Purpose of Review
The purpose of this review is to discuss the interaction between aging, progressive disease course, disability worsening, and treatment strategies in multiple sclerosis (MS).
Recent ...Findings
The transition from the relapsing-remitting phase to the progressive phase in MS often happens in the fifth decade. In MS, structural central nervous system reserve decreases with aging and MS-associated mechanisms. While clinical and subclinical disease activity decreases with aging, the post-relapse recovery potential decreases with aging as well. Moreover, the efficacy of disease-modifying treatments declines with older age.
Summary
Aging emerges as the ultimate target for prevention of progressive disease course, which is the most important determinant of disability worsening in MS. While none of our current treatment strategies targets the association between aging and progressive disease in MS, future treatment targets will likely consider the neuron-astrocyte complex, microglia, and oligodendrocyte functions impacted by the aging process.
Multiple sclerosis (MS) is an immune-mediated disease, the etiology of which involves both genetic and environmental factors. The exact nature of the environmental factors responsible for ...predisposition to MS remains elusive; however, it's hypothesized that gastrointestinal microbiota might play an important role in pathogenesis of MS. Therefore, this study was designed to investigate whether gut microbiota are altered in MS by comparing the fecal microbiota in relapsing remitting MS (RRMS) (n = 31) patients to that of age- and gender-matched healthy controls (n = 36). Phylotype profiles of the gut microbial populations were generated using hypervariable tag sequencing of the V3-V5 region of the 16S ribosomal RNA gene. Detailed fecal microbiome analyses revealed that MS patients had distinct microbial community profile compared to healthy controls. We observed an increased abundance of Psuedomonas, Mycoplana, Haemophilus, Blautia, and Dorea genera in MS patients, whereas control group showed increased abundance of Parabacteroides, Adlercreutzia and Prevotella genera. Thus our study is consistent with the hypothesis that MS patients have gut microbial dysbiosis and further study is needed to better understand their role in the etiopathogenesis of MS.
Tumor necrosis factor (TNF) inhibitors are common therapies for certain autoimmune diseases, such as rheumatoid arthritis. An association between TNF inhibitor exposure and inflammatory central ...nervous system (CNS) events has been postulated but is poorly understood.
To evaluate whether TNF inhibitor exposure is associated with inflammatory demyelinating and nondemyelinating CNS events in patients with an indication for TNF inhibitor use and to describe the spectrum of those CNS events.
A nested case-control study was conducted using the medical records of patients with autoimmune diseases treated at 3 Mayo Clinic locations (Rochester, Minnesota; Scottsdale, Arizona; and Jacksonville, Florida) between January 1, 2003, and February 20, 2019. Patients were included if their records reported International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, diagnostic codes for US Food and Drug Administration-approved autoimmune disease indication for TNF inhibitor use (ie, rheumatoid arthritis, ankylosing spondylitis, psoriasis and psoriatic arthritis, Crohn disease, and ulcerative colitis) and diagnostic codes for inflammatory CNS events of interest. Patients were matched 1:1 with control participants by year of birth, type of autoimmune disease, and sex.
TNF inhibitor exposure data were derived from the medical records along with type of TNF inhibitor, cumulative duration of exposure, and time of exposure.
The main outcome was either inflammatory demyelinating (multiple sclerosis and other diseases such as optic neuritis) or nondemyelinating (meningitis, meningoencephalitis, encephalitis, neurosarcoidosis, and CNS vasculitis) CNS event. Association with TNF inhibitor was evaluated with conditional logistic regression and adjusted for disease duration to determine the odds ratios (ORs) and 95% CIs. Secondary analyses included stratification of outcome by inflammatory demyelinating and nondemyelinating CNS events and by autoimmune disease (rheumatoid arthritis and non-rheumatoid arthritis).
A total of 212 individuals were included: 106 patients with inflammatory CNS events and 106 control participants without such events. Of this total, 136 were female (64%); the median (interquartile range) age at disease onset for patients was 52 (43-62) years. Exposure to TNF inhibitors occurred in 64 patients (60%) and 42 control participants (40%) and was associated with an increased risk of any inflammatory CNS event (adjusted OR, 3.01; 95% CI, 1.55-5.82; P = .001). These results were similar when the outcome was stratified by demyelinating and nondemyelinating CNS events. Secondary analyses found the association was predominantly observed in patients with rheumatoid arthritis (adjusted OR, 4.82; 95% CI, 1.62-14.36; P = .005).
This study found that exposure to TNF inhibitors in patients with autoimmune diseases appeared to be associated with increased risk for inflammatory CNS events. Whether this association represents de novo or exacerbated inflammatory pathways requires further research.
This article describes the dynamic evolution of multiple sclerosis (MS) through its phases and the impact of this understanding on treatment decisions.
