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ID PMID Title PublicationDate abstract
20980284 Elevated number of recently activated T cells in bone marrow of patients with rheumatoid a 2011 Jan OBJECTIVES: (1) To compare the absolute T-cell numbers in bone marrow (BM) isolated from patients with rheumatoid arthritis (RA) and osteoarthritis (OA); (2) to measure the levels of soluble interleukin 15 (IL-15) and IL-7; (3) to analyse the expression of activation markers on T cells; (4) to analyse influence of IL-15 stimulation on T-cell proliferation. METHODS: BM samples were obtained from patients undergoing joint replacement surgery. Concentrations of IL-15 and IL-7 were measured using specific ELISAs. The absolute number of T lymphocytes, their activation status and proliferation were evaluated by flow cytometry. RESULTS: BM from patients with RA contained double the number of CD3 T cells in comparison with OA (6.1 vs 2.7 × 10(6) cells/ml, p<0.008). Ratio CD3CD4:CD3CD8 was increased in RA BM, clearly indicating accumulation of CD3CD4 cells. T cells obtained from patients with RA expressed higher level of early activation markers than from OA. Elevated levels of IL-15 were found in BM plasma from patients with RA in comparison with patients with OA (1304.5±956.3 pg/ml and 760±238.7 pg/ml respectively, p<0.01). These data were confirmed by immunohistochemistry of RA BM from regions proximal and distal to the joint. Although both CD3CD4 and CD3CD8 cells proliferated after IL-15 stimulation in vitro, CD3CD4 cells from patients with RA proliferated more vigorously than those from patients with OA, reflecting the composition of T-cell subsets in BM. CONCLUSION: These results suggest that locally overproduced IL-15 may be responsible for the activation and proliferation of T cells in situ, reflected by significantly increased number of activated T cells in RA BM, possibly contributing to the pathogenesis of RA.
20026562 Hand bone mineral density is associated with both total hip and lumbar spine bone mineral 2010 Mar OBJECTIVE: RA is associated with localized bone loss in the hands, as well as generalized osteoporosis. We evaluated the relationship between hand digital X-ray radiogrammetry BMD (DXR-BMD) and total hip and lumbar spine BMD. METHODS: We conducted a cross-sectional study of 138 post-menopausal women with RA. The DXR-BMD was calculated based on digitized hand radiographs. Measurements of the total hip and lumbar spine BMD were performed by a DXA-BMD (BMDa) scan. Patient and physician questionnaires and laboratory samples supplied information on relevant covariates. Separate multivariate linear regression models were constructed to determine the cross-sectional relationship between hand DXR-BMD (independent variable) and total hip or lumbar spine BMD (dependent variables). RESULTS: The cohort comprised women with a median age of 61 years and RA disease duration of 13 years. Seventy-six per cent were either RF and/or anti-cyclic citrullinated peptide (anti-CCP) positive and most had moderate disease activity [median disease activity score-28 joint count (DAS28) 3.7]. Hand DXR-BMD was significantly associated with total hip BMD (beta = 0.61; P < 0.0001) and lumbar spine BMD (beta = 0.62; P < 0.0008) in adjusted models. CONCLUSIONS: This study suggests that hand DXR-BMD is associated with both the total hip and lumbar spine BMD among post-menopausal women with RA. The relationship between bone loss in the hands and generalized osteoporosis should be further explored in longitudinal studies of patients with RA.
19584899 Gene and pathway-based second-wave analysis of genome-wide association studies. 2010 Jan Despite the great success of genome-wide association studies (GWAS) in identification of the common genetic variants associated with complex diseases, the current GWAS have focused on single-SNP analysis. However, single-SNP analysis often identifies only a few of the most significant SNPs that account for a small proportion of the genetic variants and offers only a limited understanding of complex diseases. To overcome these limitations, we propose gene and pathway-based association analysis as a new paradigm for GWAS. As a proof of concept, we performed a comprehensive gene and pathway-based association analysis of 13 published GWAS. Our results showed that the proposed new paradigm for GWAS not only identified the genes that include significant SNPs found by single-SNP analysis, but also detected new genes in which each single SNP conferred a small disease risk; however, their joint actions were implicated in the development of diseases. The results also showed that the new paradigm for GWAS was able to identify biologically meaningful pathways associated with the diseases, which were confirmed by a gene-set-rich analysis using gene expression data.
