Natalizumab is a highly efficacious therapy (HET) for patients with relapsing remitting multiple sclerosis (RRMS). Its prolonged use is limited by the risk of progressive multifocal leukoencephalopathy (PML) in patients positive for anti-JCV antibodies. Aims of this work were to evaluate clinical and radiological efficacy at 6 and 12 months after alemtuzumab infusion in patients switching from natalizumab and the safety of this exit strategy.

This real-world, prospective, multicentric, observational study was conducted in three Italian MS centers and included a total of 35 patients with RRMS. Natalizumab treatment occurred from October 2010 to April 2021, whereas switch to alemtuzumab occurred from February 2018 to January 2023. Median washout period between the two drugs was 2 months. Patients underwent brain MRI before alemtuzumab start and then 6 and 12 months after the first alemtuzumab cycle.

No clinical relapse occurred during the washout period, nor between the first and second alemtuzumab infusion. Radiological activity was present in 4/35 (11%) and 2/35 (6%) patients, respectively, at 6 and 12 months after the first alemtuzumab administration. Expanded Disability Status Scale (EDSS) increase developed in 4/35 (11%) and 5/35 patients (14%), respectively, at 6 and 12 months. No PML occurred, nor any serious adverse event. For patients in center 1 (17 patients), follow-up continued for a median of 3.5 years; NEDA-3 (No Evidence of Disease Activity) was present in 14/17 patients (82%) at the end of follow-up. Autoimmunity occurred in 23% of patients.

Alemtuzumab is a valid exit strategy after natalizumab interruption.

The pathophysiology and presentation of relapsing multiple sclerosis (RMS) differ importantly between younger and older patients. Older patients usually suffer fewer MS relapses but present with a chronically inflammatory phenotype (inflammaging) associated with accelerated age-related changes to the adaptive and innate immune systems (immunosenescence). The efficacy of most disease-modifying therapies (DMTs) appears to decline with increasing age, likely because of a shift away from focal inflammation as the main driving force for progression of MS. These observations led to suggestions that DMT may be withdrawn for an older person with very stable MS. However, this approach risks the resumption of MS disease activity. In contrast, analyses of evaluations of immune reconstitution therapy with cladribine tablets (CladT) show that this high-efficacy DMT appears to be effective and well tolerated irrespective of age. Achieving long-term freedom from MS disease activity for an older patient with MS is feasible using this approach. Switching to CladT is a rational option for reducing the dual burdens of continuous treatment (including side effects associated with continuous immunosuppression with some DMTs) and monitoring for older people with RMS. This includes possible use as an "exit therapy", beyond which some patients may not need pharmacological therapy for their RMS in the future.

The development of disease-modifying therapies (DMTs) for the treatment of multiple sclerosis (MS) has been highly successful in recent decades. It is now widely accepted that early initiation of DMTs after disease onset is associated with a better long-term prognosis. However, the question of when and how to de-escalate or discontinue DMTs remains open and critical. This topic was discussed during an international focused workshop organized by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in 2023. The aim was to review the current evidence on the rationale for, and the potential pitfalls of, treatment de-escalation in MS. Several clinical scenarios emerged, mainly driven by a change in the benefit-risk ratio of DMTs over the course of the disease and with ageing. The workshop also addressed the issue of de-escalation by the type of DMT used and in specific situations, including pregnancy and paediatric onset MS. Finally, we provide practical guidelines for selecting appropriate patients, defining de-escalation and monitoring modalities and outlining unmet needs in this field.

Extended interval dosing (EID) of natalizumab (NTZ) every 6 weeks may reduce adverse events while maintaining efficacy. This study compared the effectiveness and safety of EID versus standard interval dosing (SID) in relapsing-remitting multiple sclerosis (RRMS) patients, focusing on treatment adherence and its impact on clinical and radiological outcomes.

This retrospective study involved 80 patients with RRMS from seven clinics: 52 received SID (300 mg every 4 weeks), and 28 received EID (300 mg every 6 weeks). Clinical and radiological disease activity, treatment adherence, and adverse events were assessed.

