Published: March 2006
ADR update

Leflunomide and Pneumonitis

Prescriber Update 27(1): 7-8.
March 2006

Ruth Savage, Medical Assessor, CARM,
New Zealand Pharmacovigilance Centre, Dunedin

There is increasing evidence that leflunomide alone or in conjunction with methotrexate can cause pneumonitis, an acute respiratory illness characterised by dyspnoea, hypoxia and lung infiltrates.  Prompt recognition is important as pneumonitis may be fatal or cause persisting disability.  Early symptoms usually include dyspnoea but may be non-specific.  Evaluation of baseline pulmonary status prior to treatment should be considered.  Inform all patients of initial warning symptoms so that these can be investigated immediately and the suspect medicines discontinued.

Pneumonitis with leflunomide can have serious consequences

Leflunomide (Arava®) is a disease-modifying anti-rheumatic agent (DMARD) with anti-inflammatory and immunomodulating properties.  It is indicated for the treatment of rheumatoid arthritis.1  Clinical trials and post-marketing surveillance indicate that leflunomide can cause pneumonitis either as monotherapy or in conjunction with methotrexate, which is also known to cause this disorder.1,2

Pneumonitis due to drug toxicity is an acute respiratory illness characterised by dyspnoea, hypoxia, and lung infiltrates.  It is distinguishable from similar illnesses caused by infective organisms (e.g. Pneumocystis carinii) by an absence of organisms in blood, initial (induced) sputum cultures or bronchial wash/brush microscopy or cultures.  Pneumonitis can be life-threatening, fatal or cause persisting respiratory compromise.3

Seven NZ reports of pneumonitis with leflunomide

The Centre for Adverse Reactions Monitoring (CARM) has received seven reports of pneumonitis occurring in patients taking leflunomide.  All seven were taking methotrexate concurrently.  There were four female and three male patients, aged 43 to 83 years. Initial symptoms were various combinations of dyspnoea, cough, fever, lethargy, weight loss and influenza-like symptoms followed by rapid progression to acute respiratory compromise.  All patients had chest x-ray or computerised tomography (CT) evidence of lung infiltrates.  Two patients required ventilatory support in intensive care.  Management consisted of discontinuation of leflunomide and methotrexate, treatment with oxygen or ventilatory support, and high-dose corticosteroids.  Because leflunomide has a long half-life of one to four weeks,1 cholestyramine was used to remove leflunomide in three patients with good effect.  Five patients recovered, one died, and the other improved but had some persisting respiratory impairment.

Methotrexate itself can cause pneumonitis, usually within the first year of use.3 In the seven patients reported to CARM, the duration of leflunomide use prior to the onset of symptoms was 12 to 36 weeks.  The duration of methotrexate use was usually longer and in four patients was greater than one year, thus supporting a causal role for leflunomide in the development of pneumonitis.  These observations, together with similar reports from Australia, have been published.2

Pre-existing pulmonary disease and use of other DMARDs may increase the risk

By 2004, it was estimated that 400,000 people had received leflunomide worldwide, and the reported incidence of pneumonitis was 1 in 5000.4  However, in a post-marketing surveillance programme in Japan, 29 of the 3658 patients developed pneumonitis and 11 patients died.5  While not all cases may have been attributable to leflunomide, these observations suggest that the incidence of pneumonitis may be greater in clinical practice than in clinical trials.  As with the New Zealand patients, the Japanese patients frequently had past or present exposure to other DMARDs and some had pre-existing pulmonary disorders.  It is possible that pre-existing pulmonary disease and other DMARDs, particularly methotrexate, may increase the likelihood of pneumonitis occurring with leflunomide.  However, it should be borne in mind that many patients benefit from combination therapy where single agents have failed.

Inform all patients of early warning symptoms and consider baseline assessment

Clinical trials and the case reports to CARM indicate that leflunomide as monotherapy, or perhaps more commonly with methotrexate, can cause pneumonitis.  Since patients with rheumatoid disease may have respiratory involvement or other lung disorders, a pre-treatment chest x-ray and evaluation of pulmonary status is useful in establishing a baseline should respiratory symptoms occur.

Patients should be informed of the early symptoms of pneumonitis and advised to seek medical attention promptly.  New or worsening pulmonary symptoms need to be investigated without delay and leflunomide stopped, if appropriate.1,6  Methotrexate should also be discontinued if it is being taken concomitantly.  Prescribers are reminded that monitoring for hepatic dysfunction and blood dyscrasias is also imperative in patients taking leflunomide.1,7  Additionally, please continue reporting leflunomide-associated adverse reactions to CARM.

Competing interests (author): none declared

  1. Aventis Pharma Limited. Arava data sheet 2 June 2004.
  2. Savage RL, Highton J, Boyd IW, Chapman P. Pneumonitis associated with leflunomide: a profile of New Zealand and Australian reports. Int Med J 2006;36(3):162-169.
  3. Vial T, Chevrel G, Descotes J. Drugs acting on the immune system. In Dukes MNG, Aronson JK (Eds). Meyler’s Side Effects of Drugs, 14th edn. Amsterdam:Elsevier; 2000:1246-1337.
  4. McCurry J. Japan deaths spark concerns over arthritis drug. Lancet 2004;363(9407):461.
  5. Aventis Pharma Inc. Dear Health Care Professional letter (Canada): Arava (leflunomide) and interstitial lung disease 21 June 2004. (accessed 28 Sept 2005).
  6. Aventis Pharma Limited. Dear Doctor letter (New Zealand): Important safety information – Arava (leflunomide) 17 December 2004.
  7. Medsafe Editorial Team. Leflunomide: Serious Multi-System Adverse Effects. Prescriber Update 2004;25(1):2-3.