The distribution of enzyme inhibitors in the joint in rheumatoid and experimental arthritis.

The enzyme inhibitors alpha 2 macroglobulin (alpha 2M) and alpha antitrypsin (alpha 1AT) have been demonstrated previously in the pannus-cartilage junction area in 12 patients with rheumatoid arthritis (RA). These deposits were present in both inflammatory cells and in the cartilage matrix. As the tissue studied came from far advanced disease removed at the time of joint replacements, the initial phase of cartilage destruction was studied in a carrageenin-induced arthritis in rabbits. Sequential studies indicated that loss of proteoglycan from cartilage was necessary before alpha 2M penetrated the matrix. Explant cultures of synovial tissue from RA and osteoarthritis (OA) joints released an inhibitor of neutrophil elastase and plasminogen activator which was neither alpha 2M nor alpha 1AT. Synovial tissue (and cartilage) enzyme inhibitors may have important implications in relation to protective mechanisms within the joint in RA and OA over and above the effect of plasma inhibitors.

Medical management of rheumatoid arthritis with emphasis on the Western Pacific Region.

There are regional differences in the prevalence and severity of Rheumatoid Arthritis in the Asian and Western Pacific Regions. Medical management of the condition will depend very much on the assessment of disease activity. Non-steroidal anti-inflammatory drugs in full dosage should always be the first choice of treatment. Their popularity however varies from country to country depending partly on the availability and partly on the cost structure that the Department of Health has been able to negotiate with the manufacturer.

Education in rheumatology.

The increasing burden of arthritis and musculoskeletal conditions in both developed and developing societies is shown by national and community-based surveys. Many complaints are sufficiently severe to cause disability and loss of time from work. Medical care is provided most often by primary health care physicians who are often inadequately trained to handle these conditions. Better medical student education that focuses on common community problems remains crucial. Strong rheumatology units with a commitment to teaching and research are necessary to redress any imbalance as new curricula are developed. Such units also have to take responsibility for primary health care physician and nurse education in how to manage common musculoskeletal problems. Arthritis Foundations and patient support groups have a role in public education and in increasing community knowledge on the causes and prevention of some common conditions so as to assist in improving overall care. New initiatives in professional and public education have given encouraging results, but further changes in community attitudes and perceptions of chronic conditions are necessary and are within the scope of most Arthritis Foundations' key objectives.

World Health Organization and International League of Associations for Rheumatology core endpoints for symptom modifying antirheumatic drugs in rheumatoid arthritis clinical trials.

The WHO/ILAR core set of endpoints for rheumatoid arthritis clinical trials signifies progress in a continuing worldwide effort. This core set includes the following measures: pain, patient global assessment, physical disability, swollen joints, tender joints, acute phase reactants, and physician global assessment; in studies of one or more years' duration, radiographs of joints should be performed.

Observations on rheumatic disease in Polynesia and the Philippines.

Two different types of study of rheumatic disease in the southwest Pacific are outlined. The Philippines study of a rural developing population is primarily oriented to intervention rather than causation, but before intervention can be effectively planned, information on the frequency and causes of rheumatic complaints is necessary. The Tokelauan investigation is a comprehensive prospective study of the total population with full medical examination of each subject allowing hypotheses to be tested concerning genetic and environmental variables.

Clinical, laboratory and genetic markers associated with erosions and remission in patients with early inflammatory arthritis: a prospective cohort study.

We investigated the relationship between clinical, laboratory and genetic markers and outcome measures in 159 patients with recent onset of inflammatory arthritis (IA). The majority of patients were managed in community-based rheumatology practice. Median duration of arthritis at baseline was 3 months with median follow-up of 4.0 years (range 0-10). Markers of disease activity and 1987 ACR criteria for rheumatoid arthritis (RA) were estimated every 6 months for the first 2 years and annually thereafter. Presence of shared epitopes (SE) was established by PCR-based method. Main outcome variables were attainment of remission and presence of erosions on X-rays of hands and feet at 3 years. Remission was seen in 34.3% of patients and was independently related to age 60 and older (odds ratio (OR) 3.2; 95% confidence interval (CI), 1.2-8.7) and inversely to the presence of rheumatoid factor (RF) (OR 8.3; 95% CI, 3.2-21.3 for persistent arthritis). Patients with two SE were likely to have persistent arthritis (P=0.006), but this was not significant when corrected for RF. Independent predictors for erosions at 3 years were RF (OR 7.5; 95% CI, 1.9-29.5) and area under the curve for number of swollen joints (OR 1.08; 95% CI, 1.02-1.16). SE status was not predictive of erosions at 3 years (OR 1.6; 95% CI, 0.7-3.7). In univariate analysis, patients possessing DERAA motif on DRB1 were less likely to have erosive disease than without this motif at 4 years (OR 0.21; 95% CI, 0.0-0.9, P=0.037) but this finding was partly explained by adjusting for RF (adjusted OR 0.24; 95% CI 0.04-1.37). In this study of recent onset IA, active disease and RF were associated with poor outcome. Whilst SE did not predict erosive disease, patients with DERAA motif may be protected against erosions whilst the presence of two SE alleles suggests persistence of arthritis.

