1Department of Rheumatology, Freeman Hospital, Newcastle-upon-Tyne and 2Department of Medicine and Rheumatology, Queen Elizabeth Hospital, Gateshead, UK.
Correspondence to: V. Saravanan, Department of Rheumatology, Queen Elizabeth Hospital, Gateshead NE9 6SX, UK. E-mail: saravana_uk{at}yahoo.co.uk
Methotrexate (MTX) is the most commonly used disease-modifying drug (DMARD) in rheumatoid arthritis (RA) [1]. It is a main anchor drug in many combination regimes with conventional DMARDs and biological agents. It has the longest drug-survival time and a good benefit/toxicity ratio [2, 3]. However, toxicity is a major reason for MTX withdrawal in RA [3]. Pneumonitis is the reason for withdrawal of MTX in 1 in 108 patient-years compared with 1 in 35 patient-years for hepatic toxicity and 1 in 58 patient-years for neutropenia [3]. There are guidelines for effective monitoring of the hepatic and haematological toxicity of MTX [4, 5]. Pneumonitis following MTX is a potentially fatal hypersensitivity reaction and is far less predictable than hepatic and haematological toxicity. Current guidelines [4, 5] advise a pretreatment chest radiograph (CXR), though there are wide variations in clinical practice in screening for lung disease prior to commencing MTX for RA. This is due to conflicting views as to whether pre-existing pulmonary disease increases the risk of MTX pneumonitis. Many studies [611] suggest that pre-existing lung disease in RA increases the risk of pneumonitis. Not all studies [12, 13] have supported this view. We discuss the evidence for predicting MTX pneumonitis in RA and the usefulness of screening for lung disease in patients with RA prior to treatment with MTX.
Prevalence and pathogenesis of methotrexate pneumonitis
MTX pneumonitis is most frequent within the first year of treatment [3, 1416] and the reported incidence of this adverse reaction varies from 0.86 to 6.9% [3, 8, 10, 14]. Our earlier work [6] reports the prevalence in RA at 1 in 80 patient-years. Most reported cases have occurred in patients with RA [15, 17], though a higher frequency (14%) has been reported in primary biliary cirrhosis [18]. Pneumonitis is not unique to MTX and has been shown to occur with sulphasalazine and gold treatment for RA.
The variable incidence and usual occurrence within a year of starting MTX suggests that pneumonitis is an idiosyncratic immune reaction rather than a dose-related toxic insult to the lung. Pneumonitis has also been seen after alteration of the immune system by anti-tumour necrosis factor therapy with infliximab in patients already established on MTX [19]. Akoun et al. [20] showed that MTX stimulated lymphokine secretion by peripheral lymphocytes of patients with pneumonitis, suggesting cell-mediated hypersensitivity. Bronchoalveolar studies and biopsies show a lymphocytic alveolitis [2124].
Risk factors
From a MEDLINE search, we identified six studies that looked at risk factors for MTX pneumonitis in RA. Pre-existing lung disease has been associated with an increased risk of MTX pneumonitis in these studies [611]. Meta-analytic methods were used to pool the odds ratio for MTX pneumonitis in the presence of pre-existing lung disease. The summarized data from these six studies are in Table 1. Although these studies varied in their design and definition of pre-existing lung disease, all suggested that it predisposed to MTX pneumonitis (pooled odds ratio of 7.5, 95% confidence interval CI 3.615.8). Pre-existing lung disease was seen in 48% of 69 patients who developed MTX pneumonitis. By comparison, only 7.4% of 1769 patients without pneumonitis had evidence of prior lung disease.
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Clinical features
Pneumonitis due to MTX presents either acutely or subacutely with cough, fever and dyspnoea. The criteria of Searles and McKendry [25] are widely accepted for defining MTX pneumonitis (Table 2). As it is mainly a diagnosis of exclusion, it is often difficult to distinguish from chest infection or exacerbations of pre-existing interstitial lung disease (ILD), which are not uncommon in patients with RA.
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Investigations
Negative microbial cultures of sputum and blood are needed before a definitive diagnosis of pneumonitis can be made. CXR may show interstitial shadows, but this is not a sensitive test. A decline in VC and TLCO is suggestive but not specific for pneumonitis. The negative predictive value of a stable TLCO when suspecting MTX pneumonitis is yet to be studied. High-resolution computed tomography (HRCT) of the lungs is more sensitive than plain radiography in drug-induced lung disease and has the added ability to distinguish between different lung diseases [26]. Atypical chest infections (e.g. Pneumocystis carinii pneumonia) and progressive rheumatoid interstitial lung disease are the most difficult to differentiate clinically from pneumonitis due to MTX. Bronchoalveolar lavage (BAL) at bronchoscopy may be needed to rule out P. carinii pneumonia. The lack of fibrosis on HRCT and the cellular distribution in BAL fluid distinguish pneumonitis from RAILD. In pneumonitis, BAL fluid will show a high lymphocyte count and CD4/CD8 ratio [2124] and transbronchial lung biopsy is likely to show Type II pneumocyte proliferation and inflammatory infiltrate with or without giant cells.
