Edith Villeneuve

Remission induction comparing infliximab and high-dose intravenous steroid, followed by treat-to-target: a double-blind, randomised, controlled trial in new-onset, treatment-naive, rheumatoid arthritis (the IDEA study)

Objectives In disease modifying antirheumatic drug (DMARD)-naive early rheumatoid arthritis (RA), to compare the efficacy of methotrexate (MTX) and infliximab (IFX) with MTX and intravenous corticosteroid for remission induction. Methods In a 78-week multicentre randomised controlled trial, double-blinded to week 26, 112 treatment-naive RA patients (1987 American College of Rheumatology classification criteria) with disease activity score 44 (DAS44)>2.4 were randomised to MTX + IFX or MTX + single dose intravenous methylprednisolone 250u2005mg. A treat-to-target approach was used with treatment escalation if DAS44>2.4. In the IFX group, IFX was discontinued for sustained remission (DAS44<1.6 for 6u2005months). The primary outcome was change in modified total Sharp-van der Heijde score (mTSS) at week 50. Results The mean changes in mTSS score at week 50 in the IFX and intravenous steroid groups were 1.20 units and 2.81 units, respectively (adjusted difference (95% CI) −1.45 (−3.35 to 0.45); p=0.132). Radiographic non-progression (mTSS<2.0) occurred in 81% vs 71% (OR 1.77 (0.56 to 5.61); p=0.328). DAS44 remission was achieved at week 50 in 49% and 36% (OR 2.13 (0.91 to 5.00); p=0.082), and at week 78 in 48% and 50% (OR 1.12 (0.47 to 2.68); p=0.792). Exploratory analyses suggested higher DAS28 remission at week 6 and less ultrasound synovitis at week 50 in the IFX group. Of the IFX group, 25% (14/55) achieved sustained remission and stopped IFX. No substantive differences in adverse events were seen. Conclusions In DMARD-naive early RA patients, initial therapy with MTX+high-dose intravenous steroid resulted in good disease control with little structural damage. MTX+IFX was not statistically superior to MTX+intravenous steroid when combined with a treat-to-target approach.

Multinational evidence-based recommendations on how to investigate and follow-up undifferentiated peripheral inflammatory arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative

Objective To develop evidence-based recommendations on how to investigate and follow-up undifferentiated peripheral inflammatory arthritis (UPIA). Methods 697 rheumatologists from 17 countries participated in the 3E (Evidence, Expertise, Exchange) Initiative of 2008–9 consisting of three separate rounds of discussions and modified Delphi votes. In the first round 10 clinical questions were selected. A bibliographic team systematically searched Medline, Embase, the Cochrane Library and ACR/EULAR 2007–2008 meeting abstracts. Relevant articles were reviewed for quality assessment, data extraction and synthesis. In the second round each country elaborated a set of national recommendations. Finally, multinational recommendations were formulated and agreement among the participants and the potential impact on their clinical practice was assessed. Results A total of 39 756 references were identified, of which 250 were systematically reviewed. Ten multinational key recommendations about the investigation and follow-up of UPIA were formulated. One recommendation addressed differential diagnosis and investigations prior to establishing the operational diagnosis of UPIA, seven recommendations related to the diagnostic and prognostic value of clinical and laboratory assessments in established UPIA (history and physical examination, acute phase reactants, autoantibodies, radiographs, MRI and ultrasound, genetic markers and synovial biopsy), one recommendation highlighted predictors of persistence (chronicity) and the final recommendation addressed monitoring of clinical disease activity in UPIA. Conclusions Ten recommendations on how to investigate and follow-up UPIA in the clinical setting were developed. They are evidence-based and supported by a large panel of rheumatologists, thus enhancing their validity and practical use.

A systematic literature review of strategies promoting early referral and reducing delays in the diagnosis and management of inflammatory arthritis

Background Despite the importance of timely management of patients with inflammatory arthritis (IA), delays exist in its diagnosis and treatment. Objective To perform a systematic literature review to identify strategies addressing these delays to inform an American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) taskforce. Methods The authors searched literature published between January 1985 and November 2010, and ACR and EULAR abstracts between 2007–2010. Additional information was obtained through a grey literature search, a survey conducted through ACR and EULAR, and a hand search of the literature. Results (1) From symptom onset to primary care, community case-finding strategies, including the use of a questionnaire and autoantibody testing, have been designed to identify patients with early IA. Several websites provided information on IA but were of varying quality and insufficient to aid early referral. (2) At a primary care level, education programmes and patient self-administered questionnaires identified patients with potential IA for referral to rheumatology. Many guidelines emphasised the need for early referral with one providing specific referral criteria. (3) Once referred, early arthritis clinics provided a point of early access for rheumatology assessment. Triage systems, including triage clinics, helped prioritise clinic appointments for patients with IA. Use of referral forms standardised information required, further optimising the triage process. Wait times for patients with acute IA were also reduced with development of rapid access systems. Conclusions This review identified three main areas of delay to care for patients with IA and potential solutions for each. A co-ordinated effort will be required by the rheumatology and primary care community to address these effectively.

