Ana Martínez-Feito

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.

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.

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.

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.

Specific association of HLA-DRB1*03 with anti-carbamylated protein antibodies in patients with RA

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.

Golimumab Tapering Strategy Based on Serum Drug Levels in Patients With Spondyloarthritis

Golimumab (GLM) is a tumor necrosis factor inhibitor (TNFi) used as Spondyloarthritis (SpA) treatment(1) . There is increasing evidence of the feasibility of using TNFi levels as a guide for clinicians to an optimized strategy(2-4) . Up to now, a few studies have investigated the predictive value of GLM-levels in the clinical response of several inflammatory diseases(5-8) , but none concerning GLM reduction therapy in SpA based on drug-levels measurement is available. This article is protected by copyright. All rights reserved.

SAT0084 Anti-carbamylated protein antibodies as potential biomarkers of disease activity in early arthritis patients

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<0.05 for all analyses). Analysis of the relation between anti-CarPA and ΔDAS28 showed association only with ΔDAS28 from baseline to M6 (p=0.005). In this period, the positive patients showed less decrease of DAS28 than the negative patients. This was independent of all the variables mentioned above and of the initial DAS28. As a result of this association, 20.5% of the anti-CarPA positive patients reached remission at M6, in comparison with 34.6% of the negative patients. In contrast, ΔDAS28 from M6 to M12 and from M12 to M24 were small and not associated with anti-CarPA. 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

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.