How many life years are lost in patients with rheumatoid arthritis? Secular cause-specific and all-cause mortality in rheumatoid arthritis, and their predictors in a long-term Australian cohort study.

BACKGROUND: There is an excess of mortality in patients with rheumatoid arthritis (RA) but no long-term Australian cohort data. AIMS: To determine median life years lost, all-cause standardised mortality ratio (SMR) and cause-specific SMR, their predictors and secular change in Australian patients with RA. METHODS: Study population was all patients seen by a rheumatologist between 1990 and 1994. Record linkage with Australian National Death Index was performed to determine fact and cause of death up to 2004. All-cause and cause-specific SMR, and median life years lost were determined. RESULTS: There were 35 (31%) deaths in the early 1990s cohort (n = 113), SMR 1.31 (95% 0.93, 1.80). There were 216 (44%) deaths in the pre-1990s established cohort (n = 495), SMR 1.73 (1.49, 1.95). Median life years lost in the early cohort was 6 years for males and 7 years for females compared with 8 and 10 years, respectively, in the established cohort. Patients with low disease activity score at baseline (DAS < 3.2), SMR was 0.8 (0.3, 2.2) and 1.5 (1.1, 2.2) for the early and established cohorts, and if DAS ≥3.2, SMR was 1.4 (1.02, 1.98) and 1.8 (1.5, 2.1) respectively. Primary cause of death was cardiovascular disease (SMR 1.43 (1.17, 1.74). Patients at most risk were those age 45-54 years. RA was listed as a comorbid condition on the death certificate in only 16% of patients. CONCLUSIONS: Within a period of 14 years, median life expectancy of patients with RA with disease onset in the early 1990s is reduced by 6-7 years. However, our results also suggest a secular reduction in excess mortality.

Effect of treatment with biological agents for arthritis in Australia: the Australian Rheumatology Association Database.

BACKGROUND: The Australian Rheumatology Association Database (ARAD), a voluntary national registry, has been established to collect health information from Australian patients with inflammatory arthritis for the purpose of monitoring the benefits and safety of new treatments, in particular the biological disease-modifying anti-rheumatic drugs (bDMARDs). These drugs are proving to be very effective, yet little is known of their long-term effectiveness or safety. Patient registries that systematically gather data on large cohorts of unselected patients are increasingly believed to be an essential means of answering questions of the long-term effectiveness and safety of new drugs. The aim of this report is to describe the role, development and structure of ARAD and provide some preliminary data. METHODS: As of 1 August 2006, 563 patients with rheumatoid arthritis prescribed a bDMARD have been enrolled in ARAD, involving 105 rheumatologists from across Australia. RESULTS: The data collected will enable examination of multiple domains of patient responses to bDMARDs, including quality of life, health-care utilization, incidence of adverse events and the effects of therapy switching. CONCLUSION: Evidence-based information about the long-term outcome of bDMARD therapy is essential for clinicians, consumers, policy-makers, drug development companies and approval agencies, to enable better care and improved outcomes for patients with inflammatory arthritis.

Arthroscopic estimation of the extent of chondropathy.

INTRODUCTION: Arthroscopy has been used to evaluate articular cartilage (AC) pathology in osteoarthritis (OA) for outcome measurement and validation of non-invasive imaging. However, many fundamental aspects of arthroscopic assessment remain un-validated. OBJECTIVES: This study evaluated arthroscopic estimates of extent of chondropathy. METHODS: Serial arthroscopic assessments were performed in a group of 15 sheep before and after bilateral stifle medial meniscectomy (MMx). Post-mortem assessments were performed in un-MMx sheep and 4 and 16 weeks post-MMx. Arthroscopic assessments of the extent of each grade of chondropathy were compared with a non-arthroscopic hybrid assessment that incorporated biomechanical, thickness and macroscopic assessments. RESULTS: Arthroscopy evaluated only 36% of AC and missed significant pathological changes, softening and chondro-osteophyte, occurring in peripheral regions. The patterns of change in arthroscopic assessments were similar to those of the non-arthroscopic assessment but there was a very strong tendency to over-estimate the extent of softened AC after MMx. In spite of these limitations arthroscopic assessments were responsive to change. Estimates of the extent of normal and softened AC were most responsive to change over time followed by estimates of superficial and deep fibrillation. Arthroscopy was as an excellent discriminator between normal and OA. Assessments of chondro-osteophyte and exposed bone were not responsive to change. CONCLUSIONS: Arthroscopic estimates of extent of chondropathy are prone to substantial error. While experience and training may reduce these errors other approaches may more effectively improve performance.

