Hamed Rezaei

In early rheumatoid arthritis, patients with a good initial response to methotrexate have excellent 2-year clinical outcomes, but radiological progression is not fully prevented: data from the methotrexate responders population in the SWEFOT trial

Objective To investigate the 2-year clinical and radiological outcomes of patients with early rheumatoid arthritis (RA; symptom duration <1 year) who had initially responded well to methotrexate monotherapy. Methods In the SWEFOT trial, all 487 patients started methotrexate (target dose 20 mg/week). After 3–4 months, 147 had low disease activity, 28-joint based disease activity score (DAS28) ≤3.2. These patients were not randomly selected but were followed in regular care for 2 years. Clinical outcomes and radiographic progression according to the van der Heijde modified Sharp (SvdH) score were analysed. Results The majority of the 147 patients continued on methotrexate monotherapy. After 1 and 2 years, DAS28 remission was achieved in 59.6% and 71.8% and mean observed DAS28 values were 2.53 and 2.25, respectively. Despite the favourable clinical course, a proportion of the patients progressed radiographically with a mean (SD) increase in the SvdH score after 2 years of 3.90 (6.84). There was no significant difference in progression between patients in DAS28 remission versus not in remission (p=0.73). At baseline, approximately half the patients had no radiographic damage, while after 2 years the proportion was approximately 20%. Conclusion Most early RA patients who achieve low disease activity after 3–4 months of methotrexate monotherapy continue to have low disease activity during 2 years follow-up, and additional treatment is needed infrequently. Some radiological progression occurs in most patients, and may be marked or severe in some, even despite sustained DAS28 remission. Close monitoring for radiological progression is thus warranted.

Current smoking status is a strong predictor of radiographic progression in early rheumatoid arthritis: results from the SWEFOT trial

Objectives To study clinical predictors for radiographic progression after 1 year in an early rheumatoid arthritis (RA) trial. Methods In the SWEFOT trial population, disease modifying antirheumatic drug (DMARD) naïve RA patients started methotrexate; 3-month responders (DAS28 <3.2) continued (n=147), while non-responders were randomised to addition of sulfasalazine+hydroxychloroquine (n=130) or infliximab (n=128). X-rays were scored by the Sharp-van der Hejde score (SHS) method and radiographic progression was defined as a ≥5 increase after 1 year. Potential baseline predictors of radiographic progression were tested using multivariable logistic regression, adjusted for potential confounders. Results 79 of 311 patients with available radiographs at baseline and follow-up had radiographic progression. The following baseline parameters were independent predictors of radiographic progression at 1 year: baseline erosions (adjusted OR=2.29, 95% CI 1.24 to 4.24), erythrocyte sedimentation rate (adjusted OR per tertile increase=1.72, 95% CI 1.12 to 2.65) and C-reactive protein (adjusted OR per tertile increase=1.52, 95% CI 1.03 to 2.26). Current smoking was an independent predictor of radiographic progression (adjusted OR=2.17, 95% CI 1.06 to 4.45). These results remained after further adjustment for treatment strategy. Three-dimensional matrix including current smoking status, erosions and C-reactive protein tertiles showed a 12–63% risk gradient from patients carrying none compared with all predictors. Rheumatoid factor (RF)/anti-cyclic citrullinated peptide (anti-CCP) positivity did not significantly predict radiographic progression using SHS increase ≥5 as cut-off. In a secondary exploratory analysis using cut-off >1, both RF and anti-CCP positivity were significant predictors in the unadjusted, but not the adjusted analyses. The other parameters also remained significant using this lower cut-off. Conclusions In addition to previously described predictors, we identified smoking as a strong independent risk factor for radiographic progression in early RA. Trial registration number NCT00764725.

