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ID PMID Title PublicationDate abstract
24549174 E26 transformation-specific-1 (ETS1) and WDFY family member 4 (WDFY4) polymorphisms in Chi 2014 Feb 17 E26 transformation-specific-1 (ETS1) and WDFY family member 4 (WDFY4) are closely related with systemic lupus erythematosus. We hypothesized that ETS1 and WDFY4 polymorphisms may contribute to rheumatoid arthritis (RA) susceptibility. We studied ETS1 rs1128334 G/A and WDFY4 rs7097397 A/G gene polymorphisms in 329 patients with RA and 697 controls in a Chinese population. Genotyping was done using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. When the WDFY4 rs7097397 AA homozygote genotype was used as the reference group, the AG genotype was associated with a significantly increased risk for RA. In the dominant model, when the WDFY4 rs7097397 AA homozygote genotype was used as the reference group, the AG/GG genotypes were associated with a significant increased susceptibility to RA. In stratification analyses, a significantly increased risk for RA associated with the WDFY4 rs7097397 AG genotype was evident among female patients, younger patients, C-reactive protein (CRP) negative patients and both anti-cyclic citrullinated peptide antibody (ACPA) positive patients and negative patients compared with the WDFY4 rs7097397 AA genotype. These findings suggested that WDFY4 rs7097397 A/G may be associated with the risk of RA, especially among younger, female patients, CRP-negative patients and both ACPA positive and negative patients. However, our results were obtained from a moderate-sized sample, and therefore this is a preliminary conclusion. To confirm these findings, validation by a larger study from a more diverse ethnic population is needed.
25295280 Serum samples that have been stored long-term (>10 years) can be used as a suitable data s 2014 OBJECTIVE: There is an unmet need for a specific cardiovascular risk (CV) algorithm for rheumatoid arthritis (RA) patients. Lipoprotein data are often not available in RA cohorts but could be obtained from frozen blood samples. The objective of this study was to estimate the storage effect on lipoproteins in long-term (>10 years) frozen serum samples. METHODS: Data were used from an inception RA cohort. Multiple serum samples from 152 patients were analyzed for lipoproteins, being frozen for 1-26 years at -20°C. Storage effect on lipoproteins was estimated using longitudinal regression analyses and a lipid decay correction factor was developed. Clinical impact of the storage effect on lipoproteins was assessed by calculating the number of patients reclassified to another CV risk group according to the SCORE risk calculator after applying the decay correction factor. RESULTS: There was a significant effect of storage time on total cholesterol (TC) (P<0.001) and high density lipoprotein cholesterol (HDL-c) levels (P<0.001), not LDL-c (P=0.83). The lipid decay correction factor was 0.03 mmol/L and 0.024 mmol/L per additional year of storage for TC and HDL-c, respectively. The TC:HDL ratio decreased after correction for storage effect. After correction, only 5% of patients were reclassified to another CV risk group. CONCLUSION: A modest storage decay effect on lipoproteins was found that is unlikely to significantly affect CV risk stratification. Serum samples that have been stored long-term (>10 years) can be used to obtain valid lipid levels for developing CV risk prediction models in RA cohorts, even without applying a decay correction factor.
23716069 Analysis and modelling of cholesterol and high-density lipoprotein cholesterol changes acr 2014 Aug OBJECTIVES: Raised total cholesterol (TC) and reduced high-density lipoprotein (HDL) cholesterol levels are established cardiovascular disease (CVD) risk factors. However, in autoimmune conditions the lipid-CVD association appears paradoxical, with inflammation as a potential confounding factor. We therefore sought to model the relationship between systemic inflammatory illness and lipid levels using C-reactive protein (CRP) as the prototypical marker of inflammation. Our hypothesis was that there would be an inverse association between raised CRP levels and both TC and HDL-cholesterol levels. METHODS: Results from samples analysed simultaneously for CRP and lipids in a 6-month period were collected retrospectively from a large city hospital laboratory database that collates results from both primary and secondary care. The relationships between CRP and lipids were determined using graphical techniques and empirical, non-parametric, best fit models. RESULTS: A total of 11 437 blood samples was included. We identified a significant (p<0.001) biphasic relationship between TC and CRP: TC increased within the healthy CRP range of less than 5 mg/l, but decreased with CRP levels above 10 mg/l. The two effects approximately cancelled each other out in the intermediate CRP range of 5-10 mg/l. There was an inverse relationship between HDL-cholesterol and CRP. CONCLUSIONS: Lipid levels change significantly during inflammatory illness in a population with both acute and chronic conditions. These results provide a strong epidemiological basis for the better understanding of lipid changes in inflammatory conditions and with anti-inflammatory therapies.
