PML risk is the main factor driving the choice of discontinuing natalizumab in a large multiple sclerosis population: results from an Italian multicenter retrospective study.

BACKGROUND: Natalizumab (NTZ) is an effective treatment for relapsing-remitting multiple sclerosis (RRMS). However, patients and physicians may consider discontinuing NTZ therapy due to safety or efficacy issues. The aim of our study was to evaluate the NTZ discontinuation rate and reasons of discontinuation in a large Italian population of RRMS patients. MATERIALS AND METHODS: The data were extracted from the Italian MS registry in May 2018 and were collected from 51,845 patients in 69 Italian multiple sclerosis centers. MS patients with at least one NTZ infusion in the period between June 1st 2012 to May 15th 2018 were included. Discontinuation rates at each time point were calculated. Reasons for NTZ discontinuation were classified as "lack of efficacy", "progressive multifocal leukoencephalopathy (PML) risk" or "other". RESULTS: Out of 51,845, 5151 patients, 3019 (58.6%) females, with a mean age of 43.6 ± 10.1 years (median 40), were analyzed. Out of 2037 (39.5%) who discontinued NTZ, a significantly higher percentage suspended NTZ because of PML risk compared to lack of efficacy [1682 (32.7% of 5151) vs 221 (4.3%), p < 0.001]; other reasons were identified for 99 (1.9%) patients. Patients discontinuing treatment were older, had longer disease duration and worse EDSS at the time of NTZ initiation and at last follow-up on NTZ treatment. The JCV index and EDSS at baseline were predictors for stopping therapy (HR 2.94, 95% CI 1.22-4.75; p = 0.02; HR 1.36, 95% CI 1.18-5.41; p = 0.04). CONCLUSIONS: Roughly 60% of MS patients stayed on NTZ treatment during the observation period. For those patients in whom NTZ discontinuation was required, it was mainly due to PML concerns.

Cancer risk for multiple sclerosis patients treated with azathioprine and disease-modifying therapies: an Italian observational study.

BACKGROUND: The risk of malignancy associated with sequential disease-modifying therapies (DMTs) for patients with multiple sclerosis (MS) is uncertain. The aim of this study was to analyze the risk of cancer in patients with MS treated with azathioprine (AZA) and the influence of sequential DMTs on the risk. METHOD: We retrospectively enrolled a cohort of AZA-treated MS patients followed in two Italian centers from 1987 to 2019. The ratio between observed and expected cancers in the Italian general population was calculated as standardized incidence ratio (SIR). Associations between AZA and DMTs and cancer were estimated by Cox proportional hazards model. RESULTS: We identified 500 AZA-treated MS patients, followed for a median time of 9.7 (0.1-45.7) years: 61.8% of them were treated with DMTs. We found 22 cases of cancer (4.4%). The SIR was 1.14 (95% CI 0.98-1.29), not significantly increased in comparison with the general population. However, the risk was significantly higher in the quintiles of age 32-45, SIR 1.21 (95% CI 1.21-1.42), and 46-51, SIR 1.11 (95% CI 1.11-1.32) than in older cases. Age at AZA treatment onset was the only covariate significantly related to cancer incidence (HR = 1.049, 95% CI 1.007-1.093). The exposure to other DMTs did not modify the risk. CONCLUSION: The risk of malignancy in MS patients after AZA was similar to that of the general population and did not change with other DMTs sequential treatments. The increased risk in the younger ages should be considered in treatment assessment.

A Deficit of CEACAM-1-Expressing T Lymphocytes Supports Inflammation in Primary Progressive Multiple Sclerosis.

