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ID PMID Title PublicationDate abstract
18023077 Early findings of small-animal MRI and small-animal computed tomography correlate with his 2008 Jun With the use of a commonly utilized animal model of rheumatoid arthritis, the central goal of this work was to determine how well the small-animal imaging tools, small-animal MRI (microMRI) and small-animal X-ray computed tomography (microCT), can detect very early histological changes that occur immediately after induction of the disease. Arthritis was induced in rats by injecting complete Freund's adjuvant into the tail. Right hind paws of living rats were evaluated with 4.7 T microMRI with T1-weighted spin echo and inversion recovery sequences. Paw specimens were also evaluated with microCT and by histological examination (n = 29). MicroMR images were scored for the presence of joint effusion, soft tissue swelling, bone marrow changes, and bone erosions. MicroCT measured bone mineral density (BMD). Histology scores were obtained from representative slides from the same rats. The correlation between BMD, MRI and histology was analyzed using linear regression analysis and analysis of covariance. MRI abnormalities were detected on day 5 after induction as joint effusion and soft tissue swelling, followed by bone marrow changes on day 6 and bone erosion on day 8. BMD measured by microCT decreased, the decrease becoming significant on day 7 (P < 0.019). Soft tissue swelling, joint effusion, and bone erosion scores on microMRI correlated with histology (r2 approximately 0.7). Bone marrow changes were seen more clearly with microMRI than by histological examination. Bone loss could be detected earlier by microCT than on histological sections. In conclusion, microMRI and microCT can be used to evaluate early disease changes within 1 week of induction in the adjuvant-induced arthritis model, and have the ability to detect certain manifestations of disease earlier than histological analysis. The use of small-animal imaging techniques potentially allows earlier diagnosis, improved subject stratification, earlier drug implementation, and therefore improved drug trials in animal models of rheumatoid arthritis.
18303163 Immunopathology of necrotising scleritis. 2008 Mar AIM: To detect the immunohistopathology of necrotising scleritis. METHODS: Immunohistochemical staining was performed on two groups of enucleated eyes with necrotising scleritis (systemic autoimmune disease and idiopathic scleritis). Deparaffinised sections were stained with CD3, CD20, CD68, CD8, CD4 and dendritic reticulum cells (DRC). RESULTS: Within the autoimmune group, about 43% of inflammatory cells stained positive with CD20, 35% with CD68, 17% with CD3, 8% with CD8, 4% with DRC and less than 1% with CD4. Within the idiopathic group of eyes, about 43% of cells stained positive for CD68, 23% for CD3, 17% for CD20, 7% for CD8, 1% for DRC and less than 1% for CD4. CONCLUSIONS: The infiltrate within the group of eyes with systemic autoimmune disease suggests that the inflammation may be driven by B cells. However, the large numbers of CD68 cells found in both groups of eyes indicate that macrophages could play a role in the necrotising process.
17491097 Hand bone densitometry: a more sensitive standard for the assessment of early bone damage 2007 Nov OBJECTIVE: To examine the role of hand dual-energy x ray absorptiometry (DEXA) compared with radiography in the assessment of bone involvement in patients with early rheumatoid arthritis (RA) who have active disease. METHODS: The study population (n = 79) had RA of <12 months' duration and were selected for poor prognostic features. Clinical data and bone mineral density (BMD) data were collected at baseline, 24 and 48 weeks. Hand radiographs were performed at baseline and 48 weeks. Bone damage analyses were performed for the group and individuals using the smallest detectable change (SDC) method. RESULTS: At baseline, mean disease duration was 8.5 months, erythrocyte sedimentation rate was 34.3 mm/hour, C-reactive protein was 40.2 mg/l, Health Assessment Questionnaire score was 1.35 and 81% of patients were positive for rheumatoid factor. Mean (95% CI) hand BMD loss was 2.5% (-3.5 to -1.5) at 24 weeks and 2.6% (-3.8 to -1.5) at 48 weeks. Individual hand bone loss exceeding the SDC was seen in 46.8% at 24 weeks and in 58.2% at 48 weeks. In the subgroup of 58 patients who had undergone radiography, radiographic joint damage score evaluated by the Sharp-van der Heijde method increased from 4.8 to 10.6 (p = 0.001). Individual hand bone loss in this subgroup exceeding the SDC was seen in 50.0% at 24 weeks and in 56.9% at 48 weeks, whereas at 48 weeks only 22.4% had deteriorated in modified Sharp score. CONCLUSION: The study results indicate that hand DEXA is a more sensitive tool than radiology (radiographic joint-damage scores), for measuring disease-related bone damage in early RA.