MS consists of three phases: (1) the high-risk ...phase, (2) the relapsing-remitting phase, and (3) the progressive phase. Increasingly, subclinical disease activity is becoming an integral part of our definition of disease course in MS. In many patients, the relapsing-remitting phase starts as subclinical activity, likely long before they present with a clinically isolated syndrome. Differentiating progressive MS subgroups is also becoming less relevant. This is illustrated by comparing progressive MS that evolves from an asymptomatic state in individuals with radiologically isolated syndrome (primary progressive MS) and symptomatic individuals with relapsing-remitting MS (secondary progressive MS). In each case, the background disease activity and pathology can be indistinguishable. These phases evolve on a continuum and largely follow the aging process with little influence by the preceding clinical activity level. Recently, it also became evident that one or a few poorly recovered relapses at the beginning of clinical manifestations of MS predict much earlier progressive MS onset.
These findings suggest that interventions to prevent progressive MS, when they become available for clinical practice, may need to be considered as early as when the asymptomatic radiologically isolated syndrome is detected. This early treatment approach is being evaluated with ongoing trials with available disease-modifying therapies. In contrast, continuing the use of disease-modifying therapy beyond a certain age may have little benefit. However, being in the progressive phase of MS is not, in itself, an argument against disease-modifying therapy use in active disease in younger patients.
In multiple sclerosis (MS), disease course is defined by a subclinical or clinical relapsing remitting phase, a progressive phase, and the overlapping phase in-between. Each phase can have ...intermittently active or inactive periods. Subclinical activity in radiologically isolated syndrome evolving to primary-progressive MS is mostly indistinguishable from relapsing-remitting MS evolving to secondary-progressive MS. The onset of progressive-phase MS is age-dependent but time and pre-progressive phase agnostic. Pathologic hallmarks of progressive MS onset also appear to be age-dependent but pre-progressive phase agnostic. Onset of progressive MS is characterized by a peak in smoldering plaques.
Severity score represents disease duration–adjusted mean rank of disability in multiple sclerosis (MS) patients from the reference population. This measure allows one to compare the relative rates of ...disease progression among patients, patient subgroups, and across epochs, which opens up new question of what accounts for the observed differences in severity, and can be used to assess correlation between disease severity and clinical, radiologic, immunologic, genetic, and environmental variables of interest. Severity score can also prove useful for developing prognostic tools in MS. This article discusses the diverse applications of severity score concept in MS research, and (re)introduces Herbert’s proposal of severity-based MS classification in the context of variability of MS severity.
Objective
The aim of this work was to evaluate the preprogressive phase in subjects with radiologically isolated syndrome (RIS) who evolve to primary progressive multiple sclerosis (PPMS).
Methods
A ...multicenter RIS cohort was previously established. Demographic, clinical, and radiological characteristics of subjects with RIS that evolved directly to PPMS were compared to those that developed a relapsing disease course from onset (clinically isolated syndrome CIS or relapsing‐remitting MS) and were also compared to two other population‐ and clinic‐based PPMS cohorts.
Results
Of the 453 subjects with RIS, 128 evolved to symptomatic MS during the follow‐up (113 developed a first acute clinical event consistent with CIS/MS, 15 evolved to PPMS). PPMS prevalence (11.7%) and onset age (mean ± standard deviation; 49.1 ± 12.1) in the RIS group were comparable to other PPMS populations (p > 0.05). Median time to PPMS was 3.5 years (range, 1.6–5.4). RIS evolved to PPMS more commonly in men (p = 0.005) and at an older age (p < 0.001) when compared to CIS/MS, independent of follow‐up duration. Subjects who evolved to PPMS had more spinal cord lesions (100%) before symptomatic evolution than those that developed CIS/MS (64%) and those that remained asymptomatic (23%) within the follow‐up period (P = 0.005). Other MRI characteristics in the preprogressive phase of PPMS were indistinguishable from CIS/MS.
Interpretation
Subjects with RIS evolve to PPMS at the same frequency as expected from general MS populations in an age‐dependent manner. Besides age, unequivocal presence of spinal cord lesions and being male predicted evolution to PPMS. Our findings further suggest that RIS is biologically part of the MS spectrum. Ann Neurol 2016;79:288–294
Therapeutic monoclonal antibodies have the potential to work as biological therapeutics. OKT3, Herceptin, Keytruda and others have positively impacted healthcare. Antibodies evolved naturally to ...provide high specificity and high affinity once mature. These characteristics can make them useful as therapeutics. However, we may be missing characteristics that are not obvious. We present a means of measuring antibodies in an unbiased manner that may highlight therapeutic activity. We propose using a microarray of random peptides to assess antibody properties. We tested twenty-four different commercial antibodies to gain some perspective about how much information can be derived from binding antibodies to random peptide libraries. Some monoclonals preferred to bind shorter peptides, some longer, some preferred motifs closer to the C-term, some nearer the N-term. We tested some antibodies with clinical activity but whose function was blinded to us at the time. We were provided with twenty-one different monoclonal antibodies, thirteen mouse and eight human IgM. These antibodies produced a variety of binding patterns on the random peptide arrays. When unblinded, the antibodies with polyspecific binding were the ones with the greatest therapeutic activity. The protein target to these therapeutic monoclonals is still unknown but using common sequence motifs from the peptides we predicted several human and mouse proteins. The same five highest proteins appeared in both mouse and human lists.
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