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ObjectiveSeveral 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

OBJECTIVE: The peptidylarginine deiminase type 4 gene (PADI4) was recently reported to be associated with rheumatoid arthritis (RA) in a Japanese population. The presence of a single-nucleotide polymorphism (SNP) located in intron 3 of PADI4 provided the strongest evidence of this association. Moreover, functional haplotypes that affect stability of transcripts were identified. However, subsequent research failed to confirm the observed association in a UK population. The present study was undertaken to further investigate the association of PADI4 with RA, using a series of population-based samples from subjects with the same ethnic background as the subjects in the original study. METHODS: DNA samples were obtained from 1,230 Japanese RA patients and 948 ethnically matched controls. Genotyping was performed using 5' allele discrimination assays. All samples were genotyped for 3 SNPs on PADI4 (padi4_94, padi4_104, and padi4_102), which comprised the reported haplotypes. Chi-square testing was performed for a case-control study and the PENHAPLO program was used for haplotype estimation. RESULTS: All tested SNPs were found to show significant differences in frequency between cases and controls (P = 0.010-0.0008), which confirmed the association observed in the original study. Odds ratios calculated for allele frequencies were 1.23, 1.21, and 1.36 in padi4_94, padi4_104, and padi4_102 respectively. CONCLUSION: Replication of association in individual samples strongly suggests that PADI4 is a true susceptibility gene for RA. [ABSTRACT FROM AUTHOR]

OBJECTIVE: High-dose chemotherapy (HDC) followed by autologous hematopoietic stem cell transplantation (HSCT) is a new treatment for patients with severe, refractory rheumatoid arthritis (RA). The present study was undertaken to assess the health status of patients with severe RA over a long-term followup period after treatment with HDC + HSCT. METHODS: Health status and utility scores were assessed in 8 patients before and after treatment with HDC + HSCT. Patients were followed up for 5 years posttransplantation. Health status was assessed by the Health Assessment Questionnaire (HAQ), the RAND-36 version of the Short Form 36 (SF-36) health survey, and the Arthritis Impact Measurement Scales (AIMS). Utility scores were calculated using the EuroQol (EQ-5D) questionnaire and the SF-36-derived utility index (called the SF-6D), from which quality-adjusted life years (QALYs) were derived. RESULTS: Most measures of health status improved compared with baseline in the first 2 years posttransplantation, notably HAQ and AIMS scores and scores on the functional status, general health, and health change summary scales of the RAND-36 version of the SF-36. Utility scores derived from the EQ-5D questionnaire and the SF-6D also increased significantly after transplantation. This was reflected in the 0.28 QALYs gained compared with baseline. For a putative 50-year-old RA patient with a life expectancy of 20 years, a threshold analysis revealed that HDC + HSCT yielded more QALYs than conventional therapy when treatment-related mortality (TRM) was <2.8%. CONCLUSION: HDC + HSCT temporarily increased the functionality and health status of patients with severe, refractory RA. With a reported TRM of 1.3%, HDC + HSCT can be considered a realistic treatment option for patients with severe RA. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Rheumatoid arthritis (RA) is characterized by inflammation and destruction of synovial joints. Fibroblast-like synoviocytes (FLS) harvested from synovial tissue of patients with RA can invade normal human cartilage in severe combined immunodeficient (SCID) mice and Matrigel basement membrane matrix in vitro. This study was undertaken to investigate the association of these in vitro characteristics with disease characteristics in patients with RA. METHODS: Synovial tissue samples from 72 RA and 49 osteoarthritis (OA) patients were obtained. Samples of different joints were collected from 7 patients with RA. The FLS invasiveness in Matrigel was studied, and the intraindividual and interindividual differences were compared. From the patients with FLS who exhibited the most extreme differences in in vitro ingrowth (most and least invasive FLS), radiographs of the hands and feet were collected and scored according to the Sharp/van der Heijde method to determine the relationship between in vitro invasion data and estimated yearly joint damage progression. RESULTS: FLS from patients with RA were more invasive than FLS from patients with OA (P < 0.001). The mean intraindividual variation in FLS invasion was much less than the mean interindividual variation (mean +/- SD 1,067 +/- 926 and 3,845 +/- 2,367 for intraindividual and interindividual variation, respectively; P = 0.035), which shows that the level of FLS invasion is a patient characteristic. The mean +/- SEM Sharp score on radiographs of the hands or feet divided by the disease duration was 4.4 +/- 1.1 units per year of disease duration in patients with the least invasive FLS (n = 9), which was much lower compared with the 21.8 +/- 3.1 units per year of disease duration in patients with the most invasive FLS (n = 9) (P < 0.001). CONCLUSION: The ex vivo invasive behavior of FLS from RA patients is associated with the rate of joint destruction and is a patient characteristic, given the much smaller intraindividual than interindividual FLS variation. [ABSTRACT FROM AUTHOR]

