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ID PMID Title PublicationDate abstract
24832834 Biological therapy in inflammatory rheumatic diseases: issues in Central and Eastern Europ 2014 May Biological drugs revolutionized the treatment of inflammatory rheumatic diseases. Access to treatment presents substantial variability across Europe. The economic level of a particular country as well as administrative restrictions have been proved as determining factors of biological drug uptake. The objective of this paper was to provide an overview of biological treatment in six selected Central and Eastern European (CEE) countries, namely in the Bulgaria, Czech Republic, Hungary, Poland, Romania and Slovakia. The literature is summarized with regard to the epidemiology, disease burden and use of biological agents in rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. Moreover, an estimate is provided on the prevalence and number of patients with biological treatment based on international and local sources. In view of the limited availability of information and uncertainty in data, there is an urgent need for development of systematic and comprehensive data collection in inflammatory rheumatic diseases in CEE countries.
24379265 [Tumors in rheumatic diseases]. 2013 Dec 11 Patients with systemic inflammatory rheumatic diseases (such as rheumatoid arthritis, lupus erythematosus, systemic sclerosis, idiopathic inflammatory myopathies, or Sjögren's syndrome) are at increased risk of cancer, including hematological malignancies (leukemias and lymphomas), as well as non-hematological cancers (e.g. lung, esophageal, prostate or ovarian cancer). This increased risk for cancer development in patients with rheumatic diseases is attributed to the immune (autoimmune) processes and the medical treatment. Due to the often similar symptoms and the occurrence of systemic paraneoplastic syndromes it is very important to evaluate the association between rheumatic diseases and cancer. This paper presents issues concerning the development of cancer in patients with rheumatic diseases and the risk of cancer associated with drugs used for the treatment of rheumatic diseases.
24972589 Modelling outcomes of complex treatment strategies following a clinical guideline for trea 2014 Oct BACKGROUND: Management of rheumatoid arthritis (RA) is characterised by a sequence of disease-modifying antirheumatic drugs (DMARDs) and biological response modifiers (BRMs). In most of the Western countries, the drug sequences are determined based on disease activity and treatment history of the patients. A model for realistic patient outcomes should reflect the treatment pathways relevant for patients with specific characteristics. OBJECTIVE: This study aimed at developing a model that could simulate long-term patient outcomes and cost effectiveness of treatment strategies with and without inclusion of BRMs following a clinical guideline for treatment decisions. METHODS: Discrete event simulation taking into account patient characteristics and treatment history was used for model development. Treatment effect on disease activity, costs, health utilities and times to events were estimated using Dutch observational studies. Long-term progression of physical functioning was quantified using a linear mixed-effects model. Costs and health utilities were estimated using two-part models. The treatment strategy recommended by the Dutch Society for Rheumatology where both DMARDs and BRMs were available (Strategy 2) was compared with the treatment strategy without BRMs (Strategy 1). Ten thousand theoretical patients were tracked individually until death. In the probabilistic sensitivity analysis, Monte Carlo simulations were performed with 1,000 sets of parameters sampled from appropriate probability distributions. RESULTS: The simulated changes over time in disease activity and physical functioning were plausible. The incremental cost per quality-adjusted life-year gained of Strategy 2 compared with Strategy 1 was 124,011. At a willingness-to-pay threshold higher than 119,167, Strategy 2 dominated Strategy 1 in terms of cost effectiveness but the probability that the Strategy 2 is cost effective never exceeded 0.87. CONCLUSIONS: It is possible to model the outcomes of complex treatment strategies based on a clinical guideline for the management of RA. Following the Dutch guideline and using real-life data, inclusion of BRMs in the treatment strategy for RA appeared to be less favourable in our model than in most of the existing models that compared drug sequences independent of patient characteristics and used data from randomised controlled clinical trials. Despite complexity and demand for extensive data, our modelling approach can help to identify the knowledge gaps in clinical guidelines for RA management and priorities for future research.
