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Methotrexate in the treatment of severe asthma
Respiratory Medicine (1993) 87 (Supplement B), 57-60
Methotrexate in the treatment of severe asthma J. L. YNTEMA*:~, C. WALKER~"AND R. AALBERS*
*Netherlands Asthma Centre and ~fSwiss Institute for Allergy and Asthma Research, Davos, Switzerland, and ~Department of Pediatric Pulmonology, State University, Nijmegen, The Netherlands
Introduction An increasing number of studies show that bronchial asthma even in its mildest form is characterized by local inflammation of the bronchial wall (1-3). Avoidance of known triggering factors like allergens, smoke and fumes, together with agressive regular therapy with bronchodilators and cromolyn or nedocromil are the cornerstones of treatment. If symptoms or changes in airway function occur more frequently, inhaled steroids may be indicated (4). The majority of patients can be treated without systemic steroids, except infrequent rescue courses during exacerbations. However, in some patients exacerbations are so frequent and severe, that increasing dosages and eventually maintenance treatment with oral corticosteroids becomes necessary. In these steroid-dependent asthmatics, long term systemic steroid therapy is associated with adrenal suppression and severe side-effects, such as obesity, diabetes, osteoporosis, myopathy, cataract, hypertension, and (in children) growth retardation. In order to reduce the long term side-effects, 'steroid-sparing' agents have been sought that would allow a reduction of the dose of corticosteroids, without losing control of asthma. It was recognized that agents used in other chronic inflammatory disorders, such as rheumatoid arthritis and psoriasis, might also have an effect in asthma. This led to the clinical evaluation of various agents with anti-inflammatory activity as steroid-sparing therapy in asthma. Several placebo-controlled studies suggest that a weekly pulse dose of methotrexate might have a beneficial effect in patients with steroid-dependent asthma, mainly by reducing the dosage of oral corticosteroids necessary to keep control of symptoms (5-7). Methotrexate Methotrexate (MTX) was introduced in the therapy of malignancies in 1948, and subsequently in the therapy of psoriasis and rheumatoid arthritis (8). More 0954-6111/93/0B0057+ 04 $08.00/0
recently it was introduced as a 'steroid-sparing' agent in the treatment of patients with severe steroiddependent asthma (9). Methotrexate is a folic acid antagonist that binds preferentially to the enzyme dihydrofolate reductase, and interferes thereby with thymidine synthesis, an essential component of DNA. As a result, D N A synthesis and cell replication are blocked (10). When given in high doses (50 mg or more per week) MTX has predominantly antineoplastic activity, and is used in the treatment of cancer. In a low-dose regimen (5-25mg week -I) it probably has an anti-inflammatory effect, which may explain its effect in the treatment of rheumatoid arthritis, dermatomyositis, psoriasis and asthma. The antiinflammatory mechanism of action is not well understood. In asthma its effectiveness might be related to its inhibitory activity on cellular immunity and the release of mediators. Methotrexate inhibits the histamine release from human basophils (11). Interleukin (IL)-I activity of mononuclear cells is also inhibited (12). Interleukin is important in the inflammatory response as (in vitro) inducer of mediator release from basophils, mast cells and endothelial cells and promotes the synthesis of other proinflammatory cytokines. However, the role of IL-1 in asthma has recently been questioned (13). In neutrophils a reduction ofchemotaxis has been demonstrated (14). Methotrexate does not seem to affect intracellular killing and phagocytosis (15). Preliminary results of a study performed in our clinic, in cooperation with the Swiss Institute for Allergy and Asthma Research, demonstrated that 8 weeks treatment of severe, steroid-dependent asthmatics did not have a significant effect on numbers of lymphocyte subsets (CD-4 and CD-8), as has been demonstrated earlier in patients with rheumatoid arthritis (16), or on markers of lymphocyte activation such as CD-23 and HLA-DR. However, in our study there appeared to be an association between a positive clinical effect of MTX treatment, measured by peak flow rate and symptom score, and an increased inhibition by dexamethasone on the proliferation response of phytohaemagglutinin 9 1993Bailli~reTindall
58
J. L. Yntema et al.
(PHA) stimulated lymphocytes in vitro. In one patient a reversed response was accompanied by a severe increase in asthma symptoms, which forced a discontinuation of MTX treatment. These findings suggests that the immunomodulatory effect of MTX in asthma is complex, and can interfere with the effect of steroids.
