Assunta Bianco

CD8+ T Cells in Facioscapulohumeral Muscular Dystrophy Patients with Inflammatory Features at Muscle MRI

Facioscapulohumeral muscular dystrophy (FSHD) is an inherited disease, and although strongly suggested, a contribution of inflammation to its pathogenesis has never been demonstrated. In FSHD patients, we found by immunohistochemistry inflammatory infiltrates mainly composed by CD8+ T cells in muscles showing hyperintensity features on T2-weighted short tau inversion recovery magnetic resonance imaging (T2-STIR-MRI) sequences. Therefore, we evaluated the presence of circulating activated immune cells and the production of cytokines in patients with or without muscles showing hyperintensity features on T2-STIR-MRI sequences and from controls. FSHD patients displaying hyperintensity features in one or more muscles showed higher CD8+pSTAT1+, CD8+T-bet+ T cells and CD14+pSTAT1+, CD14+T-bet+ cells percentages and IL12p40, IFNγ and TNFα levels than patients without muscles displaying hyperintense features and controls. Moreover, the percentages of CD8+pSTAT1+, CD8+T-bet+ and CD14+pSTAT1+ cells correlated with the proportion of muscles displaying hyperintensity features at T2-STIR sequences. These data indicate that circulating activated immune cells, mainly CD8+ T cells, may favour FSHD progression by promoting active phases of muscle inflammation.

Epstein-Barr virus antibodies in serum and cerebrospinal fluid from Multiple sclerosis, Chronic Inflammatory Demyelinating Polyradiculoneuropathy and Amyotrophic Lateral Sclerosis

Elevated anti-Epstein-Barr virus (EBV) antibody levels are present in serum of Multiple sclerosis (MS) patients but literature lacks of studies comparing anti-EBV antibody levels between MS and other neurological diseases. We evaluate anti-VCA IgG and IgM, anti-EBNA1 IgG, anti-Cytomegalovirus IgG and IgM titres in serum and cerebrospinal fluid (CSF) of 267 MS, 50 Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) and 88 Amyotrophic Lateral Sclerosis (ALS) patients. We found increased titres of anti-EBV-IgG in serum and CSF of MS subjects as compared to CIDP and ALS patients thus providing additional evidence for a possible involvement of EBV in MS.

T-bet, pSTAT1 and pSTAT3 expression in peripheral blood mononuclear cells during pregnancy correlates with post-partum activation of multiple sclerosis

In pregnant women affected by multiple sclerosis (MS) we observed increased percentages of CD4(+)CD25(+)Foxp3(+) T regulatory cells at the 1st and the 2nd trimester of gestation that was associated with a decreased T-bet expression in CD4(+) T cells. In women showing clinical relapse and/or new lesions at MRI after delivery we found, a higher expression of T-bet, pSTAT1 and pSTAT3 in CD4(+), CD8(+) T cells and CD14(+) cells, associated with an increase of IFNgamma and IL17 production by PBMC at the 3rd trimester of gestation and after delivery. Our data suggest that the expansion of circulating CD4(+)CD25(+)Foxp3(+) regulatory T cells and the lower expression of T-bet in CD4(+) T cells may account for the decreased MS activity during pregnancy. The expression of T-bet, pSTAT1 and pSTAT3 in peripheral blood CD4(+) and CD8(+) T cells and monocytes could be useful to identify MS patients who will develop a relapse after delivery.

Second-line therapy with fingolimod for relapsing-remitting multiple sclerosis in clinical practice: the effect of previous exposure to natalizumab.

Background: To evaluate efficacy and safety of fingolimod for relapsing-remitting multiple sclerosis, particularly in patients previously exposed to natalizumab. Method: Prospective observational single-centre second-line cohort study. Results: Among 71 patients treated with fingolimod 0.5 mg/day for a mean duration of 21.75 w 12.60 months, the annualized relapse rate was 0.66 (C.I. 95% 0.27-1.05) with a significant difference between 26 patients with prior natalizumab exposure (1.15; C.I. 95% 0.12-2.17) and 45 not exposed (0.38; C.I. 95% 0.18-0.57; p = 0.002). In a multivariate negative regression model, only previous exposure to natalizumab (p = 0.049) and duration of fingolimod treatment (p < 0.001) significantly correlated with the annualized relapse rate. Previous exposure to natalizumab (p = 0.028) and duration of treatment with fingolimod (p < 0.001) were confirmed by restricting the analysis to the first 12 months of treatment with fingolimod, but were no longer statistically significant by analysing only patients (n = 51) with at least 12 months of treatment with fingolimod (0.32; C.I. 95% 0.08-0.55 vs. 0.22; C.I. 95% 0.11-0.32; p = NS). No differences were observed in neuroradiological outcomes and disability progression in patients exposed to natalizumab and not exposed. The rate of discontinuation due to adverse events was 11.3%, with no differences between the two groups. Conclusions: Our study confirms efficacy and side effects of fingolimod in a second-line clinical practice cohort. Prior natalizumab exposure and duration of treatment with fingolimod are independent predictors of annualized relapse rate during the first 12 months of treatment with fingolimod, but not in the long-term, and may be influenced by the 3 months washout period between the two drugs. i 2014 S. Karger AG, Basel

Circulating CD56dim NK cells expressing perforin are increased in progressive multiple sclerosis

In this study we evaluated the percentages of CD3(-)CD56(bright), CD3(-)CD56(dim), CD3(-)CD56(bright)perforin(+) and CD3(-)CD56(dim)perforin(+) Natural Killer (NK) cells in peripheral blood from untreated secondary progressive (SP) and primary progressive (PP) multiple sclerosis (MS) patients and age and sex matched healthy subjects. Both PPMS patients and SPMS patients showed increased percentages of circulating CD3(-)CD56(dim)perforin(+) NK cells than healthy subjects. The increased percentage of CD3(-)CD56(dim) NK cells expressing perforin in patients affected by the progressive forms of MS suggests a possible role of this NK cell subpopulation in the pathogenesis of the disease.

