D. Peiteado

The immunogenicity to the first anti-TNF therapy determines the outcome of switching to a second anti-TNF therapy in spondyloarthritis patients

IntroductionAnti-TNF drugs have proven to be effective against spondyloarthritis (SpA), although 30% of patients fail to respond or experience adverse events leading to treatment discontinuation. In rheumatoid arthritis, the presence of anti-drug antibodies (ADA) against the first TNF inhibitor influences the outcome after switching. Our aim was to assess whether the response to a second anti-TNF drug is related to the previous development of ADA to the first anti-TNF drug SpA patients.MethodsForty-two SpA patients began a second anti-TNF drug after failing to respond to the first anti-TNF therapy. Clinical activity was assessed by the Ankylosing Spondylitis Disease Activity Score (ASDAS) at baseline (at the beginning of the first and second anti-TNF therapy) and at 6 months after switching. The drug and ADA levels were measured by ELISA before each administration.ResultsAll patients were treated with anti-TNF drugs and mainly due to inefficacy were switched to a second anti-TNF drug. Eleven of 42 (26.2%) developed ADA during the first biologic treatment. At baseline, no differences in ASDAS were found in patients with or without ADA to the first anti-TNF drug (3.52 ± 1.03 without ADA vs. 3.14 ± 0.95 with ADA, p = 0.399) and to the second anti-TNF drug (3.36 ± 0.94 without ADA vs. 3.09 ± 0.91 with ADA, p = 0.466). At 6 months after switching, patients with previous ADA had lower disease activity (1.62 ± 0.93 with ADA vs. 2.79 ± 1.01 without ADA, p = 0.002) and most patients without ADA had high disease activity state by the ASDAS (25 out of 31 (80.6%) without ADA vs. 3 out of 11 (27.3%) with ADA, p = 0.002).ConclusionsIn SpA the failure to respond to the first anti-TNF drug due to the presence of ADA predicts a better clinical response to a second anti-TNF drug.

Comparing Tapering Strategy to Standard Dosing Regimen of Tumor Necrosis Factor Inhibitors in Patients with Spondyloarthritis in Low Disease Activity

Objective. To compare clinical outcomes, incidence of flares, and administered drug reduction between patients with spondyloarthritis (SpA) under TNF inhibitor (TNFi) tapering strategy with patients receiving a standard regimen. Methods. In this retrospective study, 74 patients with SpA from Spain on tapering strategy (tapering group; TG) were compared with 43 patients from the Netherlands receiving a standard regimen (control group; CG). The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was measured at visit 0 (prior to starting the TNFi), visit 1 (prior to starting tapering strategy in TG and at least 6 months with BASDAI < 4 after starting the TNFi in the TG and CG), visit 2 (6 mos after visit 1), visit 3 (1 year after visit 1), and visit 4 (the last visit available after visit 1). Results. An overall reduction of the administered drug was seen at visit 4 in the TG [dose reduction of 22% for infliximab (IFX) and an interval elongation of 28.7% for IFX, 45.2% for adalimumab, and 51.5% for etanercept] without significant differences in the BASDAI between the groups at visit 4 (2.15 ± 1.55 in TG vs 2.11 ± 1.31 in CG, p = 0.883). The number of patients with flares was similar in both groups [22/74 (30%) in the TG vs 8/43 (19%) in the CG, p = 0.184]. Conclusion. The tapering strategy in SpA results in an important reduction of the drug administered, and the disease control remains similar to that of the patients with SpA receiving the standard regimen.

Decreased Th17 and Th1 cells in the peripheral blood of patients with early non-radiographic axial spondyloarthritis: a marker of disease activity in HLA-B27+ patients

OBJECTIVE To examine the frequency and phenotype of Th17 cells in the peripheral blood of patients with early non-radiographic axial SpA (early nrSpA). METHODS CD4(+) T cells were isolated from the peripheral blood of 30 early nrSpA patients, 11 AS patients and 41 age- and sex-matched healthy controls by Ficoll-Hypaque gradient and magnetic negative selection. After polyclonal stimulation, the frequency of Th17 and Th1 cells and of cells producing TNF-α or IL-10 was determined by cytometry and concentrations of IL-17, IL-22, IFN-γ, TNF-α, IL-10 and IL-4 were measured by ELISA. RESULTS Early nrSpA but not AS patients demonstrated a significantly lower percentage of circulating Th17, Th1 and Th17/Th1 cells, together with lower CD4-derived IL-17 and IFN-γ secretion, as compared with controls. In contrast, the percentage of circulating cells producing IL-10 or TNF-α, and the secretion of CD4-derived IL-10, TNF-α, IL-22 and IL-4 in early nrSpA were not different from controls. All Th17 cells were CD45RO(+)CD45RA(-) and CCR6(+). The frequency of circulating Th17, Th1 and Th17/Th1 was negatively correlated with BASDAI, BASFI, ASDAS-CRP, ASDAS-ESR, AS quality of life (ASQOL) and patients global assessment in HLA-B27(+) but not in HLA-B27(-) early nrSpA patients. A positive correlation between circulating Th17 cells and BASDAI was observed in AS. CONCLUSION A decreased percentage of Th17, Th1 and Th17/Th1 cells is apparent in peripheral blood CD4(+) T cells from early nrSpA. Th17, Th1 and Th17/Th1 cell numbers are related to disease activity indices in HLA-B27(+), but not in HLA-B27(-), early nrSpA patients.

