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ObjectiveTo make recommendations on how to report disease activity in clinical trials of rheumatoid arthritis RA endorsed by the European League Against Rheumatism EULAR and the American College of Rheumatology ACR.MethodsThe project followed the EULAR standardized operating procedures, which use a threestep approach: 1 expertbased definition of relevant research questions November 2006; 2 systematic literature search November 2006 to May 2007; and 3 expert consensus on recommendations based on the literature search results May 2007. In addition, since this is the first joint EULARACR publication on recommendations, an extra step included a meeting with an ACR panel to approve the recommendations elaborated by the expert group August 2007.ResultsEleven relevant questions were identified for the literature search. Based on the evidence from the literature, the expert panel recommended that each trial should report the following items: 1 disease activity response and disease activity states; 2 appropriate descriptive statistics of the baseline, the endpoints and change of the single variables included in the core set; 3 baseline disease activity levels in general; 4 the percentage of patients achieving a low disease activity state and remission; 5 time to onset of the primary outcome; 6 sustainability of the primary outcome; 7 fatigue.ConclusionThese recommendations endorsed by EULAR and ACR will help harmonize the presentations of results from clinical trials. Adherence to these recommendations will provide the readership of clinical trials with more details of important outcomes, while the higher level of homogeneity may facilitate the comparison of outcomes across different trials and pooling of trial results, such as in metaanalyses.

To evaluate the capacity of a pooled index of only the 3 patient self-report questionnaire measures among the 7 American College of Rheumatology (ACR) core data set (Core Data Set) measures to distinguish efficacy of active treatment of rheumatoid arthritis (RA) with leflunomide or methotrexate versus placebo in a randomized, controlled clinical trial, and to compare the results with those obtained using the ACR 20% response criteria (ACR20), Disease Activity Score (DAS), and other pooled indices. The 7 ACR Core Data Set measures of 1) joint swelling, 2) joint tenderness, 3) physician global assessment, 4) erythrocyte sedimentation rate (ESR), 5) functional disability, 6) pain, and 7) patient global assessment were combined into the following 5 pooled indices: “All Core Data Set” (all 7 measures), “Assessor Only” (measures 1–3), “Assessor + ESR” (measures 1–4), “Patient Only” (measures 5–7), and “Patient + ESR” (measures 4–7). The capacity of each of these 5 indices to detect differences between active treatment and placebo treatment was compared with that of the ACR20 and the DAS using 4 different analytic methods, each of which presented advantages and limitations. Agreement of the indices with one another and with the ACR20 and the DAS was analyzed according to pairwise kappa statistics and Z scores in multivariate logistic regression models. Each of the 5 indices, including “Patient Only,” had a similar capacity to detect greater efficacy of leflunomide and methotrexate versus placebo in this clinical trial, according to each of 4 methods, at similar levels of statistical and clinical significance. A pooled index of patient self-report questionnaire Core Data Set measures appears to be as informative as ACR20 responses, DAS scores, and pooled indices of all and assessor-derived Core Data Set measures for distinguishing between active treatment and placebo treatment in this RA clinical trial.

OBJECTIVE: To determine whether the level of inflammatory activity, determined by the erythrocyte sedimentation rate (ESR), changes over the longitudinal course of rheumatoid arthritis (RA); whether the level of inflammatory activity identified early in RA predicts longterm inflammatory status; and whether RA "bums out" after many years of inflammatory activity. METHODS: A total of 21,866 consecutive ESR determinations from 1,897 patients with RA were analyzed to determine the association of inflammatory activity, as estimated by ESR, with duration of disease. Data were modeled by generalized estimating equations and random selection fractional polynomial regression models, controlling for age, sex, and calendar date. RESULTS: In a nonlinear fashion, ESR decreased by 4 mm/h over the first 10 years of disease, remained stable over the next 25 years, and increased slightly thereafter. Patients treated more recently had lower ESR values. Patients with recent onset of RA, when stratified in quartiles of ESR, maintained their position over time. CONCLUSION: Although ESR decreases by 4 mm/h over the first 10 years of disease, it remains stable or rises thereafter. The course of RA, as modeled by the ESR, appears to be "set" early in the disease and good and bad prognosis groups can be identified within the first 2 years. There is no evidence of general "burned out" RA or a lessening of disease activity with long duration of disease. Our findings tend to suggest that the ("usually treated") natural history of RA prior to introduction of antitumor necrosis factor agents is toward some degree of improvement in the early years. If the newer and combination therapies are indeed substantially better than what has been available, they must show a shifting of the curve downward, not just in the early years where it has occurred historically, but over the entire course of the illness.

