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23797781 Relationship between pulse wave velocity and serum YKL-40 level in patients with early rhe 2013 Nov Subclinical atherosclerosis has been demonstrated in patients with early rheumatoid arthritis (ERA) without any signs of cardiovascular disease (CVD). The aim of this study was to investigate the relationship between serum YKL-40 level and arterial stiffness in patients with ERA. Forty two patients with ERA and 35 healthy controls with no history or current sign of CVD were included in the study. ERA patients with active disease, defined as DAS28 ≥ 3.2, and symptoms onset <12 months were recruited. Arterial stiffness was evaluated by carotid-femoral pulse wave velocity (CF-PWV), and the intima-media thickness carotid (IMT-C) was measured by carotid ultrasonography. Serum YKL-40 levels were measured by an enzyme-linked immunoassay method. The mean age was 43.1 ± 5.8 years in ERA patients and 41.0 ± 5.9 years in control group. The CFPWV and IMT-C of the ERA patients were determined significantly higher than the control group (P = .001, P < .001, respectively). YKL-40 levels were significantly elevated in ERA patients than controls (P = .008). The serum levels of YKL-40 in the ERA patients showed a strong correlation with CF-PWV (r = .711, P < .001) and IMT-C (r = .733, P < .001). Multiple linear regression analysis revealed that CF-PWV could be explained by serum YKL-40 levels (adjusted R² = .493, P < .001). We have shown that patients with ERA had increased CF-PWV and serum YKL-40 levels. In addition, there was an association between CF-PWV values and serum YKL-40 levels in patients with ERA. As a result, we believe that serum YKL-40 level and CF-PWV might reflect early atherosclerosis in patients with ERA.
24532833 Is tightly controlled disease activity possible with online patient-reported outcomes? 2014 Apr OBJECTIVE: To evaluate the performance of patient-reported outcomes (PRO) as primary indices for identification and prediction of a 28-joint Disease Activity Score (DAS28)>3.2 among patients with rheumatoid arthritis (RA). METHODS: Patients with RA completed monthly online PRO [Health Assessment Questionnaire (HAQ), Rheumatoid Arthritis Disease Activity Index (RADAI), visual analog scale (VAS) fatigue] and were clinically assessed every 3 months using the DAS28. Simple descriptive statistics, logistic regression, and the Bayesian joint modeling approach were used to analyze the data. The Bayesian joint model combines the scores and changes in the scores of 3 PRO to predict a DAS28>3.2 at the subsequent timepoint. RESULTS: A group of 159 patients with RA participated. Stratified summaries of the PRO by DAS28 categories at baseline provided incremental values of the PRO for more active disease. However, on an individual level, the DAS28 and the PRO fluctuated over time. The prediction of subsequent DAS score by a single instrument at single timepoints resulted in moderate sensitivity and specificity. Using the intercept and slope of the combined PRO of the first 3 measurements to predict the DAS28 state at 3 months resulted in a sensitivity of 0.81 and a specificity of 0.92. After 10-fold cross validation, the model had a sensitivity of 0.61 and specificity of 0.75 to identify patients with a DAS28>3.2. CONCLUSION: PRO showed fluctuating levels of disease activity over time, while on a group level disease activity stayed the same. Using the changes in RADAI, HAQ, and VAS fatigue over time to predict future DAS28>3.2 resulted in moderate performance after the internal cross-validation of the model (sensitivity 0.61, specificity 0.75).