18557790 Interleukin-15 stimulates macrophages to activate CD4+ T cells: a role in the pathogenesis 2009 Jan Interleukin-15 (IL-15) is a proinflammatory cytokine that is overexpressed in rheumatoid arthritis (RA), a disease characterized by activation of monocytes/macrophages (MPhi), and by expansion of autoreactive CD4(+) T cells. We hypothesized that IL-15 plays a major role for this expansion of CD4(+) T cells and modulates the phenotype of monocytes/MPhi and their interaction with CD4(+) T cells. Here, we show that IL-15 enhances the proliferation of CD4(+) T cells from patients with RA in peripheral blood mononuclear cell cocultures. To further dissect the underlying mechanisms, we employed MPhi from IL-15(-/-) or IL-15 transgenic mice. These were induced to differentiate or were stimulated with IL-15. Here we show that addition of IL-15 during differentiation of MPhi (into 'IL-15MPhi') and overexpression of IL-15 by MPhi from IL-15(tg) mice leads to increased levels of major histocompatibility complex class II expression. This resulted in enhanced stimulation of antigen-specific CD4(+) T cells in vitro and was accompanied by reduced messenger RNA expression in MPhi for immunosuppressive SOCS3. The proliferation rates of IL-15MPhi and IL-15(tg)MPhi were high, which was reflected by increased p27(Kip1) and reduced p21(Waf1) levels. In view of high serum and synovial levels of IL-15 in patients with RA, our data suggest the possibility that this excess IL-15 in RA may stimulate monocytes/MPhi to activate the characteristic autoreactive CD4(+) T cells in RA.
19609630 The scandinavian total ankle replacement: survivorship at 5 and 8 years comparable to othe 2010 Apr Ankle arthroplasty is increasingly used to treat advanced ankle arthritis. Earlier prostheses have given way to second-generation implants, on which we are accumulating medium-term data. The Scandinavian Total Ankle Replacement (STAR) is a three-component uncemented implant in wide use in Europe and the only mobile-bearing prosthesis with conditional approval in the United States. We retrospectively reviewed 45 patients (52 ankles) who had primary total ankle replacements using STAR prostheses, in order to assess survivorship and add to the pool of clinical data provided by independent practitioners required to establish this treatment as a viable alternative to arthrodesis. The minimum followup was 60 months (range, 60-110 months). Clinical outcome was determined using the AOFAS score. We determined the rate of radiographic loosening and recorded complications and the need for further surgery. Survival was 90% (95% CI 76.8 to 95.5) at 5 years and 84% (95% CI 68.9 to 92.2) at 8 years. Six of 52 ankles (11%) had component revision and two were converted to fusion. The mean postoperative AOFAS score was 78. The complication rate was 21%. Subsequent surgery, excluding component revision, was performed in nine of 52 (17%) ankles. LEVEL OF EVIDENCE: Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.
18957483 New autoantigens in rheumatoid arthritis (RA): screening 8268 protein arrays with sera fro 2009 Apr OBJECTIVE: To identify new IgG autoantibodies in sera from patients with rheumatoid arthritis (RA). METHODS: We tested serum samples from 19 patients with RA with given human leukocyte antigen (HLA)-DR genotypes, from 7 patients with spondylarthropathy, 2 patients with lupus, 4 patients with systemic sclerosis and 10 healthy individuals on 8268 human protein arrays. RESULTS: We identified four antigens (peptidyl arginine deiminase 4 (PAD4), protein kinase Cbeta1 (PKCbeta1), phosphatylinositol 4 phosphate 5 kinase type II gamma (PIP4K2C) and v raf murine sarcoma viral oncogene homologue B1 catalytic domain (BRAF)) that were recognised almost uniquely by sera from patients with RA on protein arrays. Using purified proteins, we confirmed that PAD4 and BRAF are recognised almost uniquely by patients with RA. CONCLUSION: We identified PAD4 and BRAF as RA specific autoantigens.
