Therapeutic drug monitoring (TDM) is mandatory for the immunosuppressive drug tacrolimus (Tac). For clinical applicability, TDM is performed using morning trough concentrations. With recent developments making tacrolimus concentration determination possible in capillary microsamples and Bayesian estimator predicted area under the concentration curve (AUC), AUC‐guided TDM may now be clinically applicable. Tac circadian variation has, however, been reported, with lower systemic exposure following the evening dose. The aim of the present study was to investigate tacrolimus pharmacokinetic (PK) after morning and evening administrations of twice‐daily tacrolimus in a real‐life setting without restrictions regarding food and concomitant drug timing. Two 12 hour tacrolimus investigations were performed; after the morning dose and the following evening dose, respectively, in 31 renal transplant recipients early after transplantation both in a fasting‐state and under real‐life nonfasting conditions (14 patients repeated the investigation). We observed circadian variation under fasting‐conditions: 45% higher peak‐concentration and 20% higher AUC following the morning dose. In the real‐life nonfasting setting, the PK‐profiles were flat but comparable after the morning and evening doses, showing slower absorption rate and lower AUC compared with the fasting‐state. Limited sampling strategies using concentrations at 0, 1, and 3 hours predicted AUC after fasting morning administration, and samples obtained at 1, 3, and 6 hours predicted AUC for the other conditions (evening and real‐life nonfasting). In conclusion, circadian variation of tacrolimus is present when performed in patients who are in the fasting‐state, whereas flatter PK‐profiles and no circadian variation was present in a real‐life, nonfasting setting.
The NOR-SWITCH main and extension trials demonstrated that switching from originator to biosimilar infliximab (CT-P13) is efficacious and safe across six diseases. However, a subgroup analysis of Crohn's disease (CD) in the main trial displayed a close to significant difference favouring originator infliximab, and more scientific data have therefore been requested. The aim was to assess treatment efficacy, safety, and immunogenicity in an explorative subgroup analysis in CD and ulcerative colitis (UC) in the NOR-SWITCH trials. The 52-week, randomised, non-inferiority, double-blind, multicentre, phase 4 NOR-SWITCH study was followed by a 26-week open extension trial where all patients received treatment with CT-P13. Treatment efficacy, safety, and immunogenicity in CD and UC were assessed throughout the 78-week study period. The main and extension trials included 155 and 93 patients with CD and 93 and 80 patients with UC, respectively. Demographic and baseline characteristics were comparable in both treatment arms within patient groups. There were no differences in the main and extension trials regarding changes in activity indices, C-reactive protein, faecal calprotectin, patient's and physician's global assessment of disease activity and patient-reported outcome measures in CD and UC. Moreover, comparable results were also demonstrated for trough serum levels, presence of anti-drug antibodies, and reported adverse events. Efficacy, safety, and immunogenicity of both the originator and biosimilar infliximab were comparable in CD and UC in the NOR-SWITCH main and extension trials. These explorative subgroup analyses confirm that there are no significant concerns related to switching from originator infliximab to CT-P13 in CD and UC. ClinicalTrials.gov, number NCT02148640.
Abstract Background Immunogenicity to tumour necrosis factor inhibitors is a significant clinical problem leading to treatment failure and adverse events. The study aimed to assess human leukocyte antigen (HLA) associations with anti‐drug antibody (ADAb) formation to infliximab. Methods Immune‐mediated inflammatory disease patients on infliximab therapy ( n = 612) were included. Neutralising ADAb were assessed with a drug‐sensitive assay. Next generation sequencing‐based HLA typing was performed. Results Overall, 147 (24%) patients developed ADAb. Conditional analyses indicated HLA‐DQB1 ( p = 1.4 × 10 −6 ) as a primary risk locus. Highest risk of ADAb was seen when carrying at least one of the HLA‐DQ2 haplotypes; DQB1*02:01–DQA1*05:01 or DQB1*02:02–DQA1*02:01 (OR 3.18, 95% CI 2.15–4.69 and p = 5.9 × 10 −9 ). Results were consistent across diseases and when adjusting for concomitant immunomodulator. Computational predictions indicated that these HLA‐DQ2 haplotypes bind to peptide motifs from infliximab light chain. Conclusion A genome‐wide significant association between two HLA‐DQ2 haplotypes and the risk of ADAb formation to infliximab was identified, suggesting that HLA‐DQ2 testing may facilitate personalised treatment decisions.
