Discontinuation of teriflunomide and dimethyl fumarate in a large Italian multicentre population: a 24-month real-world experience.

BACKGROUND: Teriflunomide (TRF) and Dimethyl fumarate (DMF) are licensed drugs for relapsing-remitting Multiple Sclerosis (RRMS). OBJECTIVES: We aimed to compare the rate and the time to discontinuation among persons with RRMS (pwRRMS), newly treated with TRF and DMF. MATERIALS AND METHODS: A retrospective study on prospectively collected data was performed in nine tertiary MS centers, in Italy. The 24-month discontinuation rate in the two cohorts was the primary study outcome. We also assessed the time to discontinuation and reasons of therapy withdrawn. Discontinuation of TRF and DMF was defined as a gap of treatment ≥ 60 days. RESULTS: A cohort of 903 pwRRMS (316 on TRF and 587 on DMF) was analyzed. During 24 months of follow-up, pwRRMS on TRF and DMF showed similar discontinuation rates. The analysis of predictors with Cox regression model showed differences between the two groups (p for log-rank test = 0.007); male gender [HR 2.21 (1.00-4.90); p = 0.01] and the number of previous switches [HR 1.47 (1.16-1.86); p = 0.01] were associated with higher hazard of discontinuation in the DMF group. CONCLUSIONS: In a real-world setting, pwRRMS on TRF and DMF had similar discontinuation rates over 24 months. Male pwRRMS on DMF with a previous history of therapeutic failure are at more risk of discontinuation therapy.

Natalizumab in pediatric multiple sclerosis: results of a cohort of 55 cases.

BACKGROUND: Limited information is available on the use of natalizumab (NA) in pediatric multiple sclerosis (ped-MS) patients. OBJECTIVE: The purpose of this study was to describe the long-term effects of NA in a large cohort of active ped-MS patients. METHODS: Patients with definite ped-MS were treated with NA if in the previous year they had experienced at least two relapses or a severe relapse with incomplete recovery while on immunomodulating treatment, or at least two relapses and new magnetic resonance imaging (MRI) lesions regardless of any prior treatment. RESULTS: The study included 55 patients (mean age: 14.4 years, mean number of relapses: 4.4, pre-treatment mean disease duration: 25.5 months). They received a median number of 26 infusions. Three relapses occurred during the follow-up, one female patient continued to deteriorate in cognitive functioning. Mean Expanded Disability Status Scale (EDSS) scores decreased from 2.7 to 1.9 at the last visit (p<0.001). During the follow-up the majority of patients remained free from MRI activity. Transient and mild clinical adverse events occurred in 20 patients. Mild hematological abnormalities occurred in seven patients. Anti-JCV antibodies were detected in 20/51 tested patients. CONCLUSIONS: NA was well tolerated in all patients. A strong suppression of disease activity was observed in the majority of patients during the follow-up.

Acute myeloid leukemia in Italian patients with multiple sclerosis treated with mitoxantrone.

OBJECTIVES: To evaluate the incidence and dose-dependency of mitoxantrone (MTX)-associated acute myelocytic leukemia (AML) in the network of Italian multiple sclerosis (MS) clinics. METHODS: We performed a multicenter retrospective cohort study of patients treated with MTX in MS centers under the Italian national health care system between 1998 and 2008. Demographic, disease, treatment, and follow-up information were collected using hospital records. RESULTS: Data were available for 3,220 patients (63% women) from 40 Italian centers. Follow-up (mean ± SD) was 49 ± 29 months (range 12-140 months). We observed 30 cases of AML (incidence 0.93% [95% confidence interval 0.60%-1.26%]). The mean cumulative dose was higher in patients with AML (78 vs 65 mg/m(2), p = 0.028). The median interval from the start of therapy to AML diagnosis was longer than expected at 33 months (range 13-84 months); 8 patients (27%) developed AML 4 years or more after the first MTX infusion. The rate of mortality associated with AML was 37%. CONCLUSIONS: This higher than expected risk of AML and related mortality requires that treatment decisions must be made jointly between clinicians and patients who understand their prognosis, treatment options, and treatment-related risks. The now large exposed MS population must be monitored for hematologic abnormalities for at least 6 years from the end of therapy, to ensure the rapid actions needed for early diagnosis and treatment of AML.