23116340 Shoulder function and active motion deficit in patients with rheumatoid arthritis. 2013 Aug PURPOSE: To discover whether there are differences between patients with RA with and without active motion deficit in the shoulder (passive ROM greater than active ROM) concerning disease characteristics and shoulder function, and examine the role of active motion deficit in explaining limitations of shoulder function in daily life. METHODS: This cross-sectional study included 123 patients with RA having shoulder pain. Disease activity and duration of shoulder pain and disease were registered, active and passive shoulder ROM, pain and muscle strength were measured. Shoulder function in daily life was assessed by Disability of the Arm, Shoulder and Hand (DASH). RESULTS: Patients with active motion deficit (36%) had statistical significant worse scores on disease activity, shoulder pain, muscle strength, and DASH function than those without active motion deficit (p ≤ 0.05). No differences between the groups were found for duration of shoulder pain or disease (p > 0.05). Active motion deficit, passive ROM, muscle strength and pain explained 33.7% of the variation in the DASH function score. CONCLUSION: Active motion deficit in the shoulder seems frequent in patients with RA. Together with passive ROM, muscle strength and pain, active motion deficit explained about one-third of the limitations in shoulder function in daily life.
24694790 Hand disorders in the course of systemic and chronic diseases: a review. 2014 Apr 2 Systemic and chronic diseases frequently affect function of many organs and systems, not only those from which they derive. The hand is a very complicated structure in the human body and its normal activity is related to undisturbed function of many factors. Therefore, the hand is frequently exposed to harmful effects of systemic diseases. The article reports on disorders and functional disturbances of the hand that, more frequently than in an average population, accompany selected systemic diseases: rheumatoid arthritis, gout, and scleroderma. Hand diseases related to diabetes are a subject of a separate paper. This study reviews typical disorders involving hand structures: joints, tendons and nerves. Their prevention and management is described.
25431327 Can we prevent rapid radiological progression in patients with early rheumatoid arthritis? 2015 Jan The aim of this study is to test the performance of a matrix model to predict rapid radiological progression (RRP) in a study population of early rheumatoid arthritis (RA) or undifferentiated arthritis (UA) patients. A matrix model using baseline CRP, erosion score, autoantibody status, and initial treatment choice to predict RRP (increase ≥5 points in Sharp-van der Heijde score (SHS) in 1 year) was derived from the BeSt study where patients with active RA (1987-criteria) were treated with initial monotherapy or combination therapy, aiming at low disease activity. In the IMPROVED study, patients with early RA (2010 criteria) and UA were initially treated with methotrexate and prednisone aiming at remission. A receiver operating characteristics (ROC) curve was used to assess the discriminative value of the model to predict damage progression in the IMPROVED population. Four hundred thirty-one out of 479 patients with RA and 106/122 with UA could be categorized as high, intermediate, low, or very low risk for RRP. One patient, with a very low risk profile, showed RRP. Thirty-two other patients (5 %) showed radiological progression ≥0.5 point SHS; none had a high risk profile and 22 had a very low risk profile. The area under the curve (AUC) of the ROC curve was 0.56 (95% CI 0.45; 0.68). A matrix model predicting RRP based on risk factors identified in recent onset active RA according to the 1987-criteria performed poorly in recent onset RA (2010 criteria) and UA. It appears that known risk factors for damage progression lose their impact with early remission steered treatment, so that RRP might be considered a phenomenon of the past.
24934630 New autoinjector technology for the delivery of subcutaneous methotrexate in the treatment 2014 Sep Methotrexate (MTX) is the cornerstone of treatment for rheumatoid arthritis (RA), and is widely used both as first-line therapy and as an important component of long-term therapy. Although subcutaneous MTX is typically delivered orally, parenteral administration offers benefits with respect to tolerability and systemic exposure, and may be an underutilized treatment option. The RA patient population presents specific challenges for safe and accurate administration of parenteral therapies, because of common symptoms of joint pain and limited manual dexterity. These challenges may contribute to the low incidence of parenteral MTX administration. A novel MTX autoinjector (MTXAI) was recently introduced, which is designed to facilitate subcutaneous MTX self-administration among patients with RA. Here we review the development and utility of the MTXAI in the treatment of RA, and discuss how this technology may facilitate the use of subcutaneous MTX.