Treatment
The diagnosis is often unclear at presentation. Patients with no obvious signs of a chest infection may need to be hospitalized. Stopping MTX immediately on suspecting pneumonitis alone may be all that is necessary. Oral or intravenous pulse corticosteroid treatment is often needed [17]. Patients with significant hypoxia will require intensive care with ventilation. Cyclophosphamide has been used successfully in significant pneumonitis [27].
Prognosis
A review of 123 published cases of MTX-induced pneumonitis showed a mortality of 13% [15]. The long-term prognosis of MTX pneumonitis is usually favourable [17]. Most patients recover fully and do not progress to have pulmonary fibrosis as a result of the pneumonitis. Although there are instances of successful reintroduction of MTX after pneumonitis [28], there is not enough evidence to support this.
Chronic effects of MTX
The long-term effect of MTX on the lung in RA has been of concern for many years. Longitudinal studies [12, 13, 29, 30] of lung function have been reassuring in this aspect. However, a recent Kuwaiti study [31] showed significant deterioration in lung function after 2 yr of treatment with MTX in early RA. Dawson et al. [29] showed no deterioration in lung function over 2 yr with MTX in patients with RA with or without pulmonary fibrosis diagnosed by HRCT. The experience was similar in two separate 1-yr longitudinal studies [13, 30] of around 100 RA patients treated with MTX. These studies, however, focused on the chronic pulmonary effects of MTX and were not designed to identify risk factors for MTX pneumonitis.
Sustained dry cough not accompanied by dyspnoea or constitutional symptoms is not uncommon with MTX. It is thought to be due to mucosal/airway irritation, and bronchoalveolar studies have shown this to be benign [32]. It often abates with symptomatic treatment or by discontinuing MTX temporarily.
Which RA patients should be given methotrexate?
The available evidence suggests that ILD is a risk factor for MTX pneumonitis. MTX has been reported to improve ILD due to RA [33] and is also used to treat inflammatory muscle disease with anti-synthetase antibodies, a condition associated with ILD [34]. However, the benefit of MTX in ILD has not been substantiated in a randomized trial. Patients with RA are unwilling to risk life-threatening toxicity due to DMARDs [35]. In our literature review, 48% of patients who had MTX pneumonitis had pre-existing lung disease (Table 1). We suggest avoiding MTX in patients with established ILD. Gas transfer is invariably reduced (TLCO <70% predicted) in such patients. If all RA patients with TLCO <70% are investigated for ILD by HRCT, we estimate that at least 5% of those considered for MTX may need to be treated with an alternative DMARD [36]. A more compelling reason to avoid MTX in these patients is that they may have poor lung reserve and hence are at risk of respiratory failure in the event of pneumonitis. There will be instances when the choice of DMARDs may be limited and we are compelled to use MTX for RA. The risks and benefits of using MTX in such cases should be weighed carefully. MTX has been used in the management of asthma [37] and patients with airway obstruction do not seem to be at increased risk of pneumonitis.
What baseline tests are useful prior to methotrexate?
Investigations done prior to MTX should serve two purposes. Identifying patients with ILD and poor lung reserve is the most important objective. The test should also serve as a reliable baseline for future comparison in the event of suspected pneumonitis.
A baseline CXR is done routinely according to current guidelines [4, 5] and is said to be a useful comparator in the event of future pneumonitis. Although it is easily available, CXR is less sensitive than TLCO in identifying interstitial lung disease or pneumonitis [38]. However, it would seem prudent to perform a CXR if there are signs or symptoms of lung disease.
Lung function tests are quite sensitive yet very non-specific in identifying occult lung disease. Simple spirometry to measure FEV1 and VC is readily available. Spirometry alone without TLCO is, however, less sensitive in identifying ILD [38]. In patients with an abnormal TLCO (70%), HRCT will identify the underlying lung disease and confirm/refute ILD.
Proposal
We propose screening (Fig. 1) for lung disease with lung function tests prior to commencing MTX. We suggest that all patients with RA commencing MTX have baseline lung function tests, including FEV1, VC and TLCO (corrected for haemoglobin). In patients with respiratory symptoms, MTX should be delayed until pulmonary function test (PFT) results are obtained. A mild PFT abnormality due to smoking is not a contraindication for MTX. An HRCT of the lungs should be obtained if TLCO is less than 70% of the predicted value. If HRCT confirms interstitial lung disease, MTX should be avoided and an alternative DMARD considered. Azathioprine, steroids and cyclophosphamide have all been used successfully in the treatment of ILD associated with RA [39]. If the HRCT shows only airway disease, MTX can be used and patients with symptomatic airway disease may also be treated with inhaled steroids.
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We acknowledge the implications of these recommendations for the resources needed and the costs of treatment. There may be a delay in access to PFTs in many hospitals in the UK. However, the cost of PFTs should be offset by the ability to confirm or refute MTX pneumonitis more easily in the event of an acute respiratory illness. In addition to identifying subclinical lung disease, it would be possible to avoid MTX in patients who are most at risk of respiratory failure due to pneumonitis.
Conflict of interest
The authors have declared no conflicts of interest.
References