24032521 Continuation of TNF blockade in patients with inflammatory rheumatic disease. An observati 2013 Oct BACKGROUND: Increased infection risk in inflammatory rheumatic diseases may be due to inflammation or immunosuppressive treatment. The influence of tumor necrosis factor (TNF) inhibitors on the risk of developing surgical site infections (SSIs) is not fully known. We compared the incidence of SSI after elective orthopedic surgery or hand surgery in patients with a rheumatic disease when TNF inhibitors were continued or discontinued perioperatively. PATIENTS AND METHODS: We included 1,551 patients admitted for elective orthopedic surgery or hand surgery between January 1, 2003 and September 30, 2009. Patient demographic data, previous and current treatment, and factors related to disease severity were collected. Surgical procedures were grouped as hand surgery, foot surgery, implant-related surgery, and other surgery. Infections were recorded and defined according to the 1992 Centers for Disease Control definitions for SSI. In 2003-2005, TNF inhibitors were discontinued perioperatively (group A) but not during 2006-2009 (group B). RESULTS: In group A, there were 28 cases of infection in 870 procedures (3.2%) and in group B, there were 35 infections in 681 procedures (5.1%) (p = < 0.05). Only foot surgery had significantly more SSIs in group B, with very low rates in group A. In multivariable analysis with groups A and B merged, only age was predictive of SSI in a statistically significant manner. INTERPRETATION: Overall, the SSI rates were higher after abolishing the discontinuation of anti-TNF perioperatively, possibly due to unusually low rates in the comparator group. None of the medical treatments analyzed, e.g. methotrexate or TNF inhibitors, were significant risk factors for SSI. Continuation of TNF blockade perioperatively remains a routine at our center.
25282581 The neutrophil protein S100A12 is associated with a comprehensive ultrasonographic synovit 2014 Oct 4 BACKGROUND: The calcium-binding protein S100A12 correlates with measures of disease activity in patients with rheumatoid arthritis (RA). The protein reflects neutrophil activation and the present objective was to explore in a pilot study the associations between S100A12 and other inflammatory markers, clinical assessments as well as degree of synovitis detected by a comprehensive ultrasonography (US) examination in RA patients during biologic treatment. METHODS: Twenty patients with RA were examined clinically and by use of US as well as laboratory markers S100A12, calprotectin, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) before starting adalimumab, with follow-up after 1, 3, 6 and 12 months. Ultrasonographic B-mode (BM) and power Doppler (PD) assessments of 78 joints, 36 tendons/tendon groups and 2 bursas were performed, and sum US scores calculated. Wilcoxon signed rank test assessed treatment response and Spearman rank correlation test was used to calculate correlations. RESULTS: The concentrations of S100A12 decreased after 3 months (p < 0.01) and significant correlations were found between S100A12 and the other laboratory markers during follow-up (0.50-0.62, p < 0.05). Of the clinical assessments, S100A12 had highest correlations with the assessor's global VAS (0.46-0.85, p < 0.05). Compared with CRP and ESR, S100A12 showed higher correlations with the sum US scores (both BM and PD), with median (range) correlation coefficients of 0.55 (0.35-0.78 (NS-p < 0.001)) for sum BM scores and 0.45 (0.27-0.75 (NS-p < 0.001)) for sum PD scores. CONCLUSIONS: The S100A12 protein was significantly associated with other inflammatory markers, clinical assessments as well as sum US scores, indicating that S100A12 is a potential marker of inflammation in RA patients.
