Neurofilament light as an immune target for pathogenic antibodies.

Antibodies to neuronal antigens are associated with many neurological diseases including paraneoplastic neurological disorders, epilepsy, amyotrophic lateral sclerosis and multiple sclerosis. Immunization with neuronal antigens such as neurofilament light (NF-L), a neuronal intermediate filament in axons, has been shown to induce neurological disease and spasticity in mice. Also, although antibodies to NF-L are widely used as surrogate biomarkers of axonal injury in amyotrophic lateral sclerosis and multiple sclerosis, it remains to be elucidated if antibodies to NF-L contribute to neurodegeneration and neurological disease. To address this, we examined the pathogenic role of antibodies directed to NF-L in vitro using spinal cord co-cultures and in vivo in experimental autoimmune encephalomyelitis (EAE) and optic neuritis animal models of multiple sclerosis. Here we show that peripheral injections of antibodies to NF-L augmented clinical signs of neurological disease in acute EAE, increased retinal ganglion cell loss in experimental optic neuritis and induced neurological signs following intracerebral injection into control mice. The pathogenicity of antibodies to NF-L was also observed in spinal cord co-cultures where axonal loss was induced. Taken together, our results reveal that as well as acting as reliable biomarkers of neuronal damage, antibodies to NF-L exacerbate neurological disease, suggesting that antibodies to NF-L generated during disease may also be pathogenic and play a role in the progression of neurodegeneration.

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.

Pulsed steroids followed by glatiramer acetate to prevent inflammatory activity after cessation of natalizumab therapy: a prospective, 6-month observational study.

In this study, the tolerability and safety of treatment with pulsed steroids and glatiramer acetate and the occurrence of clinical and radiological activity after natalizumab (NTZ) cessation in multiple sclerosis (MS) patients were assessed. MS patients with NTZ were discontinued after 2 years of treatment, or if adverse events or disease progressed during NTZ. They were offered as alternative treatment 1 g methylprednisolone per month during 3 months followed by daily 20 mcg glatiramer acetate and were prospectively studied. Adverse events, occurrence of immune reconstitution inflammatory syndrome, clinical exacerbations, and gadolinium-enhancing lesions in MRI performed at 3 and 6 months after NTZ cessation were recorded. EDSS change during follow-up was also recorded. A total of 18 MS patients entered the study and were followed up for a mean of 10 months (range 6-18 months). There were no significant adverse events. At month 3, no patient had clinical or radiological disease activity. At month 6, 16.6% of patients had had a relapse and 55.5% of patients showed gadolinium-enhancing lesions in the MRI. After 6 months, 33.3% of patients had a further relapse. There was no IRIS, severe relapses, or significant difference between EDSS at NTZ discontinuation and after follow-up. The alternative treatment with monthly prednisolone followed by GA prevents the development of IRIS, but not the return to previous inflammatory activity, which occurs between 5 and 6 months after NTZ withdrawal.

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.

Long-lasting remission after rituximab treatment in a case of anti-Hu-associated sensory neuronopathy and gastric pseudoobstruction.

Anti-Hu paraneoplastic syndromes are usually associated with an underlying neoplasia, although a few patients who are anti-Hu-positive never develop cancer after long-term follow-up. Tumour therapy remains the mainstay of therapeutic options, and early immune therapy in parallel is advisable. When no tumour is found, immunologically-based therapies are nowadays the only options. Recent studies have shown rituximab associated with the tumour therapy to be effective for some patients with anti-Hu paraneoplastic syndrome. We report a case of a patient with anti-Hu antibodies-associated sensory neuronopathy and gastric pseudo-obstruction without an underlying neoplasia four years after the first manifestation who has achieved sustained improvement for two years after treatment with rituximab. This case report supports the effectiveness of rituximab in these syndromes, even for cases where no underlying neoplasia is demonstrated. Further studies are warranted in order to confirm these preliminary data.