Malte Bahner

Comparison of Two Tricarbocyanine-Based Dyes for Fluorescence Optical Imaging

Optical technologies are evolving in many biomedical areas including the biomedical imaging disciplines. Regarding the absorption properties of physiological molecules in living tissue, the optical window ranging from 700 to 900 nm allows to use fluorescent dyes for novel diagnostic solutions. Here we investigate the potential of two different carbocyanine-based dyes fluorescent in the near infrared as contrast agents for in vivoimaging of subcutaneously grown tumours in laboratory animals. The primary aim was to modify the physicochemical properties of the previously synthesized dye SIDAG to investigate the effect on the in vivoimaging properties.

Detection of rheumatoid arthritis by evaluation of normalized variances of fluorescence time correlation functions

Fluorescence imaging using the dye indocyanine green as a contrast agent was investigated in a prospective clinical study for the detection of rheumatoid arthritis. Normalized variances of correlated time series of fluorescence intensities describing the bolus kinetics of the contrast agent in certain regions of interest were analyzed to differentiate healthy from inflamed finger joints. These values are determined using a robust, parameter-free algorithm. We found that the normalized variance of correlation functions improves the differentiation between healthy joints of volunteers and joints with rheumatoid arthritis of patients by about 10% compared to, e.g., ratios of areas under the curves of raw data.

SAT0392 ICG-enhanced fluorescence optical imaging in clinical remission: Longitudinal data in RA and PSA patients with pre/post comparisons

Background ICG (Indocyanine-Green) fluorescence optical imaging (FOI) is a novel imaging technology in rheumatology (1) and may be a suitable tool for monitoring of disease activity and treatment response (2). Objectives This is the first study with longitudinal data of FOI in RA and PsA patients in clinical remission. The objective was to compare clinical activity and FOI findings before, at and after achievement of clinical remission. Methods A total of 113 subjects were included in a prospective study of FOI in RA and PsA patients with low disease activity (inception cohort: disease activity ≤1 at global assessment by patient or physician, NRS 0-10). All patients received a clinical examination by an independent investigator, and blood samples were taken for measurement of systemic inflammation (ESR, CRP). Inflammatory activity in FOI was assessed by an experienced reader using the semiquantitative fluorescence optical imaging activity score (FOIAS) (1), which comprises of the measurement of joint-related fluorescence signals in an automatically generated composite image (Prima Vista Mode, PVM) and in three predefined phases of FOI (P1, P2, P3).In 38 subjects with DAS28 remission (DAS28 <2,6) at least one FOI study had been performed either prior to remission (≥3 months, n=34) or at follow-up (≥3 months, n=31). 11 subjects had sequential FOI examinations prior to and after remission. The sample with a total of 103 FOI studies was selected for further analysis. Results In most patients clinical and FOI activity were following a uniform trend (table). Cross-sectional analysis revealed a moderate correlation of (r=0.4) of DAS28 and FOIAS. FOI evidence of subclinical disease activity was more pronounced in the various phases of a FOI sequence than in PVM. 11 subjects had treatment changes (reduction of DMARDs, tapering of steroid dose) due to clinical remission. In individual patients FOIAS increased with ongoing clinical remission. In joint-to-joint comparisons, those patients showed at first decreasing FOI activity in originally symptomatic joints with the achievement of remission. When treatment was reduced at this stage, then even clinically still asymptomatic patients demonstrated an increase in FOI activity in those same joints. DAS28 TJC SJC FOIASPVM FOIASP1 FOIAS P2 FOIAS P3 FOAIS P1-3 Prior to remission (n=34) 3,87 5 3 11 9 23 7 38 At remission (n=38) 1,7 1 0 5 3 11 2 16 Follow-up (n=31) 1,98 1 0 5 1 7 1 10 Conclusions FOI is a useful tool for monitoring disease activity and treatment response in RA and PsA patients. Most subjects with clinical remission showed residual activity in FOI. Pre/post-comparisons in individual patients suggest that subclinical disease activity in FOI may announce an initiating relapse in patients with premature withdrawal of treatment. References Werner SG, Langer HE, Ohrndorf et al. Inflammation assessment in patients with arthritis using novel in vivo fluorescence optical imaging technology. Ann Rheum Dis Oct 2011, Epub ahead of print. Werner S et al. 2011 ACR/ARHP Annual Scientific Meeting, Chicago, IL, Nov. 4 -9, 2011, Poster 199 Disclosure of Interest S. Werner Grant/Research support from: Pfizer, F. Spiecker: None Declared, C. Hermsen: None Declared, M. Bahner Shareholder of: mivenion GmbH, M. Backhaus Grant/Research support from: Pfizer, H.-E. Langer Grant/Research support from: Pfizer

Detection of rheumatoid arthritis in humans by fluorescence imaging

The blood pool agent indo-cyanine green (ICG) has been investigated in a prospective clinical study for detection of rheumatoid arthritis using fluorescence imaging. Temporal behavior as well as spatial distribution of fluorescence intensity are suited to differentiate healthy and inflamed finger joints after i.v. injection of an ICG bolus.

