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We read the article by Mankia et al on the distinct ultrasound (US) imaging phenotype in palindromic rheumatism (PR) with great interest.1 The authors found characteristic US findings in PR during flares that differ from those observed in patients with early rheumatoid arthritis (RA) or anti-cyclic citrullinated peptide (CCP)+ arthralgia. US extracapsular inflammation (periarticular inflammation, subcutaneous or peritendinous oedema), in most cases without joint synovitis, is the most frequent US finding in PR. These findings disappeared after acute attacks. The authors concluded that this imaging phenotype of extracapsular inflammation is specific for PR and may be distinguished from that observed in RA or persistent arthritis. They also suggest that true US intrasynovial inflammation may predict future RA in these patients. …

Background Calprotectin and TNF antagonist (TNFa) trough serum levels are associated with disease activity. Objectives To determine if calprotectin serum levels or drug trough serum levels predict relapse in RA and PsA patients with low levels of disease activity during TNFa therapy. Methods Prospective 1-year follow-up, single center study (INMUNOREMAR cohort). RA (ACR 1987) and PsA (CASPAR) patients in clinical remission (CR) (DAS28-ESR 3.2 and increase in ΔDAS28-ESR >0.6. Univariate and multivariate regression models were used to identify predictors of disease flare. Results 103 patients (47RA, 56PsA) were included. Mean Age 57 (30–81) years. 78 (75.8%) had CR and 25 (24.2%) LDA. Mean CR/LDA duration was 58 (4–163) months. 36 patients had received treatment with ADA, 50ETN, and 17IFX. Mean biologic treatment duration 61 (7–166) months. 47.4% patients were on monotherapy, 47% on reduced dose, and 17.9% received steroids. 84 patients (91%) remained in CR/LDA for 12 months, and 12 patients (13%; 8 RA, 4 PsA) experienced flares. Patients with flares had a longer time to achieve CR/LDA [CR/LDA (n=81) 3.1 (1–6) months vs. Flare (n=12) 20 (5–31) months, p Conclusions Calprotectin and TNF trough serum levels are promising biomarkers to predict flare in RA and PsA patients with low disease activity during anti-TNF treatment. References Sanmarti et al. Ann Rheum Dis. 2015 Aug;74(8):e42. Disclosure of Interest J. Inciarte-Mundo Grant/research support from: Hospital Clinic de Barcelona (Premi E. Letang 2013); Catalan Society of Rheumatology (Research Grant 2013), M. Hernandez: None declared, V. Ruiz-Esquide: None declared, J. Ramirez: None declared, A. Cuervo: None declared, S. Cabrera-Villalba: None declared, M. Pascal: None declared, J. Yague: None declared, J. Canete: None declared, R. Sanmarti Grant/research support from: This Study was supported by an Investigator Initiated Research (IIR) from Pfizer (WS2392358)

Background Genome-wide association studies (GWAS) in Psoriatic Arthritis (PsA)patients and controls have allowed the identification of multiple variants associated with disease risk. To date, however, no GWAS for PsA phenotypes has been reported. Objectives The main objective of this study was to identify new genetic variation associated with clinical phenotypes in PsA. Methods A total of n=835 patients diagnosed with PsA using CASPAR criteria were recruited in the discovery stage and genotyped for >600,000 single nucleotide polymorphisms. GWAS were performed for clinical and biological phenotypes associated with joint and skin disease. After allelic association analysis, those SNPs with highest level of significance were analyzed in an independent cohort of n=414 PsA patients. Results In the GWAS stage, several genomic regions showing high evidence of association with different PsA phenotypes (P Conclusions Usign a GWAS approach, new loci associated with axial and peripheral disease in PsA have been identified. Disclosure of Interest None declared

Background Definitive biomarkers have not been identified to predict flares in patients with RA in clinical remission. Objectives To determine clinical, serological and ultrasonografic variables predicting disease relapse at 12 months of follow-up in a cohort of RA patients in clinical remission. Methods We included consecutively RA patients in clinical remission defined as DAS28-ESR 6months evaluated by two independent rheumatologist from our Arthritis Clinic. Complete clinical and biological assessment, determination of serum levels of angiogenic and proinflamatory cytokines, and ultrasound scans of both hands were performed at baseline and after 12 months of follow-up. Risk factors odds ratio (OR) related with 12 months flare were adjusted with multivariate logistic models. Results Sixty patients with RA in remission were included; 78.3% were female. Median age was 53 years (range: 31–74), weight was 67 kg (47–108). Disease and remission mean duration were 111.9 ± 86.4 and 37 months, respectively. 71% of patients were RF positive and 81% were ACPA positive. Patients taking low-dose prednisone, csDMARDs and bDMARDs were 16 (26%), 47 (78%) and 28 (46.7%), respectively. At baseline, 66% had power-doppler (PD) signal and 48% also had synovial hyperplasia grade ≥2, so fulfilling the criteria previously defined of ultrasound defined active sinovitis (UdAS). Twenty-six (43%) patients had disease flare during the follow-up. In the univariate analysis, disease flares were more frequent in patients with PD signal (p=0.056) or UdAS (p=0.117), and significantly less frequent in patients with mild-moderate intake of alcohol. However, in the multivariate analysis, only higher ESR levels (OR: 1.1, 95%CI: 1–1.1), higher weight (OR: 3.1, 95%CI: 1.4–7) and low-dose prednisone treatment (OR: 1.8, 95%CI: 1.2–2.8) were independent risk factors at baseline for disease flares. This model has a sensitivity of 76.9% (95%CI: 56.4–91), a specificity of 76.5% (95%CI: 58.8–89.3), a predictive positive value of 71.40% (95%CI: 52.4–88.4), a predictive negative value of 81.3% (95%CI: 62.7–91.7) and a good predictive power (ROC: 0.849, IC 95%: 74.4–95.4%). We did not find differences between angiogenic or proinflammatory cytokine serum levels and not differences in RAMRIS between patients relapsing or maintaining the remission at baseline. Conclusions This prospective study suggests that higher ESR levels, higher weight and low-dose prednisone treatment are relevant independent risk factors for development of disease flares in patients with RA in clinical remission. However, imaging data (Ultrasound or MRI) or angiogenic/cytokine serum levels were no predictors of flare in this study. Disclosure of Interest None declared

