Long-term study of the impact of methotrexate on serum cytokines and lymphocyte subsets in patients with active rheumatoid arthritis: correlation with pharmacokinetic measures

Objective To describe changes in immune parameters observed during long-term methotrexate (MTX) therapy in patients with active rheumatoid arthritis (RA) and explore correlations with simultaneously measured MTX pharmacokinetic (PKC) parameters. Design Prospective, open-label, long-term mechanism of action study. Setting University clinic. Methods MTX was initiated at a single weekly oral dose of 7.5 mg and dose adjusted for efficacy and toxicity for the duration of the study. Standard measures of disease activity were performed at baseline and every 6–36 months. Serum cytokine measurements in blood together with lymphocyte surface immunophenotypes and stimulated peripheral blood mononuclear cell (PBMC) cytokine production were assessed at each clinical evaluation. Results Cytokine concentrations exhibited multiple significant correlations with disease activity measures over time. The strongest correlations observed were for interleukin (IL)-6 (r=0.45, p<0.0001 for swollen joints and r=0.32, p=0.002 for tender joints) and IL-8 (r=0.25, p=0.01 for swollen joints). Significant decreases from baseline were observed in serum IL-1B, IL-6 and IL-8 concentrations. The most significant changes were observed for IL-6 (p<0.001). Significant increases from baseline were observed in IL-2 release from PBMCs ex vivo (p<0.01). In parallel, multiple statistically significant correlations were observed between MTX PKC measures and immune parameters. The change in swollen joint count correlated inversely with the change in area under the curve (AUC) for MTX (r=−0.63, p=0.007). Conclusions MTX therapy of patients with RA is accompanied by a variety of changes in serum cytokine expression, which in turn correlate strongly with clinical disease activity and MTX pharmacokinetics (PKCs). These data strongly support the notion that MTX mediates profound and functionally relevant effects on the immunological hierarchy in the RA lesion

Disease activity and biologic use in patients with psoriatic arthritis or rheumatoid arthritis.

To compare disease burden and biologic use among psoriatic arthritis (PsA) or rheumatoid arthritis (RA) patients recruited to the Corrona registry. Retrospective study of patients with PsA or RA enrolled in Corrona between January 2002 and March 2013 and grouped in 2-year intervals. Clinical outcomes and biologic use were assessed. Biologic use increased over time in both cohorts, with 62 and 52% of patients with PsA and RA, respectively, receiving biologics by 2012-2013. However, 25 and 35% of patients with PsA and RA, respectively, continued to experience moderate/high disease activity. Overall, the progressive increase in biologic use accompanied progressive decreases in Clinical Disease Activity Index (from 14.2 to 10.4 for RA, and 12.4 to 8.1 for PsA) and mean Health Assessment Questionnaire score (from 0.36 to 0.34, and 0.3 to 0.24). Mean patient pain, the proportion of patients reporting morning stiffness, and the mean duration of morning stiffness remained similar for both cohorts. PsA and RA treated in the rheumatology setting had a comparable impact on patient quality of life and functional ability. Disease burden improved with increased biologic utilization in both groups; however, moderate/severe disease remains in a significant proportion of PsA and RA patients

Real-world Comparative Effectiveness of Tocilizumab Monotherapy vs. Tumor Necrosis Factor Inhibitors with Methotrexate in Patients with Rheumatoid Arthritis

INTRODUCTION: Controlled clinical studies have shown that the efficacy of tocilizumab (TCZ) monotherapy is superior to that of tumor necrosis factor inhibitor (TNFi) monotherapy and comparable to that of TCZ plus methotrexate (MTX) for the treatment of rheumatoid arthritis (RA). This study compared the real-world effectiveness of TCZ monotherapy vs. TNFis plus MTX in US patients with RA. METHODS: TCZ-naive patients from the Corrona RA registry with prior exposure to \u3e /= 1 TNFi who initiated TCZ monotherapy or TNFi + MTX were included. Outcomes included mean change in Clinical Disease Activity Index (CDAI), achievement of low disease activity (LDA; CDAI \u3c /= 10), achievement of modified American College of Rheumatology (mACR) 20/50 responses, and mean change in modified Health Assessment Questionnaire (mHAQ) at 6 months. Patients initiating TNFi + MTX were grouped by MTX dose ( \u3c /= 10 mg; \u3e 10 to \u3c /= 15 mg; \u3e 15 to \u3c /= 20 mg; \u3e 20 mg); outcomes in each group were compared with TCZ monotherapy using trimmed populations (excluding patients outside the propensity score distribution overlap). RESULTS: Patients in all groups experienced improvement in CDAI at 6 months (mean change, - 6.9 to - 9.7), with no significant differences between the TCZ monotherapy and TNFi + MTX groups. Achievement of LDA and mACR responses at 6 months were comparable between the TCZ monotherapy and TNFi + MTX groups; overall, 26.8-38.0% of patients achieved LDA, 24.3-37.6% achieved mACR20 response and 13.2-20.8% achieved mACR50 response. The mean change in mHAQ at 6 months was - 0.1 in all groups. CONCLUSIONS: In this real-world population of US patients with RA who had prior TNFi exposure, there was no evidence of a difference in the effectiveness of TCZ monotherapy compared with that of TNFi + MTX, regardless of MTX dose, at 6 months for improving RA disease activity. FUNDING: Corrona, LLC. Plain language summary available for this article

