T. Jurado

Antibodies to infliximab in Remicade-treated rheumatic patients show identical reactivity towards biosimilars

Objectives The aim of this study was to determine whether antibodies to infliximab (IFX) in Remicade-treated patients cross-react with the biosimilar CT-P13. Methods 250 consecutive patients with rheumatic diseases under Remicade and 77 controls were retrospectively selected for the study. Anti-IFX antibodies at drug through levels were measured in parallel with three different bridging ELISA assays: Promonitor-ANTI-IFX kit, which uses Remicade to detect antibodies, and two more assays that use either Inflectra or Remsima with the same format. Correlation and association between each assay was studied. Results 50.4% of patients were tested positive with Promonitor-ANTI-IFX. All were antibodies to IFX (ATI)-positive when either Inflectra or Remsima assays were used. In all comparisons positive and negative percentage agreements were 100%, and correlation coefficients were ≥0.995. No differences between rheumatoid arthritis and spondyloarthritis, or between concomitant immunosuppressives, were observed. Conclusions Anti-IFX antibodies of Remicade-treated patients cross-react with either Inflectra or Remsima. Although additional epitopes may be present in the biosimilar, results suggest that epitopes influencing the immune response to IFX are also present in the biosimilar. Antibody-positive patients treated with Remicade should not be switched to the biosimilar, since antibodies will interact with the new drug and potentially lead to loss of response. This finding supports the utility for therapeutic drug monitoring before a switching strategy is considered.

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.

Infusion reactions during infliximab treatment are not associated with IgE anti-infliximab antibodies

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.

Dose-Tapering Of TNF Inhibitors in Daily Rheumatology Practice Enables the Maintenance of Clinical Efficacy While Improving Cost-Effectiveness

Background The fact that biologics consume a growing portion of health care budget has resulted in an increased attention towards therapy optimization. One of the potential ways to optimize treatment is the down-titration of the administered drug dose. Objective To assess whether the clinical activity remains stable after dose tapering of TNF inhibitors in patients with low disease activity and to evaluate the potential benefit of this strategy on the treatment costs. Method A cohort of 77 patients with low disease activity treated with TNF inhibitors (TNFi) was monitored. The patients were studied over two time periods: in the 1st period with the drug standard dose, and in the 2nd period with a reduced dose. Clinical efficacy was monitored by DAS28 in rheumatoid arthritis (RA) and by BASDAI in spondyloarthritis (SpA). Serum drug and anti-drug antibody levels were measured by ELISA. The amount of drug dispensed per patient in both periods was compared. Results In the 2nd period, although patients received a lower amount of TNF inhibitor, no differences in clinical activity were observed (DAS28 in RA patients: 2.37 ± 0.50 in the 2nd P vs 2.28 ± 0.47 in the 1st P, p=0.20; BASDAI in SpA patients: 1.90 ± 0.93 in the 2nd P vs 1.88 ± 0.95 in the 1st P, p=0.910) and circulating serum trough drug levels were lower (Infliximab: 3.2 ± 2.5 μg/ml in the 1st P vs 1.8 ± 1.5 μg/ml in the 2nd P, p<0.0001; Adalimumab: 5.5 ± 2.8 μg/ml in the 1st P vs 3.1 ± 2.1 μg/ml in the 2nd P, p<0.0001; Etanercept: 1.8 ± 1.1 μg/ml in the 1st P vs 1.3 ± 0.8 μg/ml in the 2nd P p<0.05). The amount of administered drug per patient was reduced in an average of 20% per year. Conclusion Dose tapering can be successfully performed in patients with low disease activity, resulting in remarkable savings in the amount of drug used and in the associated costs.

