leflunomide ( lef ) is a disease - modifying antirheumatic drug for treating rheumatoid arthritis ( ra ) .
its efficacy was established by double - blind , randomized controlled trials . a 5-year follow - up
study demonstrated comparative safety profile as in the phase iii trial , showing no excessive pulmonary adverse event .
however , lef - related interstitial lung disease ( ild ) was increasingly reported after introduction of lef in japan in 2003 , and diffuse alveolar damage ( dad ) was the principal histopathological change in autopsied cases . here
an 80-year - old taiwanese woman was admitted to our hospital because of shortness of breath . her medical history was notable for remote pulmonary tuberculosis , which had been cured for 5 years and ra , which had been diagnosed for 11 years .
follow - up chest radiograph taken 2 years earlier showed mild fibrocalcified lesion in right upper lung zone without obvious interstitial changes .
she was a nonsmoker and her current medication included oral prednisolone ( 10  mg / day ) , cyclosporine ( 100  mg / day ) , and lef ( 20  mg / day ) .
methotrexate ( mtx ) ( 7.5  mg / week ) was prescribed initially after the diagnosis of ra . due to poor disease control ,
she had been in her usual state of health until 2 days before admission , when progressive dyspnea on exertion developed , along with productive cough , fever , and chills . at admission ,
her vital signs were : temperature 37.3 c , heart rate 110  beats / min , blood pressure 147/89 mm hg , respiratory rate 28  breaths / min , and oxygen saturation 95% while breathing supplementary oxygenation at a rate of 10  l / min through a face mask .
laboratory examinations showed normal leukocyte count ( 5110/l ) , elevated blood urea nitrogen ( 57  mg / dl ) , creatinine ( 1.6  mg / dl ) , aspartate aminotransferase ( 93  u / l ) , c - reactive protein level ( 11.7  mg / dl ) , and mildly increased rheumatoid factor level ( 44  iu / ml ) ( normal range , 020.1  iu / ml ) .
she was intubated with ventilator support on day 2 for acute hypoxic respiratory failure . a high - resolution computed tomography of the chest on day 3 ( fig .
2a ) showed diffuse ground - glass opacities with thickened interlobular septa and patchy consolidations at bilateral lower lobes .
hrct of the chest on day 3 ( a ) showed diffuse ground - glass opacities with thickened interlobular septa , accompanied by patchy consolidations at bilateral lower lobes .
a follow - up hrct of the chest on day 16 ( b ) showed persistent diffuse bilateral ground - glass opacities and interlobular thickening without improvement .
hrct , high - resolution computed tomography . besides empirical intravenous ceftriaxone ( 2000  mg / d ) and levofloxacin ( 750  mg / d ) for presumed severe community acquired pneumonia , intravenous trimethoprim / sulfamethoxazole ( trimethoprim component 15  mg / kg / d ) , and methylprednisolone ( 60  mg / d ) were administered for suspicious pneumocystis jirovecii pneumonia and ra - associated ild .
cultures of blood , tracheal aspirate , and bronchoalveolar lavage fluid revealed no evidence of bacteria , fungus , or mycobacterium infection .
the results of rapid influenza diagnostic test and cytomegalovirus antigenemia assay were both negative . a follow - up high - resolution computed tomography of the chest on day 16 ( fig .
2b ) showed persistent diffuse bilateral ground - glass opacities and interlobular thickening without improvement .
due to poor treatment response , she received thoracoscopic wedge resection of the right upper and middle lung on day 18 .
microscopically , the airspaces were lined by hyaline membranes , with thickened alveolar septa containing inflammatory exudates , but no obvious fibrotic change .
there was no evidence of pneumocystis jiroveci , cytomegalovirus , or other microbial infection ( fig .
her condition deteriorated and she died of superimposed vancomycin - resistant enterococcal bacteremia and septic shock on day 24 .
microscopic examination of the lung ( hematoxylin and eosin stain , 40 ) revealed the airspaces lined by hyaline membranes , with thickened alveolar septa containing inflammatory exudates , compatible with diffuse alveolar damage in the acute exudative stage .
patients with ra often have pulmonary involvement , and ild is the primary manifestation . besides the underlying ra - associated ild , the other differential diagnoses include opportunistic infection such as pneumocystis jiroveci or cytomegalovirus infection due to immunosuppressive therapy or drug - induced lung disease by disease - modifying antirheumatic drugs or biologic agent . in our case , the ild may be related with lef , after excluding possible infectious causes and underlying ra - associated ild .
the prevalence of ra - associated ild varies according the different diagnostic modalities and is 19% to 56% by the use of high - resolution computed tomography of the chest , which correlates with the histopathological patterns .
lee et al found that usual interstitial pneumonia pattern is the most frequent histopathological pattern in patients with ra - associated ild ( 56% ) , followed by nonspecific interstitial pneumonia ( 33% ) and organizing pneumonia ( 11% ) . when a total of 56 patients were reviewed from 4 studies ,
the histopathological patterns included usual interstitial pneumonia pattern in 34 patients , nonspecific interstitial pneumonia in 21 and lymphocytic interstitial pneumonia in another one , with no dad pattern was identified .
