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ID PMID Title PublicationDate abstract
19117595 The risk of infections with biologic therapies for rheumatoid arthritis. 2010 Apr OBJECTIVES: To assess the risk of serious and nonserious bacterial and viral infections associated with the use of biologic therapy (abatacept, adalimumab, anakinra, etanercept, infliximab, and rituximab) in patients with rheumatoid arthritis (RA). METHODS: Information was derived from PubMed, EMBASE, and the Cochrane clinical trials register and database of systematic reviews and relevant congress abstracts up to and including February 2008. RESULTS: Compared with the general population, patients with RA have a heightened risk of infection, including tuberculosis. Long-term clinical trials and postmarketing studies indicate that anakinra and the tumor necrosis factor (TNF) inhibitors are associated with an increased risk of infections versus conventional disease-modifying antirheumatic drugs (DMARDs), especially early in the course of treatment. The most common sites of infection are the respiratory tract (including pneumonia), skin and soft tissue, and the urinary tract. The risk of tuberculosis also appears higher with TNF inhibitors (in particular, infliximab) versus DMARDs, although this can be reduced by screening and prophylaxis. TNF inhibitors do not appear to significantly increase the risk of reactivating chronic viral infections. Influenza and pneumococcal vaccinations are generally effective in the face of TNF inhibitors or abatacept. Available data suggest that the risk of infections and serious infections with abatacept and rituximab may be similar to that of the TNF inhibitors. To date, there have been no reports from clinical trials of increased tuberculosis or opportunistic infections with abatacept or rituximab. CONCLUSIONS: All marketed TNF inhibitors for compared to control RA appear to increase the risk of serious and nonserious infections compared with DMARDs. Although suggestive, data for abatacept and rituximab are less definitive and longer periods of patient exposure to these agents are needed before an assessment of their risks can be made.
19859075 What predicts obesity in patients with rheumatoid arthritis? An investigation of the inter 2010 Feb OBJECTIVE: To assess whether physical activity, diet or inflammation is a more important determinant of body mass index (BMI) and body fat (BF) in patients with rheumatoid arthritis (RA). METHODS: A total of 150 RA patients (102 female) were assessed for BMI and BF. Their habitual physical activity was assessed with the international physical activity questionnaire (IPAQ) and their energy intake with a 3-day food diary. Pro-inflammatory cytokines (interleukins, IL-1 and IL-6, and tumor necrosis factor-alpha), erythrocyte sedimentation rate, C-reactive protein, disease activity score-28 and physical function (Health Assessment Questionnaire-HAQ) were also measured. RESULTS: BMI correlated inversely with IPAQ (r=-0.511, P=0.000) and positively with energy intake (r=0.331, P=0.016) and HAQ (r=0.133, P=0.042). BF correlated inversely with IPAQ (r=-0.575, P=0.000) and positively with HAQ (r=0.201, P=0.037). Normal weight patients were more physically active compared with those who were either overweight (P=0.006) or obese (P=0.000). Underweight patients consumed significantly fewer calories compared with other patients (P<0.05 in all cases). Cytokines or HAQ did not differ between weight groups. IPAQ was the sole predictor of obesity, whereas energy intake was the sole predictor of underweight. CONCLUSIONS: Inflammation does not seem to influence BMI and BF in RA. As in the general population, high levels of habitual physical activity associate with low BMI and BF in RA. Energy intake is a major determinant of being underweight in those who consume fewer calories. Further research is needed to investigate the suitability of exercise and diet modalities, and their effects on the body composition of RA patients.
19220830 Protein biochip array technology to monitor rituximab in rheumatoid arthritis. 2009 Mar In rheumatoid arthritis (RA) there are currently no good indicators to predict a clinical response to rituximab. The purpose of this study was to monitor and determine the role of peripheral blood cytokine profiling in differentiating between a good versus poor response to rituximab in RA. Blood samples were collected at baseline and at 3 months from 46 RA patients who were treated with rituximab. Responders are defined by the presence of three of four American College of Rheumatology criteria: >or=20% decrease in C-reactive protein, visual analogical score of disease activity, erythrocyte sedimentation rate and improvement of the disease activity score (28) (four values) by >or=1.2 obtained at 3 months. Twelve cytokines were measured from serum collected on days 0 and 90 by proteomic array, including interleukin-6 (IL-6), tumour necrosis factor-alpha, IL-1a, IL-1b, IL-2, IL-8, interferon-gamma, IL-4, IL-10, monocyte chemoattractant protein-1, epidermal growth factor and vascular growth factor. We showed that C-reactive protein and IL-6 levels decrease significantly at 3 months in the responder group compared with baseline. At day 90 we identified a cytokine profile which differentiates responders and non-responders. High serum levels of two proinflammatory cytokines, monocyte chemoattractant protein-1 and epidermal growth factor, were significantly higher in the responder group at day 90 compared with non-responders. However, we were not able to identify a baseline cytokine profile predictive of a good response at 3 months. These findings suggest that cytokine profiling by proteomic analysis may be a promising tool for monitoring rituximab and may help in the future to identify responder RA patients.