18710059 [The role of interleukin-6 in rheumatoid arthritis]. 2008 Jun Cytokines such as TNF-alpha and IL-1beta play key roles in driving the inflammation and synovial cell proliferation that characterize rheumatoid arthritis (RA) joint destruction. It is, therefore, not surprising that therapies for RA have targeted these cytokines. While blockade of TNF-alpha or IL-1beta has been efficacious for many patients with RA, adequacy and maintenance of response are not universal, and increased risk of adverse events such as infections and malignancy remain a concern. Therefore, new targets in the treatment of RA continue to be examined. As interleukin-6 (IL-6) has been implicated in the pathogenesis of RA, blockade of its activity is of both scientific and clinical interest. Tocilizumab has been assessed in a number of studies in recent years, mainly in patients with rheumatoid arthritis. Data from randomized controlled clinical trials demonstrate the effectiveness of tocilizumab in improving the signs and symptoms of RA. In addition, it appears that such inhibition of IL-6 can have positive effects on functional status, an important outcome for RA patients. Finally, data suggest that treatment with this agent may also inhibit the progression of disease as assessed radiographically. Data from recent studies will help to refine the ultimate use of this novel approach to treatment, and help clinicians to optimize therapy using this approach.
18344919 Tregs and rheumatoid arthritis. 2008 Jan Regulatory T cells (Tregs) are a subset of T cells which are involved in peripheral immune tolerance. Their role in autoimmune disease which occurs through a breakdown of tolerance is of particular interest in trying to ascertain the mechanism(s) of disease progression. It is hoped that by understanding the role of Tregs in autoimmunity a reliable therapy may be developed to aid in both the treatment and potentially cure of disease. This review will focus on the naturally-occurring CD4+ CD25+ regulatory T cell subset and their possible involvement in rheumatoid arthritis.
18947370 Epigenetic modifications in rheumatoid arthritis. 2008 Over the last decades, genetic factors for rheumatoid diseases like the HLA haplotypes have been studied extensively. However, during the past years of research, it has become more and more evident that the influence of epigenetic processes on the development of rheumatic diseases is probably as strong as the genetic background of a patient. Epigenetic processes are heritable changes in gene expression without alteration of the nucleotide sequence. Such modifications include chromatin methylation and post-translational modification of histones or other chromatin-associated proteins. The latter comprise the addition of methyl, acetyl, and phosphoryl groups or even larger moieties such as binding of ubiquitin or small ubiquitin-like modifier. The combinatory nature of these processes forms a complex network of epigenetic modifications that regulate gene expression through activation or silencing of genes. This review provides insight into the role of epigenetic alterations in the pathogenesis of rheumatoid arthritis and points out how a better understanding of such mechanisms may lead to novel therapeutic strategies.
18799097 Hypoxia appears at pre-arthritic stage and shows co-localization with early synovial infla 2008 Jul OBJECTIVE: The presence of hypoxia in rheumatoid synovium has been well known, but exact correlation between hypoxia and synovitis is unclear. The aim of our study was to investigate the time and spatial relationship and the correlation of severity between hypoxia and synovitis in pre-arthritic or early stage of inflammatory joint disease. METHODS: DBA/1J mice were injected intradermally with type II collagen and adjuvant solution to induce arthritis; mice injected with only adjuvant were used as a control group. CIA and control mice were sacrificed weekly after the injection to evaluate serial pathological changes. H&E stain and hydroxyprobe-1 stain were performed to look at the status of inflammation and hypoxia. RESULTS: In serial observations of tissue pathology, we could note the inflammation of synovium developing a week after the injection of type II collagen. Hypoxic change, measured by the hydroxyprobe-1 stain, was also identified in synovium as early as 1 week after the collagen injection, prior to clinically evident arthritis. In addition, we could observe that inflammation and hypoxia co-localize in the synovium and there was a positive correlation between the severity of hypoxia and the degree of synovitis. CONCLUSION: Our results demonstrate that hypoxia takes place in synovium at the pre-arthritic stage of disease and have a close spatial relationship and a positive severity correlation with synovitis.
17235613 [Periprosthetic fractures in patients with rheumatoid arthritis]. 2007 Feb Postoperative periprosthetic fracture is a rare but serious complication after joint replacement surgery. Due to poor bone quality, multiple joint involvement with the replacement of different joints and considerable comorbidity, the presence of rheumatoid arthritis is associated with a high risk of periprosthetic fractures. For the same reasons, periprosthetic fractures in patients with rheumatoid arthritis can be very difficult to treat, and their management often requires an interdisciplinary approach. On the basis of the current literature, the present work describes different aspects of the epidemiology of periprosthetic fractures, principles of their classification, different treatment options and the results of treatment of these fractures. Special attention is paid to the situation of patients with rheumatoid arthritis.