AB0657 Discontinuation of Anti-TNF Therapy in Patients with Axial Spondyloarthritis in Clinical Practice: Prevalence and Causes

Background The majority of patients with axial spondyloarthritis (SpA) response to anti-TNF therapy. However, discontinuation of this therapy due to different reasons is still a relevant problem. Currently, there is not enough data to know exactly which is the prevalence and causes of interruption of anti-TNF therapies in clinical practice. Objectives First, to evaluate the frequency and causes of discontinuating adalimumab or infliximab as the first anti-TNF in patients with axial SpA in clinical practice. Second, to investigate the influence of anti-drug antibodies (ADA) on these causes. Methods A total of 326 patients with axial SpA who had received adalimumab (34%) or infliximab (66%) as a first anti-TNF therapy were included in this retrospective, observational study performed in a tertiary hospital. Disease activity (BASDAI, ASDAS, CRP and ESR) was measured before starting anti-TNF therapy, after 6 months and when interrupting the therapy to assess properly whether the reason for discontinuation was primary or secondary failure. Serum drug levels and/or ADA were measured at 6 months visit and at the end of anti-TNF treatment. Results A total of 99 (30.4%) patients discontinued treatment. Mean (SD) under anti-TNF therapy until discontinuation was 2.5 (2.9) years. Characteristics of these patients when initiating anti-TNF therapy are shown in Table 1. The reason to interrupt treatment was: primary failure in 22.2%, secondary failure in 36.4%, side effects 32.3%), and other reasons in 9.1%. Serum drug levels and ADA were available in 83 patients. In most patients with ADA positive (14/17), the reason for discontinuation was secondary failure. Out of those patients who discontinued due to secondary failure, 38.9% had ADA positive. Conclusions In our cohort of patients with axial SpA treated with adalimumab/infliximab, 30% of patients discontinued anti-TNF therapy. The main reason to discontinue treatment was secondary failure, which was related to the presence of ADA in almost 40% of patients. Disclosure of Interest E. Moral Grant/research support from: Funded by an unrestricted medical grant from Pfizer, C. Plasencia: None declared, V. Navarro-Compán: None declared, D. Pascual Salcedo: None declared, T. Jurado: None declared, C. Tornero: None declared, A. Pierens: None declared, M. B. Paredes: None declared, P. Bogas: None declared, I. Monjo: None declared, E. Martin Mola: None declared, A. Balsa: None declared

FRI0167 Low Levels of Infliximab at Early Stages Predict The Loss of Drug Levels and The Clinical Response at One Year of Treatment in Patients with Rheumatoid Arthritis

Background The anti-TNF monoclonal antibody Infliximab (Ifx), has proven effective in treating rheumatoid arthritis (RA), although in 40% of cases may fail, mainly due to immunogenicity. A good clinical response is usually associated with high serum drug levels; however, it is not clear why some patients have a faster drug clearance since the beginning of the therapy. Formation of immunocomplexes between antibodies to Ifx (ATI) and Ifx can increase drug clearance, leading to treatment failure. Objectives To analyze whether serum Infliximab trough levels (ITL) at the induction phase were related to Ifx disappearance and clinical outcomes at week (w) 54. The early development of immunogenicity as a related factor with low ITL was also investigated. Methods In this observational retrospective study ITL were measured from 66 RA patients from the prospective biological cohort of La Paz Hospital. Serum samples were taken at w2, w6, w14 and w22. Serum-dependent receiver operating characteristics (ROC) curves were used to establish the ITL value that better predicts the absence of Ifx at w54. ATI were measured by bridging ELISA and by an acid-dissociation method without drug interference IDK (Immundiagnostik®, Germany). Patients were grouped as ITLpos if they had detectable Ifx at w54 and ITLneg otherwise. Results ITLneg patients (n=25) had significantly lower levels at all time points than ITLpos (n=41). Based on ROC values ITL at w6 (4.44 μg/ml) had the best predictive value for disappearence of Ifx at w54 with a 70% sensitivity (95%CI 45.7–88.1), 95% specificity (95%CI 83.1–99.4) and positive likehood ratio of 14. Most patients in low disease activity or remission at w54 had at w6 ITL upper the predictive cut-off [20/44 (45%) upper cut-off vs 3/20 (15%) under cut-off p=0.02] and most EULAR responder at w54 had ITL upper the predictive cut-off at w6 [33/43 (77%) vs 10/21 (48%); p=0.08]. Treatment survival of patients with ITL upper 6w cut-off was longer: 5 years (1.6–5.0) vs 1.7 years (0.2–0.6); p=0.012. In the multiple logistic regression analysis, after adjusting for confounders (age, sex, body mass index, baseline DAS28, PCR, TNF and IL6) with ITL at w2 and at w6, the absence of Ifx levels at w54 was significantly associated with ITL under the cut-off at w2 (OR: 15.85; 95%IC 2.95–85.03; p=0.01), at w6 (OR: 86.64; 95%IC 6.58–1139.99; p=0.001) and no MTX use (OR: 12.26; 95%IC 1.83–82.22; p=0.001 for w2; OR: 6.9; 95%IC 1.04–45.84; p=0.04 for w6) Most patients with ITL under the cut-off at w6 were positive for ATI along the first year [15/20 (75%) under cut-off vs 5/44 (11%) upper cut-off, p<0.0001]. Most ATI were detected earlier by the IDK than with bridging. Conclusions Low ITL at early stages (w2 and w6) are associated with the Ifx absence, the early drop-out of the treatment and the clinical outcome at w54, being the presence of ATI the main reason for the low early circulating drug levels. We also conclude that the cut-off value at w6 (4.44 μg/ml) provides the clinicians with a useful prognostic tool of treatment efficacy. Acknowledgement This work is partially funded by a non restricted grant from Pzifer and from Leti laboratories. Disclosure of Interest None declared