23777892 Porphyromonas gingivalis and the pathogenesis of rheumatoid arthritis: analysis of various 2013 Jun 18 INTRODUCTION: We evaluated the presence of Porphyromonas gingivalis (Pg) DNA in the synovial tissue through synovial biopsy and in other compartments of rheumatoid arthritis (RA) patients in comparison with patients affected by other arthritides. Possible links with clinical, immunologic and genetic features were assessed. METHODS: Peripheral blood (PB), sub-gingival dental plaque, synovial fluid (SF) and synovial tissue samples were collected from 69 patients with active knee arthritis (32 with RA and 37 with other arthritides, of which 14 had undifferentiated peripheral inflammatory arthritis - UPIA). Demographic, clinical, laboratory and immunological data were recorded. The presence of Pg DNA was evaluated through PCR. The HLA-DR haplotype was assessed for 45 patients with RA and UPIA. RESULTS: No differences arose in the positivity for Pg DNA in the sub-gingival plaque, PB and SF samples between RA and the cohort of other arthritides. Full PB samples showed a higher positivity for Pg DNA than plasma samples (11.8% vs. 1.5%, P = 0.04). Patients with RA showed a higher positivity for Pg DNA in the synovial tissue compared to controls (33.3% vs. 5.9%, P <0.01). UPIA and RA patients carrying the HLA DRB1*04 allele showed a higher positivity for Pg DNA in the synovial tissue compared to patients negative for the allele (57.1% vs. 16.7%, P = 0.04). RA patients positive for Pg DNA in the sub-gingival plaque had a lower disease duration and a higher peripheral blood leucocyte and neutrophil count. The presence of Pg DNA did not influence disease activity, disease disability or positivity for autoantibodies. CONCLUSIONS: The presence of Pg DNA in the synovial tissue of RA patients suggests a pathogenic role of the bacterium. The higher positivity of Pg DNA in full peripheral blood and synovial tissue samples compared to plasma and synovial fluid suggests a possible intracellular localization of Pg, in particular in patients positive for HLA-DR4.
24676628 Quality of care of rural rheumatoid arthritis patients in Austria. 2014 Jun OBJECTIVES: To determine how fast rheumatoid arthritis (RA) was diagnosed in a group of patients in a rural area and whether medical care and patient satisfaction were adequate in a predominantly non-urban settlement. METHODS: When visiting their rheumatologist, patients with RA were asked to complete a questionnaire at home after the consultation and then return it to an independent opinion research centre, where the data were collected and analysed. The form comprised various areas, namely demography, aspects of the diagnosis, medical care, therapeutic measures and the illness in a personal context. RESULTS: Of 150 patients, 127 answered the questionnaire. A total of 63 % of the patients lived in settlements of less than 5,000 inhabitants, and a further 18 % in settlements of more than 5,000-50,000 inhabitants. The rheumatologist attended could be reached within 1 h for 90 % of the patients. In slightly fewer than 30 % of the respondents, the diagnosis of RA was made within 3 months, and in 44%, within 6 months. In 75 %, the diagnosis was made by a rheumatologist. After experiencing the first symptoms, 80 % of the respondents contacted their general practitioner. A high degree of satisfaction appears to originate from the information supplied by the rheumatologist attended. Most patients believed they were involved in decision making regarding their therapy. CONCLUSION: The majority of the respondents came from rural areas. RA was diagnosed within 6 months for almost half of the patients questioned. Most patients believed they were well informed and involved in therapeutic decision making.
23495093 Association of environmental and genetic factors and gene-environment interactions with ri 2013 Jul OBJECTIVE: We developed rheumatoid arthritis (RA) risk models based on validated environmental factors (E), genetic risk scores (GRS), and gene-environment interactions (GEI) to identify factors that can improve accuracy and reclassification. METHODS: Models including E, GRS, and GEI were developed among 317 white seropositive RA cases and 551 controls from the Nurses' Health Studies (NHS) and validated in 987 white anti-citrullinated protein antibody-positive cases and 958 controls from the Swedish Epidemiologic Investigation of Rheumatoid Arthritis (EIRA), stratified by sex. Primary analyses included age, smoking, alcohol, parity, weighted GRS using 31 non-HLA alleles and 8 HLA-DRB1 alleles, and the HLA × smoking interaction. Expanded models included reproductive, geographic, and occupational factors and additional GEI terms. Hierarchical models were compared for discriminative accuracy using the area under the receiver operating characteristic curve (AUC) and reclassification using the integrated discrimination improvement (IDI) and the continuous net reclassification improvement. RESULTS: The mean age at RA diagnosis was 56 years in the NHS and 51 years in the EIRA. Primary models produced AUCs of 0.716 in the NHS, 0.716 in women in the EIRA, and 0.756 in men in the EIRA. Expanded models produced improvements in discrimination with AUCs of 0.738 in the NHS, 0.724 in women in the EIRA, and 0.769 in men in the EIRA. Models including genetic factors (G) or G + GEI improved reclassification over E models; the full E + G + GEI model provided the optimal predictive ability by IDI analyses. CONCLUSION: We have developed comprehensive RA risk models incorporating E, G, and GEI that have improved the discriminative accuracy for RA. Further work developing and assessing highly specific prediction models in prospective cohorts is still needed to inform primary RA prevention trials.