The SID and EID groups differed significantly in sex distribution (78.8% female in SID vs. 46.4% in EID, p = 0.007), but median age was similar (32 vs. 36 years, p = 0.209). Clinical and radiological worsening rates were similar between the groups, with no significant differences (combined worsening: 9.6% in the SID group vs. 17.9% in the EID group, p = 0.308; radiological worsening: 5.8% in the SID group vs. 7.1% in the EID group, p = 1.00; clinical worsening: 9.6% in the SID group vs. 10.7% in the EID group, p = 1.00). Adherence rates were comparable across both dosing regimens, and no significant differences were observed in terms of treatment discontinuation. No progressive multifocal leukoencephalopathy cases were reported.

Both SID and EID provide comparable efficacy and safety profiles, with similar adherence rates. Despite the observed sex distribution imbalance, additional analyses confirmed no significant sex- or group-related differences in baseline disability or clinical worsening, strengthening the interpretation that EID preserves efficacy. Findings should still be interpreted with caution due to the study's retrospective nature and limited sample size.

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system with rapidly evolving treatment options and strategies. An iterative modified Delphi process was used to develop 80 consensus recommendations for the management of MS in Australia and New Zealand. Part 1 of these guidelines includes recommendations related to selection of initial disease-modifying therapy (DMT) for MS, assessments before commencing DMT, monitoring disease activity on DMT, switching DMT, and discontinuing DMT.

This article, Part 2, covers recommendations related to risk mitigation during treatment with DMT, managing DMT in special situations (including pregnancy, postpartum, breastfeeding, active infection including COVID-19, and malignancy), general lifestyle measures for MS, acute MS relapses, and symptomatic treatments.

Together with Part 1, this consensus statement provides practical guidance for clinicians involved in the care of adults (≥ 18 years old) with MS in Australia and New Zealand. A safe, effective and comprehensive approach to managing MS is crucial for improving long term outcomes and quality of life in individuals affected by MS.

Initiating disease modifying therapy in a patient with newly diagnosed relapsing multiple sclerosis currently offers the best opportunity to influence their subsequent disease course. This article reviews personal factors, disease presentation characteristics, and data on current disease modifying therapies from the perspective of choosing initial treatment in this setting. Although metrics for prognostication at the individual level remain unreliable, particularly for those with mild presentations, currently available data on the relative efficacy of disease modifying therapies supports offering high efficacy therapy first line to most patients with newly diagnosed relapsing multiple sclerosis.

The anti-JCV antibody index is widely used to monitor multiple sclerosis (MS) patients receiving natalizumab, as seroconversion is linked to an increased risk of progressive multifocal leukoencephalopathy. This study aimed to evaluate the prevalence and risk factors of anti-JCV antibody seroconversion in patients treated with natalizumab.

We included MS patients exposed to natalizumab treatment for at least one year, with a negative anti-JCV antibody index at baseline, and a minimum of two anti-JCV antibody assessments more than six months apart. We employed Kaplan-Meier survival analysis to assess the median time to seroconversion and the annual seroconversion rate, and univariate and multivariate Cox regression models to evaluate the covariates.

Among 96 patients followed for a median of 99 months, 29 (30.2%) patients had seroconversion. The median time to seroconversion was 8.3 years, with an annual rate of 6.1%. Seroconversion rates were higher in smokers (p = 0.02) and patients with a body mass index (BMI) over 25 kg/m2 (p = 0.006). Patients who started natalizumab at age 35 or older had a shorter median time to seroconversion (p = 0.003), and most seroconversions occurred within the first three years. No significant associations were found with gender, prior immunosuppressive treatment, MS subtype, or MS age of onset.

Anti-JCV seroconversion is more likely in patients who smoke, have a higher BMI, start natalizumab therapy after age 35, and within the first three years of treatment. For these high-risk patients, vigilant monitoring of anti-JCV antibodies is required.

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.

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.

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).

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.

Intravenous natalizumab is an effective treatment for relapsing-remitting multiple sclerosis. However, the standard treatment interval of 4 weeks may be excessive for many patients. Personalized interval extension using therapeutic drug monitoring (TDM) can result in adequate drug exposure while reducing hospital visits and healthcare costs. Here, we investigate to which extent TDM-guided personalized dosing can benefit from model-informed precision dosing (MIPD). Individual posterior PK estimates were derived using patient weight and two trough concentrations at the standard dose interval by Bayesian estimation using a newly developed population PK model. MIPD was compared to a previously deployed TDM-guided stratified personalized dosing protocol (SPD) using a decision tree to personalize dosing intervals. Accuracy (mean prediction error) of the predicted dosing intervals was 4.8% versus 24% for model-informed estimates versus decision tree, respectively, when aiming for a 10 μg/mL trough concentration, and 4.8% versus 86% when aiming for 5 μg/mL. Corresponding precision (root mean square error) was 2.3 versus 4.0, and 1.5 versus 5 μg/mL. Finally, we evaluated the feasibility of a MIPD approach to attain a therapeutic trough of 2 μg/mL. Simulating MIPD showed a reduction in the average infusions versus the standard interval by 40%, with an average dose interval of 7 weeks, while maintaining adequate drug exposure. MIPD was concluded to be superior to the conventional TDM-guided personalized dosing approach in terms of enhanced precision in individual dose interval selection, enabling more efficient interval extensions. Simulations supported the clinical deployment of natalizumab MIPD.

