Chadi Rakieh

Telomere length is shortened in SLE patients.

OBJECTIVE Patients with systemic lupus erythematosus (SLE) have a higher rate of premature death compared to the general population, suggesting a phenotype of premature senescence in SLE. Telomere length can be used to assess overall biologic aging. This study was undertaken to address the hypothesis that patients with SLE have reduced telomere length. METHODS Telomere length was measured cross-sectionally in whole blood from SLE patients and age-matched healthy female controls, using real-time quantitative polymerase chain reaction. SLE-related and cardiovascular risk factors were assessed. RESULTS We compared telomere length in 63 SLE patients and 63 matched controls with a median age of 50.8 years (interquartile range [IQR] 37-59 years) and 49.9 years (IQR 32-60 years), respectively. The median relative telomere length in SLE patients was 0.97 (IQR 0.47-1.57), compared to 1.53 (IQR 0.82-2.29) in controls (P = 0.0008). We then extended our cohort to measure telomere length in 164 SLE patients. Shorter telomere length was associated with Ro antibodies (β ± SE -0.36 ± 0.16; P = 0.023), and longer telomere length was associated with steroid therapy (0.29 ± 0.14; P = 0.046). We also noted an association of longer telomere length with increasing body mass index (β ± SE 0.07 ± 0.01; P < 0.0001) and tobacco smoking (0.64 ± 0.26; P = 0.016), as well as with the presence of carotid plaque (0.203 ± 0.177; P = 0.032). CONCLUSION Telomere length is shortened in SLE patients compared to controls and does not appear to be a reflection of disease activity or immune cell turnover. Subsets of patients such as those positive for Ro antibodies may be particularly susceptible to premature biologic aging. The predictive value of telomere length as a biomarker of future risk of damage/mortality in SLE requires longitudinal evaluation.

Tofacitinib for Treatment of Rheumatoid Arthritis

The management of rheumatoid arthritis has seen a dramatic improvement with the introduction of a range of biological disease modifying anti-rheumatic drugs (DMARDs) in recent years. Nonetheless, a proportion of patients remain resistant or intolerant to multiple conventional and biological DMARDs, so innovative strategies are needed to offer patients new therapeutic options. Tofacitinib is the first of a new class of orally active DMARDs, with immunomodulating effects through inhibition of intracellular Janus kinase (JAK) pathways. It has been recently licensed for treatment of adults with moderate to severe RA in the US, Japan, and Russia. In this review the authors evaluate the efficacy and safety of tofacitinib in RA, focusing predominantly on the phase 3 study data.

Comparative clinical utility of once-weekly subcutaneous abatacept in the management of rheumatoid arthritis.

Biologic therapies in rheumatoid arthritis are now part of standard practice for disease that proves difficult to control with conventional disease-modifying anti-rheumatic drugs. While anti-tumor necrosis factor therapies have been commonly used, other targeted biologic therapies with different mechanisms of action are becoming increasingly available. Abatacept is a recombinant fusion protein that inhibits the T-cell costimulatory molecules required for T-cell activation. Intravenous abatacept has good clinical efficacy with an acceptably low toxicity profile in rheumatoid arthritis, but the subcutaneous mode of delivery has only recently become available. In this article, we examine key efficacy and safety data for subcutaneous abatacept in rheumatoid arthritis, incorporating evidence from five large Phase III studies that included people with an inadequate response to methotrexate and an inadequate response to biologic disease-modifying anti-rheumatic drugs. The results demonstrate that subcutaneous abatacept has efficacy and safety comparable with that of intravenous abatacept and adalimumab. In addition, inhibition of radiographic progression at year 1 in relatively early rheumatoid arthritis is consistent with that of adalimumab. Subcutaneous abatacept is well tolerated, with very low rates of discontinuation in both short-term and long-term follow-up.

THU0136 Long Term Outcomes of Stopping Tumour Necrosis Factor Inhibitors (TNFI) in Patients with Established Rheumatoid Arthritis (RA) Who are in Sustained Remission: Is it Worth the Risk?

