Dried blood spots from finger prick facilitate therapeutic drug monitoring of adalimumab and anti-adalimumab in patients with inflammatory diseases.

AIMS: Development of a self-sampling method for therapeutic drug monitoring (TDM) of biologicals will enhance TDM implementation in routine care and pharmacokinetic knowledge. The aim of this study was to compare adalimumab and anti-adalimumab antibody (ADA) concentration measurements in dried blood spots (DBS) obtained from finger prick with measurements in serum obtained via venepuncture, from patients with rheumatic inflammatory diseases. METHODS: In this cross-sectional study, 161 consecutive patients were included. For clinical validation, DBS from finger prick and serum from venepuncture were collected simultaneously and adalimumab and ADA concentration were assessed by ELISA and antigen binding test (ABT), respectively. To convert DBS eluate results to values which can be compared to serum concentrations, five different methods were investigated, using a marker protein or a volumetric approach. RESULTS: Adalimumab and ADA concentrations obtained from the finger prick/DBS method correlated well with serum results from the same patient (correlation coefficient > 0.87). Interestingly, antibody concentrations (either adalimumab, ADA or total immunoglobulin G) in DBS from finger prick, but not albumin, were systematically lower compared to serum. Spike experiments demonstrated a quantitative recovery for all tested proteins in DBS, suggesting a slightly different protein composition of blood collected via finger prick vs. venepuncture. We established a correction factor to relate finger prick/DBS values with serum values (approximately 1.2). CONCLUSIONS: We show here for the first time that adalimumab and ADA serum concentrations can be satisfactorily estimated by measuring concentrations in DBS eluates, collected by finger prick. This method offers great opportunity to simplify TDM of adalimumab.

Long-term treatment response in rheumatoid arthritis patients starting adalimumab or etanercept with or without concomitant methotrexate.

OBJECTIVES: To observe long-term clinical response and drug survival in a prospective two-year cohort study in rheumatoid arthritis (RA) patients starting adalimumab or etanercept treatment, with or without methotrexate (MTX), after failure of conventional DMARD therapy, including MTX. METHODS: Disease activity score of 28 joints (DAS28) and Health Assessment Questionnaire (HAQ) were collected of 873 consecutive RA patients, treated with adalimumab or etanercept, prospectively at baseline, 4, 16, 28, 40, 52, 78 and 104 weeks of biological therapy. Sustained minimal disease activity (MDA), DAS28 <2.6 for at least 24 consecutive weeks, biological discontinuation, ΔHAQ and ΔDAS28 were compared between patients treated with or without concomitant MTX for etanercept and adalimumab separately. RESULTS: More patients treated with adalimumab and MTX (42%) achieved sustained MDA than patients without MTX (18%). The hazard ratio (HR) was 2.3 [1.4-3.9]. No significant difference was found in etanercept treatment (with MTX 33% vs. 28% without MTX), HR 1.1 [0.8-1.6]. More patients treated without MTX discontinued treatment than patients with MTX co-treatment in adalimumab (HR 2.1 [1.5-3.0]) and etanercept (HR 1.9 [1.0-3.4]). The mean decrease in DAS28 over time was higher for patients treated with MTX in adalimumab (regression coefficient (RC): 0.57, p<0.001), but was not significantly different in etanercept treatment (RC 0.05, p=0.427). No significant differences were found in ΔHAQ. CONCLUSIONS: Treatment discontinuation is lower in patients treated with MTX in both adalimumab and etanercept treatment. However, considering good clinical response, in contrast to etanercept, a synergetic effect of MTX is observed only in adalimumab treatment.

Comparing a tapering strategy to the standard dosing regimen of TNF inhibitors in rheumatoid arthritis patients with low disease activity.