Progressive multifocal leukoencephalopathy is a rare but potentially fatal disease caused by infection of the central nervous system with John Cunningham polyomavirus. Progressive multifocal leukoencephalopathy mainly occurs in immunocompromised patients, including patients on biological and targeted synthetic therapies, such as multiple sclerosis and rheumatoid arthritis patients. Early diagnosis of progressive multifocal leukoencephalopathy is crucial for patient survival. We describe a case of progressive multifocal leukoencephalopathy with significant diagnostic delay in a rheumatoid arthritis patient using rituximab. Additionally, we give an overview of available literature on progressive multifocal leukoencephalopathy in rheumatoid arthritis patients using biologicals, focusing on the diagnostic difficulties and delays, to raise awareness of this adverse event among physicians treating rheumatoid arthritis patients with immunosuppressants.

A 69-year-old white man of Dutch descent with rheumatoid arthritis treated with rituximab presented to a neurology outpatient clinic, complaining of difficulties in word-finding and reading without problems in visual acuity, several weeks after a mild traumatic head injury (patient's delay). Brain computed tomography-scan showed two hypodense white-matter lesions, initially considered to be of vascular origin (doctor's delay). However, magnetic resonance imaging, performed more than a week later, showed lesions consistent with progressive multifocal leukoencephalopathy. Immunosuppressants were then immediately discontinued. The patient agreed to repeat magnetic resonance imaging and lumbar puncture. Initial John Cunningham polyomavirus polymerase chain reaction on cerebrospinal fluid was negative. However, a subsequent lumbar puncture confirmed the diagnosis. The patient rejected experimental treatment with pembrolizumab and passed away a month after the initial presentation.

This case report emphasizes the need for increased awareness and importance of timely recognition of potential progressive multifocal leukoencephalopathy in rheumatoid arthritis patients using immunosuppressive therapies. A total of 26 other cases of rheumatoid arthritis patients using biologicals who developed progressive multifocal leukoencephalopathy were identified from the literature, and we reviewed their cases. Most (24; 92%) cases occurred during rituximab or TNF-alpha inhibitor use. There was a mean delay of 2.5 months between symptom onset and diagnosis. Information on predisposing risk factors such as lymphopenia was often not reported. Physicians and patients should be aware of the symptoms of progressive multifocal leukoencephalopathy, as early diagnosis and immediate withdrawal of immunosuppressants is crucial to improve the chance of survival. This case report highlights the importance of awareness in recognizing progressive multifocal leukoencephalopathy symptoms in nontraditional populations.

Inflammatory bowel diseases (IBDs), including ulcerative colitis (UC) and Crohn's disease (CD), are chronic and complex autoimmune conditions. Despite the advancements in biologics and small molecules, the therapeutic ceiling persists, posing significant treatment challenges and contributing to the concept of difficult-to-treat IBD. Dual-targeted therapy (DTT), combining two biologic agents or biologics with small molecules, has emerged as a novel approach to address this unmet need by targeting multiple inflammatory pathways simultaneously. Evidence suggests that DTT holds promise in improving clinical and endoscopic outcomes, especially in patients with refractory disease or extraintestinal manifestations. Safety data, while consistent with monotherapy profiles, highlight the importance of vigilant monitoring for infections and other adverse events. Continued research and high-quality trials are crucial to defining optimal DTT regimens and broadening its clinical applicability. This review explores the efficacy and safety of DTT in IBD, reporting data from clinical trials, systematic reviews, and real-world studies.

The treatment of relapsing-remitting multiple sclerosis (RRMS) is changing. There are limited data about initial treatment of RRMS in Finland.

