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Background Rheumatic and Musculoskeletal Diseases (RMDs) substantially impact the lives of patients, with complex associations between disease severity and self-perceived health status. In this regard, the Coping with Rheumatic Stressors (CORS) questionnaire was developed to measure how patients with RMDs cope with stressors such as pain, limitations or dependency. The CORS is not currently available in Spanish, and therefore the adaptation of this instrument is needed. Objective First, to cross-culturally adapt the CORS into Spanish for Spain. Secondly, to test the conceptual equivalence of the translated version in patients with axial spondyloarthritis (axSpA). Methods A translation of the CORS into Spanish was performed adhering to the forward-backward procedure described by Beaton. Two translators produced independent forward translations of the item content, response options, and instructions of the CORS into Spanish. Both versions were harmonized in a consensual version. Another translator back-translated the synthesized version into Dutch. A scientific committee including all the translators, one methodologist and a rheumatologist, held a meeting and reached consensus on discrepancies to develop a final draft version of the Spanish CORS. Then, a field test with cognitive debriefing was conducted, involving a sample of 10 patients with axSpA. Results The translation process of the CORS was completed after the discussion of some discrepancies throughout the process. The first translation was done without major complications. Back-translation presented some discrepancies. These led to minor modifications in the wording in one response option and 15 questionnaire items. The scientific committee agreed upon a final version of the questionnaire. Cognitive debriefing, led to minor modifications; for example, three respondents indicated that one of the statements in the instructions was syntactically complex (“indique cuán a menudo usted ha llevado a cabo dicho comportamiento”) which led to its adjustment. The process indicated that the final CORS Spanish questionnaire was clear and understandable to all patients. Conclusions The Spanish version of the CORS showed good cross-cultural validity and good face validity according to the field test. Before the Spanish CORS is implemented, further validation is in progress to test the psychometric properties of the instrument in patients with axSpA.

We investigated B-cell-activating factor (BAFF) in relation to response to treatment with TNF inhibitors (TNFis) in rheumatoid arthritis (RA). This was a longitudinal study including 158 patients with RA treated with TNFis and followed up for 6 months. Clinical response at 6 months of treatment was defined according to the EULAR criteria for good responders (GRs). BAFF concentration was measured in serum samples, collected at baseline and at 6 months. Associations with EULAR response were evaluated using univariable and multivariable logistic regression models. ROC analysis was performed to determine the optimal threshold of serum BAFF concentration associated with good EULAR response to treatment. After 6 months of TNFi treatment, 24% of patients were GRs. They had a lower BMI, lower baseline DAS28 and lower baseline serum BAFF concentration than non-responders. After 6 months of TNFi treatment, autoantibody-positive patients who attained GR had significantly lower serum BAFF concentrations compared with patients who did not. Serum BAFF < 968 pg/mL at 6 months represented the concentration likely to best discriminate between GR and non-GR at 6 months of TNFi treatment. Autoantibody-seropositive patients who had serum BAFF < 968 pg/mL at 6 months demonstrated a more than four-fold increased probability to be GRs compared with patients with higher BAFF concentrations. In conclusion, serum BAFF concentrations were associated with response to TNFis in seropositive RA patients, corroborating the importance of the B-cell compartment in RA.

Background: The aim of our study is to evaluate whether serum infliximab trough levels (ITL) during the early stages of treatment are predictive of long-term clinical failure in patients with axial spondyloarthritis (axSpA).Methods: Longitudinal observational study involving 81 patients with axSpA recruited from the SpA-Paz cohort and monitored during infliximab therapy. Serum ITL were measured at baseline, week 2 (W2), W6 and W12 of treatment. Disease activity was assessed by the Ankylosing Spondylitis Disease Activity Score (ASDAS) at baseline, W24 and W54, and every 6 months thereafter until therapy failure. Non-clinically important improvement was defined by ΔASDASResults: Out of the 81 patients, 45 (56%) did not achieve clinical improvement at W52. These patients had lower serum ITL at W12 compared to those who improved: ITL [median (IQR)]: 4.1(0.9-8.3) µg/ml vs 7.1(4.3-11.3)µg/ml, respectively; p=0.007). A cut-off of ITLConclusions: Serum ITL

Immunogenicity related to treatment with TNF inhibitors (TNFi) is one of the causes for the decreased attainment of clinical response in patients with rheumatoid arthritis (RA). The B-cell activating factor (BAFF) may be playing a role in the development of immunogenicity. The objective of this study was to analyse the association of baseline concentration of serum B-cell activating factor (BAFF) with immunogenicity after 6 months of TNFi treatment. A total of 127 patients with RA starting a TNFi (infliximab, adalimumab, certolizumab pegol or golimumab) were followed-up for 6 months. Serum samples were obtained at baseline and at 6 months and anti-drug antibody (ADA) and BAFF concentrations were measured. Logistic regression models were employed in order to analyse the association between BAFF concentrations and immunogenicity. Receiver operating characteristic analysis was performed to determine the BAFF concentrations with a greater likelihood of showing immunogenicity association. At 6 months, 31 patients (24%) developed ADA. A significant interaction between the age and baseline BAFF concentration was found for the development of ADA (Wald chi-square value = 5.30; p = 0.02); therefore, subsequent results were stratified according to mean age (≤ / > 55 years). Baseline serum BAFF concentration was independently associated with ADA development only in patients over 55 years (OR = 1.51; 95% CI 1.03–2.21). Baseline serum BAFF ≥ 1034 pg/mL predicted the presence of ADA at 6 months (AUC = 0.81; 95% confidence interval (CI) 0.69–0.93; p = 0.001; positive likelihood ratio = 3.7). In conclusion, our results suggest that the association of BAFF concentration and immunogenicity depends on the patient’s age. Baseline serum BAFF concentration predicts the presence of ADA within 6 months of TNFi therapy in older patients with RA.

Background: Immunogenicity related to treatment with TNF inhibitors (TNFi) is one of the causes for the decreased attainment of clinical response in patients with rheumatoid arthritis (RA). The B-cell activating factor (BAFF) may be playing a role in the development of immunogenicity. The objective of this study was to analyse the association of baseline concentration of serum BAFF with immunogenicity after 6 months of TNFi treatment.Methods: A total of 139 patients with RA starting a TNFi (infliximab, adalimumab, certolizumab pegol or golimumab) were followed-up for 6 months. Serum samples were obtained at baseline and at 6 months and anti-drug antibody (ADA) and BAFF concentrations were measured. Logistic regression models were employed in order to analyse the association between BAFF concentrations and immunogenicity. Receiver operating characteristic analysis was performed to determine the BAFF concentrations with a greater likelihood of showing immunogenicity association.Results: At 6 months, 39 patients (28%) developed ADA. A significant interaction between the age and baseline BAFF concentration was found for the development of ADA (Wald chi-square value=5.30; p=0.02); therefore, subsequent results were stratified according to mean age (≤/>55 years). Baseline serum BAFF concentration was independently associated with ADA development only in patients over 55 years (OR=1.55; 95% CI: 1.03-2.12). Baseline serum BAFF≥1034pg/mL predicted the presence of ADA at 6 months (positive likelihood ratio=3.7).Conclusions: Our results suggest that the association of BAFF concentration and immunogenicity depends on the patient’s age. Baseline serum BAFF concentration predicts the presence of ADA within 6 months of TNFi therapy in older patients with RA.

