2016 update of the EULAR recommendations for the management of early arthritis

Objectives: Since the 2007 recommendations for the management of early arthritis have been presented, considerable research has been published in the field of early arthritis, mandating an update of the 2007 EULAR recommendations for management of early arthritis. Methods: In accordance with the 2014 EULAR Standardised Operating Procedures, the expert committee pursued an approach that was based on evidence in the literature and on expert opinion. The committee involved 20 rheumatologists, 2 patients and 1 health professional representing 12 European countries. The group defined the focus of the expert committee and target population, formulated a definition of “management” and selected the research questions. A systematic literature research (SLR) was performed by 2 fellows with the help of a skilled librarian. A set of draft recommendations was proposed on the basis of the research questions and the results of the SLR. For each recommendation the categories of evidence were identified, the strength of recommendations was derived and the level of agreement was determined through a voting process. Results: The updated recommendations comprise 3 overarching principles and 12 recommendations for managing early arthritis. The selected statements involve the recognition of arthritis, referral, diagnosis, prognostication, treatment (information, education, pharmacological and non-pharmacological interventions), monitoring and strategy. Eighteen items were identified as relevant for future research. Conclusion: These recommendations provide rheumatologists, general practitioners, health professionals, patients and other stakeholders with an updated EULAR consensus on the entire management of early arthritis

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

The clinical effectiveness and cost-effectiveness of treat-to-target strategies in rheumatoid arthritis: a systematic review and cost-effectiveness analysis

Background: Treat to target (TTT) is a broad concept for treating patients with rheumatoid arthritis (RA). It involves setting a treatment target, usually remission or low disease activity (LDA). This is often combined with frequent patient assessment and intensive and rapidly adjusted drug treatment, sometimes based on a formal protocol. Objective: To investigate the clinical effectiveness and cost-effectiveness of TTT compared with routine care. Data sources: Databases including EMBASE and MEDLINE were searched from 2008 to August 2016. Review methods: A systematic review of clinical effectiveness was conducted. Studies were grouped according to comparisons made: (1) TTT compared with usual care, (2) different targets and (3) different treatment protocols. Trials were subgrouped by early or established disease populations. Study heterogeneity precluded meta-analyses. Narrative synthesis was undertaken for the first two comparisons, but was not feasible for the third. A systematic review of cost-effectiveness was also undertaken. No model was constructed as a result of the heterogeneity among studies identified in the clinical effectiveness review. Instead, conclusions were drawn on the cost-effectiveness of TTT from papers relating to these studies. Results: Sixteen clinical effectiveness studies were included. They differed in terms of treatment target, treatment protocol (where one existed) and patient visit frequency. For several outcomes, mixed results or evidence of no difference between TTT and conventional care was found. In early disease, two studies found that TTT resulted in favourable remission rates, although the findings of one study were not statistically significant. In established disease, two studies showed that TTT may be beneficial in terms of LDA at 6 months, although, again, in one case the finding was not statistically significant. The TICORA (TIght COntrol for RA) trial found evidence of lower remission rates for TTT in a mixed population. Two studies reported cost-effectiveness: in one, TTT dominated usual care; in the other, step-up combination treatments were shown to be cost-effective. In 5 of the 16 studies included the clinical effectiveness review, no cost-effectiveness conclusion could be reached, and in one study no conclusion could be drawn in the case of patients denoted low risk. In the remaining 10 studies, and among patients denoted high risk in one study, cost-effectiveness was inferred. In most cases TTT is likely to be cost-effective, except where biological treatment in early disease is used initially. No conclusions could be drawn for established disease. Limitations: TTT refers not to a single concept, but to a range of broad approaches. Evidence reflects this. Studies exhibit substantial heterogeneity, which hinders evidence synthesis. Many included studies are at risk of bias. Future work: Future studies comparing TTT with usual care must link to existing evidence. A consistent definition of remission in studies is required. There may be value in studies to establish the importance of different elements of TTT (the setting of a target, the intensive use of drug treatments and protocols pertaining to those drugs and the frequent assessment of patients). Conclusion: In early RA and studies of mixed early and established RA populations, evidence suggests that TTT improves remission rates. In established disease, TTT may lead to improved rates of LDA. It remains unclear which element(s) of TTT (the target, treatment protocols or increased frequency of patient visits) drive these outcomes. Future trials comparing TTT with usual care and/or different TTT targets should use outcomes comparable with existing literature. Remission, defined in a consistent manner, should be the target of choice of future studies. Study registration: This study is registered as PROSPERO CRD42015017336. Assessment programme

Cómo medir la actividad de la enfermedad en artritis reumatoide precoz: un nuevo reto