24954102 Diurnal variation of gait in patients with rheumatoid arthritis: The DIVIGN study. 2014 Aug BACKGROUND: Circadian variation of joint stiffness (morning stiffness) and its impact on functional ability are widely recognised in rheumatoid arthritis. Subsequent within-day variation of walking ability is important due to the increased availability of instrumented gait analysis. This study aimed to quantify diurnal variation of gait in patients with rheumatoid arthritis, and explore associations with disease characteristics. METHODS: Thirty one inpatients with rheumatoid arthritis walked at a self-selected speed along a GAITRite instrumented walkway 5 times during a single day. FINDINGS: Participants showed marked diurnal variation in gait, leading to a systematic variation throughout the day (F=19.56, P=<0.001). Gait velocity and stride length both increased, whereas the proportion of each gait cycle spent in stance phase or double support decreased, consistent with improving function throughout the day. Although absolute gait velocity correlated with disease characteristics, the magnitude of diurnal variation appeared to be independent of disease activity (rho=0.26, P=0.15), disease duration (rho=-0.19, P=0.324), and underlying functional ability (rho=0.09, P=0.65). INTERPRETATION: Although morning stiffness is well recognised in rheumatoid arthritis, this is the first time that its effect on gait has been quantified. Patients with rheumatoid arthritis exhibited a systematic change in walking ability throughout the day, which was independent of disease characteristics. These findings have important implications for the interpretation of existing data and the design of future studies. Repeat measures should be conducted at the same time of day to exclude the effects of diurnal variation.
24138441 Missing radiographic data handling in randomized clinical trials in rheumatoid arthritis. 2013 In recent years, there has been increasing interest in compounds that have potential to slow down the structural joint damage in rheumatoid arthritis (RA) patients. Radiographs are instrumental in assessing structure damage in RA. Radiographic analyses results have become essential in establishing a "delay in structural progression" claim in newly developed agents for the treatment of RA. It is well known that the radiographic progression data generally follow a nonnormal distribution that is loaded with excessive zeros. A special concern about the radiographic data analyses is the handling of the seemingly high rate of missing values due to dropout or unreadable images. There are no uniform ways to handle missing radiographic data, and such data usually show considerable sensitivity to the imputation method chosen under the complexity of the nonnormal data and the unique missing mechanism. In this research, we proposed both an innovative multiple-imputation algorithm and a novel method called the mean rank imputation method under the nonparametric framework for sensitivity analyses. A simulation study was designed using rank analysis of covariance (ANCOVA) to extensively assess and compare the finite performance of these two new methods along with four other missing data handling methods previously used in the RA trials, namely, linear extrapolation, last observation carried-forward (LOCF), median quartile bin imputation, and median imputation under various settings. Our simulation results suggest that the multiple-imputation algorithm, providing an mITT analysis population, yields an inflated type I error and artificially good power. The proposed mean rank imputation method, following a true ITT principle, both is powerful and maintains type I error at the nominal level.
23378555 Leflunomide-induced chronic cough in a rheumatoid arthritis patient with pulmonary tubercu 2013 Feb 1 A 40-year-old lady presented with clinicoradiological features suggestive of pulmonary tuberculosis, which was confirmed on sputum smear examination, and was started on four-drug antitubercular treatment. On subsequent visits, she complained of persistent cough, despite improvement in other symptoms. A careful anamnesis revealed that the patient had been taking leflunomide for rheumatoid arthritis for the last 10 years, and this was suspected to be the cause of the cough. The patient became asymptomatic upon stopping the drug, thereby confirming the hypothesis.
