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International audience; ObjectivesLupus nephritis (LN) is a frequent complication of systemic lupus erythematosus (SLE). Severe (proliferative) forms of LN are treated with induction immunosuppressive therapy (IST), followed by maintenance IST, to target remission and avoid relapses. The optimal duration of maintenance IST is unknown. The WIN-Lupus trial tested whether IST discontinuation after 2‒3 years was non-inferior to IST continuation for two more years in proliferative LN.MethodsWIN-Lupus was an investigator-initiated multicentre randomised controlled trial. Patients receiving maintenance IST with azathioprine or mycophenolate mofetil for 2–3 years, and hydroxychloroquine, were randomised (1:1) into two groups: (1) IST continuation and (2) IST discontinuation. The primary endpoint was the relapse rate of proliferative LN at 24 months. Main secondary endpoints were the rate of severe SLE flares, survival without renal relapse or severe flare, adverse events.ResultsBetween 2011 and 2016, 96 patients (out of 200 planned) were randomised in WIN-Lupus: IST continuation group (n=48), IST discontinuation group (n=48). Relapse of proliferative LN occurred in 5/40 (12.5%) patients with IST continuation and in 12/44 (27.3%) patients with IST discontinuation (difference 14.8% (95% CI −1.9 to 31.5)). Non-inferiority was not demonstrated for relapse rate; time to relapse did not differ between the groups. Severe SLE flares (renal or extrarenal) were less frequent in patients with IST continuation (5/40 vs 14/44 patients; p=0.035). Adverse events did not differ between the groups.ConclusionsNon-inferiority of maintenance IST discontinuation after 2‒3 years was not demonstrated for renal relapse. IST discontinuation was associated with a higher risk of severe SLE flares.Trial registration numberNCT01284725.

Background:Autoimmune diseases occur more frequently in females and their course and severity can be affected by gender. Antiphospholipid syndrome (APS) is a systemic autoimmune disorder in which antiphospholipid antibodies (aPL) exert a pathogenic role resulting in vascular thrombosis and/or pregnancy morbidities. Data about gender differences in thrombotic APS (t-APS) are still scarce1,2.Objectives:To evaluate the differences in frequency, disease expression and severity between females and males affected by primary t-APS.Methods:Retrospective study enrolling subjects with a formal diagnosis of primary APS (Miyakis 2006) with vascular thrombosis at onset. Women who presented with obstetric events as first aPL-related manifestation were excluded. All the patients were followed from 1967 to 2019 in four European centers: three French centers and one Italian center.Results:The study included 433 patients (68% females, 32% males). Median age at t-APS onset [31 (24-46) vs 41 (29-53) years, p] and at diagnosis [34 (27-50) vs 46 (34-57) years, p] was significantly lower in females.The most common presenting manifestations were venous thrombosis (60%) followed by arterial events (37%) and catastrophic APS (3%). Venous events were more frequent in women as compared to men (64% vs 51% p:0.012 OR:1.7 [1.1-2.5]). Sites of venous thrombosis included: limbs (35%), pulmonary (17%), cerebral (3%), portal and inferior cava (2%) and retinal (1%) veins, without gender differences. The arterial events were more frequent among men (43% vs 34% p:0.053). Strokes (27%) and myocardial infarctions (4%) were the most frequent manifestations, followed by thrombosis of limbs (2%), retina (2%) and abdominal organs (1%). Noteworthy, only men presented with visceral ischemia.During the follow-up, new thrombosis occurred in 41% of patients (179/433). 33% out of them had at least two episodes and these occurred especially among males (22% vs 10% p:0.001 OR:2.5 [1.3-4.8]). New events were mostly of the same type, but ⅓ of patients presented a switch from venous to arterial side and viceversa, with no gender differences.Complete aPL profile was available in 357 subjects: 33% had single aPL positivity, 24% double positivity and 43% triple positivity, with no differences between women and men. About 80% of the patients had a concomitant risk factor (RF) for thrombosis. Established cardiovascular RFs were more represented among men as shown in table 1. In women, estrogenic exposure was the main RFs, present in almost 40% of them.Table 1.MALESn= 137FEMALESn= 296POR [IC 95%]Traditional cardiovascular RFs, n (%)Smoke66 (48)81 (27)2.5 [1.6-3.8]Arterial hypertension59 (43)75 (25)2.2 [1.5-3.4]Dyslipidemia52 (38)72 (24)0.0041.9 [1.2-2.9]Diabetes16 (12)15 (5)0.0142.5 [1.8-5.1]Obesity13 (10)38 (13)nsOther thrombophilic factors, n (%)Estrogenic stimuli*0116 (39)-Trauma / surgery / immobilization21 (15)32 (11)nsCongenital thrombophilia9/94 (10)33/204 (16)nsData were compared using contingency tables, p value was calculated with Chi-Squared or Fisher exact test. *= hormonal therapy, pregnancy, post-partumConclusion:This gender-oriented analysis of patients with primary t-APS showed that women had the first vascular event at a younger age and mostly on the venous side, while men presented mainly with arterial events, later in life and suffered from more recurrent events. No differences were observed in the distribution of the aPL profile. The different frequency of arterial and venous events in the two groups could be attributed mainly to the presence of additional RFs rather than to biological gender-specific issues. However, it should be underlined that some RFs, such as the use of estrogens or classic cardiovascular RFs, are exclusive or more represented in one gender rather than the other, making it difficult to assess the link of causality between gender and manifestations of t-APS.References:[1]JF de Carvalho. Rheumatol Int. 2011.[2]LJ Jara. Lupus. 2005.Disclosure of Interests:None declared

Background:COVID19 due to SARS-CoV-2 infection implies an important anti-viral immune response leading to a major inflammatory syndrome with increased pro-inflammatory cytokine levels (i.e. the cytokine storm paradigm). The impact of a preexisting interstitial lung disease (ILD) on the morbi-mortality of COVID-19 is unclear. An increased mortality rate has been identified in studies that included a limited number of patients with ILD from various etiologies. To date, no studies have investigated the severity of COVID-19 in patients with preexisting ILD in a large population of rheumatic and musculoskeletal diseases (RMD-ILD). Since March 18th, 2020, the French RMD COVID19 dataset (NCT04353609) includes patients with an RMD and SARS-Cov-2 infection.Objectives:To assess the impact of a preexisting ILD on COVID-19 morbi-mortality within the French RMD COVID-19 dataset.Methods:Patients from the French RMD COVID-19 dataset were included in the analysis. COVID-19 diagnosis was established by a positive SARS-CoV-2 PCR test and/or typical symptoms or chest CT scans pattern during the period of the pandemic. Baseline phenotypic characteristics of the RMD including pre-existing ILD prior to the SARS-CoV-2 infection were collected. COVID-19 evolution was characterized as benign (ambulatory care), moderate (hospitalization outside intensive care unit [ICU]) and severe (hospitalization in ICU). Association between the ILD status and the severity and mortality rate of COVID-19 was assessed using multivariable logistic regression adjusted on sex, age, body mass index and diabetes.Results:By June 26, 2020, 897 patients were included. Pre-existing ILD was reported in 27 patients (3%): 11 patients with systemic sclerosis, 8 with rheumatoid arthritis, 2 with auto-immune myositis, 2 with mixed connective tissue disease and 4 with other RMD. Among these 27 patients (11 male, mean age 63.1 ± 16.4 y/o, 56.5% having a usual interstitial pneumonia HRCT pattern), 22 had severe infection. Death related to COVID-19, was observed in 58 patients with RMD without ILD (7.1%) and in 10 patients with RMD-ILD (37%). Having a preexisting ILD was found to be independently associated with an increased risk of severe COVID-19 (adjusted OR=7.6 [2.9 – 20.2], PConclusion:In RMD patients with SARS-CoV-2 infection, preexisting ILD was associated with an increased risk to severe COVID-19 and related mortality. Our findings suggest that RMD-ILD patients should be prioritized for COVID-19 vaccination according to the high morbi-mortality rate during SARS-CoV-2 infection.Disclosure of Interests:Pierre-Antoine Juge Consultant of: BMS, Eric Hachulla Consultant of: Actelion, Bayer, GSK and Pfizer, Grant/research support from: Actelion, Bayer, GSK and Pfizer, Christophe Richez: None declared, Elodie Drumez: None declared, Alain Duhamel: None declared, Raphael Borie: None declared, Philippe Dieudé: None declared

