Successful use of cyclosporin A for the treatment of acute interstitial pneumonitis associated with rheumatoid arthritis

D. Ogawa, H. Hashimoto, J. Wada, A. Ueno, Y. Yamasaki, M. Yamamura and H. Makino

Department of Medicine III, Okayama University Medical School, 2-5-1 Shikata-cho, Okayama 700-8558, Japan

SIR, The interstitial lung disease associated with rheumatoid arthritis (RA) is characterized by slow and insidious progression up to 10 yr [1]. However, it infrequently shows rapid progression, resulting in death within a short time after the onset of pulmonary symptoms [2]. This form of the disease is known as acute interstitial pneumonitis (AIP). Although oral corticosteroids have been used as the standard treatment for AIP, high-dose steroid therapy is frequently associated with serious side-effects without any improvement of the lung disease [3]. In this report, we describe a patient with AIP due to RA, who was successfully treated with the combination of cyclosporin A (CyA) and corticosteroids.

A 60-yr-old woman with a 15-yr history of seropositive RA developed low-grade fever and a dry cough in December 1998. She had been treated successively with gold injections and bucillamine for 10 yr; these were discontinued in 1994 because the disease became inactive. Six months before admission, she developed a sustained flare of her arthritis, she underwent treatment with loxoprofen sodium (120 mg/day), indomethacin (50 mg/day, suppository) and prednisolone (0.1 mg/kg per day; 5 mg/day). She was admitted to the community hospital on 4 January 1999 because of worsening symptoms, including high fever, cough and exertional dyspnoea. The chest X-ray showed a fine reticular shadow in both lung fields that had developed during the last 2 weeks. The patient was a non-smoker and reported no history of exposure to hazardous chemicals or dust. Since pulse therapy with 1000 mg methylprednisolone i.v. produced no effect, the patient was referred to our hospital for further evaluation and treatment. On admission, the patient complained of general fatigue and dyspnoea. No finger-clubbing, peripheral cyanosis, heart murmur or lymphadenopathy were noted, but fine crackles were audible over both sides of the chest. Laboratory data showed a white blood cell count of 14.7x103/mm3 (neutrophils 89%, lymphocytes 10%), haemoglobin 9.2 g/dl, platelet count 287x103/mm3, aspartate aminotransferase 30 IU/l, lactate dehydrogenase (LDH) 848 IU/l (normal range; 236–455), creatine kinase 13 U/l, C-reactive protein 3.9 mg/dl and erythrocyte sedimentation rate 87 mm/h. The rheumatoid factor level was 64 IU/ml by nephelometry (normal range 0–18), and antinuclear antibodies were not detectable. A tuberculin skin test was negative. Arterial blood gas analysis on breathing oxygen (12 l/min) showed a partial pressure of arterial oxygen (PaO2) of 71.1 torr and PaCO2 of 43.4 torr, with pH 7.42. The chest X-ray (Fig. 1Go, top left) demonstrated reticular shadows in both lung fields. High-resolution computed tomography (CT) of the chest (Fig. 1Go, lower left) showed bilateral and patchy high density areas and partial pleural thickening, but no obvious honeycombing. The interstitial ground-glass appearance suggested active inflammation of the lungs. Cultures for bacteria and mycoplasmas were negative. No cytomegalovirus antigenaemia was detected. A diagnosis of AIP was made on the basis of the acute clinical course, laboratory data, chest CT findings and the resistance to steroid pulse therapy. Her condition deteriorated, including worsening of the interstitial shadow on the chest X-ray, progression of hypoxaemia and hypercapnia, and a progressive rise in serum LDH up to 889 IU/l. Accordingly, treatment was begun with cyA at a dose of 5 mg/kg per day (250 mg/day) was begun on 7 January 1999, wih an increasing dose of prednisolone up to 1.2 mg/kg per day (60 mg/day). This treatment resulted in a dramatic improvement, within 3 weeks, in her symptoms and clinical findings such as serum LDH and PaO2. In April, the abnormal shadow on chest X-ray had disappeared (Fig. 1Go, top right), and only irregular thickening of the pleura without obvious honeycombing was still noted on the high-resolution chest CT (Fig. 1Go, lower right). Shortness of breath improved further and stabilized, and CyA was tapered to 2 mg/kg per day (100 mg/day) 3 months later, because the trough level of whole blood was maintained between 100 and 200 ng/ml. Prednisolone was also tapered gradually during the same period. Soluble interleukin (IL)-2 receptor, which is a marker of activated T cells [4], was reduced from 2080 to 589 U/ml (normal range 220–530 U/ml) after initiation of CyA therapy. These findings indicated a good response to immunosuppressant therapy with CyA. The patient was discharged on April 19, 1999, and was followed up in the outpatient clinic of our hospital. She remains well without any symptoms. One year after the initiation of the combination therapy, the patient was still being treated with CyA (100 mg/day) and prednisolone (5 mg/day).



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FIG. 1. Chest X-ray and CT before (left) and after (right) the initiation of combined CyA + prednisolone therapy. (Top left) Chest X-ray showing diffuse reticular infiltrates in both lung fields. (Lower two panels, left) Chest CT demonstrating bilateral patchy areas of ground-glass appearance in the outer and inner zones. Note the lack of honeycombing. (Top right) Chest X-ray showing remarkable improvement (compare with left side). (Lower two panels, right) The ground-glass appearance disappeared on chest CT 3 months after initiating the combination treatment. Note the presence of slight irregular pleural thickening but no obvious honeycombing.

 
Although the mechanisms of action of CyA are incompletely understood, CyA is known to reduce IL-2 synthesis by activated T cells and to disrupt lymphokine-dependent T lymphocyte–macrophage interaction [5], and thus prevents fibroblast-mediated fibrosis in patients with pulmonary interstitial fibrosis [6]. This may be the explanation for its apparent efficacy in interstitial lung disease, in the pathogenesis of which activated alveolar macrophages are thought to be important [6]. In addition to the suppression of IL-2, it is reported that CyA also inhibits IL-2 receptors [7]. In our case, administration of CyA suppressed soluble IL-2 receptor levels, and this was closely related to the therapeutic effect and disease activity of AIP. To our knowledge, there are only two reports of successful treatment of RA-associated AIP with CyA [2, 3]. Since the level of soluble IL-2 receptor was not examined in the previously reported cases [2, 3], this is the first report providing objective biochemical data to demonstrate the effectiveness of CyA against RA-associated AIP. The lack of reports describing the use of CyA for the treatment of RA-associated AIP warrants caution in its use; nevertheless, in our opinion, the poor prognosis of this complication of RA justifies treatment with this agent.

Notes

Correspondence to: D. Ogawa. Back

References

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Accepted 1 June 2000





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