Natalizumab therapy of multiple sclerosis: recommendations of the Multiple Sclerosis Study Group--Italian Neurological Society.

Three years after the introduction of natalizumab (NA) therapy for the second line treatment of relapsing-remitting multiple sclerosis (MS), Italian MS centers critically reviewed the scientific literature and their own clinical experience. Natalizumab was shown to be highly efficacious in the treatment of MS. However, the risk of progressive multifocal leukoencephalopathy was confirmed and defined better. This article summarizes the MS-SIN Study Group recommendations on the use of NA in MS, with particular reference to the appropriate selection and monitoring of patients as well as to the management of adverse events.

Three years of experience: the Italian registry and safety data update.

At the end of 2006, a pharmacovigilance program on natalizumab was settled by the Italian Pharmaceutical Agency, and on January 2007, multiple sclerosis patients poorly responding to the immunomodulating therapies or with an aggressive clinical form of disease from onset initiated to be registered and to receive the medication. On February 2010, almost 3,000 cases have been treated with natalizumab. The drop-out rate is 10%. Almost 800 cases received cycles of natalizumab for more than 18 months. One case of PML was reported and other adverse events are similar to those described in phase III studies. The majority of cases remained stable, while in 25% of cases, an improvement of disability was documented.

Efficacy and tolerability of natalizumab in relapsing-remitting multiple sclerosis patients: a post-marketing observational study.

To evaluate the efficacy and safety of natalizumab in patients with active relapsing-remitting multiple sclerosis (MS). We included 285 MS patients receiving natalizumab. Clinical, neuroradiological and safety data were registered every 6 months. Neutralizing antibodies (NABs) were tested after 6 months of treatment. After 1 year, the annualized relapse rate decreased to 0.26, with a significant reduction compared to the previous year (2.13). At 24 months the proportion of "relapse free" patients was 78% while that of "MRI free" patients was 69%. Considering clinical and MRI cumulative activity, "disease free" patients were 63% at 24 months. A total of 18 patients showed NABs positivity. We reported 34 cases of treatment interruptions. In conclusion, our data confirm the remarkable efficacy of natalizumab in a group of patients with higher disease activity than that of pivotal studies.

Safety and efficacy of natalizumab in children with multiple sclerosis.

OBJECTIVE: To describe the effect of natalizumab in the treatment of subjects with active multiple sclerosis (MS) treated before the age of 18 years. METHODS: Nineteen pediatric subjects with MS (mean age 14.6 +/- 2.2 years, mean number of attacks 5.2 +/- 1.9 during the pretreatment phase of 27.7 +/- 19.7 months, median pretreatment Expanded Disability Status Scale score [EDSS] 2.5, range 1.0-5.0) were treated with natalizumab at the dose of 300 mg every 28 days. After treatment initiation, patients were reassessed clinically every month; brain MRI was performed at baseline and every 6 months. RESULTS: Patients received a median number of 15 infusions (range 6-26). A transient reversible worsening of preexisting symptoms occurred in 1 subject during and following the first infusion. All the patients remained relapse-free during the whole follow-up. The median EDSS decreased from 2.5 to 2.0 at the last visit (p < 0.001). EDSS remained stable in 5 cases, decreased by at least 0.5 point in 6 cases, and decreased by at least 1 point in 8 cases. At baseline, the mean number of gadolinium-enhancing lesions was 4.1 (range 1-20). During the follow-up, no gadolinium-enhancing lesions were detected (p = 0.008); 3 patients developed new T2-visible lesions at month 6 scan but the overall number of T2 lesions remained stable during the subsequent follow-up. Transient and mild side effects occurred in 8 patients. CONCLUSIONS: Natalizumab was well-tolerated in all subjects. A strong suppression of disease activity was observed in all subjects during the follow-up. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that natalizumab, 300 mg IV once every 28 days, decreased EDSS scores in pediatric patients with MS over a mean treatment period of 15.2 months.

