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Methotrexate-induced hypersensitivity pneumonitis in a child with juvenile rheumatoid arthritis
M
Methotrexate-induced hypersensitivity pneumonitis
in a child with juvenile rheumatoid arthritis Randy Q. Cron, MD, PhD, David D. Sherry, MD, and Carol A. Wallace, MD
Low-dose methotrexate, widely used for juvenile rheumatoid arthritis, has been reported to cause pneumonitis in adults. We report on methotrexate-induced hypersensitivity pneumonitis in a child with juvenile rheumatoid arthritis. Physicians should be aware of this rare complication. (J Pediatr 1998;132:901-2)
Methotrexate, administered in low doses (5 to 30 mg/m2; 0.15 to 1.0 mg/kg) compared with doses used to treat malignant conditions (500 to 80,000 mg/m2), has been invaluable in the treatment of children with juvenile rheumatoid arthritis.1 Since the first reports of low-dose methotrexate-induced hypersensitivity pneumonitis in adults with rheumatoid arthritis in 1983,2,3 the prevalence has been estimated to be between 0.3% and 11.6% of patients receiving methotrexate.4 Methotrexate-induced HP in patients with RA is characterized by insidious onset of nonproductive cough, fever, and constitutional symptoms that progress to dyspnea and hypoxemia; and such patients frequently require hospitalization. Methotrexate-induced HP most often affects patients with RA in their sixth to eighth decades of life, with the youngest reported patient with RA being 38 years old.5 Our computer and tradi-
From the Division of Rheumatology, Department of Pediatrics, Children’s Hospital and Medical Center, Seattle, Washington. Submitted for publication Mar. 20, 1997; revisions received June 26, 1997, and Sept. 5, 1997; accepted Sept. 18, 1997. Reprint requests: Randy Cron, MD, PhD, Stanford University Medical Center, Department of Pediatrics, Division of Immunology and Transplantation Biology, 300 Pasteur Dr., Palo Alto, CA 943045208. Copyright © 1998 by Mosby, Inc. 0022-3476/98/$5.00 + 0 9/22/86309
tional literature searches failed to find any cases of HP that have been reported in children with rheumatic diseases who were treated with low-dose methotrexate. We describe a girl with polyarticular juvenile RA who was treated with methotrexate. She experienced pulmonary complications that resolved promptly when methotrexate was discontinued and corticosteroids were administered.
CASE REPORT A previously healthy 11-year-old girl (41 kg and 1.0 m2 body surface area) was diagnosed with rheumatoid factornegative, antinuclear antibody-positive (1:320) polyarticular juvenile RA in April 1995. The RA involved six joints. Nonsteroidal antiinflammatory drugs had little effect; therefore, a regimen of oral methotrexate (0.5 mg/kg/wk) and a daily vitamin with 400 µg of folate was started 4 months after presentation. Within 2 months, her morning stiffness resolved and her active joint count decreased from 6 to 2. Because she experienced gastrointestinal upset and headaches associated with methotrexate ingestion, the methotrexate was discontinued 7 months after presentation. Eight months thereafter, her disease reappeared, and methotrexate (0.5 mg/kg/wk, subcutaneously) and daily vitamins with
folate were reintroduced. One month later, she experienced a nonproductive cough, daily intermittent low-grade fevers, and constant nasal congestion with clear discharge. She had no history of passive smoke exposure and was treated with two consecutive 10-day courses of oral amoxicillin (500 mg, 3 times per day) for a presumed upper respiratory tract infection. A few months after having restarted methotrexate, the arthritis was in remission, and the complete blood count and aspartate aminotransferase level were normal. She continued to have low-grade fevers (maximal temperature of 38.9° C) and cough; and she had anorexia, malaise, dyspnea on exertion, and occasional vomiting. Sinus radiographs revealed clear sinuses. In midDecember, the methotrexate was discontinued.
