E. Kneepkens

Immunogenicity, adalimumab levels and clinical response in ankylosing spondylitis patients during 24 weeks of follow-up

Background Immunogenicity influences adalimumab levels and therefore clinical response in patients with rheumatic diseases. Objectives To study the relationship between clinical response, adalimumab levels and antidrug antibodies (ADAb) in ankylosing spondylitis (AS). Methods Observational cohort study of 115 consecutive AS patients treated with adalimumab in the Netherlands (n=85) and Taiwan (n=30), monitored during 24 weeks. Adalimumab levels and ADAb titres were determined using an ELISA and an antigen binding test (ABT), respectively, designed by Sanquin Research, Amsterdam. Response to adalimumab treatment was defined as a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) response, and disease activity was measured using the Ankylosing Spondylitis Disease Activity Score using C-reactive protein (CRP) (ASDAS). Results At baseline, median BASDAI (IQR) was 6.4 (4.5–7.6) and mean ASDAS (SD) was 3.5 (1.0). After 24 weeks, 49 (42.6%) patients were BASDAI50 responders and mean ASDAS (SD) for responders was 1.5 (1.0) vs 2.6 (1.0) for non-responders (p<0.001). Thirty-one (27.0%) patients had detectable ADAb. After 24 weeks, adalimumab levels (mg/L) (IQR) were significantly higher in ADAb-negative patients than in ADAb-positive patients (12.7 (8.2–18.0) vs 1.2 (0.0–2.0), (p<0.001)). A significant association was demonstrated between adalimumab levels and ASDAS (p=0.02; RC −1.1; 95% CI −2.0 to −0.2). Eleven (9.6%) patients had no detectable adalimumab levels and high detectable ADAb titres (>100 AU/mL). In these patients, CRP and erythrocyte sedimentation rate remained elevated during treatment. Conclusions Adalimumab levels are related to clinical response in AS patients measured with ASDAS and are influenced by ADAb detectable with an ABT.

Anti-adalimumab antibodies and adalimumab concentrations in psoriatic arthritis; an association with disease activity at 28 and 52 weeks of follow-up

Objectives To investigate the relationship between antidrug antibodies (ADA), adalimumab concentrations and clinical response in patients with psoriatic arthritis (PsA) during 52 weeks of follow-up. Methods This prospective cohort study included 103 consecutive patients with PsA. Disease Activity Score of 28 joints (DAS28), Erythrocyte Sedimentation Rate, C reactive protein and Psoriasis Area and Severity Index were assessed. Adalimumab concentrations and ADA were measured in serum trough samples, using an ELISA and a radio immunoassay, respectively. Results Adalimumab concentrations were significantly lower at 28 and 52 weeks in patients with detectable ADA compared with patients without detectable ADA (at week 28: 1.3 mg/L (IQR 0.0–3.2) versus 8.7 mg/L (IQR 5.7–11.5), p<0.001; at week 52: 0.9 mg/L (IQR 0.0–2.9) vs 9.4 mg/L (IQR 5.7–12.1), p=0.0001). DAS28 at 28 weeks (2.16 vs 2.95, p=0.023) and 52 weeks (2.19 vs 2.95, p=0.024) showed a significant difference; patients with detectable ADA had a poorer clinical outcome than patients without. Conclusions Patients with detectable ADA had lower adalimumab concentrations and a significantly poorer clinical outcome compared with patients in whom ADA were not detected.

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.

Unexpected arterial wall and cellular inflammation in patients with rheumatoid arthritis in remission using biological therapy: a cross-sectional study

BackgroundIncreasing numbers of patients (up to 40 %) with rheumatoid arthritis (RA) achieve remission, yet it remains to be elucidated whether this also normalizes their cardiovascular risk. Short-term treatment with TNF inhibitors lowers arterial wall inflammation, but not to levels of healthy controls. We investigated whether RA patients in long-term remission are characterized by normalized inflammatory activity of the arterial wall and if this is dependent on type of medication used (TNF-inhibitor versus nonbiological disease-modifying antirheumatic drugs (DMARDs)).MethodsArterial wall inflammation, bone marrow and splenic activity (index of progenitor cell activity) was assessed with 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in RA patients in remission (disease activity score (DAS28) <2.6 for >6 months) and healthy controls. We performed ex vivo characterization of monocytes using flow cytometry and a transendothelial migration assay.ResultsOverall, arterial wall inflammation was comparable in RA patients (n = 23) in long-term remission and controls (n = 17). However, RA subjects using current anti-TNF therapy (n = 13, disease activity score 1.98[1.8–2.2]) have an almost 1.2-fold higher 18F-FDG uptake in the arterial wall compared to those using DMARDs (but with previous anti-TNF therapy) (n = 10, disease activity score 2.24[1.3–2.5]), which seemed to be predominantly explained by longer duration of their rheumatic disease in a multivariate linear regression analysis. This coincided with increased expression of pro-adhesive (CCR2) and migratory (CD11c, CD18) surface markers on monocytes and a concomitant increased migratory capacity. Finally, we found increased activity in bone marrow and spleen in RA patients using anti-TNF therapy compared to those with DMARDs and controls.ConclusionsA subset of patients with RA in clinical remission have activated monocytes and increased inflammation in the arterial wall, despite the use of potent TNF blocking therapies. In these subjects, RA disease duration was the most important contributor to the level of arterial wall inflammation. This increased inflammatory state implies higher cardiovascular risk in these patients, who thus may require more stringent CV risk management.

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 …

Serum tocilizumab trough concentration can be used to monitor systemic IL-6 receptor blockade in patients with rheumatoid arthritis: a prospective observational cohort study.

