Adherence and satisfaction of smartphone- and smartwatch-based remote active testing and passive monitoring in people with multiple sclerosis: nonrandomized interventional feasibility study

Smartphone; Multiple sclerosis; Patient adherenceTeléfono inteligente; Esclerosis múltiple; Adherencia del pacienteTelèfon intel·ligent; Esclerosi múltiple; Adherència del pacientBackground: Current clinical assessments of people with multiple sclerosis are episodic and may miss critical features of functional fluctuations between visits. Objective: The goal of the research was to assess the feasibility of remote active testing and passive monitoring using smartphones and smartwatch technology in people with multiple sclerosis with respect to adherence and satisfaction with the FLOODLIGHT test battery. Methods: People with multiple sclerosis (aged 20 to 57 years; Expanded Disability Status Scale 0-5.5; n=76) and healthy controls (n=25) performed the FLOODLIGHT test battery, comprising active tests (daily, weekly, every two weeks, or on demand) and passive monitoring (sensor-based gait and mobility) for 24 weeks using a smartphone and smartwatch. The primary analysis assessed adherence (proportion of weeks with at least 3 days of completed testing and 4 hours per day passive monitoring) and questionnaire-based satisfaction. In-clinic assessments (clinical and magnetic resonance imaging) were performed. Results: People with multiple sclerosis showed 70% (16.68/24 weeks) adherence to active tests and 79% (18.89/24 weeks) to passive monitoring; satisfaction score was on average 73.7 out of 100. Neither adherence nor satisfaction was associated with specific population characteristics. Test-battery assessments had an at least acceptable impact on daily activities in over 80% (61/72) of people with multiple sclerosis

Developing a Digital Solution for Remote Assessment in Multiple Sclerosis: From Concept to Software as a Medical Device

Validación clínica; Salud digital; Salud participativaValidació clínica; Salut digital; Salut participativaClinical validation; Digital health; Participatory healthThere is increasing interest in the development and deployment of digital solutions to improve patient care and facilitate monitoring in medical practice, e.g., by remote observation of disease symptoms in the patients’ home environment. Digital health solutions today range from non-regulated wellness applications and research-grade exploratory instruments to regulated software as a medical device (SaMD). This paper discusses the considerations and complexities in developing innovative, effective, and validated SaMD for multiple sclerosis (MS). The development of SaMD requires a formalised approach (design control), inclusive of technical verification and analytical validation to ensure reliability. SaMD must be clinically evaluated, characterised for benefit and risk, and must conform to regulatory requirements associated with device classification. Cybersecurity and data privacy are also critical. Careful consideration of patient and provider needs throughout the design and testing process help developers overcome challenges of adoption in medical practice. Here, we explore the development pathway for SaMD in MS, leveraging experiences from the development of Floodlight™ MS, a continually evolving bundled solution of SaMD for remote functional assessment of MS. The development process will be charted while reflecting on common challenges in the digital space, with a view to providing insights for future developers.The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: F. Hoffmann-La Roche Ltd., Basel, Switzerland provided financial support for the publication of this manuscript

Peripheral myeloid-derived suppressor cells are good biomarkers of the efficacy of fingolimod in multiple sclerosis

