[18F]FDG PET/CT for therapeutic assessment of Abatacept in early-onset polymyalgia rheumatica.

PURPOSE: Evaluate the benefit of 2-deoxy-2-[18F]-fluoro-D-glucose ([18F] FDG) positron emission tomography/computed tomography (PET/CT) for the therapeutic assessment of Abatacept (ABA) as first-line therapy in early-onset polymyalgia rheumatica (PMR) patients. METHODS: This was an ancillary study of ALORS trial (Abatacept in earLy Onset polymyalgia Rheumatica Study) assessing the ability of ABA versus placebo to achieve low disease activity (C-Reactive Protein PMR activity score (CRP PMR-AS) ≤ to 10) without glucocorticoid (GC) at week 12 in patients with early-onset PMR. The patients underwent [18F] FDG PET/CT at baseline and after 12 weeks of treatment. Responses to treatments were evaluated according to CRP PMR-AS, Erythrocyte Sedimentation Rate (ESR) PMR-AS, Clin PMR-AS, and CRP-Imputed (Imput-CRP) PMR-AS. Quantitative score by maximal standardized uptake value (SUVmax) and combined qualitative scores according to liver uptake (Leuven, Leuven/Groningen, and Besançon Scores) were used for assessment of [18F] FDG uptake in regions of interest (ROI) usually affected in PMR. Student's t-test was applied to evaluate the clinical, biological, and [18F] FDG uptake variation difference in ABA and placebo groups between W0 and W12. Subgroup analysis by GC rescue was performed. RESULTS: At W12, there was no significant difference according to SUVmax between the ABA and the placebo groups in all ROI. Subgroup analysis according to GC administration demonstrated a significant (p 0.047) decrease in SUVmax within the left sternoclavicular joint ROI in the ABA group (- 0.8) compared to the placebo group (+ 0.6) without GC rescue. Other results did not reveal any significant difference between the ABA and placebo groups. According to combined qualitative scores, there was no significant difference between ABA and placebo groups for the direct comparison analysis and subgroup analysis according to GC rescue. CONCLUSION: [18F] FDG PET/CT uptake did not decrease significantly after ABA compared to placebo in anatomical areas usually affected in PMR patients. These results are correlated with the clinical-biological therapeutic assessment. CLINICAL TRIAL REGISTRATION: The study was approved by the appropriate ethics committee (CPP Sud-Est II Ref CPP: 2018-33), and all patients gave their written informed consent before study enrollment. The protocol was registered on Clinicaltrials.gov (NCT03632187).

The Novel OMERACT Ultrasound Scoring System for Salivary Gland Changes in Patients With Sjögren Syndrome Is Associated With MRI and Salivary Flow Rates.

OBJECTIVE: To assess the construct validity of the novel Outcome Measures in Rheumatology (OMERACT) ultrasound (US) semiquantitative scoring system for morphological lesions in major salivary glands by comparing it with magnetic resonance imaging (MRI) and unstimulated whole salivary flow rates (U-WSFRs) in patients with primary Sjögren syndrome (pSS). METHODS: Nine sonographers applied the OMERACT 0-3 grayscale scoring system for parotid (PGs) and submandibular glands (SMGs) in 11 patients with pSS who also had MRIs performed. These were evaluated by 2 radiologists using a semiquantitative 0-3 scoring system for morphological lesions. The agreement between US and MRI and the association between U-WSFRs and imaging structural lesions was determined. A score ≥ 2 for both US and MRI was defined as gland pathology. RESULTS: The prevalence of US morphological lesions in 11 patients with a score ≥ 2 was 58% for PGs and 76% for SMGs, and 46% and 41% for PGs and SMGs, respectively, for MRI. The agreement between OMERACT US scores and MRI scores was 73-91% (median 82%) in the right PG and 73-91% (median 91%) in the left PG, 55-91% (median 55%) in the right SMG and 55-82% (median 55%) in the left SMG. When relations between the presence of hyposalivation and an US score ≥ 2 were examined, agreement was 91-100% (median 83%) in both PGs and 55-91% (median 67%) in both SMGs. CONCLUSION: There is moderate to strong agreement between the OMERACT US and MRI scores for major salivary glands in patients with pSS. Similar agreement ratios were observed between the higher OMERACT US scores and presence of hyposalivation.

