Low Disease Activity Score Research Articles

Concurrent Oral 1 - Rheumatoid Arthritis: Treatment [OP4-OP9]: OP4. Inhibition of Radiographic Progression and Improvements in Physical Function at 2 Years, with Increasing Clinical Efficacy Over Time, in Rheumatoid Arthritis (Ra) Patients Treated with Tocilizumab (Tcz): The Lithe Study

Background: Patients with moderate to severe RA who remained on methotrexate (MTX) despite inadequate response were treated with TCZ in a double-blind, randomized, controlled phase 3 trial. Results of a 2-year planned analysis from this study are presented. Methods: Patients were randomized to treatment with TCZ 4 mg/kg + MTX (TCZ4), TCZ 8 mg/kg + MTX (TCZ8) or placebo + MTX (CON) every 4 weeks. If patients failed to respond (<20% improvement in swollen and tender joint count; SJC and TJC) then stepwise rescue therapy could begin at week 16. Patients with ≥ 70% improvement in SJC and TJC could continue the blinded therapy at the end of year 1 to week 104. For all other patients, open-label TCZ8 was initiated at week 52. Change from baseline in Genant-modified total Sharp score (GmTSS) and physical function (AUC of change from baseline in HAQ-DI) were the primary 2-year end points. Linear extrapolation (GmTSS) or standardization (change in HAQ-DI) was used for missing data. The impact of 2 years of treatment was examined by assessing efficacy end points over time for patients randomized to TCZ8, with the last observation carried forward for SJC and TJC in patients who received rescue therapy or withdrew. Results: The intention to treat population consisted of 398 TCZ8, 399 TCZ4 and 393 CON patients. At 2 years, exposure rates in patient-years (PY) were 1320.0, 521.9 and 284.8 in TCZ8, TCZ4 and CON patients, respectively. At year 2, patients in the TCZ8 group had 81% less radiographic progression vs CON patients (based on linear extrapolation of mean change in GmTSS). Significantly more TCZ8 patients had no radiographic progression vs CON patients (P ≤ 0.0001). AUC of change from baseline in HAQ-DI showed significant improvement in physical function in TCZ4 and in TCZ8 vs CON patients (P ≤ 0.0025). In patients initially randomized to TCZ8, a low disease activity score (LDAS; DAS28 < 3.2) was seen in > 60% of patients and the DAS28 remission (DAS28 < 2.6) rate was 48% at week 52 and continued to increase to week 104. By week 52, patients treated with TCZ8 had clinically significant improvements in SJC that were maintained through week 104. Rates per 100 PY for adverse events (AEs) were higher in TCZ8 and TCZ4 (263.6, 275.4) vs CON patients (251.4) while rates for serious AEs were comparable (11.4, 12.1, 10.9, respectively). Rates per 100 PY of AEs leading to withdrawal (7.4, 32.5, 4.8) and treatment modification (8.4, 30.7, 20.4) were higher in TCZ8 and TCZ4 vs CON patients, respectively and death rates were comparable (0.6, 0.2, 0.4). Conclusions: Treatment with TCZ + MTX inhibits radiographic progression over 2 years and improves physical function as shown by DAS28 remission, LDAS and low SJC, with a manageable safety profile. Disclosure statement: E.A., F. Hoffmann-La Roche - Employee. P.A., F. Hoffmann-La Roche - Employee. R.B.-V., F. Hoffmann-La Roche - Honoraria. R.F., Genentech - Research Funding, Honoraria. J.K., F. Hoffmann-La Roche - Research funding, Honoraria.

Cost-effectiveness modelling of biological treatment sequences in moderate to severe rheumatoid arthritis in France

Modern treatment of RA includes the use of biologics. Their cost is high and comparison between different treatment strategies is needed. Direct medical costs of RA in France were evaluated based on expert opinion. Then, simulation-decision analytical models were developed to assess four biologic treatment sequences over 2 years in patients failing to respond to at least one anti-TNF agent. Effectiveness was expressed in theoretical expected number of days (TEND) in remission or low disease activity [low disease activity score (LDAS)] based on DAS-28 scores. Direct medical costs of RA in France (excluding the cost of biologics) were estimated at euro 905 (s.d. 263) for 6 months and euro 696 (s.d. 240) for each subsequent 6 months (P < 0.001) for patients achieving LDAS and euro 1215 for 6 months (s.d. 405) for patients not achieving LDAS. Based on LDAS criteria, using abatacept after an inadequate response to the first anti-TNF agent (etanercept) appeared significantly (P < 0.01) more efficacious over a 2-year period (102 TEND) compared with using rituximab at a 6-month re-treatment interval (82 TEND). Mean cost-effectiveness ratios showed significantly lower costs (P < 0.01) per TEND with abatacept as second biologic agent (euro 278) compared with rituximab (euro 303). After an inadequate response to two anti-TNF agents, using abatacept also appeared significantly more efficacious than an anti-TNF agent (P < 0.01). All comparisons were confirmed when using remission criteria instead of LDAS. Advanced simulation models based on clinical evidence and medical practice appear to be a promising approach for comparing cost-effectiveness of biologic strategies in RA.