23305268 Long-term etanercept therapy favors weight gain and ameliorates cachexia in rheumatoid art 2013 OBJECTIVE: Rheumatoid arthritis (RA) is a chronic inflammatory disease that damages the synovial joints, and patients with it are often anorexic and cachectic with high morbidity and mortality. Biological therapy with anti-tumor necrosis factor (TNF)-α has been proven effective as a treatment for RA. However, the long-term effects of anti-TNF-α therapy on body weight, appetite, plasma gut hormones and leptin have not been investigated. METHODS: Twenty RA patients received subcutaneous injections of etanercept, a chimeric protein of human IgG1 Fc and TNF receptor p75, twice weekly for 12 consecutive months. Sequential changes in body weight, body fat, appetite rating, lipid profiles, gut hormones and leptin were measured at baseline and at 3 and 12 months after treatment. Ten RA patients who received non-biological disease modifying anti-rheumatic drugs were enrolled as the controls and were appraised at baseline and at 12 months after treatment (a nonrandomized study). RESULTS: Significant weight gain, hyperuricemia, decreased fasting plasma glucose-dependent insulinotropic polypeptide (GIP) levels, and loss of post-oral glucose suppression of plasma leptin concentration were found in the patients after the 12-month course of etanercept therapy, but not in the controls. A transient decrease in fasting plasma acyl ghrelin occurred at 3 months during etanercept treatment. Appetite score and serum lipid profiles did not change in either group. CONCLUSION: Long-term therapy with anti-TNF-α is promising in ameliorating body mass decrease in patients with active RA. Plasma levels of ghrelin, GIP and leptin may play significant roles in maintaining energy homeostasis in the anti-inflammatory responses during RA remission.
23157277 Is inclusion of the occiput necessary in fusion for C1-2 instability in rheumatoid arthrit 2013 Jan OBJECT: The atlantoaxial joint is the location most and earliest affected in patients with rheumatoid arthritis (RA). In longstanding disease, ligamentous and osseous destruction can progress and involve all cervical segments. If surgical intervention is necessary, some prefer, to be safe, undertaking fusion to the occiput, whereas others advocate 1-level fusion of C1-2. Sparing the occiput (Oc)-C1 segment would allow retention of a considerable amount of physiological range of motion and seems beneficial against subaxial overload. Previous clinical studies on this topic have provided only nonspecific data after short-term follow-up, rendering a segment-sparing approach questionable. The purpose of the present investigation was to assess long-term progression of inflammatory or degenerative destruction in the Oc-C1 segment after isolated C1-2 fusion for RA. METHODS: In a series of 113 consecutive patients with RA-related destruction restricted to the craniocervical junction, 14 individuals underwent Oc-C2 fusion and 99 underwent surgery exclusively at the C1-2 level. After a mean follow-up period of 9.4 years (range 4.9-14.7 years), 46 patients were available for clinical and radiographic examination, including CT imaging. RESULTS: None of the 46 patients needed additional surgery to extend the fusion to the occiput. Despite marked deterioration in the subaxial cervical spine, in general there were little or no changes in the atlantooccipital region. All but one patient presented with bony fusion of the fixed C1-2 level at follow-up. CONCLUSIONS: The results of this investigation suggest that if the Oc-C1 joint is free of osseous destructions on conventional radiographs and free of abnormalities on MRI scans at the time of surgery (for transarticular fixation and fusion of C1-2), there is a very low risk for relevant destruction in the following 5-14 years. Thus, no prophylactic oligosegmental approach, but rather a segment-sparing monosegmental approach, is preferred, even in patients with high inflammatory levels.
