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ID PMID Title PublicationDate abstract
17133543 Presence of significant synovitis in rheumatoid arthritis patients with disease-modifying 2006 Dec OBJECTIVE: More timely and effective therapy for rheumatoid arthritis (RA) has contributed to increasing rates of clinical remission. However, progression of structural damage may still occur in patients who have satisfied remission criteria, which suggests that there is ongoing disease activity. This questions the validity of current methods of assessing remission in RA. The purpose of this study was to test the hypothesis that modern joint imaging improves the accuracy of remission measurement in RA. METHODS: We studied 107 RA patients receiving disease-modifying antirheumatic drug therapy who were judged by their consultant rheumatologist to be in remission and 17 normal control subjects. Patients underwent clinical, laboratory, functional, and quality of life assessments. The Disease Activity Score 28-joint assessment and the American College of Rheumatology remission criteria, together with strict clinical definitions of remission, were applied. Imaging of the hands and wrists using standardized acquisition and scoring techniques with conventional 1.5T magnetic resonance imaging (MRI) and ultrasonography (US) were performed. RESULTS: Irrespective of which clinical criteria were applied to determine remission, the majority of patients continued to have evidence of active inflammation, as shown by findings on the imaging assessments. Even in asymptomatic patients with clinically normal joints, MRI showed that 96% had synovitis and 46% had bone marrow edema, and US showed that 73% had gray-scale synovial hypertrophy and 43% had increased power Doppler signal. Only mild synovial thickening was seen in 3 of the control subjects (18%), but no bone marrow edema. CONCLUSION: Most RA patients who satisfied the remission criteria with normal findings on clinical and laboratory studies had imaging-detected synovitis. This subclinical inflammation may explain the observed discrepancy between disease activity and outcome in RA. Imaging assessment may be necessary for the accurate evaluation of disease status and, in particular, for the definition of true remission.
16978395 Four-year follow-up of infliximab therapy in rheumatoid arthritis patients with long-stand 2006 Although there is strong evidence supporting the short-term efficacy and safety of anti-tumour necrosis factor-alpha agents, few studies have examined the long-term effects. We evaluated 511 patients with long-standing refractory rheumatoid arthritis treated with intravenous infusions of infliximab 3 mg/kg at weeks 0, 2, 6, and 14 and every 8 weeks thereafter for 4 years. Among the initial 511 patients included in the study, 479 could be evaluated; of these, 295 (61.6%) were still receiving infliximab treatment at year 4 of follow-up. The most common reasons for treatment discontinuation were lack of efficacy (65 patients, 13.6%), safety (81 patients, 16.9%), and elective change (38 patients, 7.9%). Analysis of disease activity scores (DAS28 [disease activity score based on the 28-joint count]) over time showed that, after the initial rapid improvement during the first 6 to 22 weeks of therapy, a further decrease in disease activity of 0.2 units in the DAS28 score per year was observed. DAS28 scores, measured at week 14 or 22, were found to predict subsequent discontinuation due to lack of efficacy. In conclusion, long-term maintenance therapy with infliximab 3 mg/kg is effective in producing further reductions in disease activity. Disease activity measured by the DAS28 at week 14 or 22 of infliximab therapy was the best predictor of long-term attrition.
17160372 Aspects of the biology of hyaluronan, a largely neglected but extremely versatile molecule 2006 Nov HA takes part in a surprisingly large number of biological processes such as embryogenesis, angiogenesis, cell motility, wound healing and cell adhesion. While substantial progress in HA research has indeed been made over the last years, many important questions have not yet been answered. One of the most pertinent questions awaiting an answer is the quest for functional differences of HA synthesized by the three HAS genes. Of similar importance would be investigations into intracellular signaling pathways involved in the activation of this gene family, a field in which to date very little is known. A better understanding of functional differences between the HAS encoding genes not only holds the promise for a better understanding of a series of biological processes but also the opportunity for selective intervention in a number of maladies characterized by abnormalities of HA levels.
18654825 Case reports: ipsilateral shoulder and elbow arthroplasty using custom interlocking prosth 2008 Oct Ipsilateral shoulder and elbow arthritis is not an uncommon problem seen in patients of upper extremity surgeons. If arthroplasty is required in both joints, there is a significant risk of periprosthetic fracture resulting from the stress riser occurring between the implants. We report the placement of custom interlocking shoulder and elbow prostheses in a patient with rheumatoid arthritis. The elbow prosthesis with an uncemented humeral component was placed followed 18 months later by a custom-designed shoulder prosthesis. An internal strut between the two prostheses was created. Seven years postoperatively, the patient was asymptomatic with no radiographic signs of impending failure.
