Clinical and ultrasound optimization in rheumatoid arthritis for patients in sustained remission, can it work as a new optimization tool?

INTRODUCTION: Some studies have noted that scores relying solely on clinical values to evaluate remission in rheumatoid arthritis (RA) may miss subclinical inflammation, which can lead to exacerbations when therapy is reduced. This opens the possibility of supporting clinical evaluation with imaging studies, one of which is ultrasound (US) evaluation, since it is an accessible tool. Therefore, we have decided to design a study to try to demonstrate the usefulness of US as a complementary measure for the decision-making process in determining the optimization of therapy in patients with RA. MATERIALS AND METHODS: A multicenter, blinded, randomized, prospective study was conducted in RA patients meeting 2010 ACR/EULAR criteria for sustained remission by DAS28-ESR, with concomitant CDAI/SDAI evaluation. Patients were classified into clinical and ultrasound groups, with treatment remission based on DAS28 or grayscale synovitis/Doppler values. Ultrasound assessments included grayscale (GS) and power Doppler (PD) for joints (A) and tendons (T). A 12 months follow-up was performed, with a subset analyzed at both 18 and 24 months. Exacerbation criteria: DAS28-ESR rise > 1.2 or CDAI/SDAI > 16. RESULTS: Across all centers, 78 patients were initially recruited, but only 46 completed the 12-month follow-up, with 28 undergoing further evaluation at 24 months. The average baseline DAS28 scores were 1.85 for the clinical group and 1.80 for the ultrasound group. During the study, 18 patients experienced disease exacerbation based on DAS28 score elevation, with 10 in the clinical group and 8 in the ultrasound group. Seven patients experienced disease exacerbation based on CDAI score elevation, all of whom were included in the clinical group. Eight patients showed disease exacerbation based on SDAI score elevation, all in the clinical group. CONCLUSION: We have demonstrated the utility of ultrasound when optimizing management of rheumatoid arthritis patients. In our patient cohort, ultrasound helps to reduce the number of exacerbations using the SDAI/CDAI index. We highlight the limitations of current assessment methods that rely solely on clinical evaluation, underscore the potential significance of evaluating subclinical synovitis, and emphasize the role of ultrasound as an objective tool in guiding therapy decisions. Our study offers valuable insights for optimizing treatment strategies in RA patients and improving their long-term outcomes.

Relationship Between Ultrasound and Physical Examination in the Assessment of Enthesitis in Patients With Spondyloarthritis: Results From the DEUS Multicenter Study.

OBJECTIVE: The study objectives were (i) to explore the agreement between the Outcome Measures in Rheumatology (OMERACT) ultrasound lesions of enthesitis and physical examination in assessing enthesitis in patients with spondyloarthritis (SpA) and (ii) to investigate the prevalence and clinical relevance of subclinical enthesitis in this population. METHODS: Twenty rheumatology centers participated in this cross-sectional study. Patients with SpA, including axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA), underwent both ultrasound scan and physical examination of large lower limb entheses. The OMERACT ultrasound lesions of enthesitis were considered, along with a recently proposed definition for "active enthesitis" by our group. Subclinical enthesitis was defined as the presence of "active enthesitis" in ≥1 enthesis in patients with SpA without clinical enthesitis (ie, number of positive entheses on physical examination and Leeds Enthesitis Index score = 0). RESULTS: A total of 4,130 entheses in 413 patients with SpA (224 with axSpA and 189 with PsA) were evaluated through ultrasound and physical examination. Agreement between ultrasound and physical examination ranged from moderate (ie, enthesophytes) to almost perfect (ie, power Doppler and "active enthesitis"). Patellar tendon entheses demonstrated the highest agreement, whereas Achilles tendon insertion showed the lowest. Among 158 (38.3%) of 413 patients with SpA with clinical enthesitis, 108 (68.4%) exhibited no "active enthesitis" on ultrasound. Conversely, of those 255 without clinical enthesitis, 39 (15.3%) showed subclinical enthesitis. Subclinical enthesitis was strongly associated with local structural damage. However, no differences were observed regarding the demographic and clinical profiles of patients with SpA with and without subclinical enthesitis. CONCLUSION: Our study underscores the need for a comprehensive tool integrating ultrasound and physical examination for assessing enthesitis in patients with SpA.

