Patient education: treatment or nice extra. The British experience.
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Biomedical subjects
Publications and source records attributed to M A Byron.
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In a cross-sectional study of 100 healthy elderly individuals, anticardiolipin antibodies (aCL) were measured using an ELISA technique. aCL were not detected in the majority of subjects (63%), and in the remaining 37% titres were within the laboratory reference range (mean +5 standard deviations) previously determined for adults of all ages. In contrast, significant titres of IgM rheumatoid factor were found in 10%, antimitochondrial antibody in 13%, antinuclear factor in 5%, anti-smooth muscle antibody in 18%, antiparietal cell antibody in 10%, and antireticulin antibody in 1%. Antibodies to single or double-stranded DNA were not detected in any subject. We conclude that, although other auto-antibodies may be present in the healthy aging population in Britain, abnormally elevated levels of aCL antibody do not occur, and when present may be an indicator of autoimmune-mediated pathology.
Antibodies to cardiolipin were measured in 100 consecutive patients with first ever stroke, on admission and at three and six months after the acute event. One hundred healthy, age- and sex-matched, British elderly individuals were also screened for antibodies to cardiolipin as a control group. Elevated levels of anticardiolipin antibody (i.e. 5 SD above the laboratory control mean) were present in none of the control group, but in 21 per cent of the patients with stroke. Thirteen of these 21 patients (62 per cent) died within three months, compared to 17 (21.5 per cent) of the seventy-nine patients without elevated levels of anticardiolipin antibodies (p less than 0.001). Six of the eight survivors with persistently elevated anticardiolipin antibodies had significant residual disability following stroke (Barthel score 0-9) compared to 11 of the 62 without (p less than 0.001). Two patients with initially raised anticardiolipin antibodies who became independent at six months showed a progressive decline in the level of these antibodies to normal. The presence of high levels of anticardiolipin antibody did not correlate with other recognized prognostic indices of stroke, except for incontinence. No correlation was noted between levels of antibody to cardiolipin, antinuclear factor, antibody to double-stranded DNA and C-reactive protein, either in the stroke patients or in the elderly control population. Hypertension was significantly more common in the patients with high anticardiolipin antibodies than in the rest of the patients in the stroke population (p = 0.33). There was no correlation between levels of anticardiolipin antibody and age. Anticardiolipin antibody may be considered as an independent prognostic marker for both mortality and clinical outcome after acute stroke.
We describe four elderly stroke patients--two men and two women--who had significantly elevated levels of anticardiolipin antibody in the absence of systemic lupus erythematosus or other connective-tissue disease.
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We have detected circulating IgG antibodies that bind with high affinity to human umbilical vein endothelial cells in 74% of patients with systemic lupus erythematosus (SLE), 30% of those with scleroderma and 28% of those with rheumatoid arthritis. IgG binding was F(ab) mediated, and did not involve immune complexes. Anti-endothelial IgG were apparently unrelated to other circulating autoantibodies, including anti-cardiolipin or antiDNA IgG. Bound IgG from SLE or scleroderma patients was displaced by IgG from certain unrelated patients whereas others were ineffective. Anti-endothelial cell IgG from all sera tested were adsorbed by human dermal fibroblasts; erythrocytes and leucocytes each adsorbed a fraction of the activity. Purified IgG did not induce complement-mediated cytotoxicity. We conclude that a discrete group of IgG antibodies is common in connective tissue disease patients, reacts predominantly with endothelial cells and dermal fibroblasts, and may be important in the pathogenesis of vascular damage.
The presence of anticardiolipin antibodies has been associated with the occurrence of spontaneous abortions in patients with systemic lupus erythematosus. Retrospective analysis of the relationship between the levels of IgG and IgM anticardiolipin antibodies in 84 patients with SLE and the prevalence of spontaneous abortions was performed. The time at which abortion occurred amongst these patients was compared with that in 26 subjects with a poor obstetric history, but without SLE. Forty-six of 84 patients had anticardiolipin antibodies and had 143 pregnancies, of which 84 (58.7 per cent) resulted in fetal loss. In contrast, amongst the 38 patients without anticardiolipin antibodies only 23 of 93 pregnancies (24.7 per cent) resulted in fetal loss. The prevalence of spontaneous abortions in the SLE patients was related to the levels of IgG anticardiolipin antibodies; IgM anticardiolipin antibodies were not associated with increased fetal loss. In SLE patients without anticardiolipin antibodies, and in the group of patients without SLE, fetal loss occurred at 14.1 +/- 7.5 (mean +/- SD) and 12.5 +/- 5.5 weeks respectively. When anticardiolipin antibodies were present fetal loss tended to occur at a later stage of pregnancy (17.4 +/- 7.1 weeks) and amongst this group 30 per cent of the pregnancy losses were in the third trimester of pregnancy. These findings demonstrate further that anticardiolipin antibodies are strongly linked to late pregnancy failure in patients with SLE.