Background: TNF inhibitors (TNFis) are widely used for the treatment of rheumatoid arthritis (RA), although the response rates to this therapy in patients with RA remains heterogeneous and < 50% achieve remission (REM).Objective: To analyze baseline peripheral blood leukocytes profiles in order to search for biomarkers identifying patients who will most likely not achieve REM under TNFi treatment.Methods: A prospective bi-center pilot study including 98 RA patients treated with TNFis and followed-up during 6 months. Patients were classified according to DAS28 as follows: those who achieved REM (DAS28 ≤ 2.6) and those who did not (DAS28 > 2.6) at 6 months after starting TNFis. These rates were also assessed by simplified disease activity index (SDAI ≤ 3.3 and SDAI > 3.3, respectively). Peripheral blood immune cells were studied by flow cytometry before treatment initiation.Results: At 6 months, 61 or 80% of patients did not achieve REM by DAS28 or SDAI, respectively. Basal leukocyte profiles differed between REM vs. non-REM patients. Non-REM patients showed lower percentages of total and naïve B cells at baseline than REM subjects. A B lymphocyte/CD4+ lymphocyte ratio (BL/CD4 ratio)

Biosimilars are replacing originator compounds due to their similar effectiveness, safety and pharmacokinetics. Our objective was to compare the differences in pharmacokinetics and clinical outcomes between the originator infliximab (Ifx) and the biosimilar CT-P13 in a patient cohort with inflammatory bowel disease (IBD). Our cohort study included 86 patients from a historical and a prospective cohort from the start of infliximab treatment to 22 weeks later. Serum infliximab, antidrug antibody levels and other serum biomarkers were measured at weeks 0, 2, 6, 14 and 22. Remission outcomes were evaluated at weeks 14 and 22. Drug levels were measured prospectively and analysed using MANOVA. Of the 86 patients, 44 (51%) and 42 (49%) were administered the originator and CT-P13, respectively. Originator trough levels were higher than the biosimilar trough levels (35 vs. 21, 20.1 vs. 11, 6.6 vs. 2.9 and 4.3 vs. 1.7 μg/mL at weeks 2, 6, 14 and 22, respectively). A post-hoc analysis demonstrated changes in mean serum drug levels over time (p

To investigate the effect of concomitant conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) with adalimumab or infliximab on maintaining serum drug and clinical outcomes after the first year of treatment in patients with rheumatoid arthritis (RA). Second, to assess the influence of methotrexate (MTX) dose on these outcomes. Ninety-two patients with RA starting infliximab (n = 67) or adalimumab (n = 25) tumor necrosis factor inhibitor (TNFi) with available drug levels and clinical improvement assessment (European League Against Rheumatism [EULAR] response) after 12 months were included. Patients were grouped according to concomitant csDMARD use: (i) TNFi monotherapy; (ii) TNFi+MTX; (iii) TNFi with csDMARDs other than MTX (TNFi+OD). Patients receiving MTX were also classified by dose as

This is the accepted version of the following article: "Rationale for Therapeutic Drug Monitoring of Biopharmaceuticals in Inflammatory Diseases", which has been published in final form at https://insights.ovid.com/crossref?an=00007691-201708000-00007; International audience; Biopharmaceuticals bring together a number of specific characteristics as compared with other drugs. However, as it is done for most drugs, an individual adjustment of their dose may be necessary. Similar to “chemical” drugs, biopharmaceuticals used in immunoinflammatory diseases have a rather narrow therapeutic range, lack good early clinical or biological marker of response, have variable pharmacokinetics, and their serum concentrations are most often related with response. Monoclonal antibodies have additional specific sources of pharmacokinetic variability. Low concentrations may increase the risks of immunization, plasmapheresis may increase their elimination, and subcutaneous formulations may be associated with decreased adherence. For all these reasons, pharmacokinetic therapeutic drug monitoring may be useful. However, few randomized controlled therapeutic drug monitoring studies have been published. For monoclonal antibodies, a precise definition of the therapeutic concentrations is challenging because of the interindividual variability in their concentration–effect relationship.

Objectives Controversy exists on the role of IgE antidrug antibodies (IgE-ADA) in infusion reactions (IR) on infliximab treatment, partly due to the lack of a positive control used for assay validation. We sought to (1) develop a robust assay to measure IgE-ADA, including a positive control, (2) determine the association between IgE-ADA and IR and (3) determine the incidence of IgE-ADA in infliximab treated patients. Methods A recombinant human IgE anti-infliximab monoclonal antibody was developed as standard and positive control. With this antibody, we set up a novel robust assay to measure IgE-ADA. IgE-ADA was determined in three retrospective cohorts (n=159) containing IR+ (n=37) and IR− (n=39), and longitudinal sera of 83 spondyloarthritis. Results IgE-ADA was found in 0/39 IR−, whereas 4/37 (11%) IR+ showed low levels (0.1–0.3 IU/mL, below the 0.35 IU/mL threshold associated with elevated risk of allergic symptoms). All patients who were IgE-ADA positive also had (very) high IgG-ADA levels. The incidence of IgE-ADA in patients with infliximab-treated spondyloarthritis was estimated at less than approximately 1%. Conclusions IgE-ADA is rarely detected in infliximab-treated patients. Moreover, the absence of IgE-ADA in the majority of IR+ patients suggests that IgE-ADA is not associated with infusion reactions.

To the Editor,While biological therapy has improved the efficacy of treatments for several inflammatory chronic diseases such as rheumatoid arthritis (RA), there remains a significant percentage of...

Background: The most common biological agents used as disease-modifying treatment in rheumatoid arthritis (RA) are TNF inhibitors (TNFi). Although these new strategies to treat RA have improved the course of the disease, approximately 30-50% of patients do not respond to this therapy. Early identification of optimal responders is crucial in the clinical setting. Objectives: The aim of this study was to investigate if baseline percentages of different leukocyte subsets in peripheral blood (PBMCs) can contribute to identify RA patients who will respond to TNFi. Methods: This was a prospective bi-center pilot study including 100 RA patients under TNFi therapy. Clinical activity was assessed at baseline and 6 months of treatment by disease activity score 28 (DAS28), considering optimal responders if they reached remission at 6 months (DAS28≤2.6). PBMCs were obtained before treatment and different leukocyte subsets were evaluated by flow cytometry (FACSCantoII instrument). The association between the percentage of PBMCs at baseline and clinical response at 6 months was evaluated through logistic regression models (odds ratio; 95% CI). All the analyses were adjusted by sex, age, disease duration, concomitant methotrexate, baseline DAS28 and seropositivity (ACPA and/or RF). Results: Demographic characteristics are shown in Table 1. After 6m of TNFi treatment, 40% of the patients achieved clinical remission. A significant association between higher percentage of total B cells (OR=1.19; 95%; CI:1.05-1.35; p=0.007) and naive B cells (Bn; OR=1,32; 95%; IC:1.08-1.61; p=0.007) at baseline and clinical response was found. The other PBMC subsets (monocytes, NK cells, CD4+ and CD8+ T cells subtypes) did not show statistical differences (Figure 1). Conclusion: Our results suggest that basal B cells profile may contribute to identify optimal responders to TNFi in RA. (Funding: ISCIII (PI16/01092, PI16/00474). Disclosure of Interests: Cristina Sobrino: None declared, Borja Hernandez-Breijo: None declared, Carlota Garcia-Hoz: None declared, Israel Nieto-Ganan: None declared, Victoria Navarro-Compan: None declared, ANA MARTINEZ-FEITO: None declared, Javier Bachiller-Corral: None declared, Gemma Bonilla: None declared, Paloma Lapuente-Suanzes: None declared, Cristina Pijoan Moratalla: None declared, DORA PASCUAL-SALCEDO Grant/research support from: Pfizer, Speakers bureau: Pfizer, Abbvie, Takeda, Alejandro Balsa Grant/research support from: Abbvie, Pfizer, Novartis, BMS, Nordic, Sanofi, Consultant for: Abbvie, Pfizer, Novartis, BMS, Nordic, Sanofi, Sandoz, Lilly, Paid instructor for: Pfizer, Speakers bureau: Pfizer, Novartis, UCB, Nordic, Sanofi, Sandoz, Lilly, Garbine Roy: None declared, Monica Vazquez: None declared, Luisa Maria Villar: None declared, Chamaida Plasencia Speakers bureau: Pfizer, MSD, Eulalia Rodriguez-Martin: None declared

