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A 70-year-old female was diagnosed as having rheumatoid arthritis (RA) in 1971, which was then treated with steroid and nonsteroidal anti-inflammatory drugs. In 1999, after total replacement of her knee joint, 4 mg of methotrexate (MTX) per week was administered. Two months after the MTX administration, 200 mg of bucillamine per day was administered. On May 10, 2001, the patient was rushed to the hospital due to fever and difficulty in breathing. Chest X-ray and computed tomography (CT) revealed shadows of ground-glass-like opacity occurring sporadically in many places in the upper lung field bilaterally and interstitial shadows mainly on the lateral side of the lower lung field bilaterally. Instead of MTX and bucillamine, which were withheld, an MTX antagonist was administered and oxygen-supported therapy was performed; consequently, the patient recovered without the need to increase the amount of steroid. The percentage of lymphocytes in the broncholaveolar lavage fluid increased to 72%, and the CD4/CD8 ratio to 3.13. The level of serum KL-6 increased while that of serum SP-D returned to the normal level at different time. Following MTX and bucillamine administration, shadows of ground-glass-like opacity occurred sporadically in many places in the upper lung field bilaterally, which is not usually observed. It is suggested that such an unusual pulmonary disorder occurred due to concomitant use of drugs or other factors.

We described a case of rheumatoid arthritis (RA) with selective IgA deficiency. A 69 year-old female with RA was admitted because of gall bladder cancer, and also had selective IgA deficiency which serum IgA level was less than 5.0 mg/dl, and IgA 1 and IgA 2 subclasses were not detected. Prior to the operation, she was given red cell compatible blood transfusion because of severe anemia. After 30 min of transfusion, she developed chill, nausea, vomiting and hypotension. These anaphylactic reactions might be induced by the presence of anti-IgA antibody, since the level of this antibody titers in her serum was elevated, assessed by the methods of ELISA and Western blotting. Although a case of RA associated with selective IgA deficiency, and also with elevated serum anti-IgA antibody level is extremely uncommon, attention should be paid to the presence of anti-IgA antibody in patients with selective IgA deficiency to avoid any unexpected anaphylactic reactions.

Bucillamine has been reported to have beneficial effects in rheumatoid arthritis. This report concerns a case of RA in which agranulocytosis developed while on a course of bucillamine. A 52-year-old female with RA developed a rapid fall in white blood cell count after 4 weeks of bucillamine treatment at daily dose of 50 mg. Agranulocytosis was diagnosed (WBC 1300/mm3, granulocytes 5%). The administration of bucillamine was halted and she was treated with only prophylactic antibiotic regime. The peripheral granulocyte count result rapidly reversed within 3 days after discontinuation of the bucilamine treatment. Anti-leukocyte antibody was detected by the leukocyte lysis phenomenon method during the period of agranulocytosis. And high intrinsic G-CSF activities were detected in the patient serum before the recovery period of agranulocytosis. Agranulocytosis is a rare side effect of bucillamine but it is potentially more harmful than other side effects. In treatment with bucillamine, therefore, the drug should be carefully administered and regular blood examinations carried out to prevent the occurrence of this side effect.

We have reported previously a first case of interstitial pneumonitis in rheumatoid arthritis treated with bucillamine in 1989. Thereafter, a dozen cases with lung injury associated with bucillamine therapy have been reported. To explore the similarities among these patients, we tried to carry out a survey concerning the lung injuries in these cases in the present study. We obtained the following results. (1) Patients with lung injury consisted of 7 females and 3 males, aged 65 years on average (59-72). (2) The total amount of bucillamine used was 20-40 g on average (5.1-144 g) during approximately 100 days. (3) Serum rheumatoid factor was positive in 9 of 10 cases. (4) HLA-DR4 was significantly (p less than 0.01) detected in all cases of lung injury associated with bucillamine. (5) Interestingly the effect of bucillamine on rheumatoid disease activity was excellent in most cases. (6) Drug lymphocyte stimulation test (DLST) using bucillamine was performed in 6 cases. Positive DLST was found in 3 of 6 cases. These results suggest that cell-mediated hypersensitivity reaction (Coombs & Gell type IV) may contribute to the development of lung injury associated with bucillamine therapy.

To explore the role of interleukins in development of arthritis, we induced collagen-induced arthritis in mice and examined interleukin activities in the inflamed joints. Arthritis developed in 90% of mice 4-5 weeks after primary immunization with type II collagen. Joint extracts from mice with collagen-induced arthritis contained high levels of interleukin 1 (IL-1)-like activity but not interleukin 2 (IL-2) or interleukin 4 (IL-4) activity. IL-1-like activities in the lesions were correlated with development of arthritis assessed by joint swelling and erythema. These results suggest that IL-1-like factor(s) may participate in the etiopathogenesis of collagen-induced arthritis in mice.

Attempts to detect immune mediators in rheumatoid arthritis synovial fluids (RA-SF) by bioassays have yielded conflicting results, and so we analyzed the immune reactions occurring within rheumatoid joints using monospecific immunoassays for cytokines such as interleukin 1 beta (IL-1 beta), interleukin 2 (IL-2) and gamma interferon (gamma-IFN). Furthermore, we examined the IL-2 inhibitors to clarify the immunoregulatory mechanism in the lesion. SF from active RA contained a significant amount of IL-1 beta and IL-2 but not gamma-IFN. In contrast IL-2 inhibitor activity was depressed in RA-SF regardless of clinical disease activity. Our results suggest that cytokine overproduction and deficiency of inhibitory signals may result in the overactivity of cytokines and the overactivity may participate in the joint lesions of RA.