Safety of Infusing Rituximab at a More Rapid Rate in Patients with Rheumatoid Arthritis: Results from the RATE-RA Study

As recommended in the current prescribing information, rituximab infusions in patients with rheumatoid arthritis (RA) take 4.25hours for the first infusion and 3.25hours for subsequent infusions, which is a burden on patients and the health care system. We therefore evaluated the safety of infusing rituximab at a faster rate for an infusion period of 2hours in patients with RA

Design characteristics of the CORRONA CERTAIN study: a comparative effectiveness study of biologic agents for rheumatoid arthritis patients

BACKGROUND: Comparative effectiveness research has recently attracted considerable attention. The Comparative Effectiveness Registry to study Therapies for Arthritis and Inflammatory Conditions (CERTAIN) is an ongoing prospective cohort study of adult patients with Rheumatoid Arthritis (RA). METHODS/DESIGN: CERTAIN uses the existing Consortium of Rheumatology Researchers of North America (CORRONA) network of participating private and academic sites in order to recruit patients fulfilling the 1987 ACR criteria that have at least moderate disease activity. Patients starting or switching biologic agents either anti-TNF therapy or a non anti-TNF biologic are eligible for enrollment, depending on the treatment selected by their physician. Enrollment is expected to be completed by March of 2014, and 2711 patients will participate in the study. As of October 7th 2013, 2234 patients have been enrolled. Patient visits and laboratory blood work are mandated every three months for one year. Safety data is collected through one year and beyond. The primary comparative effectiveness endpoint is attainment of low RA disease activity at one year among patients who have been exposed to at least one prior TNF-alpha inhibitor agent prior to enrollment. Multiple secondary effectiveness and safety endpoints will be addressed by investigating the entire population enrolled (naive and biologic experienced). DISCUSSION: The unique design features of CERTAIN will inform comparative effectiveness and safety questions for choosing biologic agents for the management of RA

Long-Term Effectiveness of Adalimumab in Patients with Rheumatoid Arthritis: An Observational Analysis from the Corrona Rheumatoid Arthritis Registry

INTRODUCTION: Current recommendations for the management of rheumatoid arthritis (RA) focus on a treat-to-target approach with the objective of maximizing long-term health-related quality-of-life in patients with RA. Published studies from randomized clinical trials have reported limited data regarding the long-term efficacy and safety of adalimumab in patients with RA. This study aims to evaluate the long-term (10+ years) persistency and effectiveness of adalimumab in patients with RA in a real-world setting. METHODS: Included in this study were biologic-naive adults with RA initiating adalimumab during follow-up enrolled in the Corrona RA registry. More than 10 years of data on persistency of adalimumab and rheumatologist-supplied reasons for discontinuation were examined. Among patients who persisted on adalimumab over the years, clinical [e.g., clinical disease activity index scores (CDAI), physician global assessment, tender joint count, and swollen joint count] and patient-reported outcomes (PRO), such as physical function, pain, fatigue, and morning stiffness, were examined. RESULTS: Of 1791 biologic-naive patients treated with adalimumab who had \u3e /=1 follow-up registry visit, 64.1% were still on therapy at 1 year and 10.2% were still on therapy by the end of year 12. Among patients who persisted on adalimumab for at least 1 year (77.1% female, mean age 53.9 years), 67.0% were in low disease activity (LDA)/remission (CDAI \u3c /=10) and had clinically meaningful improvements from baseline in all clinical assessments and PROs. Initial improvements in LDA/remission and in clinical and PRO assessments observed at year 1 were sustained in those patients who remained on adalimumab over 10 years of follow-up. Among patients who discontinued adalimumab, 61.6% were not in LDA/remission and 41.9% switched to another biologic within 12 months after discontinuing adalimumab. CONCLUSIONS: Real-world data demonstrate a sustained effectiveness of adalimumab in the treatment of RA for patients who remained on therapy for 10 years. FUNDING: Corrona, LLC and AbbVie

