Optimizing the anti-inflammatory strategies in (osteo)arthritis: local or systemic?

Arthritis is affecting millions of people globally, involvement and distribution depending on the type of arthritis. The most common arthritic conditions are osteoarthritis (OA) and rheumatoid arthritis (RA). Despite the pathogeneses being fundamentally different, both joint diseases share the same need for local treatment of synovitis. No current treatment can stop the progression of OA. Local articulate treatment including glucocorticoid (GC) injections, radiosynoviorthesis (RSO) and surgical synovectomy are the only options to relieve pain and temporally improve movability before surgical intervention. For RA, despite effective systemic treatments, similarly need for local articulate treatment is still present, especially early in the disease, but also in case of recurrent episodes of disease flare. Current evidence supports local GC injection as first line treatment for persistent synovitis in a single or a few joints. RSO provides an evident and effective alternative for GC refractory synovitis, especially in early RA. Surgical synovectomy is an invasive alternative, but with less documented efficacy. Whether one unsuccessful intraarticular GC injection is enough to change of mode of action for local treatment is still unclear and needs to be further investigated. In conclusion persistent single joint synovitis in OA and RA is well treated with local treatment. Intra-articular GC injection is considered as first line of treatment, but RSO provides an additional treatment alternative with less side effects and better evidence of efficacy than surgical synovectomy.

A novel fluorescence optical imaging scoring system for hand synovitis in rheumatoid arthritis-validity and agreement with ultrasound.

OBJECTIVES: To develop and validate a new semiquantitative fluorescence optical imaging (FOI) scoring system-the FOI Enhancement-Generated RA Score (FOIE-GRAS) for synovitis assessment in the hand. METHODS: The development of FOIE-GRAS was based on consensus of four experts in musculoskeletal imaging. Forty-six RA patients, eligible for treatment intensification and with ≥1 clinically swollen joints in the hands, and 11 healthy controls were included. FOI, ultrasound and clinical assessment of both hands were obtained at baseline and for RA patients after 3 and 6 months' follow-up. Twenty RA patients had an FOI rescan after 4 h. Synovitis was scored using FOIE-GRAS and the OMERACT ultrasound synovitis scoring system. All FOI images were scored by two readers. Inter-scan, inter- and intra-reader reliability were determined. Furthermore, FOIE-GRAS agreement with ultrasound and responsiveness was assessed. RESULTS: FOIE-GRAS synovitis was defined as early enhancement, and scores were based on the degree of coverage of the specific joint region after 3 s (0-3). Inter-scan, intra- and inter-reader intraclass correlations coefficients (ICC) were good to excellent for all baseline scores (0.76-0.98) and moderate to good for change (0.65-76).The FOIE-GRAS had moderate agreement with ultrasound (ICC 0.30-0.54) for total score, a good standardized response mean (>0.80), and moderate correlation with clinical joint assessment and DAS28-CRP. The median (interquartile range) reading time per FOI examination was 133 (109, 161) s. Scores were significantly lower in controls [1 (0, 4)] than RA patients [11 (6, 19)]. CONCLUSION: The FOIE-GRAS offers a feasible and reliable assessment of synovitis in RA, with a moderate correlation with ultrasound and DAS28-CRP, and good responsiveness.

Very low prevalence of ultrasound-detected tenosynovial abnormalities in healthy subjects throughout the age range: OMERACT ultrasound minimal disease study.

OBJECTIVES: This study aimed to determine the prevalence of ultrasound-detected tendon abnormalities in healthy subjects (HS) across the age range. METHODS: Adult HS (age 18-80 years) were recruited in 23 international Outcome Measures in Rheumatology ultrasound centres and were clinically assessed to exclude inflammatory diseases or overt osteoarthritis before undergoing a bilateral ultrasound examination of digit flexors (DFs) 1-5 and extensor carpi ulnaris (ECU) tendons to detect the presence of tenosynovial hypertrophy (TSH), tenosynovial power Doppler (TPD) and tenosynovial effusion (TEF), usually considered ultrasound signs of inflammatory diseases. A comparison cohort of patients with rheumatoid arthritis (RA) was taken from the Birmingham Early Arthritis early arthritis inception cohort. RESULTS: 939 HS and 144 patients with RA were included. The majority of HS (85%) had grade 0 for TSH, TPD and TEF in all DF and ECU tendons examined. There was a statistically significant difference in the proportion of TSH and TPD involvement between HS and subjects with RA (HS vs RA p<0.001). In HS, there was no difference in the presence of ultrasound abnormalities between age groups. CONCLUSIONS: Ultrasound-detected TSH and TPD abnormalities are rare in HS and can be regarded as markers of active inflammatory disease, especially in newly presenting RA.