Arthroscopy -- a potential "gold standard" for the diagnosis of the chondropathy of early osteoarthritis.

OBJECTIVES: The aims of this study were to: 1. Evaluate the performance of arthroscopy for the diagnosis of chondropathy and to compare it to that of direct non-arthroscopic assessments; 2. Determine intra-observer reliability of arthroscopic assessments; 3. Evaluate the effects of the arthroscopic video quality and probing upon diagnostic performance. DESIGN: The ovine medial meniscectomy (MMx) model of early osteoarthritis (OA) was used assuming that pre-MMx articular cartilage (AC) was "normal" and post-MMx AC "chondropathic". Video recordings of arthroscopic assessments of each stifle compartment were evaluated. Scores were given for the quality of the video and the amount of probing. The diagnostic performances of dynamic shear modulus (G), light microscopic assessment and superficial zone collagen birefringence assessments were evaluated and compared to that of arthroscopy. Intra-observer reliability of arthroscopic assessments was also evaluated. RESULTS: Arthroscopic assessments had high sensitivity (91-100%), specificity (62-88%) and accuracy (75-93%) for the diagnosis of chondropathy 16 weeks after MMx. Arthroscopy compared favourably with the direct non-arthroscopic assessments in the lateral compartment and was found to have extremely high intra-observer reliability (kappa 0.78-1.00). The quality of arthroscopic video recordings and the amount of probing did not significantly influence accuracy or reliability. CONCLUSIONS: Arthroscopy performs as well as direct non-arthroscopic assessments of AC for diagnosis of early OA. These results suggest that arthroscopy can be used as a "gold standard" for the validation of non-invasive assessments like magnetic resonance imaging and that arthroscopic diagnosis can be based on small amounts of video footage without AC probing.

Biomechanical, histologic and macroscopic assessment of articular cartilage in a sheep model of osteoarthritis.

OBJECTIVES: Our primary objective was to explore the full potential of the ovine medial meniscectomy (MMx) model of early osteoarthritis (OA) for studies to validate non-destructive articular cartilage (AC) assessments and therapeutic interventions. Our secondary objective was to re-evaluate the relationships between the different types of AC assessment after MMx in sheep. METHODS: Macroscopic assessments, dynamic shear modulus (G*), phase lag and AC thickness measurements were performed at a total of 5437 reference points on all six articular surfaces in four normal joints and 16 MMx ovine stifle (knee) joints. Comparisons with histologic assessments of gross structural damage, collagen organisation (birefringence) and proteoglycan content were possible at 702 of these points. RESULTS: Histologic gross structural damage and proteoglycan loss were seen throughout the joint with greatest severity (fibrillation) in closest proximity to the MMx site. Increases in AC (30-50%) thickness, reductions in G* (30-40%) and collagen birefringence intensity (15-30%) occurred more evenly throughout the joint. Macroscopic softening was evident only when G* declined by 80%. G* correlated with AC thickness (rho=-0.47), collagen organisation rho=0.44), gross structural damage (rho=-0.44) and proteoglycan content (rho=0.42). Multivariate analysis showed that collagen organisation contributed twice as much to dynamic shear modulus (t=6.66 as proteoglycan content (t=3.21). Collagen organisation (rho=0.11) and proteoglycan content (rho=0.09) correlated only weakly to phase lag. CONCLUSIONS: Macroscopic assessments were insensitive to AC softening suggesting that arthroscopic assessments of AC status might also perform poorly. Collagen integrity was more important for the maintenance of AC stiffness (G*) than proteoglycan content. The development of major AC softening and thickening throughout the joint following MMx suggested involvement of non-mechanical (e.g., protein and biochemical) chemical and cytokine mediated processes in addition to the disturbance in biomechanical loading. The ovine MMx model provides a setting in which the spectrum of AC changes associated with the initiation and progression of OA may be evaluated.