Time to achieve remission determines time to be in remission.

IntroductionThough remission is currently a treatment goal in patients with rheumatoid arthritis (RA), the number of patients who achieve and sustain remission in daily practice is still small. It is suggested that early remission will be associated with sustainability of remission. The aim was to study the association between time-to-remission and sustainability of remission in a cohort of early RA patients treated according to daily practice.MethodsFor this study, three-year follow-up data were used from the Nijmegen RA Inception Cohort of patients included between 1985 and 2005 (N = 753). Patients were included upon diagnosis (ACR criteria), were systematically evaluated at three-monthly visits and treated according to daily practice. Remission was defined according to the Disease Activity Score (DAS) <1.6 and the ACR remission criteria. Remission of at least 6 months duration was regarded as sustained remission. Predictors for time-to-remission were identified by Cox-regression analyses. The relation between time-to-remission and sustained remission was analyzed using longitudinal binary regression.ResultsN = 398 (52%) patients achieved remission with a median time-to-remission of 12 months. Male gender, younger age and low DAS at baseline were predictive to reach remission rapidly. There were n = 142 (36%) patients experiencing sustained remission, which was determined by a shorter time-to-remission only. The relationship between time-to-remission and sustained remission was described by a significant odds ratio (1.11) (1.10 to 1.12-95% CI) that was constant over the whole period 1985 to 2005. Results obtained with the ACR remission criteria were similar.ConclusionsA shorter time-to-remission is related to sustainability of remission, supporting striving for early remission in patients with RA.

N-Acetylcysteine Infusion Improves Hepatic Perfusion in the Early Stages of Systemic Sclerosis

The aim of our study is to evaluate portal and hepatic hemodynamic changes after N-acetylcysteine infusion in patients with systemic sclerosis. In an open-label study 40 patients with systemic sclerosis (SSc) were treated with 15 mg/kg/hour intravenous N-acetylcysteine for 5 consecutive hours in a single day. Hepatic flow volume, congestion index, portal flow volume, resistance index and pulse rate index were measured in each subject before and after infusion. In all patients mean hepatic flow volume (HFV) and mean portal flow volume (PFV) values after the five-hour infusion with NAC increased not significantly. In 22 selected patients with active capillaroscopic pattern, modified Rodnan Total Skin Score (mRTSS)<18 and mild-moderate score to vascular domain of disease severity scale (DSS), mean HFV increased significantly when compared with mean HFV of 18 SSc patients with late capillaroscopic pattern, mRTSS>18 and severe-end stage score to vascular domain of DSS. The results of our study demonstrate that NAC is able to increase HFV and total liver perfusion after a single infusion in SSc patients with low disease activity and severity scores.

Residual inflammation after rituximab treatment is associated with sustained synovial plasma cell infiltration and enhanced B cell repopulation

Objective:To investigate the clinical effects of rituximab treatment in relation to immunological effects of rituximab on tissue-derived B lineage cells and repopulation of circulating B cells.Methods:A total of 24 patients...

Efficacy and safety of abatacept or infliximab vs placebo in ATTEST: a phase III, multi-centre, randomised, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexate

Objectives:This double-blind trial evaluated the efficacy and safety of abatacept or infliximab vs placebo. The primary objective of this study was to evaluate the mean change from baseline in Disease...

Circulating levels of osteopontin, osteoprotegerin, total soluble receptor activator of nuclear factor‐kappa B ligand, and high‐sensitivity C‐reactive protein in patients with active rheumatoid arthritis randomized to etanercept alone or in combination with methotrexate