24960620 Treating rheumatoid arthritis to target: an Italian rheumatologists' survey on the accepta 2014 Jul OBJECTIVES: An educational programme was conducted in Italy in order to favour the diffusion of the rheumatoid arthritis (RA) treat-to-target (T2T) recommendations among Italian rheumatologists. Our objective was to measure the level of acceptance and applicability of the 10 recommendations to treat RA to a target of remission/low disease activity in the Italian rheumatology community, before and after the educational programme. METHODS: One hundred rheumatologists working throughout Italy were invited to participate in this two-stage web-based survey (S1-2). Three questions concerning agreement with, applicability of and possible barriers to the applicability of each of the ten T2T recommendations were administered before (S1) and after (S2) an educational event on the T2T strategy in RA. The agreement with each of the 10 recommendations was measured by a 10-point Likert scale. The applicability of each recommendation was assessed by a 5-point Likert scale (never, almost never, sometimes, almost always, always). Finally, three possible barriers to each recommendation applicability were identified. RESULTS: Seventy-one rheumatologists participated in S1 and 61 in S2. Level of agreement was high (mean score: 8.9 in S1, 9.1 in S2), with each recommendation receiving a score ≥7.9. The highest agreement score was achieved by recommendation 7 in both surveys. Recommendation 8 received the lowest overall agreement in both surveys. Concerning applicability, the majority of responses was 'almost always'. Following the educational programme, the mean degree of agreement with the recommendations increased significantly for recommendations 3, 4, 6, and 10. CONCLUSIONS: The level of knowledge of and agreement with the T2T recommendations for RA among Italian rheumatologists is high and increased significantly for some recommendations following a specific educational event, indicating that a deeper knowledge of the T2T strategy may increase agreement and acceptance.
24388041 Cardiovascular risk assessment in rheumatoid arthritis: impact of the EULAR recommendation 2014 Mar OBJECTIVES: To evaluate the impact of the application of the EULAR task force recommendations in the cardiovascular (CV) risk assessment of rheumatoid arthritis (RA) patients according to a national calibrated SCORE. METHODS: Two hundred and one consecutive RA patients seen at the rheumatology outpatient clinics of the University Hospital 'San Cecilio', Granada, Southern Spain, were studied. Information on demographic, classic CV risk factors, history of CV events and disease clinical features were obtained. Both the systematic coronary risk evaluation (SCORE) risk index and the modified SCORE (mSCORE) following the EULAR recommendations were performed. RESULTS: Based on the classic CV risk factors the mean ± standard deviation SCORE was 2.2 ± 2.6 (median 2). Twenty-two (11%) patients were above the threshold of high risk for the Spanish population. Following the EULAR recommendations 52 of the 124 patients (41.93%) initially classified as having intermediate risk were reclassified as having high CV risk. Therefore, the mean mSCORE was 3.3 ± 4 (median 3) and, due to this, 74 (36.8%) patients were above the threshold of high CV risk for the Spanish population. As expected, patients who had experienced CV events were older, had more CV risk factors and higher mSCORE than those without CV events. CONCLUSIONS: These observations support the claim that the mSCORE should be specifically adapted to the population to be assessed. However, the use of additional tools should be considered in an attempt to fully identify high-risk RA patients.
24641732 Glucocorticoids in the treatment of rheumatoid arthritis: still used after 65 years. 2014 May Glucocorticoids (GCs) have been used for over 65 years in the treatment of rheumatoid arthritis (RA). There is by now good evidence for their disease-modifying effects, especially in early RA. When used in a dosage of 5-10 mg, most adverse effects can adequately be monitored, though accurate monitoring and awareness for infections are important. In this paper, the Utrecht and computer-assisted management in early rheumatoid arthritis (CAMERA) studies are discussed; the Utrecht study was the first of these studies in which 10 mg prednisone daily was compared to placebo in patients with early RA. A clear disease-modifying effect was shown. In the CAMERA II study, patients with early RA were treated with a tight-control scheme of climbing dosages of methotrexate plus either 10 mg prednisone daily or placebo. After 2 years, 70% of the patients treated with a tight-control strategy without GCs had no erosions versus 82% of the patients treated with additional prednisone. Remission was reached more often and earlier on in the strategy with prednisone compared to the strategy with placebo.