Sicca syndrome in systemic sclerosis: a narrative review on a neglected issue.

SSc is an auto-immune disease characterized by life-threatening manifestations such as lung fibrosis or pulmonary arterial hypertension. Symptoms with a detrimental impact on quality of life are also reported and sicca syndrome (xerostomia, xeropthalmia) is present in up to 80% of patients with SSc. Sicca syndrome can occur in the absence of overlap with Sjögren's disease and recent studies highlight that fibrosis of minor and major salivary glands, directly linked to the pathogenesis of SSc, could be a major contributor of xerostomia in SSc. This narrative review provides an overview of the clinical presentation, diagnostic strategies, management and future perspectives on sicca syndrome in patients with SSc.

Development of a new ultrasound scoring system to evaluate glandular inflammation in Sjögren's syndrome: an OMERACT reliability exercise.

OBJECTIVE: The aim of this exercise from the OMERACT Ultrasound subgroup on Sjögren's syndrome was to develop and assess the reliability of a consensus-based semiquantitative colour Doppler US scoring system for pathologic salivary gland vascularization in patients with primary Sjögren's syndrome (pSS). METHODS: Using the Delphi method, a colour Doppler semiquantitative scoring system for vascularization of bilateral parotid and submandibular glands was developed and tested in static images and on patients (9 pSS patients and 9 sonographers). Intra-reader and inter-reader reliability of grading the salivary glands were computed by weighted Cohen and Light's kappa analysis, respectively. RESULTS: The consensus-based semiquantitative score was: grade 0, no visible vascular signals; grade 1, focal, dispersed vascular signals; grade 2, diffuse vascular signals detected in <50% of the gland; grade 3, diffuse vascular signals in >50% of the gland. In static images, the intra- and inter-reader reliability showed excellent kappa values (95% CI) of 0.90 (0.87, 0.93) and 0.80 (0.74, 0.84), respectively, for all four salivary glands together. In patients, the intra- and inter-reader reliability for all four salivary glands together was kappa = 0.84 (0.73, 0.92) and 0.70 (0.64, 0.76), respectively. CONCLUSION: The consensus-based colour Doppler US scoring for the evaluation of salivary gland vascularization in pSS showed a good inter-reader reliability and excellent intra-reader reliability in static images and in patients. The clinical application of the developed scoring system should be tested in clinical settings.

Salivary gland ultrasonography in primary Sjögren's syndrome: opportunities and challenges.

Salivary gland ultrasonography (SGUS) has an established role in detecting typical structural gland abnormalities in primary Sjögren's Syndrome (pSS). SGUS might be included in pSS classification and could be used as a prognostic and follow-up biomarker, but for this purpose additional efforts, new techniques and larger cohort studies are needed. HarmonicSS, an ongoing Horizon, EU-supported project in pSS, will apply artificial intelligence to SGUS in pSS. Many questions are still unresolved and challenging, but data collected up to now underscore the concept that SGUS will be an important tool for the study of pSS in the near future.

Ruling out septic arthritis risk in a few minutes using mid-infrared spectroscopy in synovial fluids.

OBJECTIVES: The aim of this study was to show the usefulness of a mid-infrared fibre evanescent wave spectroscopy point of care device in the identification of septic arthritis patients in a multicentre cohort, and to apply this technology to clinical practice among physicians. METHODS: SF samples from 402 patients enrolled in a multicentre cohort were frozen for analysis by mid-infrared fibre evanescent wave spectroscopy. The calibration cohort was divided into two groups of patients (septic arthritis and non-septic arthritis) and relevant spectral variables were used for logistic regression model. Model performances were tested on an independent set of 86 freshly obtained SF samples from patients enrolled in a single-centre acute arthritis cohort and spectroscopic analyses performed at the patient's bedside. RESULTS: The model set-up, using frozen-thawed SFs, provided good performances, with area under the curve 0.95, sensitivity 0.90, specificity 0.90, positive predictive value 0.41 and negative predictive value 0.99. Performances obtained in the validation cohort were area under the curve 0.90, sensitivity 0.92, specificity 0.81, positive predictive value 0.46 and negative predictive value 0.98. The septic arthritis probability has been translated into a risk score from 0 to 4 according to septic risk. For a risk score of 0, the probability of identifying a septic patient is very low (negative predictive value of 1), whereas a risk score of 4 indicates very high risk of septic arthritis (positive predictive value of 1). CONCLUSION: Mid-infrared fibre evanescent wave spectroscopy could distinguish septic from non-septic synovial arthritis fluids with good performances, and showed particular usefulness in ruling out septic arthritis. Our data supports the possibility of technology transfer. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT02860871.