Evaluation of hand bone loss by digital X-ray radiogrammetry as a complement to clinical and radiographic assessment in early rheumatoid arthritis: results from the SWEFOT trial

BackgroundTo investigate hand bone loss (HBL) measured by digital X-ray radiogrammetry (DXR) in patients with early rheumatoid arthritis (RA) receiving different treatment regimens, and to evaluate if DXR change rates during the first 12 months correlate with radiological damage after 24 months.MethodsFrom the total SWEFOT trial population, 159 patients had hand radiographs correctly timed and taken with same modality to be analyzed with DXR. All patients started treatment with methotrexate. After 3–4 months, patients with DAS28 > 3.2 were randomized to add sulfasalazine and hydroxychloroquine (triple therapy) or infliximab (MTX + INF). Those with DAS28 ≤3.2 were followed in regular care. Radiographic progression over 24 months was scored according to the Sharp van der Heijde score (SHS) and defined as >5 increase in T-SHS over 24 months. Hand bone mineral density (BMD) was measured by DXR at inclusion and 12 months and a change ≥2.5 mg/cm2/month was used as a cut-off for HBL.ResultsIn the MTX responders, triple therapy, and MTX + INF groups, the proportions with HBL were 4.1%, 22.2% and 16.4%, respectively (p = 0.01), and the mean (SD) radiological progression in these groups was 3.91 (6.72), 7.40 (14.63) and 2.72 (4.55) respectively (p = 0.06). Patients with HBL had significantly greater risk for radiographic progression, compared with patients without HBL (odds ratio 3.09, 95% CI =1.20–7.79, p = 0.02).ConclusionsNon-responders to MTX had a significantly greater risk of HBL than MTX-responders, despite the add-on therapies. Patients with HBL during the 12 months had greater risk of radiographic progression after 24 months. Evaluation of HBL may help to identify patients who are at risk of radiographic progression.

Analysis of correlation and causes for discrepancy between quantitative and semi-quantitative Doppler scores in synovitis in rheumatoid arthritis

Objectives. The aim of this study was to evaluate the association between two semi-quantitative Doppler US scoring systems (SQS), and the quantitative scoring (QS) of Doppler pixel count. Methods. Adult patients with RA and inadequate clinical response to anti-rheumatic therapy were examined with musculoskeletal US (MSUS). Dorsal MSUS of the wrists, MCP and MTP 2–5 were performed. MSUS images with sign of synovitis were collected and the QS was measured. Five assessors blinded to the QS evaluated the images independently, according to either SQS method. Association between QS and SQS was studied using correlations and multilevel models taking into account the clustering of ratings at the rater, patient and joint levels. Results. Analysis of the 1190 ratings revealed a strong correlation (&rgr; = 0.89, P < 0.0001) and significant associations (P < 0.0001) between QS and SQS. Correlations between QS and SQS according to Szkudlarek et al. (&rgr; = 0.87, P < 0.0001) or Hammer et al. (&rgr; = 0.91, P < 0.0001) were similar. A total of 239 (20.1%) images were given a SQS grade that did not match that expected based on initial QS, using pre-defined cut-offs. Main explanations for discrepancies were different perceived region of interest (40.7%) and Doppler pixel count near cut-offs between SQS grades (32.3%). Conclusion. We showed that both SQS methods correlated well with QS to assess synovitis, but SQS methods are intrinsically limited when the Doppler pixel count is close to the cut-offs between the SQS grades. Analysis discrepancies between these methods may help further revision of criteria used to assess disease activity with MSUS in RA.

AB1024 Clinically “Silent” Synovitis: Detected by Fluorescence Optical Imaging of the Hands & Wrists

