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.

A survey of outcome measurement procedures in routine rheumatology outpatient practice in Australia.

OBJECTIVE: To assess the extent to which quantitative clinical measurement is performed by rheumatologists in the longitudinal followup of patients with rheumatoid arthritis (RA), osteoarthritis (OA), ankylosing spondylitis (AS), and fibromyalgia (FM) in routine outpatient practice in Australia. METHODS: A cross sectional postal survey was conducted using an 18-item self-administered questionnaire sent to Australian Rheumatology Association (ARA) members. RESULTS: Rheumatologists (response rate = 76%, completion rate = 72%) were more likely to longitudinally follow patients with RA and AS than those with OA or FM. There was a high degree of variability in the methods used to monitor patients longitudinally. Many measures used in clinical research were used infrequently in routine clinical practice. In general, the major health status measures surveyed were not used in clinical monitoring. There was a high level of agreement (> 80%) that the characteristics required of an outcome measure for use in clinical practice should include simplicity, brevity, ease of scoring, reliability, validity, and sensitivity to change. CONCLUSION: The majority of Australian rheumatologists perform outcome measurement during the longitudinal followup of their outpatients with RA, AS, OA, and FM. However, the process lacks standardization. High performance health status measures developed for clinical research have not been widely adopted in rheumatology practices. There is agreement on the characteristics required by Australian rheumatologists for measurement procedures used in routine clinical care. Quantitative measurement in clinical practice using standardized procedures is an attainable, but as yet, unrealized opportunity.

Risk factors for osteoporosis and fracture in patients attending rheumatology outpatient clinics.

BACKGROUND: Bone mineral density (BMD) using dual energy X-ray absorptiometry (DXA) scanning is the best predictor of osteoporotic fracture but may not be cost effective for all patient groups. Risk factors (RF) other than BMD may be useful for fracture prediction. AIM: To assess the prevalence of RF for osteoporosis (OP) and fracture in patients attending a public hospital rheumatology clinic and to document physician awareness of these RF. METHODS: Two hundred and twenty rheumatology outpatients completed a self-administered questionnaire pertaining to known RF for OP and fracture. Initiatives were documented by the treating rheumatologist. RESULTS: One hundred and fifty-four females and 66 males completed questionnaires: 57% had an inflammatory disorder and 32% had received significant glucocorticoid therapy. Forty-five (68%) males and 126 (82%) females had three or more RF for OP and fracture. Diagnosis of rheumatoid arthritis or connective tissue disorder (CTD) was the variable most significantly associated with increasing numbers of RF. Antiosteoporotic medication (AOM) use at assessment (64/219, 29.2%) was accounted for primarily by the use of hormone replacement therapy in females between 45-54 years. Prednisolone use predicted intervention in 103 (48%) patients. CONCLUSION: Many rheumatology outpatients have multiple RF for OP and fracture. Infrequent AOM use could be explained by inadequate awareness of high risk patients and the lack of an ideal long term agent. With restricted outpatient resources, the feasibility of identifying high risk patients for OP and fracture would increase if the hierarchical status of RF was better understood.

Antibodies to type II collagen and HLA disease susceptibility markers in rheumatoid arthritis.

OBJECTIVE: To seek associations between antibodies to native and denatured type II collagen (NCII and DCII) and HLA in rheumatoid arthritis (RA). METHODS: One hundred fourteen patients with clinically well-defined RA were HLA-DR and DQ typed. Those who were DR4 positive were subtyped for DRB1*0401-*0408 alleles by polymerase chain reaction using allele-specific oligonucleotide probes. Antibodies to human NCII and DCII (heat-denatured) were measured by enzyme-linked immunosorbent assay. The frequency of HLA alleles was compared in patients grouped according to the presence and absence of antibodies to NCII and DCII. RESULTS: Twenty-seven patients (24%) were positive for antibodies to NCII. There was a significant increase in the frequency of HLA-DR7 in anti-NCII-positive patients compared with anti-NCII-negative patients (30% versus 9%; P = 0.019) and a significant decrease in HLA-DR3 (7% versus 28%; P = 0.044). Repeating the analyses after excluding the 16 patients who were DR7 positive revealed a significant increase in the frequency of HLA-DR1 in anti-NCII-positive patients compared with anti-NCII-negative patients (63% versus 27%; P = 0.045). Moreover, antibodies to NCII were associated with the third hypervariability region susceptibility sequence QRRAA that is present in DRB1*0101, *0404, *0405, and *0408 (84% versus 47%; P = 0.0085); 24 of 27 anti-NCII-positive patients were positive for either DR7, DR1, or DRB1*0404 or *0408. Thirty patients (26%) were positive for antibodies to DCII. There was a significant increase in the frequency of HLA-DR3 in anti-DCII-positive patients compared with anti-DCII-negative patients (40% versus 18%; P = 0.028). CONCLUSION: The genetic associations between HLA-DR alleles and antibodies to CII in RA patients is in keeping with the collagen-induced arthritis model and implicates autoimmunity to CII as a major component in the multifactorial pathogenesis of RA.

