Natalizumab-treated patients at high risk for PML persistently excrete JC polyomavirus.

Sixty-three natalizumab-treated patients with relapsing multiple sclerosis were screened for JC polyomavirus (JCV) viruria. Urinary-positive patients were longitudinally sampled for up to 24 weeks. Using methods that distinguish encapsidated virus from naked viral DNA, 17.5 % of patients were found to excrete virus, consistent with the prevalence of urinary excretion in the general population. Unexpectedly, urinary excretion was predominantly seen (>73 %) in patients with high JC antibody index (≥2.0). Active JCV infection, therefore, tends to occur in natalizumab patients that carry a high risk factor for the development of disease, directly linking JC infection to the risk factors for PML development.

Sodium intake is associated with increased disease activity in multiple sclerosis.

BACKGROUND: Recently, salt has been shown to modulate the differentiation of human and mouse Th17 cells and mice that were fed a high-sodium diet were described to develop more aggressive courses of experimental autoimmune encephalomyelitis. However, the role of sodium intake in multiple sclerosis (MS) has not been addressed. We aimed to investigate the relationship between salt consumption and clinical and radiological disease activity in MS. METHODS: We conducted an observational study in which sodium intake was estimated from sodium excretion in urine samples from a cohort of 70 relapsing-remitting patients with MS who were followed for 2 years. The effect of sodium intake in MS disease activity was estimated using regression analysis. We then replicated our findings in a separate group of 52 patients with MS. RESULTS: We found a positive correlation between exacerbation rates and sodium intake in a multivariate model adjusted for age, gender, disease duration, smoking status, vitamin D levels, body mass index and treatment. We found an exacerbation rate that was 2.75-fold (95% CI 1.3 to 5.8) or 3.95-fold (95% CI 1.4 to 11.2) higher in patients with medium or high sodium intakes compared with the low-intake group. Additionally, individuals with high-sodium intake had a 3.4-fold greater chance of developing a new lesion on the MRI and on average had eight more T2 lesions on MRI. A similar relationship was found in the independent replication group. CONCLUSIONS: Our results suggest that a higher sodium intake is associated with increased clinical and radiological disease activity in patients with MS.

Testing for urinary tract colonization before high-dose corticosteroid treatment in acute multiple sclerosis relapses: prospective algorithm validation.

BACKGROUND AND PURPOSE: To evaluate a dipstick algorithm for urinary tract colonization, prior to high-dose corticosteroid treatment in acute relapses of multiple sclerosis (MS). METHODS: Prospective cohort study of 267 consecutive patients with MS relapses requiring corticosteroid treatment in a hospital-based, ambulatory, acute MS relapse clinic. A total of 18 participants met the exclusion criteria, leaving 249 for analysis. Main outcome measures were urinary dipstick sensitivity, specificity, positive predictive value, negative predictive value and safety of antibiotic co-treatment with high-dose corticosteroids. RESULTS: Significant bacteriuria (≥10(5) colonies ml) rate in this population was 11% (95% CI, 7.1-14.9). Specificity and sensitivity of positive leucocyte esterase or nitrite were 78% and 65%. Negative predictive value of urine dipstick was 96%. No clinical adverse events occurred in the 3% (95% CI, 0.9-5.1) of patients with a false-negative dipstick. Eighteen per cent of patients were unnecessarily treated with antibiotics for 48 h. CONCLUSION: Urinary dipstick testing allows for rapid and safe management of patients suffering from an acute MS relapse. The algorithm is conservative, and future work is needed to reduce the false-positive rate.

JC Virus-DNA Detection Is Associated with CD8 Effector Accumulation in Peripheral Blood of Patients with Multiple Sclerosis under Natalizumab Treatment, Independently from JC Virus Serostatus.