24376248 Tightening up? Impact of musculoskeletal ultrasound disease activity assessment on early r 2014 Jan OBJECTIVE: To determine the level of agreement and potential impact on disease-modifying antirheumatic drug (DMARD) escalation decisions and of adding musculoskeletal ultrasound (MSUS) assessment of disease activity to the Disease Activity Score in 28 joints (DAS28) in early rheumatoid arthritis (RA). METHODS: Data were gathered from 53 early RA patients randomized to the MSUS assessment group of the Targeting Synovitis in Early Rheumatoid Arthritis study. DAS28 scores were calculated every month. MSUS was performed on patients with low disease activity (DAS28 <3.2) and on those with moderate disease activity (3.2 ≤ DAS28 <5.1) without clinically swollen joints (swollen joint count [SJC] ≤1). Fourteen joints (bilateral proximal interphalangeal joints 2 and 3, metacarpophalangeal [MCP] joints 2 and 3, the radiocarpal, and metatarsophalangeal joints 2 and 5) were examined. Active disease was defined as ≥2 joints demonstrating any power Doppler (PD) signal. Data from 414 paired DAS28 and MSUS assessments were pooled to determine the level of agreement between each method. RESULTS: A total of 369 MSUS assessments were conducted on patients with DAS28 <3.2; 92 (25%) of these assessments identified active disease. A total of 271 MSUS assessments were performed on those with DAS28 <2.6; 66 (24%) of these identified active disease. Forty-five MSUS assessments were conducted on patients with 3.2 ≤ DAS28 <5.1 and SJC ≤1; 15 (33%) of these assessments confirmed active disease. On 120 occasions (29%), MSUS findings contradicted the DAS28 and led to modified treatment decisions. The joints that most frequently exhibited PD signal were radiocarpal and index and middle MCP joints. CONCLUSION: Compared to the DAS28, global RA disease activity assessment using a limited MSUS joint set provided additional disease activity information and led to altered treatment decisions in a significant minority of occasions. This may allow further tailoring of DMARD therapy by supporting DMARD escalation in patients with continuing subclinical synovitis and preventing escalation in symptomatic patients with minimal clinical and/or ultrasonographic synovitis.
22584471 Serum osteoprotegerin concentration is associated with carotid atherosclerotic plaque in p 2013 Mar OBJECTIVE: Osteoprotegerin (OPG), a regulator of bone resorption, is involved in the pathogenesis of rheumatoid arthritis (RA) and atherosclerosis. OPG is elevated in patients with coronary artery disease, and high OPG levels are associated with cardiac disease severity and mortality in the general population. The purpose of this study was to investigate the relationship of serum OPG levels, traditional coronary risk factors, and RA-related factors to carotid atherosclerosis in RA patients. METHODS: Ninety-one RA patients were studied (85 % women, age 60 ± 10 years). Serum OPG levels were measured by an enzyme-linked immunosorbent assay. The prevalence of carotid plaque was assessed by ultrasonographic imaging in all patients. The relationship between various clinical characteristics, OPG, and carotid plaque was examined. RESULTS: Serum OPG levels were significantly higher in patients with carotid plaque than in those without plaque (median level 1,397 vs. 887 pg/mL, respectively; P = 0.006). There were no significant differences between RA patients with and without carotid plaque with respect to sex, duration of RA, blood pressure, body mass index, smoking, low-density lipoprotein cholesterol, Disease Activity Score-28, van der Heijde-modified Sharp score, and prednisolone dose. After adjusting for age, sex, and C-reactive protein, elevated levels of OPG were still associated with a higher prevalence of carotid plaque in patients with RA (P = 0.038). CONCLUSION: RA patients suffer from accelerated atherosclerosis and also have increased levels of OPG. The serum OPG level is independently associated with carotid plaque.