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.

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.

The effect of HLA-DRB1 disease susceptibility markers on the expression of RA.

The study was designed to examine the effect on clinical expression of rheumatoid arthritis (RA) of HLA alleles, particularly DR4 and DR1 that contain susceptibility sequences for RA in the third hypervariable region (HVR3) of HLA-DRB1. We studied 114 consecutive Australian patients with RA attending a hospital outpatient clinic. The effects on indices of disease severity and activity of HLA DR4 and DR1, the DRB1*04 subtypes, and the polymorphism in the RA susceptibility sequence (QRRAA or QKRAA) were examined. The patients were initially divided into 6 groups, DR4,4; DR4,1; DR1,1; DR4/X; DR1,X, and DRX/X, and then further subdivided according to the actual HVR3 susceptibility sequence. The high risk conferred by the HVR3 susceptibility sequence, present in 76%, was confirmed, but 24% of the patients with long-standing seropositive erosive RA lacked this sequence. Among these those with DR2 had early-onset severe disease, and those with DR3 had late-onset milder disease. Differences in expression correlated with polymorphisms in the susceptibility sequence, in that active RA was associated more with QRRAA than QKRAA. There was no correlation of any HLA allele with disease severity. Our finding that the presence of the HVR3 sequence confers susceptibility and also influences the clinical expression and tempo of progression of RA suggests a role in pathogenesis for antigen presentation, whether of an autoantigenic molecule or a persisting infection.

Rheumatoid arthritis antirheumatic drug trials: effects of a standardized instructional videotape on the reliability of observer-dependent outcome measures.

AIMS: A study was designed to assess the effects of a standardized instructional videotape on reducing interobserver variability for several commonly used observer-dependent outcome measures. METHODS: During a single day, six rheumatologists independently examined six patients with rheumatoid arthritis (RA) in a predetermined order using a Latin square design, before and after viewing a standardized videotape demonstrating 13 examination techniques. Reliability coefficients were calculated based on the variance components of the analysis of variance (ANOVA) table. RESULTS: Prestandardization reliability coefficients were >0.80 for all measures and remained above 0.80 following standardization. CONCLUSIONS: It is usually assumed that serial measurement in clinical trials should be performed by the same assessor because of concern regarding interobserver variability. However, the high levels of prestandardization interobserver reliability observed in this study indicate that, for these variables, serial measurements in a clinical trial could be made by different assessors, assuming they were equally skilled. This observation has important implications for outcome measurement in RA clinical trials. Although high levels of prestandardization reliability precluded the demonstration of any significant effect, we speculate that the videotape might be effective in training less-experienced assessors. Reductions in observer variability have the potential to diminish sample size requirements for RA antirheumatic drug studies. The use of a videotape to achieve this goal offers cost and convenience advantages over one-on-one training procedures, and this method should be further assessed in less-experienced assessors.

Ankylosing spondylitis antirheumatic drug trials: Effects of a standardized instructional viddeotape on the reliability of observer-dependent outcome measures.

AIMS: A study was designed to assess the effects of a standardized instruction videotape on reducing interobserver variability for several commonly used observer-dependent outcome measures. METHODS: During a single day, six rheumatologists independently examined six patients with ankylosing spondylitis (AS) in a predetermined order using a Latin square design, before and after viewing a standardized videotape demonstrating 14 examination techniques. Reliability coefficients were calculated based on the variance components of the analysis of variance (ANOVA) table. RESULTS: Prestandardization reliability coefficients were <0.80 for three measures. Following standardization 12 reliability coefficients exceeded 0.80. For the majority of measures prestandardization reliability coefficients were high and no further improvement in reliability could be demonstrated. For one measure of cervical extension, but not another, an important and beneficial effect in reliability was noted. It was not possible to achieve adequate reliability in the performance of the chest excursion measurement. CONCLUSIONS: It is usually assumed that serial measurement in clinical trials should be performed by the same assessor because of concern regarding interobserver variability. However, the high levels of prestandardization interobserver reliability observed in this study indicate that for these variables serial measurements in a clinical trial could be made by different assessors, assuming they were equally skilled. This observation has important implications for outcome measurement in AS clinical trials. Although high levels of prestandardization reliability precluded the demonstration of any significant effect, we speculate that the videotape might be effective in training less experienced assessors. Nevertheless, an alternative approach to standardization may be required for the chest excursion measurement. Reductions in observer variability have the potential to diminish sample size requirements for AS antirheumatic drug studies. The use of a videotape to achieve this goal offers cost and convenience advantages over one-on-one training procedures, and this method should be further assessed in a group of less experienced assessors.