Choosing Wisely: The Canadian Rheumatology Association’s List of 5 Items Physicians and Patients Should Question

Objective. To develop a list of 5 tests or treatments used in rheumatology that have evidence indicating that they may be unnecessary and thus should be reevaluated by rheumatology healthcare providers and patients. Methods. Using the Delphi method, a committee of 16 rheumatologists from across Canada and an allied health professional generated a list of tests, procedures, or treatments in rheumatology that may be unnecessary, nonspecific, or insensitive. Items with high content agreement and perceived relevance advanced to a survey of Canadian Rheumatology Association (CRA) members. CRA members ranked these top items based on content agreement, effect, and item ranking. A methodology subcommittee discussed the items in light of their relevance to rheumatology, potential effect on patients, and the member survey results. Five candidate items selected were then subjected to a literature review. A group of patient collaborators with rheumatic diseases also reviewed these items. Results. Sixty-four unique items were proposed and after 3 Delphi rounds, this list was narrowed down to 13 items. In the member-wide survey, 172 rheumatologists responded (36% of those contacted). The respondent characteristics were similar to the membership at large in terms of sex and geographical distribution. Five topics (antinuclear antibodies testing, HLA-B27 testing, bone density testing, bone scans, and bisphosphonate use) with high ratings on agreement and effect were chosen for literature review. Conclusion. The list of 5 items has identified starting points to promote discussion about practices that should be questioned to assist rheumatology healthcare providers in delivering high-quality care.

A systematic literature review of strategies promoting early referral and reducing delays in the diagnosis and management of infl ammatory arthritis

Background Despite the importance of timely management of patients with inflammatory arthritis (IA), delays exist in its diagnosis and treatment. Objective To perform a systematic literature review to identify strategies addressing these delays to inform an American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) taskforce. Methods The authors searched literature published between January 1985 and November 2010, and ACR and EULAR abstracts between 2007–2010. Additional information was obtained through a grey literature search, a survey conducted through ACR and EULAR, and a hand search of the literature. Results (1) From symptom onset to primary care, community case-finding strategies, including the use of a questionnaire and autoantibody testing, have been designed to identify patients with early IA. Several websites provided information on IA but were of varying quality and insufficient to aid early referral. (2) At a primary care level, education programmes and patient self-administered questionnaires identified patients with potential IA for referral to rheumatology. Many guidelines emphasised the need for early referral with one providing specific referral criteria. (3) Once referred, early arthritis clinics provided a point of early access for rheumatology assessment. Triage systems, including triage clinics, helped prioritise clinic appointments for patients with IA. Use of referral forms standardised information required, further optimising the triage process. Wait times for patients with acute IA were also reduced with development of rapid access systems. Conclusions This review identified three main areas of delay to care for patients with IA and potential solutions for each. A co-ordinated effort will be required by the rheumatology and primary care community to address these effectively.

Rheumatoid arthritis: what has changed?

Rheumatoid arthritis (RA) is the most common inflammatory arthritis affecting approximately 1% of the population. The diagnosis of RA still evokes a picture of a patient crippled with bilateral, symmetric deformities of hands and feet in the mind of most doctors. Less than 15 years ago, RAwas regarded as a chronic destructive disease leading to joint deformities and severe functional decline with work disability reported in 60% of patients after 10 years [1]. As a systemic disorder, it has also been linked to multiple organ system complications and increased mortality, predominantly due to accelerated cardiovascular disease. Fortunately, over the last two decades, significant advances in the treatment and management of RA have been made and are changing the way we perceive RA. New treatment strategies have shown their ability to slow disease progression. New biologic agents that have been shown to be able to arrest joint damage are now available. Moreover, when these agents are used in early disease, a significant proportion of patients can achieve remission, a state with no apparent disease activity or inflammation. Another major advance has been the recognition of the importance of early treatment, emphasizing the need for early diagnosis. Therefore, rheumatologists ideally see patients within weeks of symptoms onset, and as a result, the clinical course and treatment of RA have undergone major changes. Clinical presentation: what has changed?

