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Objective Patients and physicians often differ in their perceptions of rheumatoid arthritis (RA) disease activity, as quantified by the patient's global assessment (PGA) and by the evaluator's global assessment (EGA). The purpose of this study was to explore the extent and reasons for this discordance. Methods We identified variance components for the PGA and EGA in RA patients who were starting therapy with methotrexate in an academic outpatient setting. We analyzed predictors of the observed discrepancy in these measures (calculated as the PGA minus the EGA) and in their changes (calculated as the PGAchange minus the EGAchange). Results We identified 646 RA patients, and among them, 77.4% of the variability in the PGA and 66.7% of the variability in the EGA were explainable. The main determinants for the PGA were pain (75.6%), function (1.3%, by Health Assessment Questionnaire), and number of swollen joints (0.5%); those for the EGA were the number of swollen joints (60.9%), pain (4.5%), function (0.6%), C-reactive protein (0.4%), and the number of tender joints (0.3%). Increased pain led to a discrepancy toward worse patient perception, while increased numbers of swollen joints led to a discrepancy toward worse evaluator perception, both explaining 65% of the discordance between the PGA and the EGA. Likewise, changes in pain scores and numbers of swollen joints proved to be the main determinants for discrepant perceptions of changes in RA disease activity, explaining 34.6% and 12.5% of the discordance, respectively. Conclusion The most significant determinants for the cross-sectional and longitudinal discrepancy between the PGA and the EGA are pain and joint swelling, respectively. Understanding the reasons for a discordant view of disease activity will help to facilitate the sharing of decision-making in the management of RA.

Objective The binding of abatacept (CTLA-4Ig) to the B7 ligands CD80 and CD86 prevents the engagement of CD28 on T cells and thereby prevents effector T cell activation. In addition, a direct effect of CTLA-4Ig on antigen-presenting cells (APCs) could contribute to the therapeutic effect. To further elucidate the mechanism of CTLA-4Ig, we performed phenotype and functional analyses of APCs in patients with rheumatoid arthritis (RA) before and after the initiation of CTLA-4Ig therapy. Methods Peripheral blood mononuclear cells were analyzed before and at 2 and 4 weeks after the initiation of CTLA-4Ig therapy. Proportions of APCs were determined by flow cytometry. CD14+ monocytes were further analyzed for the expression of costimulatory and adhesion molecules and for their transendothelial migratory capacity in vitro. In addition, CD14+ monocytes from healthy controls were analyzed for their migratory and spreading capacity. Results Proportions and absolute numbers of monocytes were significantly increased in RA patients treated with CTLA-4Ig. The expression of several adhesion molecules was significantly diminished. In addition, monocytes displayed a significant reduction in their endothelial adhesion and transendothelial migratory capacity upon treatment with CTLA-4Ig. Likewise, isolated monocytes from healthy controls revealed a significant reduction in their migratory and spreading activity after preincubation with CTLA-4Ig or anti-CD80 and anti-CD86 antibodies. Conclusion We describe direct effects of CTLA-4Ig therapy on phenotype and functional characteristics of monocytes in RA patients that might interfere with the migration of monocytes to the synovial tissue. This additional mechanism of CTLA-4Ig might contribute to the beneficial effects of CTLA-4Ig treatment in RA patients.

Objective Both type I interferons (IFNα and IFNβ) and type II IFN (IFNγ) signal via pSTAT-1. Immunohistochemistry and the gene expression signatures of rheumatoid arthritis (RA) synovial tissue suggest an activated IFN/STAT-1 signaling pathway. The aim of this study was to determine the systemic activity of the IFN/STAT-1 signaling pathway in the peripheral blood cells of patients with RA. Methods Fluorocytometry or quantitative polymerase chain reaction was used to measure the expression of STAT-1, pSTAT-1, and IFN-inducible genes (monokine induced by interferon-γ [MIG], interferon-γ–inducible protein 10 [IP-10], and 2′,5′-oligoadenylate synthetase [OAS]) in the peripheral blood mononuclear cells (PBMCs) and purified CD14+ peripheral blood monocytes of patients with RA and healthy control subjects. PBMCs were also incubated for 48 hours with IFNs and several other cytokines to investigate influences on STAT-1 levels. To examine the significance of STAT-1 activation in RA monocytes after stimulation with IFNγ, the expression of pSTAT-1 and of the IFNγ-inducible chemokine MIG was measured using fluorocytometry. Results Levels of STAT-1 were significantly increased in peripheral lymphocytes and monocytes from patients with RA compared with those from healthy control subjects. STAT-1 levels correlated well with RA disease activity, as measured by the Disease Activity Score in 28 joints and the Clinical Disease Activity Index. Furthermore, STAT-1 messenger RNA expression in RA CD14+ monocytes correlated with the expression of other IFN-target genes, such as IP-10, OAS, or MIG. In RA PBMCs, STAT-1 expression was increased not only by IFNs but also by tumor necrosis factor. RA monocytes demonstrated a considerably higher increase in pSTAT-1 and MIG levels upon IFNγ stimulation when compared with monocytes from control subjects, indicating that RA monocytes are more sensitive to IFNγ stimulation. Conclusion In addition to supporting the role of IFNs in systemic proinflammatory activity, the results of this study further suggest preactivation of the IFNγ/STAT-1 signaling pathway, especially in RA monocytes.