Background:Systemic sclerosis (SSc) is a fibrotic autoimmune disease characterized by dermatological involvement. Skin involvement can alter appearance, which can have a psychological impact(1). Assessment of body image could be central in optimizing care. Yet, data are scarce(2).Objectives:The main objective of our study was to assess aesthetic impairment measured on a visual aesthetic scale (AES) (3) in patients with SSc compared to a group of healthy subjects. Secondary objectives were to assess associations between aesthetic impairment and standardized questionnaires for aesthetic impairment as well as clinical, biological, psychological/quality of life, and functional parameters of SSc.Methods:The “Sclero-esthet” study is a descriptive single-center study of two populations: patients with SSc, included in a referral center for systemic and autoimmune diseases at Lille Hospital, France, and healthy controls.Results:This study, from January 2017 to October 2017, included 88 patients (69 [78.4%] women) with a median age of 52 years (range: 43 to 59) and 88 controls (49 [55.7%] women) with a median age of 45 years (range: 32 to 55). Perception of physical changes assessed using the AES was greater in cases than in controls (3.7 ± 0.3 vs 2.8 ± 0.3, p=0.028), with statistical correlation with ASWAP. SSc patients with anxiety or depressive symptoms had significantly higher AES scores. Cases presented poorer quality of life than controls.Conclusion:The AES appears to be a good tool to evaluate aesthetic impairment. Correlations found with psychological and quality of life parameters support the need to improve patient management in this field.References:[1]Cash TF. Body image: past, present, and future. Body Image 2004;1(1):1–5.[2]Benrud-Larson LM, Heinberg LJ, Boling C, Reed J, White B, Wigley FM. Body image dissatisfaction among women with scleroderma: extent and relationship to psychosocial function. Health Psychol mars. 2003;22(2):130–9.[3]Nguyen C, Ranque B, Baubet T, Bérezné A, Mestre-Stanislas C, Rannou F, et al. Clinical, Functional and Health-Related Quality of Life Correlates of Clinically Significant Symptoms of Anxiety and Depression in Patients with Systemic Sclerosis: A Cross-Sectional Survey. PLoS ONE 2014;9(2).[4]Heinberg LJ, Kudel I, White B, Kwan A, Medley K, Wigley F. Assessing body image in patients with systemic sclerosis (scleroderma): Validation of the Adapted Satisfaction with Appearance Scale. Body Image 2007;4(1):79–86.Disclosure of Interests:None declared

Background:Recent studies have highlighted that ultrasound (US) examination could offer a better assessment of hand manifestations of systemic sclerosis (SSc). Indeed, US allows a simultaneous evaluation of vascular, fibrotic and inflammatory hand features of the disease. Power Doppler US can especially explore macrovascular involvement characterized by an obliteration of digital arteries or ulnar arteries. Ulnar artery occlusion (UAO) is especially frequent in SSc patients and could be a relevant marker of the severity of SSc-associated vasculopathy. Among other hand manifestations of SSc, US evaluation can notably explore tenosynovial involvement such as fibrotic tenosynovitis (TS), which is considered to be SSc-specific.Objectives:This study aims to assess the diagnostic performances of these hand US parameters for the diagnosis of SSc.Methods:244 patients with suspected SSc were consecutively included. They all had US evaluation assessing the presence of fibrotic TS and UAO. The final diagnosis of SSc was based on the evaluation of an expert, independently from US results and from any pre-established classification criteria.Results:166 patients were finally diagnosed as SSc. 62 SSc and 8 non-SSc patients had UAO (uni or bilateral) (p=0.001). 23 SSc patients and 1 non-SSc patient had US fibrotic TS (p=0.007). A US SSc-pattern (presence of UAO and/or fibrotic TS) was reported in 73 SSc patients and 9 non-SSc patients (pConclusion:The use of hand US parameters may help to refine the diagnostic strategy of SSc and their inclusion in addition with the items of the ACR/EULAR classification could be discussed.Disclosure of Interests:Marine de Saint Riquier: None declared, Alice Ballerie: None declared, François ROBIN: None declared, Nicolas Belhomme: None declared, Claire Cazalets: None declared, Catherine Droitcourt: None declared, Aleth Perdriger: None declared, Cécile Marie Yelnik: None declared, Eric Hachulla Speakers bureau: speaking fees from Actelion Pharmaceuticals,GlaxoSmithKline, and Bayer outside of the current study, Vincent Sobanski: None declared, Patrick Jégo: None declared, Guillaume Coiffier: None declared, Alain LESCOAT: None declared

Objectives To evaluate the effect of adding a 10-week treatment of adalimumab to a standardised treatment with corticosteroids on the ability to taper more rapidly corticosteroid doses in patients with newly diagnosed giant cell arteritis (GCA). Methods Patients included in this double-blind, multicentre controlled trial were randomly assigned to receive a 10-week subcutaneous treatment of adalimumab 40 mg every other week or placebo in addition to a standard prednisone regimen (starting dose 0.7 mg/kg per day). The primary endpoint was the percentage of patients in remission on less than 0.1 mg/kg of prednisone at week 26. Analysis was performed by intention to treat (ITT). Results Among the 70 patients enrolled (adalimumab, n=34; placebo, n=36), 10 patients did not receive the scheduled treatment, seven in the adalimumab and three in the placebo group. By ITT, the number of patients achieving the primary endpoint was 20 (58.9%) and 18 (50.0%) in the adalimumab and placebo arm, respectively (p=0.46). The decrease in prednisone dose and the proportion of patients who were relapse free did not differ between the two groups. Serious adverse events occurred in five (14.7%) patients on adalimumab and 17 (47.2%) on placebo, including serious infections in three patients on adalimumab and five on placebo. Two patients died in the placebo arm (septic shock and cancer) and one in the adalimumab group (pneumonia). Conclusions In patients with newly diagnosed GCA, adding a 10-week treatment of adalimumab to prednisone did not increase the number of patients in remission on less than 0.1 mg/kg of corticosteroids at 6 months. Clinical trial registration number NCT00305539.

ObjectivesTo evaluate the efficacy and safety of rituximab in patients with primary Sjögren's syndrome (pSS).MethodsThe AutoImmune and Rituximab registry has included 86 patients with pSS treated with rituximab, prospectivey followed up every 6 months for 5 years.ResultsSeventy-eight patients with pSS (11 men, 67 women), who already had at least one follow-up visit, were analysed. Median age was 59.8 years (29–83), median duration of disease was 11.9 years (3–32). Indications for treatment were systemic involvement for 74 patients and only severe glandular involvement in four patients. The median European Sjögren's Syndrome disease activity index (ESSDAI) was 11 (2–31). 17 patients were concomitantly treated with another immunosuppressant agent. Median follow-up was 34.9 months (6–81.4) (226 patient-years). Overall efficacy according to the treating physician was observed in 47 patients (60%) after the first cycle of rituximab. Median ESSDAI decreased from 11 (2–31) to 7.5 (0–26) (pConclusionsIn common practice, the use of rituximab in pSS is mostly restricted to patients with systemic involvement. This prospective study shows good efficacy and tolerance of rituximab in patients with pSS and systemic involvement.

ObjectiveTo assess the survival and prognostic factors in patients with newly diagnosed incident systemic sclerosis (SSc)–associated pulmonary arterial hypertension (PAH) in the modern management era.MethodsProspectively enrolled SSc patients in the French PAH Network between January 2006 and November 2009, with newly diagnosed PAH and no interstitial lung disease, were analysed (85 patients, mean age 64.9±12.2 years). Median follow-up after PAH diagnosis was 2.32 years.ResultsA majority of patients were in NYHA functional class III–IV (79%). Overall survival was 90% (95% CI 81% to 95%), 78% (95% CI 67% to 86%) and 56% (95% CI 42% to 68%) at 1, 2 and 3 years from PAH diagnosis, respectively. Age (HR: 1.05, 95% CI 1.01 to 1.09, p=0.012) and cardiac index (HR: 0.49, 95% CI 0.27 to 0.89, p=0.019) were significant predictors in the univariate analysis. We also observed strong trends for gender, SSc subtypes, New York Heart Association functional class, pulmonary vascular resistance and capacitance to be significant predictors in the univariate analysis. Conversely, six-min walk distance, mean pulmonary arterial and right atrial pressures were not significant predictors. In the multivariate model, gender was the only independent factor associated with survival (HR: 4.76, 95% CI 1.35 to 16.66, p=0.015 for male gender).ConclusionsIncident SSc-associated PAH remains a devastating disease even in the modern management era. Age, male gender and cardiac index were the main prognosis factors in this cohort of patients. Early detection of less severe patients should be a priority.

