Sandrine Jousse-Joulin

Brief Report: Ultrasonographic Assessment of Salivary Gland Response to Rituximab in Primary Sjögren's Syndrome

To evaluate changes in salivary gland echostructure and vascularization after rituximab treatment in patients with primary Sjögrens syndrome (SS).

Development of the Sjögren’s Syndrome Responder Index, a data-driven composite endpoint for assessing treatment efficacy

OBJECTIVESnTo determine which outcome measures detected rituximab efficacy in the Tolerance and Efficacy of Rituximab in Sjögrens Disease (TEARS) trial and to create a composite endpoint for future trials in primary SS (pSS).nnnMETHODSnPost hoc analysis of the multicentre randomized placebo-controlled double-blind TEARS trial. The results were validated using data from two other randomized controlled trials in pSS, assessing rituximab (single-centre trial in the Netherlands) and infliximab, respectively.nnnRESULTSnFive outcome measures were improved by rituximab in the TEARS trial: patient-assessed visual analogue scale scores for fatigue, oral dryness and ocular dryness, unstimulated whole salivary flow and ESR. We combined these measures into a composite endpoint, the SS Responder Index (SSRI), and we defined an SSRI-30 response as a ≥30% improvement in at least two of five outcome measures. In TEARS, the proportions of patients with an SSRI-30 response in the rituximab and placebo groups at 6, 16 and 24 weeks were 47% vs 21%, 50% vs 7% and 55% vs 20%, respectively (P < 0.01 for all comparisons). SSRI-30 response rates after 12 and 24 weeks in the single-centre rituximab trial were 68% (13/19) vs 40% (4/10) and 74% (14/19) vs 40% (4/10), respectively. No significant differences in SSRI-30 response rates were found between infliximab and placebo at any of the time points in the infliximab trial.nnnCONCLUSIONnA core set of outcome measures used in combination suggests that rituximab could be effective and infliximab ineffective in pSS. The SSRI might prove useful as the primary outcome measure for future therapeutic trials in pSS.

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

OBJECTIVESnTo 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 Sjögrens syndrome (pSS).nnnMETHODSn45 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 Sjögrens Syndrome Responder Index (SSRI)-30.nnnRESULTSnResponse 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.nnnCONCLUSIONSnIn pSS, half of the patients display an intense BAFF-driven B-cell activation and do not respond to a single course of rituximab.

Severe Health-Related Quality-of-life Impairment in Active Primary Sjögren's Syndrome Is Driven by Patient-Reported Outcomes: Data from a Large Therapeutic Trial.

To identify the principal determinants of health‐related quality of life (HRQOL) impairment in patients with active primary Sjögrens syndrome (SS) participating in a large therapeutic trial, Tolerance and Efficacy of Rituximab in Primary Sjögrens Syndrome (TEARS).

Reliability of histopathological salivary gland biopsy assessment in Sjögren’s syndrome: a multicentre cohort study

OBJECTIVEnThe aim of this study was to assess intraobserver and interobserver reliability of minor salivary gland biopsy (MSGB) in SS.nnnMETHODSnAll MSGBs available from the Tolerance and Efficacy of Rituximab in Primary Sjögrens Syndrome (TEARS) study were subjected to a standardized blinded assessment by a single specifically trained pathologist twice at a 2 month interval; both the Chisholm-Mason (CM) grade and the focus score (FS) were determined. Baseline histopathological reports by local pathologists at each study centre were compared with the first standardized blinded assessment. Agreement was assessed for the dichotomized FS (dFS) and dichotomized CM (dCM) grade, as well as for nine other histopathological features.nnnRESULTSnEighty-nine MSGBs were studied. Intraobserver κ values were 1 for dFS, 0.80 for dCM, 0.67 for germinal centre-like structures, 0.44 for fibrosis and 0.29 for confluent foci. Most of the local histopathological reports based their diagnosis on the CM grade, although the FS was often reported or the data needed to determine it were provided. Interobserver agreement κ values were 0.71 for dFS, 0.64 for dCM, 0.46 for focal lymphocytic sialadenitis, 0.42 for non-specific chronic inflammation and 0.16 for fibrosis.nnnCONCLUSIONnAlthough FS reliability was good, disparities were noted in the assessment methods used by local pathologists. The protocol for FS determination was not followed routinely, with the result that the FS was often overestimated. Germinal centre-like structures, which predict lymphoma, showed good reliability but were inconsistently reported.

