Tetsu Oyama

Somatic mutation in peripheral lymphocytes of former workers at the Okunojima poison gas factory.

The former workers at the Okunojima poison gas factory comprise a high risk group for malignant tumors such as respiratory tract cancer. Demonstration of injury to somatic cell genes in this group may provide important data for evaluating the association between mustard gas and malignant tumors. So we measured the frequency of T lymphocytes lacking the hypoxanthine guanine phosphoribosyl transferase (HGPRT) activity, by cloning with interleukin 2 (IL2). In this study, we performed cloning of T lymphocytes lacking the HGPRT activity using recombinant IL2 (rIL2) and observed an increased frequency of somatic mutation in poison gas workers who had had more chances to be exposed to mustard gas and those who had worked for a longer period. This result suggested that inhalation of small amounts of mustard gas damaged somatic cell genes, resulting in carcinogenesis.

Intractable diarrhoea associated with secondary amyloidosis in rheumatoid arthritis

OBJECTIVE To examine the clinical characteristics of intractable diarrhoea associated with secondary amyloidosis in rheumatoid arthritis (RA). METHODS Of 179 RA patients with biopsy confirmed secondary amyloidosis, 24 cases (23 women and one man) with intractable diarrhoea lasting for more than one month were retrospectively evaluated. RESULTS The mean (SD) duration of diarrhoea was 87 (64) days. Prodromal symptoms of gastrointestinal dysfunction (n = 21) and impaired peristalsis (n = 16) were observed. Laboratory data showed hypoproteinaemia (4.7 (0.85) g/dl) caused by malabsorption or protein loss and high values of C reactive protein (17.0 (9.3) mg/dl). Recurrence of intractable diarrhoea (n = 4) and transition from intractable diarrhoea to other gastrointestinal problems of amyloidosis (ischaemic colitis (n = 2) and intestinal pseudo-obstruction (n = 4)) were observed. In 19 patients (25 episodes) the duration of intravenous hyperalimentation at remission (18 episodes) was 68 (52) days. Corticosteroid pulse therapy was administered to 10 patients (11 times) and the time elapsed from the end of corticosteroid pulse therapy to the end of diarrhoea was 18 (14) days. One and five year survival rates after the onset of intractable diarrhoea were 73.4% and 38.9% . Seven of 13 patients (54%) had died as a result of infectious diseases. CONCLUSION Intractable diarrhoea associated with secondary amyloidosis in RA is a serious clinical entity and the prognosis is poor. Although it is assumed that intravenous hyperalimentation treatment and corticosteroid pulse therapy are favourable regimens for intractable diarrhoea, the patients should be monitored for possible infectious complications.

Serum KL-6: a useful marker for early detection of methotrexate-induced interstitial pneumonia

To the Editor: Interstitial pneumonia (IP) is the most significant adverse effect associated with methotrexate (MTX) therapy for rheumatoid arthritis (RA). The prompt evaluation of new respiratory symptoms in patients receiving MTX is critical for early recognition of this potentially life-threatening complication. Unfortunately, because respiratory symptoms (including dry cough and exertional dyspnea) are nonspecific, it is often difficult to detect the complication before it becomes serious. KL-6, a human MUC1 mucin preferentially expressed on type II pneumocytes, is a sensitive serum marker for alveolar damage due to IP. We experienced two cases of MTX-induced IP that were recognized by monitoring serum KL-6 levels before the emergence of chest radiographic abnormality. When a 63-year-old woman with RA (Steinbrocker stage IV, class 2) began to receive MTX, her serum KL6 level was 170U/ml (normal 500U/ml). MTX was initiated at 2.5mg weekly and increased gradually to 10mg/week during the next 8 weeks. Nine weeks after the initiation of MTX, she began to complain of a dry Letter

Sequential observation of generalized joint-resorptive phenomena in systemic mutilating rheumatoid arthritis

