Editorial Methotrexate: Does It Treat or Induce Asthma?
Airway inflammation is considered to inadequate documentation of appropriplaya major role in airway hyperrespon- ate trials of more conventional therapy siveness (1), and glucocorticosteroids are before classifying these patients as steroutinely used to reduce the inflamma- roid dependent. Recently,Mullarkey and tory response in patients with asthma. coworkers (7) expanded their observaThe long-term administration of systemic tions by evaluating the long-term benefits glucocorticosteroids, however, carries a and side effects of methotrexate in risk of significant side effects. For- steroid-dependent asthma. 1\venty-five tunately, most patients with asthma can patients who were on theophylline, an be successfullytreated with combinations undetermined dose of inhaled betaof beta-adrenergic agonists, inhaled top- adrenergic agonists, and daily doses of ical glucocorticosteroids, theophylline, 1,200 to 1,600 mg of inhaled triamcinacromolyn, and occasionally anticholiner- lone acetonide were followed for 18 to gic agents, reserving systemic glucocor- 24 months on low-dose methotrexate ticosteroids for short time periods to therapy. Unlike previous studies, the sestabilize a severe exacerbation or treat a lection of patients included a one-month potentially life-threatening attack. In the induction period. Patients who had repatient who has frequent, increasingly se- quired a minimum of 10mg/day prednivere attacks or in whom careful systemic sone the preceding year and were unable glucocorticosteroid withdrawal is met to decrease their weekly prednisone dose with repeated exacerbations, the long- by at least 2.5 to 5 mg during the inducterm administration of systemic gluco- tion phase wereconsidered steroid depencorticosteroids may be indicated. This so- dent and placed on methotrexate. In the called steroid-dependent asthmatic has 25 patients who met these criteria, it was been the focus of numerous studies possible to reduce the dose of prednisone attempting to identify other anti-inflam- from a mean of 26.9 to 6.3 mg/day on matory agents that may reduce or elimi- methotrexate (initially 7.5 mg/wk, innate the need for systemic glucocorti- creasing to 15 to 50 mg/wk). Fifteen pacosteroids. Medications such as azathio- tients wereable to discontinue prednisone prine, 6-mercaptopurine, colchicine, entirely, nine patients reduced their dose gold salts, and prostaglandin inhibitors by 50010, and only one patient failed to have all been tried with variable results respond. Adverse reactions werenoted to be mild, usually with transient elevations (2-4). In 1986, Mullarkey and colleagues (5) of liver funct.ion tests, and did not warfirst reported the potentially beneficial rant discontinuation of the drug. The ineffects of methotrexate after their obser- vestigators concluded that methotrexate vation of a patient with psoriatic arthri- was an effective and safe glucocortis and steroid-dependent asthma who ticosteroid sparing agent with minimal was able to discontinue systemic glu- long-term side effects in patients with cocorticosteroids after institution of bronchial asthma (7). Although methotrexate therapy may methotrexate therapy. 1\vo years later, Mullarkey and colleagues (6) reported a have glucocorticosteroid sparing effects double-blind crossover study of 14 pa- in asthmatics, questions can be raised tients with steroid-dependent asthma fol- about the need for long-term systemic lowed for 24 wk on low-dose methotrex- glucocorticosteroids in the patients studate. The daily prednisone dose could be ied and the apparent safety to methotrexreduced by 36.5070 without deterioration ate therapy. The term "steroid-dependent in lung function when the patients were asthma," although commonly used, lacks on methotrexate. While recognizing the uniformly defined criteria. In our expotential benefit of methotrexate in the perience, most patients classified as stetreatment of asthma, the study was con- roid dependent are not receiving the full sidered limited by the small number of spectrum of inhaled agents, including a patients, lack of long-term follow-up,and beta-adrenergic agonist, glucocortico-
steroid, cromolyn, and, in selected patients, an anticholinergic agent, are not maximizing the dose of inhaled glucocorticosteroids, are not using their inhalers properly, are not taking theophylline, or are tapering their systemic glucocorticosteroids too rapidly. A one-month attempt at tapering may not be adequate to confirm steroid dependence. Some patients taking long-term oral glucocorticosteroids may require a slower tapering than the protocol used by Mullarkey and coworkers (7). Several studies from Europe have demonstrated the beneficial effect of high-dose, inhaled glucocorticosteroids, which may be used safely and effectively to facilitate the tapering of systemic glucocorticosteroids (2, 8). It is not clear if the patients of Mullarkey and associates (5-7) were given the full benefit of inhaled agents. Information about the choice of beta-adrenergic