Can we use enthesis ultrasound as an outcome measure of disease activity in spondyloarthritis? A study at the Achilles level

OBJECTIVE The aim of this study was to evaluate the construct validity of enthesis US in the assessment of disease activity in SpA. METHODS A longitudinal Achilles enthesis US study in patients with early SpA was undertaken. Achilles US examinations were performed at baseline, 6 and 12 months and compared with clinical outcome measures collected at the baseline visit. RESULTS Bilateral Achilles enthesis of 146 early SpA patients (68 women) were analysed. Basal mean BASFI, BASRI-spine, BASDAI and Ankylosing Spondylitis Disease Activity Score (ASDAS) were 2.44 (s.d. 2.05, range 0-8), 0.67 (s.d. 0.74, range 0-3), 4.60 (s.d. 2.07, range 0-9.5) and 2.51 (s.d. 1.16, range 0-5), respectively. The mean ESR was 15.0 mm/h (s.d. 16.99, range 0-109) and the mean CRP was 8.67 mg/l (s.d. 16.98, range 1-90). At baseline, the Achilles Doppler signal and US structure alteration were significantly associated with higher CRP and ESR levels. Patients who had very high disease activity at baseline, as assessed by the ASDAS (>3.5), had a significantly higher Achilles total US score at baseline (P = 0.04), and ASDAS <1.3 predicted no Doppler signal at 6 and 12 months. Overall, the Achilles total US score was significantly higher in patients with higher levels of CRP (baseline P = 0.04, 6 months P = 0.006, 12 months P = 0.03) and ESR (baseline P = 0.02, 6 months P = 0.04, 12 months P = 0.005) at baseline. The Doppler signal at the baseline visit predicted a higher total US score at 6 and 12 months. CONCLUSION Doppler US has significant associations with other commonly accepted disease activity measures, such as ESR, CRP and ASDAS, and seems to be an objective outcome measure for enthesitis.

Decreased frequencies of circulating follicular helper T cell counterparts and plasmablasts in ankylosing spondylitis patients Naïve for TNF blockers.

Follicular helper T cells (Tfh), localized in lymphoid organs, promote B cell differentiation and function. Circulating CD4 T cells expressing CXCR5, ICOS and/or PD-1 are counterparts of Tfh. Three subpopulations of circulating CD4+CXCR5+ cells have been described: CXCR3+CCR6- (Tfh-Th1), CXCR3-CCR6+ (Tfh-Th17), and CXCR3-CCR6- (Tfh-Th2). Only Tfh-Th17 and Tfh-Th2 function as B cell helpers. Our objective was to study the frequencies of circulating Tfh (cTfh), cTfh subsets and plasmablasts (CD19+CD20-CD27+CD38high cells), and the function of cTfh cells, in patients with Ankylosing Spondylitis (AS). To this end, peripheral blood was drawn from healthy controls (HC) (n = 50), AS patients naïve for TNF blockers (AS/nb) (n = 25) and AS patients treated with TNF blockers (AS/b) (n = 25). The frequencies of cTfh and plasmablasts were determined by flow cytometry. Cocultures of magnetically sorted CD4+CXCR5+ T cells with autologous CD19+CD27- naïve B cells were established from 3 AS/nb patients and 3 HC, and concentrations of IgG, A and M were measured in supernatants. We obseved that AS/nb but not AS/b patients, demonstrated decreased frequencies of circulating CD4+CXCR5+ICOS+PD-1+ cells and plasmablasts, together with a decreased (Tfh-Th17+Tfh-Th2)/Tfh-Th1 ratio. The amounts of IgG and IgA produced in cocultures of CD4+CXCR5+ T cells with CD19+CD27- B cells of AS/nb patients were significantly lower than observed in cocultures established from HC. In summary, AS/nb but not AS/b patients, demonstrate a decreased frequency of cTfh and plasmablasts, and an underrepresentation of cTfh subsets bearing a B helper phenotype. In addition, peripheral blood CD4+CXCR5+ T cells of AS/nb patients showed a decreased capacity to help B cells ex vivo.

