Bernard M J Uitdehaag’s research while affiliated with Amsterdam University Medical Center and other places

Background: Human leukocyte antigen (HLA) genes are key regulators of immune function and have been implicated in susceptibility to various diseases. However, their role in healthy longevity remains unclear. Here, we investigate the relationship between disease associated HLA alleles and the likelihood of becoming a cognitively healthy centenarian (CHC). Methods: We imputed HLA genotypes using genetic data from 3,634 individuals, including 354 CHCs from the Dutch 100 plus Study and 3,269 middle aged healthy individuals from multiple Dutch cohorts. We examined associations between 59 HLA alleles previously linked to 12 diseases (including Alzheimer's disease (AD), ten autoimmune disorders, and SARSCoV2) and the likelihood of becoming a CHC. Logistic regression models were used to estimate odds ratios (ORs), adjusting for population structure. We then calculated centenarian effect ratios (CERs) to compare the effect sizes of HLA alleles on the chance of becoming a CHC relative to their known effects on disease susceptibility, assessing the directions of potential pleiotropic effects. Results: While the genomes of CHCs were not enriched with any specific HLA alleles, six alleles reduced the likelihood of becoming a CHC (ORs=0.59 to 0.74, FDR<0.1). These alleles clustered into three haplotypes based on linkage disequilibrium: a class II haplotype (HLA DRB1*01:01, HLA DQA1*01:01, HLA DQB1*05:01), a class I haplotype (HLA C*03:04, HLA B*40:01), and an independent class I allele (HLA A*02:01). We identified both synergistic and antagonistic pleiotropic relationships between autoimmune disease associated HLA alleles and becoming a CHC, with similar magnitudes of effect sizes. HLA alleles associated with increased risk of AD consistently exhibited synergistic pleiotropies, with a 5 to 10 fold larger effect on decreased likelihood of healthy longevity. Conclusions: Our findings highlight a complex interplay between HLA alleles associated with autoimmune disease susceptibility and healthy longevity. The strongly increased effect sizes and synergistic pleiotropic relationships between the likelihood of becoming a cognitively healthy centenarian and HLA alleles previously associated with AD, highlight the involvement of immune related mechanisms in longevity and neurodegeneration. Further studies, employing Next-Generation-Sequencing and Long Read Sequencing, preferably in diverse populations, are needed to map our findings to the full genetic resolution of the HLA region.

This cross-sectional study examines the increase in positive results for John Cunningham virus antibodies and higher risk for progressive multifocal leukoencephalopathy among patients with multiple sclerosis receiving natalizumab.

Background Natalizumab is a highly effective drug for patients with relapsing-remitting multiple sclerosis (MS). A disadvantage of this treatment is the risk of progressive multifocal leukoencephalopathy in patients who are seropositive for the John Cunningham virus (JCV). JCV seroconversion rates increase under natalizumab treatment compared with non-natalizumab using controls. The aim of this study was to assess whether lower natalizumab trough concentrations are associated with reduced JCV seroconversion compared with higher natalizumab trough concentrations. Methods Two overlapping cohorts of patients treated with intravenous natalizumab in the Netherlands were combined for this study. JCV seroconversion was assessed during periods of high (≥15 µg/mL) and low (<15 µg/mL) natalizumab trough concentrations. Low trough concentrations were mainly the result of trough concentration guided personalised extended interval dosing (EID). The seroconversion rates during high and low trough concentrations were compared using a generalised linear mixed model with a Poisson link function. Results A total of 357 patients from 21 hospitals in the Netherlands were included. The annual seroconversion rate of 8.4% observed in patients during periods of high trough concentrations (n=226) was 2.32 times higher than the seroconversion rate of 4.8% in patients during periods of low trough concentrations (n=252) (95% CI=1.32 to 4.08, p=0.0035). Conclusions The seroconversion rate observed in patients with MS with low trough concentrations was substantially lower compared with those with high trough concentrations during natalizumab treatment. This emphasises the importance of personalised EID, where intervals between infusions are prolonged to achieve lower natalizumab trough concentrations, to increase drug safety.

