Leflunomide (LEF) was one of a series of fluorine-containing chemical structures synthesized by the German company Hoeschst in the late 1970s during the development of an agricultural pesticide. In 1998, a clinical trial of leflunomide for the treatment of rheumatoid arthritis was completed in the United States, and in September of the same year, the U.S. Food and Drug Administration (FDA) approved leflunomide as a disease-modifying drug for the treatment of rheumatoid arthritis in the United States. In China, a large-scale clinical trial was completed in 1999 and was officially approved by the Chinese Drug Administration (SDA), and in March 2009, the Chinese Drug Administration approved the new indication of lupus nephritis for Leflunomide (trade name Airova) manufactured by Suzhou Changzheng-Xinkai Pharmaceutical Co. On January 27, 2004, the Japanese Ministry of Health, Labor and Welfare and Aventis (the manufacturer of LEF in Japan) jointly published a set of data: among the 3360 patients registered for LEF, 16 cases of interstitial lung disease occurred (4.8%); among them, 5 cases died (1.5%); among the deaths, 2 cases were probably related to the use of LEF. The data was published and attracted widespread attention from the global pharmaceutical community. Since then, a few cases of leflunomide causing pneumonia and interstitial pneumonia have been reported worldwide. In February and April 2004, The Lancet published two articles detailing the correlation between LEF use and the development of interstitial lung lesions, suggesting that only 80 cases of interstitial lung lesions have occurred in a population of 400,000 RA patients since the launch of LEF, with no deaths reported except in Japan. A research paper on all DMARDs and risk of infection was published in AutoimmunityReviews in November 2008. The authors meta-analyzed a large number of randomized controlled and open observational trials analyzing 16788 RA patients with a mean follow-up of 3.5 years and found that the risk of infection caused by leflunomide was not significantly elevated (HR=1.2, 95% CI: 1.0-1.5), with a mean of 3.30 cases/100 patient-years (95% CI: 1.65-5.9), and the results of the meta-analysis showed that leflunomide The results of the meta-analysis showed that leflunomide has a good safety profile and does not significantly increase the incidence of infections such as pneumonia in patients using it. In June 2008, a cohort study published in ModRheumatol of the Japanese Society for Rheumatology showed that the risk of ILD in patients with a previous history of interstitial lung injury on LEF (OddsRatios of 8.17); in addition, the application of compound doses, smoking, and low body weight (below 40 kg) also increased the risk of ILD. OddsRatios were 3.97, 3.12, and 2.91, respectively. In August 2009, the journal Rheumatology published a comprehensive analysis of the reported cases of leflunomide associated pneumonia published to date by BatsiChikura et al. at the Royal Liverpool University. The results found that a total of 32 cases (13 males and 19 females) of leflunomide-associated pneumonia have been reported in the literature up to now, all in patients with rheumatoid arthritis. All patients who developed pneumonia had a history of methotrexate application or interstitial lung disease. 80% of the cases developed leflunomide-associated pneumonia within the first 20 weeks of starting leflunomide. The vast majority of patients who developed interstitial pneumonia within 12 weeks of dosing were patients on loading doses or had a previous history of interstitial lung disease. The reported mortality rate for the 32 patients was 19%, of which 2 deaths were in patients with prior MTX-induced pneumonia. The risk of death from leflunomid-associated pneumonia was higher in patients with: (1) diffuse alveolar injury; (2) previous interstitial pneumonia; and (3) lamellar vitelliform lung lesions on HRCT. In addition, the treatment of leflunomide associated pneumonia with abciximide did not improve patient prognosis. In summary, interstitial pneumonia is a rare adverse event with leflunomide, and the major risk factors include age (elderly), smoking, severity of the patient’s disease, previous history of comorbid lung disease, and the combination of drugs that may cause lung injury (e.g., MTX). When prescribing Leflunomide, physicians should take a strict medical history, perform chest radiographs/CT examinations in suspected cases to exclude pulmonary disorders, avoid prescribing LEF to patients with prior pulmonary disease, and follow up closely while taking the drug.