AB0573 The immunogenicity of biological therapies correlates with clinical efficacy in psoriatic arthritis (psa) in long-term treatment with infliximab and adalimumab.

Background In psoriatic arthritis (PsA) with peripheral involvement classical DMARDs refractory, the anti-TNF therapy has proven to be effective. In recent years, there are some publications that demostrate the correlation between clinical activity and the anti-drug antibodies (ADA) development in rheumatic diseases such as rheumatoid arthritis (RA) and spondyloarthritis (SpA). To date, there is no studies that reveals theses findings in PsA patients treated with infliximab (Ifx) and adalimumab (Ada). Objectives To evaluate in PsA patients treated with Ifx and Ada wether the development of ADA correlate with clinical activity and biological treatment discontinuation. Methods We studied 37 patients with PsA treated with Ifx and Ada from La Paz University Hospital. Clinical activity was assessed using the Disease Activity Score 28 (DAS28), clinical improvement by the delta-DAS28 and treatment response by EULAR criteria at baseline, at 6 months, at 1 year and at > 2nd years of treatment. Ifx and Ada were administred at standard therapeutic schedule. Serum drug and ADA levels were measured by ELISA. Statistical analysis was performed using SPSS 11.0. Results Of the total of patients, 24/37 (64.9%) were treated with Ifx and 13/37 (35.1%) with Ada, being female 23 (62.1%). The mean age was 55.1 ± 12.3 years and the mean disease duration was 14.4 ± 9.9 years. The average time on biological therapy was 4.4 ± 3.2 years. Most patients received concomitantly classical DMARDs [29/37 (78.3%) with DMARDs vs 8/37 (21.7%) in monotherapy]. At baseline, clinical activity (DAS28) was higher in patients who subsequently not developed ADA (5.1 ± 0.9 without ADA vs 13.4 ± 0.6 with ADA, p = 0.021). Clinical activity (DAS28) tended to be higher in patients with ADA at all studied time points (5.4 ± 1.2 with ADA vs 2.8 ± 1.3 without ADA at 6 months, p = 0.007; 4.0 ± 1.2 with ADA vs 3.0 ± 1.3 without ADA at 1 year, p = 0.144; 2.9 ± 1.3 with ADA vs 2.4 ± 0.4 without ADA a> 2nd year, p = 0.169). Clinical improvement (delta-DAS28) was lower in patients with ADA throughout the study (-1.0 ± 1.6 with ADA vs 2.0 ± 1.4 without ADA at 6 months, p = 0.006, 0.3 ± 1.8 with ADA vs 2.1 ± 1.5 without ADA at 1 year, p = 0.052; 0.9 ± 1.5 with ADA vs 2.7 ± 0.8 without ADA a> 2nd year, p = 0.007). Patients without ADA were classified as responders more frequently based on criteria EULAR [2/5 (40%) with ADA vs. 27/30 (90%) without ADA, p = 0.006]. The median time to drug discontinuation was lower in patients with ADA (4.83 ± 1.6 years with ADA vs 7.93 ± 1.4 years without ADA, p = 0.061). The dose increase was more frequent in patients with ADA [3/6 (50%) with ADA vs 4/31 (12.9%) without ADA, p = 0.053], and in contrast, in patients without ADA was more often performed dose decrease of anti-TNF therapy [0/6 (0%) with ADA vs 15/31 (48.3%) without ADA, p = 0.053]. Conclusions The development of ADA correlates with poorer clinical response and more frequent treatment discontinuation in PsA patients in long-term treatment with Ifx and Ada. Disclosure of Interest None Declared

Value of Measuring Anti-Carbamylated Protein Antibodies for Classification on Early Arthritis Patients

Classification of patients with rheumatoid arthritis (RA) as quickly as possible improves their prognosis. This reason motivates specially dedicated early arthritis (EA) clinics. Here, we have used 1062 EA patients with two years of follow-up to explore the value of anti-carbamylated protein (anti-CarP) antibodies, a new type of RA specific autoantibodies, for classification. Specifically, we aimed to determine whether the addition of anti-CarP antibodies to IgM rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies, which are helpful in RA classification, improves it or not. Our analysis showed that incorporation of the anti-CarP antibodies to combinations of the other two antibodies (all joint by the OR Boolean operator) produces a modest increase in sensitivity (2.2% higher), at the cost of decreased specificity (8.1% lower). The cost-benefit ratio was more favorable in the patients lacking the other autoantibodies. However, it did not improve by considering different titer levels of the anti-CarP antibodies, or after exhaustively exploring other antibody combinations. Therefore, the place in RA classification of these antibodies is questionable in the context of current treatments and biomarkers. This conclusion does not exclude their potential value for stratifying patients in joint damage, disease activity, disability, or mortality categories.