agents, their dose (number of puffs), and frequency of administration is missing. Likewise, inhaled cromolyn and anticholinergics were apparently not used in any of the patients. Although cromolyn may not have a dramatic effect in all patients and anticholinergic responsiveness may only be present in a subset of patients, these agents certainly deserve to be added to the regimen before resorting to long-term systemic glucocorticosteroids. Finally, close medical followup in itself could have a beneficial effect on the patient's symptomatology. For example, the careful supervision of the patients selected for the study of Mullarkey and colleagues (7) could have facilitated the reduction of prednisone. An adequate control population would have been required to test this possibility. Methotrexate has been widely used by rheumatologists for the treatment of rheumatoid arthritis and psoriatic arthritis, and considerable body of data exists on the clinical response to and adverse effects of methotrexate in these diseases (9-11). Methotrexate is a folic acid antagonist with antineoplastic and anti-inflammatory actions. For example, methotrexate appears to inhibit neutrophil chemotaxis induced in vitro by leu-
a
1
2
kotriene B4 and C5a (12-14). Whether it is this or other factors that provide the glucocorticosteroid sparing effect of methotrexate in asthma remains unclear. The toxicity of methotrexate has been thought to be dose related; hence, low doses have been relatively well tolerated for prolonged periods of time, and most toxicities are usually reversible when the drug is stopped. The most common side effects of low-dose methotrexate are elevation of liver transaminases, gastrointestinal problems (nausea and vomiting), and stomatitis. Lesscommon side effects include bone marrow depression, cirrhosis, and pneumonitis (3, 9, 11). The true incidence of cirrhosis resulting from methotrexate therapy is not known, but it appears to be higher in patients on daily doses of methotrexate and in patients with diabetes, ethanol abuse, and obesity. Unfortunately, liverenzyme levelsneither correlate nor predict the development of cirrhosis. Hence, liver biopsies every three years or after every cumulative dose of 1,500mg have been recommended (9). Because asthma is a chronic disease, the possibility of long-term use and abuse of methotrexate may create the potential for increased toxicity and possibly the need for repeated liver biopsies. Mullarkey and coworkers (5-7) found relatively few side effects in their patients, but routine liver biopsies were not performed, perhaps because neither a three-year follow-up period nor a cumulative dose of 1,500 mg was reached. Furthermore, the investigators used extreme caution in monitoring patients for side effects and adverse drug interactions. Patients were informed about the adverse effects of methotrexate, wereinstructed to avoid alcohol and a list of drugs that interacted with methotrexate, and receivedmonthly blood examinations (7). It is unlikely that patients with asthma not enrolled in a study protocol would be followed this closely, thereby increasing the risk of developing more serious adverse effects. The pulmonary toxicity of methotrexate is not dose related and has occurred in patients on weekly, low-dose methotrexate therapy (15, 16).There is evidence that it may be aggravated by pre-existing interstitial lung disease (17-19). The acute pulmonary toxicity noted with methotrexate is typically characterized by dyspnea, dry cough, pulmonary infiltrates,
EDITORIAL
and a high incidence of eosinophilia. The incidence of coexisting airway reactivity in these patients has not been determined previously. In this issue, Jones and colleagues (20) describe a case of airway hyperresponsiveness induced by methotrexate therapy. The patient appeared to have evidence of mild interstitial fibrosis by computed tomography, although the lung volumes and carbon monoxide diffusing capacity were normal. If this observation is reproduced in a large number of' patients, it would suggest that methotrexate produces or aggravates preexisting airway hyperresponsiveness. This raises new questions not only about mechanisms of action but also about indications and guidelines for monitoring patients on methotrexate therapy. A patient with asthma treated with methotrexate who is not improving may be experiencing a methotrexate reaction and not a spontaneous worsening. Likewise, a patient suffering more severe asthma during glucocorticosteroid withdrawal may be experiencing a methotrexate reaction. Airway hyperresponsiveness is certainly a most undesirable side effect of an antiasthmatic drug. Should methotrexate be added to the traditional armamentarium of antiasthmatic drugs as suggested by Mullarkey and colleagues? This question cannot be answered without further study of the efficacy, mode of administration, and adverseeffects of methotrexate. Even if such studies favor the use of methotrexate, its use will have to be limited to the patient with truly glucocorticosteroid-dependent asthma. D.