20015354 Better assessment of physical function: item improvement is neglected but essential. 2009 INTRODUCTION: Physical function is a key component of patient-reported outcome (PRO) assessment in rheumatology. Modern psychometric methods, such as Item Response Theory (IRT) and Computerized Adaptive Testing, can materially improve measurement precision at the item level. We present the qualitative and quantitative item-evaluation process for developing the Patient Reported Outcomes Measurement Information System (PROMIS) Physical Function item bank. METHODS: The process was stepwise: we searched extensively to identify extant Physical Function items and then classified and selectively reduced the item pool. We evaluated retained items for content, clarity, relevance and comprehension, reading level, and translation ease by experts and patient surveys, focus groups, and cognitive interviews. We then assessed items by using classic test theory and IRT, used confirmatory factor analyses to estimate item parameters, and graded response modeling for parameter estimation. We retained the 20 Legacy (original) Health Assessment Questionnaire Disability Index (HAQ-DI) and the 10 SF-36's PF-10 items for comparison. Subjects were from rheumatoid arthritis, osteoarthritis, and healthy aging cohorts (n = 1,100) and a national Internet sample of 21,133 subjects. RESULTS: We identified 1,860 items. After qualitative and quantitative evaluation, 124 newly developed PROMIS items composed the PROMIS item bank, which included revised Legacy items with good fit that met IRT model assumptions. Results showed that the clearest and best-understood items were simple, in the present tense, and straightforward. Basic tasks (like dressing) were more relevant and important versus complex ones (like dancing). Revised HAQ-DI and PF-10 items with five response options had higher item-information content than did comparable original Legacy items with fewer response options. IRT analyses showed that the Physical Function domain satisfied general criteria for unidimensionality with one-, two-, three-, and four-factor models having comparable model fits. Correlations between factors in the test data sets were > 0.90. CONCLUSIONS: Item improvement must underlie attempts to improve outcome assessment. The clear, personally important and relevant, ability-framed items in the PROMIS Physical Function item bank perform well in PRO assessment. They will benefit from further study and application in a wider variety of rheumatic diseases in diverse clinical groups, including those at the extremes of physical functioning, and in different administration modes.
19865101 Genetic variants of CC chemokine genes in experimental autoimmune encephalomyelitis, multi 2010 Mar Multiple sclerosis (MS) is a complex disorder of the central nervous system, causing inflammation, demyelination and axonal damage. A limited number of genetic risk factors for MS have been identified, but the etiology of the disease remains largely unknown. For the identification of genes regulating neuroinflammation we used a rat model of MS, myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), and carried out a linkage analysis in an advanced intercross line (AIL). We thereby redefine the Eae18b locus to a 0.88 Mb region, including a cluster of chemokine genes. Further, we show differential expression of Ccl2, Ccl11 and Ccl11 during EAE in rat strains with opposite susceptibility to EAE, regulated by genotype in Eae18b. The human homologous genes were tested for association to MS in 3841 cases and 4046 controls from four Nordic countries. A haplotype in CCL2 and rs3136682 in CCL1 show a protective association to MS, whereas a haplotype in CCL13 is disease predisposing. In the HLA-DRB1* 15 positive subgroup, we also identified an association to a risk haplotype in CCL2, suggesting an influence from the human leukocyte antigen (HLA) locus. We further identified association to rheumatoid arthritis in CCL2, CCL8 and CCL13, indicating common regulatory mechanisms for complex diseases.
20736390 Anti-cyclic citrullinated peptide antibodies are a collection of anti-citrullinated protei 2011 Jan OBJECTIVE: Anti-citrullinated protein antibodies (ACPA) and anti-cyclic citrullinated peptide (anti-CCP) antibodies are a hallmark of rheumatoid arthritis and are believed to play a role in disease pathogenesis. These antibodies are typically detected in ELISA with citrullinated peptides (eg, CCP2) or proteins as antigens. The absolute concentration of anti-CCP antibodies in serum is unknown. Although antibodies to several citrullinated proteins can mainly be detected within anti-CCP-positive sera, it is currently unknown whether anti-CCP antibodies are in fact ACPA. Likewise, it is unknown to what extent antibody responses to different citrullinated antigens are crossreactive. METHODS: An affinity purification method was established in which citrullinated antigen-specific antibodies were eluted from ELISA plates and then used for detection of other citrullinated antigens in ELISA or western blot. For additional crossreactivity studies, ELISA-based inhibition assays were performed with citrullinated or control peptides as inhibitors. RESULTS: The concentration of anti-CCP IgG antibodies was estimated to be at least 30 μg/ml in patients with high anti-CCP levels (>1600 μg/ml). Affinity-purified anti-CCP antibodies were able to recognise citrullinated fibrinogen (cit-fib) and citrullinated myelin basic protein (cit-MBP) on western blot. Furthermore, antibodies specific for cit-fib and cit-MBP were crossreactive. However, additional crossreactivity studies indicated that non-overlapping antibody responses to citrullinated peptides can also exist in patients. CONCLUSIONS: This report shows for the first time that anti-CCP antibodies recognise multiple citrullinated proteins and are thus a collection of ACPA. More importantly, the data indicate that different ACPA responses are crossreactive, but that crossreactivity is not complete, as distinct non-crossreactive responses can also be detected in patients with RA.
