Neopterin production and tryptophan degradation during 24-months therapy with interferon beta-1a in multiple sclerosis patients.

BACKGROUND: Increased synthesis of neopterin and degradation of tryptophan to kynurenine, measured as kynurenine/tryptophan ratio (kyn/trp ratio), are considered in vitro markers of interferon beta-1a (IFNß-1a) activity. The aim of the study was to investigate the dynamic profile of neopterin and kyn/trp ratio in patients with relapsing remitting multiple sclerosis (RRMS) treated with two different doses of IFNß-1a over a period of 24 months. METHODS: RRMS patients (n = 101) received open-label IFNß-1a 22 mcg (low dose, LD) or 44 mcg (high dose, HD) subcutaneously (sc), three times weekly for 24 months. Serum measurements of neopterin, kyn/trp ratio and neutralizing antibodies (NAbs) were obtained before treatment (i.e., at baseline) and 48 hours post-injection every 3 months thereafter. Clinical assessments were performed at baseline and every 6 months. Changes in biomarkers over time were compared between LD- and HD-group as well as between patients with/without relapses and with/without NAbs using Analysis of Variance and Mann-Whitney tests. RESULTS: Neopterin (p < 0.001) and kyn/trp ratio (p = 0.0013) values increased over time vs baseline in both treatment groups. Neopterin values were higher (p = 0.046) in the HD-compared to the LD-group at every time point with the exclusion of months 21 and 24 of therapy. Conversely, there were no differences between the two doses groups in the kyn/trp ratio with the exclusion of month 6 of therapy (p < 0.05). Neopterin levels were significantly reduced in NAb-positive patients starting from month 9 of therapy (p < 0.05); the same result was observed for kyn/trp ratio but only at month 9 (p = 0.02). Clinical status did not significantly affect neopterin production and tryptophan degradation. CONCLUSIONS: Although differences in serum markers concentration were found following IFNß administration the clinical relevance of these findings needs to be confirmed with more detailed studies.

The prevalence of multiple sclerosis in central Italy.

BACKGROUND: The prevalence of multiple sclerosis varies considerably throughout the world. OBJECTIVE: To better define the prevalence of MS in central Italy. METHODS: This is a population-based study conducted in the province of Frosinone, which is situated in the Lazio region, central Italy. The selected prevalence day was 1 January 2007. A total of 467 patients, with a definite diagnosis of multiple sclerosis, were considered for crude, age- and sex-specific prevalence estimation. RESULTS: The overall crude prevalence rate was 95.0 cases per 100,000 (95% confidence interval (CI) 86.6-104.0). A significantly higher prevalence rate was recorded in females (134.9, 95% CI 121.0-150.1) than in males (53.3, 95% CI 44.4-63.3) (p = 0.001). Age-specific prevalence peaked in the 25-34 year, 35-44 year and 45-54 year age groups; moreover, it was found to increase up to the 35-44 year age group in males and the 45-54 year age group in females, decreasing thereafter. The female to male ratio was 2.6. CONCLUSIONS: The results confirm that MS occurs more frequently in central Italy than might be expected on the basis of the geographic-related distribution model, thus supporting the view that this is a high-risk area for the disease.

Pharmacodynamics of interferon beta in multiple sclerosis patients with or without serum neutralizing antibodies.

To analyze the in vivo biological effect of anti-interferon beta (IFN-beta) neutralizing antibodies (NABs), blood concentrations of neopterin, beta2microglobulin (Beta2-MG), mRNA-dependent myxovirusresistant protein A (MxA) and dsRNA-dependent protein kinase (PKR) were measured before (predose) and 24 hours after (postdose) IFN-beta administration in 49 patients with multiple sclerosis (MS) with (n = 25) and without (n = 24) NABs. The results indicated that predose levels of MxA-mRNA and PKR-mRNA were highly variable [coefficient of variation (CV) > 100%] among patients. A lower inter-individual variability was observed for pre-dose levels of Beta2-MG and neopterin (CVs of 29% and 44%, respectively). Significantly lower pre- and post-dose blood levels of IFN induced markers, except for postdose PKR-mRNA (p = 0.09), were seen in NAB+ compared with NAB-patients and between patients with high (> 200 t(1/10)) and low ( pound 200 t(1/10)) NAB titers. A significant inverse correlation between NAB titer and pre-dose levels of the above IFN-induced markers was found. In summary, our findings confirm that NABs affect absolute concentrations of IFN-beta induced markers and suggest that such an effect occurs in a titer-dependent manner.

Effect of MRI coregistration on serial short-term brain volume changes in multiple sclerosis.