Objective: To determine whether circulating levels of osteopontin (OPN), osteoprotegerin (OPG), total soluble receptor activator of nuclear factor‐kappa B ligand (total sRANKL), and high‐sensitivity C‐reactive protein (hsCRP) change in patients with rheumatoid arthritis (RA) during immunosuppressive therapy.Methods: Twenty‐five active RA patients were randomized to treatment with either etanercept alone or in combination with methotrexate (MTX). The treatment response after 16 weeks was assessed using the European League Against Rheumatism (EULAR) response criteria. Blood samples were taken before the start of and every fourth week during the study. OPN, OPG, and total sRANKL were measured by enzyme‐linked immunosorbent assays (ELISAs) and hsCRP by highly sensitive turbidometry.Results: At baseline, OPN and hsCRP were significantly (p<0.001) elevated compared to healthy persons. Compared to baseline only hsCRP levels decreased significantly (p<0.05 to p<0.001) in the EULAR responders through the study. OPN remained significantly (p<0.05) elevated at 16 weeks in patients with a low disease activity score (DAS⩽3.2). Total sRANKL increased significantly (p<0.05) from baseline to week 12. No statistically significant changes were observed in the non‐responders.Conclusion: Active RA patients showed increased circulating levels of hsCRP and OPN, but only hsCRP decreased during etanercept therapy. Our findings suggest that OPN, OPG, total sRANKL, and hsCRP reflect different aspects of the inflammatory process in RA.

Probability of continued low disease activity in patients with recent onset rheumatoid arthritis treated according to the disease activity score

Objective:To assess the duration and the probability of maintaining low disease activity once a low disease activity score (DAS) is achieved in recent onset rheumatoid arthritis (RA) patients.Methods:The BeSt study...

Efficacy and safety of the selective co-stimulation modulator abatacept following 2 years of treatment in patients with rheumatoid arthritis and an inadequate response to anti-tumour necrosis factor therapy

Objective:To evaluate the safety and efficacy of abatacept during 2 years of the ATTAIN (Abatacept Trial in Treatment of Anti-TNF INadequate responders) trial in patients with rheumatoid arthritis.Methods:Patients completing the...

CD73-deficient mice are resistant to experimental autoimmune encephalomyelitis (130.30)

Abstract To test the role of CD73-generated adenosine in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, we induced EAE in CD73−/− mice with standard protocols. CD73 (ecto-5’-nucleotidase) makes extracellular adenosine from AMP. Adenosine is anti-inflammatory in several settings via triggering cell surface adenosine receptors and CD73−/− mice exhibit a variety of pro-inflammatory phenotypes. However, CD73−/− mice were highly resistant to the development of EAE (mean EAE score of 0.5 vs 2.0 for WT mice). This was not because their T cells failed to be activated by EAE induction. When T cells from CD73−/− and WT mice with EAE were transferred to CD73+/+ TCRα−/− mice, disease activity was much more severe in recipients of CD73−/− T cells (mean EAE score 3.7 vs. 1.7 in WT mice). To determine whether CD73−/− T cells were defective in their ability to cross the blood brain barrier, immunohistochemistry was performed on the brains of CD73+/+ and CD73−/− mice with EAE. Consistent with the lower disease activity scores in the CD73−/− mice, there were many fewer leukocytes in their brains. The higher apparent blood brain barrier function in CD73−/− mice was confirmed with Evan’s blue dye extravasation studies. Thus, our results show that CD73is required for the entry of pathogenic T cells into the brain and suggest a novel role for CD73-generated adenosine in modulation of the blood brain barrier.

Evolution of Thiopurine Use in Pediatric Inflammatory Bowel Disease in an Academic Center

We evaluated how our use of thiopurines was altered by determination of thiopurine methyltransferase (TPMT) level and drug dose adjustment guided by a 6-mercaptopurine metabolite assay. We further examined whether these resulted in better selection of the drug dose, improved control of disease, and decreased corticosteroid use in pediatric inflammatory bowel disease (IBD). This is a retrospective review of 101 pediatric patients with IBD receiving a stable dose of azathioprine (AZA) for 4 months or longer. The study group (n = 64) consisted of patients who received AZA and had metabolite levels measured. The comparison group (n = 37) consisted of patients who were receiving AZA before the availability of metabolite measurement. The TPMT level was measured in study group patients before starting AZA. Patients with normal TPMT level received a higher starting dose of AZA than in patients who were heterozygous for TPMT deficiency (1.7 vs 0.9 mg/[kg x d], P < 0.0001). Study group patients received a higher starting dose (1.6 vs 1.2 mg/[kg x d], P = 0.001) and a higher final dose of AZA (2.4 vs 1.7 mg/[kg x d], P < 0.0001) compared with patients in the comparison group. These patients also had more dose adjustments (0.8 vs 0.4 mg/kg, P < 0.002). The number of disease exacerbations per patient per year was 55% less in the study group (95% CI, 17%-76%, P < 0.0001). The study group patients received less prednisone (P < 0.0001) and had lower disease activity scores (P < 0.05). There was no difference between groups in infliximab use or surgery rate. Azathioprine dose adjustment using a 6-mercaptopurine metabolite assay was associated with use of higher doses, improved control of disease and decreased corticosteroid use in pediatric patients with IBD.