Towards optimal cut-off trough levels of adalimumab and etanercept for a good therapeutic response in rheumatoid arthritis. Results of the INMUNOREMAR study

Sanmarti, Raimón; Inciarte-Mundo, J.; Estrada-Alarcon, Paula; García-Manrique, M.; Narváez, Javier; Rodriguez-Moréno, J; Gόmez-Centeno, A.; Pascal, Mariona; Yagüe, Jordi

doi:10.1136/annrheumdis-2015-207530

Cited by 25 publications

(20 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has been shown that patients with good response to TNFi therapy have higher drug trough serum levels than those with a poor response (28)(29)(30)(31). In accordance with the strong correlation between calprotectin and disease activity observed previously, our results show a significant inverse correlation between IFX and ETN and calprotectin, although no significant association was observed with ADA.…”

Section: Discussionsupporting

confidence: 92%

“…Only calprotectin distinguished between RA patients in clinical remission and those with low disease activity according to all indices analyzed, a finding that was also observed in PsA. Calprotectin serum levels correlated inversely with TNFi trough serum levels, which are known to be associated with a good therapeutic response (28)(29)(30)(31).…”

Section: Discussionsupporting

confidence: 52%

See 1 more Smart Citation

Serum Calprotectin Versus Acute‐Phase Reactants in the Discrimination of Inflammatory Disease Activity in Rheumatoid Arthritis Patients Receiving Tumor Necrosis Factor Inhibitors

Inciarte-Mundo

Hernández

Ruíz-Esquide

et al. 2016

Arthritis Care & Research

Self Cite

View full text Add to dashboard Cite

Objective. To compare the accuracy of serum calprotectin and acute-phase reactants (C-reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) in stratifying disease activity in rheumatoid arthritis (RA) patients receiving tumor necrosis factor inhibitors (TNFi), and to correlate calprotectin levels with TNFi trough serum levels. Methods. We conducted a cross-sectional study of 87 RA patients receiving adalimumab, etanercept (ETN), or infliximab (IFX); 56 psoriatic arthritis (PsA) patients and 40 healthy blood donors were included as controls. Associations between calprotectin, CRP, and ESR and composite articular indices (Disease Activity Score in 28 joints [DAS28], Simplified Disease Activity Index [SDAI], and Clinical Disease Activity Index) were analyzed by correlation and linear regression and the accuracy and discriminatory capacity of calprotectin by receiver operator characteristic curves (area under the curve [AUC]). Results. Calprotectin levels correlated better with all composite activity indices than CRP and ESR (all r coefficients >0.70). Calprotectin levels were significantly lower in RA and PsA patients in clinical remission compared with those with low disease activity for all articular indices. In RA, ESR discriminated between remission and low disease activity only when using DAS28, and CRP only with SDAI. In RA patients in remission/low disease activity, calprotectin but not CRP or ESR distinguished between patients with no swollen joints and those with ‡1 swollen joint (1.74 mg/ml versus 3.04 mg/ml; P 5 0.010). Using DAS28 ‡2.6 as the reference variable, calprotectin showed an AUC of 0.92; the best cutoff was ‡2.47 mg/ml with a likelihood ratio of 6.3 (95% confidence interval 2.5-15.8). Calprotectin serum levels inversely correlated with trough serum drug levels of ETN (r 5 20.671, P < 0.001) and IFX (r 5 20.729, P 5 0.017). Conclusion. Calprotectin may more accurately discriminate disease activity in RA patients receiving TNFi than acutephase reactants, even in patients with low inflammatory activity.

show abstract

Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 52%

Serum Calprotectin Versus Acute‐Phase Reactants in the Discrimination of Inflammatory Disease Activity in Rheumatoid Arthritis Patients Receiving Tumor Necrosis Factor Inhibitors

Inciarte-Mundo

Hernández

Ruíz-Esquide

et al. 2016

Arthritis Care & Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…Chen et al [39] found that the optimal cut-off trough levels for etanercept were 1.242 μg ml -1 and 0.800 μg ml -1 for a good EULAR response, assessed at the 6th and 12th month, respectively. These results were corroborated by Sanmartí et al [46], who also set the cut-off value at 1.56 μg ml -1 . Finally, Zhou et al [47] evaluated the impact of MTX coadministration on the PK of etanercept in patients with RA, concluding that it had no effect, so dose adjustment was not required with concurrent use of this drug.…”

Section: Etanerceptsupporting

confidence: 71%

“…These results were corroborated by Sanmartí et al . , who also set the cut‐off value at 1.56 μg ml –1 . Finally, Zhou et al evaluated the impact of MTX coadministration on the PK of etanercept in patients with RA, concluding that it had no effect, so dose adjustment was not required with concurrent use of this drug.…”

Section: Therapeutic Drug Monitoring (Tdm)mentioning

confidence: 99%

Is there potential for therapeutic drug monitoring of biologic agents in rheumatoid arthritis?

