Objective: The aim of this study was to investigate the effect of treat-to-target combination therapy with intensification at 13 weeks in early RA. Methods: Early RA patients were classified as being at high or low risk of worsening RA based on disease activity and prognostic factors. High risk patients received COBRA-light (prednisolone 30 mg/day tapered to 7.5 mg/day, MTX increasing to 25 mg/week), and low-risk patients received MTX monotherapy increasing to 25 mg/week. The primary outcome (target) was DAS44 < 1.6 or EULAR good response at 26 weeks. At 13 weeks, non-responders were randomized to (open-label) intensification [high-risk patients: prednisolone 60 mg/day tapered to 7.5 mg/day, addition of SSZ (2 g/day) and HCQ (400 mg/day); low-risk patients: prednisolone 30 mg/day tapered to 7.5 mg/day] or continuation. Results: In the high-risk group (n= 150), 110 patients (73%) reached the target at 13 weeks, and 9 dropped out. Non-responders were randomized to intensification (n = 15) or continuation (n= 16), and after 26 weeks, 12 (80%) vs 7 (44%) of these, respectively, reached the target [difference: 36%, (95% CI 2%, 71%); P= 0.04]. In the low-risk group (n = 40), 17 (43%) reached the target. Non-responders were randomized to intensification (n = 8) or continuation (n = 7); 4 vs 3, respectively, reached the target. Adverse event rates were higher in the high-risk group, and higher in the intensification subgroup of that group. Serious adverse events were rare. Protocol violations were frequent and mostly led to mitigation of actual treatment intensification. kConclusion: Initial combination therapy was very successful in high-risk RA, and early intensification was beneficial in patients not reaching the strict target. The low-risk group was too small for drawing conclusions. In routine practice, adherence to early intensification based on strict targets is difficult.

Objectives Persons 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.Methods Arthralgia 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.Results Due 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.Conclusions In 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.

BACKGROUND:An unfavorable body composition is often present in chronic arthritis patients. This unfavorable composition is a loss of muscle mass, with a stable or increased (abdominal) fat mass. Since it is unknown when this unfavorable composition develops, we compared body composition in disease-modifying antirheumatic drugs (DMARD)-naive early arthritis patients with non-arthritis controls and explored the association, in early arthritis patients, with disease activity and traditional cardiovascular risk factors. METHODS:317 consecutive early arthritis patients (84% rheumatoid arthritis according to 2010 ACR/EULAR criteria) and 1268 age-/gender-/ethnicity-matched non-arthritis controls underwent a Dual-energy X-ray absorptiometry scan to assess fat percentage, fat mass index, fat mass distribution and appendicular lean (muscle) mass index. Additionally, disease activity, health assessment questionnaire (HAQ), acute phase proteins, lipid profile and blood pressure were evaluated. RESULTS:Loss of muscle mass (corrected for age suspected muscle mass) was 4-5 times more common in early arthritis patients, with a significantly lower mean appendicular lean mass index (females 6% and males 7% lower, p<0.01). Patients had more fat distributed to the trunk (females p<0.01, males p = 0.07) and females had a 4% higher mean fat mass index (p<0.01). An unfavorable body composition was associated with a higher blood pressure and an atherogenic lipid profile. There was no relationship with disease activity, HAQ or acute phase proteins. CONCLUSION:Loss of muscle mass is 4-5 times more common in early arthritis patients, and is in early arthritis patients associated with a higher blood pressure and an atherogenic lipid profile. Therefore, cardiovascular risk is already increased at the clinical onset of arthritis making cardiovascular risk management necessary in early arthritis patients.