23053717 Preferences of Japanese rheumatoid arthritis patients in treatment decision-making. 2013 Sep OBJECTIVES: We investigated the decision-making preferences of rheumatoid arthritis (RA) patients using two different scales: the Decision Making Preference Scale (DMPS) and the modified Control Preference Scale (CPS). In addition, we evaluated the factors associated with patients' preferences for decision-making. METHODS: A cross-sectional study was performed using a self-administered anonymous questionnaire between October and December 2010 on 406 RA outpatients who consecutively visited 3 hospitals in Japan. The following variables were investigated: (1) DMPS, which is a subscale of the Autonomy Preference Index, composed of six items; patients responded on a 5-point Likert scale. (2) The modified CPS, in which patients were asked to choose one actual and one desired role in decision-making from among three options (passive role, collaborative role, and active role). (3) Sociodemographic data and RA-specific characteristics. Multivariate analyses were used to assess the relationship between patients' preferences and selected variables. RESULTS: The response rate was 58.6 %. There were few patients who wished to make their own decisions when they were hospitalized or illness became worse. However, the majority of patients desired to collaborate with the doctor in making treatment decisions according to the results of modified CPS. The results of modified CPS were significantly associated with the total scores of DMPS. Multivariate analysis demonstrated they younger age and not-housewife were associated with high scores of DMPS. CONCLUSIONS: Patient preferences in decision-making vary at RA outpatient clinic. Physicians need to assess decision-making preferences on an individual basis.
22531887 Relation of interleukin-6 in rheumatoid arthritis patients to systemic bone loss and struc 2013 Mar IL-6 plays a key role in local and systemic manifestation of RA. IL-6 is not only a pro-inflammatory cytokine, but also interacts in complex ways with the cells involved in bone remodeling. In RA, IL-6 may indirectly promote osteoclastogenesis by increasing the release of RANK-L by osteoblasts, and it diminishes the proliferation of osteoblasts at late differentiation stages. The aims of this work were to evaluate the level of serum IL-6 and to correlate it with the activity, severity, early development of osteoporosis, and early structural bone damage in RA patients. The following parameters were investigated in 40 RA patients and 20 healthy controls: IL-6 level, BMI, ESR, CRP, CBCs, serum ionized calcium, blood urea, serum creatinine, AST, ALT, anti-CCP, and RF. Bone mineral density was measured by dual-energy X-ray absorptiometry at lumbar spines and femoral neck. Drug history was taken stressing on steroid therapy. Data were processed and analyzed using computer-based program. IL-6 was significantly positively correlated with HAQ1, PTGA, grade of pain, ESR, platelet count, blood urea, AST level, and anti-CCP level; IL-6 showed an inverse significant correlation with T-score. IL-6 was positively correlated with TGC, DAS-28 score, and RF level. No correlation was found between T-score and morning stiffness duration, BMI, CRP, RBC, serum creatinine, and ALT. There was an inverse significant correlation between T-score and HAQ1, SJC, pain grade, DAS-28 score, PTGA, ESR, RF, anti-CCP, and IL-6. Patients with RA on steroid therapy had significantly higher TJC, SJC, and DAS-28 score, anti-CCP, and IL-6 than patients with RA not on steroid therapy. Patients with RA on steroid therapy had significantly lower T-score and lower serum ionized calcium than patients with RA not on steroid therapy. IL-6 has an important role in increasing osteoclastic activity and subsequent bone resorption in the patients with RA. Blocking IL-6 by using IL-6 inhibitors and anti-RANK-L therapy may be effective in inhibiting the inflammatory process and preventing the bone complications of RA disease.