17443378 A shot in the dark: failing to recognize the link between physical and mental illness. 2007 May A 74-year-old widowed white man with chronic rheumatoid arthritis presented with nausea and weight loss. He was diagnosed with failure to thrive and admitted for hydration. Misoprostol was determined to be the etiology of his symptoms and he was discharged home. Three days later, he killed himself with a gunshot to the head. Clinicians often fail to recognize those at high risk for suicide. Suicidal risk is increased in both psychiatric and physical illness, and particularly when both are present. Psychiatric illness, particularly depression, often underlies chronic medical illness. The purpose of this case report is to remind health care providers of the strong association between depression and chronic medical illness, and to consider this in all patients, including those who present solely with physical symptoms. Recognizing this association and screening for it, as recommended by the U.S. Preventive Services Task Force, may prevent the unnecessary tragedy of suicide.
18758893 Masked early symptoms of pneumonia in patients with rheumatoid arthritis during tocilizuma 2009 Although reports of serious infections in clinical trials for rheumatoid arthritis (RA) with tocilizumab, anti-interleukin6 (IL-6) receptor antibody, have been relatively few, there is still some concern about infections. We report here two cases of patients who developed severe pneumonia during tocilizumab treatment for RA. Both patients initially presented with only minimal clinical symptoms and modest elevations in serum C-reactive protein. Tocilizumab might suppress the early inflammatory symptoms of pneumonia.
18696072 Factors associated with functional disability in patients with rheumatoid arthritis. 2008 Dec To determine factors associated with functional disability in patients with rheumatoid arthritis (RA). A total of 100 RA patients were reviewed retrospectively. Multiple regression analysis was used to investigate associations between the dependent variable (health assessment questionnaire) and independent variables (age, disease duration, hand grip strength values, VAS and DAS-28 scores). Main factors associated with functional disability were disease activity score as reflected in a high score on the DAS-28 (r=0.68, p<0.001) and disease duration (r=0.23, p<0.05). Increased age, decreased grip strength and high pain level were associated with lower functional ability, but none of these was a predictor of disability in the regression model. The results indicate that age, disease duration, disease activity, pain intensity and hand grip strength are related to physical disability in patients with RA. However, only disease activity has an impact on physical function. Thus, treatment of RA patients should focus on early inhibition of disease activity in order to achieve a good functional outcome.
17530675 Long-term treatment with methotrexate or tumor necrosis factor alpha inhibitors does not i 2007 Jun 15 OBJECTIVE: We previously demonstrated that patients with rheumatoid arthritis (RA) have a 10-fold systemic Epstein-Barr virus (EBV) overload, very similar to that observed in healthy organ transplant recipients. Our objective was to monitor EBV load over time in patients with RA receiving methotrexate, infliximab, or etanercept to detect possible immunosuppression-associated EBV dysregulation, as described in posttransplant lymphoproliferative disease. METHODS: The EBV load in the peripheral blood mononuclear cells (PBMCs) from 19 patients receiving methotrexate, 68 patients receiving infliximab, and 48 patients receiving etanercept was monitored for durations ranging from 6 months to 5 years using a real-time polymerase chain reaction assay previously developed for that purpose. The effect of treatment duration on EBV load and the link between the Disease Activity Score in 28 joints and EBV load were analyzed by generalized estimating equations. RESULTS: Methotrexate tended to decrease EBV load over time, but this did not reach significance. Tumor necrosis factor alpha (TNFalpha) inhibitors did not significantly modify EBV load over time. Finally, high disease activity was significantly associated with high EBV load. CONCLUSION: Long-term usage of methotrexate or TNFalpha inhibitors in patients with RA does not significantly influence EBV load in PBMCs.