Objectives Adult-onset Still’s disease (AOSD) is a rare systemic autoinflammatory disease; its management is largely empirical. This is the first clinical study to determine if interleukin (IL)-18 inhibition, using the recombinant human IL-18 binding protein, tadekinig alfa, is a therapeutic option in AOSD. Methods In this phase II, open-label study, patients were ≥18 years with active AOSD plus fever or C reactive protein (CRP) levels ≥10 mg/L despite treatment with prednisone and/or conventional synthetic disease-modifying antirheumatic drugs (DMARDs). Previous biological DMARD treatment was permitted. Patients received tadekinig alfa 80 mg or 160 mg subcutaneously three times per week for 12 weeks; those receiving 80 mg not achieving early predicted response criteria (reduction of ≥50% CRP values from baseline and fever resolution) were up-titrated to 160 mg for a further 12 weeks. The primary endpoint was the occurrence of adverse events (AEs) throughout the study. Results Ten patients were assigned to receive 80 mg tadekinig alfa and 13 patients to the 160 mg dose. One hundred and fifty-five treatment-emerging AEs were recorded, and 47 were considered related to the study drug. Most AEs were mild and resolved after drug discontinuation. Three serious AEs occurred, one possibly related to treatment (toxic optic neuropathy). At week 3, 5 of 10 patients receiving 80 mg and 6 of 12 patients receiving 160 mg achieved the predefined response criteria. Conclusions Our results indicate that tadekinig alfa appears to have a favourable safety profile and is associated with early signs of efficacy in patients with AOSD. Trial registration number NCT02398435.

Objectives: To assess the prevalence and patterns of cardiac abnormalities as detected by cardiac magnetic resonance imaging (MRI) in systemic sclerosis (SSc). Methods: Fifty-two consecutive patients with SSc underwent cardiac MRI to determine morphological, functional, perfusion at rest and delayed enhancement abnormalities. Results: At least one abnormality on cardiac MRI was observed in 39/52 patients (75%). Increased myocardial signal intensity in T2 was observed in 6 patients (12%), thinning of left ventricle (LV) myocardium in 15 patients (29%) and pericardial effusion in 10 patients (19%). LV and right ventricle (RV) ejection fractions were altered in 12 patients (23%) and 11 patients (21%), respectively. LV diastolic dysfunction was found in 15/43 patients (35%). LV kinetic abnormalities were found in 16/52 patients (31%) and myocardial delayed contrast enhancement was detected in 11/52 patients (21%). No perfusion defects at rest were found. Patients with limited SSc had similar MRI abnormalities to patients with diffuse SSc. Seven of 40 patients (17%) without pulmonary arterial hypertension had RV dilatation. Conclusions: This study shows that MRI is a reliable and sensitive technique for diagnosing heart involvement in SSc and for analysing its mechanisms, including its inflammatory, microvascular and fibrotic components. Compared with echocardiography, MRI appears to provide additional information by visualising myocardial fibrosis and inflammation. RV dilatation appeared to be non-specific for pulmonary arterial hypertension but could also reflect myocardial involvement related to SSc. Further studies are needed to determine whether cardiac MRI abnormalities have an impact on the prognosis and treatment strategy.

Objectives: There is increasing concern about heart and pulmonary vascular involvement in systemic sclerosis (SSc). One of the most severe complications of SSc is pulmonary arterial hypertension (PAH). There has been an increased awareness of left ventricular (LV) diastolic abnormalities in SSc patients. However, previous studies have generally been conducted in small populations. The aims of this study were to prospectively screen for PAH and to describe echocardiographic parameters in a large group of SSc patients. Methods: This prospective study was conducted in 21 centres for SSc in France. Patients without severe pulmonary function abnormalities, severe cardiac disease and known PAH underwent Doppler echocardiography performed by a reference cardiologist. Results: Of the 570 patients evaluated, PAH was suspected in 33 patients and was confirmed in 18 by right heart catheterisation. LV systolic dysfunction was rare (1.4%). LV hypertrophy was found in 22.6%, with LV diastolic dysfunction in 17.7%. These LV abnormalities were influenced by age, gender and blood pressure. We identified a small group of 21 patients with a restrictive mitral flow pattern in the absence of any other cardiopulmonary diseases, suggesting a specific cardiac involvement in SSc. Conclusions: Left and right heart diseases, including PAH, LV hypertrophy and diastolic dysfunction, are common in SSc. However, a small subset of patients without any cardiac or pulmonary diseases have a restrictive mitral flow pattern that could be due to primary cardiac involvement of SSc. The prognostic implications of the LV abnormalities will be evaluated in the 3-year follow-up of this cohort.

Background and objectiveA germline and coding polymorphism (rs2230926) of TNFAIP3 (A20), a central gatekeeper of nuclear factor-kappa B (NF-kB) activation, was recently found associated with primary Sjögren's syndrome (pSS)-associated lymphoma in a French cohort. We aimed to replicate this association.Patients and methodsThe rs2230926 polymorphism was genotyped in cases and controls of European ancestry from two independent cohorts from UK and France. Case control association tests were performed (Fisher's test) in the two cohorts, followed by a meta-analysis of the two cohorts.ResultsThe UK cohort included 308 controls and 590 patients with pSS including 31 with a history of lymphoma. The French cohort consisted of 448 controls and 589 patients with pSS including 47 with lymphoma. In both cohorts, the rs2230926 missense polymorphism was not associated with pSS. However, in the UK cohort, the rs2230926G variant was significantly associated with pSS-associated lymphoma (OR=2.74, 95% CI (1.07 to 7.03), p=0.0423, compared with patients with pSS without lymphoma, and OR=3.12, 95% CI (1.16 to 8.41), p=0.0314, compared with healthy controls) as observed in the French cohort. The meta-analysis of the two cohorts confirmed these results (OR=2.48, 95% CI (1.87 to 3.28) p=0.0037 and OR=2.60, 95% CI (1.91 to 3.53) p=0.0031, respectively).ConclusionsThis study confirms the role of A20 impairment in pSS-associated lymphoma. Subtle germline abnormalities of genes leading to impaired control of NF-kB activation in B cells continuously stimulated by autoimmunity enhance the risk of lymphoma.

ObjectiveTo assess the effect of sildenafil, a phosphodiesterase type 5 inhibitor, on digital ulcer (DU) healing in systemic sclerosis (SSc).MethodsRandomised, placebo-controlled study in patients with SSc to assess the effect of sildenafil 20 mg or placebo, three times daily for 12 weeks, on ischaemic DU healing. The primary end point was the time to healing for each DU. Time to healing was compared between groups using Cox models for clustered data (two-sided tests, p=0.05).ResultsIntention-to-treat analysis involved 83 patients with a total of 192 DUs (89 in the sildenafil group and 103 in the placebo group). The HR for DU healing was 1.33 (0.88 to 2.00) (p=0.18) and 1.27 (0.85 to 1.89) (p=0.25) when adjusted for the number of DUs at entry, in favour of sildenafil. In the per protocol population, the HRs were 1.49 (0.98 to 2.28) (p=0.06) and 1.43 (0.93 to 2.19) p=0.10. The mean number of DUs per patient was lower in the sildenafil group compared with the placebo group at week (W) 8 (1.23±1.61 vs 1.79±2.40 p=0.04) and W12 (0.86±1.62 vs 1.51±2.68, p=0.01) resulting from a greater healing rate (p=0.01 at W8 and p=0.03 at W12).ConclusionsThe primary end point was not reached in intention-to-treat, partly because of an unexpectedly high healing rate in the placebo group. We found a significant decrease in the number of DUs in favour of sildenafil compared with placebo at W8 and W12, confirming a sildenafil benefit.Trial registration numberNCT01295736.

OBJECTIVES: In agreement with other autoimmune diseases, systemic sclerosis (SSc) is associated with a strong sex bias. However, unlike lupus, the effects of sex on disease phenotype and prognosis are poorly known. Therefore, we aimed to determine sex effects on outcomes. METHOD: We performed a prospective observational study using the latest 2013 data extract from the EULAR scleroderma trials and research (EUSTAR) cohort. We looked at (i) sex influence on disease characteristics at baseline and (ii) then focused on patients with at least 2 years of follow-up to estimate the effects of sex on disease progression and survival. RESULTS: 9182 patients with SSc were available (1321 men) for the baseline analyses. In multivariate analysis, male sex was independently associated with a higher risk of diffuse cutaneous subtype (OR: 1.68, (1.45 to 1.94); p

OBJECTIVE--To determine the factors associated with the occurrence of Pneumocystis carinii pneumonia (PCP) in Wegener's granulomatosis (WG). METHODS--We retrospectively compared a group of 12 patients with WG and PCP (PCP group), with 32 WG patients without PCP followed over the same period in the same centres (control group). RESULTS--The mean delay of onset of PCP after the start of the immunosuppressive therapy was 127 (SD 128) days. Before treatment, the clinical and biological features of the two groups were similar, except for the mean lymphocyte count which was lower in the PCP group than in the control group (1060/mm3 v 1426/mm3; p = 0.04). During treatment, both groups were lymphopenic. There was a significant difference between the lowest absolute lymphocyte count in each group (244/mm3 in the PCP group v 738/mm3 in the control group; p = 0.001). During the first three months of treatment, the lymphocyte count was less than 600/mm3 at least once in 10 of the 12 patients in the PCP group and in 11 of the 32 patients in the control group (p < 0.01). The mean cumulative dose of cyclophosphamide was greater in the PCP group than in the control group at the end of both the second (1.55 mg/kg/day v 0.99 mg/kg/day; p = 0.05) and the third (1.67 mg/kg/day v 0.97 mg/kg/day; p = 0.03) months. However, in multivariate analysis, the only two factors independently and significantly associated with the occurrence of PCP were the pretreatment lymphocyte count (p = 0.018) and the lymphocyte count three months after the start of the immunosuppressive treatment (p = 0.014). CONCLUSIONS--The severity of lymphocytopenia before and during immunosuppressive treatment is the factor best associated with PCP in WG.