17266071 Longitudinal power Doppler ultrasonographic assessment of joint inflammatory activity in e 2007 Feb 15 OBJECTIVE: To evaluate the sensitivity to change of power Doppler ultrasound (PDUS) assessment of joint inflammation and the predictive value of PDUS parameters in disease activity and radiologic outcome in patients with early rheumatoid arthritis (RA). METHODS: Forty-two patients with early RA who started therapy with disease-modifying antirheumatic drugs underwent blinded sequential clinical, laboratory, and ultrasound assessment at baseline, 3 months, 6 months, and 1 year and radiographic assessment at baseline and 1 year. For each patient, 28-joint Disease Activity Score (DAS28) was recorded at each visit. The presence of synovitis was investigated in 28 joints using gray-scale ultrasonography and intraarticular power Doppler signal. Active synovitis was defined as intraarticular synovitis detected with power Doppler signal. The ultrasound joint count for active synovitis and an overall joint index for power Doppler signal were calculated. Sensitivity to change of PDUS variables was assessed by estimating the smallest detectable difference (SDD) from the intraobserver variability. RESULTS: The SDD for ultrasound joint count for active synovitis and ultrasound joint index for power Doppler signal was lower than mean changes from baseline to 3 months, 6 months, and 1 year. Time-integrated values of PDUS parameters demonstrated a highly significant correlation with DAS28 after 1 year (r = 0.63, P < 0.001) and a stronger correlation with radiographic progression (r = 0.59-0.66, P < 0.001) than clinical and laboratory parameters (r < 0.5). CONCLUSION: PDUS is a sensitive and reliable method for longitudinal assessment of inflammatory activity in early RA. PDUS findings may have a predictive value in disease activity and radiographic outcome.
17234651 The TNFRSF1A R92Q mutation is frequent in rheumatoid arthritis but shows no evidence for a 2007 Aug OBJECTIVE: TNFRSF1A mutations cause TNFRSF1A-associated periodic syndrome (MIM#142680). A recent study suggested that the R92Q mutation was associated with polyarthritis. We aimed to search for this and other TNFRSF1A mutations in rheumatoid arthritis (RA), and to test for linkage. METHODS: The DNA of 100 trio families and 86 index cases of RA-affected sib-pair (ASP) families from the French Caucasian population were investigated by denatured high-performance liquid chromatography for TNFRSF1A mutations in exons 2 to 4. The test for association compared cases and controls (derived from un-transmitted parental chromosomes). The test for linkage relied on the transmission disequilibrium test (TDT) in trio families and cosegregation in ASP families. RESULTS: Only the R92Q mutation was detected--in 2 of the 100 index cases of trio families and in 5 (5.8%) of the index cases of ASP families, but also in 5% of the controls, showing no association with the disease. No RA linkage evidence was found in TDT and ASP RA families. CONCLUSION: This TNFRSF1A investigation in RA from the French Caucasian population showed only the R92Q mutation, with a frequency of 4.5%, but no evidence for RA association or linkage to the disease. The R92Q mutation could be considered to be a low-penetrance variant.
16783859 Psychosocial variables and fatigue: a longitudinal study comparing individuals with rheuma 2006 Aug OBJECTIVE: In individuals with rheumatoid arthritis (RA) and healthy controls, at enrollment and one year later, we evaluated relationships between diverse psychosocial characteristics and fatigue in multivariate analyses. METHODS: Participants with RA and controls completed the Fatigue Severity Scale (FSS) at enrollment and again after one year. All participants also completed measures of depressive symptoms, anxiety, role satisfaction, social support, social stress, disability, physical activity, and sleep quality at enrollment. RESULTS: A total of 122 individuals with RA and 122 controls of similar age, sex, education, employment, and marital status were enrolled. Those with RA had more fatigue compared to controls (FSS scores 4.2 +/- 1.2 vs 3.4 +/- 1.1; p < 0.0001) (possible range 1-7, higher score = more fatigue). In cross-sectional multivariate regression analysis for the RA group, more fatigue was associated with more anxiety, more disability, less social support, and more social stress (p
16922108 Bifid mandibular condyles: report of four cases. 2006 Jul Anatomic variations in the condylar morphology, like bifid mandibular condyles, are a relatively uncommon anomaly. We report four cases (two in patients and two in archived specimens) of bifid mandibular condyles with emphasis on their aetiopathogenesis and radiographic features. A case of bifid mandibular condyles in a patient with rheumatoid arthritis is reported which, to the best of our knowledge, is the first reported case in the literature. CLINICAL RELEVANCE: Anatomical variations, like bifid mandibular condyles, may mimic a fracture/tumour. Therefore, knowledge and awareness about this entity is important for a general dental practitioner.
