A. Carbonella

Memory B cell subsets and plasmablasts are lower in early than in long-standing Rheumatoid Arthritis

BackgroundAlterations of B cell subset distribution have been described in the peripheral blood (PB) of rheumatoid arthritis (RA) patients, but no data are available on differences between the onset and the established phases of the disease. The purpose of the study was to clarify whether a peculiar distribution of B cell subsets characterizes RA onset, thus leading to a more favorable clinical response to treatment, and to evaluate the possible association of a particular B cell subpopulation with response to therapy.Results122 RA patients were enrolled: 25 had symptom duration less than 3 months and were defined as having “very early RA” (VERA), and 43 had symptom duration from more than 3 months up to one year (early-RA: ERA). The other 54 RA patients had long-standing RA (LSRA). At baseline and at 6-month follow-up visit peripheral blood samples were collected and analyzed by flow cytometry for the distribution of circulating B cell subsets by staining with surface markers CD45, CD19, CD38, CD27 and IgD and intracellular marker ZAP70.VERA and ERA patients showed higher percentages and absolute counts of circulating antigen inexperienced naïve B cells (IgD + CD27-) and lower percentages and absolute numbers of double negative (IgD-CD27-) memory B cells and plasmablasts (CD38 + CD27+) compared to LSRA patients. At the multivariate analysis, a higher frequency of naïve B cells (IgD + CD27-) at baseline arose as significant predictor of CDAI remission, together with “having VERA disease” and a low disease activity at baseline.ConclusionsThe onset of RA is characterized by higher percentages and absolute numbers of naïve B cells and lower numbers of plasmablasts and double negative memory B cells compared to established RA. naïve B cells could represent a promising biomarker of outcome.

The prognostic significance of the Birmingham Vasculitis Activity Score (bvas) with systemic vasculitis patients transferred to the intensive care unit (icu)

AbstractSystemic vasculitides represent a heterogeneous group of diseases that share clinical features including respiratory distress, renal dysfunction, and neurologic disorders. These diseases may often cause life-threatening complications requiring admission to an intensive care unit (ICU). The aim of the study was to evaluate the validity and responsiveness of Birmingham Vasculitis Activity Score (BVAS) score to predict survival in patients with systemic vasculitides admitted to ICU.A retrospective study was carried out from 2004 to 2014 in 18 patients with systemic vasculitis admitted to 2 different Rheumatology divisions and transferred to ICU due to clinical worsening, with a length of stay beyond 24 hours. We found that ICU mortality was significantly associated with higher BVAS scores performed in the ward (P = 0.01) and at the admission in ICU (P = 0.01), regardless of the value of Acute Physiology And Chronic Health Evaluation (APACHE II) scores (P = 0.50). We used receiver-operator characteristic (ROC) curve analysis to evaluate the possible cutoff value for the BVAS in the ward and in ICU and we found that a BVAS > 8 in the ward and that a BVAS > 10 in ICU might be a useful tool to predict in-ICU mortality.BVAS appears to be an excellent tool for assessing ICU mortality risk of systemic vasculitides patients admitted to specialty departments. Our experience has shown that performing the assessment at admission to the ward is more important than determining the evaluation before the clinical aggravation causing the transfer to ICU.

Immunosuppressive Therapy (Methotrexate or Cyclophosphamide) in Combination with Corticosteroids in the Treatment of Giant Cell Arteritis: Comparison with Corticosteroids Alone

tion group were less likely to be prefrail or frail (P = .048). Frail persons were more likely to use anticholinergic medications (83%, n = 56) than prefrail (64%, n = 195) and robust (42%, n = 103) persons (p < .001). Mean anticholinergic scores were 0.73 1.14 for robust individuals, 1.4 1.75 for prefrail individuals, and 2.62 2.52 for frail individuals (P < .001). Factors associated with anticholinergic medication use (ADS score >0) were being prefrail or frail, having a FCI score of 2 or greater, and being aged 85 and older (Table 1). In longitudinal analysis, 84 of those who were robust in 2005 were classified as prefrail or frail in 2007. In the control group but not the intervention group, robust persons were more likely to become prefrail or frail if they used anticholinergic medications in 2005 (unadjusted P = .04).