Objective To determine the effects of tocilizumab on rheumatoid arthritis (RA) disease activity and remission assessment, using measures that do or do not comprise acute-phase reactants. Methods Simplified Disease Activity Index (SDAI) scores, Clinical Disease Activity Index (CDAI) scores, and the Disease Activity Score in 28 joints (DAS28) were calculated using data from tocilizumab trials in patients with RA in whom disease had remained active despite treatment with disease-modifying antirheumatic drugs. The CDAI does not contain an acute-phase reactant component. Disease activity states, including remission, were defined using established cut points; for the DAS28, an alternative cut point of

Objective To investigate the mechanisms leading to the influx of inflammatory hematopoietic cells into the synovial membrane and the role of tumor necrosis factor receptor I (TNFRI) and TNFRII in this process in an animal model of rheumatoid arthritis (RA). Methods We performed bone marrow transplantations in human TNF–transgenic mice using hematopoietic cells from wild-type, TNFRI−/−, TNFRII−/−, and TNFRI/II−/− mice as donors and assessed the severity of arthritis histologically. Generation of osteoclasts from the different genotypes was analyzed in vitro and in vivo. Apoptosis was analyzed using annexin V staining as well as TUNEL assays. Results Despite lacking responsiveness to TNF in their hematopoietic compartment, mice not only developed full-blown erosive arthritis but even showed increased joint destruction when compared with mice with a TNF-responsive hematopoietic compartment. We demonstrated different roles of the 2 different TNFRs in the regulation of these processes. The absence of TNFRI on hematopoietic cells did not affect joint inflammation but markedly attenuated erosive bone destruction via reduced synovial accumulation of osteoclast precursors. In contrast, the absence of TNFRII on hematopoietic cells increased joint inflammation as well as erosive bone destruction via the regulation of osteoclast precursor apoptosis. Conclusion Our findings indicate that selective blockade of TNFRI, leaving the antiinflammatory effects of TNFRII unaltered instead of unselectively blocking TNF, might be advantageous in patients with RA.

Objective To assess the impact of certolizumab pegol (CZP), a novel PEGylated anti–tumor necrosis factor, in combination with methotrexate (MTX) on productivity outside and within the home, and on participation in family, social, and leisure activities in adult patients with rheumatoid arthritis (RA). Methods The efficacy and safety of CZP (200 mg and 400 mg) plus MTX were assessed in 2 phase III, multicenter, double-blind, placebo-controlled trials (Rheumatoid Arthritis Prevention of Structural Damage [RAPID] 1 and RAPID 2). The novel, validated, RA-specific Work Productivity Survey (WPS-RA) was used to assess work place and home productivity. WPS-RA responses were collected at baseline and every 4 weeks until withdrawal/study completion. Results At baseline, 41.6% and 39.8% of subjects were employed outside the home in RAPID 1 and RAPID 2, respectively. Compared with placebo plus MTX, CZP plus MTX significantly reduced work absenteeism and presenteeism among patients working outside the home. Significant reductions in number of household days lost, household days with productivity reduced by ≥50%, and days lost due to RA for participation in family, social, and leisure activities were reported by patients in active treatment relative to placebo plus MTX. Improvements in all measures were observed with CZP plus MTX as early as week 4, and maintained until the study end (12 months in RAPID 1, 6 months in RAPID 2). Findings were consistent with clinical improvements with CZP plus MTX in both trials. Conclusion CZP plus MTX improved productivity outside and within the home and resulted in more participation in social activities compared with placebo plus MTX. These observations suggest that considerable indirect cost gains might be achieved with this therapeutic agent in RA.

Objective Joint damage is related to disease activity in rheumatoid arthritis (RA), but the degree of its progression and the temporal associations between disease activity and joint damage are unclear. The aim of this study was to evaluate whether there is a latency in the effect of disease activity on radiographic progression in patients with RA. Methods Data were obtained from the PREMIER trial, a 2-year randomized, controlled clinical trial of adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in early RA. Radiographic progression of joint damage was calculated using the modified total Sharp score in a subset of patients whose disease was in remission (Simplified Disease Activity Index ≤3.3) in the second year of the trial. The progression of damage in the second year was compared between groups of patients whose disease was already in remission for an additional period of 3, 6, or 9 months during the first year. Analysis of variance was used to test for a linear trend. Results Among 794 patients with early RA, 119 (15%) achieved sustained remission during the second year, with no difference in radiographic progression across the 3 treatment groups. Radiographic progression in the second year was significantly different between patients with 3, 6, or 9 additional months of remission during year 1 (mean change in the modified Sharp score 1.19 in those with 3 additional months of remission versus 0.20 in those with 6 additional months of remission and −0.32 in those with 9 additional months of remission; P < 0.05). The results were supported by similar findings in a series of sensitivity analyses. Conclusion These data indicate that the level of disease activity as well as the duration of remission affect subsequent progression of radiographic damage in RA. This latency between disease activity and its effects on radiographic progression should be considered when evaluating radiographic outcomes in trials of RA.