20421217 Histone deacetylase inhibitors MS-275 and SAHA induced growth arrest and suppressed lipopo 2010 Aug OBJECTIVES: MS-275 and suberoylanilide hydroxamic acid (SAHA) are histone deacetylase (HDAC) inhibitors currently tested in oncology trials. They have also been found to display potent anti-rheumatic activities in rodent models for RA. However, the anti-rheumatic mechanisms of action remain unknown. The study was carried out with the intent of determining the anti-inflammatory and anti-rheumatic mechanisms of the HDAC inhibitors. METHODS: In this study, the anti-rheumatic mechanisms of MS-275 and SAHA were investigated in several cell culture models. RESULTS: MS-275 and SAHA inhibited human RA synovial fibroblastic E11 cell proliferation in a non-cytotoxic manner. The anti-proliferative activities were associated with G(0)/G(1) phase arrest and induction of cyclin-dependent kinase inhibitor p21. In addition, MS-275 and SAHA suppressed lipopolysaccharide (LPS)-induced NF-kappaB p65 nuclear accumulation, IL-6, IL-18 and nitric oxide (NO) secretion as well as down-regulated pro-angiogenic VEGF and MMP-2 and MMP-9 production in E11 cells at sub-micromolar levels. At similar concentrations, MS-275 and SAHA suppressed LPS-induced NF-kappaB p65 nuclear accumulation and IL-1beta, IL-6, IL-18 and TNF-alpha secretion in THP-1 monocytic cells. Moreover, NO secretion in RAW264.7 macrophage cells was also inhibited. CONCLUSIONS: In summary, MS-275 and SAHA exhibited their anti-rheumatic activities by growth arrest in RA synovial fibroblasts, inhibition of pro-inflammatory cytokines and NO, as well as down-regulation in angiogenesis and MMPs. Their anti-rheumatic activities may be mediated through induction of p21 and suppression of NF-kappaB nuclear accumulation.
19325128 In vivo activated monocytes from the site of inflammation in humans specifically promote T 2009 Apr 14 Th17 cells are a recently defined subset of proinflammatory T cells that contribute to pathogen clearance and tissue inflammation by means of the production of their signature cytokine IL-17A (henceforth termed IL-17). Although the in vitro requirements for human Th17 development are reasonably well established, it is less clear what their in vivo requirements are. Here, we show that the production of IL-17 by human Th17 cells critically depends on both the activation status and the anatomical location of accessory cells. In vivo activated CD14+ monocytes were derived from the inflamed joints of patients with active rheumatoid arthritis (RA). These cells were found to spontaneously and specifically promote Th17, but not Th1 or Th2 responses, compared with resting CD14+ monocytes from the blood. Surprisingly, unlike Th17 stimulation by monocytes that were in vitro activated with lipopolysaccharide, intracellular IL-17 expression was induced by in vivo activated monocytes in a TNF-alpha- and IL-1beta-independent fashion. No role for IL-6 or IL-23 production by either in vitro or in vivo activated monocytes was found. Instead, in vivo activated monocytes promoted Th17 responses in a cell-contact dependent manner. We propose that, in humans, newly recruited memory CD4(+) T cells can be induced to produce IL-17 in nonlymphoid inflamed tissue after cell-cell interactions with activated monocytes. Our data also suggest that different pathways may be utilized for the generation of Th17 responses in situ depending on the site or route of accessory cell activation.
