Showing papers in "Arthritis & Rheumatism in 2005"

Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial.

Abstract: Objective. Several treatment strategies have proven value in the amelioration of rheumatoid arthritis (RA), but the optimal strategy for preventing long-term joint damage and functional decline is unclear. We undertook this study to compare clinical and radiographic outcomes of 4 different treatment strategies, with intense monitoring in all patients. Methods. In a multicenter, randomized clinical trial, 508 patients were allocated to 1 of 4 treatment strategies: sequential disease-modifying antirheumatic drug monotherapy (group 1), step-up combination therapy (group 2), initial combination therapy with tapered high-dose prednisone (group 3), and initial combination therapy with the tumor necrosis factor antagonist infliximab (group 4). Treatment adjustments were made every 3 months in an effort to obtain low disease activity (a Disease Activity Score in 44 joints of <2.4). Results. Initial combination therapy including either prednisone (group 3) or infliximab (group 4) resulted in earlier functional improvement than did sequential monotherapy (group 1) and step-up combination therapy (group 2), with mean scores at 3 months on the Dutch version of the Health Assessment Questionnaire (D-HAQ) of 1.0 in groups 1 and 2 and 0.6 in groups 3 and 4 (P < 0.001). After 1 year, mean D-HAQ scores were 0.7 in groups 1 and 2 and 0.5 in groups 3 and 4( P 0.009). The median increases in total Sharp/Van der Heijde radiographic joint score were 2.0, 2.5, 1.0, and 0.5 in groups 1–4, respectively (P < 0.001). There were no significant differences in the number of adverse events and withdrawals between the groups. Conclusion. In patients with early RA, initial combination therapy including either prednisone or infliximab resulted in earlier functional improvement and less radiographic damage after 1 year than did sequential monotherapy or step-up combination therapy.

Comparison of human stem cells derived from various mesenchymal tissues: Superiority of synovium as a cell source

Abstract: Objective To compare the properties of human mesenchymal stem cells (MSCs) isolated from bone marrow, synovium, periosteum, skeletal muscle, and adipose tissue. Methods Human mesenchymal tissues were obtained from 8 donors during knee surgery for ligament injury. After collagenase digestion or gradient-density separation, nucleated cells were plated at an appropriate density for expansion at the maximum rate without colony-to-colony contact. Yield, expandability, differentiation potential, and epitope profile were compared among MSCs from the 5 different tissue sources. Results Colony number per 103 nucleated cells was lower, and cell number per colony was higher, in bone marrow than in other mesenchymal tissues. When the cells were replated at low density every 14 days, bone marrow–, synovium-, and periosteum-derived cells retained their proliferation ability even at passage 10. In chondrogenesis studies in which the cells were pelleted and cultured in vitro, pellets from bone marrow–, synovium-, and periosteum-derived cells were shown to be larger and stained more extensively for cartilage matrix. Synovium-derived cells, in particular, had the greatest ability for chondrogenesis. In adipogenesis experiments, the frequency of oil red O–positive colonies was highest in synovium- and adipose tissue–derived cells. In studies of osteogenesis, the rate of alizarin red–positive colonies was highest in bone marrow–, synovium-, and periosteum-derived cells. For epitope profiling, 15 surface antigens were measured. Most appeared to have similar epitope profiles irrespective of cell source. Conclusion Our findings indicate that there are significant differences in MSC properties according to tissue source, beyond donor and experimental variation. Superiority of synovium as a potential source of MSCs for clinical applications was demonstrated.

Cardiovascular death in rheumatoid arthritis: a population-based study.

Abstract: Objective To determine whether systemic inflammation confers any additional risk for cardiovascular death among patients with rheumatoid arthritis (RA), after adjusting for traditional cardiovascular risk factors and comorbidities. Methods Using the population-based data resources of the Rochester Epidemiology Project, we assembled an incidence cohort of all Rochester, Minnesota residents ages ≥18 years who first fulfilled the American College of Rheumatology 1987 criteria for RA between January 1, 1955 and January 1, 1995. All subjects were followed up longitudinally through their complete (inpatient, outpatient) medical records, beginning at age 18 years and continuing until death, migration, or January 1, 2001. Detailed information on the occurrence of various cardiovascular risk factors (personal history of coronary heart disease [CHD], congestive heart failure, smoking, hypertension, dyslipidemia, body mass index [BMI], diabetes mellitus, menopausal status) as well as indicators of systemic inflammation and RA disease severity (rheumatoid factor [RF] seropositivity, erythrocyte sedimentation rate [ESR], joint swelling, radiographic changes, RA nodules, RA complications, RA treatments, disease duration) and comorbidities were collected on all subjects. Causes of death were ascertained from death certificates and medical records. Cox regression models were used to estimate the independent predictors of cardiovascular death. Results This inception cohort comprised a total of 603 RA patients whose mean age was 58 years, of whom 73% were women. During a mean followup of 15 years, 354 patients died and cardiovascular disease was the primary cause of death in 176 patients. Personal history of CHD, smoking, hypertension, low BMI, and diabetes mellitus, as well as comorbidities, including peripheral vascular disease, cerebrovascular disease, chronic pulmonary disease, dementia, ulcers, malignancies, renal disease, liver disease, and history of alcoholism, were all significant risk factors for cardiovascular death (P < 0.01 for each). Multivariable Cox regression analyses, controlled for cardiovascular risk factors and comorbidities, revealed that the risk of cardiovascular death was significantly higher among RA patients with at least 3 ESR values of ≥60 mm/hour (hazard ratio [HR] 2.03, 95% confidence interval [95% CI] 1.45–2.83), RA vasculitis (HR 2.41, 95% CI 1.00–5.81), and RA lung disease (HR 2.32, 95% CI 1.11–4.84). Conclusion These results indicate that markers of systemic inflammation confer a statistically significant additional risk for cardiovascular death among patients with RA, even after controlling for traditional cardiovascular risk factors and comorbidities.