Objective To analyze the minimum clinically important improvement (MCII) of disease activity measures in rheumatoid arthritis (RA) using patient-derived anchors, and to assess whether criteria for improvement differ with baseline disease activity. Methods We used data from a Norwegian observational database comprising 1,050 patients (73% women, 65% rheumatoid factor-positive, mean duration of RA 7.7 years). At 3 months after initiation of therapy, patients indicated whether their condition had improved, had considerably improved, was unchanged, had worsened, or had considerably worsened. We used receiver operating characteristic curve analysis to determine the MCII for the Disease Activity Score based on the assessment of 28 joints (DAS28), the Simplified Disease Activity Index (SDAI), and the Clinical Disease Activity Index (CDAI), and analyzed the effects of different levels of baseline disease activity on the MCII. Results On average, patients started with high disease activity and improved significantly during treatment (American College of Rheumatology 20%, 50%, and 70% improvement criteria responses were 37%, 17%, and 5%, respectively). The overall mean (95% confidence interval [95% CI]) thresholds for MCII after 3 months for the DAS28, SDAI, and CDAI were 1.20 (95% CI 1.18–1.22), 10.95 (95% CI 10.69–11.20), and 10.76 (95% CI 10.49–11.04), respectively, and the mean (95% CI) thresholds for major responses were 1.82 (95% CI 1.80–1.83), 15.82 (95% CI 15.65–16.00), and 15.00 (95% CI 14.82–15.18), respectively. With increasing disease activity, much higher changes in disease activity were needed to achieve MCII according to patient judgment. Conclusion The perception of improvement of disease activity of patients with RA is considerably different depending on the disease activity level at which they start.

Objective To analyze the content of outcome measures commonly used to assess health in patients with fibromyalgia (FM) by linking the items of the instruments with the International Classification of Functioning, Disability and Health (ICF) in order to evaluate the adequacy of currently used measures. Methods Questionnaires used in FM were identified in a structured literature search. All concepts included in the items of the questionnaires were linked to ICF categories, according to previously published linking rules, by 2 independent health professionals. The percentages of linked ICF categories addressing the different ICF components were calculated. Results Generic and symptom-specific instruments were included. From the 296 items contained in all 16 instruments, 447 concepts were extracted and then linked to 52 ICF categories of the component body functions, 1 category of the component body structure, 40 categories of the component activities and participation, and 9 categories of the component environmental factors. More than half of the concepts identified were linked to body function, fewer were linked to activities and participation, and only concepts of 4 instruments were linked to the ICF component environmental factors. Conclusion Many concepts were linked to the categories in the ICF component body functions. While linking to the broad category, purportedly similar instruments often covered widely varying areas of function at more fine-grained levels of detail. Some categories, such as environmental factors, were barely covered by any of the instruments and might constitute an important aspect of health deserving better coverage and future development.

To compare employability between patients with early and long-standing rheumatoid arthritis (RA) and examine the relationships between improvement in employability and disease stage after adjustment for demographic characteristics, disease activity, physical functioning, and response to therapy.We evaluated the employability data from 2 double-blind, randomized, placebo-controlled studies of infliximab plus methotrexate (MTX) in patients with RA. Patients were incomplete responders to MTX in 1 study and had never taken MTX in the other study. Patients age65 years were categorized as having early RA (or =3 years disease duration) or long-standing RA (3 years disease duration). Physical functioning was assessed using the Health Assessment Questionnaire (HAQ) and clinical response was determined based on the American College of Rheumatology 20% improvement criteria (ACR20).Patients with early RA were more likely to be employable at baseline than those with long-standing RA, even after adjusting for baseline HAQ scores. Among patients who were not employable at baseline but achieved an ACR20 response after 1 year of treatment, after adjusting for baseline HAQ score, the patients with early RA who had never taken MTX were 3 times more likely to become employable compared with those with long-standing RA who had an incomplete response to MTX at baseline.In 2 clinical trials, patients with early RA were more likely to show improved employment outcomes after treatment than those with long-standing RA, suggesting intervention as early as possible in the disease course maximizes an individual patient's employment potential.

Objective To investigate which members of the heterogeneous nuclear RNP (hnRNP) family are targeted by autoantibodies from patients with systemic rheumatic diseases. Methods Using a semipurified preparation of natural hnRNP proteins, 365 sera from patients with rheumatic diseases and control subjects were screened by immunoblotting for the presence of autoantibodies. Bacterially expressed recombinant hnRNP D (AUF1) proteins were used for confirming the data obtained. Binding of RNA and autoantibody to AUF1 was investigated by gel retardation assays. Expression of AUF1 in cultivated cells and synovial tissue was analyzed by indirect immunofluorescence and immunohistochemistry. Results Autoantibodies to AUF1 proteins were detected in 33% of patients with systemic lupus erythematosus, 20% of patients with rheumatoid arthritis, 17% of patients with mixed connective tissue disease, and

Objective To determine which self-report instruments best explain hand functioning measured by a generic comprehensive hand function test. Methods Six questionnaires currently used in hand osteoarthritis (OA), namely, the Arthritis Impact Measurement Scales 2 Short Form (AIMS2-SF), the Australian/Canadian Osteoarthritis Hand Index (AUSCAN), the Cochin scale, the Functional Index of Hand OA (FIHOA), the Health Assessment Questionnaire (HAQ), and the Score for Assessment and Quantification of Chronic Rheumatoid Affections of the Hands (SACRAH), were administered once in 100 patients with hand OA together with the Jebsen-Taylor Hand Function Test (JTHFT). In addition, 3 other hand function tests with short administration time were used: the Moberg Picking-Up Test (MPUT), the Button Test (BT), and grip strength. The Short Form 36 was used to describe health status. The relationship between the instruments and the JTHFT was determined by correlation analyses. Results AIMS2-SF total scores had the highest raw correlation coefficient to the JTHFT, followed by AIMS2-SF upper body limitation subscale, SACRAH stiffness subscale, and SACRAH total score. If controlled for age, the HAQ had the highest correlation coefficient. Of the 3 short hand function tests, the MPUT showed the highest raw correlation coefficient to the JTHFT; if controlled for age, the BT had the highest correlation coefficient. Conclusion To comprehensively assess hand functioning in patients with hand OA, we recommend using both a self-report instrument used more generally in various arthritides and a self-report instrument specifically developed for hand OA. If a short test is preferred, we recommend using the MPUT or BT.