19051206 Autoreactive T-cell receptor (Vbeta/D/Jbeta) sequences in diabetes are homologous to insul 2009 May The hypervariable (Vbeta/D/Jbeta) regions of T-cell receptors (TCR) have been sequenced in a variety of autoimmune diseases by various investigators. An analysis of some of these sequences shows that TCR from both human diabetics and NOD mice mimic insulin, glucagon, the insulin receptor, and the glucagon receptor. Such similarities are not found in the TCR produced in other human autoimmune diseases. These data may explain how insulin, glucagon, and their receptors are targets of autoimmunity in diabetes and also suggest that TCR mimicking insulin and its receptor may be targets of anti-insulin autoantibodies. Such intra-systemic mimicry of self-proteins also raises complex questions about how "self" and "nonself" are regulated during TCR production, especially in light of the complementarity of insulin for its receptor and glucagon for its receptor. The data presented here suggest that some TCR may be complementary to other TCR in autoimmune diseases, a possibility that is experimentally testable. Such complementarity, if it exists, could either serve to down-regulate the clones bearing such TCR or, alternatively, trigger an intra-immune system civil war between them.
19559630 A systematic review of the psychometric properties of the Constant-Murley score. 2010 Jan HYPOTHESIS: The purpose of this study was to conduct a systematic review of the psychometric evidence relating to Constant-Murley score. MATERIALS AND METHODS: A search of 3 databases (Medline, CINAHL, and EMBASE) and a manual search yielded 35 relevant publications. Pairs of raters used structured tools to analyze these articles, through critical appraisal and data extraction. A descriptive synthesis of the psychometric evidence was then performed. RESULTS: Quality ratings of 23% of the studies reviewed reached a level of 75% or higher. Studies evaluating the content validity of the Constant-Murley score suggest that the description in the original publication is insufficient to accomplish standardization between centers and evaluators. Despite this limitation, the Constant-Murley score correlates strongly (>or= 0.70) with shoulder-specific questionnaires, reaches acceptable benchmarks (rho > 0.80) for its reliability coefficients, and is responsive (effect sizes and standardized response mean > 0.80) for detecting improvement after intervention in a variety of shoulder pathologies. DISCUSSION: This systematic review provides evidence to support the use of the Constant-Murley score for specific clinical and research applications but underscores the need for greater standardization and precaution when interpreting scores. Methods to improve standardization and measurement precision are needed. Responsiveness has been shown to be excellent, but some properties still need be evaluated, particularly those related to the absolute errors of measurement and minimal clinically important difference. CONCLUSION: Given the widespread acceptance for usage of the Constant-Murley score in clinical studies and early indications that the measure is responsive, studies defining more rigid standardization of the tools/procedures are needed. LEVEL OF EVIDENCE: Level 1.
19019090 The interaction of monocytes with rheumatoid synovial cells is a key step in LIGHT-mediate 2009 Sep Formation of osteoclasts and consequent joint destruction are hallmarks of rheumatoid arthritis (RA). Here we show that LIGHT, a member of the tumour necrosis factor (TNF) superfamily, induced the differentiation into tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells (MNCs) of CD14(+) monocytes cocultured with nurse-like cells isolated from RA synovium, but not of freshly isolated CD14(+) monocytes. Receptor activator of nuclear factor-kappaB ligand (RANKL) enhanced this LIGHT-induced generation of TRAP-positive MNCs. The MNCs showed the phenotypical and functional characteristics of osteoclasts; they showed the expression of osteoclast markers such as cathepsin K, actin-ring formation, and the ability to resorb bone. Moreover, the MNCs expressed both matrix metalloproteinase 9 (MMP-9) and MMP-12, but the latter was not expressed in osteoclasts induced from CD14(+) monocytes by RANKL. Immunohistochemical analysis showed that the MMP-12-producing MNCs were present in the erosive areas of joints in RA, but not in the affected joints of osteoarthritic patients. These findings suggested that LIGHT might be involved in the progression of inflammatory bone destruction in RA, and that osteoclast progenitors might become competent for LIGHT-mediated osteoclastogenesis via interactions with synoviocyte-like nurse-like cells.