Patient-based reliability of the Outcome Measures in Rheumatology (OMERACT) ultrasound scoring system for salivary gland assessment in patients with Sjögren's syndrome.

BACKGROUND: To assess the reliability of the consensually agreed US definitions of major salivary gland lesions and the US scoring system for salivary gland assessment in patients with SS. METHODS: Nine experienced sonographers scanned and read the US images of both parotid glands (PGs) and submandibular glands (SMGs) in eight patients with primary and secondary SS in two rounds. A consensually agreed four-grade semi-quantitative scoring was applied in B-mode for morphological lesions: grade 0, normal; grade 1, mild inhomogeneity without anechoic or hypoechoic areas; grade 2, moderate inhomogeneity with focal anechoic or hypoechoic areas; grade 3, severe inhomogeneity with diffuse an- or hypoechoic areas occupying the entire gland or fibrous gland. The presence or absence of typical SS lesions, i.e. the Sjögren's signature, was scored binary. Intra- and interreader reliabilities were computed using weighted and unweighted Cohen's and Light's κ coefficients. RESULTS: The mean prevalence of grades 0-3 in PG were 43, 17, 23 and 31% and 28, 14, 33 and 32% for the SMGs, respectively. The weighted κ for intrareader reliability ranged from 0.44 to 1 for grading and 0.64 to 1 for the Sjögren's signature of PG and 0.59 to 1 and -0.09 to 0.6 for SMGs, respectively. The interreader reliability κ for grading in PG was 0.62 (95% CI 0.47, 0.74) and for Sjögren's signature it was 0.36 (95% CI 0, 0.43); in SMG it was 0.62 (95% CI 0.47, 0.72) and 0.03 (95% CI 0, 0.07) respectively. CONCLUSIONS: The consensually agreed novel US scoring system for major salivary gland lesions showed substantial intra- and interreader reliability in patients with SS. The reliability of the Sjögren's signature was moderate.

Application of the OMERACT synovitis ultrasound scoring system in juvenile idiopathic arthritis: a multicenter reliability exercise.

OBJECTIVES: To evaluate the reliability of the OMERACT paediatric ultrasound (US) synovitis definitions and scoring system in JIA. METHODS: Thirteen sonographers analysed 75 images for the presence/absence of elementary lesions (binary scoring) and for grading synovitis, synovial hypertrophy, effusion and Doppler signals. Static US images of the second metacarpophalangeal joint (MCP-II), wrist, elbow, knee and ankle in JIA patients at different ages and different disease stages were collected with standardized scanning by two experienced sonographers. Intra- and inter-reader reliability were analysed with kappa coefficients. RESULTS: Intra-reader reliability was good for binary scoring (Cohen's kappa 0.62, range 0.47-0.75), synovitis and synovial hypertrophy; excellent for Doppler signals (quadratic weighted kappa 0.77, 0.66-0.86; 0.76, 0.61-0.84; and 0.87, 0.77-0.94, respectively); and moderate for effusion (0.55, 0.24-0.76). Inter-reader reliability was good for synovitis and synovial hypertrophy (Light's kappa 0.68, 95% CI: 0.61, 0.75 and 0.63, 0.54-0.71, respectively), excellent for Doppler signals (0.85, 95% CI: 0.77, 0.90), and moderate for binary scoring and effusion (0.48, 95% CI: 0.36, 0.64 and 0.49, 0.40-0.60, respectively). We obtained the best scores for the knee (0.71, 0.54-0.85) except for Doppler signals, with reliability higher for MCP-II. We found a trend toward better results in older children. CONCLUSIONS: This is the first study establishing the reliability of the OMERACT paediatric US synovitis definitions and scoring system in the five most commonly affected joints in JIA. The reliability was good among a large group of sonographers. These results support the applicability of these definitions and scoring system in clinical practice and multicentre studies.