To perform a randomized, double-blind, crossover clinical trial of diclofenac + misoprostol versus acetaminophen in ambulatory patients with osteoarthritis of the hip or knee. Patients in 12 ambulatory care settings were eligible if they were age >40 years and if they had Kellgren/Lawrence radiographic grade 2–4 osteoarthritis of the knee or hip and a score of ≥30 mm on a 100-mm visual analog pain scale. Patients were randomized to one of two groups, 75 mg diclofenac + 200 μg misoprostol twice daily or 1,000 mg acetaminophen 4 times daily (each for 6 weeks), and were then crossed over to the other treatment for 6 weeks. A placebo was included in each treatment regimen to enable double blinding. The primary outcome measures were the Western Ontario and McMaster Universities Osteoarthritis Index and the visual analog pain scale of the Multidimensional Health Assessment Questionnaire. Safety was assessed using a standard form to review adverse events. We enrolled 227 patients, of whom 218 provided data for the first treatment period and 181 provided data for both treatment periods. Significantly higher levels of improvement in the primary outcomes were seen for diclofenac + misoprostol than for acetaminophen (P < 0.001). Adverse events were more common when patients took diclofenac + misoprostol (P = 0.046). Diclofenac + misoprostol was rated as “better” or “much better” by 57% of the 174 patients who provided such ratings for both treatment periods, while acetaminophen was rated as “better” or “much better” by 20% of these patients, and 22% reported no difference (P < 0.001). Differences favoring diclofenac + misoprostol over acetaminophen were greater in patients with more severe osteoarthritis according to baseline pain scores, radiographs, or number of involved joints. Patients with osteoarthritis of the hip or knee had significantly greater improvements in pain scores over 6 weeks with diclofenac + misoprostol than with acetaminophen, although patients with mild osteoarthritis had similar improvements with both drugs. Acetaminophen was associated with fewer adverse events.

To determine in clinical practice which rheumatoid arthritis (RA) clinical status variables are most associated with a change in disease modifying antirheumatic drug (DMARD) therapy, we studied 26,240 observations from 1905 RA patients occurring over 25 years. Variables included tender joint count, erythrocyte sedimentation rate (ESR), grip strength, visual analog scale for pain, global severity, fatigue and sleep, Health Assessment Question functional disability scale (HAQ), anxiety, depression and morning stiffness. Only the tender joint count required a physician. Observations at which a change in DMARD therapy occurred were compared to those where a change did not occur using generalized estimating equations (GEE) and classification and regression tree analysis (CART). Tender joint count, pain, global severity, and ESR were the 4 variables most strongly predictive of DMARD change. CART modeling indicated a special role for fatigue and sleep disturbance in some patients. These data add support in clinical practice for the ACR core set and the DAS set of variables. In addition, they validate the use of these variables in a practice setting. We suggest a minimum set of evaluations comprising: joint count, ESR or CRP, measures of pain and/or severity, a fatigue scale (fatigue being a surrogate for sleep disturbance), and a measure of function such as the HAQ or modified HAQ. Because only joint count requires physician participation, these evaluations are practical for the clinic, and allow quantitative measurement of RA status. With the use of quantile charts, the comparative status of RA and the change in RA status can be determined easily.

