Different clinical response to interferon beta and glatiramer acetate related to the presence of oligoclonal IgM bands in CSF in multiple sclerosis patients.

OBJECTIVE: To study the efficacy of interferon beta (IFNß) and glatiramer acetate (GA) related to the presence of oligoclonal M bands (OCMB) in the cerebrospinal fluid in relapsing-remitting multiple sclerosis (RRMS). METHOD: This is an observational, multicenter and retrospective study with prospectively collected data of patients that started treatment with IFNß or GA. Treatment decision was made blinded to the OCMB status. Time to first attack after starting therapy was compared by using Kaplan-Meier curves, and adjustment by Cox regression analysis was performed. RESULTS: Two hundred and fifty-six patients entered in the study (141-55% received IFNß; 115-45% received GA). After a mean follow-up of 41 and 65 months, 54.7% of patients remained free from further attacks (RF). The proportion of RF patients was higher in the GA group than in the IFNß group (72.2 vs. 40.4%, p < 0.001). The IFNß patients with OCMB+ presented the poorest response, 31.3% RF vs. 48.1% in IFNß without OCMB, p = 0.03. CONCLUSION: OCMB in CSF could be a biomarker of treatment response in multiple sclerosis.

Autologous hematopoietic stem cell transplantation in relapsing-remitting multiple sclerosis: comparison with secondary progressive multiple sclerosis.

The main objective of our work is to describe the long-term results of myeloablative autologous hematopoietic stem cell transplant (AHSCT) in multiple sclerosis patients. Patients that failed to conventional therapies for multiple sclerosis (MS) underwent an approved protocol for AHSCT, which consisted of peripheral blood stem cell mobilization with cyclophosphamide and granulocyte colony-stimulating factor (G-CSF), followed by a conditioning regimen of BCNU, Etoposide, Ara-C, Melphalan IV, plus Rabbit Thymoglobulin. Thirty-eight MS patients have been transplanted since 1999. Thirty-one patients have been followed for more than 2 years (mean 8.4 years). There were 22 relapsing-remitting multiple sclerosis (RRMS) patients and 9 secondary progressive multiple sclerosis (SPMS) patients. No death related to AHSCT. A total of 10 patients (32.3%) had at least one relapse during post-AHSCT evolution, 6 patients in the RRMS group (27.2%) and 4 in the SPMS group (44.4%). After AHSCT, 7 patients (22.6%) experienced progression of disability, all within SP form. By contrast, no patients with RRMS experienced worsening of disability after a median follow-up of 5.4 years, 60% of them showed a sustained reduction in disability (SRD), defined as the improvement of 1.0 point in the expanded disability status scale (EDSS) sustains for 6 months (0.5 in cases of EDSS ≥ 5.5). The only clinical variable that predicted a poor response to AHSCT was a high EDSS in the year before transplant. AHSCT using the BEAM-ATG scheme is safe and efficacious to control the aggressive forms of RRMS.

Case Report: Exacerbation of Relapses Following mRNA COVID-19 Vaccination in Multiple Sclerosis: A Case Series.

Introduction: mRNA coronavirus disease 2019 (COVID-19) vaccination has been widely used to arrest the spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Rarely, autoimmune events such as relapses in patients with multiple sclerosis (MS) have been reported after vaccination. However, the possible effects of vaccination in a patient already experiencing the symptoms of a relapse represent an unusual scenario that has not been described. Patients and Methods: This is a retrospective case series of four patients from three major tertiary referral centers that received mRNA COVID-19 vaccination after starting with symptoms of acute demyelination of the central nervous system due to non-recognized MS. A detailed description of each case, including MRI studies, serum light-neurofilament levels, and cerebrospinal fluid (CSF) cytokine profile, is provided. Case Description: All patients presented exacerbation of ongoing symptoms after vaccination (range 14-112 days first dose). All patients presented MRI features suggestive of highly active MS and fulfilled McDonald 2017 criteria at the time of presentation. All patients presented high serum light-neurofilament levels and oligoclonal G bands restricted to the CSF. Higher levels of interleukin-6 in the CSF were present in the more severe cases. Discussion: We describe exacerbation of relapses after mRNA COVID-19 vaccination. We hypothesize RNA sensors such as Toll-like receptor 7 may be activated and contribute to amplify the inflammatory response during a relapse. Conclusion: Patients should seek medical attention if experiencing acute neurological symptoms, especially before vaccination. Fast diagnostic procedures and prompt treatment should be performed in these patients. Pharmacovigilance and further study are warranted to confirm causality.

Effectiveness of rituximab vs. ocrelizumab for the treatment of primary progressive multiple sclerosis: a real-world observational study.