OP0180 Risk of Developing Clinical Synovitis in ACPA Positive Patients with Non-Specific Musculoskeletal Symptoms

Background Rheumatoid Arthritis (RA) is associated with autoantibodies including ACPA which may be present years before clinical presentation. In the pre clinical phase, patients usually present with non specific musculoskeletal (MSK) symptoms. Objectives 1- To monitor the progression In ACPA positive patients with non specific MSK symptoms to clinical synovitis (CS). 2- To investigate if demographic, clinical, imaging, and serological measures can identify patients at high risk of developing RA at pre-clinical stage. Methods Patients were recruited from rheumatology clinics and primary care. Clinical assessment and investigations including magnetic resonance imaging (MRI) and ultrasound (US) were undertaken at baseline and 3-6 month intervals or at change of symptoms. The end point was the development of CS, defined as the presence of at least one tender and swollen joint. Healthy controls were recruited as a comparator group. Results A total of 122 patients without a diagnosis of inflammatory arthritis were studied. 22 patients were found to have CS at baseline and hence were excluded from analysis. 100 patients (73% females) with a mean age of 51 years (±11.8) had no CS at baseline and were followed up for a median duration of 38.5 weeks (range 1-234 weeks). 44 patients (44%) developed CS after a median duration of 26.5 weeks (1-170 weeks); 22 patients (22%) within 6 months and 33 (33%) within 12 months. Baseline early morning stiffness (EMS) was the only clinical parameter which demonstrated significant difference between the two groups; 59 minutes in those who progressed and 19 minutes in those who did not (P=0.001). The remaining baseline demographic, clinical, and serological parameters were not significantly different between the two groups. Baseline US of wrist and hands (controls =28, patients=98) showed a mean total power Doppler (PD) of 0.2 (SD 0.5) in the controls. In patients who did not progress, mean total PD score was 0.8 (SD 1.8) compared to 2.0 (SD 3.0) in those who progressed (p=0.003). A sub group of ACPA positive patients underwent MRI of a wrist and hand (n=33). Significant difference in flexor tenosynovitis mean score was demonstrated between groups (1.8 (SD 1.6) in patients who progressed vs. 0.7 (SD 1.1) in those with no progression, p=0.024). Conclusions A significant proportion of patients in this cohort progressed to clinical synovitis, the majority within 12 months of presentation. EMS was the only clinical parameter associated with progression. US and MRI may provide a useful tool in identifying patients who may progress to CS. Disclosure of Interest C. Rakieh: None Declared, J. Nam: None Declared, L. Hunt: None Declared, E. Villeneuve: None Declared, L.-A. Bissell: None Declared, S. Das: None Declared, P. Conaghan: None Declared, D. McGonagle: None Declared, R. Wakefield: None Declared, P. Emery Consultant for: Honoraria/Advisory Board: Abbot, Pfizer, Roche, Chugai, BMS, UCB, MSD

FRI0119 Improvement in some, but not all, surrogate measures of cardiovascular disease following intensive treatment of early rheumatoid arthritis