BackgroundClinical response and remission are defined in multiple ways and measured with different instruments, resulting in substantial variation of the proportion of patients classified as being in remission. Therefore, the agreement between patient-perceived, physician-perceived remission and clinical response and remission definitions was determined in early rheumatoid arthritis (RA) patients. And secondly, differences in clinical and patient-reported outcomes, in patients in physician-perceived remission, between patients in and not in self-perceived remission were assessed.MethodsIn 84 early RA patients, who received methotrexate and glucocorticoids, DAS44, ACR/EULAR Boolean-based remission, EULAR good and ACR70 response were determined after 12 weeks. Agreement between patient-perceived (phrased: "Would you say that, at this moment, your disease activity is as good as gone?"), physician-perceived remission (based on a visual analogue scale for global disease severity) and clinical response and remission definitions were calculated with the percentage of agreement and with kappa values (which corrects for change). In patients in physician-perceived remission, improvement in clinical and patient-reported outcomes (RAID) were compared between patients in and not in self-perceived remission.ResultsAgreement between the assessed outcome measures differed enormously. The agreement between physician-perceived and patient-perceived remission was 64% (kappa 0.25, p <0.01). Physician-perceived remission had the best agreement with EULAR good response (79%), and patient-perceived remission with EULAR good and ACR70 response (both 69%). Patients not in self-perceived remission improved less on RAID components, especially on pain, sleep and emotional well-being.ConclusionOne-third of the early RA patients disagreed with the physician on being in remission. Those patients had less improvement on RAID components, especially on pain, sleep and emotional well-being. Together with the variability in clinical response and remission definitions, these results highlight the need to increase patient involvement in their own health care decisions.

AIMS To assess the prevalence, 3-year course, and associated factors of temporomandibular joint (TMJ) pain in patients with newly diagnosed rheumatoid arthritis (RA). METHODS A total of 264 patients with newly diagnosed RA were included. Patients were assessed after 3 months, 6 months, 9 months, 1 year, 1.5 years, 2 years, and 3 years. TMJ pain was scored by manual palpation, and the prevalence of TMJ pain was calculated at baseline and at all seven follow-up intervals during 3 years. Factors assessed for a potential association with TMJ pain at baseline included: demographic factors (gender and age), disease-related factors (symptom duration, rheumatoid factor [RF], anti-cyclic citrullinated protein [anti-CCP], C-reactive protein [CRP], and Disease Activity Score 28 [DAS28]), and functional factors (Health Assessment Questionnaire [HAQ] and European Quality of Life 5 Dimensions Questionnaire [EQ5D]-anxiety/depression). A stepwise logistic regression model was used to determine factors associated with TMJ pain in patients with RA. RESULTS The prevalence of TMJ pain in patients with RA was 10.6% at baseline, which decreased to 3.6% in the first year after inclusion and remained stable thereafter. Disease activity as determined by the DAS28 was significantly associated with TMJ pain (odds ratio [OR] = 1.51; 95% confidence interval [95% CI] = 1.12-2.05; P = .009) at baseline. A second logistic regression analysis was performed with the following variables of the DAS28: erythrocyte sedimentation rate (ESR), tender joint count, swollen joint count, and global health. Tender joint count (OR = 1.06; 95% CI = 1.01-1.12; P = .03) and global health (OR = 1.02; 95% CI = 1.00-1.03; P = .03) were significantly associated with TMJ pain at baseline. The remaining factors included in the analysis were not significantly associated with TMJ pain at baseline. CONCLUSION The prevalence of TMJ pain in patients with newly diagnosed RA is approximately 10% and decreases during follow-up, especially in the first year. Disease activity is a risk factor for TMJ pain in patients with newly diagnosed RA.

Objective.To investigate the prevalence of conduction disorders in patients with early arthritis and the relationship with inflammation and traditional cardiovascular (CV) risk factors.Methods.Patients with rheumatoid arthritis (RA) have a 2-fold higher risk of sudden cardiac death, possibly owing to conduction disorders. This increased risk might already be present at the clinical onset of arthritis. Therefore, we assessed electrocardiography, blood pressure, 28-joint Disease Activity Score (DAS28), lipid profile, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) level in 480 patients with early arthritis at baseline and after 1 year.Results.The prevalence of conduction disorders was 12.5%. Conduction times at baseline were not associated with DAS28, ESR, or CRP levels and did not change during antirheumatic treatment. Baseline and the improvement in DAS28 (European League Against Rheumatism response), ESR, and CRP were significantly associated with heart rate, lipid profile, and blood pressure. Elevated total cholesterol and blood pressure were associated with an increased QRS time. The change in heart rate differed 7.3 bpm between patients with the least versus largest DAS improvement.Conclusion.The prevalence of conduction disorders in patients with early arthritis was 12.5%, which is similar to the general population and was not associated with changes in inflammation markers. However, a high cholesterol was associated with a prolonged QRS time. Therefore, the emphasis of CV risk management in arthritis should not be only on treatment of disease activity but also on traditional CV risk factors. The relationship between the improvement in disease activity and heart rate is remarkable because this could imply a 10-year CV mortality risk difference of 24%.