25222917 Urinary proteome profile predictive of disease activity in rheumatoid arthritis. 2014 Nov 7 Current serum biomarkers for rheumatoid arthritis (RA) are not highly sensitive or specific to changes of disease activities. Thus, other complementary biomarkers have been needed to improve assessment of RA activities. In many diseases, urine has been studied as a window to provide complementary information to serum measures. Here, we conducted quantitative urinary proteome profiling using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and identified 134 differentially expressed proteins (DEPs) between RA and osteoarthritis (OA) urine samples. By integrating the DEPs with gene expression profiles in joints and mononuclear cells, we initially selected 12 biomarker candidates related to joint pathology and then tested their altered expression in independent RA and OA samples using enzyme-linked immunosorbent assay. Of the initial candidates, we selected four DEPs as final candidates that were abundant in RA patients and consistent with those observed in LC-MS/MS analysis. Among them, we further focused on urinary soluble CD14 (sCD14) and examined its diagnostic value and association with disease activity. Urinary sCD14 had a diagnostic value comparable to conventional serum measures and an even higher predictive power for disease activity when combined with serum C-reactive protein. Thus, our urinary proteome provides a diagnostic window complementary to current serum parameters for the disease activity of RA.
23345600 Pneumococcal polysaccharide vaccination in rheumatoid arthritis patients receiving tociliz 2013 Aug OBJECTIVES: We assessed the impact of tocilizumab (TCZ), a humanised monoclonal anti-interleukin-6 receptor antibody, on antibody response following administration of the 23-valent pneumococcal polysaccharide vaccine (PPV23). METHODS: A total of 190 patients with rheumatoid arthritis (RA) received PPV23. Patients were classified into TCZ (n=50), TCZ + methotrexate (MTX) (n=54), MTX (n=62) and RA control (n=24) groups. We measured serotype-specific IgG concentrations of pneumococcal serotypes 6B and 23F using ELISA and functional antibody activity using a multiplexed opsonophagocytic killing assay, reported as the opsonisation indices (OIs), before and 4-6 weeks after vaccination. Positive antibody response was defined as a 2-fold or more increase in the IgG concentration or as a ≥10-fold or more increase in the OI. RESULTS: IgG concentrations and OIs were significantly increased in all treatment groups in response to vaccination. The TCZ group antibody response rates were comparable with those of the RA control group for each serotype. MTX had a negative impact on vaccine efficacy. Multivariate logistic analysis confirmed that TCZ is not associated with an inadequate antibody response to either serotype. No severe adverse effect was observed in any treatment group. CONCLUSIONS: TCZ does not impair PPV23 immunogenicity in RA patients, whereas antibody responses may be reduced when TCZ is used as a combination therapy with MTX.
23526131 Is the frequency of metabolic syndrome higher in South Korean women with rheumatoid arthri 2013 Mar BACKGROUND/AIMS: To compare the frequency of metabolic syndrome (MetS) and magnitude of insulin resistance, measured by the homeostatic model assessment of insulin resistance (HOMA-IR), between South Korean women with rheumatoid arthritis (RA) and healthy subjects, and to evaluate risk factors for MetS and increased HOMA-IR in patients with RA. METHODS: In a cross-sectional setting, 84 female patients with RA and 109 age-matched healthy female subjects were consecutively recruited at a university-affiliated rheumatology center in South Korea. MetS was defined according to the Third Report of the National Cholesterol Education Program's Adult Treatment Panel (NCEP-ATP III) 2004 criteria. RESULTS: The frequency of MetS did not differ significantly between patients with RA (19%) and healthy subjects (15.6%, p = 0.566), although patients with RA had a higher HOMA-IR compared with healthy subjects (p < 0.001). Patients with RA met the NCEP-ATP III 2004 criteria for high blood pressure more often than healthy subjects (44% vs. 19.3%, p < 0.001), and low high density lipoprotein cholesterol was more prevalent in healthy subjects (33%) than in patients with RA (14.3%, p = 0.004). Although no obvious risk factors for the presence of MetS were identified in patients with RA, higher serum C-reactive protein and disease activity score assessed using the 28-joint count for swelling and tenderness-erythrocyte sedimentation rate significantly contributed to a higher HOMA-IR. CONCLUSIONS: Despite their increased insulin resistance, South Korean women with RA did not have a significantly higher frequency of MetS compared with that in healthy subjects.