FERTEL,
M.D.
Assistant Professor of Medicine Department of Pulmonary Disease University ofMiami School ofMedicine Miami, FL A.
WANNER,
M.D.
Professor of Medicine Chief, Pulmonary Division University ofMiami School ofMedicine Miami, FL References 1. Djukanovic R, Roche WR, Wilson JW, et at. Mucosal inflammation in asthma. Am Rev Respir Dis 1990; 142:434-57. 2. Barnes PJ. A new approach to the treatment of asthma: drug therapy. N Engl J Med 1989; 321:
1517-27. 3. Kaslow JE, Novey HS. Methotrexate use for asthma: a critical appraisal. Ann Allergy 1989; 62:541-5. 4. Cott GR, Cherniack RM. Steroids and "steroidsparing" agents in asthma (editorial). N Engl J Moo 1988; 318:634-6. 5. Mullarkey MF, Webb DR, Pardee NE. Methotrexate in the treatment of steroid-dependent asthma. Ann Allergy 1986; 56:347-50. 6. Mullarkey MF. Blumenstein BA, Andrade wp. Baily GA, Olason I. Wetzel CEo Methotrexate in the treatment of corticosteroid-dependent asthma. A double-blind crossover study. N Engl J Moo 1988; 318:603-7. 7. Mullarkey MF, Lammert JK, Blumenstein BA. Long-term methotrexate treatment in corticosteroiddependent asthma. Ann Intern Med 1990; 112: 577-81. 8. Smith MJ, Hudson M. High-dose beclomethasone inhaler in the treatment of asthma. Lancet 1983; 1:265-9. 9. Thgwell P, Bennett K. Gent M. Methotrexate in rheumatoid arthritis. Indications, contraindications, and safety. Ann Intern Moo 1987; 107:358~. 10. Weinblatt ME, Trentham DE. Fraser PA, et at. Long-term prospective trial of low-dose methotrexate in rheumatoid arthritis. Arthritis Rheum 1988; 31:167-75. 11. Kremer JM, Lee JK. The safety and efficacy of the use of methotrexate in long-term therapy for rheumatoid arthritis. Arthritis Rheum 1986; 29:822-31. 12. Van De Kerhof PCM, Baur FW, Maassen DE, Ground RM. Methotrexate inhibits the leukotriene B4 induced intraepidermal accumulation of polymorphonuclear leukocytes. Br J Dermatol 1985; 113:251a-5a. 13. Suarez CR, Pickett WC, Bell DH, et al. Effects of low dose methotrexate on neutrophil chemotaxis induced by leukotriene B4 and complement C5A. J Rheumatol 1987; 14:9-11. 14. Johnson JD, Summersgill JT. Raff MJ. The invited effects of methotrexate on the phagocytosisand intracellular killing of Staphylococcus nureus by human neutrophils. Cancer 1986; 57:2343-5. 15. Carson CW, Cannon OW, Egger MJ, et at. Pulmonary disease during the treatment of rheumatoid arthritis with low dose pulse methotrexate. Semin Arthritis Rheum 1987; 16:186--95. 16. St. Clair EW, Rice JR, Synderman R. Pneumonitis complicating low-dose methotrexate therapy in rheumatoid arthritis. Arch Intern Moo 1985; 145:2035-8. 17. Bell MJ, Greddie WR, Gordon DA. et at. Preexisting lung disease in patients with rheumatoid arthritis (RA) may predisposeto methotrexate lung. Arthritis Rheum 1986; 29(Suppl:S7S). 18. Searles G, McKenchry RJR. Methotrexate pneumonitis in rheumatoid arthritis: potential risk factors. Four case reports and a review of the literature. J Rheumatol 1987; 14:1164-71. 19. Cannon GW, Ward JR, Olegg 00. Acute lung disease associated with low-dose pulse methotrexate therapy in patients with rheumatoid arthritis. Arthritis Rheum 1983; 26:1269-74. 20. Jones G, Mierins E. Karsh J. Methotrexateinduced asthma. Am Rev Respir Dis lQQ1: 143: 179-81.