Personalized medicine; Responder and non-responderMedicina personalizada; Respondedor y no respondedorMedicina personalitzada; Contestador i no contestadorBackground The increasing number of treatments that are now available to manage patients with multiple sclerosis (MS) highlights the need to develop biomarkers that can be used within the framework of individualized medicine. Fingolimod is a disease-modifying treatment that belongs to the sphingosine-1-phosphate receptor modulators. In addition to inhibiting T cell egress from lymph nodes, fingolimod promotes the immunosuppressive activity of myeloid-derived suppressor cells (MDSCs), whose monocytic subset (M-MDSCs) can be used as a biomarker of disease severity, as well as the degree of demyelination and extent of axonal damage in the experimental autoimmune encephalomyelitis (EAE) model of MS. In the present study, we have assessed whether the abundance of circulating M-MDSCs may represent a useful biomarker of fingolimod efficacy in EAE and in the clinical context of MS patients. Methods Treatment with vehicle or fingolimod was orally administered to EAE mice for 14 days in an individualized manner, starting the day when each mouse began to develop clinical signs. Peripheral blood from EAE mice was collected previous to treatment and human peripheral blood mononuclear cells (PBMCs) were collected from fingolimod to treat MS patients’ peripheral blood. In both cases, M-MDSCs abundance was analyzed by flow cytometry and its relationship with the future clinical affectation of each individual animal or patient was assessed. Results Fingolimod-treated animals presented a milder EAE course with less demyelination and axonal damage, although a few animals did not respond well to treatment and they invariably had fewer M-MDSCs prior to initiating the treatment. Remarkably, M-MDSC abundance was also found to be an important and specific parameter to distinguish EAE mice prone to better fingolimod efficacy. Finally, in a translational effort, M-MDSCs were quantified in MS patients at baseline and correlated with different clinical parameters after 12 months of fingolimod treatment. M-MDSCs at baseline were highly representative of a good therapeutic response to fingolimod, i.e., patients who met at least two of the criteria used to define non-evidence of disease activity-3 (NEDA-3) 12 months after treatment. Conclusion Our data indicate that M-MDSCs might be a useful predictive biomarker of the response of MS patients to fingolimod.This work was supported by the Instituto de Salud Carlos III (PI18/00357, RD16-0015/0019, PI21/00302, all co-funded by the European Union), the Fundación Merck Salud (FMS_2020_MS), Esclerosis Múltiple España (REEM-EME-S5 and REEM-EME_2018), ADEMTO, ATORDEM and AELEM. CC-T holds a predoctoral fellowship from the Instituto de Salud Carlos III (FI19/00132, co-funded by the European Union). LC and JG-A were hired under PI18/00357 and RD16/0015/0019, respectively. DC, MCO and IM-D were hired by SESCAM

Diagnostic challenge in children with an acquired demyelinating syndrome: an illustrative case report

The clinical-radiological and biological overlap of the spectrum of pediatric demyelinating disorders makes the diagnostic process of a child with an acquired demyelinating syndrome truly challenging. We present a 9-year-old girl with subacute symptoms of severe decrease in bilateral visual acuity and gait ataxia. An urgent MRI showed inflammatory-demyelinating lesions affecting the periaqueductal gray matter, the cerebellar hemispheres, the area postrema as well as both optic nerves and chiasm. Likewise, multisegmental involvement of the cervical and dorsal spinal cord was found, with short and peripheral lesions. Anti myelin oligodendrocyte glycoprotein (MOG) antibodies (Abs) were positive in cerebrospinal fluid (CSF) and weakly in serum. Oligoclonal bands (OB) were positive in CSF. Based on all this, the diagnosis of MOG antibody disease (MOGAD) with a neuromyelitis optica spectrum disorder (NMOSD)-like picture was made. Given the good clinical and radiological recovery after the acute phase treatment, and that anti MOG Abs became negative, it was decided to keep the patient without specific treatment. However, during follow-up, while the patient was asymptomatic, a control brain MRI showed the appearance of new lesions with morphology and topography suggestive of multiple sclerosis (MS). This, added to the presence of OB, made the diagnosis of pediatric-onset MS (POMS) likely. Immunosuppressive treatment was restarted with a good response since then. Unlike adult-onset MS, children with POMS may usually not have entirely typical clinical and radiological features at presentation. In many cases, the time factor and close clinical and radiological monitoring could be critical to make an accurate diagnosis

Genomic Multiple Sclerosis Risk Variants Modulate the Expression of the ANKRD55–IL6ST Gene Region in Immature Dendritic Cells