Objective To investigate the pathologic nature of features termed “bone erosion” and “bone marrow edema” (also called “osteitis) on magnetic resonance imaging (MRI) scans of joints affected by rheumatoid arthritis (RA). Methods RA patients scheduled for joint replacement surgery (metacarpophalangeal or proximal interphalangeal joints) underwent MRI on the day before surgery. The presence and localization of bone erosions and bone marrow edema as evidenced by MRI (MRI bone erosions and MRI bone marrow edema) were documented in each joint (n = 12 joints). After surgery, sequential sections from throughout the whole joint were analyzed histologically for bone marrow changes, and these results were correlated with the MRI findings. Results MRI bone erosion was recorded based on bone marrow inflammation adjacent to a site of cortical bone penetration. Inflammation was recorded based on either invading synovial tissue (pannus), formation of lymphocytic aggregates, or increased vascularity. Fat-rich bone marrow was replaced by inflammatory tissue, increasing water content, which appears as bright signal enhancement on STIR MRI sequences. MRI bone marrow edema was recorded based on the finding of inflammatory infiltrates, which were less dense than those of MRI bone erosions and localized more centrally in the joint. These lesions were either isolated or found in contact with MRI bone erosions. Conclusion MRI bone erosions and MRI bone marrow edema are due to the formation of inflammatory infiltrates in the bone marrow of patients with RA. This emphasizes the value of MRI in sensitively detecting inflammatory tissue in the bone marrow and demonstrates that the inflammatory process extends to the bone marrow cavity, which is an additional target structure for antiinflammatory therapy.

Objective Although use of the American College of Rheumatology 20% improvement criteria (ACR20) has standardized response measurement in rheumatoid arthritis (RA) trials, the ACR20 has been criticized as less sensitive to change than are continuous measures of response, and its threshold for response (≥20%) is thought to be low. Our goal was to redefine response in RA in a manner that 1) corresponds to a clinical impression of response (clinical validity), 2) maximizes sensitivity to change, and 3) allows for calculation of the ACR20 to continue standardization of reporting. Methods We examined multiple different ways of defining response, including dichotomous definitions (patient improved versus not improved), ordinal definitions (degree of response scored on an ordinal scale), disease activity indexes, continuous definitions, and definitions that were hybrids of continuous and ordinal measures. Candidate definitions included the ACR20, ACR50, ACR70, the Disease Activity Score, the Simplified Disease Activity Index, the ACR-N, the nACR, and the European League Against Rheumatism (EULAR) response. We also tested variations on these approaches. To test clinical validity, we administered a survey involving patients from a previous trial who had various levels of improvement and asked rheumatologists whether and by how much these patients improved. To determine sensitivity to change, we collected data from 11 large multicenter trials of disease-modifying antirheumatic drugs (DMARDs) in RA comprising 3,665 patients (7 anti–tumor necrosis factor α arms, 4 conventional DMARD arms, 2 biologic arms) and ranked candidate definitions of response according to their average P value across trials in distinguishing active treatment from placebo or combination therapy versus single-drug therapy. Results All 135 tested measures had clinical validity based on survey responses, although dichotomous measures did not capture the range of responses (e.g., the ACR20 did not capture the extra clinical improvement between the ACR20 and the ACR50). In trial analyses, continuous measures had the best sensitivity to change. Among the best scoring measures was a hybrid measure that retained information on the ACR20, ACR50, and ACR70 and combined that with the mean percent improvement in core set measures. When comparing 2 treatments, this hybrid measure had an average P value much lower than that for the ACR20. If a trial needed 200 patients to have 80% power (2-sided α = 0.05) to detect a difference between treatments if it used the ACR20, the same trial would need 108 patients if the hybrid measure were used. Conclusion We suggest use of a new hybrid measure of RA response that maximizes sensitivity to change, correlates well with rheumatologists' impressions of improvement, and preserves the ACR20.

Objective To assess the occurrence of anticardiolipin antibodies (aCL) in patients with early rheumatoid arthritis (RA) receiving treatment with infliximab plus methotrexate (MTX) versus MTX alone. Methods The first 299 patients enrolled in the randomized, Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset (ASPIRE) trial who had baseline (week 0) samples available for aCL testing were included in this study. Sera were collected at weeks 0, 30, and 54 from 110 patients taking infliximab 3 mg/kg plus MTX, 98 patients taking infliximab 6 mg/kg plus MTX, and 91 patients taking placebo plus MTX. IgG and IgM aCL were measured using an anticardiolipin assay. Results IgG and IgM aCL positivity at baseline was similar in all treatment groups. Most patients were negative for IgG aCL at baseline and remained so at the last followup evaluation. One percent (2 of 208) of patients who received infliximab plus MTX and were negative for IgG aCL at baseline were positive for IgG aCL at weeks 30 and 54. A slightly higher proportion of patients who received infliximab plus MTX and were negative for IgM aCL at baseline were positive for IgM aCL at weeks 30 and 54 (4.8% [10 of 208]) as compared with patients who received placebo plus MTX (1.1% [1 of 91]), but the difference was not significant. Conclusion There was a low incidence of the development of aCL in patients with early RA who received infliximab in combination with MTX, and the difference was not significant compared with patients who received placebo plus MTX.

