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Showing papers in "Arthritis & Rheumatism in 2007"




Journal ArticleDOI
TL;DR: The results suggest an effective new therapeutic approach to target the pathogenic mechanism of autoimmune arthritis using allogeneic MSCs, which exerted their immunomodulatory function by educating antigen-specific Tregs.
Abstract: Objective Mesenchymal stem cells (MSCs) are precursors of tissue of mesenchymal origin, but they also have the capacity to regulate the immune response by suppressing T and B lymphocyte proliferation in a non–major histocompatibility complex–restricted manner. Use of MSCs as immunosuppressant agents in autoimmune diseases has been proposed and successfully tested in animal models. We explored the feasibility of using allogeneic MSCs as therapy for collagen-induced arthritis, a mouse model for human rheumatoid arthritis. Methods DBA/1 mice were immunized with type II collagen in Freund's complete adjuvant, and some of the animals received an intraperitoneal injection of allogeneic MSCs. Results A single injection of MSCs prevented the occurrence of severe, irreversible damage to bone and cartilage. MSCs induced hyporesponsiveness of T lymphocytes as evidenced by a reduction in active proliferation, and modulated the expression of inflammatory cytokines. In particular, the serum concentration of tumor necrosis factor α was significantly decreased. MSCs exerted their immunomodulatory function by educating antigen-specific Tregs. Conclusion Our results suggest an effective new therapeutic approach to target the pathogenic mechanism of autoimmune arthritis using allogeneic MSCs. However, further studies are required before these results can be translated to clinical settings.

568 citations


Journal ArticleDOI
TL;DR: An increasing degree of varus alignment is associated not only with progression of knee OA but also with development of knees OA, however, this association seems particularly applicable to overweight and obese persons.
Abstract: Objective. Although knee malalignment is assumed to correlate with knee osteoarthritis (OA), it is still unknown whether malalignment precedes the development of OA or whether it is a result of OA. The aim of this study was to assess the relationship between malalignment and the development of knee OA as well as progression of knee OA. Methods. A total of 1,501 participants in the Rotterdam study were randomly selected. Knee OA at baseline and at followup (mean followup 6.6 years) was scored according to the Kellgren/Lawrence (K/L) grading system. Alignment was measured by the femorotibial angle on radiographs at baseline. Multivariable logistic regression for repeated measurements was used to analyze the association of malalignment with the development and progression of OA. Results. Of 2,664 knees, 1,012 (38%) were considered to have normal alignment, 693 (26%) had varus alignment, and 959 (36%) had valgus alignment. A comparison of valgus alignment and normal alignment showed that valgus alignment was associated with a borderline significant increase in development of knee OA (odds ratio [OR] 1.54, 95% confidence interval [95% CI] 0.97-2.44), and varus alignment was associated with a 2-fold increased risk (OR 2.06, 95% CI 1.28-3.32). Stratification for body mass index showed that this increased risk was especially seen in overweight and obese individuals but not in non-overweight persons. The risk of OA progression was also significantly increased in the group with varus alignment compared with the group with normal alignment (OR 2.90, 95% CI 1.07-7.88). Conclusion. An increasing degree of varus alignment is associated not only with progression of knee OA but also with development of knee OA. However, this association seems particularly applicable to overweight and obese persons.

564 citations


Journal ArticleDOI
TL;DR: The hypothesis that the powerful antiinflammatory effect of anti–tumor necrosis α (anti-TNFα) therapy might lead to a reduction in the incidence of myocardial infarction (MI) in patients with RA is tested, and it is indicated that RA patients treated with anti-T NFα do not have a lower incidence of MI compared with RA patients treating with traditional DMARDs.
Abstract: OBJECTIVE: Rheumatoid arthritis (RA) is associated with an increased risk of coronary artery disease, possibly acting via shared mechanisms of inflammation. This study was undertaken to test the hypothesis that the powerful antiinflammatory effect of anti-tumor necrosis alpha (anti-TNFalpha) therapy might lead to a reduction in the incidence of myocardial infarction (MI) in patients with RA. METHODS: Using data from the British Society for Rheumatology Biologics Register, a national prospective observational study, we compared MI rates in 8,670 patients with RA treated with anti-TNFalpha and 2,170 patients with active RA treated with traditional disease-modifying antirheumatic drugs (DMARDs). RESULTS: Through July 2006, 63 MIs occurred in the anti-TNFalpha cohort during 13,233 person-years of followup and 17 MIs occurred in the DMARD cohort during 2,893 person-years of followup, equivalent to a rate of 4.8 events per 1,000 person-years and 5.9 events per 1,000 person-years, respectively. After adjustment for baseline risk factors, there was no reduction in the rate of MI in the anti-TNFalpha cohort compared with the DMARD cohort (incidence rate ratio 1.44 [95% confidence interval 0.56-3.67]). In an analysis of anti-TNFalpha-treated patients who responded to the treatment within 6 months versus those who did not, MI rates were found to be 3.5 events per 1,000 person-years in responders and 9.4 events per 1,000 person-years in nonresponders. The adjusted incidence rate ratio (95% confidence interval) for responders compared with nonresponders was 0.36 (0.19-0.69). CONCLUSION: These results indicate that RA patients treated with anti-TNFalpha do not have a lower incidence of MI compared with RA patients treated with traditional DMARDs. However, the risk of MI is markedly reduced in those who respond to anti-TNFalpha therapy by 6 months compared with nonresponders. This finding supports the notion that inflammation plays a pivotal role in MI.

552 citations


Journal ArticleDOI
TL;DR: Biologic therapy is associated with increased risk for skin cancers, but not for solid tumors or lymphoproliferative malignancies, and these associations were consistent across different biologic therapies.
Abstract: Objective Induction of malignancy is a major concern when rheumatoid arthritis (RA) is treated with biologic therapy. A meta-analysis of RA biologic clinical trials found a general increased risk of malignancy, but this risk was not found in a large observational study. We undertook this study to assess the risk of malignancy among biologic-treated patients in a large US observational database. Methods We studied incident cases of cancer among 13,001 patients during ∼49,000 patient-years of observation in the years 1998–2005. Cancer rates were compared with population rates using the US National Cancer Institute SEER (Surveillance, Epidemiology, and End-Results) database. Assessment of the risk of biologic therapy utilized conditional logistic regression to calculate odds ratios (ORs) as estimates of the relative risk, further adjusted for 6 confounders: age, sex, education level, smoking history, RA severity, and prednisone use. Results Biologic exposure was 49%. There were 623 incident cases of nonmelanotic skin cancer and 537 other cancers. The standardized incidence ratios and 95% confidence intervals (95% CIs) compared with SEER data were as follows: all cancers 1.0 (1.0–1.1), breast 0.8 (0.6–0.9), colon 0.5 (0.4–0.6), lung 1.2 (1.0–1.4), lymphoma 1.7 (1.3–2.2). Biologics were associated with an increased risk of nonmelanotic skin cancer (OR 1.5, 95% CI 1.2–1.8) and melanoma (OR 2.3, 95% CI 0.9–5.4). No other malignancy was associated with biologic use; the OR (overall risk) of any cancer was 1.0 (95% CI 0.8–1.2). Conclusion Biologic therapy is associated with increased risk for skin cancers, but not for solid tumors or lymphoproliferative malignancies. These associations were consistent across different biologic therapies.

