Osteopontin levels and increased disease activity in relapsing-remitting multiple sclerosis patients

Osteopontin (OPN) has been identified as the most prominent cytokine-encoding gene expressed within multiple sclerosis (MS) lesions. Recently, we demonstrated that OPN plasma levels were elevated in active relapsing-remitting (RR) MS patients. In this longitudinal study, a trend was observed for OPN serum levels in relation to clinical exacerbations. Moreover, OPN protein levels were significantly elevated 1 month prior to increase of gadolinium (Gd)-enhancing lesion number, whereas no relation was observed between OPN levels and increase in Gd-enhancing lesion volume. Although no robust relation between OPN and disease activity was observed, these data suggest that OPN levels are elevated prior to increased disease activity in RR MS patients.     

Efficacy of natalizumab in multiple sclerosis patients with high disease activity: a Danish nationwide study

Introduction:  Previous studies of natalizumab (Tysabri®) in relapsing multiple sclerosis (MS) patients have included patients with moderate disease activity. We studied a patient population with high disease activity.
Patients and Methods:  We analyzed data from 234 consecutive, natalizumab-treated patients, followed for at least 3 months. Three groups of patients were eligible for natalizumab therapy: patients with two or more documented relapses or sustained increase of 2 EDSS points on disease modifying therapy (DMT) in the previous year; patients switching from mitoxantrone; and patients with very active MS as de novo therapy.
Results:  During a median observation time of 11.3 months (range 3.0–21.5) the annualized relapse rate decreased to 0.68 from a pre-treatment rate of 2.53 (73% reduction). We assessed the annualized relapse rate in three subgroups: (i) 0.83 in 14 (6.0%) de novo treated patients; (ii) 0.71 in 175 (74.8%) patients with ≥2 relapses or sustained increase in EDSS of ≥2 points on a first-line DMT; and (iii) 0.56 in 45 (19.2%) patients switching from mitoxantrone. Nine anaphylactoid reactions, two severe, were reported. Out of 215 patients 7 (3%) were persistently positive for antibodies to natalizumab.
Conclusions:  Tysabri appears to be effective in MS patients with high disease activity, but the relapse rate was higher than in the pivotal study after the first treatment year. This is likely to reflect differences in disease activity before the initiation of natalizumab treatment.     

Course of relapsing-remitting multiple sclerosis before, during and after natalizumab

The consequences of interruption of natalizumab treatment are incompletely known. The objective was to assess the confirmed annualized relapse rates for patients preceding initiation, during and following suspension of natalizumab therapy. A chart review was conducted and data were analyzed using the Generalized Estimating Equations. During natalizumab therapy the confirmed annualized relapse rate was 0.08, compared to 0.52 (p = 0.0003) during the prior 12 months and to 0.35 (p = 0.0032) during the following 3 to 24 months. Similar results were found when confirmed and unconfirmed were analyzed. To conclude, following cessation of natalizumab therapy disease activity rapidly returned to pre-natalizumab levels.     

Gadolinium enhanced MRI predicts clinical and MRI disease activity in relapsing-remitting multiple sclerosis.

The aim of the study was to evaluate the predictive power of baseline gadolinium (Gd) enhanced MRI in relation to subsequent clinical and MRI activity. Sixty eight patients with clinically definite relapsing-remitting multiple sclerosis had a baseline Gd enhanced MRI and were followed up clinically and by monthly Gd enhanced MRI for six months. The occurrence of relapses during the follow up period was predicted by the presence of at least one enhancing lesion on the baseline MRI (P < 0.05). The number and volume of enhancing lesions at baseline were significantly associated with both enhancing lesions observed during the follow up period (P < 0.0001) and the accumulation of abnormality on T2 weighted images (P < 0.0001). Moreover, the presence of three or more enhancing lesions at baseline scan was consistently associated with the development of permanent abnormalities on T2 weighted images six months later. The study suggests that the number and volume of Gd enhancing lesions at a single examination are strong short term predictors of subsequent clinical and MRI activity.     

Post-natalizumab clinical and radiological findings in a cohort of multiple sclerosis patients: 12-month follow-up

There is an urgent need to identify the best strategies to prevent the loss of natalizumab (N) beneficial effects after its suspension. The objective is to evaluate the clinical and radiological disease activity and to test the efficacy of immunomodulatory/immunosuppressive drugs (IT) after N suspension. Clinical and radiological data from 54 patients 2 years before treatment (pre-N), during treatment (on-N) and after interruption, during 1-year follow-up (post-N) were retrospectively collected. Annualized relapse rate (ARR), expanded disability status scale (EDSS), presence of new T2 lesions and Gd+ (gadolinium enhancing) T1 lesions were evaluated. Pre-N ARR at 1 year was 1.74 while post-N ARR was 0.94 (p = 0.0053). We observed that post-N disease activity never raised over pre-N levels, neither post-N ARR nor post-N EDSS. In patients retreated with N after suspension, post-N ARR was significantly lower than pre-N ARR (p = 0.017), but not in patients treated with other IT or in patients not treated with any disease modifying drugs (DMD). The mean time of freedom from new T2 lesions and new Gd+ lesions was lower in post-N period compared to on-N (T2 lesions p = 0.0000, Gd+ lesions p = 0.0000). In conclusion, a “rebound” pattern was not identified in our cohort, though the disease activity rapidly returned after N, regardless of the treatment used.     

