Biomedical subjects
Publications and source records attributed to K D Muirden.
A statistically significant association of clinical rheumatoid vasculitis (excluding nodules or nail-fold infarcts only) with the HLA B8 DR3 phenotype was found when comparing 30 patients with vasculitis with 84 classic or definite rheumatoid patients without clinical vasculitis. The previously reported association on HLA DR4 with rheumatoid disease was also confirmed.
Synovial tissue from patients with rheumatoid arthritis, systemic lupus erythematosus, osteoarthritis, and having menisectomies was examined by immunofluorescence for deposits of alpha-2-macroglobulin (alpha 2M). In inflammed tissues, alpha 2M was found in the synovial lining cells and in perivascular cells. The amount of alpha 2M correlated with the degree of inflammation. Similarly, free lining cells obtained by trypsination of the intact synovial membrane contained identical inclusions. alpha 2M was not detected in the menisectomy cases and in the less inflammatory osteoarthritic specimens. In-vitro studies demonstrated uptake of alpha 2M-trypsin complexes but not of native alpha 2M by most of the cultured synovial cells whether they came from rheumatoid patients or controls. The internalised complexes disappeared within 12 hours of culture. The results suggest that alpha 2M-proteinase complexes formed in the joint are taken up by phagocytic and perivascular cells in a similar way to immune complexes.
The synovial membrane-articular cartilage junction has been studied with electron microscopy in 20 patients with rheumatoid arthritis. Material came from specimens taken at synovectomy operations in the majority in an attempt to avoid far advanced disease. Comparisons were made with osteoarthritic tissue and with one normal control case (a meniscectomy). The process of cartilage destruction in RA appears to be multifactorial in origin. The pannus showed to distinct appearances being either cellular and usually vascular, or more fibrous in appearance. These may be two phases of the one process. There was evidence of collagenase activity in junctional cells and for deeper chondrocytes playing a role of polymorphs, a cell given considerable emphasis for cartilage destruction from biochemical studies. Nutritional factors may also be involved and the invasion of rheumatoid granulation tissue may be provoked by chemotaxis from immune complexes in the cartilage surface. The place of a substance similar to tumour angiogenic factor remains uncertain from morphological evidence. The separate phases of the reaction between synovium and cartilage means that responses to various anti-rheumatic drugs may vary widely, and this fact should be appreciated by those testing drugs experimentally.
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Renal failure in patients with systemic sclerosis is usually considered irreversible. Presented are two cases of patients with scleroderma and deterioration in renal function, one of whom has responded to therapy which included immunosuppressive agents, plasma exchange, and control of blood pressure.
A reaction has been demonstrated between extracts of synovial cells removed from intact rheumatoid knee joints and autologous leucocytes. The cell mediated immunity test system used was leucocyte migration inhibition. Variable reactions were found with a spectrum of allogeneic extracts when donor leucocytes came from married or transfused females or transfused males. Leucocytes from healthy (nontransfused) males showed no reaction with any of the extracts. As a period of cell culture was used prior to preparation of this extract to remove nonspecific inhibitory substances, native immunoglobulins, and complexes, the data are best explained by the presence of a foreign pathogen or altered cell component in the synovial cells of these rheumatoid patients.
The difficulties encountered in administering D-penicillamine to 40 patients with rheumatoid arthritis (RA) over a six to 24 month period are recorded. Side-effects were frequent. Proteinuria occurred in 13 patients (33%) mainly in the fourth to the sixth month. Renal biopsies were performed in six patients and all showed light microscopy abnormalities. Electron microscopy performed in five patients revealed subepithelial deposits in all and in addition some had mesangial and subendothelial deposits. Seven patients (17.5%) developed eight episodes of thrombocytopaenia which was quickly reversed on cessation of treatment or reduction in dosage. On the positive side, there was significant improvement in most parameters of disease activity at six, 12 and 18 months compared to the pretreatment levels, but the results at two years were less impressive. Reduction in steroid dosage was considerable and was greater than half the mean pretreatment dose after two years but the absence of a control group makes the full significance of these uncertain. Patients on high and low dosage regimens were compared over a 12 month period of treatment. Although the differences were not statistically significant, withdrawals and side-effects were less frequent in the low dose group.
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On exposure to sucrose or neutral polysaccharides, cell cultures from human synovium showed cytoplasmic vacuolation, increased numbers of lysosomes, and ultrastructural changes simulating those described in rheumatoid synovial intima and similarly treated embryonic caritlage and bone. These changes were accompanied by raised intracellular lysosomal enzyme activity without corresponding increases in the extracellular level of these enzymes. Structural changes and enzymic responses were less intense during exposure to the neutral polysaccharides. The secretion of large polymers of hyaluronic acid was consistently decreased during sucrose treatment. Evidence of heightened hyaluronidase-like activity was found in cellular extracts of sucrose-treated cultures, but not in the culture medium.