Background Previous research has shown that cessation of TNFi in patients with established RA who are in sustained remission is associated with an increased risk of flare. However, it is still unknown whether the reintroduction of TNFi in those who flare following cessation has any effects on long term outcome. Objectives 1-To assess the 12 month outcomes following cessation of TNFi in patients with established RA who are in sustained remission (DAS28 < 2.6) at baseline. 2- To compare patients who restated TNFi after unsuccessful cessation with those who continued treatment. Methods Patients in sustained remission (DAS28 < 2.6) for ≥ 6 months who were on a combination of methotrexate (MTX) and TNFi as per NICE guidance were recruited. The biologic agent was stopped in patients who consented to remain on MTX monotherapy and treatment was restarted if a flare occurred (defined as >1.2 deterioration in DAS28 or worsening of symptoms requiring escalation of treatment). Clinical, serological, and imaging (ultrasound of hands and wrists) outcomes were undertaken at baseline and 12 months. Patients who continued on combination therapy throughout the 12 months (CONT) were compared to those who unsuccessfully stopped and then restarted TNFi due to flare (STOP). Results 18 patients (mean age 53.8 years) out of a total of 69 were allocated to STOP arm and 51 (mean age 48.5 years) to CONT arm. Baseline characteristics were not different between the two groups. 15/18 (83.3%) of patients flared in the cessation group compared to 13/51 (25.5%) in those who continued the biologic (p<0.001). The median time to flare was significantly shorter in those who stopped the biologic (12 vs. 26 weeks, p < 0.001). Patients flared in the CONT group for various reasons including missing a treatment dose, but the majority of flares were mild and managed symptomatically, although one patient required a change of biologic due to secondary non-response. DAS28 remission rates at month 12 were significantly greater in CONT compared to STOP group (85.7% vs. 57.1%; OR 5.35 [95%CI 1.25-22.7], p=.023). Mean scores of DAS28 (1.82 v 2.28), SDAI (4.45 v 6.83), HAQ (.60 V .93), CRP (3.2 v 4.6), and power Doppler (2.18 v 3.82) all favoured patients who continued biologic, although the results were not statistically significant. Conclusions Successful cessation of TNFi is rare in patients with established RA despite sustained remission at baseline. Re-introducing the biologic following flare is associated with poorer outcomes and lower rates of DAS28 remission at long term follow up when compared to continuing the treatment. The small sample size of STOP group in this study was due to the considerable risk of flare on cessation of the biologic, which made it unethical to continue recruiting into that arm. This may have affected the statistical significance of individual parameters other than DAS28 remission rates. It is unknown whether the failure to re-establish remission in some patients after TNFi re-introduction is related to development of drug antibodies during biologic holiday. Disclosure of Interest C. Rakieh: None Declared, B. Saleem: None Declared, K. Takase: None Declared, J. Nam: None Declared, H. Keen: None Declared, R. Wakefield: None Declared, P. Emery Consultant for: Honoraria/Advisory Board: Abbot, Pfizer, Roche, Chugai, BMS, UCB, MSD

Abatacept reduces disease activity and ultrasound power Doppler in ACPA-negative undifferentiated arthritis: a proof-of-concept clinical and imaging study.

