V. Le Guern

Tolerance and efficacy of rituximab and changes in serum B cell biomarkers in patients with systemic complications of primary Sjögren’s syndrome

Objective: To investigate the safety and efficacy of rituximab (RTX) for systemic symptoms in patients with primary Sjögren’s syndrome (pSS), and changes in B cell biomarkers. Patients and methods: The records of 16 patients with pSS according to the American European consensus group criteria were reviewed retrospectively. Results: Patients, all women, had a median age of 58.5 (range 41–71) years and a disease duration of 9.5 (range 0–25) years. RTX was prescribed for lymphoma (n = 5), refractory pulmonary disease with polysynovitis (n = 2), severe polysynovitis (n = 2), mixed cryoglobulinaemia (n = 5), thrombocytopenia (n = 1) and mononeuritis multiplex (n = 1). The median follow-up duration was 14.5 (range 2–48) months. Three patients experienced adverse events, including one mild serum sickness-like reaction with the presence of human antichimeric antibodies. Efficacy of treatment was observed in 4 of 5 patients with lymphomas and in 9 of 11 patients with systemic involvement. Dryness was improved in only a minority of patients. Corticosteroid dose was reduced in 11 patients. RTX induced decreased rheumatoid factor, γ-globulin and β2-microglobulin levels, and the level of B cell activating factor of the tumour necrosis factor family (BAFF) increased concomitantly with B cell depletion. Five patients were re-treated, with good efficacy and tolerance, except for one with probable serum sickness-like reaction. Conclusion: This study shows good efficacy and fair tolerance of RTX for systemic features. In addition, RTX allows for a marked reduction in corticosteroid use. Except for BAFF, the level of which increases, serum B cell biomarker levels decrease after taking RTX. Controlled trials should be performed to confirm the efficacy of RTX in pSS.

Rheumatoid factor and disease activity are independent predictors of lymphoma in primary Sjögren's Syndrome

To define parameters predictive of lymphoma development in patients with primary Sjögrens syndrome (SS).

Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primary Sjögren syndrome: a case–control study

Objectives: To assess subclinical central nervous system (CNS) involvement in primary Sjögren syndrome (pSS), by comparing standard brain MRI, in-depth neuropsychological testing and 99mTc-ECD brain single-photon emission computed tomography (SPECT) of patients with pSS with matched controls. Methods: 10 women (<55 years old), with pSS defined using European–American criteria, presence of anti-SSA and/or anti-SSB antibodies and no history of neurological involvement were prospectively investigated, and compared with 10 age- and sex-matched controls. All subjects underwent, within 1 month, brain MRI, neuropsychological testing, including overall evaluation and focal cognitive function assessment, and 99mTc-ECD brain SPECT. Results: 99mTc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (10/10) than controls (2/10; p<0.05). Cognitive dysfunctions, mainly expressed as executive and visuospatial disorders, were also significantly more common in patients with pSS (8/10) than controls (0/10; p<0.01). Notably, between-group comparisons enabled a significant correlation to be established between neuropsychological assessment and 99mTc-ECD brain SPECT abnormalities in patients with pSS (rs = 0.49, p<0.01). MRI abnormalities in patients and controls did not differ significantly. Conclusions: Neuropsychological testing and 99mTc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS. The strong correlation between cortical hypoperfusion in 99mTc-ECD brain SPECT and cognitive dysfunction suggests an organic aetiology of CNS dysfunction in pSS. These data should be confirmed in a larger study.

Adjunctive plasma exchanges to treat neuropsychiatric lupus: a retrospective study on 10 patients.