Comparison of 18- and 22-MHz probes for the ultrasonographic diagnosis of giant cell arteritis.

PURPOSE: Little is known about the diagnostic concordance of images provided by ultrasound probes with emitting frequencies below or above 20 MHz for the diagnosis of giant cell arteritis (GCA). METHODS: We compared, using Cohen's kappa statistic, data obtained with an 18-MHz and a 22-MHz probe for the ultrasonographic evaluation of temporal arteries in 80 patients referred for suspected GCA. RESULTS: The halo sign was found in 25% of cases with the 18-MHz probe and in 35% with the 22-MHz probe. The compression sign was positive in 42% of cases with the 18-MHz probe and 48% with the 22-MHz probe. GCA was finally diagnosed in 20 patients (25%). The kappa coefficient of agreement was 0.76 (P < .001) for the halo sign, and 0.75 (P < .001) for the compression sign. CONCLUSIONS: Images obtained by 18 MHz and 22-MHz frequency probes showed a good level of agreement for the diagnosis of GCA, but the 22-MHz probe yielded a correct diagnosis of GCA in 3 of the 7 patients in whom examination with the 18-MHz probe was negative.

A simplified radiographic score effectively predicts radiographic progression of early arthritis in a large nationwide French cohort.

OBJECTIVE: Evaluating radiographic progression is a key component of the follow-up of patients with RA. Existing scores are ill-suited to everyday clinical practice. The objective here was to validate a new simplified radiographic score (SRS) for evaluating radiographic progression in patients with early arthritis. METHODS: Patients with arthritis of <6 months' duration were included in the large, prospective, nationwide, French ESPOIR cohort. Radiographs of the hands and feet were obtained at inclusion then 1 and 5 years later. The modified Sharp scores and SRS were determined by blinded readers. Interobserver reliability and intraobserver repeatability of each score, as well as agreement between the two scores, were assessed by computing the intraclass correlation coefficients. The rates of progression over the first year and the next 4 years were determined. RESULTS: The 506 patients with complete data for the first 5 years were included. At inclusion, the intraclass correlation coefficient between the two scores was good for erosions (0.715, P < 0.001), joint space narrowing (0.892, P < 0.001) and the total score (0.896, P < 0.001). Agreement between the two scores was also good for radiographic progression after 1 year (0.781, P < 0.001). The SRS had good positive and negative predictive values for slow and for rapid progression. SRS determination was less time consuming. CONCLUSION: The SRS is effective for monitoring radiographic progression in early arthritis and is easier to use and less time-consuming than the Sharp score. The usefulness of the SRS in clinical practice deserves further evaluation.

Video clip assessment of a salivary gland ultrasound scoring system in Sjögren's syndrome using consensual definitions: an OMERACT ultrasound working group reliability exercise.

OBJECTIVE: To develop ultrasound (US) definitions and a US novel scoring system for major salivary gland (SG) lesions in patients with primary Sjögren's syndrome (pSS) and to test their intrareader and inter-reader reliability using US video clips. METHODS: Twenty-five rheumatologists were subjected to a three-round, web-based Delphi process in order to agree on (1) definitions and scanning procedure of salivary gland ultrasonography (SGUS): parotid, submandibular and sublingual glands (PG, SMG and SLG); (2) definitions for the elementary SGUS lesions in patients with Sjögren's syndrome; (3) scoring system for grading changes. The experts rated the statements on a 1-5 Likert scale. In the second step, SGUS video clips of patients with pSS and non-pSS sicca cases were collected containing various spectrums of disease severity followed by an intrareader and inter-reader reliability exercise. Each video clip was evaluated according to the agreed definitions. RESULTS: Consensual definitions were developed after three Delphi rounds. Among the three selected SGs, US assessment of PGs and SMGs was agreed on. Agreement was reached to score only greyscale lesions and to focus on anechoic/hypoechoic foci in a semiquantitative matter or, if not possible on a qualitatively (present/absent) evaluation of fatty or fibrous lesions. Intrareader reliability for detecting and scoring these lesions was excellent (Cohen's kappa 0.81) and inter-reader reliability was good (Light's kappa 0.66). CONCLUSION: New definitions for developing a novel semiquantitative US score in patients with pSS were developed and tested on video clips. Inter-reader and intrareader reliabilities were good and excellent, respectively.

