A. Levitsky

Treat-to-target in systemic lupus erythematosus: recommendations from an international task force

The principle of treating-to-target has been successfully applied to many diseases outside rheumatology and more recently to rheumatoid arthritis. Identifying appropriate therapeutic targets and pursuing these systematically has led to improved care for patients with these diseases and useful guidance for healthcare providers and administrators. Thus, an initiative to evaluate possible therapeutic targets and develop treat-to-target guidance was believed to be highly appropriate in the management of systemic lupus erythematosus (SLE) patients as well. Specialists in rheumatology, nephrology, dermatology, internal medicine and clinical immunology, and a patient representative, contributed to this initiative. The majority convened on three occasions in 2012–2013. Twelve topics of critical importance were identified and a systematic literature review was performed. The results were condensed and reformulated as recommendations, discussed, modified and voted upon. The finalised bullet points were analysed for degree of agreement among the task force. The Oxford Centre level of evidence (LoE, corresponding to the research questions) and grade of recommendation (GoR) were determined for each recommendation. The 12 systematic literature searches and their summaries led to 11 recommendations. Prominent features of these recommendations are targeting remission, preventing damage and improving quality of life. LoE and GoR of the recommendations were variable but agreement was >0.9 in each case. An extensive research agenda was identified, and four overarching principles were also agreed upon. Treat-to-target-in-SLE (T2T/SLE) recommendations were developed by a large task force of multispecialty experts and a patient representative. It is anticipated that ‘treating-to-target’ can and will be applicable to the care of patients with SLE.

Biologics in SLE: towards new approaches.

In recent years the use of biologic therapies in the management of systemic lupus erythematosus (SLE) has increased, and a number of clinical trials have highlighted both the potential and the pitfalls in the development of such agents. Many investigators reported that the off-label use of rituximab seemed promising in patients with refractory disease, but randomised trials with this agent failed. Likewise, the theoretical appeal of the co-stimulation blocker abatacept could not be confirmed in two clinical trials. Various considerations and post hoc analyses nonetheless suggest that these two biologics might have a role in the treatment of SLE. The anti-B-lymphocyte stimulator (anti-Blys) antibody belimumab demonstrated efficacy and safety in two large randomised trials and became the first approved biologic for lupus. Use in clinical practice has increased slowly, in part, due to uncertainty over which patients should be treated with this agent and in what stage of the disease. Finally, several other biologic agents are currently in advanced stages of clinical development for SLE. The overall picture that emerges is one of optimism that advances in SLE therapy will be realised through the targeted use of an increasing number of biologics.

Detection of clinically manifest and silent synovitis in the hands and wrists by fluorescence optical imaging

Objectives The correct identification of synovitis is critical for achieving optimal therapy results. Fluorescence optical imaging (FOI) is a novel modality based on the use of an intravenous fluorophore, which enables fluorescent imaging of the hands and wrists with increased focal optical signal intensities in areas of high perfusion and/or capillary leakage. The study objective was to determine the diagnostic utility of FOI in detecting apparent and clinically non-apparent active synovitis. Methods Bilateral hand and wrist joints (n=872) of 26 patients with inflammatory arthritis assessed by standard clinical examination, musculoskeletal ultrasound (MSUS) and FOI were studied. Synovitis was defined as tender and swollen joints on clinical examination, presence of synovial thickening and intra-articular Doppler signals on MSUS, and abnormal focal optical signal intensities on FOI, respectively. Subclinical synovitis was defined as being clinically non-apparent, but positively inflamed on MSUS. Results Depending on the standard used to define inflammation, FOI ranged from 73–83% sensitive and 83–95% specific for detecting manifest synovitis. For detecting clinically silent synovitis, the sensitivity, specificity and positive and negative predictive values of FOI were 80%, 96%, 77% and 97%, respectively. Conclusions The high degree of agreement between MSUS and FOI suggest its use in clinical practice, especially when MSUS is not available, in order to identify synovitis earlier and with greater confidence. FOI may be particularly useful in identifying patients with clinically non-apparent joint inflammation of the hands and/or wrists.