Tropical rheumatology. Epidemiology and community studies: Asia/Pacific region.

It has been recognized that the remarkable decline in infant mortality and the extension in human lifespan involving both developing and developed countries alike, has been influenced by social and economic developments and public health orientated measures (such as clean water and sewerage) rather more than by developments in medical research. However, the identification of important disease risk factors for a number of common conditions such as smoking, solar exposure, dietary fat and alcohol has led to further reductions in disease prevalence and mortality, at least in some countries. The varied success of strategies to reduce the mortality from circulatory, nutritional and diseases due to infection has had the predictable result of leaving communities more exposed to the chronic non-communicable diseases, especially those affecting the elderly. The COPCORD community-based studies, carried out largely in tropical Asia/Pacific countries, have indicated that the burden of musculoskeletal conditions as far as pain and disability, as well as from an economic point of view, are substantial and WHO has called for increased research and educational activities into the causes and consequences of chronic disease and in particular rheumatic diseases. To the problems of an increasing ageing population can be added the rapid growth of urban populations, new occupational stresses, lifestyle changes and a number of other factors (WHO, 1984). The common community-based rheumatic diseases are not RA or SLE that dominate admissions to hospital arthritis clinics. Pain and disability are most often caused by osteoarthritis, especially knee OA, and various soft tissue rheumatic problems producing neck, back, shoulder and elbow pain. Viral and reactive arthritis cannot be ignored and the complications from osteoporosis (although not normally considered a rheumatic condition), are a significant threat to ageing populations worldwide. It is clear that for many of these conditions, certain risk factors have been identified and that preventative strategies are becoming available although far more detailed research is still required (Wigley, 1993). Community education is an essential part of prevention and treatment and the ILAR-sponsored publication Aches and Pains--Living with Arthritis and Rheumatism (Hampton, 1992) is available in at least 10 different languages and fills an important need. Education helps to influence not only knowledge but also skills and attitudes.(ABSTRACT TRUNCATED AT 400 WORDS)

Electron microscopic studies of the synovial-cartilage junction in rheumatoid arthritis.

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.

Samuel Hyde lecture. Polypharmacy in rheumatoid arthritis--help or hindrance?

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.

A radioreceptor assay for TNF alpha-binding proteins.

A radioreceptor assay for tumour necrosis factor alpha (TNF alpha)-binding proteins was development that is suitable for use with synovial fluids and sera. This assay, an alternative to the commonly used enzyme-linked immunosorbent assays (ELISAs), is not specific for soluble tumour necrosis factor alpha receptors (sTNF-R), but detects any molecules that might compete with TNF alpha for receptor binding. It also detects molecules that might bind TNF alpha and thereby interfere with subsequent binding to receptor. In a preliminary study, the assay was used to determine levels of TNF alpha-binding activity in a test group of synovial fluids from patients with rheumatoid arthritis (RA), osteoarthritis (OA) or psoriatic arthritis (PA). Levels of binding activity were much higher than those reported for sTNF-R alone in other studies [1, 2]. Our results indicated that there may be other molecules associated with the inflamed synovium that can interfere with the binding of TNF to its receptors and so attenuate its effect in diseases such as RA.

Drug interactions in the management of rheumatoid arthritis.

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.

Study of enzyme inhibitors in the rheumatoid pannus-cartilage area.

Immunoperoxidase studies were carried out on the pannus-cartilage junction (PCJ) of patients with rheumatoid arthritis (RA) and psoriatic arthritis to investigate the distribution of the enzyme inhibitors alpha 2 macroglobulin (alpha 2 M) and alpha 1 antitrypsin (alpha 1 AT). Comparisons were made with the equivalent synovial cartilage junctional area in osteoarthritis (OA). In all 12 patients with RA, prominent deposits of alpha 2 M and alpha 1 AT were found within the PCJ whereas in OA patients and the case of psoriatic arthritis fewer or no deposits were seen. Inhibitors were localised in pannus synovial lining cells, perivascular inflammatory cells, macrophage and fibroblast-like cells invading the cartilage as well as along the junctional cartilage matrix and in the adjacent pannus-free cartilage. Deposits of immunoglobulins were found in similar areas to enzyme inhibitors. The presence of enzyme inhibitors at the PCJ suggests that this area is not unprotected against enzymatic attack. Thus the concept that pannus is a prime area for cartilage damage because aggressive, invasive cells release destructive enzymes in an environment free from inhibitors should be reviewed.

Do lymphocytes protect the rheumatoid joint?