Ultrasound assessment of hands and feet for synovitis at time of first clinical visit markedly reduces time to diagnosis in routine care.

OBJECTIVES: The role of musculoskeletal US (MSUS) in routine care for diagnosing arthritis is not fully elucidated, but US is more sensitive than clinical joint examination for detecting synovitis. Therefore, the use of US may facilitate diagnosis of arthritis. The aim of the study was to assess whether MSUS examination of hands and feet in relation to the first clinical visit had an impact on the time to reach a final diagnosis and the number of clinical follow-up visits needed after first consultation. METHODS: Two cohorts referred to the outpatient arthritis clinic with suspected arthritis were compared with each other, (i) MSUS (October 2017 to June 2018) of hands and feet performed prior to the first clinical visit and (ii) MSUS (November 2016 to June 2017) was performed ad hoc, for the following aspects: time to clinical diagnosis, number of clinical visits needed, and number of US examinations. RESULTS: In total, 163 and 109 patients were included in the MSUS and comparative cohorts, respectively. Adding MSUS to the first clinical visit reduced the time to diagnosis from mean 31 (32.2) days to 12 (17.3) days (P < 0.01). The number of clinical visits needed was reduced from mean 2.8 (1.1) to 2.1 (1.3) (P < 0.01), corresponding to a reduction of 114 visits in the MSUS cohort. A final diagnosis with inflammatory arthritis was found in 76 (47%) of patients in the MSUS cohort vs 29 (27%) in the comparative cohort (P < 0.01). CONCLUSION: In patients referred for suspected arthritis, routine MSUS in relation to the first clinical visit significantly reduces time to diagnosis and number of clinical visits needed to reach a final diagnosis.

Fluorescence optical imaging: ready for prime time?

The novel technique of fluorescence optical imaging (FOI, Xiralite), which is approved in the European Union and the USA for clinical use, has been the object of studies since 2009. Indocyanine green-based FOI can demonstrate an impaired microcirculation caused by inflammation in both hands in one examination. Several studies have investigated FOI for detection of joint inflammation by comparing FOI to magnetic resonance imaging (MRI) and/or musculoskeletal ultrasound (MSUS). The results have shown a generally good agreement (>80%) between FOI and clinical examination, MRI and MSUS by power Doppler in inflammatory joint diseases. Moreover, characteristic enhancements in skin and nails are seen in PsA, which potentially can be useful in the diagnostic process of early undifferentiated arthritis. Furthermore, FOI has been investigated for the visualisation of a disturbed microcirculation in the hands and fingers of patients with systemic sclerosis (SSc), highlighting the potential of monitoring vascular changes in SSc and other vasculopathies. The available data indicate that it is time to consider FOI as a useful part of the imaging repertoire in rheumatology clinical practice, particularly where MSUS and MRI are not easily available.

Using a DAS28-CRP-steered treat-to-target strategy does not eliminate subclinical inflammation as assessed by ultrasonography in rheumatoid arthritis patients in longstanding clinical remission.