Power Doppler signal at the enthesis and bone erosions are the most discriminative OMERACT ultrasound lesions for SpA: results from the DEUS (Defining Enthesitis on Ultrasound in Spondyloarthritis) multicentre study.

OBJECTIVES: To assess, in spondyloarthritis (SpA), the discriminative value of the Outcome Measures in Rheumatology (OMERACT) ultrasound lesions of enthesitis and their associations with clinical features in this population. METHODS: In this multicentre study involving 20 rheumatology centres, clinical and ultrasound examinations of the lower limb large entheses were performed in 413 patients with SpA (axial SpA and psoriatic arthritis) and 282 disease controls (osteoarthritis and fibromyalgia). 'Active enthesitis' was defined as (1) power Doppler (PD) at the enthesis grade ≥1 plus entheseal thickening and/or hypoechoic areas, or (2) PD grade >1 (independent of the presence of entheseal thickening and/or hypoechoic areas). RESULTS: In the univariate analysis, all OMERACT lesions except enthesophytes/calcifications showed a significant association with SpA. PD (OR=8.77, 95% CI 4.40 to 19.20, p<0.001) and bone erosions (OR=4.75, 95% CI 2.43 to 10.10, p<0.001) retained this association in the multivariate analysis. Among the lower limb entheses, only the Achilles tendon was significantly associated with SpA (OR=1.93, 95% CI 1.30 to 2.88, p<0.001) in the multivariate analyses. Active enthesitis showed a significant association with SpA (OR=9.20, 95% CI 4.21 to 23.20, p<0.001), and unlike the individual OMERACT ultrasound lesions it was consistently associated with most clinical measures of SpA disease activity and severity in the regression analyses. CONCLUSIONS: This large multicentre study assessed the value of different ultrasound findings of enthesitis in SpA, identifying the most discriminative ultrasound lesions and entheseal sites for SpA. Ultrasound could differentiate between SpA-related enthesitis and other forms of entheseal pathology (ie, mechanical enthesitis), thus improving the assessment of entheseal involvement in SpA.

Ultrasonography in rheumatology: time to learn from patient views.

OBJECTIVE: The objective of this observational, descriptive, cross-sectional, multicentre study was to assess the perceived quality and grade of satisfaction expressed by patients with chronic arthropathies regarding the use of musculoskeletal (MSK) ultrasonography by rheumatologists as an integrated clinical care tool. METHODS: All Spanish rheumatology departments with MSK ultrasonography incorporated in their healthcare services were invited to participate in the study. A Spanish-language survey was offered to fill out anonymously to all consecutive patients with chronic arthropathies under follow-up in the rheumatology outpatient clinics who attended their centre for a period of 3 months. The survey consisted of three sections. The first section contained patients' demographics, disease data, frequency of performing rheumatological ultrasound and information about who performed their ultrasound assessments. The second section consisted of 14 questions about patient's experience and opinion on different aspects of the management, performance and perceived usefulness of performing ultrasound, to be answered on a Likert scale 1-5. The third section of the survey was addressed to the rheumatologist ultrasonographers. RESULTS: Nine hundred and four patients from 16 university hospital rheumatology departments completed the survey. All questions reached an overall favourable response ≥ 80%. Patients who reported usual ultrasound examinations in their rheumatology care and those in which it was their attending rheumatologist who performed the ultrasound assessments responded more favourably. CONCLUSION: Our encouraging patient-centred results may be useful in facilitating the implementation of rheumatological ultrasound in rheumatology care worldwide. Key Points • This is the largest multicentre survey carried out in patients with chronic joint diseases designed to assess their experience and perceived benefits with the use of ultrasonography performed by rheumatologists in daily practice. • Musculoskeletal ultrasound incorporated into rheumatology care was very well accepted and valued by most patients. • The patients perceived that ultrasonography helps not only their rheumatologist but also themselves to better understand their condition. • The patients believed that ultrasonography helps them accept and comply with the proposed treatment.