514 citations


Journal ArticleDOI
TL;DR: It is indicated that MTX could be considered as a therapeutic option in addition to standard-of-care treatment with corticosteroids for patients with GCA, and adjunctive treatment with MTX lowers the risk of relapse and reduces exposure to cortiosteroids.
Abstract: Objective To reevaluate the efficacy and safety of adjunctive low-dose methotrexate (MTX) in giant cell arteritis (GCA). Methods An individual patient data meta-analysis of 3 randomized placebo-controlled trials in patients with newly diagnosed GCA was performed. Treatment consisted of initial high-dose corticosteroids and randomly assigned oral MTX therapy (7.5–15 mg/week) or placebo. Time-to-event outcomes were compared between groups using Cox proportional hazards models stratified by trial, and continuous outcomes were compared by calculating weighted mean differences. Results The combined data set comprised 161 patients, of whom 84 received MTX and 77 received placebo. The mean duration of followup was 54.7 weeks (SD 39.2 weeks). Hazard ratios (HRs) for a first and second relapse of GCA were 0.65 (P = 0.04) and 0.49 (P = 0.02), respectively, in patients receiving MTX as compared with patients receiving placebo. Accordingly, a predicted 3.6 individuals (95% confidence interval [95% CI] 2.2–56.8) and 4.7 individuals (95% CI 3.3–21.9) need to be treated with MTX to prevent the occurrence of one first or one second relapse, respectively, up to 48 weeks. Use of MTX resulted in a reduction in the corticosteroid cumulative dose by 842 mg within 48 weeks (P < 0.001). Moreover, MTX treatment was associated with a higher probability of achieving sustained discontinuation of corticosteroids for ≥24 weeks (HR 2.84, P = 0.001). Dropout rates and occurrence of adverse events did not differ between treatment groups. Conclusion In GCA, adjunctive treatment with MTX lowers the risk of relapse and reduces exposure to corticosteroids. These findings indicate that MTX could be considered as a therapeutic option in addition to standard-of-care treatment with corticosteroids for patients with GCA.

509 citations


Journal ArticleDOI
TL;DR: The results described here indicate that SF constituents contribute, individually and in combination, both at physiologic and pathophysiologic concentrations, to the boundary lubrication of apposing articular cartilage surfaces.
Abstract: Objective To determine whether the synovial fluid (SF) constituents hyaluronan (HA), proteoglycan 4 (PRG4), and surface-active phospholipids (SAPL) contribute to boundary lubrication, either independently or additively, at an articular cartilage–cartilage interface. Methods Cartilage boundary lubrication tests were performed with fresh bovine osteochondral samples. Tests were performed using graded concentrations of SF, HA, and PRG4 alone, a physiologic concentration of SAPL, and various combinations of HA, PRG4, and SAPL at physiologic concentrations. Static (μstatic, Neq) and kinetic ( ) friction coefficients were calculated. Results Normal SF functioned as an effective boundary lubricant both at a concentration of 100% ( = 0.025) and at a 3-fold dilution ( = 0.029). Both HA and PRG4 contributed independently to a low μ in a dose-dependent manner. Values of decreased from ∼0.24 in phosphate buffered saline to 0.12 in 3,300 μg/ml HA and 0.11 in 450 μg/ml PRG4. HA and PRG4 in combination lowered μ further at the high concentrations, attaining a value of 0.066. SAPL at 200 μg/ml did not significantly lower μ, either independently or in combination with HA and PRG4. Conclusion The results described here indicate that SF constituents contribute, individually and in combination, both at physiologic and pathophysiologic concentrations, to the boundary lubrication of apposing articular cartilage surfaces. These results provide insight into the nature of the boundary lubrication of articular cartilage by SF and its constituents. They therefore provide insight regarding both the homeostatic maintenance of healthy joints and pathogenic processes in arthritic disease.

497 citations


Journal ArticleDOI
TL;DR: The transition from no or minor pain to more severe pain was influenced by physical and psychosocial work place factors together with individual and health-related factors.
Abstract: Objective. To quantify the relative contribution of work-related physical and psychosocial factors, individual factors, and health-related factors to the development of more severe musculoskeletal pain in the neck and upper limbs and the back and lower limbs. Methods. In this cohort study of 5,604 workers from industrial and service companies, we collected information on work-related physical and psychosocial exposures and on individual and health-related factors. Questionnaires were completed at baseline by 4,006 participants (71.5%) and after 24 months by 3,276 (82%). At followup, participants with no or minor pain were included in Cox regression analyses to determine which factors predicted more severe regional pain. Results. Of the 4,006 baseline respondents, only 7.7% were free of regional pain. A total of 1,513 participants were free of severe pain at baseline and completed the 24-month followup. Highly repetitive work predicted arm pain, heavy lifting and prolonged standing predicted low back pain, and heavy pushing or pulling predicted lower limb pain. Low job satisfaction predicted neck/shoulder pain and lower limb pain, whereas other psychosocial work place factors were only of marginal importance. High levels of fear avoidance were associated with arm pain and lower limb pain. A high body mass index was highly associated with lower limb pain. Conclusion. Very few workers are totally free of pain in musculoskeletal regions, and we question the concept of incidence of musculoskeletal pain. The transition from no or minor pain to more severe pain was influenced by physical and psychosocial work place factors together with individual and health-related factors.