SAT0331 Effect of Methotrexate on the Immnunogenicity of TNF Inhibitors in Spondyloartrhitis Patients

Background The spondyloarthritis (SpA) patients treated under TNF inhibitors (TNFi) with detectable antidrug antibodies (ADA) often develop loss of efficacy. Concomitant therapy with methotrexate (MTX) appears to reduce the the immunogenicity of biological drugs. Objectives To analyze if the use of combined therapy with MTX and TNFi can reduce the incidence of ADA and whether its effect is MTX dose dependent in SpA patients. Methods In this retrospective observational study, 162 SpA patients (including ankylosing spondylitis, Psoriatic SpA, SpA associated with inflammatory bowel disease and undifferentiated SpA) were included. The patients are treated with infliximab (Ifx) or adalimumab (Ada). The presence of ADA were measured at baseline and before each administration by ELISA to complete a follow up of 3 years. The patients were divided in two groups [MTX-15 (dose <15 mg/week) and MTX+15 (≥15 mg/week)] to study the influence of baseline MTX dose on immunogenicity. The statistical analysis was performed using SPSS 11.0. Results Eighty nine out of 162 (54,9%) patients were male. Eighty five out of 162 (52,5%) patients received Ifx and 77 out of 162 (47,5%) Ada. The mean duration of treatment was 13.38±9.19 years to Ifx and 12.71±10.46 years for Ada. Forty five patients received MTX weekly at baseline [25/85 (29.4%)in Ifx and 20/77 (26%)in Ada]. The mean dose of MTX was 15,9±4.76 mg/week. Twenty nine out of 162 (17,9%) patients developed ADA, and ADA presence was significantly higher in SpA patients on Ifx therapy [21/85 (24.7%) in Ifx vs 8/77 (10.4%) in Ada, p=0.018)]. The presence of ADA was less frequent in SpA patients taking MTX [3/162 (1.8%) with MTX vs 26/162 (16%) without MTX, p=0.021]. No statistically differences were observed in the influence of baseline MTX dose on the ADA appearance (in Ifx: 2/18 (11,1%) in MTX+15 vs 1/9 (11,1%)in MTX-15, p=1,0; in Ada: 1/17 (5,9%) in MTX+15 vs 0/4 (0,0%)in MTX-15, p=1,0). Conclusions In this cohort of SpA patients treated with Ifx and Ada, the use of MTX has a preventive effect on the ADA development. However, the baseline MTX dose is not a determinant factor to get this effect. Further prospective studies are needed to confirm these data. Disclosure of Interest A. Villalba Yllan: None declared, C. Plasencia Grant/research support: Pfizer, D. Pascual-Salcedo Grant/research support: Pfizer, Speakers bureau: Pfizer, D. Peiteado: None declared, L. Nuño: None declared, G. Bonilla: None declared, R. del Moral: None declared, A. Balsa Grant/research support: Pfizer, Speakers bureau: Pfizer, Roche, Abbvie, E. Martin Mola Speakers bureau: Pfizer, Roche, Abbvie, Amgen DOI 10.1136/annrheumdis-2014-eular.5819

Increased frequency of circulating CD19+CD24hiCD38hi B cells with regulatory capacity in patients with Ankylosing spondylitis (AS) naïve for biological agents

