Hematopoietic Stem Cell Transplantation in People With Active Secondary Progressive Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Uncontrolled evidence suggests that autologous hematopoietic stem cell transplantation (AHSCT) can be effective in people with active secondary progressive multiple sclerosis (SPMS). In this study, we compared the effect of AHSCT with that of other anti-inflammatory disease-modifying therapies (DMTs) on long-term disability worsening in active SPMS. METHODS: We collected data from the Italian Bone Marrow Transplantation Study Group and the Italian Multiple Sclerosis Register. Patients were considered eligible if treatment had been started after the diagnosis of SPMS. Disability worsening was assessed by the cumulative proportion of patients with a 6-month confirmed disability progression (CDP) according to the Expanded Disability Status Scale (EDSS) score. Key secondary endpoints were the EDSS time trend after treatment start and the prevalence of disability improvement over time. Time to first CDP was assessed by means of proportional hazard Cox regression models. A linear mixed model with a time × treatment group interaction was used to assess the longitudinal EDSS time trends. Prevalence of improvement was estimated using a modified Kaplan-Meier estimator and compared between groups by bootstrapping the area under the curve. RESULTS: Seventy-nine AHSCT-treated patients and 1975 patients treated with other DMTs (beta interferons, azathioprine, glatiramer-acetate, mitoxantrone, fingolimod, natalizumab, methotrexate, teriflunomide, cyclophosphamide, dimethyl fumarate, and alemtuzumab) were matched to reduce treatment selection bias using propensity score and overlap weighting approaches. Time to first CDP was significantly longer in transplanted patients (hazard ratio [HR] = 0.50; 95% CI = 0.31-0.81; p = 0.005), with 61.7% of transplanted patients free from CPD at 5 years. Accordingly, EDSS time trend over 10 years was higher in patients treated with other DMTs than in AHSCT-treated patients (+0.157 EDSS points per year compared with -0.013 EDSS points per year; interaction p < 0.001). Patients who underwent AHSCT were more likely to experience a sustained disability improvement: 34.7% of patients maintained an improvement (a lower EDSS than baseline) 3 years after transplant vs 4.6% of patients treated by other DMTs (p < 0.001). DISCUSSION: The use of AHSCT in people with active SPMS is associated with a slowing of disability progression and a higher likelihood of disability improvement compared with standard immunotherapy. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that autologous hematopoietic stem cell transplants prolonged the time to CDP compared with other DMTs.

Antibiotic Use and Risk of Multiple Sclerosis: A Nested Case-Control Study in Emilia-Romagna Region, Italy.

INTRODUCTION: Known risk factors for multiple sclerosis (MS) include smoking, a low vitamin D status, obesity, and EBV, while the inflammatory feature of the disease strongly suggests the presence of additional infectious agents. The association between use of antibiotics and MS risk that could shed light on these factors is still undetermined. We aimed to evaluate the association between antibiotics and MS risk, in the Emilia-Romagna region (RER), Italy. METHODS: All adult patients with MS seen at any RER MS center (2015-2017) were eligible. For each of the 877 patients included, clinical information was collected and matched to 5 controls (RER residents) (n = 4,205) based on age, sex, place of residence, and index year. Information on antibiotic prescription was obtained through the linkage with the RER drug prescription database. RESULTS: Exposure to any antibiotic 3 years prior to the index year was associated with an increased MS risk (OR = 1.52; 95% CI = 1.29-1.79). Similar results were found for different classes. No dose-response effect was found. DISCUSSION/CONCLUSIONS: Our results suggest an association between the use of antibiotics and MS risk in RER population. However, further epidemiological studies should be done with information on early life and lifestyle factors.

Increased age and male sex are independently associated with higher frequency of blood-cerebrospinal fluid barrier dysfunction using the albumin quotient.