Poor accuracy and interobserver reliability of knee arthroscopy measurements are improved by the use of variable angle elongated probes.

OBJECTIVES: (a)To determine the accuracy and reliability of arthroscopic measurements of cartilage lesion diameter in an artificial right knee model; (b) to determine whether the use of a set of variable angle elongated probes improves performance; and (c) to identify other sources of variability. METHODS: Ovoid "lesions" were drawn on the five cartilage surfaces of four plastic knees models. Two observers assessed these 20 lesions arthroscopically, measuring two diameters in orientations parallel and orthogonal to the probe. Observer 1 (orthopaedic surgeon) and observer 2 (arthroscopic rheumatologist) made two sets of measurements, firstly with the conventional probe and five months later with the variable angle elongated (VAE) probes. The knees were disarticulated to determine true lesion diameter. RESULTS: Observer 1 had negligible bias and good accuracy regardless of orientation or probe type. Observer 2 demonstrated both bias and poor accuracy using the conventional probe. Both improved using VAE probes. Poor interobserver reliability with conventional probes also improved using VAE probes. Major sources of variability could be traced to the probe type, the characteristics of the operator, and the orientation of the lesion in relation to the probe; the lesion location itself did not cause variability. CONCLUSIONS: Variation in accuracy and poor interobserver reliability of measurements with conventional methods of cartilage lesion diameter measurement improved when specially designed measurement probes were used. Arthroscopic measurements performed as well as most clinical and radiographic measures. These findings have important implications for the use of arthroscopy as an outcome in multicentre trials where arthroscopists have different levels of experience.

Synovial membrane p53 protein immunoreactivity in rheumatoid arthritis patients.

OBJECTIVES: To examine the expression of the p53 protein in synovial membrane of rheumatoid arthritis (RA) patients and to compare this with the expression in normal synovial tissues in subjects without RA. METHODS: Immunohistological expression of the p53 protein was studied using a streptavidin-biotin-peroxidase method and the monoclonal antibody DO-7, an antibody directed against both wild and mutant forms of p53 protein, in synovial tissues of RA patients (n=10) and from subjects with no known joint disease (n=4). RESULTS: p53 protein expression was present in a small percentage of synovial cells in the majority of the RA patients (n=8; 80%) and in half of the normal control cases with no inflammatory joint disease (n=2; 50%). No sample had more than 5% cells staining with intranuclear pattern. The difference in synovial p53 immunoreactivity between the RA patients and normal controls is not statistically significant (p= 0.64; chi(2) contingency test). CONCLUSIONS: This study has shown that p53 protein is only weakly expressed in the rheumatoid synovial membrane, with a low percentage of p53 protein immunostaining cells present, with intranuclear staining. These results suggest this is wild type p53 protein rather than mutant protein. These findings suggest that synovial p53 protein expression may not be important in the pathogenesis of RA and may only represent a reactive repair process to DNA damage secondary to the immune and inflammatory reactions associated with the disease.

Intraarticular variability of synovial membrane histology, immunohistology, and cytokine mRNA expression in patients with rheumatoid arthritis.

OBJECTIVE: To assess the variability of synovial histology, immunohistology, and cytokine mRNA expression at different sites within the knee joints of subjects with rheumatoid arthritis receiving slow acting antirheumatic drugs. The effects of intraarticular bupivacaine and adrenaline, and a comparison of synovial fluid cell and synovial membrane cytokine expression, were also investigated. METHODS: Arthroscopically directed synovial biopsies were taken at 3 or 4 predetermined sites from the knee joints of 11 patients. Histology for synovial lining layer, sublining cellularity and vascularity, and immunohistology for T cells, T cell subsets, and macrophages were assessed. Messenger RNA expression of interleukins 1beta, 2, 4, 6, 8, 10, granulocyte-monocyte colony stimulating factor, tumor necrosis factor-alpha, and interferon-gamma was detected using the reverse transcription/polymerase chain reaction technique. RESULTS: Synovial histology, immunohistology, and cytokine mRNA expression did not vary significantly. CD8 cell immunohistology was variable. Intraarticular bupivacaine and adrenaline did not change synovial characteristics. Synovial fluid cell and membrane cytokine expression did not match in 35% of comparisons. CONCLUSION: Biopsies from the suprapatellar pouch, medial gutter, and cartilage-pannus junction will provide a representative sample of synovial membrane pathology in patients with rheumatoid arthritis.