Neuropsychiatric manifestations of systemic lupus erythematosus (NPSLE) are among the main causes of morbidity and mortality attributed to lupus activity. Conventional NPSLE treatment combines CS and immunosuppressants, but some symptoms do not respond. We retrospectively evaluated the adjunction of plasma exchanges (PE) to treat 13 NPSLE flares occurring in 10 patients (mean age, 30 years) between 1989 and 2002. NP manifestations were the first SLE symptoms for seven patients, with a mean of 3.2 NP manifestations/flare. All patients received CS and cyclophosphamide pulses. A mean of 15 PE/flare were performed. All patients improved within a mean of 3 (median: 2.5; range: 1.5—8) weeks thereafter. Complete remissions of 7/13 flares were obtained within a mean of 7 (median: 4; range: 2—22) weeks. Partial remissions were achieved for the remaining six flares, characterized by new NP manifestations during three and insufficient control of the others. Other SLE manifestations regressed for all patients with the mean European consensus lupus activity measurement score declining from pretreatment 6.9 to 1.2. A regimen combining CS, cyclophosphamide and PE is effective against severe NPSLE, with acceptable toxicity. Lupus (2007) 16, 817—822.

CXCL13 and CCL11 Serum Levels and Lymphoma and Disease Activity in Primary Sjögren's Syndrome.

Non‐Hodgkins lymphoma (NHL) is a severe complication of primary Sjögrens syndrome (SS). Ectopic germinal centers (GCs) in the salivary glands are predictors of the occurrence of NHL. Given the association between CCL11 and CXCL13 and ectopic GCs, we assessed the link between these chemokines and NHL, as well as the association between these chemokines and disease activity, in patients with primary SS.

Neonatal lupus syndrome: Literature review

Neonatal lupus syndrome is associated with transplacental passage of maternal anti-SSA/Ro and anti-SSB/La antibodies. Children display cutaneous, hematological, liver or cardiac features. Cardiac manifestations include congenital heart block (CHB); endocardial fibroelastosis and dilated cardiomyopathy. The prevalence of CHB in newborns of anti-Ro/SSA positive women with known connective tissue disease is between 1 and 2% and the risk of recurrence is around 19%. Skin and systemic lesions are transient, whereas CHB is definitive and associated with significant morbidity and a mortality of 18%. A pacemaker must be implanted in 2/3 of cases. Myocarditis may be associated or appear secondly. Mothers of children with CHB are usually asymptomatic or display Sjogrens syndrome or undifferentiated connective tissue disease. In anti-Ro/SSA positive pregnant women, fetal echocardiography should be performed at least every 2 weeks from the 16th to 24th week gestation. An electrocardiogram should be performed for all newborn babies. The benefit of fluorinated corticosteroid therapy for CHB detected in utero remains unclear. Maternal use of hydroxychloroquine may be associated with a decreased recurrent CHB risk in a subsequent offspring. A prospective study is actually ongoing to confirm these findings.

Pathogénie des vascularites systémiques primitives (II): vascularites ANCA-négatives

Points essentiels ● La pathogenie des vascularites systemiques associees aux anticorps anti-cytoplasme de polynucleaires neutrophiles (ANCA) est incompletement elucidee. ● Parmi les vascularites ANCA-positives qui interessent les vaisseaux de petit calibre, on distingue la granulomatose de Wegener (GW), la polyangeite microscopique (MPA) et le syndrome de Churg et Strauss (SCS). Au cours de ces pathologies, les ANCA constituent un outil precieux d’aide au diagnostic. ● Des ANCA diriges contre la proteinase 3 sont detectes chez plus de 90 % des malades atteints de forme systemique de GW, tandis que des ANCA anti-myeloperoxydase (MPO) sont presents chez 60 a 75 % des malades atteints de MPA et 40 a 60 % des malades atteints de SCS. ● Le role pathogene des ANCA est bien documente in vivo, et le transfert passif des ANCA anti-MPO est suffisant pour induire des lesions de glomerulonephrite extra-capillaire dans un modele de souris invalidees pour le gene de la MPO et immunisees avec cet antigene. In vitro, chez la souris et chez l’homme, les ANCA anti-proteinase 3 sont capables d’activer les polynucleaires neutrophiles en presence de TNF-α et contribuent a la survenue des lesions. ● Des lymphocytes T (LT) pourraient jouer un role dans la pathogenie de la GW, des LT helper de type 1 ayant ete detectes dans les tissus de patients ayant une GW localisee, tandis que des LT helper de type 2 ont ete identifies au sein de lesions de vascularites de malades ayant une forme systemique de GW. ● Les polynucleaires eosinophiles pourraient jouer un role dans la pathogenie du SCS.