parambil et al found 5 patients with ra had dad on surgical lung biopsy during a 7-year period from 1996 to 2002 at mayo clinic , but 1 patient was confounded by lef treatment .
to date , dad is still a rare histopathological pattern in ra - associated ild , and the dad pattern seen in our patient is less likely due to the underlying ra - associated ild .
lef is an isoxazole immunomodulatory agent that inhibits dihydroorotate dehydrogenase and thus de novo pyrimidine synthesis after being metabolized to its active metabolite a771726 , which has a half - life of 2 weeks .
lef was launched in the usa in 1998 and in europe the following year as a disease - modifying antirheumatic drug and approved by japanese government for treatment of ra in april 2003 .
although ild was rarely reported as a complication of lef usage worldwide ( 0.02% ) , post - marketing surveillance in japan revealed that , during the first few months after approval , 16 patients developed de novo or exacerbated ild , 9 of whom died .
case reports in japan were published successively , and dad was the histopathological pattern in 2 autopsied cases .
after that , the study committee for leflunomide - induced lung injury organized by the japan college of rheumatology analyzed the data of post - marketing surveillance obtained from sanofi - aventis japan . during the period from september 2003 to june 2006 , 61 ( 1.2% ) of 5054 ra patient receiving lef
the duration of lef usage before symptom onset was 138.1    174.7 ( 61204 ) days .
cholestyramine wash - out therapy , given orally at 8 g 3 times a day , can reduce plasma level by 40% in 24  hours , and to undetectable plasma levels in 11 days .
multivariable logistic regression analysis identified pre - existing ild , cigarette smoking , a low body weight ( < 40  kg vs  >  50  kg ) and the use of a loading dose as independent risk factors for lef - related ild , among which pre - existing ild was the most important one . a canadian nested case - control study showed that lef increased the risk of ild , but the effect was restricted in subjects with previous mtx use or pre - existing ild .
patients with a fatal outcome were more likely to have pre - existing ild , extremely high serum c - reactive protein and low albumin levels , severe hypoxemia and mechanical ventilation and persistent blood lymphopenia throughout the course . based on the findings ,
the study committee for leflunomide - induced lung injury proposes that lef should not be used in patients with pre - existing ild and a loading dose is not recommended . in vitro studies showed lef could induce epithelial - mesenchymal transition of mouse pulmonary epithelial cell , which subsequently promoted pulmonary fibrosis .
the phenomenon occurs in the presence of other fibrosis - inducing stimuli such as bleomycin but does not do this in the absence of these stimuli .
this may explain why previous mtx use or pre - existing ild is a risk factor for lef - related ild .
outside japan , cases of lep - related ild were reported in korea , canada , new zealand , and australia with similar higher prevalence rate in korea ( 10/1010 = 1% ) than in other countries .
thus , racial or genetic difference may further predispose the development of lef - related ild , and taiwanese ra patients may also have higher risk due to similar racial and genetic background . in taiwan ,
lef was licensed in september 2003 for the treatment of mtx - unresponsive or mtx - intolerable ra patients .
theoretically , lef is more likely to be prescribed in ra patients with previous mtx use or pre - existing ild ( to avoid mtx exposure ) , who then have increasing risk for lef - induced ild . in our patient
, lef may be a potential cause of dad , supported by the history of previous mtx exposure , lack of infection evidence after extensive survey , and dad pattern on pathological examination .
however , due to prolonged lef treatment ( 3291 days ) , the causative role of lef in dad in our patient can not be confirmed .
nevertheless , our case still hints that lef - related dad may occur even if lef has been prescribed for a prolonged period . when acute ild develops in a ra patient , surgical lung biopsy may be needed early in the course to help diagnosis and prognosis .
 abstractpatients with rheumatoid arthritis ( ra ) often have pulmonary involvement , and interstitial lung disease ( ild ) is the primary manifestation , in which diffuse alveolar damage ( dad ) is a rare histopathologic pattern . 
 leflunomide ( lef ) is a frequently prescribed disease - modifying antirheumatic drug for treating ra . 
 lef - related ild in the form of dad has been reported in patients with ra , with the duration of lef treatment before symptom onset ranging from 6 to 1204 days.we present a case of elderly woman with ra under prolonged lef treatment for > 9 years ( 3291 days ) , who had acute respiratory failure with the initial presentation of exertional dyspnea , fever , chills , and productive cough for 2 days . 
 the histopathologic result of surgical lung biopsy was compatible with dad . 
 she was diagnosed as having lef - related ild , based on correlated clinical history , compatible histopathologic examination and excluding possible infection after extensive survey.although the causative role of lef can not be confirmed , this case still hints that lef - related dad may occur even if lef has been prescribed for a prolonged period . 
Introduction
Case report
Discussion