Meningeal involvement in Wegener's granulomatosis.

We describe a rare neurological manifestation of Wegener's granulomatosis, meningeal involvement, which occurred despite therapy resulting in disease quiescence in other organs. Clinical, radiographic, and neuropathological features are described.

Sacral insufficiency fractures in the elderly.

Sacral insufficiency fractures are not uncommon in elderly patients. We have diagnosed 20 cases in a five-year period, and have reviewed the clinical records, radiographs, CT and bone scans. We also assessed the degree of osteoporosis by measuring bone density using dual-energy X-ray absorptiometry and bone histomorphometry, and monitored the patients' functional outcome. Bone scans were positive in all 20 patients, CT showed a fracture or sclerosis in 7 of 12 patients and was useful in excluding malignancy. Plain radiographs were the least helpful, showing sclerosis in only 4 of the 20 patients. Involutional osteoporosis with a reduced bone formation rate was the most common underlying cause. Seventeen patients had complete resolution of pain within nine months, and no patient lost independence in daily activities. Increased awareness of these fractures may help to avoid unnecessary investigation and treatment. Bedrest and analgesia followed by rehabilitation provide good relief of symptoms.

Septic arthritis of the shoulder after mastectomy and radiotherapy for breast carcinoma.

We report five patients who developed septic arthritis of the shoulder after cancer of the ipsilateral breast had been treated by surgery and radiotherapy. Lymphoedema was present in all cases. The infections were not obvious, having subacute onsets, and delays in diagnosis led to destruction of the joint in all but one patient.

A controlled, prospective study to evaluate the effectiveness of a back school in the relief of chronic low back pain.

Ninety-two chronic low back pain patients were randomly allocated to two groups to evaluate the effectiveness of a back school compared with an exercise-only regimen according to specified outcome variables. The data from 78 patients with 7 years mean duration of symptoms was analyzed. Three assessments were made: before treatment and 6 and 16 weeks after treatment. Changes in patients' levels of pain, functional disability, and other related variables were compared in the two groups. Almost all variables showed an improvement at 6 weeks. At 16 weeks, functional disability and pain levels showed a significant difference. Back school patients continued to make an improvement. This method of managing low back pain makes maximal use of limited resources and appears to be effective, especially in the longer term.

Clinical features and followup study of HLA-B27 positive patients presenting with peripheral arthritis.

A comparison was made between HLA-B27 positive patients with peripheral arthritis and patients with ankylosing spondylitis (AS). The distribution of peripheral joint involvement in HLA-B27 positive seronegative arthritis was not the same as that in AS; significant differences were also noted in the sex ratio and incidence of uveitis. Followup of the patients with peripheral arthritis revealed that 25% had developed a further criterion for Reiter's syndrome, 45% had persistent seronegative arthritis and in 55% the arthritis had resolved.

Spinal movements in ankylosing spondylitis and the effect of treatment.

Fourteen male patients with ankylosing spondylitis, admitted for a 2-week period of inpatient treatment, had their spinal mobility assessed on admission and at the end of treatment by clinical measures and a three-dimensional radiographic technique. The patients were given injections of low-dose corticotrophin (ACTH) or placebo under a double-blind protocol. Initially all the patients had restricted movements compared with normal. After treatment all showed some improvement of mobility but no additional benefit accrued from ACTH. Clinical measures of mobility must be interpreted with care as the changes in these measurements were not closely reflected in the lumbar movements measured radiographically. Changes seen in plain radiographs were of little predictive value for improvements in mobility.

A prospective study of lumbar spinal movements before and after discectomy using biplanar radiography. Correlation of clinical and radiographic findings.