BACKGROUND: The cerebrospinal fluid (CSF)/serum quotient of albumin (QAlb) is the most used biomarker for the evaluation of blood-cerebrospinal fluid barrier (B-CSF-B) permeability. For years QAlb was considered only as an age-related parameter but recently it has also been associated to sex. The aim of the present study was to explore the impact of sex in the determination of B-CSF-B dysfunction. METHODS: The analysis was retrospectively conducted on subjects consecutively admitted to the neurological ward. CSF and serum albumin levels were measured by immunonephelometry and pathological QAlb thresholds were considered: 6.5 under 40 years, 8.0 in the age 40-60 and 9.0 over 60 years. RESULTS: 1209 subjects were included in the study. 718 females and 491 males (age: 15-88 years): 24.6% of patients had a diagnosis of multiple sclerosis, 23.2% suffered from other inflammatory neurological diseases, 24.6% were affected by non-inflammatory neurological diseases, and for 27.6% of patients the final neurological diagnosis could not be traced. Dysfunctional B-CSF-B was detected more frequently (44 vs. 20.1%, p < 0.0001) and median QAlb value were higher (7.18 vs. 4.87, p < 0.0001) in males than in females in the overall study population and in all disease subgroups. QAlb and age were positively correlated both in female (p < 0.0001) and male (p < 0.0001) patients, however the slopes of the two regression lines were not significantly different (p = 0.7149), while the difference between the elevations was extremely significant (p < 0.0001) with a gap of 2.2 units between the two sexes. Finally, in a multivariable linear regression analysis increased age and male sex were independently associated with higher QAlb in the overall study population (both p < 0.001) and after stratification by age and disease group. CONCLUSIONS: Accordingly, identification and validation of sex-targeted QAlb thresholds should be considered as a novel tool in an effort to achieve more precision in the medical approach.

Increased Levels of Endothelin-1 in Cerebrospinal Fluid Are a Marker of Poor Visual Recovery after Optic Neuritis in Multiple Sclerosis Patients.

BACKGROUND: Multiple sclerosis (MS), a chronic inflammatory and degenerative disease of the central nervous system, typically features immune-mediated focal demyelination and secondary axonal degeneration. Cerebral hypoperfusion of the normal-appearing white matter (NAWM) has been reported in MS patients and may be mediated by elevated levels of endothelin-1 (ET-1), a most potent vasoconstrictive peptide released from reactive astrocytes in MS focal lesions. Optic neuritis (ON) is one of the most frequent manifestations of MS and also shows peripapillary vascular hypoperfusion in combination with disc swelling. AIMS: We aimed to compare serum and cerebrospinal fluid (CSF) levels of ET-1 as a potential prognostic marker of MS-ON in two groups of patients differing for severity of MS-ON clinical presentation. MATERIALS AND METHODS: A cross-sectional study to compare serum and CSF levels of ET-1 between patients with clinically aggressive MS-ON (A-MS-ON) and nonaggressive MS-ON (NA-MS-ON) according to conventional ophthalmological criteria, including optical coherence tomography. CSF and serum concentrations of ET-1 were measured using a commercially available ELISA method. RESULTS: Sixteen patients consecutively referred to the Units of Neurology for visual disturbances attributable to MS were recruited, 11 (69%) patients with A-MS-ON and 5 (31%) with NA-MS-ON. Median CSF ET-1 levels and CSF/serum ET-1 quotient were significantly higher in patients with A-MS-ON (0.30 vs. 0.56 ng/ml) as compared to NA-MS-ON (0.16 vs. 0.16). CONCLUSIONS: Severity and failure in the recovery from ON in MS patients may depend from vascular hypoperfusion of the optic nerve induced by high intrathecally produced ET-1, a potential prognostic marker of ON recovery in MS. The detection of CSF ET-1 levels may allow identifying groups of ON patients potentially benefitting from treatment with ET-1 antagonists (e.g., bosentan).

The real-world effectiveness of natalizumab and fingolimod in relapsing-remitting multiple sclerosis. An Italian multicentre study.

BACKGROUND: Both natalizumab and fingolimod are highly effective in the treatment of relapsing-remitting MS (RRMS). In the absence of head-to-head trials, some observational studies have compared their efficacy with conflicting results. OBJECTIVES: To investigate the efficacy of natalizumab and fingolimod in a cohort of RRMS patients in an observational, retrospective study. METHODS: We included all consecutive RRMS patients who started natalizumab or fingolimod in three MS centres with a follow-up to 24 months and analysed clinical and brain MRI data after propensity score (PS) matching. RESULTS: After 1:1 PS-matching, we retained 102 patients in both groups, with similar baseline features. After 24 months, although both drugs resulted highly effective, patients treated with natalizumab had a lower relapse risk (HR 0.59 CI 95% 0.35-1.00, p = 0.048) and higher time to first relapse. MRI-combined-unique-activity was found in 31.8% of natalizumab vs 43.2% of fingolimod treated patients (p = 0.28). We found a higher proportion of patients with confirmed regression of disability (19.2 vs 6.7%, p = 0.03) and 2-year no evidence of disease activity (NEDA-3, 39.0% vs 22.0%, p = 0.04) in the natalizumab group. CONCLUSIONS: Both drugs were highly effective in our cohort. Natalizumab proved superior in inducing regression of disability and 2-year-NEDA-3.