Background: There is great interest in the identification of prognostic biomarkers informing early therapeutic decisions for the improvement of rheumatoid arthritis (RA) evolution. Promising results in early arthritis (EA) patients indicate the anti-carbamylated protein antibodies (ACarPA) may serve this function. In effect, they are associated with high baseline disease activity and, in our patients, with less improvement in the first 6-months of follow-up. This association was independent of sex, age at diagnosis, time since symptoms onset, smoking and the year of onset. However, the influence of the treatment has not been explored yet. Objectives: We aimed to explore the influence of the initial treatment on the persistent high disease activity associated with the presence of ACarPA in EA patients. Methods: Samples were obtained at the first visit of two EA cohorts from Hospital Universitario La Paz and Hospital Universitario La Princesa, which recruit patients within one year from the clinical onset. Information on the initial treatment and the disease activity at the baseline and at 6-months of follow-up was available from 546 patients. Treatment was categorized according to the use of corticosteroids, methotrexate (MTX) and other DMARDs, and considering changes in the first 6 months. In addition, MTX dose was considered either quantitatively or as a dichotomous variable (≥ 12.5 mg and Results: A large fraction (83%) of the EA patients received specific treatment from the initial visit. It comprised DMARD (50.1%), corticosteroids (10.6%), or a combination of both (39.3%). The most common DMARD was MTX (82.2%), whereas less frequently used medications included sulfasalazine (5.4%), leflunomide (3.2%), hydroxychloroquine (8.1%) and other (1.0%). The 35.5% of the treated patients maintained the treatment during the 6-month follow-up. The presence of ACarPA was associated with a 0.45 higher mean baseline DAS28 and with less decrease of DAS28 (ΔDAS28) from the baseline to 6 months of follow-up (β = 0.08, p = 0.016), as already communicated. This latter association persisted without modification after accounting for the initial treatment (DMARD, corticosteroids, and changes in treatment). In addition, it was independent of the consideration of all DMARDs in a single group, or separated into two categories: MTX and the other. Similarly, the association was independent on MTX dose, defined both as a categorical or a quantitative variable. Conclusion: The association of ACarPA with a persistently increased disease activity in EA patients is independent of the initial treatment. These results reinforce the possibility that ACarPA can be useful as prognostic biomarkers for the first 6 months of evolution and indicate the need for personalized management of the patients carrying ACarPA. Acknowledgement: Supported by grants PI17/01606 and RD16/0012/0014 of the Instituto de Salud Carlos III (Spain) that are partially financed by FEDER. Disclosure of Interests: Cristina Regueiro : None declared, Ana Ortiz: None declared, Laura Nuno: None declared, Diana Peiteado: None declared, Alejandro Villalva: None declared, Dora Pascual Salcedo: None declared, ANA MARTINEZ-FEITO: None declared, Alejandro Balsa Grant/research support from: Abbvie, Pfizer, Novartis, BMS, Nordic, Sanofi, Consultant for: Abbvie, Pfizer, Novartis, BMS, Nordic, Sanofi, Sandoz, Lilly, Paid instructor for: Pfizer, Speakers bureau: Pfizer, Novartis, UCB, Nordic, Sanofi, Sandoz, Lilly, Isidoro Gonzalez-Alvaro: None declared, Antonio Gonzalez: None declared

Background Infliximab (Ifx) has proven to be effective in patients with axial spondyloarthritis (axSpA). Several variables may affect pharmacokinetic-pharmacodynamic of Ifx and its relation with clinical response, such as: disease activity (inflammatory burden), the development of anti-drug antibodies (ADA) and the concomitant use of conventional synthetic disease modifying anti-rheumatic drugs The improvement of patient’s management by achieving optimal serum drug concentration associated with good clinical response is the main goal of therapeutic drug monitoring (which can be helpful in the prediction of clinical response to biological treatment. Objectives To identify clinical and serological variables at early stages of treatment that can predict clinical response in patients with axSpA treated with Ifx. Methods Observational study including 81 patients with axSpA recruited from the axSpA-Paz cohort treated with Ifx and monitored during 24 weeks (W). Serum Ifx levels and ADA were measured by capture ELISA and by bridging ELISA respectively at baseline, W2, W6, W14 and W24. Disease activity was assessed at baseline and W24 by the Ankylosing Spondylitis Disease Activity Score (ASDAS) and clinical response was defined by ΔASDAS≥1.1 (clinically important improvement). The association between clinical response at W24 and clinical and serological variables was evaluated by univariable and multivariable logistic regression analyses. Serum Ifx levels at W2, 6 and 14 as a categorical variable (above o under the corresponding median value of levels at each time week), age, sex, HLA-B27, methotrexate (MTX), sulfasalazine, body mass index, smoke status, prednisone, C-reactive protein and ASDAS at baseline were included as independent variables. Receiver operating characteristic (ROC) curves for the outcome of clinical response after 24 weeks of treatment were employed to determine the best cut-off values for the predictors (serum Ifx concentrations and baseline ASDAS). Ifx survival was evaluated through Kaplan-Meier curves. Results In the univariable analyses, higher serum Ifx trough levels at W14 (OR: 3.9; 95%CI: 1.5-10.4); higher baseline ASDAS (OR: 1.9; 95%CI: 1.1-3.1) and MTX use (OR: 3.3; 95%CI: 1.2-8.7) were associated with a better clinical response at W24. Patients with concomitant MTX had higher serum Ifx trough levels (median and IQR) than patients without MTX and these differences were significant at W6: 26.37(16-41.4) versus 16.9(11.4-26.9); p=0.008; at W14: 8.4(5.4-13.9) versus 4.1(1.8-7.8); p=0.003 and at W22: 5.1(2.2-8.3) versus 3.1(0.6-5.4); p=0.006 and; respectively). In the multivariable analysis, higher ASDAS at baseline (OR: 1.8; CI 95%: 1.1-3.0) and higher serum Ifx trough levels at W14 (OR: 3.6; CI 95%: 1.3-10.4) remained significantly associated. Serum Ifx concentration at W14 ≥ 6.7 μg/mL and a disease activity score at baseline ≥ 3.5 were found to be associated with higher ΔASDAS at W24 (OR: 16; 95%CI: 3.6-71.7). No patient with Ifx levels at W14 ≥ 6.7 μg/mL developed ADA during the 24 weeks follow up. The combination of both variables was used to predict clinical response with a sensitivity of 87.5%, specificity of 69.6%, PPV of 75% and NPV of 84.2%. Conclusion Elevated baseline ASDAS and high serum Ifx trough levels at W14 are associated with better clinical response at 24 weeks in patients with axSpA under Ifx therapy. A predictive model based on these variables is suggested to identify early responders to Ifx treatment. Disclosure of Interests ANA MARTiNEZ-FEITO: None declared, Chamaida Plasencia Speakers bureau: Pfizer, MSD, Borja Hernandez-Breijo: None declared, Victoria Navarro-Compan: None declared, Diana Peiteado: None declared, Alejandro Villalva: None declared, Laura Nuno: None declared, Irene Monjo: None declared, Cristina Diego: None declared, DORA PASCUAL-SALCEDO Grant/research support from: Pfizer, Speakers bureau: Pfizer, Abbvie, Takeda, Alejandro Balsa Grant/research support from: Abbvie, Pfizer, Novartis, BMS, Nordic, Sanofi, Consultant for: Abbvie, Pfizer, Novartis, BMS, Nordic, Sanofi, Sandoz, Lilly, Paid instructor for: Pfizer, Speakers bureau: Pfizer, Novartis, UCB, Nordic, Sanofi, Sandoz, Lilly