BACKGROUND: Subclinical synovitis by ultrasound is a frequent finding in rheumatoid arthritis (RA) patients in remission and has been shown to be related to erosive progression, risk of flare and unsuccessful drug tapering, but it has not been investigated how a DAS28 T2T-steered strategy in routine care affects the presence of subclinical synovitis in RA patients in remission. The aim of the current study was to investigate the presence of ultrasound-detected subclinical inflammation in RA patients in long-term remission receiving either biological or conventional disease-modifying anti-rheumatic drugs (bDMARD/csDMARD) and, finally, to investigate the presence of ultrasound remission using different ultrasound remission criteria. METHODS: Eighty-seven RA patients (42 patients receiving bDMARD and 45 csDMARD) received DAS28-CRP-steered treatment in routine care and had achieved DAS28-CRP-remission for > 1 year without radiographic progression. Twenty-four joints were scored 0-3 by ultrasound (elbows, wrists, knees, ankles, metacarpophalangeal and metatarsophalangeal joints 2-5) for grey-scale synovial hypertrophy (GS) and colour Doppler activity (CD) using the OMERACT scoring system. Ultrasound remission was defined as strict (GS score = 0 and CD score = 0), semi-strict (GS score < 1 and Doppler score = 0) and Doppler remission (Doppler score = 0). RESULTS: No differences between treatment groups were found for GS sum score and Doppler sum score (median (range) 6 (0-19) and 0 (0-12), respectively). A Doppler score > 0 in at least 1 joint was seen in 44%, a GS score > 1 in at least 1 joint in 93% and a GS score > 2 in at least 1 joint in 54% of patients. Strict ultrasound remission was only observed in bDMARD patients (7%; p = 0.01). Thirty-seven per cent were in semi-strict ultrasound remission and 56% in Doppler remission (no significant difference between groups) with similar results across the subgroups of patients who also fulfilled the ACR-EULAR Boolean-, CDAI- and SDAI-remission criteria. CONCLUSIONS: Ultrasound frequently detected subclinical synovitis in RA patients in longstanding DAS28-remission obtained through a DAS28-CRP-steered strategy. This was independent of treatment and applied ultrasound remission criteria. Strict ultrasound remission was rare.

Flares in rheumatoid arthritis: do patient-reported swollen and tender joints match clinical and ultrasonography findings?

OBJECTIVES: To investigate how patient-reported flares in RA are related to clinical joint examination and inflammation detected by US. METHODS: Eighty RA patients with DAS28-CRP <3.2 and no swollen joints at baseline were followed for 1 year. In case of patient-reported hand flare with swollen and tender joints (SJ and TJ, respectively), patients underwent clinical examination for SJ/TJ and US of bilateral wrists, MCP and PIP 1st-5th, six extensor tendon compartments and wrist flexor tendons for synovitis/tenosynovitis. Percentage agreement and kappa were calculated between patient-reported SJ and TJ, clinical examination for SJ/TJ and US findings indicative of inflammation. With US as reference, sensitivity, specificity, positive/negative predictive value and accuracy of patient-reported and clinically examined joints were determined. RESULTS: Hand flare was reported by 36% (29/80) of patients. At time of flare, all clinical and ultrasonographic measures of disease activity deteriorated compared with baseline. Agreement between patient-reported SJ/TJ, clinically examined SJ/TJ and US was slight (kappa = 0.02-0.20). Patients and clinicians agreed in 79-93% of joints, more frequently on SJ than TJ. With US as reference, specificities were 86-100% and 88-100%, and sensitivities 12-34% and 4-32% for patient-reported SJ/TJ and clinically examined SJ/TJ, respectively. CONCLUSION: Over 12 months of follow-up, hand flare was reported by every third RA patient. Self-reported flares were associated with increased disease activity as determined by clinical examination and US. Patient-reported joint assessment may aid in capturing flares between routine clinical visits.

The Use of the OMERACT Ultrasound Tenosynovitis Scoring System in Multicenter Clinical Trials.

OBJECTIVE: To test the sensitivity to change of the Outcome Measures in Rheumatology Clinical Trials (OMERACT) ultrasound (US) scoring system for tenosynovitis when applied in a multicenter design. METHODS: RA patients with US-verified tenosynovitis were recruited when scheduled for treatment intensification. Tenosynovitis was assessed at baseline, and 3 and 6 months followup, using the semiquantitative OMERACT scoring system. RESULTS: Expressed in median (25th; 75th percentiles), the overall greyscale and Doppler score decreased significantly from baseline at 4 (2; 7) and 3 (2; 6), to 6 months at 2 (0; 3) and 0 (0; 1, p < 0.01), respectively, and showed high responsiveness (standardized response mean ≥ 0.8). CONCLUSION: The OMERACT US scoring system for tenosynovitis showed high responsiveness, supporting its use for diagnosing and monitoring tenosynovitis in multicenter trials.

