RESEARCH - Factors associated with fatal outcome of Arava-induced lung injury in Japanese RA patients

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Rheumatology Advance Access published online on August 3, 2009

Rheumatology, doi:10.1093/rheumatology/kep227

Factors associated with fatal outcome of leflunomide-induced lung

injury in Japanese patients with rheumatoid arthritis

Takeo Sato1, Shigeko Inokuma1, Akira Sagawa2, Takemasa Matsuda3,

Tamiko Takemura4, Takeshi Otsuka5, Yukihiko Saeki6, Tsutomu Takeuchi7,

Tetsuji Sawada8 on behalf of the Study Committee for

Leflunomide-induced Lung Injury, Japan College of Rheumatology

1Department of Allergic Diseases and Rheumatology, Japanese Red Cross

Medical Center, Tokyo, 2Sagawa Akira Rheumatology Clinic, Sapporo,

3The Center for Rheumatic Diseases, Kagoshima Red Cross Hospital,

Kagoshima, 4Department of Pathology, Japanese Red Cross Medical

Center, Tokyo, 5Munakata Medical Association Hospital, Fukuoka,

6Division of Allergy and Clinical Immunology, National Hospital

Organization, Osaka-Minami Medical Center, Osaka, 7Division of

Rheumatology and Clinical Immunology, Saitama Medical Center, Saitama

Medical University, Saitama and 8Department of Allergy and

Rheumatology, University of Tokyo School of Medicine, Tokyo, Japan.

Abstract

Objective. To elucidate the factors associated with poor prognosis of

LEF-induced lung injury in patients with RA.

Methods. The background and clinical and laboratory features of

LEF-induced lung injury were examined and compared between patients

who died of and who recovered from it.

Results. Among 22 patients who developed LEF-induced lung injury, 9

died of and 13 recovered from it. The patients who died tended to have

pre-existing interstitial pneumonia (8/9 vs 6/13, P = 0.07). The

loading and maintenance doses, serum concentration of the LEF

metabolite A771726 and administration period did not differ between

the groups. Patients who died had more frequently hypoxaemia of <60

Torr and mechanical ventilation, and had a high serum CRP level (19.3

± 9.4 vs 10.1 ± 8.1 mg/dl, P = 0.03) and a low albumin level (2.7 ±

0.6 vs 3.3 ± 0.5 g/dl, P = 0.03) at the lung injury onset. The

peripheral blood lymphocyte count decreased in both groups at the lung

injury onset, and it remained low until fatal outcome, in contrast to

a re-increase upon recovery (406 ± 394 vs 1203 ± 399/µl, P = 0.006).

The main histopathological finding in two autopsied patients was

diffuse alveolar damage, in contrast to the alveolitis observed in a

biopsied patient who recovered.

Conclusions. Pre-existing interstitial pneumonia, extremely high serum

CRP and low albumin levels, severe hypoxaemia and mechanical

ventilation indicated poor prognosis. Peripheral blood lymphocytopenia

developed in association with lung injury, and a sustained low

lymphocyte count indicated a fatal outcome.

Not an MD