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Journal of Crohn's and Colitis: 10 (9)

Editor-in-Chief

Laurence J. Egan, Ireland

Associate Editors

Shomron Ben-Horin, IsraelSilvio Danese, ItalyPeter Lakatos, HungaryMiles Parkes, UKJesús Rivera-Nieves, USABritta Siegmund, GermanyGijs van den Brink, NLSéverine Vermeire, Belgium

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Methotrexate-induced pneumonitis in a patient with Crohn's disease

Giovanna Margagnoni, Valeria Papi, Annalisa Aratari, Luca Triolo, Claudio Papi
DOI: http://dx.doi.org/10.1016/j.crohns.2009.11.007 211-214 First published online: 1 June 2010

Abstract

Pulmonary toxicity is a well recognised but infrequent adverse event of treatment with methotrexate. The vast majority of cases have occurred in patients with rheumatoid arthritis; here we present the case of a 44-year old woman with ileo-colonic Crohn's disease who developed methotrexate pneumonitis. The patient had a 10 year history of Crohn's disease and, in the last 18 months, she was treated with oral methotrexate because of steroid-dependency and intolerance to thiopurines. She was admitted to the hospital because of acute dyspnoea, non-productive cough and fever. High-resolution CT scan showed diffuse bilateral areas of ground-glass opacity, and pulmonary function tests disclosed a mild obstructive pattern with a decrease in carbon monoxide diffusing capacity. Blood cultures for pathogenic bacteria or fungi were negative as well as serologic tests against major pneumotropic agents. Methotrexate-induced lung injury was considered: the drug was discontinued and the patient received a steroid course with rapid symptomatic improvement. After 4 weeks pulmonary function tests and high-resolution chest CT scan were normal. To our knowledge this is the second reported case of methotrexate-induced pneumonitis occurring in a patient with Crohn's disease. A definite diagnosis has been made not invasively according to clinical, laboratory and radiological criteria and excluding any infectious aetiology of the pulmonary findings.

Keywords
  • Crohn's disease
  • Methotrexate
  • Pneumonitis

1 Introduction

Methotrexate (MTX) is an analogue of folic acid that inhibits cellular proliferation by competitively inhibiting the enzyme dihydrofolate reductase, thereby blocking the conversion of dihydrofolate to tetrahydrofolate. In addition to its anti-proliferative effects, MTX has anti-inflammatory and immunomodulating properties and is widely used in the treatment of chronic inflammatory disorders, mainly rheumatoid arthritis and psoriasis.1 MTX has been shown to be effective also for inducing and maintaining remission in steroid-dependent Crohn's disease (CD)2,3 and is commonly employed as a second line steroid-sparing agent.4

More than 50% of patients treated with MTX eventually develop at least one adverse reaction, most commonly involving the skin, gastrointestinal tract, or central nervous system. Most of these reactions are not life-threatening, but up to 30% of patients treated for more than 5 years with MTX discontinue the therapy because of unacceptable toxicity.5 Major and potentially life-threatening adverse effects include pulmonary toxicity, hepatotoxicity, and haematologic effects.6

The prevalence of pulmonary toxicity ranges from less than 1% to approximately 7%7 but the precise frequency is difficult to assess because some reports have included patients who were receiving other cytotoxic medications, or had underlying disease involving the lungs and pleura.8 Most reported cases of MTX-induced pulmonary toxicity have occurred in patients with rheumatoid arthritis: this may simply reflect the population of patients receiving MTX but it has been suggested that pre-existing lung disease, particularly rheumatoid pleuro-pulmonary involvement, may increase the risk of MTX lung injury.7,9

Here we describe the case of a female patient, with no history of pulmonary disease, who developed MTX pneumonitis on the background of long-standing ileo-colonic CD. To our knowledge, only one case report of MTX-induced pneumonitis in a patient with CD has been previously reported in the literature.10

2 Case report

A 44-year old woman was admitted to the hospital because of dyspnoea, non-productive cough and fever (38.5 °C) lasting for less than 1 week. The patient was a non smoker and had no history of pulmonary disease. Ten years earlier, in 1998, ileo-colonic CD was diagnosed. In 2005, because of steroid-dependency, azathioprine 2.5 mg/kg/day was started, but the drug was discontinued after a few weeks because of acute pancreatitis. On January 2007 a severe relapse complicated by peripheral arthritis occurred: infliximab 5 mg/kg was administered at 0, 2 and 6 week intervals; the patient entered remission within 2 weeks but a severe allergic reaction occurred during the third infusion of infliximab and treatment was discontinued. Oral MTX 15 mg weekly was administered as maintenance treatment. The drug was well tolerated and the patient was symptom-free in the subsequent 18 months.

