EULAR points to consider for conducting clinical trials and observational studies in individuals at risk of rheumatoid arthritis

BackgroundDespite growing interest, there is no guidance or consensus on how to conduct clinical trials and observational studies in populations at risk of rheumatoid arthritis (RA).MethodsAn European League Against Rheumatism (EULAR) task force formulated four research questions to be addressed by systematic literature review (SLR). The SLR results informed consensus statements. One overarching principle, 10 points to consider (PTC) and a research agenda were proposed. Task force members rated their level of agreement (1–10) for each PTC.ResultsEpidemiological and demographic characteristics should be measured in all clinical trials and studies in at-risk individuals. Different at-risk populations, identified according to clinical presentation, were defined: asymptomatic, musculoskeletal symptoms without arthritis and early clinical arthritis. Study end-points should include the development of subclinical inflammation on imaging, clinical arthritis, RA and subsequent achievement of arthritis remission. Risk factors should be assessed at baseline and re-evaluated where appropriate; they include genetic markers and autoantibody profiling and additionally clinical symptoms and subclinical inflammation on imaging in those with symptoms and/or clinical arthritis. Trials should address the effect of the intervention on risk factors, as well as progression to clinical arthritis or RA. In patients with early clinical arthritis, pharmacological intervention has the potential to prevent RA development. Participants’ knowledge of their RA risk may inform their decision to participate; information should be provided using an individually tailored approach.ConclusionThese consensus statements provide data-driven guidance for rheumatologists, health professionals and investigators conducting clinical trials and observational studies in individuals at risk of RA.

Inhibition of histone deacetylase 6 suppresses inflammatory responses and invasiveness of fibroblast-like-synoviocytes in inflammatory arthritis

Background To investigate the effects of inhibiting histone deacetylase (HDAC) 6 on inflammatory responses and tissue-destructive functions of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA). Methods FLS from RA patients were activated with interleukin (IL)-1β in the presence of increasing concentrations of M808, a novel specific HDAC6 inhibitor. Production of ILs, chemokines, and metalloproteinases (MMPs) was measured in ELISAs. Acetylation of tubulin and expression of ICAM-1 and VCAM-1 were assessed by Western blotting. Wound healing and adhesion assays were performed. Cytoskeletal organization was visualized by immunofluorescence. Finally, the impact of HDAC6 inhibition on the severity of arthritis and joint histology was examined in a murine model of adjuvant-induced arthritis (AIA). Results HDAC6 was selectively inhibited by M808. The HDAC6 inhibitor suppressed the production of MMP-1, MMP-3, IL-6, CCL2, CXCL8, and CXCL10 by RA-FLS in response to IL-1β. Increased acetylation of tubulin was associated with decreased migration of RA-FLS. Inhibiting HDAC6 induced cytoskeletal reorganization in RA-FLS by suppressing the formation of invadopodia following activation with IL-1β. In addition, M808 tended to decrease the expression of ICAM-1 and VCAM-1. In the AIA arthritis model, M808 improved the clinical arthritis score in a dose-dependent manner. Also, HDAC6 inhibition was associated with less severe synovial inflammation and joint destruction. Conclusion Inhibiting HDAC6 dampens the inflammatory and destructive activity of RA-FLS and reduces the severity of arthritis. Thus, targeting HDAC6 has therapeutic potential.

Risk Factors for Developing Rheumatoid Arthritis in Patients With Undifferentiated Arthritis and Inflammatory Arthralgia

Currently, there is an increasing interest in treating patients at risk of rheumatoid arthritis (RA) to prevent the development of this chronic disease. In this sense, research has focused attention on the early identification of predictive factors of this disease. Autoantibodies and markers of systemic inflammation can be present before clinical arthritis and RA development. So, the phase of inflammatory arthralgia preceding clinical arthritis is an important part of the window of opportunity and, starting treatment might prevent progression to chronic arthritis. Additionally, the early diagnosis and treatment initiation, in patients with inflammatory arthritis at risk of persistence and/or erosive progression, are fundamental because may allow optimal clinical responses, better chances of achieving sustained remission, preventing irreversible organ damage and optimizing long-term outcomes. This review aims to give an overview of clinical risk factors for developing RA, both in suspected arthralgia and in undifferentiated arthritis. Besides taking into consideration the role of serological markers (immunological and acute phase reactants) and clinical features assessed at consultation such as: articular affection and patient's clinical perception. Other features as sociodemographic and environmental factors (lifestyle habits, microbiota, periodontal disease among others), have been included in this revision to give an insight on strategies to prevent development of RA and/or to treat it in early stages.