The aim of the present study was to develop and clinically validate a high-throughput assay for serum IgA and IgG antibodies against transglutaminase-2 (TG2) and to determine appropriate assay cut-offs for large-scale population screening for celiac disease. An automated method was developed using dual label time-resolved fluorometry on the AutoDELFIA platform. Individuals (n = 1920) from the general population were screened. Subjects with serum anti-TG2 concentrations above a preliminary cut-off (>0.3 mg*/L anti-TG2 IgA or >0.5 mg*/L anti-TG2 IgG) were offered endoscopic examination and biopsy. A diagnosis of celiac disease was given if villous atrophy (Marsh grade 3) was found. The assay had a limit of quantification of 0.25 mg*/L (anti-TG2 IgA) and 0.60 mg*/L (anti-TG2 IgG) with imprecision (CV) < 16% and <18% respectively. A total of 66 individuals were above the preliminary cut-off, and 56 underwent endoscopy. Of these, 26 were diagnosed with celiac disease. Sixty-eight percent of subjects with anti-TG2 IgA ≥ 0.7 mg*/L or anti-TG2 IgG ≥ 1.0 mg*/L had biopsy-proven celiac disease, and utilization of these higher cut-offs identified 96% of biopsy-positive patients. At the time of endoscopy, all individuals with anti-TG2 IgA > 2.0 mg*/L had celiac disease, and this cut-off identified 88% of newly diagnosed celiac patients. Eight percent (2/26) of the newly diagnosed patients had primarily anti-TG2 IgG. In this study we developed and clinically validated a robust and automated assay suitable for celiac disease screening in the general population.
Aims To explore the pharmacodynamics of mycophenolic acid (MPA) through inosine monophosphate dehydrogenase (IMPDH) capacity measurement and purine levels in peripheral blood mononuclear cells (PBMC) longitudinally during the first year after renal transplantation (TX). Methods PBMC were isolated from renal recipients 0–4 days prior to and 6–9 days, 5–7 weeks and 1 year after TX (before and 1.5 hours after dose). IMPDH capacity and purine (guanine and adenine) levels were measured in stimulated and nonstimulated PBMC. Results Twenty‐nine patients completed the follow‐up period, of whom 24 received MPA. In stimulated PBMC, the IMPDH capacity (pmol 10 −6 cells min −1 ) was median (interquartile range) 127 (95.8–147) before TX and thereafter 44.9 (19.2–93.2) predose and 12.1 (4.64–23.6) 1.5 hours postdose across study days after TX. The corresponding IMPDH capacity in nonstimulated PBMC was 5.71 (3.79–6.93), 3.35 (2.31–5.62) and 2.71 (1.38–4.08), respectively. Predose IMPDH capacity in nonstimulated PBMC increased with time, reaching pre‐TX values at 1 year. In stimulated PBMC, both purines were reduced before (median 39% reduction across days after TX) and after (69% reduction) dose compared to before TX. No alteration in the purine levels was observed in nonstimulated PBMC. Patients needing dose reductions during the first year had lower pre‐dose IMPDH capacity in nonstimulated PBMC (1.87 vs 3.00 pmol 10 −6 cells min −1 , P = .049) at 6–9 days. Conclusion The inhibitory effect of MPA was stronger in stimulated PBMC. Nonstimulated PBMC became less sensitive to MPA during the first year after TX. Early IMPDH capacity appeared to be predictive of dose reductions.
