Decision Making with Ultrasound in Rheumatology

The _first aim_ of this thesis was to evaluate the added value of ultrasound in clinical decision making in patients with arthralgia, patients with psoriasis and monitoring RA patients. Our _second aim_ was to increase sensitivity of power Doppler ultrasound for MCP joints. Early diagnosis of rheumatoid arthritis and thereby facilitating early initiation of effective disease-modifying drugs can slow down disease progression and diminish joint damage. With the introduction of the 2010 ACR/EULAR classification criteria for RA we are able to classify patients as having RA at an earlier stage. We described which cut point of the 2010 criteria would enable us to earlier identify RA patients among recent onset inflammatory arthritis patients. _Part one – Ultrasound in clinical practice_ Since physical examination reached its maximum to identify synovitis, the first chapters of this thesis focus on the added value of ultrasound in daily clinical practice. Firstly, we described the association of ultrasound inflammation and the development of inflammatory arthritis in an early arthralgia cohort. Secondly, the frequency of ultrasound enthesitis in primary care psoriasis patients with musculoskeletal complaints was explored. The course of ultrasound inflammation and clinical findings in the feet in newly diagnosed RA patients was investigated next. In addition, the association of the presence of ultrasound synovitis and health status in RA patients who are in clinical remission was studied. And last we evaluated if ultrasound synovitis is a biomarker for clinical flare in RA patients who are tapering their medication. _Part two – Experimental technical research_ The performance of the power Doppler modality of several ultrasound machines was compared by a flow phantom. The same flow phantom was used to compare conventional ultrasound with high-frame rate Doppler ultrasound. And we also give the results of high-frame rate Doppler ultrasound imaging in RA patients to evaluate whether it was possible to detect higher levels of vascularisation than with conventional ultrasound

Is shoulder involvement in clinically suspect arthralgia an early feature of rheumatoid arthritis? A longitudinal ultrasound study

Pathophysiology and treatment of rheumatic disease

High-Frame-Rate Power Doppler Ultrasound Is More Sensitive than Conventional Power Doppler in Detecting Rheumatic Vascularisation

Early recognition of joint inflammation will increase treatment efficacy in rheumatoid arthritis (RA). Yet, conventional power Doppler (PD) ultrasound might not be sufficiently sensitive to detect minor inflammation. We investigated the sensitivity of high-frame rate Doppler, combined with singular value decomposition technique, to suppress tissue signals, for microvascular flow in a flow phantom setup and in a proof-of-principle study in healthy controls and in RA patients with different disease activities. In the flow phantom, minimal detectable flow velocity was a factor 3 lower with high-frame-rate PD than with conventional PD ultrasound. In the proof-of-principle study we detected a positive PD signal in all volunteers, diseased or healthy, with high-frame-rate PD ultrasound. We saw a gradual increase in PD signal in RA patients depending on disease activity. In conclusion, high-frame rate Doppler is more sensitive in detecting vascularisation than conventional PD ultrasound

Evidence and clinical relevance of maternal-fetal cardiac coupling:A scoping review

BACKGROUND: Researchers have long suspected a mutual interaction between maternal and fetal heart rhythms, referred to as maternal-fetal cardiac coupling (MFCC). While several studies have been published on this phenomenon, they vary in terms of methodologies, populations assessed, and definitions of coupling. Moreover, a clear discussion of the potential clinical implications is often lacking. Subsequently, we perform a scoping review to map the current state of the research in this field and, by doing so, form a foundation for future clinically oriented research on this topic.METHODS: A literature search was performed in PubMed, Embase, and Cochrane. Filters were only set for language (English, Dutch, and German literature were included) and not for year of publication. After screening for the title and the abstract, a full-text evaluation of eligibility followed. All studies on MFCC were included which described coupling between heart rate measurements in both the mother and fetus, regardless of the coupling method used, gestational age, or the maternal or fetal health condition.RESULTS: 23 studies remained after a systematic evaluation of 6,672 studies. Of these, 21 studies found at least occasional instances of MFCC. Methods used to capture MFCC are synchrograms and corresponding phase coherence indices, cross-correlation, joint symbolic dynamics, transfer entropy, bivariate phase rectified signal averaging, and deep coherence. Physiological pathways regulating MFCC are suggested to exist either via the autonomic nervous system or due to the vibroacoustic effect, though neither of these suggested pathways has been verified. The strength and direction of MFCC are found to change with gestational age and with the rate of maternal breathing, while also being further altered in fetuses with cardiac abnormalities and during labor.CONCLUSION: From the synthesis of the available literature on MFCC presented in this scoping review, it seems evident that MFCC does indeed exist and may have clinical relevance in tracking fetal well-being and development during pregnancy.</p