Education is one of the major commitments of EULAR. Over time EULAR has developed a broad educational program which today includes courses, both physical and online, rheumatology textbooks, DVDs demonstrating diagnostic and treatment practices, as well as workshops and young rheumatologist sessions scheduled at the annual EULAR congress. In addition, EULAR provides various forms of education and training grants to individuals. Listed below is an overview of the current offers: EULAR Live Courses EULAR ultrasound course EULAR ultrasound trainer course EULAR epidemiology course EULAR postgraduate course EULAR capillaroscopy course EULAR Scientific Endorsement Course on systemic lupus erythematosus European workshop for rheumatology research (ewrr) EULAR On-Line Courses EULAR on-line course on rheumatic diseases EULAR on-line course on connective tissue diseases EULAR on-line course on systemic sclerosis EULAR on-line introductory ultrasound course EULAR on-line course in paediatric rheumatology EULAR on-line course for health professionals Except for the rheumatic diseases on-line course, which lasted 2 years (with 42 Modules), all other courses correspond to a one-year training course (with 7 to 10 Modules each). Each module consists of: –a main review text including learning objectives, pictures, summary points and key references –at least two in-depth discussions expanding on clinical problems –two interactive clinical cases with questions and answers –assessment questions at the end of each module The EULAR Bookshelf EULAR textbook on rheumatic diseases EULAR textbook on systemic sclerosis Coming soon: EULAR textbook on paediatric rheumatology Musculoskeletal ultrasound in rheumatology Atlas of capillaroscopy in rheumatic diseases EULAR training DVDS: Principles of the musculoskeletal history and examination and a second one dedicated to the GALS examination (G = gait, A = arms, L = legs, S = spine) EULAR Educational Grants Training bursaries for young rheumatologists Educational visits for health professionals in rheumatology EULAR Fellow Sessions During the Annual Congress EULAR Awards presented at the Annual Congress EMEUNET the Emerging EUlar NETwork, is a EULAR working group of young clinicians and researchers in rheumatology promoting education and research Further information: http://www.eular.org/edu_publications.cfm Disclosure of Interest None declared

Background Patients with anti-RNA polymerase III antibodies (anti-RNAP) have an increased risk of malignancies synchronous to the onset of Systemic Sclerosis (SSc). In a multicentre EUSTAR case-control study, however, only moderate odd ratio was observed (OR 3.85, 95%CI 1.3–10.9), except than for breast cancer (OR 20.2, 95%CI 1.4–355) (1). Defining clinical and demographic features characteristic of anti-RNAP+ SSc patients who suffer from simultaneous malignancy would be useful to individuate risk factors who can guide the clinicians in every-day practice to screen anti-RNAP+ SSc patients for cancer. Objectives To individuate risk factors for malignancies synchronous to the onset of SSc in anti-RNAP+ patients. Methods EUSTAR centers were asked to participate to this study, providing data on malignancy history of their anti-RNAP+ patients in a dedicated form. Results Among 158 anti-RNAP+ SSc patients collected from 13 EUSTAR centers, 14 cases of malignancies synchronous to the onset of SSc were identified. When compared with the other 144 anti-RNAP+ patients, patients with synchronous malignancies had an older mean age at SSc onset (65.3 yrs (SD 10.0) vs 49.3 (SD13.3); p Conclusions Anti-RNAP+ SSc patients of older age, and with diffuse cutaneous subset, are particularly at risk for malignancies synchronous to the onset of SSc. The risk of malignancies other than breast cancers is greatly increased in male patients. These risk factors may help in the screening for cancer in these patients. References M.G. Lazzaroni et al. Anti-RNA Polymerase III Antibodies in Patients with Systemic Sclerosis: A Eustar Multicenter Collaborative Study. Ann Rheum Dis 2015;74:Suppl 2 88 doi:10.1136/annrheumdis-2015-eular.1728 Disclosure of Interest None declared

Background Systemic sclerosis (SSc) remains a devastating condition associated with a high risk of mortality. However, the main causes of death and risk factors for mortality are only partially known. Objectives To investigate causes and independent predictors of death in a large European population of SSc-patients. Methods We performed a longitudinal observational study using the latest 2014 data extract from the EUSTAR cohort. We looked at (i) deaths and causes of death (SSc, non-SSc) and (ii) effect of demographics, disease characteristics and comorbidities on mortality. Investigators from each center were asked to indicate the single primary cause of death according to standardized definitions. Associated factors with mortality were analyzed first in univariate analysis using t-test, chi2 or fisher exact test as necessary, followed by multivariable Cox modeling. Based on cox multivariate analysis, a simple score was generated (SScore) by adding the integer of each hazard ratio of variables independently associated with mortality. The ability of the SScore was compared to the previous modified 5-factor score to predict overall and 5-years mortality, and SSc-related mortality during follow-up using C-statistics. Results A total of 11,194 SSc-patients were included: 86% of women, 31% of diffuse cutaneous forms, and mean disease duration: 5.9 [2.4–11.8] years. During mean follow-up of 27±33 months, 1072 (9.6%) patients died. Of these, 617 patients (58%) died from SSc-related cause, 270 from non-SSc cause (25%), whereas the cause of death remains unknown in 185 (17%). Main causes of death were lung fibrosis (14.7%) followed by PAH (12.9%), primary heart involvement (10.5%), cancer (11.5%), infections (8%) and atherosclerosis (4.8%). The SScore comprised the following predictors: male gender (2 points), upper gastrointestinal involvement (2), proteinuria (5), LVEF The accuracy of the previous 5-factor score was lower than the SScore to predict total mortality (p=0.005) and 5 years-mortality (p=0.003). Further analyses looked at various subsets of SSc: by example, DcSSc patients had reduced survival as compared to LcSSc and causes of death were different: in DcSSc, the main causes of death were pulmonary fibrosis (18.6%), primary heart involvement (13.3%) and cancer (10.0%), whereas PAH (18.1%), cancer (12.8%) and pulmonary fibrosis (11.6%) were the leading causes in LcSSc (Figure). Conclusions Using the largest worldwide available cohort of SSc patients in which 1072 deaths have been recorded and characterized, we provide insight into the causes of deaths and emphasis on the contribution of the cardiopulmonary system. In addition, we have established a new score to estimate the 5-year survival of SSc patients. Disclosure of Interest None declared

IntroductionSystemic sclerosis (SSc)-related pulmonary arterial hypertension (PAH) has emerged as a major mortality prognostic factor. Mutations of transforming growth factor beta (TGFβ) receptor genes strongly contribute to idiopathic and familial PAH.ObjectiveTo explore the genetic bases of SSc–PAH, we combined direct sequencing and genotyping of candidate genes encoding TGFβ receptor family members.Materials and methodsTGFβ receptor genes, BMPR2, ALK1, TGFR2 and ENG, were sequenced in 10 SSc–PAH patients, nine SSc and seven controls. In addition, 22 single-nucleotide polymorphisms (SNP) of these four candidate genes were tested for association in a first set of 824 French Caucasian SSc patients (including 54 SSc–PAH) and 939 controls. The replication set consisted of 1516 European SSc (including 219 SSc–PAH) and 3129 controls from the European League Against Rheumatism Scleroderma Trials and Research group network.ResultsNo mutation was identified by direct sequencing. However, two repertoried SNP, ENG rs35400405 and ALK1 rs2277382, were found in SSc–PAH patients only. The genotyping of 22 SNP including the latter showed that only rs2277382 was associated with SSc–PAH (p=0.0066, OR 2.13, 95% CI 1.24 to 3.65). Nevertheless, this was not replicated with the following result in combined analysis: p=0.123, OR 0.79, 95% CI 0.59 to 1.07.ConclusionsThis study demonstrates the lack of association between these TGFβ receptor gene polymorphisms and SSc–PAH using both sequencing and genotyping methods.