Reliability of a consensus-based ultrasound definition and scoring for enthesitis in spondyloarthritis and psoriatic arthritis: an OMERACT US initiative.

OBJECTIVES: To evaluate the reliability of consensus-based ultrasound (US) definitions of elementary components of enthesitis in spondyloarthritis (SpA) and psoriatic arthritis (PsA) and to evaluate which of them had the highest contribution to defining and scoring enthesitis. METHODS: Eleven sonographers evaluated 40 entheses from five patients with SpA/PsA at four bilateral sites. Nine US elementary lesions were binary-scored: hypoechogenicity, thickened insertion, enthesophytes, calcifications, erosions, bone irregularities, bursitis and Doppler signal inside and around enthesis. Kappa statistics were used to evaluate reliability. Sonographers were also asked to state which lesions can be considered as inflammatory or structural and should be included in the final definition of enthesitis. Only the lesions, scored as present in at least 75% of the entheses considered as having an enthesitis, were included in the final definition. RESULTS: The prevalence of detected lesions was quite low except for enthesophytes (55%) and bone irregularities (54%). Reliability ranged from poor to good (the lowest for thickened enthesis (kappa 0.1 (95% CI 0 to 0.7)) and the highest for enthesophytes (kappa 0.6 (95% CI 0.5 to 0.7)). When adjusted for low prevalence, kappa values increased for all lesions, with the best result observed for detecting Doppler signal at insertion (0.9) and for bursitis (0.8). The US components included in the final definition were hypoechogenicity, increased thickness at enthesis, erosions and calcifications/enthesophytes and Doppler signal at insertion. CONCLUSION: By using a consensus-based stepwise approach, a final reliable US score and definition of enthesitis in SpA/PsA were produced. Further studies are sought for implementing this score in clinical trials and practice.

Assessing polymyalgia rheumatica activity when C-reactive protein is unavailable or uninterpretable.

Objective: The PMR activity score (PMR-AS) includes the CRP value, which may be lacking or invalid owing to anti-IL-6 therapy. Our objective was to develop alternatives to PMR-AS that do not require CRP. Methods: We used the Club Rhumatisme et Inflammation (CRI; 89 patients with PMR) and the Tolerance and Efficacy of tocilizumab iN pOlymyalgia Rheumatica (TENOR; 20 patients with recent-onset PMR naive to glucocorticoid who received three tocilizumab infusions, at weeks 0, 4 and 8, followed by prednisone from weeks 12 to 24) cohorts. In the CRI cohort, we evaluated correlations between PMR-AS items to select the best item for imputing CRP. Then we calculated the PMR-AS with (PMR-AS) and without (clin-PMR-AS) CRP and we used the linear regression between PMR-AS and clin-PMR-AS to obtain CRP-imputed (CRP-imp) PMR-AS. Finally, we evaluated agreement between clin-PMR-AS, CRP-imp PMR-AS, PMR-AS and ESR-PMR-AS in the TENOR cohort during tocilizumab therapy. Results: In the CRI cohort, agreement between PMR-AS and clin-PMR-AS was excellent (κ = 0.90). Linear regression between PMR-AS and clin-PMR-AS [CRP-imp PMR-AS = 1.12(clin-PMR-AS)+0.26] allowed us to build the CRP-imp PMR-AS. Mean (s.d.) values were as follows: 8.40 (9.76) for PMR-AS, 7.24 (8.58) for clin-PMR-AS and 7.84 (9.61) for CRP-imp PMR-AS. CRP-imp PMR-AS agreed more closely with PMR-AS than did clin-PMR-AS. The results in the TENOR cohort confirmed that CRP-imp PMR-AS or ESR-PMR-AS could be used. Conclusion: Alternatives to the PMR-AS obtained without CRP can be used to monitor PMR activity in everyday practice in patients without available CRP values and in those receiving IL-6 antagonist therapy.

Normal sonoanatomy of small joints in healthy children: changes in cartilage and vascularisation according to age and gender.

