Acute progression of interstitial lung disease: a complication of etanercept particularly in the presence of rheumatoid lung and methotrexate treatment

Abstract

, We report two patients on etanercept who presented withsevere diffuse alveolar infiltrates culminating in ground-glasschange on high resolution computed tomography (HRCT) of thelung.The first, a 64-yr-old woman with an 11-yr-history of sero-negative rheumatoid arthritis (RA) had failed to achieve optimalcontrol of her RA with multiple disease modifying antirheumaticdrugs (DMARDs) and only showed a partial response to oralmethotrexate 22.5mg/week since 2002. Etanercept was introducedat 25mg twice a week. She developed acute breathlessness after sixinjections (3 weeks).She was an ex-smoker who had stopped 10yrs previously. Shehad no pre-existing rheumatoid lung disease but did have chronicobstructive pulmonary disease (COPD). Full pulmonary functiontests done 5yrs earlier showed the evidence of previous chronicobstructive airways disease, her corrected transfer factor (DLCO)corrected was 13.18 (55%) with a KCO 2.86 (62%). Chest X-ray(CXR) showed emphysema.She was admitted with a 3-day history of increasing shortness ofbreath (SOB) at rest without cough. HRCT of the chest showedwidespread ground-glass change throughout both lung bases, andchanges of bullous emphysema.Etanercept was discontinued. She was commenced on 40mgoral prednisolone and broad-spectrum antibiotics. Her SOBrecovered quickly but her joint symptoms flared and she wasrestarted on oral methotrexate 25mg/week to good effect. RepeatHRCT scan after 4 months showed significant improvement inground-glass changes with some minimal residual interstitialfibrotic change and bullae.The second case, a 61-yr-old lady, with RA for 10 yrs similarlyhad failed multiple DMARDS. A methotrexate dose of 25mg hadbeen started in 1999. She had known rheumatoid lung disease, andprevious pulmonary function tests showed restrictive lung diseasewith DLCO 2.06 (33%) and KCO 1.02 (63%). HRCT chestscan 1yr earlier prior to treatment showed pulmonary fibrosissuggestive of UIP, with no ground-glass change.She presented with a 2-week-history of breathlessness after 12injections (6 weeks) of etanercept, 25mg twice a week. There wasno evidence of infection or heart failure. CXR showed new diffusereticulonodular shadowing. CT pulmonary angiography (CTPA)confirmed widespread ground-glass change with no evidence ofpulmonary embolism.She was treated with broad spectrum intravenous antibiotics.The etanercept and methotrexate were stopped. Despite this andadding methylprednisolone 500mg/day for 3 days and changingantibiotics, she developed worsening hypoxia and was intubated.Bronchoalveolar lavage showed no evidence of TB, bacterial orpneumocystis Carinii infection.She developed metabolic acidosis, progressive renal failure andlater cardiacarrhythmias,anddespiteintensivetreatmentshe died.Both our patients had pre-existing lung disease, they hadenquiry into respiratory symptoms at 3 month intervals andannual CXR prior to the commencement of etanercept and weresymptomatically stable. Also,both wereonmethotrexate andbothdeveloped acute respiratory symptoms within 3 and 6 weeks ofcommencing etanercept, respectively, which culminated in accel-erated interstitial lung disease. The patient with COPD presentedearlier and recovered quickly with oral steroids aloneafter discontinuing etanercept and subsequently was able torecommence methotrexate 25mg/week with adequate joint diseasecontrol but no recurrence of respiratory symptoms. The patientwith poorer respiratory reserve developed progressive lung diseaseand died despite aggressive treatment.Lungdiseaseisawell-knowncomplicationofmethotrexate,andcases of accelerated methotrexate pneumonitis are also reportedwithin 2–3 doses of infliximab. Our patient who survived restartedmethotrexate safely, hence we do not postulate this as a cause [1].Infliximab has been reported to accelerate lung nodulosis [2, 3],and it has been reported as causing a reversible, biopsy proven,non-caseating granulomatous lung disease in RA [4]. In both ourpatients, lung biopsies were taken, which may have been thehistological change of the respiratory disease. Four further casesof reversible non-caseating granulomatous reaction temporallyrelatedtoetanercepttherapyhavealsobeenreported,twoofwhichhad previous pulmonary fibrosis [5]. Our two cases demonstrate alittle-known complication of etanercept, one of which was fatal. Itis noticeable that the patient who died also had rheumatoid lungdisease, whilst the patient with COPD survived. Previously reportsfrom the Biologics register [6], and published reports have raisedthe concern of increased mortality in patients with RA andpre-existing rheumatoid lung disease on azathiaprine whenanti-TNF was added [7]. On the basis of these two cases cautionneeds to be extended to those with pre-existing lung disease, takingmethotrexate when etanercept is added, particularly if the lungdisease is due to rheumatoid involvement. Extra caution should betaken in patients with rheumatoid lung and poor respiratoryreserve. Patients should be prompted to contact the rheumatologydepartment if symptoms of acute breathlessness occur, especiallysoon after the introduction of etanercept.The authors have declared no conflict of interest.K. L