Background A high proportion of patients with rheumatoid arthritis (RA) in clinical remission (CR) present subclinical synovitis when evaluated by sonography. Most prospective studies on baseline biomarkers of radiographic progression in this patients not include immunological biomarkers that could be of interest to better identify the residual inflammatory activity. Objectives To determine clinical, serological and ultrasonografic variables predicting progression of structural damage as evaluated by MRI at 12 months (mo.) of follow-up in a cohort of RA patients in CR. Methods We included 42 RA patients in CR defined as DAS28-ESR 6 mo. Complete clinical and biological assessment, ultrasonography of two hands and MRI of dominant hand were performed at baseline and after 12 mo. We analyzed risk factors related with RAMRIS progression with multivariate lineal models. Results 42 patients were included (76.7% female). Mean age was 53.5 years, body mass index (BMI) 26.7 kg/m 2 . Disease and remission median duration were 94 and 37 mo. respectively. 73.8% RF[+] patients and 85.7% ACPA [+]. RAMRIS 10.3 and erosion (RAMRIS) 18.8. At baseline, 66.7% had power-doppler (PD) signal and 45.2% also had synovial hyperplasia grade ≥2, so fulfilling the criteria of previously defined ultrasound defined active synovitis (UdAS) 1 . The risk factors more related with RAMRIS progression at 12 mo. were baseline RAMRIS, BMI, disease duration, low-dose prednisone treatment, absence of csDMARDs treatment and presence of UdAS. Synovitis as defined by only PD positive signal was no associated to erosions. We excluded the baseline RAMRIS in the multivariate model because it was the strongest predictor factor. We observed that higher serum levels of calprotectin and ENA78 at baseline were significant predictors. Absence of csDMARD treatment, disease duration and the presence of UdAS also remained as independent predictive factors (Table 1). Conclusions This prospective study confirms a high prevalence of UdAS in patients with RA in CR, which is an independent risk factor to develop structural damage progression at 12 months of follow-up. Baseline RAMRIS, BMI, disease duration, absence of csDMARDs therapy, UdAS, and baseline levels of calprotectin and ENA78, were independent predictors of RAMRIS progression. References Ramirez J, et al. Patients with rheumatoid arthritis in clinical remission and ultrasound-defined active synovitis exhibit higher disease activity and increased serum levels of angiogenic biomarkers. Arthritis Res Ther. 2014;16(1):R5 Disclosure of Interest None declared

Background Tocilizumab (TCZ) is a humanized anti-IL-6R monoclonal antibody approved for the treatment of active rheumatoid arthritis (RA). Response to treatment may depend on the dose and dose interval as well as on the achieved trough serum levels. Objectives To analyze serum trough levels of TCZ in two cohorts of RA patients on chronic treatment with TCZ and their relationship with disease activity and clinical remission. To establish a cut-off point of TCZ serum levels with high discriminative capacity for clinical remission state. Methods Cross-sectional study of two cohorts (Barcelona, Spain and Lausanne, Switzerland) including all RA patients on chronic treatment with IV TCZ. Demographic data, disease activity measured by DAS28, acute phase reactants, TCZ trough levels (detectable levels ≥1μg/ml) (LISA TRACKER Tocilizumab Theradiaag, France) and IL6 serum levels (ELISA) were analyzed. All samples were collected just before treatment infusion. TCZ levels were correlated with different clinical and serological parameters. Multivariate logistic regression was used to determine the variables associated with remission (DAS28≤2.6). Receiver operating characteristic (ROC) curve analysis was used to determine the discriminatory capacity of the area under the curve (AUC) of TCZ levels in predicting remission. Results 82 RA patients were included (40 Barcelona Cohort, 42 Lausanne Cohort) (90% were women, mean age 55.5±13 years, disease duration of 13.7±8 years, 60.3% anti-CCP+, 22.2% on monotherapy, 37.2% received low dose glucocorticoids and 26.8% were on reduced dose of TCZ). The mean DAS28 was of 2.5±1.1 and 44 patients (54.3%) were in remission. Swiss patients had a lower disease activity and were more frequently in remission, had less glucocorticoids use and were less frequently on a reduced dose. 25 patients (30.5%) had undetectable levels of TCZ ( Conclusions Detectable levels of TCZ (≥1 μg/ml) in RA patients on chronic treatment with TCZ were associated with lower disease activity and, especially, with lower CRP levels in the unvaried analysis, and with clinical remission in the multivariate analysis. The cut-off point with the greatest discriminative capacity for clinical remission was of 3.48 μg/ml. Disclosure of Interest None declared