OBJECTIVES: The metacarpophalangeal (MCP) and metatarsophalangeal (MTP) joints may be involved in juvenile idiopathic arthritis. Our goal was to describe their normal sonoanatomy in healthy children, according to age and gender. METHODS: We studied 41 consecutive healthy children (20 girls, 21 boys; age 2-15 years) divided into four age groups: 2-4 years (n=9), 5-7 years (n=11), 8-12 years (n=12), and 13-15 years (n=9). Longitudinal ultrasound axis of the MCP and MTP joints were obtained. The evolution of the cartilage thickness and vascularisation of these joints were studied according to age and gender. The MCP or MTP joints were the statistical unit. RESULTS: At all sites, on B-mode images, cartilage thickness was associated with age (p<0.0001). Cartilage thickness at different sites was significantly greater in boys than in girls (p≤0.05). Blood vessels were seen within the cartilage, with differences across age groups. CONCLUSIONS: This study provides children's age- and gender-specific sonoanatomy data of MCP and MTP and confirms the importance of using colour Doppler or Power Doppler to study cartilage vascularisation.

Efficacy of first-line tocilizumab therapy in early polymyalgia rheumatica: a prospective longitudinal study.

BACKGROUND: Glucocorticoids are the cornerstone treatment of polymyalgia rheumatica (PMR) but induce adverse events. OBJECTIVES: To evaluate the efficacy and safety of first-line tocilizumab in PMR. METHODS: In a prospective open-label study (ClinicalTrials.gov: NCT01713842), 20 glucocorticoid-free patients fulfilling Chuang's PMR criteria, with symptom onset within the last 12 months and a PMR activity score (PMR-AS) >10, each received three tocilizumab infusions at 4-week intervals, without glucocorticoids, followed by oral prednisone from weeks 12 to 24 (0.15 mg/kg if PMR-AS ≤10 and 0.30 mg/kg otherwise). The primary end point was the proportion of patients with PMR-AS≤10 at week 12. RESULTS: Baseline median PMR-AS was 36.6 (IQR 30.4-43.8). At week 12, all patients had PMR-AS≤10 and received the low prednisone dosage. Median PMR-AS at weeks 12 and 24 was 4.5 (3.2-6.8) and 0.95 (IQR 0.4-2), respectively (p<0.001 vs baseline for both time points). No patient required rescue treatment. Positron emission tomography-CT showed significant improvements. The most common adverse events were transient neutropenia (n=3) and leucopenia (n=5); in one patient, the second tocilizumab infusion was omitted due to leucopenia. CONCLUSIONS: Tocilizumab monotherapy is effective in recent-onset PMR. Randomised controlled trials are warranted. TRIAL REGISTRATION NUMBER: NCT01713842.

Blood and salivary-gland BAFF-driven B-cell hyperactivity is associated to rituximab inefficacy in primary Sjögren's syndrome.

OBJECTIVES: To determine whether B-cell markers (blood and minor salivary gland [SG] B-cell depletion [BCD], autoantibodies, B-cell-activating factor [BAFF]) are associated with clinical response to rituximab in patients with primary Sjögren's syndrome (pSS). METHODS: 45 patients with pSS were included: in group I, 14 received low-dose rituximab (two 375-mg/m(2) infusions) in an open-labelled study; in group II, 17 received full-dose rituximab (two 1000-mg infusions) and 14 received a placebo in a randomized, controlled study. The proportion of SG B cells was assessed using pixel-based software analyses of digitized double-immunostained (CD3/CD20) whole SGs. Response was defined at week-24 according to the Sjögren's Syndrome Responder Index (SSRI)-30. RESULTS: Response rate was 50% in both groups of rituximab-treated patients. Duration of blood BCD was similar in both groups despite the difference in rituximab dosage, and was highly correlated with residual serum-rituximab levels at week-16. SG B-cell dynamics mirrored blood B-cell levels, with a drastic decrease in SG B-cells at week-12 (group I), but an increase in ∼ 50% of patients in group II by week-24, in whom blood B cells had already returned. Duration of BCD was not associated with the clinical response, but responders had lower baseline proportions of SG B cells. Baseline serum BAFF level was correlated with the proportion of SG B-cells and other B-cell-activation markers, and was associated with the clinical response with higher levels in non-responders. CONCLUSIONS: In pSS, half of the patients display an intense BAFF-driven B-cell activation and do not respond to a single course of rituximab.