the long-acting ß 2 agonists, and particularly salmeterol, became available, and salmeterol has been shown to increase the control of asthma in patients not controlled by inhaled glucocorticoids (30-31). For all these reasons, the case-reports and the clinical studies of methotrexate in the treatment of glucocorticoid dependent asthmatics not placebo-controlled nor double-blinded (101-105,119) may show positive effects of treatment due at least in part to the effect of placebo. For this reason these studies should not be considered in the literature supporting this treatment modality.
Another consideration regard the aim of therapy. The present consensus on asthma management is that control should be (2):
- Minimally (ideally no) chronic symptoms, including nocturnal symptoms.
- Minimal (infrequent) exacerbations.
- No emergency visits.
- Minimally (ideally no) need for as needed ß 2 agonist.
- No limitations on activities, including exercise.
- Peak expiratory flow (PEF) circadian variation of less than 20 percent.
- (Near) normal PEF.
- Minimal (or no) adverse effect from medicine.
In fact, the benefits of methotrexate treatment should be carefully balanced with side effects (Table 1).
Methotrexate side effects can be classified as mild-moderate and severe-fatal (106). Both may develop after either short- or long-term treatment. Side-effects of short-term treatment with methotrexate in systemic glucocorticoid dependent asthma are usually mild-moderate, the most common being nausea, anorexia, and alopecia (92-100). Serum aminotransferase values may increase after methotrexate (92-100), and thus liver function must be monitored. Most clinicians would stop methotrexate if serum aminotransferase values exceed three times the normal levels (107). These mild-moderate side effects are usually reversible after suspension of methotrexate treatment (106).
The combination of methotrexate and prednisolone has been associated with Pneumocystis carinii pneumonia in at least four asthmatic patients, which was fatal in one of these cases (97,108,109). Theoretically, routinely Pneumocystis carinii pneumonia prophylaxis with trimethoprim/sulfamethoxazole can increase bone marrow toxicity.
A severe acute interstitial pneumonitis developed during methotrexate treatment in one systemic glucocorticoid-dependent asthmatic, probably as an idiosyncratic reaction to methotrexate. The pneumonitis reversed after suspension of methotrexate (110). Mullarkey recommends to obtain a chest radiograph and a measurement of carbon monoxide-diffusing capacity (DLCO) in each patient to be treated with methotrexate, and that the drug should not be administrated if DLCO is lower than 60 percent predicted (111). The long-term side effects of low-dose methotrexate have not yet been assessed in asthma, but can be expected from experience of the treatment of other chronic inflammatory diseases such as rheumathoid arthritis and psoriasis. A potential serious side effect is represented by a insidious interstitial pulmonary fibrosis particularly in lower zones of the lung, which is probably dose related and not reversible (112). Another potential, serious side effect of long-term treatment with low-dose methotrexate is represented by hepatic fibrosis and cirrhosis, which are no predictable and may develop also in the absence of serum liver enzyme elevations (107,113). Factors strongly associated with increased risk of chronic liver injury from methotrexate are represented by active or recent alcoholism, renal insufficiency or failure, preexisting liver disease, daily methotrexate dosing schedule (107). Patient to be treated with methotrexate should stop alcohol, monitor renal function and hepatic enzymes every 1-2 months (107). In some patient at risk, a pretreatment liver biopsy and one or more follow-up liver biopsy (e.g. every 1-2 years, or after each 1.5 g cumulative dose (or sooner if liver injury is suspected, biochemical or clinically) (107). Methotrexate use is contraindicated in acute hepatitis and active alcoholism (107). Disturbance of haemopoiesis (particularly macrocytosis and slight neutropenia) is common with the higher doses of methotrexate used for treatment of neoplasms (114), but rare with low dose (92-100), but blood cells count also require observation.
Another concern is that long-term treatment with methotrexate may actually cause asthma. In fact, has been reported a single patient with rheumatoid arthritis which developed asthma and airway hyperresponsiveness to methacoline while taking methotrexate, and disappeared on stopping the drug but do nor reappear after his reintroduction (115).
Patients without serum varicella zoster antibodies receiving low-dose methotrexate are at risk for disseminated varicella (111ab). Patients at risk should be treated with varicella zoster immune globulin within 96 hours after the exposure to chickenpox (111c). Patients with characteristic varicella skin lesions should be treated with oral or intravenous acyclovir and closely followed (111c). Severe abdominal or back pain is a herald of visceral involvement, and these patients should be hospitalized, treated with intravenous acyclovir, and monitored in an intensive care facility (111c).
Methotrexate is embryotoxic and teratogen and should be avoided in both males and females asthmatic patients who do not use effective contraception (1,111,114). Although no controlled studies have been designated to investigate the possible oncogenicity of methotrexate the treatment of patients with rheumatoid arthritis or psoriasis with low-dose methotrexate can be associated in very few cases with onset of neoplasms (116ab).
Folinic acid, is used as a "rescue therapy" to reduce the toxic effects of high dose methotrexate in the treatment of neoplasms (114) and folic acid to reduce toxicity of low dose methotrexate in the treatment of rheumatoid arthritis (117). The effect of folinic or folic acid supplementation on side-effects of treatment with methotrexate of systemic glucococorticoid dependent asthmatics has not yet been evaluated.
Drug interactions with methotrexate
Approximately 35% of the methotrexate in blood is bound to plasma proteins, and may be displaced from plasma albumin by a number of drugs, including certain antibiotics (sulfonamides, tetracycline, chloramphenicol), salicylates and phenytoin; caution should be used if these are given concomitantly (114).
Most of the methotrexate is excreted in the urine by a combination of glomerular filtration and active tubular secretion (methotrexate is a weak organic acid). Therefore the concurrent use of drugs that reduce renal blood flow (e.g. nonsteroidal anti-inflammatory drugs) or that are weak organic acids (e.g. aspirin or piperacillin) can delay methotrexate excretion (114). Particular caution must be exercised in treating patients with renal insufficiency (114). Methotrexate has an unpredictable effect on theophylline metabolism with a mean reduction in hepatic clearance of 19% (118).
The data now available indicate that methotrexate should not be prescribed to every systemic glucocorticoid-dependent asthmatic. In fact, while methotrexate may be advantageous in selected patients, every attempt to control asthma with regular antiasthma agents should be made.
Most studies on the effects of methotrexate in the treatment of systemic glucocorticoid-dependent asthmatics include small numbers of patients and all are of relatively short duration (46). Thus large long-term multicentre trials are urgently needed. In these studies, a uniform accepted definition of systemic glucocorticoid-dependent asthmatics should be used (46). For the time being, we reinforce the recommendation of the NHLBI/WHO panel (2) that methotrexate and other systemic glucocorticoids sparing drugs should be considered experimental medications, and used only in selected patients under the supervision of an asthma specialist with previous experimental experience (2).
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