FRI0168 Effect of Methotrexate in The Presence of Drug and The Appearance of Antibodies against TNF Inhibitors in Patients with Rheumatoid Arthritis

Background Several factors influence pharmacokinetics of TNFinhibitors (TNFi). One relevant factor is the formation of anti drug- antibodies (ADA) associated with low drug levels and a worse clinical response. Recent publications in rheumatoid arthritis (RA) 1,2 have demonstrated a beneficial effect of concomitant use of anti-TNF drugs and methotrexate (MTX), with a dose-dependent effect. Objectives To analyze the MTX influence on the presence of drug and appearance of ADA in a cohort of RA patients treated with Infliximab (Ifx), Adalimumab (Ada) or Etanercept (Etn) with a long follow-up (3 years). Methods This is a retrospective study that analyzed patients with RA treated with Ifx (112 patients), Ada (71 patients) and Etn (110 patients), in a prospective observational biological cohort from the University Hospital La Paz, Madrid, Spain. Patients were grouped according to the use of MTX: no MTX, low dose (≤12.5 mg/week), intermediate dose (12.5–20 mg/week) and high dose (≥20 mg/week). Levels of drug and ADA were measured by capture and bridging ELISA respectively at baseline, 0.5, 1, 2 and 3 years. All samples were obtained just before drug administration. Statistical analysis was performed using GraphPad Prism 5.0 software. Results Out of 293 RA patients with a TNFi treatment; 184 (71 with Ifx, 40 with Ada and 73 with Etn) were included. In this cohort, 111 (61%) were on MTX and 72 (39%) were on monotherapy. Most patients with high dose of MTX had levels of drug over 3 years of treatment (93% with MTX ≥20 mg/week vs 77% without MTX; p=0.01) being significant since 0.5 years (≥60% with MTX 20 mg/week vs 39% without MTX; p=0.02) To analyze the ADA development, patients treated with Ifx and Ada were grouped and we observed a trend to a higher percentage of ADA in the group which did not receive MTX (n=37) compared to those who received high-dose MTX (n=27) although not statistically significant (32% vs 19%, p=0.21). Analysing by separate drugs MTX significantly reduced the immunogenicity of Ada, (53% in patients with MTX vs 15% in monotherapy; p=0.02). When we study the lack of circulating drug (Ifx, Ada and Etn) as an indicator of immunogenicity, patients who did not receive MTX (n=56) had higher absence of drug than patients with high-dose MTX (n=61) (34% vs 10%, respectively; p<0.01). This effect was significant since 0.5 years of treatment (16% MTX ≥20 mg/week vs 3% without MTX; p=0.017) Conclusions In our cohort of RA patients the concomitant use of MTX has a positive effect in the persistence of TNFi levels together with a decrease of immunogenicity. Furthermore, the MTX has a dose-dependent effect being greater at high dose of MTX. References Krickaert C et al.ARD 2012; 71:11. Vogelzang E H et al.ARD 2015; 74:2 Acknowledgement This work is partially funded by a non restricted grant from Pfizer Disclosure of Interest None declared