THU0430 Image pattern in fluorescence optical imaging of the hands: Does xiralite support differential diagnosis? A feasibility study

Background Fluorescence optical imaging is a novel tool for assessment of disease activity of inflammatory joint disorders of the hands (1). Initially developed for assessment of inflammatory activity in the hands, represented by an altered microcirculation, it became quickly apparent, that different underlying diseases appear with a variation of image patterns. Optical Evaluation of Rheumatoid Arthritis (OPERA1) is a prospective, multicenter use study with optical imaging in a variety of inflammatory joint disorders of the hands. Objectives With this analysis on a small sample of patients from the OPERA study, the feasibility of fluorescence optical imaging to provide differential diagnostic patterns was evaluated. The hypothesis under evaluation was that rheumatoid arthritis (RA), psoriatic arthritis (PsA), and osteoarthritis (OA) have distinct image patterns in fluorescence optical imaging. Methods From the OPERA1 study, 120 patients with RA, with PsA, and with OA (40 each) were randomly selected. All image sets were evaluated by a single, experienced radiologist to a previously defined set of variables representing image patterns and dynamic image characteristics. First, univariate multinomial regression analyses were performed to determine the significance of factors to differentiate between at least two of the three diagnoses (RA, PsA, OA). Significant factors were included into a multivariate model using backward selection of factors to obtain a final model using p-values ≥0.05 as exclusion criterion. Significant results suggest that patterns of significant factors may provide potential for differentiating between the diagnoses. Results From the factors evaluated, the image pattern (p<0.0001, fig. 1) and signal continuity between DIP and nailbed (p=0.0027) were found to significantly differentiate between RA, PSA, and OA in the final multivariate analysis. In the univariate analyses, also late phase signal (p=0.0016), overall signal intensity (p=0.031), a discontinuous signal in the phalanx (p=0.0056), and an arcuate signal pattern in the phalanx (p=0.0106) were found as significant factors. Early enhancement (p=0.295) and duration of the enhancement (p=0.064) were not found to significantly differentiate between the three diagnoses. Figure 1. Example image of OA (left), PsA (middle), and RA (right) showing typical image patterns. A signal discontinuity between nailbed and DIP joint is commonly seen in OA, while PsA has signal continuity in this region. OA also has a signal pattern aligning with osseous structures, while PsA and RA are more joint related. PsA also shows a signal continuity in the distal fingers together with streaky signals surrounding the joints, while RA is more confined. Conclusions This single reader feasibility study shows, that the hypothesis of distinct imaging patterns in fluorescence optical imaging depending on the underlying disease may hold true. A well designed prospective, blinded multi-reader analysis needs to be performed for further evaluation of this hypothesis and its proof. References Werner SG et al. Inflammation assessment in patients with arthritis using novel in vivo fluorescence optical imaging technology. Ann Rheum Dis 2012, doi:10.1136/ard.2010.148288 Disclosure of Interest M. Bahner Shareholder of: mivenion GmbH, Employee of: mivenion GmbH, C. Schwenke: None Declared, M. Schirner Shareholder of: mivenion GmbH, Employee of: mivenion GmbH

AB0733 Treatment monitoring of fluorescence optical imaging (foi) using automated, computer-based quantitative assessment

Background Fluorescence optical imaging (FOI) with the Xiralite® system is clinically available for diagnostic imaging of inflammation and has been shown to be a suitable tool to assess treatment response in subjects with RA and PsA. Changes in FOI are measured using the semi-quantitative fluorescence optical imaging activity score (FOIAS) which allows for a low inter-reader variability1. Most recently, an automatic, computer-based image analysis of FOI (DACT) has been described and validated in healthy subjects2. Objectives To evaluate an automatic computer-based analysis of FOI in patients with RA or PsA under treatment. Methods 30 patients with rheumatoid (RA) or psoriatic (PsA) arthritis were examined before starting treatment (visit 1) and at follow-up (visit 2). Treatment response was assessed using DAS28, cFOIAS and the automated calculated DACT. First, 3 readers analyzed all 60 image data sets individually. For articular location of increased signal intensities (ISI) the FOIAS was used. For extraarticular location the signals were graded semiquantitatively on a scale of 0 to 2. These values were added to a single number representing the overall fluorescence signal intensity of the hands (cFOIAS). For DACT composite images were generated automatically. Using dedicated parameters of the histograms, automatic extraction of the hands from the image background was performed by the computer. The algorithm separated the hands from the forearm in a standardized manner by using a multiple of the length of the middle finger. A threshold in the fluorescence intensity curve was set to discriminate high and low intensity areas. The area of high intensity was calculated and the values of each patient were divided by the 95th percentile of normal individuals which was defined as reference value. DACT was expressed as high signal intensity area patient / healthy reference. DACT in healthy individuals equals 1. Then cFOIAS and DACT values were compared. Results 60 left and 60 right hands were correctly extracted from the auto-scaled composite image of the first 240 seconds. The intra-individual variation of the extraction procedure measured as intensity area of the hand in the consecutive procedures was 1.1 % + 1.0 (range: 0.04 – 4.9). cFOIAS scores strongly correlate with automated calculated DACT (0.86 / reader 1, 0.84 / reader 2 and 0.85 / reader 3). Agreement of declining DAS28 with declining cFOIAS was found in 16/30 (reader 1), 17/30 (reader 2) and 15/30 (reader 3) treatment courses. Agreement of declining DAS28 with declining DACT was found in 16/30 treatment course. Conclusions This first clinical trial in patients with RA or PsA under treatment with follow-up FOI exams demonstrates that automatic, computer-based image analysis of FOI to calculate DACT values is technically feasible, offers high reproducibility and high agreement with cFOIAS score reading, while agreement of DACT value with DAS28 was only moderate. Even very low changes of the DACT value can be measured and considered as statistically significant. References Werner SG et al. Indocyanine Green Enhanced Optical Imaging Using for Monitoring of Treatment Response. Arthritis & Rheumatism 2011: 63 (10); S73 Schirner M. et al. Methods for automated, computer-based quantitative assessment of fluorescence optical imaging. Ann Rheum Dis 2012;71(Suppl3):711 Disclosure of Interest M. Bahner Shareholder of: mivenion GmbH, Employee of: mivenion GmbH, S. Werner: None Declared, M. Cziumplik Employee of: mivenion GmbH, J. Berger Employee of: mivenion GmbH, H.-E. Langer: None Declared, M. Schirner Shareholder of: mivenion GmbH, Employee of: mivenion GmbH

