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Defective regulation of apoptosis may play a role in the development of autoimmune diseases, and the proto-oncogene bcl-2 is known to inhibit cells from undergoing apoptosis. We studied the rate of apoptosis with the expression of bcl-2 in peripheral blood lymphocytes of patients with systemic lupus erythematosus (SLE). A lower proportion of lymphocytes were bcl-2+ in SLE patients with active disease (median 84.9%) than in patients with inactive disease or normal (medians 95.3% and 97.1% respectively, p < 0.05). The rate of apoptosis of freshly isolated PBL was significantly higher in SLE patients than in normal (medians 1.2% vs 0.5%, p < 0.05). After 48-hour culture the apoptotic rate was further increased in SLE patients, particularly those with active disease (SLE overall 34.2%, active 62% inactive 27.5%, normal 11.25%). These findings support the theory that in SLE patients increased apoptosis may provide a source of extracellular nuclear antigens which stimulate the autoimmune response and form immune complexes with autoantibodies.

Objectives: This study was performed to study the clinical presentations, treatment, and outcome of six cases of nocardial infection in the systemic lupus erythematosus (SLE) population living in Hong Kong and compare these cases with those reported in the English literature., Methods: Records of 215 SLE patients who attended our lupus and rheumatology clinics were reviewed, and cases of nocardial infection were retrieved and studied in detail. A Medline search from 1966 to 1995 was performed to identify other reported cases. The microbiology, diagnosis, and treatment strategies of nocardiosis were assessed., Results: Six cases of nocardiosis were found in our lupus series, giving a prevalence of 2.8%. Another 26 cases of nocardial infection in SLE were reported in the literature. All except one were caused by Nocardia asteroides. The lung was the commonest site of involvement (81%), followed by the central nervous system (CNS) (13%). The mortality was high (35%), especially when the CNS was involved (75%). Sulphonamides were the mainstay of treatment, and adjunctive surgical procedures may be needed for suppurative complications., Conclusions: Nocardiosis has been increasingly recognized in SLE. Although still uncommon, it is an important opportunistic infection because it is curable and mortality is usually caused by delay in diagnosis and treatment. A high index of suspicion, an aggressive approach to diagnosis, and early empirical therapy are essential principles of management.

Aims: To study the expression of interleukin-2 receptor (IL-2R), interleukin-4 receptor (IL-4R) and interleukin-6 receptor (IL-6R) on peripheral blood lymphocytes (PBL) in patients with systemic lupus erythematosus (SLE); to correlate the level of expression of these receptors with SLE disease activity., Methods: Peripheral blood lymphocytes were studied by a high sensitivity flow cytometry technique using monoclonal antibodies directed against CD25 (IL-2R alpha chain), CD122 (IL-2R beta chain), CD124 (IL-4R), and CD126 (IL-6R). SLE disease activity was scored using the SLE Disease Activity Index, C3 and C4 concentrations, anti-dsDNA level, and absolute lymphocyte count., Results: Compared with normal controls, PBL from patients with SLE had a higher percentage of CD25+ cells (median 20.8% v 16.5%) and a lower percentage of CD122+ cells (median 13.1% v 22.4%). The difference in CD122+ cells was greater in the CD122weak population than the CD122strong (natural killer cell) population. The percentages of CD124+ and CD126+ PBLs in patients with SLE and controls were similar. On CD25+ cells, the relative antigenic level of the IL-2R alpha chain was significantly higher in patients with SLE (median 2.01 v 1.81). The relative antigenic levels of CD122+, CD124+ and CD126+ cells were similar in patients and controls. Neither the percentages nor the relative antigenic levels of all of these cytokine receptors were correlated with any of the parameters of disease activity., Conclusion: Lymphocyte activation in patients with SLE was evident from the increase in CD25 expression on PBL, with a reciprocal decrease in CD122 expression. As the expression of IL-2R, IL-4R, IL-6R did not correlate with disease activity, it seems that these cytokine/receptor systems do not play a direct role in disease activation in SLE.