Obesity is a strong predictor of worse clinical outcomes and treatment responses in early rheumatoid arthritis: results from the SWEFOT trial

Objectives The aim of this paper was to analyse the impact of obesity, in addition to known predictors, on disease outcome in early rheumatoid arthritis (RA). Methods Body mass index (BMI) was available in 260 patients from the Swedish pharmacotherapy trial (SWEFOT). Differences in disease activity (DAS28), functional impairment (HAQ), pain (Visual Analogue Scale, VAS-pain) and radiographic damage were evaluated over 24 months between BMI categories (obese BMI >30, n=43; overweight BMI=25–29.9, n=74; normal BMI <25, n=143) using non-parametric testing. Predictors of European League Against Rheumatism non-remission (DAS28 ≥2.6) at 24 months of follow-up were evaluated using binary univariate and multivariate logistic regression. Results Obesity at baseline was associated with worse continuous-scale clinical outcomes over 24 months (DAS28, HAQ and VAS-pain at last visit: obese vs normal: p<0.001; obese vs overweight: p<0.05). Furthermore, obese patients compared with non-obese patients had significantly greater odds of non-remission at 24 months (adjusted OR (aOR) 5.2; 95% CI 1.8 to 15.2). Other independent predictors were female sex (aOR 2.6; 95% CI 1.1 to 5.8), current smoking (aOR 2.6; 95% CI 1.1 to 6.3) and HAQ (per-unit increase, aOR 1.9; 95% CI 1.1 to 3.4). The pattern was similar among seropositive and seronegative patients; and in the subgroups of methotrexate responders and patients randomised at 3 months to add-on of sulfasalazine+hydroxychloroquine, although not significant with add-on of infliximab. Obesity had no independent association to radiographic progression. Conclusions In this early RA trial reflecting today’s standard treatment, obesity, in addition to sex, smoking and functional impairment strongly lowered the chance of attaining good clinical outcomes, including remission, today’s treatment goal. This highlights the importance of considering lifestyle modification as one of the cornerstones of RA care. Trial registration number NCT00764725; Post-results. WHO database at the Karolinska University Hospital: CT20080004.

A5.02 Fluorescence optical imaging coupled with ultrasound radiography for detecting subtle hand inflammation in early rheumatoid arthritis

Objectives Fluorescence Optical Imaging (FOI) is an emerging modality that uses an intravenous fluorophore to display altered microcirculation (abnormal perfusion/capillary leakage) in synovial tissues in the hands. FOI can be analyzed visually (FOI-v) or by using automated Disease ACTivity (DACT). Using musculoskeletal ultrasound (MSUS) as a validated reference measure, we previously showed FOI to be highly sensitive and specific in detecting clinically manifest and silent synovitis in patients with various rheumatic diseases. Here, we analyze whether the same is true for early rheumatoid arthritis (eRA). Methods Hands and wrists ineRA patients were assessed by clinical examination, MSUS and FOI-DACT. Active inflammation was defined as having synovial-hypertrophy/effusions and intra-articular Doppler signaling on MSUS, and as increased optical-intensities on FOI-v. Scores on DACT ≥ 1 was considered indicative of disease activity. Results 39 eRA patients were studied [72% females, 56% previous/current smokers, 54% RF(+) and 69% ACCP(+)]. Of the 1326 joints in these patients, 303 were inflamed by clinical assessment, 380 by MSUS, and 400 by FOI-v. The percentages of patients and (mean ± SD) joints by clinical, MSUS and FOI-v were 69%(7.8 ± 8.1), 95%(9.7 ± 7.7), and 95%(10.3 ± 7.2), respectively. Using MSUS as reference, FOI-DACT was 95%(35/37) accurate in identifying patients with active disease, 24%(9/37) of whom had erosive RA. Good correlations noted between MSUS and FOI-v (rho = 0.803; p < 0.001), clinical assessment and FOI-v (rho = 0.732; p < 0.001), and MSUS and clinical (rho = 0.793; p < 0.001). The sensitivity, specificity, NPV and PPV of inflammation by FOI-v was 81%(308/380), 90%(854/946), 61%, and 96% respectively. Of the clinically negative but MSUS positive (145/1023) joints, 68%(98/145) were also FOI-v positive. Remarkably, one patient had 15 joints that were FOI-DACT positive and MSUS negative, but a month later, the same joints became MSUS positive. Although the wrists and MCPs were frequently inflamed, DIP joint inflammation was also seen in 34 and 14 joints in 12 patients by FOI-DACT and MSUS, respectively. Nine of these patients had osteoarthritis by conventional radiography. Conclusions As reported for established rheumatic diseases, here we show high correlations and agreements between clinical examination, MSUS and FOI-v in detecting subtle inflammation in early RA as well. Moreover, DACT-FOI emerges as a useful automated quantitative scoring method for synovial inflammation in eRA. Reference Kisten Y, Györi N, af Klint E, et al. 2015 Detection of clinically manifest and silent synovitis in the hands and wrists by fluorescence optical imaging. RMD Open. 1: e000106. doi:10.1136/ rmdopen-2015-000106(http://rmdopen.bmj.com/content/1/1/e000106.full.pdf+html)

