Improvement In Disease Activity Score Research Articles

Metabolomics profiling of the free and total oxidised lipids in urine by LC-MS/MS: application in patients with rheumatoid arthritis.

Oxidised lipids, covering enzymatic and auto-oxidation-synthesised mediators, are important signalling metabolites in inflammation while also providing a readout for oxidative stress, both of which are prominent physiological processes in a plethora of diseases. Excretion of these metabolites via urine is enhanced through the phase-II conjugation with glucuronic acid, resulting in increased hydrophilicity of these lipid mediators. Here, we developed a bovine liver-β-glucuronidase hydrolysing sample preparation method, using liquid chromatography coupled to tandem mass spectrometry to analyse the total urinary oxidised lipid profile including the prostaglandins, isoprostanes, dihydroxy-fatty acids, hydroxy-fatty acids and the nitro-fatty acids. Our method detected more than 70 oxidised lipids biosynthesised from two non-enzymatic and three enzymatic pathways in urine samples. The total oxidised lipid profiling method was developed and validated for human urine and was demonstrated for urine samples from patients with rheumatoid arthritis. Pro-inflammatory mediators PGF2α and PGF3α and oxidative stress markers iPF2α- IV, 11-HETE and 14-HDoHE were positively associated with improvement of disease activity score. Furthermore, the anti-inflammatory nitro-fatty acids were negatively associated with baseline disease activity. In conclusion, the developed methodology expands the current metabolic profiling of oxidised lipids in urine, and its application will enhance our understanding of the role these bioactive metabolites play in health and disease.Electronic supplementary materialThe online version of this article (doi:10.1007/s00216-016-9742-2) contains supplementary material, which is available to authorized users.

Impact of methotrexate dose on efficacy of adalimumab in Japanese patients with rheumatoid arthritis: Results from registered data analyses

Objective: Upper limit of methotrexate (MTX) for patients with rheumatoid arthritis (RA) was recently increased from 8 to 16 mg/week in Japan. We therefore examined the effect of concomitant MTX dose on the efficacy of adalimumab (ADA) in clinical practice.Method: Sixty-one consecutive RA patients treated with ADA were followed for minimum 52 weeks and retrospectively compared by MTX dose; patients receiving concomitant MTX of 10 mg/week or more (MTX ≥10 mg group) and <10 mg/week (MTX <10 mg group). Disease activity and remission were evaluated by the disease activity score 28 (DAS28) criteria.Results: The MTX ≥10 mg group consistently showed better improvement in DAS28 and resulted in more patients (52.8%) with DAS28-remission compared with the MTX <10 mg group (26.1%). Multivariate analysis showed that MTX ≥10 mg had a significant effect on DAS28 remission with odds ratio of 5.12. ADA retention rate was 72.2% in MTX ≥10 mg group compared with 52.0% in MTX <10 mg group. Discontinuation of ADA due to adverse events were comparable in the MTX ≥10 mg and MTX <10 mg groups (11.1% vs. 12.0%).Conclusions: These findings support the critical role of concomitant MTX in the efficacy of ADA, and recommend use of MTX ≥10 mg in Japanese RA patients.

No predictive effect of body mass index on clinical response in patients with rheumatoid arthritis after 24weeks of biological disease-modifying antirheumatic drugs: a single-center study.

The aim of this study was to determine whether body mass index (BMI) is associated with clinical response to biologics in patients with rheumatoid arthritis (RA). We enrolled 68 patients with RA who were treated with biological disease-modifying antirheumatic drugs (bDMARDs). Biologics included abatacept, tocilizumab, and tumor necrosis factor-α (TNF-α) blockers (etanercept and adalimumab). Baseline BMI (kg/m(2)) was classified as normal (BMI < 23.0), overweight (23.0 ≤ BMI < 25.0), or obese (BMI ≥ 25.0). Improvement of disease activity score 28 (DAS28) and achievement of the European League Against Rheumatism (EULAR) remission and responses between baseline and 24weeks were our measures of clinical improvement. Mean baseline BMI before treatment with bDMARDs in patients with RA was 22.2 (SD 3.6). DAS28-ESR and DAS28-CRP were significantly reduced from baseline after 24weeks of treatment with bDMARDs (p < 0.001 of both). ∆DAS28-ESR and ∆DAS28-CRP were not found among patients with normal, overweight, or obese BMI (p = 0.133 and p = 0.255, respectively) nor were EULAR responses or EULAR remission (p = 0.540 and p = 0.957, respectively). Logistic regression analysis showed no relationship of BMI with EULAR clinical responses (p = 0.093 for good response and p = 0.878 for EULAR remission). This study reveals that BMI is not a predictive factor of clinical response to bDMARDs in patients with RA.