23065319 Automated radiofrequency-based US measurement of common carotid intima-media thickness in 2013 Feb OBJECTIVE: To compare the carotid intima-media thickness (IMT) assessed with automated radiofrequency-based US in RA patients treated with synthetic vs synthetic and biologic DMARDs and controls. METHODS: Ninety-four RA patients and 94 sex- and age-matched controls were prospectively recruited at seven centres. Cardiovascular (CV) risk factors and co-morbidities, RA characteristics and therapy were recorded. Common carotid artery (CCA)-IMT was assessed in RA patients and controls with automated radiofrequency-based US by the same investigator at each centre. RESULTS: Forty-five (47.9%) RA patients had been treated with synthetic DMARDs and 49 (52.1%) with synthetic and biologic DMARDs. There were no significant differences between the RA patients and controls in demographics, CV co-morbidities and CV disease. There were significantly more smokers among RA patients treated with synthetic and biologic DMARDs (P = 0.036). Disease duration and duration of CS and synthetic DMARD therapy was significantly longer in RA patients treated with synthetic and biologic DMARDs (P < 0.0005). The mean CCA-IMT was significantly greater in RA patients treated only with synthetic DMARDs than in controls [591.4 (98.6) vs 562.1 (85.8); P = 0.035] and in RA patients treated with synthetic and biologic DMARDs [591.4 (98.6) vs 558.8 (95.3); P = 0.040). There was no significant difference between the mean CCA-IMT in RA patients treated with synthetic and biologic DMARDs and controls (P = 0.997). CONCLUSION: Our results suggest that radiofrequency-based measurement of CCA-IMT can discriminate between RA patients treated with synthetic DMARDs vs RA patients treated with synthetic and biologic DMARDs.
25022467 Infection risk in patients with rheumatoid arthritis treated with etanercept or adalimumab 2014 Oct OBJECTIVES: To compare the risk of infection for rheumatoid arthritis (RA) patients who took etanercept or adalimumab medication in a nationwide population. METHODS: RA patients who took etanercept or adalimumab were identified in the Taiwan's National Health Insurance Research Database. The composite outcome of serious infections, including hospitalization for infection, reception of an antimicrobial injection, and tuberculosis were followed for 365 days. A Kaplan-Meier survival curve with a log-rank test and Cox proportional hazards regression were used to compare risks of infection between the two cohorts of tumor necrosis factor (TNF)-α antagonists users. Hazard ratios (HRs) were obtained and adjusted with propensity scores and clinical factors. Sensitivity analyses and subgroup analyses were also performed. RESULTS: In total, 1660 incident etanercept users and 484 incident adalimumab users were eligible for the analysis. The unadjusted HR for infection of the etanercept users was significantly higher than that of the adalimumab users (HR: 1.93; 95% confidence interval (CI): 1.09-3.42; p=0.024). The HRs were 2.04 (95% CI: 1.14-3.65; p=0.016) and 2.02 (95% CI: 1.13-3.61; p=0.018) after adjusting for propensity scores and for propensity scores in addition to clinical factors, respectively. The subgroup analyses revealed that HRs for composite infection was significantly higher in patient subgroups of older age, female, as well as patients who did not have DM, COPD, and hospitalization history at the baseline. CONCLUSION: In this head-to-head cohort study involving a nationwide population of patients with RA, etanercept users demonstrated a higher risk of infection than adalimumab users. Results of this study suggest the possible existence of an intra-class difference in infection risk among TNF-α antagonists.