Altered CD39 and CD73 Expression in Rheumatoid Arthritis: Implications for Disease Activity and Treatment Response.

In rheumatoid arthritis (RA) synovium, ATP, and ADP are released, sparking inflammation. Ectoenzymes CD39 and CD73 metabolize these purine nucleotides, generating anti-inflammatory adenosine. Therefore, dysregulated CD39 and CD73 expression may impact RA development. We assessed CD39 and CD73 expression in peripheral blood from 15 healthy controls (Cs) and 35 RA patients at baseline and after 3 and 6 months of tocilizumab treatment using flow cytometry. Additionally, ectoenzyme expression was examined on cultured T cells to understand activation and IL-6 effects. At baseline, RA patients exhibited a lower CD8+CD39-CD73+ cell percentage, which inversely correlated with DAS28. Additionally, they had lower percentages of Treg CD39+CD73+ and CD39-CD73- cells. Good responders tended to have lower B CD39+CD73+ cell percentages at baseline and 3 months. Additionally, Treg, CD8+ T and B cells inversely correlated with DAS28. T-cell activation increased CD39 and decreased CD73 expression, regardless of IL-6. IL-6 reduced IFNγ-secreting CD4+ T-cell percentage in Cs, but increased the percentage of IFNγ-secreting CD4+ and CD8+ T cells in RA patients. These findings indicate differing CD39 and CD73 expression in RA and Cs, influenced by T-cell activation and IL-6. Correlations between these molecules and RA activity suggest their role in dysregulated inflammation in RA.

Reliability assessment of the definition of ultrasound enthesitis in SpA: results of a large, multicentre, international, web-based study.

OBJECTIVES: To investigate the reliability of the OMERACT US Task Force definition of US enthesitis in SpA. METHODS: In this web exercise, based on the evaluation of 101 images and 39 clips of the main entheses of the lower limbs, the elementary components included in the OMERACT definition of US enthesitis in SpA (hypoechoic areas, entheseal thickening, power Doppler signal at the enthesis, enthesophytes/calcifications, bone erosions) were assessed by 47 rheumatologists from 37 rheumatology centres in 15 countries. Inter- and intra-observer reliability of the US components of enthesitis was calculated using Light's kappa, Cohen's kappa, Prevalence And Bias Adjusted Kappa (PABAK) and their 95% CIs. RESULTS: Bone erosions and power Doppler signal at the enthesis showed the highest overall inter-reliability [Light's kappa: 0.77 (0.76-0.78), 0.72 (0.71-0.73), respectively; PABAK: 0.86 (0.86-0.87), 0.73 (0.73-0.74), respectively], followed by enthesophytes/calcifications [Light's kappa: 0.65 (0.64-0.65), PABAK: 0.67 (0.67-0.68)]. This was moderate for entheseal thickening [Light's kappa: 0.41 (0.41-0.42), PABAK: 0.41 (0.40-0.42)], and fair for hypoechoic areas [Light's kappa: 0.37 (0.36-0.38); PABAK: 0.37 (0.37-0.38)]. A similar trend was observed in the intra-reliability exercise, although this was characterized by an overall higher degree of reliability for all US elementary components compared with the inter-observer evaluation. CONCLUSIONS: The results of this multicentre, international, web-based study show a good reliability of the OMERACT US definition of bone erosions, power Doppler signal at the enthesis and enthesophytes/calcifications. The low reliability of entheseal thickening and hypoechoic areas raises questions about the opportunity to revise the definition of these two major components for the US diagnosis of enthesitis.

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.

Reliability assessment of ultrasound muscle echogenicity in patients with rheumatic diseases: Results of a multicenter international web-based study.