Background Palindromic rheumatism (PR) is an intermittent arthritis, may evolve to rheumatoid arthritis (RA), particularly in patients with citrullinated peptide/protein antibodies (ACPA), but not all patients progress to RA. Differences in ACPA isotypes have been shown between patients with established and preclinical RA. It is unclear whether ACPA isotypes differ between patients with longstanding PR and RA. Objectives To determine whether there are differences in the recognition of epitopes between patients with longstanding PR and established RA by analysis of different ACPA fine specificities and isotypes Methods Case-control study. Cases: patients with pure PR, with no evolution to RA or other rheumatic disease at study entry. Controls: patients with established RA (ACR-87) matched by sex, disease duration and ACPA positivity (commercial CCP2 test [Eurodiagnostica]; NV Results We included 108 patients: 54 PR and 54 RA. 62.9% were female and 66.7% in both groups were CCP2 positive. No significant differences between groups in mean age (51.2±11.3 y vs 54.7±11.8 years) and disease duration (11.6±10.7 y vs. 8.3±6.1 years) were found. PR patients had a lower frequency of ACPA isotypes than RA, which was significant in the case of IgA and IgM against p18 (PR-IgA 18.5% vs RA-IgA 51.8%; p Conclusions Patients with PR had a lower frequency of isotypes of ACPA than RA patients, especially in the case of p18 (isotypes IgA and IgM) and p55 (isotypes IgA and IgG). PR patients with fewer ACPA isotypes may have a better prognosis and without progression to RA. Disclosure of Interest None declared

Background Calprotectin is a major S100 leucocyte protein, associated with disease activity in rheumatoid arthritis (RA) patients. Calprotectin is a potentially biomarker more sensitive of disease activity than conventional acute-phase reactans. Objectives To evaluate the performance of calprotectin serum levels in stratifying disease activity in RA patients treated with TNF inhibitors (TNFi) compared with acute phase reactants. Methods Cross-sectional study, including consecutive RA patients (ACR 1987 criteria) from our arthritis unit receiving etanercept, adalimumab or infliximab. DAS28, SDAI, CDAI, joint counts, ESR, CRP and calprotectin serum trough levels were measured. Associations between calprotectin, ESR and CRP and articular indices were analysed by correlation and linear regression. Results 87 patients were included; mean duration of biological treatment was 82±46 months. 47 patients were in remission/low disease activity (DAS28≤3.2), and 40 had moderate/high disease activity (DAS28>3.2). Serum calprotectin levels were higher in active patients than in those in remission/low disease activity (2.21±1μg/mL vs. 4.28±2μg/mL, p≤0.001). Calprotectin, CRP and ESR distinguished between patients in remission/low disease activity and those with moderate/high disease active disease, according to all indices assessed. Calprotectin levels were significantly-lower in patients in remission compared to those with low disease activity according to all articular indices analysed, whereas ESR discriminated between disease states only according to DAS28, and CRP only according to SDAI. Calprotectin, but not CRP or ESR, strongly correlated with all composite indices and the 28 SJC/TJC (all r coefficients over 0.50). In patients in remission/low disease activity, calprotectin but not CRP or ESR, distinguished between patients with no swollen joints and those with ≥1 swollen joints (1.95±1μg/mL vs. 3.07±1μg/mL, p=0.010). Adjusted analysis showed a significant association between serum calprotectin levels and DAS28 according to different covariates (combined therapy, reduced dose, use of glucocorticoids, disease duration, autoantibody status and erosive disease). Backward selection of variables did not substantially modify the association between calprotectin and DAS28. The accuracy analysis with “activity by DAS28≤3.2” as the reference variable showed an AUC of 0.846 (95% CI 0.763 to 0.930, p≤0.001) with a cut-off calprotectin value of ≥3.2. μg/mL. The cut-off had a sensitivity of 77.5% and a specificity of 81.9%. Conclusions Calprotectin is an accurate biomarker of disease activity in RA patients receiving TNFi therapy and show a better correlation with all disease states, including remission and low disease activity, than acute phase reactants (ESR and CRP). Disclosure of Interest None declared

Background Dose reduction of biological therapy in patients with chronic arthritis (CA) with a good clinical response is a common pattern in clinical practice. However, most published studies are based on cross-sectional data in small groups of patients. Objectives To analyse the evolution of CA patients receiving low doses of biologics and to describe predictive factors associated with maintaining reduced doses of biological therapy. Methods Observational, longitudinal, prospective study that analysed the evolution of 153 patients treated with standard or reduced doses of biologics with a two-year follow up. Variables analysed were: age, sex, diagnosis and disease duration, previous treatment (sDMARD, bDMARD), current bDMARD and dosage, duration of biological treatment. In patients on reduced doses: concomitant therapy (sDMARD, steroids), ESR and CRP were collected. In rheumatoid arthritis (RA) patients, autoantibody status, erosions, and DAS-28 score were analysed. A logistic regression model was used to identify factors associated with maintaining the reduced dose after 2 years. The confidence interval of the area under the ROC curve was estimated by bootstrap technique to internally validate the predictive capacity of the model. Results 153 patients were included between June and November 2011: 82 RA, 29 ankylosing spondylitis (AS), 20 psoriatic arthritis (PsA) and 22 with other diagnoses: 70 patients (45.7%) were on reduced doses of biologics. This cohort was followed prospectively for 2 years. Of the 153 patients initially included, 142 remained on biologics at 2 years and 11 discontinued (6 on lower doses and 5 on standard doses: 3 due to adverse events (malignancies), 2 to pregnancies, 2 to prolonged remission, 1 to death and 3 lost to follow-up). After 2 years of follow-up, 56 patients remained on low-dose biological therapy (39.4%) and 8 (5.6%) required an increase in the dose to the standard regimen. By contrast, 19 patients receiving the standard dose were on reduced doses at two years. 75 (52.8%) patients were on a reduced dose after two years follow up. In patients (37 RA, 13 PsA) in whom the DAS-28 score was analysed (mean ± SD), 17.9% (8 AR, 2 PsA) had low disease activity (2.8±0.2) and 71.4% (29 AR 11, PsA) were in remission (1.9±0.5). Univariate analysis, showed that patients who remained on a reduced dose after 2 years had less use of concomitant steroids in 2011 [9% vs. 45% (p Conclusions In our cohort, 87.5% of patients receiving reduced doses in 2011 remained on them after 2 years of follow up. Factors associated with the maintenance of a clinical response with reduced biological doses in the multivariate model were lower previous use of steroids and a lower DAS-28 score. Disclosure of Interest None declared

