Review: The Nutritional Management of Multiple Sclerosis With Propionate

Over the last 15 years there has been an accumulation of data supporting the concept of a gut-brain axis whereby dysbiosis of the gut microbiota can impact neurological function. Such dysbiosis has been suggested as a possible environmental exposure triggering multiple sclerosis (MS). Dysbiosis has been consistently shown to result in a reduction in short-chain fatty acid (SCFA) producing bacteria and a reduction in stool and plasma levels of propionate has been shown for MS patients independent of disease stage and in different geographies. A wealth of evidence supports the action of propionate on T-cell activity, resulting in decreased T-helper cell 1 (Th1) and T-helper cell 17 (Th17) numbers/activity and increased regulatory T cell (Treg cell) numbers/activity and an overall anti-inflammatory profile. These different T-cell populations play various roles in the pathophysiology of MS. A recent clinical study in MS patients demonstrated that supplementation of propionate reduces the annual relapse rate and slows disease progression. This review discusses this data and the relevant mechanistic background and discusses whether taming of the overactive immune system in MS is likely to allow easier bacterial and viral infection.

Evaluation of efficacy and tolerability of first-line therapies in NMOSD

ObjectiveTo compare the efficacy and the risk of severe infectious events of immunosuppressive agents used early as first-line therapy in patients with neuromyelitis optica spectrum disorder (NMOSD).MethodsWe retrospectively included patients with NMOSD and a seropositive status for aquaporin 4 or myelin oligodendrocyte glycoprotein antibodies beginning first-line immunosuppressants within 3 years after the disease onset. The main outcome was occurrence of relapse after the initiation of immunosuppressants; the secondary outcome was the annual relapse rate (AAR).ResultsA total of 136 patients were included: 62 (45.6%) were treated with rituximab (RTX), 42 (30.9%) with mycophenolate mofetil (MMF), and 23 (16.9%) with azathioprine (AZA). Compared with RTX-treated patients, the risk of relapse was higher among MMF-treated patients (hazard ratio [HR], 2.74 [1.17–6.40]; p = 0.020) after adjusting for age at disease onset, sex, antibody status, disease duration, ARR before treatment, corticosteroid intake, and relapse location. We did not observe any difference between RTX-treated and AZA-treated patients (HR, 2.13 [0.72–6.28]; p = 0.17). No interaction was found between the antibody status and immunosuppressive treatments. ARR was lower with RTX than with MMF (p = 0.039), but no difference was observed with AZA. We observed 9 serious infectious events with MMF, 6 with RTX, and none with AZA.ConclusionsThe use of first-line RTX in NMOSD appears more effective than MMF in suppressing clinical activity, independent of the antibody status.Classification of evidenceThat study provides Class III evidence that for patients with NMOSD, first-line RTX is superior to MMF to reduce the risk of relapse.

Increased serum IL-36β and IL-36γ levels in patients with neuromyelitis optica spectrum disorders: Association with disease activity

Background: Interleukin 36 (IL-36) cytokines belong to the IL-1 family and play an important role in some autoimmune diseases. However, the relationship between IL-36 and neuromyelitis optica spectrum disorders (NMOSD) remains unclear. Methods: We determined serum IL-36α, IL-36β and IL-36γ levels and assessed correlations with clinical characteristics in 50 NMOSD patients and 30 healthy controls (HC). Results: The concentrations of serum IL-36β and IL-36γ were significantly higher in patients with NMOSD than in HCs and decreased during remission. Serum IL-36β levels were positively correlated with the annual relapse rate (ARR), spinal cord lesion length and Expanded Disability Status Scale (EDSS) scores. Conclusions: Serum IL-36β and IL-36γ levels were related to disease activity in NMOSD patients and may be important biomarkers of NMOSD.

Increased serum IL-36β and IL-36γ levels in patients with neuromyelitis optica spectrum disorders: Association with disease activity

Abstract Background: Interleukin 36 (IL-36) cytokines belong to the IL-1 family and play an important role in some autoimmune diseases. However, the relationship between IL-36 and neuromyelitis optica spectrum disorders (NMOSD) remains unclear. Methods: We determined serum IL-36α, IL-36β and IL-36γ levels and assessed correlations with clinical characteristics in 50 NMOSD patients and 30 healthy controls (HC). Results: The concentrations of serum IL-36β and IL-36γ were significantly higher in patients with NMOSD than in HCs and decreased during remission. Serum IL-36β levels were positively correlated with the annual relapse rate (ARR), spinal cord lesion length and Expanded Disability Status Scale (EDSS) scores. Conclusions: Serum IL-36β and IL-36γ levels were related to disease activity in NMOSD patients and may be important biomarkers of NMOSD.