Objectives: To investigate the inter/intra-reliability of ultrasound (US) muscle echogenicity in patients with rheumatic diseases. Methods: Forty-two rheumatologists and 2 radiologists from 13 countries were asked to assess US muscle echogenicity of quadriceps muscle in 80 static images and 20 clips from 64 patients with different rheumatic diseases and 8 healthy subjects. Two visual scales were evaluated, a visual semi-quantitative scale (0-3) and a continuous quantitative measurement ("VAS echogenicity," 0-100). The same assessment was repeated to calculate intra-observer reliability. US muscle echogenicity was also calculated by an independent research assistant using a software for the analysis of scientific images (ImageJ). Inter and intra reliabilities were assessed by means of prevalence-adjusted bias-adjusted Kappa (PABAK), intraclass correlation coefficient (ICC) and correlations through Kendall's Tau and Pearson's Rho coefficients. Results: The semi-quantitative scale showed a moderate inter-reliability [PABAK = 0.58 (0.57-0.59)] and a substantial intra-reliability [PABAK = 0.71 (0.68-0.73)]. The lowest inter and intra-reliability results were obtained for the intermediate grades (i.e., grade 1 and 2) of the semi-quantitative scale. "VAS echogenicity" showed a high reliability both in the inter-observer [ICC = 0.80 (0.75-0.85)] and intra-observer [ICC = 0.88 (0.88-0.89)] evaluations. A substantial association was found between the participants assessment of the semi-quantitative scale and "VAS echogenicity" [ICC = 0.52 (0.50-0.54)]. The correlation between these two visual scales and ImageJ analysis was high (tau = 0.76 and rho = 0.89, respectively). Conclusion: The results of this large, multicenter study highlighted the overall good inter and intra-reliability of the US assessment of muscle echogenicity in patients with different rheumatic diseases.

The ovarian reserve as measured by the anti-Müllerian hormone is not diminished in patients with rheumatoid arthritis compared to the healthy population.

OBJECTIVES: Rheumatoid arthritis (RA) is the most prevalent chronic inflammatory arthritis, affecting 0.5-1% worldwide population and predominates in females. Altered fertility has been reported due to a decrease in ovarian reserve secondary to sustained inflammation. The anti-Müllerian Hormone (AMH) is currently the most reliable biomarker of ovarian reserve. However, few and contradictory studies have been reported to analyse the relationship between fertility in RA female patients and AMH. The aim of present study is to determine the AMH serum concentrations in a long-standing RA patient group and control group. We also sought to determine the correlation between AMH serum levels and disease activity measured by different parameters and the effect of biological DMARDs. METHODS: Serum AMH levels were measured in 60 women with long-standing RA aged 20-50 y.o. and compared to 59 healthy women. AMH was assessed by an electrochemiluminescence immunoassay method (ECLIA, Roche Diagnostics) and a large data set of clinical and molecular data was annotated. Demographic parameters, RA disease activity measured by DAS28 score and inflammatory biomarkers such as ESR, CRP, lymphocyte CD4+, CD8+, NK cells, IL-10 and IL-6 were determined. A comprehensive gynaecological self-administered questionnaire was given. Serum AMH levels were age-correlated. Differences between groups were calculated using Student's t-test or Mann-Whitney U-test for continuous variables and Fisher's exact test for categorical variables. Multivariate analysis was conducted by the partial correlation coefficient. Linear regression analysis was performed to study the effect of different variables on proportional AMH change. p-values <0.005 were considered significant. RESULTS: The median age was similar in AR and control groups (37.4±6.23 vs. 37.3±6.27 p=0.937). Mean disease duration was 8.37±5.36 years. The number of previous treatments was <3 in 71.7% of patients and ≥3 in 28.3%. Disease activity measured by DAS28 was 2.89± 1.54. The age-adjusted mean serum concentration of AMH was 1.27 ng/ml [IQR 0.42; 2.24] in RA patients and 1.31 ng/ml [IQR 0.46; 3.09] in controls (p=0.608). Neither disease activity (p=0.862), nor current or previous bDMARDs treatments (p=0.871) were associated with AMH levels. However, a negative linear correlation was observed between AMH and IL-10 levels (p=0.033). CONCLUSIONS: Our study shows that ovarian reserve determined by AMH serum levels is not reduced in rheumatoid arthritis patients compared with healthy controls. In our series, AMH levels were not affected by disease activity, however, a significant correlation was observed between AMH and IL-10 levels. These results support the role of cytokines profile in the female reproductive system and will focus further investigations in this critical area, mainly once biological DMARDs have been recommended in RA pregnant patients.