Objectives. No proven treatment exists for ACPA-negative undifferentiated arthritis (UA). The aim of this study was to evaluate whether abatacept is effective in treating poor prognosis, ACPA-negative UA, including its effect on power Doppler on US (PDUS). Methods. A proof-of-concept, open-label, prospective study of 20 patients with DMARD-naïve, ACPA-negative UA (⩾2 joint synovitis) and PDUS ⩾ 1 with clinical and 20-joint US (grey scale/PDUS) assessments at baseline, 6, 12, 18 and 24 months. All patients received 12 months of abatacept (monotherapy for minimum first 6 months). The primary end point was a composite of the proportion of patients that at 6 months achieved DAS44 remission, a maximum of one swollen joint for at least 3 consecutive months and no radiographic progression (over 0–12 months). Results. Twenty of the 23 patients screened were enrolled [14 female; mean (S.D.) age 53.4 (11.2) years, symptom duration 7.5 (0.9) months]. Two (10%) achieved the composite primary end point. A reduction in the mean (S.D.) DAS44 was observed from a baseline value of 2.66 (0.77) to 2.01 (0.81) at 6 months and to 1.78 (0.95) at 12 months. The DAS44 remission rates were 6/20 (30%; 95% CI: 15, 51%) at 6 months and 8/20 (40%; 95% CI: 22, 62%) at 12 months. A striking decrease in the median (interquartile range; IQR) total PDUS score was noted from 10 (4–23) at baseline to 3 (2–12) and 3 (0–5) at 6 and 12 months, respectively. Conclusion. This report is a first in potentially identifying an effective therapy, abatacept monotherapy, for poor-prognosis, ACPA-negative UA, supported by a clear reduction in PDUS. These data justify evaluation in a controlled study.

Emergence of proinflammatory autoreactive T-cell responses in preclinical rheumatoid arthritis

Abstract Background 5 million people suffer from rheumatoid arthritis (RA) and every year 25 000 people will develop this disease in the UK. In an emerging model, the pathogenesis of RA can be understood as a development of sequential phases that precede clinically apparent disease. Autoimmunity with anti-immunoglobulin G rheumatoid factors (RF) and anti-citrullinated protein antibodies (ACPA) can be detected in the blood up to 13 years before onset of clinical synovitis (joint swelling). Regulatory T cells (Tregs) are an important component of the immune system that dampen and limit damage caused by excessive immune activity, and their dysfunction is found in RA. We aimed to identify autoreactive T cells to a known RA-associated antigen and to determine whether the quality of the response (regulatory vs inflammatory) is associated with health, preclinical RA, and RA. Methods 41 patients were recruited from studies in the Division of Rheumatic & Musculoskeletal Disease, University of Leeds. 21 patients had preclinical RA (ACPA-positive with arthralgia but no evidence of clinical synovitis) and 20 had RA (ACPA-positive RA). Healthy volunteers (19 employees of the University of Leeds and Leeds Teaching Hospitals Trust) were controls. We measured T-cell responses to the RA-associated autoantigen, citrullinated vimentin (CitVim): peripheral blood mononuclear cells were incubated with peptide pools covering the entire sequence of CitVim for 72 h. Interleukin (IL) 10 (regulatory) and interferon (IFN) γ (inflammatory) responses were measured by ELISPOT. The study has ethics approval from the Leeds (West) Research Ethics (references 06/Q1205/169 and 04/Q1206/107). Findings Autoreactive T-cell reactivity was detected in healthy controls, preclinical RA, and RA. However, the quality of this response differed between the groups: health was associated with IL-10 responses, whereas in preclinical RA there was an emergence of IFN-γ responses, which were also present in a proportion of RA patients (healthy volunteers, preclinical RA, and RA with IFN-γ responses were 11% [2/19], 32% [7/21], and 45% [9/20] and with IL-10 responses were 89% [17/19], 68% [14/21], and 55% [11/20], respectively; χ 2 7·516, df=2, p=0·0233). Looking at the balance of regulation and inflammatory responses, we found a sequential reduction in the ratio of IL10 to IFNγ from health to preclinical RA to RA. There was a significant effect of disease status on the ratios with significant difference between health and preclinical RA and health and RA. The IL10:IFNγ ratio for healthy controls was significantly different from the preclinical RA and the RA groups (mean 1·255 [SD 1·383] vs 0·3892 [1·548] vs 0·1943 [1·395], ANOVA and Tukey test F =5·275, p=0·0062. We also found that the magnitude of the IFN-γ CitVim response increased after neutralising IL10 in four patients with preclinical RA. Interpretation We report that a distinction can be made between health, preclinical RA, and RA in the context of the quality of autoimmune T-cell responses. We have found a sequential change in the balance of IL-10 and IFN-γ responses from health (which favours a regulatory phenotype) to preclinical RA and then to established RA (which favours a relatively inflammatory phenotype). We have also shown that autoreactive IL-10 Treg responses are actively inhibiting IFN-γ responses in patients with preclinical RA. It is plausible that such a regulatory T-cell response plays an important part in preventing disease in health and also progression to disease in preclinical RA. Perhaps approaches to strengthen this regulatory response in people with preclinical disease could prevent progression to disease. Such immunomodulatory approaches are used in allergy practice and in studies in the prevention of diabetes. Funding None.