The immune regulatory mechanisms that modulate Th1 and Th17 immune responses are altered in multiple sclerosis (MS). The inhibitory TIM-3/Gal-9 pathway, in particular, is impaired in primary progressive MS (PPMS). Recent results showed that carcinoembryonic Ag-related cell adhesion molecule 1 (CEACAM-1), a molecule expressed on activated T lymphocytes, endows TIM-3 with inhibitory function and facilitates the maturation and cell surface expression of TIM-3. We analyzed by flow cytometry CEACAM-1 expression on myelin basic protein (MBP)-stimulated CD4+ and CD8+ T lymphocytes of 56 MS patients with a diagnosis of either PPMS (n = 16), relapsing-remitting MS (n = 20), or benign MS (n = 20) and 40 age- and sex-matched healthy controls. The expression of TIM-3 and annexin V (AV) as well as the production of IFN-γ and the intracellular concentration of HLA-B-associated transcript 3 (Bat3), a molecular adaptor that binds the intracellular tail of TIM-3 promoting both proliferation and proinflammatory cytokine production, were analyzed as well in the same cells. Results showed the following in PPMS: 1) CD4+/CEACAM-1+, CD4+/TIM-3+, CD8+/TIM-3+, CD4+/CEACAM-1+/TIM-3+, and CD8+/CEACAM-1+/TIM-3+ T lymphocytes as well as CEACAM-1 mean fluorescence intensity on CD4+ T lymphocytes were significantly reduced; 2) apoptotic CD4+/AV+/CEACAM-1+ and CD8+/AV+/CEACAM-1+ T lymphocytes were significantly reduced; and 3) Bat3-expressing CD4+ and CD8+ T cells were significantly increased. Notably, a specular immunologic scenario was seen in benign MS. CEACAM-1 expression is reduced in PPMS; this exacerbates MBP-specific inflammatory T cell response and reduces the apoptosis of MBP-specific T lymphocytes, possibly as a consequence of the upregulation of Bat3 seen in these patients.

Pediatric CD8+/CD56+ mycosis fungoides with cytotoxic marker expression: A variant with indolent course.

Mycosis fungoides is predominantly a disease of older patients, but occasionally occurs in children. We report a rare case of CD8+/CD56+ mycosis fungoides with cytotoxic marker (perforin, TIA-1, and granzyme B) expression in a 10-year-old boy. Disease presented with three asymptomatic, slowly progressive erythematous and scaling plaques, surrounded by hypochromic alone in the left tight and lower trunk. UVB narrow band associated with topical corticosteroids resulted in complete remission in about 2 months, and no recurrence at 2-year follow-up. Three similar cases have been retrieved in children through PubMed search, showing similar clinical presentation with erythematous scaling lesions, good response to skin-directed treatments and a favorable prognosis.

HLA alleles modulate EBV viral load in multiple sclerosis.

BACKGROUND: The etiopathology of multiple sclerosis (MS) is believed to include genetic and environmental factors. Human leukocyte antigen (HLA) alleles, in particular,  are associated with disease susceptibility, whereas Epstein Barr Virus (EBV) infection has long been suspected to play a role in disease pathogenesis. The aim of the present study is to evaluate correlations between HLA alleles and EBV infection in MS. METHODS: HLA alleles, EBV viral load (VL) and serum anti-EBV antibody titers were evaluated in EBV-seropositive MS patients (N = 117) and age- and sex-matched healthy controls (HC; N = 89). RESULTS: Significantly higher DNA viral loads (p = 0.048) and EBNA-1 antibody titer (p = 0.0004) were seen in MS compared to HC. EBV VL was higher in HLA-B*07+ (p = 0.02) and HLA-DRB1*15+ (p = 0.02) MS patients, whereas it was lower in HLA-A*02+ (p = 0.04) subjects. EBV VL was highest in HLA-A*02-/B*07+/DRB1*15+ patients and lowest in HLA-A*A02+/B*07-/DRB1*15- individuals (p < 0.0001). HLA-B*07 resulted the most associated allele to EBV VL after multiple regression analysis considering altogether the three alleles, (p = 0.0001). No differences were observed in anti-EBV antibody titers in relationship with HLA distribution. CONCLUSIONS: Host HLA-B*07 allele influence EBV VL in MS. As HLA-class I molecules present antigens to T lymphocytes and initiate immune response against viruses, these results could support a role for EBV in MS.

White Matter Tract Injury is Associated with Deep Gray Matter Iron Deposition in Multiple Sclerosis.

BACKGROUND AND PURPOSE: With respect to healthy controls (HCs), increased iron concentrations in the deep gray matter (GM) and decreased white matter (WM) integrity are common findings in multiple sclerosis (MS) patients. The association between these features of the disease remains poorly understood. We investigated the relationship between deep iron deposition in the deep GM and WM injury in associated fiber tracts in MS patients. METHODS: Sixty-six MS patients (mean age 50.0 years, median Expanded Disability Status Scale 5.25, mean disease duration 19.1 years) and 29 HCs, group matched for age and sex were imaged on a 1.5T scanner. Susceptibility-weighted imaging and diffusion tensor imaging (DTI) were used for assessing high-pass filtered phase values in the deep GM and normal appearing WM (NAWM) integrity in associated fiber tracts, respectively. Correlation analyses investigated the associations between filtered phase values (suggestive of iron content) and WM damage. RESULTS: Areas indicative of increased iron levels were found in the left and right caudates as well as in the left thalamus. MS patients presented with decreased DTI-derived measures of tissue integrity in the associated WM tracts. Greater mean, axial and radial diffusivities were associated with increased iron levels in all three GM areas (r values .393 to .514 with corresponding P values .003 to <.0001). Global NAWM diffusivity measures were not related to mean filtered phase values within the deep GM. CONCLUSIONS: Increased iron concentration in the deep GM is associated with decreased tissue integrity of the connected WM in MS patients.