FRI0062 Obesity Is Associated with Worse Clinical Outcomes Yet Limited Radiographic Progression in Early Rheumatoid Arthritis: Table 1.

Background In RA, being overweight or obese has previously been shown to be associated with worse clinical outcomes (1, 2), yet also less radiographic damage (2, 3). Objectives To confirm if body mass index (BMI) is associated with worse clinical disease activity or inversely associated with radiographic outcomes in early RA. Methods BMI, categorized as normal (<25, n=141), overweight (25–29.9, n=74), and obese (≥30, n=43), was available in 258 patients who were enrolled in the Swedish pharmacotherapy (SWEFOT) trial. After initial methotrexate for 3 months, non-responders were randomized to triple therapy or anti-TNF therapy, while responders continued on methotrexate. Disease activity (DAS28), functional impairment (HAQ), VAS-pain, and radiographic damage (Sharp van der Heijde score, SHS) were evaluated regularly. Here, results are shown at 24 months of follow-up. Results Treatment allocation and baseline outcome measures did not differ across the BMI categories. In a dose-response manner, higher BMI at baseline was associated with worse clinical outcomes over 24 months (DAS28, HAQ, and VAS-pain) (Table). Patients with normal (58%) or overweight (50%) BMI had a proportionally greater chance of attaining 24-month clinical remission (DAS28<2.6) than obese patients (23.1%) (OR 3.2 [95% CI 1.6–6.3], p<0.001; OR 2.2 [95% CI 1.2–4.1], p=0.007, respectively). Among absolute radiographic scores, no significant differences were observed, yet radiographic progression (ΔSHS≥1, baseline-24 months) was halted more frequently (56.3%) among obese patients than normal/overweight patients combined (37.6%) (OR 1.9 [95% CI 1.0–3.6], p=0.049) (obese vs. normal (40%), OR 1.7 [95% CI 0.9–3.1], p=0.101; obese vs. overweight (32.7%), OR 1.8 [95% CI 1.1–3.2], p=0.032).Table 1. Outcome measures after 24 months of disease-modifying antirheumatic agents Outcomes [Medians (IQR)] Normal (n=141) Overweight (n=74) Obese (n=43) P valuea DAS28 2.4 (1.7, 3.4)* 2.6 (2.2, 3.8)† 3.2 (2.8, 4.8)†* p<0.001 HAQ 0.3 (0.0, 0.8)* 0.5 (0.0, 1.0)† 0.8 (0.4, 1.3)†* p<0.001 VAS-pain 18.5 (6.0, 35.0)* 25.0 (8.0, 47.0)† 39.0 (22.0, 61.0)†* p<0.001 ESR 10.0 (6.0, 18.0)* 13.5 (8.0, 23.0) 18.0 (11.0, 26.0)* p=0.008 SHS 7.0 (2.0, 16.3) 6.5 (2.0, 14.0) 5.0 (0.8, 13.0) p=0.519 aKruskal-Wallis test (individual comparisons: Mann-Whitney U test; post-hoc comparisons: Dunn-Bonferroni (DB) correction). †Overweight vs. Obese: DAS28, p=0.012 (DB, p=0.020; adjusted, p=0.060); HAQ, p=0.030 (DB, p=0.021; adjusted. p=0.062); VAS Pain, p=0.025 (DB, p=0.023, adjusted: p=0.069). *Normal vs. Obese: Mann-Whitney or DB + adjustment, p<0.001 (erythrocyte sedimentation rate (ESR): p=0.003 (DB, p=0.003, adjusted: p=0.009)). Conclusions Obesity at diagnosis was found to be a strong predictor of worse long-term clinical outcomes in early RA – including disease activity, functional impairment, and pain; thus confirming previous findings. Nonetheless – as has also been previously shown – obesity was associated with a better chance of halting radiographic progression. References Sandberg ME, et al. Ann Rheum Dis. 2014 Nov;73(11):2029–33; Vidal C, et al. J Rheumatol. 2015 Dec;42(12):2261–9; Baker JF, et al. Ann Rheum Dis. 2014 Nov;73(11):1923–8 Disclosure of Interest A. Levitsky: None declared, S. Saevarsdottir: None declared, K. Brismar: None declared, K. Hambardzumyan: None declared, C. Lourdudoss: None declared, R. van Vollenhoven Grant/research support from: AbbVie, BMS, GSK, Pfizer, Roche, and UCB, Consultant for: AbbVie, Biotest, BMS, Crescendo, GSK, Janssen, Lilly, Merck, Pfizer, Roche, UCB, and Vertex