The significance of alteration of lumbar spinal motion in cases of herniated disc was examined using a three-dimensional x-ray technique (biplanar radiography) before and 3 months after discectomy. Fifteen consecutive cases of disc herniation were studied prospectively. Predictions of clinical examination, myelography, and motion study for the level and site of the lesion were correlated with the operative findings for their accuracy in localization of the lesion. Changes in lumbar spinal motion after surgery were also correlated with the clinical results. The clinical and myelographic predictions were similar to previously published studies. The present study showed that patients with a sequestrated or prolapsed disc lesion (as opposed to bulging disc) had an abnormally large lateral bend or axial rotation during flexion and extension at the level above, which reduced after surgery. Primary lumbar spinal motions (flexion and extension) were generally reduced to half of the normal value and were not significantly altered by surgery. The restriction of lumbar spinal motion was not significantly reflected in the clinical results, which were satisfactory in most cases. Discectomy by fenestration and minimal resection of the lamina did not produce instability.

The effect of low-back pain on lumbar spinal movements measured by three-dimensional X-ray analysis.

Back pain patients have restricted spinal movements, and the pattern of disturbance from normal movements may indicate the pathology and the functioning of the lumbar spine. Biplanar radiography was used to measure the three-dimensional intervertebral movements of patients with back pain alone and with back pain plus nerve tension signs demonstrated by restricted straight leg raise. Statistically significant decreases in flexion/extension compared with a normal control group were demonstrated for both groups. Accompanying coupled movements were increased only in those patients without nerve tension signs indicating asymmetrical muscle action, while those with tension signs had symmetric splinting particularly of the lower levels. Conservative treatments had no effect either clinically or on the movements. Caudal epidural injections produced clinical improvement and increased movements demonstrating relaxation of muscle splinting. Biplanar radiography, although capable of differentiating between the groups was not able to provide clinically useful information concerning individual patients with this type of back pain.

Three-dimensional x-ray analysis of normal movement in the lumbar spine.

Biplanar radiography was used to assess the normal three-dimensional movements of the lumbar spine in the erect posture in a group of asymptomatic volunteers. The primary movements investigated were flexion and extension, while the three-dimensional analysis also measured any associated coupled lateral bends and axial rotations. The results showed that each intervertebral joint had a total range of flexion and extension of approximately 14 degrees, the lower levels moving slightly more than the upper levels. All the intervertebral joints had more movement in flexion than extension from the upright position, except for the L5/S1 joint, which showed no consistent pattern, some subjects extending more than flexing. Coupled movements of 4 degrees or more in flexion and 3 degrees or more in extension were shown to be abnormal.

Correlation between radiographic and clinical measurement of lumbar spine movement.

Clinical and radiological techniques were used to examine the lumbar movements of 11 male subjects with no history of low back pain. The clinical techniques were shown liable to large errors, particularly where distances between skin marks were measured. The use of an inclinator was the only clinical technique found to be reproducible by different observers. Comparison with the radiological techniques showed that the clinical measures only gave indices of back movement which did not reflect true intervertebral movement.

Enteric-coated pelletized aspirin. Gastrointestinal blood loss and bioavailability.

Eleven patients suffering from arthritis received, in a randomized cross-over study, anti-inflammatory doses of two aspirin formulations: Enpryn, capsules containing enteric-coated pellets; Rhusal, an enteric-coated tablet. No significant difference was found between the two formulations with respect to gastrointestinal microbleeding, plasma salicylate levels and urinary recovery of salicylate. Bioavailability studies carried out on 10 healthy male volunteers demonstrated that absorption from the enteric-coated pellet capsules was sustained and complete.

Clinical significance of immune complexes in rheumatoid disease.

Circulating immune complexes were measured by the Clq binding assay in 49 cases of rheumatoid disease. Raised levels showed a positive correlation with activity of the arthritis, the number of involved joints and the erythrocyte sedimentation rate. No correlation was found with age, sex, duration of disease, rheumatoid nodules, presented of radiographic joint erosions or other haematological and serological parameters. In 12 patients the arthritis subsequently remitted and this remission in disease activity correlated with reduced levels of immune complexes.