Rheumatology Advance Access originally published online on March 9, 2006
Rheumatology 2006 45(7):787-789; doi:10.1093/rheumatology/kel075
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EDITORIAL |
Drug-related pulmonary problems in patients with rheumatoid arthritis
Department of Medicine and Rheumatology, Queen Elizabeth Hospital, Gateshead, UK
Correspondence to: C. Kelly, Queen Elizabeth Hospital, Sheriff Hill, Gateshead Health NHS Trust, Tyne and Wear NE9 6SX, UK. E-mail: clive.kelly{at}ghnt.nhs.uk
There has been growing concern lately over the development of serious lung disease in patients with rheumatoid arthritis (RA) receiving certain categories of drug therapy. The Committee on Safety of Medicines [1] and the National Patient Safety Agency [2] have issued new recommendations on monitoring for pulmonary symptoms in patients taking methotrexate. The development of acute pulmonary infiltrates in patients taking leflunomide [3–6] and worsening of pre-existing interstitial fibrosis with the use of some anti-TNF agents, notably infliximab [7], have sparked concerns over the safety of these drugs. However, anxiety about drug-related lung disease is not new to rheumatologists. The literature on disease-modifying anti-rheumatic drugs (DMARDs) is dotted with reports of ‘penicillamine-induced bronchiolitis’, ‘gold lung’ and even sulphasalazine-induced pneumonitis. We have to consider the possibility that pneumonitis occurring de novo or the worsening of pre-existing interstitial fibrosis in RA may be due to modification of the rheumatoid disease process in the lung by certain drugs. As clinicians caring for patients with potential multisystem disorders, how can we minimize the risk of iatrogenic lung disease while ensuring that our patients can continue to receive effective disease modification?
The link between lung disease and RA has been recognized for many years [8, 9]. Initial estimates that interstitial lung involvement was present in under 5% of RA patients have been shown to be gross underestimates with the advent of better imaging techniques [10], and airway obstruction is now accepted as an equally important feature of RA [11], probably linked to disease activity and severity [12]. As patients become less limited by their joint disease due to treatment, an increasing number report breathlessness as a result of respiratory involvement. Respiratory disease is over-represented as a cause of death in recent large surveys of RA populations [13].
The increased prevalence of respiratory infections in RA patients has persisted over several decades but these infections are now more likely to be acute rather than chronic. Whereas the incidence of bronchiectasis has fallen sharply, up to 2% of the RA population develop an acute respiratory infection requiring hospitalization annually [14]. Whilst patients on methotrexate are at no greater risk of developing infection than other RA patients, the mortality from such infections is double that expected in the non-rheumatoid population, and failure to mount an appropriate leucocytosis is a major risk factor for death.
Pneumonitis as a consequence of treatment with methotrexate is now a frequent feature as the use of this agent increases. The reported incidence of ‘methotrexate pneumonitis’ in RA varies widely, from 0.86% to 6.9%, the risk being maximal in the first year of treatment. Its overall frequency is 1 in every 100 patient-years [15]. Pulmonary toxicity is specifically described as a complication of methotrexate treatment in the British National Formulary (BNF). Mortality estimates from methotrexate pneumonitis vary [16, 17] but are around 20% in most series. Prevention of cases is as important as rapid identification and treatment. Patients at greater risk of pneumonitis include smokers and those with underlying lung disease [16, 18]. Prior identification of the latter group using pretreatment pulmonary function tests (PFTs) and chest radiographs will allow the opportunity to offer an alternative agent. Although PFTs are less readily available, markedly reduced gas transfer is the single most predictive test for the later development of pneumonitis [19]. However, many cases of pneumonitis have been reported in patients with normal lungs at baseline, although the outcome is generally more favourable in these patients as a result of their greater pulmonary reserve. All patients commencing methotrexate should be made aware of the need to report new or deteriorating respiratory symptoms promptly.
There is no evidence that repeated routine PFTs in asymptomatic patients have any role in assessing the ongoing risk of pneumonitis. However, in RA patients who report new respiratory symptoms while on methotrexate, PFTs are much easier to interpret when baseline values are available for comparison. Our experience suggests that most such patients can continue therapy as their repeat PFT shows no significant change from baseline. Without this yardstick, many of these patients would have their methotrexate stopped unnecessarily. Acute or subacute breathlessness, often with cough and fever, may herald the onset of pneumonitis. Fixed bibasal lung crackles and hypoxia are usually noted, together with eosinophilia and radiological evidence of pulmonary infiltrates. Treatment involves immediate cessation of methotrexate and, usually, the commencement of steroids. In severe cases, intravenous administration of methylprednisolone may be required but in most cases oral therapy with prednisolone is sufficient. Given the long terminal half-life of methotrexate, consideration should also be given to the concomitant use of folinic acid.
Differentiation of methotrexate pneumonitis from acute respiratory infection is not always easy, in spite of the accepted diagnostic criteria [20]. In the absence of eosinophilia, it may be necessary to treat for both conditions, especially if there is delay in accessing further investigations, such as bronchoalveolar lavage or high-resolution CT (HRCT). In patients with unilateral signs, infection is more likely; prompt intravenous antibiotics and plasma expanders are needed, especially in those without an appropriate neutrophil leucocytosis. In our experience, reversal of methotrexate effects with folinic acid is useful in such patients. Tachypnoea and hypotension are usually markers of severe disease and indicate an increased risk of death [21], often associated with positive blood cultures and raised serum lactate. Such patients should be promptly referred to the critical care team and may need inotropic support and assisted ventilation.