451 citations


Journal ArticleDOI
TL;DR: Although improvement of symptoms in TA usually follows glucocorticoid therapy, relapses usually occur with dosage reduction, and chronic morbidity and disability occur in most patients with TA in the US.
Abstract: Objective To describe the clinical, laboratory, and radiographic manifestations of Takayasu arteritis (TA) in a cohort from the US, evaluate the response to interventions, remission and relapse rates, and disease progression, and compare these observations with those from other cohorts in the US, Japan, India, Italy, and Mexico. Methods Seventy-five patients were retrospectively studied using a uniform database that included clinical, laboratory, and imaging data. Vascular imaging studies were performed at least yearly to monitor disease progression. Results Common manifestations at disease onset included loss or asymmetry of pulses (57%), limb blood pressure discrepancy (53%), and bruits (53%). Eleven percent of patients were asymptomatic prior to disease diagnosis. Initial angiographic studies showed aortic abnormalities in 79% of patients and frequent involvement of the subclavian (65%) and carotid (43%) arteries. Ninety-three percent of longitudinally followed patients attained disease remission of any duration, but only 28% sustained remission of at least 6 months' duration after prednisone was tapered to <10 mg daily. Both angioplasty and vascular surgery were initially successful, but recurrent stenosis occurred in 78% of angioplasty and 36% of bypass/reconstruction procedures. More than two-thirds of patients had difficulty performing routine daily activities and approximately one-fourth of all patients were unable to work. Our cohort was similar to the National Institutes of Health, Italian, Japanese, and Mexican cohorts in terms of the predominance of female subjects and disease manifestations, but differed from the Indian cohort in that the latter group had a higher frequency of male subjects, abdominal aorta and renal artery involvement, and hypertension. Conclusion Although improvement of symptoms in TA usually follows glucocorticoid therapy, relapses usually occur with dosage reduction. Attempts to restore vascular patency are often initially successful, but restenosis occurs frequently. Chronic morbidity and disability occur in most patients with TA in the US.

433 citations


Journal ArticleDOI
TL;DR: The utility of clinical and biochemical outcome measures and the feasibility of multicenter trials of early dcSSc were confirmed, and the first evaluation of a systemically administered and repeatedly dosed anti-TGFbeta1 drug CAT-192 was reported.
Abstract: Objective. To evaluate CAT-192, a recombinant human antibody that neutralizes transforming growth factor beta 1 (TGF beta 1), in the treatment of early-stage diffuse cutaneous systemic sclerosis (dcSSc). Methods. Patients with SSc duration of < 18 months were randomly assigned to the placebo group or to 1 of 3 CAT-192 treatment groups: 10 mg/kg, 5 mglkg, 0.5 mg/kg. Infusions were given on day 0 and weeks 6, 12, and 18. The primary objective of this study was to evaluate the safety, tolerability, and pharmacokinetics of CAT-192. Secondary outcomes included the modified Rodnan skin thickness score (MRSS), the Scleroderma Health Assessment Questionnaire, assessment of organ-based disease, serum levels of soluble interleukin-2 receptor, collagen propeptides (N propeptide of type I [PINP] and type III collagen), and tissue levels of messenger RNA for procollagens I and III and for TGF beta 1 and TGF beta 2. Results. Forty-five patients were enrolled. There was significant morbidity and mortality, including I death in the group receiving 0.5 mg/kg of CAT-192 and 3 deaths in the group receiving 5 mg/kg of CAT-192. There were more adverse events and more serious adverse events in patients receiving CAT-192 than in those receiving placebo, although these events were not more frequent in the high-dose treatment group. The MRSS improved in all groups during the study, but there was no evidence of a treatment effect for CAT-192. Improvement in the MRSS correlated with the disease duration (r = -0.54, P = 0.0008). Changes in the PINP level from baseline correlated with changes in the MRSS (r = 0.37, P = 0.027). Conclusion. We report the first evaluation of a systemically administered and repeatedly dosed anti-TGF beta 1 drug. In this pilot study, CAT-192, in doses up to 10 mg/kg, showed no evidence of efficacy. The utility of clinical and biochemical outcome measures and the feasibility of multicenter trials of early dcSSc were confirmed. (Less)

Journal ArticleDOI
TL;DR: Development of knee pain is associated with an increase in BMLs as revealed on MRI, and multiple logistic regression was used to assess whether an increased BML score is predictive of the development of kneePain.
Abstract: Objective Results of cross-sectional studies have suggested that bone marrow lesions (BMLs) visualized on magnetic resonance imaging (MRI) are related to knee pain, but no longitudinal studies have been done. This study was undertaken to determine whether enlarging BMLs are associated with new knee pain. Methods Subjects ages 50–79 years with knee osteoarthritis (OA) or at high risk of knee OA were asked twice at baseline about the presence of knee pain, aching, or stiffness (classified as frequent knee pain) on most days; absence of knee pain was the baseline eligibility criterion. At 15 months' followup, subjects were again queried twice about frequent knee pain. A case knee was defined as absence of knee pain at baseline but presence of knee pain both times at followup. Controls were selected randomly from among knees with absence of pain at baseline. All MR images were scored for volume of BMLs in the medial, lateral, and patellofemoral compartments. We focused on the maximal change in BML score among the knee compartments from baseline to 15 months. Multiple logistic regression, with adjustments for demographic and clinical variables, was used to assess whether an increased BML score is predictive of the development of knee pain. Results Among case knees, 54 of 110 (49.1%) showed an increase in BML score within a compartment, whereas only 59 of 220 control knees (26.8%) showed an increase (P < 0.001 by chi-square test). A BML score increase of at least 2 units was much more common in case knees than in control knees (27.5% versus 8.6%; adjusted odds ratio 3.2, 95% confidence interval 1.5–6.8). Among case knees with increased BMLs, most already had BMLs at baseline, with enlarging BMLs at followup, but among the subset of knees with no BMLs at baseline, new BMLs were more common in case knees (11 [32.4%] of 34) than in control knees (9 [10.8%] of 83). Conclusion Development of knee pain is associated with an increase in BMLs as revealed on MRI.

Journal ArticleDOI
TL;DR: New cases of ATB still occur in patients treated with all available TNF antagonists due to lack of compliance with recommendations to prevent reactivation of LTBI, and continuous evaluation of recommendations is required to improve clinical practice.
Abstract: Objective To evaluate the causes of new cases of active tuberculosis (ATB) in patients treated with tumor necrosis factor (TNF) antagonists included in the national registry BIOBADASER (Base de Datos de Productos Biologicos de la Sociedad Espanola de Reumatologia) after the dissemination of recommendations to prevent reactivation of latent tuberculosis infection (LTBI). Methods Incidence rate of ATB per 100,000 patient-years and 95% confidence intervals (95% CIs) were calculated in patients entering BIOBADASER after March 2002 and were stratified by compliance with recommendations (complete or incomplete). ATB rates in BIOBADASER were compared with the background rate and the rate in the rheumatoid arthritis cohort EMECAR (Estudio de la Morbilidad y Expresion Clinica de la Artritis Reumatoide) not treated with TNF antagonists. In addition, rates of ATB among patients treated with adalimumab, etanercept, and infliximab were estimated and compared only for treatments started after September 2003, when all 3 drugs became fully available. Results Following March 2002, a total of 5,198 patients treated with a TNF antagonist were registered in BIOBADASER. Fifteen ATB cases were noted (rate 172 per 100,000 patient-years, 95% CI 103–285). Recommendations were fully followed in 2,655 treatments. The probability of developing ATB was 7 times higher when recommendations were not followed (incidence rate ratio 7.09, 95% CI 1.60–64.69). Two-step tuberculosis skin test for LTBI was the major failure in complying with recommendations. Conclusion New cases of ATB still occur in patients treated with all available TNF antagonists due to lack of compliance with recommendations to prevent reactivation of LTBI. Continuous evaluation of recommendations is required to improve clinical practice.