Although natalizumab (anti-α4 integrin) represents an effective therapy for relapsing remitting multiple sclerosis (RRMS), it is associated with an increased risk of developing progressive multifocal leukoencephalopathy (PML), caused by the polyomavirus JC (JCV). The aim of this study was to explore natalizumab-induced phenotypic changes in peripheral blood T-lymphocytes and their relationship with JCV reactivation. Forty-four patients affected by RRMS were enrolled. Blood and urine samples were classified according to natalizumab infusion number: 0 (N0), 1-12 (N12), 13-24 (N24), 25-36 (N36), and over 36 (N > 36) infusions. JCV-DNA was detected in plasma and urine. T-lymphocyte phenotype was evaluated with flow cytometry. JCV serostatus was assessed. Ten healthy donors (HD), whose ages and sexes matched with the RRMS patients of the N0 group, were enrolled. CD8 effector (CD8 E) percentages were increased in natalizumab treated patients with detectable JCV-DNA in plasma or urine compared to JCV-DNA negative patients (JCV-) (p < 0.01 and p < 0.001, resp.). Patients with CD8 E percentages above 10.4% tended to show detectable JCV-DNA in plasma and/or urine (ROC curve p = 0.001). The CD8 E was increased when JCV-DNA was detectable in plasma or urine, independently from JCV serology, for N12 and N24 groups (p < 0.01). As long as PML can affect RRMS patients under natalizumab treatment with a negative JCV serology, the assessment of CD8 E could help in the evaluation of JCV reactivation.

Decreased urinary level of melatonin as a marker of disease severity in patients with multiple sclerosis.

Melatonin has both pro-inflammatory and anti-inflammatory properties depending on the stage of inflammation. Despite its therapeutic effect in alleviation of some symptoms of multiple sclerosis; the precise role of melatonin in MS pathogenesis remains a topic of debate. The aim of this study was to measure the urine level of one of melatonin products which is an index of serum melatonin level, in MS patients in the acute phase of relapse and control patients. We also analyzed different clinical and cognitive indices in order to find any correlation with melatonin level. Twenty eight patients who were diagnosed as relapsing-remitting MS, according to the revised McDonald criteria, along with 10 age- and sex-matched control subjects were recruited in our study. Here we showed that urine 6-sulphatoxymelatonin levels (aMT6s; the major metabolite of melatonin) were significantly lower in MS patients compared to control group. Interestingly, urine aMT6s levels significantly correlated with MS Functional Composite score, but not Expanded Disability Severity Score. Based on above findings, there might be new hope in developing a quantitative and objective measure to assess the MS severity especially in neurodegenerative diseases. However, our results should be analyzed cautiously. We didn't evaluate simultaneous level of 25-OH Vitamin D. It has been recently reported that there is a negative correlation between melatonin and vitamin D levels. Further studies are needed to confirm this hypothesis.

NMR-Based Metabolomics Separates the Distinct Stages of Disease in a Chronic Relapsing Model of Multiple Sclerosis.

Relapsing experimental allergic encephalomyelitis (Cr-EAE) is commonly used to explore the pathogenesis and efficacy of new therapies for MS, but it is unclear whether the metabolome of Cr-EAE is comparable to human multiple sclerosis (MS). For MS, the diagnosis and staging can be achieved by metabolomics on blood using a combination of magnetic resonance spectroscopy and partial least squares discriminant analysis (PLS-DA). Here, we sought to discover whether this approach could be used to differentiate between sequential disease states in Cr-EAE and whether the same metabolites would be discriminatory. Urine and plasma samples were obtained at different time-points from a clinically relevant model of MS. Using PLS-DA modelling for the urine samples furnished some predictive models, but could not discriminate between all disease states. However, PLS-DA modelling of the plasma samples was able to distinguish between animals with clinically silent disease (day 10, 28) and animals with active disease (day 14, 38). We were also able to distinguish Cr-EAE mice from naive mice at all-time points and control mice, treated with complete Freund's adjuvant alone, at day 14 and 38. Key metabolites that underpin these models included fatty acids, glucose and taurine. Two of these metabolites, fatty acids and glucose, were also key metabolites in separating relapsing-remitting MS from secondary-progressive MS in the human study. These results demonstrate the sensitivity of this metabolomics approach for distinguishing between different disease states. Furthermore, some, but not all, of the changes in metabolites were conserved in humans and the mouse model, which could be useful for future drug development.