Multiple Sclerosis in Italy: A 40-Year Follow-Up of the Prevalence in Ferrara.

BACKGROUND: To assess a longitudinal follow-up of the prevalence of multiple sclerosis (MS) through 4 decades in the province of Ferrara, northern Italy, and reappraise the current rates on December 31, 2016. METHODS: We conducted a community-based intensive prevalence study, by adopting a complete enumeration approach. MS cases were identified from administrative health data and medical records from the Units of Neurology and Motor Rehabilitation, Ferrara University Hospital, from other provincial neurological structures and from archives of the National Pension Institute and National Health Insurance scheme of the study area. Case ascertainment method and case definition are analogous to those adopted in previous surveys in the same area of study. RESULTS: On December 31, 2016, 685 patients (478 women and 207 men) affected by definite or probable MS (Poser's criteria) were living in the province of Ferrara (population 386,896), yielding a crude prevalence ratio of 194.91 (95% CI 180.4-209.6) per 100,000, 260.8 (95% CI 238.10-285.82) for women and 123.1 (95% CI 106.98-141.21) for men The prevalence ratio was 26.9 per 100,000 in 1978, increased to a value of 46.1 per 100,000 in 1981, 69.4 per 100,000 in 1993, 120.9 per 100,000 in 2004. Female to male ratio was 2.31 (1.2 on December 31, 1978). The mean duration of the disease at prevalence day was 17.5 ± 11.9 years (13.9 ± 10.8 years in 1978). The mean age at prevalence day was 52.04 ± 10.8 years (13.8 ± 10.8 years in 1978). CONCLUSION: Our study has confirmed the province of Ferrara is an area at high risk for MS, in line with epidemiological data from the regions of continental and insular Italy. The sharp increase in MS prevalence over time in this population can be imputed in part to a greater exposition to risk factors in genetically susceptible subjects but also to an increased survival and improved ascertainment. So, the results suggest that both methodologic and environmental factors are essential in determining the real distribution of MS. The need to get reliable estimates of MS prevalence must be highlighted as a public health and research priority, essential to support planning and prioritization of care services and to reduce the overall burden of chronic disease.

First-line disease-modifying drugs in relapsing-remitting multiple sclerosis: an Italian real-life multicenter study on persistence.

OBJECTIVE: The introduction of oral disease-modifying drugs (DMDs) in addition to the available, injectable, ones for relapsing-remitting multiple sclerosis (RRMS) could be expected to improve medication persistence due to a greater acceptability of the route of administration. The aim of the study was to compare the proportion of patients discontinuing injectable DMDs (interferon beta 1a/1b, pegylated interferon, glatiramer acetate) with those discontinuing oral DMDs (dimethylfumarate and teriflunomide) during an observation period of at least 12 months. Secondary aims were to compare the time to discontinuation and the reasons for discontinuation between the two groups and to explore the demographic and clinical factors associated with DMD discontinuation. METHODS: In this prospective, multi-center, real-life observational study, patients commencing any first-line DMD between 1 January 2015 and 31 July 2016 were enrolled and followed up for at least 12 months or until the drug was discontinued. RESULTS: Of the 520 included patients, 262 (49.6%) started an injectable and 258 (50.4%) an oral DMD. There was no difference in the proportion of patients on oral (n = 62, 24%) or on injectable (n = 60, 23%) DMDs discontinuing treatment, the most frequent reason being adverse events/side-effects. Higher baseline Expanded Disability Status Scale (EDSS) scores and younger age increased the odds of treatment withdrawal. Time to treatment discontinuation was not different between the two groups and was not influenced by the initiated DMD (oral versus injectable), even after adjustment for baseline differences. CONCLUSION: The route of administration alone (i.e. oral versus injectable) was not a significant predictor of persistence with first-line DMDs in RRMS.

De novo exonic duplication of ATP1A2 in Italian patient with hemiplegic migraine: a case report.