Bastida

Ruiz

Pascal

et al. 2017

Brit J Clinical Pharma

Self Cite

View full text Add to dashboard Cite

The use of biologics has significantly changed the management of rheumatoid arthritis over the last decade, becoming the cornerstone treatment for many patients. The current therapeutic arsenal consists of just under 10 biologic agents, with four different mechanisms of action. Several studies have demonstrated a large interindividual pharmacokinetic variability, which translates to unpredictability in clinical response among individuals. The present review focuses on the pharmacokinetics and pharmacodynamics of biologic agents approved for rheumatoid arthritis. The literature relating to their concentration-effect relationship and the use of pharmacokinetic-pharmacodynamic modelling to optimize drug regimens is analysed. Due to the scarcity and complexity of these studies, the current dosing strategy is based on clinical indexes/aspects. In general, dose individualization for biologics should be implemented increasingly in clinical practice as there is a direct benefit for treated rheumatoid arthritis patients. Moreover, there is an indirect benefit in terms of cost-effectiveness.

show abstract

“…In patients with RA receiving 40 mg of Humira ® every other week, adalimumab mean steady-state trough concentrations range from approximately 5 to 9 μg/mL [39]. Previous studies have reported that the cut-off trough levels of etanercept and adalimumab for a good therapeutic response in patients with RA are 1.046 to 1.56 μg/mL and 1.274 to 1.336 μg/mL, respectively [40, 41]. Therefore, etanercept was used at sub-therapeutic and therapeutic concentrations (0.1 and 1 μg/mL), and adalimumab was used at therapeutic and higher concentrations (1 and 10 μg/mL) in our study.…”

Section: Methodsmentioning

confidence: 99%

The immunomodulatory effects of TNF-α inhibitors on human Th17 cells via RORγt histone acetylation

Lin

et al. 2016

Oncotarget

View full text Add to dashboard Cite

The presence of interleukin (IL)-17-related cytokines correlates with rheumatoid arthritis (RA) pathogenesis. Epigenetic modifications, including histone acetylation, regulate gene expression in RA pathogenesis. Tumour necrosis factor-alpha (TNF-α) inhibitors such as etanercept and adalimumab, represent a breakthrough in RA treatment. We aimed to investigate the effects of etanercept and adalimumab on human Th17-polarized cells and the possible intracellular regulators of these effects, including the Th17-specific transcription factors signal transducer, activator of transcription 3 (STAT3), retinoid-related orphan receptor γ-T (RORγt) and epigenetic modification. Human CD4+ T cells from healthy subjects and patients with RA were pretreated with TNF-α inhibitors and then being polarized into IL-17-producing cells. The Th17-related cytokine levels in the culture supernatants were determined with an enzyme-linked immunosorbent assay. Intracellular signalling was investigated by western blot, real-time RT-PCR, and chromatin immunoprecipitation. Th17-polarized cells from patients with RA produced more IL-17A, IL-17F and IL-22 than those from healthy subjects. Etanercept and adalimumab suppressed IL-17A, IL-17F and IL-22 levels in Th17-polarized cells from healthy subjects and patients with RA. Western blot analysis revealed that etanercept and adalimumab decreased mitogen-activated protein kinase-phospho-p38, nuclear factor-κB-phospho-p65, phospho-STAT3 and RORγt levels. Etanercept and adalimumab decreased histone (H)3 and H4 acetylation in the RORγt gene promotor region by decreasing the recruitment of the acetyltransferases p300, CBP and PCAF. The present study broadens our knowledge of the mechanisms underlying the immunomodulatory effects of TNF-α inhibitors in rheumatoid arthritis treatment.

show abstract

Towards optimal cut-off trough levels of adalimumab and etanercept for a good therapeutic response in rheumatoid arthritis. Results of the INMUNOREMAR study

Cited by 25 publications

References 5 publications

Serum Calprotectin Versus Acute‐Phase Reactants in the Discrimination of Inflammatory Disease Activity in Rheumatoid Arthritis Patients Receiving Tumor Necrosis Factor Inhibitors

Serum Calprotectin Versus Acute‐Phase Reactants in the Discrimination of Inflammatory Disease Activity in Rheumatoid Arthritis Patients Receiving Tumor Necrosis Factor Inhibitors

Is there potential for therapeutic drug monitoring of biologic agents in rheumatoid arthritis?

The immunomodulatory effects of TNF-α inhibitors on human Th17 cells via RORγt histone acetylation

Contact Info

Product

Resources

About