Extensional rupture of model non-Newtonian fluid filaments

We present molecular dynamics computer simulations of filaments of model non-Newtonian liquid stretched in a uniaxial deformation to the point of breaking. The liquid consists of Lennard-Jones monomers bound into chains of 100 monomers by nonlinear springs, and several different constant velocity and constant strain rate deformations are considered. Generally we observe nonuniform extensions originating in an interplay between the stretching forces and elastic and capillary restoring mechanisms, leading to highly uneven shapes and alternating stretched and unstretched regions of liquid. Except at the fastest pulling speeds, the filaments continue to thin indefinitely and break only when depleted of molecules, rather than common viscoelastic rupture mechanisms.Comment: 7 pages text, 14 pages (eps) figure

Comparative effectiveness and safety of rituximab versus subsequent anti-tumor necrosis factor therapy in patients with rheumatoid arthritis with prior exposure to anti-tumor necrosis factor therapies in the United States Corrona registry

INTRODUCTION: Patients with active rheumatoid arthritis (RA) despite anti-tumor necrosis factor(anti-TNF)agent treatment can switch to either a subsequent anti-TNF agent or a biologic with an alternative mechanism of action, such as rituximab; however, there are limited data available to help physicians decide between these 2 strategies. The objective of this analysis was to examine the effectiveness and safety of rituximab versus a subsequent anti-TNF agent in anti-TNF-experienced patients with RA using clinical practice data from the Corrona registry. METHODS: Rituximab-naive patients from the Corrona registry with prior exposure to \u3e /=1 anti-TNF agent who initiated rituximab or anti-TNF agents (2/28/2006-10/31/2012) were included. Two cohorts were analyzed: the trimmed population (excluding patients who fell outside the propensity score distribution overlap) and the stratified-matched population (stratified by 1 vs \u3e /=2 anti-TNF agents, then matched based on propensity score). The primary effectiveness outcome was achievement of low disease activity (LDA)/remission (Clinical Disease Activity Index \u3c /=10) at 1 year. Secondary outcomes included achievement of modified American College of Rheumatology (mACR) 20/50/70 responses and meaningful improvement ( \u3e /=0.25) in modified Health Assessment Questionnaire (mHAQ) score at 1 year. New cardiovascular, infectious and cancer events were reported. RESULTS: Estimates for LDA/remission, mACR response and mHAQ improvement were consistently better for rituximab than for anti-TNF agent users in adjusted analyses. The odds ratio for likelihood of LDA/remission in rituximab versus anti-TNF patients was 1.35 (95 % CI, 0.95-1.91) in the trimmed population and 1.54 (95 % CI, 1.01-2.35) in the stratified-matched population. Rituximab patients were significantly more likely than anti-TNF patients to achieve mACR20/50 and mHAQ improvement in the trimmed population and mACR20 and mHAQ in the stratified-matched population. The rate of new adverse events per 100 patient-years was similar between groups. CONCLUSIONS: In anti-TNF-experienced patients with RA, rituximab was associated with an increased likelihood of achieving LDA/remission, mACR response and physical function improvement, with a comparable safety profile, versus subsequent anti-TNF agent users. TRIAL REGISTRATION: ClinicalTrials.gov NCT01402661. Registered 25 July 2011

Impact of rituximab on patient-reported outcomes in patients with rheumatoid arthritis from the US Corrona Registry

To evaluate the impact of rituximab on patient-reported outcomes (PROs) in a US-based observational cohort of patients with rheumatoid arthritis (RA). Patients with active RA, prior exposure to \u3e /=1 tumor necrosis factor inhibitor (TNFi) and who newly initiated rituximab were identified. Changes in PROs were assessed 1 year after rituximab initiation. PRO measures included Clinical Disease Activity Index (CDAI); patient global disease activity, pain and fatigue (visual analog score; 0-100); morning stiffness (hours); modified Health Assessment Questionnaire (mHAQ; 0-3); and EuroQoL EQ-5D. Of the 667 patients who newly initiated rituximab, baseline PRO and clinical measures indicated that patients were substantially impacted by their RA disease and quality of life; 54% of patients had high disease activity. One year after rituximab initiation, 49.0, 47.1, 49.8, and 23.2% of patients reported clinically meaningful improvements in patient global, pain, fatigue, and mHAQ, respectively. Morning stiffness and EuroQol EQ-5D domains improved in 48 and 19-32% of patients, respectively. These real-world registry data demonstrated that patients with long-standing, refractory RA experienced improvements in PROs 1 year after initiating rituximab