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The advent of biologic therapy has transformed the outcomes of patients with Rheumatoid Arthritis (RA), but has also highlighted important issues for their development. Early attempts at T-cell driven therapies gave mixed results with difficulties extrapolating from non-human models to first in man trials. There is currently one T-cell modulating therapy - abatacept - licenced for use in RA. Cytokine inhibition has proven to be more fruitful with a number of anti-TNF and IL6 agents either licenced for use in RA or in development. The B-cell depleting therapy rituximab has also shown good efficacy as a chemotherapy agent repurposed for RA treatment. Overall the biologics show good efficacy in RA and have been shown to retard progression of radiographic joint damage. However, this benefit comes with a burden of increased infection risk and a financial cost significantly higher than conventional disease modifying therapies. As a result current UK licencing holds the biologics in reserve following failure of a conventional therapy and the presence of moderate to severely active disease. The long term use of the biologics in RA has highlighted the risk of immunogenicity, with significant proportions of patients developing anti-drug antibodies and losing therapeutic effect. The side effect profile and cost also raise the question around duration of therapy and trials of drug tapering following disease remission are now taking place with several biologic agents. Our inability to stratify patients to the most appropriate biologic drug (stratified or precision medicine) has also catalysed a large and critically important research agenda. Beyond identifying new biologic targets, the development of biosimilar agents will likely drive the future shape of the RA biologics market as lower cost alternatives are developed, thereby improving access to these therapies.

The last 20 years have seen a transformation in the landscape of rheumatoid arthritis, which has changed from being a life limiting condition to a chronic but often remitting illness. The importance of early disease control, the better use of existing therapies, and the development of new therapies have all been key to this success. The future of therapy now lies in the identification of stratifying biomarkers, to allow more rational delivery of treatment. The ultimate goal remains the reintroduction of immune tolerance to potentially achieve a 'cure.', (© 2014 Royal College of Physicians.)

Introduction: A significant proportion of patients with primary Sjögren's syndrome (PSS) is functionally impaired and experience difficulties participating in various aspects of everyday life. There is currently no evidence of efficacy for non-pharmacological interventions aimed specifically at supporting the patients with PSS to improve their participation and ability to perform daily activities. This paper describes a research protocol for a mixed-methods study to develop an intervention to improve these outcomes. The protocol follows the Medical Research Council framework for complex interventions., Methods and Analysis: We will use group concept mapping with the patients, adults who live with them and healthcare professionals to identify factors which prevent people with PSS from participating in daily life and performing daily activities. The factors will be prioritised by participants for importance and feasibility and will inform an intervention to be delivered within a National Health Service (NHS) setting. Evidence-based intervention techniques will be identified for the prioritised factors and combined into a deliverable intervention package. Key stakeholders will comment on the intervention content and mode of delivery through focus groups, and the data will be used to refine the intervention. The acceptability and feasibility of the refined intervention will be evaluated in a future study., Ethics and Dissemination: The study has been approved by an NHS Research Ethics Committee, REC Reference: 13/NI/0190. The findings of this study will be disseminated in peer-reviewed journals and through presentation at national and international conferences., Trial Registration Number: UKCRN Study ID: 15939., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Rheumatoid arthritis (RA) has long been recognised as a highly heterogeneous disease of immune dysregulation. Despite an ever-growing appreciation of the role of circulating autoantibodies in the development of 'seropositive' disease, the pathogenesis of seronegative RA remains poorly understood. Accumulating evidence suggests that RA 'serotypes', in fact, reflect distinct disease entities that, despite their clinical overlap, diverge in respect of genetic architecture, cellular pathology and even therapeutic responsiveness. Focussing on seronegative RA, this review considers these concepts and their implications for the management of patients with this challenging, though sometimes overlooked, condition., (Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.)

Eligibility for anti-tumour necrosis factor (TNF) therapy in most European countries is restricted to severe, active rheumatoid arthritis (RA). The DAS28 score is a marker of disease severity and incorporates one of two inflammatory markers, erythrocyte sedimentation rate (ESR) or C-reactive protein. We aimed to determine the relation between genetic variants known to affect ESR and levels of ESR in patients with active RA. DNA samples were genotyped for four single-nucleotide polymorphisms (SNPs) rs7527798 (CR1L), rs6691117 (CR1), rs10903129 (TMEM57) and rs1043879 (C1orf63). The association between SNPs and baseline ESR, baseline DAS28-ESR, and change in DAS28-ESR was evaluated. Baseline ESR was significantly associated with CR1 rs6691117 genotype (P=0.01). No correlation was identified between baseline DAS28-ESR or change in DAS28-ESR. In conclusion, genetic variation in the gene encoding CR1 may alter ESR levels but not DAS28-ESR, indicating no adjustment for CR1 genotype is required in the assessment of patients with severe active RA.

Purpose of Review: To provide an overview of recent advances and future possibilities for therapeutic tolerance., Recent Findings: Allograft survival despite complete immunosuppressant withdrawal has been demonstrated in selected renal-transplant recipients with haematopoietic chimerism. Early clinical trials of mesenchymal stromal cell therapy have shown promising results in several autoimmune diseases. Regulatory T cells show potential benefit in graft versus host disease, although challenges to ex-vivo expansion remain. Targeted modulation of T-cell function in vivo with monoclonal antibodies has shown beneficial effects in phase II/III trials of multiple sclerosis (alemtuzumab) and type I diabetes mellitus (teplizumab, otelixizumab). Emerging data from animal models suggest an important role for the commensal microbiome in the maintenance and disruption of immune tolerance with parallels in human studies., Summary: After years of slow progress, recent research has reduced the translational gap between animal models and clinical therapeutic tolerance. Early detection of autoimmunity, potentially at preclinical stages, offers a window of opportunity for tolerogenic therapy. Reliable biomarkers of tolerance are urgently needed to provide objective measurements of the effectiveness of tolerogenic therapies, and to allow intelligent immunosuppressant withdrawal in patients whose autoimmune disease is stable., Video Abstract Available: See the Video Supplementary Digital Content 1 (http://links.lww.com/COR/A8).