C. Krieckaert

Lower etanercept levels are associated with high disease activity in ankylosing spondylitis patients at 24 weeks of follow-up

Background Previous data have shown that etanercept levels are associated with clinical response in rheumatoid arthritis. However, for ankylosing spondylitis (AS), data regarding this topic are inconclusive. Objectives To investigate the relationship between etanercept levels and clinical response in patients with AS. Methods Observational prospective cohort study of 162 patients with AS =treated with etanercept, monitored during 24 weeks of treatment. Etanercept trough levels were determined, retrospectively, using an ELISA. Disease activity was measured using AS Disease Activity Score (ASDAS), including C-reactive protein (CRP) and Bath AS Disease Activity index (BASDAI). Active disease was defined as ASDAS≥2.1. Since etanercept is a drug administered at home there might have been some variation in trough level sampling. Results At 24 weeks etanercept levels were significantly higher in patients with ASDAS<2.1, (3.8 mg/L; IQR 2.5–5.2) compared with patients with ASDAS≥2.1 (2.3 mg/L; IQR 1.2–3.4; p≤0.001). Generalised estimating equation analysis demonstrated a statistically significant association between etanercept levels and ASDAS, BASDAI, CRP and erythrocyte sedimentation rate (all p<0.001). When patients were categorised into quartiles according to etanercept levels, the lowest quartile (etanercept<1.80 mg/L) comprised 35% of all patients with ASDAS≥2.1 while the highest quartile comprised only 14%. Conclusions Disease activity and inflammation are associated with etanercept levels in patients with AS at 24 weeks of treatment. Measuring etanercept levels might help in identifying overtreatment and undertreatment and optimise etanercept therapy in AS.

Golimumab trough levels, antidrug antibodies and clinical response in patients with rheumatoid arthritis treated in daily clinical practice

Tumour necrosis factor inhibitors (TNFi) are effective in the majority of patients with rheumatoid arthritis (RA),1 however, an important reason for non-response is low drug level due to immunogenicity.2 To our knowledge, no data collected during a prospective observational study is currently available regarding the relationship between golimumab level, immunogenicity and response in RA. This prospective observational cohort consisted of 37 consecutive adult patients with RA, according to the American College of Rheumatology 1987 revised criteria,3 in whom golimumab 50 mg subcutaneously once monthly was initiated according to the judgment of the rheumatologist, and who were recruited from two departments (Spain and The Netherlands). The study was approved by both Medical Ethics Committees. Clinical response was defined as Disease Activity Score using 28 joint count (DAS28) <3.2, calculated with erythrocyte sedimentation rate (ESR) (mm/h). Patients were eligible for inclusion when clinical data and sera of baseline with ≥ one follow-up visit were available. Clinical measurements and trough-level sera were collected at baseline and 4, 16, 28 and 52 weeks (The Netherlands), or half yearly (Spain), thereafter. Golimumab levels were measured analogously to adalimumab4 using TNF for capture and rabbit antigolimumab for detection …

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.

Adalimumab trough concentrations in patients with rheumatoid arthritis and psoriatic arthritis treated with concomitant disease-modifying antirheumatic drugs

Several factors—including immunogenicity—influence pharmacokinetics of adalimumab. The formation of antidrug antibodies (ADAb) leads to lower adalimumab trough concentrations in patients with rheumatoid arthritis (RA) or psoriatic arthritis (PsA),1 ,2 and thus associated with a diminished clinical response.3 A previous paper demonstrated that methotrexate (MTX) had a dose-dependent effect on the percentage of patients that tested positive for ADAb against adalimumab.4 Moreover, prior research has shown that patients with RA concomitantly treated with MTX had higher adalimumab trough concentrations than patients without, which was also dose dependent, resulting in a more frequently achieved European League Against Rheumatism good response status.5 ,6 These studies suggest an additional beneficial effect of concomitant MTX therapy for patients with RA treated with adalimumab. However, in PsA, the benefit of MTX is not yet clear.7 Also, some patients do …

Successful reduction of overexposure in patients with rheumatoid arthritis with high serum adalimumab concentrations: an open-label, non-inferiority, randomised clinical trial