Our objectives were to study the trends of initial disease-modifying treatments (DMTs) for patients with RRMS from 2013 to 2022, treatment delays, factors associated with DMT choice, DMT switch patterns, and the effect of the COVID-19 pandemic.

This retrospective register study used secondary data from the Finnish MS register. The DMTs were classified into medium-efficacy DMTs (meDMTs; beta interferons, glatiramer acetate, fumarates, and teriflunomide) and high-efficacy DMTs (heDMTs; alemtuzumab, cladribine, daclizumab, natalizumab, ocrelizumab, ofatumumab, and rituximab).

The inclusion criteria were fulfilled by 2479 individuals. From 2013 to 2022, the proportion of heDMTs as the initial therapy increased by 5.3-fold from 6.9% to 43.7% (p < 0.001). Median diagnostic delay decreased from 10.1 to 4.6 months (p < 0.001). The COVID-19 pandemic did not cause treatment delays. Higher disease activity and younger age were associated with the choice of heDMT as the initial DMT. heDMTs were the preferred second DMT in patients switching due to lack of efficacy.

In Finland, the treatment of RRMS has shifted toward earlier diagnosis and earlier initiation of heDMTs, likely improving the prognosis of the patients.

Given the introduction of new advanced therapies for inflammatory bowel diseases (IBDs), expanded risk mitigation strategies are essential.

To create a comprehensive set of statements on assessment procedures and vaccinations before starting monoclonal antibodies, Janus kinase (JAK) inhibitors or sphingosine-1-phosphate (S1P) modulators for IBD.

We examined literature, guidelines and drug product information regarding vaccination and assessment recommendations for initiating advanced IBD therapies. Using a modified Delphi approach, delegates voted anonymously on the acceptability of these statements prior to and following consensus discussion.

We developed eight statements on the domains of infectious diseases screening, vaccinations and assessments prior to commencing JAK inhibitors and S1P modulators. Six statements received agreement. Pre-advanced therapy screening for infectious diseases was established, and the vaccination protocol was revised. Malignancy, cardiovascular and thromboembolic risk assessments are necessary before initiating JAK inhibitors. Those starting S1P modulators need cardiac and ophthalmic assessments.

These consensus statements combine vaccination and assessments on the currently available advanced therapies for IBD as a single comprehensive document that may reduce IBD complications associated with use of advanced therapies. Knowledge gaps identified during the consensus process will provide further research opportunities.

How changes in the quality of anti-viral antibody (Ab) responses due to pre-existing or acquired CD4 T cell insufficiency affect virus evolution during persistent infection are unknown. Using mouse polyomavirus (MuPyV), we found that CD4 T cell depletion before infection results in short-lived plasma cells secreting low-avidity antiviral IgG with limited BCR diversity and weak virus-neutralizing ability. CD4 T cell deficiency during persistent infection incurs a shift from a T-dependent (TD) to T-independent (TI) Ab response, resembling the pre-existing TI Ab response. CD4 T cell loss before infection or during persistent infection is conducive for emergence of Ab-escape variants. Cryo-EM reconstruction of complexes of MuPyV virions with polyclonal IgG directly from infected mice with pre-existing or acquired CD4 T cell deficiency enabled visualization of shortfalls in TI IgG binding. By debilitating the antiviral IgG response, CD4 T cell deficiency sets the stage for outgrowth of variant viruses resistant to neutralization.

SUMMARYCentral nervous system (CNS) infections can be caused by various pathogens, including bacteria, viruses, fungi, and parasites. Molecular diagnostic methods are pivotal for identifying the different causative pathogens of these infections in clinical settings. The efficacy and specificity of these methods can vary per pathogen involved, and in a substantial part of patients, no pathogen is identified in the cerebrospinal fluid (CSF). Over recent decades, various molecular methodologies have been developed and applied to patients with CNS infections. This review provides an overview of the accuracy of nucleic acid amplification methods in CSF for a diverse range of pathogens, examines the potential value of multiplex PCR panels, and explores the broad-range bacterial and fungal PCR/sequencing panels. In addition, it evaluates innovative molecular approaches to enhance the diagnosis of CNS infections.