Pixantrone: a B-cell-depleting immunosuppressant for multiple sclerosis patients with active disease

Background: Mitoxantrone has been approved for patients with worsening relapsing–remitting (RR) or secondary progressive multiple sclerosis (SPMS), but its long-term use is limited by its cardiotoxicity. Pixantrone (PIX) is an analog of mitoxantrone. Objectives: The aim of this open-label, multicenter, noncomparative Phase I/II trial was to explore the immunosuppressive effect of PIX, its impact on clinical disease activity and cerebral gadolinium-enhanced (Gd+) lesions, and its safety. Methods: Eighteen patients with active RRMS and SPMS (⩾ 1 cerebral Gd+ lesion) despite approved immunomodulatory therapy received four intravenous PIX injections every 21 days. A neurological examination, hematology, lymphocyte subsets, and biochemistry were performed at Day 1, Weeks 3, 6 and 9, and Months 3, 6, 9 and 12. Echocardiography was performed before each infusion, at Months 3, 6 and 12. Cerebral MRI was performed at baseline, and at Months 6 and 12. Results: CD19+ cells were reduced by 95% at Month 3 and by 47% at Month 12. Gd+ lesions were reduced by 86% at Month 12 ( p = 0.01). The annual relapse rate was reduced by 87% ( p < 10−4). Two patients experienced a transient reduction in left ventricular fraction. Conclusion: These preliminary data indicate the efficacy of PIX in active RRMS and SPMS.

Distinct features between longitudinally extensive transverse myelitis presenting with and without anti-Aquaporin 4 antibodies

Objectives: Longitudinally extensive transverse myelitis (LETM) with spinal cord lesions spanning three or more vertebral segments is a key feature of neuromyelitis optica (NMO). However, the role of anti-aquaporin 4 (anti-AQP4) antibody, a sensitive biomarker of NMO, in the conversion of LETM to NMO remains uncertain. Methods: Thirty first-ever LETM patients were retrospectively analysed and divided into two groups according to the presence of anti-AQP4 antibodies. Results: Eighteen (60%) patients presented with anti-AQP4 antibodies. Fifteen (83.33%) anti-AQP4 (+) LETM patients converted to NMO, while only three of 12 (25%, p = 0.002) anti-AQP4 (-) LETM patients progressed to NMO, over a mean follow-up period of 5.63 years. Seven (38.89%) anti-AQP4 (+) and one (8.33%) anti-AQP4 (-) LETM patients received interferon-β1a treatment, respectively. Anti-AQP4 (+) LETM patients demonstrated a higher immunogamma globulin (IgG) index (0.68 ± 0.43 versus 0.47 ± 0.19, p = 0.018), annual relapse rate (0.72 ± 0.31 versus 0.42 ± 0.17, p = 0.01) and Kurtzke Expanded Disability Status Scale (4.28 ± 2.22 versus 2.67 ± 2.26, p = 0.031), than anti-AQP4 (-) LETM patients. In spinal magnetic resonance imaging (MRIs), more than half (58.33%) of the anti-AQP4 (+) LETM patients were observed to have central grey matter-predominant involvement in the axial view, while peripheral white matter-predominant involvement (51.85%) was the most common pattern observed in the anti-AQP4 (-) LETM patients. Conclusion: Anti-AQP4 (+) LETM demonstrated a high conversion rate to NMO (83.33%), suggesting that anti-AQP4 (+) LETM may represent an early, isolated syndrome of NMO spectrum disorder. The greater number of patients receiving interferon-β treatment in anti-AQP4 (+) LETM may contribute to its high annual relapse rate.

Response to Interferon-Beta Treatment in Afro-Caribbeans with Multiple Sclerosis

Background. Multiple sclerosis (MS) patients of African ancestry have a more aggressive disease course than white patients and could be resistant to interferon-beta (INFB).Methods. We studied the impact of INFB in treatment-naive Afro-Caribbean (AC) with clinically definite MS using our European Database for Multiple Sclerosis (EDMUS) (2003–2010). Main outcome measures were annual relapse rate after 2 years of treatment, proportion of exacerbation-free subjects 48 weeks after initiating INFB, and time to first relapse.Results. 76 AC-MS (59F/17M) were identified. Annual relapse rate of 1.29 decreased to 0.83 (−35.6%) after 2 years of treatment. The proportion of relapse-free patients at 48 weeks was 46.2%. Median time to first relapse was 52 weeks.Conclusion. INFB is not strong enough to control AC-MS patients in many cases which is problematic in a population of worse MS prognosis.