HLA-A*01 is associated with late onset of Alzheimer's disease in Italian patients.

In this study, the distribution of HLA-A alleles was analyzed in Italian Alzheimer's Disease (AD)patients. Interaction between HLA alleles, APOE genotypes, age of onset, and gender were also analyzed. The results were compared to those obtained in healthy controls (HC). One hundred-seventy-three AD patients and 258 age-and-sex-matched healthy controls were enrolled in the study. AD patients were classified according to age at the onset of disease using quartiles of the distribution. HLA-A genotyping was performed by PCR-SSP; APOE genotyping was performed by RFLP. A correlation between late disease onset and HLA-A*01 was observed. Thus, HLA-A*01, calculated as number of alleles, was significantly more present in patients with age of onset > 74.0 years than in HC (20% vs 10.5%; p=0.014); the distribution of this allele was skewed also in patients 68.1-74 years of age (16.3%), even if the difference did not reach statistical significance. The relative risk ratio (RRR) of AD onset calculated by a multinomial logistic regression adjusted for sex and presence of APOE-4 confirmed a significant association of HLA-A*01 with AD onset > 74.0 years of age (RRR=2.2; 95%CI: 1.1-4.6; p=0.033). A high RRR (2.04) was also present in patients 68.1-74 years (p=0.064). Lower age of disease onset did not correlate with HLA-A*01. Data herein suggest that the presence of HLA-A*01 results in delayed AD development, even in patients carrying APOE-4. These results could offer new insights into the etiopathogenesis of Alzheimer's disease.

Analysis of Chlamydia pneumoniae-specific oligoclonal bands in multiple sclerosis and other neurologic diseases.

OBJECTIVE: Paired serum and cerebrospinal fluid (CSF) specimens were investigated for Chlamydia pneumoniae-specific oligoclonal bands (OCBs) to determine band specificity in multiple sclerosis (MS). MATERIAL AND METHODS: Serum and CSF samples were collected from patients with relapsing-remitting MS (n = 56), other inflammatory (n = 18) or non-inflammatory (n = 15) neurologic diseases, and from 10 healthy controls. OCBs were determined with affinity immunoblotting of C. pneumoniae-specific IgG onto antigen-coated nitrocellulose paper after protein separation with agarose isoelectric focusing. RESULTS: Chlamydia pneumoniae-specific OCBs were present in 5 of 56 patients with MS, and in 3 of 18 patients with other inflammatory neurologic diseases. CONCLUSIONS: The intrathecal production of C. pneumoniae-specific oligoclonal IgG occurs in a minority of patients with MS. This intrathecal anti-C. pneumoniae reactivity is likely part of a polyspecific humoral immune response in MS.

Ctla4 and multiple sclerosis in the Italian population.

CTLA4 protein is a receptor molecule that plays a critical role as a negative regulator of the immune response. Therefore, genetic variations in CTLA4 may confer susceptibility to autoimmune diseases such as multiple sclerosis (MS). In order to investigate the association of two CTLA4 polymorphisms (+49 A/G and -318 C/T) with multiple sclerosis, sporadic MS patients and healthy controls from Italy were genotyped through direct DNA sequencing. Considering single-loci variations, no differences in the allelic and genotypic frequencies between patients and controls were found. However, considering a putative interaction at the two loci, the T/G combination was more frequently observed in patients than in controls. This result suggests that this allelic combination of the CTLA4 polymorphisms may be involved in the susceptibility to MS in the Italian population.

Association between the tumor necrosis factor-alpha -308 G/A gene polymorphism and migraine.