The impact of angles of insonation on left and right ventricular global longitudinal strain estimation in fetal speckle tracking echocardiography

OBJECTIVES: Two-dimensional speckle tracking echocardiography has been considered an angle-independent modality. However, current literature is limited and inconclusive on the actual impact of angle of insonation on strain values. Therefore, the primary objective of this study was to assess the impact of angles of insonation on the estimation of fetal left ventricular and right ventricular global longitudinal strain. Secondarily, the impact of different definitions for angles of insonation was investigated in a sensitivity analysis.METHODS: This is a retrospective analysis of a prospective longitudinal cohort study with 124 healthy subjects. The analyses were based on the four-chamber view ultrasound clips taken between 18+0 and 21+6 weeks of gestation. Angles of insonation were categorized into three groups: up/down, oblique and perpendicular. The mean fetal left and right ventricular and global longitudinal strain values corresponding to these three groups were compared by an ANOVA test corrected for heteroscedasticity.RESULTS: Fetal left and right ventricular global longitudinal strain values were not statistically different between the three angles of insonation (p-value &gt;0.062 and &gt;0.149, respectively). When applying another definition for angles of insonation in the sensitivity analysis, the mean left ventricular global longitudinal strain value was significantly decreased for the oblique compared to the up/down angle of insonation (p-value 0.041).CONCLUSIONS: There is no evidence of a difference in fetal left and right ventricular global longitudinal strain between the different angles of insonation in fetal two-dimensional speckle tracking echocardiography.</p

Multi-modal 3-Dimensional Visualization of Pediatric Neuroblastoma:Aiding Surgical Planning Beyond Anatomical Information

Background: Patient-specific 3D models of neuroblastoma and relevant anatomy are useful tools for surgical planning. However, these models do not represent the heterogenous biology of neuroblastoma. This heterogeneity is visualized with the ADC and 123I-MIGB-SPECT-CT imaging. Combining these multi-modal data into preoperative 3D heatmaps, may allow differentiation of the areas of vital and non-vital tumor tissue. We developed a workflow to create multi-modal preoperative 3D models for neuroblastoma surgery. Methods: We included 7 patients who underwent neuroblastoma surgery between 2022 and 2023. We developed 3D models based on the contrast enhanced T1-weighted MRI scans. Subsequently, we aligned the corresponding ADC and 123I-MIBG-SPECT-CT images using rigid transformation. We estimated registration precision using the Dice score and the target registration error (TRE). 3D heatmaps were computed based on ADC and 123I-MIBG uptake. Results: The registration algorithm had a median Dice score of 0.81 (0.75–0.90) for ADC and 0.77 (0.65–0.91) for 123I-MIBG-SPECT. For the ADC registration, the median TRE of renal vessels was 4.90 mm (0.86–10.18) and of the aorta 4.67 mm (1.59–12.20). For the 123I -MIBG-SPECT imaging the TRE of the renal vessels was 5.52 mm (1.71–10.97) and 5.28 mm (3.33–16.77) for the aorta. Conclusions: We successfully developed a registration workflow to create multi-modal 3D models which allows the surgeon to visualize the tumor and its biological behavior in relation to the surrounding tissue. Future research will include linking of pathological results to imaging data, to validate these multi-modal 3D models. Level of Evidence: Level IV. Type of Study: Clinical Research.</p

Very different performance of the power Doppler modalities of several ultrasound machines ascertained by a microvessel flow phantom