Prevention of infection is also an important consideration. Several recent articles have indicated the need for annual immunization of RA patients against influenza and 5-yearly pneumococcal vaccination [22], although the immune response to this may be blunted by methotrexate [23]. Active cooperation between primary and secondary care can achieve impressive results in immunizing this at-risk population. Our recent article suggests a mechanism for the identification and treatment of acute lung disease in RA patients on methotrexate [24]. Since adopting these recommendations along with increasing the uptake of influenza vaccination, we have noted a marked fall in the mortality associated with methotrexate therapy.
Leflunomide has been licensed for use in the UK for 5 yr and sporadic reports of pulmonary disease occurring in patients treated with this agent have been received. A survey from Japan [3] reports an increased risk of acute pneumonitis in leflunomide-treated patients and reports a national incidence of 0.5%, although it acknowledges that this is five times greater than that encountered in the West. This warning is not highlighted in the most recent edition of the BNF, in which leflunomide merits only a mention of ‘interstitial lung disease’ in other reported side-effects, although the Committee on Safety of Medicines reports 17 cases in the UK of which five were fatal. The BNF does not describe the presence of prior lung disease as a contra-indication to its use. Leflunomide has been previously advocated and employed as an alternative to methotrexate in patients who have underlying lung disease. We have used it effectively and without problems in such patients and even in those with previous methotrexate pneumonitis. There is no evidence that its combination with methotrexate increases the risk of pneumonitis beyond that which methotrexate itself carries.
However, in a neighbouring district, the death of a patient with emphysema from acute pulmonary fibrosis while on leflunomide led to the coroner recently ruling that all patients commencing leflunomide should be told of its potential for causing lung disease. This may have an impact on the manufacturer's recommendations and on patients’ willingness to use this agent. Patients on leflunomide who develop acute dyspnoea should be investigated and treated as described for methotrexate pneumonitis, the important difference being the need for washout therapy with cholestyramine or activated charcoal (rather than the use of folinic acid).
Concerns have recently been raised over the potential effect of TNF blockade on the lung. There are several reports that infliximab infusions administered for active articular disease have caused acceleration of underlying rheumatoid interstitial lung disease, culminating in the death of some patients. These patients were on azathioprine prior to commencement of TNF therapy and were felt to have had stable lung disease [7]. This led to the British Society for Rheumatology issuing a warning over the continued use of infliximab in patients with established interstitial lung disease [25].
More recently, data on patients receiving etanercept for RA indicate that this agent can also potentiate an acute pneumonitis with ground glass shadowing on HRCT and histological evidence of a granulomatous pneumonitis [26]. Although some reports have included patients taking methotrexate in addition, this appears to be distinct from methotrexate pneumonitis and is almost exclusively confined to patients with prior significant lung disease, patients with interstitial damage faring less well than those with airway disease.
Given our present understanding of rheumatoid interstitial lung disease and drug-related pulmonary complications, the following recommendations seem appropriate:
- Include the assessment of the respiratory system as part of the routine work-up of all patients with RA
- Obtain PFT and/or chest radiographs in all patients in whom methotrexate therapy is considered, regardless of chest symptoms.
- If the clinical examination or the above investigation(s) suggest significant lung disease, consider HRCT to clarify the diagnosis.
- If interstitial lung disease is confirmed, consider an alternative agent to methotrexate. Leflunomide is less likely to cause pneumonitis but can no longer be recommended as a safe option. Sulphasalazine and Myocrisin (sodium aurothiomalate) have not been proved to carry an increased risk of lung disease in this setting.
- If the interstitial lung disease is felt to be a greater threat to the patient's well-being than their joint disease, consider steroids with either azathioprine or cyclophosphamide.
- If investigations demonstrate bronchiectasis, methotrexate is again best avoided as such patients are subject to recurrent chest infections and their response to infection may be blunted by this agent.
- If investigations demonstrate airways disease, the risk of pneumonitis appears much less, and methotrexate may be used with caution.
- Repeat PFT or HRCT is best reserved for patients who develop dyspnoea while on methotrexate, which should be discontinued if the gas transfer falls by 20% from baseline or ground glass opacification is seen on HRCT.
- Leflunomide carries a smaller risk of inducing acute pulmonary disease but is probably best avoided in patients with established underlying lung disease. However, it is not presently considered necessary to screen asymptomatic patients prior to commencing treatment.
- On present evidence, the use of infliximab and etanercept in patients with proven interstitial lung disease cannot be recommended. These agents are already contra-indicated in patients with bronchiectasis or recurrent chest infections.
The authors have declared no conflicts of interest.
References
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- National Patient Safety Agency. Methotrexate: patient information leaflet. London: NPSA,2004.
- Ito S, Sumida T. Interstitial lung disease associated with leflunomide. Intern Med 2004;43:1103–4.[CrossRef][ISI][Medline]
- Kamata Y, Nara H, Kamimura T et al. Rheumatoid arthritis complicated with acute interstitial pneumonia induced by leflunomide as an adverse reaction. Intern Med 2004;43:1201–4.[CrossRef][ISI][Medline]
- McCurry J. Japan deaths spark concerns over arthritis drug. Lancet 2004;363:461.[ISI][Medline]
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