Non-invasive vagus nerve stimulation for rheumatoid arthritis: a proof-of-concept study.

BACKGROUND: Vagus nerve stimulation delivered with an implanted device has been shown to improve rheumatoid arthritis severity. We aimed to investigate the safety and efficacy of non-invasive stimulation of the auricular branch of the vagus nerve for the treatment of patients with moderately to severely active rheumatoid arthritis. METHODS: This prospective, multicentre, open-label, single-arm proof-of-concept study enrolled patients aged 18-80 years with active rheumatoid arthritis who had an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (DMARDs) and up to one biological DMARD. Biological DMARDs were stopped at least 4 weeks before enrolment and concomitant use was not allowed during the study. All eligible participants were assigned to use a non-invasive, wearable vagus nerve stimulation device for up to 30 min per day, which delivered pulses of 20 kHz. Follow-up visits occurred at week 1, week 2, week 4, week 8, and week 12 after the baseline visit. The primary endpoint was the mean change in Disease Activity Score of 28 joints with C-reactive protein (DAS28-CRP) at week 12 compared with baseline. Secondary endpoints included the mean change in the Health Assessment Questionnaire-Disability Index (HAQ-DI), the proportion of patients with a minimal clinically important difference of 0·22 on HAQ-DI, the proportion achieving American College of Rheumatology (ACR) 20, ACR50, and ACR70 response, and safety analysis. This study is registered with ClinicalTrials.gov (NCT04116866). FINDINGS: Of 35 patients screened for eligibility, 30 (86%) were enrolled at six centres in Spain between Dec 27, 2018, and Oct 24, 2019, of whom 27 (90%) completed the week 12 visit. The mean change in DAS28-CRP at 12 weeks was -1·4 (95%CI -1·9 to -0·9; p<0·0001) from a mean baseline of 5·3 (SD 1·0). 11 (37%) of 30 patients reached DAS28-CRP of 3·2 or less, and seven (23%) patients reached DAS28-CRP of less than 2·6 at week 12. The mean HAQ-DI change was -0·5 (95%CI -0·7 to -0·2; p<0·0001) from a mean baseline of 1·6 (SD 0·7), and 17 (57%) patients reached a minimal clinically important difference of 0·22 or more. ACR20 responses were reached by 16 (53%) patients, ACR50 responses by 10 (33%) patients, and ACR70 by five (17%) patients. Four adverse events were reported, none of which were serious and all of which resolved without intervention. INTERPRETATION: Use of the device was well tolerated, and patients had clinically meaningful reductions in DAS28-CRP. This was an uncontrolled, open-label study, and the results must be interpreted in this context. Further evaluation in larger, controlled studies is needed to confirm whether this non-invasive approach might offer an alternative treatment for rheumatoid arthritis. FUNDING: Nesos.

Incidence of COVID-19 in a cohort of adult and paediatric patients with rheumatic diseases treated with targeted biologic and synthetic disease-modifying anti-rheumatic drugs.

