Alternative Pharmacotherapies for Steroid-Dependent Asthma

cyclosporine double-blind, placebo-controlled emergency department forced expiratory flow in 1 s forced vital capacity hydroxychloroquine intravenous immunoglobulin magnesium sulfate methotrexate peak expiratory flow rate troleandomycin A small minority of patients with asthma have severe unremitting disease that can be controlled only by long-term use of daily or high-dose alternate-day systemic corticosteroids. The occurrence of serious adverse effects resulting from this therapy has spurred the quest for better ways to treat severe steroid-dependent asthma. A number of nonsteroidal agents with putative anti-inflammatory activity have been investigated. Experience with four oral drugs that have been studied in double-blind, placebo-controlled (DBPC) trials will be reviewed. These agents are methotrexate (MTX), troleandomycin (TAO), cyclosporine (CSA), and gold. Other agents that have been used in uncontrolled studies have aroused interest and will also be discussed briefly: intravenous immunoglobulin (IVIG), hydroxychloroquine (HCQ), and dapsone. Finally, studies with magnesium sulfate (MgSO4) infusion in acute asthma and preliminary information on use of inhaled furosemide will be summarized. Immunosuppressives were tried in patients with severe asthma in reports dating back to the early 1950s. By the 1970s, accumulated experience with three classes of immunosuppressives—the folic acid antagonist MTX, the purine analogue azathioprine and its metabolite 6-mercaptopurine, and the nitro gen mustard-derived alkylating agents chlorambucil and cyclophosphamide—led to a plea for a halt to their widespread use in inflammatory diseases of unknown etiology.1Steinberg A.D. An approach to the use of immunosuppressive drugs in nonmalignant disease.J Allergy Clin Immunol. 1973; 52: 242-250Abstract Full Text PDF PubMed Scopus (15) Google Scholar This plea was based on both lack of curative efficacy and toxicity, criteria that stand us in good stead today as we evaluate more recent efforts in this area. Methotrexate is a folic acid antagonist that inhibits dihydrofolate reductase, thereby interfering with thymidine synthesis and thus blocking DNA synthesis and cell division. At high doses (>50 mg/wk), MTX is a useful antineoplastic agent on this basis.2Reid D.J. Segars L.W. Methotrexate for the treatment of chronic steroid-dependent asthma.Clin Pharm. 1993; 12: 762-767PubMed Google Scholar, 3Yntema J.L. Walker C. Aalbers R. Methotrexate in the treatment of severe asthma.Respir Med. 1993; 87: 57-60Abstract Full Text PDF PubMed Scopus (3) Google Scholar However, at low doses (5 to 25 mg/wk), it has less toxicity and retains anti-inflammatory effects. The mechanisms of anti-inflammatory action are not well understood, but may include inhibition of histamine release from basophils, inhibition of cytokine release, eg, interleukin-1, from mononuclear cells, and reduction of neutrophil chemotaxis.4Geddes D.M. Methotrexate in asthma.Clin Exp Allergy. 1991; 21: 541-543Crossref PubMed Scopus (9) Google Scholar, 5Calderon E. Coffey R.G. Lockey R.F. Methotrexate in bronchial asthma.J Allergy Clin Immunol. 1991; 88: 274-276Abstract Full Text PDF PubMed Scopus (11) Google Scholar There is also a possible interfering effect on steroid metabolism. Efficacy of MTX at low doses in rheumatic diseases prompted investigation in severe asthma. After an open-label study suggested possible benefit, wider interest in MTX was aroused by the initial study of Mullarkey et al6Mullarkey M.F. Blumentstein B.A. Andrade W.P. et al.Methotrexate in the treatment of corticosteroid-dependent asthma.N Engl J Med. 1988; 318: 603-607Crossref PubMed Scopus (206) Google Scholar reported in 1988. In this DBPC 24-week crossover trial completed by 14 patients requiring daily oral corticosteroids, low-dose oral MTX (15 mg/wk) resulted in a 36.5% reduction in prednisone use (mean dose reduction from 26 to 17 mg/d) compared with placebo (p=0.01). An open-label long-term follow-up in 25 patients treated at least 18 months reported mean reduction in daily prednisone use from 27 to 