Disease-modifying therapies alter gut microbial composition in MS.

Objective: To determine the effects of the disease-modifying therapies, glatiramer acetate (GA) and dimethyl fumarate (DMF), on the gut microbiota in patients with MS. Methods: Participants with relapsing MS who were either treatment-naive or treated with GA or DMF were recruited. Peripheral blood mononuclear cells were immunophenotyped. Bacterial DNA was extracted from stool, and amplicons targeting the V4 region of the bacterial/archaeal 16S rRNA gene were sequenced (Illumina MiSeq). Raw reads were clustered into Operational Taxonomic Units using the GreenGenes database. Differential abundance analysis was performed using linear discriminant analysis effect size. Phylogenetic investigation of communities by reconstruction of unobserved states was used to investigate changes to functional pathways resulting from differential taxon abundance. Results: One hundred sixty-eight participants were included (treatment-naive n = 75, DMF n = 33, and GA n = 60). Disease-modifying therapies were associated with changes in the fecal microbiota composition. Both therapies were associated with decreased relative abundance of the Lachnospiraceae and Veillonellaceae families. In addition, DMF was associated with decreased relative abundance of the phyla Firmicutes and Fusobacteria and the order Clostridiales and an increase in the phylum Bacteroidetes. Despite the different changes in bacterial taxa, there was an overlap between functional pathways affected by both therapies. Interpretation: Administration of GA or DMF is associated with differences in gut microbial composition in patients with MS. Because those changes affect critical metabolic pathways, we hypothesize that our findings may highlight mechanisms of pathophysiology and potential therapeutic intervention requiring further investigation.

Advanced Symptom Management in Multiple Sclerosis.

Meaningful symptom management can have a profound impact on quality of life. It can challenge time parameters during clinic, and therefore thought should be given to strategies that can improve efficiency and thereby make the undertaking more tenable. For any given symptom, the building blocks of care, such as vitamin D status, exercise/physical therapy, nutrition, and stress management, and ensuring disease-modifying therapy coverage, should be maximized. For each symptom, there are pharmacologic and nonpharmacologic interventions. Patient expectations should be queried early in the encounter so that time can be budgeted accordingly.

Clinic to in-home telemedicine reduces barriers to care for patients with MS or other neuroimmunologic conditions.

OBJECTIVE: To describe the routine use of telemedicine-enabled neurologic care in an academic outpatient MS and neuroimmunology clinic and quantify its role in reducing patient burden. METHODS: Between January 2017 and December 2017, we surveyed patients and MS neurologists after 50 consecutive routinely scheduled televideo visits and a convenience sample of 100 in-clinic visits. Summary statistics were calculated and comparisons performed. RESULTS: Overall, 98% televideo participants found the technology easy to use, and only 17% believed that an in-person examination would have more effectively addressed their needs for the visit. MS neurologists reported achieving their clinical goals in 47/48 (98%) of televideo visits and an adequate physical examination with 2 exceptions (possible cauda equina syndrome and visual field loss). Three emergency department referrals were avoided due to televideo availability. Telemedicine reduced travel burden, including a mean (±SD) travel distance of 160 (±196) miles and avoiding overnight lodging and air travel. Telemedicine also reduced indirect costs, including time off work (65% of employed patients) and caregiver burden (30% avoided caregiver time off from work/obligations). Across 8 domains of provider interpersonal communication skills, telemedicine and in-clinic participants rated only 1 domain to be different (eye contact), and overall, 96% of in-clinic and 100% of telemedicine participants agreed/strongly agreed that their clinical goals had been met. CONCLUSIONS: When incorporated as part of the continuum of MS/neuroimmunology care, clinic to in-home telemedicine reduces travel and caregiver burden and enables efficient, convenient, and effective follow-up.

Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models.

The gut microbiota regulates T cell functions throughout the body. We hypothesized that intestinal bacteria impact the pathogenesis of multiple sclerosis (MS), an autoimmune disorder of the CNS and thus analyzed the microbiomes of 71 MS patients not undergoing treatment and 71 healthy controls. Although no major shifts in microbial community structure were found, we identified specific bacterial taxa that were significantly associated with MS. Akkermansia muciniphila and Acinetobacter calcoaceticus, both increased in MS patients, induced proinflammatory responses in human peripheral blood mononuclear cells and in monocolonized mice. In contrast, Parabacteroides distasonis, which was reduced in MS patients, stimulated antiinflammatory IL-10-expressing human CD4+CD25+ T cells and IL-10+FoxP3+ Tregs in mice. Finally, microbiota transplants from MS patients into germ-free mice resulted in more severe symptoms of experimental autoimmune encephalomyelitis and reduced proportions of IL-10+ Tregs compared with mice "humanized" with microbiota from healthy controls. This study identifies specific human gut bacteria that regulate adaptive autoimmune responses, suggesting therapeutic targeting of the microbiota as a treatment for MS.