Dosage and Pharmacokinetics of MTX Methotrexate may be given by the oral or parenteral route. The dosage varies, depending on the disease for which it is being used, the clinical effect and the tolerance of side-effects. The average dose employed for asthma in adults as well as adolescents is 15 mg, given as a once weekly 'pulse dose', but doses as high as 50 mg have been required for clinical improvement (17). Oral and parenteral administration are equally effective. The parenteral route may offer an advantage with respect to hepatotoxicity, since the liver is bypassed. Sixty percent of the orally administered drug is absorbed, with a direct relationship between dose and plasma concentration. The plasma half-life is 2 h. Approximately 50% of the drug is protein-bound and can be displaced by drugs such as salicylates, penicillins, tetracyclins and sulphas. About 9(~95% of the drug is excreted unchanged in the urine after 24-30 h (8). The serum concentration of methotrexate can be measured to assure complete clearance of the drug from the vascular compartment in 24 h. Levels are determined 1 h after the weekly dose and 24 h later. Acceptable concentrations at 1 h are approximately 6 x 10 7M, and undetectable levels at 24 h (19).
Side-effects and Toxicity Early side-effects are nausea and vomiting, mucosal ulcerations, abdominal cramps and diarrhea. These side effects seem to occur less frequently when the parenteral route of administration is used. The oral dose can be divided into two or three fractions at 8-h intervals when there is gastrointestinal intolerance. Together with dermatitis and alopecia these side effects are considered as mild, and usually do not require reduction of the dose. Hepatotoxicity and neutropenia are considered as moderate side effects. About onethird of all patients receiving MTX, regardless of the dose, will experience abnormalities in liver function tests. The long-term significance of this is not fully understood. Most clinicians reduce the dose or temporarily stop the treatment if hepatic enzyme values increase to more than three times normal. The hepatic enzyme abnormalities are usually rapidly reversible. The correlation of low dose MTX treatment with the ultimate development of hepatic fibrosis is not well established. Unfortunately this can only be revealed
by liver biopsy, as there seems to be a poor correlation between liver function tests and ultrastructural changes (20). In children treated for leukemia with a long-term high dose MTX a 20% incidence of fibrosis has been reported (21). Although debatable in low dose treatment of rheumatoid arthritis and asthma, a liver biopsy after administration a cumulative dose of 1.5 g MTX has been advocated (22). Severe side effects of low dose MTX treatment are relatively infrequent. After prolonged administration occurrence of acute interstitial pneumonitis has been described. This serious and potentially fatal side effect has been reported predominantly in patients with rheumatoid arthritis (23,24). Preexisting lung disease has been suggested as a precipitant factor (25), and extensive lung function studies, including DLCO, are mandatory before MTX treatment is decided. Sporadic fatality after infection with Pneumocystis carinii has been described by several authors (26-27). One case was reported in which a patient with rheumatoid arthritis developed bronchial hyperresponsiveness and asthma as a result of low dose MTX therapy (28). MTX is teratogenic, so appropriate anti-conceptive precautions are necessary. Neurotoxicity, nephrotoxicity and oncogenesis do not appear to be problems at low dose levels (29). Leucovorin, a derivative of folinic acid, is used as a 'rescue therapy' to reduce the toxic effects of high dose MTX in the treatment of cancer. Recently a doubleblind study in patients with rheumatoid arthritis showed, that supplementation with 1 mg daily also significantly lowered toxicity of low-dose MTX, without affecting efficacy (30). In asthma the effect of leucovorin supplementation has not been evaluated.