Glioblastoma in multiple sclerosis: a case report

Cerebral tumor and multiple sclerosis (MS) relapses can show overlapping clinical and magnetic resonance imaging features. In a previous study we observed in relapsing MS patients increased T-bet, pSTAT1, and pSTAT3 expressions in circulating mononuclear cells. During the data analysis we observed that T-bet, pSTAT1, and pSTAT3 expression was not increased in circulating mononuclear cells from a relapsing-remitting (RR)MS patient with recent onset of new neurological signs due to glioblastoma multiforme. In conclusion, our patient represents an exemplary case which suggests that T-bet, pSTAT1, and pSTAT3 expression in peripheral blood mononuclear cells (PBMCs) might be useful to differentiate MS relapses from other noninflammatory diseases.

Type 1 immune response in progressive multiple sclerosis

The aim of the study was to evaluate the type-1 immune response by analyzing T-bet expression in circulating T and B cells in Primary Progressive (PP) and Secondary Progressive (SP) Multiple Sclerosis (MS) patients. We found higher percentages of circulating CD4+T-bet+ and CD8+T-bet+ T cells in SPMS and PPMS than in remitting-relapsing MS patients and controls. Moreover, in SPMS, we observed a positive correlation between the percentages of circulating CD4+T-bet+ or CD8+T-bet+ T cells and disease severity. The increased percentages of Th1 and Tc1 cells suggest that MS progressive forms, unlike RRMS, are characterized by a permanent peripheral type-1 immune activation.

Severe dyspnoea with alteration of the diffusion capacity of the lung associated with fingolimod treatment

In phase II clinical trial, fingolimod at a dose of 5.0mg (ten times higher than the currently approved dose) induced dyspnoea and decreased forced expiratory flow in some patients, probably trought an airways constriction S1P4-mediated. In phase III trials, respiratory adverse events associated with fingolimod treatment as dyspnoea, cough, oropharingeal pain and nasal congestion are reported with the same incidence of placebo. Here we report two cases of severe dyspnoea with alteration of the diffusion capacity of the lung associated with fingolimod treatment, which led to permanent treatment withdrawal.

Liver injury after pulsed methylprednisolone therapy in multiple sclerosis patients

High‐dose pulsed methylprednisolone‐related liver injury cases have been reported in the literature, but a prospective study in patients with multiple sclerosis (MS) has never been performed. The aim of this study was to evaluate the prevalence and severity of liver injury in patients with MS after pulsed methylprednisolone therapy.

Acyclovir-related kidney injury during alemtuzumab infusion

Alemtuzumab is a monoclonal antibody against CD52 approved for patients with active relapsing–remitting multiple sclerosis (RRMS) [1]. Concerning renal safety, cases of anti-glomerular basement membrane disease and membranous glomerulonephritis have been reported (incidence of 0.3 % on a safety population of 1486 patients followed for a median of 43.2 months). Glomerulopathies are probably related to the emergence of autoreactive B cells during the reconstitution period in genetically predisposed individuals, with an onset ranging from 4 to 39 months after the last alemtuzumab dose [2]. Monthly serum creatinine, urinalysis and symptom monitoring are required for at least 4 years (Table 1). Besides glomerulopathies, non-autoimmune kidney injury occurring during infusion of alemtuzumab has not been described so far. We report the case of a 25-year-old man with a history of highly active RRMS, non-responder to interferon beta and glatiramer acetate, not eligible to natalizumab and intolerant to fingolimod. After fingolimod was withdrawn, the patient complained of right-sided weakness and MRI showed seven new gadolinium-enhancing cerebral lesions. We planned treatment with alemtuzumab 12 mg intravenously for five consecutive days, associated with methylprednisolone 1 g/day, chlorphenamine maleate 10 mg/day and oral acyclovir 200 mg twice daily. Baseline evaluation was unremarkable, including renal function. On the second day of infusion, urinalysis showed marked glycosuria (3 g/L) associated with hypophosphatemia (2.3 mg/dl), hypouricemia (2.1 mg/dl), traces of albuminuria, and a urinary pH of 6.5. Urine microscopy was negative. Serum glucose, creatinine, sodium, potassium, calcium and magnesium were normal. These findings suggested a proximal (Fanconi like) tubulopathy. Acyclovir was stopped and replaced by oral famciclovir 120 mg twice daily, while alemtuzumab infusion was continued. The subsequent course showed gradual improvement, with complete normalization 2 days after the last alemtuzumab infusion. Treatment with famciclovir was continued for 28 days, without further signs of tubular damage. Patients treated with alemtuzumab may suffer infusion-related side effects thought to be attributable to a cytokine release syndrome [3, 4]. Concomitant medication with methylprednisolone, antipyretics and antihistamines can alleviate these side effects. Patients treated with alemtuzumab are at increased risk of herpesvirus infection (about 16 % in clinical trials). Prophylactic treatment with acyclovir 200 mg twice daily during alemtuzumab infusion and for 28 days thereafter is effective in reducing the risk of herpetic infections [5]. Several mechanisms of acyclovir-related nephrotoxicity have been described including direct renal tubular toxicity, acute interstitial nephritis and crystal nephropathy [6]. In fact, acyclovir, being relatively insoluble in urine, is rapidly filtered by glomeruli and secreted by renal tubules, possibly producing high urinary concentrations, especially in patients with decreased urine flow rates [7]. Risk factors for acyclovir-induced kidney injury include & Assunta Bianco assunta_bianco@yahoo.it