Background Some disease-modifying treatments (DMTs) for multiple sclerosis (MS) increase the risk of infection, but it remains unknown how the risk compares between trials and observational studies. Objective To assess the current state of observational research on the risk of infection in people with MS and using DMTs. Methods PubMed and Embase were searched for observational studies published on or before 4 April 2023 describing infection in people with MS, with a comparison of at least 1 DMT to no DMT or another DMT. We examined which DMT contrasts and types of infection were studied and how often; and compared observational results of the most frequently studied DMT to trial data from a network meta-analysis. Results Out of 5373 search records 22 papers were eligible, of which 5 reported relative risks (RRs). In total, 9 DMTs were studied. Out of 45 possible contrasts, 9 were not studied, and 19 once. The most assessed specific type of infection was neurological ( n = 11/22 studies). Natalizumab was the most studied DMT contrasting 7 other DMTs or no DMT, with 12 RRs reported. Point estimates of the RRs (compared to no DMT) for respiratory and urinary tract infections were in opposite direction compared to trial data. Conclusion Observational study data on the risk of infection in people with MS on DMT are sparse. The growing availability of real-world data on MS and DMT use provides an opportunity to study specific infections on DMT, which is particularly valuable to populations underrepresented in trials.

Background and objectives: Progression independent of relapse activity (PIRA) is increasingly used as a measure of disability worsening in multiple sclerosis (MS) and is believed to reflect the more chronic neurodegenerative aspect of MS. However, while conceptually appealing, PIRA and its counterpart relapse-associated worsening (RAW) have not been validated as outcome measures for clinical trials. Here, we study the co-occurrence of MRI activity in patients experiencing PIRA and RAW in a clinical trial setting. To illustrate the problem of random variation and measurement error of these new outcomes, we contrasted PIRA and RAW with similarly defined improvement. Methods: We reanalyzed individual patient-level data of AFFIRM (NCT00027300) and SENTINEL (NCT00030966), 2 multicenter randomized controlled trials investigating natalizumab compared with interferon beta or placebo in RRMS, with trial visits occurring every 3 months for 2 years. We calculated 3-month-confirmed disability worsening (3M-CDW), RAW, and PIRA events based on worsening on the Expanded Disability Status Scale, 9-hole peg test, or timed 25-foot walk for every trial visit. We related worsening and improvement events to MRI activity throughout follow-up and contrasted worsening of disability with similarly defined improvement. Results: Our analysis included 2,113 participants, 42.4% of whom developed radiologic disease activity during follow-up. Only 8% of participants had a 3M-CDW event. Although the majority of those 3M-CDW events were PIRA (6.8%) and not RAW (0.9%), 42.2% of participants with PIRA had MRI activity in the first year of follow-up and 30.9% in the second. Improvement events exceeded PIRA events throughout follow-up and occurred in all trial arms. Finally, there was no difference in time-to-PIRA between participants with and without radiologic disease activity. Discussion: PIRA and RAW in their current definitions do not reliably distinguish between disability worsening due to inflammatory disease activity and neurodegeneration in RRMS. In addition, PIRA and RAW have similar and troubling issues of random variation and measurement error as currently used trial outcome measures. Our analysis requires confirmation in other clinical data sets; a meaningful next step would be to study the co-occurrence of PIRA with radiologic disease activity in a setting with more comprehensive MRI monitoring.

Objective To assess the interrelationship between cortical lesions and cortical thinning and volume loss in people with multiple sclerosis within cortical networks, and how this relates to future cognition. Methods In this longitudinal study, 230 people with multiple sclerosis and 60 healthy controls underwent 3 Tesla MRI at baseline and neuropsychological assessment at baseline and 5‐year follow‐up. Cortical regions (N = 212) were divided into seven functional networks. Regions were defined as either lesional or normal‐appearing cortex based on presence of a cortical lesion on artificial intelligence‐generated double inversion‐recovery scans. Cortical volume and thickness were determined within lesional or normal‐appearing cortex. Results Prevalence of at least one cortical lesion was highest in the limbic (73%) followed by the default mode network (70.9%). Multiple sclerosis‐related cortical thinning was more pronounced in lesional (mean Z‐score = 0.70 ± 0.84) compared to normal‐appearing cortex (−0.45 ± 0.60; P < 0.001) in all, except sensorimotor, networks. Cognitive dysfunction, particularly of verbal memory, visuospatial memory, and inhibition, at follow‐up was best predicted by baseline network volume of normal‐appearing cortex of the default mode network [B (95% CI) = 0.31 (0.18; 0.43), P < 0.001]. Mediation analysis showed that the effect of cortical lesions on future cognition was mediated by volume loss of the normal‐appearing instead of lesional cortex, independent of white matter lesion volume. Interpretation Multiple sclerosis‐related cortical thinning was worse in lesional compared to normal‐appearing cortex, while volume loss of normal‐appearing cortex was most predictive of subsequent cognitive decline, particularly in the default mode network. Mediation analyses indicate that cortical lesions impact cognitive decline plausibly by inducing atrophy, rather than through a direct effect.

