Sustained improvements in MRI outcomes with abatacept following the withdrawal of all treatments in patients with early, progressive rheumatoid arthritis

Objectives: To assess structural damage progression with subcutaneous abatacept (ABA) in the Assessing Very Early Rheumatoid arthritis Treatment (AVERT) trial following abrupt withdrawal of all rheumatoid arthritis (RA) medication in patients achieving Disease Activity Score (DAS)-defined remission or low disease activity. Methods: Patients with early, active RA were randomised to ABA plus methotrexate (ABA/MTX) 125 mg/week, ABA 125 mg/week or MTX for 12 months. All RA treatments were withdrawn after 12 months in patients with DAS28 (C reactive protein (CRP)) <3.2. Adjusted mean changes from baseline in MRI-based synovitis, osteitis and erosion were calculated for the intention-to-treat population. Results: 351 patients were randomised and treated: ABA/MTX (n=119), ABA (n=116) or MTX (n=116). Synovitis and osteitis improved, and progression of erosion was statistically less with ABA/MTX versus MTX at month 12 (−2.35 vs −0.68, −2.58 vs −0.68, 0.19 vs 1.53, respectively; p<0.01 for each) and month 18 (−1.34 vs −0.49 −2.03 vs 0.34, 0.13 vs 2.0, respectively; p<0.01 for erosion); ABA benefits were numerically intermediate to those for ABA/MTX and MTX. Conclusions: Structural benefits with ABA/MTX or ABA may be maintained 6 months after withdrawal of all treatments in patients who have achieved remission or low disease activity

Efficacy and safety of secukinumab, a fully human anti-interleukin-17A monoclonal antibody, in patients with moderate-to-severe psoriatic arthritis: a 24-week, randomised, double-blind, placebo-controlled, phase II proof-of-concept trial

Objective: To evaluate the efficacy and safety of secukinumab, a fully human, anti-interleukin (IL)-17A monoclonal antibody, in patients with psoriatic arthritis (PsA). Methods: 42 patients with active PsA fulfilling ClASsification for Psoriatic ARthritis (CASPAR) criteria were randomly assigned (2:1) to receive two intravenous secukinumab doses (10 mg/kg; n=28) or placebo (n=14) 3 weeks apart. The primary endpoint was the proportion of American College of Rheumatology (ACR) 20 responses at week 6 for secukinumab versus placebo (one-sided p<0.1). Results: Primary endpoint: ACR20 responses at week 6 were 39% (9/23) for secukinumab versus 23% (3/13) for placebo (p=0.27). ACR20 responses were greater with secukinumab versus placebo at week 12 (39% (9/23) vs 15% (2/13), p=0.13) and week 24 (43% (10/23) vs 18% (2/11), p= 0.14). At week 6, ‘good’ European League Against Rheumatism response was seen in 21.7% (5/23) secukinumab versus 9.1% (1/11) placebo patients. Compared with placebo at week 6, significant reductions were observed among secukinumab recipients for C reactive protein (p=0.039), erythrocyte sedimentation rate (p=0.038), Health Assessment Questionnaire Disability Index (p=0.002) and Short Form Health Survey (SF-36; p=0.030) scores. The overall adverse event (AE) frequency was comparable between secukinumab (26 (93%)) and placebo (11 (79%)) recipients. Six serious AEs (SAEs) were reported in four secukinumab patients and one SAE in one placebo patient. Conclusions: Although the primary endpoint was not met, clinical responses, acute-phase reactant and quality of life improvements were greater with secukinumab versus placebo, suggesting some clinical benefit. Secukinumab exhibited satisfactory safety. Larger clinical trials of secukinumab in PsA are warranted

The Family Name as Socio-Cultural Feature and Genetic Metaphor: From Concepts to Methods

A recent workshop entitled The Family Name as Socio-Cultural Feature and Genetic Metaphor: From Concepts to Methods was held in Paris in December 2010, sponsored by the French National Centre for Scientific Research (CNRS) and by the journal Human Biology. This workshop was intended to foster a debate on questions related to the family names and to compare different multidisciplinary approaches involving geneticists, historians, geographers, sociologists and social anthropologists. This collective paper presents a collection of selected communications

Down-titration of biologics for the treatment of rheumatoid arthritis: A systematic literature review