Background Rheumatoid arthritis (RA) is a chronic inflammatory disease with the typical characteristic of synovitis of small-sized and medium-sized joints that leads to cartilage and bone damage. TNF inhibitors (TNFi) are widely used for the treatment of rheumatoid arthritis (RA) however, there are still no objective indicators of clinical response to TNFi therapy. Objectives To analyse the change of peripheral blood mononuclear cells (PBMC) profile after 6 months (m) of treatment with TNFi in order to find cellular indicators of response. Methods Prospective bi-center pilot study including 100 RA patients receiving TNFi therapy. PBMC were isolated from patients at baseline and 6m of treatment, and were analysed by flow-cytometry. Clinical activity at baseline and 6m of TNFi treatment was assessed by DAS28. Clinical remission (DAS28≤2.6) after 6m of treatment was considered as optimal response. The association between clinical remission and the percentage of change (Δ, 6m-0m) within each PBMC subset was analysed through univariate logistic regression model (odds ratio; 95% CI; β; p-value). All the analyses were adjusted by sex, age, disease duration, concomitant-methotrexate, seropositivity (ACPA and/or Rheumatoid factor) and baseline-DAS28. Results Demographic characteristics before starting TNFi therapy are shown in Table 1. After 6m of TNFi treatment, 40% patients achieved clinical remission. Decreased percentage of B cells (ΔCD19+) was found after 6m of TNFi treatment in optimal responders, while suboptimal responders did not show differences with the baseline (OR: 0.78; 95% CI: 0.63-0.97; β: -0.25; p: 0.027) (Figure 1). This effect was essentially owing to a reduction of naive B cells (OR: 0.76; 95% IC: 0.62-0.94; β: -0.27; p: 0.011) (Figure 1). No significant association was found between the other PBMC subsets (monocytes, NK cells, CD4+ T cells and CD8+ T cells) and clinical remission (Figure 1). Conclusion Our results suggest that B cells may be useful as a cellular indicator of response to TNFi in RA patients. Acknowledgement ISCIII (PI16/00474; PI16/01092) Disclosure of Interests Borja Hernandez-Breijo: None declared, Israel Nieto-Ganan: None declared, Cristina Sobrino: None declared, Victoria Navarro-Compan: None declared, ANA MARTiNEZ-FEITO: None declared, Carlota Garcia-Hoz: None declared, Paloma Lapuente-Suanzes: None declared, Javier Bachiller-Corral: None declared, Gemma Bonilla: None declared, Cristina Pijoan Moratalla: None declared, Garbine Roy: None declared, Monica Vazquez: None declared, Alejandro Balsa Grant/research support from: Abbvie, Pfizer, Novartis, BMS, Nordic, Sanofi, Consultant for: Abbvie, Pfizer, Novartis, BMS, Nordic, Sanofi, Sandoz, Lilly, Paid instructor for: Pfizer, Speakers bureau: Pfizer, Novartis, UCB, Nordic, Sanofi, Sandoz, Lilly, Luisa Maria Villar: None declared, DORA PASCUAL-SALCEDO Grant/research support from: Pfizer, Speakers bureau: Pfizer, Abbvie, Takeda, Eulalia Rodriguez-Martin: None declared, Chamaida Plasencia Speakers bureau: Pfizer, MSD

Background The aim of our study was to investigate the influence of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) and body mass index (BMI) on circulating drug levels and clinical response to tumour necrosis factor inhibitor (TNFi) therapy in axial spondyloarthritis (axSpA) patients. Methods Prospective observational study during 1 year with 2 cohorts (Madrid and Amsterdam) including 180 axSpA patients treated with standard doses of infliximab or adalimumab. Patients were stratified by BMI, being 78 (43%) normal weight (18.5–24.9 kg/m2) and 102 (57%) overweight/obese (≥ 25.0 kg/m2). After the first year of treatment, TNFi trough levels were measured by capture ELISA. Clinical response to TNFi was defined as ∆BASDAI ≥ 2 and clinical remission as BASDAI

Research in rheumatoid arthritis (RA) is increasingly focused on the discovery of biomarkers that could enable personalized treatments. The genetic biomarkers associated with the response to TNF inhibitors (TNFi) are among the most studied. They include 12 SNPs exhibiting promising results in the three largest genome-wide association studies (GWAS). However, they still require further validation. With this aim, we assessed their association with response to TNFi in a replication study, and a meta-analysis summarizing all non-redundant data. The replication involved 755 patients with RA that were treated for the first time with a biologic drug, which was either infliximab (n = 397), etanercept (n = 155) or adalimumab (n = 203). Their DNA samples were successfully genotyped with a single-base extension multiplex method. Lamentably, none of the 12 SNPs was associated with response to the TNFi in the replication study (p > 0.05). However, a drug-stratified exploratory analysis revealed a significant association of the NUBPL rs2378945 SNP with a poor response to etanercept (B = -0.50, 95% CI = -0.82, -0.17, p = 0.003). In addition, the meta-analysis reinforced the previous association of three SNPs: rs2378945, rs12142623, and rs4651370. In contrast, five of the remaining SNPs were less associated than before, and the other four SNPs were no longer associated with the response to treatment. In summary, our results highlight the complexity of the pharmacogenetics of TNFi in RA showing that it could involve a drug-specific component and clarifying the status of the 12 GWAS-drawn SNPs., This work was supported by the Instituto de Salud Carlos III (ISCIII, Spain) through grants PI14/01651, PI17/01606 and RD16/0012/0014 to AG and PI12/01909 to JJG-R. These grants are partially financed by the European Regional Development Fund of the EU (FEDER). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Background: The patients with RA benefit from early identification soon after the first clinical symptoms appear. The 2010 ACR/EULAR classification criteria were developed to fulfill this need and their application has been demonstrated to be effective. However, there is still room for improvement. Therefore, we aimed to evaluate the potential of the concordant presence of RF, anti-CCP and anti-carbamylated protein antibodies to improve current RA classification among early arthritis (EA) patients. Methods: Data from the first visit of 1057 patients in two EA prospective cohorts were used. The serological scores from the 2010 ACR/EULAR criteria and the concordant presence of the three RA autoantibodies were assessed relative to a gold standard consisting of the RA classification with the 1987 ACR criteria at the 2 years of follow-up. Results: The concordant presence of three antibodies showed predictive characteristics allowing for direct classification as RA (positive predictive value = 96.1% and OR = 80.9). They were significantly better than the corresponding to the high antibody titers defined as in the 2010 classification criteria (PPV = 88.8%, OR = 26.1). In addition, the concordant presence of two antibodies was also very informative (PPV = 82.3%, OR = 15.1). These results allowed devising a scoring system based only on antibody concordance that displayed similar overall performance as the serological scoring system of the 2010 criteria. However, the best classification was obtained combining the concordance and 2010 serological systems, a combination with a significant contribution from each of the two systems. Discussion: The concordant presence of RA autoantibodies showed an independent contribution to the classification of EA patients that permitted increased discrimination and precision., This work was supported by the Instituto de Salud Carlos III (Spain) through grants [PI17/01606 and RD16/0012/0014 to AG; RD16/0012/0011 to IG-A and RD16/0012/0012 to AB]. These grants are partially financed by the European Regional Development Fund of the EU (FEDER). CR was supported by Ministerio de Educacion Cultura y Deporte (Spain) through a FPU pre-doctoral fellowship [FPU15/03434]. LR-M was supported by a Xunta de Galicia predoctoral contract.