Objective To establish the safety and efficacy of repeat infusions of tocilizumab (previously known as MRA), a humanized anti–interleukin-6 (IL-6) receptor antibody, alone and in combination with methotrexate (MTX), for the treatment of rheumatoid arthritis (RA). Methods The study group comprised 359 patients with active RA in whom the response to MTX was inadequate. During a stabilization period, these patients received their current dose of MTX for at least 4 weeks. Following stabilization, they were randomized to 1 of 7 treatment arms, as follows: tocilizumab at doses of 2 mg/kg, 4 mg/kg, or 8 mg/kg either as monotherapy or in combination with MTX, or MTX plus placebo. Results A 20% response (improvement) according to the American College of Rheumatology criteria (ACR20 response) was achieved by 61% and 63% of patients receiving 4 mg/kg and 8 mg/kg of tocilizumab as monotherapy, respectively, and by 63% and 74% of patients receiving those doses of tocilizumab plus MTX, respectively, compared with 41% of patients receiving placebo plus MTX. Statistically significant ACR50 and ACR70 responses were observed in patients receiving combination therapy with either 4 mg/kg or 8 mg/kg of tocilizumab plus MTX (P < 0.05). A dose-related reduction in the Disease Activity Score in 28 joints was observed from week 4 onward, in all patients except those receiving monotherapy with 2 mg/kg of tocilizumab. In the majority of patients who received 8 mg/kg of tocilizumab, the C-reactive protein level/erythrocyte sedimentation rate normalized, while placebo plus MTX had little effect on these laboratory parameters. Tocilizumab was mostly well tolerated, with a safety profile similar to that of other biologic and immunosuppressive therapies. Alanine transaminase and aspartate transaminase levels followed a sawtooth pattern (rising and falling between infusions). There were moderate but reversible increases in the nonfasting total cholesterol and triglyceride levels and reversible reductions in the high-density lipoprotein cholesterol and neutrophil levels. There were 2 cases of sepsis, both of which occurred in patients who were receiving combination therapy with 8 mg/kg of tocilizumab plus MTX. Conclusion These results indicate that targeted blockade of IL-6 signaling is a highly efficacious and promising means of decreasing disease activity in RA.

Objective To identify disease characteristics leading to progression of joint damage in patients with early rheumatoid arthritis (RA) treated with methotrexate (MTX) versus those treated with infliximab plus MTX. Methods Patients who had not previously been treated with MTX with active RA were randomly assigned to receive escalating doses of MTX up to 20 mg/week plus placebo or infliximab at weeks 0, 2, and 6, and every 8 weeks thereafter through week 46. Radiographic joint damage was assessed using the modified Sharp/van der Heijde score (SHS). The relationship between disease activity measures at baseline and week 14, as well as those averaged over time, were examined in relation to the change in SHS from baseline through week 54. Results C-reactive protein (CRP) levels, erythrocyte sedimentation rate (ESR), and swollen joint count were associated with greater joint damage progression in the MTX-only group, while none of these parameters was associated with progression in the infliximab plus MTX group. Mean changes in SHS among patients in the highest CRP (≥3 mg/dl) and ESR (≥52 mm/hour) tertiles in the MTX-only group were 5.62 and 5.89, respectively, compared with 0.73 and 1.12 in the infliximab plus MTX group (P < 0.001). Patients with greater joint damage at baseline (SHS ≥10.5) showed less progression with infliximab plus MTX compared with MTX alone (−0.39 versus 4.11; P < 0.001). Patients receiving MTX alone who had persistently active disease at week 14 showed greater radiographic progression of joint damage than those taking MTX plus infliximab. Conclusion High CRP level, high ESR, or persistent disease activity was associated with greater radiographic progression in the group taking MTX alone, while little radiographic progression was seen in patients receiving both MTX and infliximab, regardless of the abnormal levels of these traditional predictors.

Objective Several composite scores are available to assess the activity of rheumatoid arthritis (RA). Criteria for remission and active RA based on these continuous scores are important for use in clinical practice and clinical trials. We aimed to reevaluate or to define such criteria for the Disease Activity Score in 28 joints (DAS28) and the Simplified Disease Activity Index (SDAI). Methods We sampled patient profiles from an observational RA database that included clinical and laboratory variables. Thirty-five rheumatology experts classified these profiles into 1 of 4 categories: remission, low, moderate, or high disease activity. Cutoff values were estimated by mapping scores on the DAS28 and SDAI to these ratings, and analyses of agreement (kappa statistics) and a diagnostic testing approach (receiver operating characteristic curves) were used to validate the estimates. The final criteria were validated using 2 observational cohorts (a routine cohort of 767 patients and an inception cohort of 91 patients). Results Results from the 3 analyses were very similar and were integrated. The criteria for separating remission, low, moderate, and high disease activity based on the SDAI were scores of 3.3, 11, and 26, respectively; those based on the DAS28 were scores of 2.4, 3.6, 5.5, respectively. In the routine cohort, these cutoff values showed substantial agreement (weighed κ = 0.70) and discriminated between groups of patients with clearly different functional capacities (P < 0.001). In the inception cohort, these cutoff scores differentiated responders (those with a 20% response on the American College of Rheumatology improvement criteria) from nonresponders (P < 0.01), as well as patients with and without radiologic progression (P < 0.05). Conclusion New criteria for levels of RA disease activity were determined and internally validated. These criteria, which are based on current and explicit expert judgment, are valuable in this era of rapidly advancing therapeutic approaches.