OBJECTIVE: In a sibpair study of osteoarthritis (OA) patients, we investigated whether, upon stimulation with lipopolysaccharide (LPS), variations in the innate ex vivo production of interleukin-1beta (IL-1beta), IL-1 receptor antagonist (IL-1Ra), IL-10, and tumor necrosis factor alpha (TNFalpha) in whole-blood assays contribute to the risk of OA. METHODS: Data from 305 patients with OA at multiple sites (hand, knee, hip, and spine), whose median age was 60 years (range 43-79 years), were compared with those from 137 controls. OA was defined in accordance with the American College of Rheumatology criteria. Whole-blood samples were stimulated with LPS (10 ng/ml). In the supernatants, cytokines were measured by enzyme-linked immunosorbent assay. Odds ratios (ORs) were used as measures of the relative risk of OA in relation to quartiles of IL-1beta, IL-1Ra, TNFalpha, and IL-10 production. The ORs were adjusted for sex and age, and 95% confidence intervals (95% CIs) were computed using robust standard errors to take into account the intrafamily effect. RESULTS: Subjects in the highest quartile of IL-1beta and IL-1Ra had an increased risk of OA (OR 3.3, 95% CI 1.4-7.9 and OR 8.0, 95% CI 3.7-17.4, respectively), while subjects in the lowest quartile of IL-10 had a 3-fold increased risk of OA (OR 3.1, 95% CI 1.5-6.5). High innate ex vivo production of TNFalpha was not associated with an increased risk of OA. CONCLUSION: Subjects with a high innate ex vivo production of IL-1beta and IL-1Ra and low innate ex vivo production of IL-10 have an increased risk of OA. These results suggest that a proportion of the genetic susceptibility to OA may be encoded for by variations in innate cytokine activity. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To evaluate the efficacy and safety of repeated administration of infliximab plus methotrexate (MTX) over a 2-year period in patients with rheumatoid arthritis (RA) who previously experienced an incomplete response to MTX. METHODS: Four hundred twenty-eight patients were randomly assigned to receive MTX plus placebo or infliximab at a dose of 3 or 10 mg/kg plus MTX for 54 weeks, with an additional year of followup. The protocol was later amended to allow for continued treatment during the second year. Of 259 patients who entered the second year of treatment, 216 continued to receive infliximab plus MTX for 102 weeks. Ninety-four of these 259 patients experienced a gap in therapy of >8 weeks before continuing therapy. Infusions were administered at weeks 0, 2, and 6, followed by treatment every 4 weeks or every 8 weeks (alternating with placebo infusions in the interim 4-week visits) at a dose of 3 or 10 mg/kg for a total of 102 weeks (including the gap in therapy). For safety and efficacy assessments, data on the patients who were randomized to receive treatment, irrespective of whether treatment was administered for 102 weeks, were evaluated using all actual observations available. The efficacy measures included the Health Assessment Questionnaire (HAQ) (physical function), Short Form 36 health survey (SF-36) (health-related quality of life), total radiographic scores (structural damage), and the American College of Rheumatology 20% improvement criteria (ACR20) (signs and symptoms). RESULTS: The infliximab plus MTX regimens resulted in significantly greater improvement in HAQ scores (P < or = 0.006) and SF-36 physical component summary scores (P < or = 0.011) compared with the MTX-only group. There also was stability in the SF-36 mental component summary score among patients who received the infliximab plus MTX regimens. Median changes from baseline to week 102 in the total radiographic score were 4.25 for patients who received the MTX-only regimen and 0.50 for patients who received the infliximab plus MTX regimen. The proportion of patients achieving an ACR20 response at week 102 varied from 40% to 48% for the infliximab plus MTX groups compared with 16% for the MTX-only group. CONCLUSION: Throughout 102 weeks of therapy, infliximab plus MTX provided significant, clinically relevant improvement in physical function and quality of life, accompanied by inhibition of progressive joint damage and sustained improvement in the signs and symptoms of RA among patients who previously had an incomplete response to MTX alone. [ABSTRACT FROM AUTHOR]