The effect of natalizumab on cognitive function in patients with relapsing-remitting multiple sclerosis: preliminary results of a 1-year follow-up study

The objective of the study was to assess the natalizumab effect on the course of cognitive impairment in patients with relapsing-remitting multiple sclerosis (MS). Patients with active relapsing-remitting MS (n = 17) were treated with natalizumab for 1 year. The quasi control group included patients (n = 7) with clinically stable MS. Assessment of disease course [expanded disability status scale (EDSS); number of relapses] and neuropsychological impairment [Wisconsin card sorting test (WCST); controlled oral word associations; verbal/non-verbal memory tests; paced auditory serial addition test] was conducted at baseline and after 1 year. Natalizumab-treated patients experienced significantly fewer relapses compared with the previous year (P < 0.05). At 1-year follow-up, EDSS score was unchanged and neuropsychological assessments of memory/executive functions showed a significant improvement in natalizumab-treated patients (all P < 0.05). No changes were observed in the quasi control group. This preliminary study suggests that natalizumab could be effective in ameliorating cognitive functions in patients with active relapsing-remitting MS, over 1-year follow-up.     

Cognitive dysfunction in patients with relapsing-remitting multiple sclerosis

Cognitive dysfunction is considered one of the clinical markers of multiple sclerosis (MS). However, in the literature there are inconsistent reports on the prevalence of cognitive dysfunction, and separate data for the relapsing-remitting (RR) type of the disease are not always presented. In this study, we submitted 461 RRMS patients to a battery of neuropsychological tests to investigate their impairment in various cognitive domains. As a consequence of the exclusion criteria, the sample is not fully representative of the entire population of RRMS patients. In this selected sample, when only the eight scores of a core battery (Mental Deterioration Battery) were considered (with respective cutoffs), it emerged that 31% of the patients were affected by some degree of cognitive deficit. In particular, 15% had mild, 11.2% moderate and 4.8% had severe impairment. Information processing speed was the most frequently impaired area, followed by memory. When two other tests (SDMT and MCST) were added and cognitive domains were considered, it emerged that 39.3% of the patients were impaired in two or more domains. When four subgroups were obtained by means of cluster analysis and then compared, it emerged that information processing speed and memory deficits differentiated the still cognitively unimpaired from the mildly impaired MS patients. Significant associations were found between cognitive and clinical characteristics. However, due to the large sample size, clinically irrelevant relationships may also have emerged. Even with the limitations imposed by the sample selection and the possible underestimation of the prevalence and severity of cognitive dysfunction, these results seem to provide further evidence that information processing speed deficit may be an early and important marker of cognitive impairment in MS patients.     

Fingolimod reduces recurrence of disease activity after natalizumab withdrawal in multiple sclerosis

After discontinuation of natalizumab (NAT), multiple sclerosis (MS) disease activity often recurs. We assessed the recurrence of clinical disease activity during the first year after switching from NAT to fingolimod (FTY) in patients with relapsing-remitting MS. The number of relapses and the annualized relapse rate (ARR) before, during and after NAT discontinuation were determined and compared between 26 MS patients who switched to FTY within 24 weeks, and 10 MS patients who remained without disease modifying therapy (therapy free group = TFG). Median follow-up post-NAT discontinuation was 55.1 weeks. In a subgroup (n = 20), the occurrence of contrast-enhancing-lesions (Gd+) on magnetic resonance imaging (MRI) was determined. Eleven patients (42 %) in the FTY group and seven patients (70 %) in the TFG had one or more relapses after cessation of NAT during follow-up (p < 0.05). One of the 11 (9 %) patients in the FTY group and 6/9 (67 %) patients in the TFG showed Gd+ lesions during follow-up (p < 0.05). Patients who switched to FTY ≤ 12 weeks after NAT discontinuation (n = 9) showed a trend for a lower post-NAT ARR compared to patients who started FTY therapy >12 weeks after NAT was stopped (n = 17). Most relapses in the FTY group occurred just before or within 8 weeks after starting FTY. Our observation suggests that initiation of FTY treatment after NAT discontinuation reduces the recurrence of disease activity compared to withdrawal without further immunomodulatory treatment. In the FTY group the ARR tended to depend on the time interval between discontinuation of NAT and initiation of FTY.     