Drug Interactions with MTX There are many drug interactions that may occur with methotrexate. Blockade of the renal tubular excretion and displacement from plasma proteins are the most important mechanisms by which drugs like certain antibiotics (sulphas, tetracyclines, penicillins), salicylate, fenytoin, barbiturates, probenicid and some NSAID's interfere with the bioavailability of MTX. Increased toxicity may be the result and patients should either avoid these drugs or use them very cautiously, strictly adhering to dose regimens and sometimes to monitoring plasma levels of MTX. The use of alcohol should be avoided to prevent toxic liver damage.
Clinical Studies After the first report from Mullarkey et al. on the beneficial effects of MTX in a patient with psoriatic
M e t h o t r e x a t e and asthma
arthritis and steroid-dependent asthma who was able to discontinue steroid treatment completely (9), the effectiveness of M T X as a steroid-sparing agent has been demonstrated in several uncontrolled and doubleblind placebo-controlled studies (5 7). One studycould not confirm this (26). Outcome variables in all studies were the oral corticosteroid dose as a percentage of the dose in the run-in period, and parameters of asthma control such as peak flow values, lung function and symptom scores. However, there are some flaws inherent to these studies. Unfortunately, the term 'steroid-dependent asthma' is not uniformly defined. N o w the 'optimal' dose of oral steroids and other anti-inflammatory therapy was determined before the patients were enrolled into the study was not specified.
Conclusions Though side effects of M T X in asthma seem to be rather mild, and are rapidly revealed by good monitoring, the a m o u n t of studies available is still limited, and the follow-up periods are relatively short. Hence, considering only these clinical studies, there is a danger of underestimating severe side effects and long-term toxic effects of M T X in asthma. Moreover, the efficacy of M T X in asthma is still unpredictable. It is unknown why some asthmatics do respond well to treatment with a low dose, and why other patients do not or need a much higher dose. The possibility of potential serious toxicity restricts its current use to a selected group of patients w h o experience serious side effects from long-term treatment with systemic steroids. The use of M T X in these patients seems to be justified as long as no better result could be achieved with an alternative therapy. M T X could play a disease modifying role, decreasing the dose and long-term side effects of systemic steroids without losing control of symptoms. Before advocating the use of M T X to other groups of asthmatics more clinical and fundamental studies are needed.
References 1. Beasley R, Roche WR, Roberts JA, Holgate ST. Cellular events in the bronchi in mild asthma and after bronchial provocation. Am Rev Respir Dis 1989; 139: 806-817. 2. Laitinen LA, Heino M, Laitinen A, Kava T, Haahtela T. Damage of the airway epithelium and bronchial reactivity in patients with asthma. Am Rev Respir Dis 1985; 131:599 606. 3. Djukanovic R, Wilson JW, Britten KM et al. Quantitation of mast cells =nd eosinophils in the bronchial mucosa of symptomatic atopic asthmatics and healthy control subjects using immunohistochemistry. Am Rev Respir Dis 1990; 142: 836-871.
59