Longer-term effects of prolonged selective interleukin-1β blockade with canakinumab were evaluated in the largest cohort of cryopyrin-associated periodic syndrome (CAPS) patients studied to date.Adult and paediatric CAPS patients (n=166, including canakinumab-naive and pretreated patients from previous studies) received canakinumab subcutaneously 150 mg or 2 mg/kg (≤40 kg) every 8 weeks for up to 2 years. Response and relapse was assessed using scores for disease activity, skin rash and C-reactive protein (CRP) and/or serum amyloid A (SAA) levels.Complete response was achieved in 85 of 109 canakinumab-naive patients (78%; 79/85 patients within 8 days, and five patients between days 10 and 21). Of 141 patients with an available relapse assessment, 90% did not relapse, their CRP/SAA levels normalised (10 mg/l) by day 8, and remained in the normal range thereafter. Median treatment duration was 414 days (29-687 days). Upward adjustments of dose or frequency were needed in 24.1% patients; mostly children and those with severe CAPS. Predominant adverse events (AE) were infections (65.7%) of mostly mild-to-moderate severity. Serious AE reported in 18 patients (10.8%) were mainly infections and were responsive to standard treatment. The majority of patients (92%) reported having no injection-site reactions and only 8% patients reported mild-to-moderate reactions. Patients receiving vaccination (15%) showed normal immune response.Subcutaneous canakinumab 150 mg every 8 weeks was well tolerated and provided substantial disease control in children and adults across all CAPS phenotypes. Higher canakinumab doses in younger patients and more severe CAPS disease were efficacious in achieving complete responses without evidence of increased AE.NCT00685373 (clinicaltrials.gov).

ObjectiveTo identify a core set of preliminary items considered as important for the very early diagnosis of systemic sclerosis (SSc).MethodsA list of items provided by European League Against Rheumatism (EULAR) Scleroderma Trial and Research(EUSTAR) centres were subjected to a Delphi exercise among 110 experts in the field of SSc. In round 1, experts were asked to choose the items they considered as the most important for the very early diagnosis of SSc. In round 2, experts were asked to reconsider the items accepted after the first stage. In round 3, the clinical relevance of selected items and their importance as measures that would lead to an early referral process were rated using appropriateness scores.ResultsPhysicians from 85 EUSTAR centres participated in the study and provided an initial list of 121 items. After three Delphi rounds, the steering committee, with input from external experts, collapsed the 121 items into three domains containing seven items, developed as follows: skin domain (puffy fingers/puffy swollen digits turning into sclerodactily); vascular domain (Raynaud's phenomenon, abnormal capillaroscopy with scleroderma pattern) and laboratory domain (antinuclear, anticentromere and antitopoisomerase-I antibodies). Finally, the whole assembly of EUSTAR centres ratified with a majority vote the results in a final face-to-face meeting.ConclusionThe three Delphi rounds allowed us to identify the items considered by experts as necessary for the very early diagnosis of SSc. The validation of these items to establish diagnostic criteria is currently ongoing in a prospective observational cohort.

Objectives: To describe clinical characteristics and muscle pathological features of patients with systemic sclerosis (SSc) and myopathy, and analyze their impact on muscle outcome. Methods: Thirty-five patients with myopathy and available muscle biopsy were identified from the charts of four hospital centers and restrospectively investigated for clinical, biological and histological parameters associated with muscular prognosis. Results: Twenty-six (74%) cases had diffuse SSc. Median time from SSc diagnosis was 5 years (range 0-23) at myopathy onset. Main myopathological features were mononuclear inflammation (63%), muscle atrophy (60%), necrosis (59%), regeneration (44%), fibrosis (24%) and/or microangiopathy (27%). After a median follow-up of 4.4 years (range 1-11 years), 24 patients (69%) showed complete or partial muscle remission. Among all clinical, biological and pathological features, only histological muscle inflammation was associated with good muscle prognosis in multivariate analysis (OR= 44.7 [2.8-704.7]). In particular, patients without muscle inflammation had a poor response to corticosteroids (38% of favourable response versus 90% in patients with inflammation). Conclusion: Muscle histopathology is critical in the therapeutic management of SSc-associated myopathy, because patients without muscle inflammation are unlikely to get benefit from corticosteroid therapy.

Primary Sjogren’s syndrome (pSS) is a complex disease involving both genetic and environmental factors. Among the genetic susceptibility factors, HLA-DRB1 has been extensively studied as a strong candidate gene and the association of HLA - DRB1*0301 (DR3) with pSS has been frequently reported among Caucasians.1 2 As the Tumour Necrosis Factor α ( TNFα ) gene is located within the HLA region, its contribution to disease susceptibility has also been studied. We have previously reported a significant association of TNF-308A allele with pSS, in strong linkage disequilibrium with HLA-DRB1*03 .3 This association was restricted to patients with anti-SSB antibodies. TNF exerts its action through two cell …

Background Most data on the clinical associations of anti-RNA polymerase III (RNAP) antibodies in patients with Systemic Sclerosis (SSc) derive from single-center studies or relatively small positive case number reports. Objectives To analyse the clinical associations of anti-RNAP in a large cohort of patients with different geographic and ethnic origin using the multicenter EUSTAR database. Methods Patients from the EUSTAR database were included when the item anti-RNAP was fulfilled in at least one visit, and considered anti-RNAP+ when scored positive in at least one determination. In a second phase, EUSTAR centers were asked to participate to a case-control study, fulfilling a supplementary form dedicated to skin involvement progression, gastric antral vascular ectasia (GAVE), and malignancies. Malignancies diagnosed between 6 months before and 12 months after the onset of SSc were defined as “synchronous to the onset of SSc”. Centers were asked to match anti-RNAP+ cases with anti-RNAP- SSc controls, paired for sex, cutaneous subset, and disease duration. Univariate methods were used to compare patients with and without anti-RNAP. Results Among 11,399 SSc patients registered in the EUSTAR database, 4,986 had anti-RNAP antibodies status available including 223 anti-RNAP+ (4.5%) and 4,763 anti-RNAP-. The differences between the two groups are shown in Figure 1. There was no difference as far as ethnicity (Caucasians: 94.2% vs 95.0%), age at disease onset, disease duration, length of follow-up, and other parameters included in the database. Ten centers participated in the case-control study, collecting 126 anti-RNAP+ cases (23% male, 59% with diffuse cutaneous involvement), and 137 anti-RNAP- matched patients. A trend toward a higher peak of modified Rodnan Skin Score (RSS) in anti-RNAP+ patients was observed (p:0.07). Interval time between the first symptom of SSc other than Raynaud9s phenomenon and the peak of RSS was shorter in anti-RNAP+ cases than in controls (p:0.008; log-rank test). Other differences between the two groups are shown in Figure 1. Conclusions Analysis of a large, multicenter database and a dedicated case-control study confirm that anti-RNAP is one of the most useful markers available to stratify SSc patients in subsets with peculiar clinical features. These include rapid progression of skin involvement, GAVE, and an increased risk of diagnosis of cancer simultaneous to the onset of SSc. This information should guide monitoring and follow-up in anti-RNAP+ SSc patients. Disclosure of Interest None declared

Background Systemic sclerosis (SSc) is classically dichotomized in limited or diffuse cutaneous subsets associated with different prognosis. However, it appears that SSc is a highly heterogeneous disease, with probably more subtle clinical phenotypes. Objectives The primary objective of our study was to identify and characterize homogeneous phenotypes in the EUSTAR SSc population using a cluster analysis. The secondary objective is to assess the survival in the different clusters. Methods The participants were SSc patients of the EUSTAR prospective cohort. Inclusion criteria were: age ≥18 years, fulfilled American College of Rheumatology criteria for SSc, and had a calculable follow up. Hierarchical clustering based on the Ward method was performed using 25 clinically meaningful variables. The clinical relevance of the clusters was analysed by their characteristics and survival outcomes. Survival curves were plotted by the Kaplan-Meier method. Crud and adjusted (on the age at diagnosis and gender) Cox models were performed. Results A total of 6.927 patients were analyzed. Cluster analysis identified 5 clusters (Table 1). The first cluster C1 (n=1,963) was mainly characterized by a low Rodnan skin score contrasting with a relatively similar percentage of anti topoisomerase 1 and anti-centromere Ab (28% and 40%) and a high percentage of lung fibrosis (48%); the second cluster C2 (n=1,186) by a large majority of limited SSc (89%) and anti-centromere (79%) and the lowest percentage of lung fibrosis (22%); the third cluster C3 (n=1,249) and the fourth cluster C4 (n=856) by a high percentage of diffuse SSc/anti topoisomerase 1 (72%/50% and 92%/77% respectively) and the highest proportion of male patients. Digital ulcers, renal crisis/anti RNA polymerase III antibodies, joint involvement were more frequently found in C4 than in the other clusters. Patients in the cluster C5 (n=1,673) were mainly female patients, older than in the other clusters, had a rather low mean Rodnan skin score, a high percentage of anti-topoisomerase 1 antibodies (46%) and a high percentage of lung fibrosis. Concerning survival, C2 had the best survival and C4 the worst. When compared to C1, C2 to C5 clusters had a significantly different prognosis (C2: adjusted hazard ratio [95% CI]: 0.70 [0.51-0.96]; C3: 2.27 [1.76-2.94]; C4: 4.52 [3.57-5.72]; and C5: 1.94 [1.51-2.44]. Conclusions This cluster analysis on the largest ever worldwide database of SSc patients showed 5 different clusters characterized by different sex ratio, maximum Rodnan skin scores, autoantibodies status, joint and organ involvement as well as by a different prognosis. Autoantibodies status seemed to play an important role for association with organ involvement. Although systemic sclerosis is a heterogeneous disease, this study shows that homogeneous groups beyond the classical limited/diffuse dichotomy can be delineated in this disease. Disclosure of Interest None declared