17009228 Pharmacogenomic and metabolic biomarkers in the folate pathway and their association with 2006 Oct OBJECTIVE: To evaluate the contribution of metabolites (methotrexate [MTX] and folate polyglutamate [PG] levels) and pharmacogenetic biomarkers in the folate pathway to the effects of MTX in patients with rheumatoid arthritis not previously treated with this antifolate. METHODS: Forty-eight MTX-naive adult patients were enrolled in a prospective longitudinal study. MTX therapy was initiated at 7.5 mg/week and was increased every 4-6 weeks until a therapeutic response was achieved. Response was assessed using the Disease Activity Score in 28 joints (DAS28). Red blood cell (RBC) MTX and folate PG levels were measured with 9 common polymorphisms in the folate pathway. Statistical analyses consisted of generalized linear models and multivariate regressions. RESULTS: After 6 months of therapy, the median weekly MTX dosage was 17.5 mg and the median decrease in the DAS28 was 2.0. There was a large interpatient variability in RBC MTXPG levels (median 35 nmoles/liter [interquartile range 28-51] at month 6). Patients with a lesser decrease in the DAS28 (fewer improvements) had lower RBC MTXPG levels (P < 0.05) despite the higher MTX dose administered (P < 0.05). RBC folate PG levels decreased significantly during treatment, and a lesser decrease in RBC folate PGs was associated with a lesser decrease in the DAS28 (P < 0.05). Primary side effects were gastrointestinal and neurologic in nature. Risk genotypes associated with toxicity were in gamma-glutamyl hydrolase (-401CC), 5-aminoimidazole-4-carboxamide ribonucleotide transformylase (347GG), methylenetetrahydrofolate reductase (1298AC/CC), methionine synthase (2756AA), and methionine synthase reductase (66GG). CONCLUSION: RBC MTXPG levels are a useful means by which to monitor therapy. The genetic associations presented generate hypotheses, and confirmation in independent cohorts is warranted.
18004190 Development of a model to measure symptom status in persons living with rheumatoid arthrit 2007 Nov BACKGROUND: Rheumatoid arthritis (RA) is a chronic illness with a constellation of symptoms. The management of which is important for quality of life. Our review of the literature indicated that there is currently no standardized approach to measuring the symptom status of persons living with RA. OBJECTIVE: The purpose of this study is to report the development and initial validation of a structure to measure symptom status in persons living with RA. METHODS: For this secondary analysis, there were 901 female patients with complete symptom checklists available from the Arthritis, Rheumatism, and Aging Medical Information System. A tentative structure using exploratory factor analysis was developed, the structure was replicated in a separate sample using confirmatory factor analysis, and then hypothesized relationships with an external criterion (functional health) was tested using structural equation modeling. The symptom checklist contains 31 symptoms. The stem question is, "Have you had any of the following symptoms during the past 6 months; if yes mark all that apply." RESULTS: A two-factor structure for measuring symptom status was identified, RA Pain Symptoms and General Symptoms. Using the external criterion, we also demonstrated that the two factors were different and that the RA Pain Symptoms Factor had a stronger impact on functional health. This provides evidence of the discriminant as well as predictive validity of the RA Pain Symptoms Factor. DISCUSSION: Effective symptom management is an important outcome for nursing practice. Because the assessment of symptoms is the first step in symptom management, the identification of a measurement structure is an essential step.
18557992 High mobility group box-1 protein as a tumor necrosis factor-independent therapeutic targe 2008 Rheumatoid arthritis (RA) remains a prevalent disease worldwide that causes significant morbidity and mortality despite recent therapeutics. High mobility group box-1 (HMGB1) protein, originally appreciated as an intranuclear DNA binding protein, has been implicated as an integral mediator in the pathogenesis of animal arthritides and RA disease in humans. Our current understanding of HMGB1 has promoted the development of targeting therapies that have improved outcomes in animal models of inflammation. In the previous issue of Arthritis Research & Therapy, Sundberg and colleagues address, for the first time in a prospective cohort study, whether HMGB1 expression is dependent upon tumor necrosis factor activity in patients with RA.
18716780 Causes of death in patients with rheumatoid arthritis autopsied during a 40-year period. 2008 Oct We studied causes of death (CoDs) between 1952 and 1991 assessed by a clinician before autopsy and then determined at autopsy by a pathologist in 369 subjects with rheumatoid arthritis (RA) and 370 subjects without RA (non-RA). We analysed clinical data for RA subjects between 1973 and 1991. In RA subjects, leading autopsy-based CoDs were RA, cardiovascular diseases and infections. Between diagnoses of CoDs by the clinician and those determined by the pathologist, RA subjects had lower agreement than did the non-RA regarding coronary deaths (Kappa reliability measure: 0.33 vs. 0.46). In non-RA subjects, autopsy-based coronary deaths showed a decline since the 1970s with no such decline in RA. Between subjects treated at any time during RA with disease-modifying anti-rheumatic drugs and those without, autopsy-based CoDs were similar. Coronary death being less accurately diagnosed in RA subjects may indicate that coronary heart disease in RA patients often remains unrecognized.