Airway inflammation is considered to inadequate documentation of appropriplaya major role in airway hyperrespon- ate trials of more conventional therapy siveness (1), and glucocorticosteroids are before classifying these patients as steroutinely used to reduce the inflamma- roid dependent. Recently,Mullarkey and tory response in patients with asthma. coworkers (7) expanded their observaThe long-term administration of systemic tions by evaluating the long-term benefits glucocorticosteroids, however, carries a and side effects of methotrexate in risk of significant side effects. For- steroid-dependent asthma. 1\venty-five tunately, most patients with asthma can patients who were on theophylline, an be successfullytreated with combinations undetermined dose of inhaled betaof beta-adrenergic agonists, inhaled top- adrenergic agonists, and daily doses of ical glucocorticosteroids, theophylline, 1,200 to 1,600 mg of inhaled triamcinacromolyn, and occasionally anticholiner- lone acetonide were followed for 18 to gic agents, reserving systemic glucocor- 24 months on low-dose methotrexate ticosteroids for short time periods to therapy. Unlike previous studies, the sestabilize a severe exacerbation or treat a lection of patients included a one-month potentially life-threatening attack. In the induction period. Patients who had repatient who has frequent, increasingly se- quired a minimum of 10mg/day prednivere attacks or in whom careful systemic sone the preceding year and were unable glucocorticosteroid withdrawal is met to decrease their weekly prednisone dose with repeated exacerbations, the long- by at least 2.5 to 5 mg during the inducterm administration of systemic gluco- tion phase wereconsidered steroid depencorticosteroids may be indicated. This so- dent and placed on methotrexate. In the called steroid-dependent asthmatic has 25 patients who met these criteria, it was been the focus of numerous studies possible to reduce the dose of prednisone attempting to identify other anti-inflam- from a mean of 26.9 to 6.3 mg/day on matory agents that may reduce or elimi- methotrexate (initially 7.5 mg/wk, innate the need for systemic glucocorti- creasing to 15 to 50 mg/wk). Fifteen pacosteroids. Medications such as azathio- tients wereable to discontinue prednisone prine, 6-mercaptopurine, colchicine, entirely, nine patients reduced their dose gold salts, and prostaglandin inhibitors by 50010, and only one patient failed to have all been tried with variable results respond. Adverse reactions werenoted to be mild, usually with transient elevations (2-4). In 1986, Mullarkey and colleagues (5) of liver funct.ion tests, and did not warfirst reported the potentially beneficial rant discontinuation of the drug. The ineffects of methotrexate after their obser- vestigators concluded that methotrexate vation of a patient with psoriatic arthri- was an effective and safe glucocortis and steroid-dependent asthma who ticosteroid sparing agent with minimal was able to discontinue systemic glu- long-term side effects in patients with cocorticosteroids after institution of bronchial asthma (7). Although methotrexate therapy may methotrexate therapy. 1\vo years later, Mullarkey and colleagues (6) reported a have glucocorticosteroid sparing effects double-blind crossover study of 14 pa- in asthmatics, questions can be raised tients with steroid-dependent asthma fol- about the need for long-term systemic lowed for 24 wk on low-dose methotrex- glucocorticosteroids in the patients studate. The daily prednisone dose could be ied and the apparent safety to methotrexreduced by 36.5070 without deterioration ate therapy. The term "steroid-dependent in lung function when the patients were asthma," although commonly used, lacks on methotrexate. While recognizing the uniformly defined criteria. In our expotential benefit of methotrexate in the perience, most patients classified as stetreatment of asthma, the study was con- roid dependent are not receiving the full sidered limited by the small number of spectrum of inhaled agents, including a patients, lack of long-term follow-up,and beta-adrenergic agonist, glucocortico-
steroid, cromolyn, and, in selected patients, an anticholinergic agent, are not maximizing the dose of inhaled glucocorticosteroids, are not using their inhalers properly, are not taking theophylline, or are tapering their systemic glucocorticosteroids too rapidly. A one-month attempt at tapering may not be adequate to confirm steroid dependence. Some patients taking long-term oral glucocorticosteroids may require a slower tapering than the protocol used by Mullarkey and coworkers (7). Several studies from Europe have demonstrated the beneficial effect of high-dose, inhaled glucocorticosteroids, which may be used safely and effectively to facilitate the tapering of systemic glucocorticosteroids (2, 8). It is not clear if the patients of Mullarkey and associates (5-7) were given the full benefit of inhaled agents. Information about the choice of beta-adrenergic agents, their dose (number of