B Lymphocytes in Multiple Sclerosis: Bregs and BTLA/CD272 Expressing-CD19+ Lymphocytes Modulate Disease Severity.

B lymphocytes contribute to the pathogenesis of Multiple Sclerosis (MS) by secreting antibodies and producing cytokines. This latter function was analyzed in myelin olygodendrocyte protein (MOG)-stimulated CD19+ B lymphocytes of 71 MS patients with different disease phenotypes and 40 age-and sex-matched healthy controls (HC). Results showed that: 1) CD19+/TNFα+, CD19+/IL-12+ and CD19+/IFNγ+ lymphocytes are significantly increased in primary progressive (PP) compared to secondary progressive (SP), relapsing-remitting (RR), benign (BE) MS and HC; 2) CD19+/IL-6+ lymphocytes are significantly increased in PP, SP and RR compared to BEMS and HC; and 3) CD19+/IL-13+, CD19+/IL-10+, and CD19+/IL-10+/TGFß+ (Bregs) B lymphocytes are reduced overall in MS patients compared to HC. B cells expressing BTLA, a receptor whose binding to HVEM inhibits TcR-initiated cytokine production, as well as CD19+/BTLA+/IL-10+ cells were also significantly overall reduced in MS patients compared to HC. Analyses performed in RRMS showed that fingolimod-induced disease remission is associated with a significant increase in Bregs, CD19+/BTLA+, and CD19+/BTLA+/IL-10+ B lymphocytes. B lymphocytes participate to the pathogenesis of MS via the secretion of functionally-diverse cytokines that might play a role in determining disease phenotypes. The impairment of Bregs and CD19+/BTLA+ cells, in particular, could play an important pathogenic role in MS.

Comparative efficacy of interferon ß versus glatiramer acetate for relapsing-remitting multiple sclerosis.

Interferon ß (INFß) and glatiramer acetate (GA) are widely used in patients with relapsing-remitting multiple sclerosis (RRMS). However, it is still unclear whether they have different efficacy. We performed a systematic search of head-to-head trials for gaining objective reliable data to compare the two drugs, using the Cochrane Collaboration methodology. We identified five randomised-controlled trials (RCTs) (2858 participants) comparing directly INFß versus GA in RRMS. All studies were at high risk for attrition bias. Both therapies showed similar efficacy at 24 months, considering clinical (patients with relapse or progression) and one MRI activity (enhancing lesions) measure. At 3 years, evidence from a single study showed that the relapse rate was higher in the INFß group than in the GA group (risk ratio 1.40, 95% CI 1.13 to 1.74, p 0.002). However, the average reduction in T2-weighted and T1-weighted lesion volume was significantly greater in the INFß group than in the GA group (mean difference (MD) -0.58, 95% CI -0.99 to -0.18, p 0.004, and MD -0.20, 95% CI -0.33 to -0.07, p 0.003, respectively). The number of participants who dropped out of the studies because of adverse events was similar in the two groups. These data support clinicians in the use of these therapies, based on their similar safety and efficacy in the prevention of disease activity, although the different effect on MRI measures and the different tolerability might have a role in the therapeutic choice at the individual level.

Interferons-beta versus glatiramer acetate for relapsing-remitting multiple sclerosis.