BACKGROUND: Sporadic Hemiplegic Migraine is a rare form of migraine headache. Mutations in three different genes, two ion-channel genes and one encoding an ATP exchanger, CACNA1A, ATP1A2 and SCN1A are all responsible for the FHM phenotype, thus indicating a genetic heterogeneity for this disorder. Here, we described a de novo exonic duplication of ATP1A2 in an Italian patient with Hemiplegic Migraine. CASE PRESENTATION: We describe the case of a young woman (33 year old) who suffered from the age of 8 years of episodic weakness of the limbs, associated to other subjective and objective features. From aged 25, she developed neurological symptoms, like dizziness, blurred vision and an MRI scan revealed aspecific peritrigonal white matter hyperintensities. Aged 32 she suffered of right hemisomatic sudden-onset paresthesias, hypoesthesia and hyposthenia and the patient was genetically investigated for sporadic hemiplegic migraine. CONCLUSIONS: Here we report, for the first time, an exonic duplication in the ATP1A2 associated with hemiplegic migraine. The variation identified involves exon 21 of the ATP1A2 and is expected to alter the function of the alpha(2) subunit of the Na(+)/K(+) pump; the de novo nature of the duplication further supports its pathogenic role. To date, no other CNVs have been described in the ATP1A2 but only point mutations are reported. The novel mutation may result impaired M9 transmembrane domain, in a loss-of-function of the alpha(2) Na(+)/K(+)-ATPase with glutamate accumulation, alteration of synaptic function and neurotransmission.

Definitive childlessness in women with multiple sclerosis: a multicenter study.

The frequency of definitive childlessness in women with multiple sclerosis (MS) may be higher than in the general population. MS may also affect decisions on the delivery procedure and on breast-feeding issues. Aim of the study was to assess the frequency of childlessness and its possible causes, the proportion of cesarean deliveries (CD), and the frequency of breast-feeding in patients and controls who have reached the end of their reproductive period. Female MS patients (>43 years) and controls (>45 years) filled out a questionnaire. We enrolled 303 patients and 500 controls. MS was associated with a higher frequency of childlessness (22 vs 13%) and less patients were in a stable relationship (83 vs 89%). There was no difference in the reported rates of infertility and miscarriages, while elective abortions were more frequent in patients (20 vs 12%). MS did not significantly affect the frequency of CD or of breast-feeding. MS-related reasons for childlessness, reported by 16% of childless patients, included disability/fear of future disability, fear of genetically transmitting MS, fear of not starting/discontinuing treatments, and discouragement by physician. Definitive childlessness is more frequent in women with MS compared to controls. A portion of voluntary childlessness may be avoided through correct/tailored information to patients.

Evaluation of Clinical Gait Analysis parameters in patients affected by Multiple Sclerosis: Analysis of kinematics.

BACKGROUND: Clinical Gait Analysis is commonly used to evaluate specific gait characteristics of patients affected by Multiple Sclerosis. The aim of this report is to present a retrospective cross-sectional analysis of the changes in Clinical Gait Analysis parameters in patients affected by Multiple Sclerosis. METHODS: In this study a sample of 51 patients with different levels of disability (Expanded Disability Status Scale 2-6.5) was analyzed. We extracted a set of 52 parameters from the Clinical Gait Analysis of each patient and used statistical analysis and linear regression to assess differences among several groups of subjects stratified according to the Expanded Disability Status Scale and 6-Minutes Walking Test. The impact of assistive devices (e.g. canes and crutches) on the kinematics was also assessed in a subsample of patients. FINDINGS: Subjects showed decreased range of motion at hip, knee and ankle that translated in increased pelvic tilt and hiking. Comparison between the two stratifications showed that gait speed during 6-Minutes Walking Test is better at discriminating patients' kinematics with respect to Expanded Disability Status Scale. Assistive devices were shown not to significantly impact gait kinematics and the Clinical Gait Analysis parameters analyzed. INTERPRETATION: We were able to characterize disability-related trends in gait kinematics. The results presented in this report provide a small atlas of the changes in gait characteristics associated with different disability levels in the Multiple Sclerosis population. This information could be used to effectively track the progression of MS and the effect of different therapies.

Development and validation of a new algorithm for attribution of neuropsychiatric events in systemic lupus erythematosus.