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

AB0259 Anti-Carbamylated Protein (ANTI-CARP) Antibodies Are Present in the Sera of Individuals at Different Stages of the Inflammatory Arthritis Continuum

Background In inflammatory arthritis (IA) the spectrum varies from individuals “at-risk” to the full rheumatoid arthritis phenotype. ACPA are highly specific for RA and associated with severe progression. Recently, anti-carbamylated protein (anti-CarP) antibodies have been identified in the sera of individuals with RA and prior to diagnosis, predicting a risk of persistence and possibly a more severe disease course [1,2]. Objectives To assess the presence of anti-CarP antibodies at different stages of the IA continuum; to establish association with other antibodies; to evaluate its role in diagnosis and association with disease progression. Methods 647 individuals were assayed for anti-CarP. This included individuals who were ACPA positive with arthralgia but no clinical synovitis, individuals with IA signs and/or symptoms, newly diagnosed RA (2010 ACR/EULAR criteria) and an established disease cohort. Anti-CarP antibodies of the IgG isotype were detected using carbamylated fetal calf serum (Ca-FCS) as the capture antigen as described before [1]. A reference range for anti-CarP positivity was determined using 205 healthy Dutch blood donors. ACPA status was determined using cyclic citrullinated-peptide 2 (CCP2) commercial assays and recommended cut offs. The anti-CarP-assay was performed by investigators not aware of the diagnosis. Results Table 1 details Anti-CarP positivity in the 4 groups: ACPA+ arthralgia, IA symptoms, new RA and established RA; and in the latter 3 groups, Anti-CarP rates in the ACPA negative subgroups. Anti-CarP antibodies were observed in both anti-CCP positive and anti-CCP negative patients. Table 1. % Anti-CarP positivity ACPA+ arthralgia IA symptoms New RA Established RA ACPA− n/a 6.0% (10/167) 16.4% (9/55) 13.3% (4/30) ACPA+ 40.6% (50/123) 28.0% (7/25) 53.3% (81/152) 33.0% (31/94) Total 40.6% (50/123) 8.8% (17/193) 43.5% (90/207) 28.2% (35/124) In the ACPA+ arthralgia group, 54 (43.9%) subjects progressed to clinical inflammatory arthritis during follow-up (range 5-61months) of whom 29 (53.7%) were anti-CarP positive. 48/123 individuals had CCP titre >3x limit of normal; all but one was anti-CarP positive. On a univariable basis Anti-CarP positivity was weakly associated with progression at 12 months and progression (ever). Conclusions Anti-CarP is present in patients at different stages of the IA continuum at variable proportions. In a proportion of ACPA negative individuals it may offer an additional marker for persistent disease. Correlation with disease activity will determine the clinical utility of this test in an inflammatory arthritis clinic. References Shi J, Knevel R, Suwannalai P, van der Linden MP, Janssen GM, van Veelen PA, et al. Autoantibodies recognizing carbamylated proteins are present in sera of patients with rheumatoid arthritis and predict joint damage. Proceedings of the National Academy of Sciences of the United States of America. 2011 Oct 18; 108(42):17372-17377. Shi J, van de Stadt LA, Levarht EW, Huizinga TW, Hamann D, van Schaardenburg D, et al. Anti-carbamylated protein (anti-CarP) antibodies precede the onset of rheumatoid arthritis. Annals of the rheumatic diseases. 2013 Dec 13. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.2577