OP0178 The Body Mass Index: A Determinant of Remission in Early Rheumatoid Arthritis

Background There are evidences that obesity determines higher disease activity status in rheumatoid arthritis (RA) and that obesity possibly affects the response to therapy in long standing RA. There are only few data about early RA (ERA), showing that obesity associates with a less erosive disease, with no clear explanation. Objectives To evaluate whether the body weight could influence the outcomes in patients with ERA in terms of disease remission and treatment after 6 and 12 month of follow-up. Methods 346 patients with ERA (symptoms duration <12 months), treated according to a treat-to-target strategy aiming at remission (strict follow-up visits, treatment with methotrexate up to 25 mg/week±steroids; then a combination with a TNF blocker if at least a good response according to EULAR criteria was not obtained), were enrolled. At each visit the ACR/EULAR core data set was registered. Baseline BMI was collected. Clinical remission was evaluated according to DAS and CDAI (Clinical Disease Activity Index) values. The BMI was categorized into three classes, as a BMI <25 Kg/m2 (normal weight), 25-30 (overweight) and >30 (obese), according to the NIH classification. Logistic regression models were applied to determine the influence of the independent variables that reached the value of p<0.25 at the univariate analysis, on the dependent variables “DAS and CDAI remission at 12th month and anti-TNF therapy at 12th month”. Results Of the 346 ERA patients (76.3% female, age 54.6±14.0 years, 32.9% very ERA, 70.2% seropositive, baseline DAS 3.6±1.1), 168 (48.6%) were normal weight, 135 (39%) overweight and 43 (12.4%) obese. The BMI values correlated with age (r=0.23, p<0.001), baseline inflammatory markers (ESR: r=0.14, p=0.009, CRP: r=0.19, p<0.001), DAS (r=0.18, p=0.001), CDAI (r=0.14, p=0.01), HAQ (r=0.17, p=0.001). Overweight and obese patients reached a lower rate of remission, both with DAS and CDAI criteria, at 6 and 12 month follow-up visits (sustained DAS remission at 12th month: 49.1% in normal, 28.7% in overweight, 34.1% in obese, p=0.008; CDAI remission at 12th month: 50%, 37.1%, 31% in normal, overweight and obese, respectively, p=0.07). Moreover, an higher percentage of obese and overweight ERA patients were under anti-TNF treatment after 12 months of follow-up (28.1% of obese, 28.8% of overweight, 16.2% of normal weight). At the multivariate analysis, the independent baseline variables associated with the risk of “not obtaining a sustained DAS remission at 12th month follow-up” were female gender (OR (95% CI): 2.44 (1.56-21.45)), baseline HAQ≥1.5 (OR: 1.56 (1.47-5.94)) and a BMI≥25 (OR: 2.22 (1.13-4.1)), whereas the variables identifying the “non-CDAI remission at 12th month” were female sex (OR: 1.97 (1.04-3.73)), baseline HAQ≥1.5 (OR: 1.76 (1.0-3.15)) and a BMI≥25 (OR: 1.81 (1.04-3.13)). The independent variables associated with the probability of being in anti-TNF therapy at 12th month follow-up were an age <55 years (OR: 2.7 (1.4-5.3)), baseline DAS≥3.7 (OR: 2.27 (1.19-4.34) and BMI≥25 (OR: 2.36 (1.21-4.59)). Conclusions Data suggest that in ERA patients, not only obesity but also overweight, associates with a lower percentage of success in obtaining remission. Overweight ERA subjects required 2.4 times more anti-TNF therapy, than normal weight to achieve the outcomes. BMI is one of the few modifiable variables influencing the major outcomes in RA. Disclosure of Interest None Declared

