Contrast-Enhanced Ultrasound for the Monitoring of the Efficacy of Intra-Articular Glucocorticosteroids in 2 Patients with Inflammatory Knee Joint Synovitis

We present two patients: one 33-year-old woman with HLA-B27-positive spondyloarthritis (SpA) and one 41-year-old man with rheumatoid arthritis (RA) with inflammatory knee joint synovitis (KJS) who were successfully monitored by contrast-enhanced ultrasound (CEUS) using the second-generation contrast agent SonoVue^® before and after intra-articular injection of glucocorticosteroids (GC).

Because of recurrent knee swelling, we performed a standardized ultrasound examination of the superior and lateral recess of the affected knee in both patients according to a previously described protocol following the EULAR recommendations (Song IH et al. Ann Rheum Dis 2009; 68: 75 – 83) using a 12 – 5 MHz linear transducer (ESAOTE, Technos MPX). Power Doppler ultrasound (PD-US) was performed with a Doppler frequency of 6.3 MHz, pulse repetition frequency of 500 Hz, gain of 103, and a low wall filter. We additionally performed a contrast-enhanced ultrasound (CEUS) examination after intravenous bolus injection of 4.8 ml of SonoVue^® using a 3 – 8 MHz linear transducer. Contrast enhancement in the superior recess was graded semiquantitatively based on the calculation of slope values (Song IH et al. Ann Rheum Dis 2009; 68: 75 – 83). Slope values are determined by a so-called time-intensity analysis, which is a dedicated technology (CnTI™, ESAOTE) operating at a low mechanical index (MI = 0.098; most examinations have been performed with an MI of 0.098). In both cases the patient’s knee was punctured and GCs (40 mg rimexolone, a crystalline glucocorticoid solution) were administered intra-articularly.

On follow-up in the setting of routine patient care which took place 7 and 14 days after i. a.-GC injection in patient 1 and after 24 days in patient 2, we found a marked improvement of all clinical, laboratory and ultrasound parameters in patient 1, while disease activity remained elevated in all parameters in patient 2 ([Table 1], [Fig. 1], [2]). In both cases CEUS using SonoVue^® was able to demonstrate the change in disease activity.

Table 1 Summary of baseline and follow-up ultrasound findings in one patient with spondyloarthritis and one patient with rheumatoid arthritis.[1]

parameters		patient 1 with SpA			patient 2 with RA
		BL	FU 1 after 7 days	FU 2 after 14 days	BL	FU after 24 days
pain	VAS, pain at rest (0 – 100 mm)	28	5	4	37	80
laboratory parameters	C-reactive protein (mg/l) (reference 5 mg/l)	26.2	–	2.8	7.6	8.6
	ESR (mm in first hour)	23	–	5	66	74
B-mode	Eff sup rec (in mm)	15.0	3.5	4.7	7.9	6.8
	Eff lat rec (in mm)	14.6	6.0	7.5	5.9	4.5
	Syn sup rec (in mm)	5.2	0.9	1.1	2.8	2.0
	Syn lat rec (in mm)	2.6	2.0	0	2.3	1
PD-US	PD-US sup rec (grade 0 – 3)	2	0	0	1	2
	PD-US lat rec (grade 0 – 3)	3	2	1	1	2
CEUS	slope values	23.1	8.8	3.5	11.0	43.9
	grading	2	0	0	1	3

¹ Abbreviations: US = ultrasound; SpA = spondyloarthritis; UC = ulcerative colitis; RA = rheumatoid arthritis; eff: effusion; syn: synovial hypertrophy; sup: superior; lat: lateral; rec: recess; PD-US: power Doppler ultrasound; CEUS: contrast-enhanced ultrasound; BL: baseline; FU: follow-up. Pain was assessed for pain at rest on a visual analog scale (0 – 100 mm). PD-US was graded on a semiquantitative scale from 0 – 3 (0: no PD-US; 1: mild PD-US, single color marked vessel; 2: medium PD-US; 3: strong PD-US, large confluent marked vessel > 50 % of examined area. Contrast medium enhancement measured as slope values was graded in the same way (0: no contrast medium enhancement; 1: mild; 2: moderate; 3: strong contrast medium enhancement).

Fig. 1 a, b Patient 1 with knee joint synovitis (KJS) in the setting of spondyloarthritis showed marked improvement in all parameters after intra-articular injection of glucocorticosteroids including parameters such as pain, CRP level, ESR, B-mode ultrasound (US) parameters (effusion and synovial hypertrophy in the superior and lateral recess), power Doppler (PD) US grading, and contrast-enhanced (CE) US as measured by slope values. Patient 2 with KJS in the setting of rheumatoid arthritis showed worsening of parameters. CEUS showed the best correlation with pain data assessed by the visual analog scale (VAS). Abbreviations: VAS: visual analog scale; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; PD-US: power Doppler ultrasound; CEUS: contrast-enhanced ultrasound (measured as slope values).