19012363 Cost-effectiveness of sequential therapy with tumor necrosis factor antagonists in early r 2009 Jan OBJECTIVE: To estimate the comparative lifetime cost-effectiveness of sequenced therapy with tumor necrosis factor (TNF) antagonists as the initial therapeutic intervention for patients with early rheumatoid arthritis (RA). METHODS: Because patients with RA switch regimens many times throughout the course of disease, sequenced therapeutic interventions were modeled, continuing until the last effective agent failed or death occurred. The model used published clinical outcomes from short-term, randomized controlled trials. Direct treatment costs and costs of lost productivity were modeled for each of 5 alternative treatment sequences. Incremental cost-effectiveness ratios are expressed as quality-adjusted lifeyears (QALY) gained. RESULTS: Treatment sequences that included TNF antagonists produced a greater number of QALY than conventional disease modifying antirheumatic drug regimens alone. The cost-effectiveness of sequenced therapy initiated with adalimumab plus methotrexate (MTX) extendedly dominated both infliximab-plus-MTX-initiated and etanercept sequences. The cost of adalimumab plus MTX per QALY was US $47,157 excluding productivity losses, and $19,663 including productivity losses. A supplementary sequence that incorporated adalimumab-plus-MTX-initiated first-line therapy followed by another TNF antagonist as second-line therapy was modeled; this sequence resulted in additional QALY gained and extendedly dominated all single-TNF strategies. CONCLUSION: Of the 3 single-TNF antagonist sequences, the adalimumab-plus-MTX-initiated sequence was cost-effective in producing the greatest number of QALY. Multiple TNF strategies, such as the supplementary sequence modeled in this analysis, may be cost-effective in producing even greater health gain.
19604445 Methylenetetrahydrofolate reductase polymorphisms and methotrexate: no association with re 2009 May OBJECTIVE: MTHFR is an enzyme involved in the folate pathway. It has been suggested that common polymorphisms in its gene (C677T and A1298C) could be related to different methotrexate (MTX) response and toxicity in rheumatoid arthritis (RA) patients. Agreement has not been found yet and there is no data on rheumatic Italian patients. The aim of this study is to determine if a genetic screening can help in planning the treatment in these patients. METHODS: We enrolled 84 Northern Italian patients affected by RA (n=79), psoriatic arthritis (n=4) and ankylosing spondylitis (n=1), who received MTX. Subjects who achieved at least ACR20 response in 6 months and maintained it during the following 6 months were defined as "responders"; those who did not obtain a disease control after 6 months of MTX were classified as "non responders". Patients who experienced MTX adverse events were defined "with toxicity", those who did not, as "without toxicity". Genotypes were determined by polymerase chain reaction. RESULTS: Genotype frequency was consistent with that reported in a healthy population from Italy. We did not find any statistically significant difference in genotype/allele distribution between the groups. In patients receiving folic acid supplementation MTX toxicity was recorded only in 18 cases (24%), while all the 8 patients not receiving it experienced MTX adverse events (p=0.00). CONCLUSION: In our study we did not find any association between MTHFR genotype/allele and MTX response or toxicity. At the moment there is not sufficient evidence for MTHFR screening in patients who are candidate for MTX.