Objective High adalimumab serum concentrations do not result in better response in patients with rheumatoid arthritis (RA), suggesting overexposure. We investigated whether patients with adalimumab concentrations >8 µg/mL can prolong their dosing interval by 50% without a clinically relevant change in disease activity. Methods Consecutive patients with RA, treated with adalimumab 40 mg every other week for at least 28 weeks, were approached for this randomised, open-label, non-inferiority trial. Patients with adalimumab trough concentrations >8 µg/mL were randomly (1:1) assigned to dose-interval prolongation of once every 3 weeks or continuation of every other week. Primary outcome was the change in disease activity score of 28 joints (ΔDAS28-ESR) after 28 weeks, with a non-inferiority margin of 0.6 points. Results In total, 147 patients were screened. Fifty-five patients had concentrations >8 µg/mL and were randomised. Mean ΔDAS28 after 28 weeks was –0.14±SD 0.61 in the prolongation group and 0.30±0.52 in the continuation group. Mean difference was significantly in favour of the prolongation group: 0.44 (95% CI 0.12 to 0.76, p=0.01). Conclusions Adalimumab-treated patients with RA with trough concentrations >8 µg/mL can prolong their standard dosing interval to once every 3 weeks without loss of disease control. Trial registration number NTR3509; Results.

SAT0333 The Influence of Golimumab Levels on Clinical Response in Spondyloarthritis Patients at 52 Weeks of Follow-Up

Background Previously an association has been demonstrated between drug levels and clinical activity in Spondyloarthritis (SpA) patients treated with Infliximab, Adalimumab or Etanercept. Until now, there is not enough evidence about the correlation between Golimumab (Gol) trough levels and clinical outcomes in SpA patients Objectives to study the association between Gol trough levels,clinical activity and C reactive protein (CRP)in SpA patients treated with Gol Methods In this prospective observational study we have included 30 SpA patients (pts) treated with Gol once monthly (24 pts from Spain and 6 pts from Netherlands). The clinical activity and improvement were measured by Ankylosing Spondylitis Disease Activity Score (ASDAS) and delta-ASDAS, respectively, at baseline (30 pts), 6 month (26 pts) and 1 year (20 pts). An important clinically improvement (ICI) was considered when delta-ASDAS was ≥1.1.Gol levels were measured by a TNF-capture ELISA, designed by Sanquin, Amsterdam. To carry out the statistical analysis the Gol levels were stratified in two groups: Group-1 (Gol levels ≤1.5 μg/ml, n=18 patients) and Group-2 (Gol levels=≥1.5 μg/ml, n=12 patients). Last observation was carried forward for pts who dropped out before 1 year or if pts did not have follow-up to 1 year Results At baseline the mean age was 45±1.67 years and the disease duration was 11±7.86 years. Most patients were men (21/30, 70%) and HLA-B27 positive (19/24, 79.2%). All SpA pts had active disease at baseline measured by ASDAS (3,61±0.95). At 6 months, Gol trough levels were significantly higher in pts with inactive disease (ID) than those with moderate-high disease activity (M-HDA) by ASDAS (Mdn, IQR:1.78,1.61-2.49μg/ml in ID vs 1.08,0.61-1.61 μg/ml in M-HDA, p=0.018) (Fig. 1). Gol levels were higher in patients with an important clinical improvement at 6 months, but not statiscally significant (1.61,0.98-2.14 μg/ml with ICI vs 1.08,0.42-1.71μg/ml without ICI, p=0.128). At the end of this study, Gol drug levels were not statistical significant different (1.6,0.81-1.99μg/ml with ID vs 1.08,0.77-1.80 μg/ml with M-HDA, p=0.382) (fig.1), although Gol levels were higher in patients with ICI (1.80,0.94-2.02μg/ml with ICI vs 0.85,0.34-1.55μg/ml without ICI, p=0.020). The CRP levels were lower in patients with higher Gol levels in the different studied time points (At 6 months:0.54±0.47 mg/l in Group-2 vs 18.04±40.95 mg/l in Group-1, p=0.001; at the end of the study: 0.62±0.64 mg/l in Group-2 vs 10.50±33.16 mg/l in Group-1, p=0.003) Figure 1 Conclusions In our 30 SpA patients the Gol trough levels were higher in patient with inactive disease at 6 months and in those who reached an important clinically improvement at 1 year. CRP was lower in SpA with Gol high levels along the study Disclosure of Interest C. Plasencia Grant/research support: Pfizer, E. Kneepkens: None declared, C. Krieckaert Speakers bureau: Abbvie, Pfizer, A. Balsa Grant/research support: Pfizer, Speakers bureau: Pfizer, UCB, D. Pascual-Salcedo Grant/research support: Pfizer, Speakers bureau: Pfizer, M. Nurmohamed Grant/research support: Abbvie, BMS, MSD, Pfizer, UCB and Roche, Consultant for: Abbott, BMS, Pfizer and Roche, Paid instructor for: Abbvie, Pfizer and Roche, Speakers bureau: Abbvie, Pfizer and Roche, T. Rispens: None declared, D. Van der Kleij: None declared, G. Wolbink Grant/research support: Pfizer, Speakers bureau: Pfizer, Amgen DOI 10.1136/annrheumdis-2014-eular.3225