Purpose The purpose of this study was to describe the intensity and patterns of antibiotic drug use among people with multiple sclerosis (pwMS) in the Netherlands. Methods People with prevalent MS between 1 January 2018 and 31 December 2020 were identified using ambulatory hospital records from the PHARMO Database Network that contains routinely collected healthcare data from the Netherlands. Out‐patient pharmacy dispensing data were used to assess type of antibiotic, dosage, and amounts dispensed. Antibiotic intensity in defined daily doses (DDD)/1000 patient‐days (PD) was calculated together with frequency of dispensing of the same (prolongation) or different (switch) antibiotic up to 3 days after the end of the last antibiotic prescription; and stratified by sex, age, polypharmacy (use of > 4 out‐patient prescription drugs for > 29 days), type of disease‐modifying treatment, and Sars‐CoV‐2‐related lockdown. Results A total of 1960 (37.8%) out of 5179 pwMS were dispensed ≥ 1 antibiotic. Of the 8762 dispensing events, 27.6%% were part of a prolongation, and 16.3% of a switch. Overall antibiotic use among pwMS was 18.8 DDD/1000 PD (95% confidence interval [95% CI]: 18.7–19.0) compared to 7.77–8.90 DDD/1000 PD in the general out‐patient population, as reported by the Dutch Working Party on Antibiotic Policy. Antibiotic use was higher among women, increased with age, and was higher in people with polypharmacy and lower during lockdown. Nitrofurantoin was the most commonly dispensed antibiotic (41.7%). Conclusions The intensity of antibiotic use is considerably higher among pwMS than the general population. This reflects the burden of infection in this susceptible population.

Importance Increasing numbers of people with multiple sclerosis (MS) use disease-modifying therapy (DMT). Long-term stable disease while taking such medications provides a rationale for considering DMT discontinuation given patient burden, costs, and potential adverse effects of immunomodulating therapy. Objective To investigate whether first-line DMT can be safely discontinued in patients with long-term stable MS. Design, Setting, and Participants This multicenter, rater-blinded, noninferiority randomized clinical trial was conducted between July 1, 2020, and March 20, 2023, at 14 Dutch centers. Data analysis was performed between July 2023 and January 2024. Key inclusion criteria were relapse-onset MS, aged 18 years or older, without relapses, and without substantial magnetic resonance imaging (MRI) activity in the previous 5 years under first-line DMT. Participants were randomized 1:1 to discontinue or continue first-line DMT. Intervention Discontinuation of first-line DMT. Main Outcome and Measure The primary outcome was significant inflammatory disease activity, defined as relapse and/or 3 or more new T2 lesions or 2 or more contrast-enhancing lesions on brain MRI. Results Of 163 potentially eligible participants, 89 participants were included in the trial at the moment of early termination. Forty-four participants (49.4%) were assigned to the continue group and 45 participants (50.6%) were assigned to the discontinue group. Median (IQR) age was 54.0 (49.0-59.0) years, and 60 participants (67.4%) were female. Two participants in the continue group were lost to follow-up. After a median (IQR) follow-up time of 15.3 (11.4-23.9) months, the trial was prematurely terminated because of inflammatory disease activity recurrence above the predefined limit. In total, 8 of 45 participants in the discontinue group (17.8%) vs 0 of 44 participants in the continue group reached the primary end point and had recurrent, mostly radiological inflammation. Two of these 8 participants had a clinical relapse. Median (IQR) time to disease activity was 12.0 (6.0-12.0) months. Conclusions and Relevance In this randomized clinical trial, even in patients with long-term MS stable for over 5 years, first-line DMT discontinuation can lead to recurrence of inflammatory disease activity. Although this study cohort was relatively small, the recurrence of inflammation in the discontinue group was significantly higher than in the continue group and also higher than in the previously published DISCOMS trial, which only included individuals aged 55 years or older. This study provides additional data, especially in a younger population and including longitudinal biomarker measurements, for informed decision-making in cases when treatment discontinuation is considered. Trial Registration ClinicalTrials.gov Identifier: NCT04260711