19464664 Prostaglandin E2 activates Rap1 via EP2/EP4 receptors and cAMP-signaling in rheumatoid syn 2009 Jun The small GTPase Rap1 is implicated in a variety of cellar functions. In this study, we investigated the effect of prostaglandin E(2) (PGE(2)) on Rap1 activation in rheumatoid synovial fibroblasts (RSF). Rap1 was expressed in RSF, and GTP-bound active Rap1 (GTP-Rap1) was rapidly increased by PGE(2). The effect of PGE(2) was mimicked by an EP2 receptor agonist, an EP4 agonist and a cAMP-elevating agent forskolin with association to the increase of cAMP, but not by an EP1 or an EP3 agonist. RSF expressed the downstream signaling partners of cAMP, exchange protein directly activated by cAMP (Epac1) and protein kinase A (PKA). Both 8-pCPT-2-O-Me-cAMP (an Epac-specific cAMP analog) and 6-Bnz-cAMP (a PKA-specific cAMP analog) activated Rap1 in RSF. Activation of Rap1 by PGE(2) via cAMP-signaling may play an important role in the articular pathology of rheumatoid arthritis (RA).
19381635 Disease burden of psoriatic arthritis compared to rheumatoid arthritis, Hungarian experime 2009 Dec The objectives of this study were to assess the costs of psoriatic arthritis (PsA) in Hungary and to identify key cost drivers among demographic and clinical variables and to compare cost-of-illness of PsA and rheumatoid arthritis (RA). Cross-sectional retrospective survey of 183 consecutive patients from eight rheumatology centres was conducted. Mean direct medical, direct non medical, indirect and total costs were 1,876, 794, 2,904 and 5,574 euros/patient/year, respectively. Total costs were in significant linear relationship with health assessment questionnaire score and psoriatic area severity index. Costs of RA were higher in all domains than of PsA. Our study was the first from the Eastern European region that provides cost-of-illness data on PsA. Our study revealed that functional status and severity of skin symptoms were the key cost drivers. The costs of PsA in Hungary were lower than in the high-income European countries.
19843577 Decreased ERK and JNK signaling contribute to gene overexpression in "senescent" CD4+CD28- 2010 Jan An inflammatory and cytotoxic CD4+CD28- T cell subset infiltrates atherosclerotic plaques and is implicated in plaque rupture and myocardial infarctions. This pathologic subset develops with replicative stress and is found in patients with chronic inflammatory diseases such as RA as well as with aging. CD4+CD28- cells overexpress genes normally suppressed by DNA methylation in CD4+CD28+ T cells, such as KIR, perforin, and CD70. How this subset over expresses methylation-sensitive genes is unknown. DNA methylation patterns are maintained in proliferating cells by Dnmts, which are up-regulated during mitosis by the ERK and JNK signaling pathways. We hypothesized that defects in these signaling pathways contribute to altered gene expression in human CD4+CD28- cells through effects on DNA methylation. We report that signaling through the ERK and JNK pathways is decreased in CD4+CD28- relative to CD4+CD28+ cells from the same individuals and that ERK and JNK pathway inhibition decreases Dnmt1 and -3a levels, which in turn, causes demethylation and overexpression of the TNFSF7 (CD70) gene. We also report that CD4+CD28- T cells overexpress PP5, a stress-induced inhibitor of the ERK and JNK signaling pathways that may contribute to the signaling defects. We conclude that decreased ERK and JNK signaling in the CD4+CD28- subset, arising with replicative stress, can lead to the overexpression of normally suppressed genes through effects on Dnmts and consequently, chromatin structure.
21225729 Retropharyngeal abscess in the setting of immune modulation for rheumatoid arthritis. 2010 EDUCATIONAL OBJECTIVE: At the conclusion of this presentation, the participants should be familiar with the management of serious head and neck infections occurring inpatients on biologic agents for rheumatoid arthritis. OBJECTIVES: Present a case of retropharyngeal abscess managed in a patient on abatacept, a T cell immune modulator, for rheumatoid arthritis. Review the literature on the relationship between biologic agents for rheumatoid arthritis and head and neck infections. STUDY DESIGN: Case report. METHODS: Retrospective case review including a review of the relevant literature. RESULTS: The case of a 62-year-old woman with retropharyngeal abscess is presented. Her medical history was significant for rheumatoid arthritis treated with abatacept, a T-cell immune modulator. She presented with progressive odynophagia and neck pain, and a computed tomography scan revealed large retropharyngeal abscess extending to the superior mediastinum with bilateral pleural effusions. Transcervical incision and drainage was performed and infectious disease consultation was obtained. Full recovery was achieved after a month long course of intravenous antibiotics. CONCLUSIONS: Biologic agents that achieve selective immune modulation have revolutionized the treatment of rheumatoid arthritis. However, there is a small but significant risk of serious infection that accompanies these drugs. Otolaryngologists should be vigilant for signs and symptoms of serious head and neck infection in patients who are on biologic agents for rheumatoid arthritis. Management of these patients must account for their diminished immune response to infection.