OBJECTIVE: There are insufficient data on the effects of long-term intensive exercise in patients with rheumatoid arthritis (RA). We undertook this randomized, controlled, multicenter trial to compare the effectiveness and safety of a 2-year intensive exercise program (Rheumatoid Arthritis Patients In Training [RAPIT]) with those of physical therapy (termed usual care [UC]). METHODS: Three hundred nine RA patients were assigned to either the RAPIT program or UC. The primary end points were functional ability (assessed by the McMaster Toronto Arthritis [MACTAR] Patient Preference Disability Questionnaire and the Health Assessment Questionnaire [HAQ]) and the effects on radiographic progression in large joints. Secondary end points concerned emotional status and disease activity. RESULTS: After 2 years, participants in the RAPIT program showed greater improvement in functional ability than participants in UC. The mean difference in change of the MACTAR Questionnaire score was 2.6 (95% confidence interval [95% CI] 0.1, 5.2) over the first year and 3.1 (95% CI 0.7, 5.5) over the second year. After 2 years, the mean difference in change of the HAQ score was -0.09 (95% CI -0.18, -0.01). The median radiographic damage of the large joints did not increase in either group. In both groups, participants with considerable baseline damage showed slightly more progression in damage, and this was more obvious in the RAPIT group. The RAPIT program proved to be effective in improving emotional status. No detrimental effects on disease activity were found. CONCLUSION: A long-term high-intensity exercise program is more effective than UC in improving functional ability of RA patients. Intensive exercise does not increase radiographic damage of the large joints, except possibly in patients with considerable baseline damage of the large joints. [ABSTRACT FROM AUTHOR]

AIM: To compare the long-term effectiveness of care delivered by a clinical nurse specialist (CNS) with inpatient team care and day patient team care in patients with rheumatoid arthritis and increasing functional limitations. Background. The role of CNSs in the management of patients with rheumatoid arthritis (RA) is evolving, and their effectiveness in comparison with care provided by a rheumatologist alone has been established. However, long-term controlled studies showing how the effectiveness of CNSs compares with that of other forms of co-ordinated care, such as multidisciplinary team care, are lacking. METHODS: Two hundred and ten patients rheumatoid arthritis patients were randomized to care delivered by a CNS in a rheumatology outpatient clinic (12 weeks), inpatient team care (2 weeks) and day patient team care (3 weeks). Clinical assessments recorded on study entry, weeks 12, 26, 52, 78 and 104 comprised the health assessment questionnaire (HAQ) and MacMaster Toronto Arthritis (MACTAR) patient preference interview as primary outcome measures. Grip strength, walk test, RAND-36, Rheumatoid Arthritis Quality of Life questionnaire and disease activity score (DAS) were applied as secondary outcome measures. RESULTS: No significant differences in medical treatment, use of services of other health professionals, introduction of adaptive equipment or number of hospitalizations were observed between the three treatment groups during 2 year follow-up, except that visits to nurse specialists were more frequent and home help was less frequent in the CNS group. A comparison of clinical outcomes among the three groups and a comparison between the nurse specialist and inpatient and day patient care groups together did not show any significant differences. Within all three groups functional status, quality of life and disease activity improved significantly (P < 0.05). In general, the results obtained after 12 weeks remained stable until 104 weeks after the start of the study. CONCLUSION: Care provided by a CNS in an outpatient rheumatology clinic has a similar long-term clinical outcome to inpatient and day patient team care in patients with rheumatoid arthritis. A CNS intervention appears to be an effective innovation in the care for patients with rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

