Ultrasound Synovitis Research Articles

Associations between power Doppler ultrasound findings and B-mode synovitis and clinical arthritis in juvenile idiopathic arthritis using a standardised scanning approach and scoring system

ObjectivesTo describe power Doppler (PD) ultrasound findings in joint regions with B-mode (BM) synovitis using a standardised scanning protocol and scoring system in patients with juvenile idiopathic arthritis (JIA). Further,...

Flare during tapering of biological DMARDs in patients with rheumatoid arthritis in routine care: characteristics and predictors

ObjectiveTo identify predictors of flare in a 2-year follow-up study of patients with rheumatoid arthritis (RA) in sustained clinical remission tapering towards withdrawal of biological disease-modifying anti-rheumatic drugs (bDMARDs).MethodsSustained clinical...

Criteria Associated with Treatment Decisions in Juvenile Idiopathic Arthritis with a Focus on Ultrasonography: Results from the JIRECHO Cohort.

The treatment of children with juvenile idiopathic arthritis (JIA) to prevent disability is a major challenge in paediatric rheumatology. The presence of synovitis, which is difficult to detect in children, is associated with structural damage. Musculoskeletal ultrasonography (MSUS) can be used in patients with JIA to reveal subclinical synovitis. The primary aim was to determine whether the use of MSUS was associated with therapeutic modification in patients with JIA. The secondary aim was to identify other factors associated with therapeutic decisions. We conducted an observational study based on the JIRECHO multi-centre cohort, which was developed to provide a systematic MSUS follow-up for patients with JIA. Follow-up occurred every 6months and included clinical and MSUS examinations. We included children who underwent MSUS of the elbows, wrists, second metacarpophalangeal joints, knees and ankles, which was performed by expert sonographers. Clinical and biological data, disease activity scores and information on therapeutics were collected. A total of 185 visits concerning 112 patients were recorded. Three groups were defined according to the therapeutic decision: escalation (22%, n = 40), de-escalation (14%, n = 26) or stable (64%, n = 119). In the "therapeutic escalation" group: the presence of ultrasonographic synovitis in B-mode and the presence of grade 2 or 3 synovitis in B-mode were not significantly more frequent than in the "stable therapeutic or de-escalation" group (80% versus 65%, p = 0.06; 33% versus 19%, p = 0.06), and the patient's and physician's visual analogue scale (VAS) scores, the clinical JADAS and the C-reactive protein level were significantly higher, but only physician's VAS score remained in the model of logistic regression. In the "therapeutic de-escalation" group: there was no difference in the presence of US synovitis compared with the "stable therapeutic or escalation" group (62% versus 69%, p = 0.48). Even though US synovitis tended to be more frequent in patients with therapeutic escalation, the study did not show that the presence of synovitis in MSUS was statistically associated with therapeutic modifications in patients with JIA. Treatment remained stable despite the presence of US synovitis.

Optimizing Reliability of Real-Time Sonographic Examination and Scoring of Joint Synovitis in Rheumatoid Arthritis.

Musculoskeletal ultrasound real-time image acquisition and scoring are complex, and many factors affect reliability. Static image reliability does not guarantee real-time scoring. This study aimed to identify factors and solutions to improve real-time scoring reliability for the grey scale and power Doppler evaluation of synovitis. We also report on using a novel musculoskeletal ultrasound synovitis rule-based scoring atlas. In four stages, we evaluated inter- and intra-reader reliability among three ultrasonographers (US1-3). Intra- and inter-reader reliability was calculated using weighted-kappa, intraclass correlation coefficient, and Spearman correlation. Reliability statistics were compared between stages using permutation tests to compute empirical distributions for differences in those statistics. At each stage, factors that diminished reliability were identified and addressed. After intensive reliability exercises, a RA MSUS atlas with in-depth scoring rules was generated to improve interpretive reliability. The three ultrasonographers had good to excellent intra-reader reliability for real-time acquisition scoring over 2432 views (weighted kappa 0.52-0.80, intraclass correlation coefficient 0.59-0.86, and Spearman correlation 0.64-0.86). Inter-reader reliability was good to excellent between US1/US2 and US1/US3 (weighted kappa 0.51-0.66, intraclass correlation coefficient 0.66-0.75, Spearman correlation 0.59-0.73). US1 achieved significant improvement in intra-reader reliability from stage 1 to stage 2 (p<0.05, weighted-kappa 0.63 to 0.80, intraclass correlation coefficient 0.71 to 0.86, Spearman 0.67 to 0.86) with use of the atlas. Conclusion: This rheumatoid arthritis musculoskeletal ultrasound study addressed complex factors affecting musculoskeletal ultrasound acquisition-scoring reliability. Systematic identification and amelioration of many factorsand using a novel rule-based scoring atlassignificantly improved intra-reader reliability.