Background Patients with rheumatoid arthritis (RA) have an elevated risk of cardiovascular disease (CVD), predominantly ischaemic heart disease (IHD). Systemic inflammation is thought to be a key contributor to this risk and it is hoped early therapeutic suppression of inflammation will reduce cardiovascular (CV) events in the long term. Insulin resistance, associated with metabolic syndrome, N-terminal pro-brain natriuretic peptide (NT-proBNP) and atherogenic lipid profiles have been proposed as potential surrogate measures of atherosclerosis in RA. Each has been shown to correlate with systemic inflammation, but their utility in RA above measurement of the acute phase response remains unknown. Objectives To determine whether suppression of inflammation in early RA influences surrogate measures of atherosclerosis, including the homeostasis model assessment of insulin resistance (HOMA-IR), NT-proBNP and dyslipidaemia. Methods CRP, fasting glucose and lipids, and in a sub-group, NT-proBNP and fasting insulin, were measured at baseline and week 26 in DMARD naïve RA patients, with 3-12 months symptoms, recruited into the Infliximab as Induction therapy for Early rheumatoid Arthritis (IDEA) multicentre double-blind randomised controlled trial. Patients met the 1987 ACR criteria. Treatment was randomised to IFX +MTX or MTX with 250mg IV methylprednisolone as induction therapy. 120mg IM methylprednisolone was given if DAS>2.4 at 3 time points within the first 26 weeks. HOMA-IR was calculated at each time point. Descriptive statistics, Wilcoxon and paired t-test, and Spearman’s correlation were performed. Results Data from 112 patients (69% female, mean age 53 years, 55% RF and 70% anti-CCP positive) were analysed. At baseline, 9% were on a statin and 14% an anti-hypertensive agent. 4 patients had known IHD and were excluded from the subsequent analysis. The median (range) CRP was 13mg/l (0-30) with CRP normal (<5.0mg/l) in 33%. Baseline CRP negatively correlated with HDL (rho -2.78, p=0.024) and total cholesterol (TC) (rho -2.33, p=0.026). 15%, 30%, 39%, and 25% had at risk levels for HDL, LDL, TC and triglyceride (TG), respectively1. In the subgroup of 79 patients with data on NT-proBNP and fasting insulin, 17% and 38% of patients had raised levels of NT-proBNP and HOMA-IR, respectively. Comparing week 26 to baseline, there was a significant fall in CRP (p<0.001; normal levels in 64%) and HOMA-IR (p=0.008; abnormal in 19%), but not NT-proBNP (p=0.132; elevated in 17%). With respect to the dyslipidaemia, HDL and TC rose (p<0.001 and p<0.001 respectively), but there was no significant change in LDL or TG. 5%, 46%, 61%, and 20% had at risk levels for HDL, LDL, TC and TG, respectively. Conclusions In this study, suppression of inflammation was associated with improvement in insulin resistance and increased HDL, but no significant change in NT-proBNP, TG or LDL following 26 weeks intensive RA treatment. Further analyses of biomarkers at week 78 and drug specific effects are underway. Long term follow up is being performed to determine if those patients with persistently abnormal CV biomarkers develop subclinical or overt CVD in the future despite intensive early treatment for RA. References JAMA. 2001;285(19):2486-97 Disclosure of Interest L.-A. Bissell: None Declared, S. Mackie: None Declared, L. Kozera: None Declared, J. Nam: None Declared, A. Burska: None Declared, E. Hensor: None Declared, H. Keen: None Declared, E. Villeneuve: None Declared, H. Donica: None Declared, P. Conaghan: None Declared, J. Andrews: None Declared, P. Emery: None Declared, A. Morgan Grant/Research support from: Supported in part by a research grant from Investigator-Initiated Studies Program of Merck Sharp & Dohme Limited. The opinions expressed in this paper are those of the authors and do not necessarily represent those of Merck Sharp & Dohme Limited

OP0156 Inhibition of structural damage with two intensive treatment strategies using infliximab or high dose intravenous steroid followed by treat to target in DMARD naÏve rheumatoid arthritis (the idea study) – a preliminary report