Exposure to natalizumab, an efficacious treatment for relapsing-remitting multiple sclerosis (RRMS), is associated with increased risk of progressive multifocal leukoencephalopathy (PML). Compared with every-4-week (Q4W) dosing, extended-interval dosing of natalizumab is associated with decreased risk of PML. Clinical efficacy was maintained in the majority of patients switched to every-6-week (Q6W) dosing in the phase 3b NOVA clinical trial. In this article, we report pharmacokinetics (PK) and pharmacodynamics (PD) of Q6W vs Q4W dosing in NOVA.

In NOVA study Part 1, participants with RRMS (aged 18-60 years) and Expanded Disability Status Scale score <5.5, who were stable on IV natalizumab Q4W dosing for ≥12 months, were randomized to continue IV Q4W dosing or switched to IV Q6W dosing of natalizumab and followed for 72 weeks. Exploratory outcomes were measurements of trough serum natalizumab concentration, α4-integrin saturation, and soluble vascular cell adhesion molecule-1 (sVCAM-1) concentration. A mixed model of repeated measures was used to estimate mean treatment differences between groups. Patient-level PK and PD data were examined in those with relapse or radiologic disease activity.

In NOVA, 486 (Q6W, n = 245; Q4W, n = 241) and 487 (Q6W, n = 246; Q4W, n = 241) participants were included in the PK and PD populations, respectively. Mean trough natalizumab concentrations ranged from 10 to 21 μg/mL (Q6W) and 33-38 μg/mL (Q4W), and mean α4-integrin saturation remained above 65.5% (Q6W) and above 77.9% (Q4W). In the Q6W group, mean sVCAM-1 levels increased 23.6% by week 24 and remained elevated throughout the study, while mean sVCAM-1 levels remained generally stable in the Q4W group. Most participants with T2 lesion activity or relapse activity, in either treatment arm, maintained trough natalizumab levels >10 μg/mL and trough α4-integrin saturation >50%.

Compared with Q4W dosing, Q6W dosing was associated with a 60%-70% decrease in mean trough natalizumab levels and a 9%-16% decrease in mean α4-integrin saturation. At the patient level, neither natalizumab concentration nor α4-integrin saturation was consistently predictive of lesion or relapse activity, suggesting that trough natalizumab and α4-integrin saturation measurements should be interpreted with caution in clinical practice.

ClinicalTrials.gov, NCT03689972; EudraCT, 2018-002145-11. Submitted 2018-09-27. First patient enrolled: 2018-12-26. https://clinicaltrials.gov/study/NCT03689972.

The blood-brain barrier and glial cells, particularly astrocytes, interact with each other in neuroimmune diseases. In the inflammatory environment typical of these diseases, alterations in vascular endothelial cell surface molecules and weakened cell connections allow immune cells and autoantibodies to enter the central nervous system. Glial cells influence the adhesion of endothelial cells by changing their morphology and releasing various signaling molecules. Multiple sclerosis has been the most studied disease in relation to vascular endothelial and glial cell interactions, but these cells also significantly affect the onset and severity of other neuroimmune conditions, including demyelinating and inflammatory diseases. In this context, we present an overview of these interactions and highlight how they vary across different neuroimmune diseases.

Current therapeutic strategies for inflammatory bowel disease (IBD) have reached a plateau in the rates of response and/or remission achieved with a single therapeutic agent. Consequently, the advanced combination therapy (ACT) strategy has emerged as a novel treatment concept for IBD. ACT involves the use of two different targeted therapies, whether biologic or small molecules, with the primary goal of overcoming the therapeutic plateau. Real-world evidence is accumulating among patients undergoing ACT, especially those dealing with concurrent IBD and extraintestinal manifestations or grappling with medically refractory IBD. The recently conducted VEGA study, a randomized clinical trial, has provided crucial insights by demonstrating that the short-term combination of dual biological agents can lead to superior disease control compared to single agents in patients diagnosed with ulcerative colitis (UC). This suggests that ACT holds promise as a therapeutic option to enhance disease control effectively. However, there is still limited evidence of ACT in UC patients who have proven refractory to biologic therapy and patients with Crohn's disease. This review aims to discuss whether ACT represents the optimal approach for overcoming the therapeutic ceiling in IBD.