Ultrasonographic Evaluation of Sub-Clinical Synovitis in Juvenile Idiopathic Arthritis: The Disease Classification and Management.

Ultrasonography (USG) is a perfect device for analyzing more than one joint in rather brief intervals of time and is well accepted by children with no harmful ionizing radiation, usually does not require sedation, and can be carried out without difficulty in an outpatient setting. To demonstrate the ability of ultrasonography (USG) in detecting clinical and subclinical synovitis in children with juvenile idiopathic arthritis (JIA) and compare the USG findings with clinical findings. 20 patients with JIA diagnosed according to the ILAR criteria were include. A total of 208 joints were examined both clinically and ultrasonographically for detection of synovitis. The presence of subclinical synovitis detected by USG was sought and its effect on the classification of JIA was assessed. USG assessment was done using the High-Resolution Linear probe including both grey scale and Power Doppler assessment. The mean age of patients was 10.2 years with average disease duration of 5.9 months. A total of 49 joints (23.5%) had clinical synovitis and 59 joints (28.4%) had USG synovitis out of a total of 208 joints. A total of 14 joints had subclinical synovitis (8.8% out of the 159 clinically normal joints) upon USG. USG additionally brought about classifying three patients as having poly articular disorder who had been considered as oligo articular upon clinical examination. USG assessment of subclinical synovitis in JIA patients is an essential component of classifying the disease and detects more joints with synovitis than clinical examination; however, both are complimentary and should be used in combination in all patients with JIA.

The role of ultrasonographic synovial assessment in rheumatoid arthritis patients with concomitant fibromyalgia.

This study aimed to compare the prevalence and musculoskeletal ultrasonography (US) findings of rheumatoid arthritis (RA) patients with concomitant fibromyalgia (FM) according to the 1990 American College of Rheumatology (ACR) FM classification criteria or the 2016 ACR FM diagnostic criteria. This cross-sectional study included 63 patients (17 males, 46 females; mean age: 48.2±7.1 years; range, 18 to 62 years) with RA. Medical history and laboratory data were obtained from electronic records. Clinical examination, composite disease activity measures, functional status, and the German 7-joint ultrasound score were assessed to evaluate disease activity and synovial inflammation. The patients were divided into three groups: patients who met only the 2016 ACR criteria, patients who met only the 1990 ACR criteria, and patients who met both criteria. In patients with RA, concomitant FM prevalence was 34.9% according to the 2016 ACR FM diagnostic criteria versus 23.8% according to the 1990 ACR FM classification criteria. Rheumatoid arthritis patients with FM had high tender joint count and disease activity scores, while musculoskeletal US findings were similar. Patients who met only the 2016 ACR FM diagnostic criteria had significantly higher gray-scale US and power Doppler US synovitis scores than patients who satisfied only ACR 1990 FM classification criteria (p=0.03 and p=0.02, respectively). Synovial inflammation is a prominent sign in RA patients diagnosed with FM according to the 2016 ACR FM diagnostic criteria. The higher disease activity seen in the presence of FM in RA patients is associated with FM rather than synovitis.

P215 In a treatment-naïve, early rheumatoid arthritis cohort, baseline ultrasound power Doppler synovitis and tenosynovitis are highly associated with remission when treated with first line etanercept + methotrexate (MTX) but not MTX alone