23592527 Association of epicardial adipose tissue with cardiometabolic risk and metabolic syndrome 2013 Sep OBJECTIVE: Patients with rheumatoid arthritis (RA) have increased coronary atherosclerosis possibly related to increased prevalence of visceral adiposity, insulin resistance, and metabolic syndrome. Epicardial adipose tissue (EAT), a type of visceral fat, may contribute to cardiometabolic risk. The aim of this study was to measure EAT volume in patients with RA and determine its relationship with cardiometabolic risk markers and coronary artery calcium. METHODS: EAT volume and coronary artery calcium score were measured by noncontrast cardiac computed tomography and compared in RA patients (n = 162) and controls (n = 89). The relationships between EAT volume and markers of cardiometabolic risk in RA were examined with adjustment for age, race, and sex. RESULTS: Among RA patients, EAT volume was positively associated with interleukin-6 (P = 0.03), triglycerides (P = 0.004), hypertension (P = 0.01), homeostatic model of insulin resistance (HOMA) (P < 0.001), smoking history (P = 0.04), and homocysteine level (P = 0.001), and negatively associated with high-density lipoprotein (P = 0.005). With further adjustment for waist circumference (a measure of visceral obesity), EAT volume remained independently associated with triglycerides, HOMA, current smoking, and homocysteine level (all P < 0.05). EAT volume was not associated with corticosteroid use or coronary artery calcium score. Patients with metabolic syndrome had significantly greater EAT volume (P < 0.001) and each increase in metabolic syndrome criteria was associated, on average, with a 20% increase (95% confidence interval 14-26%) in EAT volume (P < 0.001). CONCLUSION: EAT volume is associated with metabolic syndrome and cardiometabolic risk factors, including insulin resistance, triglycerides, current smoking, and homocysteine levels, but not with coronary artery calcium in RA patients.
24129130 The BeSt way of withdrawing biologic agents. 2013 Jul OBJECTIVES: Treat-to-target strategies in the management of patients with rheumatoid arthritis (RA) involve intensifying medication as long as low disease activity or remission is not achieved. Our aim was to discuss reasons and opportunities for tapering and discontinuing medication when the target is achieved, in particular of biological agents. METHODS: Data from the Behandel Strategieën (BeSt) study are presented, a multicentre randomised clinical trial comparing 4 treatment strategies in patients with recent onset active RA (1987 criteria): 1. Sequential monotherapy, 2. Step up to combination therapy (both starting with methotrexate (MTX) monotherapy), 3. Initial combination therapy with MTX, sulfasalazine and prednisone and 4. Initial combination therapy with MTX and infliximab. Treatment adjustments involving dose increases, drug changes or expansion to combination therapy occurred based on three-monthly calculations of the Disease Activity Score (DAS), with a target of ≤2.4. If this was achieved for 2 consecutive evaluations, treatment was tapered (combinations to monotherapy, monotherapy to maintenance dose). Prednisone and infliximab (either as part of initial treatment or as delayed treatment after failure on earlier therapies in arms 1, 2 and -for infliximab- 3) were always tapered and discontinued before other drugs. The outcomes of discontinuation of infliximab are presented. RESULTS: 77/120 (64%) of patients who started initial infliximab were able to discontinue infliximab, whereas 27/109 (25%) of patients who started delayed infliximab in arms 1-3 could discontinue infliximab. Discontinuation was independent of previous dose increases in order to achieve low DAS. After discontinuation of infliximab, 16 of 27 patients (59%) in arms 1-3 and 34 of 77 patients (44%) in arm 4 suffered a DAS flare >2.4 and had to restart treatment. Median time without infliximab treatment was 17 (IQR 3-47) months, and 29 of the 61 patients (58%) who needed to restart had been at least 1 year without infliximab. Restarting infliximab resulted in DAS ≤2.4 in all patients, and there was no progression of radiological damage. Presence of shared epitope, smoking, and a long treatment with infliximab were independent predictors of infliximab restart. CONCLUSIONS: Data on infliximab discontinuation in the BeSt study suggest that this possible in 1 in 4 patients, or more if infliximab was the initial treatment, who have had at least 6 consecutive months of low disease activity. While MTX is continued, about 50% of patients can permanently stop infliximab without radiological damage progression, the others regain low disease activity after restarting infliximab. Treat to target strategies using biologic agents should include strategies for discontinuation.
