Rheumatoid lung nodulosis and osteopathy associated with leflunomide therapy

Clin Rheumatol. 2006 May;25(3):384-8. doi: 10.1007/s10067-005-0024-1. Epub 2005 Oct 7.


Background: Leflunomide (LEF) is indicated in adults for the treatment of active rheumatoid arthritis (RA). LEF inhibits dehydroorotate dehydrogenase, a key enzyme of the pyrimidine synthesis in activated lymphocytes. Among rare adverse effects, fatal interstitial lung disease has been recently reported during treatment of RA with LEF in Japan. Clinical trials outside Japan do not suggest that LEF causes an excess of pulmonary adverse effects. Development and increase of peripheral rheumatoid nodules in typical sites of RA patients following LEF therapy has been recently reported.

Objectives: Two cases with new and accelerated development of rheumatoid lung nodulosis during LEF therapy were described in this study.

Methods: LEF treatment was administered to two male patients (77 and 66 years old) with long-standing active seropositive nodular RA with failure of multiple second line drugs and without lung involvement. Clinical and laboratory assessment using the American College of Rheumatology response criteria, chest computed tomography (CT), quantification of serum rheumatoid factor (RF), and monocyte count of peripheral blood along with routine laboratory follow up were performed on both patients before and during therapy. In case 1, a bone scan was performed due to sustained limbs pain. Open lung biopsy was performed in case 1 and core lung biopsy in case 2.

Results: Both patients achieved full clinical remission during 2 months of LEF therapy. In case 1, the first complaints were limbs pain after 10 months of treatment associated with intensive bone uptake on a bone scan consistent with hypertrophic pulmonary osteopathy. Productive cough developed after 3 months of the therapy in case 2. Initially, these complaints were not attributed to therapy. New lung disease was present on CT with cherry-like progressive cavitary nodules, predominantly involving the basal segments of the right lung. The first lung lesions were found by CT 13 months (case 1) and 7 months (case 2) after the beginning of therapy and were erroneously related to bronchiectasia in case 2. In both cases, the lung biopsy showed necrosis surrounded by epithelioid mononuclear inflammation with giant cells, consistent with rheumatoid lung node. The time that elapsed between the beginning of the first symptoms to LEF discontinuation was very long: 13 months in case 1 and 24 months in case 2. Discontinuation of LEF therapy was followed by an arrest in growth of lung nodules, resolution of limb pain, and gradual improvement of bone scan. A significant decrease of monocyte count and RF level in peripheral blood was observed during LEF therapy in both cases.

Conclusion: For the first time, we described rheumatoid lung nodulosis as complication of successful LEF therapy for RA. Hypertrophic pulmonary osteopathy with severe limbs pain and dry cough were the first manifestations of the lung nodulosis. Monocytopenia during LEF therapy is proposed to be involved in pathogenesis of this rare complication of LEF therapy.

Publication types

  • Case Reports

MeSH terms

  • Aged
  • Antirheumatic Agents / adverse effects*
  • Arthritis, Rheumatoid / complications
  • Arthritis, Rheumatoid / drug therapy*
  • Arthritis, Rheumatoid / pathology
  • Humans
  • Isoxazoles / adverse effects*
  • Leflunomide
  • Lung Diseases / chemically induced*
  • Lung Diseases / pathology
  • Male
  • Osteoarthropathy, Secondary Hypertrophic / chemically induced*
  • Osteoarthropathy, Secondary Hypertrophic / diagnostic imaging
  • Osteoarthropathy, Secondary Hypertrophic / pathology
  • Radionuclide Imaging
  • Radiopharmaceuticals / pharmacokinetics
  • Rheumatoid Nodule / chemically induced*
  • Rheumatoid Nodule / pathology
  • Technetium Tc 99m Medronate / pharmacokinetics


  • Antirheumatic Agents
  • Isoxazoles
  • Radiopharmaceuticals
  • Leflunomide
  • Technetium Tc 99m Medronate