Elizabeth Crabtree-Hartman

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.

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

Significance We have experimentally investigated the immunoregulatory effects of human gut microbiota in multiple sclerosis (MS). We have identified specific bacteria that are associated with MS and demonstrated that these bacteria regulate T lymphocyte-mediated adaptive immune responses and contribute to the proinflammatory environment in vitro and in vivo. Thus, our results expand the knowledge of the microbial regulation of immunity and may provide a basis for the development of microbiome-based therapeutics in autoimmune diseases. 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.

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.

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.

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

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.

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. Ann Neurol 2014;76:633–642

Precision medicine in chronic disease management: the MS 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. Ann Neurol 2014;76:633–642

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.

Long-term evolution of multiple sclerosis disability in the treatment era: MS Disability

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.

Precision medicine in chronic disease management: The multiple sclerosis BioScreen: MS 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. Ann Neurol 2014;76:633–642