4. National Heart, Lung, and Blood Institute, National Institutes of Health. International Consensus Report on Diagnosis and Treatment of Asthma. Clin Exp Allergy 1992; 22 (Suppl.): 34. 5. Mullarkey MF, Blumenstein BA, Andrade WP et al. Methotrexate in the treatment of corticosteroiddependent asthma: A double-blind crossover study. N EnglJMed 1988; 318:603 607. 6. Dyer PD, Vaughan TR, Weber RW. Methotrexate in the treatment of steroid-dependent asthma. J Allergy Clin Immuno11991; 88:208 212. 7. Shiner RJ, Nunn A J, Chung KF, Geddes DM. Randomized, double-blind, placebo controlled trial of methotrexate in steroid-dependent asthma. Lancet 1990; 336: 137-140. 8. Gubner R, August S, Ginsburg V. Therapeutic suppression of tissue reactivity. II: Effect of aminopterin in rheumatoid arthritis and psoriasis. Am J Med Sci 1951; 221: 176-180. 9. Mullarkey MF, Webb DR, Pardee NE. Methotrexate in the treatment of steroid-dependent asthma. Ann Allergy 1986; 56:347 350. 10. Calabresi P, Parks RE. Chemotherapy of neoplastic diseases. In: Goodman A, Gilman LS, Rail TW, Murad F, eds. The Pharmacological Basis of Therapeutics. Seventh edn. New York, Macmillan, 1985; 1264. 11. Nolte H, Skov PS. Inhibition ofbasophil histamine release by methotrexate. Agents Actions 1988; 23:173-I 76. 12. Segal R, Mozes E, Yaron M, Tartakovsky B. The effects of methotrexate on the production and activity of interleukin-1. Arthritis" Rheum 1989; 32:370 377. 13. Vacchiarelli A, Siracusa A, Cenci E, Puliti M, Abbritti G. Effect of corticosteroid treatment on interleukin-I and turnout necrosis factor secretion in by monocytes from subjects with asthma. Clin Exp Allergy 1992; 22:365 370. 14. Cream JJ, Pole DS. The effect of methotrexate and hydroxyurea an neutrophil chemotaxis. Br J Dermatol 1980; 102:192 196. 15. Johnson JD, Summergill JT, RaffMJ. Thein vitro effects of methotrexate on the phagocytosis and intracellular killing of S. aureus by human neutrophils. Cancer 1986; 57:2343 2345. 16. Andersen PA, West SG, O'Dell JR, Via SS, Caypool RG, Kotzen BL. Weekly pulse methotrexate in rheumatoid arthritis. Clinical and immunological effect in a randomized double-blind study. Ann Intern Med 1985; 103: 489 496. 17. Mullarkey MF, Lammert JK, Blumenstein BA. Longterm methotrexate treatment in corticosteroid-dependent asthma. Ann Intern Med 1990; 112:577-581. 18. Kremer JM, Galivan J, Streckfuss A, Kamen B. Methotrexate metabolism analysis in blood and liver of rheumatoid arthritis patients. Arthritis Rheum 1986;29:832 835. 19. Wallace CA, Bleyer WA, Sherry DD et al. Methotrexate levels in juvenile rheumatoid arthritis patients (abstract). Arthritis Rheum 1988; 31: $26. 20. Lewis JH, Schiff E. Methotrexate-induced chronic liver injury: guidelines for detection and prevention. Am J Gastroenterol 1988; 88:1337 1345. 21. Wiedrich T, Keller D, Sunita A, Gilbert E. Adverse histopathologic effects of chemotherapeutic agents in childhood leukemia and lymphoma. Pediatr Pathol 1984; 2: 267 283. 22. Health and Public Policy Committee, American College of Physicians. Methotrexate in rheumatoid arthritis. Ann Intern Med 1987; 107: 418-419.
60
J. L . Y n t e m a et al.
23. Cannon GW, Ward JR, Clegg DO. Acute tung disease associated with low-dose pulse methotrexate therapy in patients with rheumatoid arthritis. Arthritis Rheum 1983; 26:1269 1274. 24. Searles G, McKenchry RJR. Methotrexate pneumonitis in rheumatoid arthritis: potential risk factors. Four case reports and a review of the literature. J. Rheumato11987; 14:1164-1171. 25. Bell M J, Geddie WR, Gordon DA, Reynolds WJ. Preexisting lung disease in patients with rheumatoid arthritis may predispose to methotrexate lung. Arthritis Rheum 1986; 29 (Suppl.): 573. 26. Erzurum SC, Left JA, Cochran JE et al. Lack of benefit of methotrexate in severe, steroid-dependent asthma. A
27. 28. 29. 30.
double-blind, placebo-controlled study. Ann Intern Med 1991; 114:353 360. Kuitert LM, Harrison AC. Pneumocystis carinii pneumonia as a complication of methotrexate treatment of asthma. Thorax 1991: 46:936 937. Jones G, Mierins E, Karsh J. Methotrexate-induced asthma. Am Rev Respir Dis 1991; 143" 179 181. Katz WA. Diagnosis' and Management of Rheumatic Diseases. Second edn. Philadelphia: JB Lippincott Company, 1988. Morgan S, Bagott JE, Vaughn WH, Yuong PK, Austin JV, Krumdieck CL. The effect of folic acid supplementation on the toxicity of low-dose methotrexate in patients with rheumatoid arthritis. Arthritis' Rheum 1990; 33:9-18.