Objectives: To investigate the incidence of COVID-19 in a cohort of adult and paediatric patients with rheumatic diseases receiving targeted biologic and synthetic disease modifying anti-rheumatic drugs (tDMARDs) and to explore the possible effect of these treatments in the clinical expression of COVID-19. Methods: A cross-sectional study comprising of a telephone survey and electronic health records review was performed including all adult and paediatric patients with rheumatic diseases treated with tDMARDs in a large rheumatology tertiary centre in Barcelona, Spain. Demographics, disease activity, COVID-19 related symptoms and contact history data were obtained from the start of the 2020 pandemic. Cumulative incidence of confirmed cases (SARS-CoV-2 positive PCR test) was compared to the population estimates for the same city districts from a governmental COVID-19 health database. Suspected cases were defined following WHO criteria and compared to those without compatible symptoms. Results: 959 patients with rheumatic diseases treated with tDMARDs were included. We identified 11 confirmed SARS-CoV-2 positive cases in the adult cohort and no confirmed positive cases in the paediatric cohort. COVID-19 incidence rates of the rheumatic patient cohort were very similar to that of the general population [(0.48% (95% CI 0.09 to 0.87%)] and [0.58% (95% CI 0.56 to 0.60%)], respectively. We found significant differences in tDMARDs proportions between the suspected and non-suspected cases (p=0.002). Conclusion: Adult and paediatric patients with rheumatic diseases on tDMARDs do not seem to present a higher risk of COVID-19 or a more severe disease outcome when compared to general population.

Measuring inflammation in rheumatoid arthritis with a new clinical and ultrasound index: development and initial validation.

With the aim to develop and validate a clinical + ultrasound (US) inflammation score in rheumatoid arthritis (RA) for use in clinical practice, a mixed-method study was conducted. The theoretical development of the index was achieved with qualitative methodology (discussion group and Delphi survey). Subsequently, a cross-sectional study was carried out to analyse issues related to scoring and validation of the new index. RA patients underwent clinical [28 swollen and tender joints count, patient and physician global assessment (PhGA), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP)], and US assessments [synovitis or tenosynovitis by grey-scale (GS) and power Doppler (PD) of 42 structures]. An index was created based on statistical models and expert interaction. Construct validity was tested by correlation with DAS28, SDAI, CDAI, and PhGA. Reliability was evaluated in a subgroup of patients with the intraclass correlation coefficient (ICC). US assessment, CRP, and swollen joints were the items that passed the prioritization phase (Delphi study). For the cross-sectional study, 281 patients were randomly divided into design (n = 141) and validation samples (n = 140). The combination of US sites chosen (7 bilaterally) detected the maximum proportion of synovitis and PD present. Three scoring methods were tested: semiquantitative (0-3 GS + 0-3 PD), dichotomous (0/1 GS + 0/1 PD), and qualitative (0/1 based on algorithm). All showed strong correlation with activity measures (ρ ≥ 0.60), and reliability (ICC 0.89-0.93). The index with best parameters of validity, feasibility, and reliability was the qualitative. The final index chosen was the sum of swollen joint count, US qualitative score, and CRP. The UltraSound Activity score is a valid and reliable measure of inflammation in RA equal to the sum of 28 SJC, a simplified (0/1) US assessment of 11 structures and CRP. It is necessary further investigation to demonstrate additional value over existing indices.

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.

The combination of IL-6 and its soluble receptor is associated with the response of rheumatoid arthritis patients to tocilizumab.

