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. 2020 Feb 4;7(3):e678.
doi: 10.1212/NXI.0000000000000678. Print 2020 May 4.

Wearing-off at the end of natalizumab dosing intervals is associated with low receptor occupancy

Gerd Haga Bringeland  1 , Nello Blaser  2 , Kjell-Morten Myhr  2 , Christian Alexander Vedeler  2 , Sonia Gavasso  2
Affiliations

Wearing-off at the end of natalizumab dosing intervals is associated with low receptor occupancy

Gerd Haga Bringeland et al. Neurol Neuroimmunol Neuroinflamm. .

Abstract

Objective: We aimed to investigate whether wearing-off symptoms at the end of the natalizumab dosing interval were associated with clinical and demographic patient characteristics or natalizumab receptor occupancy (RO) on leukocytes.

Methods: In this cross-sectional study of 40 patients with relapsing-remitting MS (RRMS) receiving natalizumab at the Department of Neurology, Haukeland University Hospital, we recorded clinical and demographic data including age, body mass index (BMI), working status, smoking habits, disease characteristics, treatment duration, vitamin D levels, and wearing-off symptoms. We quantified neurofilament light chain in serum and measured natalizumab RO in leukocyte subtypes by high-parameter mass cytometry. Associations with wearing-off symptoms were analyzed.

Results: Eight (20.0%) patients who reported regular occurrence of wearing-off symptoms, 9 (22.5%) who sometimes had wearing-off symptoms, and 23 (57.5%) who did not have wearing-off symptoms were evaluated. Patients who regularly had wearing-off symptoms had lower natalizumab RO than patients who reported having such symptoms sometimes or never. The former group also had higher BMI and higher frequency of sick leave. High BMI was associated with low RO. No other demographic or disease characteristics were associated with the phenomenon.

Conclusions: Low RO may explain the wearing-off phenomenon observed in some patients with RRMS treated with natalizumab, and high BMI may be the underlying cause.

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Figures

Figure 1
Figure 1. Natalizumab receptor occupancy (RO) in patients reporting wearing-off symptoms never, sometimes, or regularly
(A) Manually gated PBLs visualized on a viSNE map. RO was analyzed in 11 cell subtypes: CD8+ central memory (TCM), effector memory (TEM), effector memory RA (TEMRA) cells; CD4+ TEM, TCM, and TEMRA cells; CD34+ cells; memory B cells; natural killer (NK) cells; monocytes; and conventional dendritic cells (cDCs). Neutrophils were not included in RO analysis. (B) Spider plot of median RO values in 11 cell subtypes in patients before and after natalizumab infusion. (C) RO values in 11 cell subtypes before and after natalizumab infusion. p values (Kruskal-Wallis test) comparing ROs in different wearing-off groups. (D) Left: median RO values in cell clusters significantly different between wearing-off groups (SAM analysis in CITRUS). Right: significant cell clusters are visualized on the viSNE map. PBL = peripheral blood leukocyte; SAM = Significance Analysis of Microarrays.
Figure 2
Figure 2. Linear regression analysis demonstrates an association between RO and BMI
Plot of receptor occupancies (A) before and (B) after infusion for indicated cell types as a function of BMI. Solid lines have slopes that are significantly different from zero (p < 0.05), and dashed lines have slopes that are not significantly different from zero. BMI = body mass index; RO = receptor occupancy.
See this image and copyright information in PMC

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