Methotrexate in the treatment of severe asthma J. L. YNTEMA*:~, C. WALKER~"AND R. AALBERS*
*Netherlands Asthma Centre and ~fSwiss Institute for Allergy and Asthma Research, Davos, Switzerland, and ~Department of Pediatric Pulmonology, State University, Nijmegen, The Netherlands
Introduction An increasing number of studies show that bronchial asthma even in its mildest form is characterized by local inflammation of the bronchial wall (1-3). Avoidance of known triggering factors like allergens, smoke and fumes, together with agressive regular therapy with bronchodilators and cromolyn or nedocromil are the cornerstones of treatment. If symptoms or changes in airway function occur more frequently, inhaled steroids may be indicated (4). The majority of patients can be treated without systemic steroids, except infrequent rescue courses during exacerbations. However, in some patients exacerbations are so frequent and severe, that increasing dosages and eventually maintenance treatment with oral corticosteroids becomes necessary. In these steroid-dependent asthmatics, long term systemic steroid therapy is associated with adrenal suppression and severe side-effects, such as obesity, diabetes, osteoporosis, myopathy, cataract, hypertension, and (in children) growth retardation. In order to reduce the long term side-effects, 'steroid-sparing' agents have been sought that would allow a reduction of the dose of corticosteroids, without losing control of asthma. It was recognized that agents used in other chronic inflammatory disorders, such as rheumatoid arthritis and psoriasis, might also have an effect in asthma. This led to the clinical evaluation of various agents with anti-inflammatory activity as steroid-sparing therapy in asthma. Several placebo-controlled studies suggest that a weekly pulse dose of methotrexate might have a beneficial effect in patients with steroid-dependent asthma, mainly by reducing the dosage of oral corticosteroids necessary to keep control of symptoms (5-7). Methotrexate Methotrexate (MTX) was introduced in the therapy of malignancies in 1948, and subsequently in the therapy of psoriasis and rheumatoid arthritis (8). More 0954-6111/93/0B0057+ 04 $08.00/0
recently it was introduced as a 'steroid-sparing' agent in the treatment of patients with severe steroiddependent asthma (9). Methotrexate is a folic acid antagonist that binds preferentially to the enzyme dihydrofolate reductase, and interferes thereby with thymidine synthesis, an essential component of DNA. As a result, D N A synthesis and cell replication are blocked (10). When given in high doses (50 mg or more per week) MTX has predominantly antineoplastic activity, and is used in the treatment of cancer. In a low-dose regimen (5-25mg week -I) it probably has an anti-inflammatory effect, which may explain its effect in the treatment of rheumatoid arthritis, dermatomyositis, psoriasis and asthma. The antiinflammatory mechanism of action is not well understood. In asthma its effectiveness might be related to its inhibitory activity on cellular immunity and the release of mediators. Methotrexate inhibits the histamine release from human basophils (11). Interleukin (IL)-I activity of mononuclear cells is also inhibited (12). Interleukin is important in the inflammatory response as (in vitro) inducer of mediator release from basophils, mast cells and endothelial cells and promotes the synthesis of other proinflammatory cytokines. However, the role of IL-1 in asthma has recently been questioned (13). In neutrophils a reduction ofchemotaxis has been demonstrated (14). Methotrexate does not seem to affect intracellular killing and phagocytosis (15). Preliminary results of a study performed in our clinic, in cooperation with the Swiss Institute for Allergy and Asthma Research, demonstrated that 8 weeks treatment of severe, steroid-dependent asthmatics did not have a significant effect on numbers of lymphocyte subsets (CD-4 and CD-8), as has been demonstrated earlier in patients with rheumatoid arthritis (16), or on markers of lymphocyte activation such as CD-23 and HLA-DR. However, in our study there appeared to be an association between a positive clinical effect of MTX treatment, measured by peak flow rate and symptom score, and an increased inhibition by dexamethasone on the proliferation response of phytohaemagglutinin 9 1993Bailli~reTindall
58
J. L. Yntema et al.
(PHA) stimulated lymphocytes in vitro. In one patient a reversed response was accompanied by a severe increase in asthma symptoms, which forced a discontinuation of MTX treatment. These findings suggests that the immunomodulatory effect of MTX in asthma is complex, and can interfere with the effect of steroids.