Journal ArticleDOI
TL;DR: Rheumatoid arthritis patients who are switched to a second anti-TNF drug have high rates of continuation, although among those who must discontinue treatment, the reasons for stopping a second drug are related to the Reasons for stopping the first drug.
Abstract: Objective Patients with rheumatoid arthritis (RA) who experience treatment failure with one anti–tumor necrosis factor (anti-TNF) agent, due to either inefficacy or toxicity, are frequently switched to a second anti-TNF agent, although the benefits of switching are unknown. The present study was undertaken to compare drug continuation rates between the first course and second course of anti-TNF therapy. Methods The study involved a prospective cohort of RA patients from a UK national register of new anti-TNF treatment starts (n = 6,739; 876 starting adalimumab, 2,826 starting etanercept, and starting 3,037 infliximab). Over a mean 15 months of followup, 841 patients stopped taking the first drug due to inefficacy and 1,023 stopped the first drug due to toxicity, of whom 503 and 353, respectively, were switched to a second anti-TNF agent. Kaplan-Meier survival curves were plotted to determine continuation rates for each course, and Cox regression was used to compare each course for the risk of stopping and the reason for stopping (inefficacy or toxicity). Results Overall, 73% of patients who switched to a second anti-TNF agent remained on the new therapy by the end of followup. First drug discontinuation due to inefficacy was associated with an increased rate of second drug discontinuation due to inefficacy (hazard ratio [HR] 2.7, 95% confidence interval [95% CI] 2.1–3.4) but not toxicity (HR 1.1, 95% CI 0.9–1.5). Similarly, first drug discontinuation due to toxicity was associated with an increased rate of second drug discontinuation due to toxicity (HR 2.3, 95% CI 1.9–2.9) but not inefficacy (HR 1.2, 95% CI 0.8–1.6). Conclusion RA patients who are switched to a second anti-TNF drug have high rates of continuation, although among those who must discontinue treatment, the reasons for stopping a second drug are related to the reasons for stopping the first drug. This large data set from the UK provides the first estimates of the magnitude of these effects in patients with long-standing severe RA.

Journal ArticleDOI
TL;DR: The findings indicate that the prevalence of metabolic syndrome is remarkably high among individuals with gout, given the serious complications associated with metabolic syndrome, and this frequent comorbidity should be recognized and taken into account in long-term treatment and overall health of individuals withGout.
Abstract: Objective To determine the prevalence of metabolic syndrome among patients with gout and to examine the association between the 2 conditions in a nationally representative sample of US adults. Methods Using data from 8,807 participants age ≥20 years in the Third National Health and Nutrition Examination Survey (1988–1994), we determined the prevalence of metabolic syndrome among individuals with gout and quantified the magnitude of association between the 2 conditions. We used both the revised and original National Cholesterol Education Program Adult Treatment Panel III (NCEP/ATP III) criteria to define metabolic syndrome. Results The prevalence (95% confidence interval [95% CI]) of metabolic syndrome according to revised NCEP/ATP III criteria was 62.8% (51.9–73.6) among individuals with gout and 25.4% (23.5–27.3) among individuals without gout. Using 2002 census data, ∼3.5 million US adults with a history of gout have metabolic syndrome. The unadjusted and age- and sex-adjusted odds ratios (95% CI) of metabolic syndrome for individuals with gout were 4.96 (3.17–7.75) and 3.05 (2.01–4.61), respectively. With the original NCEP/ATP criteria, the corresponding prevalences were slightly lower, whereas the corresponding odds ratios were slightly higher. The stratified prevalences of metabolic syndrome by major associated factors of gout (i.e., body mass index, hypertension, and diabetes) remained substantially and significantly higher among those with gout than those without gout (all P values <0.05). Conclusion These findings indicate that the prevalence of metabolic syndrome is remarkably high among individuals with gout. Given the serious complications associated with metabolic syndrome, this frequent comorbidity should be recognized and taken into account in long-term treatment and overall health of individuals with gout.

Journal ArticleDOI
TL;DR: Despite the apparent dominant role of ADAMTS-5 in genetically modified mice, the data suggest that both ADAMts-4 and ADAM TS-5 contribute to the structural damage that characterizes human OA.
Abstract: Objective Recent published studies have shown that cartilage from ADAMTS-5–knockout mice, but not ADAMTS-4– or ADAMTS-1–knockout mice, is significantly protected from degradation. The present study was undertaken to evaluate the respective roles of these enzymes in human cartilage breakdown, using a small interfering RNA (siRNA) approach to assess the effects of inhibition of each enzyme in normal and osteoarthritic (OA) explants. Methods The activities of siRNA specifically targeting ADAMTS-1, -4, and -5 were assessed by transfection into primary human chondrocytes and cultured human cartilage explants. At 24 hours, a cytokine stimulus was applied to normal, but not OA, samples to initiate a catabolic response. At designated times, total RNA was isolated and gene expression was measured by quantitative real-time reverse transcription–polymerase chain reaction. Aggrecan release and aggrecanase-generated neoepitope formation were determined by dye binding analysis and Western blotting, respectively. Results Human chondrocytes and explants were efficiently transfected with siRNA that specifically decreased the expression of each targeted gene. Suppression of ADAMTS-4 and ADAMTS-5, individually or in combination, attenuated the degradation of aggrecan in cytokine-stimulated normal cartilage. A reduction in aggrecan degradation was also observed following siRNA-mediated knockdown of either gene in unstimulated OA cartilage. In contrast, knockdown of ADAMTS-1 failed to inhibit aggrecan loss. Conclusion Despite the apparent dominant role of ADAMTS-5 in genetically modified mice, our data suggest that both ADAMTS-4 and ADAMTS-5 contribute to the structural damage that characterizes human OA.