20131240 Fluoxetine and citalopram exhibit potent antiinflammatory activity in human and murine mod 2010 Mar OBJECTIVE: Selective serotonin reuptake inhibitors (SSRIs), in addition to their antidepressant effects, have been reported to have antiinflammatory effects. The aim of this study was to assess the antiarthritic potential of 2 SSRIs, fluoxetine and citalopram, in murine collagen-induced arthritis (CIA) and in a human ex vivo disease model of rheumatoid arthritis (RA). METHODS: Following therapeutic administration of SSRIs, paw swelling was assessed and clinical scores were determined daily in DBA/1 mice with CIA. Joint architecture was examined histologically at the end of the treatment period. Cultures of human RA synovial membranes were treated with SSRIs, and cytokine production was measured. Toll-like receptor (TLR) function was examined in murine and human macrophages, human B cells, and human fibroblast-like synovial cells treated with SSRIs. RESULTS: Both SSRIs significantly inhibited disease progression in mice with CIA, with fluoxetine showing the greatest degree of efficacy at the clinical and histologic levels. In addition, both drugs significantly inhibited the spontaneous production of tumor necrosis factor, interleukin-6, and interferon-gamma-inducible protein 10 in human RA synovial membrane cultures. Fluoxetine and citalopram treatment also inhibited the signaling of TLRs 3, 7, 8, and 9, providing a potential mechanism for their antiinflammatory action. CONCLUSION: Fluoxetine and citalopram treatment selectively inhibit endosomal TLR signaling, ameliorate disease in CIA, and suppress inflammatory cytokine production in human RA tissue. These data highlight the antiarthritic potential of the SSRI drug family and provide further evidence of the involvement of TLRs in the pathogenesis of RA. The SSRIs may provide a template for potential antiarthritic drug development.
19933745 Synovial immunopathology in haemochromatosis arthropathy. 2010 Jun BACKGROUND: Hereditary haemochromatosis (HH) is a common autosomal recessive inherited disorder that frequently causes arthritis. The pathophysiology of musculoskeletal involvement is, however, unclear. OBJECTIVE: To analyse synovial tissue obtained at surgery from patients with HH arthropathy and compare it qualitatively and quantitatively with specimens from patients with rheumatoid arthritis (RA) and osteoarthritis (OA). METHODS: Synovial tissue from 15 patients with HH, 20 with RA and 39 with OA was obtained during surgery. A synovitis grading system was used to determine the severity of synovial inflammation. Using immunohistochemistry, synovial neovascularisation and infiltration of macrophages, neutrophils and lymphocytes were quantitatively assessed. RESULTS: Synovitis in HH arthropathy largely resembles OA with mild infiltration of mononuclear cells and lymphocytes, formation of synovial microvessels and a low degree of synovial hyperplasia. While many features of HH arthropathy are reminiscent of OA, macrophage and especially neutrophil invasion is clearly more prominent in HH arthropathy than in primary OA and mimics features of RA. This finding was observed particularly in synovial tissue of HH samples with marked haemosiderin deposition. DISCUSSION: The histological picture of the synovium in HH arthropathy largely resembles a process reminiscent of OA. Neutrophil invasion is, however, markedly increased in HH arthropathy, especially in joints with iron deposition. Accumulation of neutrophils may be crucial for the production of matrix enzymes, which enables cartilage degradation and more rapidly progressive articular damage.
