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Summary Background Opicinumab is a human monoclonal antibody against LINGO-1, an inhibitor of oligodendrocyte differentiation and axonal regeneration. Previous findings suggested that opicinumab treatment might enhance remyelination in patients with CNS demyelinating diseases. We aimed to assess the safety and efficacy of opicinumab in patients with relapsing multiple sclerosis. Methods We did a randomised, double-blind, placebo-controlled, dose-ranging, phase 2 study (SYNERGY) at 72 sites in 12 countries. Participants (aged 18–58 years) with relapsing multiple sclerosis (relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis with relapses) were randomised in a 1:2:2:2:2 ratio by an interactive voice and web response system to opicinumab 3 mg/kg, 10 mg/kg, 30 mg/kg, or 100 mg/kg, or placebo. An identical volume of study drug was administered intravenously once every 4 weeks. All participants self-administered intramuscular interferon beta-1a as background anti-inflammatory treatment once a week. The primary endpoint was the percentage of participants achieving confirmed disability improvement over 72 weeks, which was a multicomponent endpoint measured by the Expanded Disability Status Scale, the Timed 25-Foot Walk, the Nine-Hole Peg Test, and the 3 s Paced Auditory Serial Addition Test. The primary endpoint was analysed under intention-to-treat principles. This study is registered at ClinicalTrials.gov , number NCT01864148 . Findings Between Aug 13, 2013, and July 31, 2014, 419 patients were enrolled and randomly assigned either placebo (n=93) or opicinumab 3 mg/kg (n=45), 10 mg/kg (n=95), 30 mg/kg (n=94; one patient did not receive the assigned treatment), or 100 mg/kg (n=92). The last patient visit was on March 29, 2016. Confirmed disability improvement over 72 weeks was seen in 45 (49%) of 91 patients assigned to placebo, 21 (47%) of 45 assigned to opicinumab 3 mg/kg, 59 (63%) of 94 assigned to opicinumab 10 mg/kg, 59 (65%) of 91 assigned to opicinumab 30 mg/kg, and 36 (40%) of 91 assigned to opicinumab 100 mg/kg. A linear dose-response in the probability of confirmed disability improvement was not seen (linear trend test p=0·89). Adverse events occurred in 79 (85%) patients assigned placebo and in 275 (85%) assigned any dose of opicinumab. The most common adverse events of any grade in patients assigned any dose of opicinumab included influenza-like illness (140 [43%] with any dose of opicinumab vs 37 [40%] with placebo), multiple sclerosis relapses (117 [36%] vs 30 [32%]), and headache (51 [16%] vs 23 [25%]). Serious adverse events reported as related to treatment were urinary tract infection in one (1%) participant in the the placebo group, suicidal ideation and intentional overdose in one (1%) participant in the 30 mg/kg opicinumab group, bipolar disorder in one (1%) participant in the 100 mg/kg opicinumab group, and hypersensitivity in four (4%) participants in the 100 mg/kg opicinumab group. One patient in the opicinumab 30 mg/kg group died during the study due to a traffic accident, which was not considered related to study treatment. Interpretation Our findings did not show a significant dose-linear improvement in disability compared with placebo in patients with relapsing multiple sclerosis. Further studies are needed to investigate whether some subpopulations identified in the study might benefit from opicinumab treatment at an optimum dose. Funding Biogen.

Acquired demyelinating syndromes (ADS) represent acute neurologic illnesses characterized by deficits persisting for at least 24 hours and involving the optic nerve, brain, or spinal cord, associated with regional areas of increased T2 signal on conventional MRI. In contrast to the 75% of adult patients presenting with clinically isolated syndrome (CIS) who are eventually diagnosed with clinically defined multiple sclerosis (MS),1 the majority of children presenting with ADS have a monophasic illness with a good overall prognosis: more than 90% of children achieve a full neurologic recovery.2 Over the last decade, neuroimaging studies have focused on differentiating between MS and its mimics, and correlating radiologic measures with clinical outcome and neuropsychological testing in pediatric MS.3