OP0217 Defining Disease Activity Sates and Minimal Clinically Important Improvement (MCII) with the EULAR Primary SjÖGren's Syndrome Disease Activity Index (ESSDAI)

Objectives To determine disease activity levels and clinically important changes with the recently developed and validated [1] EULAR Sjögrens Syndrome Disease Activity Index (ESSDAI), and to assess their relevance for conducting clinical trials. Methods Patients from 2 large prospective cohorts (EULAR [multicenter international] n=395, ASSESS [multicenter French] n=395), have been followed for 6 months and 1 year, respectively. Physician completed ESSDAI, evaluated disease activity according to a 4 point scale, and assessed if the patients were in minimal disease activity (MDA). A ROC curve analysis and an anchoring method using MDA definition was used to determine disease activity levels of ESSDAI. At follow-up visit, physicians assessed whether disease activity has improved or not. An anchoring method based on this evaluation of change was used to estimate the minimum clinically important improvement (MCII) of ESSDAI. Data from recent clinical trials evaluating biologics [2-4] were used to assess the relevance of these thresholds. Results According to data from the 2 cohorts, low (ESSDAI <5), moderate (5 ≤ ESSDAI ≤13) and high (ESSDAI≥14) activity levels were defined. Fifty-four and 37% of patients from EULAR and ASSESS real life cohorts and 70 to 77% of patients from recent trials had at least moderately active disease (ESSDAI≥5). The MCII of the ESSDAI was defined as an improvement of at least 3 to 4 points. Based on recent trial data, the cutoff of 3 could be retained, because it was the best to discriminate between patients from placebo and treated arms. Conclusions In conclusion, this study, involving 2 independent large cohorts of primary SS patients allows determining disease activity levels and clinically relevant changes with ESSDAI. We hope that the results of this study will help to conduct more effectively clinical trials for evaluation of biologics in primary SS. Our proposal is to use the threshold of moderate activity as entry criteria (patients with ESSDAI≥5), and to define response to treatment as a significant improvement of ESSDAI (at least 3 points). References Seror R, Theander E, Brun JG, et al. Validation of EULAR primary Sjogrens syndrome disease activity (ESSDAI) and patient indexes (ESSPRI). Ann Rheum Dis 2014. Mariette X, Seror R, Quartuccio L, et al. Efficacy and safety of belimumab in primary Sjogrens syndrome: results of the BELISS open-label phase II study. Ann Rheum Dis 2013. Meijer JM, Meiners PM, Vissink A, et al. Effectiveness of rituximab treatment in primary Sjogrens syndrome: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2010;62:960-8. Devauchelle-Pensec V, Mariette X, Jousse-Joulin S, et al. Tolerance and efficacy of Rituximab in primary Sjögrens syndrome (TEARS): Results of a randomized controlled trial. Ann Rheum Dis 2012;71:75. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.4399

Factors influencing influenza-vaccination in adults under immunosuppressive therapy for a systemic inflammatory disease.