Increased unrecognized coronary heart disease and sudden deaths in rheumatoid arthritis: A population-based cohort study

Abstract: Objective To examine the risk of clinical coronary heart disease (CHD) in patients with rheumatoid arthritis (RA) compared with age- and sex-matched non-RA subjects, and to determine whether RA is a risk factor for CHD after accounting for traditional CHD risk factors. Methods We assembled a population-based incidence cohort of 603 Rochester, Minnesota residents ages ≥18 years who first fulfilled the American College of Rheumatology (ACR) 1987 criteria for RA between January 1, 1955 and January 1, 1995, and 603 age- and sex-matched non-RA subjects. All subjects were followed up through their complete inpatient and outpatient medical records, beginning at age 18 years until death, migration, or January 1, 2001. Data were collected on CHD events and traditional CHD risk factors (diabetes mellitus, hypertension, dyslipidemia, body mass index, smoking) using established diagnostic criteria. CHD events included hospitalized myocardial infarction (MI), unrecognized MI, coronary revascularization procedures, angina pectoris, and sudden CHD deaths. Conditional logistic regression and Cox regression models were used to estimate the risk of CHD associated with RA, both prior to and following RA diagnosis, after adjusting for CHD risk factors. Results During the 2-year period immediately prior to fulfillment of the ACR criteria, RA patients were significantly more likely to have been hospitalized for acute MI (odds ratio [OR] 3.17, 95% confidence interval [95% CI] 1.16–8.68) or to have experienced unrecognized MIs (OR 5.86, 95% CI 1.29–26.64), and less likely to have a history of angina pectoris (OR 0.58, 95% CI 0.34–0.99) compared with non-RA subjects. After the RA incidence date, RA patients were twice as likely to experience unrecognized MIs (hazard ratio [HR] 2.13, 95% CI 1.13–4.03) and sudden deaths (HR 1.94, 95% CI 1.06–3.55) and less likely to undergo coronary artery bypass grafting (HR 0.36, 95% CI 0.16–0.80) compared with non-RA subjects. Adjustment for the CHD risk factors did not substantially change the risk estimates. Conclusion Patients with RA have a significantly higher risk of CHD when compared with non-RA subjects. RA patients are less likely to report symptoms of angina and more likely to experience unrecognized MI and sudden cardiac death. The risk of CHD in RA patients precedes the ACR criteria–based diagnosis of RA, and the risk cannot be explained by an increased incidence of traditional CHD risk factors in RA patients.

Adalimumab for the treatment of patients with moderately to severely active psoriatic arthritis: Results of a double‐blind, randomized, placebo‐controlled trial

Abstract: Objective Adalimumab, a fully human, anti–tumor necrosis factor monoclonal antibody, was evaluated for its safety and efficacy compared with placebo in the treatment of active psoriatic arthritis (PsA). Methods Patients with moderately to severely active PsA and a history of inadequate response to nonsteroidal antiinflammatory drugs were randomized to receive 40 mg adalimumab or placebo subcutaneously every other week for 24 weeks. Study visits were at baseline, weeks 2 and 4, and every 4 weeks thereafter. The primary efficacy end points were the American College of Rheumatology 20% improvement (ACR20) response at week 12 and the change in the modified total Sharp score of structural damage at week 24. Secondary end points were measures of joint disease, disability, and quality of life in all patients, as well as the severity of skin disease in those patients with psoriasis involving at least 3% of body surface area. Results At week 12, 58% of the adalimumab-treated patients (87 of 151) achieved an ACR20 response, compared with 14% of the placebo-treated patients (23 of 162) (P < 0.001). At week 24, similar ACR20 response rates were maintained and the mean change in the modified total Sharp score was −0.2 in patients receiving adalimumab and 1.0 in those receiving placebo (P < 0.001). Among the 69 adalimumab-treated patients evaluated with the Psoriasis Area and Severity Index (PASI), 59% achieved a 75% PASI improvement response at 24 weeks, compared with 1% of the 69 placebo-treated patients evaluated (P < 0.001). Disability and quality of life measures were also significantly improved with adalimumab treatment compared with placebo. Adalimumab was generally safe and well-tolerated. Conclusion Adalimumab significantly improved joint and skin manifestations, inhibited structural changes on radiographs, lessened disability due to joint damage, and improved quality of life in patients with moderately to severely active PsA.

Efficacy and safety of infliximab in patients with ankylosing spondylitis: results of a randomized, placebo-controlled trial (ASSERT).

Abstract: Objective The signs and symptoms of ankylosing spondylitis (AS) respond inadequately to nonsteroidal antiinflammatory drugs, corticosteroids, and disease-modifying antirheumatic drugs in quite a number of patients. Tumor necrosis factor inhibitors have demonstrated success in reducing AS disease activity in a limited number of clinical trials. The objective of this multicenter, randomized, placebo-controlled study was to evaluate the efficacy and safety of infliximab in patients with AS. Methods Patients were randomly assigned to receive infusions of placebo or 5 mg/kg infliximab at weeks 0, 2, 6, 12, and 18. Efficacy was assessed using the ASsessment in Ankylosing Spondylitis (ASAS) International Working Group criteria, the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), night pain, patient's global assessment, the Bath Ankylosing Spondylitis Functional Index (BASFI), the Bath Ankylosing Spondylitis Metrology Index (BASMI), chest expansion, the Mander enthesis index, the total swollen joint index, the C-reactive protein level, and the Short Form 36 (SF-36) health survey questionnaire. The primary end point in this study was the proportion of patients with a 20% improvement response according to the ASAS International Working Group criteria (ASAS20 responders) at week 24. Results Of the 357 patients screened, 201 were assigned to receive 5 mg/kg infliximab and 78 were assigned to receive placebo. After 24 weeks, 61.2% of patients in the infliximab group were ASAS20 responders compared with 19.2% of patients in the placebo group (P < 0.001). Clinical benefit was observed in patients receiving infliximab as early as week 2 and was maintained over the 24-week study period. Patients receiving infliximab also showed significant improvements in the BASDAI, BASFI, BASMI, chest expansion, and physical component summary score of the SF-36. Adverse events were reported by 82.2% of patients receiving infliximab and by 72.0% of patients receiving placebo; however, most adverse events in both treatment groups were mild or moderate in severity. Conclusion Infliximab was well tolerated and effective in a large cohort of patients with AS during a 24-week study period.

Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody–associated vasculitis

Abstract: Objective. Standard therapy for antineutrophil cytoplasmic antibody-associated systemic vasculitis (AASV) with cyclophosphamide (CYC) and prednisolone is limited by toxicity. This unblinded, prospective, randomized, controlled trial was undertaken to determine whether methotrexate (MTX) could replace CYC in the early treatment of AASV. Methods. Patients with newly diagnosed AASV, with serum creatinine levels <150 mu moles/liter, and without critical organ manifestations of disease were randomized to receive either standard oral CYC, 2 mg/kg/day or oral MTX, 20-25 mg/week; both groups received the same prednisolone regimen. All drug treatments were gradually tapered and withdrawn by 12 months. Followup continued to 18 months. The primary end point was the remission rate at 6 months (noninferiority testing). Results. One hundred patients were recruited from 26 European centers; 51 patients were randomized to the MTX group and 49 to the CYC group. At 6 months, the remission rate in patients treated with MTX (89.8%) was not inferior to that in patients treated with CYC (93.5%) (P = 0.041). In the MTX group, remission was delayed among patients with more extensive disease (P = 0.04) or pulmonary involvement (P = 0.03). Relapse rates at 18 months were 69.5% in the MTX group and 46.5% in the CYC group; the median time from remission to relapse was 13 months and 15 months, respectively (P = 0.023, log rank test). Two patients from each group died. Adverse events (mean 0.87 episodes/patient) included leukopenia, which was less frequent in the MTX versus the CYC group (P = 0.012), and liver dysfunction, which was more frequent in the MTX group (P = 0.036). Conclusion. MTX can replace CYC for initial treatment of early AASV. The MTX regimen used in the present study was less effective for induction of remission in patients with extensive disease and pulmonary involvement and was associated with more relapses than the CYC regimen after termination of treatment. The high relapse rates in both treatment arms support the practice of continuation of immunosuppressive treatment beyond 12 months.