OBJECTIVES: The aim of this study is to compare clinical outcomes, incidence of flares and administered drug reduction between rheumatoid arthritis (RA) patients under TNF inhibitors (TNFi) tapering strategy and RA patients on standard regimen. METHODS: Two groups of RA patients on TNFi with DAS28<3.2 were compared: the tapering group (TG: 67 pts from Spain) and the control group with standard therapy regimen (CG: 77 pts from the Netherlands). DAS28 was measured at different time points: visit 0 (prior starting TNFi), visit 1 (prior to start tapering in TG and with DAS28<3.2 in TG and CG), visit 2 (6 months after visit 1), visit 3 (1 year after visit 1), visit 4 (the last visit available after visit 1) and visit-flare (visit with the worst flare between visit 1 and visit 4). RESULTS: Despite the reduction of administered drug at visit 4 in the TG (interval elongation of 32.8% in infliximab, 52.9% in adalimumab and 52.6% in etanercept), the DAS28 remained similar between groups at the end of the study (DAS28: 2.7±0.9 in TG vs. 2.5±1 in CG, p=0.1). No differences were seen in the number of patients with flares [26/67 (38.9%) in the TG vs. 30/77 (39%) in the CG, p=0.324] and only nineteen out of 136 patients (14%) had anti-drug antibodies at the end of the study. CONCLUSIONS: The tapering strategy of TNFi in RA patients result in a reduction of the drug administered, while the disease control is not worse than patients on the standard regimen.

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.

Medication-Related Hospital Readmissions Within 30 Days of Discharge: Prevalence, Preventability, Type of Medication Errors and Risk Factors.

Background: Hospital readmission rates are increasingly used as a measure of healthcare quality. Medicines are the most common therapeutic intervention but estimating the contribution of adverse drug events as a cause of readmissions is difficult. Objectives: To assess the prevalence and preventability of medication-related readmissions within 30 days after hospital discharge and to describe the risk factors, type of medication errors and types of medication involved in these preventable readmissions. Design: A cross-sectional observational study. Setting: The study took place across the cardiology, gastroenterology, internal medicine, neurology, psychiatry, pulmonology and general surgery departments in the OLVG teaching hospital, Netherlands. Participants: Patients with an unplanned readmission within 30 days after discharge from an earlier hospitalization (index hospitalization: IH) were reviewed. Measurements: The prevalence and preventability of medication-related readmissions were assessed by residents in multidisciplinary meetings. A senior internist and hospital pharmacist reassessed the prevalence and preventability of identified cases. Generalized estimating equation with logistic regression was performed to identify risk factors of potentially preventable medication-related readmissions. Results: Of 1,111 included readmissions, 181 (16%) were medication-related, of which 72 (40%) were potentially preventable. The number of medication changes at IH (Adjusted odds ratio [ORadj]: 1.14; 95% CI: 1.05-1.24) and having ≥3 hospitalizations 6 months before IH (ORadj: 2.11; 95% CI: 1.12-3.98) were risk factors of a preventable medication-related readmission. Of these preventable readmissions, 35% were due to prescribing errors, 35% by non-adherence and 30% by transition errors. Medications most frequently involved were diuretics and antidiabetics. Conclusion: This study shows that 16% of readmissions are medication-related, of which 40% are potentially preventable. If the results are confirmed in larger multicentre studies, this may indicate that more attention should be paid to medication-related harm in order to lower the overall readmission rates.

Preventability of unplanned readmissions within 30 days of discharge. A cross-sectional, single-center study.