24040234 Lack of association of variants previously associated with anti-TNF medication response in 2013 Treatment strategies blocking tumor necrosis factor (anti-TNF) have proven very successful in patients with rheumatoid arthritis (RA), showing beneficial effects in approximately 50-60% of the patients. However, a significant subset of patients does not respond to anti-TNF agents, for reasons that are still unknown. The aim of this study was to validate five single nucleotide polymorphisms (SNPs) of PTPRC, CD226, AFF3, MyD88 and CHUK gene loci that have previously been reported to predict anti-TNF outcome. In addition, two markers of RA susceptibility, namely TRAF1/C5 and STAT4 were assessed, in a cohort of anti-TNF-treated RA patients, from the homogeneous Greek island of Crete, Greece. The RA patient cohort consisted of 183 patients treated with either of 3 anti-TNF biologic agents (infliximab, adalimumab and etanercept) from the Clinic of Rheumatology of the University Hospital of Crete. The SNPs were genotyped by TaqMan assays or following the Restriction Fragments Length Polymorphisms (RFLPs) approach. Disease activity score in 28 joints (DAS28) at baseline and after 6 months were available for all patients and analysis of good versus poor response at 6 months was performed for each SNP. None of the 7 genetic markers correlated with treatment response. We conclude that the gene polymorphisms under investigation are not strongly predictive of anti-TNF response in RA patients from Greece.
23339296 Anti-cyclic citrullinated peptide antibody titer predicts time to rheumatoid arthritis ons 2013 Jan 22 INTRODUCTION: The diagnostic, predictive and prognostic role of anti-cyclic citrullinated peptide (CCP) antibodies in rheumatoid arthritis (RA) patients is widely accepted. Moreover, detection of these antibodies in subjects presenting with undifferentiated arthritis (UA) is associated with a significant risk to develop the disease. On the other hand, clinical and prognostic significance of evaluating anti-CCP levels in subjects with inflammatory arthritis at disease onset has not been fully clarified. The goal of this prospective study is to analyze the value and prognostic significance of anti-CCP titer quantification in UA subjects. METHODS: Serial anti-CCP assays were measured in 192 consecutive patients presenting with UA lasting less than 12 weeks. Clinical and serological data and arthritis outcome were evaluated every 6 months until two years of follow-up. RESULTS: Anti-CCP positivity, at both low and high titer, and arthritis of hand joints significantly predicted RA at two years, risk increasing in subjects with high anti-CCP titers at baseline. Moreover, time to RA diagnosis was shorter in patients with high anti-CCP2 titers at enrollment with respect to those with low antibody concentration. CONCLUSIONS: Presence of anti-CCP antibodies, at both low and high concentration, is significantly associated with RA development in subjects with recent onset UA. However, time interval from the onset of the first symptoms to the fulfilment of the classification criteria appears to be directly related to the initial anti-CCP level.
24634201 Late-onset neutropenia in patients with rheumatoid arthritis after treatment with rituxima 2014 May OBJECTIVE: Late-onset neutropenia (LON) is an adverse effect of rituximab (RTX) in hematological malignancies, a finding that was recently reported in rheumatoid arthritis (RA). The aim of our study was to estimate its incidence in RA. METHODS: We retrospectively reviewed complete blood (cell) count of patients with RA who received RTX between October 2007 and July 2011 to identify neutropenia (≤ 1.5 × 10(9)) up to 12 months following RTX. RESULTS: One hundred eight patients received RTX, median age 64 years (range 25-86). A total of 237 cycles were given. Five patients developed LON after a median of 151 days (71-184). Two developed pneumonia. CONCLUSION: LON occurs infrequently after RTX, but can present with infection.
23919377 Identification of a linear epitope recognized by a monoclonal antibody directed to the het 2014 Rheumatoid arthritis (RA) is a chronic autoimmune disorder, characterized by progressive joint destruction and disability. Classical autoantibodies of RA are rheumatoid factors and citrulline antibodies. Patients positive for these autoantibodies are usually associated with a progressive disease course. A subgroup of RA patients does not express citrulline antibodies, instead are approximately 35% of these anti-citrulline-negative patients reported to express autoantibodies to the heterogeneous nucleoriboprotein A2, a ribonucleoprotein involved in RNA transport and processing also referred to as RA33. In the absence of citrulline antibodies, RA33 antibodies have been suggested to be associated with a milder disease course. In this study we screened the reactivity of a monoclonal antibody to RA33-derived peptides by modified enzyme-linked immunosorbent assays (ELISA). Terminally truncated resin-bound peptides were applied for determination of the functional epitope necessary for antibody recognition. In addition, screening of substituted peptides by modified ELISA identified amino acids necessary for antibody reactivity. A potential epitope was identified in the region 71-79 (PHSIDGRVV), where the amino acids Ser, Ile and Asp were found to be essential for antibody reactivity. These amino acids were found to contribute to the antibody-antigen interface through side-chain interactions, possibly in combination with a positively charged amino acid in position 77. Moreover, the amino acids in the N-terminal end (Pro and His) were found to contribute to the interface through backbone contributions. No notable reactivity was found with RA-positive patient sera, thus screening of RA33 antibodies does not seem to be a supplementary for the diagnosis of RA.
