The relationship between ultrasound and physical examination in the assessment of enthesitis in SpA patients: results from the DEUS multicentre study

OBJECTIVES: i) To explore the agreement between the OMERACT ultrasound lesions of enthesitis and physical examination in assessing enthesitis in spondyloarthritis (SpA) patients; ii) To investigate the prevalence and clinical relevance of subclinical enthesitis in this population. METHODS: Twenty rheumatology centres participated in this cross-sectional study. SpA patients, including axial SpA (axSpA) and psoriatic arthritis (PsA) patients, 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 SpA patients without clinical enthesitis (i.e., number of positive entheses on physical examination and Leeds Enthesitis Index score =0). RESULTS: 4130 entheses in 413 SpA patients (224 axSpA/189 PsA) were evaluated through ultrasound and physical examination. Agreement between ultrasound and physical examination ranged from moderate (i.e., enthesophytes) to almost perfect (i.e., power Doppler and 'active enthesitis'). Patellar tendon entheses demonstrated the highest agreement, whereas Achilles tendon insertion showed the lowest. Among 158/413 (38.3%) SpA patients 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 SpA patients with and without subclinical enthesitis. CONCLUSIONS: Our study underscores the need for a comprehensive tool integrating ultrasound and physical examination for assessing enthesitis in SpA patients.

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.

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.

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.