puffs), and frequency of administration is missing. Likewise, inhaled cromolyn and anticholinergics were apparently not used in any of the patients. Although cromolyn may not have a dramatic effect in all patients and anticholinergic responsiveness may only be present in a subset of patients, these agents certainly deserve to be added to the regimen before resorting to long-term systemic glucocorticosteroids. Finally, close medical followup in itself could have a beneficial effect on the patient's symptomatology. For example, the careful supervision of the patients selected for the study of Mullarkey and colleagues (7) could have facilitated the reduction of prednisone. An adequate control population would have been required to test this possibility. Methotrexate has been widely used by rheumatologists for the treatment of rheumatoid arthritis and psoriatic arthritis, and considerable body of data exists on the clinical response to and adverse effects of methotrexate in these diseases (9-11). Methotrexate is a folic acid antagonist with antineoplastic and anti-inflammatory actions. For example, methotrexate appears to inhibit neutrophil chemotaxis induced in vitro by leu-
a
1
2
kotriene B4 and C5a (12-14). Whether it is this or other factors that provide the glucocorticosteroid sparing effect of methotrexate in asthma remains unclear. The toxicity of methotrexate has been thought to be dose related; hence, low doses have been relatively well tolerated for prolonged periods of time, and most toxicities are usually reversible when the drug is stopped. The most common side effects of low-dose methotrexate are elevation of liver transaminases, gastrointestinal problems (nausea and vomiting), and stomatitis. Lesscommon side effects include bone marrow depression, cirrhosis, and pneumonitis (3, 9, 11). The true incidence of cirrhosis resulting from methotrexate therapy is not known, but it appears to be higher in patients on daily doses of methotrexate and in patients with diabetes, ethanol abuse, and obesity. Unfortunately, liverenzyme levelsneither correlate nor predict the development of cirrhosis. Hence, liver biopsies every three years or after every cumulative dose of 1,500mg have been recommended (9). Because asthma is a chronic disease, the possibility of long-term use and abuse of methotrexate may create the potential for increased toxicity and possibly the need for repeated liver biopsies. Mullarkey and coworkers (5-7) found relatively few side effects in their patients, but routine liver biopsies were not performed, perhaps because neither a three-year follow-up period nor a cumulative dose of 1,500 mg was reached. Furthermore, the investigators used extreme caution in monitoring patients for side effects and adverse drug interactions. Patients were informed about the adverse effects of methotrexate, wereinstructed to avoid alcohol and a list of drugs that interacted with methotrexate, and receivedmonthly blood examinations (7). It is unlikely that patients with asthma not enrolled in a study protocol would be followed this closely, thereby increasing the risk of developing more serious adverse effects. The pulmonary toxicity of methotrexate is not dose related and has occurred in patients on weekly, low-dose methotrexate therapy (15, 16).There is evidence that it may be aggravated by pre-existing interstitial lung disease (17-19). The acute pulmonary toxicity noted with methotrexate is typically characterized by dyspnea, dry cough, pulmonary infiltrates,
EDITORIAL
and a high incidence of eosinophilia. The incidence of coexisting airway reactivity in these patients has not been determined previously. In this issue, Jones and colleagues (20) describe a case of airway hyperresponsiveness induced by methotrexate therapy. The patient appeared to have evidence of mild interstitial fibrosis by computed tomography, although the lung volumes and carbon monoxide diffusing capacity were normal. If this observation is reproduced in a large number of' patients, it would suggest that methotrexate produces or aggravates preexisting airway hyperresponsiveness. This raises new questions not only about mechanisms of action but also about indications and guidelines for monitoring patients on methotrexate therapy. A patient with asthma treated with methotrexate who is not improving may be experiencing a methotrexate reaction and not a spontaneous worsening. Likewise, a patient suffering more severe asthma during glucocorticosteroid withdrawal may be experiencing a methotrexate reaction. Airway hyperresponsiveness is certainly a most undesirable side effect of an antiasthmatic drug. Should methotrexate be added to the traditional armamentarium of antiasthmatic drugs as suggested by Mullarkey and colleagues? This question cannot be answered without further study of the efficacy, mode of administration, and adverseeffects of methotrexate. Even if such studies favor the use of methotrexate, its use will have to be limited to the patient with truly glucocorticosteroid-dependent asthma. D.