At admission, vital signs were as follows: blood pressure 140/85 mm Hg; pulse rate 100/min; respiratory rate 20/min. Chest auscultation found crackles in both lung fields. Laboratory studies revealed an increased erythrocyte sedimentation rate (56 mm/h) and CRP levels (2.8 mg/dl; normal range < 0.8 mg/dl); mild anemia (Hb 11.2 g/dl) and leukocytosis (14.200/mm3; neutrophils 68%, lymphocytes 25%, eosinophils 6% and monocytes 1%). Hepatic and renal function tests were in the normal range. Chest roentgenogram showed bilateral diffuse interstitial infiltration; arterial blood gas analysis disclosed pH 7.475; pO2 103.6 mm Hg; pCO2 29.3 mm Hg; HCO3 21.3 mmol/l and O2 saturation 95.4%. High-resolution CT scan showed diffuse bilateral areas of ground-glass opacity: no architectural distortion, lymphadenopathy, atelectasis, or pleural effusions could be detected (Fig. 1). Pulmonary function tests disclosed a mild obstructive pattern with a decrease in carbon monoxide diffusing capacity (DLCO = 57%). Blood cultures for pathogenic bacteria or fungi were negative. Serologic tests for Listeria serotype O and H were negative as well as IgM antibodies against Chlamidia pneumoniae, Legionella pneumophila, Coxiella burneti, Mycoplasma pneumoniae and major pneumotropic viruses. MTX-induced lung injury was considered: the drug was discontinued and the patient received a 4 week course of systemic steroids (Prednisone 1 mg/kg/day) and a 1 week antibiotic course (Chlarithromycin 1 g/day). Symptoms improved within 3 days and the patient was symptom-free within 1 week. After 4 weeks pulmonary function tests and high-resolution chest CT scan were normal (Fig. 2).

Figure 1

High-resolution chest CT scans showing diffuse bilateral areas of ground-glass opacity without architectural distortion, lymphadenopathy, atelectasis, or pleural effusions.

Figure 2

High-resolution chest CT scan after 4 weeks of steroid treatment.

3 Discussion

Pneumonitis is a potentially serious adverse event of treatment with MTX, occurring most frequently in patients with rheumatoid arthritis. Although MTX pulmonary toxicity is largely unpredictable, several risk factors have been identified, particularly pre-existing lung disease or abnormal pulmonary function tests prior to therapy.9,11

The precise mechanisms by which MTX results in pulmonary injury are unknown and probably the pathogenesis is multifactorial, including a hypersensitivity reaction, a direct toxic effect, and an impaired host resistance to acquired or latent viral infection.7,8 An idiosyncratic mechanism, unrelated to folate antagonism, is supported by the observation that pulmonary toxicity is dose and route of administration independent, but none of the proposed mechanisms accounts for the observation that pulmonary toxicity may remit despite continued therapy and may not recur upon re-challenge.1,8

In the majority of patients, MTX pulmonary toxicity develops within the first year of therapy and may present in an acute, sub acute, or chronic form. Acute presentation is generally non-specific, with fever, chills, malaise, cough, dyspnoea, and chest pain: rapid progression to respiratory failure may also occur. Sub acute presentation is characterized by dyspnoea, non-productive cough, fever, crackles, and cyanosis; progression to pulmonary fibrosis is observed in approximately 10% of patients.12 Most patients recover from methotrexate pneumonitis. However, some physiologic abnormalities may persist, and there is an approximate 1% mortality rate.8

No test is diagnostic of MTX-induced pneumonitis; bronchoalveolar lavage (BAL) and lung biopsy are considered the primary ways to establish the diagnosis. Typical, although not specific, findings observed at BAL are lymphocytic predominance, an increase of CD4+ lymphocytes and CD4/CD8 ratio, and the presence of atypical epithelial cells.13 Pulmonary histology is characterized by alveolitis with epithelial cell hyperplasia and cytologic dysplasia, and, eventually, small granulomas and eosinophilic infiltration, suggesting hypersensitivity pneumonitis. Approximately 10% of patients will demonstrate fibrosis on lung biopsy.14 In the majority of patients, however, a definite diagnosis can be made by non invasive tests, according to clinical, laboratory and radiological criteria and excluding pulmonary infection, as suggested by Searles and McKendry15 (Table 1).

View this table:
Table 1

Diagnostic criteria of methotrexate pneumonitis.15

Major criteria
Hypersensitivity pneumonitis by histopathology without evidence of pathogenic organisms
Radiologic evidence of pulmonary interstitial or alveolar infiltrates
Blood cultures (if febrile) and initial sputum cultures (if sputum is produced) negative for pathogenic organisms
Minor criteria
Shortness of breath for < 8 weeks
Non-productive cough
O2 saturation ≤ 90% on room air at the time of initial evaluation
DLCO ≤ 70% that predicted for age
Leukocyte count ≤ 15,000 cells/mm3

“definite” major criteria 1 or 2 + 3 in cojunction with at least 3 minor criteria.

“probable” major criteria 2 + 3 in cojunction with at least 2 minor criteria.

    In our patient, the diagnosis of MTX-induced pneumonitis can be considered definite according to the radiologic evidence of pulmonary interstitial infiltrates, the negative blood cultures (major criteria 2 and 3) in conjunction with 4 minor criteria (shortness of breath for < 8 weeks, non-productive cough, DLCO < 70, leukocyte count < 15,000 cells/mm3). A complete resolution of pneumonitis was observed after MTX withdrawal and a course of systemic steroids.

    Pneumonitis can occur rarely in inflammatory bowel disease patients receiving MTX; a definite diagnosis can be made not invasively according to clinical, laboratory and radiological criteria and excluding any infectious aetiology of the pulmonary findings. Discontinuation of MTX and systemic corticosteroids are the cornerstone of management.

    References

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