SAT0093 Hand Joint Inflammation on Fluorescence Optical Imaging Reveal Distinct Patterns in Seropositive and Seronegative Early Rheumatoid Arthritis

Background Detection of abnormal Rheumatoid Arthritis (RA) related autoantibodies, Rheumatoid Factor (RF) and Anti-Citrullinated Peptide Antibody (ACPA), along with Musculoskeletal ultrasound (MSUS) play a critical role in the diagnosis of early RA (eRA). Fluorescence optical imaging (FOI) is an emerging modality designed for the hands and wrists that detects subclinical hand joint inflammation1 and may therefore prove valuable in the assessment of eRA. Objectives Here, we analyzed the FOI results of eRA patients and investigate whether patterns of hand joint inflammation may distinguish seropositive from seronegative RA. Methods In FOI, Inflammation is considered positive, when altered microcirculation (capillary leakage/perfusion) is seen as abnormally increased focal optical signal intensities by visual inspection of the entire image series in real-time (360 seconds all 34 joints: 3 wrists, 5 MCPs, 5 PIPs and 4 DIPs, bilaterally are evaluated using post-processing imaging techniques). Unsupervised ascending hierarchical clustering was used to identify clusters of patients with different patterns of joint involvement in FOI. The robustness of the clustering was verified using another clustering method (k-means), and agreement between the 2 methods was assessed using Cohens kappa. Baseline clinical and biological characteristics of patients were compared between the clusters using non-parametric tests. Results Out of 1326 joints of 39 eRA patients (26 females; 9 with erosive RA; 54% RF+; and 69% ACPA+), 400 (30%) were considered positively inflamed by FOI. The mean (±SD) number of active joints detected by FOI was 10.3 ± 7.2. Clustering of joint involvement according to the FOI distinguished 2 separate clusters of patients: Cluster1 (n=29) and Cluster2 (n=10). The proportion of seropositive patients was significantly higher in cluster 1 versus cluster 2 (26/29 versus 3/10, p<0.01) (figure). The distribution of inflammation throughout the joints, except for right MCP2, PIPs 5, left MCP1 & DIPs in cluster 2 displayed distinguishable patterns (p<0.05) compared to cluster 1, which showed joint inflammation to be largely concentrated around wrists, right MCP2, bilateral MCP3, and to a lesser degree around PIPs 2–4, and left MCP2. The DIPs showed no significant differences between clusters. Conclusions Two separate patterns of inflammatory joint involvement may be distinguished in early RA, using fluorescence optical imaging. The proportion of seropositive patients was significantly different between these patterns, suggesting that FOI identifies patterns of joint involvement that are different for seropositive and seronegative RA. References Kisten Y, Györi N, af Klint E, et al. 2015 Detection of clinically manifest and silent synovitis in the hands and wrists by fluorescence optical imaging. RMD Open 2015;1: e000106. doi:10.1136/ rmdopen-2015-000106 (http://rmdopen.bmj.com/content/1/1/e000106.full.pdf+html) Disclosure of Interest None declared

AB0981 Hand Joint Inflammation in Early Ra: Clinical Ultrasound and Fluorescence Optical Imaging Diagnostics