23804220 The clinical utility of accelerometry in patients with rheumatoid arthritis. 2013 Sep OBJECTIVES: To assess habitual physical activity levels in patients with RA compared with healthy control participants and to compare these measures with health-related quality of life and disease activity in the RA patients. METHODS. Fifty RA patients [age 48 (13) years] and 22 BMI, sex and geographically matched control participants were recruited. Habitual physical activity was measured using an Actical accelerometer worn on the hip for 2 consecutive weeks. Patients completed the Short Form-36 (SF-36) and modified Health Assessment Questionnaires (HAQ-DI). Disease activity was assessed using the Simplified Disease Activity Index (SDAI). RA patients were further categorized as more physically active (n = 25) and less physically active (n = 25) according to their average activity counts. RESULTS: The RA group spent more time in sedentary activity than the control group (71% vs 62% of the day respectively, P = 0.002) and had bimodal decreases in diurnal physical activity compared with the control group in the morning (P < 0.001) and late afternoon (P < 0.001). HAQ-DI, when adjusted for age and disease duration, was negatively correlated with physical activity in the RA group (r = -0.343, P = 0.026). The more physically active patients scored better than the less physically active patients on every component of the SF-36. CONCLUSION: Patients with RA lead a significantly more sedentary lifestyle than healthy controls and show diurnal differences in physical activity due to morning stiffness and fatigue. Higher levels of habitual physical activity may be protective of functional capacity and are highly associated with improved health-related quality of life in RA patients.
25274884 Prognosis of seronegative patients in a large prospective cohort of patients with early in 2014 Dec OBJECTIVE: Rheumatoid factor (RF) and anticitrullinated protein antibodies (ACPA) are believed to be associated with more severe rheumatoid arthritis; however, studies in early inflammatory arthritis (EIA) have yielded conflicting results. Our study determined the prognosis of baseline ACPA-negative and RF-negative patients. METHODS: Patients enrolled in the Canadian Early Arthritis Cohort had IgM RF and IgG anticyclic citrullinated peptide antibodies 2 (anti-CCP2) measured at baseline. Remission was defined as a Disease Activity Score of 28 joints (DAS28) < 2.6 using logistic regression accounting for confounders at 12-month and 24-month followup. RESULTS: Of the 841 patients, 216 (26%) were negative for both RF and anti-CCP2. Compared to seropositive subjects, seronegative subjects were older (57 ± 15 vs 51 ± 14 yrs), more males proportionately (31% vs 23%), and had shorter length of symptoms (166 ± 87 vs 192 ± 98 days), and at baseline had higher mean swollen joint count (SJC; 8.8 ± 6.8 vs 6.5 ± 5.6), DAS28 (5.0 ± 1.6 vs 4.8 ± 1.5), and erosive disease (32% vs 24%, p < 0.05). Treatment was similar between the 2 groups. At 24-month followup, seronegative compared to seropositive subjects had greater mean change (Δ ± SD) in disease activity measures: ΔSJC counts (-6.9 ± 7.0 vs -5.1 ± 5.9), ΔDAS28 (-2.4 ± 2.0 vs -1.8 ± 1.8), and ΔC-reactive protein (-11.0 ± 17.9 vs -6.4 ± 17.5, p < 0.05). Accounting for confounders, antibody status was not significantly associated with remission. However, at 12-month followup, ACPA-positive subjects were independently more likely to have new erosive disease (OR 2.94, 95% CI 1.45-5.94). CONCLUSION: Although seronegative subjects with EIA have higher baseline DAS28 compared to seropositive subjects, they have a good response to treatment and are less likely to develop erosive disease during followup.