Early detection of pulmonary arterial hypertension in systemic sclerosis: a French nationwide prospective multicenter study.

Abstract: Objective Screening allows for early management of pulmonary arterial hypertension (PAH), a severe complication of systemic sclerosis (SSc). Since no consensus has been reached on the method and criteria for optimal screening, we sought to develop an algorithm based on symptoms, Doppler echocardiography, and right heart catheterization (RHC) for application to a nationwide multicenter SSc population in France. Methods This prospective study was conducted from September 2002 to July 2003 by experts at 21 SSc centers. At each center, SSc patients without severe pulmonary function abnormalities underwent Doppler echocardiography by an experienced cardiologist. Patients with a peak velocity of tricuspid regurgitation (VTR) of >3 meters/second or 2.5–3 meters/second with unexplained dyspnea were asked to undergo RHC to confirm PAH according to international guidelines. Results Of the 599 patients analyzed, 29 had known PAH and 33 had suspected PAH, based on Doppler echocardiography, and underwent RHC. Of these 33, 18 were found to have PAH, 3 had left ventricular dysfunction, and 12 had no PAH. Newly diagnosed cases of PAH were of mild severity (mean ± SD pulmonary artery pressure [mPAP] 30 ± 9 mm Hg, mean ± SD total pulmonary resistance [TPR] 524 ± 382 dynes × second/cm5). Hemodynamic findings in patients with known PAH were mPAP 49 ± 17 mm Hg and TPR 1,007 ± 615 dynes × second/cm5. The estimate of PAH prevalence was 7.85% (95% confidence interval 5.70–10.00). Conclusion This screening algorithm, based on dyspnea, Doppler echocardiographic evaluation of VTR, and RHC, enabled early detection of PAH at a mild stage. Whether mild PAH will evolve to severe PAH in reported cases and whether this early diagnosis translates into improved prognosis for patients with mild PAH will be evaluated in the ongoing 3-year followup of this cohort.

Secondary gait changes in patients with medial compartment knee osteoarthritis: Increased load at the ankle, knee, and hip during walking

Abstract: Objective This study tested the hypothesis that gait changes related to knee osteoarthritis (OA) of varied severity are associated with increased loads at the ankle, knee, and hip. Methods Forty-two patients with bilateral medial compartment knee OA and 42 control subjects matched for sex, age, height, and mass were studied. Nineteen patients had Kellgren/Lawrence (K/L) radiographic severity grades of 1 or 2, and 23 patients had K/L grades of 3 or 4. Three-dimensional kinematics and kinetics were measured in the hip, knee, and ankle while the subjects walked at a self-selected speed. Results Patients with more severe knee OA had greater first peak knee adduction moments than their matched control subjects (P = 0.039) and than patients with less severe knee OA (P < 0.001). All patients with knee OA made initial contact with the ground with the knee in a more extended position than that exhibited by control subjects. An increased axial loading rate was present in all joints of the lower extremity. Patients with more severe knee OA had lower hip adduction moments compared with their matched control subjects. Conclusion The secondary gait changes observed among patients with knee OA reflect a potential strategy to shift the body's weight more rapidly from the contralateral limb to the support limb, which appears to be successful in reducing the load at the knee in only patients with less severe knee OA. The increased loading rate in the lower extremity joints may lead to a faster progression of existing OA and to the onset of OA at joints adjacent to the knee. Interventions for knee OA should therefore be assessed for their effects on the mechanics of all joints of the lower extremity.

Infections in patients with rheumatoid arthritis treated with biologic agents.

Abstract: Objective To estimate the incidence rates of serious and nonserious infections in patients with rheumatoid arthritis (RA) who start treatment with a biologic agent, and to compare these rates with those in patients with RA who receive conventional treatment Methods Patients enrolled in the German biologics register between May 2001 and September 2003 were included Treating rheumatologists assessed adverse events and serious adverse events All adverse events and serious adverse events experienced within 12 months after study entry were analyzed Propensity score methods were applied to estimate which part of a rate increase was likely to be attributable to differences in patient characteristics Results Data were available for 512 patients receiving etanercept, 346 patients receiving infliximab, 70 patients receiving anakinra, and 601 control patients treated with disease-modifying antirheumatic drugs The total number of adverse events per 100 patient-years was 226 (95% confidence interval [95% CI] 187–272) among patients receiving etanercept, 283 (95% CI 231–347) among patients receiving infliximab, and 68 (95% CI 50–94) among controls (P < 00001) Significant differences in the rate of serious adverse events were also observed For patients receiving etanercept, those receiving infliximab, and controls, the total numbers of serious adverse events per 100 patient-years were 64 (95% CI 45–91), 62 (95% CI 40–95), and 23 (95% CI 13–39), respectively (P = 00016) After adjusting for differences in the case patient mix, the relative risks of serious adverse events were 22 (95% CI 09–54) for patients receiving etanercept and 21 (95% CI 08–55) for patients receiving infliximab, compared with controls Conclusion Patients treated with biologic agents have a higher a priori risk of infection However, our data suggest that this risk is increased by treatment with tumor necrosis factor inhibitors

Nonsteroidal antiinflammatory drugs reduce radiographic progression in patients with ankylosing spondylitis: A randomized clinical trial