HP RA
Hypersensitivity pneumonitis Rheumatoid arthritis
One week later, she appeared chronically ill, had lost 2.5 kg, and reported shortness of breath and chest pain. Her lungs were clear to auscultation, and no evidence of active arthritis was noted. Her leukocyte count was normal at 5400 × 109/L with a normal eosinophil count (3%). She received oral amoxicillinclavulanate (500 mg of amoxicillin and 125 mg of clavulanate 3 times per day for 10 days). One week later, the result of a chest radiograph was normal, but pulmonary function testing revealed a decreased forced vital capacity at 70% of normal for her height, gender, and age. Tests for lung diffusion capacity, exercise tolerance, and viral infection were not performed. A presumptive diagnosis of 901
CRON, SHERRY, AND WALLACE
methotrexate-induced pneumonitis was made, and she received daily oral prednisone (1.2 mg/kg/day). After skipping 2 doses of methotrexate, and within 2 days of receiving high dose corticosteroids, her condition had dramatically improved. Her cough, anorexia, malaise, and fevers resolved over the next several days; and she became more physically active. The prednisone dose was tapered over a 2-month period, and her forced vital capacity returned to normal. The arthritis remained in remission for 4 more months before returning in her knees.
DISCUSSION Methotrexate-induced HP is a rare side effect in patients with RA treated with low-dose methotrexate. Recent prospective methotrexate treatment studies of patients with RA have yielded a combined prevalence rate for reported methotrexate-induced HP of 0.6%.6,7 More than 60 cases of methotrexate-induced HP in patients with RA have been reported, and two independent sets of criteria have been established for making the diagnosis.8,9 The Searles and McKendry criteria require five of the following nine features for a diagnosis of probable methotrexate-induced HP: (1) acute onset shortness of breath, (2) fever greater than 38.0° C, (3) tachypnea and a nonproductive cough, (4) radiologic evidence of pulmonary interstitial or alveolar infiltrates, (5) a leukocyte cell count <15,000 × 109/L, (6) negative blood and sputum cultures for pathogens, (7) pulmonary function tests demonstrating restrictive pulmonary function with decreased diffusion capacities, (8) PO2 on room air of less than 55 mm Hg at admission, and (9) biopsy histopathologic features consistent with bronchiolitis or interstitial pneumonitis without evidence of pathogenic organisms.8 The criteria of Carson et al.9 re-
902
THE JOURNAL OF PEDIATRICS MAY 1998 quired three of the four following findings to make the diagnosis of probable methotrexate-induced pulmonary disease: (1) clinical course consistent with a hypersensitivity reaction, (2) resolution of infiltrates on chest radiograph after discontinuing methotrexate, (3) exclusion of infection or other pulmonary disease, and (4) pathologic findings consistent with drug-induced injury. In a recent case-control study of patients with RA, there was good concordance of the two sets of criteria for establishing a diagnosis of methotrexate-induced HP.5 The child described in this report was notably less severely affected than adult patients with RA; therefore, a histopathologic examination, bronchoalveolar lavage, determination of arterial blood gases, and sputum and blood cultures were not performed. The condition of the child improved dramatically within days of methotrexate withdrawal and administration of high-dose corticosteroids. She did not respond to prior empiric treatment with antibiotics for possible sinusitis, which is often confused with methotrexate-induced HP.9 According to the criteria of Searles and McKendry,8 our patient fit the diagnosis of probable methotrexate-induced pneumonitis (5 of 9 criteria met) without the availability of some laboratory and the histopathologic data. Unlike adult patients with RA with methotrexate-induced HP, this pediatric patient had no rales on auscultation of the chest, the results of her chest radiograph were normal, and she was rheumatoid factor-negative and anti-nuclear antibody–positive. Searles and McKendry8 have noted that the findings of chest radiographs may be entirely normal in methotrexate-induced HP. Thus this patient appears to represent the youngest reported patient with chronic arthritis to experience methotrexate-induced HP. In summary, with the increasing use of methotrexate to treat childhood rheumatic disorders, physicians need to
be aware of the potential for methotrexate-induced pulmonary complications so methotrexate can be swiftly discontinued and treatment with high-dose corticosteroids can be started.