OBJECTIVE The aim of this study was to evaluate flu vaccination rates and influencing factors in patients with systemic inflammatory diseases. METHODS All patients presenting with a systemic inflammatory disease and taking immunosuppressants, who were hospitalized or had consulted in our internal medicine department between January 2 and 31, 2006, were included in the study. The information concerning flu vaccination was collected with a standardized form. RESULTS One hundred and thirty-seven patients (mean age 53.1+/-17.6years; 40 [29%] male patients) were included: 39 (28%) had received flu vaccination in 2005 including 14 (16.7%) of the 84 patients with no other indication for flu vaccination than IS-induced immunodepression and 25 (47.2%) of the 53 patients with other flu vaccination indication(s) (p<0.001). The most frequent reasons for non-vaccination were: absence of physician recommendation (58%), fear of adverse effects (35%) and concern on vaccine clinical effectiveness (5%). The vaccination rate was significantly higher (49%) among patients who remembered having received a voucher from the French National Health Insurance Agency versus 18% among those who did not (OR=4.2 [95%CI, 1.92-9.19] p<0.05). This correlation remained significant after adjustment for confounding factors in a logistic regression model. CONCLUSION Influenza-vaccination coverage is low in patients receiving immunosuppressive therapy for systemic inflammatory diseases. We have to increase the influenza-vaccination coverage in this population.

FRI0411 A Multicenter Prospective Evaluation of the Risk Profile in Pregnant Patients with Persistent Positivity for Antiphospholipid Antibodies (APL)

Background Antiphospholipd antibodies positivity (aPL) are considered as risk factors for a poor obstetric outcome. Several clinical and laboratory features have been associated with the risk of a pregnancy failure. Objectives To determine risk factors of having poor pregnancy outcome in patients (pts) with established aPL positivity with or without a diagnosis of primary antiphospholipid syndrome (APS) despite the administration of the accepted “conventional treatment” (low dose aspirin (LDA) and heparin (H)) when indicated. Methods We considered 276 pregnancies in 193 women prospectively followed in the 3 Institutions involved between 2000 and 2014. None of the pts had a concomitant systemic autoimmune disease. Data were collected from clinical charts using a common database and included the 3 assays to detect aPL. We considered as “poor pregnancy outcome” the occurrence of a pregnancy loss (early miscarriages and fetal loss), perinatal deaths, preterm deliveries before the 34 weeks and HELLP Syndrome. Results Among the 193 pts, 127 fulfilled the classification criteria for APS and 66 did not. According to their clinical history and/or the laboratory, the patients were divided in 4 groups: 87 pts with pure obstetric APS (O-PAPS, 121 pregnancies), 40 thrombotic with or without obstetric APS (T-PAPS, 66 pregnancies), 32 incomplete APS (incomplete clinical or laboratory criteria, 47 pregnancies) and 34 aPL carriers without any clinical manifestation prior to the index pregnancy (42 pregnancies). The mean age at the pregnancy onset was 32.5 years (SD 5.09), the global rate of live births was 86.9%; poor obstetrical outcome was observed in 48 pregnancies (17.4%); the outcome in the groups is detailed in table 1. In the table 2 we reported the several features that resulted, at the univariate analysis, with a significant prevalence among the pts with poor obstetric outcome regardless of the group. A thrombotic event occurred in 5 pts: 2 during pregnancies (1 O-APS and 1 aPL carrier) and 3 during puerperium, with 2 deep venous thrombosis with pulmonary embolism in 1 O-APS and 1 T-APS and 1 myocardial infarction after an early miscarriage in a T-APS. Finally 1 T-APS had a catastrophic syndrome during puerperium, and 3 pts (2 T-APS and 1 aPL carrier) had an onset or a relapse of mild-moderate thrombocytopenia (without HELLP syndrome). The combination of LDA plus H was administered in 94% of pregnancies that fulfilled the criteria for APS, while the rate was 57% for the incomplete APS and 39% for aPL carriers. Conclusions Our preliminary results show that, regardless of a high rate of use of the conventional therapy, a poor obstetrical outcome and the occurrence of several severe maternal complications were not uncommon, especially in T-PAPS and aPL carriers. Several factors (irrespectively of the diagnosis) seem to be associated with serological, clinical and acquired features. Disclosure of Interest None declared