Journal ArticleDOI
TL;DR: Safety data indicated that the 6-mg/kg dose may provide a more favorable risk/benefit profile for infliximab in the treatment of juvenile rheumatoid arthritis, and achievement of the primary efficacy end point at 3 months did not differ significantly between inflIXimab-treated and placebo-treated patients.
Abstract: Objective. To evaluate the safety and efficacy of infliximab in the treatment of juvenile rheumatoid arthritis (JRA). Methods. This was an international, multicenter, randomized, placebo-controlled, double-blind study. One hundred twenty-two children with persistent polyarticular JRA despite prior methotrexate (MTX) therapy were randomized to receive infliximab or placebo for 14 weeks, after which all children received infliximab through week 44. Patients received MTX plus infliximab 3 mg/kg through week 44, or MTX plus placebo for 14 weeks followed by MTX plus infliximab 6 mg/kg through week 44. Results. Although a higher proportion of patients in the 3 mg/kg infliximab group than in the placebo group had achieved responses according to the American College of Rheumatology (ACR) Pediatric 30 (Pedi 30) criteria for improvement at week 14 (63.8% and 49.2%, respectively), the between-group difference in this primary efficacy end point was not statistically significant (P = 0.12). By week 16, after the crossover from placebo to infliximab 6 mg/kg when all patients were receiving infliximab, an ACR Pedi 30 response was achieved in 73.2% of all patients. By week 52, ACR Pedi 50 and ACR Pedi 70 responses had been reached in 69.6% and 51.8%, respectively, of patients. Infliximab was generally well tolerated, but the safety profile of infliximab 3 mg/kg appeared less favorable than that of infliximab 6 mg/kg, with more frequent occurrences of serious adverse events, infusion reactions, antibodies to infliximab, and newly induced antinuclear antibodies and antibodies to double-stranded DNA observed with the 3 mg/kg dose. Conclusion. While infliximab at 3 mg/kg and 6 mg/kg showed durable efficacy at 1 year, achievement of the primary efficacy end point at 3 months did not differ significantly between infliximab-treated and placebo-treated patients. Safety data indicated that the 6-mg/kg dose may provide a more favorable risk/benefit profile. These results warrant further investigation in children with JRA. © 2007, American College of Rheumatology.

Journal ArticleDOI
TL;DR: This meditation-based intervention alleviated depressive symptoms among patients with fibromyalgia and significantly in treatment versus control participants over the 3 assessments.
Abstract: Objective Depressive symptoms are common among patients with fibromyalgia, and behavioral intervention has been recommended as a major treatment component for this illness. The objective of this study was to test the effects of the Mindfulness-Based Stress Reduction (MBSR) intervention on depressive symptoms in patients with fibromyalgia. Methods This randomized controlled trial examined effects of the 8-week MBSR intervention on depressive symptoms in 91 women with fibromyalgia who were randomly assigned to treatment (n = 51) or a waiting-list control group (n = 40). Eligible patients were at least 18 years old, willing to participate in a weekly group, and able to provide physician verification of a fibromyalgia diagnosis. Of 166 eligible participants who responded to local television news publicizing, 49 did not appear for a scheduled intake, 24 enrolled but did not provide baseline data, and 2 were excluded due to severe mental illness, leaving 91 participants. The sample averaged 48 years of age and had 14.7 years of education. The typical participant was white, married, and employed. Patients randomly assigned to treatment received MBSR. Eight weekly 2.5-hour sessions were led by a licensed clinical psychologist with mindfulness training. Somatic and cognitive symptoms of depression were assessed using the Beck Depression Inventory administered at baseline, immediately postprogram, and at followup 2 months after the conclusion of the intervention. Results Change in depressive symptoms was assessed using slopes analyses of intervention effects over time. Depressive symptoms improved significantly in treatment versus control participants over the 3 assessments. Conclusion This meditation-based intervention alleviated depressive symptoms among patients with fibromyalgia.

Journal ArticleDOI
TL;DR: This study provides evidence for the efficacy of MTX treatment in postponing the diagnosis of RA, as defined by the ACR 1987 criteria, and retarding radiographic joint damage in UA patients.
Abstract: Objective To determine whether patients with undifferentiated arthritis (UA; inflammatory, nontraumatic arthritis that cannot be diagnosed using current classification criteria) benefit from treatment with methotrexate (MTX). Methods The PRObable rheumatoid arthritis: Methotrexate versus Placebo Treatment (PROMPT) study was a double-blind, placebo-controlled, randomized, multicenter trial involving 110 patients with UA who fulfilled the American College of Rheumatology (ACR) 1958 criteria for probable RA. Treatment started with MTX (15 mg/week) or placebo tablets, and every 3 months the dosage was increased if the Disease Activity Score was >2.4. After 12 months, the study medication was tapered and discontinued. Patients were followed up for 30 months. When a patient fulfilled the ACR criteria for RA (primary end point), the study medication was changed to MTX. Joint damage was scored on radiographs of the hands and feet. Results In 22 of the 55 patients (40%) in the MTX group, UA progressed to RA compared with 29 of 55 patients (53%) in the placebo group. However, in the MTX group, patients fulfilled the ACR criteria for RA at a later time point than in the placebo group (P = 0.04), and fewer patients showed radiographic progression over 18 months (P = 0.046). Conclusion This study provides evidence for the efficacy of MTX treatment in postponing the diagnosis of RA, as defined by the ACR 1987 criteria, and retarding radiographic joint damage in UA patients.

Journal ArticleDOI
TL;DR: In this article, the authors evaluated the risk of serious bacterial infections associated with tumor necrosis factor α (TNFα) antagonists among rheumatoid arthritis (RA) patients.
Abstract: Objective To evaluate the risk of serious bacterial infections associated with tumor necrosis factor α (TNFα) antagonists among rheumatoid arthritis (RA) patients. Methods A retrospective cohort study of US RA patients enrolled in a large health care organization identified patients who received either TNFα antagonists or methotrexate (MTX). Administrative data were used to identify hospitalizations with possible bacterial infections; corresponding medical records were abstracted and reviewed by infectious disease specialists for evidence of definite infections. Proportional hazards models evaluated time-dependent infection risks associated with TNFα antagonists. Results Hospital medical records with claims-identified suspected bacterial infections were abstracted (n = 187) among RA patients who received TNFα antagonists (n = 2,393; observation time 3,894 person-years) or MTX (n = 2,933; 4,846 person-years). Over a median followup time of 17 months, the rate of hospitalization with a confirmed bacterial infection was 2.7% among the patients treated with TNFα antagonists compared with 2.0% among the patients treated with MTX only. The multivariable-adjusted hazard ratio (HR) of infection among the patients who received TNFα antagonists was 1.9 (95% confidence interval [95% CI] 1.3–2.8) compared with patients who received MTX only. The incidence of infections was highest within 6 months after initiating TNFα antagonist therapy (2.9 versus 1.4 infections per 100 person-years; multivariable-adjusted HR 4.2, 95% CI 2.0–8.8). Conclusion The multivariable-adjusted risk of hospitalization with a physician-confirmed definite bacterial infection was ∼2-fold higher overall and 4-fold higher in the first 6 months among patients receiving TNFα antagonists versus those receiving MTX alone. RA patients were at increased risk of serious infections, irrespective of the method used to define an infectious outcome. Patients and physicians should vigilantly monitor for signs of infection when using TNFα antagonists, particularly shortly after treatment initiation.