Background Altered microcirculation (abnormal perfusion/capillary leakage) of synovial tissue can be detected early using Fluorescence Optical Imaging (FOI). FOI utilizes an intravenous fluorophore1,2 that displays high-resolution hand images that can be analyzed visually (FOI-v) in real-time, or by using digital Disease ACTivity (DACT) scoring methods. We previously reported FOIs sensitivity and specificity in detecting silent synovitis in various rheumatic diseases1. Objectives Here, we test the diagnostic performance of FOI-DACT in detecting subtle hand joint inflammation in early rheumatoid arthritis (eRA), as compared to clinical evaluation and MusculoSkeletal UltraSound (MSUS). Methods Fingers and wrists of patients with eRA were assessed by clinical examination, MSUS and FOI-DACT imaging. Inflammation was defined as having synovial hypertrophy/effusions and intra-articular Doppler signaling on MSUS, and as increased optical intensities on FOI-v. Scores of DACT≥1 were considered indicative of disease activity. Results 1326 joints of 39 eRA patients [72% females, 56% previous/current smokers, 54% RF(+) and 69% ACPA(+)] were studied. The incidence and mean number ±SD of joints inflamed by clinical, MSUS and FOI-v were 23% (7.8±8.1), 29% (9.7±7.7) and 30% (10.3±7.2), respectively. Using MSUS as a reference, FOI-DACT was 95% (35/37) accurate in identifying patients with active disease, 24% (9/37) of whom had erosive RA. High correlations and agreements emerged between MSUS and FOI-v (r=0.803, p<0.001; kappa±SE:0.70±0.02 [95% CI 0.67–0.75]), clinical and FOI-v (r=0.732, p<0.001; kappa±SE:0.56±0.03 [95% CI 0.51–0.61]) and MSUS and clinical (r=0.793, p<0.001; kappa±SE:0.59±0.03 [95% CI 0.54–0.64]). The sensitivity, specificity, NPV and PPV of inflammation by FOI-v was 81% (308/380), 90% (854/946), 61%, and 96% respectively. Of the clinically negative but MSUS positive (145/1023) joints, 68% (Subclinical: 98/145) were also FOI positive. Remarkably, one patient had 15 joints that were FOI-DACT positive and MSUS negative, but a month later, the same joints became MSUS positive. Although the wrists and MCPs were frequently inflamed, DIP joint inflammation was noted in 12 patients by FOI-DACT and MSUS. Nine of these patients had osteoarthritis by conventional radiography. Conclusions In early RA, Fluorescence Optical Imaging (FOI) coupled with digital Disease ACTivity (DACT) scoring correlates well with MSUS, and has a high positive predictive value. FOI-DACT emerges as a useful automated quantitative scoring method for synovial inflammation, and may be used in monitoring the effects of therapy. References Kisten Y, Györi N, af Klint E, et al. 2015 Detection of clinically manifest and silent synovitis in the hands and wrists by fluorescence optical imaging. RMD Open 2015;1: e000106. doi: 10.1136/rmdopen-2015-000106 (http://rmdopen.bmj.com/content/1/1/e000106.full.pdf+html) Glimm AM, Werner SG, et al. Analysis of distribution and severity of inflammation in patients with osteoarthitis compared to rheumatoid arthritis by ICG-enhanced fluorescence optical imaging and musculoskeletal ultrasound: a pilot study. Annals of the Rheumatic Diseases. Published online Aug. 26, 2015. (http://dx.doi.org/10.1136/annrheumdis-2015-207345). Disclosure of Interest None declared

Predicted vs. observed radiographic progression in early rheumatoid arthritis (POPeRA): results from a randomized trial