Background Rheumatoid arthritis is associated with an increased cardiovascular (CV) risk. There is mounting evidence that inflammation is involved in the pathogenesis thereof (1). An unfavorable body composition is, independently, associated with an increased CV risk, and often present in established arthritis patients. This unfavorable composition is a loss of muscle mass (sarcopenia), in the presence of a stable or even increased (abdominal) fat mass (sarcopenic obesity) (2). Objectives Currently it is unknown when this unfavorable body composition develops. Therefore, we compared body composition in DMARD-naïve early arthritis patients with non-arthritis controls and explored the association with disease activity and traditional CV risk factors. Methods A total of 317 consecutive early arthritis patients and 1268 age, gender and ethnicity matched non-arthritis controls (3) had a Dual-energy X-ray absorptiometry scan to assess lean (muscle) mass index (LMI), fat mass index (FMI), fat mass distribution (arms and legs versus trunk) and android to gynoid fat mass ratio. For the obesity definition, the cut offs of Gallaher et al. were applied. For the sarcopenia definition, cut offs based on the control group were applied (mean minus two times SD). In addition, a disease activity score, erythrocyte sedimentation rate, lipid profile (total cholesterol, HDL, LDL and triglycerides) and blood pressure assessments were done. Results Early arthritis patients (84% fulfilling the 2010 ACR/EULAR criteria) had a significantly lower mean LMI (p<0.01) compared with controls. Female patients had a higher mean FMI (p<0.01) and more fat was distributed to the trunk in patients (females p<0.01, males p=0.07) (table). The prevalence of an unfavorable body composition (i.e. sarcopenia and sarcopenic obesity) was higher than in controls, for females 5.0% versus 1.3%, OR: 4.2, p<0.01 and for males 8.2% versus 1.5%, OR: 5.7, p<0.01 (figure). A higher FMI, more android fat and more fat distributed to the trunk were associated with higher blood pressure and lipid levels (and lower HDL levels). There was no clear relationship between body composition parameters and disease activity. Conclusions Patients at the clinical onset of arthritis more often have an unfavorable body composition (sarcopenia and sarcopenic obesity) than non-arthritis controls. An unfavorable body composition was associated with higher blood pressure and lipid levels (and lower HDL levels). References Curr Vasc Pharmacol 2010; 8(2):285–292. Age (Dordr) 2015; 37(6):121. Eur J Epidemiol 2015; 30(8):661–708. Disclosure of Interest None declared

The type I interferon (IFN) signature in rheumatoid arthritis (RA) has shown clinical relevance in relation to disease onset and therapeutic response. Identification of the cell type(s) contributing to this IFN signature could provide insight into the signature’s functional consequences. The aim of this study was to investigate the contribution of peripheral leukocyte subsets to the IFN signature in early arthritis.

OBJECTIVES The aim of this study is to compare clinical outcomes, incidence of flares and administered drug reduction between rheumatoid arthritis (RA) patients under TNF inhibitors (TNFi) tapering strategy and RA patients on standard regimen. METHODS Two groups of RA patients on TNFi with DAS28<3.2 were compared: the tapering group (TG: 67 pts from Spain) and the control group with standard therapy regimen (CG: 77 pts from the Netherlands). DAS28 was measured at different time points: visit 0 (prior starting TNFi), visit 1 (prior to start tapering in TG and with DAS28<3.2 in TG and CG), visit 2 (6 months after visit 1), visit 3 (1 year after visit 1), visit 4 (the last visit available after visit 1) and visit-flare (visit with the worst flare between visit 1 and visit 4). RESULTS Despite the reduction of administered drug at visit 4 in the TG (interval elongation of 32.8% in infliximab, 52.9% in adalimumab and 52.6% in etanercept), the DAS28 remained similar between groups at the end of the study (DAS28: 2.7±0.9 in TG vs. 2.5±1 in CG, p=0.1). No differences were seen in the number of patients with flares [26/67 (38.9%) in the TG vs. 30/77 (39%) in the CG, p=0.324] and only nineteen out of 136 patients (14%) had anti-drug antibodies at the end of the study. CONCLUSIONS The tapering strategy of TNFi in RA patients result in a reduction of the drug administered, while the disease control is not worse than patients on the standard regimen.