Background The detection of sub-clinical synovial inflammation (“silent synovitis”) would be of critical importance for the detection of rheumatoid arthritis (RA) & other inflammatory arthritides, in its earliest pathophysiological stage (”pre-RA”). It has been suggested that ultrasound (US) with power or colour Doppler, can be a useful technology to achieve this. Ultrasound however, requires specially trained/skilled operators. Fluorescence optical imaging (FOI, “Rheumascan”) is a novel imaging modality based on the use of an intravenous fluorescence dye, that allows imaging of the hands & wrists, with increased focal optical signal intensities in areas of high perfusion &/or capillary leakage. This diagnostic tool, is operator independent, & can be well carried out by a rheumatology nurse. Objectives Here, we investigated whether FOI (Rheumascan) could be used in lieu of US (colour Doppler) for ascertaining hand & wrist sub-clinical synovitis. Methods A total of 748 hand & wrist joints (6 wrist, 10 MCPs, 10 PIPs & 8 DIPs) in 22 patients (7 male & 15 female), aged between 19 & 84 years, with inflammatory arthritis (RA:9, JIA, polyarthritis, psoriatic arthritis, SLE & other diagnoses, 1-2 each) were examined clinically, by US & FOI. Joints were considered clinically inflamed when both swollen and tender, & non-inflamed otherwise. Ultrasound was considered positive for “active” synovitis if both thickening on grey scale & Doppler signals were present. FOI was considered positive in joints that displayed focal signal intensities, by visual inspection of recorded images & video clips. Results Out of 748 joints evaluated, 72 (10%) were considered inflamed by clinical examination and 676 (90%) were not. Of the clinically non-inflamed joints, exactly 95 (14%) were inflamed by US. Of these joints, 72 (76%) were inflamed by FOI and 23 (24%) were not. Thus, the sensitivity of FOI for detecting clinically “silent” synovitis when defined as a positive US in the absence of clinical inflammation was 76%. Out of the 581 joints that were non-inflamed clinically and non-inflamed by ultrasound, 24 (4%) had inflammation by FOI, yielding a specificity of 96% (557/581). Conclusions Under the assumption that US can correctly identify sub-clinical synovitis in clinically non-inflamed joints (using the combination of clinical examination & US as the “gold standard”), the sensitivity of FOI for detecting clinically “silent synovitis” in the hands & wrists is 76% and the specificity 95%. These metrics suggest that it may be a useful diagnostic tool in the setting of identifying patients with very early synovial inflammation of the hands &/or wrists. Acknowledgements To all the patients & participants of the study. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.2215

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)

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

THU0455 Evaluating Psoriatic Skin Lesions in Psoriasis and Psoriatic Arthritis: Ultrasound as A Complementary Measure

Background Currently, the diagnosis and assessment of psoriatic arthritis (PsA) and psoriasis (PsO) skin lesions are mostly done by visual inspections, and when in doubt, supplemented by biopsies. Although PsA is primarily assessed by physical examination, the utility of ultrasound (US) is beneficial. Objectives The aim of this proof of concept study was to determine the performance of ultrasound (using advanced imaging software applications) in assessing skin lesions and inflammation in selected PsA and PsO patients. Methods A rheumatologist and dermatologist assessed the PsA and PsO patients respectively. PsA examination included the standard clinical joint assessments, and we thereafter evaluated the hands & wrists and symptomatic joints with US for synovitis & tenosynovitis (including nail beds & tendons). Blinded by the clinical results and treatment plans, the epidermal, dermal and subcutaneous tissue thicknesses of 2 of the most affected psoriasis lesions were US scanned using high frequency B-Mode, automated Color Doppler quantification (CDQ; measured over 4 seconds) and elastography applications (measuring lesion size, depth, hyperemia and tissue elasticity). The skin tissue adjacent to the psoriasis lesions, as well as the unaffected skin on the contralateral side (self-control) was measured. Results A total of 270 skin depth measurements (2 of the most affected lesions, 3 intervals apart, at 3 different sites described above) of 5 PsA/PsO patients were analyzed. Epidermal thickness differed significantly between the adjacent and control tissue layers [F (2,27) =30.95, MSE =0.76, p<0.001]. Similar findings were evident for dermal thickness differences [F (2,27) =5.05, MSE =1.59, p=0.014]. In contrast and as expected, subcutaneous tissue thicknesses showed no significant differences. US using color Doppler revealed the presence of hyperemia in 80% of the examined lesions by CDQ resulted in flow averages ranging from 0.016–0.655 for minimum ratios to 0.103–0.241 for maximum ratios. Of these Doppler active lesions, 60% were echogenic (some with acoustic shadowing). Contrary, 20% of the psoriasis lesions showed no obvious Doppler activity, displaying reduced tissue stiffening on elastography (suggesting healed lesions). Two of 10 (20%) lesions showed no abnormal findings (soft on elastography) having no acoustic shadows, and low-level CDQ activity (minimum 0.016:0.034 and maximum 0.103:0.135 ratios). Ultrasound displayed the presence of synovitis, tenosynovitis, and nail-bed hyperemia together with altered microcirculation & hand psoriasis skin perfusion in PsA patients. Conclusions Ultrasound metrics of skin tissue (plaque characteristics, tissue depth & elasticity, and Doppler activity quantification) has potential as a complementary measure for the clinical assessment of PsA and PsO. 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

