Fluorescence Optical Imaging for Treatment Monitoring in Patients With Early and Active Rheumatoid Arthritis in a 1-Year Follow-Up Period

Anne-Marie Glimm; Lisa Ines Sprenger; Ida Kristin Haugen; Ulrich Mansmann; Sandra Hermann; Thomas Häupl; Paula Hoff; Gerd-Rüdiger Burmester; Marina Backhaus; Lien Le; Sarah Ohrndorf


Arthritis Res Ther. 2019;21(209) 

In This Article


This study is a subproject (No. 7) of the Arthromark project as a national research network in Germany funded by the Federal Ministry of Education and Research (BMBF). The main goal of the several Arthromark subprojects is the identification of new biomarkers including the application and assessment of new and modern imaging techniques in terms of making a diagnosis and follow-up examinations in patients with RA, psoriasis arthritis, and spondyloarthritis.[31]

In this subproject, we included 42 patients with early (disease duration < 24 months) and active (DAS28 > 3.2) RA, who started therapy with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or escalated therapy with initiation of biologic therapy (bDMARD) after failure of conventional therapy. Over a period of 1 year, patients were examined clinically and by US (for further description of additional US, see Additional file 1) five times (baseline, after 6 weeks, and 3, 6, and 12 months). FOI was performed at baseline and after 12 months in 35 patients who were included in these analyses (in seven patients, the 12-month visit was not performed).

Clinical and Laboratory Examination

A clinical assessment of tender (28 tender joint count (TJC)) and swollen joints (28 swollen joint count (SJC)) was performed. Patients self-reported their evaluation of the global disease activity and the current general joint pain (both on a visual analog scale (VAS) 0–100 mm). Clinical and laboratory examination was accomplished on the same day as the imaging (FOI; US) examinations. Usually, FOI was ordinarily performed after the US examination. The laboratory investigation included the assessment of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). The rheumatoid factor (RF) and anti-citrullinated peptide antibodies (ACPA) were determined at inclusion.

The Disease Activity Score DAS28 was calculated based on the 28-TJC, 28-SJC, ESR or CRP, and patient's global VAS.[1] The calculation of the difference between DAS28 value at baseline or the prior visit and current value gave information of response to therapy after EULAR response criteria[32–34] (a definition is presented in Additional file 1: Table S1). Based on the EULAR response (Table S1), patients were assigned to a group of responders (DAS28(ESR) ≤ 3.2 and improvement of > 0.6) or non-responders (DAS28(ESR) > 3.2). This process was done to evaluate treatment monitoring by FOI.

Fluorescence Optical Imaging (FOI)

FOI (Xiralite® System) was performed following a standardized procedure.

The examination term lasted 6 min, recording one image per second and adding up to a cluster of 360 images.[21,22] A bolus of indocyanine green (ICG) as fluorescence optical dye with a dose of 0.1 mg/kg body weight was injected intravenously 10 s after the beginning of the examination.[21,22]

The attached software system enabled a visualization of invasion and distribution of ICG in the hands. An image sequence in the film modus and an automatically generated image in the PrimaVistaMode (PVM) were analyzed to evaluate the distribution and enhancement of ICG. For the film modus, three phases in position to the fingertips were defined regarding signal intensities depending on individual perfusion.[22] Phase 1 (p1) included the period between starting the investigation, application of the dye, and increased signal intensities in the fingertips,[22] which means an increasing intensity of fluorescence signal. The time period of persisting high signal intensities as plateau in the fingertips was defined as phase 2 (p2).[22] Investigators do identify this phase on red color signs of the enhancement in the fingertips. The time point without signal intensity meaning only yellow sparkles in the fingertips as a signal for clearance determined the beginning of phase 3 (p3).[22]

Enhancement of ICG can be graded by false-color illustration, which is identical between different scans, time points, and patients. It defines white enhancement as high intensities and concentration of ICG. Red, yellow, and green enhancement follows in a descending order of ICG concentration. For analyzing the joint activity by FOI, the evaluation at the joint level included a combination of size, shape, and color of the signal in a semiquantitative grading system (FOIAS; fluorescence optical imaging activity score): 0 = no signal enhancement, green to yellow signals; 1 = low signal intensity (≤ 25% of the joint area affected), yellow-red signals including red signals with yellow spots; 2 = moderate signal intensity (> 25%, ≤ 50% of the joint area affected), strong red signals including red signals with white spots; 3 = strong signal intensity (> 50% of the joint area affected), white signals.[21,22] If there was a discrepancy between the intensity of the color and the size of the enhancement, the lower grade of the scoring system was assigned. In detail, enhancements with a discrepancy between two subsequent grades (1 and 2 or 2 and 3) were evaluated with the lower grade number. Differences of signal color and size between grades far apart (e.g., grades 1 and 3) were scored with the intermediate grade (e.g., grade 2).

The ICG distribution in the three phases (p1, p2, p3) and in PrimaVistaMode (PVM) was assessed for the joint regions of 30 joints per patient, including the bilateral wrist, metacarpophalangeal joints (MCP) I–V, proximal interphalangeal joints (PIP) II-V, distal interphalangeal joints (DIP) II-V, and interphalangeal joint of the thumb (IP).[21] The scoring of color intensity, size, and shape of ICG enhancement was performed by an agreement-based consensus of two investigators (SO; LS).

We calculated the number of affected joints and sum scores (FOIAS; fluorescence optical imaging activity score) for each phase (0–90 scales). In addition, the sum scores of the left hand and the right hand were individually calculated.

Statistical Analyses

Wilcoxon signed rank tests were done to compare clinical data (TJC, SJC, DAS28(ESR)) and FOIAS between two visits (baseline (V0) and 12 months (V12)). Furthermore, Mann-Whitney U tests were performed to test for the statistical significance of the difference of score change between responders and non-responders to DAS28 changes under treatment. In addition, we examined whether the FOIAS was correlated with clinical outcome and ultrasound data by use of Spearman's correlation coefficients including the analysis assessing specific points of time and the change between two points of time. The significance level of 0.05 (5%) was used. p values were not adjusted for multiple testing due to the explorative character of the analyses. Statistical analyses were performed with the statistical program R.[35] If not specified otherwise, the descriptive statistics provided median values (1. quartile; 3. quartile).