In a group of 299 migraine patients and 306 control subjects, the association of the -308 G/A polymorphism in the tumor necrosis factor-alpha gene (TNFalpha) with the occurrence and clinical characteristics of migraine was tested. Homozygosity for the G allele was associated with an increased risk of migraine (odds ratio [OR] = 2.85, p < 0.001). When the patients were divided into subgroups, the association was confirmed in patients affected by migraine without aura (OR = 3.30, p < 0.001) but not in migraine with aura. These data suggest that the TNFalpha gene or a linked locus significantly modulates the risk for migraine.

Multiple sclerosis in children under 10 years of age.

Despite the consistent amount of information accumulated in recent years on multiple sclerosis (MS) in childhood, many clinicians still view this condition as an exclusively young adult-onset disease and do not consider that it may occur and manifest even during infancy and pre-school age, suggesting that the number of MS cases in the paediatric age group may have been underestimated. Thus, the need to have practical parameters for therapeutic, counselling and educational purposes in such settings as caring for patients whose onset of disease is at very early ages may increasingly arise for practising clinicians. In addition, the clinical and radiographic criteria for the diagnosis of MS have not been validated in a paediatric MS population; accordingly, inclusion age at onset (such as for research purposes) is generally over 10 years. To highlight the peculiarities that characterise MS when it begins at this young age we have reviewed the literature and summarised our preliminary results with the national registry of the Italian Society of Paediatric Neurology (SINP) Study Group on Childhood MS in the group of MS patients with the earliest onset of disease (i.e., <10 years of age).

An MRI study of Chlamydia pneumoniae infection in Italian multiple sclerosis patients.

We amplified sequences of the Chlamydia pneumoniae (CP) major-outer membrane protein in the cerebrospinal fluid (CSF) from 23 of 107 (21.5%) relapsing-remitting or secondary progressive multiple sclerosis (MS) patients and two of 77 (2.6%) patients with other neurological diseases (OND) (P = 0.00022). CP+ patients showed magnetic resonance imaging (MRI) evidence of more active disease (P = 0.02) compared to CP- MS patients and tended to have an anticipation of age at disease onset (32.3 +/- 12 versus 28.5 +/- 10 years; P = ns) causing a longer disease duration (7.5 +/- 5 versus 4.4 +/- 4 years; P = 0.016) at the time of clinical evaluation. These findings, although indirectly, suggest that CP infection of the central nervous system (CNS) might affect disease course in a subgroup of MS patients.

Interleukin-1B polymorphism is associated with age at onset of Alzheimer's disease.

Interleukin-1alpha (IL-1alpha) and IL-1beta are two pro-inflammatory cytokines involved in the pathogenesis of Alzheimer's disease (AD). The genes coding for IL-1alpha (IL-1A) and for IL-1beta (IL-1B) are clustered in chromosome 2q14-2q14.2. In a previous work, we investigated the role of IL-1A promoter polymorphism (-889 position) in AD pathogenesis: IL-1A -889 TT genotype was associated with sporadic early onset AD. We now report the study on polymorphism of exon 5 IL-1B in position +3953, the nearest polymorphism to -889 IL-1A. We found that the genotype distribution of IL-1B +3953 varied significantly between patients with early and late onset of AD (P<0.0001). Patients carrying IL-1B +3953 CT or TT genotypes had 4 or 5 years anticipation of AD onset (P=0.0034; odds ratio for early onset, 3.01) and 7 years anticipation if they also carried the IL-1A -889 TT genotype (P<0.0001; odds ratio for early onset, 7.4). These data further support a role for inflammation-related genes in AD or indicate linkage disequilibrium with an unknown chromosome 2 locus.

Genetic association of acyl-coenzyme A: cholesterol acyltransferase with cerebrospinal fluid cholesterol levels, brain amyloid load, and risk for Alzheimer's disease.