Recent advances in multiple sclerosis (MS) management have shifted perspectives on treatment strategies, advocating for the early initiation of high-efficacy disease-modifying therapies (heDMTs). This perspective review discusses the rationale, benefits, and challenges associated with early heDMT initiation, reflecting on the obsolescence of the traditional "first-line" and "second-line" treatment classifications. The article emerges from the last update of the consensus document of the Spanish Society of Neurology on the treatment of MS. During its development, there was a recognized need to further discuss the concept of treatment lines and the early use of heDMTs. Evidence from randomized controlled trials and real-world studies suggests that early heDMT initiation leads to improved clinical outcomes, including reduced relapse rates, slowed disease progression, and decreased radiological activity, especially in younger patients or those in early disease stages. Despite the historical belief that heDMTs involve more risks and adverse events compared to moderate-efficacy DMTs (meDMTs), some studies have reported comparable safety profiles between early heDMTs and meDMTs, though long-term safety data are still lacking. The review also addresses the need for a personalized approach based on patient characteristics, prognostic factors, and preferences, explores the importance of therapeutic inertia, and highlights the evolving landscape of international and national guidelines that increasingly advocate for early intensive treatment approaches. The article also addresses the challenges of ensuring access to these therapies and the importance of further research to establish long-term safety and effectiveness of DMTs in MS.

While John Cunningham virus (JCV) is known to cause neuronal damage in progressive multifocal leukoencephalopathy (PML) among natalizumab-treated MS patients, its association with axonal loss in non-PML conditions remains unclear.

In a cohort of 128 natalizumab-treated MS patients, serum neurofilament (sNfL) levels and JCV antibody titres were measured.

Among 128 patients (mean age = 38.4 years, 71.9% female), 51 (40%) were JCV positive. NfL levels increased by 15.3% for JCV index <0.7 (95% confidence interval [CI] = 0.963-1.381), by 18.6% for index 0.7-1.5 (95% CI = 1.009-1.394) and by 21.1% for index >1.5 (95% CI = 1.040-1.409) compared to JCV negative patients.

These findings indicate a potential link between JCV burden and neuroaxonal degeneration in natalizumab-treated MS patients.

Recently, novel biologics or small molecular drugs have been introduced for overcoming the unmet needs associated with anti-tumor necrosis factor α agents for inflammtory bowel disease (IBD) treatment. Among these novel drugs, anti integrin agents block leukocyte trafficking to the intestine by blocking the interaction between integrin and cell adhesion molecules. Vedolizumab (anti-α4β7) is most widely used anti-integrin approved in both ulcerative colitis and Crohn's disease .It has been shown to be effective in both induction and maintenance therapy with a favorable safety profile due to gut selectivity. Several models incorporating clinical, genetic, immune and gut microbial markers to predict response to vedolizumab in IBD have been developed. Etrolizumab (anti-β7) blocks leukocyte trafficking via α4β7 and cell adhesion via αEβ7 integrins. In addition, the introduction of subcutaneous vedolizumab showed similar efficacy and safety with improved patients' convenience. Other investigational anti-integrin therapies include abrilumab (anti-α4β7 IgG2), PN-943 (orally administered and gut-restricted α4β7 antagonist peptide), AJM300 (orally active small molecule inhibitor of α4), and ontamalimab (anti-MAdCAM-1 IgG).

Circulating T cells, which migrate from the periphery to sites of tissue inflammation, play a crucial role in the development of various chronic inflammatory conditions. Recent research has highlighted subsets of tissue-resident T cells that acquire migratory capabilities and re-enter circulation, referred to here as "recirculating T cells." In this review, we examine recent advancements in understanding the biology of T cell trafficking in diseases where T cell infiltration is pivotal, such as multiple sclerosis and inflammatory bowel diseases, as well as in metabolic disorders where the role of T cell migration is less understood. Additionally, we discuss current insights into therapeutic strategies aimed at modulating T cell circulation across tissues and the application of state-of-the-art technologies for studying recirculation in humans. This review underscores the significance of investigating T trafficking as a novel potential target for therapeutic interventions across a spectrum of human chronic inflammatory diseases.

