Francesca Vitetta

Treatment of Relapsing-Remitting Multiple Sclerosis After 24 Doses of Natalizumab: Evidence From an Italian Spontaneous, Prospective, and Observational Study (the TY-STOP Study)

IMPORTANCE The evaluation of therapeutic choices is needed after 24 doses of natalizumab in patients with multiple sclerosis (MS). OBJECTIVE To evaluate the effect of therapeutic choices on the mean annualized relapse rate and on magnetic resonance imaging MS activity after 24 doses of natalizumab in patients with relapsing-remitting MS. DESIGN, SETTING, AND PARTICIPANTS The TY-STOP study, which recruited participants between October 22, 2010, and October 22, 2012, at 8 Italian MS centers (secondary care outpatient clinics) among 124 adult patients who demonstrated no clinical or magnetic resonance imaging MS activity after 24 doses of natalizumab. INTERVENTIONS Natalizumab, no treatment, interferon beta, glatiramer acetate, or fingolimod. MAIN OUTCOMES AND MEASURES The primary end point was the mean annualized relapse rate. Statistical analyses were performed in 124 patients with complete follow-up data among 130 patients who were recruited and stratified into study groups. In the intent-to-treat group, the decision was made to continue or interrupt natalizumab after 24 doses. In the as-treated group, natalizumab continuers received natalizumab, natalizumab switchers changed to different therapies, and natalizumab quitters discontinued natalizumab during the study year. RESULTS No significant differences in demographic or baseline clinical characteristics were found among the study participants. In the intent-to-treat group (n = 124), clinical (P = .004) and radiologic (P = .02) MS activity was significantly lower in patients continuing natalizumab (n = 43) than in patients interrupting natalizumab (n = 81), with a protective effect of natalizumab continuation on both outcomes (odds ratio [OR], 0.33; 95% CI, 0.15-0.70 for clinical activity and OR, 0.35; 95% CI, 0.15-0.79 for radiologic activity). In the as-treated group (n = 124), clinical (P = .003) and radiologic (P = .03) MS activity was significantly lower in natalizumab continuers than in natalizumab switchers or quitters, confirming a protective effect of natalizumab on the risk of relapse in natalizumab continuers compared with natalizumab quitters (OR, 4.40; 95% CI, 1.72-11.23) and natalizumab switchers (OR, 3.28; 95% CI, 0.99-10.79). No disease rebound was observed in natalizumab quitters. After natalizumab discontinuation, 1 patient developed progressive multifocal leukoencephalopathy during the observation period, with complete recovery. CONCLUSIONS AND RELEVANCE This study provides class III evidence of an increased risk of MS activity resumption after natalizumab discontinuation. Therapy discontinuation after 24 doses in natalizumab-responding patients should be considered only if the risk of progressive multifocal leukoencephalopathy is high and outweighs the benefits of continuing the drug. TRIAL REGISTRATION Osservatorio Nazionale Sulla Sperimentazione Clinica dei Medicinali No. 131/2010.

Cerebrospinal fluid oligoclonal IgM bands predict early conversion to clinically definite multiple sclerosis in patients with Clinically Isolated Syndrome

We reviewed the records of 391 patients who had presented with a Clinically Isolated Syndrome and selected 205 who had performed a baseline spinal tap and MRI scan. We studied cerebrospinal fluid (CSF) and serum IgM oligoclonal bands (IgMOB) using agarose gel isoelectric focusing and analyzed the impact of baseline clinical, MRI and CSF variables on the risk of conversion to clinically definite multiple sclerosis, i.e. on the risk of a clinical relapse. At survival analysis, a lower age at onset, an onset with optic neuritis and the presence of CSF-restricted IgMOB increased the risk of a relapse. Only the presence of CSF-restricted IgMOB predicted a relapse within one year.

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

Abstract 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.

Cerebrospinal fluid CXCL13 in clinically isolated syndrome patients: Association with oligoclonal IgM bands and prediction of Multiple Sclerosis diagnosis.