A common polymorphism of the gene encoding acyl-coenzyme A: cholesterol acyltransferase 1 (SOAT1), which is involved in the regulation of beta-amyloid peptide generation, is associated with low brain amyloid load (P=0.03) and with low cerebrospinal fluid levels of cholesterol (P=0.005). This polymorphism of SOAT1 is also associated with reduced risk for Alzheimer's disease in ethnically distinct populations (P=0.0001, odds ratio: 0.6, 95% confidence interval 0.4-0.8).

Interleukin-10 promoter polymorphism in sporadic Alzheimer's disease.

Proinflammatory cytokines and acute-phase proteins play an important role in Alzheimer's disease (AD) neurodegeneration, and common polymorphisms of genes controlling their high production have been shown to be associated with AD. Thus, AD patients display a proinflammatory genotype and the control of inflammation might play a protective role in AD development. By sequence-specific probes, we have evaluated the role of anti-inflammatory cytokine interleukin(IL)-10 in AD, by analysing in 132 AD patients and 213 healthy controls the prevalence of three different haplotypes, involving three single-nucleotide polymorphisms (SNPs) at -1082 (G-->A), -819 (C-->T) and -592 (C-->A) nucleotides of IL-10 promoter, associated with different IL-10 production. The percentage of -1082A carrier subjects was significantly increased among AD patients, and this increase was mainly due to the increase of ATA haplotype. Analysing these results according to the well-known genetic risk factor APOE-e4 allele, no significant differences were observed in SNP IL-10 allele distribution between AD patients carrying the genotype or not. So we may conclude that the presence of -1082A allele and in particular of -1082A/-819T/-592A haplotype, associated with a low production of anti-inflammatory cytokine IL-10, may be considered as an additive and independent genetic risk factor for AD.

High incidence and increasing prevalence of MS in Enna (Sicily), southern Italy.

Twenty years after a first survey, a follow-up study was performed on the prevalence of MS in Enna (Sicily), southern Italy. The prevalence of definite MS rose from 53 to 120.2 per 100,000 population. The incidence of definite MS for the period 1986 to 1995 was 5.7 per 100,000 per year. The innermost part of Sicily shows an elevated prevalence of MS, second only to Sardinia in the Mediterranean area.

Neuroinflammation and the genetics of Alzheimer's disease: the search for a pro-inflammatory phenotype.

The role of interleukin 1 (IL-1) and interleukin 6 (IL-6) in the pathogenesis of Alzheimer's disease (AD) is reviewed within the framework of "inflamm-aging", i.e., the characteristic chronic pro-inflammatory status which develops in old age, and neuroinflammation, i.e., the peculiar inflammatory process which is present in the brain of AD patients. In particular, the data suggesting that several IL-1 and IL-6 gene polymorphisms can contribute to the risk of developing AD are reviewed. The possibility as well as the difficulty in identifying a pro-inflammatory phenotype, and its importance for the prevention, diagnosis and therapy of AD and other age-related pathologies are discussed.

Pharmacogenomics of neurodegenerative diseases.

Current knowledge of sporadic degenerative disorders suggests that, despite their multifactorial etiopathogenesis, genetics plays a primary role in orchestrating the pathological events, and even dramatically changes the disease phenotype from patient to patient. Genes may act as susceptibility factors, increasing the risk of disease development, or may operate as regulatory factors, modulating the magnitude and severity of pathogenic processes or the response to drug treatment. The goal of pharmacogenomics is the application of this knowledge to elaborate more specific and effective treatments and to tailor therapies to individual patients according to their genetic profile. Here, we outline the leading theories on the etiopathogenesis of neurodegenerative diseases, including amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer disease, and we review the potential role of genetic variations, such as gene mutations and polymorphisms, in each context. We also suggest potential targets for new therapeutic approaches and variability factors for current treatments based on genotype features. Finally, we propose a few options of preventive therapeutic interventions in patients with a high genetic risk of disease.