BACKGROUND: Interferons (IFNs)-beta and glatiramer acetate (GA) were the first two disease-modifying therapies (DMTs) approved 15 years ago for the treatment of multiple sclerosis (MS). DMTs prescription rates as first or switching therapies and their costs have increased substantially over the past decade. As more DMTs become available, the choice of a specific DMT should reflect the risk/benefit profile, as well as the impact on quality profile. As MS cohorts enrolled in different studies can vary significantly, head-to-head trials are considered the best approach for gaining objective reliable data when two different drugs are compared. The purpose of this study is to summarise available evidence on the comparative effectiveness of IFNs-beta and GA on disease course through a systematic review of head-to-head trials. OBJECTIVES: To assess whether IFNs-beta and GA differ in terms of safety and efficacy in the treatment of patients with relapsing-remitting MS (RRMS). SEARCH METHODS: We searched the Trials Specialised Register of the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group (29 October 2013) and the reference lists of retrieved articles. We contacted trialists and pharmaceutical companies. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing directly IFNs-beta versus GA in study participants affected by RRMS. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as expected by The Cochrane Collaboration. MAIN RESULTS: Five trials contributed to this review. A total of 2858 participants were randomly assigned to IFNs (1679) and GA (1179). The treatment duration was three years for one study and two years for the other four RCTs. The IFNs analysed in comparison with GA were IFN-beta 1b 250 mcg (two trials, 933 participants), IFN-beta 1a 44 mcg (two trials, 441 participants) and IFN-beta 1a 30 mcg (two trials, 305 participants). Enrolled participants were affected by active RRMS. All studies were at high risk for attrition bias.Both therapies showed similar clinical efficacy at 24 months, given the primary outcome variables (number of participants with relapse (risk ratio (RR) 1.04, 95% confidence interval (CI) 0.87 to 1.24) or progression (RR 1.11, 95% CI 0.91 to 1.35)). However at 36 months, evidence from a single study suggests that relapse rates were higher in the group given IFNs than in the GA group (RR 1.40, 95% CI 1.13 to 1.7, P value 0.002).Secondary magnetic resonance imaging (MRI) outcomes analysis showed that effects on new or enlarging T2- or gadolinium (Gd)-enhancing lesions at 24 months were similar (mean difference (MD) -0.01, 95% CI -0.28 to 0.26, and MD -0.14, 95% CI -0.30 to 0.02, respectively). However, the reduction in T2- and T1-weighted lesion volume was significantly greater in the groups given IFNs than in the GA groups (MD -0.58, 95% CI -0.99 to -0.18, P value 0.004, and MD -0.20, 95% CI -0.33 to -0.07, P value 0.003, respectively).The number of participants who dropped out of the study because of adverse events was similar in the two groups (RR 0.95, 95% CI 0.64 to 1.40).The quality of evidence for primary outcomes was judged as moderate for clinical end points, but for safety and some MRI outcomes (number of active T2 lesions), quality was judged as low. AUTHORS' CONCLUSIONS: The effects of IFNs-beta and GA in the treatment of patients with RRMS, including clinical (e.g. patients with relapse, risk to progression) and MRI (Gd-enhancing lesions) activity measures, seem to be similar or to show only small differences. When MRI lesion load accrual is considered, the effect of the two treatments differs, in that IFNs-beta were found to limit the increase in lesion burden as compared with GA. Evidence was insufficient for a comparison of the effects of the two treatments on patient-reported outcomes, such as quality of life measures.

Oxidative stress is differentially present in multiple sclerosis courses, early evident, and unrelated to treatment.

BACKGROUND: Oxidative stress is well documented in multiple sclerosis (MS) lesions, but its correspondence at peripheral level is still controversial. Objective. To evaluate peripheral oxidative stress markers in MS patients. METHODS: We studied total blood levels of Coenzyme Q10 (CoQ10), oxidized and reduced forms of glutathione, malondialdehyde, reactive oxygen species (ROS), anti-oxidized-low-density lipoproteins (anti-oxLDL) antibodies, and antioxidant power (PAO) in 87 patients with different MS clinical phenotypes and in 77 controls. RESULTS: CoQ10 was lower whereas anti-oxLDL antibodies titer was higher in MS patients than in controls. The benign variant of MS displayed both higher CoQ10 and higher anti-oxLDL than other MS clinical variants. Female patients had lower CoQ10 and PAO and higher ROS than male patients. Differences were greater in younger patients with shorter disease duration. Surprisingly, there was no difference for these markers between treated and untreated patients. CONCLUSION: We found lower antioxidant agents and higher anti-oxLDL antibodies in MS, and the highest antibody titers occurred in the benign form. We suggest that natural anti-oxLDL antibodies can be protective against MS, saving blood brain barrier integrity. Our findings also suggest that milder MS is associated with a distinct oxidative stress pattern, which may provide a useful biomarker of disease prognosis.

Mitoxantrone for multiple sclerosis.