Relationship Between Lymph Node Volume and Pain Following Certolizumab Therapy for Rheumatoid Arthritis Flare: A Pilot Study.

OBJECTIVESThe mechanisms that trigger flare in rheumatoid arthritis (RA) are unknown. In murine arthritis models, dysfunctional lymph node (LN) drainage is associated with joint flare. To examine if LN alterations are associated with RA flare, we analyzed the change in LN volume via contrast-enhanced magnetic resonance imaging (CE-MRI) in patients with active joint flare at baseline and 16 weeks after certolizumab pegol (CZP) therapy. We also assessed the changes in popliteal or epitrochlear LN volumes versus the Rheumatoid and Arthritis Outcome Score (RAOS) (knee), or the Michigan Hand Questionnaire (MHQ; wrist/hand), and Disease Activity Score 28 (DAS28), at baseline and 16 weeks.RESULTSTotal LN volume in 7 of 10 patients with measurable LN on CE-MRI significantly decreased 16 weeks after CZP therapy (mean decrease 37%; P = 0.0019). Improvement in knee pain measured by the RAOS (P = 0.03) inversely correlated with a decrease in total popliteal LN volume (R2 = 0.94). All patients demonstrated significant improvement in DAS28 (mean decrease 1.48; P = 0.0002). For flare in the hand, significant improvement in activities of daily living (ADL) as measured by the MHQ was observed (left hand mean improvement 20%; P = 0.02; right hand mean improvement 37%; P = 0.03).CONCLUSIONRA patients with the smallest change in LN volume during anti-tumor necrosis factor (anti-TNF) therapy experienced the greatest pain relief in symptomatic knee joints. Moreover, the remarkably linear inverse correlation between LN volume and joint pain observed in this small clinical pilot provides initial evidence to support the concept that dynamic changes in draining LN volume are a biomarker of clinical response to therapy in RA.

Predictors of Response to (Etanercept) in the Treatment of Iraqi Patients with Active Rheumatoid Arthritis

Background: Since the introduction of tumour necrosis factor-alpha (TNF-α) inhibitors including etanercept, their efficacy and safety in treatment of rheumatoid arthritis (RA) have been studied in many randomized controlled clinical trials. However, data regarding predictors of clinical response to anti-TNF therapy are still sparse.Objective: To assess the predictors of response to etanercept in treatment of Iraqi patients with active RA.Methods: An open label single group prospective study was conducted over 15 months on 190 Iraqi patients with RA. All the included patients were given etanercept at a dose of 50 mg by subcutaneous injection ona weeklybases. Each patient was followed at regular intervals of baseline,1, 3 and 6 months for disease activity using Disease Activity Score 28 (DAS28). Also we assess six different patients characteristics (age, gender, disease duration, the presence of rheumatoid factor, smoking status and the concomitant use of methotrexate) as predictors to etanercept response.Results: Data analysis showed a significant improvement in DAS28 with etanercept use over a period of 6 months. Females were more respondent to treatment than males. The concomitant use of methotrexate showed highly significant correlation with the treatment response. The other variables had no significant effect on response to treatment.Conclusion: Female gender and concomitant use of methotrexate have a significant correlation with response to etanercept treatment.

Effects of enteral nutritional support on malnourished patients with inflammatory bowel disease by subjective global assessment.

