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ObjectiveTo determine whether autologous hematopoietic stem cell transplantation (aHSCT) is able to induce durable disease remission in people with multiple sclerosis (MS), we analyzed the long-term outcomes after transplantation in a large cohort of patients with MS.MethodsTo be included, a minimum dataset (consisting of age, MS phenotype, Expanded Disability Status Scale [EDSS] score at baseline, information on transplantation technology, and at least 1 follow-up visit after transplantation) was required.ResultsTwo hundred ten patients were included (relapsing-remitting [RR] MS 122 [58%]). Median baseline EDSS score was 6 (1–9); mean follow-up was 6.2 (±5.0) years. Among patients with RRMS, disability worsening–free survival (95% confidence interval [CI]) was 85.5% (76.9%–94.1%) at 5 years and 71.3% (57.8%–84.8%) at 10 years. In patients with progressive MS, disability worsening–free survival was 71.0% (59.4%–82.6%) and 57.2% (41.8%–72.7%) at 5 and 10 years, respectively. In patients with RRMS, EDSS significantly reduced after aHSCT (p = 0.001; mean EDSS change per year −0.09 [95% CI −0.15% to −0.04%]). In patients with RRMS, the use of the BCNU+Etoposide+Ara-C+Melphalan (BEAM) + anti-thymocyte globulin (ATG) conditioning protocol was independently associated with a reduced risk of no evidence of disease activity 3 failure (hazard ratio 0.27 [95% CI 0.14–0.50], p < 0.001). Three patients died within 100 days from aHSCT (1.4%); no deaths occurred in patients transplanted after 2007.ConclusionsaHSCT prevents disability worsening in the majority of patients and induces durable improvement in disability in patients with RRMS. The BEAM + ATG conditioning protocol is associated with a more pronounced suppression of clinical relapses and MRI inflammatory activity.Classification of EvidenceThis study provides Class IV evidence that for people with MS, aHSCT induces durable disease remission in most patients.

International audience; Multiple sclerosis is a heterogenous disease. Although several EMA-approved disease-modifying treatments including biopharmaceuticals are available, their efficacy is limited, and a certain percentage of patients are always nonresponsive. Drug efficacy monitoring is an important tool to identify these nonresponsive patients early on. Currently, detection of antidrug antibodies and quantification of biological activity are used as methods of efficacy monitoring for interferon beta and natalizumab therapies. For natalizumab and alemtuzumab treatments, drug level quantification could be an essential component of the overall disease management. Thus, utilization and development of strategies to determine treatment response are vital aspects of multiple sclerosis management given the tremendous clinical and economic promise of this tool.

This is the accepted version of the following article: "Rationale for Therapeutic Drug Monitoring of Biopharmaceuticals in Inflammatory Diseases", which has been published in final form at https://insights.ovid.com/crossref?an=00007691-201708000-00007; International audience; Biopharmaceuticals bring together a number of specific characteristics as compared with other drugs. However, as it is done for most drugs, an individual adjustment of their dose may be necessary. Similar to “chemical” drugs, biopharmaceuticals used in immunoinflammatory diseases have a rather narrow therapeutic range, lack good early clinical or biological marker of response, have variable pharmacokinetics, and their serum concentrations are most often related with response. Monoclonal antibodies have additional specific sources of pharmacokinetic variability. Low concentrations may increase the risks of immunization, plasmapheresis may increase their elimination, and subcutaneous formulations may be associated with decreased adherence. For all these reasons, pharmacokinetic therapeutic drug monitoring may be useful. However, few randomized controlled therapeutic drug monitoring studies have been published. For monoclonal antibodies, a precise definition of the therapeutic concentrations is challenging because of the interindividual variability in their concentration–effect relationship.