24170633 How does Chinese medicine target cytokine imbalance in rheumatoid arthritis? 2013 Nov Rheumatoid arthritis (RA) manifests as an imbalance between pro- and anti-inflammatory cytokines. Cytokine imbalance is suggested to play critical roles in the development of RA. Currently, various treatments for RA, including biological agents such as antibodies against inflammation mediators, or Chinese herbal medicines, intervene the disease by restoring the balance of cytokines. Chinese medicine (CM) can not only suppress the expression of pro-inflammatory cytokines, but also induce the expression of cytokines with anti-inflammatory and immunomodulatory effects. Thus, Chinese medicine can effectively reduce inflammatory cell infiltration into synovial tissue, pannus formation, and degradation of the extracellular matrix surrounding cartilage cells, thereby reducing subchondral bone damage. This paper reviews the changes of cytokine profiling during development of RA and discuss the mechanisms by which Chinese medicine restores the cytokine balance.
25505001 Drug adherence, response and predictors thereof for tocilizumab in patients with rheumatoi 2015 Jul OBJECTIVE: To evaluate drug adherence, clinical response and predictors thereof for tocilizumab in patients with RA in routine care based on prospectively collected data from the Swedish biologics register, Anti-Rheumatic Therapies in Sweden. METHODS: RA patients who had started with tocilizumab from September 2008 until March 2012 were identified. Cox regression and logistic regression models were used. RESULTS: A total of 530 RA patients were included, of whom 80.6% were female, 64.7% were on concomitant DMARDs, of which 300 were on MTX and 12% were biologic naive. The overall 6 month, 1 and 2 year estimated drug continuations were 79%, 64% and 50%, respectively. In the multivariate analyses, a low initial level of CRP [hazard ratio (HR) 0.76/1 S.D. (95% CI 0.63, 0.91)], high HAQ score [HR 1.23/1 S.D. (95% CI 1.06, 1.44)] and prior exposure to different biologics [HR 1.43 (95% CI 1.12, 1.83)] were predictors for drug termination, whereas concomitant DMARD therapy was not. European League Against Rheumatism (EULAR) good, moderate, and no response were achieved by 184 (46.7%), 133 (33.8%) and 77 (19.5%) patients, respectively. Predictors for EULAR good response vs no response (at 2.5-8 months) were low HAQ [odds ratio (OR) 0.56/1 S.D. (95% CI 0.40, 0.78)], high 28-joint DAS [OR 2.0/1 S.D. (95% CI 1.44, 2.78)] and not being on prednisolone [OR 0.47 (95% CI 0.25, 0.88)] at baseline. CONCLUSION: In this RA cohort treated with tocilizumab, the estimated 1 year drug continuation was 64% and 80% of the patients achieved a EULAR response. Drug discontinuation was not predicted by no concomitant DMARD, but by low CRP, high HAQ and prior exposure to biologics.
22810731 Taurine and inflammatory diseases. 2014 Jan Taurine (2-aminoethanesulfonic acid) is the most abundant free amino acid in humans and plays an important role in several essential biological processes such as bile acid conjugation, maintenance of calcium homeostasis, osmoregulation and membrane stabilization. Moreover, attenuation of apoptosis and its antioxidant activity seem to be crucial for the cytoprotective effects of taurine. Although these properties are not tissue specific, taurine reaches particularly high concentrations in tissues exposed to elevated levels of oxidants (e.g., inflammatory cells). It suggests that taurine may play an important role in inflammation associated with oxidative stress. Indeed, at the site of inflammation, taurine is known to react with and detoxify hypochlorous acid generated by the neutrophil myeloperoxidase (MPO)-halide system. This reaction results in the formation of less toxic taurine chloramine (TauCl). Both haloamines, TauCl and taurine bromamine (TauBr), the product of taurine reaction with hypobromous acid (HOBr), exert antimicrobial and anti-inflammatory properties. In contrast to a well-documented regulatory role of taurine and taurine haloamines (TauCl, TauBr) in acute inflammation, their role in the pathogenesis of inflammatory diseases is not clear. This review summarizes our current knowledge concerning the role of taurine, TauCl and TauBr in the pathogenesis of inflammatory diseases initiated or propagated by MPO-derived oxidants. The aim of this paper is to show links between inflammation, neutrophils, MPO, oxidative stress and taurine. We will discuss the possible contribution of taurine and taurine haloamines to the pathogenesis of inflammatory diseases, especially in the best studied example of rheumatoid arthritis.