17915099 Malignancy and rheumatoid arthritis. 2007 Oct The occurrence of cancer is not an infrequent event in patients with rheumatoid arthritis (RA). Indeed, following diagnosis of RA at a typical age (55 years), one in five patients will be diagnosed with cancer. In the vast majority of such cases, the cancer has nothing to do with RA or its treatment; rather, it represents the "background" risk applicable to all humans. In some cases, the cancer occurs as a result of factors also associated with the risk of developing RA (eg, smoking), even though no direct link exists between the cancer and the RA. In a fraction of cases, however, the cancer is causally associated with the RA disease or its treatments. This review summarizes our current understanding of the occurrence of cancer in RA, possible links to RA disease and to traditional and newer RA treatments.
17056470 Application of biomarkers in the clinical development of new drugs for chondroprotection i 2006 Nov Emerging evidence supports the concept that biochemical markers are clinically useful non-invasive diagnostic tools for the monitoring of changes in cartilage turnover in patients with destructive joint diseases such as osteoarthritis (OA) and rheumatoid arthritis (RA). Epidemiological studies demonstrated that measurements of different degradation products of proteins in the extracellular matrix of hyaline cartilage in urine or serum samples are (1) increased in OA or RA patients compared with healthy individuals, (2) correlate with disease activity, and (3) are predictive for the rate of changes in radiographic measures of cartilage loss. The present review provides an updated list of available biomarkers and summarize the research data arguing for their clinical utility. In addition, it addresses the question whether or not the monitoring of biomarkers during different treatment modalities could be a useful approach to characterize the chondro-protective effects of approved and candidate drugs. Finally, it briefly reviews the in vitro/ex vivo experimental settings - isolated chondrocyte cultures and articular cartilage explants - that can assist in the verification of novel markers, but also studies assessing direct effects of drug candidates on chondrocytes. Collectively, biomarkers may acquire a function as established efficacy parameters in the clinical development of novel chondro-protective agents.
15988600 Catalase and PPARgamma2 genotype and risk of rheumatoid arthritis in Koreans. 2006 Mar Catalase (CAT) and peroxisome proliferator activated receptor-gamma2 (PPARgamma2) are important regulators of oxidative stress and inflammation, and may contribute to the development of rheumatoid arthritis (RA). We investigated the association between CAT and PPARgamma2 genotypes and risk and severity of RA using 474 cases and 400 controls. Genotyping for the -262C-->T polymorphism of CAT and the Pro12Ala polymorphism of PPARgamma2 was performed by PCR-RFLP analysis. Severity of RA was assessed by the anatomical stage according to Steinbrocker, and a Korean language version of a Health Assessment Questionnaire (KHAQ). No association was observed between CAT and PPARgamma2 genotypes and risk of RA. Our results suggest that genetic polymorphisms of CAT and PPARgamma2 do not play a significant role in the susceptibility to RA among Koreans.
17974597 Psychometric properties of the Rheumatoid Arthritis Disease Activity Index (RADAI) in a co 2008 Jun OBJECTIVES: To examine the psychometric properties of the self-administered Dutch Rheumatoid Arthritis Disease Activity Index (RADAI) and its short form (RADAI-SF) in patients with rheumatoid arthritis starting anti-tumour necrosis factor treatment. METHOD: Internal consistency was assessed with Cronbach's alpha. A confirmatory factor analysis (CFA) was carried out to test the single-factor structure. Construct validity was examined by correlating RADAI and RADAI-SF scores with Disease Activity Score in 28 joints (DAS28). Internal responsiveness was evaluated with the paired t test and the standardised response mean (SRM). External responsiveness was assessed with receiver operating characteristic analysis and the SRM, using the EULAR response criterion as external criterion. Change scores were correlated with changes in DAS28. RESULTS: At baseline and after 3 months' treatment, respectively, 191 and 171 patients completed the RADAI. The internal consistency of the RADAI and the RADAI-SF was satisfactory. CFAs confirmed the single-factor structure of both RADAI versions, but the short form provided the best model fit. Moderate correlations were found with the DAS28. SRMs of the RADAI and the RADAI-SF were, respectively, 0.76 and 0.80. Both versions had moderate accuracy to distinguish responders from non-responders. Changes scores were moderately correlated with DAS28 change scores. CONCLUSIONS: This study showed satisfactory psychometric properties of the Dutch version of the RADAI. Omission of the tender joint count (RADAI-SF) produced comparable results and is justified for research purposes. The tender joint count might be useful as additional clinical information in patient management.