Dapsone is increasingly used in the treatment of rheumatic diseases. It is indicated in many inflammatory skin conditions characterized by polymorphonuclear cell infiltration. Minor reactions to the drug are very common, but severe idiosyncratic reactions are rare considering the large number of patients taking this drug worldwide. We describe 2 patients with cutaneous lupus erythematosus who developed severe dapsone reaction after low dose therapy, with a fatal outcome in one. Physicians should be aware of the potentially lethal side effects of dapsone.

A case of Graves' ophthalmopathy and relapsing polychondritis is reported. The eye condition responded to Cyclosporin A. The association of the two conditions is discussed.

Objective: To compare the efficacy, tolerance and safety of 50-150 micrograms orally administered iloprost given twice a day versus placebo in patients with Raynaud's syndrome., Methods: The study was multicentre (n = 3), double blind and placebo controlled. Sixty three patients who had eight or more vasospastic attacks per week were enrolled. After a one week run-in period, all patients received either iloprost or placebo treatment to a maximum tolerated dose of 150 micrograms twice a day for 10 days. Diary cards assessed the duration and severity of the vasospastic attacks. Side effects were monitored by direct questioning. A global assessment of treatment efficacy was made by the patient at the end of treatment and two weeks later., Results: Patient opinion tended to favour iloprost at the end of the 10 day treatment phase (p = 0.09) and this was significant at day 24 (the follow up visit) (p = 0.011). Although the duration and severity of attacks tended to decrease in the iloprost treated group, these results tended not to reach statistical significance (for severity p = 0.06 at end of treatment, p = 0.09 on day 24)., Conclusion: Iloprost administered intravenously has been shown to be of benefit in the treatment of the Raynaud's syndrome associated with systemic sclerosis, but this route of administration is inconvenient. This study evaluated the use of iloprost administered orally to patients with Raynaud's syndrome. Patient documented improvement was significantly improved by iloprost. Diary card analysis showed a trend in favour of iloprost, but these results did not reach statistical significance.

Objective: To assess red blood cell deformability (RCD) in patients with rheumatoid arthritis (RA) without extraarticular manifestations and in RA with vasculitic complications (RV), and to assess whether in vitro dipyridamole improves RCD., Methods: An improved filtration technique was used to measure RCD in 15 patients with RA, 18 patients with RV, and 20 age- and sex-matched normal control subjects. Washed erythrocytes suspended in buffer, at 5% hematocrit, were filtered through 4.7 mu Nuclepore Hemafil PC membranes. The initial steady-state relative filtration pressure (iRFP) was used as an index to assess RCD. A lower iRFP value reflects increased deformability, a higher value reflects a decrease. For each sample, 2 cell suspensions were prepared, one blank (control) and one containing 5 microM dipyridamole., Results: The mean iRFP values of cells obtained from patients with RV were significantly higher than those of cells obtained from normal controls. There were no appreciable differences in iRFP between RA patients and normal controls. When the erythrocytes were pretreated in vitro with 5 microM dipyridamole before filtration, their deformability improved markedly (iRFP values were reduced) in all study subjects, compared with untreated cells., Conclusion: RCD is reduced in patients with RV, and treatment with dipyridamole may be beneficial if reduced RCD contributes to impaired microvascular perfusion.