Background and objectives The functional relevance of synovial ectopic lymphoid neogenesis (ELN) in rheumatoid arthritis (RA) remains unknown. As ELN correlates with the degree of tissue inflammation we investigated whether ELN was associated with specific cytokine profiles. Materials and methods Paired synovial tissue (ST) (n = 63) and fluid (SF) (n = 44) was obtained from the inflamed knee joints of RA patients. Synovial inflammation and ELN was determined by immunohistology. CD21L was used as molecular marker of ELN. Cytokine expression was determined by ELISA and quantitative PCR in SF and ST, respectively. Results 48% of ST displayed ELN by histology. ELN+ samples had increased T and B lymphocyte infiltration (p Conclusion Synovial ELN in RA is strongly associated with increased expression of IL-23/IL-17-related cytokines. Whether patients depicting synovial ELN respond differently to therapeutic targeting of this pathway remains to be determined.

Background The dosage of rituximab (RTX) approved for the treatment of active rheumatoid arthritis (RA) is two intravenous (iv.) 1 g infusions, separated by two weeks. However, it has recently been reported that, after initial treatment with the standard dosage, RTX retreatment at a lower dose may have comparable efficacy and be more cost-effective 1 Objectives To analyse whether retreatment with RTX at a lower dose (1 g total dose) is equally effective in maintaining the clinical response as the standard dosage of cycles of 2g Methods Observational, descriptive, retrospective study. We analysed the long-term efficacy of RTX retreatment with 1 g (total dose) cycles (2 iv. 500 mg infusions separated by 2 weeks; or 1 g iv single infusion) in routine clinical practise. All patients had initially been treated with at least one 2g (total dose) cycle, with a good response according to clinical judgment. The main efficacy variables were: mean DAS-28 score at the last follow-up visit and at the follow-up visit previous to RTX dose reduction; need to increase the RTX dose to the standard 2g dose; treatment withdrawal due to inefficacy. Secondary variables were: erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) values after retreatment in order to analyse variations between the last follow-up visit (dosage of 1g total dose) and the follow-up visit previous to RTX dose reduction (2g total dose). Results From 2006 to 2013, 53 patients (86.8% RA) attended by our Department received at least, one cycle of 2g RTX (standard dosage); 41 out of 53 (77.3%) had a good response. Since September 2011, RTX retreatment was administered at a reduced 1g (total dose)/cycle in 29 patients (mean age: 59.5±10.4 years; 86.2% female; disease duration 11.7±7.9 years; 79.3% positive for rheumatoid factor/anti-cyclic citrullinated peptides). 79.3% of patients received concomitant disease-modifying antirheumatic drugs (DMARD) and 86.2% glucocorticoids. The mean number of RTX cycles received per patient before RTX dose reduction was 2.03±1.35. No increase in the DAS-28 score was found at the last follow-up visit (2.85±0.98) compared to the follow-up visit previous to RTX dose reduction (3.66±1.17) (p Conclusions After an initial favourable response to the standard dose of RTX, posterior retreatment with a total dose of 1g/cycle maintained the clinical response over time and was more cost-effective References Mariette X et al. Ann Rheum Dis. 2013 May 30 Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.3535

Objectives Ectopic lymphoid neogenesis (ELN) occurs in 30-50% of the rheumatoid synovial samples but its functional relevance remains unknown. As ELN correlates with the degree of tissue inflammation we investigated here whether ELN was associated with specific cytokine profiles. Methods Paired synovial tissue (ST) (n=63) and fluid (SF) (n=44) was obtained from the inflamed knee joints of rheumatoid arthritis (RA) patients. Synovial inflammation and ELN was determined by immunohistology. CD21L was used as molecular marker of ELN. Cytokine expression was determined by ELISA and quantitative PCR in SF and ST, respectively. Results 48% of ST displayed ELN by histology. ELN+ samples had increased T and B lymphocyte infiltration (p Conclusions Synovial ELN in RA is specifically associated with increased expression of IL-23/IL-17-related cytokines. Whether patients depicting synovial ELN respond differently to therapeutic targeting of this pathway remains to be determined. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.5179