FERTEL,
M.D.
Assistant Professor of Medicine Department of Pulmonary Disease University ofMiami School ofMedicine Miami, FL A.
WANNER,
M.D.
Professor of Medicine Chief, Pulmonary Division University ofMiami School ofMedicine Miami, FL References 1. Djukanovic R, Roche WR, Wilson JW, et at. Mucosal inflammation in asthma. Am Rev Respir Dis 1990; 142:434-57. 2. Barnes PJ. A new approach to the treatment of asthma: drug therapy. N Engl J Med 1989; 321:
1517-27. 3. Kaslow JE, Novey HS. Methotrexate use for asthma: a critical appraisal. Ann Allergy 1989; 62:541-5. 4. Cott GR, Cherniack RM. Steroids and "steroidsparing" agents in asthma (editorial). N Engl J Moo 1988; 318:634-6. 5. Mullarkey MF, Webb DR, Pardee NE. Methotrexate in the treatment of steroid-dependent asthma. Ann Allergy 1986; 56:347-50. 6. Mullarkey MF. Blumenstein BA, Andrade wp. Baily GA, Olason I. Wetzel CEo Methotrexate in the treatment of corticosteroid-dependent asthma. A double-blind crossover study. N Engl J Moo 1988; 318:603-7. 7. Mullarkey MF, Lammert JK, Blumenstein BA. Long-term methotrexate treatment in corticosteroiddependent asthma. Ann Intern Med 1990; 112: 577-81. 8. Smith MJ, Hudson M. High-dose beclomethasone inhaler in the treatment of asthma. Lancet 1983; 1:265-9. 9. Thgwell P, Bennett K. Gent M. Methotrexate in rheumatoid arthritis. Indications, contraindications, and safety. Ann Intern Moo 1987; 107:358~. 10. Weinblatt ME, Trentham DE. Fraser PA, et at. Long-term prospective trial of low-dose methotrexate in rheumatoid arthritis. Arthritis Rheum 1988; 31:167-75. 11. Kremer JM, Lee JK. The safety and efficacy of the use of methotrexate in long-term therapy for rheumatoid arthritis. Arthritis Rheum 1986; 29:822-31. 12. Van De Kerhof PCM, Baur FW, Maassen DE, Ground RM. Methotrexate inhibits the leukotriene B4 induced intraepidermal accumulation of polymorphonuclear leukocytes. Br J Dermatol 1985; 113:251a-5a. 13. Suarez CR, Pickett WC, Bell DH, et al. Effects of low dose methotrexate on neutrophil chemotaxis induced by leukotriene B4 and complement C5A. J Rheumatol 1987; 14:9-11. 14. Johnson JD, Summersgill JT. Raff MJ. The invited effects of methotrexate on the phagocytosisand intracellular killing of Staphylococcus nureus by human neutrophils. Cancer 1986; 57:2343-5. 15. Carson CW, Cannon OW, Egger MJ, et at. Pulmonary disease during the treatment of rheumatoid arthritis with low dose pulse methotrexate. Semin Arthritis Rheum 1987; 16:186--95. 16. St. Clair EW, Rice JR, Synderman R. Pneumonitis complicating low-dose methotrexate therapy in rheumatoid arthritis. Arch Intern Moo 1985; 145:2035-8. 17. Bell MJ, Greddie WR, Gordon DA. et at. Preexisting lung disease in patients with rheumatoid arthritis (RA) may predisposeto methotrexate lung. Arthritis Rheum 1986; 29(Suppl:S7S). 18. Searles G, McKenchry RJR. Methotrexate pneumonitis in rheumatoid arthritis: potential risk factors. Four case reports and a review of the literature. J Rheumatol 1987; 14:1164-71. 19. Cannon GW, Ward JR, Olegg 00. Acute lung disease associated with low-dose pulse methotrexate therapy in patients with rheumatoid arthritis. Arthritis Rheum 1983; 26:1269-74. 20. Jones G, Mierins E. Karsh J. Methotrexateinduced asthma. Am Rev Respir Dis lQQ1: 143: 179-81.