THU0422 ICG-enhanced fluorescence optical imaging reveals subclinical disease activity in rheumatoid and psoriatic arthritis patients who have achieved clinical remission:

Background Both MRI and ultrasonography (US) detect subclinical disease activity in most remission and low disease activity patients with rheumatoid arthritis (RA) (1, 2). Fluorescence optical imaging (FOI) has been shown to be not only a sensitive detector of synovitis (3), but also a useful tool in assessing treatment response in patients with RA and psoriatic arthritis (PsA) (4). Objectives This is the first data on FOI in RA and PsA patients in clinical remission. The objective was to evaluate FOI as a method to detect subclinical disease activity in these patients. Methods Admission criteria of this prospective study was patient or physician global assessment of disease activity of 10% or less on a visual analogue scale (VAS 0-10), thus resulting in the inclusion of 113 consecutive patients into the inception cohort. Admitted patients received a clinical examination by an independent investigator, and blood samples were taken for measurement of systemic inflammation (ESR, CRP). With these data, patients in DAS28 remission (DAS28 <2.6), SDAI remission (SDAI ≤3.3), CDAI remission (CDAI ≤2.8) and 2011 ACR/EULAR remission (Boolean based definition) were determined. Inflammatory activity in FOI was assessed by an experienced reader using the semiquantitative fluorescent optical imaging activity score (FOIAS) (3), which comprises of the measurement of joint-related fluorescent signal in an automatically generated composite image (Prima Vista Mode, PVM) and in three predefined phases of FOI (P1, P2, P3). Results 78-87% of patients in remission showed remaining inflammatory activity in the PVM (table). DAS28 <2,6 SDAI ≤3,3 CDAI ≤2,8 Boolean Criteria PVM 65/83 (78%) 53/61 (87%) 48/56 (86%) 41/47 (87%) Phase I 17/83 (20%) 15/61 (25%) 14/56 (25%) 13/47 (28%) Phase II 81/83 (98%) 60/61 (98%) 55/56 (98%) 46/47 (98%) Phase III 39/83 (47%) 32/61 (52%) 27/56 (48%) 24/47 (51%) Differences in the occurrence of inflammatory activity between the phases were significant to highly significant, with the lowest incidence of activity in P1 (20-28%). When excluding low signal enhancement and only regarding moderate to strong enhancement (≥2 on the semiquantitative score of 0-3), incidence of inflammatory activity was lower: 43% in PVM, 13% in P1, 78% in P2 and 17% in P3 for the DAS28 remission group. Comparing inflammatory activity in RA and PsA patients in DAS28 remission revealed no significant difference, though a clear trend towards more P1-activity in PsA patients could be observed (18% vs. 29% in RA and PsA patients, respectively). Conclusions Frequency of subclinical disease activity observed in FOI is similar to that stated in MRI and US remission studies. Frequency of P1-activity in FOI is comparable to the reported frequency of power Doppler signal in patients with low disease activity or in remission (1), which is consistent with the previously established high agreement rates between P1 and power Doppler sonography (3). The prognostic value of subclinical FOI activity in remission patients is yet to be determined. References Gandjbakhch F et al. Ann Rheum Dis2011 Dec;70(12):2159-62. Foltz V et al. Arthritis Rheum. 2012 Jan;64(1):67-76. Werner S et al. Ann Rheum Dis 2011;70, Online First, published on Oct. 12, 2011. Werner S et al. 2011 ACR/ARHP Annual Scientific Meeting, Chicago, IL, Nov. 4-9, 2011, Poster 199 Disclosure of Interest F. Spiecker: None Declared, S. Werner Grant/Research support from: Pfizer, C. Hermsen: None Declared, M. Bahner Shareholder of: mivenion GmbH, M. Backhaus Grant/Research support from: Pfizer, H.-E. Langer Grant/Research support from: Pfizer