Background Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial inflammation which may lead to irreversible joint damage, reduced mobility and decreased quality of life. Although clinical remission can often be achieved with DMARD therapy, remission is often not observed on imaging and the presence of bone edema on MRI is the current best predictor of radiographic progression. Another marker associated with radiographic outcomes is 14–3-3η, which is a joint-derived protein whose serological expression is independent of CRP1, modifiable over time2, and linked with the upregulation of factors that drive the joint damage process3. Objectives Examine whether patients who achieve clinical remission at year 1 (Yr1) but remain 14–3-3η positive have worse radiographic outcomes by year 3 (Yr3). Methods Baseline (BL) and Yr1 plasma 14–3-3η protein titres were measured in a cohort of 360 early RA patients from the Reade Institute; all patients were treatment naïve at BL. 14–3-3η positivity was based on the cut-off ≥0.19 ng/ml. Mean (SD) patient age was 55 (12) years and 74% were female. Radiographic progression at Yr3, across the whole cohort and in those patients that achieved Yr1 DAS28 ESR remission (<2.6), was assessed as well as ΔSHS of ≥1, 3 and 5 points from Yr1 to Yr3. Mann-Whitney and Fisher Exact testing was performed to determine the significance (p≤0.05) of group differences and the association with marker positivity, respectively. Results At BL and Yr1, 245 (68%) and 210 (58%) of patients were 14–3-3η positive. Patients who were positive at baseline or Yr1 had significantly worse radiographic progression by Yr3 than 14–3-3η negative patients; BL 14–3-3η positivity (+ve vs.-ve): [2.0 (0.0–7.5) vs. 0.0 (0.0–4.0), p=0.019] and Yr1 14–3-3η positivity (+ve vs. -ve): [2.0 (0.0–8.0) vs. 0.0 (0.0–4.0), p=0.0012]. A total of 109 (30%) patients achieved Yr1 DAS28 remission. Patients who achieved remission yet were 14–3-3η positive at Yr1 experienced significantly worse radiographic progression by Yr3 than negative patients [1.0 (0.0 -5.0) vs. 0.0 (0.0–2.0), p=0.016]. A similar and significant trend for radiographic progression was observed in patients who did not achieve clinical remission and were 14–3-3η positive at Yr1 versus those who were 14–3-3η negative [2.0 (0.0–11.0) vs. 1.0 (0.0–5.0), p=0.029]. The table below demonstrates that positivity for 14–3-3η at both BL and Yr1, across the whole cohort as well as in those achieving clinical remission, is associated with radiographic progression. Yr1 positivity was more strongly associated with ΔSHS ≥5 than BL. Conclusions Patients who achieve DAS28 remission at Yr1 but remain 14–3-3η positive are at risk of future radiographic progression. As expected with a modifiable biomarker such as 14–3-3η, serial assessment is more informative than baseline assessment. References Ann Rheum Dis 2013;72(Suppl 3):592; Arthritis Rheum. 2011. 63 (Suppl 10):428; Arthritis Res Ther 2014,16.2:R99. Disclosure of Interest D. van Schaardenburg Consultant for: Augurex Life Sciences Corp., S. Turk: None declared, W. Maksymowych Consultant for: Augurex Life Sciences Corp., (Co-inventor of 14–3-3η), A. Marotta Employee of: Augurex Life Sciences Corp., (Co-inventor of 14–3-3η)

Multiple lymphocyte subsets like T and B cells have been connected to joint infiltration and inflammation in rheumatoid arthritis (RA). Identification of leucocyte subsets that are dysregulated in arthritis development could provide insight into the aetiology of RA. This study aimed to investigate the composition of the peripheral blood components, i.e. CD14+ monocytes, CD4+ and CD8+ T lymphocytes (CD3+), CD80+, C-X-C chemokine receptor 3 (CXCR3)+ and CD27+ B lymphocytes (CD19+), CD16+CD56+CD3− natural killer (NK) cells and activated CD56+CD3+ T cells, for association with arthritis development in patients with arthralgia.