The pathology of the synovial membrane in rheumatoid arthritis can be characterized by the prominence of two major features which appear to vary independently of one another. These are synovial lining-cell proliferation and infiltration with inflammatory cells, predominantly lymphocytes. In a series of 42 synovectomies from 36 patients it has been shown that extensive joint damage is associated with a synovial picture of marked lining-cell proliferation and a sparsity of lymphocytes. Cases with heavy lymphocyte infiltration tend to show less damage to articular cartilage and bone despite a similar duration of disease. These results have been compared with the picture in leprosy, where a similar pathological spectrum is associated with changes in cell-mediated immunity necessary for the control of infection.

Cellular immunity to possible synovial antigens in rheumatoid arthritis.

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.

Correlation of histopathological features of pannus with patterns of damage in different joints in rheumatoid arthritis.

The cartilage-pannus junction has been studied in multiple sections from 23 rheumatoid joints. Changes suggesting a metaplastic reaction of the articular cartilage, termed transitional fibroblastic zone, were commonly found in hips and knees, but were rarely present in metatarsophalangeal joints, in which an invasive pannus with cartilage degradation in close association with inflammatory cells was seen. Thus when multiple sections from rheumatoid joints were examined a transitional fibroblastic zone was found in 1/15 (7%) sections from metatarsophalangeal joints compared with 29/57 (51%) and 15/48 (31%) sections from knee and hip joints respectively. In contrast, an invasive pannus occurred in 11/15 (73%) sections from metatarsophalangeal joints compared with 22/57 (39%) sections from knees and 19/48 (40%) sections from hips. These findings led to the suggestion that this pathological variation between different joints may explain the predominance of erosive change in small joints as compared with joint space narrowing with secondary osteoarthritis found in large joints in rheumatoid arthritis. Inappropriate comparisons between different joints may in part explain the variation in findings of previous histopathological studies.

Leg ulcers in rheumatoid arthritis.

A retrospective study over an eight-year period of 33 episodes of leg ulceration in 26 patients with rheumatoid arthritis requiring inpatient management is reported. the aetiology of the ulcers was found to be multifactorial. The most common factors were venous insufficiency (45.5%), trauma or pressure (45.5%) and arterial insufficiency (36.4%). Vasculitis (18.2%) and Felty's syndrome (12.1%) were less frequent causes, and pyoderma gangrenosum was rare. Most patients had seropositive erosive disease with high rheumatoid factor titres and significant functional impairment; over half were on maintenance corticosteroids. Colonisation of the ulcers by organisms, predominantly Staphylococcus aureus, was common (69.7%). Skin grafting was required in 63.3%, but the rate of complete take was only 42.9% despite multiple attempts. Hospitalisation was prolonged (mean 47.9 days) and the recurrence rate requiring further hospitalisation was 26.9%. The diagnosis of vasculitis and the limited role of biopsy in establishing its presence are discussed.

Lysosomal activation by neutral saccharides in cell cultures of synovium.

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.

Deposits of alpha 2M in the rheumatoid synovial membrane.

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.

Epidemiology of rheumatic disease in rural Thailand: a WHO-ILAR COPCORD study. Community Oriented Programme for the Control of Rheumatic Disease.

OBJECTIVE: To determine the prevalence rates of musculoskeletal disorders in a rural population of Thailand. METHODS: Nurses applied the WHO-ILAR COPCORD Core Questionnaire to 2463 rural subjects 15 years of age and over. Respondents who had current musculoskeletal pain were examined by 2 rheumatologists within one week after the interview survey. Radiographic and serologic examinations were carried out when required to classify categories of rheumatic disease. RESULTS: Response rates of the interview survey and examination were 99.7 and 94.2%, respectively. Musculoskeletal pain ever by interview was found in 36.2% of respondents. Of these, 22.7, 12.5, 6.5, and 5% had back, knee, hip region, and neck pain, respectively. Four hundred thirty-one cases (17.6%) who had musculoskeletal pain within 7 days of the interview were examined by rheumatologists, who confirmed 12.8, 5.7, 0.08, and 3.4% had back, knee, hip, and neck abnormalities, respectively. Four hundred fifty-eight (18.6%) had past musculoskeletal pain. Total disability rate was 3%, comprising 3.3% in women and 2.6% in men. Treatment rates by self-medication for current and past musculoskeletal pain were 60.3% in women, 65.7% in men. Therapy was by physician 52.1%, paramedics 9.7%, and masseur 6.8%. The rates of disease prevalence were osteoarthritis 11.3%, myofascial pain syndrome 6.3%, low back pain 4.0%, arthralgia 3.2%, gout 0.16%, rheumatoid arthritis and seronegative spondyloarthropathy each 0.12%, and mixed connective tissue disease and unclassified autoimmune disease each 0.04%. CONCLUSION: Back and knee pain caused the greatest burdens of disease, resulting mostly from joint degeneration.