Biologic therapies have improved the management of rheumatoid arthritis (RA) and the treat-to-target approach has resulted in many patients achieving remission. In the current treatment landscape, clinicians have begun considering dose reduction/tapering for their patients. Rheumatology guidelines in Asia, Europe, and the United States include down-titration of biologics but admit that the level of evidence is moderate. We conducted a systematic literature review to assess the published studies that evaluate down-titration of biologics in RA. The published literature was searched for studies that down-titrated the following biologics: abatacept, adalimumab, certolizumab, etanercept, golimumab, infliximab, rituximab, and tocilizumab. Eligible studies included randomized controlled trials (RCTs), non-RCTs, observational, and pharmacoeconomic studies. The outcomes of interest were (1) efficacy and health-related quality of life, (2) disease flares, and (3) impact on cost. Eleven full-text publications were identified; only three were RCTs. Study results suggest that dosing down may be an option in many patients who have achieved remission or low disease activity. However, some patients are likely to experience a disease flare. Across the studies, the definition of disease flare and the down-titration criteria were inconsistent, making it difficult to conclude which patients may be appropriate and when to attempt down-titration. Studies have evaluated the practice of dosing down biologic therapy in patients with RA; however, a relatively small number of RCTs have been published. Although down-titration may be an option for some patients in LDA or remission, additional RCTs are needed to provide guidance on this practice

Accelerated versus standard epirubicin followed by cyclophosphamide, methotrexate, and fluorouracil or capecitabine as adjuvant therapy for breast cancer (UK TACT2; CRUK/05/19): quality of life results from a multicentre, phase 3, open-label, randomised, controlled trial

BACKGROUND: Adjuvant chemotherapy for patients with early breast cancer improves outcomes but its toxicity affects patients' quality of life (QOL). The UK TACT2 trial investigated whether accelerated epirubicin improves time to recurrence and if oral capecitabine is non-inferior to cyclophosphamide, methotrexate, and fluorouracil (CMF) for efficacy with less toxicity. Results showed no benefit for accelerated epirubicin and capecitabine was non-inferior. As part of the QOL substudy, we aimed to assess the effect of chemotherapies on psychological distress, physical symptoms, and functional domains. METHODS: TACT2 was a multicentre, phase 3, open-label, parallel-group, randomised, controlled trial done in 129 UK centres. Participants were aged 18 years or older with histologically confirmed node-positive or high-risk node-negative invasive primary breast cancer, who had undergone complete excision, and due to receive adjuvant chemotherapy. Patients were randomly assigned (1:1:1:1) to four cycles of 100 mg/m2 epirubicin either every 3 weeks (standard epirubicin) or every 2 weeks with 6 mg pegfilgrastim on day 2 of each cycle (accelerated epirubicin), followed by four 4-week cycles of either CMF (600 mg/m2 cyclophosphamide intravenously on days 1 and 8 or 100 mg/m2 orally on days 1–14; 40 mg/m2 methotrexate intravenously on days 1 and 8; and 600 mg/m2 fluorouracil intravenously on days 1 and 8 of each cycle) or four 3-week cycles of 2500 mg/m2 capecitabine (1250 mg/m2 given twice daily on days 1–14 of each cycle). The randomisation schedule was computer generated in random permuted blocks, stratified by centre, number of nodes involved (none vs 1–3 vs ≥4), age (≤50 years vs >50 years), and planned endocrine treatment (yes vs no). QOL was one of the secondary outcomes and is reported here. All patients from a subset of 44 centres were invited to complete QOL questionnaires (Hospital Anxiety and Depression Scale [HADS] and European Organisation for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire 30-item core module [QLQ-C30] and Quality of Life Questionnaire breast module [QLQ-BR23]) at baseline, end of standard or accelerated epirubicin, end of CMF or capecitabine, and at 12 and 24 months after randomisation. The QOL substudy prespecified two coprimary QOL outcomes assessed in the intention-to-treat population: overall QOL (reported elsewhere) and HADS total score. Prespecified secondary QOL outcomes were EORTC QLQ-C30 subscales of physical function, role function, and fatigue and EORTC QLQ-BR23 subscales of sexual function and systemic therapy side-effects. This trial is registered with ISRCTN, ISRCTN68068041, and ClinicalTrials.gov, NCT00301925. FINDINGS: From Dec 16, 2005, to Dec 5, 2008, 4391 patients (20 [0·5%] of whom were male) were enrolled in TACT2; 1281 (85·8%) of 1493 eligible patients were included in the QOL substudy. Eight (0·6%) participants in the QOL substudy were male and 1273 (99·4%) were female. Median follow-up was 85·6 months (IQR 80·6–95·9). Analysis was performed on the complete QOL dataset (as of Sept 15, 2011) when all participants had passed the 24-month timepoint. Prerandomisation questionnaires were completed by 1172 (91·5%) patients and 1179 (92·0%) completed at least one postrandomisation questionnaire. End-of-treatment HADS depression score (p=0·0048) and HADS total change score (p=0·0093) were worse for CMF versus capecitabine. Accelerated epirubicin led to worse physical function (p=0·0065), role function (p<0·0001), fatigue (p=0·0002), and systemic side-effects (p=0·0001), but not sexual function (p=0·36), compared with standard epirubicin during treatment, but the effect did not persist. Worse physical function (p=0·0048), sexual function (p=0·0053), fatigue (p<0·0001), and systemic side-effects (p<0·0001), but not role functioning (p=0·013), were seen for CMF versus capecitabine at end of treatment; these differences persisted at 12 months and 24 months. INTERPRETATION: Accelerated epirubicin was associated with worse QOL than was standard epirubicin but only during treatment. These findings will help patients and clinicians make an informed choice about accelerated chemotherapy. CMF had worse QOL effects than did capecitabine, which were persistent for 24 months. The favourable capecitabine QOL compared with CMF supports its use as an adjuvant option after neoadjuvant chemotherapy in patients with triple-negative breast cancer