19851212 Malignant variant of sclerosing perivascular epithelioid cell tumor arising in the adnexa. 2009 Nov The perivascular epithelioid cell family of tumors (PEComas) includes angiomyolipoma, lymphangioleiomyomatosis, clear-cell "sugar" tumor of the lung and a variety of extrapulmonary epithelioid and spindle-cell tumors referred to by various names. PEComas are now widely recognized histologically, and have been reported to occur at most anatomical sites, including the female genital tract. However, a distinctive variant of PEComa, designated "sclerosing PEComa," has only recently been described in the literature. All 13 of the cases of sclerosing PEComa reported thus far have been in women (mean age of 49 y), with a predilection for the retroperitoneum. Only one of the reported cases showed transition to a high-grade malignant phenotype. We report the first case of sclerosing PEComa arising in the uterine adnexa, with high-grade malignant transformation.
19291304 Microparticle-induced release of B-lymphocyte regulators by rheumatoid synoviocytes. 2009 INTRODUCTION: In the present study, we investigated the ability of microparticles isolated from synovial fluids from patients with rheumatoid arthritis or osteoarthritis to induce the synthesis and release of key cytokines of B-lymphocyte modulation such as B cell-activating factor, thymic stroma lymphopoietin, and secretory leukocyte protease inhibitor by rheumatoid fibroblast-like synoviocytes. METHODS: Microparticles were analyzed in synovial fluids from patients with rheumatoid arthritis, osteoarthritis, microcristalline arthritis, and reactive arthritis. In addition, microparticle release after activation from various cell lines (CEM lymphocyte and THP-1 cells) was assessed. Microparticles were isolated by differential centrifugation, and quantitative determinations were carried out by prothrombinase assay after capture on immobilized annexin V. B cell-activating factor, thymic stroma lymphopoietin, and secretory leukocyte protease inhibitor release was evaluated by enzyme-linked immunosorbent assay. RESULTS: Microparticles isolated from synovial fluids obtained from rheumatoid arthritis and osteoarthritis patients or microparticles derived from activated THP-1 cells were able to induce B cell-activating factor, thymic stroma lymphopoietin, and secretory leukocyte protease inhibitor release by rheumatoid arthritis fibroblast-like synoviocytes. Conversely, CEM-lymphocytes-derived microparticles generated by treatment with a combination of PHA, PMA and Adt-D did not promote the release of B cell-activating factor but favored the secretion of thymic stroma lymphopoietin and secretory leukocyte protease inhibitor by rheumatoid arthritis fibrobast-like synoviocytes. However, microparticles isolated from actinomycin D-treated CEM lymphocytes were not able to induce B cell-activating factor, thymic stroma lymphopoietin, or secretory leukocyte protease inhibitor release, indicating that microparticles derived from apoptotic T cells do not function as effectors in B-cell activation. CONCLUSIONS: These results demonstrate that microparticles are signalling structures that may act as specific conveyors in the triggered induction and amplification of autoimmunity. This study also indicates that microparticles have differential effects in the crosstalk between B lymphocytes and target cells of autoimmunity regarding the parental cells from which they derive.
19306196 Health-related Internet use by patients with somatic diseases: frequency of use and charac 2009 Jan The aim of this study was to explore the percentage of Dutch patients using the Internet to search for information about their illness. In addition, we studied patients' usage of health-related Internet applications, such as online patient support groups. The final objective of this study was to explore which demographic, health and psychological characteristics are related to patients' health-related Internet use. In order to answer these research questions we sent a written questionnaire to a representative sample of patients with breast cancer, rheumatoid arthritis and fibromyalgia. The overall total response rate was 69% (N = 679). In total, 52% of the patients used the Internet to search for information about their illness. However, only 15% of the respondents had ever read along with an online patient support group. An even smaller proportion of the patients (4%) had send postings to such a group. Online communication with health professionals was not commonly practiced. A younger age, a higher education and employment appeared to be the only significant predictors of patients' health-related Internet use. Patients' health-related Internet use could not be predicted by health and psychological characteristics. Although, about half of the patients made use of the Internet for health-related reasons, mostly their health-related Internet use was restricted to seeking information about their illness.