BACKGROUND: IL-6 contributes significantly to the chronic inflammatory process of rheumatoid arthritis (RA). Tocilizumab, a humanized anti-human IL-6 receptor antibody that blocks the signaling originated by the IL-6/IL-6R complex, is an effective treatment. However, predictors of the response to tocilizumab are still required. We aimed to combine IL-6 and soluble IL-6R (sIL-6R) levels to identify groups of responses. METHODS: Heparinized blood and clinical data from 63 RA patients were collected before treatment and after 3 and 6 months. Two-step clustering (SPSS v.18) was used to establish the relationship between IL-6 and sIL-6R. Then, we compared European League Against Rheumatism (EULAR) response criteria with remission achievement in the groups of patients. RESULTS: Three statistical significant clusters of RA patients (i.e., g1, g2, and g3) were defined by serum concentrations of IL-6 and sIL-6R at baseline. All groups of RA patients had higher IL-6 and sIL-6R levels than healthy donors. The levels of IL-6 expressed as median (IQR) in g1 patients were 124(90-183)pg/ml, in g2 12.3(4.4-24)pg/ml, and in g3 60.1(30-146)pg/ml (p < 0.001). The levels of sIL-6R expressed as mean ± sd in g1 patients were 250.5 ± 72ng/ml, in g2 269.1 ± 125ng/ml, and in g3 732.7 ± 243ng/ml (p < 0.001). Disease activity score (DAS)28, C-reactive protein, and erythrocyte sedimentation rate were comparable in the three groups at baseline. Disease duration in g3 was the longest (median(IQR) years: g1 = 11(5-15), g2 = 12(8-20), and g3 23(16-26); p = 0.006), with years of disease evolution being correlated with sIL-6R levels (R = 0.417, p < 0.001). Simple and Clinical Disease Activity Index (SDAI and CDAI) decreased significantly in the three groups. However, EULAR response criteria and remission achievement at 6m was different in the three groups (p = 0.03 and 0.04, respectively). In all. 17 out of the 18 patients in g1 had a good or moderate response to tocilizumab. Conversely, the percentage of patients with no response to tocilizumab was higher in g3 than in g1 and g2. We also observed different changing patterns of IL-6 and sIL-6R levels among the three groups. CONCLUSIONS: RA patients could be easily stratified prior to therapeutic intervention with two molecules related to the pathway blocked by tocilizumab. G1 patients, who had the best response to tocilizumab, had the highest level of IL-6 and the lowest level of sIL-6R.

VARIAR Study: Assessment of short-term efficacy and safety of rituximab compared to an tumor necrosis factor alpha antagonists as second-line drug therapy in patients with rheumatoid arthritis refractory to a first tumor necrosis factor alpha antagonist. / Estudio VARIAR: VAloración de la eficacia y seguridad a corto plazo en artritis reumatoide del uso de RItuximab comparado con Antagonistas del factor de necrosis tumoral alfa en segunda línea terapéutica en pacientes con artritis reumatoide Refractarios a un primer antagonista del factor de necrosis tumoral alfa.

OBJECTIVE: to compare the short-term efficacy and safety of rituximab (RTX) therapy versus anti-TNF in rheumatoid arthritis (RA) patients after discontinuation of a first anti-TNF agent. METHODS: prospective observational multicenter study in the clinical practice setting, involving patients with severe RA refractory to a first anti-TNF agent, who received either RTX or a second anti-TNF (2TNF), comparing the efficacy endpoints, EULAR response (Good/Moderate) and safety at 6 months. RESULTS: 103 patients enrolled, 82 completed 6-month follow-up, 73.7% women. Baseline data for RTX and 2TNF groups, respectively: TJC, 8.6 and 6.6; SJC, 8.8 and 7.5; DAS28 score, 5.45 (±1.28) and 5.18 (±1.21) (p=0.048), ESR, 41 and 38.7mmHg; and HAQ, 1.2 and 1.0. Improvement was observed in all parameters, with no significant differences (except for a more marked reduction in ESR with RTX). There were no serious adverse events. CONCLUSIONS: RTX use as second-line therapy after anti-TNF failure led to improvements in the efficacy and functional variables at 6 months, with no serious adverse events. These results were comparable to those observed in patients who used a second anti-TNF agent in the same clinical scenario.

Three-dimensional volumetric ultrasound: a valid method for blinded assessment of response to therapy in rheumatoid arthritis.