OBJECTIVE: The aim of this study was to develop and validate an algorithm to assist the attribution of neuropsychiatric (NP) events to underlying disease in SLE patients. METHODS: Phase 1 identified and categorized candidate items to be included in the algorithm for the attribution of an NP event to SLE and their relative weights through a literature-informed consensus-driven process. Using a retrospective training cohort of SLE, phase 2 validated items selected in phase 1 and refined weights through a data-driven process, fitting items as independent variables and expert evaluation (clinical judgement) as reference standard in logistic models. Phase 3 consisted of a validation process using an external multicentre retrospective SLE cohort. RESULTS: Phase 1 identified four different items: timing of the NP event, type of event, confounding factors and favouring factors. The training and validating cohorts included 228 and 221 patients, respectively. Each patient experienced at least one NP event characterized using the ACR case definition. In these samples, items selected in phase 1 showed good performance in discriminating patients with NPSLE: the area under the receiver operating characteristic curve using dichotomous outcomes was 0.87 in the training set and 0.82 in the validating set. Relevant cut-offs of the validated score identify events with a positive predictive value of 100% (95% CI 93.2, 100) and 86.3% (95% CI 76.2, 93.2) in the training and validating cohorts, respectively. CONCLUSION: A new algorithm based on a probability score was developed and validated to determine the relationship between NP events and SLE.

Previous treatment influences fingolimod efficacy in relapsing-remitting multiple sclerosis: results from an observational study.

OBJECTIVE: Fingolimod (FTY) is licensed as a disease-modifying treatment in highly active relapsing-remitting multiple sclerosis. The aim of the study was to evaluate the efficacy and safety of FTY in a real-life setting and to explore the possible role of clinical and MRI parameters, including previous treatment type, in predicting its efficacy. METHODS: Clinical and MRI data was collected on 127 patients assigned to treatment with FTY in six multiple sclerosis centers in Emilia-Romagna, Italy, between August 2011 and June 2013. RESULTS: During a mean follow-up period of 10 months (range 1-22), we observed a total of 47 relapses in 39 patients (30.7%); new T2 lesions or gadolinium-enhancing (Gd+) lesions were present at follow-up MRI in 32/71 patients (45%). Expanded disability status scale (EDSS) at the end of the follow-up period was not different when compared to the baseline EDSS. Serious adverse events occurred in three patients (2.4%). A higher proportion of patients previously treated with natalizumab showed clinical (41%) or MRI activity (54%). Previous treatment with natalizumab increased the risk of a relapse within 30 days (versus immunomodulatory drugs; OR: 4.3; p = 0.011) and at survival analysis (versus remaining patients; HR: 1.9; p = 0.046). Study limitations include a small population sample, a short observation period with variable timing of follow-up MRI and different baseline characteristics of patients previously treated with natalizumab compared to those treated with immunomodulatory drugs. CONCLUSIONS: This study confirms the efficacy of FTY in reducing relapse rate in patients previously treated with immunomodulatory drugs, while it seems to be less effective in patients discontinuing natalizumab. Due to the short duration of follow-up it is not possible to evaluate disability progression; however, no difference was observed between the groups.

Factors and comorbidities associated with central nervous system involvement in systemic lupus erythematosus: a retrospective cross-sectional case-control study from a single center.

To evaluate, by a retrospective cross-sectional case-control study from a single center, the distribution of a number of factors and comorbidities potentially related to central nervous system involvement in SLE Italian patients, a number of "generic" (i.e. not strictly SLE related) and "specific" (i.e. SLE related) risk factors were checked and their distribution analyzed in SLE patients with (NPSLE) and without (SLE) neuropsychiatric (NP) involvement. One hundred and fifty-three SLE patients with NP involvement observed from 1999 to 2008 and 247 SLE patients without NP manifestations, matched for sex, age and disease duration were included in the study. A neuropsychiatric (NP) event represented the heralding symptom of the disease in 40.5% of NPSLE. Headache, cerebrovascular events, mood disorders and seizures were the most frequent NP manifestations. NPSLE patients had a major cumulative number of the investigated factors than controls without NP involvement. Antiphospholipid antibodies (aPL), lupus anticoagulant (LA), Antiphospholipid antibodies syndrome (APS), Raynaud's phenomenon, smoke, assumption of contraceptives and higher cumulative dose of glucocorticosteroids (GC) were significantly more commonly observed among NPSLE. APS and systemic arterial hypertension were more frequently detected among patients with focal NP manifestations, especially cerebrovascular events. aPL, LA, APS, Raynaud's phenomenon, smoke, contraceptives intake and higher cumulative dose of GC did prove more frequently detected in NPSLE patients than in controls. In particular, overall, arterial hypertension should be regarded as a potential independent "risk factor" for focal involvement, especially for cerebrovascular events.

