Which is the best PML risk stratification strategy in natalizumab-treated patients affected by multiple sclerosis?

Abstract

Background: The risk of progressive multifocal leukoencephalopathy (PML), a brain infection caused by John Cunningham virus (JCPyV), is the main limitation to the use of natalizumab, highly effective in the treatment of relapsing remitting multiple sclerosis (RRMS) patients. Establishing the PML risk against expected benefits represents an obligatory requirement of MS treatment algorithm. In order to achieve this goal, the aims of this study were to establish if JCPyV-DNA detection and non-coding control region (NCCR) arrangements could play a role of biomarkers, supporting anti-JCPyV antibodies measurement, actually the only parameter for PML risk stratification. Methods: Thirty RRMS patients in treatment with natalizumab were enrolled. Urine and blood samples were collected according to this calendar: baseline (T0), 4 (T1), 8 (T2), 12 (T3), 16 (T4), 20 months (T5) after beginning of natalizumab therapy. After JCPyV DNA extraction, a specific quantitative-PCR (Q-PCR) and arrangements' analysis of NCCR and Viral Capsid Protein 1 (VP1) were carried out. Results: Q-PCR detected JCPyV DNA in urine and blood from baseline (T0) to 20 natalizumab infusions (T5), although JC viral load in urine was significantly higher compared to viremia, at all selected time points. A contextual analysis of the anti-JCPyV-antibodies versus JCPyV-DNA detection revealed that viral DNA preceded the antibodies' presence in the serum. During the first year of natalizumab treatment, sequences isolated from blood displayed an archetype JCPyV NCCR structure with the occurrence of point mutations, whereas after one year NCCR reorganizations were observed in plasma and PBMC with duplication of NF-1 binding site in box F, duplication of box C and partial or total deletion of box D. VP1 analysis showed the amino acid change mutation S269F in plasma and S267L in PBMC, involving the receptor-binding region of VP1. Phylogenetic analysis suggested a stability and a similarity across different isolates of the JCPyV VP1. Conclusions: We highly recommend considering JCPyV-DNA detection and NCCR reorganizations as viral biomarkers in order to accurately identify JCPyV-infected patients with a specific humoral response not yet detectable and to identify NCCR arrangements correlated with the onset of neurovirulent variants. Specifically, to date, 13 disease-modifying therapies (DMTs) for treatment of relapsing-remitting multiple sclerosis (RRMS), the most prevalent MS phenotype, have been approved by the Food and Drug Administration (FDA) and have changed the scenery for care of RRMS patients (Tintore et al., 2019). Although these newer drugs allowed long periods of disease activity-free remission (Giovannoni et al., 2018),

Teriflunomide Inhibits JCPyV Infection and Spread in Glial Cells and Choroid Plexus Epithelial Cells

“…In the two patients with PML, both CSF and plasma were strongly positive for JCPyV genomes when either the bulk biofluid or the EV fraction was tested. Consistent with other reports of viral genomes in EV, only a fraction of the total genome copy numbers were found to be associated with the EV [ 30 , 31 ]. It is unclear whether this is because there were fewer viral genomes in the EV compared with the total or whether this represents a loss of EV during processing, which included size-exclusion chromatography and ultrafiltration.…”

“…Moreover, choroid plexus epithelial cells play an important role in communicating between the blood and the brain using EV [ 29 ]. Several groups have shown that EV harbor JCPyV genomes both in vivo and in vitro and contribute significantly to virus invasion of naïve cells [ 30 , 31 ]. EV are also capable of carrying mutant viruses that can only infect cells when associated with these vesicles [ 13 , 14 , 32 ].…”

“…The trend, however, points to increased viral genomes in natalizumab-treated patients versus patients who did not receive natalizumab. Risk stratification based on ddPCR or quantitative PCR would clearly be more sensitive and accurate than relying on the current standard of measuring antibody indices [ 31 , 33 , 34 ]. None of the CSF samples from non-PML patients were positive.…”

Managing multiple sclerosis in the Covid19 era: a review of the literature and consensus report from a panel of experts in Saudi Arabia

“…The MSIF counselled caution in the use of higher efficacy DMTs where rates of Covid-19 disease are high, with retreatments with anti-CD20 agents or cladribine tablets recommended when a prevailing high level of local Covid-19 infection has reduced. The patient's individualised risk of progressive multifocal leukoencephalopathy (PML; Bloomgren et al, 2012;Prezioso et al, 2020) should be considered in parallel with consideration of local Covid-19 infection rates before starting natalizumab, and the use of alemtuzumab was recommended only when Covid-19 rates are low. The MSIF also added a note of caution to the use of anti-CD20 DMT therapy for patients with primary progressive MS (PPMS) at higher levels of disability, as the likelihood of comorbidity in this population may complicate a Covid-19 infection further during the use of this treatment.…”

Blood-Brain Barrier: More Contributor to Disruption of Central Nervous System Homeostasis Than Victim in Neurological Disorders

“…Natalizumab, a monoclonal antibody (McAb) mainly used in treatment of relapsing-remitting MS, can prevent leukocyte adherence and blocks integrin α-4 on ECs, thereby protecting the BBB (Haarmann et al, 2015). However, as an efficient inflammatory suppressant, it also inhibits immune surveillance and leads to progressive multifocal leukoencephalopathy (PML), an infectious disease caused by John Cunningham virus (Prezioso et al, 2020), which unfortunately restricts its clinical application.…”