24725539 Orphan receptor GPR15/BOB is up-regulated in rheumatoid arthritis. 2014 Jun Chemokine receptors on leukocytes mediate the recruitment and accumulation of these cells within affected joints in chronic inflammatory diseases such as rheumatoid arthritis (RA). Identification of involved receptors offers potential for development of therapeutic interventions. The objective of this study was to investigate the expression of orphan receptor GPR15/BOB in the synovium of RA and non-RA patients and in peripheral blood of RA patients and healthy donors. GPR15/BOB protein and messenger RNA expression were examined in RA and non-RA synovium by immunofluorescence and reverse-transcription polymerase chain reaction (RT-PCR) respectively. GPR15/BOB expression on peripheral blood leukocytes was analysed by flow cytometry and GPR15/BOB messenger RNA was examined in peripheral blood monocytes by RT-PCR. GPR15/BOB protein was observed in CD68+ and CD14+ macrophages in synovia, with greater expression in RA synovia. GPR15/BOB protein was expressed in all patient synovia whereas in non-RA synovia expression was low or absent. Similarly GPR15/BOB messenger RNA was detected in all RA and a minority of non-RA synovia. GPR15/BOB protein was expressed on peripheral blood leukocytes from RA and healthy individuals with increased expression by monocytes and neutrophils in RA. GPR15/BOB messenger RNA expression was confirmed in peripheral blood monocytes. In conclusion GPR15/BOB is expressed by macrophages in synovial tissue and on monocytes and neutrophils in peripheral blood, and expression is up-regulated in RA patients compared to non-RA controls. This orphan receptor on monocytes/macrophages and neutrophils may play a role in RA pathophysiology.
25438985 Patients with rheumatoid arthritis have better functional and working ability but poorer g 2015 May OBJECTIVES: Better treatment strategies and therapeutic options have changed the treatment of rheumatoid arthritis (RA) during the past decade. Our objective was to examine clinical and patient-reported outcomes in patients with RA treated in 1998-99 and 2011-12. METHOD: The cross-sectional observational study included 303 consecutive outpatients (n = 103 in 1998-99 and n = 200 in 2011-12) from the same outpatient clinic. Patient questionnaires included patients' sociodemographics, the Health Assessment Questionnaire (HAQ) for functional ability, the Nottingham Health Profile (NHP) for health-related quality of life (HRQoL), self-reported general health (GH), and operations performed due to RA. A clinical examination was conducted for all patients. Comorbidities according to the Charlson Comorbidity Index (CCI), anti-rheumatic drugs and medications were recorded and the HAQ and NHP dimensions calculated. The results from these two patient cohorts were compared. RESULTS: The cohorts were comparable with regard to age, sex, and RA duration while the patients in the 2011-12 cohort were less often seropositive for rheumatoid factor (RF), had a better socioeconomic situation, better functional and working ability, and a decreased rate of RA surgery. The patients in 2011-12 had higher comorbidities and poorer GH while the HRQoL dimensions did not differ between the cohorts except for better mobility in 2011-12. Methotrexate (MTX) and combinations of conventional anti-rheumatic drugs were more frequently used in 2011-12. Biologicals were used only in 2011-12. CONCLUSIONS: According to our results, more active anti-rheumatic therapy coincides with better RA-related outcomes. However, the result was the opposite with regard to overall health and comorbidities. Is this a new challenge in the treatment RA?