Latent gammaherpesvirus exacerbates arthritis through modification of age-associated B cells

Epstein-Barr virus (EBV) infection is associated with rheumatoid arthritis (RA) in adults, though the nature of the relationship remains unknown. Herein, we examine the contribution of viral infection to the severity of arthritis in mice. We provide the first evidence that latent gammaherpesvirus infection enhances clinical arthritis, modeling EBV's role in RA. Mice latently infected with a murine analog of EBV, gammaherpesvirus 68 (gHV68), develop more severe collagen-induced arthritis and a Th1-skewed immune profile reminiscent of human disease. We demonstrate that disease enhancement requires viral latency and is not due to active virus stimulation of the immune response. Age-associated B cells (ABCs) are associated with several human autoimmune diseases, including arthritis, though their contribution to disease is not well understood. Using ABC knockout mice, we provide the first evidence that ABCs are mechanistically required for viral enhancement of disease, thereby establishing that ABCs are impacted by latent gammaherpesvirus infection and provoke arthritis.

POS0385 DURING DEVELOPMENT OF RHEUMATOID ARTHRITIS, INTERMETATARSAL BURSITIS MAY OCCUR BEFORE CLINICAL JOINT SWELLING: A LARGE MRI STUDY IN PATIENTS WITH CLINICALLY SUSPECT ARTHRALGIA

Background:Inflammation of the synovial lining is a hallmark of rheumatoid arthritis (RA). A synovial lining is not only present at synovial joints and tendon sheaths but also at bursae. Inflammation of the synovium-lined intermetatarsal bursae in the forefoot, intermetatarsal bursitis (IMB), was recently identified with MRI. It is specific for early RA and present in the majority of RA patients at diagnosis. During development of RA, MRI-detectable subclinical synovitis and tenosynovitis often occur before clinical arthritis presents. Whether IMB is also present in a pre-arthritis stage is unknown.Objectives:To assess the occurrence of IMB in patients with clinically suspect arthralgia (CSA) and its association with progression to clinical arthritis in a large MRI-study.Methods:We studied 524 consecutive patients presenting with CSA. CSA was defined as recent-onset arthralgia of small joints that is likely to progress to RA based on the clinical expertise of the rheumatologist. Participants underwent unilateral contrast-enhanced 1.5T MRI of the forefoot, metacarpophalangeal (MCP) joints and wrist at baseline. Thereafter patients were followed for detection of clinical arthritis, as identified at physical joint examination by the rheumatologist. Baseline MRIs were evaluated for IMB at all 4 intermetatarsal spaces. Also synovitis, tenosynovitis and osteitis were assessed in line with the RA MRI scoring system (summed as RAMRIS-inflammation). Both IMB and RAMRIS-inflammation were dichotomised into positive/negative using data from age-matched symptom-free controls as a reference. Cox regression analysed the association of IMB with progression to clinical arthritis; multivariable analyses were used to adjust for RAMRIS-inflammation which is known to associate with progression to clinical arthritis. Analyses were repeated stratified for ACPA-status, since ACPA-positive and ACPA-negative RA are considered separate entities with differences in pathophysiology.Results:The baseline MRIs showed ≥1 IMB in 35% of CSA-patients. Patients with IMB were more likely to also have synovitis (OR 2.5 (95%CI 1.2–4.9)) and tenosynovitis (8.9 (3.4–22.9)) on forefoot MRI, but not osteitis (0.9 (0.5–1.8)). Patients were followed for median 25 months (IQR 19–27). IMB-positive patients developed clinical arthritis more often than IMB-negative patients (HR 3.0 (1.9-4.8)). This association was independent of RAMRIS-inflammation (adjusted HR 2.2 (1.4–3.6)). In stratified analyses, IMB was more frequent in ACPA-positive than in ACPA-negative CSA (68% vs. 30%, p<0.001). Moreover IMB predicted clinical arthritis development in ACPA-positive CSA (HR 2.5 (1.1–5.7)) but not in ACPA-negative CSA patients (1.0 (0.5–2.2)).Conclusion:One-third of CSA patients have IMB. IMB is frequently present in conjunction with subclinical synovitis and tenosynovitis. It precedes the development of clinical arthritis, and in particular the development of ACPA-positive RA. These results reinforce the notion that not only intra- but also juxta-articular synovial inflammation is involved in the development of RA.Disclosure of Interests:None declared