Tenosynovitis Evaluation Using Image Fusion and B-Flow - A Pilot Study on New Imaging Techniques in Rheumatoid Arthritis Patients.

Aim The aim of this study was to compare the assessment of tenosynovitis by ultrasound (US) and magnetic resonance imaging (MRI) using the image fusion technique and to investigate whether US B-flow imaging (BFI) is an alternative to Doppler US when assessing tenosynovitis. Materials and Methods 15 patients with rheumatoid arthritis (RA) had US-verified tenosynovitis in the wrist/hand. An MRI was performed of the wrist/hand with subsequent repeated US and image fusion. Images were compared in three steps: 1. Visual image comparison, 2. Quantitative measurement of transverse areas of the affected tendon and tendon sheath, using two tendon measures on MRI, area 1 and area 2, excluding and including partial volume artifacts, respectively, 3. Assessment using the OMERACT semi-quantitative scoring systems for US and MRI. Furthermore, BFI was assessed as: 0: No flow, 1: Focal flow, 2: Multifocal flow, 3: Diffuse flow, in the tendon sheath. Results The median areas on US and MRI (areas 1 and 2) were 0.16 cm2 (25;75 pctl: 0.10; 0.25), 0.9 cm2 (0.06; 0.18) and 0.13 cm2 (0.10; 0.25), respectively, for included tendons and 0.18 cm2 (0.13; 0.26), 0.27 cm2 (0.20; 0.45) and 0.23 cm2 (0.16; 0.40) for tendon sheaths. No statistically significant difference was found between US tendon area and MRI tendon area 2 (Wilcoxon's test; p = 0.47). Overall, the agreement between grayscale and color Doppler (CD) US and MRI tenosynovitis visualization and scoring was good, but not between CD and BFI. Conclusion US and MRI have high agreement using image fusion for the assessment of tenosynovitis when partial volume artifacts are taken into account. BFI is not an alternative to CD for the measurement of slow flow in tenosynovitis.

Intramuscular versus ultrasound-guided intratenosynovial glucocorticoid injection for tenosynovitis in patients with rheumatoid arthritis: a randomised, double-blind, controlled study.

OBJECTIVE: The aim of this study was to compare the efficacy of intramuscular versus ultrasound (US)-guided intratenosynovial glucocorticoid injection in providing disease control after 2, 4 and 12 weeks in patients with rheumatoid arthritis(RA) with tenosynovitis. METHODS: Fifty patients with RA and tenosynovitis were randomised into two double-blind groups: (A) 'intramuscular group', receiving intramuscular injection of betamethasone and US-guided intratenosynovial isotonic saline injection and (B) 'intratenosynovial group' receiving saline intramuscularly and US-guided intratenosynovial betamethasone injection. All patients were in stable disease-modifying anti-rheumatic drug treatment prior to and during the study. Patients were excluded, and considered non-responders, if any treatments were altered during the follow-up period. 'US tenosynovitis remission', defined as US tenosynovitis grey-scale score ≤1 and colour Doppler score=0, was assessed at week 4 (primary outcome), and weeks 2 and 12, using non-responder imputation for missing data. RESULTS: US tenosynovitis remission at week 4 was achieved in 25% (6/24) in the 'intramuscular group' versus 64% (16/25) in the 'intratenosynovial group', that is, a difference of -39 percentage point (pp) (CI -65pp to -13pp), Fisher exact test p=0.001. Corresponding values for the 'intramuscular group' versus the 'intratenosynovial group' at 2 and 12 weeks were 21% (5/24) versus 48% (13/25), that is, a difference of -27pp (CI -53pp to -2pp), p=0.072 and 8% (2/24) versus 44% (11/25), that is, difference of -36pp (-58pp to -13pp), p=0.003. Most US, clinical and patient-reported scores improved more in the 'intratenosynovial group' at all follow-up visits. CONCLUSIONS: In this randomised double-blind clinical trial, patients with RA and tenosynovitis responded significantly better to US-guided intratenosynovial glucocorticoid injection than to intramuscular glucocorticoid injection, both at 4 and 12 weeks follow-up. TRIAL REGISTRATION NUMBER: EudraCT nr: 2013-003486-34.