Abstract Background/Aims Clinical remission is the treatment target in rheumatoid arthritis (RA). In a treatment-naïve, early RA trial (VEDERA: ‘Very early Etanercept and Methotrexate versus Methotrexate with/without Delayed Etanercept in RA’), we previously reported the presence of ultrasound power Doppler synovitis (PDUS) at diagnosis that improved in the majority with treatment. For this study, we aimed to investigate specifically for an association of baseline PDUS and PD tenosynovitis (PDTS) with subsequent clinical remission (DAS28ESR ≤ 2.6) in VEDERA, also comparing the two treatment groups. Methods The ‘VEDERA’ trial randomised 120 treatment-naïve, new-onset RA patients to either first-line etanercept+methotrexate (ETN+MTX) or methotrexate treat-to-target (MTX-TT) regime with escalation to ETN+MTX if not in DAS28ESR remission at week 24. Clinically symptomatic and dominant hand (MCP 1-5, wrist, flexor tendons 1-5 and extensor carpii ulnaris tendon) ultrasound assessments were completed at baseline, weeks 12, 24 and 48. PDUS and PDTS were assessed semi-quantitatively and converted to dichotomous (absent = total score 0, present = total score ≥ 1) for this logistic regression analysis. Results At baseline, 68% (81/120) demonstrated PDUS and 68% also demonstrated PDTS overall. In the MTX-TT group, 63% (38/60) had PDUS and 62% (37/60) had PDTS at baseline. In ETN+MTX group, 72% (43/60) had PDUS and 75% (45/60) had PDTS at baseline. As per randomised trial, there were no differences in baseline demographics, DAS28ESR and HAQ between the groups. Overall, baseline PDUS was associated with week 24 remission and baseline PDTS was associated with week 24 and 48 remission (table 1). Baseline PDUS was particularly associated with week 24 remission in the ETN+MTX group, with a high OR (95% CI) of 6.83(1.2 - 38.91) compared to the MTX-TT group [1.75(0.5 - 6.14)]. Baseline PDTS was also associated with a high OR for week 48 remission in the ETN+MTX group (OR [95% CI] 9.13[1.77 - 47.02]) in contrast to an absence of association in the MTX-TT group. Conclusion Baseline PDUS and PDTS are associated with remission in early RA patients treated with TNF-inhibitor treatment. These measures may be useful to stratify patients early for TNF bDMARD to attain the target of clinical remission in RA. Disclosure R. Shukla: None. R. Hum: Other; R.H holds an Academic Clinical Fellowship funded by the National Institute for Health Research (NIHR) through the Integrated Academic Training (IAT) Programme. P. Ho: None. R.J. Wakefield: None. P. Emery: None. M.H. Buch: None.

P217 Describing the evolution of concordance/discordance between DAS28-ESR and ultrasound power Doppler synovitis in a treatment-naïve early RA cohort

Abstract Background/Aims Discordance between DAS28-ESR and ultrasound (US)-detected power Doppler synovitis (PDUS) can lead to unnecessary DMARD cycling. Using DAS28-ESR and PDUS in an early RA trial cohort, we aimed to identify and describe concordance and discordance at diagnosis and evaluate their proportional change in response to treatment. Methods The ‘VEDERA’ trial randomised 120 treatment-naïve, new-onset RA patients to first-line etanercept + methotrexate (ETN+MTX) or methotrexate treat-to-target (MTX-TT) with escalation to ETN+MTX if not in DAS28-ESR remission at week 24. Clinical and US assessments were completed at baseline, weeks 12/24/48. Remission was DAS28-ESR ≤2.6 and active disease was DAS28-ESR &amp;gt;2.6. PDUS presence was defined as total PDUS score ≥ 1. Active concordance was defined as active disease with PDUS while active discordance was defined as active disease without PDUS. Remission concordance was defined as remission without PDUS while remission discordance was defined as remission with PDUS. Descriptive analyses were undertaken to address the above aims. Results At baseline all patients had active disease - 67% (81/120) were concordant and 33% (39/120) were discordant. Baseline DAS28-ESR and individual components were higher in the concordant compared to discordant group. In the active concordant group, from baseline to weeks 24 and 48 respectively, 30% (24/81) and 20% (16/81) persisted, and 26% (22/81) and 38% (31/81) became remission concordant; while 30% (24/81) and 35% (28/81) shifted to active discordance at weeks 24 and 48 respectively and 14% (11/81) and 7% (6/81) became remission discordant. In the active discordant group, from baseline to weeks 24 and 48 respectively, 72% (28/39) and 49% (19/39) persisted and only one and two patients were remission discordant; while 8% (3/39) and 15% (6/39) shifted to active concordance at weeks 24 and 48 respectively and 18% (7/39) and 31% (12/39) became remission concordant. Conclusion Discordance of DAS28 is typically associated with later RA. In this report, a third of patients shifted from active concordance to discordance following DMARD treatment early in the RA pathway. Further study is needed to understand how these patients compare to those that started and persisted with active discordance, and also later discordant RA patients. Disclosure R. Shukla: None. D.A. Selby: None. P. Emery: None. D. Plant: None. M.H. Buch: None.