OP0252 Adalimumab Serum Concentrations in Patients with Rheumatoid Arthritis or Psoriatic Arthritis Taking Concomitant DMARD Therapy

Background An important factor influencing pharmacokinetics of adalimumab is immunogenicity. There is a dose-dependent effect of methotrexate (MTX) on the amount of anti-drug antibodies produced against adalimumab [1]. Consequently, patients concomitantly treated with MTX have higher adalimumab trough levels than patients without concomitant MTX, resulting in a more beneficial clinical response [2]. Whether other disease modifying anti-rheumatic drugs (DMARDs) have a comparable effect on adalimumab levels has not yet been investigated. Objectives To investigate the effect of co-treatment with different DMARDs on adalimumab trough levels in patients with rheumatoid arthritis (RA) or psoriatic arthritis (PsA). Methods In this observational cohort study at the Jan van Breemen Research Institute | Reade, Amsterdam a total of 375 consecutive patients (272 RA patients and 103 PsA patients) treated with adalimumab were included. Adalimumab trough concentrations were measured at 0, 4, 16 and 28 weeks of treatment, using an enzyme-linked immunosorbent assay (ELISA). Data was analysed using the General Estimating Equation. Last observation carried forward was used for patients stopping adalimumab therapy prematurely. In addition, in 29 patients the last available drug level before adalimumab dose was increased to 40 mg sc every week was carried forward. Results Four groups of adalimumab treated patients were compared: monotherapy (n=67); concomitant MTX (n=224); concomitant other DMARDs (leflunomide, hydroxychloroquine, sulphasalazine or a combination of these) (n=26) and MTX + other DMARDs (n=58). Adalimumab trough levels are shown in figure 1. These levels were significantly higher in patients with concomitant DMARD treatment as compared to monotherapy: monotherapy vs. other DMARDs p=0.011; monotherapy vs. MTX p<0.001; and monotherapy vs. MTX + other DMARDs p<0.001. There was no statistical difference between both MTX groups and the other DMARDs group (p=0.579 [MTX vs. other DMARDs] and p=0.352 [MTX + other DMARDs vs. other DMARDs]). Conclusions Adalimumab trough concentrations are the highest in patients concomitantly taking MTX, with or without other DMARDs. Patients on adalimumab monotherapy had the lowest levels. Other DMARDs than MTX also seem to have a beneficial effect on adalimumab trough concentrations, however, these results have to be interpreted carefully, since only 26 patients were included in the “other DMARDs” group. References Krieckaert et al. ARD 2012. Pouw et al. ARD 2013 online first. Disclosure of Interest C. Krieckaert Speakers bureau: Pfizer, Abbvie, E. Vogelzang: None declared, M. Pouw: None declared, M. Nurmohamed Grant/research support: Abbvie, BMS, MSD, Pfizer, UCB and Roche, Consultant for: Abbott, BMS, Pfizer and Roche, Speakers bureau: AbbVie, Pfizer and Roche., G. Wolbink Grant/research support: Pfizer, Speakers bureau: Pfizer, Amgen DOI 10.1136/annrheumdis-2014-eular.3618

