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Rheumatology Advance Access originally published online on November 28, 2006
Rheumatology 2007 46(3):553-554; doi:10.1093/rheumatology/kel397
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Cavitating pneumonia, a severe complication of leflunomide therapy in chronic polyarthritis

G. A. W. Bruyn, T. L. Jansen, A. Ten Brinke1, M. De Vries1, P. M. Houtman and E. N. van Roon2

Department of Rheumatology, 1Department of Pulmonology and 2Department of Pharmacology, Medisch Centrum Leeuwarden, 8934 AD Leeuwarden, The Netherlands.

Correspondence to: T. L. Jansen. E-mail: t.jansen{at}znb.nl

SIR, Leflunomide (LEF) selectively inhibits dihydro-orotate dehydrogenase, a key enzyme in the de novo synthesis of pyrimidines. The active metabolite, A77 1726, is a potent inhibitor of lymphocyte proliferation in vitro. LEF inhibits progression in rheumatoid (RA) and psoriatic arthritis (PsorA) [1–3]. LEF safety data have focused mainly on liver toxicity, diarrhoea, rash, alopecia and hypertension [1–3]. Unlike methotrexate (MTX), LEF was considered relatively safe for lungs. Emerging data report uncommon adverse effects including vasculitis [4, 5] and fatal acute interstitial pneumonitis in Japanese [6, 7].

From 1998 to 2005, we performed a prospective study in 136 adult Caucasian patients with active RA or PsorA who started with LEF 20 mg/day. The hospital Ethical Committee granted permission for research in this cohort. All patients gave oral and written informed consent to publish the study. Serum concentrations of the active metabolite A77 1726 were measured with reversed phase HPLC-UV chromatography [8]. Mean duration of LEF therapy was 33 months, ranging 5–50 months. In this cohort, five patients were encountered with cavitating pneumonia developing after LEF was initiated, i.e. 3.7% risk. None of these five were DMARD naïve nor had had pre-treatment with anti-tumour necrosis factor (TNF-{alpha}). All received a combination treatment consisting of LEF with glucocorticoids (Table 1). In four patients, polymicrobial infection was documented from cultures of sputum, bronchoalveolar lavage fluid and/or biopsies. A full recovery was attained due to antibiotics; so far, no lung nor lymphomatous malignancy developed.


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  		TABLE 1. Clinical data of patients on daily leflunomide therapy and cavitary lung lesions

 
These five patients developed pulmonary infectious events that were not fully understood: the clinical picture was atypical when compared with the familiar pneumonia syndrome. An insidious onset, general malaise, anaemia, little or no fever, a lack of sharp thoracic pain at onset, no rigors and few sputum production was characteristic in these patients. Chest radiography revealed one or more pulmonary lesions with cavitation, but not on previous radiographs. We used the method as described by Naranjo et al. [9] to estimate the likelihood of a causal relationship between LEF and the pulmonary syndrome: range 0–10 (<1 denotes a very doubtful relationship between the adverse event and the drug; 1–4 possible; 5–8 probable and >9 a definite relationship). In our patients, Naranjo scores of 4 were reached, i.e. a possible relationship between LEF and the cavitary lung lesions.

The risk of developing cavitating pneumonia in our cohort was 3.7%, whereas cavitating pneumonia is not noted in the package insert for LEF although 1339 patients were included in the pre-marketing safety database. This suggests that either the rate of 3.7% exaggerates the true risk, or that our cohort differs from patients included in the pre-marketing safety database regarding susceptibility to bronchopulmonary adverse events. In contrast to patients included in the phase III studies, our inception cohort consisted of patients with a variety of comorbidities, which may have increased a pulmonary infection rate. Several risk factors for pulmonary infectious disease were present in our patients. Two patients had known chronic obstructive pulmonary disease or asthma, and in three out of five, a history of smoking was present. None of our patients had been treated with anti-TNF-{alpha}, also known to increase risk of infection, notably tuberculosis; sometimes associated with micro-organisms that may cause cavitating pneumonia as well [10]. In combination with infliximab, LEF has been associated with pharmacological A77 1726 level and cavitating pneumonia in 1 out of 20 exposed patients, i.e. 5% [11]. Four of the five patients received MTX, associated with opportunistic pulmonary infections in the past [12]. The common risk factor, however, in our patients was treatment with LEF in combination with a low-dose prednisone.

In all our patients, proof of infection was found. The microbial profile of the isolates consisted of a wide variety of pathogenic bacteria including Staphylococcus aureus, Enterobacter cloacae, Haemophilus influenzae, Pseudomonas aeruginosa, and Streptococcus pneumoniae; in addition, evidence of slowly growing bacteria like Actinomyces and opportunistic fungi like Candida and Aspergillus were present. In three out of five patients, polymicrobial infection was documented by culture of more than one micro-organism. This suggests pulmonary susceptibility for colonization of pathogenic micro-organism(s), due to microbial and/or host effects such as pulmonary toxicity due to LEF and/or MTX [13]. An alternative explanation may be phagocytosis failure [14]: inhibited neutrophil migration following LEF or MTX [15]. The effects of LEF and MTX may add up in patients receiving both drugs, although activated T cells may well be preferentially inhibited by LEF [16]. In vitro, LEF induced a decrease of macrophages positive for intracellular TNF-{alpha} and interleukin (IL)-1ß, and a decrease of extracellular concentration of TNF-{alpha}. LEF induces a reduced expression of intercellular adhesion molecule-1 (ICAM-1) and cyclo-oxygenase-2 (COX-2) on cultured synovial macrophages [17]. Arguments of specific LEF-induced lung toxicity were not found, as normal therapeutic levels of the metabolite A77 1726 were present [18].

All of our five patients had a good outcome with antibiotics. Alertness of clinicians for these serious respiratory infections in patients treated with LEF and low dose predniso(lo)ne is warranted. Because of the protracted clinical pattern, strategies for secondary prevention of these infections should be looked for.


   References
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 References
 

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  2. Van Roon EN, Jansen TL, Mourad L, et al. (2004) Leflunomide in active rheumatoid arthritis: a prospective study in daily practice. Br J Clin Pharmacol 58:201–8.[CrossRef][Web of Science][Medline]
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  10. Arend SM, Kuijper EJ, Allaart CF, Muller WH, Van Dissel JT. (2004) Cavitating pneumonia after treatment with infliximab and prednisone. Eur J Clin Microbiol Infect Dis 23:638–41.[Web of Science][Medline]
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Accepted 25 March 2006


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