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Neutropenia is common in patients with systemic lupus erythematosus (SLE) but mechanisms of cell depletion remain obscure. To investigate the possible autoimmune aetiology of neutropenia in SLE, sera from 31 patients with this disorder were tested for anti-granulocyte activity. Granulocyte-binding immunoglobulins were detected by indirect immunofluorescence, and the ability of patient sera to opsonize granulocytes was determined by measuring the chemiluminescent response of human monocytes to granulocytes sensitized by test sera. Sera from 22 of the 31 patients bound IgG to granulocyte cell membranes and/or to nuclei, but only membrane-binding antibodies opsonized the cells for recognition by monocytes. There was no correlation between neutrophil count and the level of granulocyte-binding IgG as measured by indirect immunofluorescence. In contrast, opsonic activity and neutrophil count were inversely correlated (r = 0.5; P less than 0.05). However, opsonic activity was present in sera from most non-neutropenic patients. In patients with SLE, impaired reticuloendothelial system function may allow sensitized granulocytes to remain in the circulation.
Fibrinolytic and other factors have been measured in 73 patients with systemic lupus erythematosus or related conditions to determine whether clinical thrombosis, a common feature of these disorders, is associated with defective fibrinolysis. Twenty five of 72 (35%) patients, compared with two of 22 (9%) controls, showed a low level of plasminogen activator activity in response to venous occlusion, suggesting decreased fibrinolytic potential. In addition, mean plasma levels of von Willebrand factor antigen and fibronectin were markedly raised in the patients (mean (SD) 384.5 (277)% and 727 (436) mg/l respectively) compared with healthy controls (100 (50)% and 306 (65) mg/l). These data suggest a degree of endothelial cell dysfunction. No clear correlation was found between a history of thrombosis and any plasma factor measured, except for prolongation of clotting tests suggestive of the 'lupus anticoagulant'.
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The results of a postal questionnaire to consultant rheumatologists (80% response rate) suggest that most comply with current teaching regarding the indications for systemic corticosteroids in articular rheumatoid arthritis (RA). They are prescribed as a last resort and most frequently in the elderly. However, a review of 100 consecutive RA out-patients revealed 24 patients currently taking corticosteroids at a mean prednisolone dosage of 5.6 mg daily. Only two had been prescribed these drugs for extra-articular problems. In 11 cases the treatment was not initiated by a rheumatologist. The discrepancies between the two surveys are discussed.
Morphoea and keratoconjunctivitis sicca developed in a woman with seronegative rheumatoid arthritis six years after augmentation mammoplasty. Previous reports of post-mammoplasty connective tissue disease have followed the use of silicone gel, whereas the more 'biologically inert' saline-filled silastic implants were used in this case.
Linear growth was recorded in 36 children with juvenile chronic arthritis. In 20, the hypothalamic-pituitary-adrenal axis (HPA axis) was assessed by insulin-induced hypoglycaemia, the results of which correlated well with resting cortisol levels. Three groups were identified according to type of corticosteroid regimen administered. Group 1 (6 children), receiving daily corticosteroid therapy, were clearly suppressed and failing to grow. Group 2 (13 children) had received an alternate-day regimen from the initiation of corticosteroid therapy; they were not suppressed and growth was satisfactory in 11. Group 3 (17 children) were receiving alternate-day therapy, but had had daily corticosteroid in the past; they showed no clear pattern of suppression or growth. Factors influencing the recovery of the HPA axis and resumption of growth were assessed. No difference was found in the individual growth of 7 children who commenced alternate-day therapy before the age of 5, compared with matched controls. It is suggested that daily divided doses of corticosteroid should not be used. Ideally, a single morning dose (up to 2 mg/kg) alternate-day regimen should be employed, as this regimen has minimal effects on HPA function and growth, even in young children. For very severe systemic features, it may be necessary to add a small single dose on the alternate day.
Haemorrhagic complications, though uncommon in SLE, may be life-threatening in individual patients, and they require treatment along appropriate lines. Thrombotic problems are more commonly encountered, and are a significant cause of morbidity and mortality. Not only is clinical thrombosis important in SLE, but there is increasing evidence that low-grade coagulopathy contributes substantially to many of the pathological features seen in lupus. The mechanisms involved in the pathogenesis of thrombosis have been discussed and their possible interrelationship is summarized in Figure 4, though it remains speculation that low-grade coagulopathy predisposes to clinical thrombosis. Several of these mechanisms may be operating during periods of disease activity; this was suggested in a recent study of clinical and histological features in SLE (Kant et al, 1981). The study was designed to look at the prevalence of glomerular thrombosis in SLE, and its significance as a histological feature. A striking association was observed between the presence of a circulating anticoagulant and the appearance of glomerular thrombosis on renal biopsy. Also, factor VIII levels were significantly increased and circulating platelets decreased in association with "active' histological features. On later re-biopsy glomerulosclerosis was a much more common finding if the first biopsy showed thrombosis, suggesting that thrombosis is a marker of more severe disease activity and inflammation. A greater understanding of the mechanisms promoting thrombosis will undoubtedly provide insight into the pathogenesis of SLE, as well as suggesting new therapeutic possibilities.
In a quest for a objective assessment of synovitis of the knee, the value of circumferential measurements of the knee at two levels has been tested. Measurement 1 cm above the patella was shown to be more precise and to correlate better with the quantity of synovial fluid aspirated than measurement at mid-patellar level. The size of change necessary for statistical significance frequently exceeded the change likely to be found in clinical practice. The precision of measurement is greater in normal than in rheumatoid knees, and can be increased by using the mean of duplicate measurements rather than a single measurement. In clinical trials, the use of one observer throughout will increase the reliance that can be placed on the changes in measurements.