FRI0144 Adalimumab trough level in blood corresponding with clinical response

Background Adalimumab is a recombinant human IgG1 monoclonal antibody with high specific binding to human tumor necrosis factor a (TNF). Since 2002 the drug has been approved for the treatment of rheumatoid arthritis (RA) and while several tests have been developed for testing drug levels and immunogenicity, the correlation between serum trough concentrations of this drug and therapeutic effect in clinical practice has not been studied yet. We propose that monitoring drug levels could make this treatment more cost-effective, specially considering the high costs of biologicals. Objectives To investigate the correlation between clinical improvement and serum trough concentrations of adalimumab in RA patients, 6 months after start of treatment. Methods Prospective cohort consisting of 201 patients treated with 40mg adalimumab every two weeks. Six months after start of treatment serum trough adalimumab levels were measured by ELISA. Clinical improvement was defined as the difference in Disease Activity Score 28 (DAS28) of the patients before start of the treatment, and after six months. Randomizing data as groups of ten patients gives a median trough and median Delta DAS28 (DDAS28). These findings were studied in a concentration-effect curve. Results After 6 months of treatment, serum trough concentrations varied between 0 to 33 ug/mL. Patients without detectable adalimumab did not respond clinically. All of these patients had developed anti-adalimumab antibodies. In patients with serum levels ranging from 3 to 12 ug/mL clinical response seemed to be related to serum adalimumab levels. Higher levels of adalimumab did not contribute further to clinical improvement. Conclusions This study indicates that serum trough levels of adalimumab fluctuate widely. To achieve clinical effect in RA, serum levels of 3 to 12 ug/mL could be sufficient. Hence, this suggests that presently a significant amount of patients is overtreated. Obviously, monitoring of drug levels is needed leading to personalized medication schemes allowing a more rational usage of this drug. Disclosure of Interest None Declared

THU0157 Comparison of Clinical Outcomes between Rheumatoid Arthritis Patients under TNF Inhibitors Using A Tapering Strategy or Standard Therapy Regimen in Daily Clinical Practice

Background There is sparse evidence about the disease control after longterm tapering of TNF inhibitors (TNFi)in rheumatoid arthritis (RA)patients (pts) Objectives To compare the clinical outcomes in RA pts on tapering strategy with RA patients on standard regimen of TNFi with a longterm followup Methods In this observational study 144 RA pts under TNFi therapy [infliximab (Ifx), adalimumab (Ada) or etanercept (Etn)] were included. Two groups were compared: Group1 (67 pts from Spain) on tapering strategy and Group2 (77 pts from Netherlands) on standard therapy. Pts were matched on duration of inactive disease before inclusion and duration of the follow-up. Disease activity had to be low (DAS28<3.2) for at least 6 months before inclusion. The tapering strategy included dose reduction and/or interval elongation, however if a flare occurred treatment could be intensified. The clinical activity was measured by DAS28 at different time points: visit-0 (at baseline, just before starting the biological), visit-1 (Group1: just before starting tapering; Group2: after at least 6 months in low disease activity) and visit-2 (the last visit available after visit-1) Results Sixty seven RA pts were in tapering group (Group 1: 23 with Ifx, 23 with Ada and 21 with Etn) and 77pts in control group (Group 2: 22 with Ifx, 27 with Ada and 28 with Etn). Most pts were rheumatoid factor positive [52/67 (77.6%) in Group 1 vs 58/75 (77.3%) in Group 2, p=0.968]. No significant differences were seen in disease duration (years) (16.49±7.17 in Group1 vs 17.49±7.79 in Group 2, p=0.489), time (years) in inactive disease before visit-1 (1.14±0.95 in Group 1 vs 0.92±0.54 in Group 2, p=0.421) and following (years) between visit-1and visit-2. (2.38±1.17in Group 1 vs 2.41±0.86 in Group 2, p=0.327). No statistical differences were found in clinical activity (DAS28) and percentage of patients with flares (see Table). Although the dropout was similar in both groups, the secondary inefficacy was more frequent in the tapering group (see Table).The overall drug administered was reduced in tapering group at visit-2 in comparison with the group on standard therapy regimen (an elongation in administration interval of 32.8% in Ifx, 52.9% in Ada and 52.6% in Etn) RA patients (total=144) Group 1: Tapering group Group 2: Control group p values n=67 n=77 DAS28 (m ± SD)  Visit 0 4.86±0.97 4.77±0.91 0.560  Visit 1 2.27±0.63 2.11±0.67 0.116  Visit 2 2.72±0.94 2.46±0.98 0.123 Percentage of patients with flares, n/N (%) 28/67 (41.8%) 36/75(48%) 0.458 Reasons to dropout (number of patients)  Remission 4/67(5.9%) 4/77 (5.2%)  Secondary inefficacy 6/67(8.9%) 2/77 (2.6%)  Dropout for others reasons 4/67 (5.9%) 7/77 (9.1%) Interval administration in weeks at visit-2, m ± SD  Ifx: 11.91±2.73 8.00±0.00 <0.001  Ada: 4.25±1.61 2.00±0.00 <0.001  Etn: 2.11±0.89 1.00±0.00 <0.001 Conclusions The tapering strategy in a cohort of RA patients with inactive disease results in an important reduction in the drug administered while the clinical course is similar to a RA cohort without tapering. However, a small percentage of RA patients on tapering seems to be more prone to dropout due to secondary inefficacy Disclosure of Interest : C. Plasencia Grant/research support: Pfizer, G. Wolbink Grant/research support: Pfizer, Speakers bureau: Pfizer, Amgen, C. Krieckaert Speakers bureau: Abbvie, Pfizer, E. Kneepkens: None declared, S. Turk: None declared, M. Bonilla: None declared, A. Villalba: None declared, M. Nurmohamed Grant/research support: Abbvie, BMS, MSD, Pfizer, UCB, Roche, Consultant for: BMS, Pfizer, Roche, Speakers bureau: Abbvie, Pfizer, Roche, C. Diego: None declared, E. Martín-Mola Speakers bureau: Abbvie, UCB, Pfizer, Roche, D. Pascual-Salcedo Grant/research support: Pfizer, Speakers bureau: Pfizer, A. Balsa Grant/research support: Pfizer, Speakers bureau: Pfizer, Abbvie, Roche DOI 10.1136/annrheumdis-2014-eular.2133