Abstract: OBJECTIVE: A 2-year randomized controlled trial was performed to test the hypothesis that long-term, continuous treatment with nonsteroidal antiinflammatory drugs (NSAIDs), in comparison with NSAID treatment on demand only, influences radiographic progression in patients with ankylosing spondylitis (AS). METHODS: Patients with AS (n = 215), who had previously participated in a 6-week, randomized, double-blind clinical trial that compared celecoxib, ketoprofen, and placebo, were randomly allocated to receive either continuous treatment with NSAIDs or on-demand treatment with NSAIDs for a period of 2 years. All patients began treatment with celecoxib, at a starting dosage of 100 mg twice daily; patients could increase this dosage to 200 mg twice daily or could switch to another NSAID while maintaining the same treatment strategy. Structural changes were assessed by radiographs of the lumbar and cervical spine and scored according to the modified Stoke Ankylosing Spondylitis Spine Score by one observer who was blinded to the treatment strategy and temporal order of the radiographs. Statistical analyses included a between-group comparison of 1) radiographic progression scores (by Mann-Whitney U test), 2) time-averaged values of variables reflecting signs and symptoms of AS (by linear regression analysis), and 3) the frequency of reported site-specific adverse events (by chi-square test or Fisher's exact test, as appropriate). RESULTS: Complete sets of radiographs were available for 76 of the 111 patients in the continuous-treatment group and for 74 of the 104 patients in the on-demand group. The mean +/- SD scores for radiographic progression were 0.4 +/- 1.7 in the continuous-treatment group and 1.5 +/- 2.5 in the on-demand treatment group (P = 0.002). Parameters reflecting signs and symptoms were not statistically significantly different between groups. The between-group difference in radiographic progression did not disappear after adjusting for baseline values of radiographic damage or disease activity variables and for time-averaged values of disease activity variables, nor after input of missing data. Relevant adverse events tended to occur more frequently in the continuous-treatment group than in the on-demand group (for hypertension, 9% versus 3%; for abdominal pain, 11% versus 6%; for dyspepsia, 41% versus 38%), but the differences were not statistically significant. CONCLUSION: A strategy of continuous use of NSAIDs reduces radiographic progression in symptomatic patients with AS, without increasing toxicity substantially.

Effectiveness of recommendations to prevent reactivation of latent tuberculosis infection in patients treated with tumor necrosis factor antagonists.

Abstract: Objective. To investigate the impact of official recommendations regarding the management of latent tuberculosis (TB) infection on the rate of active TB in patients receiving treatment with tumor necrosis factor (TNF) antagonists. Methods. Data on active TB rates and on screening and treatment of latent TB infection were extracted from the BIOBADASER (Spanish Society of Rheumatology Database on Biologic Products), a registry of patients with rheumatic conditions treated with TNF antagonists. The rates of active TB among the BIOBADASER patients were compared with those in the background Spanish population, and BIOBADASER patients with rheumatoid arthritis (RA) were compared with a cohort of RA patients from the EMECAR (Morbidity and Clinical Expression of Rheumatoid Arthritis) study who were not treated with TNF antagonists and were followed up for 5 years. Results. Active TB developed in 34 patients, of whom 32 started taking TNF antagonists prior to the official recommendations on latent TB infection (preOR) and 2 began treatment after the recommendations were issued (post-OR). All cases of TB occurred during treatment with infliximab, and 28 of these patients had RA. Pre-OR, the active TB rate in BIOBADASER patients was 20.9-fold higher than in the background Spanish population, while RA patients in the BIOBADASER had rates 22.6- and 6.2-fold higher than the background and EMECAR populations, respectively. Post-OR, 324 patients with a tuberculin skin test result >5 mm and/or chest radiograph findings suggestive of past TB were treated for 9 months with isoniazid (INH). Post-OR, active TB rates among the BIOBADASER patients decreased by 78% (incidence risk ratio [IRR] 0.22, 95% confidence interval [95% CI] 0.03–0.88; P 0.008), while among RA patients in the BIOBADASER, the rate dropped by 83% and reached the EMECAR rate (IRR 1.0, 95% CI 0.02–8.2). There were no INH treatment– related hospitalizations or deaths. Conclusion. Strategies to treat latent TB infection that are tailored to the at-risk population can effectively and safely lessen the likelihood of active TB in patients treated with TNF antagonists.

Pregabalin for the treatment of fibromyalgia syndrome: results of a randomized, double-blind, placebo-controlled trial.

Abstract: Objective Fibromyalgia syndrome (FMS) is characterized by widespread musculoskeletal pain and lowered pain threshold. Other prominent symptoms include disordered sleep and fatigue. FMS affects an estimated 2% of the population, predominantly women. This trial was designed to evaluate the efficacy and safety of pregabalin, a novel α2-δ ligand, for treatment of symptoms associated with FMS. Methods This multicenter, double-blind, 8-week, randomized clinical trial compared the effects of placebo with those of 150, 300, and 450 mg/day pregabalin on pain, sleep, fatigue, and health-related quality of life in 529 patients with FMS. The primary outcome variable was the comparison of end point mean pain scores, derived from daily diary ratings of pain intensity, between each of the pregabalin treatment groups and the placebo group. Results Pregabalin at 450 mg/day significantly reduced the average severity of pain in the primary analysis compared with placebo (−0.93 on a 0–10 scale) (P ≤ 0.001), and significantly more patients in this group had ≥50% improvement in pain at the end point (29%, versus 13% in the placebo group; P = 0.003). Pregabalin at 300 and 450 mg/day was associated with significant improvements in sleep quality, fatigue, and global measures of change. Pregabalin at 450 mg/day improved several domains of health-related quality of life. Dizziness and somnolence were the most frequent adverse events. Rates of discontinuation due to adverse events were similar across all 4 treatment groups. Conclusion Pregabalin at 450 mg/day was efficacious for the treatment of FMS, reducing symptoms of pain, disturbed sleep, and fatigue compared with placebo. Pregabalin was well tolerated and improved global measures and health-related quality of life.

Activation of the interferon‐α pathway identifies a subgroup of systemic lupus erythematosus patients with distinct serologic features and active disease

Abstract: Objective Gene-expression studies have demonstrated increased expression of interferon (IFN)–inducible genes (IFIGs) in peripheral blood mononuclear cells (PBMCs) of many patients with systemic lupus erythematosus (SLE), with a predominant effect of type I IFN This study examined the hypothesis that increased disease severity and activity, as well as distinct autoantibody specificities, characterize SLE patients with activation of the type I IFN pathway Methods Freshly isolated PBMCs from 77 SLE patients, 22 disease controls, and 28 healthy donors were subjected to real-time polymerase chain reaction for 3 IFIGs that are preferentially induced by IFNα, and the data were used to derive IFNα scores for all individuals Expression of IFIGs was significantly higher in SLE patients compared with disease controls or healthy donors SLE patients with high and low IFNα scores were compared for clinical manifestations of disease, disease severity, disease activity, serologic features, and potential confounders, by bivariate and multivariate analyses Results SLE patients with a high IFNα score had a significantly higher prevalence of renal disease, a greater number of American College of Rheumatology criteria for SLE, and a higher Systemic Lupus International Collaborating Clinics damage index (SDI) score than did SLE patients with low IFNα scores Patients with high scores showed increased disease activity, as measured by lower C3 levels, hemoglobin levels, absolute lymphocyte counts, and albumin levels, and a higher anti–double-stranded DNA (dsDNA) titer, erythrocyte sedimentation rate, and SLE Disease Activity Index 2000 score The presence of antibodies specific for Ro, U1 RNP, Sm, and dsDNA, but not phospholipids, was significantly associated with a high IFNα score Logistic regression analysis confirmed that renal disease, higher SDI scores, low complement levels, and presence of anti–RNA binding protein (RBP) autoantibodies were associated with a high IFNα score Conclusion Activation of the IFNα pathway defines a subgroup of SLE patients whose condition is characterized by increased disease severity, including renal disease, increased disease activity, reflected in complement activation, and autoreactivity to RBP

Sustained benefits of infliximab therapy for dermatologic and articular manifestations of psoriatic arthritis: results from the infliximab multinational psoriatic arthritis controlled trial (IMPACT).