Which and How Many Patients Should Be Included in Randomised Controlled Trials to Demonstrate the Efficacy of Biologics in Primary Sjögren’s Syndrome?

Objective The goal of this study was to determine how the choice of the primary endpoint influenced sample size estimates in randomised controlled trials (RCTs) of treatments for primary Sjögren’s syndrome (pSS). Methods We reviewed all studies evaluating biotechnological therapies in pSS to identify their inclusion criteria and primary endpoints. Then, in a large cohort (ASSESS), we determined the proportion of patients who would be included in RCTs using various inclusion criteria sets. Finally, we used the population of a large randomised therapeutic trial in pSS (TEARS) to assess the impact of various primary objectives and endpoints on estimated sample sizes. These analyses were performed only for the endpoints indicating greater efficacy of rituximab compared to the placebo. Results We identified 18 studies. The most common inclusion criteria were short disease duration; systemic involvement; high mean visual analogue scale (VAS) scores for dryness, pain, and fatigue; and biological evidence of activity. In the ASSESS cohort, 35 percent of patients had recent-onset disease (lower than 4 years), 68 percent systemic manifestations, 68 percent high scores on two of three VASs, and 52 percent biological evidence of activity. The primary endpoints associated with the smallest sample sizes (nlower than 200) were a VAS dryness score improvement higher to 20 mm by week 24 or variable improvements (10, 20, or 30 mm) in fatigue VAS by week 6 or 16. For patients with systemic manifestations, the ESSDAI change may be the most logical endpoint, as it reflects all domains of disease activity. However, the ESSDAI did not improve significantly with rituximab therapy in the TEARS study. Ultrasound score improvement produced the smallest sample size estimate in the TEARS study. Conclusion This study provides valuable information for designing future RCTs on the basis of previously published studies. Previous RCTs used inclusion criteria that selected a small part of the entire pSS population. The endpoint was usually based on VASs assessing patient complaints. In contrast to VAS dryness cut-offs, VAS fatigue cut-offs did not affect estimated sample sizes. SGUS improvement produced the smallest estimated sample size. Further studies are required to validate standardised SGUS modalities and assessment criteria. Thus, researchers should strive to develop a composite primary endpoint and to determine its best cut-off and assessment time point.

Normal sonoanatomy of the paediatric entheses including echostructure and vascularisation changes during growth

AbstractObjectivesTo describe the sonoanatomy of paediatric lower-limb entheses according to age and gender. We studied sites that most commonly involved entheses in spondyloarthritis.MethodsWe studied 41 consecutive healthy children (20 girls, 21 boys; age 2–15xa0years) divided into four age groups: 2–4xa0years (nu2009=u20099), 5–7xa0years (nu2009=u200911), 8–12xa0years (nu2009=u200912) and 13–15xa0years (nu2009=u20099). Ultrasound was used to obtain both transverse and longitudinal views of each enthesis. We assessed the echostructural components of the lower limb entheses and the vascularisation of the entheses and cartilage according to the different anatomical sites and age and gender.ResultsAt all sites on B-mode, cartilage and tendon thicknesses showed positive or negative correlations with age (Pu2009<u20090.0001). Side-to-side correlations were good (Pu2009<u20090.0001 overall) and stronger for cartilage (r, 0.77–0.97) than for tendon thickness (r, 0.58–0.63). Agreement between the two sides for discrete data was very good to excellent (kappa, 0.77–1). Cartilage thickness at the various sites was significantly greater in boys than in girls (Pu2009≤u20090.05). Tendon thickness was not significantly influenced by gender. Blood vessels were seen within the cartilage with differences across age groups.ConclusionsThis study provides the first data on normal entheseal sonoanatomy and vascularisation in children.Key Points• The tendons of children exhibit the same fibrillar structure as adultsn • Tendon thickness at enthesis insertion in children is not influenced by gendern • Cartilage thickness in children decreases with advancing age and varies with gender

Time-course of ultrasound abnormalities of major salivary glands in suspected Sjögren's syndrome