Objective: Although in benign multiple sclerosis (BMS) locomotor disability is absent or only minimal, subclinical cognitive impairment seems to occur in many cases. Diffusion tensor (DT) MRI enables us to quantify the extent of “actual” tissue damage, which goes undetected when using conventional MRI. Against this background, we investigated the extent of structural brain damage underlying cognitive dysfunction in BMS, with the ultimate aim to move a first step toward a more reliable definition of this disease phenotype. Methods: Conventional and DT MRI scans of the brain were acquired from 62 BMS patients. Thirty-six secondary progressive multiple sclerosis (SPMS) patients and 19 healthy subjects served as controls. In BMS patients, neuropsychological tests exploring memory, attention, and frontal lobe functions were administered. Normalized brain volume (NBV), mean diffusivity (MD), and fractional anisotropy (FA) of the normal-appearing white matter (NAWM) and MD of the gray matter (GM) were computed. Results: Twelve BMS patients (19%) fulfilled predefined criteria for cognitive impairment. BMS patients had abnormal MD and FA values from both NAWM and GM. Whereas BMS patients without cognitive impairment had lower T2 LV ( p = 0.03), higher NBV ( p = 0.006), and lower average GM MD ( p = 0.03) than SPMS patients, BMS patients with cognitive impairment did not significantly differ from SPMS patients for any MRI-derived metric. Conclusions: In benign multiple sclerosis (BMS), cognitive dysfunction is associated with severe structural brain damage, which resembles that of patients with a much more disabling disease course. A reliable definition of BMS should, therefore, include the preservation of cognitive functioning as an additional requisite. GLOSSARY: BMS = benign multiple sclerosis; DT = diffusion tensor; EDSS = Expanded Disability Status Scale; FA = fractional anisotropy; FDR = false discovery rate; FOV = field of view; GM = gray matter; LV = lesion volume; MD = mean diffusivity; MP-RAGE = magnetization-prepared rapid-acquisition gradient echo; MS = multiple sclerosis; NAWM = normal-appearing white matter; NBV = normalized volume; PASAT = Paced Auditory Serial Attention Test–3" Version; PGSE = pulsed-gradient echo-planar; ROCF = Rey–Osterrieth Complex Figure; SPMS = secondary progressive multiple sclerosis; TE = echo time; TR = repetition time; WM = white matter.

Antibodies against interferon-beta (IFN-beta) can appear in a relevant number of patients. The subset of antibodies that can neutralize IFN-beta activity are called neutralizing antibodies. This review focuses on their impact both on therapeutic efficacy and on bioactivity of IFN-beta, and on the management of antibody-positive patients.When IFN-betas were first used, neutralizing antibodies were not considered important. However, recent clinical, biologic, and immunologic data have demonstrated that they reduce or abolish the therapeutic efficacy of IFN-beta in 10-20% of patients. Quantification of antibodies using various biologic methods make it difficult to compare among different laboratories, and hence, standardization of assay procedures is necessary. Despite these technical difficulties, data consistently show differences in immunogenicity among the different IFN-beta products and the negative effects of neutralizing antibodies on the clinical efficacy of IFN-betas. Because the therapeutic action of IFN-beta depends on activation of IFN-inducible genes, new methods for the quantification of the biologic activity of IFN-beta have been developed, and a good correlation has been found between the presence of neutralizing antibodies and abrogation of IFN-beta bioactivity.Quantification of neutralizing antibodies and the in-vivo bioactivity of IFN-beta through IFN-beta-inducible gene products such as Myxovirus protein A, offer valuable information on IFN-beta therapy. Important questions such as the optimal therapeutic strategy for managing neutralizing antibodies positive patients require further study in clinical trials.

Objective:We undertook an observational retrospective study to investigate the usefulness of aquaporin-4 (AQP4) antibodies (Ab) titration in the management of patients with neuromyelitis optica (NMO) treated with rituximab (RTX) by studying (1) the correlation between AQP4-Ab titer and disease activity, (2) the influence of RTX on antibody levels, and (3) the association between AQP4-Ab levels and responsiveness to RTX.Methods:A cell-based assay was used for AQP4-Ab titration in 322 serum samples from 7 patients with NMO treated with RTX (median follow-up 65 months), according to a treatment-to-target approach. Serum samples were collected every month following standardized procedures.Results:(1) In group analysis, AQP4-Ab titers correlated with the disease activity, showing higher titers during and preceding relapses than during remission. However, in individual analysis, an increase in AQP4-Ab titers and CD19+ B cells did not always precede a relapse. (2) A reduction of AQP4-Ab titers in the short-term and long-term period was observed during RTX treatment. (3) Reduction of AQP4-Ab titers was observed in responder patients both 3 months after RTX infusion and in the long-term follow-up. In one nonresponder patient, AQP4-Ab levels never decreased during the treatment period.Conclusions:Titration of AQP4-Abs could be useful in the clinical management of patients with NMO treated with RTX: titration before each reinfusion and 3 months after each reinfusion may provide information about responsiveness to RTX. Although a relationship among AQP4-Ab levels, disease activity, and response to RTX was observed, the usefulness of AQP4-Ab titration to predict relapses is limited.

Myxovirus A (MxA) is a protein that is specifically induced by treatment with type I cytokines and has proven to be a reliable biomarker of interferon-beta (IFNbeta) bioactivity. IFNbeta-induced MxA can be measured as either protein or mRNA in the blood of IFNbeta-treated patients with MS. In patients with MS who are treated with IFNbeta, loss of the MxA response is caused by high levels of anti-IFNbeta antibodies and is a sensitive marker of lost bioactivity.