Dosage and Pharmacokinetics of MTX Methotrexate may be given by the oral or parenteral route. The dosage varies, depending on the disease for which it is being used, the clinical effect and the tolerance of side-effects. The average dose employed for asthma in adults as well as adolescents is 15 mg, given as a once weekly 'pulse dose', but doses as high as 50 mg have been required for clinical improvement (17). Oral and parenteral administration are equally effective. The parenteral route may offer an advantage with respect to hepatotoxicity, since the liver is bypassed. Sixty percent of the orally administered drug is absorbed, with a direct relationship between dose and plasma concentration. The plasma half-life is 2 h. Approximately 50% of the drug is protein-bound and can be displaced by drugs such as salicylates, penicillins, tetracyclins and sulphas. About 9(~95% of the drug is excreted unchanged in the urine after 24-30 h (8). The serum concentration of methotrexate can be measured to assure complete clearance of the drug from the vascular compartment in 24 h. Levels are determined 1 h after the weekly dose and 24 h later. Acceptable concentrations at 1 h are approximately 6 x 10 7M, and undetectable levels at 24 h (19).
Side-effects and Toxicity Early side-effects are nausea and vomiting, mucosal ulcerations, abdominal cramps and diarrhea. These side effects seem to occur less frequently when the parenteral route of administration is used. The oral dose can be divided into two or three fractions at 8-h intervals when there is gastrointestinal intolerance. Together with dermatitis and alopecia these side effects are considered as mild, and usually do not require reduction of the dose. Hepatotoxicity and neutropenia are considered as moderate side effects. About onethird of all patients receiving MTX, regardless of the dose, will experience abnormalities in liver function tests. The long-term significance of this is not fully understood. Most clinicians reduce the dose or temporarily stop the treatment if hepatic enzyme values increase to more than three times normal. The hepatic enzyme abnormalities are usually rapidly reversible. The correlation of low dose MTX treatment with the ultimate development of hepatic fibrosis is not well established. Unfortunately this can only be revealed
by liver biopsy, as there seems to be a poor correlation between liver function tests and ultrastructural changes (20). In children treated for leukemia with a long-term high dose MTX a 20% incidence of fibrosis has been reported (21). Although debatable in low dose treatment of rheumatoid arthritis and asthma, a liver biopsy after administration a cumulative dose of 1.5 g MTX has been advocated (22). Severe side effects of low dose MTX treatment are relatively infrequent. After prolonged administration occurrence of acute interstitial pneumonitis has been described. This serious and potentially fatal side effect has been reported predominantly in patients with rheumatoid arthritis (23,24). Preexisting lung disease has been suggested as a precipitant factor (25), and extensive lung function studies, including DLCO, are mandatory before MTX treatment is decided. Sporadic fatality after infection with Pneumocystis carinii has been described by several authors (26-27). One case was reported in which a patient with rheumatoid arthritis developed bronchial hyperresponsiveness and asthma as a result of low dose MTX therapy (28). MTX is teratogenic, so appropriate anti-conceptive precautions are necessary. Neurotoxicity, nephrotoxicity and oncogenesis do not appear to be problems at low dose levels (29). Leucovorin, a derivative of folinic acid, is used as a 'rescue therapy' to reduce the toxic effects of high dose MTX in the treatment of cancer. Recently a doubleblind study in patients with rheumatoid arthritis showed, that supplementation with 1 mg daily also significantly lowered toxicity of low-dose MTX, without affecting efficacy (30). In asthma the effect of leucovorin supplementation has not been evaluated.
Drug Interactions with MTX There are many drug interactions that may occur with methotrexate. Blockade of the renal tubular excretion and displacement from plasma proteins are the most important mechanisms by which drugs like certain antibiotics (sulphas, tetracyclines, penicillins), salicylate, fenytoin, barbiturates, probenicid and some NSAID's interfere with the bioavailability of MTX. Increased toxicity may be the result and patients should either avoid these drugs or use them very cautiously, strictly adhering to dose regimens and sometimes to monitoring plasma levels of MTX. The use of alcohol should be avoided to prevent toxic liver damage.