Background We recently observed that 45% of patients with RA in clinical remission had ultrasound-defined synovitis (grade 2 or higher synovial hypertrophy (SH) and power Doppler signal). These patients had greater disease activity, less use of low-dose corticosteroids and higher serum levels of bFGF (Ramirez J, et al. Arthritis Res Ther 2014). Objectives We here describe the pathological findings and their correlation with sonographic features in a subset of patients with synovial biopsy. Methods At baseline, we obtained 6-8 ultrasound-guided synovial biopsies of all RA patients in remission and Power Doppler signal who signed informed consent. CD3 (T lymphocytes), CD20 (B lymphocytes), CD68 (macrophages), CD117 (mast cells) and bFGF were quantified by Immunoperoxidase staining and Digital Image Analysis (Olympus). The number of vessels/mm 2 was quantified on hematoxylin-eosin stained sections. Serum bFGF was analysed by ELISA (RayBiotech). We performed ultrasound scans of both knees and hands (wrists, metacarpophalangeal [MCP], proximal interphalangeal [PIP] flexor and extensor tendons of the hand) (Acuson Antares®, Siemens AG, Erlangen, Germany) with a 8-12 MHz linear probe. We independently quantified SH and power Doppler signal (grade 0 -3) and obtained a global ultrasound score for each patient as grade of synovial hypertrophy + grade of power Doppler signal in each assessed joint. Results We included 19 patients, 13 females, aged 52.1 (8.9) years, with disease duration of 77 (47.4) months (Mean (SD)). 57.9% and 89.5% of patients were positive for rheumatoid factor and anti-citrulline antibodies, respectively; 84.2% were treated with ≥1 DMARD and 57.9% were on biological therapy. On ultrasound, 78.9% of patients had grade 2 or higher SH, and 68.4% ultrasound-defined active synovitis (SH≥2 + power Doppler signal) in at least 1 joint. A significant positive correlation between the individual global ultrasound score and the density of CD3 + T cells (p=0.02) and CD20+ B cells (p=0.002) was found, and a non- significant trend with CD117+ mast cells density (p=0.09). bFGF expression and number of vessels per area in synovial tissue were non-significantly higher (p=0.11 and p=0.14, respectively) in patients with ultrasound-defined active synovitis. A significant correlation between bFGF expression in synovial tissue and serum bFGF levels (p=0.045) was also found. Conclusions We found a significant correlation between the grade of infiltration of synovium by T and B lymphocytes and global ultrasound score and between bFGF expression in synovial tissue and serum, suggesting that ultrasound-defined synovitis in patients in clinical remission have a histological and biological correlate. Therefore, bFGF could be a biomarker of subclinical synovitis in RA patients in remission. Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.4410

Background Rituximab (RTX) is a biologic therapy approved for the treatment of active rheumatoid arthritis (RA) refractory to tumour necrosis factor antagonists. It causes B cell depletion, with a progressive reduction of the levels of immunoglobulin (Ig) that may be associated with an increased risk of infection. Objectives To analyse the long-term safety of treatment with RTX in patients with RA and other inflammatory arthritides, and especially the risk of severe infections. Methods We made a retrospective descriptive study including patients treated by the Rheumatology Department of a tertiary hospital from June 2006 to December 2013 who had received at least one cycle of treatment with RTX. We analysed: demographic data (age, sex), diagnosis and disease duration, positive rheumatoid factor (RF) or anti-cyclic citrullinated peptide antibodies (anti-CCP); previous biologic treatment; concomitant treatment: disease-modifying antirheumatic drugs (DMARD) and/or concomitant glucocorticoids (GC); number of cycles received; levels of immunoglobulin (Ig) and adverse effects, especially severe infections. Results 53 patients were included (85% female, mean age 58.9±12.9) until December 2013, who received a total of 169 cycles of RTX (mean: 3.3±2.2 cycles/patient) during 7 years. Diagnoses were: RA (75.5%), overlap syndrome (11.3%), systemic lupus erythematosus (5.7%), psoriatic arthritis (3.7%), seronegative oligoarthritis (1.9%) and juvenile idiopathic arthritis (1.9%). Mean disease duration was 15.1±8.4 years, 79.2% were RF/anti-CCP positive, 67.9% had received prior biological treatment, 37.7% had received ≥2 or more biologic drugs, 77.3% received concomitant DMARDs (47.2% methotrexate, 30.2% leflunomide, 11.3% hydroxychloroquine and 3.8% mycophenolate mofetil) and 79.2% received GC. A progressive, significant decrease in IgG levels (p=0.018), IgM (p=0.018) and IgA (0.05), already evident after the first RTX cycle, was observed, although only 13.2% of patients had Ig levels below the normal range. Twenty-five adverse events were reported, of which 19 were considered drug-related: 2 infusion reactions, 2 cases of leukopenia and 15 infections (7 respiratory tract, 5 urinary tract, 2 joint infections and 1 case of bacteremia), and 4 of which were considered serious according to medical criteria, although no patient discontinued RTX for those reasons. No opportunistic infection or malignancy was reported. Patients with low Ig levels did not have a greater number of infections than those with normal Ig levels. Conclusions After prolonged exposure to RTX, serious adverse effects, including infections, were stable over time and multiple treatment courses, and showed a good safety profile, even in patients with reduced Ig levels. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.3495

