Yoshifumi Tada

Avascular necrosis of bone in systemic lupus erythematosus: possible role of haemostatic abnormalities.

The pathogenesis of avascular necrosis of bone (ANB) was investigated in 111 patients with systemic lupus erythematosus (SLE) (24 with ANB, 87 without ANB); patients ages, corticosteroid treatment, clinical and laboratory features associated with SLE, and haemostatic profiles were all taken into account. The mean ages of patients with and without ANB at the time of diagnosis of SLE was 24.1 and 31.2 years respectively. The mean maximal daily dose of prednisolone in the group with ANB was 50.8 mg, which was significantly higher than the dose (41.8 mg) in the group without ANB. Disease features of SLE, such as Raynauds phenomenon, hyperlipidaemia, nephrotic syndrome, hypertension, and disease activity, were not found to be related to ANB. The percentage of patients who had lupus anticoagulant as well as a shorter activated partial thromboplastin time was greater in those with ANB than in those without. Multiple factors may be involved in the pathogenesis of ANB in SLE, and it is suggested that haemostatic abnormalities, which could be influenced by corticosteroids and young ages, play some part in the development of ANB.

A defect in the protein kinase C system in T cells from patients with systemic lupus erythematosus

To determine whether there is an intrinsic defect in T cells from patients with systemic lupus erythematosus (SLE), we studied signal transduction systems, assaying the total protein kinase C (PKC) levels and the phorbol myristate acetate (PMA)-induced activation of PKC in PHA-treated T cells. T cells from SLE patients showed a decrease in proliferation in response to PMA, but not to PHA, thereby suggesting the existence of an intrinsic abnormality in the PKC-mediated activation pathway. Total PKC activity in the T cells from SLE patients was significantly decreased. Although stimulation with PMA induced a translocation of PKC from the cytosol to the particulate fraction, translocated PKC activity after 2 nM PMA treatment was decreased in the SLE T cells. Furthermore, PMA-induced phosphorylation of 80-kDa substrates was also decreased in SLE T cells. These results suggest that there is a reduced PKC activity and an impaired PKC activation in response to PMA in the SLE T cells, a finding which may explain, if partially, the defect in T cell activation in patients with SLE.

Liver abnormalities and liver membrane autoantibodies in systemic lupus erythematosus.

The hepatic involvement of 57 patients with systemic lupus erythematosus (SLE) was studied with special reference to liver membrane autoantibody (LMA). Liver abnormalities were found predominantly in patients with active SLE (27/48 (56%) in active SLE v 3/20 (15%) in inactive SLE). They were, however, rather mild or moderate and tended to disappear as the disease activity of SLE decreased. In this respect the liver abnormalities observed in this study differed from those in patients with lupoid hepatitis. The incidence of LMA in active SLE (8/11 (73%] was significantly greater than that in inactive SLE (4/12 (33%)). The mean LMA index value in active SLE was 8.3, which was also greater than the 2.9 in inactive SLE. Furthermore, in active SLE the mean LMA titre was significantly higher in patients with liver abnormalities than in those without. These results suggest that LMA may be associated with the activity of SLE and may be one of the factors which cause transient liver abnormalities.

Increased production of the third component of complement (C3) by monocytes from patients with systemic lupus erythematosus.

We measured in vitro C3 production by peripheral blood monocytes from patients with systemic lupus erythematosus (SLE), and found it to be significantly greater than that from normal controls. We also found that monocytes from SLE patients with active disease produced a markedly larger amount of C3 than those from SLE patients with inactive disease. Production of C3 by monocytes correlated with serum levels of anti‐dsDNA antibodies and inversely correlated with serum C3 levels in SLE patients. Serial measurement of C3 in the culture supernatant from each SLE patient showed that C3 production by monocytes fell in parallel with a decrease of disease activity. The effect of corticosteroids was ruled out as there was no relation between the level of C3 production by monocytes and the dose of prednisolone. This seems to be the first study in which the C3 production was assayed at a cellular level in SLE patients, and this study suggests that the local C3 production is increased in SLE patients.

Case report: nifedipine-rifampicin interaction attenuates the effect on blood pressure in a patient with essential hypertension.

A 72-year-old woman with 5-year history of essential hypertension developed peritoneal tuberculosis. The patients hypertension, which had been well-controlled by long-acting nifedipine, deteriorated after the administration of rifampicin, an antitubercular agent. During use of nifedipine and rifampicin, both the peak plasma concentration and the area under the curve of nifedipine decreased markedly to about 40% of those without rifampicin. The findings suggest that rifampicin may increase the elimination of nifedipine, presumably by induction of its hepatic metabolism. Nisoldipine, another calcium antagonist, also failed to lower the patients blood pressure, when given in combination with rifampicin. Taken together, these findings indicate that more caution should be urged when calcium antagonist is prescribed along with rifampicin.

Haemostatic factors associated with vascular thrombosis in patients with systemic lupus erythematosus and the lupus anticoagulant.

To elucidate the mechanism of vascular thrombosis in patients with systemic lupus erythematosus and the lupus anticoagulant changes in factors associated with haemostasis were investigated. The lupus anticoagulant was associated with an increased incidence of thrombosis, particularly cerebral thrombosis. Concentrations of fibrinopeptide A and fibrinopeptide B beta 15-42 were significantly raised in the plasma of patients with systemic lupus erythematosus and the anticoagulant compared with concentrations in patients without the lupus anticoagulant. The tendency towards formation of thrombosis was not found in all lupus patients with the anticoagulant, however. Concentrations of thromboxane B2 were remarkably raised in the plasma of the two patients with the lupus anticoagulant who had recently had thrombosis. Concentrations of 6-keto-prostaglandin F1 alpha, protein C, antithrombin III, and plasminogen were similar in both groups. No significant decrease in serum stimulatory activity on prostacyclin production by cultured aortic endothelial cells was noted in lupus patients with the anticoagulant, but inhibition was present in the two patients with recent thrombosis. These results indicate that although patients with the lupus anticoagulant are not always in a hypercoagulable state, haemostatic abnormalities found in some patients with the anticoagulant may be predictive of thrombotic events.

Okadaic acid enhances human T cell activation and phosphorylation of an internal substrate induced by phorbol myristate acetate

Okadaic acid is a potent tumor promoter and an inhibitor of serine/threonine-specific protein phosphatases. We studied the effect of okadaic acid in human T cell activation and phosphorylation of internal substrates. Okadaic acid at up to 4 nM enhanced phorbol myristate acetate (PMA)-induced proliferation and CD25 (IL-2 receptor, p55) expression, although it showed no activation by itself. Okadaic acid induced hyperphosphorylation of a 60 kDa protein in T cells as well as non-T cells, as reported in fibroblasts and keratinocytes. Preincubation with 4 nM okadaic acid enhanced PMA induced phosphorylation of the 80 kDa protein, an internal substrate of protein kinase C in T cells. These results suggest that okadaic acid inhibited dephosphorylation of protein kinase C specific substrates, and as a result, enhanced T cell activation mediated by protein kinase C pathway.