21085019 Observational cross-sectional study revealing less aggressive treatment in Japanese elderl 2010 Dec BACKGROUND: Elderly patients with rheumatoid arthritis (RA) have more aging-related complications than nonelderly patients with RA. OBJECTIVES: The objective of the study was to investigate the treatment status of elderly patients with RA. METHODS: Between January and March 2008, 969 patients with RA were enrolled in this observational cross-sectional study. Prescription of disease-modifying antirheumatic drugs (DMARDs) and corticosteroids and laboratory data related to RA, including matrix metalloproteinase 3, rheumatoid factor, and anti-cyclic citrullinated peptide antibody levels, were compared between the elderly and the nonelderly patients. RESULTS: Fewer DMARDs were prescribed to the elderly patients (1.40 [SD, 0.57] vs. 1.51 [SD, 0.61]; P = 0.029). Furthermore, a lower percentage of patients received methotrexate (MTX) (47.2% vs. 56.9%; P = 0.0001), a lower average dosage of MTX was administered (5.46 [SD, 1.66] mg/wk vs. 5.96 [SD, 1.77] mg/wk; P = 0.0001), and fewer biologic DMARDs were used (1.46% vs. 5.59% for infliximab, P = 0.0008; 0.58% vs. 3.19% for etanercept, P = 0.0038) in the elderly group. The laboratory data suggested that the disease status was uncontrolled to a greater extent, and complications were more common in the elderly group. CONCLUSION: Elderly patients with RA receive less aggressive treatment than nonelderly patients with RA, despite laboratory evidence for poorly controlled disease status among the elderly. The use of a less aggressive regimen could be attributed to the higher prevalence of complications and problems. Therefore, the elderly with RA should be considered a different patient population from the viewpoint of treatment and be administered specialized medical care.
19789202 Rheumatoid factor positivity rather than anti-CCP positivity, a lower disability and a low 2009 Dec OBJECTIVES: We explored clinical factors associated with a major response to rituximab (RTX) (e.g. ACR >/=50, and European League against Rheumatism (EULAR) moderate to good response) in patients with active long-standing RA and inadequate response to anti-TNF agents or traditional DMARDs. METHODS: RTX was used in 110 RA patients in six different Italian centres. The mean disease activity score on 28 joints (DAS28) was 6.4 +/- 0.99 and the mean HAQ was 1.63 +/- 0.68 at baseline. Thirty-two patients (29.1%) underwent RTX after the failure of DMARD therapy, 37 (33.6%) had failed or were intolerant to at least two anti-TNF agents, and 41 (37.3%) had failed or were intolerant to one anti-TNF agent. Univariate and multivariate analyses were performed. RESULTS: The number of previous anti-TNF agents (P = 0.043), HAQ (P = 0.023), RF positivity (P < 0.0001) and anti-cyclic citrullinated peptide (anti-CCP) positivity (P = 0.003) were associated with ACR response >or=50 between month +4 and month +6 after starting RTX by univariate analysis. Multivariate analysis confirmed that a lower HAQ, a lower number of anti-TNF agents failed before RTX and RF positivity, but not anti-CCP positivity, were the selected variables associated with an ACR response >or=50, with an accuracy of 84% of the model. Only RF positivity correlated with EULAR moderate to good response both in the univariate and in the multivariate analysis, with an accuracy of 79% of the model. CONCLUSION: RF-positive rather than anti-CCP-positive RA patients with lower baseline disability and a lower number of previously failed TNF blockers may be the best candidates to RTX.
20028652 IFN-gamma regulates the requirement for IL-17 in proteoglycan-induced arthritis. 2010 Feb 1 The contribution of the proinflammatory cytokines IFN-gamma and IL-17 to the pathogenesis of experimental arthritis is controversial. In proteoglycan (PG)-induced arthritis (PGIA), severe arthritis is dependent on the production of IFN-gamma, whereas IL-17 is dispensable. In collagen-induced arthritis and Ag-induced arthritis, although high levels of IFN-gamma are secreted, disease is exacerbated in IFN-gamma or IFN-gamma receptor-deficient mice due to the ability of IFN-gamma to suppress IL-17 expression. In the current study, we investigated the effect of IFN-gamma on the IL-17 response and its consequences in PGIA. In PG-immunized IFN-gamma(-/-) mice, despite reduction in arthritis, the PG-specific CD4(+) T cell IL-17 response was significantly increased. Elevated IL-17 contributed to development of arthritis, as disease in IFN-gamma/IL-17(-/-) was significantly reduced in comparison with either IFN-gamma(-/-) or IL-17(-/-) mice. A contribution of IFN-gamma and IL-17 to the development of arthritis was also identified in T-bet(-/-) mice. PG-specific CD4(+) T cells from T-bet(-/-) mice produced reduced IFN-gamma and elevated concentrations of IL-17. Both IFN-gamma and IL-17 contribute to arthritis, as T-bet(-/-) mice lacking IL-17 (T-bet/IL-17(-/-)) were resistant, whereas wild-type, T-bet(-/-), and IL-17(-/-) mice were susceptible to PGIA. T cell proliferation and autoantibody production did not correlate with development of disease; however, expression of cytokines and chemokines in joint tissues demonstrate that IFN-gamma and IL-17 cooperatively contribute to inflammation. These results demonstrate that both IFN-gamma and IL-17 have the potential to induce PGIA, but it is the strength of the IFN-gamma response that regulates the contribution of each of these Th effector cytokines to disease.