Background Up to 35% of patients with shoulder pain have a full-thickness rotator cuff tear. It has been proven a deleterious effect of corticosteroid on collagen. However, the influence of corticosteroid injection in the incidence of rotator cuff tears is unknown. Objectives The aim of this study was to evaluate the risk of corticosteroid injection in the incidence of full-thickness rotator cuff tear. Secondary outcomes were the incidence of full-thickness rotator cuff tear between patients with partial-thickness rotator cuff tear and the improvement in shoulder pain and function. Methods Prospective, open-label study. Patients with unilateral painful shoulder without previous local steroid injection were recluted. Clinical and ultrasound assessment were practiced in the first (day 0) and the last visit (day 90). Patients with full-thickness rotator cuff tear were excluded. Patients received a standard subacromial infiltration of 1 cc of triamcinolona depot. 1cc of mepivacaina was injected in 7 patients for clinical decision (mainly poorly controlled diabetes). A radiologist and a rheumatologist experienced in musculoeskeletical ultrasound performed the ultrasound scans and clinical examination, respectively, of shoulder pain. Results 89 patients with shoulder pain were evaluated. 47 (52.8%) had full-thickness rotator cuff tear in the first visit and were excluded. 42 patients completed the study (29 women and 13 men, the mean age of patients was 61.1 years-old). 35 received an injection of 1 cc of triamcinolone depot and 7 were infiltrated with mepivacaine (2 patients for steroid allergy and 5 patients with poorly controlled diabetes). At the end of the study, 7 full-thickness rotator cuff tears were found. 1/7 (14.2%) in the mepivacaine group and 6/35 (17.1%) in the triamcinolone depot group. Among 18 patients who had a partial-thickness rotator cuff tear in the first visit, 6 suffered a complete tear of the rotator cuff after 3 months (1/4 in the mepivacaine group and 5/14 in the triamcinolone depot group). 4/7 patients (57.1%) had a great improvement in shoulder pain (more than 80% in VAS score) in the mepivacaine group, while 14/35 (40%) had it in the triamcinolone depot group. Only one patient worsened the symptoms, because of a new full-thickness rotator cuff tear. 39 patients (92.8%) recovered the normal range of movement after 3 months. Conclusions Subacromial steroid injection did not increase the rate of full-thickness rotator cuff tear expected in a population with shoulder pain. More than half patients with shoulder pain have a full-thickness rotator cuff tear in the first visit. Disclosure of Interest None Declared

Background Biological therapy has shown its efficacy in different chronic inflammatory arthropathies during the last decade. However, in practice, clinical efficacy is reduced in some patients, suggesting that drug-induced immunogenicity may be a possible mechanism Objectives To analyze the development of tumor necrosis factor (TNF) antagonist antibodies (AB) and determine serum drug levels in patients in whom loss of efficacy or adverse treatment effects occur over time. Methods Descriptive, retrospective study of patients attended by a rheumatology department of a tertiary hospital between February and December 2012 who were on active treatment with TNF antagonists and in whom loss of efficacy, inefficacy or adverse treatment effects occurred. Patients were included according to clinical judgement and not according to an established protocol. We measured antidrug AB and drug serum levels using an ELISA immunoassay (Promonitor®). Only patients on infliximab (IFX), etanercept (ETN) or adalimumab (ADA) treatment were analyzed. All blood samples were obtained in the 24 h before the next scheduled dose of treatment. Only patients with positive AB were finally analysed. The following variables were collected: demographic variables; diagnosis and disease duration; previous and current treatment; reason for the analysis; antidrug levels and serum drug concentrations; and clinical decision. Results Seventy patients were included; 67% female; mean age 51±14 years. Main diagnoses were: rheumatoid arthritis (RA) (52.8%); ankylosing spondylitis (AS) (18.6%); psoriatic arthritis (PsA) (10%); and miscellaneous (18.6%) which included, among others, Behcet disease (BD), undifferentiated spondyloarthropathy and juvenile idiopathic arthritis (JIA). The reason for the analysis was: loss of efficacy in 78.6% of patients, adverse events (11.4%), partial response (7.2%), and inefficacy (2.8%). Twelve patients (17.1%) developed antidrug AB: 7 anti-ADA and 5 anti-IFX, representing 24% and 31%, respectively, of patients on these treatments included in the study. Antidrug AB were found directly in 9/12 patients and by a dissociation method in the remaining 3 patients. In 10 patients, serum drug levels were undetectable, and in 2 cases (1 ADA and 1 IFX), both found by the dissociation method, suboptimal (suboptimal level ADA: 0.04-0.80 ng/ml and IFX: 0.05-1.50 ng/ml). Diagnoses were: 6 RA; 3 AS; 1 PsA; 1 JIA and 1 BD. Seven out of 12 patients received concomitant synthetic DMARDs (4 leflunomide and 3 methotrexate), and the remaining five received biological therapy in monotherapy. Five out of 12 have been treated previously with another biological agent (2 anti-TNF and 3 non anti-TNF), which had been discontinued due to inefficacy or adverse events. After the development of antidrug AB, 10 patients discontinued current biological therapy: 7 patients were switched to another anti-TNF agent, with a good response, and 2 to a non anti-TNF drug. Conclusions In our study, around 20% of patients with a loss of efficacy or adverse events to a TNF antagonist developed antidrug AB, which were only observed in patients receiving monoclonal antibodies. Disclosure of Interest None Declared

