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

Kneepkens, E.; Oever, I. van den; Plasencia, C.; Pascual‐Salcedo, Dora; Vries, Annick de; Hart, Mia van der; Nurmohamed, Michael T.; Balsa, Alejandro; Rispens, Theo; Wolbink, Gertjan

doi:10.1080/03009742.2016.1183039

Cited by 33 publications

(39 citation statements)

References 41 publications

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“…There are inherent problems with each of the currently available biomarkers in respect of disease activity. It is known, for example, that secretion of CRP is largely IL-6 and TNFα dependant, and novel therapies such as tocilizumab ( 23 ), tumor necrosis factor α inhibition ( 24 ) and indeed, tofacitinib, interrupt this pathway. This may lead to a decrease in CRP, which does not necessarily reflect a decrease in disease activity.…”

Section: Discussionmentioning

confidence: 99%

The Utility and Limitations of CRP, ESR and DAS28-CRP in Appraising Disease Activity in Rheumatoid Arthritis

et al. 2018

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Introduction: Identifying and quantifying inflammatory disease activity in rheumatoid arthritis remains a challenge. Many studies have suggested that a large proportion of patients may have active inflammation, but normal inflammatory markers. Although various disease activity scores have been validated, most rely to a large degree on biomarkers such as CRP and ESR. In this study, we examine the utility and limitations of these biomarkers, as well as the DAS28-CRP in appraising disease activity in RA.Methods: Two hundred and twenty three consecutive rheumatoid arthritis reporting knee arthralgia underwent synovial sampling of the affected knee via needle arthroscopy. The synovium was examined by microscopy with H+E staining as well as immunohistochemistry, and related to the ESR, CRP and DAS28-CRP on blood samples taken immediately before arthroscopy.Results: Although a statistically significant positive correlation was observed between CRP and the level of inflammation in the biopsy retrieved (n = 197, rho = 0.43, CI 0.30–0.54, p < 0.0001), there was histological evidence of inflammation in the synovium in 49.4% of the patients who had a normal CRP. A positive correlation was also observed between ESR and the level of inflammation in the biopsy retrieved (n = 188, rho = 0.29, CI 0.15–0.42 p < 0.0001). A statistically significant but weak positive correlation was observed between the DAS28-CRP and synovial inflammation (n = 189, rho = 0.23, CI 0.09–0.37, p = 0.0011). Only the CD19 infiltrate in the synovium correlated with serum CRP (n = 70, rho = 0.32, CI 0.08–0.52, p = 0.0068).Conclusion: CRP has a moderately strong relationship with disease activity, but there are significant pitfalls in the use of this biomarker in RA, and therefore a need interpret CRP results judiciously. The results of this study underline the heterogeneity of RA, and the need to develop improved panels of biomarkers, to better stratify RA, and to identify the cohort for whom inflammatory activity cannot be measured accurately with CRP.

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Section: Discussionmentioning

confidence: 99%

The Utility and Limitations of CRP, ESR and DAS28-CRP in Appraising Disease Activity in Rheumatoid Arthritis

et al. 2018

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“…ADA toward certolizumab pegol were associated with lower drug concentration but not with a lower clinical response 92. Furthermore, ADA have been detected toward etanercept (although non-neutralizing antibodies), rituximab, tocilizumab and abatacept, but no impact on drug exposure and response has been observed 18,31,91,95,96. TDM-based treatment optimization of infliximab, adalimumab and etanercept has been explored in a few studies, overall suggesting a cost-effectiveness 13,14,16,35,97.…”

Section: Current Status Of Tdm In Inflammatory Diseasesmentioning

confidence: 95%

Practical recommendations for the use of therapeutic drug monitoring of biopharmaceuticals in inflammatory diseases

Dreesen¹,

Bossuyt²,

Mulleman³

et al. 2017

CPAA

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Biopharmaceuticals directed against tumor necrosis factor-alpha, integrins, interleukins, interferons and their receptors have become key agents for the management of inflammatory diseases in the fields of gastroenterology, rheumatology, dermatology and neurology. However, response to these treatments is far from optimal. Therapeutic failure has been attributed in part to inadequate serum concentrations of the drug and the formation of antidrug antibodies (ADA). Therapeutic drug monitoring (TDM) based on drug concentrations and ADA represents a pharmacologically sound tool for guiding dosage adjustments to optimize exposure. Although becoming standard practice in tertiary care centers, the widespread accessibility and recognition of TDM is hindered by several hurdles, including a lack of education of health care providers on TDM. In this paper, the Monitoring of monoclonal Antibodies Group in Europe (MAGE) provides an introduction on the fundamental principles of the concept of TDM, aiming to educate clinicians and assist them in the process of implementing TDM of anti-inflammatory biopharmaceuticals.

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“…Tocilizumab completely inhibits the IL-6 receptor at ;4 mg/mL, the same concentration needed to see clinical improvement in rheumatologic conditions. [16][17][18] Intraventricular, but not IV delivery of tocilizumab, in this study achieves these therapeutic concentrations within the CSF. One important limitation is that this study uses physiologically and neurologically normal NHP with an intact blood-brain barrier at the time of tocilizumab administration.…”

Section: The National Cancer Institute Institutional Animal Care and Usementioning

confidence: 99%

“…The simplified prognostic score as proposed by the SLSG was calculated at the time of diagnosis and before treatment initiation. [16][17][18] Criteria for rituximab initiation were bulky/ symptomatic splenomegaly, cytopenias, B symptoms, and autoimmune manifestations. Treatment included an induction phase consisting of 6 weekly rituximab infusions (375 mg/m 2 ).…”

Section: The National Cancer Institute Institutional Animal Care and Usementioning

confidence: 99%

Improved CNS exposure to tocilizumab after cerebrospinal fluid compared to intravenous administration in rhesus macaques

Nellan

McCully

Garcia

et al. 2018

Blood

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transferrin endocytosis and recycling assays showed a significantly enhanced rate of recycling suggestive of a gain-of-function effect. However, the phenotypic overlap with our patients suggests that the p.Gly425Arg variant is also pathogenic, leading to a milder phenotype within the same spectrum. Therefore, pathogenic RBSN variants, in homozygous or heterozygous state, should also be considered in cases of unexplained transient neutropenia, particularly when neurologic abnormalities and/or myelofibrosis are also present.

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

Cited by 33 publications

References 41 publications

The Utility and Limitations of CRP, ESR and DAS28-CRP in Appraising Disease Activity in Rheumatoid Arthritis

The Utility and Limitations of CRP, ESR and DAS28-CRP in Appraising Disease Activity in Rheumatoid Arthritis

Practical recommendations for the use of therapeutic drug monitoring of biopharmaceuticals in inflammatory diseases

Improved CNS exposure to tocilizumab after cerebrospinal fluid compared to intravenous administration in rhesus macaques

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