Autoimmune; Multiple sclerosisAutoinmune; Esclerosis múltipleAutoimmune; Esclerosi múltipleIntronic single-nucleotide polymorphisms (SNPs) in the ANKRD55 gene are associated with the risk for multiple sclerosis (MS) and rheumatoid arthritis by genome-wide association studies (GWAS). The risk alleles have been linked to higher expression levels of ANKRD55 and the neighboring IL6ST (gp130) gene in CD4+ T lymphocytes of healthy controls. The biological function of ANKRD55, its role in the immune system, and cellular sources of expression other than lymphocytes remain uncharacterized. Here, we show that monocytes gain capacity to express ANKRD55 during differentiation in immature monocyte-derived dendritic cells (moDCs) in the presence of interleukin (IL)-4/granulocyte-macrophage colony-stimulating factor (GM-CSF). ANKRD55 expression levels are further enhanced by retinoic acid agonist AM580 but downregulated following maturation with interferon (IFN)-γ and lipopolysaccharide (LPS). ANKRD55 was detected in the nucleus of moDC in nuclear speckles. We also analyzed the adjacent IL6ST, IL31RA, and SLC38A9 genes. Of note, in healthy controls, MS risk SNP genotype influenced ANKRD55 and IL6ST expression in immature moDC in opposite directions to that in CD4+ T cells. This effect was stronger for a partially correlated SNP, rs13186299, that is located, similar to the main MS risk SNPs, in an ANKRD55 intron. Upon analysis in MS patients, the main GWAS MS risk SNP rs7731626 was associated with ANKRD55 expression levels in CD4+ T cells. MoDC-specific ANKRD55 and IL6ST mRNA levels showed significant differences according to the clinical form of the disease, but, in contrast to healthy controls, were not influenced by genotype. We also measured serum sgp130 levels, which were found to be higher in homozygotes of the protective allele of rs7731626. Our study characterizes ANKRD55 expression in moDC and indicates monocyte-to-dendritic cell (Mo–DC) differentiation as a process potentially influenced by MS risk SNPs.This research was supported by grants to KV from MINECO (SAF2016-74891-R), Instituto de Salud Carlos III (FIS-PI20/00123), Gobierno Vasco RIS3 (Ref. 2019222043), and Red Española de Esclerosis Múltiple (REEM; RD16/0015/0005). NV and LMV were supported by ISCIII (FIS-PI18/00572) and REEM (RD16/0015/0001). RTN is a recipient of a fellowship from the Secretaría Nacional de Ciencia y Tecnología e Innovación (SENACYT; Convocatoria Doctorado de Investigación Ronda III, 2018; Ref. BIDP-III-2018-12) of the Gobierno Nacional, República de Panamá

Role of B Cell Profile for Predicting Secondary Autoimmunity in Patients Treated With Alemtuzumab

Células B; Alemtuzumab; AutoinmunidadLimfòcits B; Alemtuzumab; AutoimmunitatB cells; Alemtuzumab; AutoimmunityObjective: To explore if baseline blood lymphocyte profile could identify relapsing remitting multiple sclerosis (RRMS) patients at higher risk of developing secondary autoimmune adverse events (AIAEs) after alemtuzumab treatment. Methods: Multicenter prospective study including 57 RRMS patients treated with alemtuzumab followed for 3.25 [3.5-4.21] years, (median [interquartile range]). Blood samples were collected at baseline, and leukocyte subsets determined by flow cytometry. We had additional samples one year after the first cycle of alemtuzumab treatment in 39 cases. Results: Twenty-two patients (38.6%) developed AIAEs during follow-up. They had higher B-cell percentages at baseline (p=0.0014), being differences mainly due to plasmablasts/plasma cells (PB/PC, p=0.0011). Those with no AIAEs had higher percentages of CD4+ T cells (p=0.013), mainly due to terminally differentiated (TD) (p=0.034) and effector memory (EM) (p=0.031) phenotypes. AIAEs- patients also showed higher values of TNF-alpha-producing CD8+ T cells (p=0.029). The percentage of PB/PC was the best variable to differentiate both groups of patients. Baseline values >0.10% closely associated with higher AIAE risk (Odds ratio [OR]: 5.91, 95% CI: 1.83-19.10, p=0.004). When excluding the 12 patients with natalizumab, which decreases blood PB/PC percentages, being the last treatment before alemtuzumab, baseline PB/PC >0.1% even predicted more accurately the risk of AIAEs (OR: 11.67, 95% CI: 2.62-51.89, p=0.0007). The AIAEs+ group continued having high percentages of PB/PC after a year of alemtuzumab treatment (p=0.0058). Conclusions: A PB/PC percentage <0.1% at baseline identifies MS patients at low risk of secondary autoimmunity during alemtuzumab treatment.​This work was supported by grants from Red Española de Esclerosis Múltiple (REEM) (RD16/0015/0001; RD16/0015/0004; RD16/0015/0006; RD16/0015/0013) and PI18/00572 integrated in the Plan Estatal I+D+I and co-funded by ISCIII-Subdirección General de Evaluación and Fondo Europeo de Desarrollo Regional (FEDER, “Una manera de hacer Europa”)

Adherence and satisfaction of smartphone- And smartwatch-based remote active testing and passive monitoring in people with multiple sclerosis : Nonrandomized interventional feasibility study