Polyomaviruses are species-specific DNA viruses that can cause disease in immunocompromised individuals. Despite their role as the causative agents for several diseases, there are no currently approved antivirals for treating polyomavirus infection. Brincidofovir (BCV) is an antiviral approved for the treatment of poxvirus infections and has shown activity against other double-stranded DNA viruses. In this study, we tested the efficacy of BCV against polyomavirus infection in vitro and in vivo using mouse polyomavirus (MuPyV). BCV inhibited virus production in primary mouse kidney cells and brain cortical cells. BCV treatment of cells transfected with MuPyV genomic DNA resulted in a reduction in virus levels, indicating that viral inhibition occurs post-entry. Although in vitro BCV treatment had a limited effect on viral DNA and RNA levels, drug treatment was associated with a reduction in viral protein, raising the possibility that BCV acts post-transcriptionally to inhibit MuPyV infection. In mice, BCV treatment was well tolerated, and prophylactic treatment resulted in a reduction in viral DNA levels and a potent suppression of infectious virus production in the kidney and brain. In mice with chronic polyomavirus infection, therapeutic administration of BCV decreased viremia and reduced infection in the kidney. These data demonstrate that BCV exerts antiviral activity against polyomavirus infection in vivo, supporting further investigation into the use of BCV to treat clinical polyomavirus infections.

Widespread in the human population and able to persist asymptomatically for the life of an individual, polyomavirus infections cause a significant disease burden in the immunocompromised. Individuals undergoing immune suppression, such as kidney transplant patients or those treated for autoimmune diseases, are particularly at high risk for polyomavirus-associated diseases. Because no antiviral agent exists for treating polyomavirus infections, management of polyomavirus-associated diseases typically involves reducing or discontinuing immunomodulatory therapy. This can be perilous due to the risk of transplant rejection and the potential development of adverse immune reactions. Thus, there is a pressing need for the development of antivirals targeting polyomaviruses. Here, we investigate the effects of brincidofovir, an FDA-approved antiviral, on polyomavirus infection in vivo using mouse polyomavirus. We show that the drug is well-tolerated in mice, reduces infectious viral titers, and limits viral pathology, indicating the potential of brincidofovir as an anti-polyomavirus therapeutic.

B cells are critical to the pathogenesis of multiple sclerosis (MS), an autoimmune disease of the central nervous system. B cell depletion using anti-CD20 monoclonal antibodies (mAbs) has proven to be an extremely successful treatment strategy, with profound suppression of both clinical and radiological evidence of focal inflammatory disease. Several anti-CD20 mAbs are now licensed for use in MS, with ublituximab being the latest to gain regulatory approval. The unique properties of each of the anti-CD20 mAb may result in nuanced differences in timing, duration and depth of B cell depletion, with the potential for such differences to have a clinical relevance to both drug efficacy and adverse effects. In this review, we summarize the design, development, and current place in MS therapy for ublituximab.

One strategy to mitigate progressive multifocal leukoencephalopathy (PML) risk is to switch to other highly effective disease-modifying therapies (DMTs). However, the optimal switch DMT following natalizumab (NTZ) discontinuation is yet to be determined.

The objective of the study is to determine the most effective and tolerable DMTs to switch to following NTZ discontinuation due to John Cunningham virus (JCV) antibody positivity.

This is a multicenter observational cohort study that included all stable relapsing-remitting multiple sclerosis (MS) patients who were treated with NTZ for at least 6 months before switching therapy due to JCV antibody positivity.

Of 321 patients, 255 switched from NTZ to rituximab/ocrelizumab, 52 to fingolimod, and 14 to alemtuzumab, with higher annualized relapse rate (ARR) in fingolimod switchers (0.193) compared with rituximab/ocrelizumab or alemtuzumab (0.028 and 0.032, respectively). Fingolimod switchers also had increased disability progression (p = 0.014) and a higher proportion developed magnetic resonance imaging (MRI) lesions compared with rituximab/ocrelizumab (62.9% vs. 13.0%, p < 0.001, and 66.6% vs. 24.0%, p < 0.001, respectively). Mean drug survival favored rituximab/ocrelizumab or alemtuzumab over fingolimod (p < 0.001).

Our study shows superior effectiveness of rituximab/ocrelizumab and alemtuzumab compared with fingolimod in stable patients switching from NTZ due to JC virus antibody positivity.

Progressive multifocal leukoencephalopathy (PML) is a potentially life-threatening complication among Multiple Sclerosis (MS) patients under natalizumab treatment, with serum anti-JCV antibody titers being used for stratification risk. Given the critical role of interferon (IFN)/B-cell activating factor (BAFF) axis in humoral immune responses against viruses, we explored whether it is involved in the generation of serum anti-JCV antibodies among these patients.