We appreciate the insightful comments by authors Gaynor and Ciancio to our study that showed a significant association between high estimated tacrolimus clearance and biopsy-proven acute rejection (BPAR) the first 90 days after transplantation.1,2 The authors raise 2 concerns. First, in viewing of the Kaplan-Meier freedom-from-BPAR comparisons (Figures 1–3 in the original article), the unfavorable effect of higher tacrolimus clearance is most pronounced in the first 2 weeks after transplantation. In a new logistic regression analysis (Table 1) (where timing of BPAR is not a component), the odds ratio for BPAR the first 90 days after transplantation showed strikingly similar results as in the Cox regression (Table 2 in the original article). Therefore, timing of BPAR does not seem to affect the overall conclusions of our study.TABLE 1: Multivariate logistic regression model of risk factors associated with BPAR the first 90 days after transplantationSecondly, we agree that evaluating tacrolimus clearance as a time-dependent covariate would have strengthened our analyses. Unfortunately, the necessary data to perform such analysis were not available. Apparent clearance of tacrolimus decreases during the first months after transplantation,3 and we understand the authors’ concern that estimating clearance at earlier time points for patients experiencing BPAR may have introduced systematic differences. As discussed in the original article, using the 8-week clearance values for all patients regardless of BPAR led to similar results as the original analysis. We chose to report the pre-BPAR data for those patients, since there is a theoretical risk that the steroid-based antirejection treatment may influence tacrolimus metabolism, also at the 8-week estimates for at least some patients. We also agree that the use of different strengths of maintenance steroids may affect tacrolimus clearance. However, when excluding the high-risk patients who start on 80 mg prednisolone as compared to 20 mg in standard-risk patients, the multivariate analysis (published as Supplemental Digital Content to the original article, Table S1, SDC,https://links.lww.com/TP/B443) showed the same results as the analysis based on the whole population. Actually, several factors may affect the clearance and/or bioavailability of tacrolimus, including steroids, body size and composition, cytochrome P450 enzyme genotypes, concomitant food or drug intake, etc. However, irrespective of the underlying determinants of individual apparent clearance, our analysis indicates that this crude clearance approximation may provide a simple marker to identify patients at higher risk for acute rejection episodes.
The aim of the study was to assess RF cross-reactivity to animal antibodies used in immunoassays, and to test if selected commercial immunoassays are vulnerable to interference from RF, causing false test results. Our study included samples from patients with RF-positive rheumatoid arthritis (RA) and controls (patients with RF-negative RA and psoriatic arthritis), included in an early arthritis-cohort. Reactivity to mouse IgG1, mouse IgG2a, rabbit IgG, bovine IgG, sheep/goat IgG and human IgG was analysed using in-house interference assays. RF-positive sera with strong reactivity to mouse IgG1 were analysed in three commercial immunoassays. To reveal interference, results before and after addition of blocking aggregated murine IgG1 were compared. Samples from 124 RF-positive RA patients and 66 controls were tested. We found considerably stronger reactivity toward animal antibodies, particularly mouse IgG1 (73% vs. 12%) and rabbit IgG (81% vs. 6%), in sera from RF-positive RA-patients compared to controls (p < 0.001). After selecting samples for testing in commercial assays, interference was revealed in 6/30 sera in the Architect β-hCG assay, 7/10 sera in the 27-plex cytokine assays, and in 2/33 samples in the Elecsys Soluble Transferrin Receptor assay. Our study revealed considerable RF reactivity to animal antibodies used in immunoassays and RF was associated with falsely elevated results in immunoassays used in clinical care and research. Clinicians, laboratorians, researchers and assay manufacturers must be alert to the risk of falsely elevated test results in RF-positive RA patients.
De prognose van reumatoide artritis (RA) is de laatste tien jaar sterk verbeterd door nieuwe therapeutische mogelijkheden. Een van deze middelen blokkeert TNF, een pro-inflammatoir cytokine (eiwit dat invloed heeft op het immuunsysteem). Dertig procent van de patienten reageert echter niet op het medicijn. Ruth Klaasen zocht naar biomarkers en kenmerken bij de patient die kunnen voorspellen bij wie het middel werkt (de respons). Ze vond een aantal biomarkers die de respons op groepsniveau voorspellen. Op basis hiervan kunnen bestaande behandelalgoritmen verder worden verfijnd. Ook keek Klaasen naar de relatie tussen (adipo)cytokines en botdichtheid in relatie tot de klinische respons op TNF-blokkade in RA.