Introduction: In many patients with rheumatoid arthritis (RA) subclinical disease activity can be detected with ultrasound (US), especially using power Doppler US (PDUS). However, PDUS may be highly dependent on the type of machine. This could create problems both in clinical trials and in daily clinical practice. To clarify how the PDUS signal differs between machines we created a microvessel flow phantom.Methods: The flow phantom contained three microvessels (150, 1000, 2000 microns). A syringe pump was used to generate flows. Five US machines were used. Settings were optimised to assess the lowest detectable flow for each US machine.Results: The minimal detectable flow velocities showed very large differences between the machines. Only two of the machines may be able to detect the very low flows in the capillaries of inflamed joints. There was no clear relation with price. One of the lower-end machines actually performed best in all three vessel sizes.Conclusions: We created a flow phantom to test the sensitivity of US machines to very low flows in small vessels. The sensitivity of the power Doppler modalities of 5 different machines was very different. The differences found between the machines are probably caused by fundamental differences in processing of the PD signal or internal settings inaccessible to users. Machines considered for PDUS assessment of RA patients should be tested using a flow phantom similar to ours. Within studies, only a single machine type should be used

Absence of ultrasound inflammation in patients presenting with arthralgia rules out the development of arthritis

Background: To decrease the burden of disease of rheumatoid arthritis (RA), patients at risk for RA need to be identified as early as possible, preferably when no clinically apparent synovitis can be detected. Up to now, it has been fairly difficult to identify those patients with arthralgia who develop inflammatory arthritis (IA), but recent studies using ultrasound (US) suggest that earlier detection is possible. We aimed to identify patients with arthralgia developing IA within 1year using US to detect subclinical synovitis at first consultation. Methods: In a multi-centre cohort study, we followed patients with arthralgia with at least two painful joints of the hands, feet or shoulders without clinical synovitis over 1year. Symptom duration was<1year, and symptoms were not explained by other conditions. At baseline and at 6 and 12months, data were collected for physical examinations, laboratory values and diagnoses. At baseline, we examined 26 joints ultrasonographically (bilateral metacarpophalangeal joints 2-5, proximal interphalangeal joints 2-5, wrist and metatarsophalangeal joints 2-5). Scoring was done semi-quantitatively on greyscale (GS; 0-3) and power Doppler (PD; 0-3) images. US synovitis was defined as GS≥2 and/or PD≥1. IA was defined as clinical soft tissue swelling. Sensitivity and specificity were used to assess the diagnostic value of US for the development of IA. Univariate logistic regression was used to analyse the association between independent variables and the incidence of IA. For multivariate logistic regression, the strongest variables (p<0.157) were selected. Missing values for independent variables were

Modification of a sonographic enthesitis score to differentiate between psoriatic arthritis and young healthy volunteers

Objectives: We aimed to describe sonographic structural and inflammatory changes in entheses of patients with recently diagnosed psoriatic arthritis (PsA), patients with established PsA, and young healthy volunteers, and to investigate whether the MAdrid Sonographic Enthesitis Index (MASEI) enables us to distinguish these groups in an extreme comparison. Method: New and established PsA patients and healthy volunteers (aged 20–30 years) were recruited. The triceps, quadriceps, patellar, Achilles and elbow extensor tendon insertion, and plantar fascia entheses were investigated sonographically for structural changes, erosions, calcifications, increased thickness, bursitis, and power Doppler (PD) signal according to the MASEI. Results: The study included 25 new and 25 established PsA patients, and 25 healthy volunteers. Increased thickness and PD signal in knee entheses were common for patients and healthy volunteers, while changes at other locations predominantly occurred in patients only. PD was recoded (1, one spot; 1.5, two or three spots; 2, confluent signal; 3, severe confluent signal) and thickness of knee entheses excluded. This resulted in different modified MASEI scores between PsA patients and young healthy controls: median (interquartile range) modified MASEI of 13 (10–22.5) in new PsA, 13.5 (9.5–18) in established PsA, and 3 (1–8.5) in healthy volunteers (p = 0.002). Conclusions: Structural ultrasound changes and PD in entheses are common in both new and established PsA and healthy controls. MASEI score did not differentiate PsA patients from young healthy volu