Background Primary Sjogren9s syndrome (pSS) is a systemic autoimmune disease characterized by B-cell hyperactivation. In some patients, multiple autoantibodies develop, including anti-neutrophil cytoplasmic antibody (ANCA), which could lead to the development of ANCA-associated vasculitis (AAV). Objectives To describe clinical presentation, therapy and prognosis of patients diagnosed with both pSS and AAV. Methods Nation-wide survey in France collecting information on cases of AAV associated with pSS. The study was completed by a systematic review of the literature. Results This work identified 6 new cases of coexisting pSS and AAV: 2 microscopic polyangiitis (MPA), 2 MPO-ANCA renal-limited AAV, 1 granulomatosis with polyangiitis (GPA), and 1 eosinophilic granulomatosis with polyangiitis (EGPA). The systematic literature search identified 15 previously published cases. Among the 21 patients, 18 were females. Mean age at diagnosis of AAV was 64±10 years with mean pSS duration of 76±122 months. All individuals with pre-existent pSS experienced at least one extra-glandular manifestation attributable to pSS before AAV diagnosis. p-ANCA with anti-MPO specificity were found in 80% (16/20), c-ANCA with anti-PR3 specificity in 9.5% (2/20) and isolated c-ANCA in 14.3% (3/21). Vasculitis involved kidneys (n=13), lungs (n=6), peripheral nerves (n=5), skin (n=5), central nervous system (n=2), small bowel (n=1), muscle (n=1), and sinuses (n=1). The mean follow-up duration of AAV was 20.5 (±31.1) months. A favourable response to treatment was observed in 76.2% of cases (16/21), stabilization in 19% of cases (4/21) and one death was reported. Conclusions This work shows that AAV may occur in patients with pSS. These are most commonly p-ANCA associated vasculitis with anti-MPO specificity. The AAV may reveal an underlying pSS or arise during its evolution. In this latter case, its occurrence appears to be correlated with extra-glandular manifestations of pSS. Disclosure of Interest None declared

Objectives To determine whether the extent of salivary gland involvement, assessed using unstimulated whole salivary flow (UWSF), histological focus score or salivary gland ultrasonography (SGUS), is associated with the response to rituximab in patients with primary Sjogren9s syndrome (pSS). Methods 35 pSS patients form the randomized TEARS study, which compared rituximab to placebo, had either centralized salivary gland biopsy or SGUS, at inclusion. Among rituximab-treated patients, 50% were considered responders according to the Sjogren9s Syndrome Responder Index (SSRI)-30 definition of the response at week 24. Results SGUS score was positively correlated to the focus score (r=0.61) and inversely correlated to UWSF (r=-0.68). Conversely, the focus score was not correlated with UWSF. No patients with grade 4 SGUS score responded to rituximab, compared to 88% of patients with SGUS score ≤3. The median focus score at inclusion was 0.3 (0.0-1.3) in the responders versus 4.0 (2.7-5.3) in the non-responders (p=0.02). Conversely, baseline UWSF was not associated with the response. Conclusions pSS patients with the highest histologic or morphologic salivary gland involvement do not respond to rituximab after 6 months, suggesting that a single 1gX2 rituximab course could be an unsufficient treatment for patients with the highest salivary gland B cell activity. Disclosure of Interest None declared

Objective: To investigate the safety and efficacy of rituximab (RTX) for systemic symptoms in patients with primary Sjogren’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.

Background: Anti-filaggrin antibodies (AFA) are among the most specific antibodies for rheumatoid arthritis, so procedures for their detection should be included in early biological diagnoses. AFA can be detected by indirect immunofluorescence (anti-keratin antibodies, AKA) or by new enzyme immunoassays (EIA). Their comparative performance needs to be established. Objective: To compare these technical procedures to optimise the serological diagnosis of rheumatoid arthritis. Methods: Results obtained using AKA and EIA were compared in 271 sera from 140 patients with rheumatoid arthritis at various stages, 98 patients with other autoimmune diseases, and 33 healthy subjects. EIA were successively undertaken with citrullinated linear filaggrin peptide (home made EIA) or cyclic citrullinated peptide (CCP2, commercial kits). Rheumatoid factor (RF) was assessed by EIA in all patients. Results: Anti-CCP2 kits showed the best sensitivity and specificity (65% and 96%, respectively). Among the 140 patients with rheumatoid arthritis, those with very recent disease (less than six months’ duration, n = 21) were studied as a separate group. In this group, the sensitivity of anti-CCP2 kits decreased to ~50%. Nevertheless this assay remained the most accurate when compared with AKA or home made EIA using linear filaggrin peptides. The combination of anti-CCP2 and RF only slightly increased the sensitivity of the diagnosis of very early rheumatoid arthritis. Conclusions: Kits using citrullinated cyclic peptides (CCP2) were more suitable than either AKA or EIA using linear filaggrin peptides for the diagnosis of early rheumatoid disease.

Background In patients with idiopathic pulmonary arterial hypertension (PAH), 6-minute walking test (6MWT) correlates well with the hemodynamic parameters like cardiac index and is a robust prognosis factor. In PAH associated with systemic sclerosis (SSc-PAH) however, data are more scarce and still a matter of debate. Various comorbidities caused by the underlying systemic disease (interstitial lung disease, musculoskeletal involvement, heart involvement, anemia, depression, ...) may be confounding factors, interfering with the interpretation of the 6MWT. Moreover, no study has evaluated the correlation between the 6MWT and the hemodynamics (i.e. the gold standard test to assess the severity of PAH) in this population yet. Objectives The aims of this study were to assess whether there is a correlation between the initial 6MWT and the hemodynamic parameters measured during the right heart catheterization (RHC), in SSc-PAH patients without interstitial lung disease (ILD). Methods Seventy-five patients with SSc-PAH and without any ILD on chest HRCT, prospectively enrolled in the French PAH Network, were included. Several data were collected at baseline regarding the clinical status (age, sex, BMI, NYHA functional class, SSc subtype), the 6WMT (total distance, heart rate (HR) and ΔHR, SaO2 and ΔSaO2, Borg score), the RHC (mRAP, mPAP, sPAP, dPAP, cardiac output and index, PVR, TPR, systolic stroke volume), the PFT (FEV1, FVC, TLC, DLCO/VA, PaO2, PaCO2) and the transthoracic echocardiography. The correlation of the 6MWT total distance with each hemodynamic parameter, but also with other data, was studied by linear regression. Results Univariate analysis showed a statistically significant correlation between the 6MWT total distance and all the RHC hemodynamic parameters, especially the mPAP ( R 2 =0.10, p =0.0045), cardiac index ( R 2 =0.20, p R 2 =0.18, p =0,0001). A similar correlation was also found with age and NYHA class, especially classes 3&4. In multivariate analysis, the 6WMT total distance was significantly and independently correlated with the cardiac index ( R 2 =0,26, p R 2 =0,08, p =0,018). Those 2 parameters accounted for 34% of the 6MWT total distance, the cardiac index explaining the majority of this distance. Conclusions To our knowledge, this study is the first to prove a correlation between the initial 6MWT total distance and the hemodynamic parameters of PAH severity, in SSc-PAH patients without ILD. It further establishes the relevance of this test in assessing the severity of the PAH in this population. Although potentially confounding comorbities are frequent, the 6MWT remains a relevant way to assess the severity of the PAH in SSc patients without ILD. However, other factors are probably involved in the 6MWT total distance, since the studied parameters accounted for only a third of it. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.1378