Abstract: Objective To investigate the efficacy and tolerability of infliximab therapy for the articular and dermatologic manifestations of active psoriatic arthritis (PsA). Methods One hundred four patients with PsA in whom prior therapy with at least 1 disease-modifying antirheumatic drug (DMARD) had failed were recruited into this investigator-initiated, multicenter, randomized, double-blind, placebo-controlled clinical trial. During the initial blinded portion of the study, patients received infusions of infliximab (5 mg/kg) or placebo at weeks 0, 2, 6, and 14. After week 16, patients initially assigned to receive placebo crossed over to receive infliximab 5 mg/kg every 8 weeks through week 50, while patients initially randomized to infliximab continued to receive active treatment at the same dose through week 50. The primary efficacy outcome was achievement of the American College of Rheumatology 20% criteria for improvement in rheumatoid arthritis (ACR20) at week 16. Additional predefined clinical efficacy assessments included the Psoriasis Area and Severity Index (PASI) score, the ACR50 and ACR70 criteria, the Disease Activity Score in 28 joints, the Health Assessment Questionnaire, ratings of enthesitis and dactylitis, and the Psoriatic Arthritis Response Criteria score. Results The proportion of infliximab-treated patients who achieved an ACR20 response at week 16 (65%) was significantly higher than the proportion of placebo-treated patients who achieved this response (10%). In addition, 46% of infliximab-treated patients achieved an ACR50 response, and 29% achieved an ACR70 response; no placebo-treated patient achieved these end points. Among patients who had PASI scores of ≥2.5 at baseline, 68% of infliximab-treated patients achieved improvement of ≥75% in the PASI score at week 16 compared with none of the placebo-treated patients. Continued therapy with infliximab resulted in sustained improvement in articular and dermatologic manifestations of PsA through week 50. The incidence of adverse events was similar between the treatment groups. Conclusion Therapy with infliximab at a dose of 5 mg/kg significantly improved the signs and symptoms of arthritis, psoriasis, dactylitis, and enthesitis in patients with active PsA that had been resistant to DMARD therapy. With continued infliximab treatment, benefits were sustained through 50 weeks. The benefit-to-risk ratio appeared favorable in this study population.

Autoantibodies to a 140-kd polypeptide, CADM-140, in Japanese patients with clinically amyopathic dermatomyositis

Abstract: Objective To identify novel autoantibodies specific for dermatomyositis (DM), especially those specific for clinically amyopathic DM (C-ADM). Methods Autoantibodies were analyzed by immunoprecipitation in 298 serum samples from patients with various connective tissue diseases (CTDs) or idiopathic pulmonary fibrosis (IPF). Antigen specificity of the sera was further examined by immunoblotting and indirect immunofluorescence (IF). The disease specificity and clinical features associated with the antibody of interest were determined. Results Eight sera recognized a polypeptide of ∼140 kd (CADM-140 autoantigen) by immunoprecipitation and immunoblotting. Immunoreactivity was detected in the cytoplasm, and indirect IF revealed a granular or reticular pattern. Anti–CADM-140 antibodies were detected in 8 of 42 patients with DM, but not in patients with other CTDs or IPF. Interestingly, all 8 patients with anti–CADM-140 antibodies had C-ADM. Among 42 patients with DM, those with anti–CADM-140 autoantibodies had significantly more rapidly progressive interstitial lung disease (ILD) when compared with patients without anti–CADM-140 autoantibodies (50% versus 6%; P = 0.008). Conclusion These results indicate that the presence of anti–CADM-140 autoantibodies may be a novel marker for C-ADM. Further attention should be directed to the detection of rapidly progressive ILD in those patients with anti–CADM-140 autoantibodies.

Refining the complex rheumatoid arthritis phenotype based on specificity of the HLA-DRB1 shared epitope for antibodies to citrullinated proteins.

Abstract: Objective The main genetic risk factor for rheumatoid arthritis (RA), the HLA region, has been known for 25 years. Previous research has demonstrated, within the RA population, an association between HLA-DRB1 alleles carrying the shared epitope (SE) and antibodies directed against cyclic citrullinated peptides (anti-CCP antibodies). We undertook this study to make the first comparison of SE allele frequencies in the healthy population with those in RA patients who do or do not harbor anti-CCP antibodies. Methods HLA-DRB1 typing was performed in 408 RA patients from the Leiden Early Arthritis Clinic (the Leiden EAC; a Dutch population-based inception cohort in which disease course was followed up over time), in 423 healthy Dutch controls, and in 720 affected members of 341 US multiplex (sibpair) families of Caucasian origin from the North American RA Consortium (NARAC) with well-established disease and fulfilling the American College of Rheumatology classification criteria for RA. The presence of anti-CCP antibodies was determined by enzyme-linked immunosorbent assay. Results For the Leiden EAC, the odds ratio (OR) describing the association of 2 copies of the SE allele with anti-CCP positivity (using no copies of the SE allele in the healthy control group as the referent) was 11.79 (P Conclusion HLA-DRB1 alleles encoding the SE are specific for disease characterized by antibodies to citrullinated peptides, indicating that these alleles do not associate with RA as such, but rather with a particular phenotype.