Validity and sensitivity to change of the semi-quantitative OMERACT ultrasound scoring system for tenosynovitis in patients with rheumatoid arthritis.

OBJECTIVES: The aim was to evaluate the metric properties of the semi-quantitative OMERACT US scoring system vs a novel quantitative US scoring system for tenosynovitis, by testing its intra- and inter-reader reliability, sensitivity to change and comparison with clinical tenosynovitis scoring in a 6-month follow-up study. METHODS: US and clinical assessments of the tendon sheaths of the clinically most affected hand and foot were performed at baseline, 3 and 6 months in 51 patients with RA. Tenosynovitis was assessed using the semi-quantitative scoring system (0-3) proposed by the OMERACT US group and a new quantitative US evaluation (0-100). A sum for US grey scale (GS), colour Doppler (CD) and pixel index (PI), respectively, was calculated for each patient. In 20 patients, intra- and inter-observer agreement was established between two independent investigators. A binary clinical tenosynovitis score was performed, calculating a sum score per patient. RESULTS: The intra- and inter-observer agreements for US tenosynovitis assessments were very good at baseline and for change for GS and CD, but less good for PI. The smallest detectable change was 0.97 for GS, 0.93 for CD and 30.1 for PI. The sensitivity to change from month 0 to 6 was high for GS and CD, and slightly higher than for clinical tenosynovitis score and PI. CONCLUSION: This study demonstrated an excellent intra- and inter-reader agreement between two investigators for the OMERACT US scoring system for tenosynovitis and a high ability to detect changes over time. Quantitative assessment by PI did not add further information.

EFSUMB COMPASS for Rheumatologists dissemination and implementation--an international survey.

AIM: The European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) competency assessment (COMPASS) for rheumatologists performing musculoskeletal ultrasound (MSUS) was developed and published 2 years ago. It consists of a 3 level competency system. The objective of this study was to evaluate how the EFSUMB COMPASS has been disseminated and implemented and to assess the potential obstacles encountered. MATERIALS AND METHODS: A questionnaire was developed and distributed by e-mail to all rheumatologists certified as EFSUMB level 3. RESULTS: Seventeen (85%) rheumatologists considered that the EFSUMB COMPASS is useful for training MSUS. The majority of them (17; 85%) had informed their colleagues or national rheumatology societies about the EFSUMB COMPASS. The most common obstacle encountered for the implementation of the COMPASS was the lack of time for supervision of the trainees (9; 45%). A total of 83 rheumatologists had been trained and assessed for competency in the three EFSUMB levels. CONCLUSION: This survey highlights the current status of EFSUMB COMPASS implementation in European countries with an expected increased number of rheumatologists being able to train and assess new trainees. Still, more efforts should be done for a higher implementation of EFSUMB COMPASS across European countries.

Three-dimensional Doppler ultrasound findings in healthy wrist and finger tendon sheaths - can feeding vessels lead to misinterpretation in Doppler-detected tenosynovitis?

BACKGROUND: The aim was to investigate the presence of feeding vessels in or in close proximity to extensor and flexor tendon sheaths at the wrists level and in finger flexor tendon sheaths in healthy controls, using 3D ultrasound (US), which may cause pitfalls, in order to ensure correct interpretation of Doppler signals when diagnosing tenosynovitis. METHOD: Forty healthy participants (20 women and 20 men age 23-67 years) without prior history of arthritis, tendon diseases or present pain in their hands were included. Twenty participants had 3D Doppler US of the second and third finger and twenty of the right wrist. US was carried out using a GE Logiq E9 unit with a 3D US probe. The colour Doppler settings were to published recommendation. RESULTS: The feeding vessels in or in close proximity to the tendon sheaths were found in the flexor and extensor tendons sheaths at least once in each participant. No significant difference in feeding vessels was seen between the radial and carpal level in the wrist (p = 0.06) or between the second and third flexor tendon sheath (p = 0.84). CONCLUSION: Doppler findings in or in close proximity to the tendon sheaths were common in wrists and fingers in healthy participants. These feeding vessels can be a source of error, not only due to their presence but also because they may be interpreted as being inside the tendon sheath due to blooming and reverberations artefacts. These vessels should be taken into consideration when diagnosing Doppler tenosynovitis.