24350658 The influence of foetal prednisone exposure on the cortisol levels in the offspring. 2014 Jun OBJECTIVE: Pregnant women suffering from autoimmune disease use glucocorticoids. Glucocorticoids can partly diffuse to the foetus and may influence the development of the foetal hypothalamic-pituitary-adrenal axis, especially in early stage of pregnancy. The objective was to investigate whether prednisone exposure in utero influences the cortisol levels of the prepubertal children. DESIGN: Mothers participated in a prospective cohort study on rheumatoid arthritis (RA) and pregnancy. Children were exposed (n = 44) or nonexposed (n = 65) to prednisone in utero. Salivary cortisol levels were taken from all children during 1 day: at awakening, 30 min after awakening, 1 p.m. and bedtime. Cortisol levels between groups were also analysed using area under the curve (AUC), cortisol awakening response (CAR) and slope. RESULTS: The mean age (SD) of the children was 6·98 (1·23). The difference in mean (SD) cortisol level at '1 p.m.' was 5·42 nm (4·08) in the prednisone-exposed and 3·97 nm (4·00) in the nonexposed (P = 0·03). Prednisone-exposed children had a higher AUC (β = 13·28; P = 0·02), even after correction for RA disease activity. No differences were found on CAR, slope or blood pressure. The cortisol levels of the nonexposed were more similar to the age-specific references than the prednisone-exposed. CONCLUSION: Prednisone use during pregnancy is associated with a higher daytime cortisol level, in the prepubertal offspring, not yet accompanied with clinical outcomes. This conclusion will have no consequences at this moment, but it does raise questions concerning prednisone exposure in utero and the long-term consequences for the offspring.
23841912 Alternate virtual populations elucidate the type I interferon signature predictive of the 2013 Jul 10 BACKGROUND: Mechanistic biosimulation can be used in drug development to form testable hypotheses, develop predictions of efficacy before clinical trial results are available, and elucidate clinical response to therapy. However, there is a lack of tools to simultaneously (1) calibrate the prevalence of mechanistically distinct, large sets of virtual patients so their simulated responses statistically match phenotypic variability reported in published clinical trial outcomes, and (2) explore alternate hypotheses of those prevalence weightings to reflect underlying uncertainty in population biology. Here, we report the development of an algorithm, MAPEL (Mechanistic Axes Population Ensemble Linkage), which utilizes a mechanistically-based weighting method to match clinical trial statistics. MAPEL is the first algorithm for developing weighted virtual populations based on biosimulation results that enables the rapid development of an ensemble of alternate virtual population hypotheses, each validated by a composite goodness-of-fit criterion. RESULTS: Virtual patient cohort mechanistic biosimulation results were successfully calibrated with an acceptable composite goodness-of-fit to clinical populations across multiple therapeutic interventions. The resulting virtual populations were employed to investigate the mechanistic underpinnings of variations in the response to rituximab. A comparison between virtual populations with a strong or weak American College of Rheumatology (ACR) score in response to rituximab suggested that interferon β (IFNβ) was an important mechanistic contributor to the disease state, a signature that has previously been identified though the underlying mechanisms remain unclear. Sensitivity analysis elucidated key anti-inflammatory properties of IFNβ that modulated the pathophysiologic state, consistent with the observed prognostic correlation of baseline type I interferon measurements with clinical response. Specifically, the effects of IFNβ on proliferation of fibroblast-like synoviocytes and interleukin-10 synthesis in macrophages each partially counteract reductions in synovial inflammation imparted by rituximab. A multianalyte biomarker panel predictive for virtual population therapeutic responses suggested population dependencies on B cell-dependent mediators as well as additional markers implicating fibroblast-like synoviocytes. CONCLUSIONS: The results illustrate how the MAPEL algorithm can leverage knowledge of cellular and molecular function through biosimulation to propose clear mechanistic hypotheses for differences in clinical populations. Furthermore, MAPEL facilitates the development of multianalyte biomarkers prognostic of patient responses in silico.