As rheumatoid arthritis (RA) patients have been shown to have impaired plasma fibrinolysis and fish oil has been suggested to be useful for RA, this study investigated the effects of fish oil on fibrinolytic parameters in patients with RA. Forty-five RA patients were randomised to receive either fish oil (1.7 gm eicosapentaenoic acid and 1.1 gm docosahexaenoic acid/day) or placebo treatment for at least 6 months. Plasma levels of fibrinogen, tissue-plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI) activity were measured at 3-month intervals. In the fish oil treatment group, plasma levels of fibrinogen and t-PA activity were reduced at 6 months when compared with baseline [fibrinogen: 3.2 (2.85-3.53) milligrams vs 3.89 (3.56-4.22) milligrams, mean (95% confidence intervals for mean), p < 0.02; t-PA activity 1.4 (1.01-1.78) units/ml vs 1.94 (1.55-2.33) units/ml, p < 0.01]. No significant changes in plasma PAI activity were seen during the treatment period in these patients. Placebo treatment did not significantly alter the plasma levels of fibrinogen or t-PA and PAI activity. In conclusion, fish oil supplementation does not appear to produce an improvement in plasma fibrinolysis. Indeed, plasma fibrinogen levels and t-PA activity were reduced. This could be due to an effect of fish oil on acute phase protein production. Alternatively, as t-PA is produced on an "on demand" basis, its reduction may be related to the lowering of fibrinogen levels following fish oil therapy.

1. Prostacyclin (PGI2) and its analogues may be useful in peripheral vascular disease. However, most have to be given intravenously due to their metabolic instability. 2. We have investigated the pharmacological effects of cicaprost, a synthetic PGI2 analogue which is metabolically stable and bioavailable after oral administration, in eight healthy male volunteers. 3. This was a double-blind, placebo-controlled, cross-over study. The volunteers were given either placebo, 5 micrograms, 7.5 micrograms or 10 micrograms cicaprost (at 09.00 h, 14.00 h, 19.00 h and again at 09.00 h the following day) on four separate occasions each 14 days apart. 4. Platelet aggregation induced by collagen and ADP in platelet rich plasma (PRP) and whole blood were measured prior to and 1 h after the trial medication. Laser Doppler flowmetry measured skin blood flow on the face before and after medication. 5. There was a statistically significant dose relationship in the inhibition of platelet aggregation induced by 2 microM ADP and 0.4 microgram ml-1 collagen in PRP and 2 microM ADP and 0.6 microgram ml-1 collagen in whole blood by cicaprost (P = 0.008, P = 0.34, P = 0.011 and P = 0.036, respectively). The threshold dose was 7.5 micrograms. Attenuation of anti-platelet effects was seen with the 14.00 h and 19.00 h doses. This may be due to a decrease in absorption after meals or to the development of tachyphylaxis. 6. Similar dose dependent effects of cicaprost on skin blood flow were also found (P = 0.01 and P = 0.006 for maximum output signal and red blood cell flux, respectively). The threshold dose was 7.5 micrograms. 7. In conclusion, cicaprost has significant anti-platelet and vasodilatory effects when given in doses of 7.5 micrograms and 10 micrograms three times a day in healthy male volunteers.

Cicaprost is a new synthetic prostacylin analogue which is metabolically stable and bioavailable after oral administration; in previous studies it has been shown to have vasodilator antiplatelet effects. In this pilot study, we investigated the clinical efficacy of and patient tolerance to two dosage levels of cicaprost (2.5 micrograms tds and 5 micrograms tds) in the treatment of Raynaud's phenomenon secondary to systemic sclerosis (SSc). This was a three centre, double-blind, placebo controlled study of 49 patients carried out over four winter months. For a period of 10 days, 16 patients were given a placebo, 16 received cicaprost 2.5 micrograms tds and 17 received cicaprost 5 micrograms tds. Response was assessed based on the total number and duration of Raynaud's attacks, the average severity of the attacks, the number of painful attacks as a proportion of all attacks, a digital ulcer count, and the patients' opinion of the treatment. Although the clinical and laboratory parameters of digital vasospasm did not show statistically significant improvement in those who received cicaprost compared with those on the placebo, the severity of attacks lessened in the patients who received cicaprost 5 micrograms tds, and a statistically significant difference was seen in the average severity at week 2 post-treatment (p = 0.02). The apparent lack of overall significance was probably related to the short treatment period and relatively low doses of cicaprost used in this exploratory study. Longer studies with dose titration are probably needed to demonstrate the beneficial effects, if any, of cicaprost in patients with Raynaud's secondary to SSc, and these are being planned.