17705865 Hand bone loss as an outcome measure in established rheumatoid arthritis: 2-year observati 2007 The aim of this 2-year longitudinal observational study was to explore hand bone loss as a disease outcome measure in established rheumatoid arthritis (RA). A cohort of 215 patients with RA (170 women and 45 men, aged 20-70 years) were recruited from the Oslo RA registry and studied for changes in hand bone mass during a 2-year follow-up. Digital X-ray radiogrammetry (DXR) was used to measure cortical hand bone mineral density (BMD) and metacarpal cortical index, whereas dual-energy X-ray absorptiometry (DXA) was used to assess whole hand BMD, which measures total cortical and trabecular bone. DXA-BMD total hip and spine and informative data for disease and therapy were also collected. Hand bone loss could be revealed over a 2-year follow-up measured by DXR-BMD (-0.90%, P < 0.01), but not by DXA-BMD (0.00%, P = 0.87). DXA-BMD hand bone loss was only observed in patients with disease duration < or = 3 years and not in patients with longer disease duration (-0.96% versus 0.24%, P < 0.01), whereas loss of DXR-BMD was independent of disease duration. Disease activity (measured by the disease activity score including 28 joints) independently predicted loss of DXR-BMD but not changes in the DXA-BMD hand in the multivariate analysis. The change in DXR metacarpal cortical index was highly correlated to DXR-BMD (r = 0.94, P < 0.001). These data suggest that DXR-BMD may be a more appropriate technique to identify RA-related bone involvement in hands compared with DXA-BMD measurement, but further studies are needed to explore this hypothesis.
20108506 The study of angiogenesis in early rheumatoid arthritis--clinical, immunohistochemical and 2008 Jul OBJECTIVE: The objective of the study was to analyze several immunohistochemical, histological, and morphometrical aspects of angiogenesis in early rheumatoid arthritis synovium. We aimed to identify possible correlations between the histological and immunohistochemical patterns and the serum levels of VEGF, as well as with clinical and biological markers of disease activity. METHODS: 35 patients with early rheumatoid arthritis below 12 months from the onset, naive for DMARDs, underwent clinical standard examination as well as serum determinations for CRP, RF. anti-CCP2 antibodies and VEGF. DAS28 value has been determined for each patient in order to assess the disease activity. We performed biopsy sampling through arthroscopy, the synovium fragments beeing histopathologically processed, in order to elaborate a total histological score. Immunohistochemical analysis has been performed with quantification of synovial VEGF, VEGF-R1 and CD34 expression. Standard and activated microvascular density (sMVD and aMVD) have been evaluated through double immunostaining (CD34/ VEGF-R1). RESULTS: VEGF and VEGF-R1 have been identified with high prevalence in endothelial cells, in lining and sublining synovial cells, as well as in inflammatory cells. The study focuses on the analysis of aMVD, a valuable parameter, representative for active angiogenesis, which proved to correlate significantly with the serum levels of VEGF, the composite histological score as well as with VEGF-R1 and DAS28. CONCLUSION: The statistic analysis of the data support VEGF-R1 and aMVD as markers with predictive value regarding activity and progression in early stages of rheumatoid arthritis. The validation of preliminary conclusions oblige to continuous research through extending the study group and inclusion of several others biomarkers involved in synovial angiogenesis.