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)

Serum IL-4, IL-10 and IL-6 levels in inflammatory arthritis.

As the available in vitro and in vivo data suggest that interleukin (IL)-4 and IL-10 have immunosuppressive activity, our hypothesis was that serum IL-4 and IL-10 levels would correlate inversely with parameters of inflammation in patients with inflammatory arthritis. IL-4 was detected in the serum of 12 out of 140 patients with rheumatoid arthritis (RA), which was increased compared to the proportion found with patients with osteoarthritis (OA; P < 0.02). In addition, IL-4 was detected in the serum of 2 of 19 patients with systemic lupus erythematosus (SLE), 2 of 24 patients with psoriatic arthritis and 1 of 5 patients with Behçet's syndrome. No IL-4 was detected in patients with the following conditions: OA (58 patients), gout (17 patients), ankylosing spondylitis (6 patients), Reiter's syndrome (6 patients), polymyalgia rheumatica (6 patients), temporal arteritis (5 patients) and scleroderma (3 patients). No IL-10 was detected in any of the sera tested. We discuss the possible relevance of these results to the regulation of the immune response evident in inflammatory arthritis.

The prevalence of soft tissue rheumatism. A who-ilar copcord study.

The prevalence of various forms of soft tissue rheumatism, including painful low back syndrome (PLBS), painful restricted shoulder syndrome (PRSS), and epicondylitis without an underlying specific rheumatic disease, and the resultant loss of time from work were determined in a total population of 4,683 rural and 1,103 urban subjects aged 15 years and over in Central Java, Indonesia. In the rural study, 763 respondents with, and 355 respondents without complaints were examined. The urban survey evaluated 925 subjects. Prevalence rates in the rural and urban subjects were 20.0% and 25.8%, respectively, for PLBS, 14.5% and 16.2%, respectively, for PRSS, and 5.8% and 7.5%, respectively, for epicondylitis. Lost time from work in the rural and urban subjects was 9% and 2.2%, respectively, for PLBS, 5% and 1.1%, respectively for PRSS, and 2% and 1.3%, respectively for epicondylitis. The mean number of lost work days per year in the rural and urban subjects were 15.3 and 21.1, respectively, for PLBS, 8.1 and 15.2, respectively, for PRSS, and 3.9 and 2.3, respectively for epicondylitis. Thus, these forms of soft tissue rheumatism exerted significant effects on community life, apart from causing pain and discomfort. Work days lost directly means diminished income in populations lacking any form of unemployment benefits.

Case study: World Health Organization-International League of Associations for Rheumatology Community-Oriented Programme for the Control of Rheumatic Diseases (WHO-ILAR COPCORD) in Indonesia and Brazil.

The three-stage World Health Organization-International League of Associations for Rheumatology Community Oriented Programme for Control of Rheumatic Disease (WHO-ILAR COPCORD) is described. Stage I results from Indonesia and Brazil are presented. This is a needs-based approach that offers efficiency in large-scale survey research that aims to estimate the prevalence of rheumatic diseases. It saves human resources, time, and cost in the collection of epidemiologic data. Awaited with interest are the results of the next two stages of COPCORD, which involve the development of educational programs on rheumatic disease and the evaluation of their impact on the burden of illness.

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.

Specificity of antibodies to type II collagen in early rheumatoid arthritis.

OBJECTIVE: To analyze the antibody response to native type II collagen in early rheumatoid arthritis (RA), examining the immunoglobulin isotypes, and polypeptide epitopes recognized, in patients followed over a 2-year period from within 6 months of the first occurrence of symptoms. METHODS: Sera from 16 patients were studied, of whom 10 had antibodies to native type II collagen and 6 did not. The clinical and laboratory assessment, carried out initially and at 6 monthly intervals included the number of 1958 ARA criteria fulfilled, Ritchie index, erythrocyte sedimentation rate, rheumatoid factor and radiological assessment. An ELISA was used to measure IgG, IgA and IgM antibodies, and immunoblotting to identify the number and location of epitopes, using polypeptides prepared by cyanogen bromide digestion of human type II collagen. RESULTS: Antibodies to type II collagen were present in all sequential serum samples for the 10 antibody positive patients. None of the 6 patients who initially lacked antibodies developed them. The antibodies were of IgG isotype in 9, of IgA isotype in 8, and of IgM isotype exclusively in one. At the initial clinical assessment patients with antibodies to collagen were indistinguishable from those without. At 12 and 24 months patients with antibodies fulfilled significantly more ARA criteria than antibody negative patients. The patterns of antibody reactivity to collagen polypeptides by immunoblotting were constant over time but differed from patient to patient. CONCLUSION: The presence of an established and persisting IgG antibody response to type II collagen in early RA before cartilage destruction is evident points to a subset of RA, perhaps equivalent to the collagen induced model in animals, in which this immune response is intrinsic to pathogenesis.

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.