An automated filtration technique has been used to investigate the effect of dipyridamole (DP) on red blood cell deformability in patients identified as having rigid red cells. They were patients on haemodialysis (HD) for chronic renal failure (n = 18), patients with peripheral vascular disease (PVD, n = 23) and controls (hospital outpatients, n = 33). Leucocytes and platelets were removed from heparinised blood by filtration through Imugard wool. Washed red cell suspensions in buffer at 5% haematocrit, without or with 5 microM DP, were filtered through Nuclepore Hemafil Membranes with 4.7 microns pores. The initial steady state relative filtration pressure (iRFP) was used to assess cell deformability. A low iRFP value reflects increased deformability and vice versa. The mean iRFP values were 0.33, 0.393 and 0.403 for controls, PVD and HD patients respectively, indicating that the red cells in the two groups of patients were significantly more rigid. DP reduced the iRFP to 0.266, 0.278 and 0.263 for controls, PVD and HD patients respectively. The results suggest that DP may be beneficial when red cell rigidity contributes to impaired microvascular perfusion.

We have previously documented raised levels of factor VIII von Willebrand factor antigen (FVIII vWF Ag), an endothelial product, in patients with vascular diseases and suggested that levels of this relate to disease activity. No one has yet investigated patients with Raynaud's phenomenon (RP) alone to see if the severity of vasospastic attacks relates to FVIII vWF Ag. We studied 22 patients with RP. None of these patients fulfilled diagnostic criteria for a connective tissue disease but all had severe symptoms which warranted referral to hospital. We measured the FVIII vWF Ag and the procoagulant factor VIII (FVIII:c) levels in these patients. FVIII:c is not an endothelial product and is released by different mechanisms, thus it forms an active control to FVIII vWF Ag. FVIII vWF Ag measurements were carried out using the Laurell method and FVIII:c was assessed using the technique described by Nilsson. Patients were asked to complete diaries over a 2-week winter period. The frequency and duration of all Raynaud's attacks were recorded. There were significant positive correlations between FVIII vWF Ag and the total number and duration of RP attacks over the 2-week period (P less than 0.005, r = 0.67 and P less than 0.05, r = 0.40, respectively; Spearman's rank correlation). No correlation was found between levels of FVIII:c and the same clinical parameters. It has been suggested that patients with clinical evidence of vascular damage have elevated plasma levels of FVIII vWF Ag. Our present study has demonstrated correlations between FVIII vWF Ag levels and the clinical severity of vasospasm in patients with RP.(ABSTRACT TRUNCATED AT 250 WORDS)

Modern balloon angioplasty plays an important role in the treatment of localized arterial lesions in patients with peripheral vascular disease (PVD). However, the process of angioplasty produces a situation of acute ischaemia followed by reperfusion and animal studies have shown such situation to be associated with an increase in free radical (FR) generation. FRs cause tissue damage and may be prothrombotic and may therefore contribute to the occurrence of restenosis. Release of FRs during reperfusion has not been fully investigated in humans. We studied the FR activity in 44 patients with PVD in the superficial or popliteal arteries receiving angioplasty treatment. Thirty patients had stenotic lesions and 14 had totally occlusive disease. Baseline blood samples were taken from the arterial catheter for the assay of malondialdehyde (MDA) (spectrophotometric thiobarbituric acid assay) immediately before and after balloon inflation. MDA is a measure of lipid peroxidation which is an indicator of FR activity. MDA levels during reperfusion were significantly higher than those immediately prior to balloon inflation [8.4 (0.29) vs 8.1 (0.24) mumol/l, respectively; mean increase--0.34 (0.13) mumol/l; [mean (sem)] p less than 0.01 (paired Wilcoxon rank test)] in the stenotic lesions. Such changes were not observed in the totally occlusive lesions [7.26 (0.39) vs 7.26 (0.48) mumol/l, respectively; p = 0.75]. Our study has shown increased FR release following angioplasty in patients with stenotic, but not occlusive, peripheral vascular lesions. Angioplasty of the stenotic lesions creates++ a situation of acute ischaemia and reperfusion whereas that of the occlusive lesions leads to the reperfusion of a chronically ischaemic area.(ABSTRACT TRUNCATED AT 250 WORDS)