OBJECTIVES: To identify the preventability, determinants and causes of unplanned hospital readmissions within 30 days of discharge using a multidisciplinary approach and including patients' perspectives. DESIGN: A prospective cross-sectional single-center study. SETTING: Urban teaching hospital in Amsterdam, the Netherlands. PARTICIPANTS: 430 patients were included. Inclusion criteria were: age ≥ 18 years, discharged from one of seven participating clinical departments and an unplanned readmission within 30 days. METHODS: Residents from the participating departments individually assessed whether the readmission was caused by healthcare, the preventability and possible causes of readmissions using a tool. Thereafter, the preventability of the cases was discussed in a multidisciplinary meeting with residents of all participating departments and clinical pharmacists. The primary outcome was the proportion of readmissions that were potentially preventable. Secondary outcomes were the determinants for a readmission, causes for preventable readmissions, the change in the final decision on preventability after the multidisciplinary meeting and the value of patient interviews in assessing preventability. Differences in characteristics of potentially preventable readmissions (PPRs) and non-PPRs were analyzed using multivariable logistic regression. RESULTS: Of 430 readmissions, 56 (13%) were assessed as PPRs. Age was significantly associated with a PPR (adjusted OR: 2.42; 95%, CI 1.23-4.74; p = 0.01). The main causes for PPRs were diagnostic (30%), medication (27%) and management problems (27%). During the multidisciplinary meeting, the final decision on preventability changed in 11% of the cases. When a patient interview was available, it was used as a source of information to assess preventability in 26% of readmissions. In 7% of cases, the patient interview was mentioned as the most important source. CONCLUSION AND IMPLICATIONS: 13% of readmissions were potentially preventable with diagnostic, medication or management problems being main causes. A multidisciplinary review approach and including the patient's perspective could contribute to a better understanding of the complexity of readmissions and possible improvements.

Association between concomitant csDMARDs and clinical response to TNF inhibitors in overweight patients with axial spondyloarthritis.

BACKGROUND: The aim of our study was to investigate the influence of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) and body mass index (BMI) on circulating drug levels and clinical response to tumour necrosis factor inhibitor (TNFi) therapy in axial spondyloarthritis (axSpA) patients. METHODS: Prospective observational study during 1 year with 2 cohorts (Madrid and Amsterdam) including 180 axSpA patients treated with standard doses of infliximab or adalimumab. Patients were stratified by BMI, being 78 (43%) normal weight (18.5-24.9 kg/m2) and 102 (57%) overweight/obese (≥ 25.0 kg/m2). After the first year of treatment, TNFi trough levels were measured by capture ELISA. Clinical response to TNFi was defined as ∆BASDAI ≥ 2 and clinical remission as BASDAI < 2 and CRP ≤ 5 mg/L. Logistic regression models were employed to analyse the association between concomitant csDMARDs and BMI with drug levels and clinical response. RESULTS: Seventy-nine patients (44%) received concomitant csDMARDs. The administration of concomitant csDMARDs (OR 3.82; 95% CI 1.06-13.84) and being normal weight (OR 18.38; 95% CI 2.24-150.63) were independently associated with serum TNFi drug persistence. Additionally, the use of concomitant csDMARDs contributed positively to achieve clinical response (OR 7.86; 95% CI 2.39-25.78) and remission (OR 4.84; 95% CI 1.09-21.36) in overweight/obese patients, but no association was found for normal-weight patients (OR 1.10; 0.33-3.58). CONCLUSIONS: The use of concomitant csDMARDs with TNFi may increase the probability of achieving clinical response in overweight/obese axSpA patients. Further research studies including larger cohorts of patients need to be done to confirm it.

Capillary blood microsampling to determine serum biopharmaceutical concentration: Mitra® microsampler vs dried blood spot.

AIM: For assessment of concentrations of biopharmaceuticals, for example, therapeutic drug monitoring, dried blood sampling of capillary blood is a convenient alternative to traditional venepuncture sampling. We investigated an alternative to dried blood spot collection on filter paper: sampling capillary blood using the Mitra® microsampler. MATERIALS AND METHODS:  Therapeutic monoclonal antibodies were spiked in whole blood, sampled using filter paper and Mitra microsampler and concentrations measured using specific ELISAs. RESULTS: Good recoveries of adalimumab, infliximab, ustekinumab, vedolizumab, tocilizumab, natalizumab and rituximab were found up to 1 month of storage at room temperature, averaging 95.2% for the Mitra microsampler and 92.9% for Whatman® paper. Both hemoglobin and potassium yield satisfactory estimates for the volume of the cellular fraction of blood samples in combination with the Mitra microsampler. CONCLUSION: We established practical protocols for the estimation of serum/plasma concentrations of therapeutic antibodies via capillary blood microsampling.