Background and objectives A subgroup of rheumatoid arthritis (RA) patients displays elevated type I IFN response gene (IRG) expression in peripheral blood, which has shown clinical relevance in relation to disease onset and therapy response. Identification of the cell type(s) contributing to this IFN signature could provide insight into its functional consequences and pathologic role in RA. This study aimed to investigate the contribution of the major peripheral leukocyte subsets to the IFN signature in RA. Methods Blood was collected from 26 early RA patients and lysed directly or separated into mononuclear cells (PBMCs) and polymorphonuclear granulocytes (PMNs). Using flow cytometry, PBMCs were sorted into CD4+ T cells, CD8+ T cells, CD19+ B cells and CD14+ monocytes. mRNA expression levels of three IRGs (RSAD2, IFI44L and MX1), as well as type I IFN receptors IFNAR1 and IFNAR2, were determined in blood and cell subsets by qPCR. IRG expression was averaged to calculate an IFN score for each sample. Results Patients were designated “IFNhigh” (n = 8) and “IFNlow” (n = 18) based on the IFN score cutoff in peripheral blood from healthy controls. As expected, IFN scores were significantly higher in all cell subsets from IFNhigh patients compared to IFNlow patients. This difference was remarkably large for the PMN fraction (mean 25-fold, p < 0.0001) compared to the other subsets (mean 6–9-fold, p ≤ 0.0009). Moreover, the relative contribution of the PMN fraction was significantly higher than expected from its relative abundance in blood alone (3-fold, p = 0.008), whereas this was 3–7-fold lower for the other subsets (p ≤ 0.063). Both IFNAR1 and IFNAR2 expression was highest in the PMN fraction compared to the other subsets, suggesting increased sensitivity of PMNs to type I IFNs. Concordantly, we observed IFNAR1 and IFNAR2 upregulation compared to healthy controls selectively in RA PMNs (p ≤ 0.0077) but not in the PBMCs. Conclusions PMNs are the main contributors to the whole blood type I IFN signature in RA patients, which seems due to increased sensitivity to type I IFN signalling. Considering the well-established role of neutrophils in the pathology of RA, this further supports a pathologic role of type I IFN activity in the disease.

Background With the advent of biological therapy a range of new drugs have come available for patients with rheumatoid arthritis (RA). Tocilizumab (TCZ) was registered more recently for patients with RA. Obviously, data on long-term efficacy and safety in daily clinical practice is important as results obtained in short-term clinical registration trials might differ from those observed in long-term daily clinical practice. Objectives To ascertain the efficacy of long- term TCZ treatment for RA Methods From May 2009 to August 2014, 40 consecutive patients have been included in the TCZ RA cohort Patients were eligible for inclusion if disease activity was high despite previous treatment with TNF-inhibitor and in the absence of contraindications for the start of TCZ. TCZ was given, intravenously, in a dose of 8 mg/kg once every 4 weeks. Visits were performed regularly based on a fixed protocol. At every visits, disease activity was measured using Disease Activity Score of 28 joints (DAS28). Improvement after baseline as measured using the ΔDAS28. In addition, the Health Assessment Questionnaire was performed at baseline and half yearly thereafter. To investigate the course of DAS28 and improvement over time a t-test was used. Results The mean age was 53 years (SD:18), and 29 (73%) were female. At baseline, the median disease duration was 9 (5-18) years, 29 (74%) were rheumatoid factor positive, 25 (66) had erosive disease, 29 (76%) were anti-CCP positive. At baseline, 22 (56%) used methotrexate (MTX), 24 (62%) used prednisolone, and 11 (28%) a DMARD other than MTX. On average patients had used 3.4 (SD:1.3) DMARDs, and 2.0 (0-3.0) biologicals. The maximum follow-up duration was 4.7 years, during which a total of 23 (58%) patients were stillon drug, and 17 (43%) patients have dropped out 8 patients (47%) due to adverse events, 7 patients (41%) stopped due to inefficacy, and 2 patients (12%) stopped for other reasons. The median follow-up duration was 0.48 (IQR:0.23-1.97) years for patients currently on TCZt, and 1.02 (0.25-1.96) years for drop-outs. The mean DAS-28 dropped significantly from 5.3 (SD: 1.7) at baseline to 3.2 (1.3) at 12 weeks. This improvement sustained and increased further over 3 years, see figure. The mean score on the health assessment questionnaire (HAQ) dropped from 1.6 (0.7) to 1.3 (0.8) at 12 weeks of treatment, and remained stable after that, see figure. Conclusions This cohort of RA patients treated with TCZ intravenously followed long term showed that the initial good response on tocilizumab persists for at least 3 years of follow-up based on DAS28 and HAQ, in patients who remained on TCZ treatment. 43% of patients dropped out during 5 years of follow-up. Disclosure of Interest None declared