Prostacyclin (PGI2) and its analogues are useful treatments for patients with secondary Raynaud's syndrome (RS). However, they have to be given intravenously, causing inconvenience to patients. Cicaprost is an orally available analogue of PGI2 and has been shown to inhibit platelet aggregation in both in vitro and animal studies. We recently investigated the effects of cicaprost on whole blood platelet aggregation, red cell deformability, white cell function (polymorphonuclear cell aggregation, elastase release and free radical activity) and plasma fibrinolysis in 14 patients with systemic sclerosis (SSc) and secondary RS. Patients received cicaprost (2.5 micrograms or 5 micrograms t.i.d.) or matching placebo tablets orally for 10 days. Blood samples were taken at baseline and 2 hours after administration of the last treatment for the above mentioned assays. No changes were observed in any of the cellular elements and parameters measured in the 3 groups of patients studied. Our study suggests that cicaprost, at doses up to 5 micrograms t.i.d., fails to modify the blood coagulation elements and factors in patients with RS secondary to SSc. Further studies using higher doses and longer study periods are planned.

Raynaud's syndrome (RS) is characterized by intense blood vessel spasm resulting in finger blanching. Treatment primarily involves vasodilation. Thromboxane A2 (TXA2) has been shown to be a potent vasoconstrictor and platelet aggregant. It may be possible to produce a vasodilatory and anti-thrombotic effect by blockade of the TXA2 receptors. ICI 192,605 is a potent TXA2 receptor antagonist and we studied its effects on platelet aggregation and digital blood flow in patients with RS. Sixteen patients with RS completed this double-blind, randomized, placebo controlled study. Each patient was seen on three separate occasions and was given ICI 192,605 (100 mg orally) on one occasion and matching placebo tablets on the other two. We measured platelet aggregation using platelet rich plasma (PRP) stimulated by U46619, a thromboxane (TX) mimetic. The concentration of U46619 required to cause just over 50% platelet aggregation before the administration of either ICI 192,605 or placebo (pre-dose) was noted. The same concentration of U46619 was used to stimulate the PRP sample at 1 h after the administration of ICI 192,605 or placebo (post-dose) and the percentage of platelet aggregation was again noted. Fingertip skin blood flow was also measured 1.25 h post-dose using a laser Doppler flowmeter. Patients were seated in a temperature controlled chamber which was initially heated to 40 degrees C to induce centrally mediated vasodilatation. The temperature was then lowered to 12 degrees C followed by rewarming to 40 degrees C. Steady blood flow values at these temperatures were measured and the rates of cooling and rewarming were also noted.(ABSTRACT TRUNCATED AT 250 WORDS)

Atrial natriuretic factor (ANF) binding sites have been shown to be present on human platelet membranes. We investigated the effect of an infusion of ANF 5 pmol.kg-1.min-1 on platelet aggregation in whole blood ex-vivo in 8 normal volunteers. Spontaneous platelet aggregation, collagen (0.6-2 micrograms.m.-1)-induced or ADP (0.5-2.0 microM)-induced aggregation was not affected by ANF. Plasma aldosterone was however significantly attenuated by ANF. These results show that a pharmacological dose of ANF does not affect platelet aggregation in man. These results suggest that the high plasma levels of ANF normally achieved in chronic heart failure or acute myocardial infarction are unlikely to contribute to the platelet hyperractivity, often observed in these conditions.