Cerebrospinal fluid (CSF) CXCL13 was shown to correlate with markers of intrathecal inflammation and CSF oligoclonal IgM bands (IgMOB) have been associated with a more severe Multiple Sclerosis (MS) course. We correlated CSF CXCL13 levels with clinical, MRI and CSF parameters, including CSF IgMOB, in 110 Clinically Isolated Syndrome (CIS) patients. CSF CXCL13 levels correlated with CSF cell count, total protein, IgG Index and with the presence of CSF IgGOB and IgMOB. CSF CXCL13 levels ≥15.4 pg/ml showed a good positive predictive value and specificity for a MS diagnosis and for a clinical relapse within one year from onset.

Cerebrospinal fluid amounts of HLA-G in dimeric form are strongly associated to patients with MRI inactive multiple sclerosis

Background: The relevance of human leukocyte antigen (HLA)-G in dimeric form in multiple sclerosis (MS) is still unknown. Objective: To investigate the contribution of cerebrospinal fluid (CSF) HLA-G dimers in MS pathogenesis. Methods: CSF amounts of 78-kDa HLA-G dimers were measured by western blot analysis in 80 MS relapsing–remitting MS (RRMS) patients and in 81 inflammatory and 70 non-inflammatory controls. Results: CSF amounts of 78kDa HLA-G dimers were more frequent in RRMS than in inflammatory (p<0.01) and non-inflammatory controls (p<0.001) and in magnetic resonance imaging (MRI) inactive than in MRI active RRMS (p<0.00001). Conclusion: Our findings suggest that HLA-G dimers may be implicated in termination of inflammatory response occurring in MS.

iNKT Cells in Secondary Progressive Multiple Sclerosis Patients Display Pro-inflammatory Profiles

Background Multiple sclerosis (MS), an autoimmune disease with neurodegeneration and inflammation is characterized by several alterations of different T cell subsets. However, few data exist on the role of iNKT lymphocytes. Objective To identify possible changes in the phenotype of iNKT cells in patients with different clinical forms of MS and find alterations in their polyfunctionality [i.e., ability to produce simultaneously up to four cytokines such as IL-17, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and IL-4]. Methods We studied a total of 165 patients, 91 with a relapsing–remitting form [RR; 31 were treated with interferon (IFN)1a-β, 25 with natalizumab (NAT), 29 with glatiramer acetate; 17 were newly diagnosed RR without treatment, 19 not-active RR without treatment]. Forty-four patients had a progressive MS: 20 primary progressive (PP) and 24 secondary progressive (SP). A total of 55 age- and sex-matched subjects represented healthy controls (CTR). Among fresh peripheral blood mononuclear cells, iNKT cells were identified by flow cytometry. Moreover, the capability of iNKT cells to produce different cytokines (IL-17, TNF-α, IFN-γ, and IL-4) after in vitro stimulation were evaluated in 18 RR (11 treated with NAT and 7 with IFN), 4 PP, 6 SP, and 16 CTR. Results No main differences were found in iNKT cell phenotype among MS patients with different MS forms or during different treatments. However, the polyfunctional response of iNKT cells showed Th1 and Th17 profiles. This was well evident in patients with SP form, who are characterized by high levels of inflammation and neurodegeneration, and exhibited a sustained increase in the production of Th17 cytokines. Patients treated with NAT displayed lower levels of iNKT cells producing IL-17, TNF-α, and IFN-γ. Conclusion Our data suggest that the progressive phase of the disease is characterized by permanent iNKT activation and a skewing towards an inflammatory phenotype. Compared to other treatments, NAT was able to modulate iNKT cell function.