24757149 A computer simulation approach to assessing therapeutic intervention points for the preven 2014 Apr OBJECTIVE: To use a novel computational approach to examine the molecular pathways involved in cartilage breakdown and to use computer simulation to test possible interventions for reducing collagen release. METHODS: We constructed a computational model of the relevant molecular pathways using the Systems Biology Markup Language, a computer-readable format of a biochemical network. The model was constructed using our experimental data showing that interleukin-1 (IL-1) and oncostatin M (OSM) act synergistically to up-regulate collagenase protein levels and activity and initiate cartilage collagen breakdown. Simulations were performed using the COPASI software package. RESULTS: The model predicted that simulated inhibition of JNK or p38 MAPK, and overexpression of tissue inhibitor of metalloproteinases 3 (TIMP-3) led to a reduction in collagen release. Overexpression of TIMP-1 was much less effective than that of TIMP-3 and led to a delay, rather than a reduction, in collagen release. Simulated interventions of receptor antagonists and inhibition of JAK-1, the first kinase in the OSM pathway, were ineffective. So, importantly, the model predicts that it is more effective to intervene at targets that are downstream, such as the JNK pathway, rather than those that are close to the cytokine signal. In vitro experiments confirmed the effectiveness of JNK inhibition. CONCLUSION: Our study shows the value of computer modeling as a tool for examining possible interventions by which to reduce cartilage collagen breakdown. The model predicts that interventions that either prevent transcription or inhibit the activity of collagenases are promising strategies and should be investigated further in an experimental setting.
23740460 CCL19, a B cell chemokine, is related to the decrease of blood memory B cells and predicts 2013 Sep OBJECTIVE: Migration of B cells from peripheral blood to the synovium in patients with rheumatoid arthritis (RA) may predict clinical response to rituximab (RTX). We undertook this study to investigate whether serum levels of chemokines involved in B cell trafficking are correlated with blood levels of memory B cells or serum levels of B cell activation biomarkers before B cell depletion and whether chemokine levels predict RTX responsiveness. METHODS: Blood B cell subsets were analyzed by flow cytometry (CD27, IgD), and serum B cell activation biomarkers (rheumatoid factor, anti-cyclic citrullinated peptide, free light chains, IgG, IgA, IgM, and BAFF) were measured in 208 RA patients and 70 control subjects. Serum CCL19, CXCL12, and CXCL13 chemokine levels in patients and controls were determined by enzyme-linked immunosorbent assay. The first course of RTX was administered to RA patients, and the response was evaluated at week 24 according to European League Against Rheumatism (EULAR) criteria. Results were expressed as the odds ratio (OR) and 95% confidence interval (95% CI). RESULTS: Levels of all chemokines were increased in RA patients compared with controls, and levels were inversely correlated with CD27+ memory B cell frequency. CCL19 and CXCL13 levels correlated with levels of 6 serum B cell biomarkers and 4 serum B cell biomarkers, respectively. By univariate analysis, the CCL19 level was positively associated with EULAR response (OR 1.43 [95% CI 1.08-1.90], P = 0.01). By multivariate analysis, the CCL19 level was predictive of a response to RTX (OR 1.48 [95% CI 1.06-2.06], P = 0.02), but this did not persist after adjustment for autoantibody status. CONCLUSION: CXCL13 and CCL19 reflect blood B cell disturbances and their levels correlate with those of other serum B cell biomarkers. CXCL13 and CCL19 are, therefore, surrogate measures for serum B cell biomarkers in RA. Serum CCL19 measurement is a new hallmark of the B cell-mediated RA subtype and may predict clinical response to RTX.