Background:Infliximab (Ifx) has proven effective in treating rheumatoid arthritis (RA) and spondyloarthropathies (SpA), although around 40% of cases fails, mainly due to immunogenicity. Formation of immunocomplexes between antibodies to Ifx (ATI) and Ifx can increase drug clearance, leading to treatment failure. Standard ELISA assays which are drug -sensitive are frequently used, being able to detect only free ATI. Interest in drug-tolerant assays to measure total ATI (free and complexed) is increasing.Objectives:To compare the development of ATI using both drug-tolerant and drug-sensitive assays at early stages of Ifx therapy. To analyse the relationship of ATI detected by both assays with the drop-out of treatment.Methods:This is a prospective observational study including 45 patients with RA and 61 with axial-SpA treated with standard doses of Ifx (3mg/kg and 5mg/kg, respectively) enrolled at Biological Therapy Unit of Hospital La Paz. Serum samples were obtained at 2, 6, 12 and 22 weeks (W) after Ifx initiation. The data about discontinuation for inefficacy was obtained from the database. ATI presence was evaluated by a drug-sensitive in-house two-site (bridging) ELISA (bELISA) and a drug-tolerant commercial ELISA assay (Immundiagnostik®,IDK). All comparisons were performed throughout non-parametrical test. In SpA group, due to the low number of ATI+ patients at W12 by bELISA the statistical analysis to compare both assays were not performed.Results:ATI detection by both assays at early stages (≤22 W) of treatment is shown in Table 1a. ATI were always detected earlier by IDK than bELISA and also in RA than in SpA patients probably reflecting the effect of lower Ifx doses. Three out of 106 (3%) vs 0 (0%) patients had ATI at W 2 and 62 (58%) vs 20 (18%) patients at W22, by IDK and bELISA, respectively.Table 1.Patient characteristics of all included patientsW2W6W12W22ARSpAARSpAARSpAARSpAa) ATI+ patients (n, %) at early stagesbELISA003(7%)010(22%)1(2%)13(29%)7(12%)IDK1(2%)2(3%)7(16%)2(3%)16(36%)16(26%)28(62%)34(56%)b) Patients who discontinued (n, %) Ifx therapy considering ATI status at early stagesbELISA+9(90%)*1(100%)*12(92%)4(57%)bELISA-23(66%) 22(37%)20(63%)19(35%)IDK+15(94%)*7(44%)24(86%)13(38%)IDK-17(59%)11(24%)13(77%)10(27%)*pOnce ATIs appeared, regardless both methods, they persisted throughout the follow-up, indicating that immunogenicity was not transient.At W22, only 13/28 (46%) and 7/34 (21%) patients with ATI detected by IDK were also positive by bELISA in RA and SpA, respectively.ATI levels by IDK were higher in ATI+ by bELISA than in ATI- patients at early stages: ATI levels by IDK at W12: 91[74-348] ng/ml ATI+ vs 21.7[15-59.5] ng/ml ATI- (pFree IFX in serum was not detected in bELISA ATI+ patients. In IDK ATI+ patients low circulating Ifx levels were present as compare to ATI- since W6 to the end of follow-up (pMore ATI+ patients dropped out Ifx at W12 and W22 regardless de assay (Table 1.b), being statistically significant for both assays in patients with RA and only for bELISA in patients with SpA.Conclusion:ATI measured by a drug-tolerant assay are always detected earlier than ATI detected by bELISA, indicating that immunogenicity, at least with Ifx, is usually an early event. High levels of ATI by IDK are associated with an earlier detection by bELISA in case of RA patients. ATI detected only by drug tolerant assays are associated with low levels of circulating Ifx but not with a complete drug neutralization and may do not have clinical relevance compared to ATI detected by bELISA. Many patients have low levels of ATI which can only be detected by drug tolerant assays after long-term of follow-up.The reasons why ATI levels rise rapidly in some patients while in others remain low are currently unknown but may be relevant if the clinical effect of immunogenicity is to be minimized.Acknowledgements:We are grateful to all the rheumatologists and nurses of the Daycare Department for Biologics and to the laboratory technicians of the Immunological UnitDisclosure of Interests:ANA MARTÍNEZ-FEITO: None declared, Borja Hernández-Breijo: None declared, Marta Novella-Navarro: None declared, Victoria Navarro-Compán Grant/research support from: AbbVie, Janssen, Lilly, Novartis, Pfizer, and UCB, Cristina Diego: None declared, Irene Monjo: None declared, Laura Nuño: None declared, Alejandro Villalva: None declared, Diana Peiteado: None declared, DORA PASCUAL-SALCEDO: None declared, Pilar Nozal: None declared, Alejandro Balsa Grant/research support from: Abbvie, Pfizer, Novartis, Roche.Amgen, Sandoz, Lilly, UCB. Personal fees and non- financial support from BMS. Grants, personal fees and non- financial support from Nordic., Chamaida Plasencia Grant/research support from: AbbVie, Lilly, Novartis, Pfizer,Sanofi, Biogen and UCB.

Background:In clinical practice no more than 50% of the patients treated with TNF inhibitors (TNFi) achieve remission (REM). Previous investigations suggested that peripheral blood mononuclear cells (PBMC) may be markers associated with the TNFi treatment success1.Objectives:This study aims to analyse the intracellular cytokine production by PBMC and its association with REM achievement after 6 months (m) of TNFi treatment in patients with RA.Methods:This was a prospective study including 62 patients with RA starting the 1st TNFi. PBMC were isolated from patients at baseline and after 6m of treatment with TNFi and cryopreserved until studied. In vitro stimulation and intracellular cytokine production by PBMC was performed as follow: in the presence of 2µg/mL brefeldin and 2µmol/L monensin monocytes were stimulated with 20ng/mL LPS during 4h whereas lymphocytes were stimulated with 50ng/mL phorbol 12-myristate 13-acetate and 750ng/mL ionomycin for 4h at 37°C. To identify IL10-producing B cells, PBMC were pre-incubated with 3µg/mL of CpG oligonucleotide during 20h at 37°C prior to stimulation. Intracellular cytokine production (TNFα, IL6, GM-CSF, IL10) by the different cell subsets (monocytes, CD4+ and CD8+ T cells, naïve and memory B cells) was analysed by flow-cytometry. Clinical activity at baseline and after 6m was assessed by DAS28-ESR. REM was defined as DAS28≤2.6 at 6m. The association between cytokine production by each PBMC subset and REM was analysed through univariable and multivariable logistic regression models. Receiving operating curve (ROC) analysis was used to select the optimal ratio of cytokine production associated with REM status.Results:After 6m of TNFi treatment, 30 (48%) patients achieved REM. No significant differences between REM and non-REM groups were observed for patients’ characteristics at baseline except for DAS28, which was lower in the REM group (non-REM: 5.4±0.9; REM: 4.3±0.9; p+ T cells (IL10 B/TNF CD4) at 6m was found for non-REM patients (non-REM: 0.31 vs REM: 0.54; p=0.007). Based on a ROC analysis, we found that a (IL10 B/TNF CD4)Table 1.Baseline predictors of reduction of disease activity at 12 months from start of abatacept. Linear regression.Baseline patients’ characteristicsTotal patients (n=62)DAS28>2.6(n=32; 52%)DAS28≤2.6(n=30; 48%)p-valueAge (years)53±1253±1352±100.8Female55 (89)30 (94)25 (83)0.2Disease duration (years)8 (4-11)8 (4-12)7 (3-11)0.7RF positive49 (79)23 (72)26 (87)0.1ACPA positive54 (87)26 (81)28 (93)0.2Smoking habit (n=55)0.2Non-smokers26 (47)16 (55)10 (38) Smoker29 (53)13 (45)16 (51)Body mass index (kg/m2)25.9±5.625.8±5.726.0±5.60.9DAS284.9±1.05.4±0.94.3±0.9Concomitant csDMARDs60 (97)32 (100)28 (93)0.3MTX [±OD]46 (74)26 (81)20 (67)0.3Only OD14 (23)6 (19)8 (26)0.3Prednisone36 (58)19 (59)17 (57)0.9Conclusion:Our results show that the proinflammatory IL10 B/TNF CD4 ratio is associated with non-REM status. It could be useful to analyse the success of TNFi treatment in patients with RA.References:[1]Rodríguez-Martín E, et al. Front Immunol. 2020; 11: 1913.Acknowledgements:ISCIII (PI16/00474; PI16/01092)Disclosure of Interests:Borja Hernández-Breijo: None declared, Eulalia Rodríguez-Martín: None declared, Carlota García-Hoz: None declared, Victoria Navarro-Compán Speakers bureau: Abbvie, Janssen, Lilly, MSD, Novartis, Pfizer and UCB, Grant/research support from: Abbvie, Janssen, Lilly, MSD, Novartis, Pfizer and UCB, Cristina Sobrino: None declared, ANA MARTÍNEZ-FEITO: None declared, Israel Nieto-Gañán: None declared, Javier Bachiller-Corral Speakers bureau: Abbvie, MSD, BMS and Roche, Grant/research support from: Pfizer, Paloma Lapuente-Suanzes: None declared, Gemma Bonilla: None declared, Cristina Pijoán-Moratalla: None declared, Mónica Vázquez: None declared, Alejandro Balsa Speakers bureau: Abbvie, BMS, Nordic, Novartis, Pfizer, Sandoz, Sanofi, Roche and UCB, DORA PASCUAL-SALCEDO: None declared, Luisa María Villar: None declared, Chamaida Plasencia Speakers bureau: AbbVie, Lilly, Novartis, Pfizer, Sanofi, Biogen and UCB