Journal ArticleDOI
TL;DR: Data show that imatinib mesylate at biologically relevant concentrations has potent antifibrotic effects in vitro and in vivo, without toxic side effects, and is a promising candidate for the treatment of fibrotic diseases such as SSc.
Abstract: OBJECTIVE: Imatinib mesylate is a clinically well-tolerated small molecule inhibitor that exerts selective, dual inhibition of the transforming growth factor beta (TGFbeta) and platelet-derived growth factor (PDGF) pathways. This study was undertaken to test the potential use of imatinib mesylate as an antifibrotic drug for the treatment of dermal fibrosis in systemic sclerosis (SSc). METHODS: The expression of extracellular matrix (ECM) proteins in SSc and normal dermal fibroblasts was analyzed by real-time polymerase chain reaction, Western blot, and Sircol collagen assay. Proliferation capacity was assessed with the MTT assay. Cell viability was analyzed by mitochondrial membrane potential and by annexin V/propidium iodide staining. Bleomycin-induced experimental dermal fibrosis was used to assess the antifibrotic effects of imatinib mesylate in vivo. RESULTS: Imatinib mesylate efficiently reduced basal synthesis of COL1A1, COL1A2, and fibronectin 1 messenger RNA in SSc and normal dermal fibroblasts, in a dose-dependent manner. The induction of ECM proteins after stimulation with TGFbeta and PDGF was also strongly and dose-dependently inhibited by imatinib mesylate. These results were confirmed at the protein level. Imatinib mesylate did not alter proliferation or induce apoptosis and necrosis in dermal fibroblasts. Consistent with the in vitro findings, imatinib mesylate reduced dermal thickness, the number of myofibroblasts, and synthesis of ECM proteins in experimental dermal fibrosis, without evidence of toxic side effects. CONCLUSION: These data show that imatinib mesylate at biologically relevant concentrations has potent antifibrotic effects in vitro and in vivo, without toxic side effects. Considering its favorable pharmacokinetics and clinical experience with its use in other diseases, imatinib mesylate is a promising candidate for the treatment of fibrotic diseases such as SSc.

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TL;DR: This study supports the idea of a multidimensional approach to examining low back and neck problems and suggests the need for further research to address potentially modifiable psychological factors and health behaviors in these populations.
Abstract: Objective To estimate the US prevalence and psychological and health behavior correlates of low back pain and/or neck pain. No current US national prevalence estimates of low back and neck pain exist and few studies have investigated the associations between low back and neck pain, psychological factors, and health behaviors in a representative sample of US community dwellers. Methods We analyzed data obtained from adults ages 18 years or older (n = 29,828) who participated in the 2002 National Health Interview Survey, a cross-sectional, population-based survey of US adults. Results The 3-month US prevalence of back and/or neck pain was 31% (low back pain: 34 million, neck pain: 9 million, both back and neck pain: 19 million). Generally, adults with low back and/or neck pain reported more comorbid conditions, exhibited more psychological distress (including serious mental illness), and engaged in more risky health behaviors than adults without either condition. Conclusion Low back and neck pain are critical public health problems. Our study supports the idea of a multidimensional approach to examining low back and neck problems and suggests the need for further research to address potentially modifiable psychological factors and health behaviors in these populations.

Journal ArticleDOI
TL;DR: The present data demonstrate the differential regulation of IL-17 and RORgammat expression in human CD4+ T cells compared with murine cells, which may have important implications in the pathogenesis of human autoimmunity as compared with mouse models.
Abstract: Objective Interleukin-17 (IL-17)–producing T helper cells have been proposed to represent a separate lineage of CD4+ cells, designated Th17 cells, which are regulated by the transcription factor retinoic acid–related orphan receptor γt (RORγt). However, despite advances in understanding murine Th17 differentiation, a systematic assessment of factors that promote the differentiation of naive human T cells to Th17 cells has not been reported. The present study was undertaken to assess the effects on naive human CD4+ T cells of cytokines known to promote murine Th17 cells. Methods Human naive and memory CD4+ T cells isolated from peripheral blood were activated and cultured with various cytokines. Cytokine production was measured by enzyme-linked immunosorbent assay and flow cytometry. Messenger RNA was measured by quantitative polymerase chain reaction. Results In response to anti-CD3/anti-CD28 stimulation alone, human memory T cells rapidly produced IL-17, whereas naive T cells expressed low levels. Transforming growth factor β1 and IL-6 up-regulated RORγt expression but did not induce Th17 differentiation of naive CD4+ T cells. However, IL-23 up-regulated its own receptor and was an important inducer of IL-17 and IL-22. Conclusion The present data demonstrate the differential regulation of IL-17 and RORγt expression in human CD4+ T cells compared with murine cells. Optimal conditions for the development of IL-17–producing T cells from murine naive precursors are ineffective in human T cells. Conversely, IL-23 promoted the generation of human Th17 cells but was also a very potent inducer of other proinflammatory cytokines. These findings may have important implications in the pathogenesis of human autoimmunity as compared with mouse models.