Low-dose corticosteroids reduce relapses in neuromyelitis optica: a retrospective analysis

Neuromyelitis optica (NMO) is a relapsing neurologic disease characterized by severe optic neuritis and transverse myelitis. A disease-modifying therapy for NMO has not been established. We retrospectively analysed the effect of low-dose corticosteroid (CS) monotherapy on the annual relapse rate in nine patients with NMO. We divided the clinical course in each patient into two periods; the CS Period in which CS was administered, and the No CS Period in which CS was not administered. Periods related to other immunological therapies, such as high-dose methylprednisolone, immunosuppressants, interferon-beta, and plasma exchange, were excluded. As a result, the annual relapse rate during the CS Periods [median, 0.49 (range, 0—1.31)] was found to be significantly lower than that during the No CS Periods [1.48 (0.65—5.54)]. As for the dose of CS, relapses occurred significantly more frequently with `10 mg/day or less' than with `over 10 mg/day' (odds ratio: 8.75). The results of the present study suggest a beneficial effect of low-dose CS monotherapy in reducing relapses in NMO. Multiple Sclerosis 2007; 13: 968—974. http://msj.sagepub.com

Multiple sclerosis-associated retrovirus in early multiple sclerosis: a six-year follow-up of a Sardinian cohort

The human endogenous retroviruses (HERV)-W family contains an extracellular particle detected in multiple sclerosis (MS) patients and designated as MS-associated retrovirus (MSRV). Through nested RT-PCR assays specific for pol MSRV gene, we preliminary reported that its presence in the cerebrospinal fluid (CSF) of early MS patients could be indicative of a poor prognosis upon a three-year follow-up. In the present clinical study, we enlarged our blind observation up to six years. At study entry, 10 MS patients were MSRV- and eight were MSRV+ in the CSF, both groups having a similar mean age and Expanded Disability Status Scale (EDSS) score. After six year follow-up, the mean EDSS significantly differed between the MSRV- and MSRV+ cohorts (4.3 versus 2.2; P = 0.004), as did the annual relapse rate (0.5 in the MSRV- versus 0.3 in the MSRV+; P = 0.01). Finally, two MSRV- patients entered the progressive phase, whilst none of the MSRV+ group entered this phase, and 9/10 MSRV- versus 2/8 MSRV+ patients were treated with immunomodulatory or immunosuppressive drugs (P = 0.009). In conclusion, we found that the presence of MSRV virions in the CSF at the onset of MS is associated, not only with disability accumulation, but also with a higher rate of clinical re-exacerbations. With the known potential pathogenic effects of MSRV given in the literature, further investigations on MSRV are warranted.

Clinical characteristics of multiple sclerosis in Taiwan: a cross-sectional study

This study reviewed the clinical characteristics of multiple sclerosis (MS) in Taiwanese patients from 1993 to 2001. Of the 75 MS patients with a mean age of onset of 35.6±12.6 years, the female-to-male ratio was 4.4 (61/14). In 42 (56%) optico-spinal MS (OS-MS) patients, the age of onset (37.6±11.1 years) tended to be older than conventional MS (C-MS) patients (33.1±14.1 years, P = 0.08). In 60 cerebrospinal fluid (CSF) specimens, raised IgG index (>0.7) and oligoclonal bands were noted in 26 (43.3%) and two (3.3%) cases, respectively. The frequency of raised IgG index was lower in OSMS (31.3%) than in C-MS (57.1%, P = 0.07). The CSF total protein concentrations were significantly higher in OS-MS (64.5 mg/dL) than in C-MS (46.6 mg/dL, P = 0.047). The mean annual relapse rate was 54.1%, and was significantly higher within the first year (59.7%, P<0.001). The mean annual relapse rate in OS-MS (62.7%) was significantly higher than in C-MS (41.2%, P = 0.01). The differences in the annual relapse rate and total protein concentration in CSF between OS-MS and C-MS suggest probably two distinct immunopathogenesis. The higher first year relapse rate of MS patients in Taiwan may address the importance of early intervention with immunomodulatory therapy.