Objective: Early arthritis patients referred to an Early Arthritis Clinic (EAC) (n = 233) were compared to 241 patients from the routine out-patient clinic with respect to lag time between the onset of symptoms and the visit to the rheumatologist, clinical presentation and the consistency of the diagnosis after 1 yr. [ABSTRACT FROM PUBLISHER]

Methotrexate (MTX) is one of the most widely prescribed drugs in the treatment of rheumatoid arthritis (RA). The mechanism by which MTX exerts its anti-rheumatic effect has not yet been defined. The aim of the present study was to investigate the effect of MTX treatment (7.5-15 mg/week) on synovial tissue in RA. For this purpose, synovial biopsies were taken from 11 RA patients before and 16 weeks after initiation of MTX therapy. Immunohistochemistry was performed using monoclonal antibodies (MAb) specific for CD3, CD4, CD8, CD22, CD25, CD38, CD68, MAb67, Ki67, interferon gamma (IFN-γ), interleukin (IL)-1β, tumour necrosis factor alpha (TNF-α), E-selectin, ICAM-1 and VCAM-1. All parameters for disease activity improved during the period of treatment. Immunohistochemical analysis revealed a statistically significant decrease in scores for CD3, CD8, CD38, CD68, Ki67, IL-1β, TNF-α and the adhesion molecules E-selectin and VCAM-1. The observed decrease in synovial scores for inflammatory cells, monokines and adhesion molecules suggests that the anti-inflammatory effect of MTX is, in part, dependent on a reduction in monokine-inducible vascular adhesion molecules and subsequent reduction of cell traffic into joints. [ABSTRACT FROM PUBLISHER]

A prerequisite for comparative histology of synovial tissue by means of biopsies is insight into the distribution of a marker under study. This investigation focuses on the variation in the presence of T cells and signs of T-cell activation within the rheumatoid joint. For this purpose, multiple slides from several pieces of synovial tissue from different parts of a joint were stained and scored for the expression of CD3, CD25, HLA-DR, Ki67 and interferon-γ. The variation in scores for the presence of T cells and markers of activation was more pronounced in slides prepared from different pieces of tissue than in slides from one piece of tissue. Based on multiple analysis of variance, methods are suggested to establish a reliable overall score for the expression of a certain marker within a joint. Following validation, such methods may prove to be useful by allowing semiquantitative histology of synovial tissue for studies on arthritis. [ABSTRACT FROM PUBLISHER]

Female sex hormones affect susceptibility to systemic lupus erythematosus (SLE). To determine the effect of female sex hormones at onset of SLE on the survival of these patients, a retrospective survey was performed. The charts of 168 females SLE patients were evaluated to study the disease course, in particular the presence and kind of SLE criteria. Patients were classified as either belonging to the 'high female sex hormone at onset (HH)' or 'low female sex hormone at onset (LH)' group according to age at diagnosis. The statistics of the Dutch population, matched for age, were used to control for differences in life expectancy in these groups. A Cox regression model revealed that the relative mortality risk of HH patients vs HH controls was 4.2 times higher than the relative mortality risk of LH patients compared to LH controls. No differences in the frequency of SLE criteria between HH and LH patients were found that could explain the observed difference in mortality risk. [ABSTRACT FROM PUBLISHER]