Journal ArticleDOI
TL;DR: Investigation of the structural effect of disease-causing mutations on cryopyrin provides insight into potential molecular mechanisms by which cryopyrsin mutations can inappropriately activate an inflammatory response.
Abstract: Objective The cryopyrinopathies are a group of rare autoinflammatory disorders that are caused by mutations in CIAS1, encoding the cryopyrin protein. However, cryopyrin mutations are found only in 50% of patients with clinically diagnosed cryopyrinopathies. This study was undertaken to investigate the structural effect of disease-causing mutations on cryopyrin, in order to gain better understanding of the impact of disease-associated mutations on protein function. Methods We tested for CIAS1 mutations in 22 patients with neonatal-onset multisystem inflammatory disease/chronic infantile neurologic, cutaneous, articular syndrome, 12 with Muckle-Wells syndrome (MWS), 18 with familial cold-induced autoinflammatory syndrome (FCAS), and 3 probands with MWS/FCAS. In a subset of mutation-negative patients, we screened for mutations in proteins that are either homologous to cryopyrin or involved in the caspase 1/interleukin-1β signaling pathway. CIAS1 and other candidate genes were sequenced, models of cryopyrin domains were constructed using structurally homologous proteins as templates, and disease-causing mutations were mapped. Results Forty patients were mutation positive, and 7 novel mutations, V262A, C259W, L264F, V351L, F443L, F523C, and Y563N, were found in 9 patients. No mutations in any candidate genes were identified. Most mutations mapped to an inner surface of the hexameric ring in the cryopyrin model, consistent with the hypothesis that the mutations disrupt a closed form of cryopyrin, thus potentiating inflammasome assembly. Disease-causing mutations correlated with disease severity only for a subset of known mutations. Conclusion Our modeling provides insight into potential molecular mechanisms by which cryopyrin mutations can inappropriately activate an inflammatory response. A significant number of patients who are clinically diagnosed as having cryopyrinopathies do not have identifiable disease-associated mutations.

Journal ArticleDOI
TL;DR: In patients who present with UA, the risk of developing RA can be predicted, thereby allowing individualized decisions regarding the initiation of treatment with disease-modifying antirheumatic drugs in such patients.
Abstract: Objective In patients with undifferentiated arthritis (UA), methotrexate is effective for inhibiting symptoms, structural damage, and progression to rheumatoid arthritis (RA) However, 40-50% of patients with UA experience spontaneous remission Thus, adequate decision-making regarding treatment of patients with early UA requires identification of those patients in whom RA will develop Methods A prediction rule was developed using data from the Leiden Early Arthritis Clinic, an inception cohort of patients with recent-onset arthritis (n = 1,700) The patients who presented with UA were selected (n = 570), and progression to RA or another diagnosis in this group was monitored for 1 year of followup The clinical characteristics with independent predictive value for the development of RA were selected using logistic regression analysis The diagnostic performance of the prediction rule was evaluated using the area under the curve (AUC) Cross-validation controlled for overfitting of the data (internal validation) An independent cohort of patients with UA was used for external validation Results The prediction rule consisted of 9 clinical variables: sex, age, localization of symptoms, morning stiffness, the tender joint count, the swollen joint count, the C-reactive protein level, rheumatoid factor positivity, and the presence of anti-cyclic citrullinated peptide antibodies Each prediction score varied from 0 to 14 and corresponded to the percent chance of RA developing For several cutoff values, the positive and negative predictive values were determined The AUC values for the prediction rule, the prediction model after cross-validation, and the external validation cohort were 089, 087, and 097, respectively Conclusion In patients who present with UA, the risk of developing RA can be predicted, thereby allowing individualized decisions regarding the initiation of treatment with disease-modifying antirheumatic drugs in such patients

Journal ArticleDOI
TL;DR: The results suggest that a chronically high inflammatory response in genetically predisposed individuals promotes an increased risk of CV events and CV mortality in RA.
Abstract: Objective Cardiovascular (CV) disease is the most common cause of mortality in patients with rheumatoid arthritis (RA). We assessed the contribution of epidemiologic features, clinical features, routine laboratory markers of inflammation, and HLA–DRB1 alleles to CV mortality in patients with RA prospectively followed at a single referral center in Spain. Methods Patients fulfilling the 1987 American College of Rheumatology classification criteria for RA seen at the rheumatology outpatient clinic of Hospital Xeral-Calde, Lugo between March and September 1996 were included. HLA–DRB1 phenotype, epidemiologic data, and clinical data were assessed at that time. Patients were prospectively followed and clinical records were examined until patient's death or September 1, 2005. Results A total of 182 consecutive patients were assessed. Compared with the general Spanish population, the age- and sex-standardized mortality ratio by CV cause was 1.78. CV mortality adjusted by age at disease onset and sex was associated with chronic inflammation determined by C-reactive protein level (CRP; hazard ratio [HR] 1.14, P < 0.001) and erythrocyte sedimentation rate (ESR; HR 1.05, P = 0.003). Patients with HLA–DRB1*04 shared epitope alleles (HR 4.15, P = 0.030), in particular those HLA–DRB1*0404 positive (HR 6.65, P = 0.002), had increased risk of CV mortality. Increased risk of CV events was also associated with CRP level (HR 1.09, P = 0.001), ESR (HR 1.03, P = 0.003), and HLA–DRB1*0404 (HR 4.47, P = 0.002). Conclusion Our results suggest that a chronically high inflammatory response in genetically predisposed individuals promotes an increased risk of CV events and CV mortality in RA.