Background In published case reports, tocilizumab (TCZ) exhibits a brilliant efficacy on AA amyloidosis in almost all patients 1 . Objectives We investigated the efficacy and safety of TCZ in AA amyloidosis in a multicentric study of unselected cases. Methods Using the Club Rhumatismes Inflammation (CRI) network and the French TCZ registry REGATE, we contacted by mail rheumatology and internal medicine departments from France, Switzerland and North Africa to gather data from consecutive patients with histologically proven AA amyloidosis who were treated by at least 1 TCZ infusion. Efficacy was defined as a sustained decrease of proteinuria and/or stable or improved glomerular filtration rate (GFR) as well as by the TCZ maintenance. Results Twelve AA amyloidosis patients were treated by TCZ in monotherapy (mean ± SD age 63±16.2 years, amyloidosis duration 20.6±31.4 months). Eight patients had rheumatoid arthritis (RA) whose 6 who have previously failed to anti-TNF. Eleven patients had renal involvement with 2 patients already in haemodialysis (not included in the renal efficacy assessment). For the nine others, baseline GFR and proteinuria were 53.6±32.8 mL/min and 5±3.3 g/24h. TCZ was efficient on 6 cases of 8 RA patients (87.5%) according to EULAR response (4 good and 2 moderate responders). As expected, all CRP decreased. Renal amyloidosis (n=9) progressed in 3 patients and was stabilized in 3 patients. Three patients improved since they experienced a sustained decrease in proteinuria (of 42%, 82% and 96% respectively). Patients who responded or stabilized under TCZ had a higher CRP level at baseline or a proteinuria due to nephrotic syndrome with a preserved GFR at baseline (Table). Among the 6 RA patients previously treated by anti-TNF, amyloidosis was improved in 1 and was stabilized in 3 cases. Three serious adverse events occurred (2 diverticulitis and 1 major calciphylaxia due to renal failure). Finally, 7/12 (58%) patients pursued TCZ. Conclusions Efficacy of TCZ in AA amyloidosis is variable depending on the severity of the renal disease and on the inflammatory status at the treatment onset. Discrepancy between our study on unselected consecutive patients and the reported cases in the literature may be explained by publication bias. TCZ should be proposed as early as possible in the course of renal AA amyloidosis and in patients who are refractory to anti-TNF therapy. References Hakala M et al Ann Rheum Dis 2013;72:464-5. Disclosure of Interest : A. Courties Shareholder of: none, Grant/research support: none, Consultant for: none, Employee of: none, Paid instructor for: none, Speakers bureau: none, G. Grateau Shareholder of: none, Grant/research support: none, Consultant for: none, Employee of: none, Paid instructor for: none, Speakers bureau: none, P. Philippe Shareholder of: none, Grant/research support: Roche-Chugai, Consultant for: none, Employee of: none, Paid instructor for: none, Speakers bureau: none, R.-M. Flipo Shareholder of: none, Grant/research support: Roche-Chugai, Consultant for: none, Employee of: none, Paid instructor for: none, Speakers bureau: none, L. Astudillo Shareholder of: none, Grant/research support: none, Consultant for: none, Employee of: none, Paid instructor for: none, Speakers bureau: none, B. Aubry-Rozier Shareholder of: none, Grant/research support: none, Consultant for: none, Employee of: none, Paid instructor for: none, Speakers bureau: none, I. Fabreguet Shareholder of: none, Grant/research support: none, Consultant for: none, Employee of: none, Paid instructor for: none, Speakers bureau: none, W. Fahd Shareholder of: none, Grant/research support: none, Consultant for: none, Employee of: none, Paid instructor for: none, Speakers bureau: none, O. Fain Shareholder of: none, Grant/research support: Roche-Chugai, Consultant for: none, Employee of: none, Paid instructor for: none, Speakers bureau: none, P. Guggenbuhl Shareholder of: none, Grant/research support: none, Consultant for: none, Employee of: none, Paid instructor for: none, Speakers bureau: none, E. Hachulla Shareholder of: none, Grant/research support: none, Consultant for: none, Employee of: none, Paid instructor for: none, Speakers bureau: none, T. Papo Shareholder of: none, Grant/research support: none, Consultant for: none, Employee of: none, Paid instructor for: none, Speakers bureau: none, C. Richez Shareholder of: none, Grant/research support: Roche-Chugai, Consultant for: none, Employee of: none, Paid instructor for: none, Speakers bureau: none, J. Sibilia Shareholder of: none, Grant/research support: none, Consultant for: none, Employee of: none, Paid instructor for: none, Speakers bureau: none, J. Morel Shareholder of: none, Grant/research support: none, Consultant for: none, Employee of: none, Paid instructor for: none, Speakers bureau: none, F. Berenbaum Shareholder of: none, Grant/research support: Roche-Chugai, Consultant for: none, Employee of: none, Paid instructor for: none, Speakers bureau: none, J. Sellam Shareholder of: none, Grant/research support: Roche-Chugai, Consultant for: none, Employee of: none, Paid instructor for: none, Speakers bureau: none DOI 10.1136/annrheumdis-2014-eular.2343

Background Pulmonary arterial hypertension (PAH) affects up to 15% of patients with connective tissue diseases (CTD) and is one of the leading causes of mortality in systemic sclerosis (SSc) and mixed connective tissue disease (MCTD). Previous recommendationswere developed as part of larger efforts in PAH and did not provide detailed recommendations in CTD-PAH. Objectives To develop recommendations for screening and early detection of CTD-PAH using rigorous data-driven and consensus-building methodology. Methods We performed a systematic review for the screening and diagnosis of PAH in CTD by searching available databases. Using the RAND/UCLA methodology, we developed case scenarios followed by 2 stages of voting—first one was voted anonymously by 10 international experts on 1 (inappropriate) -9 (appropriate) scale and 2 nd voting after face-to-face meeting. Results The key recommendations include: All patients with SSc should be screened for PAH. MCTD or other CTD’s with scleroderma features (referred hereon as scleroderma-spectrum disorders) should be screened similar to patients with SSc. Screening of asymptomatic patients is not recommended for MCTD or other CTD patients without features of scleroderma. RHC is mandatory for diagnosis of PAH. Acute vasodilator testing is not required as part of the evaluation of PAH in patients with SSc, SSc-spectrum disorders, or other CTDs. Initial screening evaluation in patients with SSc and scleroderma-spectrum disorders include pulmonary function test (PFT) including diffusion capacity carbon monoxide (DLCO), Transthoracic echocardiogram (TTE), NT- Pro BNP, and DETECT algorithm if DLCO% 3 years disease duration. In SSc and SSc-spectrum disorders, TTE and PFT should be performed on an annual basis or TTE, PFT, and NT-Pro BNP if new signs or symptoms develop. Conclusions We provide consensus-based and evidence-driven recommendations for screening and early detection of CTD-PAH. It is our hope that these recommendations will lead to early detection of CTD-PAH and ultimately improve patient outcomes. Disclosure of Interest None Declared

Background Pulmonary arterial hypertension (PAH) is one of the leading causes of death in systemic sclerosis (SSc). Management of patients with SSc-associated PAH (SSc-PAH) is rapidly evolving and recently reported survival is better than in historical cohorts (albeit still unsatisfactory). However, no data have been reported on purely incident cohorts of patients recruited in the modern management era (2006-2011). Objectives This study describes the characteristics and outcome of SSc patients prospectively enrolled in the multicentre French PAH registry since 2006 Methods SSc patients (according to American College of Rheumatology and/or Leroy and Medsger’s criteria) enrolled in the registry between January 2006 and November 2009 were prospectively included if they had a precapillary PAH confirmed by right heart catheterization 70%. Results 100 SSc patients were included; 81% were women. Mean age at PAH diagnosis was 65±12 yrs, 86% of patients had limited cutaneous SSc, 80% were in New York Heart Association functional class (NYHA FC) III or IV and 15% had ILD on HRCT, mean FVC and the ratio of diffusing capacity of the lung for carbon monoxide/alveolar volume (DLCO/VA) were 92±20% and 54±20% of predicted values, respectively. At baseline, mean 6-minute walk distance (6MWD) was 266±119m and mean pulmonary vascular resistances were 674±346 dyn.sec.cm -5 . Median follow up was 2.4 years with 45 deaths observed; overall survival was 86%, 72%, 52% and 36% at 1, 2, 3 and 4 years, respectively. Univariate analysis identified age (HR: 1.04), NYHA functional class (HR: 4,03), desaturation after 6-minute walk test (HR: 0.90), DLCO/VA (HR: 0.98), presence of an ILD (HR: 2.63) and cardiac index (HR: 0.53) as factors prognostic of survival. Other parameters did not reach statistical significance (p Conclusions These results confirm the poor prognosis for incident and newly diagnosed SSc-PAH patients even in the modern era of treatment. NYHA functional class, age and presence of an ILD at the diagnosis of PAH were important prognosis factors. Poor right ventricular hemodynamic function and desaturation during the 6-min walk test were also associated with mortality. As 80% of patients are still diagnosed with a NYHA function class III/IV which appears as one of the most important prognosis factor, screening allowing an earlier diagnosis should be a priority. Disclosure of Interest D. Launay Consultant for: GSK, Actelion, Pfizer, O. Sitbon Consultant for: Actelion, BayerSchering, GSK, Lilly, Novartis, Pfizer and United Therapeutics, J.-F. Cordier Consultant for: GSK, ACTELION, PFIZER, LILLY, E. Hachulla Consultant for: GSK, Actelion, Pfizer, L. Mouthon Consultant for: Octapharma, CSL Behring, LFB Biotechnologies, Cytheris, Actelion, Pfizer, GSK and Lilly, V. Gressin Shareholder of: actelion, Employee of: actelion, L. Rottat: None Declared, P. Clerson: None Declared, G. Simonneau Consultant for: Actelion, BayerSchering, GSK, Novartis, Pfizer and United Therapeutics, M. Humbert Consultant for: Actelion, BayerSchering, GSK, Novartis, Pfizer and United Therapeutics