OBJECTIVE: To assess the responsiveness and repeatability of volumetric power Doppler ultrasound (PDUS) evaluation of synovitis and bone erosions in rheumatoid arthritis (RA). METHODS: Twenty-three patients with RA (19 women, mean age 52.7 ± 12.6 yrs, mean disease duration 10.1 ± 8.6 yrs) were prospectively enrolled. All patients were beginning therapy with rituximab because of disease activity despite therapy with synthetic disease-modifying antirheumatic drugs and tumor necrosis factor-blocking agents. Patients underwent clinical, laboratory, and volumetric PDUS examination at baseline, 6 months, and 12 months. Ten centers participated in the study. Four centers recruited the patients and performed the volumetric acquisitions of PDUS images, while the remaining 6 centers assessed the PDUS volumes, blinded to the identity of patients and date of the visits. The most symptomatic hand and foot were scored for B-mode synovitis, synovial PD signal, and bone erosions. The repeatability of the volumetric PDUS assessment was investigated. RESULTS: An overall improvement in clinical and PDUS measurements was found at the followup assessments. The mean indexes for synovial PD signal and bone erosions and the number of sites with abnormalities decreased significantly throughout the followup (p < 0.05). The intraacquisition, intrareader reliability was excellent for all PDUS measurements (intraclass correlation coefficients > 0.9). CONCLUSION: The results of our pilot study suggest that volumetric PDUS can be responsive and repeatable in multicenter cohort studies of RA. This technique may minimize assessment biases and reduce acquisition variability in open-label and observational studies.

A multicentre study on high-frequency ultrasound evaluation of the skin and joints in patients with psoriatic arthritis treated with infliximab.

OBJECTIVES: Our objective was to describe the ultrasound features of patients with PsA in joints and skin and their changes after treatment with infliximab. METHODS: Eight hospitals recruited PsA active patients. Clinical (joint count for pain, TJC, and swelling, SJC, pain VAS, ESR, C-reactive protein and PASI) and US variables (plaque thickness, PD signal of dermal lesions, synovitis, erosions, and PD signal, assessed by 4-category ordinal scales) were independently recorded at baseline and 4, 12 and 24-week after starting treatment with infliximab. The results were analysed with paired T, Wilcoxon test, ANOVA and marginal homogeneity test. RESULTS: Changes in 24 patients from baseline to last available data were significant for clinical variables, pain VAS, TJC and SJC as well as for ESR, CRP (all p<0.0005). Dermatological PASI changed from 14.6±14.9 to 2.1±4.1 and plaque thickness from 3.34±1.75 mm to 1.74±0.96 mm (both p<0.0005); synovitis and PD signal improved (both p<0.0005). Psoriatic plaque PD improved across the study (p<0.0005) with no signal increasing from 36.4% to 88.9% and positive PD signal decreasing from 63.6% to 11.1% of the plaques. CONCLUSIONS: Treatment with anti-TNF-α infliximab improves the symptoms of patients with PsA at joint and psoriatic skin levels from a clinical and ultrasonographic perspective.

Validity, reproducibility, and responsiveness of a twelve-joint simplified power doppler ultrasonographic assessment of joint inflammation in rheumatoid arthritis.

OBJECTIVE: To investigate the validity, reproducibility, and responsiveness of a simplified power Doppler ultrasound (PDUS) assessment of joint inflammation compared with a comprehensive 44-joint PDUS assessment in patients with rheumatoid arthritis (RA) who started therapy with a biologic agent. METHODS: A total of 160 patients with active RA who started a biologic agent were prospectively recruited in 18 Spanish centers. The patients underwent clinical and laboratory assessment and blinded PDUS examination at baseline and 6 months. A PDUS examination of 128 synovial sites in 44 joints was performed. US synovitis and PD signal were semiquantitatively graded from 1 to 3 in all synovial sites. US count and index for synovitis and PD signal were obtained. PDUS intraobserver and interobserver reliability were evaluated. A process of data reduction based on the frequency of involvement of synovial sites by both synovitis and PD signal was conducted. Construct and discriminant validity of a simplified PDUS assessment was investigated. RESULTS: A PDUS simplified assessment including 24 synovial sites from 12 joints detected 100% of patients with synovitis and 91% of patients with PD signal. There was a highly significant correlation between the 44-joint count and index for synovitis and PD signal and the 12-joint count and index for synovitis and PD signal at baseline and 6 months (r = 0.84-0.90, P < 0.0005). The smallest detectable difference was lower than the mean change in simplified PDUS variables. CONCLUSION: A 12-joint PDUS assessment of RA joint inflammation may be a valid, feasible method for multicenter monitoring of therapeutic response to biologic agents.