Background:According to the EULAR recommendations, the therapeutic target in patients with RA should be remission (REM). However, no more than 50% of the patients treated with TNF inhibitors (TNFi) attains this outcome. Previous investigations suggested the peripheral blood mononuclear cells (PBMC) as markers associated with the TNFi treatment success1,2. Granulocyte-monocyte colony-stimulating factor (GM-CSF) plays a relevant role in the pathogenesis of rheumatoid arthritis (RA) because it promotes the macrophage differentiation, survival and activation3.Objectives:To analyse the intracellular cytokine production by PBMC and its association with REM attainment after 6 months (m) of TNFi treatment in patients with RA.Methods:This was a prospective bi-center pilot study including 36 patients with RA. PBMC were isolated from patients at baseline and after 6m of treatment with TNFi and cryopreserved until studied. Intracellular cytokine production by PBMC was stimulated in the presence of 2µg/mL brefeldin as follow: monocytes were stimulated with 20ng/mL LPS during 4h; and simultaneously lymphocytes were stimulated with 50ng/mL phorbol 12-myristate 13-acetate (PMA) and 750ng/mL ionomycin during 4h at 37°C. To identify IL-10-producing B cells, PBMC were pre-incubated with 3µg/mL of CpG oligonucleotide during 20h at 37°C prior to stimulation in presence of 2µmol/L monensin. Intracellular cytokine production (TNFα, IL6, GM-CSF, IL10) by the different cell subsets (monocytes, CD4+and CD8+T cells, naïve and memory B cells) was analysed by flow-cytometry. Clinical activity at baseline and after 6m was assessed by DAS28. REM was defined as DAS28≤2.6 at 6m. The association between REM and the change in cytokine production (Δ, 6m-0m) by each PBMC subset was analysed through univariable and multivariable logistic regression models.Results:Seventy-eight percent of the patients were female. After 6m of TNFi treatment, 47% patients attained REM. Univariable analyses was performed to investigate the association between REM and the baseline variables. Male sex (OR: 12.6; 95% CI: 1.35-117.57; p=0.03) and having lower baseline DAS28 (OR: 0.4; 95% CI: 0.19-0.85; p=0.02) were independently associated with attaining REM after 6m of TNFi. In the multivariable analysis, only being male (OR: 19.7; 95% CI: 1.4-273.9; p=0.03) remained independently associated with REM after 6m of treatment. Therefore, further analyses were adjusted by sex. Decreased production of GM-CSF by CD4+T cells percentage was found after 6m of TNFi treatment in REM patients (0m: 6.07%; 6m: 3.87%; p=0.007) while no-REM patients did not show differences with the baseline (0m: 3.70%; 6m: 3.75%; p=0.9). The decrease was significantly associated with attaining REM (OR: 0.56; 95% CI: 0.33-0.95; p: 0.03). No significant association was found between any other analysed intracellular cytokine produced by the different PBMC subsets and REM.Conclusion:GM-CSF intracellular production by CD4+T cells was significantly decreased by TNFi treatment only in patients who attained REM. Therefore, our results suggest that GM-CSF production by CD4+T cells may be a useful marker of REM to TNFi in RA.References:[1] Sobrino C, et al. Ann Rheum Dis. 2019; 78 (S2): A1665.[2] Hernández-Breijo B, et al. Ann Rheum Dis. 2019; 78 (S2): A711.[3] Avci AB, et al. Clin Exp Rheumatol. 2016; 34 (S98), 39-44.Figure. 1:Association between the change in intracellular cytokine production (Δ, 6m-0m) by each PBMC subset and REM. Adjusted logistic regression analyses were performed for each cytokine.Acknowledgments:ISCIII (PI16/00474; PI16/01092)Disclosure of Interests:Borja Hernández-Breijo: None declared, Chamaida Plasencia: None declared, Carlota García-Hoz: None declared, Cristina Sobrino: None declared, Victoria Navarro-Compán Consultant of: Abbvie, Lilly, Novartis, Pfizer, UCB, Speakers bureau: AbbVie, MSD, Lilly, Novartis, Pfizer, UCB, ANA MARTÍNEZ-FEITO: None declared, Israel Nieto-Gañán: None declared, Paloma Lapuente-Suanzes: None declared, Javier Bachiller-Corral: None declared, Gemma Bonilla: None declared, Cristina Pijoan Moratalla: None declared, Garbiñe Roy: None declared, Mónica Vázquez Díaz: None declared, Alejandro Balsa Grant/research support from: BMS, Roche, Consultant of: AbbVie, Gilead, Lilly, Pfizer, UCB, Sanofi, Sandoz, Speakers bureau: AbbVie, Lilly, Sanofi, Novartis, Pfizer, UCB, Roche, Nordic, Sandoz, Luisa María Villar: None declared, DORA PASCUAL-SALCEDO Grant/research support from: Pfizer, Novartis & Progenika, Speakers bureau: Pfizer, Merck, Novartis, Takeda, Menarini & Grifols, Eulalia Rodríguez-Martín: None declared