Work disability is common in rheumatoid arthritis (RA), and accounts for a large fraction of its costs. People with RA who are work disabled have more joint involvement, radiographic damage, and/or laboratory abnormalities than people who are working. However, analysis of predictive and associative markers in 15 studies of work disability indicate that the demographic variables, such as age, occupation, level of education, and duration of disease, as well as functional status in activities of daily living (ADL) identified on a patient questionnaire, appear to identify work status more than physiological variables. Work disability results from complex interactions of a medical disease, demographic variables, social conditions, and government policies. Some patients with RA are work disabled before they see a rheumatologist. Improved work disability outcomes in RA will require attention to social, economic, and political issues, and wider physician and public education concerning RA, in addition to improved medical management of disease.

Predictors of longterm mortality in rheumatoid arthritis (RA) include patient questionnaire measures, grip strength, walk time, physician and patient assessment of global status, joint examination abnormalities, erythrocyte sedimentation rate (ESR), and morning stiffness. In the rheumatology literature, these measures have been analyzed primarily according to mean values in groups or regression analyses, which are valuable to recognize that mortality in RA is predicted by more severe disease, but do not provide the clinician with specific goals of therapy. Goals for therapeutic intervention are often expressed either as complete remission or as statistically significant differences versus a placebo, as in a 20% or even 50% response of a measure such as the American College of Rheumatology Core Data Set. Remission may be too stringent, while statistically significant efficacy of a drug compared to placebo may not necessarily indicate effectiveness to control longterm damage. An alternative approach might be to identify possible target values for therapeutic efficacy that markers of a poor prognosis be "near normal" rather than necessarily at normal or remission levels, as has been explored in management of hypertension and diabetes. However, it remains uncertain whether the goal of therapy should be a "near normal" or entirely normal values for a clinical marker. Better control of quantitative markers that predict early mortality could provide a valuable approach to improving outcomes in RA.

There is general agreement regarding the most appropriate examinations and methods to use to evaluate change in status in randomized controlled trials (RCT). However, no guidelines exist to aid in determining and evaluating actual status rather than change in status, particularly when applied to individual patients with rheumatoid arthritis (RA). In addition, methods appropriate for clinical trials may not be useful in evaluating individual patients because of time constraints. This report reviews current methods of evaluation and develops modified methods, based on data bank research that will be useful in clinical practice and in the evaluation of RCT and observational studies. Using data from longitudinal observational data banks, further reduction in the number of joints examined is evaluated to reconcile the time constraints of clinical practice with the need to maintain reliability and validity. Percentile methods to determine severity status are applied to the variables used in RCT and extended further to observational studies and routine clinical practice. Shortened joint counts, based on modifications of the Ritchie method, are identified that allow for examination of groups of 18 (clinical-18) and 16 (clinical-16) joints, the clinical-16 omitting the metatarsophalangeal joints. Using percentile charts, actual severity valuations are given to the variables evaluated in the clinic as well as in RCT. Disease activity status of clinic patients can be determined quantitatively thus allowing clinicians further insight into the status and prognosis of their patients. By quantifying disease activity severity, clinicians and 3rd party payers can better evaluate the appropriateness of and response to disease modifying antirheumatic drugs and biologic therapies. Further, RCT can be evaluated as to severity status of patients participating, and the generalizability of RCT can be better evaluated.

Chronic low back patients reported their satisfaction with the treatment they received for back pain from GPs and osteopaths practising in the same surgery. Although levels of satisfaction were high for all treatments, patients reported significantly higher scores for satisfaction with the osteopathic treatment. The difference was stronger for aspects of care/communication and competence, and weaker for satisfaction with efficacy. These findings are discussed in reference to patients’ expectations, novelty, time spent with patients, number of visits, and patients’ age.

To examine the psychological impact of surgical accidents and assess the adequacy of explanations given to the patients involved.

Rheumatoid arthritis (RA), previously considered to be a benign controllable disease with a good prognosis in the majority of patients, is now known to be a severe, progressive disease in terms of radiographic damage, severe functional deterioration, progressive work disability and premature mortality. The traditional approach to RA therapy (from less toxic to more toxic drugs) is inadequate and the risk of drug toxicity is generally overestimated while that of severe disease is underestimated. Consequently, aggressive treatment could be considered in an attempt to reverse the inflammation prior to long-term end-organ damage, rather than in response to such damage. As patients with RA may progress to an anticipated 5-year survival similar to that in patients with cardiovascular or neoplastic disease, RA should be viewed as an urgent medical problem - a "medical emergency" - in order to control the long-term consequences of the disease process.