162 consecutive patients with relapsing-remitting MS under natalizumab treatment were included. Serum anti-JCV antibodies were measured at baseline, as well as 12 and 24 months after treatment initiation. Type I and II IFN-inducible genes and BAFF expression were quantitated in peripheral blood by qRT-PCR. Moreover, BAFF rs9514828, rs1041569, and rs9514827 gene variants were assessed by RFLP-PCR.

While type I and II IFN inducible gene expression were not associated with anti-JCV serum titers, the latter were significantly correlated with BAFF gene expression. Of interest, the TTT haplotype of the studied BAFF variants was more frequently detected in male, but not female anti-JCV (+) MS patients compared to anti-JCV (-) counterparts at baseline, as well as at 12 months and 24 months of natalizumab treatment. Measures of clinical validity/utility for the BAFF TTT haplotype showed 88% specificity, 45%, positive predictive value, and sensitivity of 70% for the discrimination of anti-JCV (+) male MS patients after 24 months of treatment.

Our study suggests an implication of the BAFF axis in the production of serum anti-JCV antibodies. Additionally, the BAFF TTT haplotype derived from the rs9514828, rs1041569, and rs9514827 variants may represent a novel risk factor for anti-JCV seropositivity and indirectly for PML development among male MS patients treated with natalizumab.

Adverse drug reactions are a common cause of morbidity in health care. The US Food and Drug Administration (FDA) evaluates individual case safety reports of adverse events (AEs) after submission to the FDA Adverse Event Reporting System as part of its surveillance activities. Over the past decade, the FDA has explored the application of artificial intelligence (AI) to evaluate these reports to improve the efficiency and scientific rigor of the process. However, a gap remains between AI algorithm development and deployment. This viewpoint aims to describe the lessons learned from our experience and research needed to address both general issues in case-based reasoning using AI and specific needs for individual case safety report assessment. Beginning with the recognition that the trustworthiness of the AI algorithm is the main determinant of its acceptance by human experts, we apply the Diffusion of Innovations theory to help explain why certain algorithms for evaluating AEs at the FDA were accepted by safety reviewers and others were not. This analysis reveals that the process by which clinicians decide from case reports whether a drug is likely to cause an AE is not well defined beyond general principles. This makes the development of high performing, transparent, and explainable AI algorithms challenging, leading to a lack of trust by the safety reviewers. Even accounting for the introduction of large language models, the pharmacovigilance community needs an improved understanding of causal inference and of the cognitive framework for determining the causal relationship between a drug and an AE. We describe specific future research directions that underpin facilitating implementation and trust in AI for drug safety applications, including improved methods for measuring and controlling of algorithmic uncertainty, computational reproducibility, and clear articulation of a cognitive framework for causal inference in case-based reasoning.

Use of natalizumab (NTZ) is precluded in many Multiple Sclerosis (MS) patients by the risk of progressive multifocal leukoencephalopathy (PML). Regardless, some patients may commence natalizumab for short term disease control in spite of being seropositive, and others may seroconvert whilst on treatment. In these circumstances, discontinuation of NTZ should not occur until a clear exit strategy is established to prevent post-NTZ disease reactivation, which often exceeds the severity of disease activity prior to NTZ treatment. The objective of this systematic review was to summarise the available evidence for CD20-monoclonal antibodies (CD20mAb) as a suitable NTZ exit strategy, and to identify whether a superior switch protocol can be established.

In accordance with PRISMA guidelines, a total of 2393 references were extracted from a search of three online databases (PubMed, Scopus, MEDLINE). Following the application of inclusion/exclusion criteria, a total of 5 studies representing 331 patients were included.

The overall incidence of clinical relapse during washout periods ranging from 4.4-10.7 weeks was 0 %. The incidence of clinical relapse during two-year follow-up ranged from 1.8 % to 10 % for switches to all types of CD20 monoclonal antibody. The weighted mean for clinical relapse at 12 months was 8.8 %. Three studies reported an annualised relapse rate (ARR) ranging from 0.02-0.12 with a weighted mean ARR of 0.07. The overall incidence of PML during washout was 0 % and the overall incidence of PML within 6 months follow-up was 0.6 %.

This systematic review provides the first attempt at identifying a superior switch protocol in patients at risk of PML transitioning from NTZ to a CD20mAb. Our results indicate that CD20mAb's are a suitable transitional option for patients who discontinue NTZ, with our cohort demonstrating very low rates of carryover PML and low rates of clinical relapse. The most appropriate washout period is unclear due to confounding factors but is likely between 4 and 12 weeks.