POS0379 DETERMINING IN WHICH PRECLINICAL STAGE HLA-SHARED EPITOPE ALLELES AND SMOKING EXERT THEIR EFFECT IN THE DEVELOPMENT OF RHEUMATOID ARTHRITIS

Background:The HLA shared epitope (SE) and smoking are the best known genetic and environmental risk factors for rheumatoid arthritis (RA) development; however, at which pre-RA stage they exert their effect is unknown. The following stages are discerned: an asymptomatic stage in which autoimmune responses can develop, a symptomatic stage (clinically suspect arthralgia (CSA)), and development of clinically apparent inflammatory arthritis (IA). Studies in the general asymptomatic population revealed contrasting results on the associations between SE-alleles and smoking and the presence of anti-citrullinated protein antibodies (ACPA). Furthermore, studies on these risk factors in the symptomatic pre-RA phase are scarce and these data might teach us whether SE-alleles and smoking are involved in symptom development and/or progression to clinical arthritis.Objectives:We aimed to determine at which pre-RA stage SE and smoking exert their effect. In this respect, the analyses were focused on the presence of ACPA, but associations for other anti-modified protein antibodies (anti-carbamylated and anti-acetylated protein antibodies (anti-CarP and AAPA, respectively)) were also studied.Methods:Results from the literature on the association of SE and smoking with ACPA in the asymptomatic population were summarized in inverse-variance weighted meta-analyses. In addition 577 CSA-patients were studied. Associations of SE and smoking with IgG ACPA were studied at baseline (CSA-onset), to assess an effect on symptom development. Additionally, patients were monitored for the development of clinically apparent inflammatory arthritis (IA) for median 2 years and associations of SE, smoking and auto-antibodies with progression to IA were determined. Analyses were stratified for ACPA-status and associations in ACPA-positive patients were validated in meta-analyses with other arthralgia-cohorts. Finally analyses were repeated for anti-CarP and AAPA.Results:Meta-analyses showed that SE is not associated with ACPA-positivity in the asymptomatic population (OR 1.06 (95%CI 0.69-1.64)), whereas smoking was associated (OR 1.37 (1.15-1.63)). At CSA-onset, both SE and smoking associated with ACPA-positivity (OR 2.08 (1.24-3.49) and OR 2.41 (1.31-4.43), respectively). During follow-up of CSA-patients SE associated with IA-development (HR 1.86 (1.23-2.82)), in contrast to smoking. SE conferred risk for IA-development in ACPA-negative CSA-patients (HR 1.71 (0.99-2.96)) and in ACPA-positive patients (CSA-cohort HR 1.29 (0.67-2.47); meta-analysis three arthralgia-cohorts HR 1.52 (1.08-2.15)). Investigating the other autoantibodies revealed that SE and smoking were not associated with anti-CarP or AAPA-positivity at CSA-onset; longitudinally AAPA associated with progression to IA independent from ACPA and RF (HR 1.79 (1.02-3.16)), whilst anti-Carp did not.Conclusion:SE and smoking act in partly different pre-RA stages. Although SE does not associate with ACPA in the general population, it does mediate symptom-development and further progression to clinical arthritis. Smoking confers risk to development of ACPA and/or joint symptoms, but is not further involved in IA-development. The time-specific biologic pathways that are underlying need further exploration. These data enhance the understanding of the timing of key genetic and environmental risk factors in the trajectory of RA development.Disclosure of Interests:None declared

The impact of genetic background and sex on the phenotype of IL-23 induced murine spondyloarthritis