Factors and comorbidities associated with first neuropsychiatric event in systemic lupus erythematosus: does a risk profile exist? A large multicentre retrospective cross-sectional study on 959 Italian patients.

OBJECTIVE: To analyse risk factors and comorbidities potentially associated with CNS involvement in a large cohort of Italian patients affected by SLE. METHODS: A number of generic (not strictly SLE related) and specific (disease related) risk factors to which all patients have been exposed in the span of 5 years before the first neuropsychiatric (NP) event or before the last available observation were checked for and their distribution was analysed in 959 SLE patients with and without NP involvement; all the first NP events that occurred in a time frame of 10 years were recorded and categorized as SLE related or SLE unrelated. RESULTS: Three hundred and twenty-six SLE patients with and 633 SLE patients without NP manifestations were included in the study. A total of 469 NP events were recorded. Headache (26.1%), cerebrovascular events (22.7%), mood disorders (8.9%), seizures (14.4%) and cognitive dysfunctions (9.5%) were the most frequent SLE-related NP events. More risk factors [mean 4.52 (2.44) vs 3.73 (2.01); P < 0.0001] were observed in patients with than without NP involvement. Overall, aPLs, LA and APS were factors more strongly associated with NP involvement. CONCLUSIONS: In SLE, NP involvement and aPLs were confirmed as closely related. Furthermore, other modifiable generic risk factors, such as hypertension, carotid vasculopathy and dyslipidaemia, appeared to be related to the occurrence of cerebral vascular accident (CVA) and cognitive dysfunctions, suggesting the need for a more intensive preventive strategy to optimize the management of NP lupus.

Concomitant rheumatoid arthritis and amyotrophic lateral sclerosis: report of two new cases and review of literature.

To describe a rare association between rheumatoid arthritis (RA) and amyotrophic lateral sclerosis (ALS). Two new cases of patients with RA who developed amyotrophic lateral sclerosis (ALS), one receiving anti-TNFα agents, were reported. Only other five cases of this rare association have been previously described in literature. The simultaneous presence of the two diseases represents a difficult diagnostic challenge because RA may mimic some musculoskeletal symptoms of ALS. There is no evidence in favor of a common pathophysiologic mechanism, and thus the possibility of a fortuitous association must be raised. A neurotoxic side effect of various drugs for RA treatment could be considered. Casual or causal association remains a difficult choice. The possibility of a coincidental association must be raised but neurologic side effects of TNFα blockers lead to discussion.

Altered miRNA expression in T regulatory cells in course of multiple sclerosis.

OBJECTIVES: Multiple sclerosis (MS) is a chronic inflammatory response against constituents of the central nervous system. It is known that regulatory T cells (Tregs) play a key role in the autoimmune balance and their improper function may facilitate the expansion of autoaggressive T cell clones. Recently, microRNAs (miRNAs) have been involved in autoimmune disorders and their loss-of-function in immune cells was shown to facilitate systemic autoimmune disorders. Here, we analyzed the miRNA expression profile in Tregs from MS-RR. METHODS: We assessed miRNA genome-wide expression profile by microarray analysis on CD4(+)CD25(+high) T cells from 12 MS relapsing-remitting patients in stable condition and 14 healthy controls. Since CD4(+)CD25(+high) T cells comprise both T regulatory cells (CD4(+)CD25(+high)CD127(dim/-)) and T effector cells (CD4(+)CD25(+high)CD127(+)), we performed a quantitative RT-PCR on CD4(+)CD25(+high)CD127(dim/-) and CD4(+)CD25(+high)CD127(+) cells isolated from the same blood sample. RESULTS: We found 23 human miRNAs differentially expressed between CD4(+)CD25(high)bona fide Treg cells from MS patients vs. healthy donors, but, conversely, among the deregulated miRNAs, members of the miR-106b-25 were found down-regulated in MS patients when compared to healthy donors in CD4(+)CD25(high)CD127(dim/-) T regulatory cells. More interesting, the ratio between Treg/Teff showed an enrichment of these microRNA in T regulatory cells derived from patients if compared to healthy controls. CONCLUSION: miR-106b and miR-25 were previously shown to modulate the TGF-ß signaling pathway through their action on CDKN1A/p21 and BCL2L11/Bim. TGF-ß is involved in T regulatory cells differentiation and maturation. Therefore, the deregulation of this miRNA cluster may alter Treg cells activity in course of MS, by altering TGF-ß biological functions.

