NASHVILLE, Tennessee–A case of pulmonary alveolar proteinosis (PAP) in a rheumatoid arthritis (RA) patient being treated with leflunomide (Arava®, Aventis Pharmaceuticals) suggests that this diagnosis should be considered in working up a patient who develops diffuse lung disease while on disease-modifying antirheumatoid arthritis drug (DMARD) therapy. Drs. Noel R. Wardwell, Jr., Robert Miller, and Lorraine B. Ware describe this case in the recent edition of Respirology.¹

The authors, who are in the division of allergy, pulmonary, and critical care medicine at Vanderbilt University in Nashville, Tennessee, write, "This is the first reported association of PAP with leflunomide therapy and highlights the need for aggressive diagnosis of lung disease complicating rheumatoid arthritis, especially while on immunosuppressive therapy. This patient initially appeared to have rheumatoid arthritis-associated interstitial lung disease, a process with a dismal prognosis. By contrast, his final diagnosis of PAP was associated with almost a 75% survival rate at 5 years…."

Could Have Been Worse: PAP Not RA Interstitial Lung Disease

The 42-year-old male patient had no pulmonary symptoms prior to starting leflunomide 20 mg/day and prednisone 10 mg/day for RA. After 1 month of treatment he was hospitalized for shortness of breath, fever, couth, and pleuritic chest pain, with chest computed tomography (CT) showing bilateral alveolar infiltrates without adenopathy. He was treated with antibiotics for pneumonia, improved, and was discharged. After another month, he was rehospitalized for continued dyspnea and low-grade fevers. Chest x-ray and CT were unchanged. Transbronchial biopsies showed focal organizing pneumonia, but special stains identified no organisms. Bronchoalveolar lavage (BAL) fluid was slightly cloudy and contained 67% macrophages, 28% neutrophils, 5% lymphocytes, and 0% eosinophils, and the diagnosis was RA-associated interstitial lung disease.

The dose of prednisone was increased to 60 mg/day and leflunomide was discontinued, resulting in gradual improvement in pulmonary symptoms. Restarting leflunomide 3 weeks later led to worsening respiratory failure, and the patient was again hospitalized.

Open lung biopsy showed PAS-positive intra-alveolar exudate consistent with pulmonary alveolar proteinosis (PAP). Postoperatively the patient required mechanical ventilation and high concentrations of oxygen. The authors write, "He was treated initially with serial bronchoscopic high volume lobar lavages in an attempt to reduce his oxygen requirement to a point that he could tolerate one-lung ventilation for whole lung lavage." The lavage return fluid was cloudy, consistent with PAP. Following the lung washing, the patient improved enough to be extubated and undergo whole lung lavage of the right lung under general anesthesia, after which he was weaned to intermittent oxygen with exertion while leflunomide was discontinued and prednisone was tapered. This was followed several weeks later by lung lavage of the left lung under general anesthesia.

"Since that time, his symptoms, hypoxaemia, and pulmonary infiltrates have resolved despite continuation of prednisone therapy at 20 mg/day for many months. He continues to have refractory joint and limb pain," Wardwell et al report.

More Attention to Pulmonary Symptoms Urged in RA

Aryeh Fischer, MD, assistant professor of medicine in the Autoimmune Lung Center, division of rheumatology at National Jewish Medical and Research Center, Denver, Colorado, comments, ""This is an exceedingly rare complication of this drug, but in general, rheumatologists need to have a more heightened awareness of the impact RA and its treatment has on the lungs. First of all, RA itself can have a myriad of pulmonary manifestations. This includes interstitial lung disease, airways disease (bronchiolitis), pleural disease, and even pulmonary vascular disease. Complicating things even more in patients with RA are the drug treatment options and their potential for causing lung disease. As an example, aspirin (in high doses), gold, methotrexate, sulfasalazine, leflunomide, and the anti-TNFs can all cause pulmonary toxicity. To complicate things even more, RA patients — particularly those on prednisone — are at increased risk for respiratory infections such as pneumonia."

Dr. Fischer advises that at each patient encounter, the RA patient should be asked about the following:

In addition, Dr. Fishcer advises getting a baseline chest X-ray prior to initiating any DMARD therapy, have a low threshold to obtain complete pulmonary function tests and ambulatory pulse-oximetry, and obtain a high-resolution CT image when parenchymal or airways disease is suspected.

"Collaborative care with our pulmonology colleagues is a critical component to any RA patient who experiences dyspnea or cough," Dr. Fischer added.

References