H. P. McNeil

Immunology and clinical importance of antiphospholipid antibodies

Having reviewed the literature on the association of aPL antibodies with clinical manifestations, it is clear that this group of autoantibodies are of considerable importance. The presence of aPL antibodies in some but not all individuals confers a risk of a clinical syndrome characterized by recurrent arterial or venous thrombosis, thrombocytopenia, hemolytic anemia, or positive Coombs test, and in females, recurrent idiopathic fetal loss. In SLE, the risk is approximately 40%, compared with a risk of 15% in the absence of aPL antibodies. However, only one half of persons possessing these antibodies have SLE, and overall the risk is around 30%. In some circumstances, such as in chlorpromazine or infection-associated aPL antibodies, there appears to be no increased risk. At the other end of the spectrum are seen patients whose only clinical manifestations comprise features of this clinical syndrome, and this entity has been designated the primary antiphospholipid syndrome (PAPS). aPL antibodies are also important because they are not uncommon. They have been found frequently in women with idiopathic recurrent fetal loss (30%), in non-autoimmune patients with ischemic heart disease (20%), or venous thrombosis (up to 30%), or stroke (4-47%), and in chronic immune thrombocytopenia (30%). These autoantibodies can be detected using sensitive solid-phase immunoassays employing the CL antigen, or in appropriate coagulation tests to detect LA activity. These assays are simple to perform but require care in selection of the best test and in interpretation of results. Current tests do not distinguish between those persons at risk of the clinical events and those not at risk. Detection of specific isotypes (especially IgG) and antibody level may aid in such a designation. Treatment of aPL antibody-associated syndromes remains a controversial subject. Since thromboses are associated with significant morbidity and potential mortality, there is a good argument for long-term preventive antithrombotic therapy, at least for as long as the antibodies are detectable, in those patients in whom clinical complications have previously occurred. It is not generally recommended that this treatment be offered to individuals in whom aPL antibodies are detected but who have not suffered previous thromboses, since the risk of such events does not appear to be equal within a group of aPL antibody-positive persons. This particularly applies to pregnant women, since live births and uncomplicated pregnancies are observed regularly in the presence of aPL antibodies without specific treatment. A previous history of at least one unexplained, late fetal loss is considered a prerequisite before intervention in subsequent pregnancies.(ABSTRACT TRUNCATED AT 400 WORDS)

Synovial mast cell responses during clinical improvement in early rheumatoid arthritis

OBJECTIVES To determine the synovial mast cell response in early rheumatoid arthritis (RA) during clinical improvement, and to examine for relations with clinical and histological parameters of disease activity. METHODS Twenty two synovial samples were obtained from six patients with RA using needle arthroscopy. The mean disease duration at baseline was eight months, and two to three further samples were obtained over a mean follow up period of 15 months during which treatment initiated clinical improvement occurred. Sections were immunostained to detect MCT and MCTC mast cells and correlations were sought between clinical and histological data. RESULTS The overall mean synovial mast cell density was 40.3 cells/mm2, with regional densities of 60.6 and 34.2 mast cells/mm2 in the superficial and deeper synovial layers respectively. The MCT subset predominated, outnumbering MCTC by 3:1. There was a significant correlation between the histological inflammation index and the MCT density, (r = 0.4, p < 0.05) but not the MCTC subset. The regional distribution and predominant subset of mast cells varied in individual patient’s synovia over time, with a trend towards restriction of the mast cell response to the superficial synovium during clinical improvement. CONCLUSIONS The mast cell response in early RA is characterised by substantial expansion of predominantly MCTmast cells that correlates with histological indices of inflammation. During clinical improvement, this expansion tended to become more superficial. Taken together with previous studies of long duration RA, which implicate MCTC cells in synovial damage and disease progression, these results suggest that MCT and MCTC mast cells may possess distinct functions in the spectrum of inflammatory events occurring during RA.