17552046 Effects of high-dose atorvastatin on antiinflammatory properties of high density lipoprote 2007 Jul OBJECTIVE: Patients with rheumatoid arthritis (RA) have a 2-3-fold increased risk of myocardial infarction. Recent work suggests that plasma high density lipoproteins (HDL) from patients with RA are more proinflammatory than HDL from controls. We examined the effects of atorvastatin 80 mg daily on the inflammatory properties of HDL and clinical disease activity in RA. METHODS: Twenty subjects with active RA (mean Disease Activity Score 5.13 +/- 0.92) without dyslipidemia and no history of coronary artery disease were randomized in a double-blind placebo-controlled trial to receive 80 mg of atorvastatin (A) or placebo (P) daily in addition to stable antirheumatic drug therapy. Disease activity variables were followed over 12 weeks and the anti-/proinflammatory properties of HDL were determined by a cell-free assay (CFA) that measures lipid oxidation products. RESULTS: After 12 weeks, subjects completing the A protocol had a mean reduction in CFA values of 14.8 +/- 21.7%, while subjects completing P protocol had a mean increase in CFA values of 7.1 +/- 13.2% (p = 0.026). There was a trend for a decrease in highly sensitive C-reactive protein (hs-CRP) over 12 weeks in the A group compared to an increase in hs-CRP in the P group (p > 0.05), but changes in measures of clinical disease activity and plasma cytokine/intercellular adhesion molecule-1 levels were not significantly different in the A and P groups. CONCLUSION: In patients with active RA, HDL was rendered more antiinflammatory by high-dose atorvastatin compared to placebo. Functional characterization of HDL may warrant further investigation as a method of cardiovascular risk assessment in RA patients without traditional coronary risk factors. (ClinicalTrials.gov number NCT00356473).
18000669 [Synovitis score: value of histopathological diagnostics in unclear arthritis. Case report 2007 Dec Histopathological assessment of synovial biopsies has an established value. The value for inflammatory joint diseases without standardized rating mechanisms was, however, unknown until recently. The exemplary use of the synovitis score in four cases all including recurrent bruises of the knee joint portrays its value for diagnosis and therapy. Usage of the score includes assessing the enlargement of the lining layer, cellular density of synovial stroma and leucocyte infiltration by giving each a score of 0-3 points and adding them. Presence of high-grade synovitis (>or=4 points) in all cases displayed the reason for the joint bruises within a primarily inflammatory, rheumatoid circle. In this report we show the broad variety of uses for the synovitis score dealing with cases of Lyme arthritis, rheumatoid arthritis, seronegative monarthritis and HLA-B27-positive peripheral arthritis.
16443552 Reversible Epstein-Barr virus-negative lymphadenopathy and bone marrow involved by Hodgkin 2006 Jan We report a case of spontaneous regression of Epstein-Barr virus (EBV)-negative methotrexate-associated lymphadenopathy occurring with Hodgkin's lymphoma in the bone marrow of a 48-year-old woman with rheumatoid arthritis. Following 10 years of treatment with low-dose methotrexate, the patient developed pancytopenia, hypercalcemia, and elevated levels of liver enzymes over the course of 2 months. A computed tomography scan of the abdomen revealed splenomegaly and enlarged abdominal lymph nodes. A bone marrow biopsy demonstrated cellular marrow with 2 paratrabecular granuloma-like lesions composed of histiocytes, fibroblasts, small lymphocytes, a few plasma cells, and scattered CD30(+)CD15(+) Hodgkin's cells, including a classic Reed-Sternberg cell. The results of EBV studies of the bone marrow were negative. Within a month from withdrawal of methotrexate treatment, the patient's symptoms and the abnormalities in the laboratory results had regressed completely. A positron emission tomography scan failed to detect lymphadenopathy. Twelve months later, the patient remains free of symptoms.
17938521 Decreased levels of circulating alpha2-Heremans-Schmid glycoprotein/Fetuin-A (AHSG) in pat 2007 OBJECTIVE: Alpha2-Heremans Schmid glycoprotein/Fetuin-A (AHSG) is a circulating negative acute-phase protein, which inhibits bimineralization. It is often considered as a potential mediator between chronic inflammation and cardiovascular diseases. The metabolism of AHSG in patients with rheumatoid arthritis (RA) is unknown. METHODS: Serum AHSG concentrations were measured in 102 patients with RA using a newly developed indirect enzyme-linked immunosorbent assay (ELISA). RESULTS: The serum AHSG levels in the RA patients were significantly lower than that in healthy volunteers (249.8 +/- 84.1 vs 425.0 +/- 93.0 microg/ml, P<0.0001). Serum C-reactive protein concentration and erythrocyte sedimentation rate were inversely correlated, while albumin, hemoglobin and total cholesterol were positively correlated with AHSG. Current serum AHSG levels did not affect the presence of aortic calcification, whereas cumulative glucocorticoid dosage was significantly related to aortic calcification (P=0.005). CONCLUSION: Serum AHSG levels were significantly decreased in patients with RA. The levels reflected inflammatory and malnutritional conditions. Its role in the development of cardiovascular diseases or inflammatory bone resorption remain uncertain in RA patients.