Twelve traditional paradigms concerning the diagnosis, prevalence, morbidity and mortality of rheumatoid arthritis have provided much of the conventional wisdom in textbooks and clinical practice. Reassessment of these paradigms may lead to new insights and improved outcomes in rheumatoid arthritis.

AKR/J thymocytes derived from fetal liver cells do not produce virus when they differentiate in lethally irradiated B10.K mice, whereas spleen and bone marrow cells are virus producers. In contrast, B10.K thymocytes that differentiate in lethally irradiated AKR mice become virus producers. These results suggest that infection of the thymus in AKR mice is initiated in thymic stromal cells.

Doctors in different specialities differ in personality, attitudinal and other measures. These differences might be the result of self-selection, or an effect of socialization in undergraduate and postgraduate training or of specialist selection. In two studies we assessed the association between personality and other measures in applicants to medical school, since associations at that stage must reflect self-selection, rather than the effects of training. In study 1, preferences for 11 medical specialities were assessed in 509 medical school applicants being interviewed at University College London Medical School in 1989-1990. A large range of demographic, biographical and personality measures was also obtained in these individuals. Canonical correlation suggested five independent dimensions that linked career preferences with background measures. An exploratory stepwise multiple regression was used to find the most significant predictors for each career speciality and a number of strong patterns emerged, many of which made intuitive sense in terms of conventional stereotypes of doctors in those specialities. Study 2 was a direct a priori test of the significance of the important variables identified in study 1. Five hundred and sixty-three interviewees at UCLSM during 1991-1992 completed identical questionnaires to those used in Study 1 and the validity of the predictors found in Study 1 was assessed by fitting the same regression equations as had previously been identified. For 10 of the 11 careers the variables produced a highly significant prediction of preference. It is concluded that personality differences between doctors in different specialities are in part the result of self-selection, and not just the result of training or selection.

A late-passage derivative of SC-1 cells with stable relative resistance to N- and B-tropic viruses but with retained sensitivity to NB-tropic viruses has been identified. Dual resistance was seen with the XC plaque assay, as well as reverse transcriptase assay and radioimmunoassay for viral p30. Evidence was found for resistance in clonal derivatives. These findings suggest a possible instability in determinants of cellular resistance to endogenous retroviruses and may be useful in further analysis of resistance to retrovirus infection.

A Sepharose 4B chromatographic method for purification of retroviruses is described which was less time consuming, increased purified virus yields, conserved viral glycoprotein, and increased recovery of biological infectivity in comparison with conventional sucrose gradient ultracentrifugation techniques.

We have evaluated the possible involvement of TGF-beta in rheumatoid arthritis by assay of 16 cell-free synovial fluids for the presence of its active and "latent" forms. Evidence has been obtained for TGF-beta-like activity in synovial effusions by four criteria: (a) TGF-beta receptor competition, (b) soft-agar colony formation of AKR-2B and NRK-49F indicator cells, (c) immunological neutralization of the biological activity, and (d) biochemical activation of a latent form.

Antisera to purified structural proteins of Rauscher murine leukemia virus, the major envelope glycoprotein, gp69/71, and the major internal protein, p30, were studied by immunofluorescence of viable and fixed virus-infected cells and by virus neutralization. Group-specific and type-specific determinants of gp69/71 were demonstrated by immunofluorescence and virus neutralization tests, indicating that these determinants are located in the cytoplasm and probably on the cell surface as well as on virus envelope. Antisera against p30 showed anti-group and anti-interspecies activities by immunofluorescence with no virus-neutralizing activity. Both antigenic determinants of gp69/71 were sensitive to guanidine-hydrochloride and to a lesser degree to ether treatment, whereas the group-specific determinants of p30 were relatively stable to these treatments.