Clinical Studies After the first report from Mullarkey et al. on the beneficial effects of MTX in a patient with psoriatic
M e t h o t r e x a t e and asthma
arthritis and steroid-dependent asthma who was able to discontinue steroid treatment completely (9), the effectiveness of M T X as a steroid-sparing agent has been demonstrated in several uncontrolled and doubleblind placebo-controlled studies (5 7). One studycould not confirm this (26). Outcome variables in all studies were the oral corticosteroid dose as a percentage of the dose in the run-in period, and parameters of asthma control such as peak flow values, lung function and symptom scores. However, there are some flaws inherent to these studies. Unfortunately, the term 'steroid-dependent asthma' is not uniformly defined. N o w the 'optimal' dose of oral steroids and other anti-inflammatory therapy was determined before the patients were enrolled into the study was not specified.
Conclusions Though side effects of M T X in asthma seem to be rather mild, and are rapidly revealed by good monitoring, the a m o u n t of studies available is still limited, and the follow-up periods are relatively short. Hence, considering only these clinical studies, there is a danger of underestimating severe side effects and long-term toxic effects of M T X in asthma. Moreover, the efficacy of M T X in asthma is still unpredictable. It is unknown why some asthmatics do respond well to treatment with a low dose, and why other patients do not or need a much higher dose. The possibility of potential serious toxicity restricts its current use to a selected group of patients w h o experience serious side effects from long-term treatment with systemic steroids. The use of M T X in these patients seems to be justified as long as no better result could be achieved with an alternative therapy. M T X could play a disease modifying role, decreasing the dose and long-term side effects of systemic steroids without losing control of symptoms. Before advocating the use of M T X to other groups of asthmatics more clinical and fundamental studies are needed.
References 1. Beasley R, Roche WR, Roberts JA, Holgate ST. Cellular events in the bronchi in mild asthma and after bronchial provocation. Am Rev Respir Dis 1989; 139: 806-817. 2. Laitinen LA, Heino M, Laitinen A, Kava T, Haahtela T. Damage of the airway epithelium and bronchial reactivity in patients with asthma. Am Rev Respir Dis 1985; 131:599 606. 3. Djukanovic R, Wilson JW, Britten KM et al. Quantitation of mast cells =nd eosinophils in the bronchial mucosa of symptomatic atopic asthmatics and healthy control subjects using immunohistochemistry. Am Rev Respir Dis 1990; 142: 836-871.
59
4. National Heart, Lung, and Blood Institute, National Institutes of Health. International Consensus Report on Diagnosis and Treatment of Asthma. Clin Exp Allergy 1992; 22 (Suppl.): 34. 5. Mullarkey MF, Blumenstein BA, Andrade WP et al. Methotrexate in the treatment of corticosteroiddependent asthma: A double-blind crossover study. N EnglJMed 1988; 318:603 607. 6. Dyer PD, Vaughan TR, Weber RW. Methotrexate in the treatment of steroid-dependent asthma. J Allergy Clin Immuno11991; 88:208 212. 7. Shiner RJ, Nunn A J, Chung KF, Geddes DM. Randomized, double-blind, placebo controlled trial of methotrexate in steroid-dependent asthma. Lancet 1990; 336: 137-140. 8. Gubner R, August S, Ginsburg V. Therapeutic suppression of tissue reactivity. II: Effect of aminopterin in rheumatoid arthritis and psoriasis. Am J Med Sci 1951; 221: 176-180. 