24267267 Immune response profiling in early rheumatoid arthritis: discovery of a novel interaction 2013 INTRODUCTION: It remains challenging to predict the outcomes of therapy in patients with rheumatoid arthritis (RA). The objective of this study was to identify immune response signatures that correlate with clinical treatment outcomes in patients with RA. METHODS: A cohort of 71 consecutive patients with early RA starting treatment with disease-modifying antirheumatic drugs (DMARDs) was recruited. Disease activity at baseline and after 21 to 24 weeks of follow-up was measured using the Disease Activity Score in 28 joints (DAS28). Immune response profiling was performed by analyzing multi-cytokine production from peripheral blood cells following incubation with a panel of stimuli, including a mixture of human cytomegalovirus (CMV) and Epstein-Barr virus (EBV) lysates. Profiles identified via principal components analysis (PCA) for each stimulus were then correlated with the ΔDAS28 from baseline to follow-up. A clinically meaningful improvement in the DAS28 was defined as a decrease of ≥1.2. RESULTS: A profile of T-cell cytokines (IL-13, IL-4, IL-5, IL-2, IL-12, and IFN-γ) produced in response to CMV/EBV was found to correlate with the ΔDAS28 from baseline to follow-up. At baseline, a higher magnitude of the CMV/EBV immune response profile predicted inadequate DAS28 improvement (mean PCA-1 scores: 65.6 versus 50.2; P = 0.029). The baseline CMV/EBV response was particularly driven by IFN-γ (P = 0.039) and IL-4 (P = 0.027). Among patients who attained clinically meaningful DAS28 improvement, the CMV/EBV PCA-1 score increased from baseline to follow-up (mean +11.6, SD 25.5), whereas among patients who responded inadequately to DMARD therapy, the CMV/EBV PCA-1 score decreased (mean -12.8, SD 25.4; P = 0.002). Irrespective of the ΔDAS28, methotrexate use was associated with up-regulation of the CMV/EBV response. The CMV/EBV profile was associated with positive CMV IgG (P <0.001), but not EBV IgG (P = 0.32), suggesting this response was related to CMV exposure. CONCLUSIONS: A profile of T-cell immunity associated with CMV exposure influences the clinical response to DMARD therapy in patients with early RA. Because CMV latency is associated with greater joint destruction, our findings suggest that changes in T-cell immunity mediated by viral persistence may affect treatment response and possibly long-term outcomes of RA.
24454853 Inverse association between air pressure and rheumatoid arthritis synovitis. 2014 Rheumatoid arthritis (RA) is a bone destructive autoimmune disease. Many patients with RA recognize fluctuations of their joint synovitis according to changes of air pressure, but the correlations between them have never been addressed in large-scale association studies. To address this point we recruited large-scale assessments of RA activity in a Japanese population, and performed an association analysis. Here, a total of 23,064 assessments of RA activity from 2,131 patients were obtained from the KURAMA (Kyoto University Rheumatoid Arthritis Management Alliance) database. Detailed correlations between air pressure and joint swelling or tenderness were analyzed separately for each of the 326 patients with more than 20 assessments to regulate intra-patient correlations. Association studies were also performed for seven consecutive days to identify the strongest correlations. Standardized multiple linear regression analysis was performed to evaluate independent influences from other meteorological factors. As a result, components of composite measures for RA disease activity revealed suggestive negative associations with air pressure. The 326 patients displayed significant negative mean correlations between air pressure and swellings or the sum of swellings and tenderness (p = 0.00068 and 0.00011, respectively). Among the seven consecutive days, the most significant mean negative correlations were observed for air pressure three days before evaluations of RA synovitis (p = 1.7 × 10(-7), 0.00027, and 8.3 × 10(-8), for swellings, tenderness and the sum of them, respectively). Standardized multiple linear regression analysis revealed these associations were independent from humidity and temperature. Our findings suggest that air pressure is inversely associated with synovitis in patients with RA.