Relationship of urinary myelin basic protein-like material with cranial magnetic resonance imaging in advanced multiple sclerosis.

BACKGROUND: A significant correlation exists between disability and the volume of black holes (BHL VOL), defined as hypointense lesions on T1-weighted cranial magnetic resonance imaging. A consistent correlation has also been reported between urinary myelin basic protein-like material (MBPLM) and the transition toward secondary progression (SP) from relapsing-remitting (RR) multiple sclerosis (MS). OBJECTIVE: To improve the management of MS through a noninvasive and cost-effective test for monitoring disease activity or disease status. DESIGN AND METHODS: From 662 patients with MS (86 with RR MS, 259 with SP MS without continued attacks, and 317 with SP MS with continued attacks), 24-hour urine samples were obtained at enrollment in the phase 3 Linomide (roquinimex) drug study. The urine specimens were analyzed for MBPLM and correlated with clinical features and findings on cranial magnetic resonance imaging. RESULTS: Significant but weak correlations existed between urinary MBPLM and BHL VOL in all patients with MS (r = 0.114, P =.003; n = 662), patients with SP MS without attacks (r = 0.185, P =.003; n = 259), and all patients with SP MS (r = 0.122, P =.003; n = 576). No significant correlations were detected in the RR MS group or any of the disease groups or subgroups whose Expanded Disability Status Scale score was 5.0 or lower. In subgroup analysis, the most significant correlation was detected between urinary MBPLM after adjustment for creatinine and BHL VOL in patients with SP MS with an Expanded Disability Status Scale score of 5.5 or higher but without continued relapses (r = 0.417, P<.001; n = 138). CONCLUSIONS: In patients with advanced SP MS, urinary MBPLM may possibly serve as an indicator of failed remission and axonal damage. Urinary MBPLM correlates with disease status in MS, especially the transition of RR MS to SP MS with advancing disability.

Increased urinary nitric oxide metabolites in patients with multiple sclerosis correlates with early and relapsing disease.

Nitric oxide (NO) has been implicated in the immunopathogenesis of MS as a potential mediator of neuronal loss. To investigate the role of.NO in the development of progressive disease we measured the NO metabolites (nitrate and nitrite) and neopterin, in the urine of 129 patients with demyelinating disease (DD): 23 with clinically isolated syndromes compatible with demyelination and in 46 relapsing remitting (RR) and 60 patients with progressive MS. Eighty-nine of these 129 patients underwent Gd-enhanced MRI. In addition 58 normal control subjects (NC), 19 AIDS and 35 rheumatoid arthritis (RA) patients were studied. Patients with DD, AIDS and RA had significantly elevated urinary nitrate plus nitrite (nit : creat. urine) and neopterin (neopt : creat.urine) to creatinine ratios compared to NC subjects. (Median[25th - 75th%] nit : creat.urine: NC=1183[962 - 1365] vs DD=1245[875 - 2403], AIDS=1686[1231 - 2531], and RA=1950[1214 - 2726] mumol/mol, P<0.001 and median[25th - 75th%] neopt : creat.urine: NC=99[76 - 151] vs DD=163[119 - 266], AIDS=972[653 - 1456], and RA=389[257 - 623] mu mol/mol, P<0.001). Patients with early DD and RR MS had significantly elevated nit : creat.urine compared to patients with progressive MS (nit : creat. urine: 1612[1020 - 2733] vs 1159[790 - 1641] mu mol/mol, P=0.006). The nit : creat.urine and neopt : creat.urine did not correlate with clinical relapse or MRI activity. Excretion of.NO metabolites is increased in patients with early or relapsing-remitting disease.NO appears to be a double-edged sword, mediating tissue damage and modulating complex immunological functions which may be protective in MS.