6 mg (p=0.0001), with 15 patients tapered off the dose of prednisone and another 9 reducing doses by >50%.7Mullarkey M.F. Lammert J.K. Blumenstein B.A. Long-term methotrexate treatment in corticosteroid-dependent asthma.Ann Intern Med. 1990; 112: 577-581Crossref PubMed Scopus (88) Google Scholar Since the initial study of Mullarkey et al,6Mullarkey M.F. Blumentstein B.A. Andrade W.P. et al.Methotrexate in the treatment of corticosteroid-dependent asthma.N Engl J Med. 1988; 318: 603-607Crossref PubMed Scopus (206) Google Scholar there have been a number of published DBPC trials of MTX in patients with steroid-dependent asthma.8Shiner R.J. Nunn A. Chung K.F. et al.Randomised, double-blind, placebo-controlled trial of methotrexate in steroid-dependent asthma.Lancet. 1990; 336: 137-140Abstract PubMed Scopus (124) Google Scholar, 9Dyer P.D. Vaughan T.R. Weber R.W. Methotrexate in the treatment of steroid-dependent asthma.J Allergy Clin Immunol. 1991; 88: 208-212Abstract Full Text PDF PubMed Scopus (67) Google Scholar, 10Erzurum S.C. Leff J.A. Cochran J.E. et al.Lack of benefit of methotrexate in severe, steroid-dependent asthma.Ann Intern Med. 1991; 114: 353-360Crossref PubMed Scopus (119) Google Scholar, 11Trigg C.J. Davies R.J. Comparison of methotrexate 30 mg per week with placebo in chronic steroid-dependent asthma: a 12-week double-blind cross-over study.Respir Med. 1993; 87: 211-216Abstract Full Text PDF PubMed Scopus (36) Google Scholar, 12Taylor D.R. Flannery E.M. Herbison G.P. Methotrexate in the management of severe steroid dependent asthma.NZ Med J. 1993; 106: 409-411PubMed Google Scholar, 13Coffey M.J. Sanders L.W. Eschenbacher W.L. et al.The role of methotrexate in the management of steroid-dependent asthma.Chest. 1994; 105: 117-121Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar In two of these, a steroid-sparing effect of MTX was found. In the largest, Shiner et al8Shiner R.J. Nunn A. Chung K.F. et al.Randomised, double-blind, placebo-controlled trial of methotrexate in steroid-dependent asthma.Lancet. 1990; 336: 137-140Abstract PubMed Scopus (124) Google Scholar studied 60 patients using a 4-week run-in period, a 24-week parallel group trial, and a 10-week follow-up period. A mean reduction of 50% baseline prednisolone dose (mean, 14 mg/d) was achieved with oral MTX, 15 mg/wk, compared with 14% with placebo (p<0.005). Only in the second half of the trial period (>12 weeks) did a difference in steroid tapering emerge from that achieved in the placebo group. Also, after stopping MTX treatment, steroid requirement returned almost to baseline. Dyer et al9Dyer P.D. Vaughan T.R. Weber R.W. Methotrexate in the treatment of steroid-dependent asthma.J Allergy Clin Immunol. 1991; 88: 208-212Abstract Full Text PDF PubMed Scopus (67) Google Scholar studied ten subjects completing a DBPC trial featuring a 3-week run-in taper period, randomized treatment for 12 weeks, and a 4-week washout followed by crossover for another 12 weeks. In this study, a 30% reduction in prednisone use (8 vs 12 mg/d) was seen with oral MTX, 15 mg/wk, compared with placebo (p<0.01). In contrast to these generally positive results, four recent DBPC trials of low-dose MTX have yielded negative results that seriously question a broad role for MTX in asthma treatment. Erzurum et al10Erzurum S.C. Leff J.A. Cochran J.E. et al.Lack of benefit of methotrexate in severe, steroid-dependent asthma.Ann Intern Med. 1991; 114: 353-360Crossref PubMed Scopus (119) Google Scholar studied 18 patients randomized to receive placebo or intramuscular MTX (5 mg the first week, 10 mg the second week, then 15 mg/wk for 4 weeks). Following this “MTX initiation” period, a steroid taper was attempted over 13 weeks while treatment with study drug was continued. Following this, patients were categorized by success or failure to taper steroid dose by ≥33%. Placebo patients failing to taper were placed on a regimen of open MTX, while those randomized to MTX during the DBPC trial were continued on a regimen of open MTX. In this study, patients receiving placebo were able to taper steroid dosage as well as those receiving MTX (40% reduction in both groups). One patient who received MTX died of Pneumocystis pneumonia. Increase of open-label MTX dose to 30 mg did not improve outcome. Trigg and Davies11Trigg C.J. Davies R.J. Comparison of methotrexate 30 mg per week with placebo in chronic steroid-dependent asthma: a 12-week double-blind cross-over study.Respir Med. 1993; 87: 211-216Abstract Full Text PDF PubMed Scopus (36) Google Scholar used a higher oral MTX dose of 30 mg/wk orally in their DBPC crossover study. In 12 patients who completed the study, frequent adverse effects occurred, requiring MTX dose reduction in 7. There was no reduction in mean steroid requirement with MTX vs placebo, although mean forced expiratory flow in 1 s (FEV1) improved. Taylor et al12Taylor D.R. Flannery E.M. Herbison G.P. Methotrexate in the management of severe steroid dependent asthma.NZ Med J. 1993; 106: 409-411PubMed Google Scholar studied nine patients in a DBPC crossover trial of 24 weeks with oral MTX, 15 mg/wk. Again, there was no difference in dose of prednisone (14 mg/d with MTX vs 13 with placebo) at the end of the 48-week trial period. Coffey et al13Coffey M.J. Sanders L.W. Eschenbacher W.L. et al.The role of methotrexate in the management of steroid-dependent asthma.Chest. 1994; 105: 117-121Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar studied 11 patients with mean enrollment prednisone dose of 28 mg/d using a 12-week treatment period crossover design, also at an oral MTX dose of 15 mg/wk. This study featured a 4- to 10-week initial phase to optimize pulmonary function prior to randomization; this required a mean steroid dose of 30 mg/d. Both groups tapered steroid therapy approximately 20% during the trial, and both improved pulmonary function. Coffey et al13Coffey M.J. Sanders L.W. Eschenbacher W.L. et al.The role of methotrexate in the management of steroid-dependent asthma.Chest. 1994; 105: 117-121Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar identified a subgroup of three MTX “responders” who reduced steroid dose >33% while receiving MTX but not placebo. Recent unpublished open-label studies suggest that MTX may succeed when other alternative pharmacotherapies (eg, TAO, HCQ, or gold) fail, but the converse was not observed. Recent longer-term data suggest that MTX effect, when present, seems to plateau after 1 year and does not persist if the drug therapy is discontinued. Discontinuation occurs because of inability to further reduce steroid therapy, noncompliance, toxic reactions, or change to another alternative therapy. It is difficult to reconcile results from all of these studies. Problems in interpretation may result from the following: inconsistent definition of steroid-dependent asthma; failure to objectively define asthma severity and to stratify patients by pulmonary function, bronchial reactivity, or both; inconsistent use of steroid-tapering run-in periods; small sample sizes insufficient to rule out type II errors; insufficient duration; lack of standardized conventional treatment approaches; and (for oral MTX trials) failure to assure compliance. Methotrexate toxic reactions can be grouped into mild-moderate and severe-fatal categories. The former include nausea and vomiting, alopecia, mucosal ulcers, hepatic dysfunction, and neutropenia, all of which are reversible with dose alteration or temporary discontinuation.4Geddes D.M. Methotrexate in asthma.Clin Exp Allergy. 1991; 21: 541-543Crossref PubMed Scopus (9) Google Scholar, 5Calderon E. Coffey R.G. Lockey R.F. Methotrexate in bronchial asthma.J Allergy Clin Immunol. 1991; 88: 274-276Abstract Full Text PDF PubMed Scopus (11) Google Scholar, 14Kaslow J.E. Novey H.S. Methotrexate for asthma: a critical appraisal.Ann Allergy. 