To investigate the prevalence of malnutrition in patients with inflammatory bowel disease (IBD) by subjective global assessment (SGA) and the effects of oral nutritional support on the clinical parameters, consumption of energy, macronutrients and fiber intake in the Study and Control groups, prospectively. A total of 38 (28 Male; 10 Female) hospitalized patients with moderate or severe IBD (13 with Crohn's disease (CD); 25 with Ulcerative colitis (UC)) were included. At stage 1, the disease severity, clinical symptoms and, signs, food consumption and nutritional status by using subjective global assessment (SGA) were recorded. At stage 2, the patients were blindly randomized into a Study Group and Controls. In the Study Group, a standard enteral product was added into the regulated hospital diets, but for the Controls, deficits were regulated by only hospital diets for 3 weeks. the independent variables were the group, the disease and its activity, age, Body body mass index (BMI), weight loss history, the hospitalization period; the dependent variables were SGA, bowel movements, change in nutritional status, disease severity, clinical findings, and also consumption of macronutrients. Prevalance of malnutrition (SGA-B or SGA-C) for all the patients was 92.1% at the beginning and 71.1% at the end of study. Improvements in disease activity score for the patients with UC were statistically significant in both the Study Group and the Controls (p=0.006 for the Study Group and p=0.001 for the Controls, respectively). Macronutrients, total and water soluble fiber consumption levels improved, with statistically significant differences for all the groups. The prevalence of malnutrition is a major problem in patients with IBD. Not only the regulation of hospital food, but also enteral nutritional support, improved their levels of malnutrition, as well as their energy, macronutrients, and fiber consumption, and SGA is an easy method for nutritional monitoring.

THU0161 Increase in Circulating TH17 Cells during Anti-TNF Therapy in Rheumatoid Arthritis Patients is Associated with Improvement in Joint Inflammation

BackgroundAnti-TNFα agents have revolutionised treatment of rheumatoid arthritis (RA), although a significant proportion of patients respond inadequately. Studies in murine and human arthritis have paradoxically shown that anti-TNF treatment can...

OP0148 Effectiveness of Conventional DMARDS Using A Treat to Target Strategy in the Context of A Large Cohort of Rheumatoid Arthritis Patients

BackgroundThe importance of early effective therapy, implications of disease activity in progression and use of composite disease activity measures in rheumatoid arthritis (RA), led to developing of defined therapeutic targets...

FRI0031 Better Outcomes of Disease Activity in A Large Cohort of Rheumatoid Arthritis Patients Treated under Treat to Target Recommendations

BackgroundThe importance of early effective therapy, implications of disease activity in progression and use of composite disease activity measures in rheumatoid arthritis (RA), led to developing of defined therapeutic targets...

FRI0262 Effectiveness of Biological Therapy Using A Treat to Target Strategy in Patients with Rheumatoid Arthritis

BackgroundThe implications of disease activity in progression and use of composite disease activity measures in rheumatoid arthritis (RA), led to developing of defined therapeutic targets and tools to achieve them...

Circulating Th17 cells and joint inflammation during anti-tumour necrosis factor therapy in rheumatoid arthritis

BackgroundAnti-tumour necrosis factor (TNF) agents have revolutionised the treatment of rheumatoid arthritis, although a substantial proportion of patients respond inadequately. Studies in murine and human arthritis have paradoxically shown that anti-TNF treatment can increase circulating interleukin-17-producing T helper (Th17) cells but the association of these changes with treatment responses remains unclear. To investigate immune correlates of anti-TNF treatment response in patients with rheumatoid arthritis we did a longitudinal study using serial clinical, ultrasonographic, and T-cell immunological assessments. Methods25 patients with rheumatoid arthritis naive to biological therapy were followed at four predetermined protocol visits during the first 12 weeks of anti-TNF-alpha treatment. 16 patients were treatment responders, as defined by improvement in disease activity score in 28 joints (DAS28) by more than 1·2 from baseline. Nine patients were non-responders (change in DAS28 score <1·2 from baseline). Changes in synovial thickening and vascularity of metacarpophalangeal joints were quantitatively assessed by power Doppler ultrasonography (PDUS). Changes in the frequency of circulating Th17 cells were evaluated by ELISPOT and intracellular cytokine staining of peripheral blood mononuclar cells. Statistical analysis included Wilcoxon signed rank matched pairs test and Spearman's rank correlation. Written informed consent was obtained from study participants, and ethics approval was obtained from the local ethics committee. This study is registered with ClinicalTrials.gov, number NCT01060098. FindingsELISPOT analysis showed a significant increase in circulating IL17-producing cells 12 weeks after anti-TNF initiation (baseline vs 12 weeks: mean 466 spSFC/106 [SD 277] vs 759 [510]; p=0·003). Fluorescence-activated cell sorting analysis confirmed significant increase in CD4+IL17+ cells at treatment week 12 (baseline vs 12 weeks: mean 0·78% [0·5] vs 1·1 [0·5]; p=0·01). The dynamics of changes in circulating Th17 cells during anti-TNF-alpha treatment were the same in treatment responders and non-responders and in patients treated with different types of anti-TNF alpha agents, suggesting a class effect. The increase in circulating Th17 cells during treatment correlated with reduction in synovial vascularity (r=−0·68, p=0·007) and synovial thickening (r=−0·39; p=0·04) as determined by PDUS. Higher numbers of circulating Th17 cells at baseline were associated with poorer response to anti-TNF-alpha treatment as defined by DAS28 score and ultrasonographic measures. InterpretationThis is the first study, to our knowledge, that links changes in circulating Th17 cells evaluated by cellular assays with resolution of ultrasonographic features of synovitis during anti-TNF treatment. The findings could mean that Th17 cells are redistributed from inflamed joints during treatment or that TNFα could have a role in the regulation of Th17 cell production. FundingThe Kennedy Trust for Rheumatology Research, Imperial College Healthcare Charity, UK Medical Research Council.