19858163 Investigation of the role of tumour necrosis factor-{alpha}, interleukin-1{beta}, interleu 2010 Apr Collagen-induced arthritis (CIA) in rats is a widely used preclinical animal model of rheumatoid arthritis (RA). However, CIA development in Sprague-Dawley (SD) rats is less severe in terms of inflammatory response compared with other strains. Therefore, a modified CIA model called MCIA, using N-acetylmuramyl dipeptide (MDP), has been developed in the less sensitive SD rat strains. This work was conducted to better understand the immunopathological role and contributions of the pro-inflammatory T-helper type 1 (Th-1) cytokines and inflammatory mediators, interleukin-1 (IL-1beta), tumour necrosis factor-alpha (TNF-alpha) and nitric oxide (NO); the anti-inflammatory T-helper type 2 (Th-2) cytokine, IL-10 and autoantibodies such as rheumatoid factor (RF)-immunoglobulin M (IgM) in this newly developed RA model. TNF-alpha, NO and RF-IgM levels were significantly increased, while IL-1beta levels were not affected in this MCIA rat model. The levels of IL-10 were lower than the baseline when compared with controls. IN CONCLUSION: (1) the immunological features represented in the MCIA rat model favour the Th-1 cytokine profile over Th-2 and (2) RF-IgM can be used as a diagnostic test in preclinical RA models.
19070550 Can End-of-day reports replace momentary assessment of pain and fatigue? 2009 Mar This study evaluated the ability of end-of-day (EOD) ratings to accurately reflect momentary (EMA) ratings on 10 widely used pain and fatigue items. Rheumatology patients (n = 105) completed >or=5 randomly scheduled EMA assessments of each item per day as well as EOD ratings. Correlations were high between EOD and EMA ratings of the 5 pain items (r = .90 to .92) and somewhat lower for the 5 fatigue/energy items (r = .71 to .86). To examine the ability of EOD ratings to represent 1 week of EMA ratings, 7 EOD ratings were averaged and correlated with EMA (r >or= .95 for pain items, r = .88 to .95 for fatigue/energy items). Further, averaging only 3 to 5 EOD ratings achieved very high correlations with 1 week of EMA ratings. Within-subject correlations of EOD with mean daily EMA across 7 days confirmed patients' ability to provide daily ratings that accurately reflect their day-to-day variation in symptom levels. These EOD results were compared to traditional recall ratings collected in the same protocol. It was concluded (1) that EOD ratings were a better representation of EMA than were recall ratings, and (2) that EOD ratings across a reporting period can replace EMA for studies targeting average levels of pain or fatigue. PERSPECTIVE: This study in chronic pain patients demonstrated that end-of-day ratings of pain are highly accurate representations of average levels of pain experience across a day; ratings of fatigue were somewhat less accurate, though still at a level that would be valid.
19604430 The COX-2 inhibitor market withdrawals and prescribing patterns by rheumatologists in pati 2009 May OBJECTIVE: To examine effects of the COX-2 inhibitor market withdrawals on NSAID utilization among patients at increased risk of gastrointestinal (GI) and cardiovascular (CV) toxicities. METHODS: A prospective cohort study was conducted using patients enrolled in the Consortium of Rheumatology Researchers of North America (CORRONA) Registry. The study population included rheumatoid arthritis (RA) and psoriatic arthritis (PsA) patients prescribed NSAIDs by rheumatologists from 1/1/2003 to 12/31/2005. Three cohorts were defined based on calendar year. The primary outcome assessed whether or not an NSAID gastroprotective strategy was prescribed. Secondary outcomes included rates of COX-2 inhibitor utilization and gastroprotective co-therapy utilization, stratified by the presence of cardiac and GI risk factors. RESULTS: NSAID gastroprotection utilization decreased from 65.1% in 2003 to 47.7% (p<0.001) in 2005. COX-2 inhibitor use decreased from 55.1% to 29.2% (p<0.001), whereas nonselective NSAIDs (nsNSAIDs) use increased from 50.2% to 73.9% (p=<0.01). Among patients with two or more risk factors for NSAID related GI bleeding, gastroprotection decreased from 74.4% in 2003 to 60.9% (p<0.01). For patients with two or more CV risk factors from 2003 to 2005, COX-2 inhibitor utilization decreased significantly, whereas nsNSAID utilization increased significantly. CONCLUSIONS: The COX-2 inhibitor withdrawals resulted in a rapid decline in NSAID gastroprotection prescribed by participating U.S. rheumatologists despite the availability of other gastroprotective options. Channeling toward nsNSAID use was widespread, including among patients at increased CV risk. Longer term follow-up is required to determine the clinical significance of these changes in NSAID prescribing, particularly for NSAID-related GI and CV-related toxicities.