Impact of Stopping Tumor Necrosis Factor Inhibitors on Rheumatoid Arthritis Patients' Burden of Disease.

OBJECTIVE: To determine the impact of stopping tumor necrosis factor inhibitor (TNFi) treatment on patient-reported outcomes (PROs) of physical and mental health status, health utility, pain, disability, and fatigue in patients with established rheumatoid arthritis (RA). METHODS: In the pragmatic, 12-month POET trial, 817 RA patients with ≥6 months of remission or stable low disease activity were randomized 2:1 to stopping or continuing TNFi. In case of flare, TNFi was restarted at the discretion of the rheumatologist. PROs were assessed every 3 months. RESULTS: TNFi was restarted within 12 months in 252 of 531 patients (47.5%) in the stop group. At 3 months, mean PRO scores were significantly worse in the stop group, and a larger proportion of patients experienced a minimum clinically important difference (MCID) on all PROs. Effect sizes (ES) were strongest for health utility (ES -0.24) and pain (ES -0.30). Mean scores improved again after this point, but disability scores remained significantly different at 12 months. After 12 months, the relative risk of experiencing an MCID ranged from 1.16 for mental health status to 1.58 for fatigue. Mean PRO scores for patients restarting TNFi within 6 months were no longer significantly different from those that did not restart TNFi at 12 months. CONCLUSION: Stopping TNFi had a significant negative short-term impact on a broad range of PROs. Long-term negative consequences appeared to be limited, and outcomes in patients needing to restart TNFi within the first 6 months tended to be restored at 12 months.

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.

Continuous Improvement of Physical Functioning in Ankylosing Spondylitis Patients by Tumor Necrosis Factor Inhibitors: Three-Year Followup and Predictors.

OBJECTIVE: To establish the 3-year outcome and course of physical functioning and spinal mobility impairments in patients routinely treated with tumor necrosis factor inhibitors (TNFi) and to find predictors of physical functioning and spinal mobility impairments. METHODS: Ankylosing spondylitis (AS) patients eligible for TNFi were followed in a 3-year prospective observational study. Prediction models were developed with linear mixed modeling. Bath Ankylosing Spondylitis Functional Index (BASFI) and Bath Ankylosing Spondylitis Metrology Index (BASMI) were used as outcome measures for physical functioning and spinal mobility. RESULTS: A total of 257 patients were included and treated with etanercept (n = 174) or adalimumab (n = 83). Physical functioning improved significantly during the first 6 months after the start of TNFi. The BASFI score decreased from mean ± SD 5.4 ± 2.4 to 3.3 ± 2.6 at 6 months, and stabilized thereafter (BASFI third year score mean ± SD 3.6 ± 2.5). The BASMI showed no significant changes over time. Lower baseline BASFI and BASMI scores predicted a better level of physical functioning and spinal mobility after 3 years of TNFi therapy. Other predictors for a better 3-year outcome and course of physical functioning included absence of comorbidity, physical activity, younger age, and lower body mass index at baseline. CONCLUSION: Physical functioning in routinely TNFi-treated AS patients improved up to 6 months and stabilized thereafter. Therefore, it would be better to extend the period of evaluation of TNFi treatment to 6 months rather than the 3 months currently used. The risk factors of long-term physical functioning found in this study might help to identify patients at risk at an earlier stage and improve treatment strategy.

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

BACKGROUND: Increasing 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)). METHODS: Arterial wall inflammation, bone marrow and splenic activity (index of progenitor cell activity) was assessed with (18)F-fluorodeoxyglucose ((18)F-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. RESULTS: Overall, 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 (18)F-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. CONCLUSIONS: A 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.

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.