PMS15 - Improvement in Disease Activity Scores Associated with Early Versus Late Initiation of Biologic Therapy in Patients with Rheumatoid Arthritis: Results of a European Chart Review Study

Recent research has suggested that patients may have a “window of opportunity” to reverse immune dysregulation associated with RA onset through aggressive early treatment. This study aimed to evaluate the outcomes associated with early versus late biologic treatment in RA. Adults (≥18 years) with confirmed RA diagnosis between January 2008 and December 2010, who received biologic therapy for ≥3 months and had ≥12 months follow-up were included in this retrospective, observational medical chart review study in Spain, Germany, and United Kingdom. Physicians abstracted outcomes including 28-joint disease activity scores (DAS28) alongside treatment received. Patients were classified as receiving early biologic treatment if started within 1 year of RA diagnosis. Outcomes included DAS28 reduction of ≥1.2 from scores at biologic start and remission (DAS28<2.6). Time to reaching these outcomes was evaluated using Kaplan-Meier survival curves and log rank tests. Of 328 patients included, 310 (178 early; 132 late) had DAS28 measurements and were demographically similar between early vs. late treatment (overall: mean age 47.9 at diagnosis, 71.0% female, 96.1% white). Overall, 73.5% of patients had a DAS28 decrease ≥1.2 points and 44.5% achieved remission. More early versus late biologic treated patients had a DAS28 decrease ≥1.2 (79.2% vs 65.9%, p=0.009) but there was no significant difference in the time to this decrease. More early vs. late biologic treated patients achieved remission (51.1% vs. 35.6%, p=0.009), with a significant difference in survival curves when indexing on time since RA diagnosis (p<0.001) and biologic start (p=0.024). There were no significant differences outcomes across countries. This chart review contributes to the growing literature surrounding outcomes associated with early biologic treatment. Within this study, RA patients who were treated early were more likely to achieve clinically significant improvement and to reach remission earlier in their RA disease trajectory than those treated later.

Efficacy and safety of reducing duration of infliximab infusion

Objective. To evaluate the safety and efficacy of reducing the duration of infliximab infusion for rheumatoid arthritis (RA) treatment.Methods. The first 6 infliximab infusions were each administered over a 2-h period. If no adverse reaction was observed, infusion times were shortened to 1 h starting with the seventh infusion with further shortening to 30 min starting with the thirteenth infusion. Subjects were divided into two groups: shortened infusion time group, in which infusion times were shortened as above; and constant infusion time group, in which infusion time was 2 h. Incidence of infusion reactions and improvement in disease activity score for 28 joints (DAS-28) erythrocyte sedimentation rate (ESR) for total infusions were compared for the seventh to twelfth and thirteenth to eighteenth infusions.Results. The incidences of infusion reactions after the seventh to twelfth and thirteenth to eighteenth infusions in the shortened infusion time group were 0.53% and 0.58%, respectively. In the constant infusion time group, these were 0.70% and 0.67%, respectively. Furthermore, shortening the infusion duration did not affect the DAS-28 (ESR) improvement rate.Conclusions. We established that this stage-wise shortening of infusion duration, first to 1 h and then to 30 min, did not compromise the safety or efficacy of treatment.

SAT0072 Effectiveness of Using a Treat to Target Strategy in a Large Cohort Of Rheumatoid Arthritis Patients During 2 Years In A Real-Life Setting

BackgroundThe importance of early effective therapy, implications of disease activity in progression and use of composite disease activity measures in rheumatoid arthritis (RA), led to developing of defined therapeutic targets...