Correction to: On-drug and drug-free remission by baseline symptom duration: abatacept with methotrexate in patients with early rheumatoid arthritis

Clinical outcomes in patients with early rheumatoid arthritis (RA) were assessed by baseline symptom duration in the Assessing Very Early Rheumatoid arthritis Treatment trial (ClinicalTrials.gov; NCT01142726). Patients with early, active RA were randomized to subcutaneous (SC) abatacept 125 mg/week plus methotrexate (MTX), SC abatacept alone, or MTX monotherapy for 12 months. All RA treatments were withdrawn after 12 months in patients with Disease Activity Score in 28 joints (C-reactive protein; DAS28-CRP)  3 to ≤ 6 months, or > 6 months) and treatment group. No clinically significant differences were seen in baseline demographics or characteristics across symptom duration groups. Irrespective of baseline symptom duration, a numerically higher proportion of abatacept plus MTX-treated patients achieved DAS-defined remission at month 12 and sustained remission at month 18 compared with MTX monotherapy. A numerically higher proportion of abatacept plus MTX-treated patients with symptom duration ≤ 3 months maintained DAS-defined remission after complete treatment withdrawal from 12 to 18 months compared with longer symptom duration groups. This subgroup also had the fastest onset of clinical response (DAS28-CRP < 2.6) after initiation of treatment. Health Assessment Questionnaire–Disability Index response was similar regardless of baseline symptom duration. Overall, symptom duration of ≤ 3 months was associated with a faster onset of clinical response and higher rates of drug-free remission following treatment with abatacept plus MTX

The super-correlator/super-amplitude duality: Part I

We extend the recently discovered duality between MHV amplitudes and the light-cone limit of correlation functions of a particular type of local scalar operators to generic non-MHV amplitudes in planar N=4 SYM theory. We consider the natural generalization of the bosonic correlators to super-correlators of stress-tensor multiplets and show, in a number of examples, that their light-cone limit exactly reproduces the square of the matching super-amplitudes. Our correlators are computed at Born level. If all of their points form a light-like polygon, the correlator is dual to the tree-level amplitude. If a subset of points are not on the polygon but are integrated over, they become Lagrangian insertions generating the loop corrections to the correlator. In this case the duality with amplitudes holds at the level of the integrand. We build up the superspace formalism needed to formulate the duality and present the explicit example of the n-point NMHV tree amplitude as the dual of the lowest nilpotent level in the correlator.Comment: 56 page

EULAR recommendations for terminology and research in individuals at risk of rheumatoid arthritis: report from the Study Group for Risk Factors for Rheumatoid Arthritis

The Study Group for Risk Factors for Rheumatoid Arthritis was established by the EULAR Standing Committee on Investigative Rheumatology to facilitate research into the preclinical and earliest clinically apparent phases of rheumatoid arthritis (RA). This report describes the recommendation for terminology to be used to define specific subgroups during different phases of disease, and defines the priorities for research in this area. Terminology was discussed by way of a three-stage structured process: A provisional list of descriptors for each of the possible phases preceding the diagnosis of RA were circulated to members of the study group for review and feedback. Anonymised comments from the members on this list were fed back to participants before a 2-day meeting. 18 participants met to discuss these data, agree terminologies and prioritise important research questions. The study group recommended that, in prospective studies, individuals without RA are described as having: genetic risk factors for RA; environmental risk factors for RA; systemic autoimmunity associated with RA; symptoms without clinical arthritis; unclassified arthritis; which may be used in a combinatorial manner. It was recommended that the prefix ‘pre-RA with:’ could be used before any/any combination of the five points above but only to describe retrospectively a phase that an individual had progressed through once it was known that they have developed RA. An approach to dating disease onset was recommended. In addition, important areas for research were proposed, including research of other tissues in which an adaptive immune response may be initiated, and the identification of additional risk factors and biomarkers for the development of RA, its progression and the development of extra-articular features. These recommendations provide guidance on approaches to describe phases before the development of RA that will facilitate communication between researchers and comparisons between studies. A number of research questions have been defined, requiring new cohorts to be established and new techniques to be developed to image and collect material from different sites