Objectives: The aim of this study was to apply a previously published method for evaluating radiographic progression, namely, predicted vs. observed radiographic progression in early rheumatoid arthritis (POPeRA), to the Swedish pharmacotherapy (SWEFOT) trial. Method: In SWEFOT, 487 patients with eRA were given methotrexate (MTX), and non-responders were randomized to group A [triple therapy: MTX + sulfasalazine (SSZ) + hydroxychloroquine (HCQ)] and group B [anti-tumour necrosis factor (anti-TNF) therapy: MTX + infliximab]. Responders continued on MTX. Predicted progression for 343 eligible patients was calculated based on the baseline total Sharp/van der Heijde score (SHS) divided by symptom duration, compared to observed progression at 12 and 24 months. Results: Observed radiographic progression was reduced from predicted by a mean of 50.1% (A), 72.3% (B), and 73.9% (MTX) at 12 months and by 87.2, 89.8, and 87.8% at 24 months, respectively. Among completers, reductions of 56.7% (A) and 76.5% (B) at 12 months and of 91.0% and 96.0% at 24 months, respectively, were observed. At 12 months, there were no significant between-group differences. At 24 months, progression was reduced more in group B than in group A (first quartile difference 8.5% favouring group B) and in MTX [n = 316, 89.8% (sd ± 32.0) vs. 87.2% (± 32.2), p = 0.021; vs. 87.8% (± 27.8), p = 0.013, respectively]. Conclusions: The POPeRA method confirms the original SWEFOT finding in that anti-TNF therapy was statistically marginally superior (2.6%) to triple therapy in preventing radiographic progression at 24 months among initial MTX non-responders. The simulation provided through POPeRA may facilitate comparisons of the relative efficacy of various treatments in preventing radiographic progression.

A4.19 The quantification of digital activity fluorescence optical imaging of hand and wrist inflammation in rheumatic diseases

Background and objectives The objective detection and quantification of disease activity in its earliest pathophysiological stage is critical for achieving optimal therapy results. Fluorescence optical imaging (FOI) is a novel imaging modality for the hands and wrists, and automated quantification of the ensuing images using DACT (Disease ACTivity)-FOI as a novel algorithm representing activity. This study was designed to determine the utility of FOI as a diagnostic tool, and whether it could be used in lieu of colour/power Doppler ultrasound (US) to quantify and ascertain apparent and non-apparent active synovitis Materials and methods A total of 872 hand/wrist joints in 26 patients (18 female, 8 male, average age 51.5 years) with various rheumatic diseases (RA: 12, JIA, SLE, DM, FM, PsA and polyarthritis 1–2 each) were examined by standard clinical assessment, US and DACT-FOI. Joints swollen and tender or swollen only were considered clinically inflamed. Active synovitis was defined as having synovial thickening and Doppler activity on US. Joints positive by FOI displayed abnormal focal optical intensities by visual inspection. Silent synovitis was defined as showing synovitis by US but not clinically. The DACT value was digitally quantified per patient by an automated computer-based algorithm of the composite image (240 frames). After clinical, US and FOI positive joints for each hand were calculated, the sensitivity, specificity and kappa statistics computed and compared with the mean DACT values for all patients Results Out of 872 joints, 142 (16%) were inflamed clinically, 241 (28%) by US, and 229 (26%) by FOI. There was moderate agreement for synovitis detection between clinical examination and US (kappa 0.524 ± 0.033; 95% CI: 0.459–0.589) and between clinical examination and FOI (kappa 0.450 ± 0.035; 95% CI: 0.381–0.519). Of the 241 inflamed joints by US, 196 (81%) were also inflamed by FOI, while only 119 (49%) were inflamed clinically. Agreement between US and FOI in synovitis detection was good (kappa 0.773 ± 0.024; 95% CI: 0.725–0.821). Depending on the gold standard used to define inflammation, FOI was 73%–83% sensitive and 86%–95% specific for detecting synovitis. Out of 730 non-inflamed joints by clinical examination, 608 (83%) were non-inflamed by US and 605 (83%) were non-inflamed by FOI. Of these clinically non-inflamed joints, 122 (17%) were inflamed by US. For detecting silent synovitis, FOI was 80% (98/122) sensitive and 96% (581/608) specific. The number (mean ± SD) of active joints detected by clinical, US and FOI was 5.4 ± 7.6; 9.4 ± 9.8; and 9.3 ± 9.7 respectively, and the overall automated disease activity DACT-FOI was 4.3 ± 2.1. There was a strong positive correlation (r = 0.556; p = 0.003) between the clinical detection of synovitis and DACT-FOI. The mean DACT values also correlated significantly with US (r = 0.479; p = 0.013) and semi-quantitative FOI (r = 0.515; p = 0.007) Conclusion FOI and the automated analysis DACT-FOI were technically feasible with high reproducibility and agreement with clinical scoring and US. For detecting synovitis semi-quantitatively, FOI had a lower sensitivity but similar specificity compared to US. FOI may be particularly useful in identifying patients with clinically non-apparent hand/wrist inflammation (silent synovitis).