BACKGROUND: This is an updated Cochrane review of the previous published version.Mitoxantrone (MX) has been shown to be moderately effective in reducing the clinical outcome measures of disease activity in multiple sclerosis (MS) patients. OBJECTIVES: The main objective was to assess the efficacy and safety of MX compared to a control group in relapsing-remitting (RRMS), progressive relapsing (PRMS) and secondary progressive (SPMS) MS participants. SEARCH METHODS: We searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Specialised Register (June 2012) and reference lists of articles. We also undertook handsearching and contacted trialists and pharmaceutical companies. SELECTION CRITERIA: Randomised, double-blinded, controlled trials (RCTs) comparing the administration of MX versus placebo or MX plus steroids treatment versus placebo plus steroids treatment were included. DATA COLLECTION AND ANALYSIS: The review authors independently selected articles for inclusion. They independently extracted clinical, safety and magnetic resonance imaging (MRI) data, resolving disagreements by discussion. Risk of bias was evaluated to assess the quality of the studies. Treatment effect was measured using odds ratios (OR) with 95% confidence intervals (CI) for the binary outcomes and mean differences (MD) with 95% CI for the continuous outcomes. If heterogeneity was absent, a fixed-effect model was used. MAIN RESULTS: Three trials were selected and 221 participants were included in the analyses. MX reduced the progression of disability at two years follow-up (proportion of participants with six months confirmed progression of disability (OR 0.30, 95% CI 0.09 to 0.99 and MD -0.36, 95% CI- 0.70 to -0.02; P = 0.04)). Significant results were found regarding the reduction in annualised relapse rate (MD -0.85, 95% CI -1.47 to -0.23; P = 0.007), the proportion of patients free from relapses at one year (OR 7.13, 95% CI 2.06 to 24.61; P = 0.002) and two years (OR 2.82, 95% CI 1.54 to 5.19; P = 0.0008), and the number of patients with active MRI lesions at six months or one year only (OR 0.24, 95% CI 0.10 to 0.57; P = 0.001). Side effects reported in the trials (amenorrhoea, nausea and vomiting, alopecia and urinary tract infections) were more frequent in treated patients than in controls, while no major adverse events have been reported. These results should be considered with caution because of the heterogeneous characteristics of included trials in term of drug dosage, inclusion criteria and quality of included trials. Moreover, it was not possible to estimate the long-term efficacy and safety of MX. AUTHORS' CONCLUSIONS: MX shows a significant but partial efficacy in reducing the risk of MS progression and the frequency of relapses in patients affected by worsening RRMS, PRMS and SPMS in the short-term follow-up (two years). No major neoplastic events or symptomatic cardiotoxicity related to MX have been reported; however studies with longer follow-up (not included in this review) have raised concerns about the risk of systolic disfunction (˜12%) and therapy-related acute leukaemias (0.8%), which are increasingly reported in the literature.MX should be limited to treating patients with worsening RRMS and SPMS and with evidence of persistent inflammatory activity after a careful assessment of the individual patients' risk and benefit profiles. Assessment should also consider the present availability of alternative therapies with less severe adverse events.

JC virus detection and JC virus-specific immunity in natalizumab-treated multiple sclerosis patients.

BACKGROUND: The use of natalizumab in multiple sclerosis (MS) may favour JC virus reactivation; this phenomenon is usually asymptomatic but can, albeit rarely, evolve into frank progressive multifocal leucoencephalopathy (PML). METHODS: JCV-specific CD8+ T lymphocytes were evaluated by flow cytometry over a 24-month period in 24 natalizumab-treated MS patients in whom JCV DNA was or was not detected in blood using quantitative real-time polymerase chain reaction; all these cases were asymptomatic. RESULTS: Perforin- and grazymes-containing VP-1-specific CD8+ T lymphocytes were reduced whereas CD107a-expressing cells were increased in JCV positive patients, suggesting an active degranulation of these cells; naïve CD8+ T lymphocytes were also decreased whereas memory cells were increased in patients in whom JCV reactivation was observed. CONCLUSION: The presence of a CD8+ T lymphocyte-mediated effector immune response offers a greater insight into reactivation of JCV and its clinical sequelae, and may help the monitoring of patients on natalizumab therapy.

Assessment of disease activity in multiple sclerosis phenotypes with combined gadolinium- and superparamagnetic iron oxide-enhanced MR imaging.