THU0153 Improvements in disease activity score by baseline status: Pooled analysis of five phase 3 studies with tofacitinib (CP-690,550) in patients with active rheumatoid arthritis

BackgroundTofacitinib (CP-690,550) is a novel, oral Janus kinase inhibitor being investigated as a targeted immunomodulator in rheumatoid arthritis.ObjectivesTo assess efficacy of tofacitinib 5 and 10 mg twice-daily (BID) using disease...

THU0251 Effectiveness of Conventional Dmards Using a Treat to Target Strategy in the Context of a Large Cohort of Rheumatoid Arthritis Patients

BackgroundThe importance of early effective therapy, implications of disease activity in progression and use of composite disease activity measures in rheumatoid arthritis (RA), led to developing of defined therapeutic targets...

SAT0112 Using treat to target recommendations in a large cohort of rheumatoid arthritis patients in a real-life setting

BackgroundThe importance of early effective therapy, implications of disease activity in progression and use of composite disease activity measures in rheumatoid arthritis (RA), led to developing of defined therapeutic targets...

FRI0181 Effectiveness of biological therapy using a treat to target strategy in patients with rheumatoid arthritis

BackgroundThe importance of early effective therapy, implications of disease activity in progression and use of composite disease activity measures in rheumatoid arthritis (RA), led to developing of defined therapeutic targets...

Exposure‐Exposure Relationship of Tocilizumab, an Anti–IL‐6 Receptor Monoclonal Antibody, in a Large Population of Patients With Rheumatoid Arthritis

Relationships between tocilizumab exposure and response were evaluated using data from 4 phase III studies. Increased tocilizumab exposure was associated with improvements in Disease Activity Score using 28 joints (DAS28) and American College of Rheumatology (ACR) criteria and with a decrease in inflammation markers. A population pharmacokinetic/pharmacodynamic (PKPD) model was developed to describe data from 2 studies. An indirect-response model with a sigmoid E(max) (maximal drug effect) inhibitory drug effect on DAS28 "production" rate adequately described the relationship between tocilizumab concentration and DAS28. Mean minimum serum tocilizumab concentration at steady state was greater than the EC(50) (concentration at which 50% of E(max) on DAS28 is reached) with the 8-mg/kg dose but not with the 4-mg/kgdose. Simulations within a large rheumatoid arthritis (RA) population showed that DAS remission rates were 38% for 8 mg/kg and 24% for 4 mg/kg. Tocilizumab was more potent in RA patients with higher baseline interleukin-6 levels, but this effect was not clinically significant. Other covariates (eg, presence of neutralizing antitocilizumab antibodies) did not demonstrate a clinically meaningful effect on tocilizumab DAS28 dose-response relationships. These data support clinical observations that tocilizumab 8 mg/kg is more effective than 4 mg/kg in reducing disease activity.

Exposure-Exposure Relationship of Tocilizumab, an Anti-IL-6 Receptor Monoclonal Antibody, in a Large Population of Patients With Rheumatoid Arthritis.

Relationships between tocilizumab exposure and response were evaluated using data from 4 phase III studies. Increased tocilizumab exposure was associated with improvements in Disease Activity Score using 28 joints (DAS28) and American College of Rheumatology (ACR) criteria and with a decrease in inflammation markers. A population pharmacokinetic/pharmacodynamic (PKPD) model was developed to describe data from 2 studies. An indirect-response model with a sigmoid Emax (maximal drug effect) inhibitory drug effect on DAS28 "production" rate adequately described the relationship between tocilizumab concentration and DAS28. Mean minimum serum tocilizumab concentration at steady state was greater than the EC50 (concentration at which 50% of Emax on DAS28 is reached) with the 8-mg/kg dose but not with the 4-mg/kgdose. Simulations within a large rheumatoid arthritis (RA) population showed that DAS remission rates were 38% for 8 mg/kg and 24% for 4 mg/kg. Tocilizumab was more potent in RA patients with higher baseline interleukin-6 levels, but this effect was not clinically significant. Other covariates (eg, presence of neutralizing antitocilizumab antibodies) did not demonstrate a clinically meaningful effect on tocilizumab DAS28 dose-response relationships. These data support clinical observations that tocilizumab 8 mg/kg is more effective than 4 mg/kg in reducing disease activity.