REFERENCES 1. Wallace CA, Sherry DD. Preliminary report of higher dose methotrexate treatment in juvenile rheumatoid arthritis. J Rheumatol 1992;19:1604-7. 2. Cannon GW, Ward JR, Clegg DO, Samuelson CO, Abbott TM. Acute lung disease associated with low-dose pulse methotrexate therapy in patients with rheumatoid arthritis. Arthritis Rheum 1983;26:1269-74. 3. Engelbrecht JA, Calhoon SL, Scherrer JJ. Methotrexate pneumonitis after lowdose therapy for rheumatoid arthritis. Arthritis Rheum 1983;26:1275-8. 4. Barrera P, Laan RFJM, van Riel PLCM, Dekhuijzen PNR, Boerbooms AMT, van de Putte LBA. Methotrexate-related pulmonary complications in rheumatoid arthritis. Ann Rheum Dis 1994;53:434-9. 5. Carroll GJ, Thomas R, Phatouros CC, Atchison MH, Leslie A-L, Cook NJ, et al. Incidence, prevalence, and possible risk factors for pneumonitis in patients with rheumatoid arthritis receiving methotrexate. J Rheumatol 1994;21:51-4. 6. Hanrahan PS, Scrivens GA, Russell AS. Prospective long term follow-up of methotrexate therapy in rheumatoid arthritis: toxicity, efficacy and radiological progression. Br J Rheumatol 1989; 28:147-53. 7. Furst DE, Erikson N, Clute L, Koehnke R, Burmeister LF, Kohler JA. Adverse experience with methotrexate during 176 weeks of a long term prospective trial in patients with rheumatoid arthritis. J Rheumatol 1990;17:1628-35. 8. Searles G, McKendry RJR. Methotrexate pneumonitis in rheumatoid arthritis: potential risk factors. Four case reports and a review of the literature. J Rheumatol 1987;14:1164-71. 9. Carson CW, Cannon GW, Egger MJ, Ward JR, Clegg DO. Pulmonary disease during the treatment of rheumatoid arthritis with low dose pulse methotrexate. Semin Arthritis Rheum 1987;16:18695.
Methotrexate-induced hypersensitivity pneumonitis
in a child with juvenile rheumatoid arthritis Randy Q. Cron, MD, PhD, David D. Sherry, MD, and Carol A. Wallace, MD
Low-dose methotrexate, widely used for juvenile rheumatoid arthritis, has been reported to cause pneumonitis in adults. We report on methotrexate-induced hypersensitivity pneumonitis in a child with juvenile rheumatoid arthritis. Physicians should be aware of this rare complication. (J Pediatr 1998;132:901-2)
Methotrexate, administered in low doses (5 to 30 mg/m2; 0.15 to 1.0 mg/kg) compared with doses used to treat malignant conditions (500 to 80,000 mg/m2), has been invaluable in the treatment of children with juvenile rheumatoid arthritis.1 Since the first reports of low-dose methotrexate-induced hypersensitivity pneumonitis in adults with rheumatoid arthritis in 1983,2,3 the prevalence has been estimated to be between 0.3% and 11.6% of patients receiving methotrexate.4 Methotrexate-induced HP in patients with RA is characterized by insidious onset of nonproductive cough, fever, and constitutional symptoms that progress to dyspnea and hypoxemia; and such patients frequently require hospitalization. Methotrexate-induced HP most often affects patients with RA in their sixth to eighth decades of life, with the youngest reported patient with RA being 38 years old.5 Our computer and tradi-
From the Division of Rheumatology, Department of Pediatrics, Children’s Hospital and Medical Center, Seattle, Washington. Submitted for publication Mar. 20, 1997; revisions received June 26, 1997, and Sept. 5, 1997; accepted Sept. 18, 1997. Reprint requests: Randy Cron, MD, PhD, Stanford University Medical Center, Department of Pediatrics, Division of Immunology and Transplantation Biology, 300 Pasteur Dr., Palo Alto, CA 943045208. Copyright © 1998 by Mosby, Inc. 0022-3476/98/$5.00 + 0 9/22/86309
tional literature searches failed to find any cases of HP that have been reported in children with rheumatic diseases who were treated with low-dose methotrexate. We describe a girl with polyarticular juvenile RA who was treated with methotrexate. She experienced pulmonary complications that resolved promptly when methotrexate was discontinued and corticosteroids were administered.