Long-term evolution of multiple sclerosis disability in the treatment era.

OBJECTIVE: To characterize the accrual of long-term disability in a cohort of actively treated multiple sclerosis (MS) patients and to assess whether clinical and magnetic resonance imaging (MRI) data used in clinical trials have long-term prognostic value. METHODS: This is a prospective study of 517 actively managed MS patients enrolled at a single center. RESULTS: More than 91% of patients were retained, with data ascertained up to 10 years after the baseline visit. At this last assessment, neurologic disability as measured by the Expanded Disability Status Scale (EDSS) was stable or improved compared to baseline in 41% of patients. Subjects with no evidence of disease activity (NEDA) by clinical and MRI criteria during the first 2 years had long-term outcomes that were no different from those of the cohort as a whole. 25-OH vitamin D serum levels were inversely associated with short-term MS disease activity; however, these levels had no association with long-term disability. At a median time of 16.8 years after disease onset, 10.7% (95% confidence interval [CI] = 7.2-14%) of patients reached an EDSS ≥ 6, and 18.1% (95% CI = 13.5-22.5%) evolved from relapsing MS to secondary progressive MS (SPMS). INTERPRETATION: Rates of worsening and evolution to SPMS were substantially lower when compared to earlier natural history studies. Notably, the NEDA 2-year endpoint was not a predictor of long-term stability. Finally, the data call into question the utility of annual MRI assessments as a treat-to-target approach for MS care. Ann Neurol 2016;80:499-510.

Rebound Syndrome in Patients With Multiple Sclerosis After Cessation of Fingolimod Treatment.

IMPORTANCE: The appropriate sequencing of agents with strong immune system effects has become increasingly important. Transitions require careful balance between safety and protection against relapse. The cases presented herein highlight that rebound events after ceasing fingolimod treatment may happen even with short washout periods (4 weeks) and may perpetuate despite steroid treatment or the immediate use of fast-acting immune therapies, such as rituximab. OBJECTIVE: To describe rebound syndrome in patients with multiple sclerosis (MS) after cessation of fingolimod treatment. DESIGN, SETTING, AND PARTICIPANTS: Clinical and demographic data were extracted from electronic medical records from the University of California, San Francisco, Multiple Sclerosis Center from January 2014 to December 2015. Magnetic resonance images were reviewed by MS neurologists (J.S.G., E.W., B.N., and E.C.H.). Rebound syndrome was defined as new severe neurological symptoms after ceasing fingolimod treatment, with the development of multiple new or enhancing lesions exceeding baseline activity. We reviewed the PubMed database from January 2010 to December 2015 for similar cases of severe disease reactivation after ceasing fingolimod treatment using search terms fingolimod and either rebound or reactivation. Participants were included if they stopped receiving fingolimod between January 2014 and December 2015. Five patients were identified who experienced rebound after ceasing fingolimod treatment. EXPOSURES: Each patient received treatment with oral fingolimod for various durations. MAIN OUTCOMES AND MEASURES: Occurrence of rebound after ceasing fingolimod treatment. RESULTS: The mean (SD) age of the 5 female patients presented in this case series was 35.2 (6.4) years. Of the 46 patients that stopped fingolimod treatment within the 2-year period, 5 (10.9%) experienced severe relapse 4 to 16 weeks after ceasing fingolimod treatment. Despite varying prior severity of relapsing-remitting course, all participants experienced unexpectedly severe clinical relapses accompanied by drastic increases in new or enhancing lesions seen on magnetic resonance imaging evidenced by a median (range) increase of 9 (0->30) new gadolinium-enhancing lesions and a median (range) of 9 (0->30) new T2 lesions. New lesion development persisted for 3 to 6 months despite treatment with corticosteroids (n = 3) and initiation of B-cell depleting therapy (n = 2). In addition, 11 patients were identified through literature review reported as having severe relapses consistent with a rebound syndrome and similar features to our 5 cases. CONCLUSIONS AND RELEVANCE: These cases provide evidence for a fingolimod rebound syndrome at a clinically relevant frequency, highlighting the need to determine the best methods for sequencing or discontinuing MS therapies. A large prospective registry or population-based study would be helpful to confirm this rebound phenomenon and to determine contributing factors, including immune biomarkers, that increase risk for this syndrome.

Reduction of CD8(+) T lymphocytes in multiple sclerosis patients treated with dimethyl fumarate.