P246 Revision to musculoskeletal domain of BILAG-2004 index to incorporate ultrasound findings

Abstract Background/Aims The BILAG-2004 index grades musculoskeletal (MSK) inflammation as mild (C), moderate (B) and severe (A), based on clinical features. In a recent study, 27% of SLE patients with MSK pain have ultrasound (US) synovitis without swelling, and respond better to therapy than those with normal ultrasound. We aimed to revise the MSK domain of the BILAG-2004 index to improve its utility in modern practice. Methods An MSK sub-committee reviewed the existing BILAG-2004 MSK definitions and glossary, then re-analysed data from recent studies to propose revised definitions. Results The new definitions/changes are: (i) BILAG-C arthralgia (if US is not performed) is defined as a classical inflammatory symmetrical small-joint distribution of symptomatic joints on clinical assessment, based on the features most associated with US inflammation in a previous study. If US is performed, all previous BILAG-C patients are reclassified: (ii) BILAG-B now includes patients without swelling if they have significant synovitis/tenosynovitis on US in symptomatic joints/tendons; (iii) patients with arthralgia without swelling are scored as BILAG-D instead of C, if US of the symptomatic joints has been performed and is normal; (iv) a more detailed definition of functional impairment is provided for BILAG-A. Data from 221 symptomatic SLE patients (BILAG-A-C) in two recent studies were re-analysed in the light of the above changes. 121/221 (54.8%) were graded clinically as having arthralgia / myalgia (BILAG-C) on BILAG-2004 . Of these, 53/121 (43.8%) had evidence of synovitis (GS &amp;gt; 1 or PD &amp;gt; 0) or tenosynovitis (GS &amp;gt; 0 or PD &amp;gt; 0) on US. The effect on grading if US were performed on all BILAG C cases is shown in table 1. Conclusion Future versions of the BILAG index will allow the use of US to classify patients who are graded as mild inflammatory arthritis (BILAG-C) to moderate (BILAG-B) or non-inflammatory pain (BILAG-D/E). Although US is not required for all assessments it may be used when there is diagnostic uncertainty. This is in keeping with clinical practice in inflammatory arthritis care, and similar to use of other investigations (e.g. renal biopsy) that contribute to BILAG assessments of other systems. Disclosure R.D. Sandler: None. E.M. Vital: None. A. Prabu: None. C. Riddell: None. K.I. Mahmoud: None. L. Teh: None. C.J. Edwards: None. C. Yee: None.

P253 Ultrasound demonstrates continued improvement in psoriatic arthritis synovitis and enthesitis with secukinumab: 52-week results from a Phase 3 study

Abstract Background/Aims Power Doppler ultrasound (PDUS) is a sensitive non-invasive imaging tool to visualize a wide range of articular and periarticular inflammation in psoriatic arthritis (PsA). ULTIMATE (NCT02662985) is the first large RCT that used ultrasound with Global OMERACT ultrasound synovitis score (GLOESS) as the primary endpoint, to demonstrate early benefits of secukinumab on synovitis in patients with PsA through 12 weeks. Here we report the responsiveness of ultrasound on synovitis and enthesitis, clinical efficacy, and safety of secukinumab up to 52 weeks. Methods This was a 52-week study with 12-week double-blind placebo-controlled treatment followed by 12-week open-label treatment and 6-month open-label extension treatment in all patients. Synovitis and ultrasound enthesitis response were measured by GLOESS and Global OMERACT enthesitis score (definitions 1 and 2) at patient level, respectively. Other assessments across key PsA manifestations of joints (ACR responses), enthesitis, (SPARCC), skin (PASI responses), dactylitis (LDI) and physical function (HAQ-DI) were also evaluated. Data are presented as observed. Results A total of 166 patients were enrolled, of which 90% (75/83) of secukinumab and 83% (69/83) of placebo-secukinumab participants completed 52 weeks. A continued improvement in GLOESS was observed in both secukinumab and placebo-secukinumab groups after switching to active therapy at Week 12 through Week 52 and a similar trend of improvement in Global OMERACT enthesitis score (definition 1 and 2) was observed up to 52 weeks in both groups (Table). At 52 weeks, sustained clinical response rates were observed in secukinumab (ACR20, 89%; ACR50, 68%; ACR70, 48%; PASI 90, 59%; PASI 100, 55%) and placebo-secukinumab groups (ACR20, 84%; ACR50, 72%; ACR70, 47%; PASI 90, 74%; PASI 100, 48%). Mean changes from baseline at Week 52 in HAQ-DI and SPARCC were -3.0 and -0.8 and -3.6 and -0.7 for secukinumab and placebo-secukinumab, respectively. There were no new or unexpected safety findings. Conclusion ULTIMATE demonstrated the responsiveness of ultrasound on both synovitis and enthesitis outcomes in PsA supporting its use in clinical trials, and confirmed the rapid and continued benefits of secukinumab through 52 weeks. Sustained efficacy was also observed across key clinical PsA manifestations with a safety profile consistent with previous reports. Disclosure P.G. Conaghan: Consultancies; AbbVie, AstraZeneca, BMS, Eli Lilly, Galapagos, Gilead, Novartis, Pfizer. Member of speakers’ bureau; AbbVie, AstraZeneca, BMS, Eli Lilly, Galapagos, Gilead, Novartis, Pfizer. M.A. D’Agostino: Consultancies; Sanofi, Novartis, BMS, Janssen, Celgene, Roche, AbbVie, UCB, Eli Lilly. Member of speakers’ bureau; Sanofi, Novartis, BMS, Janssen, Celgene, Roche, AbbVie, UCB, Eli Lilly. G. Schett: Member of speakers’ bureau; AbbVie, BMS, Celgene, Janssen, Eli Lilly, Novartis, Roche, UCB. C. Guerrero: None. P. Hanova: None. T. Cazenave: None. M.S. Stoenoiu: Honoraria; Roche, AbbVie, BMS, Gilead, Jonsson, MSD, Novartis, Pfizer, UCB. Member of speakers’ bureau; Roche, AbbVie, UCB. Grants/research support; Roche, AbbVie, UCB. M. Backhaus: Honoraria; Roche, AbbVie, BMS, Gilead, Jonsson, MSD, Novartis, Pfizer, UCB. Member of speakers’ bureau; Roche, AbbVie, UCB. Grants/research support; Roche, AbbVie, UCB. G. Mouterde: Consultancies; AbbVie, Lilly. Honoraria; AbbVie, BMS, Lilly, Novartis, Pfizer, Roche, Chugai, UCB. Grants/research support; Celgene, Pfizer. M. Boers: Consultancies; BMS, Novartis, Pfizer, GSK. A. Duggan: Other; Employee of Novartis. P. Goyanka: Other; Employee of Novartis MSD. C. Gaillez: Shareholder/stock ownership; Novartis, BMS. Other; Employee of Novartis.