Neuromyelitis optica (NMO) (and NMO spectrum disorder) is an autoimmune inflammatory disease of the CNS primarily affecting spinal cord and optic nerves. Reliable and sensitive biomarkers for onset, relapse, and progression in NMO are urgently needed because of the heterogeneous clinical presentation, severity of neurologic disability following relapses, and variability of therapeutic response. Detecting aquaporin-4 (AQP4) antibodies (AQP4-IgG or NMO-IgG) in serum supports the diagnosis of seropositive NMO. However, whether AQP4-IgG levels correlate with disease activity, severity, response to therapy, or long-term outcomes is unclear. Moreover, biomarkers for patients with seronegative NMO have yet to be defined and validated. Collaborative international studies hold great promise for establishing and validating biomarkers that are useful in therapeutic trials and clinical management. In this review, we discuss known and potential biomarkers for NMO.

The etiology of multiple sclerosis (MS) remains unclear. However, as with almost all common complex traits, genetic and environmental components have important roles, both independently and interactively, in disease susceptibility. Stochastic and epigenetic effects cannot be overlooked [1–3] – see Figure 16.1. In MS, much of the work on molecular genetics (e.g. linkage studies, candidate genes, genome wide association studies (GWAS)) [4] and genetic epidemiology (“a science which deals with the aetiology, distribution, and control of disease in groups of relatives and with inherited causes of disease in populations” [2,5]) has focused on adults. Nevertheless, it is reasonable to expect, at least to some extent, overlap with the pediatric MS population, as defined in this textbook by Chabas and Waubant. This is not to say that pediatric-onset MS cases have been specifically excluded from molecular genetic studies. Rather, in most instances, all ascertained patients have been included, but identification has been through adult-orientated neurologists and clinics [6–8]. With the increasing recognition of pediatric MS as a distinct entity [9,10], it is now becoming very clear that genetic/genetic epidemiological data must be compared and contrasted for the following groups.

About 3-5% of all patients with multiple sclerosis experience the onset of their disease under the age of 16. A significant proportion of paediatric multiple sclerosis patients develop significant cognitive disturbances and persistent physical disability. The high relapse rate and the morbidity in the paediatric multiple sclerosis population has triggered the use of disease-modifying therapies that have been shown to reduce relapse rate, disease progression and cognitive decline in adult patients with multiple sclerosis. Hard evidence for the right treatment and its appropriate timing is scarce in paediatric multiple sclerosis. Nevertheless, expertise in this field has grown thanks to recent open-label trials and experience generated in specialized centres. In spring 2009, a first meeting was held in Rotterdam with clinicians from 11 European countries (one from Canada) that are all active in the management of paediatric multiple sclerosis. One of the aims was to generate a common view on the management of paediatric multiple sclerosis patients. The result of this meeting is presented here to help standardize treatment and to support clinicians with less experience in this field.

In GWA studies, CLEC16A has been identified as a risk gene for several major autoimmune diseases, including multiple sclerosis (MS). We show that CLEC16A is increased in MS and functionally links to HLA-II, and uncovered the molecular mechanism of CLEC16A as key regulator of HLA-II antigen presentation. We used the human melanoma cell line MelJuSo and primary moDC as APC models to silence CLEC16A with different siRNA and lentiviral shRNA. CLEC16A knockdown in MelJuSo cells and moDC resulted in cytoplasmic dispersion and strong accumulation of HLA-II+ late endosomes, suggesting impaired formation of multivesicular late endosomal compartments, i.e. MIIC. Indeed, in CLEC16A shRNA transductants, MIIC contained no or a few abnormally enlarged internal vesicles and showed an increased number of HLA-II molecules as compared to scrambled shRNA transductants of MelJuSo cells. CLEC16A associated with Rab7-interacting lysosomal protein (RILP) and the homotypic fusion and protein sorting (HOPS) complex, two members of the dynein motor complex regulating late endosomal trafficking and maturation. In addition, CLEC16A silencing disrupted RILP-mediated recruitment of HLA-II+ late endosomes to perinuclear regions. We reveal direct involvement of CLEC16A in the machinery regulating late endosomal processing of HLA-II. This novel C-type lectin function supports a pathogenic role of CLEC16A in autoimmune disease by promoting HLA-II antigen presentation via the formation of MIIC.