Effect of Infliximab Dose Increase in Rheumatoid Arthritis at Different Trough Concentrations: A Cohort Study in Clinical Practice Conditions

Background Evidence supporting treatment intensification in rheumatoid arthritis (RA) is limited and controversial. We explored outcomes of infliximab dose increases and accounted for pre-existing trough levels in patients with active RA. Methods This study was a retrospective study of 42 RA patients who received increased infliximab following an insufficient response (DAS28 >3.2). Serum concentrations of infliximab and antibodies to infliximab (ATI) and DAS28 and EULAR clinical response parameters were recorded for 1 year. Analyses were performed in three patient groups that were defined by infliximab serum concentration prior to treatment enhancement: no detectable, low (<1.1 μg/mL) or high (≥1.1 μg/mL) drug levels. Results No circulating infliximab was detected in 20 patients (47.6%), but 13 (31%) and 9 (21.4%) patients exhibited low and high levels, respectively. ATI was only detected in patients with no detectable drug levels because the drug interferes with ELISA. DAS28 disease activity globally showed a modest improvement after dose escalation, but this improvement did not persist after 6 and 12 months. Infliximab serum levels increased significantly in the high group (p = 0.016), but no increase was achieved in the low and no detectable groups. The three study groups exhibited similar disease activity over time, and no improvement was observed in the non-responder EULAR rates. Conclusion These results suggest that the efficacy of an infliximab dose increase is limited, and the response is independent of the infliximab trough serum concentration that is achieved prior to escalation.

Predictive Value of Serum Infliximab Levels at Induction Phase in Rheumatoid Arthritis Patients

Background: The Infliximab, has proven effective in treating rheumatoid arthritis (RA). A good clinical response is usually associated with high serum drug levels. Development of antibodies toward Infliximab (ATI) can increase drug clearance, leading to treatment failure. Aims: To analyze whether serum Infliximab trough levels (ITL) at the induction phase are associated with Infliximab clearance and clinical outcomes at week(W) 54 and to investigate the association with immunogenicity development. Methods: Observational retrospective study in which ITL from 66 RA patients were measured by capture ELISA at W0, W2, W6, W14 and 22. Patients were classified as ITLpos if Infliximab was detectable at W54 and ITLneg otherwise. ATI were assayed by bridging ELISA and by two drug-tolerant assays. ITL cut-off values were established by ROC curves. The association between ITL at early-stage and clearance of Infliximab at W54 was analyzed by univariable and multivariable logistic regression. Results: ITLneg patients (n=25) always had significantly lower Infliximab levels than ITLpos (n=41). An ITL value of 4.4 μg/mL at W6 best predicted W54 Infliximab absence. In the multivariable analysis, only ITL below the cut-off at W6 (OR: 86.6; 95%CI: 6.58-1139.99) and non-use of methotrexate (OR: 6.9; 95%CI: 1.04-45.84) remained significantly associated with W54 Infliximab absence. ATI were more frequent in patients with ITL below the cut-off at W6. Conclusions: In RA, ITL at induction phase are inversely associated with Infliximab clearance and clinical outcomes at W54. ATI was the main reason for low early ITL. A predictive value of ITL at W6 was found as a useful prognostic measure of treatment efficacy.