THU0525 Metaflammation, PEDF and Chemerin: Potential Systemic Factors Which Link Obesity to Response to Therapy in Early Rheumatoid Arthritis

Background Obesity per se is a systemic, low-grade inflammatory state and the adipose tissue is an endocrine organ that releases bioactive substances, including pro-inflammatory cytokines, like TNFα and IL6 and specific adipokines. There are only few data about early RA (ERA), suggesting that obesity associates with disease outcomes. In this work we aimed to evaluate whether the body weight, and fat metabolic (PEDF-Pigment Epithelium-Derived Factor) and meta-inflammatory parameters (Chemerin), could be associated with the outcomes in terms of disease remission and treatment in ERA patients (symptoms duration <12 months). Methods 166 ERA patients, treated according to a treat-to-target strategy, were enrolled. At each visit the ACR/EULAR core data set was registered. Baseline BMI was collected and baseline interleukin-6, PEDF and Chemerin plasma levels were evaluated by ELISAs methods. PEDF gene expression was evaluated in adipose tissue of overweight and obese subjects (30 ERA and 10 osteoarthritis (OA) patients as control cohort). Results Of the 166 ERA patients (75.9% female, age 55.4±14.6 years, 34.3% very ERA, 66.9% seropositive, baseline DAS 3.4±1.0), 76 (45.8%) were normal weight, 67 (40.4%) overweight and 23 (13.9%) obese. Overweight and obese patients showed a higher disease activity at baseline compared to normal-weight patients (DAS: 3.6±1.0 vs 3.3±0.9, p=0.02). At baseline, BMI values correlated with baseline PEDF (r=0.33, p<0.001) and chemerin (r=0.31, p<0.001) plasma levels. Moreover, chemerin plasma levels correlated with age (r=0.31, p<0.001), baseline inflammatory markers (IL-6: r=0.28, p<0.001; ESR: r=0.39, p<0.001, CRP: r=0.35, p<0.001), swollen joint count (r=0.26, p<0.001), tender joint count (r=0.23, p<0.001), HAQ (r=0.24, p=0.002), DAS (r=0.34, p<0.001), CDAI (r=0.28, p<0.001) and SDAI (r=0.32, p<0.001). On the other hand, PEDF plasma levels correlated only with age (r=0.35, p<0.001) and baseline inflammatory markers (ESR: r=0.17, p=0.03, CRP: r=0.22, p=0.01). At 6 and 12 months none of the patients had a significant reduction of body-weight. A significant reduction of the disease activity at 6 and 12 months follow-up was observed in the three subgroup of ERA patients (normal-weight, overweight and obese patients). In the same manner, circulating chemerin levels significantly decreased over time; conversely, the circulating levels of PEDF remained unchanged. These findings were observed both in patients reaching and not reaching remission at 12 months of follow up. In adipose tissue, PEDF relative gene expression was 1.2±0.6 times higher in ERA patients compared to OA. Conclusions In ERA patients, PEDF and chemerin seem to be biomarkers of obesity and metaflammation, respectively. Chemerin seems to be linked to RA disease activity and to treatment response, irrespective of body weight cathegory, supporting its dual role in inflammation and metabolism and providing a link between chronic inflammation and obesity. Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.4936

Giant Cell Arteritis

Giant cell arteritis (GCA) is vasculitis characterized by a granulomatosus infiltrate, that typically occurs in medium and large arteries. This systemic autoimmune disease can cause sudden and potentially bilateral sequential vision loss in the elderly. GCA frequently occurs together with polymyalgia rheumatica. Both are syndromes of unknown cause, but genetic and environmental factors might have a role in their pathogenesis. The clinical findings in GCA are broad, but commonly include visual loss, headache, scalp tenderness, jaw claudication, cerebrovascular accidents, aortic arch syndrome, thoracic aorta aneurysm, and dissection. Glucocorticosteroids are the cornerstone of treatment, but some patients have a chronic course and might need glucocorticosteroids for several years. Adverse events of glucocorticosteroids affect more than 50 % of patients. Trials of steroid-sparing drugs have yielded conflicting results. The understanding of the molecular mechanisms involved in the pathogenesis of GCA recently has indicated new targets for therapy.