Prevalence and clinical significance of antineutrophil cytoplasmic antibodies in Churg-Strauss syndrome

Abstract: Objective Churg-Strauss syndrome (CSS) is classified among the so-called antineutrophil cytoplasmic antibody–associated systemic vasculitides (AASVs) because of its clinicopathologic features that overlap with the other AASVs. However, while antineutrophil cytoplasmic antibodies (ANCAs) are consistently found in 75–95% of patients with Wegener's granulomatosis or microscopic polyangiitis, their prevalence in CSS varies widely and their clinical significance remains uncertain. We undertook this study to examine the prevalence and antigen specificity of ANCAs in a large cohort of patients with CSS. Moreover, we evaluated the relationship between ANCA positivity and clinicopathologic features. Methods Immunofluorescence and enzyme-linked immunosorbent assay were used to determine the presence or absence of ANCAs in 93 consecutive patients at the time of diagnosis. The main clinical and pathologic data, obtained by retrospective analysis, were correlated with ANCA status. Results ANCAs were present by immunofluorescence in 35 of 93 patients (37.6%). A perinuclear ANCA (pANCA) pattern was found in 26 of 35 patients (74.3%), with specificity for myeloperoxidase (MPO) in 24 patients, while a cytoplasmic ANCA pattern, with specificity for proteinase 3, was found in 3 of 35 patients (8.6%). Atypical patterns were found in 6 of 30 patients with anti-MPO antibodies (20.0%). ANCA positivity was associated with higher prevalences of renal disease (51.4% versus 12.1%; P < 0.001) and pulmonary hemorrhage (20.0% versus 0.0%; P = 0.001) and, to a lesser extent, with other organ system manifestations (purpura and mononeuritis multiplex), but with lower frequencies of lung disease (34.3% versus 60.3%; P = 0.019) and heart disease (5.7% versus 22.4%; P = 0.042). Conclusion ANCAs are present in ∼40% of patients with CSS. A pANCA pattern with specificity for MPO is found in most ANCA-positive patients. ANCA positivity is mainly associated with glomerular and alveolar capillaritis.

Very early treatment with infliximab in addition to methotrexate in early, poor-prognosis rheumatoid arthritis reduces magnetic resonance imaging evidence of synovitis and damage, with sustained benefit after infliximab withdrawal: Results from a twelve-month randomized, double-blind, placebo-controlled trial

Abstract: Objective Anti–tumor necrosis factor α agents are among the most effective therapies for rheumatoid arthritis (RA). However, their optimal use is yet to be determined. This 12-month double-blind study attempted remission induction using standard therapy with or without infliximab in patients with early, poor-prognosis RA. The primary end point was synovitis (measured by magnetic resonance imaging [MRI]). Clinical observations continued to 24 months. Methods All patients had fewer than 12 months of symptoms. Assessments included full metrologic evaluation, laboratory tests, radiographs, functional evaluation using the Health Assessment Questionnaire (HAQ), and quality of life measurement using the RA Quality of Life (RAQoL) questionnaire. MRI was performed at 0, 4, 14, and 54 weeks; MR images were scored blindly. Patients received methotrexate (MTX) and were randomized to receive either infliximab or placebo for 12 months. Results Twenty patients were recruited (mean age 52 years, mean symptom duration 6 months, mean C-reactive protein level 42 mg/liter, and 65% rheumatoid factor positive). At 1 year, all MRI scores were significantly better, with no new erosions in the infliximab plus MTX group; a greater percentage of infliximab plus MTX–treated patients fulfilled the American College of Rheumatology (ACR) 50% and 70% improvement criteria (78% versus 40% in the placebo plus MTX group and 67% versus 30%, respectively) and had a greater functional benefit (P < 0.05 for all comparisons). Importantly, at 1 year after stopping induction therapy, response was sustained in 70% of the patients in the infliximab plus MTX group, with a median Disease Activity Score in 28 joints (DAS28) of 2.05 (remission range). At 2 years, there were no significant between-group differences in the DAS28, ACR response, or radiographic scores, but differences in the HAQ and RAQoL scores were maintained (P < 0.05). Conclusion Remission induction with infliximab plus MTX provided a significant reduction in MRI evidence of synovitis and erosions at 1 year. At 2 years, functional and quality of life benefits were sustained, despite withdrawal of infliximab therapy. These data may have significant implications for the optimal use of expensive biologic therapies.

Intake of purine‐rich foods, protein, and dairy products and relationship to serum levels of uric acid: The Third National Health and Nutrition Examination Survey

Abstract: Objective Various commonly consumed foods have long been suspected of affecting the serum uric acid level, but few data are available to support or refute this impression. Our objective was to evaluate the relationship between dietary factors and serum uric acid levels in a nationally representative sample of men and women in the US. Methods Using data from 14,809 participants (6,932 men and 7,877 women) ages 20 years and older in the Third National Health and Nutrition Examination Survey (for the years 1988–1994), we examined the relationship between the intake of purine-rich foods, protein, and dairy products and serum levels of uric acid. Diet was assessed with a food-frequency questionnaire. We used multivariate linear regression to adjust for age, sex, total energy intake, body mass index, use of diuretics, β-blockers, allopurinol, and uricosuric agents, self-reported hypertension and gout, serum creatinine level, and intake of alcohol. Results The serum uric acid level increased with increasing total meat or seafood intake and decreased with increasing dairy intake. After adjusting for age, the differences in uric acid levels between the extreme quintiles of intake were 0.48 mg/dl for total meat (95% confidence interval [95% CI] 0.34, 0.61; P < 0.001 for trend), 0.16 mg/dl for seafood (95% CI 0.06, 0.27; P = 0.005 for trend), and –0.21 mg/dl for total dairy intake (95% CI –0.37, –0.04; P = 0.02 for trend). After adjusting for other covariates, the differences between the extreme quintiles were attenuated but remained significant (P < 0.05 for all comparisons). The total protein intake was not associated with the serum uric acid level in multivariate analyses (P = 0.74 for trend). Those who consumed milk 1 or more times per day had a lower serum uric acid level than did those who did not drink milk (multivariate difference –0.25 [95% CI –0.40, –0.09]; P < 0.001 for trend). Similarly, those who consumed yogurt at least once every other day had a lower serum uric acid level than did those who did not consume yogurt (multivariate difference –0.26 [95% CI –0.41, –0.12]; P < 0.001 for trend). Conclusion These findings from a nationally representative sample of adults in the US suggest that higher levels of meat and seafood consumption are associated with higher serum levels of uric acid but that total protein intake is not. Dairy consumption was inversely associated with the serum uric acid level.

Weight loss reduces knee‐joint loads in overweight and obese older adults with knee osteoarthritis

Abstract: Objective. To determine the relationship between change in body mass and knee-joint moments and forces during walking in overweight and obese older adults with knee osteoarthritis (OA) following an 18-month clinical trial of diet and exercise. Methods. Data were obtained from 142 sedentary, overweight, and obese older adults with self-reported disability and radiographic evidence of knee OA who underwent 3-dimensional gait analysis. Gait kinetic outcome variables included peak knee-joint forces and peak internal knee-joint moments. Mixed regression models were created to predict followup kinetic values, using followup body mass as the primary explanatory variable. Baseline body mass was used as a covariate, and thus followup body mass was a surrogate measure for change in body mass (i.e., weight loss). Results. There was a significant direct association between followup body mass and peak followup values of compressive force (P 0.001), resultant force (P 0.002), abduction moment (P 0.03), and medial rotation moment (P 0.02). A weight reduction of 9.8N (1 kg) was associated with reductions of 40.6N and 38.7N in compressive and resultant forces, respectively. Thus, each weight-loss unit was associated with an 4-unit reduction in knee-joint forces. In addition, a reduction in body weight of 9.8N (1 kg) was associated with a 1.4% reduction (0.496 Nm) in knee abduction moment. Conclusion. Our results indicate that each pound of weight lost will result in a 4-fold reduction in the load exerted on the knee per step during daily activities. Accumulated over thousands of steps per day, a reduction of this magnitude would appear to be clinically meaningful.