Central nervous system involvement in Sjögren's syndrome: unusual, but not unremarkable--clinical, serological characteristics and outcomes in a large cohort of Italian patients.

OBJECTIVES: To perform an observational retrospective cross-sectional case-control study to evaluate prevalence, clinical patterns and outcomes of CNS involvement in a large cohort of primary SS (pSS) patients. METHODS: A total of 424 pSS patients, diagnosed according to the 2002 criteria proposed by the American-European Consensus Group, were checked for CNS involvement after exclusion of secondary causes. Demographic, clinical, seroimmunological data were compared between patients with and without CNS involvement. Neuroimaging data were also analysed. RESULTS: CNS involvement was detected in 25 (5.8%) patients (24 females and 1 male) both at disease onset (52%) and later (48%) with a mean latency after diagnosis of 7 years. Diffuse (40%), focal/multifocal (36%), multiple sclerosis (MS)-like disease (20%) and isolated optic neuritis (4%) were the most common CNS clinical pictures. Disease duration, lung involvement and decreased C(4) were associated with CNS involvement, while articular manifestations were more frequently observed in patients without neurological complications. Most cases had an acute, often recurrent course with spontaneous remission or only mild neurological impairment. CONCLUSIONS: CNS involvement represents a rare but not negligible complication of pSS, which may occur with a bimodal temporal pattern, both at onset and later, prompting attention in the differential diagnosis of apparently isolated neurological syndromes. Lung involvement emerged as the strongest risk factor for CNS involvement with a relative risk of 7.9, along with disease duration and decreased C(4).

A possible paraneoplastic neuromyelitis optica associated with lung cancer.

Neuromyelitis optica is associated with antibodies to aquaporin-4 channels and has been classically defined as the occurrence of bilateral optic neuritis and transverse myelitis with no other neurological involvement. We describe here a 63-year-old woman who presented to our local hospital with an acute, bilateral visual loss followed by progressive paraparesis. Medical evaluations revealed a lung tumor and spinal MRI showed multiple cervical-dorsal hyperintense T(2) lesions with mild mass effect. Testing for NMO-Ig resulted positive. Patient's diagnosis was thus consistent with a possible paraneoplastic neuromyelitis optica associated with non-small cell lung cancer and evidence of NMO-Ig.

Subcutaneous Interferon Beta-1a Has a Positive Effect on Cognitive Performance in Mildly Disabled Patients with Relapsing-Remitting Multiple Sclerosis: 2-Year Results from the COGIMUS Study.

The effect of interferon (IFN) beta-1a (44 and 22 µg subcutaneously [sc] three times weekly [tiw]) on cognition in mildly disabled patients with relapsing-remitting multiple sclerosis (McDonald criteria; Expanded Disability Status Scale =4.0) was assessed by validated neuropsychological testing at baseline and at regular intervals for up to 2 years in this ongoing open-label, 3-year study. Year-2 data were available for 356 patients (22 µg, n = 175; 44µg, n = 181). The proportion of patients with impaired cognitive function was stable during the study: 21.4% at baseline and 21.6% at 2 years. At 2 years, the proportion of patients with =3 impaired cognitive tests was significantly lower in the 44 µg treatment group (17.0%) compared with the 22 µg group (26.5%; p = 0.034), although there was already a trend towards a higher proportion of patients with cognitive impairment in the 22 µg group at baseline. Factors associated with impairment in = three cognitive tests after 2 years were age (odds ratio [OR]: 1.05; 95% confidence interval [CI]: 1.00-1.09), verbal intelligence quotient (OR: 0.95; 95% CI: 0.92-0.98), and having = three impaired cognitive tests at baseline (OR: 11.60; 95% CI: 5.94-22.64). These interim results show that IFN beta-1a sc tiw may have beneficial effects on cognitive function as early as 2 years after treatment initiation, but the final 3-year data of the study are required to confirm these results.