Objective Leflunomide, a potent disease-modifying antirheumatic drug of the isoxazole class, exhibits antiinflammatory, antiproliferative, and immunosuppressive effects by largely unknown mechanisms, although alterations of pyrimidine synthesis have been proposed. Successful immune responsiveness requires T cell activation by interaction with antigen-presenting cells (APCs), and integrin activation and formation of an immunologic synapse (IS). In this study, we evaluated the impact of the active leflunomide metabolite teriflunomide on T cell integrin activation, evolution of the IS, and antigen-specific formation of stable T cell/APC conjugates. Methods Effects of pharmacologic concentrations of teriflunomide on CD3/CD28- and lymphocyte function–associated antigen 1–induced signal transduction and activation of primary human T cells were investigated. Furthermore, T cells were stimulated with superantigen- and antigen-pulsed APCs to study relocalization of molecules to the IS and T cell/APC conjugate formation. Results Teriflunomide inhibited T cell receptor (TCR)/CD3–mediated calcium mobilization, but other critical T cell signaling events, including activation of MAPK and NF-κB, remained unaltered. In contrast, inhibition of TCR/CD3-triggered β1,2 integrin avidity and integrin-mediated costimulation (outside-in signaling) by teriflunomide revealed a striking interference with integrin function that was independent of altered pyrimidine synthesis. Moreover, teriflunomide abolished molecule relocalization to the IS and induction of T cell/APC conjugates. Conclusion These data show that the active metabolite of leflunomide prevents the interaction of T cells with APCs to form an IS. Since IS formation is crucial for eliciting an immune response, this novel mechanism could underlie the beneficial effects of leflunomide in immune-mediated disorders such as rheumatoid arthritis.

Objective: To validate the International Classification of Functioning, Disability and Health (ICF) Comprehensive Core Set for Rheumatoid Arthritis (RA) from the patient perspective. Methods: Patients with RA were interviewed about their problems in daily functioning. Interviews were tape recorded and transcribed verbatim. Interview texts were divided into meaning units. The concepts contained in these meaning units were linked to the ICF according to 10 established linking rules. Of the transcribed data, 15% were analyzed and linked by a second health professional. The degree of agreement was calculated using the kappa statistic. Results: Twenty-one patients were interviewed. Two hundred twenty different concepts contained in 367 meaning units were identified in the qualitative analysis of the interviews and linked to 109 second-level ICF categories. Of the 76 second-level categories from the ICF RA Core Set, 63 (83%) were also found in the interviews. Twenty-five second-level categories, which are not part of the current ICF RA Core Set, were identified in the interviews. The result of the kappa statistic for agreement was 0.62 (95% boot-strapped confidence interval 0.59-0.66). Conclusion: The validity of the ICF RA Core Set was supported by the perspective of individual patients. However, some additional issues raised in this study but not covered in the current ICF RA Core Set need to be investigated.

Objective To assess the relationship between inflammation and joint destruction in rheumatoid arthritis (RA) patients who have not responded clinically to treatment. Methods Changes from baseline to week 54 in clinical variables and measures of radiographic progression were compared between patients who received infliximab (3 mg/kg or 10 mg/kg every 4 or 8 weeks) plus methotrexate (MTX) and those who received MTX plus placebo in the Anti–Tumor Necrosis Factor Trial in RA with Concomitant Therapy trial. Results At week 54, patients who did not show 20% improvement by American College of Rheumatology criteria (ACR20 nonresponders) while receiving infliximab plus MTX exhibited mild but statistically significant improvement in clinical variables, including the 28-joint Disease Activity Score (DAS28) (P < 0.001), tender joint count (P = 0.014), swollen joint count (P < 0.001), and C-reactive protein (CRP) level (P < 0.001). Whereas the clinical and CRP changes among ACR20 nonresponders to infliximab plus MTX were small and much lower than among ACR20 responders to this treatment, radiographic progression among ACR20 nonresponders to infliximab plus MTX was significantly inhibited (P < 0.001) compared with ACR20 nonresponders to MTX plus placebo. Radiographic progression was much greater in patients receiving MTX plus placebo than in patients receiving infliximab plus MTX, irrespective of ACR response status (mean change in modified Sharp/van der Heijde score 6.0 in ACR20 responders and 7.2 in ACR20 nonresponders in the MTX plus placebo–treated group, versus 0.1 in ACR20 responders and 1.2 in ACR20 nonresponders in the infliximab plus MTX–treated group). Furthermore, among patients who were ACR20 nonresponders through week 54, patients who were DAS nonresponders at weeks 30 and 54, and patients without any improvement in individual clinical variables, those receiving infliximab plus MTX still demonstrated inhibition of structural damage that was statistically significant compared with inhibition in patients who received MTX plus placebo (P < 0.05 to P < 0.001). Conclusion Even in patients without clinical improvement, treatment with infliximab plus MTX provided significant benefit with regard to the destructive process, suggesting that in such patients these 2 measures of disease are dissociated.