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Medicina. Fecha de lectura: 06-06-2014The objective of our research was to evaluate the use of composite indices to measure disease activity in rheumatoid arthritis (RA), with a special focus in early disease. It has been well established that early initiation of treatment improves patient outcomes. However, treatments used in patients with RA are not exempt of side effect; therefore, it is vital to adjust the treatment to each patient’s disease activity. This thesis is divided into a number of parts and chapters. The first part provides a general introduction about the options available for measuring disease activity in patients with RA, points to consider when addressing patients with an early disease, as well as the framework on how to improve or develop new instruments for measurement. In this opening section the aim and outline of the research and individual studies is also included, as well as the methodology followed to address the questions posed. The second part contains the results of the different studies that support this thesis. A first chapter highlights some limitations of the available instruments; concretely, we address the study of such limitations in an early arthritis register, in which we propose new cut-­‐offs for a version of the most widely used composite index, the DAS28 with CRP, given its limitations. The following chapter focuses on the choice of an appropriate instrument in patients with early disease, including the search for available instruments and recommendations on how to investigate and follow-­‐up undifferentiated peripheral inflammatory arthritis. A final chapter covers the development of a new composite index appropriate for patients with early disease. The third part of the thesis is a discussion of all the presented results pondered by the strength and limitations of the study approaches. Finally, the conclusions illustrate the significance of improving measures in RA and future perspectives on this topicEl objetivo de nuestra investigación fue evaluar el uso de índices compuestos para medir la actividad de la enfermedad en la artritis reumatoide (AR), con un enfoque especial en la enfermedad precoz. Ha sido claramente establecido cómo el tratamiento precoz mejora las medidas de desenlace del paciente. Sin embargo, los tratamientos que se utilizan en la AR no están exentos de efectos adversos por lo que es importante ajustar los tratamientos a la actividad de la enfermedad de cada paciente. Esta tesis está dividida en distintas partes y capítulos. La primera parte consiste en una introducción general sobre la opciones disponibles para medir la actividad de la enfermedad en pacientes con AR, qué aspectos hay que considerar cuando se evalúan pacientes con enfermedad precoz, y una estrategia para mejorar o desarrollar nuevos instrumentos de medida. En esta parte inicial también se incluyen los objetivos, una descripción de la metodología de investigación y los estudios individuales así como la metodología seguida en cada pregunta de investigación. La segunda parte incluye los resultados de los diferentes estudios que apoyan esta tesis. En el primer capítulo se destacan algunas de las limitaciones de los instrumentos disponibles. En concreto presentamos un estudio de la limitación de estos índices en un registro de artritis precoz, en el cual proponemos nuevos puntos de corte para el índice compuesto más empleado, el DAS28 calculado con PCR. El siguiente capítulo se centra en la elección del instrumento apropiado en pacientes con enfermedad precoz, e incluye una búsqueda de los instrumentos disponibles y recomendaciones sobre cómo investigar y hacer el seguimiento de los pacientes con artritis inflamatoria periférica indiferenciada. El capítulo final se centra en el desarrollo de un nuevo índice compuesto que sea apropiado para pacientes con enfermedad precoz. La tercera parte de la tesis es una discusión de todos los resultados presentados haciendo hincapié en las fortalezas y limitaciones de los citados estudios. Finalmente, las conclusiones ilustran el significado de mejorar las medidas en la AR y cuáles son las perspectivas futuras en este tem

Antibodies to citrullinated alpha-enolase peptide in rheumatoid arthritis

Antibodies to cyclic citrullinated peptides (CCP) are diagnostically specific for rheumatoid arthritis (RA) and provide valuable prognostic information. The antigens recognised in vivo by these antibodies are still a matter of investigation and the candidates include citrullinated α-enolase. This thesis describes the identification of an immunodominant epitope, citrullinated α-enolase peptide 1 (CEP-1) . Antibodies to CEP-1 showed a diagnostic specificity of 97%, and sensitivity of 38%. A quantitative CEP-1 ELISA was developed and tested in multiple cohorts of early and established RA with a sensitivity of 25-60%. The relationship of anti-CEP-1 antibodies with the major risk factors for RA, the HLA-DRB1 'shared epitope' (SE), PTPN22 and smoking, were examined in 1497 patients and 872 controls in a collaborative study involving patients from Sweden and the UK. A previously described association between SE and anti-CCP antibodies was found to be strongest in the subset that was also positive for anti-CEP-1 antibodies. In the Swedish case-control analysis, the combination of SE, PTPN22 and smoking was preferentially associated with this subset (odds ratio 37 versus 2 for the anti-CEP-1-/anti-CCP+ subset). A novel gene association with this subset, Bromodomain-containing protein 2, was also detected by dense SNP mapping of the MHC region. The prognostic value of anti-CEP-1 antibodies was examined in 680 patients from two early RA cohorts. Only a weak predictive value for clinical outcomes was found, with no significant differences when comparing anti-CCP antibody positive patients with and without anti-CEP-1 antibodies. Furthermore, no predictive value for response to anti-TNF agents was demonstrated in 450 patients from the British Society of Rheumatology Biologics Register. These findings suggest that autoimmunity to at least one epitope on citrullinated α-enolase is a powerful probe for the aetiology of RA (genes and environment), but not for the downstream results of pathogenesis such as clinical outcome and response to treatment

Early intensive treatment normalises excess mortality in ACPA-negative RA but not in ACPA-positive RA

Pathophysiology and treatment of rheumatic disease