INTRODUCTION: Ocrelizumab, an antiCD-20 antibody, is the only drug approved to treat patients with primary progressive multiple sclerosis (pwPPMS). Not all candidates receive this treatment due to prescription limitations. Rituximab, another antiCD-20 antibody, has been used off-label in pwPPMS before and after ocrelizumab approval. However, studies comparing effectiveness of both drugs are lacking. OBJECTIVE: To evaluate effectiveness of rituximab and ocrelizumab in pwPPMS under real-life conditions. METHODS: We conducted a multicentric observational study of pwPPMS that started ocrelizumab or rituximab according to clinical practice, with a minimum follow-up of 1 year. Data was collected prospectively and retrospectively. Primary outcome was time to confirmed disability progression at 3 months (CDW). Secondary outcome was serum neurofilament light chain levels (sNFL) at the end of follow-up. RESULTS: 95 out 111 pwPPMS fulfilled inclusion criteria and follow-up data availability: 49 (51.6%) received rituximab and 46 (48.4%) ocrelizumab. Rituximab-treated patients had significantly higher baseline EDSS, disease duration and history of previous disease-modifying treatment (DMT) than ocrelizumab-treated patients. After a mean follow-up of 18.3 months (SD 5.9), 26 patients experienced CDW (21.4%); 15 (30.6%) in the rituximab group; and 11 (23.9%) in the ocrelizumab group. Survival analysis revealed no differences in time to CDW. sNFL were measured in 60 patients and no differences between groups were found. INTERPRETATION: We provide real-world evidence of effectiveness of ocrelizumab and rituximab in pwPPMS. No differences in time to CDW were found between treatments. However, this study cannot establish equivalence of treatments and warrant clinical trial to confirm our findings.

Oligoclonal M bands and cervical spinal cord lesions predict early secondary progressive multiple sclerosis.

Objective: To determine baseline cerebrospinal fluid and magnetic resonance imaging (MRI) variables at the onset of a clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS) that predict evolution to secondary progressive MS (SPMS). Methods: 276 CIS patients with a minimum follow-up of 10 years were studied. Baseline presence of oligoclonal IgG and IgM bands (OCGB and OCMB respectively); number of brain T2 lesions (B-T2L), brain gadolinium enhancement lesions (brain-GEL), cervical spinal cord T2 lesions (cSC-T2L); and fulfillment of 2017 McDonald criteria among other variables were collected. Results: 14 patients ended up with a non-MS condition. 138/276 CIS patients fulfilled 2017 McDonald criteria. Mean age was 32.4 years, 185 female. 227 received treatment, 95 as CIS. After a mean follow-up of 12 years, 36 patients developed SPMS. Conversion to SPMS was associated with OCGB (p = 0.02), OCMB (p = 0.0001); ≥ 9 B-T2L (p = 0.03), brain-GEL (p = 0.03), and cSC-T2L (p = 0.03). However, after adjusting for sex, age, BT2L, brain-GEL, SC-T2, and OCMB status, only OCMB (HR 4.4, 1.9-10.6) and cSC-T2L (HR 2.2, 1.0-6.2) suggested an independent association with risk of conversion to SPMS. Patients with both risk factors had a HR of 6.12 (2.8-12.9). Discussion: OCMB and SC-T2 lesions are potential independent predictors of conversion to SPMS.

Revision of the risk of secondary leukaemia after mitoxantrone in multiple sclerosis populations is required.

The objective in this paper is to compare the cumulative incidence and incidence density of therapy-related acute myeloid leukaemia in two cohorts of patients with multiple sclerosis treated with mitoxantrone, and with previously reported data in the literature. Six new cases of acute myeloid leukaemia were observed by prospectively following two Spanish series of 142 and 88 patients with worsening relapsing multiple sclerosis and secondary-progressive disease treated with mitoxantrone. A literature review shows 32 further cases of acute myeloid leukaemia reported, 65.6% of which are therapy-related acute promyelocytic leukaemia. Five cases in the cohorts fulfilled the diagnostic criteria for acute promyelocytic leukaemia, and one patient was diagnosed with pre-B-acute lymphoblastic leukaemia. Acute myeloid leukaemia latency after mitoxantrone discontinuation was 1 to 45 months. The accumulated incidence and incidence density was 2.82% and 0.62%, respectively, in the Valencian cohort, and 2.27% and 0.44% in the Catalonian cohort. In the only seven previously reported series, the accumulated incidence varied from 0.15% to 0.80%. The real incidence of acute myeloid leukaemia after mitoxantrone therapy in the multiple sclerosis population could be higher as evidenced by the growing number of cases reported. Haematological monitoring should continue for at least 5 years after the last dose of mitoxantrone. These data stress the necessity of re-evaluating this risk.

Novel P397S MAPT variant associated with late onset and slow progressive frontotemporal dementia.