Synovial cell lines were isolated by instillation of trypsin or chymotrypsin into intact knee joints of patients with persistent rheumatoid effusions resistant to conventional therapy. Morphology and growth in the primary phase were compared with rheumatoid cells isolated from excised synovium and nonrheumatoid synovial cells obtained from intact joints of cadavers or amputated limbs. Cell populations from all sources included varying proportions of macrophage-like and fibroblast-like cells, with only 1-3% multinucleated cells. In medium supplemented with calf serum alone, rheumatoid cells from intact joints showed negligible changes in morphology. However, in the presence of nonrheumatoid, autologous rheumatoid or homologous rheumatoid serum a rapid increase occurred in size of the macrophage-like cells and numbers of polykaryocytes, including some giant syncytial cells. These effects were directly proportional to serum concentration and were identical in fresh or heat-inactivated serum. In most of these rheumatoid cell lines no multiplication occurred, regardless of serum type or concentration. In rheumatoid synovial cells from excised synovium, human serum induced both polykaryocytosis and rapid growth of fibroblasts. Nonrheumatoid synovial cells grew rapidly but few polykaryocytes developed, mostly with less than 6 nuclei. Evidence of viral infection in rheumatoid synovial cells was sought by electron microscopy after stimulation of polykaryocytosis by human serum. In one of the cultures many cells were found with intranuclear particles possessing characteristics of the adenovirus group.
This paper reports a double-blind crossover trial comparing mefenamic acid (1500 mg/day) with ibuprofen (1200 mg/day) in the treatment of patients with rheumatoid arthritis receiving maintenance salicylate therapy. Both drugs were used in three divided doses. Mefenamic acid compared favourably with ibuprofen. In the adopted dose regimes the side effects from both drugs were mild and almost exclusively gastrointestinal.
Only some of the areas of drug interactions of relevance to those treating rheumatic diseases have been mentioned and there are still enormous gaps in our knowledge. It is likely that some potential areas of danger have been over-emphasised, being based on speculation rather than real data or purely animal experiments using non-clinical doses of drugs. We are learning how certain drugs can stimulate or inhibit the metabolism of other drugs through effects on liver enzymes systems. For example, the metabolism of corticosteroids is induced by phenylbutazone (and also by phenobarbital and phenytoin). The patient with active rheumatoid arthritis with a low serum albumin would be unusually susceptible to changes induced by combinations of highly protein-bound anti-inflammatory drugs. Finally, although drug interactions are responsible for adverse effects it has been suggested that a more frequent cause of therapeutic failure is not drug interactions but the increase in the number of drug defaulters when more than one drug is prescribed.
The use of multiple drugs in treating rheumatoid arthritis is based on the assumption that their effects are additive. Sometimes the results are unexpected or the added drug may confer no additional benefit to the patient whilst leaving him more liable to undesirable side-effects. Some form of polypharmacy may be necessitated by the different pharmacological properties of our drugs. Certain drugs have been judged on their steroid-sparing effects allowing lower doses to be used and thereby reducing the toxicity of corticosteroids. It is likely that some potential areas of danger from interacting drugs have been over-emphasized, being based on speculative rather than real data or purely on animal experiments using non-clinical doses. The patient with active RA with a low serum albumin would be unusually susceptible to changes induced by combinations of strongly bound anti-inflammatory drugs. He would also be highly susceptible to side-effects, as has been shown with prednisone. Side-effects here are doubled when the patients serum albumin is below 2.5g/100ml(lewis et al.1971). I believe we should continue to ask ourselves whether by subtracting one or more drugs from the patients cocktail we may not produce a most welcome benefit for both patient and doctor and, I suppose we could even add, the hard-pressed tax payer.
Two patients with severe rheumatoid arthritis and aortic regurgitation, developed progressive symptoms of left ventricular failure. Symptoms were inadequately controlled by medical therapy. Surgical treatment was at first considered with great reluctance because of the theoretical risk of operative and postoperative complications in patients with a diffuse disease of connective tissue. The suspected complications did not materialize. Valvular replacement should be considered in patients with severe valvular disease associated with rheumatoid arthritis.
A patient with epidemic polyarthritis was studied within 48 hours of onset when specific serum antibodies were still low. The synovial fluid showed a fall in hyaluronic acid level and rise in protein levels though the immune globulins, and especially IgM, rose to a lesser degree and remained well below the levels in the serum. Attempts to grow virus from synovial fluid or blood lymphocytes failed despite the use of several new techniques. The complement components C'3 and C'4 were not depleted in serum or synovial fluid. The synovial fluid was devoid of neutrophil leucocytes, and contained predominantly monocytes and macrophages which were remarkable for mitotic and for enhanced and indiscriminate phagocytic activity. From this and other evidence, an explanation is proposed for the cytological response and difficulties in recovering infective virions in virus-induced arthritis. No virus antigen was detected in the supernatant synovial fluid and electron microscopy showed virus-like particles only in cytolysosomes.
Salicylates form the basis of drug treatment in rheumatoid arthritis. Despite their use for many decades, there is considerable confusion about what constitutes a regime which will ensure anti-inflammatory properties. We have found that blood vessels in the proposed therapeutic range can be maintained overnight on a four times daily dose regime, using either soluble aspirin (in the form of "Disprin") or aloxiprin ("Palaprin Forte"), and on a 12 hourly regine using an aspirin-sustained release aspirin combination ("BiPrin"). Because of variation in the levels reached using a fixed dosage schedule, treatment should be individualised. No correlation was found between dosage levels and either disease activity or serum albumin levels. No significant alteration in free or total salicylate levels was found following the addition of indomethacin to therapy.
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