Objectives: To investigate the pharmacokinetics (PK) and dynamics of tocilizumab (TCZ) in daily practice. Method: An observational study of 66 consecutive RA patients treated with TCZ 8 mg/kg once every 4 weeks intravenously, monitored for 24 weeks. Spearman’s rank test was used to investigate the correlation between TCZ concentration and C-reactive protein (CRP). Clinical improvement was assessed at week 24 using the Disease Activity Score in 28 joints (DAS28) compared to baseline, and its relationship with TCZ concentration was investigated using linear regression analyses. TCZ trough concentrations and anti-drug antibodies were measured using an enzyme-linked immunosorbent assay (ELISA) and antigen binding test, respectively. Results: At baseline, 26 patients (39.4%) had a CRP level above 10 mg/L with a median (interquartile range, IQR) of 37.7 (21.9–49.7) mg/L. A TCZ concentration above 1 mg/L was sufficient to normalize CRP levels. Spearman’s rank test showed a correlation coefficient of −0.460 (p < 0.0001). The TCZ concentration varied widely, with concentrations < 1 mg/L in 17–31% of patients, depending on the time point of measurement. Anti-TCZ antibodies were detected in one sample. Linear regression analyses showed a coefficient of 0.080 with a 95% confidence interval (CI) of 0.039–0.113 (p < 0.001) for the association between TCZ concentration and ΔDAS28. No confounders were identified. Conclusions: The TCZ standard regimen results in a wide variety of serum TCZ trough concentrations; this is mostly due to target binding and to a lesser extent to immunogenicity. The majority of patients obtained TCZ concentrations > 1 mg/L, which is sufficient for CRP normalization. Therefore, dose taper strategies might be possible in a substantial proportion of patients.

SAT0391 A Diminished Clinical Response at 28 and 52 Weeks of Adalimumab Treatment in Patients with Psoriatic Arthritis is Associated with Anti-Drug Antibodies

Background Immunogenicity, the formation of anti-drug antibodies (ADA), has important clinical implications for the treatment with adalimumab of patients with rheumatic diseases, since ADA are associated with lower effective drug levels, resulting in an absent or diminished response in some patients. In contrast to rheumatoid arthritis research on immunogenicity and clinical response in patients with psoriatic arthritis (PsA) is scarce. Objectives To investigate the relationship between ADA, adalimumab drug levels and clinical response in a large, long-term follow-up cohort of patients with PsA during 52 weeks of follow-up. Methods This prospective cohort study included 103 consecutive patients diagnosed with PsA and treated with 40 mg adalimumab subcutaneously every other week. Disease activity score in 28 joints (DAS28), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and psoriasis area and severity index (PASI) were assessed at baseline and after 4, 16, 28, 40 and 52 weeks of treatment. Adalimumab concentrations and ADA were measured in serum trough samples, using an enzyme linked immunosorbent assay (ELISA) and a radio immunoassay (RIA), respectively. Results After 52 weeks of treatment, 23 (22%) patients had detectable ADA. Serum adalimumab concentrations were significantly lower at 28 and 52 weeks in patients with detectable ADA compared to patients without detectable ADA (at week 28: 1.3 mg/L [IQR 0.0-3.2] vs 8.7 mg/L [IQR 5.7-11.5], p<0.0001; at week 52: 0.9 mg/L [IQR 0.0-2.9] vs 9.4 mg/L [IQR 5.7-12.1], p=0.0001). DAS28 at 28 weeks (2.16 vs 2.95, p=0.023) and 52 weeks (2.19 vs 2.95, p=0.024) showed a significant difference; patients with detectable ADA had a poorer clinical outcome than patients without (see Table 1). Conclusions ADA was detected in 22% of the adalimumab treated PsA patients during 52 weeks of follow-up. These patients had lower adalimumab serum concentrations and a significantly poorer clinical outcome for DAS28 and CRP at week 28 and 52 compared to patients in whom ADA were not detected. Disclosure of Interest E. Vogelzang: None declared, E. Kneepkens: None declared, M. Nurmohamed: None declared, A. van Kuijk: None declared, T. Rispens Speakers bureau: Pfizer and Abbvie, G. Wolbink Grant/research support: Pfizer, Speakers bureau: Pfizer and Amgen, C. Krieckaert Speakers bureau: Pfizer and Abbvie DOI 10.1136/annrheumdis-2014-eular.2162

The Effects of 5-year Etanercept Therapy on Cardiovascular Risk Factors in Patients with Psoriatic Arthritis

Objective. To investigate the effects of etanercept (ETN) on lipid metabolism and other known cardiovascular disease (CVD) risk factors in patients with psoriatic arthritis (PsA). Methods. In an observational cohort of 118 consecutive patients with PsA, CVD risk factors were assessed over 5 years. Mixed-model analyses were performed to investigate the effects of ETN therapy on CVD risk factors over time. Results. Disease Activity Score in 28 joints, C-reactive protein (CRP), and erythrocyte sedimentation rate decreased during therapy with ETN. There was an increase in total cholesterol (TC), high-density lipoprotein cholesterol (HDLc), and low-density lipoprotein cholesterol. The TC/HDLc ratio remained unaltered. The apolipoprotein B to apolipoprotein A-I (apoB/apoA-I) ratio decreased significantly. An increase in CRP was associated with an increase in the apoB/apoA-1 ratio. Conclusion. Serum lipid concentrations showed small changes over a 5-year period of ETN therapy and were inversely associated with inflammatory markers. Other CVD risk factors remained stable. The apoB/apoA-1 ratio decreased over time and an increase in disease activity was associated with an increase in this ratio. However, this modest lipid modulation cannot explain the observed beneficial CV effects of ETN, and ETN likely exerts those effects through inflammation-related mechanisms.