Objective. Trials of rheumatoid arthritis (RA) treatments report the average response in multiple outcome measures for treated patients. It is more clinically relevant to test whether individual patients improve with treatment, and this identifies a single primary efficacy measure. Multiple definitions of improvement are currently in use in different trials. The goal of this study was to promulgate a single definition for use in RA trials. Methods. Using the American College of Rheumatology (ACR) core set of outcome measures for RA trials, we tested 40 different definitions of improvement, using a 3‐step process. First, we performed a survey of rheumatologists, using actual patient cases from trials, to evaluate which definitions corresponded best to rheumatologists' impressions of improvement, eliminating most candidate definitions of improvement. Second, we tested 20 remaining definitions to determine which maximally discriminated effective treatment from placebo treatment and also minimized placebo response rates. With 8 candidate definitions of improvement remaining, we tested to see which were easiest to use and were best in accord with rheumatologists' impressions of improvement. Results. The following definition of improvement was selected: 20% improvement in tender and swollen joint counts and 20% improvement in 3 of the 5 remaining ACR core set measures: patient and physician global assessments, pain, disability, and an acutephase reactant. Additional validation of this definition was carried out in a comparative trial, and the results suggest that the definition is statistically powerful and does not identify a large percentage of placebo‐treated patients as being improved. Conclusion. We present a definition of improvement which we hope will be used widely in RA trials.

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Guidelines and recommendations developed and/or endorsed by the American

Objective To assess if it is better to intensively treat all early RA patients with drug combinations or reserve this for those who do not appropriately respond to methotrexate monotherapy and assess if the combination therapy of methotrexate plus etanercept is superior to the combination of methotrexate plus sulfasalazine plus hydroxychloroquine. Methods The TEAR study is a 2-year, randomized, double-blind trial. Using a 2×2 factorial design, participants were randomized to one of four treatment arms: immediate combination therapy of methotrexate plus etanercept; or oral triple therapy (methotrexate plus sulfasalazine plus hydroxychloroquine); or initial methotrexate monotherapy with a step-up to one of the combination therapies (all arms included matching placebos). The primary outcome was an observed-group analysis of DAS28-ESR scores from weeks 48 to 102. Results At the week 24 step-up period, those receiving immediate combination therapy (etanercept plus methotrexate; or triple therapy) demonstrated greater reduction in DAS28-ESR compared to those on initial methotrexate monotherapy (DAS28-ESR: 3.6 vs. 4.6, p<0.0001), with no differences between regimens of combination therapy. For weeks 48 through 102, participants randomized to step-up arms had a DAS28-ESR clinical response that was not different than those who received initial combination therapy, regardless of the treatment arm (3.2 vs. 3.2, p=0.75). There was no significant difference in DAS28-ESR between participants receiving oral triple therapy versus combination methotrexate plus etanercept (3.1 vs. 3.2, p=0.42). By week 102, there was a small, statistically significant difference in change in radiographic measurements from baseline between methotrexate plus etanercept compared to oral triple therapy (0.64 vs. 1.69, p= 0.047). The absolute difference at week 102 was small. Conclusions There were no differences in the mean DAS28-ESR during weeks 48-102 between participants randomized to methotrexate plus etanercept or triple therapy, regardless of whether they received immediate combination treatment or step-up from methotrexate monotherapy. At 24 months, immediate combination treatment with either strategy was more effective than methotrexate monotherapy prior to step-up. Initial use of methotrexate monotherapy with the addition of sulfasalazine plus hydroxychloroquine; or etanercept, if necessary after 6 months, is a reasonable therapeutic strategy for early RA. The combination of etanercept plus methotrexate resulted in a statistically significant, but clinically small, radiographic benefit over oral triple therapy.