24868914 [Proteolytic activity of IgG-antibodies of mice, immunized by calf thymus histones]. 2014 Mar The main goal of the study was to determine the ability of histones to induce production of the proteolytically active IgG-antibodies in BALB/c mice. In order to perform this study 8 mice were immunized with the fraction of total calf thymus histones. IgGs were isolated from the serum of the immunized and not immunized animals by means of precipitation with 33% ammonium sulfate, followed by affinity chromatography on protein G-Sepharose column. Histones, myelin basic protein (MBP), lysozyme, BSA, ovalbumin, macroglobulin, casein and cytochrome c served as substrates for determining the proteolytic activity. It was found that IgGs from the blood serum of immunized mice are capable of hydrolyzing histone H1, core histone and MBP. On the contrary, the proteolytic activity of IgGs from the blood serum of not immunized mice was not detected. The absence of proteolytical enzymes in the fraction of IgGs was proven by HPLC chromatography. High levels of proteolytic activity toward histones have been also detected in affinity purified IgGs from blood serum of patients with rheumatoid arthritis, but not in healthy donors. These data indicate that eukaryotic histones may induce production of protabzymes in mammals. The possible origin of these protabzymes and their potential biological role in mammalians is discussed.
23471526 Resistin in inflammatory and degenerative rheumatologic diseases. Relationship between res 2013 Aug AIMS OF THE STUDY: To assess and compare resistin levels in the serum and synovial fluid of patients with rheumatoid arthritis (RA; an inflammatory rheumatologic disease) and osteoarthritis (OA; a degenerative rheumatologic disease) and to study the relationship between resistin levels and prognostic factors of RA disease progression. PATIENTS AND METHODS: This study included a total of 50 patients: 25 with RA and 25 with OA. Full case history was documented for all patients and all underwent a thorough clinical examination and laboratory testing. Body mass index (BMI) values were also calculated. Radiographs were made of OA patients' knees and RA patients' hands. Disease Activity Score 28 (DAS28) was calculated for RA patients. Serum and synovial fluid samples were obtained from the effused knees of all patients and tested for resistin level. RESULTS: Serum resistin levels were higher in RA patients than in those with OA (p < 0.01). Synovial fluid resistin levels were also higher in RA than OA patients (p < 0.001). While serum resistin levels correlated with Larsen score and total leukocyte count (TLC), synovial fluid resistin levels correlated with rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) levels in addition to Larsen score and TLC. CONCLUSION: Resistin levels were found to be higher in the serum and synovial fluid of RA patients than in those with OA. This may suggest a role for resistin in inflammatory rheumatologic diseases. The observed statistically significant correlation between synovial fluid resistin levels and RF, ACPA and Larsen score may suggest that high synovial fluid resistin levels can be considered a poor prognostic factor for RA progression. However, further studies employing a larger cohort of patients are needed to confirm the relevance of resistin as a prognostic marker in RA patients.
23475981 Ultrasound colour Doppler is associated with synovial pathology in biopsies from hand join 2014 Apr OBJECTIVES: Little is known regarding the association between ultrasound-determined pathological synovial blood flow and synovial pathology in rheumatoid arthritis (RA). We therefore examined the association between colour Doppler ultrasound imaging and synovitis assessed by histopathology and specific cell markers by immunohistochemistry in patients with RA. METHODS: 81 synovial sites from wrist and finger joints from 29 RA patients were evaluated by ultrasound colour Doppler and subsequently biopsied by needle arthroscopy. The association between ultrasound colour fraction and an overall synovitis score and immunohistochemical staining for CD3, CD68, Ki67 and von Willebrand factor was investigated, including repeated samples from the same patients. The overall synovitis score (total 0-9) assessed synovial lining hyperplasia (0-3), stromal activation (0-3) and inflammatory infiltration (0-3). Data were clustered within patients, thus a linear mixed model was applied for the statistical tests. Parsimony in the statistical models was achieved omitting covariates from the model in the case of what was judged no statistical significance (p>0.1). RESULTS: Doppler colour fraction showed an association with the overall synovitis score (approximated Spearman, approximately r=0.43, p=0.003). The density of all immunohistochemical stainings showed a significant association with Doppler colour fraction: von Willebrand factor (approximately r=0.44, p=0.01), CD68 (approximately r=0.53, p=0.02), Ki67 (approximately r=0.57, p=0.05) and CD3 (approximately r=0.57, p=0.0003). CONCLUSIONS: Colour Doppler activity is associated with the extent of inflammation present in the synovial biopsies from RA patients. However, synovial pathology was also seen in biopsies taken from Doppler negative sites.