OBJECTIVEnTo evaluate whether major salivary-gland ultrasonography (SGUS) abnormalities change over time in patients with suspected primary Sjögrens syndrome (pSS) during the natural course of the disease.nnnMETHODSnWe studied patients with suspected pSS who were included in the Brittany cohort of suspected pSS and underwent SGUS at least twice, as part of the routine diagnostic workup done at baseline then at least 1 year later as an additional investigation deemed appropriate by the physician. The evaluation criteria were the semi-quantitative SGUS score (0-4) for each parotid and submandibular gland, the highest SGUS score among the four glands, and the sum of SGUS scores for the four glands. These scores were compared in patients with and without pSS according to the workup at baseline, and their changes over time were assessed.nnnRESULTSnOf 49 included patients, 29 received a diagnosis of pSS at baseline; none of the remaining 20 patients was diagnosed with pSS at either evaluation. The mean (SD) sum of SGUS scores at baseline was 8.9 (5.6) in patients with and 2.1 (2.9) in those without pSS (P<0.01). Mean time between SGUSs was 1.9 (1.6) years. None of the evaluation criteria changed between the two SGUSs in the overall population, pSS group, or group without pSS. Similar results were found in the subgroup with recent-onset symptoms.nnnCONCLUSIONnSGUS abnormalities assessed using a semi-quantitative score did not change significantly during a follow-up of nearly 2 years after an initial evaluation for suspected pSS.

Predictive value of tender joints compared to synovitis for structural damage in rheumatoid arthritis

Objective To evaluate the predictive value of tender joints compared to synovitis for structural damage in rheumatoid arthritis (RA). Methods A post hoc analysis was performed on a prospective 2-year study of 59 patients with active RA starting on antitumour necrosis factor (TNF). Tenderness and synovitis was assessed clinically at baseline, followed by blinded ultrasound assessment (B-mode and power Doppler ultrasound (PDUS)) on the hands and feet (2 wrists, 10 metacarpophalangeal, 10 proximal interphalangeal and 10 metatarsophalangeal (MTP) joints). Radiographs of these joints were performed at baseline and at 2u2005years. The risk of radiographic progression with respect to the presence of baseline tenderness or synovitis, as well as its persistence (after 4u2005months of anti-TNF), was estimated by OR (95% CI). Results Baseline tender joints were the least predictive for radiographic progression (OR=1.53 (95% CI 1.02 to 2.29) p<0.04), when compared to synovitis (clinical OR=2.08 (95% CI 1.39 to 3.11) p<0.001 or PDUS OR=1.80 (95% CI 1.20 to 2.71) p=0.005, respectively). Tender joints with the presence of synovitis were predictive of radiographic progression (OR=1.89 (95% CI 1.25 to 2.85) p=0.002), especially seen in the MTP joints. Non-tender joints with no synovitis were negatively predictive (OR=0.57 (95% CI 0.39 to 0.82) p=0.003). Persistence of tender joints was negatively predictive (OR=0.38 (95% CI 0.18 to 0.78) p=0.009) while persistence of synovitis was predictive (OR=2.41 (95% CI 1.24 to 4.67) p=0.01) of radiographic progression. Conclusions Synovitis is better than tenderness to predict for subsequent structural progression. However, coexistence of tenderness and synovitis at the level of an individual joint is predictive of structural damage, particularly in the MTP joints. Trial registration number NCT00444691.

Eosinophilia predicts poor clinical outcomes in recent-onset arthritis: results from the ESPOIR cohort

Objectives To determine the prevalence of eosinophilia in patients with recent-onset arthritis suggestive of rheumatoid arthritis (RA) and to describe their features and outcomes. Methods We performed an ancillary study of data from a French prospective multicentre cohort study monitoring clinical, laboratory and radiographic data in patients with inflammatory arthritis of 6u2005weeks to 6u2005months duration. We determined the proportion of patients with eosinophilia, defined as a count >500/mm3, at baseline and after 3u2005years. Features of patients with and without baseline eosinophilia were compared. Results Baseline eosinophilia was evidenced in 26 of 804 (3.2%) patients; their mean eosinophil count was 637.7±107/mm3. Baseline eosinophilia was ascribed to atopic syndrome in 6 of 26 (23.1%) patients. After 3u2005years, patients with eosinophilia had higher Health Assessment Questionnaire scores (0.9 vs 0.5, p=0.004), higher patient visual analogue scale activity score and morning stiffness intensity (p=0.05), and were more often taking disease-modifying antirheumatic drugs (p=0.02). Baseline eosinophilia was not associated with presence of extra-articular manifestations. Conclusions Eosinophilia is rare in recent-onset arthritis suggestive of RA, and is usually directly related to the rheumatic disease. Our data suggest that patients with mild eosinophilia at diagnosis could respond worse to the treatment than those without.