Rituximab treatment in patients with primary Sjögren's syndrome: an open-label phase II study.

Abstract: Objective To investigate the safety and efficacy of B cell depletion treatment of patients with active primary Sjogren's syndrome of short duration (early primary SS) and patients with primary SS and mucosa-associated lymphoid tissue (MALT)-type lymphoma (MALT/primary SS). Methods Fifteen patients with primary SS were included in this phase II trial. Inclusion criteria for the early primary SS group were B cell hyperactivity (IgG >15 gm/liter), presence of autoantibodies (IgM rheumatoid factor, anti-SSA/SSB), and short disease duration ( Results Significant improvement of subjective symptoms and an increase in salivary gland function was observed in patients with residual salivary gland function. Immunologic analysis showed a rapid decrease of peripheral B cells and stable levels of IgG. Human anti-chimeric antibodies (HACAs) developed in 4 of 15 patients (27%), all with early primary SS. Three of these patients developed a serum sickness-like disorder. Of the 7 patients with MALT/primary SS, complete remission was achieved in 3, and disease was stable in 3 and progressive in 1. Conclusion Findings of this phase II study suggest that rituximab is effective in the treatment of primary SS. The high incidence of HACAs and associated side effects observed in this study needs further evaluation.

The challenge of diagnosis and classification in early ankylosing spondylitis: do we need new criteria?

Abstract: Ankylosing spondylitis (AS) is a common chronic inflammatory disease with an estimated prevalence of 0.2–1.2% (1–4). The disease typically starts during the third decade of life and has a substantial socioeconomic impact on the patient and society (5–7). Until recently, the treatment options for AS were limited. The mainstays of treatment were regular physical therapy and nonsteroidal antiinflammatory drugs (NSAIDs) (8). In contrast, disease-modifying antirheumatic drugs (DMARDs) as well as corticosteroids, which are quite effective in some of the other chronic inflammatory diseases such as rheumatoid arthritis (RA), show only very limited or no efficacy in AS (9–11). Thus, in the past, a delayed diagnosis did not have much of an adverse consequence because of the lack of highly effective therapeutic choices. Most recently, it has been convincingly demonstrated that the tumor necrosis factor (TNF )– blocking agents infliximab and etanercept have a strong and prompt effect on almost all features of AS, such as clinical disease activity, physical function, spinal mobility, peripheral arthritis, enthesitis, and levels of acutephase reactants (12–19). In several studies of AS patients whose disease was refractory to NSAIDs and physical therapy, 50% of the patients have demonstrated at least a 50% improvement when treated with either of the two TNF -blocking compounds. It has also been shown that active juxtaarticular bony inflammation (“bone edema”), as detected by magnetic resonance imaging (MRI), can be suppressed (20,21), and it is hoped that this kind of treatment will also favorably influence long-term outcome, including reduction or prevention of radiologic progression. Recent data also show that AS patients with a short disease duration and good functional status are more likely to respond to TNF -blocking agents than patients with longstanding disease and impaired function (22). Thus, an early and reliable diagnosis of AS has now become an important and very relevant issue.

Role of interleukin-1 and tumor necrosis factor alpha in matrix degradation of human osteoarthritic cartilage.

Abstract: Objective To determine whether interleukin-1 (IL-1) or tumor necrosis factor alpha (TNFalpha), or both, plays a role in the excessive degradation that is observed in cultured osteoarthritic (OA) articular cartilage. Methods Antagonists of IL-1 and TNFalpha, namely, IL-1 receptor antagonist and the PEGylated soluble TNFalpha receptor I, respectively, were added at different concentrations to explant cultures of nonarthritic (5 obtained at autopsy) and OA (15 obtained at arthroplasty) articular cartilage. The cleavage of type II collagen (CII) by collagenase was measured by an immunoassay in cartilage and culture media. Proteoglycan (mainly aggrecan) content and degradation were measured by a colorimetric assay for glycosaminoglycan (GAG) content in cartilage and culture media. Reverse transcriptase-polymerase chain reaction was used to analyze gene expression of matrix metalloproteases (MMPs) 1, 3, and 13, CII, aggrecan, IL-1, and TNFalpha. Results Antagonists of IL-1 and TNFalpha inhibited the increase in CII cleavage by collagenase as well as the increase in GAG release observed in OA cartilage compared with normal cartilage. Inhibition was significant in tissue from some patients but not from others, although significant inhibition was observed when all the results were analyzed together. An increase in the GAG content in cartilage was seen in 4 of 15 cases. However, this increase was not significant when all the data were combined. Preliminary results indicated no effect of these antagonists on nonarthritic cartilage from 3 different donors. Independent analyses of gene expression in cultured cartilage from 9 other OA patients revealed that IL-1 or TNFalpha blockade, either alone and/or in combination, frequently down-regulated MMP-1, MMP-3, and MMP-13 expression. Expression of IL-1 and TNFalpha was inhibited by either antagonist or by the combination in essentially half the cases. The combined blockade up-regulated aggrecan and CII gene expression in approximately half the cases. Conclusion These results suggest that the autocrine/paracrine activities of TNFalpha and IL-1 in articular cartilage may play important roles in cartilage matrix degradation in OA patients but not in all patients. Inhibition of either or both of these cytokines may offer a useful therapeutic approach to the management of OA by reducing gene expression of MMPs involved in cartilage matrix degradation and favoring its repair.

Remission and active disease in rheumatoid arthritis: defining criteria for disease activity states.

Abstract: 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.

Evidence of radiographic benefit of treatment with infliximab plus methotrexate in rheumatoid arthritis patients who had no clinical improvement: a detailed subanalysis of data from the anti-tumor necrosis factor trial in rheumatoid arthritis with concomitant therapy study.

Abstract: 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.

Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept - Twelve-month results of a phase IIb, double-blind, randomized, placebo-controlled trial

Abstract: Objective. To determine the clinical efficacy, safety, and immunogenicity of abatacept (CTLA-4Ig), a selective costimulation modulator, in patients with rheumatoid arthritis (RA) that has remained active despite methotrexate (MTX) therapy. Methods. This was a 12-month, multicenter, randomized, double-blind, placebo-controlled study. A total of 339 patients with active RA despite MTX therapy were randomly assigned to receive 10 mg/kg abatacept (n = 115), 2 mg/kg abatacept (n = 105), or placebo (n = 119). This report focuses on the results observed at month 12 of a phase IIb trial. Results. A significantly greater percentage of patients treated with 10 mg/kg abatacept met the American College of Rheumatology 20% improvement criteria (achieved an ACR20 response) at I year compared with patients who received placebo (62.6% versus 36.1%; P < 0.001). Greater percentages of patients treated with 10 mg/kg abatacept also achieved ACR50 responses (41.7% versus 20.2%; P < 0.001) and ACR70 responses (20.9% versus 7.6%; P = 0.003) compared with patients who received placebo. For patients treated with 10 mg/kg abatacept, there were also statistically significant and clinically important improvements in modified Health Assessment Questionnaire scores compared with patients who received placebo (49.6% versus 27.7%; P < 0.001). Abatacept at a dosage of 10 mg/kg elicited an increase in rates of remission (Disease Activity Score in 28 joints of < 2.6) compared with placebo at I year (34.8% versus 10.1%; P < 0.001). The incidence of adverse events was comparable between the groups, and no significant formation of neutralizing antibodies was noted. Conclusion. Abatacept was associated with significant reductions in disease activity and improvements in physical function that were maintained over the course of 12 months in patients with RA that had remained active despite MTX treatment. Abatacept was found to be well tolerated and safe over the course of 1 year. Abatacept in combination with MTX has the potential to play an important role in future RA therapy.

Spondyloarthritis research consortium of Canada magnetic resonance imaging index for assessment of sacroiliac joint inflammation in ankylosing spondylitis

Abstract: Objective To develop a feasible magnetic resonance imaging (MRI)–based scoring system for sacroiliac joint inflammation in patients with ankylosing spondylitis (AS) that requires minimal scan time, does not require contrast enhancement, evaluates lesions separately at each articular surface, and limits the number of sacroiliac images that are scored. Methods A scoring method based on the assessment of increased signal denoting bone marrow edema on T2-weighted STIR sequences was used. MRI films were assessed blindly in random order at 2 sites by multiple readers. Intra- and interreader reliability was assessed by intraclass correlation coefficient (ICC); the 24-week response of patients with AS randomized to placebo:infliximab (3:8) was assessed by effect size and standardized response mean. The reliability and responsiveness of the scoring method were compared for STIR and gadolinium diethylenetriaminepentaacetic (Gd-DTPA)–enhanced MRI sequences. Results We scanned 11 patients with AS with clinically active disease and 11 additional patients randomized to the trial of infliximab therapy. ICC for total sacroiliac joint STIR score ranged from 0.90 to 0.98 (P < 0.00001) and interobserver ICC for combined readers from the 2 sites was 0.84 (P < 0.0001). ICC for change scores was lower for STIR (ICC 0.53) than for Gd-DTPA–enhanced sequences (ICC 0.79). Responsiveness was poor, although fusion was evident in one-third of patients who received treatment (placebo:infliximab) and inflammation scores were low. Conclusion The Spondyloarthritis Research Consortium of Canada MRI index is a feasible and reproducible index for measuring sacroiliac joint inflammation in patients with AS.

Positive effects of moderate exercise on glycosaminoglycan content in knee cartilage: A four-month, randomized, controlled trial in patients at risk of osteoarthritis

Abstract: Objective To evaluate the effects of moderate exercise on glycosaminoglycan (GAG) content in knee cartilage in subjects at high risk of knee osteoarthritis (OA). Methods Forty-five subjects (16 women, mean age 46 years, mean body mass index 26.6 kg/m2) who underwent partial medial meniscus resection 3–5 years previously were randomized to undergo a regimen of supervised exercise 3 times weekly for 4 months or to a nonintervention control group. Cartilage GAG content, an important aspect of the biomechanical properties of cartilage, was estimated by delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC), with results expressed as the change in the T1 relaxation time in the presence of Gd-DTPA (T1[Gd]). Results Thirty of 45 patients were examined by dGEMRIC at baseline and followup. The exercise group (n = 16) showed an improvement in the T1(Gd) compared with the control group (n = 14) (15 msec versus −15 msec; P = 0.036). To study the dose response, change in the T1(Gd) was assessed for correlation with self-reported change in physical activity level, and a strong correlation was found in the exercise group (n = 16, rS = 0.70, 95% confidence interval [95% CI] 0.31–0.89) and in the pooled group of all subjects (n = 30, rS = 0.74, 95% CI 0.52–0.87). Conclusion This in vivo cartilage monitoring study in patients at risk of knee OA who begin exercising indicates that adult human articular cartilage has a potential to adapt to loading change. Moderate exercise may be a good treatment not only to improve joint symptoms and function, but also to improve the knee cartilage GAG content in patients at high risk of developing OA.

The risk of congestive heart failure in rheumatoid arthritis: a population-based study over 46 years.

Abstract: Objective It is hypothesized that the systemic inflammation associated with rheumatoid arthritis (RA) promotes an increased risk of cardiovascular (CV) morbidity and mortality. We examined the risk and determinants of congestive heart failure (CHF) in patients with RA. Methods We assembled a population-based, retrospective incidence cohort from among all individuals living in Rochester, Minnesota, in whom RA (defined according to the American College of Rheumatology 1987 criteria) was first diagnosed between 1955 and 1995, and an age- and sex-matched non-RA cohort. After excluding patients in whom CHF occurred before the RA index date, all subjects were followed up until either death, incident CHF (defined according to the Framingham Heart Study criteria), migration from the county, or until January 1, 2001. Detailed information from the complete medical records (including all inpatient and outpatient care provided by all local providers) regarding RA, ischemic heart disease, and traditional CV risk factors was collected. Cox models were used to estimate the effect of RA on the development of CHF, adjusting for CV risk factors and/or ischemic heart disease. Results The study population included 575 patients with RA and 583 subjects without RA. The CHF incidence rates were 1.99 and 1.16 cases per 100 person-years in patients with RA and in non-RA subjects, respectively (rate ratio 1.7, 95% confidence interval [95% CI] 1.3–2.1). After 30 years of followup, the cumulative incidence of CHF was 34.0% in patients with RA and 25.2% in non-RA subjects (P< 0.001). RA conferred a significant excess risk of CHF (hazard ratio [HR] 1.87, 95% CI 1.47–2.39) after adjusting for demographics, ischemic heart disease, and CV risk factors. The risk was higher among patients with RA who were rheumatoid factor (RF) positive (HR 2.59, 95% CI 1.95–3.43) than among those who were RF negative (HR 1.28, 95% CI 0.93–1.78). Conclusion Compared with persons without RA, patients with RA have twice the risk of developing CHF. This excess risk is not explained by traditional CV risk factors and/or clinical ischemic heart disease.