1989; 62: 541-545PubMed Google Scholar These occur, in many if not most treated patients. It also seems possible that MTX can induce as well as treat asthma.15Jones G. Mierins E. Karsh J. Methotrexate-induced asthma.Am Rev Respir Dis. 1991; 143: 179-181Crossref PubMed Scopus (42) Google Scholar, 16Fertel D. Wanner A. Methotrexate: does it treat or induce asthma?.Am Rev Respir Dis. 1991; 143: 1-2Crossref PubMed Scopus (12) Google Scholar Severe-fatal toxic reactions are rare but, based on experience with rheumatic diseases, may increase with time.17Cott G.R. Cherniack R.M. Steroids and ‘steroid-sparing’ agents in asthma.N Engl J Med. 1988; 318: 634-636Crossref PubMed Scopus (28) Google Scholar These include hepatic fibrosis (not correlated with liver enzyme dysfunction), bone marrow suppression, pulmonary fibrosis, and Pneumocystis carinii pneumonitis.4Geddes D.M. Methotrexate in asthma.Clin Exp Allergy. 1991; 21: 541-543Crossref PubMed Scopus (9) Google Scholar, 5Calderon E. Coffey R.G. Lockey R.F. Methotrexate in bronchial asthma.J Allergy Clin Immunol. 1991; 88: 274-276Abstract Full Text PDF PubMed Scopus (11) Google Scholar, 10Erzurum S.C. Leff J.A. Cochran J.E. et al.Lack of benefit of methotrexate in severe, steroid-dependent asthma.Ann Intern Med. 1991; 114: 353-360Crossref PubMed Scopus (119) Google Scholar, 14Kaslow J.E. Novey H.S. Methotrexate for asthma: a critical appraisal.Ann Allergy. 1989; 62: 541-545PubMed Google Scholar, 18Tsai J.J. Shin J.F. Chen C.H. et al.Methotrexate pneumonitis in bronchial asthma.Int Arch Allergy Immunol. 1993; 100: 287-290Crossref PubMed Scopus (17) Google Scholar, 19Vallerand H. Cossart C. Milosevic D. et al.Fatal Pneumocystis pneumonia in asthmatic patient treated with methotrexate.Lancet. 1992; 339: 1551Abstract PubMed Scopus (25) Google Scholar Liver biopsy every 3 years or after cumulative dose of 1.5 g is recommended.2Reid D.J. Segars L.W. Methotrexate for the treatment of chronic steroid-dependent asthma.Clin Pharm. 1993; 12: 762-767PubMed Google Scholar, 4Geddes D.M. Methotrexate in asthma.Clin Exp Allergy. 1991; 21: 541-543Crossref PubMed Scopus (9) Google Scholar Methotrexate has an unpredictable effect on theophylline metabolism with a mean reduction in hepatic clearance of 19%,20Glynn-Barnhart A.M. Erzurum S.C. Leff J.A. et al.Effect of low-dose methotrexate on the disposition of glucorticoids and theophylline.J Allergy Clin Immunol. 1991; 88: 180-186Abstract Full Text PDF PubMed Scopus (16) Google Scholar and may have an effect on steroid metabolism. Methotrexate is teratogenic. In 1991, Stempel et al21Stempel D.A. Lammert J. Mullarkey M.F. Use of methotrexate in the treatment of steroid-dependent adolescent asthmatics.Ann Allergy. 1991; 67: 346-348PubMed Google Scholar reported use of open-label MTX in five children aged 10 to 16 years for 1 to 3 years. Three of the five were able to discontinue treatment with oral steroids while receiving MTX and the other two had >50% dose reductions. All had improved asthma control and tolerated MTX well. Guss and Portnoy22Guss S. Portnoy J. Methotrexate treatment for severe asthma in children.Pediatrics. 1992; 89: 635-639PubMed Google Scholar treated seven children aged 3 to 14 years for 4 to 17 months with open-label MTX. Three were able to discontinue treatment with oral steroids. Methotrexate therapy was stopped owing to gastrointestinal adverse effect in one and noncompliance in one, while five continued taking the drug without major toxic reactions. Doses in these studies ranged from 2.5 to 25 mg/wk given orally or by intramuscular injection. Although controversy and confusion persist, it seems reasonable to make the following provisional conclusions about MTX use in steroid-dependent asthma: (1) MTX may be a steroid-sparing agent in some steroid-dependent asthmatics; (2) no predictive factors for “responders" have been found; (3) no consistent effect on airflow or bronchial responsiveness from MTX has been found; (4) steroid-sparing effects may require prolonged (>3 months) treatment to be seen and are unlikely to occur after 1 year; (5) steroid-sparing effects disappear when MTX treatment is discontinued; (6) mild-moderate adverse effects are common, and severe-fatal adverse effects may occur; doses higher than 15 mg/wk appear unacceptably toxic; (7) every effort should be made to taper steroid doses before employing MTX, even if the patient has failed multiple prior attempts at weaning; and (8) MTX should be viewed as a “riskrisk” proposition vs long-term oral steroid therapy.