Abb. 1 a, b Patient 1 mit Gonarthritis im Rahmen einer Spondyloarthritis zeigte eine merkliche Verbesserung in allen erfassten Parametern nach intraartikulärer Injektion von Glukokortikoiden einschließlich Schmerz, C-reaktivem Protein, Blutsenkungsgeschwindigkeit, B-Mode-Ultraschall-Parametern (Erguss und synoviale Hypertrophie im superioren und lateralen Recessus), Power-Doppler(PD-)US-Graduierung und kontrastmittelgestütztem Gelenkultraschall gemessen als Slope-Werte. Patient 2 mit Gonarthritis im Rahmen einer rheumatoiden Arthritis zeigte eine Verschlechterung der gemessenen Parameter. Der kontrastmittelgestützte Gelenkultraschall zeigte die beste Korrelation mit dem Schmerz. Abkürzungen: VAS: visuelle Analogskala; CRP: C-reaktives Protein; ESR: Blutsenkungsgeschwindigkeit (erythrocyte sedimentation rate); PD-US: Power Doppler Ultraschall; CEUS: kontrastmittelgestützter Ultraschall (gemessen als Slope-Werte).

Fig. 2 Illustration of baseline and follow-up findings after 14 days in patient 1 with knee joint synovitis (KJS) due to spondyloarthritis and associated ulcerative colitis. Marked improvement in B-mode (effusion in superior recess), power Doppler (PD) US grading, contrast-enhanced (CE) US grading and slope values derived from time intensity curves where the abscissa characterizes the time value in seconds (time) and the ordinate shows an averaged intensity value – related to a precise second/frame (intensity). Abbreviations: PD-US = power Doppler ultrasound; CEUS = contrast-enhanced ultrasound.

Abb. 2 Illustration der Baseline und Follow-up-Befunde nach 14 Tagen bei Patient 1 mit Gonarthritis im Rahmen einer Spondyloarthritis und assoziierter Colitis ulcerosa. Merkliche Verbesserung der B-Mode-Befunde (Erguss im superioren Recessus), Power-Doppler-Einteilung, kontrastmittelgestütztem Gelenkultraschall und Slope-Werten, die von der Intensitätskurve abgeleitet werden, in der die Abszisse die Zeit in Sekunden darstellt (Zeit) und die Ordinate die durchschnittliche Intensität – bezogen auf präzise Sekunden/Rahmen (Intensität). Abkürzungen: PD-US = Power-Doppler-Ultraschall; CEUS = kontrastmittelgestützter Ultraschall (contrast-enhanced ultrasound).

Interestingly, worsening of the clinical disease activity in the RA patient as shown on the visual analog scale (VAS) assessment and C-reactive protein (CRP) elevation was better revealed by CEUS compared to B-mode ultrasound or PD-US ([Table 1], [Fig. 1b]).

The anti-inflammatory effect of intra-articular and systemic GC in rheumatic KJS is well established and has been successfully monitored in prospective studies by PD-US (Newman J et al. Radiology 1996; 198: 582 – 584) and by CEUS using the first-generation contrast agent Levovist. However, there are no such longitudinal treatment studies for CEUS with the use of the second-generation contrast medium SonoVue^®.

In a recent study we showed that contrast-enhanced ultrasound (CEUS) using the contrast medium SonoVue^® is more sensitive than B-mode or power Doppler ultrasound (PD-US) for detecting the higher vascularization of synovial processes in knee osteoarthritis (OA) in comparison to contrast-enhanced magnetic resonance imaging (CE-MRI) (Song IH et al. Ann Rheum Dis 2009; 68: 75 – 83).

Our finding that CEUS is a valid method for assessing hypervascularization is consistent with the higher sensitivity of CEUS (97.3 %) compared to B-mode and PD-US (about 60 %) found by Klauser et al. when assessing 113 different joints including 36 knee joints in RA patients in a cross-sectional study (Klauser A et al. Eur Radiol 2005; 15: 2404 – 2410). There were similar findings in a retrospective study in 15 RA knee joints (Kleffel T et al. Fortschr Röntgenstr 2005; 177: 835 – 841) as well as in our previously performed prospective study in 41 knee OA patients showing that CEUS using SonoVue^® is a suitable tool for assessing hypervascularization compared to CE-MRI (Song IH et al. Ann Rheum Dis 2009; 68: 75 – 83).

PD-US, which has been extensively studied and compared to MRI (Szkudlarek M. Eur Radiol 2003; 13: 163 – 168) and histological findings (Walther M et al. Radiology 2002; 225: 225 – 231) can be considered the reference standard in our study. Furthermore, CEUS has shown a good correlation with CE-MRI and has proven to be a valid instrument for monitoring the anti-inflammatory effect of disease-modifying antirheumatic drugs (DMARDs) and tumor necrosis factor alpha (TNFα) inhibitors (Ohrndorf S et al. Ultraschall in Med 2011 Nov 3. [Epub ahead of print]).

Further investigations are needed to determine whether our findings in rheumatic KJS are valid in larger patient populations. These studies must show whether CEUS using SonoVue^® is actually sensitive enough to justify its use for monitoring post-therapeutic changes. So far, in the EFSUMB (European Federation of Societies for Ultrasound in Medicine and Biology) guidelines, CEUS is described as a method which can be used for the further assessment of the degree of vascularization in joints of patients with RA and which may provide useful information on the response to treatment for guiding therapeutic strategy. The technique has the potential to be utilized at dedicated centers using a standardized methodology (Piscaglia F et al. Ultraschall in Med 2012; 33: 33 – 59).

In conclusion, the cases presented here for the first time show that CEUS using the second-generation contrast medium SonoVue^® seems to be a valid instrument for monitoring disease activity and may be used as a model to evaluate the efficacy of anti-inflammatory drugs in KJS in the setting of rheumatic diseases. CEUS compared to PD-US may offer the advantage of better quantification of synovial perfusion.