Background The cryopyrin-associated periodic syndrome (CAPS) is a rare inherited inflammatory disease associated with mutations in NLRP3.It includes disorders of increasing severity, including the familial cold autoinflammatory syndrome (FCAS), the Muckle–Wells syndrome (MW), and neonatal-onset multisystem inflammatory disorder (NOMID) (also known as he chronic infantile neurologic, cutaneous, and articular syndrome: CINCA).Articular symptoms are frequently described in CAPS but their frequency have been poorly investigated. Objectives Our objectives were to describe the type and frequency of articular symptoms in a cohort of CAPS patients follwed in adults or paediatricien departments in France. Methods We conducted a retrospective study concerning articular manifestations (joint, bone and muscle symptoms) in patients with CAPS. Paediatricians, internal medicine and rheumatologists were contacted. Medical data were collected using standardized questionnary and radiographs if available were analysed. Results 75 patients were included, (12 FCAS, 45 MW, 12 CINCA/NOMID and 6 unclassified. 53% were females (40/75).Among them, 47 are adults (mean age: 31.8±15 years) and 28 are children (11±4.5 years). Disease onset was 4.7±2 years, however the age at the diagnosis was 18±4.5 years. The first symptoms were more frequently cutaneous (61%), fever (20%) articular (17%) and neurological (10%). 56 (74%) had a familial history of CAPS. 9 (12%) patients had CAPS without mutation. During the follow-up, only 17 (23%) did not have articular symptoms. For the remaining 55 (75%) had arthralgia and 46 (60%) had synovitis. The more affected joints were respectively the ankles (66%), knees (45%), hips (33%), feet (25%) and hands (21%). Only one patient with CINCA/NOMID had typical arthropathy with bone abnormalities enlarged, deformed femora and patellae. These arthragia were considered as predominant for 20% of the patients Radiographs were rarely performed. Tendinopathies occured in 12 (16%) of the patients and myalgia in 26 (35%). Conclusions Articular symptoms are frequent in patients with CAPS and considered as invalidating in 20% but they are poorly investigated by radiographs. Bone deformities are rare. Arthralgia can affected hand and feet. Disclosure of Interest None Declared

Background The pathophysiology of lymphomas in auto immune disease (AID) involves persistent inflammation and activation of autoimmune B cells leading to NF-kB activation. The TNFAIP3 gene encodes the A20 protein, a central gatekeeper of NF-kB activation. Germinal abnormalities in TNFAIP3 have been associated with different AID and somatic mutations of the gene have been observed in several lymphoma subtypes, particularly MALT lymphoma, the lymphoma subtype most frequently associated with pSS. Objectives To investigate whether TNFAIP3 abnormalities are involved in the lymphomagenesis process in pSS. Methods The discovery set was constituted by 584 pSS patients including 25 patients with lymphoma and 451 controls of Caucasian ancestry, addressed by 48 Ancestry Informative Markers. Three SNPs encompassing the TNFAIP3 locus located on 6q23 (rs13192841, rs2230926 and rs6922466) and known to be associated with SLE and RA were genotyped. 19 additional patients with pSS and lymphoma were used for extension and replication. We sequenced all TNFAIP3 exons in germinal and lymphoma DNA from 20 pSS patients with lymphoma. Functional abnormalities of A20 were assessed by gene reporter assays. Results The 3 TNFAIP3 SNPs were not significantly associated with risk of pSS. But multivariate analysis demonstrated a significant association between the rs2230926 SNP (coding for an amino acid substitution in exon 3) and pSS complicated by lymphoma: OR vs controls = 3.36 (95%CI 1.34 - 8.42) p= 0.0097, OR vs pSS without lymphoma = 3.26 [95%CI 1.31 – 8.12], p=0.011. TNFAIP3 gene sequencing of germinal DNA from 43 patients with pSS and lymphoma confirmed the more frequent presence of the rs2230926G risk variant in 11/43 patients (25.6%, versus 11% in controls, p=0.018). Twelve of the 20 (60%) patients with paired germinal and lymphoma TNFAIP3 sequence data had functional abnormalities of A20. The frequency was even higher (77%) among pSS patients with MALT lymphoma (n=28). Mutated A20 variants (rs2230926G and GG insertion) were both less effective than the wild type A20 in inhibiting NF-kB-dependent activation (p Conclusions This study demonstrates that A20 inactivation plays a key role in lymphomagenesis in the context of autoimmunity. It supports a scenario in which the presence of germinal and/or somatic abnormalities of genes leading to impaired control of NF-kB activation in B cells continuously stimulated by autoimmunity enhances the risk of lymphoma. Disclosure of Interest None Declared

Background Systemic sclerosis or Scleroderma (SSc) is an autoimmune disease affecting mostly women with a higher incidence between 40 and 60 years old. Several HLA class II genes have been associated with SSc depending on the clinical subset of the disease, limited cutaneous SSc (lc-SSc) or diffuse cutaneous SSc (dc-SSc) or on specific autoantibodies, anticentromere antibodies (ACA) or antitopoisomerase (ATA) antibodies, respectively hallmarks of the above clinical subsets. HLA-G is a non classical HLA molecule with tolerance functions that may play a role in inflammatory diseases. A 14 bp sequence insertion/deletion polymorphism (rs16375) in the 3′-untranslated region of the HLA-G gene has been associated to levels of soluble HLA-G (sHLA-G). The insertion is associated with lower levels. Objectives In the current study, the authors propose to analyse this polymorphism in patients with SSc compared to healthy individuals. The authors furthermore stratified patients according to sex, clinical subsets and autoantibody status. Patients and methods The authors genotyped 145 patients with SSc and 95 healthy controls by a previously developed two step multiplex SNaPshot method several HLA-G Single Nucleotide polymorphisms and the -14bp Ins/Del polymorphism. Results Patients with SSc tend to have higher frequency of ins/ins (29/145, 20.0%) genotypes compared with healthy controls (11/95, 11.6%, p=0.008). The frequency of Ins alleles compared to Del alleles is significantly increased among patients with SSc (p=0.024). This association reveals interesting patterns when patients are divided by sex (women, N=110 and men, N=35). Men had similar frequencies of Del/Del, Del/Ins, Ins/Ins genotypes than healthy controls (respectively, 45.7%, 42.9%, 11.4% and 50.5%, 37.9%, 11.6%), whereas women had different proportions of genotypes with Del/Del: 36.4%, Del/Ins: 40.9% and Ins/Ins: 22.7%. The difference in genotype repartition was statistically significant in women with SSc compared with healthy controls (p=0.047) and the difference in allele frequency even stronger (Ins: 43.1% compared with 30.5%, p=0.008). Apart from the gender association an association with dcSSc with the Ins allele (p=0.004), and a marginal association with lcSSc (p=0.08)were also observed. Interestingly both autoantibody subgroups, ATA and ACA, were associated with higher Ins allele frequencies (p=0.018 and p=0.03, respectively). Conclusion Women with SSc but not men have a genotype of low sHLA-G secretor. Further studies need to be conducted to better understand this gender dichotomy and its meaning in tolerance in a disease affecting mostly women in their childbearing years.

The high cost of IV immunoglobulins is often considered to be a disadvantage of this treatment. However, this does not take into account the benefits gained—for example, the savings achieved in the costs of corticosteroids and immunosuppressive drugs and, above all, the improvement in quality of life achieved through functional improvement, as noticed in inflammatory myopathies and Still's disease.1–3 It is precisely to minimise the costs of IV immunoglobulin treatments and to enable patients to remain at home that we have developed the administration of IV immunoglobulins at home when sequential treatments are necessary. Between January 1995 and March 2000 30 patients (18 women, 12 men) were enrolled, with a mean (SD) age of 44 (0.9) for the women and 51 (0.9) years for the men (range 21–74). All the patients had …