Matrix metalloproteinase-3 as a marker of subclinical activity in rheumatoid arthritis patients: Relation to ultrasonographic activity

BackgroundRheumatoid arthritis (RA) is a chronic disease which may result in progressive joint destruction even with clinical remission. Ultrasound (US) can detect subclinical disease activity and matrix metalloproteinase 3 (MMP-3) has a role in disease activity in RA. Aim of the workTo evaluate the level of MMP-3 in RA patients and its ability to predict sonographic activity in patients with clinical remission or low disease activity (LDA). Patients and methodsThis study included 45 RA patients with a disease activity score (DAS28) <3.2 and 45 matched healthy control. US evaluation using modified German US7 score was performed and accordingly patients were classified into those with sonographic remission (grey scale 0–1) or activity. MMP-3 level was assessed by enzyme-linked immunosorbent assay. Results.The mean age of the patients was 45 ± 9.5 years and 86.7% were females. Sonographic remission was achieved in 20 (44.4 %) patients. There was a significant difference in serum MMP-3 between patients and control (17 ± 4.5 vs 6.3 ± 2.2 ng/ml; p < 0.0001). There was no difference between patients with clinical remission (n = 37) and those with LDA (n = 8). Serum MMP-3 tended to be higher in patients with sonographic activity than in those with sonographic remission (18 ± 5.3 vs 15.6 ± 2.8 ng/ml; p = 0.3). Serum MMP-3 significantly correlated with erythrocyte sedimentation rate (p = 0.002) and synovitis score (p = 0.002). ConclusionSerum MMP-3 was higher in RA patients than in control and was associated with the ultrasound synovitis score. However, serum MMP-3 was not able to differentiate patients with sonographic remission from those with subclinical activity.

Importance of baseline musculoskeletal ultrasound findings in the prognosis of rheumatoid arthritis.

To investigate the prognostic value of baseline musculoskeletal ultrasound (MSUS) findings for rheumatoid arthritis (RA). We retrospectively analyzed 138 patients with RA. Patients' first MSUS record was considered as the baseline expression. The subsequent MSUS changes that showed alleviation or progression were regarded as the cutoff point. Grayscale ultrasound (GSUS) synovitis, power Doppler ultrasound (PDUS) synovitis, PDUS tenosynovitis (TS), and bone erosion were scored using a semi-quantitative scale. According to the ultrasound (US) results of the cutoff point, patients were divided into the alleviation group and the progression group. Laboratory results (erythrocyte sedimentation rate [ESR], C-reactive protein [CRP], rheumatoid factor [RF], anticyclic citrullinated peptide [anti-CCP] antibody, and anti-keratin antibody [AKA]), disease activity score in 28 joints (DAS28)-ESR, and US scores were compared between the two groups to analyze the prognostic value of US findings in RA. The alleviation group had higher levels of CRP, synovitis, TS, GSUS synovitis, PDUS synovitis, PDUS TS, and US total scores at baseline than the progression group (p < 0.05). The alleviation group received more aggressive treatment in their initial approach than the progression group (p < 0.05). The frequency of US examinations in the alleviation group was more than that in the progression group at follow-up (p < 0.05). Presence of baseline synovitis (OR 0.248, p = 0.006) and a higher GSUS synovitis score (OR 0.521, p = 0.006) were negatively correlated with RA progression. Presence of baseline synovitis and higher GSUS synovitis score do not always indicate worse prognosis of RA, which can be improved with aggressive treatment. Regular MSUS follow-up may have positive influences on prognosis. Key Points • The presence of synovitis at baseline and higher GSUS synovitis score do not necessarily imply poor prognosis of RA. • Prompt and powerful therapy and regular ultrasound follow-up can slow down the progression of RA and improve its prognosis. • Patients with slight and less arthritis at baseline might be ignored and get worse prognosis due to mild treatment strategies and irregular MSUS examination.