24261754 Drug free REmission/low disease activity after cessation of tocilizumab (Actemra) Monother 2014 Jan OBJECTIVES: To investigate the duration of remission and low disease activity (LDA) after cessation of tocilizumab (TCZ) treatment in rheumatoid arthritis patients who showed remission or LDA as assessed by DAS28 in response to preceding TCZ monotherapy, and to explore the factors contributing to prolonged efficacy duration. METHODS: Disease activity was monitored for 56 weeks. The rate of continued efficacy was estimated by Kaplan-Meier curves. RESULTS: A total of 187 patients were eligible. At baseline of this study, median disease duration was 7.8 years, preceding TCZ treatment period was 4.0 years and DAS28 was 1.5. The rate of continued LDA at 52 weeks was 13.4 % according to the Kaplan-Meier estimate. 19 patients (10 %) were completely drug-free and 17 patients (9.1 %) fulfilled DAS28 remission at 52 weeks. Multivariate Cox regression analysis identified low serum IL-6 and normalisation of MMP-3 levels at cessation of TCZ as independent predictive markers for longer duration of LDA. In patients with low serum IL-6 (<12.9 pg/mL) and normal MMP-3 levels, the rate of continued LDA reached 38.0 % at 52 weeks. CONCLUSIONS: TCZ monotherapy may induce biologics-free remission or LDA without concomitant use of synthetic DMARDs. Serum levels of IL-6 and MMP-3 are useful markers for identifying patients who could discontinue TCZ without acute disease flare.
25167379 Why is there persistent disease despite biologic therapy? Importance of early intervention 2014 This short article hypothesizes that the major reason for persistent disease despite biologic therapy is the inappropriately late timing of therapy with biologic agents. There is clear evidence to support this hypothesis. This short review will indicate that patients treated at an earlier phase of disease can achieve a clinical remission rate of 70% and a response rate of above 95%.
25228525 [Role of Porphyromonas gingivalis in rheumatoid arthritis and inflammatory spondyloarthrop 2014 Sep 17 The most recent studies confirm the link between rheumatoid arthritis (RA) and periodontal disease. RA patients have higher prevalence of chronic periodontitis and periodontal disease is often more severe in these patients. Both RA and PD show similar pathophysiological mechanisms and risk factors. Autoimmunity to citrullinated peptides is the primary element in the pathogenesis of RA, not found in other diseases. Porphyromonas gingivalis, the major periodontal pathogen associated with the etiology of chronic periodontitis, is the only bacterium currently known to produce the enzyme peptidylarginine deiminase (PAD) allowing protein citrullination. This bacterium likely fulfils a significant role in the pathogenesis of RA due to its capacity for citrullination of its own protein and host peptides, which may result in a loss of immune tolerance. A few epidemiological studies also indicate the potential link between spondyloarthropathies and periodontal disease.
24521737 The patient perspective on remission in rheumatoid arthritis: 'You've got limits, but you' 2015 Jun OBJECTIVES: The aim of rheumatoid arthritis (RA) treatment is remission. As treatment should be targeted at outcomes relevant to patients, it is important to understand how patients perceive remission, and to assess whether the current definition of remission adequately reflects these perceptions. The objective of this study is to explore the patient perspective on remission in RA. METHODS: Nine focus-group discussions in Austria, The Netherlands and UK were conducted, including patients in American College of Rheumatology (ACR)/ European League of Rheumatology (EULAR) remission, self-declared remission and in moderate/high disease activity. Moderators employed a prespecified interview guide helped to engage patients in a discussion on their experience with remission. Inductive thematic analysis was performed within each country, and identified themes were discussed across countries. RESULTS: 47 RA patients (66% women, disease duration 9 years) participated. Three major themes of patient-perceived remission emerged: (1) symptoms would either be absent or strongly reduced, (2) impact of the disease on daily life would diminish by increased independence, ability to do valued activities, improved mood and ability to cope; (3) leading to a return to normality, including work, family role and perception of others. Patients felt the concept of remission was influenced by ageing, side effects of medication, comorbidities, accrued damage to joints and disease duration. Opinions on duration of state, the role of medication and measurement instruments varied widely. CONCLUSIONS: Patients characterise remission by the absence or reduction of symptoms, but more directly by decreased daily impact of their condition and the feeling of a return to normality. The next step is to study whether an additional patient-perceived measure of remission may add value to the ACR/EULAR definition of remission.