17315483 [Genetic epidemiology of rheumatoid arthritis: what to expect from Latin America?]. 2006 Dec Rheumatoid arthritis is a chronic and systemic autoimmune disease characterized by inflammation and destruction of the synovial joints. It affects approximately 0.5% of the Latin-American population and is three times more common in women than in men. Evidence of familial aggregation (lambdas=2-17) was the first indication of a genetic susceptibility to disease. As in other autoimmune diseases, it has a complex genetic basis. Results from whole-genome scans indicate that the HLA region contains a significant and consistent set of linked loci. However, HLA accounts for only one-third of the genetic susceptibility of disease, indicating that non-HLA genes are also involved in the disease susceptibility. In Latin-America, association with HLA-DRB1*0404 and TNF -308A alleles has been uniformly established; however, many other candidate genes remain to be studied. The identification of genetic factors conferring susceptibility to rheumatoid arthritis will contribute to the knowledge of the pathogenic mechanisms, ability to predict its occurrence, the development of diagnostic tools, prognosis, and treatment. The genetic epidemiology of rheumatoid arthritis is herein reviewed; a set of recommendations is provided for the design, analysis and interpretation of genetic association studies in the context of Latin-American populations.
17404485 [Inhibition of the joint destruction in RA by TNF-blocking agents]. 2007 Apr Tumor necrosis factor (TNF) -inhibitory biological response modifiers include neutralizing antibodies and receptor-immunoglobulin G (IgG) fusion proteins. These agents induce an amelioration of clinical signs and symptoms in most of the patients within a few weeks. Moreover, their inhibitory, or often repairing, effects on joint destruction are further excellent even in Japanese patients receiving a relatively lower dose of methotrexate (MTX) probably due to the direct inhibition of osteoclast activation through TNF.
18415764 Combination drug strategy in recent-onset rheumatoid arthritis suppresses collagen I degra 2008 Mar OBJECTIVE: To assess whether serum C-terminal cross-linking telopeptide of type I collagen (ICTP), a marker of type I collagen degradation, has any additional value in the assessment of treatment effect in patients with early rheumatoid arthritis (RA). METHODS: A total of 182 patients were randomized to treatment either with three disease-modifying anti-rheumatic drugs (DMARDs) and low-dose prednisolone (COMBI) or with a single DMARD with or without low-dose prednisolone (SINGLE). We investigated the prognostic value of serum ICTP level for the progression of joint destruction in X-rays (Larsen's score) from baseline to 2 years. RESULTS: There was a statistically significant decrease in serum ICTP levels from baseline to 1 year. At 6 months, the serum ICTP level was lower in the COMBI patients compared to that of the SINGLE cases (p = 0.008, after adjustment for baseline ICTP). When grouping the patients according to serum ICTP tertiles at 6 months, there was a statistically significant trend for increasing median change in Larsen score from baseline to 2 years from lowest to highest ICTP tertile in the SINGLE patients [p = 0.008, after adjustment for 28-joint Disease Activity Score (DAS28) score and RF status at baseline], while in the COMBI, the change remained low in all ICTP tertiles. CONCLUSIONS: The COMBI strategy for recent-onset RA results in early suppression of type I collagen degradation, which is reflected in radiological joint damage at 2 years. Serum ICTP at 6 months may be useful for identifying those RA patients whose treatment should be intensified to prevent further joint damage.