SAT0632 Quantification of Hand and Wrist Synovitis Using Digital Activity Fluorescence Optical Imaging

Background The objective detection and quantification of inflammatory disease activity is critical for achieving optimal therapy results. Fluorescence optical imaging (FOI) is a novel modality designed for imaging the hands and wrists, and the automated quantification of the ensuing scans using DACT (Disease ACTivity)-FOI is a novel algorithm for analyzing these images. Objectives To determine the utility of DACT-FOI in the assessment of hand and wrist inflammation. Methods Bilateral finger and wrist joints (n=1360) of 40 patients with inflammatory arthritis were studied. Synovitis was defined as tender and swollen joints on clinical examination, presence of synovial thickening/effusion and intra-articular Doppler signals on ultrasound (MSUS), and abnormal focal optical signal intensities on FOI, respectively. The DACT score used an automatically generated algorithm of the composite images (of 240 frames per second) to achieve a quantified score for each patient. Using dedicated image parameters and size correction, the enhanced pixels were extracted automatically from the image background, and the high signal intensities calculated. The DACT-FOI formula was based on fluorescence intensity curve thresholds that were used to discriminate intensity variations, and then divided by the 95th centile of intensities in normal individuals as the reference value. DACT-FOI ≤1 was referred to as normal digital activity signals. Subclinical synovitis was defined as being clinically non-inflamed but inflamed on MSUS. Results Out of the 1360 joints evaluated, 215 (16%) were inflamed clinically, 329 (24%) by MSUS, and 347 (26%) by FOI. For overall hand and wrist disease activity (n=40), the number (mean ± SD) of active joints detected by clinical, MSUS and semi-quantitative FOI was 5.4±7.0; 8.2±7.8; and 8.7±7.8, respectively. The automated digital activity (±SD) calculation by DACT-FOI was 3.8 (±2.1). Correlations of high statistical significance was denoted as ** when p<0.01. A strong positive correlation (r =0.458**; p=0.003) between clinical synovitis and DACT-FOI was demonstrated. The mean DACT values also correlated significantly with MSUS (r =0.442**; p=0.004) and semi-quantitative FOI (r =0.439**; p=0.005). There was a highly significant correlation of synovitis detection between clinical examination and MSUS (r =0.730**; p=0.000) and between clinical examination and semi-quantitative FOI (r =0.577**; p=0.000). Agreement between MSUS and FOI in synovitis detection was good, and revealed strong correlations (0.816**; p=0.000). Out of the non-inflamed joints by clinical examination, 142/1145 (12%) were inflamed by MSUS, of which 102/142 (72%) were also inflamed by FOI. Thus, for detecting subclinical synovitis, the sensitivity, specificity, and positive and negative predictive values of FOI were 72% (102/142), 93% (934/1003), 77% and 91%, respectively. Conclusions FOI and the automated analysis DACT-FOI were technically feasible with high reproducibility and strong agreement with clinical scoring. Therefore, this objective digitally quantified measurement of inflammatory disease activity in the hands & wrists may be useful both in diagnosis and in monitoring the effects of clinical therapy. Disclosure of Interest None declared