High Sensitivity C Reactive Protein in Patients with Rheumatoid Arthritis Treated with Antibodies against IL-6 or Jak Inhibitors: A Clinical and Ultrasonographic Study.

Background: We examined whether high-sensitivity CRP (hsCRP) reflected the inflammatory disease status evaluated by clinical and ultrasound (US) parameters in RA patients receiving IL-6 receptor antibodies (anti-IL-6R) or JAK inhibitors (JAKi). Methods: We conducted a cross-sectional study of patients with established RA receiving anti-IL-6R (tocilizumab, sarilumab) or JAKi (tofacitinib, baricitinib). Serum hsCRP and US synovitis in both hands were measured. Associations between hsCRP and clinical inflammatory activity were evaluated using composite activity indices. The association between hsCRP and US synovitis was analyzed. Results: 63 (92% female) patients (42 anti- IL-6R and 21 JAKi) were included, and the median disease duration was 14.4 (0.2–37.5) years. Most patients were in remission or had low levels of disease. Overall hsCRP values were very low, and significantly lower in anti-IL-6R patients (median 0.04 mg/dL vs. 0.16 mg/dL). Anti-IL-6R (82.4%) patients and 48% of JAKi patients had very low hsCRP levels (≤0.1 mg/dL) (p = 0.002). In the anti-IL-6R group, hsCRP did not correlate with the composite activity index or US synovitis. In the JAKi group, hsCRP moderately correlated with US parameters (r = 0.5) but not clinical disease activity, and hsCRP levels were higher in patients with US synovitis (0.02 vs. 0.42 mg/dL) (p = 0.001). Conclusion: In anti-IL-6R RA-treated patients, hsCRP does not reflect the inflammatory disease state, but in those treated with JAKi, hsCRP was associated with US synovitis.

Plasma calprotectin as a biomarker of ultrasound synovitis in rheumatoid arthritis patients receiving IL-6 antagonists or JAK inhibitors

Objectives:To analyse the accuracy of plasma calprotectin in patients with rheumatoid arthritis (RA) receiving monoclonal antibodies against IL-6 receptors (anti-rIL-6) or JAK inhibitors (JAKis) in detecting ultrasound (US) synovitis and compare it with acute phase reactants [high-sensitivity C-reactive protein (hs-CRP) and ESR].Methods:An observational cross-sectional study of RA patients receiving anti-rIL-6 (tocilizumab or sarilumab) or JAKi, (baricitinib or tofacitinib) was made. Plasma calprotectin for the diagnosis of US synovitis [synovial hypertrophy grade (SH) ⩾ 2 plus power Doppler signal (PD) ⩾ 1] was analysed using receiver operating characteristic curves (ROCs). The performance of ESR and hs-CRP was also studied. The three ROC curves were compared to determine which had the highest discriminatory power. Associations between plasma calprotectin and US scores were made using correlation analysis.Results:Sixty-three RA patients were included. Mean plasma calprotectin levels were significantly higher in patients with US synovitis than in those without (0.89 ± 0.85 vs 0.30 ± 0.12 μg/ml; p = 0.0003). A moderate correlation between calprotectin and all US scores (HS score Rho = 0.479; PD score Rho = 0.492; and global score Rho = 0.495) was found. The discriminatory capacity of plasma calprotectin showed an AUC of 0.795 (95% CI: 0.687–0.904). The AUC of hs-CRP and ESR was 0.721 and 0.564, respectively. hs-CRP serum levels showed a low positive correlation with the three US scores (Rho < 0.40). After analysis according to the drugs administered, the correlation disappeared in patients receiving anti-rIL-6.Conclusion:Plasma calprotectin may be a sensitive biomarker of synovial inflammation in RA patients treated with anti-rIL-6 or JAKi.