[Objective]: Recognition of a new type of rheumatoid arthritis (RA)-specific autoantibody, the anti-carbamylated protein antibodies (anti-CarP), has provided an opportunity to improve the management and understanding of RA. The current study was undertaken to assess the relationship between anti-CarP antibodies and HLA-DRB1 alleles in RA. [Methods]: Serum samples were obtained from 3 different collections, comprising a total of 1,126 RA patients. Serum reactivity against in vitro carbamylated fetal calf serum proteins was determined by enzyme-linked immunosorbent assay. HLA-DRB1 alleles were determined using either hybridization techniques or imputation from HLA-dense genotypes. Results of these analyses were combined in a meta-analysis with data from 3 previously reported cohorts. The carrier frequencies of the common HLA-DRB1 alleles were compared between the antibody-positive RA subgroups and the double-negative subgroup of RA patients stratified by anti-citrullinated protein antibody (ACPA)/anti-CarP antibody status, and also between the 4 RA patient strata and healthy controls. [Results]: Meta-analysis was conducted with 3,709 RA patients and 2,305 healthy control subjects. Results revealed a significant increase in frequency of HLA-DRB1*03 carriers in the ACPA-/anti-CarP+ subgroup as compared to ACPA-/anti-CarP- RA patients and healthy controls; this was consistently found across the 6 sample collections. This association of HLA-DRB1*03 with ACPA-/anti-CarP+ RA was independent of the presence of the shared allele (SE) and any other confounders analyzed. No other allele was specifically associated with the ACPA-/anti-CarP+ RA patient subgroup. In contrast, frequency of the SE was significantly increased in the ACPA+/anti-CarP- and ACPA+/anti-CarP+ RA patient subgroups, without a significant distinction between them. Furthermore, some alleles (including HLA-DRB1*03) were associated with protection from ACPA+ RA. [Conclusion]: These findings indicate a specific association of HLA-DRB1*03 with ACPA-/anti-CarP+ RA, suggesting that preferential presentation of carbamylated peptides could be a new mechanism underlying the contribution of HLA alleles to RA susceptibility., Supported by the Instituto de Salud Carlos III and FEDER (grant RD16/0012/0012 to Dr. Balsa, grants PI14/00442 and RD16/0012/0011 to Dr. Gonzalez-Alvaro, and grants RD16/0012/0014 and PI17/01606 to Dr. Gonzalez). Ms Regueiro's work was supported by the Ministerio de Educacion Cultura y Deporte (FPU pre-doctoral fellowship FPU15/03434)

Background Several factors influence on the pharmacokinetics(PK) of TNF inhibitors(TNFi). One of the most relevant influencing factors is the development of antidrug- antibodies(ADA), which is associated with low circulating drug levels and loss of clinical efficacy. Previous studies, mostly about Adalimumab (Ada), have demonstrated a beneficial effect of concomitant use of methotrexate(MTX) in patients(pts) under TNFi therapy by reduction of immunogenicity. There are other csDMARDs(OD) as leflunomide, hydroxycloroquine or sulfasalazine which may have also an effect on PK. Objectives To investigate the effect of csDMARDs on the presence of serum TNFi levels and on the clinical response during the first year of Ada or Infliximab(Ifx) treatment in RA pts. Secondly, to evaluate if MTX has a dose-dependent effect on these outcomes. Methods This is an inception cohort including pts with RA starting Ifx or Ada in a tertiary hospital since 1999. At baseline, 6 and 12 months clinical(DAS28, EULAR response and ΔDAS28) and serological(drug and ADA levels) parameters were measured. Patients were clustered according to the use of concomitant csDMARDs at baseline in three groups: i)TNFi monotherapy;ii)TNFi +MTX;iii)TNFi +OD. Pts within the TNFi +MTX group were also classified according to the MTX dose:MTX Results A total of 92 RA pts[Ada(n=25) or Ifx(n=67)] under TNFi were included. The number and percentage of pts in each group were as follows:TNFi monotherapy,12 pts(13%);TNFi +MTX, 59 pts(64%);TNFi +OD 21 pts(23%). According to MTX dose, the distribution was:TNFi +MTX Conclusions In RA pts under Ifx or Ada treatment, the presence of TNFi in serum, the clinical response and the TNFi survival are influenced by MTX but not by OD. Moreover, a MTX dose-dependent effect is closely associated with these outcomes. Disclosure of Interest None declared

Background There is evidence of the correlation between serum levels of calprotectin MRP8/14 and disease activity in Juvenile Idiopathic Arthritis (JIA), but the same correlation with other rheumatic diseases in children such as autoinflammatory diseases has not been studied as much. Objectives To analyse calprotectin MRP8/14 in serum of patients with juvenile idiopathic arthritis (JIA) and various autoinflammatory diseases with different degrees of activity. To check if there is a correlation between serum MRP8/14 and disease activity. Methods Study in two phases: 1) Initial, transversal, in JIA and/or autoinflammatory disease patients, determining serum MRP8/14 (by ELISA test) and collecting clinical data: number of active joints, Visual Analogue Scale parents/patients (VASp), VAS physician (VASph); and analytical: C-Reactive Protein (CPR) and white cells blood count (WBC) (among others). 2) Second prospective phase, repeating the same analysis 3–6 months later. Disease activity was assessed by Juvenile Arthritis Disease Activity Score (JADAS) in AIJ; and by VASp, VASph and CRP in autoinflammatory diseases. Results The sample included 90 patients (25 males) between the ages of 1 and 21 years (median 11.1); 61 diagnosed with JIA (excluding systemic category), and 29 with different autoinflammatory diseases (including systemic JIA). 69 patients (20 males, with median age 11.2, 48 AIJ, 21 autoinflammatory) participated in the prospective phase. The main results are shown in table 1. MRP=myeloid related proteins. JADAS=Juvenile arthritis disease activity score. ACJ=active joints count. VASm=visual analogue scale–physician. VASp=visual analogue scale-parents/patient. CRP=C reactive Protein. Conclusions In patients with non-systemic JIA, a positive correlation was found between serum MRP8/14 and JADAS, VASph, VASp, CRP, WBC, neutrophilia and (inversely) haemoglobin. In autoinflammatory diseases positive correlation has been found with VASm, CRP, leukocytosis, neutrophilia, thrombocytosis and (inversely) haemoglobin. MRP8/14 seems to behave as a marker of activity in both JIA and autoinflammatory diseases, although with a stronger association in the latter. Disclosure of Interest None declared

Background In patients with axial spondyloarthritis (axSpA), the use of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), such as methotrexate (MTX) and sulfasalazine (SSZ), as well as the body mass index (BMI) have been associated with circulating TNFi levels. Recently, BMI has also been associated with TNFi clinical response but csDMARDs have not shown any significant clinical improvement for axial manifestations1. However, no study has assessed in the same population the influence of both factors -csDMARDs and BMI- on drug serum levels and clinical response Objectives To investigate the influence of csDMARD and BMI on circulating drug levels and clinical response to TNFi therapy in axSpA patients Methods A 1 year follow-up prospective observational study with two cohorts (Madrid and Amsterdam) including 180 axSpA patients treated with standard doses of infliximab (41%) or adalimumab (59%). Laboratory and clinical parameters were collected every 6 months. Patients were stratified by BMI: normal-weight (18.5–24.9 kg/m2) and overweight-obesity (>25.0 kg/m2). TNFi trough levels were measured by capture ELISA2. Clinical response to TNFi was defined as ▵BASDAI ≥2. The association between concomitant csDMARDs and BMI with drug levels and clinical response to TNFi at 1 year was analysed through multivariate log-regression models (odds ratio and 95% CI). The presence of significant interactions between covariates was tested and all models were adjusted for age, gender, HLA-B27, disease duration, TNFi-type (for drug levels) and baseline BASDAI and CRP (for clinical response) Results Seventy-nine out of 180 patients (44%) received concomitant csDMARDs (MTX 14%, SSZ 20% and MTX +SSZ 10%), 78 (43%) patients were normal-weight and 102 (57%) overweight-obese. Mean (SD) age and disease duration was 47(13) and 11(9) years respectively, 59% were males, 73% HLA-B27 +and 78% had r-axSpA. Concomitant csDMARDs (OR: 3.82; IC 95%: 1.06–13.84) and being overweight-obese (OR: 18.38; IC 95%: 2.24–150.63) were independently associated with serum TNFi drug presence. Furthermore, a significant interaction between csDMARDs and BMI with clinical response was found. While the use of concomitant csDMARD contributed positively to achieve clinical response in overweight-obese patients (OR: 7.86; IC 95%: 2.39–25.78), no association was found for normal-weight patients (OR: 1.10; 0.33–3.58). Additionally, sensitivity analysis using remission status and ASDAS were performed and showed results along the same line Conclusions In patients with axSpA, TNFi drug persistence is positively influenced by the use of concomitant csDMARDs and especially by being normal-weight. However, TNFi clinical response is associated with the use of concomitant csDMARDs only in overweight-obese, but not in normal-weight patients. Based on this, the use of concomitant csDMARDs in patients with axSpA could be beneficial in overweight patients References [1] van der Heijde D, et al. Ann Rheum Dis. 2017;76(6):978–991. [2] Pascual- Salcedo D, et al. Rheumatology (Oxford). 2011;50(8):1445–52. Disclosure of Interest None declared