Our objective was to study the frequency of circulating CD19+CD24hiCD38hi B cells (Breg) in AS patients. To this end, peripheral blood was drawn from AS patients naïve for TNF blockers (AS/nb) (n = 42) and healthy controls (HC) (n = 42). Six patients donated blood for a second time, 6 months after initiating treatment with anti-TNFα drugs. After isolation by Ficoll-Hypaque, PBMCs were stained with antibodies to CD3, CD4, CD19, CD24, and CD38, and examined by cytometry. For functional studies, total CD19+ B cells were isolated from PBMCs of 3 HC by magnetical sorting. Breg-depleted CD19+ B cells were obtained after CD19+CD24hiCD38hi B cells were removed from total CD19+ cells by cytometry. Total CD19+ B cells or Breg-depleted CD19+ B cells were established in culture and stimulated through their BCR. Secretion of IFNγ was determined by ELISA in culture supernatants. When compared with HC, AS/nb patients demonstrated a significantly increased frequency of Breg cells, which was independent of disease activity. Anti-TNFα drugs induced a significant reduction of circulating Breg numbers, which were no longer elevated after six months of treatment. Functional in vitro studies showed that the secretion of IFNγ was significantly higher in Breg-depleted as compared with total CD19+ B cells, indicating that Breg can downmodulate B cell pro-inflammatory cytokine secretion. In summary, an increased frequency of circulating CD19+CD24hiCD38hi B cells is observed in AS/nb patients, that is not related with disease activity; anti-TNFα drugs are able to downmodulate circulating Breg numbers in AS.

OP0253 The Early Infliximab Levels Monitoring Can Predict the Developement of Anti-Drug Antibodies in a Cohort of Rheumatoid Arthritis Patients Treated with Infliximab

Background There is strong evidence that correlates the antibodies to infliximab appearance (ATI) with a poor clinical response, but for now sparse literature has demonstrated the predictive value of early serum infliximab (Ifx) levels monitoring with the ADA development Objectives To analize if serum Ifx levels at weeks 2, 6 and 14 can predict the ADA appearance at 6 months and 1 year in rheumatoid arthritis (RA) patients.and to define a predictive cutt-off Methods In this restrospective observational study, 83 RA patients (pts) under Ifx therapy were included. All patients fulfilled the 1987 ACR criteria to be included. The clinical activity was measured by DAS28. The drug and ATI levels were measured at baseline and before each infusion by capture and bridging ELISA, respectively. The data about ATI status were available in 44 patients at 6 months and 42 patients at 1 year. In the statistical study was used receiver-operator characteristics (ROC) analysis to obtain a representative cut-off value for Ifx levels between ATIpositive(+) and negative(−) patients at 6 months and 1 year Results Seventy four out of 83 RA patients were female and most of patients had positive rheumatoid factor (62/83, 74.7%) and ACPA (70/83, 84.3%).The mean of the disease duration was 15.46±8.96 years and the time on biological therapy 5.42±3.49 years. At baseline, all patients had active disease measured by DAS28 (5.49±1.35). Fourteen out of 44 (31.8%)patients were ATI+ at 6 months and 12 out of 42 (28.6%) at 1 year. The area under the curve to predict presence of ATI at 6 months was 0.790 (95%CI 0.624-0.957,p=0.002) at week 2, 0.885 (95%CI 0.766-1.000,p=0.001)at week 6 and 0.966 (95%CI 0.913-1.000,p=0.0001) at week 14. For the predictive value of ATI development at 1 year, the area under the curve was 0.773 (95%CI 0.604-0.942,p=0.002)at week 2, 0.853 (95%CI 0.725-0.982,p=0.001) at week 6 and 0.951 (95%CI 0.877-1.000,p=0.001) at week 14. The cut off of Ifx levels to predict ATI appearance at 6 months and 1 year are shown in Table Cutt off Sensitivity Specificity LR+ ATI status at 6 months  Ifx levels at week 2 26931 ng/ml 59% 88% 5.03  Ifx levels at week 6 9984 ng/ml 70% 94% 11.90  Ifx levels at week 14 392 ng/ml 93% 94% 15.86 ATI status at 1 year  Ifx levels at week 2 26931 ng/ml 57% 86% 4.00  Ifx levels at week 6 9984 ng/ml 68% 90% 7.15  Ifx levels at week 14 890 ng/ml 86% 95% 18.13 Conclusions The early Ifx levels monitoring has a high value to discriminate what RA patients on Ifx therapy will develop ATI during the treatment. These findings can help to know what patients are more likely to develop a secondary inefficacy associated to immunogenicity Disclosure of Interest P.-R. Chamaida Grant/research support: Pfizer, D. Pascual-Salcedo Grant/research support: Pfizer, Speakers bureau: Pfizer, M. Bonilla: None declared, A. Villalba: None declared, M. Lόpez-Casla: None declared, D. Peiteado: None declared, S. García-Carazo: None declared, S. Ramiro: None declared, K. Franco: None declared, D. Cajigas: None declared, E. Martín-Mola Speakers bureau: Pfizer, Roche, Abbvie, UCB, A. Balsa Grant/research support: Pfizer, Speakers bureau: Pfizer, Roche, Abbvie DOI 10.1136/annrheumdis-2014-eular.3237