OBJECTIVE: To test the effect of serial magnetic resonance (MR) coregistration on short-term brain volume changes using different semiautomated and automated brain volume techniques in patients with relapsing-remitting (RR) multiple sclerosis (MS). Coregistration is frequently used to increase precision in serial MR imaging (MRI) analyses. However, the effect of coregistration on measurement of whole brain volume changes from serial scans in the short term has not been tested in MS patients. METHODS: Twenty-eight patients with RR MS [mean disease duration: 4.9 years, mean age: 34.4 years and mean expanded disability status scale (EDSS): 1.4] were scanned at baseline and monthly for a period of 3 months with 2D spin-echo T1-weighted sequences obtained with nongapped 3 mm axial slices. Percent brain parenchymal fraction change (PBPFC) was calculated by a semiautomated (Buffalo) and, separately, by two automated (Buffalo automated and SIENAX) techniques, whereas percent brain volume change (PBVC) was calculated by the SIENA technique. For coregistration of serial images we used a robust, fully automated linear image coregistration tool. PBPFC and PBVC were calculated before and after coregistration, comparing scans from the following time periods: (1) baseline to month 3; (2) baseline to month 1; (3) month 1 to 2 and (4) month 2 to 3. RESULTS: The highest median PBPFCs measured on non-coregistered images were detected for the baseline-to-month-3 time period and ranged from -0.11% for Buffalo semiautomated to -0.45% for Buffalo automated (p = ns). On coregistered images, the highest PBPFCs were detected for the baseline-to-month-3 time period and ranged from 0.3% for Buffalo semiautomated, -0.3% for Buffalo automated, 0.02% for SIENAX and -0.02% for SIENA (PBVC). At all time points of the study, no significant differences of median volume changes were measured on coregistered and non-coregistered images when comparing the results among the segmentation algorithms. CONCLUSIONS: Over a 3 month period we did not detect short-term changes in normalized brain volumes using different measurement techniques. A longer observation period is needed to assess whether coregistration can affect the measurement of long-term brain volume changes.

Duloxetine for the treatment of overactive bladder syndrome in multiple sclerosis: a pilot study.

OBJECTIVES: Overactive bladder (OAB) syndrome represents one of the main urinary disorders associated with multiple sclerosis (MS). At present, no widely accepted effective treatment is available. Duloxetine, an antidepressant acting as a selective serotonin-norepinephrine reuptake inhibitor, has been shown to be effective in the treatment of some symptoms of stress urinary incontinence and OAB because of etiology other than MS.The present study aims at establishing the efficacy and tolerability of duloxetine in the treatment of OAB in patients affected by remitting-relapsing MS and secondary progressive MS. MATERIALS AND METHODS: Twenty-three patients with MS, 13 of which with remitting-relapsing MS and 10 with secondary progressive MS, have been treated with duloxetine and placebo for a total period of 8 weeks during a single-blinded cross-over trial. At each programmed visit, patients have been screened for the following: (1) quantitative evaluation of maximal bladder capacity and postmicturition residual volume; (2) questionnaire administration to evaluate bladder disorder--Overactive Bladder Questionnaire, quality of life--Visual Analogue Scale-Quality of life, fatigue--Fatigue Severity Scale, and depression--Beck Depression Inventory. RESULTS: Three patients did not complete the study because of duloxetine-related adverse events. A statistically significant improvement in bladder disorder, as measured by OAB-Q, has been observed after duloxetine treatment compared with both basal levels and placebo with values of 21.8 ± 1.1 versus 34.2 ± 1.2 (P < 0.0001) and 21.8 ± 1.1 versus 30.1 ± 1.7 (P < 0.003), respectively.In addition, a decrease in postmicturition residual volume has also been observed compared with basal level (6.8 ± 3.2 ml vs 38.1 ± 12.2 ml, P = 0.06) together with an improvement in quality of life (7.1 ± 0.5 vs 6.3 ± 0.4, P = 0.07). Both these changes were close to being statistically significant. CONCLUSIONS: It emerges from this study that duloxetine might become an effective therapeutic alternative to be investigated in a larger number of MS patients for the treatment of OAB. Duloxetine should be considered a first-choice drug in the treatment of MS patients presenting both depression and OAB; in addition, it should also be considered as a suitable alternative or as concomitant treatment in MS patients with OAB but not experiencing depression.

Safety and tolerability in relapsing-remitting multiple sclerosis patients treated with high-dose subcutaneous interferon-beta by Rebiject autoinjection over a 1-year period: the CoSa study.

OBJECTIVES: Approved multiple sclerosis (MS) treatments include subcutaneous and intramuscular interferon beta (IFN-beta) Patient satisfaction during long-term IFN-beta treatment is crucial. This study investigated the satisfaction of patients with relapsing-remitting MS treated with IFN-beta-1a (Rebif) by the autoinjection system, Rebiject. MATERIALS AND METHODS: This prospective observational study recruited subjects with relapsing-remitting MS (n = 76) from 19 neurological centers in Italy who were eligible for subcutaneous IFN-beta-1a treatment either as a first immunomodulatory therapy or as a switch from other treatments. Patients received IFN-beta-1a 44 mug 3 times weekly via the Rebiject system. A questionnaire on the use of Rebiject and the most common adverse effects related to IFN-beta-1a administration was completed monthly under the supervision of trained nurses. RESULTS: Satisfaction with treatment was reported by 80.2% of patients who received at least 1 dose. Advantages reported for the Rebiject system included its convenience (53% of all patients), ease of use (25%), reduced trauma and pain (11% and 6%, respectively), and reduced local skin reactions (5%). No significant changes from baseline were observed regarding the frequency or severity of local reactions. CONCLUSIONS: During the 1-year observation of this small cohort, most patients considered the Rebiject system to be convenient, with a third of the patients feeling that the system was easier to use than conventional procedures. Rebiject was also associated with less pain and trauma in some patients. Use of Rebiject may facilitate IFN-beta-1a administration and may lead to an increase in compliance and adherence, thus increasing the effectiveness of treatment.