PURPOSE: To compare magnetic resonance (MR) imaging features of multiple sclerosis (MS) lesions after the administration of a gadolinium-based contrast agent and ultrasmall superparamagnetic iron oxide (USPIO) particles among the clinical phenotypes of MS and over time. MATERIALS AND METHODS: This study was approved by the local ethics committee, and written informed consent was obtained from all patients. Twenty-four patients with MS (10 with relapsing and 14 with progressive forms) underwent clinical and gadolinium- and USPIO-enhanced MR examinations at baseline and 6-month follow-up. The number of lesions that enhanced with gadolinium alone, USPIO alone, or both was compared with the Pearson χ2 or Fisher exact test, and lesion sizes were compared with the Wilcoxon Mann-Whitney U test. At 6-month follow-up, the lesion signal intensity on precontrast T1-weighted images and the enhancement after repeat injection of the contrast agent were compared with the baseline postcontrast imaging features by using the McNemar test. RESULTS: Fifty-six lesions were considered active owing to contrast enhancement at baseline; 37 lesions (66%) in 10 patients enhanced with gadolinium. The use of USPIO helped detect 19 additional lesions (34%), and two additional patients were classified as having active disease. Thus, the use of both agents enabled detection of 51% (19 of 37 lesions) more lesions than with gadolinium alone. Enhanced lesions were more frequently observed in the relapsing compared with the progressive forms of MS (P<.0001). USPIO enhancement, in the form of ringlike patterns, could also be observed on T1-weighted images in patients with progressive MS, enabling the detection of five lesions in addition to the five detected with gadolinium in this phenotype. Lesions that enhanced with both contrast agents at baseline were larger (mean size, 6.5 mm±3.8; P=.001) and were more likely to persistently enhance at 6-month follow-up (seven of 27 lesions, P<.0001) compared with those that enhanced only with gadolinium (mean size, 4.9 mm±2.2; one of nine lesions) or USPIO (mean size, 3.5 mm±1.5; 0 of 17 lesions). CONCLUSION: The combination of gadolinium and USPIO in patients with MS can help identify additional active lesions compared with the current standard, the gadolinium-only approach, even in progressive forms of MS. Lesions that enhance with both agents may exhibit a more aggressive evolution than those that enhance with only one contrast agent.

Opposite effects of interferon-ß on new B and T cell release from production sites in multiple sclerosis patients.

The release of newly produced B and T lymphocytes from the production sites was analyzed in 30 multiple sclerosis patients treated with interferon-beta by measuring T-cell receptor excision circles and k-deleting recombination excision circles. We found that the therapy induces opposite effects on B- and T-cell mobilization in 33% of patients. New B-cell production, which peaks after 6 months of therapy and then decreases to levels that, however, are still higher than in controls, may cause a renewal of the B-cell compartment. On the contrary, the decreased number of newly produced T lymphocytes observed at 12 months of treatment and the association between reduced thymic output and low peripheral T lymphocytes can be a cause of leukopenia, a frequent side effect of the therapy.

Costimulatory pathways in multiple sclerosis: distinctive expression of PD-1 and PD-L1 in patients with different patterns of disease.

T lymphocytes costimulatory molecules, including CD80, CD86, CD28, CTLA4, PD-1, PD-L1, and B7-H3, are associated with the preferential production of pro- or anti-inflammatory cytokines. We analyzed the expression of these molecules and myelin basic protein (MBP)-specific IL-10 and IFN-gamma production in patients with multiple sclerosis (MS) with relapsing-remitting acute (AMS, n = 40) or stable (SMS, n = 38). Twenty-two patients successfully undergoing therapy with glatimer acetate (n = 12) or IFNbeta (n = 10) were also analyzed. MBP-specific and PD-1-expressing T lymphocytes, PD-L1-expressing CD19(+) cells, and PD-L1(+)/IL-10(+)/CD14(+) and CD19(+) cells were significantly augmented in SMS patients. Additionally, MBP-specific and annexin V-expressing CD4(+) and CD8(+) (apoptotic) T lymphocytes were augmented and pAkt-positive (proliferating) cells were decreased in SMS compared with AMS patients. PD-1 ligation resulted in the increase of pAkt(+) lymphocytes in AMS patients alone. B7-H3 expression and IFN-gamma production were comparable in all individuals but the PD-L1(+)/IL-10(+) over B7-H3(+)/IFN-gamma(+) ratio was significantly lower in AMS compared with SMS patients. Finally, PD-L1 expression on immune cells was reduced in treated patients, suggesting that therapy-induced disease remission is not associated with the modulation of the expression of this molecule. The PD-1/PD-L1 pathway plays an important role in modulating immune functions in MS patients; monitoring and targeting these proteins could offer diagnostic and therapeutic advantages.