THU0231 Disease Characteristics, Treatment Response and Remission in A Prospective Early Rheumatoid Arthritis Cohort: Does Autoantibody Seropositivity Matter?

Objectives To assess possible differences in the major outcome (disease remission) over time in anti-citrullinated peptide antibodies (ACPA) and rheumatoid factor (RF)-IgM seropositive and seronegative early rheumatoid arthritis (ERA) cohorts. Methods A total of 265 ERA patients with a disease duration less than 12 months [154 (58.3%) seropositive for both ACPA and RF-IgM and 110 (41.7%) double seronegative] were enrolled in the study. ERA patients were naïve to DMARD therapy and fulfilled the 2010 American College of Rheumatology criteria for RA. At baseline, patients were treated with methotrexate (up to 20 mg weekly) and, when necessary, steroids at low dosage for three months; then a combination with a TNF blocker (adalimumab 40 mg every two weeks, or etanercept 50 mg weekly) was started if patients showed a severe disease activity, according to DAS value. At baseline and every 3 months demographic and immunological data and the ACR/EULAR core data set [erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), swollen joint count (SJC), tender joint count (TJC), physician and patient global assessment, pain, health assessment questionnaire (HAQ)] were recorded. At each visit, clinical improvement and remission were evaluated according to DAS [1,2] and ACR/EULAR Boolean criteria [3]. Results At baseline, seropositive subjects were younger at diagnosis (p=0.02) and more smokers (p=0.001). There were no differences in gender, symptom duration, inflammatory parameters (ESR and CRP) and presence of erosions between seropositive and seronegative subjects. Seropositive patients showed a lower average of TJC (p=0.03) and SJC (p=0.01) compared with seronegative ones. Similar percentages of good-EULAR response and DAS-remission were seen over time between seropositive [Good-response (3 months: 54.6%; 6 months: 73.7% and 12 months: 78.3%) and DAS-remission (3 months: 36.1%; 6 months: 50.9% and 12 months: 57.4%)] and seronegative patients [Good-response (3 months: 59.5%, p=0.52; 6 months: 69.2%, p=0.50; 12 months: 73.8, p=0.47, respecvtively) and DAS-remission (3 months: 36.5%, p=0.96; 6 months: 46.2%, p=0.52; 12 months: 57.5%, p=0.99)]. The ACR/EULAR Boolean remission rate was higher in seropositive (6 months: 40.4%, 12 months: 45.2%) compared to seronegative patients (6 months: 23.4%, p=0.02; 12 months: 35.0%, p=0.15). Similar percentage of subjects started a combination therapy with a TNF blocker in the two cohorts. Conclusions In our seropositive e seronegative ERA cohorts, the major outcome, i.e. disease remission, was similar when using a T2T algorythm. A deeper understanding of the biological basis of the two subsets of the disease is clearly the major missing point. References van Gestel AM., Arthritis and Rheumatism, 1996. Prevoo ML, British Journal of Rheumatology, 1996. Felson DT, Arthritis Rheum. 2011 Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.4294

OP0222 (Collagen Specific-)T Cell Related Parameters Provide Information for the Management of Rheumatoid Arthritis Patients