Mutations in the MAPT gene cause frontotemporal dementia with tau deposits. We report the novel p.P397S MAPT variant in eight subjects from five apparently nonrelated families suffering from frontotemporal dementia with autosomal dominant pattern of inheritance. In silico analysis reported conflicting evidence of pathogenicity. The segregation analysis support that this variant is likely pathogenic. The mean age at onset (61.4 years) and mean disease duration (13.9 years) of these subjects and their affected relatives were significantly higher compared with our series of p.P301L MAPT mutation carriers. These findings suggest that p.P397S variant could be a new MAPT mutation associated with a less aggressive phenotype than other MAPT mutations.

Positron emission tomography: a false negative result in cystic encephalic mestastases from a small cell bronchial carcinoma.

Lung cancer represents one of the most common malignant diseases. Many investigations are used in the staging study including, most recently, PET. We present a case of cystic cerebral metastases (with no oedema) from a small cell carcinoma which were not detected by PET.

Fingolimod: efectividad y seguridad en la práctica clínica habitual. Estudio observacional, retrospectivo y multicéntrico en la provincia de Alicante / Fingolimod: effectiveness and safety in routine clinical practice. An observational, retrospective, multi-centre study in the province of Alicante

INTRODUCCIÓN: Los estudios postautorización son importantes para confirmar si los resultados de los ensayos clínicos se reproducen en la práctica clínica habitual. OBJETIVO: Evaluar la efectividad y seguridad del fingolimod en la práctica clínica en la provincia de Alicante. PACIENTES Y MÉTODOS: Estudio multicéntrico retrospectivo de pacientes con esclerosis múltiple remitente tratados con fingolimod. Se recogen las características demográficas, clínicas y farmacológicas. Se describe la efectividad del fármaco -tasa anualizada de brotes (TAB) y porcentaje de pacientes libres de brotes- al año y a los dos años de tratamiento en relación con el año previo y datos de efectos secundarios. RESULTADOS: Se incluyó a 89 pacientes. El tratamiento previo fue inmunomodulador (interferón beta o acetato de glatiramero) en 54 pacientes y natalizumab en 32. Cincuenta pacientes cambiaron por fracaso con el inmunomodulador y 31 por serología positiva del virus JC (VJC+). La TAB global disminuyó el 67,3% el primer año (p < 0,0001) y el 84,1% el segundo (p = 0,0078). Disminuyó en los pacientes con fracaso del inmunomodulador (el 85,6% el primer año, p < 0,0001; el 88,9% el segundo año, p = 0,0039) y aumentó de forma no significativa en los pacientes VJC+ en el primer año. El porcentaje de pacientes libres de brotes en la población global aumentó del 32,6 al 68,1% en el primer año (p < 0,0019) y al 82,6% en el segundo (p = 0,0215). Este aumento no se observó en los pacientes VJC+. Trece pacientes tuvieron efectos secundarios, que obligaron a la retirada del fármaco en dos de ellos. CONCLUSIÓN: En la práctica clínica de la provincia de Alicante, el fingolimod mostró una efectividad y una seguridad ligeramente superiores a las de los ensayos clínicos

INTRODUCTION: Post-authorisation studies are important to confirm whether the outcomes of clinical trials are reproduced in usual clinical practice. AIMS: To evaluate the effectiveness and safety of fingolimod in clinical practice in the province of Alicante. PATIENTS AND METHODS: A retrospective multi-centre study was conducted with remitting multiple sclerosis patients treated with fingolimod. Demographic, clinical and pharmacological data were collected. We report on the effectiveness of the drug -annualised relapse rate (ARR) and percentage of patients free from attacks- at one and at two years after treatment in relation to the previous year, and data concerning side effects are also provided. RESULTS: The sample consisted of 89 PATIENTS: Previous treatment was with immunomodulators (interferon beta or glatiramer acetate) in 54 patients and natalizumab in 32. Fifty patients changed due to failure with the immunomodulator and 31 owing to positive serology for JC virus (JCV+). Overall ARR decreased by 67.3% the first year (p < 0.0001) and by 84.1% the second (p = 0.0078). It diminished in patients with immunomodulator failure (85.6% the first year, p < 0.0001; 88.9% the second year, p = 0.0039) and increased in a non-significant manner in JCV+ patients in the first year. The percentage of patients free from relapses in the overall population increased from 32.6% to 68.1% in the first year (p < 0.0019) and to 82.6% in the second (p = 0.0215). This increase was not observed in JCV+ PATIENTS: Side effects were reported by 13 patients, which led to the drug being withdrawn in two of them. CONCLUSIONS: In clinical practice in the province of Alicante, levels of effectiveness and safety of fingolimod proved to be slightly higher than those found in clinical trials (AU)

Positron emission tomography: a false negative result in cystic encephalic mestastases from a small cell bronchial carcinoma

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Lung cancer represents one of the most commonmalignant diseases. Many investigations are used inthe staging study including, most recently, PET. Wepresent a case of cystic cerebral metastases (with nooedema) from a small cell carcinoma which werenot detected by PET