Dactylitis is an indicator of a more severe phenotype independently associated with greater SJC, CRP, ultrasound synovitis and erosive damage in DMARD-naive early psoriatic arthritis

ObjectiveTo characterise the impact of dactylitis in disease-modifying antirheumatic drug (DMARD)-naive early psoriatic arthritis (PsA).MethodsPatients with early PsA meeting the classification criteria for PsA (CASPAR) were recruited. Clinical outcomes were...

Ultrasound subclinical synovitis in anti-CCP-positive at-risk individuals with musculoskeletal symptoms: an important and predictable stage in the rheumatoid arthritis continuum.

ObjectivesTo investigate whether anti-CCP2-positive at-risk individuals with musculoskeletal (MSK) symptoms but without clinical synovitis (CCP2+ at-risk) develop US subclinical synovitis before inflammatory arthritis and if US subclinical synovitis can be predicted.MethodsFirst, US scans of CCP2+ at-risk individuals who developed inflammatory arthritis (‘progressors’) were reviewed for subclinical synovitis prior to inflammatory arthritis development. Patients in whom the pre-progression US scan was negative but the scan was conducted >6 months before progression were excluded. Subsequently, regression analyses were performed to identify predictors of US synovitis in CCP2+ at-risk individuals without baseline US abnormalities who had one or more longitudinal US scan and a complete dataset.ResultsUS subclinical synovitis was detected in one or more scan in 75 of 97 progressors (77.3%) {median time to inflammatory arthritis development from first evidence of US synovitis 26.5 weeks [interquartile range (IQR) 7–60]}, in whom one or more scan was available, excluding those with a negative scan >6 months from inflammatory arthritis development (n = 38). In 220 CCP2+ at-risk individuals with normal baseline US scans, who had one or more longitudinal US scan and a complete dataset, US synovitis was detected in 69/220 (31.4%) [median time to first developing US synovitis 56.4 weeks (IQR 33.0–112.0)]. In the multivariable analysis, only anti-CCP3 antibodies were predictive for the development of US synovitis [odds ratio 4.75 (95% CI 1.97, 11.46); P < 0.01].ConclusionsIn anti-CCP2+ at-risk individuals, a stage of subclinical synovitis usually precedes the development of inflammatory arthritis. Anti-CCP2+/CCP3+ individuals without clinical or US subclinical synovitis may represent the optimal window of opportunity for intervention to prevent joint disease.

Response to secukinumab on synovitis using Power Doppler ultrasound in psoriatic arthritis: 12-week results from a phase III study, ULTIMATE

ObjectivesTo investigate the dynamics of response of synovitis to IL-17A inhibition with secukinumab in patients with active PsA using Power Doppler ultrasound.MethodsThe randomized, placebo-controlled, Phase III ULTIMATE study enrolled PsA patients with active ultrasound synovitis and clinical synovitis and enthesitis having an inadequate response to conventional DMARDs and naïve to biologic DMARDs. Patients were randomly assigned to receive either weekly subcutaneous secukinumab (300 or 150 mg according to the severity of psoriasis) or placebo followed by 4-weekly dosing thereafter. The primary outcome was the mean change in the ultrasound Global EULAR and OMERACT Synovitis Score (GLOESS) from baseline to week 12. Key secondary endpoints included ACR 20 and 50 responses.ResultsOf the 166 patients enrolled, 97% completed 12 weeks of treatment (secukinumab, 99%; placebo, 95%). The primary end point was met, and the adjusted mean change in GLOESS was higher with secukinumab than placebo [−9 (0.9) vs −6 (0.9), difference (95% CI): −3 (−6, −1); one-sided P=0.004] at week 12. The difference in GLOESS between secukinumab and placebo was significant as early as one week after initiation of treatment. All key secondary endpoints were met. No new or unexpected safety findings were reported.ConclusionThis unique ultrasound study shows that apart from improving the signs and symptoms of PsA, IL-17A inhibition with secukinumab leads to a rapid and significant reduction of synovitis in PsA patients.Trial registrationClinicalTrials.gov; NCT02662985.