Background The developmental risk of Rheumatoid Arthritis (RA) is strongly linked to HLA-DRB1*04 (DR4) and *01 (DR1). In RA, activated immune cells, as CD4+T cells, B cells, dendritic cells and macrophages infiltrate the synovial tissue. In a previous work, we found that huCollp261-273-specific T cell repertoire analyzed in peripheral blood of DR4+ RA patients was restricted to a limited number of TCR rearrangements. This collagen-specific repertoire appears modulated by disease activity (1). The two most used TCR-beta chains were TRBV25-TRBJ2.2 and TRBV6-4-TRBJ2-3. Objectives To examine the frequency and the distribution of huCollp261-273-specific T cells and the role of DR alleles in RA patients in order to find new biomarker for the management of the disease. Methods HLA genotyping was performed using the Innogenetics® kit, following the manufacturers protocol. TCR repertoire analysis: Peripheral blood mononuclear cells (PBMCs) were purified from whole blood and TCR BV-JB analysis was performed as previously described. (1) Patients: we analyzed 100 samples from RA patients, 57 with a high disease activity (DAS >3.7) and 43 with a low disease activity (DAS≤2.4). Results The presence of TRBV25-TRBJ2.2 and TRBV6-4-TRBJ2-3 in T cells was significantly associated with disease activity in the group of DR4+ RA patients. The usage of these two receptors described two non-overlapping groups of RA patients, with subjects using TRBV6-4+ displaying a significantly higher disease activity. The combination of TCR usage in DR4+ subjects and of DR haplotypes in RA patients described four distinct responses to treatment with Disease Modifying Antirheumatic Drugs (DMARDs) and biologic agents. Fifty percent of DR4+ TRBV25- patients responded to DMARDs and the remaining responded well to biologic agents; DR4+ TRBV25+ patients failed to respond to DMARDs but displayed a good response to biologic agents and this latter group might therefore be candidate to treatment with biologic agents. In the group of DR4-, DR1- or DR7-patients, the DR11 allele appeared highly enriched in subjects displaying a high disease activity. Accordingly, within the group of DR4-, DR1- DR7- RA patients, we observed that 50% of all patients achieved a good response after DMARDs treatment; among patients non-responder to DMARDs, however, it appeared that DR11+ subjects responded to a lesser extent than DR11- patients to biologic agents. Conclusions These findings showed that the analysis of collagen specific T cells repertoire and HLA-DR haplotype can provide useful information to a personalized treatment in RA patients. References Ria F., et al. Arthritis Research & Therapy, 2008. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.4311

AB0566 Arthritis in Systemic Vasculitis: A Retrospective Analysis

Background Few data are available on the prevalence of arthritis in vasculitides. Objectives To evaluate the prevalence and the features of arthritis in our cohort of patients with systemic vasculitis. Methods Data were collected from 206 patients with systemic vasculitides referred to our center from 2008 to 2013, excluding the cases of overlap between vasculitis and definite inflammatory arthritis. Of the 206 patients (mean age 58.0±16.7 years, 65.5% females), 105 had large vessel vasculitis (64 Giant cell arteritis, 24 Aortitis and Periaortitis, 10 Takayasu, 7 Central Nervous System Vasculitis), 101 had small-medium vessel vasculitis (36 Granulomatosis Polyangiitis (GPA), 20 Microscopic polyangitis (MPA), 14 Eosinophilic granulomatosis Polyangiitis (EGPA), 12 Cryoglobulinemic vasculitis, 10 Panarteritis nodosa (PAN), 4 ANCA-positive vasculitis, 3 Shonlein Henoch purpura and 3 gastrointestinal vasculitis). We performed a clinical, laboratoristic and radiological evaluation. Results Twenty-five out of 206 (12.1%) had arthritis. All 25 patients had small-medium vessel vasculitis (28% (7/25) GPA, 20% (5/25) MPA, 16% (4/25) Cryoglobulinemic syndrome, 16% (4/25) EGPA, 12% (3/25) Henoch-Shonlein purpura, 8% (2/25) PAN). None of the patients in the group of large-vessel vasculitis had arthritis. We observed 14 cases of oligoarthritis, 10 of poliarthritis and only 1 case of monoarthritis. The most frequently involved joint was the ankle. Nineteen patients developed arthritis at the onset of vasculitis, 4 patients had arthritis before vasculitis and only 2 patients had arthritis during vasculitis flares. None had radiographic erosions at X-ray. Nine of 25 patients performed ultrasound which showed capsular distension, tenosynovitis, synovitis with low grade or absent Power Doppler positivity. We divided patients suffering from small-medium vessel vasculitis into two groups: arthritic patients (25) and patients without arthritis (76). The two groups had the same demographics (age and sex) and laboratoristic (ESR increasing, CPR increasing, ANCA positivity, Rheumatoid Factor (RF) positivity, complement reduction) features. The only difference between the two groups was the cutaneous involvement: purpura appeared in 64% (16/25) of patients with arthritis vs 34.2% (26/76) of patients without arthritis (p=0.01). Arthritis had a good clinical response to therapy for vasculitis and it did not reappear during vasculitis flares. Conclusions Arthritis is a possible manifestation of systemic vasculitis, particularly of small-medium vessel vasculitis, usually occurring at the disease onset. It is usually oligoarticular and non-erosive, showing the same incidence in males and females. It seems to be associated with cutaneous involvement while no association with ANCA antibodies or RF was seen. Arthritis shows a good response to vasculitis treatment and it does not recur during vasculitis flares. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.4954