17216673 Predicting physical activity and general health perception among patients with rheumatoid 2007 Jan OBJECTIVE: To describe changes over one year in physical activity, body functions, and disease activity in patients with rheumatoid arthritis (RA) and to identify predictors for physical activity and general health perception. METHODS: One hundred two patients with RA were recruited for the study (median age 57 yrs, range 19-84; median disease duration 15 mo, range 4-78; 76% women). Self-reported data on physical activity and health locus of control, tests of lower extremity function, grip force, joint range of motion, balance, and measures of disease activity, including pain, general health perception, Health Assessment Questionnaire (HAQ), and Disease Activity Score (DAS28), were collected on 2 occasions, one year apart. Each variable was dichotomized to fit logistic regression models, performed to identify which variables predicted physical activity and general health perception over one year. RESULTS: Physical activity was stable, while lower extremity function, grip force, and range of motion improved and DAS28 decreased significantly over one year. A high physical activity level at baseline was the only predictor of high physical activity (odds ratio 3.85, 95% confidence interval 1.67-9.09) one year later. Low pain (OR 8.47, 95% CI 2.97-24.39), high physical activity (OR 3.72, 95% CI 1.39-10.10), and good lower extremity function (OR 2.94, 95% CI 1.04-8.33) were identified as predictors of good general health perception. CONCLUSION: While pain is a well known predictor of general health perception, to our knowledge, this is the first study to identify predictive factors related to physical activity and lower extremity function as important for perceived health among patients with RA.
16988840 Analysis of p53 and Bak gene mutations in lymphoproliferative disorders developing in rheu 2007 Feb PURPOSE: Individuals affected by rheumatoid arthritis (RA) occasionally develop lymphoproliferative disorders (RA-LPD). To study the molecular changes underscoring the RA-LPD, mutations of p53 and Bak gene were analyzed in RA-LPD with (MTX-LPD) or without methotrexate treatment for RA (non-MTX-LPD). METHODS: Histology and immunophenotype were immunohistochemically examined in 32 cases of MTX-LPD and 21 of non-MTX-LPD. Polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) followed by direct sequencing was employed to detect the mutations of p53 and Bak gene. RESULTS: Frequency of p53 mutations in non-MTX-LPD (47.6%) was significantly higher than that in MTX-LPD (15.6%) (P < 0.05). Among the cases with non-Hodgkin's lymphoma (NHL), the largest category of RA-LPD, the frequency of p53 mutations in the non-MTX-NHL (47.6%) was significantly higher than that in the MTX-NHL (14.8%) (P < 0.05). Interval between the onset of RA and LPD development was significantly longer in LPD with p53 gene mutations (median 228 months) than that without mutations (133 months). LPD with p53 gene mutations had more advanced diseases and an unfavorable prognosis than those without mutations. CONCLUSIONS: MTX-LPD and non-MTX-LPD show similar findings in clinical characteristics, histology, EBV positive rate, and frequency of Bak gene mutations. Whereas the non-MTX-LPD is distinct from the MTX-LPD in its significantly higher p53 mutation frequency.
16287927 Costs and course of disease and function in early rheumatoid arthritis: a 3-year follow-up 2006 Mar OBJECTIVE: To calculate direct and indirect costs and to study disease activity and functional ability over 3 yr in early rheumatoid arthritis (RA). METHODS: Three hundred and three patients with early (< or = 1 yr) RA were recruited during a period of 27 months (1996-1998). Data were recorded during 3 yr to assess disease activity, functional ability, medication, health-care utilization and days lost from work. RESULTS: Within 3 months, improvements were seen regarding all recorded variables assessing disease activity and functional ability, but 15% had sustained high or moderate disease activity throughout the study period. Indirect costs exceeded direct costs in all 3 yr. The average direct costs were 3704 Euros (3297 US Dollars) in year 1 and 2652 Euros ( 2360 US Dollars ) in year 3. All costs decreased, except those for medication and surgery. Compared with men, women had more ambulatory care visits and used more complementary medicine. The indirect costs were 8871 Euros ( 7895 US Dollars) in year 1 and remained essentially unchanged; this was similar for both sexes. Almost 50% were on sick leave or early retirement at inclusion. Sick leave decreased but was offset by an increase in early retirement. The 14 patients who eventually received TNF inhibitors incurred higher costs even before prescription of anti-TNF therapy. CONCLUSION: Disease activity and functional ability improved within 3 months after diagnosis of early RA. Direct costs decreased, except for medication and surgery. Indirect costs remained unchanged. Fifteen per cent of the patients had high or moderate disease activity in all 3 yr, indicating a need for more aggressive early anti-rheumatic therapy.