Background Accumulation of B cells in synovial lymphoneogenesis (LN) structures could drive antibody-independent synovial inflammation through the development of specific T cell responses or by enhancing cytokine production. This might result in differences in the disease phenotype between patients with and without synovial LN, which might have prognostic interest. Objectives We analyzed whether synovial lymphoid neogenesis (LN) in rheumatoid arthritis (RA) is associated with specific patterns of inflammatory cytokine expression in synovial tissue (ST) and Synovial fluid (SF), and the potential association of cytokine expression with disease activity and response to therapy. Methods Paired ST (n=63) and SF (n=44) samples were obtained by arthroscopy from the inflamed knee of RA patients. A second ST sample was obtained after a mean of 8±5 months of treatment in 21 patients who started therapy with TNF-alpha antagonists. ST samples were immunostained for CD3 (T cell), CD20 (B cell), and MECA-79 epitope (high endothelial vessels). Total ST mRNA was extracted and gene expression of CCR7, LT-beta, IL-7, IL-10, IL-17A, IL-21, IL-22, IL-23, TNF-alpha, IL-1b, and IL-6 was measured by quantitative real-time PCR. SF concentration of Th1, Th2, Th17 and proinflammatory cytokines was determined by Quantibody® Human Th17 Array. Clinical and biological data were collected at inclusion and after a median follow-up of 2.4 years. Results Thirty out of 63 patients (47.6%) had LN, which was associated with a significantly higher expression of ST CCR7 (p=0.009), IL-21 (p=0.009) and IL-23 (p=0.016). LN-positive patients also had significantly higher SF levels of IL-23 (p=0.018) and IL-17F (p=0.028). SF levels of IFN-gamma, TGF-beta1 and IL-21 were higher in LN-positive patients, but the difference did not reached statistical significance. LN-positive patients had significantly higher DAS28 at inclusion (p=0.039). In the group of patients sequentially biopsied before and after anti-TNF-alpha blocker therapy, EULAR good response was only associated with a decrease on IL-10 mRNA expression (p=0.035). Conclusions RA patients with histological LN exhibit higher expression of Th17/23 related cytokines and higher disease activity as compared to LN-negative patients. Only reduction in IL-10 mRNA expression after anti-TNF-alpha therapy was associated with a better EULAR response. Disclosure of Interest None Declared

Background Rheumatoid arthritis (RA) and Psoriatic arthritis (PsA) are two chronic inflamatory diseases mediated by the immune system with joints as main targets. Both diseases seem to exhibit a Th1/Th17 pattern, but studies including joint cytokines and clinical variables are scarse and inconclusive. Objectives To compare concentrations of Th1, Th2, Th17/23 and other proinflammatory cytokines in Synovial fluid, as well as their relation with disease activity, between RA and PsA patients. Methods Synovial fluid was obtained from a inflammed knee joint of RA and PsA patients. SF concentrations of Th1, Th2, Th17 and proinflammatory cytokines were determined by Quantibody® Human Th17 Array (RayBiotech, GA, USA). Clinical and biological data were collected at inclusion. Results 82 RA and 48 PsA patients were included. 78% and 21% of them were women; mean age was 57 and 47.6 years; disease duration 10.2 and 9.3 years; DAS28 4.94 and 3.80 (p

Background Biological agents are used to treat chronic arthritis according to the standard doses from phase III clinical trials. However, in some patients, a good response to treatment may allow the dosage to be reduced, the timing lengthened, and costs reduced. Objectives To analyze a strategy of dosage reduction of biological agents in patients with chronic arthritis attended by the rheumatology department of a tertiary hospital. Methods We performed a cross-sectional study that included all patients, attended consecutively between June 2011 and November 2011 by a single investigator, that had received at least one dose of a biological agent in 2011. Data analyzed were: demographic characteristics; diagnosis and disease duration; DMARD therapy; dosage, type and duration of biological agent used; time on reduced dosage and reason for dosage reduction. The reduced dosage was defined as a lower dosage than recommended in the product technical details and was not based on a structured protocol. Results We included 170 patients (67.1% women) with a mean age of 51.1±14.3 years. Diagnoses were: 56.5% rheumatoid arthritis (RA), 18.8% ankylosing spondylitis (AS), 11.8% psoriatic arthritis (PsA) and 12.9% miscellaneous (MISC), which included 9 juvenile idiopathic arthritis, 3 undifferentiated spondyloarthropathy, 3 uveitis, 2 connective tissue disorder and 1 SAPHO. Mean disease duration was 14.5±8 years, with no differences between conditions. Mean duration of current biological therapy was 47.7±35.6 months, with 134 patients receiving TNF blockers and 36 patients receiving non anti-TNF (abatacept, rituximab and tocilizumab). 53% of patients received concomitant therapy with DMARDs, mainly in the RA group, and 28.2% had received one or more biological agent. At the time of analysis, 76 patients (44.7%) received low dosages of biologicals (51.3% of etanercept patients, 23.7% adalimumab, 14.5% tocilizumab and 10.5% infliximab). The distribution of diseases was: 51.3% RA, 23.7% AS, 13.2% PsA and 11.8% MISC. The most-commonly used low dosage was 50 mg every 15 days for etanercept, 40 mg every 3 weeks for adalimumab, 5 mg/kg every 9-10 weeks for infliximab and 6 mg every 4 weeks for tocilizumab. The reason for dosage reduction was disease remission in 68 patients (89.5%) and low activity in 8 (10.5%). The mean time of dosage reduction was 17.2±21.1 months. The medical decision at the time of the data collection was to keep the low dosage of biological treatment in 63 patients (82.9%) due to low disease activity and/or remission, assessed on clinical judgment and regular scores. Conclusions Near half our chronic arthritis patients receiving biological therapy were able to reduce the dosage to below that of established clinical guidelines, preserving remission or low disease activity in many cases. This dosage reduction was observed both in RA and spondyloarthropathies, and with different mechanisms of drug action. Disclosure of Interest None Declared