AB0004 Collagen-specific tcr repertoire usage in rheumatoid arthritis and cytokine secretion.

Background We have previously reported the characterization of the TCR-beta chain repertoire of T cells specific for Human Collagen II p261-273 in DR4+ RA patients and DR4+healthy controls (1). Objectives We observed that it is possible to identify a limited number of TCR-beta chain recurrently used in patients during the acute presentation of the disease, as opposed to the same patients after disease amelioration, versus healthy control subjects. We could also show that a part of this repertoire is spontaneously enriched in the Synovial fluid. Methods We examined the usage of the two more commonly used TCR-beta chains (BV11 and BV13) in 85 consecutive samples from RA patients of various HLA DR haplotype (25 DR4+, 13 DR1+, 11 DR7+ and 37 of other haplotypes; one patient was DR4+ DR1+) at acute presentation (47) or remission (38) of disease. Peripheral Blood Mononuclear Cells (PBMC) were isolated, cultured in the absence or presence of collagen peptide and examined by immunoscope, as described. In addition, we examined the ability of collagen-specific individual T cells of 3 DR4+ patients to secrete IL-17 and IL-13 upon stimulation in vitro with the peptide, in the absence or presence of bacteria-derived products, following the method recently described (2). Results Confirming the previously reported observations, 40 (6/15) and 50 (7/15)% of RA patients in acute disease display the presence of BV11+ or BV13+ T cells. Pooling patients positive for either or both TCRs, the frequency of positive samples increased only to 8/16. The frequency of the same T cells in the collagen-specific repertoire residual after induction of remission decreases to 1/11 and 2/10, respectively. Two more groups of RA patients displayed collagen-specific T cells using similar BV11 and BV13 beta chains, namely DR1+ patients (2/9 in each case) and DR7+ patients (3/6 in each case). In the case of DR7+ patients, however, the frequency of positive samples did not decrease following remission of symptoms. Three out of 18 patients with other haplotypes showed usage of BV11+ cells and 1/19 used BV13+ cells. We examined the ability of a total of 17 individual T cells from 3 DR4+patients (1 in acute disease and 2 in remission) to secrete IL-17 and IL-13. When PBMC were stimulated in the presence of peptide only, just 1 T cells was able to secrete IL-17 and 1 IL-13, both observed in the patient in acute disease. However, when stimulation with the peptide was associated with the presence of bacterial products, 3 more individual T cells became able to secrete IL-17. Conclusions We confirm that BV11 and BV13+ cells are bystander of the acute presentation of the disease in DR4+ patients. The relative high frequency of usage of these clonotipic TCRs in DR1+ and DR7+ patients is possibly due to the similarities in presentation of the antigen between these DR alleles. The secretion of the highly pro-inflammatory cytokine IL-17 is modulated by endogenous or exogenous factors (possibly interacting with PRRs) which may thereby influence the severity of local damage. References Ria F et al, Arth Res Ther 2008, 10:R135. Nicolò C et al, J Immunol 2010, 184:222-235. Disclosure of Interest None Declared