CASE REPORT A previously healthy 11-year-old girl (41 kg and 1.0 m2 body surface area) was diagnosed with rheumatoid factornegative, antinuclear antibody-positive (1:320) polyarticular juvenile RA in April 1995. The RA involved six joints. Nonsteroidal antiinflammatory drugs had little effect; therefore, a regimen of oral methotrexate (0.5 mg/kg/wk) and a daily vitamin with 400 µg of folate was started 4 months after presentation. Within 2 months, her morning stiffness resolved and her active joint count decreased from 6 to 2. Because she experienced gastrointestinal upset and headaches associated with methotrexate ingestion, the methotrexate was discontinued 7 months after presentation. Eight months thereafter, her disease reappeared, and methotrexate (0.5 mg/kg/wk, subcutaneously) and daily vitamins with
folate were reintroduced. One month later, she experienced a nonproductive cough, daily intermittent low-grade fevers, and constant nasal congestion with clear discharge. She had no history of passive smoke exposure and was treated with two consecutive 10-day courses of oral amoxicillin (500 mg, 3 times per day) for a presumed upper respiratory tract infection. A few months after having restarted methotrexate, the arthritis was in remission, and the complete blood count and aspartate aminotransferase level were normal. She continued to have low-grade fevers (maximal temperature of 38.9° C) and cough; and she had anorexia, malaise, dyspnea on exertion, and occasional vomiting. Sinus radiographs revealed clear sinuses. In midDecember, the methotrexate was discontinued.
HP RA
Hypersensitivity pneumonitis Rheumatoid arthritis
One week later, she appeared chronically ill, had lost 2.5 kg, and reported shortness of breath and chest pain. Her lungs were clear to auscultation, and no evidence of active arthritis was noted. Her leukocyte count was normal at 5400 × 109/L with a normal eosinophil count (3%). She received oral amoxicillinclavulanate (500 mg of amoxicillin and 125 mg of clavulanate 3 times per day for 10 days). One week later, the result of a chest radiograph was normal, but pulmonary function testing revealed a decreased forced vital capacity at 70% of normal for her height, gender, and age. Tests for lung diffusion capacity, exercise tolerance, and viral infection were not performed. A presumptive diagnosis of 901
CRON, SHERRY, AND WALLACE
methotrexate-induced pneumonitis was made, and she received daily oral prednisone (1.2 mg/kg/day). After skipping 2 doses of methotrexate, and within 2 days of receiving high dose corticosteroids, her condition had dramatically improved. Her cough, anorexia, malaise, and fevers resolved over the next several days; and she became more physically active. The prednisone dose was tapered over a 2-month period, and her forced vital capacity returned to normal. The arthritis remained in remission for 4 more months before returning in her knees.