Background Calprotectin (CLP) is an important proinflammatory factor of innate immunity released from activated granulocytes and macrophages during inflammation, which has also been identified in synovial fluid. It is a potential pro-inflammatory biomarker reflecting joint damage. CLP levels in synovial fluid are well correlated with levels in plasma, which allows measuring it easily in patients with rheumatoid arthritis (RA). However, the additional value of CLP over other biomarkers is unclear Objectives To study the association of baseline CLP serum levels with the clinical response and serum drug levels in patients under biological therapy at 6 and 12 months after starting treatment. Methods Prospective observational study including 109 patients with RA who started biological treatment (Infliximab(Ifx);Adalimumab(Ada);Etanercept(Etn);Certolizumab(Ctz);Golimumab(Glm); Tocilizumab(Tcz) and Rituximab(Rtx) in a tertiary hospital since 1999 to 2016. Serum CLP levels were measured by ELISA with the commercial kit CALPROLAB (Lysaker, Norway). Levels of biological drug and ADA were measured by capture and bridging ELISA respectively, except Certolizumab which was measured by Sanquin Diagnostic Service. Clinical response was assessed by ΔDAS28. Serological and clinical parameters were evaluated at baseline, 6 and 12 months. For analysis, linear regression models adjusted for confounders (age, sex, BMI, DMARDs, smoking status) and with standardised beta as estimate were employed. Results Out of 109 studied patients, 22% patients received Ifx, 6% Ada, 16% Etn, 18% Ctz, 5% Glm, 25% Tcz and 9% Rtx. Most patients were woman (84%), with a median (IQR) age of 62 (52.3–73.1) and disease duration of 9.5 (4.8–15.3). At baseline, CLP levels directly correlated well with CRP and DAS28(r=0.411;p Conclusions In patients with RA initiating biological therapy, baseline CLP concentrations are inversely correlated with the circulating drug levels along the treatment. However, the additional value of CLP as a predictor of clinical response remains unclear. Acknowledgements This work has been supported by a SORCOM grant at 2016 Disclosure of Interest None declared

Background It has become increasingly clear that appropriate initial management of rheumatoid arthritis (RA) increases the chances of success and improves long-term prognosis. Therefore, rheumatologists need prognostic biomarkers to select patients requiring aggressive management. It is possible that anti-carbamylated protein antibodies (anti-CarPA) may serve as such biomarkers because they are associated with erosions and their progression, and with mortality in some studies. Recently, the possibility that they are also associated with disease activity in early arthritis (EA) has been examined by several studies with discordant results. Objectives We aimed to explore the relationship between variation in disease activity and anti-CarPA in EA patients. Methods EA patients from two prospective clinics, Hospital Universitario La Paz (n=492) and Hospital Universitario La Princesa (n=501), were included. DAS28 was available at baseline and at months 6 (M6), 12 (M12) and 24 (M24) of follow-up. Anti-CarPA were determined in baseline serum samples by ELISA using in vitro carbamylated fetal calf serum. Student t test and main effects general linear regression were used for analysis. Results The 27.4% of EA patients that were positive for anti-CarPA showed higher DAS28 at baseline than the negative patients (4.93 vs 4.31, p=1.6x10– 8 ). The difference persisted at all visits during follow-up (3.60 vs 3.19 at M6; 3.47 vs 3.09 at M12; and 3.31 vs 2.79 at M24; all with p≤0.001). These differences were independent of patient sex and age, smoking, time since symptoms onset, the specific EA clinic and the year of onset. In addition, they persisted after accounting for the presence of RF or ACPA at baseline (p=1.3x10– 5 , and p=5.7x10– 5 , respectively) and at later visits (p Conclusions Anti-CarPA were associated with high disease activity at presentation and with less improvement in the first 6 months of follow-up in EA patients. These results reinforce the possibility that anti-CarPA could be useful in the clinic as prognostic biomarkers. Acknowledgements Supported by grants PI14/01651 and RD16/0012/0014,/0011,/0012 of the Instituto de Salud Carlos III (Spain) that are partially financed by the ERDF Disclosure of Interest None declared

Background Rituximab (Rtx), a monoclonal antibody against CD20+, induces transient depletion of B cells and was approved for the treatment of patients with active rheumatoid arthritis (RA). Previous data1 showed that Rtx is particularly effective on autoimmune diseases in which auto-antibodies (auto-Ab) are produced. Based on this, it is hypothesised that auto-Ab produced by short-lived plasma cells expressing CD20 are targets of Rtx. Given this scenario, the immunogenicity related to the use of Infliximab (Ifx) or Adalimumab (Ada) could be cleared by Rtx. Objectives First, to analyse the persistence of anti-drug antibodies (ADA) after switching to either a 2nd biological therapy (TNFi or Rtx) after 12 months of follow-up. Second, to evaluate whether the reduction of ADA levels are influenced by the mechanism of action of the second biological therapy (BT). Methods Dataset from a prospective cohort including all patients with RA starting BT at the Unit of Complex Therapy in a tertiary hospital was used. For this study, data from 21 patients who had experienced previous failure to Ifx (57%) or Ada (43%) related to ADA detection and then switched to a 2nd TNFi (Ifx, Ada, Etanercept or Certolizumab) or to Rtx was analysed. Additionally, patients should have both determinations of ADA levels: at the end of the first BT and 12 months after switching. ADA were determined by a bridging ELISA. The proportion of patients with ADA positive levels at 12 months was determined. Also, the relative reduction (in median) of ADA levels between patients switching to a 2nd TNFi vs Rtx in both visits was compared. Results Out of 21 ADA positive patients with RA, 15 (71%) switched to a 2nd TNFi and 6 (29%) to Rtx. Demographic characteristics of patients are shown in table 1. ADA remained positive in 80% of patients at 12 months after switching BT. The percentage of patients with undetectable ADA levels at 12 months was higher in the group of patients treated with Rtx compared with patients receiving a 2nd TNFi (33% vs 13%, respectively). The median ADA levels (AU/ml) values at baseline and at 12 months were 536 and 123 for Rtx and 3625 and 1842 for TNFi. The relative reduction of median ADA levels between baseline and 12 months visits was higher in patients with Rtx than in patients treated with TNFi (−78% vs −50%, respectively). Conclusions Despite discontinuing TNFi, ADA titters remain positive in a high proportion of patients with RA after one year. Over time, ADA levels decrease in patients who switch to a second BT, being this effect more pronounced in patients receiving Rtx than a 2nd TNFi. This effect could be explained by the intrinsic action mechanism of Rtx on plasmatic CD20 +cells. Reference [1] Huang H, et al. Rituximab specifically depletes short-lived autoreactive plasma cells in a mouse model of inflammatory arthritis. PNAS2010Mar 9;107(10):4658–63. Disclosure of Interest None declared