9. Mullarkey MF, Webb DR, Pardee NE. Methotrexate in the treatment of steroid-dependent asthma. Ann Allergy 1986; 56:347 350. 10. Calabresi P, Parks RE. Chemotherapy of neoplastic diseases. In: Goodman A, Gilman LS, Rail TW, Murad F, eds. The Pharmacological Basis of Therapeutics. Seventh edn. New York, Macmillan, 1985; 1264. 11. Nolte H, Skov PS. Inhibition ofbasophil histamine release by methotrexate. Agents Actions 1988; 23:173-I 76. 12. Segal R, Mozes E, Yaron M, Tartakovsky B. The effects of methotrexate on the production and activity of interleukin-1. Arthritis" Rheum 1989; 32:370 377. 13. Vacchiarelli A, Siracusa A, Cenci E, Puliti M, Abbritti G. Effect of corticosteroid treatment on interleukin-I and turnout necrosis factor secretion in by monocytes from subjects with asthma. Clin Exp Allergy 1992; 22:365 370. 14. Cream JJ, Pole DS. The effect of methotrexate and hydroxyurea an neutrophil chemotaxis. Br J Dermatol 1980; 102:192 196. 15. Johnson JD, Summergill JT, RaffMJ. Thein vitro effects of methotrexate on the phagocytosis and intracellular killing of S. aureus by human neutrophils. Cancer 1986; 57:2343 2345. 16. Andersen PA, West SG, O'Dell JR, Via SS, Caypool RG, Kotzen BL. Weekly pulse methotrexate in rheumatoid arthritis. Clinical and immunological effect in a randomized double-blind study. Ann Intern Med 1985; 103: 489 496. 17. Mullarkey MF, Lammert JK, Blumenstein BA. Longterm methotrexate treatment in corticosteroid-dependent asthma. Ann Intern Med 1990; 112:577-581. 18. Kremer JM, Galivan J, Streckfuss A, Kamen B. Methotrexate metabolism analysis in blood and liver of rheumatoid arthritis patients. Arthritis Rheum 1986;29:832 835. 19. Wallace CA, Bleyer WA, Sherry DD et al. Methotrexate levels in juvenile rheumatoid arthritis patients (abstract). Arthritis Rheum 1988; 31: $26. 20. Lewis JH, Schiff E. Methotrexate-induced chronic liver injury: guidelines for detection and prevention. Am J Gastroenterol 1988; 88:1337 1345. 21. Wiedrich T, Keller D, Sunita A, Gilbert E. Adverse histopathologic effects of chemotherapeutic agents in childhood leukemia and lymphoma. Pediatr Pathol 1984; 2: 267 283. 22. Health and Public Policy Committee, American College of Physicians. Methotrexate in rheumatoid arthritis. Ann Intern Med 1987; 107: 418-419.
60
J. L . Y n t e m a et al.
23. Cannon GW, Ward JR, Clegg DO. Acute tung disease associated with low-dose pulse methotrexate therapy in patients with rheumatoid arthritis. Arthritis Rheum 1983; 26:1269 1274. 24. Searles G, McKenchry RJR. Methotrexate pneumonitis in rheumatoid arthritis: potential risk factors. Four case reports and a review of the literature. J. Rheumato11987; 14:1164-1171. 25. Bell M J, Geddie WR, Gordon DA, Reynolds WJ. Preexisting lung disease in patients with rheumatoid arthritis may predispose to methotrexate lung. Arthritis Rheum 1986; 29 (Suppl.): 573. 26. Erzurum SC, Left JA, Cochran JE et al. Lack of benefit of methotrexate in severe, steroid-dependent asthma. A
27. 28. 29. 30.
double-blind, placebo-controlled study. Ann Intern Med 1991; 114:353 360. Kuitert LM, Harrison AC. Pneumocystis carinii pneumonia as a complication of methotrexate treatment of asthma. Thorax 1991: 46:936 937. Jones G, Mierins E, Karsh J. Methotrexate-induced asthma. Am Rev Respir Dis 1991; 143" 179 181. Katz WA. Diagnosis' and Management of Rheumatic Diseases. Second edn. Philadelphia: JB Lippincott Company, 1988. Morgan S, Bagott JE, Vaughn WH, Yuong PK, Austin JV, Krumdieck CL. The effect of folic acid supplementation on the toxicity of low-dose methotrexate in patients with rheumatoid arthritis. Arthritis' Rheum 1990; 33:9-18.