To compare the content of clinical, occupation-based instruments that are used in adult rheumatology and musculoskeletal rehabilitation in occupational therapy based on the International Classification of Functioning, Disability and Health (ICF).Clinical instruments of occupational performance and occupation in adult rehabilitation and rheumatology were identified in a literature search. All items of these instruments were linked to the ICF categories according to 10 linking rules. On the basis of the linking, the content of these instruments was compared and the relationship between the capacity and performance component explored.The following 7 instruments were identified: the Canadian Occupational Performance Measure, the Assessment of Motor and Process Skills, the Sequential Occupational Dexterity Assessment, the Jebson Taylor Hand Function Test, the Moberg Picking Up Test, the Button Test, and the Functional Dexterity Test. The items of the 7 instruments were linked to 53 different ICF categories. Five items could not be linked to the ICF. The areas covered by the 7 occupation-based instruments differ importantly: The main focus of all 7 instruments is on the ICF component activities and participation. Body functions are covered by 2 instruments. Two instruments were linked to 1 single ICF category only.Clinicians and researchers who need to select an occupation-based instrument must be aware of the areas that are covered by this instrument and the potential areas that are not covered at all.

Improved standards for the evaluation of therapeutic interventions in systemic lupus erythematosus (SLE) are needed. The purpose of this study by a committee of the American College of Rheumatology was to define clinically meaningful improvement, no change, or worsening in 6 existing clinical measures of SLE disease activity. This represents an important step in a disease in which some organ symptoms get better and others get worse. It is intended to help investigators develop sample size estimates based on meaningful effect sizes and to gauge the clinical relevance of any observed change in disease activity.Medical records from 310 patients drawn from 3 sources were abstracted into a standard format. Each vignette included clinical and laboratory data obtained during 2-3 visits. Ratings on the following 6 instruments were obtained for the same patients during the visit or retrospectively: the British Isles Lupus Assessment Group (BILAG), the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), the revised Systemic Lupus Activity Measure (SLAM-R), the European Consensus Lupus Activity Measure (ECLAM), the Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA)-SLEDAI, and the Responder Index for Lupus Erythematosus (RIFLE). From this pool of vignettes, 5 common vignettes and 10 randomly selected vignettes were rated through a secure Web site by 88 international experts on SLE. The experts, who were blinded to the activity measure scores, were asked to rate each patient's clinical condition as worsened, improved, or unchanged relative to the previous visit. These ratings were transformed by statistical procedures into performance characteristic curves that related a change on a particular SLE activity measure to the physicians' agreement on whether that patient had worsened, improved, or remained the same clinically. These were discussed by the committee members, who were blinded to the actual instrument used. The committee then voted on what level of expert agreement would be used to determine clinically meaningful change.The physician ratings on the 5 common vignettes revealed considerable variation in their clinical appraisals. Overall, the 6 SLE activity measures showed excellent separation of clinical conditions as being worsened, improved, or the same. The committee voted to take 70% agreement by physicians as the point on the performance characteristic curves at which meaningful change in a score could be identified. For each instrument, we computed the units of change required to indicate improvement or worsening.To our knowledge, these are the first response criteria in any disease where a clinically relevant change has been determined a priori and mapped to standardized measures. This criterion should aid the clinical evaluation of new therapies, improve comparability between trials, and facilitate innovative trial designs.

Objective To investigate the safety of therapeutic tumor necrosis factor α (TNFα) blockade in patients with systemic lupus erythematosus (SLE), in whom this proinflammatory cytokine is significantly increased and may be involved in the disease pathogenesis. Methods In an open-label study, 6 patients with moderately active SLE (4 with nephritis and 3 with arthritis refractory to other therapies) were given 4 300-mg doses of infliximab, a chimeric anti-TNFα antibody, in addition to immunosuppression with azathioprine or methotrexate. Results The only significant adverse events observed were urinary tract infection in 3 patients, 1 of which was accompanied by Escherichia coli bacteremia, and a prolonged febrile episode of putatively viral origin in 1 of them. These patients had similar infectious conditions in the past. In none of the patients was it necessary to terminate the treatment prematurely. Levels of antibodies to double-stranded DNA and cardiolipin increased in 4 patients each, but this was not associated with a decrease in serum complement levels, with vascular events, or with flares. In contrast, disease activity declined during therapy. All 3 patients with joint involvement experienced remission of arthritis, which relapsed 8–11 weeks after the last infliximab infusion. In the 4 patients with lupus nephritis, proteinuria decreased significantly within 1 week after initiation of therapy and was diminished by ≥60% within 8 weeks, remaining at low levels until the end of the observation period (at least several months). Conclusion Infliximab did not lead to adverse events related to an increase in SLE activity, although autoantibodies to double-stranded DNA and cardiolipin increased, as expected. This finding, coupled with the clinical improvement in the inflammatory manifestations of the disease, indicates that further study in larger controlled trials is warranted.

To find evidence for the presence of endothelial precursor cells, which can induce new vessel formation, in the synovial tissue of patients with rheumatoid arthritis (RA) and osteoarthritis (OA).Precursor cells in the synovial tissue of 18 RA patients and 15 OA patients were identified by immunohistochemistry, morphometric analysis, and confocal laser scanning microscopy using the following phenotype markers: CD31, CD34, STRO-1, CD133, vascular endothelial growth factor receptor 2 (VEGFR-2), and CXCR4. The presence of CD31, CD34, CD133, VEGFR-2, and CXCR4 messenger RNA in the synovial tissue was determined by reverse transcriptase-polymerase chain reaction, and the message for CXCR4 was quantified by an RNase protection assay.A population of cells that expressed CD34 on their surface but lacked the endothelial cell marker CD31 was found in the synovial tissue of RA and OA patients. CD34+,CD31- cells were detected in close proximity to STRO-1+ and CD133+ cells, forming cell clusters in the sublining area of the synovial membrane. Within these cell clusters, CD34+,CD31- precursor cells were located on the inside surrounded by STRO-1+ cells and with CD133+ cells on the outside. CD34+ precursor cells in the cell layer expressed high levels of the chemokine receptor CXCR4, while VEGFR-2 was expressed on CD34+ and CD133+ cells, and alpha-smooth muscle actin was expressed on STRO-1+ cells.The presence of endothelial precursor cells in the synovial tissue of RA and OA patients provides evidence for vasculogenesis induced by precursor cells that arise in situ or from circulating progenitors.