THU0114 Abatacept as an effective treatment in the management of poor prognosis ACPA negative undifferentiated arthritis

Background A goal in the management of undifferentiated arthritis (UA) is to prevent its progression to rheumatoid arthritis (RA). A preliminary study suggested abatacept may delay progression of ACPA positive UA to RA1. No therapy (including MTX) has been shown to be effective in ACPA negative patients however. Power Doppler (PD) on ultrasound (US) is a powerful predictive factor of persistent inflammatory arthritis in these patients2. Objectives To evaluate whether Abatacept is effective in poor prognosis ACPA negative patients and its effect on US PD Methods In this pilot, open-label, prospective study, patients with ACPA negative UA (≥2 joint synovitis) and PD ≥1 were recruited. Additional key inclusion criteria: symptom duration ≥3 months, ≤18 months and DMARD-naive. All patients receive 12 months of abatacept monotherapy. Primary endpoint is proportion of patients in DAS44 remission at 6 months. Clinical and US [Grey Scale (GS)/PD] assessments are undertaken at baseline, 6, 12, 18, 24 months. 20 joints are scanned, each assigned GS and PD score (maximum of 3); giving maximum totals scores of 60 for each. Descriptive and non-parametric statistics has been applied. Results 20/23 patients screened were enrolled [15 female, 5 male; mean (SEM) age 53.2 (2.48) years, symptom duration 7.5 (0.9) months]. 19/20 and 13/20 have reached 6 and 12 months respectively. Significant median DAS44/DAS28 reduction was seen from baseline to 6 and 12 months (Table 1). At month 6, 6/19 (32%) achieved DAS28 remission; 5/19 (26%) DAS44 remission; at 12 months, 6/13 (46%; 1 missing value) achieved DAS28 remission; 5/13 (39%) DAS44 remission. Small GS and PD reduction was seen at 6 months but significant PD reduction at 12 months (Table 1). Of patients in remission the median (range) PD fell from 5 (2-23) at baseline to 1.0 (1-12) and 2.0 (0-8) at 6 and 12 months respectively. Table 2 details change in PD at 6 months based on baseline number of PD positive joints. Conclusions This preliminary report suggests abatacept monotherapy confers clinical improvement in poor prognosis ACPA negative UA. It also demonstrates the ability of abatacept to reduce US PD signal, particularly in patients with higher baseline PD activity, consistent with higher burden of inflammatory disease. Complete data should provide additional insights. This study is supported by Bristol Myers Squibb. References Emery P, et al. Impact of T-cell costimulation modulation in patients with undifferentiated inflammatory arthritis or very early rheumatoid arthritis: a clinical and imaging study of abatacept (the ADJUST trial). Ann Rheum Dis. 2010; 69(3):510-6. Freeston J, et al. A diagnostic algorithm for persistence of very early inflammatory arthritis: the utility of power Doppler ultrasound when added to conventional assessment tools. Ann rheum Dis 2010; 69(2):417-9. Disclosure of Interest M. Buch Grant/Research support from: Bristol-Myers Squibb, Pfizer, Consultant for: Abbott, Roche, Bristol-Myers Squibb, J. Freeston: None Declared, C. Rakieh: None Declared, E. Middleton: None Declared, A. L. Tan: None Declared, D. Pickles: None Declared, J. Ward: None Declared, S. Horton: None Declared, S. Das: None Declared, R. Wakefield: None Declared, P. Emery Grant/Research support from: Bristol-Myers Squibb, Pfizer, Consultant for: Abbott, Roche, Bristol-Myers Squibb, Pfizer

Biologic drugs: properties and use in the treatment of RA

Steve Chaplin, Dr Chadi Rakieh and Professor Philip Conaghan provide an overview of the properties of biologics and their current recommended place in the treatment of RA. Copyright