DISCUSSION Methotrexate-induced HP is a rare side effect in patients with RA treated with low-dose methotrexate. Recent prospective methotrexate treatment studies of patients with RA have yielded a combined prevalence rate for reported methotrexate-induced HP of 0.6%.6,7 More than 60 cases of methotrexate-induced HP in patients with RA have been reported, and two independent sets of criteria have been established for making the diagnosis.8,9 The Searles and McKendry criteria require five of the following nine features for a diagnosis of probable methotrexate-induced HP: (1) acute onset shortness of breath, (2) fever greater than 38.0° C, (3) tachypnea and a nonproductive cough, (4) radiologic evidence of pulmonary interstitial or alveolar infiltrates, (5) a leukocyte cell count <15,000 × 109/L, (6) negative blood and sputum cultures for pathogens, (7) pulmonary function tests demonstrating restrictive pulmonary function with decreased diffusion capacities, (8) PO2 on room air of less than 55 mm Hg at admission, and (9) biopsy histopathologic features consistent with bronchiolitis or interstitial pneumonitis without evidence of pathogenic organisms.8 The criteria of Carson et al.9 re-
902
THE JOURNAL OF PEDIATRICS MAY 1998 quired three of the four following findings to make the diagnosis of probable methotrexate-induced pulmonary disease: (1) clinical course consistent with a hypersensitivity reaction, (2) resolution of infiltrates on chest radiograph after discontinuing methotrexate, (3) exclusion of infection or other pulmonary disease, and (4) pathologic findings consistent with drug-induced injury. In a recent case-control study of patients with RA, there was good concordance of the two sets of criteria for establishing a diagnosis of methotrexate-induced HP.5 The child described in this report was notably less severely affected than adult patients with RA; therefore, a histopathologic examination, bronchoalveolar lavage, determination of arterial blood gases, and sputum and blood cultures were not performed. The condition of the child improved dramatically within days of methotrexate withdrawal and administration of high-dose corticosteroids. She did not respond to prior empiric treatment with antibiotics for possible sinusitis, which is often confused with methotrexate-induced HP.9 According to the criteria of Searles and McKendry,8 our patient fit the diagnosis of probable methotrexate-induced pneumonitis (5 of 9 criteria met) without the availability of some laboratory and the histopathologic data. Unlike adult patients with RA with methotrexate-induced HP, this pediatric patient had no rales on auscultation of the chest, the results of her chest radiograph were normal, and she was rheumatoid factor-negative and anti-nuclear antibody–positive. Searles and McKendry8 have noted that the findings of chest radiographs may be entirely normal in methotrexate-induced HP. Thus this patient appears to represent the youngest reported patient with chronic arthritis to experience methotrexate-induced HP. In summary, with the increasing use of methotrexate to treat childhood rheumatic disorders, physicians need to
be aware of the potential for methotrexate-induced pulmonary complications so methotrexate can be swiftly discontinued and treatment with high-dose corticosteroids can be started.
REFERENCES 1. Wallace CA, Sherry DD. Preliminary report of higher dose methotrexate treatment in juvenile rheumatoid arthritis. J Rheumatol 1992;19:1604-7. 2. Cannon GW, Ward JR, Clegg DO, Samuelson CO, Abbott TM. Acute lung disease associated with low-dose pulse methotrexate therapy in patients with rheumatoid arthritis. Arthritis Rheum 1983;26:1269-74. 3. Engelbrecht JA, Calhoon SL, Scherrer JJ. Methotrexate pneumonitis after lowdose therapy for rheumatoid arthritis. Arthritis Rheum 1983;26:1275-8. 4. Barrera P, Laan RFJM, van Riel PLCM, Dekhuijzen PNR, Boerbooms AMT, van de Putte LBA. Methotrexate-related pulmonary complications in rheumatoid arthritis. Ann Rheum Dis 1994;53:434-9. 5. Carroll GJ, Thomas R, Phatouros CC, Atchison MH, Leslie A-L, Cook NJ, et al. Incidence, prevalence, and possible risk factors for pneumonitis in patients with rheumatoid arthritis receiving methotrexate. J Rheumatol 1994;21:51-4. 6. Hanrahan PS, Scrivens GA, Russell AS. Prospective long term follow-up of methotrexate therapy in rheumatoid arthritis: toxicity, efficacy and radiological progression. Br J Rheumatol 1989; 28:147-53. 7. Furst DE, Erikson N, Clute L, Koehnke R, Burmeister LF, Kohler JA. Adverse experience with methotrexate during 176 weeks of a long term prospective trial in patients with rheumatoid arthritis. J Rheumatol 1990;17:1628-35. 8. Searles G, McKendry RJR. Methotrexate pneumonitis in rheumatoid arthritis: potential risk factors. Four case reports and a review of the literature. J Rheumatol 1987;14:1164-71. 9. Carson CW, Cannon GW, Egger MJ, Ward JR, Clegg DO. Pulmonary disease during the treatment of rheumatoid arthritis with low dose pulse methotrexate. Semin Arthritis Rheum 1987;16:18695.