JCV detection in multiple sclerosis patients treated with natalizumab

Natalizumab therapy is associated with an increased risk of progressive multifocal leukoencephalopathy (PML). Because the prognosis of established PML is uniformly dismal, identification of highly susceptible patients to the disease may improve outcomes. We wanted to investigate whether serial plasma and cerebrospinal fluid (CSF) screening for polyomavirus would identify patients with laboratory evidence of viral infection prior to the development of clinical PML. Two hundred MS patients had pre-treatment CSF/plasma screening for JC virus (JCV) and BK virus (BKV) DNA, and thereafter every six treatments of natalizumab. In all positive patients treatment is stopped (due to potential risk of PML), they have follow-up clinical examinations and plasma/CSF JCV/BKV tests until all evaluations are normal. No patient developed clinical evidence of PML. Eight of the 200 patients had detectable JCV or BKV DNA. Five patients were positive for BKV DNA in the CSF and three patients were positive for JCV DNA (one in plasma, two in CSF). After cessation of natalizumab treatment, all patients converted to undetectable viral DNA. Screening for JCV in CSF in natalizumab-treated patients could help identify those at heightened risk for developing PML and discontinuing treatment in these patients may abort development of the clinical illness.     

Immune surveillance in multiple sclerosis patients treated with natalizumab

OBJECTIVE: Our objective was to test whether natalizumab, an antibody against very late activating antigen (VLA)-4, interferes with central nervous system immune surveillance as assessed by leukocyte cell numbers and cellular phenotypes in cerebrospinal fluid (CSF) and peripheral blood. METHODS: Cell numbers and cellular phenotypes in CSF and peripheral blood were analyzed in multiple sclerosis (MS) patients treated with natalizumab, untreated MS patients, and patients with other neurological disease (OND). JC virus DNA in the CSF and peripheral blood was quantified by kinetic polymerase chain reaction. RESULTS: CSF leukocyte counts, CD4(+) and CD8(+) T cells, CD19(+) B cells, and CD138(+) plasma cells were significantly lower in natalizumab-treated MS patients compared with OND patients and untreated MS patients. JC virus DNA was not detected in CSF or peripheral blood from natalizumab-treated patients. Six months after cessation of natalizumab therapy, low lymphocyte counts in the CSF persisted. The patient with the highest total leukocyte and CD4(+) and CD8(+)T-cell counts in the CSF experienced a clinical relapse. INTERPRETATION: These data suggest that natalizumab treatment results in a prolonged decrease of lymphocytes in the CSF and are consistent with the hypothesis that natalizumab impairs immune surveillance of the central nervous system.     

Serum matrix metalloproteinase-3 levels correlate with disease activity in relapsing-remitting multiple sclerosis

BACKGROUND: Adhesion molecules and matrix metalloproteinases (MMPs) are known to be relevant to the ongoing development and disappearance of areas of demyelination in the white matter of the CNS of multiple sclerosis (MS) patients. This study examined whether serum matrix metalloproteinase-3 (MMP-3) levels correlate with disease activity in MS. METHODS: Serum MMP-3 levels in 47 consecutive patients with relapsing-remitting MS were measured by immunoassay every 4 weeks over a 15 month period. RESULTS: During the study period, 48 clinical relapses occurred. Serum MMP-3 levels within 1 month of relapse were significantly higher than during the remission phase. Sequential analysis showed that serum MMP-3 levels had increased transiently at the time of clinical relapse but returned to the normal range within a month. CONCLUSIONS: Circulatory MMP-3 levels are correlated with disease activity in relapsing-remitting MS. This may contribute to the breakdown of the blood-brain barrier at the time of relapse.     

Effect of open label pulse cyclophosphamide therapy on MRI measures of disease activity in five patients with refractory relapsing-remitting multiple sclerosis.

OBJECTIVE: To evaluate the response to cyclophosphamide (CTX) of five patients who failed an average three treatments with multiple other therapeutic agents, using serial monthly MRI measures. METHODS: Five patients with relapsing-remitting multiple sclerosis (MS) and documented MRI disease activity were started on monthly pulse intravenous CTX at a dose of 1 g/m2. CTX was administered without an induction phase according to the protocol similar to the treatment of lupus nephritis. The five patients were followed with monthly MRI and clinical evaluation for a mean of 28 months. RESULTS: All the patients showed a rapid reduction in the contrast-enhancing lesion frequency and in three patients there was a decrease in the T2 lesion load within the first 5 months after starting CTX treatment. The administration of CTX during overnight hospitalization was safe and well tolerated. CONCLUSIONS: These findings suggest that aggressive immunosuppressive therapy may be useful in some rapidly deteriorating refractory patients and further controlled study should be considered in order to full evaluate this type of treatment as a potential therapy in MS.