Correlation of Ultrasound Synovitis Joint Count with Disease Activity and Its Longitudinal Variation with Treatment Response to Etanercept in Rheumatoid Arthritis

More research is needed into rheumatoid arthritis (RA), and ultrasound (US) synovitis is a promising factor for assisting in the management of RA; however, related research is extremely limited. The goal of this study was to evaluate the correlation of US synovitis joint count with clinical features, and its longitudinal changes with treatment response to etanercept in RA. We consecutively enrolled 117 people with active RA being treated with etanercept. US synovitis joint count was evaluated in 28 joints at baseline (W0), week 4 (W4), week 12 (W12) and week 24 (W24) after initiation of etanercept treatment. The mean (±standard deviation), median, inter-quartile range, and total range of the US synovitis joint count at W0 were 9.3 ± 4.0, 9.0, 7.0–11.0 and 2.0–21.0, respectively. US synovitis joint count was positively associated with tenderness joint count, swollen joint count, erythrocyte sedimentation rate, 28-joint Disease Activity Score based on erythrocyte sedimentation rate and Health Assessment Questionnaire–Disability Index score. Then participants were categorized into response and non-response groups according to their response status at W24. Further analyses showed that US synovitis joint count gradually decreased from W0 to W24, and displayed a more notable declining trend in the response group compared with the non-response group. In addition, US synovitis joint count at W0 and W4 was similar between groups, but at W12 and W24 it was markedly decreased in the response group compared with the non-response group. In conclusion, US synovitis joint count correlates with disease activity, and its longitudinal decrease is associated with treatment response to etanercept in RA.

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

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. 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. 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)]. 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.

Biological measures of synovial inflammation predict pain, symptoms, and ultrasound measures of synovitis in knee OA

Purpose: Synovial inflammation (synovitis or effusion-synovitis) measured via clinical imaging (i.e., magnetic resonance imaging (MRI), ultrasound (US)) has been shown to be related to worse outcomes in people with knee OA, including worse pain, higher risk of OA incidence and progression, and increased risk of requiring a total knee arthroplasty (TKA). Recent studies have shown associations between synovial histopathology and structural features of knee OA and MRI measures of synovitis. However, the relationship between histopathology and patient symptoms remains unclear. Histopathology measures of synovial inflammation represent a set of measures that are related to biological disease activity in OA. Therefore, the aim of this study was to establish the link between synovial inflammation and clinical outcomes. Methods: Patients were recruited from the Western Ontario Registry for Early Osteoarthritis (WOREO): Knee Study. Ninety-two people with severe symptoms and radiographic damage (Kellgren-Lawrence (KL) grades 3 or 4) undergoing surgery for end-stage knee OA were included. Patients completed the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire specific to each knee and a self-reported patient global assessment (PGA). An investigator global assessment (IGA) was also completed for each patient. Musculoskeletal-US was used to measure effusion-synovitis in suprapatellar mid-line, lateral, and medial windows (0-3; None-Severe; summed (0-9) and maximum effusion depth (mm). Power Doppler signal was also assessed as absent or present (0 or 1). Lateral suprapatellar synovial biopsies were obtained at time of surgery. Routine histopathology was scored in six domains, on 5 slides per patient; mean scores were binned into categories 0, 0.5-1.5, and 2-3 (none, mild, moderate-severe). Composite histopathology scores were created based on previously published literature, principal component analysis (Eigen values ≥ 1.0), and biological rationale. We fitted a series of multivariate linear or logistic regression models to evaluate the association of histopathology (individual and composite) scores with clinical outcomes and US imaging measures of synovitis. All analyses were adjusted for age, sex, and body mass index (BMI). Robust sandwich estimators were used. Results include unstandardized β coefficients or odds ratios (OR) with 95% confidence intervals (CIs). All analyses completed using StataIC 15.1. Results: A total of 92 patients were included (Table 1). Of the 6 histopathology domains, more severe perivascular edema was most strongly associated with lower (worse) KOOS pain, ADL, and QoL subscale scores (Table 2). Synovial lining and sub-synovial infiltrate scores were significantly associated with more severe effusion-synovitis measured by US grading and maximum effusion depth (Table 3). Vascularization was associated with higher synovitis score, while more severe fibrosis was associated with high QoL scores (Table 2) and lower US synovitis score (Table 3). Synovial histopathology principal components accounted for approximately 70% of the variance in the dataset but there were minimal associations with clinical and imaging outcomes (Table 4). The histopathology inflammatory composite scores were most strongly associated with KOOS subscale scores (Table 4). Conclusions: Inflammation measured with synovial histopathology is associated with knee-specific pain, symptoms and US imaging measures of inflammation in patients with end-stage knee OA. These findings may help us to better understand OA overall. We provide biological evidence supporting the known relationship between knee inflammation and OA outcomes, which is largely based on imaging assessment in the literature.View Large Image Figure ViewerDownload Hi-res image Download (PPT)View Large Image Figure ViewerDownload Hi-res image Download (PPT)View Large Image Figure ViewerDownload Hi-res image Download (PPT)