20192995 CD4+CD25+ regulatory T cells in autoimmune arthritis. 2010 Jan CD4(+)CD25(+) regulatory T (Treg) cells can play a critical role in the prevention of autoimmunity, as evidenced by the cataclysmic autoimmune disease that develops in mice and humans lacking the key transcription factor forkhead box protein 3 (Foxp3). At present, however, how and whether Treg cells participate in the development of rheumatoid arthritis (RA), which has both systemic manifestations and a joint-targeted pathology that characterizes the disease, remains unclear. In this review, we describe work that has been carried out aimed at determining the role of Treg cells in disease development in RA patients and in mouse models of inflammatory arthritis. We also describe studies in a new model of spontaneous autoimmune arthritis (TS1 x HACII mice), in which disease is caused by CD4(+) T cells recognizing a neo-self-antigen expressed by systemically distributed antigen-presenting cells. We show that TS1 x HACII mice develop arthritis despite the presence of CD4(+)CD25(+)Foxp3(+) Treg cells that recognize this target autoantigen, and we outline steps in the development of arthritis at which Treg cells might potentially act, or fail to act, in the development of inflammatory arthritis.
19269146 Evaluation of labial microvessels in Sjogren syndrome: a videocapillaroscopic study. 2009 Jun Sjögren's syndrome (SS) is a chronic autoimmune rheumatic disease characterized by a progressive lymphocytic infiltration of exocrine glands, especially salivary and lachrymal ones, leading to xerostomia, parotid gland enlargement, and xerophtalmia. SS may occur alone (primary) or in association with almost any of the autoimmune rheumatic diseases (secondary), the most frequent being rheumatoid arthritis. The aim of this study is to describe the capillaroscopic pattern of the labial mucosa in patients with SS. METHODS: A total of 20 patients affected by SS and 20 healthy controls were examined. The patients with conditions that compromise microcirculation, such as diabetes, hypertension, hyperlipidemia or some pharmacological treatments, were not included in the study. All the patients were non-smokers. Labial capillaroscopy has been used to investigate the features of microcirculation. Visibility, course, tortuosity, as well as the possible presence of microhemorrhage, the average calibre of the capillary loops and the number of visible capillary loops per square millimetre were evaluated for each patient. RESULTS: The results show evident alterations in the capillaries and a typical conformation of the labial microcirculation in SS patients. CONCLUSION: Labial microcirculation alterations occur in SS patients. The study of the microcirculation in autoimmune pathology such as SS could provide new understanding on the dynamics of the pathology and could help to complete the diagnosis.
19740085 Is elevated noradrenaline an aetiological factor in a number of diseases? 2009 Oct 1 Here I put forth the hypothesis that noradrenaline (NA), which is a signalling molecule in the brain and sympathetic nervous system (SNS), is an aetiological factor in a number of diseases. 2 In a previous paper (Fitzgerald, Int. J. Cancer, 124, 2009, 257), I examined evidence that elevated NA is a factor in various types of cancer. Here I extend the argument to several other diseases, including diabetes mellitus, open-angle glaucoma, osteoarthritis and rheumatoid arthritis and asthma. 3 The principal hypothesis is that, largely as a result of genetics, elevated noradrenergic tone in the SNS predisposes a large number of individuals to a broad range of diseases. 4 For each of the above five diseases, I briefly examine the following four lines of evidence to assess the hypothesis: i) whether pharmacological studies in rodents that manipulate NA levels or receptors affect these diseases; ii) whether pharmacological manipulation of NA in humans affects these diseases; iii) whether bipolar disorder, excessive body weight, and hypertension, which may all three involve elevated NA, tend to be comorbid with these diseases and iv) whether psychological stressors tend to cause or exacerbate these conditions, since psychological stress is associated with increased release of NA. 5 The four lines of evidence tend to support the hypothesis.