OBJECTIVE: To evaluate the influence of dimethyl fumarate (DMF, Tecfidera) treatment of multiple sclerosis (MS) on leukocyte and lymphocyte subsets. METHODS: Peripheral blood leukocyte and lymphocyte subsets, including CD3(+), CD4(+), and CD8(+) T cells; CD19(+) B cells; and CD56(+) natural killer (NK) cells, were obtained at baseline and monitored at 3 months, 6 months, and 12 months after initiation of DMF treatment. RESULTS: Total leukocyte and lymphocyte counts diminished after 6 months of DMF therapy. At 12 months, lymphocyte counts had decreased by 50.1% (p < 0.0001) and were below the lower limit of normal (LLN) in one-half of patients. CD3(+) T lymphocyte counts fell by 44.2% (p < 0.0001). Among subsets, CD8(+) T cell counts declined by 54.6% (p < 0.0001), whereas CD4(+) T cell counts decreased by 39.2% (p = 0.0006). This disproportionate reduction of CD8(+) T cells relative to CD4(+) T cells was significant (p = 0.007) and was reflected by a 35.5% increase in the CD4/CD8 ratio (p = 0.007). A majority of CD8(+) T cell counts, but not CD4(+) T cell counts, were below the LLN even when total lymphocyte counts were greater than 500 cells/µL. CD19(+) B cell counts were reduced by 37.5% (p = 0.035). Eosinophil levels decreased by 54.1% (p = 0.006), whereas levels of neutrophils, monocytes, basophils, and NK cells were not significantly altered. CONCLUSION: Subsets of peripheral blood leukocytes and lymphocytes are differentially affected by DMF treatment of MS. Reduction of CD8(+) T cells is more pronounced than that of CD4(+) T cells. These findings may have implications for cell-mediated antiviral immunity during DMF treatment.

Precision medicine in chronic disease management: The multiple sclerosis BioScreen.

We present a precision medicine application developed for multiple sclerosis (MS): the MS BioScreen. This new tool addresses the challenges of dynamic management of a complex chronic disease; the interaction of clinicians and patients with such a tool illustrates the extent to which translational digital medicine-that is, the application of information technology to medicine-has the potential to radically transform medical practice. We introduce 3 key evolutionary phases in displaying data to health care providers, patients, and researchers: visualization (accessing data), contextualization (understanding the data), and actionable interpretation (real-time use of the data to assist decision making). Together, these form the stepping stones that are expected to accelerate standardization of data across platforms, promote evidence-based medicine, support shared decision making, and ultimately lead to improved outcomes.

Switching multiple sclerosis patients with breakthrough disease to second-line therapy.

BACKGROUND: Multiple sclerosis (MS) patients with breakthrough disease on immunomodulatory drugs are frequently offered to switch to natalizumab or immunosuppressants. The effect of natalizumab monotherapy in patients with breakthrough disease is unknown. METHODS: This is an open-label retrospective cohort study of 993 patients seen at least four times at the University of California San Francisco MS Center, 95 had breakthrough disease on first-line therapy (60 patients switched to natalizumab, 22 to immunosuppressants and 13 declined the switch [non-switchers]). We used Poisson regression adjusted for potential confounders to compare the relapse rate within and across groups before and after the switch. RESULTS: In the within-group analyses, the relapse rate decreased by 70% (95% CI 50,82%; p<0.001) in switchers to natalizumab and by 77% (95% CI 59,87%; p<0.001) in switchers to immunosuppressants; relapse rate in non-switchers did not decrease (6%, p =  0.87). Relative to the reduction among non-switchers, the relapse rate was reduced by 68% among natalizumab switchers (95% CI 19,87%; p = 0.017) and by 76% among the immunosuppressant switchers (95% CI 36,91%; p = 0.004). CONCLUSIONS: Switching to natalizumab or immunosuppressants in patients with breakthrough disease is effective in reducing clinical activity of relapsing MS. The magnitude of the effect and the risk-benefit ratio should be evaluated in randomized clinical trials and prospective cohort studies.

Sex differences in multiple sclerosis.

Sex and sex hormones affect the CNS and the immune system differentially, and thus a sexual dimorphism may be anticipated across arenas in multiple sclerosis (MS). Information from the past few decades has elucidated the impact of sex on broad aspects of MS, such as susceptibility, disease course, and radiologic phenotypes. Specific concerns regarding family planning and managing reproductive issues influenced by MS are likely to arise, given the typical age of onset during reproductive years. Thus, information regarding reproductive health in male and female patients with MS can potentiate the role of the neurologist in the management of these important aspects of clinical care.