Recurrent Varicella following Steroids and Fingolimod in a Multiple Sclerosis Patient

Dear Sir, We found the recent article on fingolimod significantly increasing the frequencies of T regulatory cells (Treg) in Multiple Sclerosis (MS) patients (Serpero et al. 2013) to be of particular interest for the assessment of the drug’s mechanism of action. However, there is also increasing interest on fingolimod-induced mechanisms of reduced antiviral immunologic competence following the occurrence of encephalitides and deaths due to herpes viruses during treatment with fingolimod (Cohen et al. 2010; Ratchford et al. 2012) and the growing concern on the effects of fingolimod on immunosurveillance. We would like to share our observation of a case of recurrent varicella during treatment with fingolimod following treatment with steroids and briefly explore possible mechanisms which may have facilitated a viral reactivation, including the combination of fingolimod-induced lymphopenia and steroids. In addition, we present cytofluorimetric data, which are in accordance with those by Serpero et al. (2013), and hypothesize that the relative increase of Treg, which inhibit immune responses, may be involved in the reduced antiviral immunity in fingolimod-treated patients. A 52-year-old woman who had presented with two Multiple Sclerosis (MS) relapses during treatment with betainterferon in the preceding year, started treatment with natalizumab on January 23rd, 2013. On February 27th, shortly after initiating the second natalizumab infusion, she had an anaphylactic reaction which lead to hospitalization. She was treated with high-dose iv methylprednisolone for 2 days followed by oral prednisone (50 mg, which was tapered off in 12 days and discontinued on March 12th 2013). Her medical history was otherwise uneventful and she was not taking any concomitant medication. She had a moderate disability (Expanded Disability Status Scale: 3; range 0–10) due to left hemiparesis and mild gait ataxia. She reported a history of varicella disease. Following preliminary exams, inclusive of lymphocyte typing, which was normal, and of anti-Varicella Zoster Virus (VZV) IgG and IgM serum titers which revealed positive IgG (0,86) and negative IgM (0,04) titers (range of positivity: 0.21–6.00), confirming acquired varicella immunity, she started treatment with fingolimod on April 22nd. On April 27th a few pruriginous papular lesions gradually started appearing on her abdomen and right arm. Repeat VZV serology (May 7th) showed unchanged IgG (1.03) and IgM (0.03) serum titers and blood chemistry and full blood count only revealed a drug-related leucopenia with marked lymphopenia (0.56× 10 cells/mm). In the following days the number of papules gradually increased, spreading to other regions (trunk, lower limbs), and vesicles appeared. Fingolimod was discontinued D. Ferraro (*) : F. Vitetta :A. M. Simone : L. Federzoni : P. F. Nichelli : P. Sola Neurology Unit, Department of Neurosciences, University of Modena and Reggio Emilia, Nuovo Ospedale Civile Sant’Agostino Estense, Via Pietro Giardini, 1355, 41126 Modena, Italy e-mail: perdiana@tin.it

Methylprednisolone-induced Toxic Hepatitis After Intravenous Pulsed Therapy for Multiple Sclerosis Relapses.

High-dose, intravenous methylprednisolone (MP) is the only recommended first-line treatment for multiple sclerosis relapses. However, there are increasing reports on liver toxicity induced by this treatment regimen. We report of 4 multiple sclerosis patients with no history of viral/metabolic liver disorders or alcohol/hepatotoxic drug intake, who developed hypertransaminasaemia following intravenous MP. In 2 of the patients, liver biopsy showed periportal fibrosis, piecemeal necrosis, and inflammatory cell infiltrates. A rechallenge test confirmed a causal association in 1 case. MP-induced liver toxicity may be more frequent than commonly thought and it is important to report this adverse reaction, which is potentially lethal, and to raise awareness on the potential hepatotoxicity of corticosteroid pulses.

Severe anemia in a patient with multiple sclerosis treated with natalizumab

We prescribed natalizumab (NAT) treatment in July 2009 for a 51-year-old woman with a 16-year history of relapsing-remitting multiple sclerosis (RRMS), but no other notable medical history, because of disease progression observed on MRI. Previous treatment consisted of azathioprine (1997–2003) and interferon-β-1a (2003–2009), with no adverse events reported. The patient was free of further clinical relapses during NAT treatment and MRI lesion load remained stable.

Pearls & Oy-sters: Rapidly progressive dementia Prions or immunomediated?

Voltage-gated potassium channel (VGKC) antibody–associated encephalitis is a well-known form of limbic encephalitis characterized by acute to subacute onset of confusion and cognitive impairment, mediotemporal seizures, and psychiatric disturbances.