19734236 The inhibitory Fc gamma IIb receptor dampens TLR4-mediated immune responses and is selecti 2009 Oct 1 Rheumatoid arthritis (RA) is a common autoimmune disease leading to profound disability and premature death. Although a role for FcgammaRs and TLRs is accepted, their precise involvement remains to be elucidated. FcgammaRIIb is an inhibitory FcR important in the maintenance of tolerance. We hypothesized that the inhibitory FcgammaRIIb inhibits TLR responses on monocyte-derived dendritic cells (DC) and serves as a counterregulatory mechanism to dampen inflammation, and we surmised that this mechanism might be defective in RA. The expression of the inhibitory FcgammaRIIb was found to be significantly higher on DCs from RA patients having low RA disease activity in the absence of treatment with antirheumatic drugs. The expression of activating FcgammaRs was similarly distributed among all RA patients and healthy controls. Intriguingly, only DCs with a high expression of FcgammaRIIb were able to inhibit TLR4-mediated secretion of proinflammatory cytokines when stimulated with immune complexes. In addition, when these DCs were coincubated with the combination of a TLR4 agonist and immune complexes, a markedly inhibited T cell proliferation was apparent, regulatory T cell development was promoted, and T cells were primed to produce high levels of IL-13 compared with stimulation of the DCs with the TLR4 agonist alone. Blocking FcgammaRIIb with specific Abs fully abrogated these effects demonstrating the full dependence on the inhibitory FcgammaRIIb in the induction of these phenomena. This TLR4-FcgammaRIIb interaction was shown to dependent on the PI3K and Akt pathway.
20497952 Specific serum protein biomarkers of rheumatoid arthritis detected by MALDI-TOF-MS combine 2010 Jul OBJECTIVES: To identify novel serum protein biomarkers and establish diagnostic pattern for rheumatoid arthritis (RA) by using proteomic technology. METHODS: Serum proteomic spectra were generated by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) combined with weak cationic exchange magnetic beads. A training set of spectra, derived from analyzing sera from 22 patients with RA, 26 patients with other autoimmune diseases and 25 age- and sex-matched healthy volunteers, was used to train and develop a decision tree model with a machine learning algorithm called decision boosting. A blinded testing set, including 21 patients with RA, 24 patients with other autoimmune diseases and 25 healthy people, was used to examine the accuracy of the model. RESULTS: A decision tree model was established, consisting of four potential protein biomarkers whose m/z values were 4966.88, 5065.3, 5636.97 and 7766.87, respectively. In validation test, the decision tree model could differentiate RA from other autoimmune diseases and healthy people with the sensitivity of 85.71% and specificity of 87.76%, respectively. CONCLUSIONS: The present data suggested that MALDI-TOF-MS combined with magnetic beads could screen and identify some novel serum protein biomarkers related to RA. The proteomic pattern based on the four candidate biomarkers is of value for laboratory diagnosis of RA.
21224040 A mouse model of chikungunya virus-induced musculoskeletal inflammatory disease: evidence 2011 Jan Chikungunya virus (CHIKV), an emerging mosquito-borne Alphavirus, causes debilitating rheumatic disease in humans that can last for weeks to months. Starting in 2004, a CHIKV outbreak in the Indian Ocean region affected millions of people, and infected travelers introduced CHIKV to new regions. The pathogenesis of CHIKV is poorly understood, and no approved vaccines or specific therapies exist. A major challenge to the study of CHIKV disease is the lack of a small animal model that recapitulates the major outcomes of human infection. In this study, the pathogenesis of CHIKV in C57BL/6J mice was investigated using biological and molecular clones of CHIKV isolated from human serum (CHIKV SL15649). After 14-day-old mice were inoculated with CHIKV SL15649 in the footpad, they displayed reduced weight gain and swelling of the inoculated limb. Histologic analysis of hind limb sections revealed severe necrotizing myositis, mixed inflammatory cell arthritis, chronic active tenosynovitis, and multifocal vasculitis. Interestingly, these disease signs and viral RNA persisted in musculoskeletal tissues for at least 3 weeks after inoculation. This work demonstrates the development of a mouse model of CHIKV infection with clinical manifestations and histopathologic findings that are consistent with the disease signs of CHIKV-infected humans, providing a useful tool for studying viral and host factors that drive CHIKV pathogenesis and for evaluating potential therapeutics against this emerging viral disease.