Background: Current clinical assessments of people with multiple sclerosis are episodic and may miss critical features of functional fluctuations between visits. Objective: The goal of the research was to assess the feasibility of remote active testing and passive monitoring using smartphones and smartwatch technology in people with multiple sclerosis with respect to adherence and satisfaction with the FLOODLIGHT test battery. Methods: People with multiple sclerosis (aged 20 to 57 years; Expanded Disability Status Scale 0-5.5; n=76) and healthy controls (n=25) performed the FLOODLIGHT test battery, comprising active tests (daily, weekly, every two weeks, or on demand) and passive monitoring (sensor-based gait and mobility) for 24 weeks using a smartphone and smartwatch. The primary analysis assessed adherence (proportion of weeks with at least 3 days of completed testing and 4 hours per day passive monitoring) and questionnaire-based satisfaction. In-clinic assessments (clinical and magnetic resonance imaging) were performed. Results: People with multiple sclerosis showed 70% (16.68/24 weeks) adherence to active tests and 79% (18.89/24 weeks) to passive monitoring; satisfaction score was on average 73.7 out of 100. Neither adherence nor satisfaction was associated with specific population characteristics. Test-battery assessments had an at least acceptable impact on daily activities in over 80% (61/72) of people with multiple sclerosis. Conclusions: People with multiple sclerosis were engaged and satisfied with the FLOODLIGHT test battery. FLOODLIGHT sensor-based measures may enable continuous assessment of multiple sclerosis disease in clinical trials and real-world settings

Circulating EZH2-positive T cells are decreased in multiple sclerosis patients

BACKGROUND: Recent studies in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis (MS), suggest an involvement of the histone methyltransferase enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) in important processes such as cell adhesion and migration. METHODS: Here, we aimed to expand these initial observations by investigating the role of EZH2 in MS. mRNA expression levels for EZH2 were measured by real-time PCR in peripheral blood mononuclear cells (PBMC) from 121 MS patients (62 untreated and 59 receiving treatment) and 24 healthy controls. RESULTS: EZH2 expression levels were decreased in PBMC from untreated patients compared to that from controls, and treatment significantly upregulated EZH2 expression. Expression of miR-124 was increased in MS patients compared to controls. Blood immunophenotyping revealed EZH2 expression mostly restricted to CD4+ and CD8+ T cells, and circulating EZH2+ CD4+ and CD8+ T cells were decreased in untreated MS patients compared to controls. CD8+ T cells expressing EZH2 exhibited a predominant central memory phenotype, whereas EZH2+ CD4+ T cells were of effector memory nature, and both T cell subsets produced TNF-α. EZH2+ T cells were enriched in the cerebrospinal fluid compartment compared to blood and were found in chronic active lesions from MS patients. EZH2 inhibition and microarray analysis in PBMC was associated with significant downregulation of key T cell adhesion molecules. CONCLUSION: These findings suggest a role of EZH2 in the migration of T cells in MS patients. The observation of TNF-α expression by CD4+ and CD8+ T cells expressing EZH2 warrants additional studies to explore more in depth the pathogenic potential of EZH2+-positive cells in MS

Lesion topographies in multiple sclerosis diagnosis

To assess the contributions of cortico-juxtacortical and corpus callosum lesions to multiple sclerosis diagnosis and to compare the value of ≥1 vs ≥3 periventricular lesions in clinically isolated syndromes (CIS). Step 1: We evaluated lesion topography classifications in 657 patients with CIS with stepwise Cox proportional hazards regression models considering second attack as the outcome. Step 2: We established 2 dissemination in space (DIS) versions according to the periventricular lesion cutoffs of ≥1 and ≥3 and assessed their performance at 10 years with second attack as the outcome, first individually and then combined with dissemination in time (DIT) in all cases (n = 326), by age, and by CIS topography. Step 1: The models (hazard ratios [95% confidence interval]) favored ≥1 over ≥3 periventricular lesions (2.5 [1.7-3.6]) and cortico-juxtacortical over juxtacortical lesions (1.4 [1.0-1.8]). Callosal lesions were not selected. Step 2: DIS specificity with ≥1 periventricular lesions was slightly lower than with ≥3 (59.1 vs 61.4) and the same after adding DIT (88.6). Regarding age, ≥3 periventricular lesions improved DIS specificity over ≥1 lesions in the 40-49 years of age bracket (66.7 vs 58.3). This difference disappeared when adding DIT (83.3). Optic neuritis had a similar pattern when evaluating CIS topographies. Our results comply with the Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS) consensus recommendation of combining cortical and juxtacortical lesions into a single term when possible. Concerning periventricular lesions, maintaining the current ≥1 cutoff in the McDonald criteria does not compromise specificity in typical CIS cases, but attention should be paid to older patients or optic neuritis cases