Binding specificity of lupus anticoagulants and anticardiolipin antibodies

Antiphospholipid antibodies have been found to be strongly associated with syndromes characterised by spontaneous arterial and venous thromboses, recurrent miscarriage, immune thrombocytopenia, and occasionally neurological manifestations. These antibodies can be detected using solid phase immunoassays, and by their effect on prolonging phospholipid dependent clotting tests. This latter phenomenon is termed the lupus anticoagulant (LA). The relationship between anticardiolipin antibodies (ACA) and the LA activity of plasma was investigated in 14 patients. Plasma of these patients exhibited both LA activity and high levels of ACA. The patients included 7 with systemic lupus erythematosus, 6 without and 1 chlorpromazine induced lupus anticoagulant. 7 patients had a history of thrombosis and 7 did not, despite high antibody levels. Plasma was incubated in a serial fashion with solid phase cardiolipin and the residual ACA level and LA activity were monitored using a solid phase enzyme linked immunoassay, and the kaolin clotting time (KCT) and activated partial thromboplastin time (APTT) respectively. There was no correlation between baseline ACA levels and parameters of LA activity (dKCT or dAPTT) in contrast to previous reports. However, there was a concurrent reduction in both LA and ACA levels over 24 hours during incubation with cardiolipin in all patients. The rate of reduction of both parameters was highly correlated (r = 0.99. p less than 0.001). The relative reduction of LA activity versus ACA level varied between patients, and may represent different affinities for phospholipid in thromboplastin versus phospholipid in solid phase. Thus, despite the lack of concordance between LA and ACA in many patients, the two activities can be removed concurrently in vitro, suggesting similar binding specificities of the antibodies. The incomplete concordance could be explained by varying affinities for different structural presentations of the lipid antigen.

Acute gout management during hospitalization: a need for a protocol

Aim: To review systematically the management of acute gout during hospitalization.

ORIGINAL ARTICLE: Long-term outcomes of vertebroplasty for osteoporotic compression fractures

Introduction: This study aimed to determine outcomes of percutaneous vertebroplasty for osteoporotic vertebral compression fractures (VCFs).

Headache as the initial presentation of Wegener's granulomatosis

In Wegeners granulomatosis (WG), neurological involvement is rare at onset. We present an unusual case where headache was the initial, dominant presentation of WG.nnA 34 year old white man presented with a three month history of headache. The headaches were migratory, throbbing, and were accentuated with head movement. Physical examination was normal. Computed tomography (CT) of the sinuses was normal. The patient was diagnosed with non-specific vascular headaches, and was prescribed pizotifen, which alleviated his headaches.nnOne month later, the patient developed a red right eye. Bilateral papilloedema was noted. He was now unable to work because of the headache. Magnetic resonance imaging (MRI) of the brain disclosed a normal ventricular system, but pronounced gadolinium enhancement of the meninges around the entire …

ORIGINAL ARTICLE: Long-term outcomes of vertebroplasty for osteoporotic compression fractures: Outcomes of vertebroplasty

Introduction: This study aimed to determine outcomes of percutaneous vertebroplasty for osteoporotic vertebral compression fractures (VCFs).

Enhancing academic physician training

Dr A. Wilson should be applauded for her article about problems in the training process and career structure for academic clinicians. Building on Dr Wilson’s suggestion for funding of non-clinical positions to facilitate research training, I would suggest that the College and its special societies examine a range of flexible options for advanced training with universities, health services and researchfunding bodies. For example, the college could take leadership in establishing a limited number of 4-year and 5-year advanced training fellowships thatwould include achievement of a Masters or PhD degree, respectively, in addition to clinical training in the chosen specialty that would be integrated throughout the extended training period. A 5-year fellowship could be jointly funded by contributions from the health service (equivalent to 3 years salary) and research-funding bodies (scholarship stipends), which after combiningwould be averaged over the 5-year period. I believe that health services would be highly receptive to offering a 5-year contract to a registrar undertaking a combined clinical position/PhD with such a fellowship. Selection into such prestigious fellowships would be highly competitive, would occur in the year preceding advanced training andwould require the participation of the college, health service, relevant university and research-funding body, be it the National Health and Medical Research Council, a specialty foundation or the college’s own research foundation. This is just one example of the type of innovation that could introduce real flexibility into advanced training and begin to remove barriers to academic physician career pathways outlined by Dr Wilson. Major structural reform within universities is also needed to invigorate academicmedicine tomake it amore desired career pathway. The old model of every teaching hospital having its own clinical school is no longer viable in a highly competitive research environment. Medical faculties would do better to form single large schools of clinical medicine, paralleling the way many universities have amalgamated their biomedical science units into single schools of medical or biomedical sciences and single schools of population health. Large academic units within medical faculties offer several advantages for the research mission of the university. First, research that is strategic, collaborative and coordinated is more likely to be successful in the current environment than that undertaken from the interests of a single clinical academic within one teaching hospital. Second, it is possible that relationships and collaborations between clinical academics and with biomedical scientists or population health researchers will form within a single larger school structure, which breaks down competitive perceptions between single-hospital clinical schools. Third, clinical, health services and translational research can be enhanced if coordinated from a single school, yet still be undertaken at numerous sites. In addition to strengthening research productivity, a large single school of clinical medicine is more likely to provide the critical mass of clinical academics to provide mentoring, role modelling and support needed to make academic medicine a more desired career pathway.