SAT0157 Tocilizumab Serum Trough Levels Correlate with Clinical Activity in Rheumatoid Arthritis

Background Tocilizumab (TCZ), a humanized anti-IL-6 receptor antibody, represents a new treatment strategy for RA patients.Several studies have demonstrated the association between high serum levels of TNF-inhibitors and a good clinical response in patients with RA. Little evidence exists on this relationship for other biological therapies. Objectives To evaluate the association between TCZ serum through levels and disease activity in a cohort of RA patients after one year of treatment with TCZ. Methods 34 RA patients treated with Tocilizumab were included. Clinical activity was assessed using the Disease Activity Score 28 (DAS28-ESR) and the Clinical and Simplified Activity Index (CDAI and SDAI), serological improvement by C-Reactive Protein- CRP- and Erythrocyte Sedimentation Rate-ESR, clinical improvement by the delta-DAS 28 and response to treatment using EULAR criteria at baseline and after one year of treatment. We stratified all patients into quartiles according to the tocilizumab levels (μg/ml) as follows: IQR1: <3,4, IQR2: 3,4–11,2, IQR3: 11,2–18,5 and IQR4 >18.5. A last observation carried forward analysis (LOCF) was performed at the first year of treatment, so patients that dropped out of the therapy before this period were included. Blood samples were collected just before intravenous (i.v) infusion. Serum drug levels were determined by a capture enzymelinked immunosorbent assay (ELISA). Results The baseline demographic and clinical characteristics are shown in Table 1. When patients were categorised into quartiles, IQR1 comprised 8 (24,2%) patients; IQR2, 7 (21,2%); IQR3, 8 (24,2%) and IQR4, 10 (30,3%). Clinical activity (DAS28, CDAI and SDAI) was statistically significant higher in patients with lower serum through levels at the first year [DAS28 (IQR1: 4,46 ±1,5, IQR2: 2,58 ± 0,87, IQR 3: 3,6± 0,79; IQR4: 2,17 ± 0,74; p=0,001), CDAI (IQR1: 23±13,9, IQR2: 7,72 ± 4,44, QIR 3: 13,38± 4,35, IQR4: 6,33 ± 4,62; p=0,003) and SDAI (IQR1: 19,46 ±15,5, IQR2: 9,51± 7,4, IQR3: 12,59 ± 6,31, IQR4: 4,55 ± 3,73; p=0,005)] and also was the number of swollen joints (IQR1: 7,5 ± 6,6, IQR2: 2,29 ±2,06, IQR3: 5,63 ± 4,3, IQR4: 1,1 ± 1,6, p=0,013) and tender joints (IQR1: 5,5 ± 5,7, IQR2: 1,71 ± 2,06, IQR3: 3,13 ± 2,8, IQR4: 0,8 ± 0,9, p=0,014). In addition, the EULAR reponse was worse in those patients with lower serum drug levels [non-responders: 4 (66,7%) in IQR1 vs 1 (16,7%) in IQR2 vs 1 (16,7%) in IQ3 vs 0 (0%) in IQR4, moderate responders: 3 (37,5%) in IQR1 vs 0 (0%) in IQR2 vs 4 (50%) in IQR3 vs 1 (12,5%) in IQR4 and good responders: 1 (5,3%) in IQR1 vs 6 (31,6%) in IQR2 vs 3 (37,5%) in IQR3 vs 9 (47,4%) in IQR4, p=0,006]. In terms of acute-phase reactants, the mean ESR tended to be higher in patients with lower TCZ levels (IQR1: 22,6±14,8 vs IQR2: 5,6±1,6 vs IQR 3: 9,4 ±3,5 vs IQR4: 6,4 ± 3,5, p=0,005), and also CRP levels (RIQ1: 10,2±17,4 vs RIQ2: 2,3 ± 3,4 vs RIQ3 0,56 ± 0,4 vs RIQ 4: 0,42 ± 0,66, p=NS)]. Conclusions The presence of low serum Tocilizumab levels correlates with a worse clinical disease activity. Consequently, measurement of Tocilizumab levels is a valuable tool that might help in the clinical management of patients with Rheumatoid Arthritis. Disclosure of Interest C. Tornero Marín Grant/research support from: Funded by an unrestricted medical grant from Pfizer., C. Plasencia: None declared, D. Pascual Salcedo: None declared, T. Jurado: None declared, M. B. Paredes: None declared, I. Monjo: None declared, E. Moral: None declared, A. Pieren: None declared, G. Bonilla Hernán: None declared, D. Peiteado: None declared, P. Bogas: None declared, L. Nuño: None declared, A. Villalba Yllan: None declared, E. Martín Mola: None declared, A. Balsa Criado: None declared