To examine the destructive course of systemic mutilating rheumatoid arthritis (RA) associated with the opera glass hand syndrome and severe generalized resorptive arthropathy, 49 (1.4%) patients were radiographically selected out of 3400 RA patients registered in this center. Of them, a retrospective chronological study was possible in 37 patients. Mean durations from the onset of RA to the opera glass hand syndrome and severe systemic resorptive arthritis were 16.3±6.5 and 16.9±7.0 years, respectively, and the progression rate of mutilating changes, especially of systemic joints, was significantly more rapid when changes started early after the onset of RA (r=−0.654,P<0.001). In five patients who were followed up during almost the whole mutilating process, an exponential increase of the number of joints involved, small and large joints alike, was observed in parallel with severe involvement of the cervical spine and elevated levels of ESR and CRP, within 4–5 years after the onset of the first mutilating change (rapid destructive pattern). From radiographical (massive, progressive bone erosion or cysts) and histopathological (extensive invasion of the synovia, bone and bone marrow by polygonal histiocytes, multi-nuclear giant-cells or osteoclasts) findings from these five cases, we suggest synovia—bone and/or synovia—bone marrow interaction are important factors for rapid bone resorption in mutilating RA.

High serum KL-6 levels predict the deterioration of pulmonary function in patients with rheumatoid arthritis

KL-6 has been reported to be a serum marker for interstitial pneumonitis (IP). The purpose of this study was to determine the predictive value of KL-6 on the deterioration of vital capacity (VC) in rheumatoid arthritis (RA) patients with IP. In 32 RA patients we evaluated both the serum KL-6 level and VC in a prospective design. The diagnosis of IP was determined by clinical symptoms, chest X-ray, high-resolution computed tomography (HRCT) scanning and/or pulmonary function tests. Findings such as reticulonodular and/or cystic shadows on HRCT scanning were accepted as IP signs. The IP signs with ground-glass opacity were set as active. The mean period of observation was 31.2 (5.6) months. The initial and/or final serum KL-6 levels were more than 520 U/ml in seven patients (H-KL group). In the other 25 patients, both the initial and final KL-6 levels were 520 U/ml or less (L-KL group). Among the H-KL group patients, their percent VC (%VC) was significantly reduced (P < 0.01) during the observation period. No significant changes of KL-6 and %VC levels were seen in the L-KL group. Thus, we conclude that in RA patients with IP, abnormal levels of serum KL-6 may predict the deterioration of VC.

Soluble interleukin-6 receptor in rheumatoid arthritis

To investigate the pathophysiologic role of soluble interleukin-6 receptor (sIL-6R) in patients with rheumatoid arthritis (RA), serum sIL-6R levels were measured in 15 RA patients and 15 healthy control subjects using a sandwich enzyme-linked immunosorbent assay. Correlation analysis was performed between sIL-6R levels and clinical variables such as joint score, Lansbury’s index, C-reactive protein and platelet counts. Levels of sIL-6R and IL-6 were also measured in paired samples of serum and synovial fluid obtained at the same time from nine RA patients. Serum sIL-6R levels in RA patients (153.9±56.9 ng/ml) were significantly higher than those of control subjects (115.1±19.1 ng/ml;P<0.05). However, sIL-6R levels did not correlate with any clinical characteristic of RA. sIL-6R was detectable in synovial fluid, but was invariably lower than in serum, in contrast to IL-6 (i.e. much higher in synovial fluid). It correlated neither with total cell nor neutrophil number in synovial fluid. Serum C-reactive protein levels were significantly correlated with IL-6 in synovial fluid, but not with sIL-6R in synovial fluid. These results indicate that serum sIL-6R levels are increased in RA patients. High levels of serum sIL-6R did not seem to be derived from the site of local inflammation. The readily detectable sIL-6R in synovial fluid may co-operate with IL-6 in the pathogenesis of synovitis in RA.

ANALYSES OF BRONCHOALVEOLAR LAVAGE FLUID (BALF) IN MRL-LPR/LPR MICE

We performed bronchoalveolar lavage (BAL) in MRL-lpr/lpr (MRL/l) and MRL- +/+ (MRL/n) mice and evaluated various cellular and humoral components of the bronchoalveolar lavage fluid (BALF) to clarify the pathogenic mechanism of pulmonary fibrosis in MRL/l mouse. The numbers of macrophages, neutrophils and lymphocytes, N-Acetyl-beta-glucosaminidase (beta-NAG), and fibronectin increased in the BALF from MRL/l mice than that from MRL/n mice, but no significant differences were observed in total protein, beta-glucuronidase, acid phosphatase, or phospholipid level. Increased fibronectin level in the BALF from MRL/l mice may be related with pathogenesis of pulmonary fibrosis.