To investigate the role of tumor necrosis factor (TNF) in systemic bone loss of chronic inflammatory conditions, such as rheumatoid arthritis (RA), and to address the therapeutic potential of osteoclast blockade.We investigated systemic bone changes in human TNF transgenic (hTNFtg) mice, which spontaneously developed severe inflammatory arthritis.Osteodensitometry revealed a significant decrease in trabecular bone mineral density (BMD) (-37%) in hTNFtg mice, and histomorphometry revealed a dramatic loss of bone volume (-85%) compared with wild-type controls. Osteoclast-covered bone surface and serum levels of deoxypyridinoline crosslinks were significantly elevated, suggesting increased osteoclast-mediated bone resorption in hTNFtg mice. Osteoprotegerin (OPG) completely blocked TNF-mediated bone loss by increasing BMD (+89%) and bone volume (+647%). Most strikingly, formation of primary spongiosa was dramatically increased (+563%) in hTNFtg mice after OPG treatment. Osteoclast-covered bone surface and serum levels of deoxypyridinoline crosslinks were significantly decreased by OPG, suggesting effective blockade of osteoclast-mediated bone resorption. OPG did not influence levels of hTNF, TNF receptor I (TNFRI), interleukin-1beta (IL-1beta), and IL-6. However, OPG decreased bone formation parameters (osteoblast-covered bone surface and serum osteocalcin levels), which were elevated in hTNFtg mice. In contrast to OPG, bisphosphonates and anti-TNF treatment did not affect generalized bone loss in hTNFtg mice. Anti-TNF, however, did not affect levels of TNF and TNFRI at the concentrations tested. These data indicate that generalized bone loss due to increased TNF can be blocked by OPG.OPG may represent a potent tool for preventing generalized loss of bone mass in chronic inflammatory disorders, especially RA.

To study the effects of osteoclast-targeted therapies, such as osteoprotegerin (OPG) and pamidronate, on joint inflammation and bone destruction using a tumor necrosis factor alpha (TNF alpha)-transgenic mouse model.Mice were placed into 5 groups that received either OPG, pamidronate, a combination of both agents, infliximab as a positive control, or phosphate buffered saline as a negative control. Treatment was initiated at the onset of arthritis, continued over 6 weeks, and thereafter, the clinical, radiologic, and histologic outcomes were assessed.A significant improvement in clinical symptoms, as assessed by the reduction of paw swelling, was only found in the infliximab group, whereas all other treatment groups failed to show significant improvement. However, when assessing structural damage with radiographic analysis, a significant retardation of joint damage was evident in animals treated with OPG (55% reduction of erosions), pamidronate (50% reduction of erosions) the combination therapy of OPG and pamidronate (64% reduction of erosions), and with infliximab (66% reduction of erosions). Confirming these data, quantitative histologic analysis revealed a significant reduction in the size of bone erosions in all treatment groups (OPG 56%, pamidronate 53%, OPG and pamidronate 81%, and infliximab 46%) compared with the control group. Furthermore, a significant reduction of osteoclast numbers was seen in animals treated with OPG alone or in combination with pamidronate as well as in animals treated with infliximab.These data suggest that OPG alone or in combination with bisphosphonates is an effective therapeutic tool for the prevention of TNF alpha-mediated destruction of bone by reducing the number of bone-resorbing cells in the inflammatory tissue.

Objective To compare and investigate antihistone and antichromatin antibody responses as well as clinical variables in patients with systemic lupus erythematosus (SLE) who were either positive (LEC+) or negative (LEC−) for the lupus erythematosus (LE) cell phenomenon. Methods The binding properties of LEC+ and LEC− SLE sera to chromatin-associated nuclear antigens (histones H1, H2A, H2B, H3, H4; complexes of H2A–H2B, [H2A–H2B]–DNA, H1–DNA; total and H1-stripped chromatin; native and denatured DNA) were investigated. In addition, sera from patients with drug-induced lupus (by procainamide, hydralazine, or quinidine), as well as from patients with rheumatoid arthritis and osteoarthritis, were assessed. Enzyme-linked immunosorbent assay was used to detect specific antibody binding. Results Mirroring the important role of histone H1 in the formation of LE cells, anti–histone H1 reactivity was 8-fold higher in LEC+ sera than in LEC− sera. In addition, reactivities to most of the other antigens tested, i.e., other histones and histone–DNA complexes as well as chromatin and DNA, were significantly higher in LEC+ sera than in LEC− sera. All but 1 serum sample from the patients with drug-induced lupus were negative for LE cell formation as well as for anti–histone H1 reactivity, but displayed high antibody reactivities to histone–DNA complexes, including chromatin. Sera from patients with rheumatoid arthritis and osteoarthritis did not show significant binding to these antigens. When comparing the clinical features of LEC+ and LEC− SLE patients, severe organ involvement, including nephritis and central nervous system involvement, was common in the LEC+ group, but rare in the LEC− group. Conclusion A positive LE cell phenomenon not only correlated with the presence of high anti–histone H1 antibody levels in SLE, but also indicated serologically and clinically active disease with major organ involvement.