Low density lipoproteins and the triglyceride-rich lipoproteins of human serum each contain proteins of high molecular weight termed apolipoprotein B,which have previously been thought to be identical. We have isolated four species of apolipoprotein B with unique molecular weights and amino acid compositions. We have assigned numerical designations to these species in a centile system based upon their relative apparent Mr in NaDodSO4. One which we term B-100, with an apparent Mr of 549,000 ± 7650 (SD) determined by NaDodSO4 gel electrophoresis, predominates in low density and very low density lipoproteins and is also present in chylomicrons from thoracic duct lymph or from plasma. Substantial amounts of two large proteins designated B-74 (apparent Mr 407,000 ± 5790) and B-26 (apparent Mr 144,500 + 8970), which appear to be complementary fragments or constituents of the B-100 protein, are found in the low density lipoproteins of many individuals. A distinct protein, B-48, with an apparent Mr of 264,000 i 8150 is a major and constant constituent of chylomicrons from thoracic duct lymph or from plasma.The lipoproteins of human serum contain at least 12 species of proteins' (apolipoproteins) (1). The most abundant of these, apolipoprotein B (apo B) shares with another species, apolipoprotein E, the ability to interact with high-affinity receptors on cell membranes (2). apo B is distinguished by its apparent inability to transfer among lipoprotein particles, by its extreme insolubility in aqueous buffers after the lipid moiety is removed, and by its insolubility in 4.2 M tetramethylurea (3). Studies of apo B solubilized with various denaturing solvents and amphiphilic agents have yielded widely varying estimates of molecular weight (1, 4-7).We describe here the presence of four major molecular species of apo B. One of these is nearly the sole form in very low density lipoproteins (VLDL). It also appears in low density lipoproteins (LDL) and chylomicrons from thoracic duct lymph and plasma. Two others appear to be fragments or components of the former and appear only in LDL. The fourth, distinguished by both its molecular weight and amino acid composition, is found only in chylomicrons.MATERIALS AND METHODS Preparation of Lipoproteins. Serum was prepared from blood obtained from donors who had fasted for 12-16 hr. Lipoproteins of serum were separated by repetitive preparative ultracentrifugation in a 40.3 rotor, at 12°C, in a Beckman model L ultracentrifuge (8). VLDL were separated in the p < 1.006 g/cm3 fraction of serum from normolipidemic individuals after centrifugation for 18 hr. The ultracentrifugation was repeated once. Chylomicrons were judged to be absent from preparations of VLDL by the absence of a visible supernatant layer after refrigeration for 24 hr at 40C and by the absence of lipoproteinsThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "ad- Measures to Prevent Nonspecific Degradation of apo B. Gentamycin sulfate, ...

ABSTRACT

In this population, health care quality appears to be suboptimal for arthritis, comorbid disease, and health care maintenance. Patterns of care that included relevant specialists were associated with substantially higher quality across all domains. Patterns that included generalists were associated with substantially higher quality health care maintenance than patterns that included neither a generalist nor a relevant specialist. The optimal roles of primary care physicians and specialists in the care of patients with complex conditions should be reassessed. JAMA. 2000;284:984-992

Objectives Reverse cholesterol transport (RCT) is a major antiatherogenic function of high density lipoprotein (HDL). In the current work, the authors evaluated whether the RCT capacity of HDL from rheumatoid arthritis (RA) patients is impaired when compared to healthy controls. Methods HDL was isolated from 40 patients with RA and 40 age and sex matched healthy controls. Assays of cholesterol efflux, HDL’s antioxidant function and paraoxanase-1 (PON-1) activity were performed as described previously. Plasma myeloperoxidase (MPO) activity was assessed by a commercially available assay. Results Mean cholesterol efflux capacity of HDL was not significantly different between RA patients (40.2%±11.1%) and controls (39.5%±8.9%); p=0.75. However, HDL from RA patients with high disease activity measured by a disease activity score using 28 joint count (DAS28>5.1), had significantly decreased ability to promote cholesterol efflux compared to HDL from patients with very low disease activity/clinical remission (DAS28<2.6). Significant correlations were noted between cholesterol efflux and the DAS28 (r=−0.39, p=0.01) and erythrocyte sedimentation rate, (r=−0.41, p=0.0009). Higher plasma MPO activity was associated with worse HDL function (r=0.41/p=0.009 (antioxidant capacity); r=0.35, p=0.03 (efflux)). HDL’s ability to promote cholesterol efflux was modestly but significantly correlated with its antioxidant function (r=−0.34, p=0.03). Conclusions The cholesterol efflux capacity of HDL is impaired in RA patients with high disease activity and is correlated with systemic inflammation and HDL’s antioxidant capacity. Attenuation of HDL function, independent of HDL cholesterol levels, may suggest a mechanism by which active RA contributes to increased cardiovascular (CV) risk.