Background Overexpression of IL-23 in adult mice by means of hydrodynamic tail vein injection of IL-23 minicircles has been reported to result in spondyloarthritis-like disease. The impact of genetic background and sex on the disease phenotype in this model has not been investigated. Methods We compared male B10.RIII mice with male C57BL/6 mice, and male with female B10.RIII mice after hydrodynamic injection of IL-23 enhanced episomal vector (EEV) at 8–12 weeks of age. We monitored clinical arthritis scores, paw swelling, and body weight. Animals were euthanized after two weeks and tissues were harvested for histology, flow cytometry and gene expression analysis. Serum cytokine levels were determined by ELISA. Findings Male B10.RIII mice developed arthritis in the forepaws and feet within 6 days after IL-23 EEV injection; they also exhibited psoriasis-like skin disease, colitis, weight loss, and osteopenia. In contrast to previous reports, we did not observe spondylitis or uveitis. Male C57BL/6 mice injected with IL-23 EEV had serum IL-23 levels comparable with B10.RIII mice and developed skin inflammation, colitis, weight loss, and osteopenia but failed to develop arthritis. Female B10.RIII mice had more severe arthritis than male B10.RIII mice but did not lose weight. Conclusions The phenotype of IL-23 induced disease in mice is controlled by genetic background and sex of the animals. The development of extra-articular manifestations but absence of arthritis in C57BL/6 mice suggests that organ-specificity of IL-23 driven inflammation is genetically determined. The mechanisms behind the strain-specific differences and the sexual dimorphism observed in this study may be relevant for human spondyloarthritis and warrant further exploration.

Bone Erosions Detected by Ultrasound Are Prognostic for Clinical Arthritis Development in Patients With ACPA and Musculoskeletal Pain

Anti-citrullinated protein antibodies (ACPA) often precede onset of rheumatoid arthritis (RA) by years, and there is an urgent clinical need for predictors of arthritis development among such at-risk patients. This study assesses the prognostic value of ultrasound for arthritis development among ACPA-positive patients with musculoskeletal pain. We prospectively followed 82 ACPA-positive patients without clinical signs of arthritis at baseline. Ultrasound at baseline assessed synovial hypertrophy, inflammatory activity by power Doppler, and erosions in small joints of hands and feet. We applied Cox regression analyses to examine associations with clinical arthritis development during follow-up (median, 69 months; range, 24–90 months). We also compared the ultrasound findings among the patients to a control group of 100 blood donors without musculoskeletal pain. Clinical arthritis developed in 39/82 patients (48%) after a median of 6 months (range, 1–71 months). One or more ultrasound erosions occurred in 13/82 patients (16%), with none in control subjects (p &lt; 0.001). Clinical arthritis development was more common among patients with baseline ultrasound erosions than those without (77 vs. 42%, p = 0.032), and remained significant in a multivariable Cox regression analysis that included previously described prognostic factors (HR 3.9, 95% CI 1.6–9.4, p = 0.003). Ultrasound-detected tenosynovitis was more frequent among the patients and associated with clinical arthritis development in a univariable analysis (HR 2.5, 95% CI 1.1–5.7, p = 0.031), but did not remain statistically significant in multivariable analysis. Thus, bone erosions detected by ultrasound are independent predictors of clinical arthritis development in an ACPA-positive at-risk population.Trial Registration: Regional Ethics Committee in Linköping, Sweden, Dnr M220-09. Registered 16 December 2009, https://etikprovningsmyndigheten.se/.

Atorvastatin is unlikely to prevent rheumatoid arthritis in high risk individuals: results from the prematurely stopped STAtins to Prevent Rheumatoid Arthritis (STAPRA) trial

ObjectivesPersons at high risk of rheumatoid arthritis (RA) might benefit from a low-risk pharmacological intervention aimed at primary prevention. Previous studies demonstrated disease-modifying effects of statins in patients with RA as well as an association between statin use and a decreased risk of RA development. A randomised, double-blind, placebo-controlled trial investigated whether atorvastatin could prevent arthritis development in high-risk individuals.MethodsArthralgia patients with anticitrullinated protein antibody (ACPA) >3 xULN or ACPA and rheumatoid factor, without (a history of) arthritis, were randomised to receive atorvastatin 40 mg daily or placebo for 3 years. The calculated sample size was 220 participants. The primary endpoint was clinical arthritis. Cox regression analysis was used to determine the effect of atorvastatin on arthritis development.ResultsDue to a low inclusion rate, mainly because of an unwillingness to participate, the trial was prematurely stopped. Data of the 62 randomised individuals were analysed. Median follow-up was 14 (inner quartiles 6–35) months. Fifteen individuals (24%) developed arthritis: 9/31 (29%) in the atorvastatin group; 6/31 (19%) in the placebo group: HR 1.40, 95% CI 0.50 to 3.95.ConclusionsIn this small set of randomised high-risk individuals, we did not demonstrate a protective effect of atorvastatin on arthritis development. The main reason for the low inclusion was unwillingness to participate; this may also impede other RA prevention trials. Further research to investigate and solve barriers for prevention trial participation is needed.