Journal ArticleDOI
TL;DR: It is found that WS contains more informative proteins, peptides, and mRNA, as compared with gland-specific saliva, that can be used in generating candidate biomarkers for the detection of primary SS.
Abstract: Sjogren’s syndrome (SS), which was first described in 1933 by the Swedish physician Henrik Sjogren (1), is a chronic autoimmune disorder clinically characterized by a dry mouth (xerostomia) and dry eyes (keratoconjunctivitis sicca). The disease primarily affects women, with a ratio of 9:1 over the occurrence in men. While SS affects up to 4 million Americans, about half of the cases are primary SS. Primary SS occurs alone, whereas secondary SS presents in connection with another autoimmune disease, such as rheumatoid arthritis or systemic lupus erythematosus (SLE). Histologically, SS is characterized by infiltration of exocrine gland tissues by predominantly CD4 T lymphocytes. At the molecular level, glandular epithelial cells express high levels of HLA–DR, which has led to the speculation that these cells are presenting antigen (viral antigen or autoantigen) to the invading T cells. Cytokine production follows, with interferon (IFN) and interleukin-2 (IL-2) being especially important. There is also evidence of B cell activation with autoantibody production and an increase in B cell malignancy. SS patients exhibit a 40-fold increased risk of developing lymphoma. SS is a complex disease that can go undiagnosed for several months to years. Although the underlying immune-mediated glandular destruction is thought to develop slowly over several years, a long delay from the start of symptoms to the final diagnosis has been frequently reported. SS presumably involves the interplay of genetic and environmental factors. To date, few of these factors are well understood. As a result, there is a lack of early diagnostic markers, and diagnosis usually lags symptom onset by years. A new international consensus for the diagnosis of SS requires objective signs and symptoms of dryness, including a characteristic appearance of a biopsy sample from a minor or major salivary gland and/or the presence of autoantibody such as anti-SSA (2–4). However, establishing the diagnosis of primary SS has been difficult in light of its nonspecific symptoms (dry eyes and mouth) and the lack of both sensitive and specific biomarkers, either body fluid– or tissue-based, for its detection. It is widely believed that developing molecular biomarkers for the early diagnosis of primary SS will improve the application of systematic therapies and the setting of criteria with which to monitor therapies and assess prognosis (e.g., lymphoma development). Saliva is the product of 3 pairs of major salivary glands (the parotid, submandibular, and sublingual glands) and multiple minor salivary glands that lie beneath the oral mucosa. Human saliva contains many informative proteins that can be used for the detection of diseases. Saliva is an attractive diagnostic fluid because testing of saliva provides several key advantages, including low cost, noninvasiveness, and easy sample collection and processing. This biologic fluid has been used for the survey of general health and for the diagnosis of diseases in humans, such as human immunodeficiency virus, periodontal diseases, and autoimmune diseases (5–8). Our laboratory is active in the comprehensive analysis of the saliva proteome (for more information, see www.hspp.ucla.edu), thus providing the technologies and expertise to contrast proteomic constituents in primary SS with those in control saliva (9–11). Thus far, we have identified over 1,000 proteins in whole saliva (WS). In addition, we have recently identified and cataloged ~3,000 messenger RNAs (mRNA) in human WS (12). These studies have provided a solid foundation for the discovery of biomarkers in the saliva of patients with primary SS. We have previously demonstrated proteome- and genome-wide approaches to harnessing saliva protein and mRNA signatures for the detection of oral cancer in humans (13,14). There have been continuous efforts in the search for biomarkers in human serum or saliva for the diagnosis of primary SS. Some gene products were found at elevated levels in SS patient sera or saliva, including β2-microglobulin (β2m), soluble IL-2 receptor, IL-6, anti-Ro/SSA, anti-La/SSB, and anti–α-fodrin autoantibodies (15–20). However, none of them individually is sensitive or specific enough to use for the confirmative diagnosis of SS (15). Therefore, it is crucial to use emerging proteome- and genome-wide approaches to discover a wide spectrum of informative and discriminatory biomarkers that can be combined to improve the sensitivity and specificity for the detection of primary SS.

Journal ArticleDOI
TL;DR: PDUS is a sensitive and reliable method for longitudinal assessment of inflammatory activity in early rheumatoid arthritis and may have a predictive value in disease activity and radiographic outcome.
Abstract: 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.

Journal ArticleDOI
TL;DR: PAD-2 and PAD-4 are the only PAD isotypes expressed in the synovial tissue of patients with RA and those with other arthritides, and both enzymes were demonstrable within or in the vicinity of citrullinated fibrin deposits.
Abstract: Objective Autoantibodies to citrullinated proteins (ACPAs) are specific for rheumatoid arthritis (RA) and probably are involved in its pathophysiology Citrullyl residues, posttranslationally generated by peptidyl arginine deiminase (PAD), are indispensable components of ACPA-targeted epitopes The aim of this study was to identify which PAD isotypes are expressed in the synovial tissue (ST) of patients with RA and are involved in the citrullination of fibrin, the major synovial target of ACPAs Methods Expression of all PAD isotypes, including the recently described PAD type 6 (PAD-6), was explored by reverse transcription–polymerase chain reaction and immunoblotting, first in blood-derived mononuclear leukocytes from healthy donors, then in ST samples from 16 patients with RA and 11 control patients (4 with other arthritides and 7 with osteoarthritis [OA]) In ST samples from patients with RA, PADs were localized by immunohistochemistry Results In lymphocytic and monocytic cells and, similarly, in ST samples from patients with RA, the PAD-2, PAD-4, and PAD-6 genes were found to be transcribed, but only PAD-2 and PAD-4 enzymes were detected PAD-2 was also expressed in ST from control patients, including those with OA, while PAD-4 was preferentially expressed in ST from patients with other arthritides In RA, the expression levels of PAD-2 and PAD-4 were correlated with the intensity of inflammation (cell infiltration, hypervascularization, and synovial lining hyperplasia), and both enzymes were demonstrable within or in the vicinity of citrullinated fibrin deposits Conclusion PAD-2 and PAD-4 are the only PAD isotypes expressed in the ST of patients with RA and those with other arthritides Inflammatory cells are a major source, but PAD-4 also comes from hyperplastic synoviocytes Both isotypes are probably involved in the citrullination of fibrin

Journal ArticleDOI
TL;DR: The results suggest that asymptomatic, persistently aPL-positive individuals do not benefit from low-dose aspirin for primary thrombosis prophylaxis, have a low overall annual incidence rate of acute thromBosis, and develop vascular events when additional thROMbosis risk factors are present.
Abstract: Objective To determine the efficacy of a daily dose of 81 mg aspirin in primary thrombosis prevention in asymptomatic, persistently antiphospholipid antibody (aPL)–positive individuals (those with positive aPL but no vascular and/or pregnancy events). Methods The Antiphospholipid Antibody Acetylsalicylic Acid (APLASA) study was a multicenter, randomized, double-blind, placebo-controlled clinical trial in which asymptomatic, persistently aPL-positive individuals were randomized to receive a daily dose of 81 mg of aspirin or placebo. In a separate observational and parallel study, asymptomatic, persistently aPL-positive individuals who were taking aspirin or declined randomization were followed up prospectively. Results In the APLASA study, 98 individuals were randomized to receive aspirin or placebo (mean ± SD followup period 2.30 ± 0.95 years), of whom 48 received aspirin and 50 received placebo. In the observational study, 74 nonrandomized individuals were followed up prospectively (mean ± SD followup period 2.46 ± 0.76 years); 61 received aspirin and 13 did not. In the APLASA study, the acute thrombosis incidence rates were 2.75 per 100 patient-years for aspirin-treated subjects and 0 per 100 patient-years for the placebo-treated subjects (hazard ratio 1.04, 95% confidence interval 0.69–1.56) (P = 0.83). Similarly, in the observational study, the acute thrombosis incidence rates were 2.70 per 100 patient-years for aspirin-treated subjects and 0 per 100 patient-years for those not treated with aspirin. All but 1 patient with thrombosis in either study had concomitant thrombosis risk factors and/or systemic autoimmune disease at the time of thrombosis. Conclusion Our results suggest that asymptomatic, persistently aPL-positive individuals do not benefit from low-dose aspirin for primary thrombosis prophylaxis, have a low overall annual incidence rate of acute thrombosis, and develop vascular events when additional thrombosis risk factors are present.