Pulmonary Function in Patients Receiving Long-term Low-dose Methotrexate

doi:10.1378/chest.109.4.933

Chest

Volume 109, Issue 4, April 1996, Pages 933-938

https://doi.org/10.1378/chest.109.4.933 Get rights and content

Study objective

Acute interstitial pneumonitis is the main pulmonary side effect during methotrexate (MTX) treatment for rheumatoid arthritis. The aim of the study was to determine the following: (1) the incidence of MTX-induced pneumonitis during low-dose long-term MTX treatment for chronic arthritis; (2) whether periodic pulmonary function tests were useful for detecting MTX pneumonitis before clinical symptoms; and (3) whether any subclinical abnormality of pulmonary function was present in asymptomatic patients receiving MTX treatment.

Design

Pulmonary function tests, including diffusing capacity for carbon monoxide (Dco) measurements, were performed in 124 patients receiving low-dose MTX for rheumatologic diseases at the time of initiating treatment, and then at 3 months, 6 months, and at 6-month intervals thereafter. Mean duration of treatment was 23 months.

Results

MTX treatment was interrupted in six patients for acute onset of clinical symptoms; criteria for diagnosis of MTX pneumonitis were fullfilled in four cases (incidence: 3.2%); no risk factor could be identified. No significant decrease in pulmonary function parameters could be observed before the onset of clinical symptoms of MTX pneumonitis, and this adverse effect could not be predicted by periodic function tests. A statistically significant decrease was found in FVC (−2.2%, p=0.04), FEV₁ (-5.0%, p<0.001), and diffusing capacity per alveolar volume, DCO/V_A(−4.8%, p=0.03), but not Dco (-1.3%, p>0.05), in the 118 other asymptomatic patients during MTX treatment.

Conclusion

We found minor subclinical alterations in pulmonary function in asymptomatic patients receiving low-dose long-term MTX treatment, but periodic pulmonary function tests did not allow us to detect MTX-induced pneumonitis before clinical symptoms. Therefore, we recommend that these tests should not be systematically performed while patients are receiving treatment.

Section snippets

Population Studied

We prospectively studied each patient who was beginning low-dose weekly MTX therapy, in a department of rheumatology, from 1985 to 1992. We studied 124 patients for a mean period of 23 months (range, 1 to 85 months). The patients were treated for rheumatoid arthritis (115 patients), psoriatic rheumatism (6 patients), or systemic lupus erythematosus (3 patients). MTX treatment was begun after all conventional treatments, including salazopyrine, D-penicillamine, and gold therapy, had led to

Incidence of MTX Pneumonitis

Four patients developed MTX pneumonitis according to criteria from Searles and Mc Kendry;¹⁶ three had a definite diagnosis, defined as the presence of at least six criteria; one had a probable diagnosis with five criteria. Two other cases were not taken into account as the criteria were insufficient: one patient with four criteria (possible diagnosis) and one patient with three criteria. This result corresponds to an incidence of 4 cases among 124 patients (3.2%). Drug-induced bronchospasm was

Discussion

Most of the studies estimating the frequency of MTX pneumonitis concern the antineoplastic use of high-dose MTX and are retrospective studies.⁶ It has been considered that a low-dose MTX regimen may reduce the incidence of such problems. Varying incidences are reported in studies on the use of MTX in the treatment of rheumatoid arthritis: from 0.3%²² to 11.6%¹³ in retrospective studies, and from 0.7%²³ to 7.7%²⁴ in prospective studies (review in reference 14). We personally observed four cases

ACKNOWLEDGMENTS

We thank Louis Ayzac, MD, for statistical analysis. We thank Jérome Dumortier, MD, Line Lamboley, MD, and Maurice Bouvier, MD, who took part in the study. We thank Jean-François Cordier, MD, for critical comments on the manuscript.

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There is growing awareness that some forms of RA-ILD transition from asymptomatic or “subclinical” stages before an eventual clinical diagnosis. Subclinical ILD involves groups of patients who have specific radiological, physiological and in some cases histo-pathological abnormalities but are either asymptomatic or have symptoms that have not been attributed to ILD [17,18]. Little work has been conducted to show the preclinical and early radiological and functional manifestations in asymptomatic RA patients.
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To characterize and define the frequency of radiological and functional abnormalities capable of identifying “subclinical” RA-ILD with particular concern to the effect of methotrexate (MTX) therapy.
Sixty patients with RA were recruited with no respiratory manifestations. They were classified into two groups: group 1 included 35 patients receiving MTX and group 2 included 25 patients receiving only nonsteroidal anti-inflammatory drugs. Patients were also classified according to chest high resolution CT (HRCT) as RA-ILD or RA-noILD. Pulmonary function test (PFT) abnormalities were also used to further characterize occult respiratory defects.
38.3% of RA patients had subclinical ILD (25% in group 1 and 13.3% in group 2), while 61.7% were RA-no ILD. The percentage of patients with RA-ILD was insignificantly more in group 1 than group 2 (42.9% and 32% respectively). HRCT score revealed minimal to mild involvement in both groups. Long-standing RA with mean articular duration >50 months carries a significant risk for ILD. Other variables as age, gender, smoking, disease activity or rheumatoid factor seropositivity were not significant risk factors for development of RA-ILD.
Lung involvement should always be considered in patients with RA particularly those on MTX therapy even in the absence of chest symptoms. A tight control by PFTs, chest radiography and/or HRCT is necessary. Further studies evaluating the potential effect of MTX on progressive ILD with RA are needed.

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Chest

Clinical Investigations: DrugsPulmonary Function in Patients Receiving Long-term Low-dose Methotrexate

Study objective

Design

Results

Conclusion

Section snippets

Population Studied

Incidence of MTX Pneumonitis

Discussion

ACKNOWLEDGMENTS

Am J Med

The pharmacology and clinical use of methotrexate

N Engl J Med

Efficacy of low dose methotrexate in rheumatoid arthritis

N Engl J Med

Comparison of low-dose oral pulse methotrexate and placebo in the treatment of rheumatoid arthritis

Arthritis Rheum

Long-term prospective study of the use of methotrexate in the treatment of rheumatoid arthritis: update after a mean of 90 months

Arthritis Rheum

Methotrexate-induced pneumonitis

Medicine

Drug-induced pulmonary disease: I. Cytotoxic drugs

Am Rev Respir Dis

Methotrexate pneumonitis after low-dose therapy for rheumatoid arthritis

Arthritis Rheum

Acute lung disease associated with low-dose pulse methotrexate therapy in patients with rheumatoid arthritis

Arthritis Rheum

Pneumonitis complicating low-dose methotrexate therapy in rheumatoid arthritis

Arch Intern Med

Low dose methotrexate pneumonitis in rheumatoid arthritis

Thorax

Successful reintroduction of methotrexate after pneumonitis in two patients with rheumatoid arthritis

Ann Rheum Dis

Acute pneumonitis associated with low dose methotrexate treatment for rheumatoid arthritis: report of five cases and review of published reports

Thorax

Methotrexate-related pulmonary complications in rheumatoid arthritis

Ann Rheum Dis

Predictive factors for bleomycin-induced pneumonitis

Am Rev Respir Dis

Methotrexate pneumonitis in rheumatoid arthritis: potential risk factors: four case reports and a review of the literature

J Rheumatol

Single breath carbon monoxide diffusing capacity (transfer factor): recommendations for a standard technique

Am Rev Respir Dis

Clinical Investigations: Drugs
Pulmonary Function in Patients Receiving Long-term Low-dose Methotrexate