Background Early intensive treatment with infliximab (IFX), high dose IV steroids and treating to target have been shown to be effective for remission induction in pts with early RA. Objectives To compare MTX+IFX vs. MTX+high dose IV steroid as induction therapy on radiographic progression in pts with DMARD naïve RA. Methods A 78 wk RCT of pts with early (3-12 months symptoms),DMARD naïve RA (1987 ACR criteria, DAS>2.4). Pts were randomised to 1of 2 grps:IFX or IVsteroid. Treatment was blinded to wk 26 then guided using a treat to target approach. Both grps received MTX 10mg wkly increasing to 20mg by wk 6. The IFX grp received: IFX 3mg/kg (wks 0,2,6,14,22)+dose adjustment from wk 26 according to DAS44. The IVsteroid grp received: IV methylprednisolone (MP) 250mg at wk 0, placebo infusions at wks 2,6,14,22 & from wk 26 treatment escalation as follows if DAS >2.4: add SSZ+HCQ, then stop SSZ+HCQ & add LEF, then 1 of the following: MTXs/c+LEF or MTX+ciclosporin or MTX+LEF+prednisolone 5-7.5mg dly.IM MP 120mg was administered if DAS >2.4 at wks 6,14,22,38,50 & 62 for both grps. Other biologics were allowed from wk 26 per NICE guidelines. Radiographs of hands & feet done at 0,26,52 & 78 wks were scored using the modified Sharp-van der Heijde (vdH-S) method by 2 independent radiologists blinded to treatment grp;mean of the readers’ scores was taken. Smallest detectable change was calculated to be 2 units. Results 112 pts were randomised to MTX+IFX (n=55) or MTX+IVsteroid (n=57). Baseline mean (SD) age IFX 53.7 (13.3) vs. IVsteroid grp 53.1 (12.8); mean (SD) DAS28CRP IFX 4.2 (1.1) vs. IVsteroid 3.6 (1.1). Remission (DAS<1.6) at wk 50 was achieved in 51.9% (28/54) in the IFX & 35.7% (20/56) in the IVsteroid grp (p=0.088). Baseline median (IQR) joint space narrowing (JSN), erosion (ERO) and total vdH-S scores (TS) in the IFX (n=42) and IVsteroid (n=51) grps were: JSN 2.0 (0.0-7.5) and 1.5 (0.0-7.0), ERO 0.0 (0.0-1.6) and 0.5 (0.0-2.5), TS 3.0 (0.0-9.5) and 2.5 (0.5-9.5) respectively. At wk 52 (primary endpt), the median change in total vdH-S score was 0.0 (0.0-1.1) units in the IFX and 0.0 (0.0-2.0) units in the IVsteroid arm (p=0.157); median changes did not differ at 26 wks [IFX=0.0 (0.0-0.6) IVsteroid=0.0 (0.0-1.0), p=0.295] or 78 wks [IFX=0.0 (0.0-2.6) IVsteroid=0.5 (0.0-2.4), p=0.325]. Similar results were seen for JSN and ERO scores. Proportions of pts with radiographic non-progression (vdH-S <2.0) in the IFX and IVsteroid arms were 37/4 (88.1%) vs. 43/5 (84.3%) respectively at 26 wks (Pearson’s chi-sq p=0.601); 36/42 (85.7%) vs. 39/51 (76.5%) at 52 wks (p=0.261); 31/42 (73.8%) vs. 36/51 (70.6%) at 78 wks (p=0.730). No between-grp differences were seen with non-progression defined as change≤0.5: 29/42 (69.0%) in the IFX and 29/51 (56.9%) in the IVsteroid grp (p=0.227) at 52 wks. Conclusions In this study of DMARD naïve pts with moderate to severe RA, initial therapy with IFX+MTX and high dose IV steroid+MTX, together with tight disease control prevented radiographic progression in a significant majority of patients. Disclosure of Interest None Declared

Naïve T cells predict MTX induced remission in early arthritis

Background We previously reported that immunological parameters can predict 6 month response to treatment in early rheumatoid arthritis independently of the drug received. Normal naïve CD4 T cells frequency, notably predicted patient ability to achieve remission. The aim of the current study is to determine whether T cell subset analysis (within 4 h of blood collection) can predict remission and/or lack of response to methotrexate (MTX) followed by MTX-escalation and/or addition of other disease-modifying antirheumatic drugs (DMARDs) with the aim of inducing remission (treat to target concept). Methods 28 patients with <12 months EIA were recruited and treated with initial MTX-protocol. Clinical response was evaluated using DAS28 at 6 and 12 months. Symptom duration, C reactive protein (CRP), rheumatoid factor (RF), anticitrullinated peptide antibody (ACPA), disease activity score 28 (DAS28) were recorded. 6 colour flow cytometry was performed using standard protocols. Another 31 patients with similar characteristics were randomized to treatment with MTX+TNF-inhibitor (TNF-i) Results 14/28 patients (50%) achieved remission (DAS28<2.6) when treated under the MTX ‘treat to target’ protocol at both 6 and 12 months. 7patients (25%) showed no response (<1.2 improvement of DAS28) at 6 months and 8 (28%) at 12 months. CRP, symptom duration, RF or ACPA were not associated with either induction of remission or no-response. The only predictor of remission at 6 month was higher naïve T-cell frequency at baseline (p<0.0001) with trends (p=0.150) at 12 months for both naïve T cells and DAS28. Lack of response (<1.2 reduction of DAS28) at 6 months was associated with baseline higher DAS28 (p=0.048) and higher IRC (p=0.050) but with no predictor at 12 months. Responses from the 31 patients in the TNF-I group were: 14 (45%) patients achieved remission at 6 months and 18 (58%) at 12 months Only one patients did not respond at 6 months but 4 (13%) at 12 months. No single predictor of remission or lack of response could be found in this group. Six patients in this TNF-i group combined the lack of response to MTX-prognostic factors (IRC>3% and DAS28>4 at baseline. Only one achieved remission at 6 months. Seven patients treated with TNF-i lacked the good MTX-prognostic factors (naïve T cell<35% and DAS28<4): 3 achieved remission at 6 months and 4 (57%) at 12 months. Conclusion These data are preliminary however they suggested that, in patients that lack good MTX-prognostic factors, the use of TNF-inhibitor may improve remission rate. They further confirmed previous findings and suggest that transferring flow cytometry protocols from a research lab to routine hospital service may be useful.