SAT0125 Comparing the long-term clinical outcome of etanercept and adalimumab treatment with respect to immunogenicity

Objectives To compare rates of sustained low and minimal disease activity and ACR/EULAR remission during 3-year follow-up in rheumatoid arthritis (RA) patients treated with etanercept and adalimumab in routine care. Methods 407 RA patients previously unexposed to tumor necrosis factor antagonists were treated with etanercept (n=203) or adalimumab (n=204) and assessed at 3- and later 6 month intervals. Clinical parameters and anti-adalimumab antibodies (AAA) were measured at each time point. Clinical response was defined as sustained (at least 12 consecutive months) low disease activity (sLDA; DAS28 <3.2), minimal disease activity (sMDA; DAS28 <2.6) or ACR/EULAR remission (sSDAI). Non-overlapping response rates were calculated. Results In the adalimumab group, 13% reached sLDA but not sMDA, 15% reached sMDA but not sSDAI and 16% reached sSDAI remission. In the etanercept group corresponding rates were 16%, 11% and 12%, respectively (overall test for linear trend: p=0.42). Adalimumab-treated patients without antibodies (AAA–; n=150, 74%) had best outcomes and AAA+ patients the worst, with etanercept-treated patients in between (p<0.0001). Differences were most apparent in the sSDAI and sMDA categories. For example, 40% of AAA–, 23% of etanercept and 4% of AAA+ patients achieved at least sMDA (Fig. 1). Figure 1 Conclusions Overall, etanercept and adalimumab treatment appeared similar in inducing a good long-term clinical outcome. The occurrence of AAA hampered the long-term clinical efficacy of adalimumab. Treatment response rates to adalimumab might be increased by strategies that counteract the development of AAA. Disclosure of Interest C. Krieckaert: None Declared, A. Jamnitski: None Declared, M. Nurmohamed Grant/Research support from: Abbott, Roche, Pfizer, Consultant for: Abbott, Roche, Phizer, MSD, UCB, SOBI and BMS, Speakers Bureau: Abbott, Roche, Pfizer, P. Kostense: None Declared, M. Boers Consultant for: Roche, GSK, Novartis, Speakers Bureau: UCB, Abbott, G. Wolbink Grant/Research support from: Pfizer, Speakers Bureau: Pfizer, Amgen