A reassessment of the plateauing relationship between T2 lesion load and disability in MS.

OBJECTIVE: A recent cross-sectional study has shown a plateauing relationship between T2 lesion volume (T2LV) and disability in patients with multiple sclerosis (MS). In this analysis, which also included longitudinal observations, we investigated whether such a relationship is a consequence of the decreased frequency of "inflammatory" events occurring in more disabled patients, rather than reflecting their disability status. METHODS: The placebo arms of 2 clinical trials were analyzed. One cohort consisted of 548 patients with relapsing-remitting (RR) MS enrolled in a 14-month, randomized, double-blind, placebo-controlled trial of oral glatiramer acetate. The second cohort consisted of 358 patients with secondary progressive (SP) MS still experiencing relapses enrolled in a 3-year, randomized, double-blind, placebo-controlled trial of interferon beta-1b. RESULTS: At baseline, T2LV was associated with disease duration (p < 0.001), age at MS onset (p < 0.001), and disability (p < 0.001). The relationship between baseline T2LV and Expanded Disability Status Scale (EDSS) was not significantly different between patients with RRMS and SPMS. At a multivariate analysis, T2LV change was associated with the number of on-trial relapses (p < 0.001) and age at MS onset (p = 0.02). The correlations of T2LV change with baseline EDSS and EDSS changes were not significant. CONCLUSIONS: We showed that the plateauing relationship between T2 lesion volume and disability in multiple sclerosis is not always present and is likely due to the reduced frequency of "inflammatory" events in the most common form of secondary progressive multiple sclerosis.

Glatiramer acetate in multiple sclerosis.

Glatiramer acetate (Copaxone) is a disease-modifying agent approved by several health authorities worldwide for the treatment of relapsing-remitting multiple sclerosis. Although its primary target is the inflammatory component of the disease, there are emerging pieces of evidence suggesting that glatiramer acetate might also have a neuroprotective effect. In this review, the results of glatiramer acetate clinical trials and other relevant studies as well as the place of glatiramer acetate among other approved disease-modifying treatments for relapsing-remitting multiple sclerosis are discussed critically.

Can glatiramer acetate reduce brain atrophy development in multiple sclerosis?

The assessment of brain volume changes on serial magnetic resonance imaging (MRI) scans can provide an objective measure of progressive atrophy reflecting the neurodegenerative aspects of multiple sclerosis (MS) pathology. The present article reviews the results of studies assessing the effect of glatiramer acetate (GA) treatment in preventing MS-related, MRI-measurable brain volume decrease. Whilst data from the extended, open-label follow-up of the US trial seem to indicate that long-term treatment with GA might prevent the loss of brain parenchyma in relapsing-remitting MS patients, longitudinal data from the European/Canadian MRI trial suggest that, over a short-term period of treatment, GA does not have a clear-cut impact on the decrease of brain volume. The effect of GA on MS-related brain atrophy might, therefore, be delayed and dissociated in time from those exerted on other clinical and MRI measures of disease activity. However, the modest magnitude of this effect makes it difficult to evaluate its impact on the actual disease progression. Further studies of adequate duration are now required to address this issue, as well as to confirm the sustained efficacy of GA treatment over long periods of follow-up.

Immunological patterns identifying disease course and evolution in multiple sclerosis patients.

Reliable, and easy to measure, immunological markers able to denote disease characteristics in multiple sclerosis (MS) patients are still lacking. We applied a multivariate statistical analysis on results obtained by measuring-by real-time RT-PCR-mRNA levels of 25 immunological relevant molecules in PBMCs from 198 MS patients. The combined measurement of mRNA levels of IL-1beta, TNF-alpha, TGF-beta, CCL20 and CCR3 was able to distinguish MS patients from healthy individuals. CXCR5, CCL5, and CCR3 combined mRNA levels identify primary progressive MS patients while TNF-alpha, IL-10, CXCL10 and CCR3 differentiate relapsing MS patients. Our results indicate that multi-parametric analysis of mRNA levels of immunological relevant molecules in PBMCs may represent a successful strategy for the identification of putative peripheral markers of disease state and disease activity in MS patients.