Background The dosages of biological agents used to treat rheumatoid arthritis (RA) have been established by randomized clinical trials. However, lower dosages of these agents may be prescribed in clinical practice in patients with a good response, resulting in reduced costs Objectives To analyze the frequency and characteristics of a dosage reduction strategy for biological therapies in a cohort of patients with RA attended by the rheumatology department of a tertiary hospital Methods Cross-sectional study, including all consecutive patients with a diagnosis of RA (1987 ACR criteria), attended by one investigator from June 2011 to November 2011, that had received at least east one dose of a biologic agent in 2011. Data analyzed were: demographic characteristics; disease duration; disease activity measured by the DAS28-ESR; serum CRP; rheumatoid factor (RF) and anti-CCP2; DMARD therapy; dosage, type and duration of biological agent used; time on reduced dosage and reason for dosage reduction. The reduced dosage was defined as a lower dosage than recommended in the manufacturer’s technical specification for each product and was not based on a structured protocol. Results We included 96 patients (87.5% female) with RA with a mean age of 56.1±12.7 years and a mean disease duration of 14.3±8.5 years. RF and/or antiCCP2 were positive in 82.6% of the patients, 71.9% received concomitant therapy with DMARDs and 29.2% had received one or more previous biologic agent. Mean duration of current biologic therapy was 40.3±34.8 months. The biological agents used were TNF antagonists in 66 patients and non anti-TNF (abatacept, rituximab and tocilizumab) in 30 patients. At the time of analysis 38 patients (39.5%) received low dosages of biologicals (52.6% of etanercept patients, 23.7% adalimumab patients and 23.7% of tocilizumab patients). The most-commonly low dosage used was 50 mg every 10-15 days for etanercept, 40 mg every 3 weeks for adalimumab and 6 mg every 4 weeks for tocilizumab. The reason for dosage reduction was remission in 34 patients (89.4%) and low disease activity in 4 (10.6%). The mean time of dosage reduction was 11.4±11.5 months. At the time of analysis, the mean DAS28-ESR and CRP in patients with reduced doses were lower than those of patients without dosage reduction (2.57 vs. 3.47, p=0.09) and (0.37 vs 1.09, p=0.007), respectively), with higher remission rates (76.3% vs 30.7%, p

Background There is strong evidence that rheumatoid arthritis (RA) ACPA positive patients have a different clinical outcome than those that are ACPA negative. However, among these patients there is limited data about the synovial fluid (SF) and synovial cells differences. Objectives To analyse the synovial cellular infiltrate and the SF Th1, Th2, Th17/IL-23 and pro-inflammatory cytokine pattern in a cohort of patients with RA according to the presence or absence of ACPA in the serum. Methods A cross-sectional study in a single center was done and included 300 consecutive RA patients. We defined a patient as ACPA negative if their serum was negative to 2 different ACPA antibodies [commercial CCP2 and chimeric fibrin/filaggrin citrullinated antibodies]. Synovial biopsies and SF were obtained by knee arthroscopy. Cellular infiltrate in lining and sublining layers was analyzed by immunohistochemistry and digital analysis, including neutrophils (CD15), macrophages (CD68), mast-cells (CD117), endothelial cells (CD31/34) as well as presence of lymphoid neogenesis [follicular aggregate grade ≥.2, T/B cell segregation and high endothelial venules (MECA-79 epitope)]. SF concentrations of Th1, Th2, Th17 and pro-inflammatory cytokines were determined by Quantibody® Human Th17 Array (RayBiotech, GA, USA). Results Eighty three patients underwent arthroscopy due to active disease. The mean age at the time of arthroscopy was 56±12 yrs, with a mean disease duration of 73±76 months. Most of the patients were female (63%) with erosive disease (73%). RF was positive in 78% and ACPA in 64 (77%) patients. There were no clinical differences in terms of disease activity, remission rates, erosive disease or biologic treatment, among ACPA positive and ACPA negative patients. Immunohistochemical analysis did not achieve a significant difference between the 2 groups. Also, there were no differences in presence of lymphoid neogenesis or number and grade of follicular aggregates according to ACPA status. SF analysis was available in 51 patients (40 ACPA positive/11 negative). ACPA positive patients had significantly higher levels of IL-1b, IL-10, IL-4, IL-17F and CCL-20 than ACPA negative patients (Table). There were no significant differences in the other cytokines including GM-CSF, IFNg, IL-2, IL-5, IL-6, IL-12p70, IL-13, IL-17, IL-21, IL-22, IL-23, TGFb, TNFa and TNFb. Conclusions In our cohort of patients with RA, there where no significant differences in synovial cell infiltrates and lymphoid neogenesis according to ACPA status. However, ACPA positive patients had higher levels of T-cells derived and pro-inflammatory cytokines. Given that our ACPA positive and negative patients had no differences in systemic (disease activity) or local (CD68+ cells, SF-IL-6 levels) inflammation, these results suggest different pathogenic mechanisms between these RA subgroups Disclosure of Interest None Declared