IMPORTANCE Hematopoietic stem cell transplantation (HSCT) represents a potentially useful approach to slow or prevent progressive disability in relapsing-remitting multiple sclerosis (MS).

OBJECTIVE To compare the effect of nonmyeloablative HSCT vs disease-modifying therapy (DMT) on disease progression.

DESIGN, SETTING, AND PARTICIPANTS Between September 20, 2005, and July 7, 2016, a total of 110 patients with relapsing-remitting MS, at least 2 relapses while receiving DMT in the prior year, and an Expanded Disability Status Scale (EDSS; score range, 0-10 [10 = worst neurologic disability]) score of 2.0 to 6.0 were randomized at 4 US, European, and South American centers. Final follow-up occurred in January 2018 and database lock in February 2018.

INTERVENTIONS Patients were randomized to receive HSCT along with cyclophosphamide (200mg/kg) and antithymocyte globulin (6mg/kg) (n = 55) or DMT of higher efficacy or a different class than DMT taken during the previous year (n = 55).

MAIN OUTCOMES AND MEASURES The primary end point was disease progression, defined as an EDSS score increase after at least 1 year of 1.0 point or more (minimal clinically important difference, 0.5) on 2 evaluations 6 months apart, with differences in time to progression estimated as hazard ratios. RESULTS Among 110 randomized patients (73 [66%] women; mean age, 36 [SD, 8.6] years), 103 remained in the trial, with 98 evaluated at 1 year and 23 evaluated yearly for 5 years (median follow-up, 2 years; mean, 2.8 years). Disease progression occurred in 3 patients in the HSCT group and 34 patients in the DMT group. Median time to progression could not be calculated in the HSCT group because of too few events; it was 24 months (interquartile range, 18-48 months) in the DMT group (hazard ratio, 0.07; 95% CI, 0.02-0.24; P < .001). During the first year, mean EDSS scores decreased (improved) from 3.38 to 2.36 in the HSCT group and increased (worsened) from 3.31 to 3.98 in the DMT group (between-group mean difference,-1.7; 95% CI,-2.03 to -1.29; P < .001). There were no deaths and no patients who received HSCT developed nonhematopoietic grade 4 toxicities (such as myocardial infarction, sepsis, or other disabling or potential life-threatening events).

CONCLUSIONS AND RELEVANCE In this preliminary study of patients with relapsing-remitting MS, nonmyeloablative HSCT, compared with DMT, resulted in prolonged time to disease progression. Further research is needed to replicate these findings and to assess long-term outcomes and safety.

Objectives: To determine whether treatment with autologous hematopoietic stem cell transplantation (HSCT) can induce sustained complete remission in patients with multiple sclerosis (MS).

Material and methods: Case series of patients with relapsing‐remitting MS (n = 10) treated at a single center between 2004 and 2007 and followed up for 10 years. The patients were treated with a BEAM/ATG conditioning regimen (n = 9) or a cyclophosphamide/ATG conditioning regimen (n = 1) followed by infusion of unmanipulated autologous hematopoietic stem cells. The primary endpoint was sustained complete remission. Sustained complete remission was defined as “no evidence of disease activity‐4,” sustained for a period of at least 5 years without any ongoing disease‐modifying treatment. Furthermore, MS was considered as “resolved” if intrathecal IgG production and cerebrospinal fluid neurofilament light levels were normalized as well.

Results: Five out of 10 patients were in sustained complete remission at the end of the study. In three of them, MS was resolved.

Conclusions: Our data demonstrate that sustained complete remission after autologous HSCT for MS is possible.

BACKGROUND: Several disease-modifying drugs (DMD) are available for the treatment of MS, and most patients with relapsing-remitting disease are currently treated. Data on when and how DMD treatment can be safely discontinued are scarce.

METHODS: Fifteen MS patients, treated with natalizumab for >5 years without clinical and radiological signs of inflammatory disease activity, suspended treatment and were monitored with MRI examinations and clinical follow-up to determine recurrence of disease activity. This group was compared with a retrospectively analysed cohort comprising 55 MS patients treated with first-line DMDs discontinuing therapy in the time period of 1998-2015 after an analogous stable course.

RESULTS: Natalizumab discontinuers were followed for on average 19 months, and follow-up data for 56 months were available for first-line DMD quitters. Two-thirds of natalizumab treated patients experienced recurrent inflammatory disease activity, and one third had recurrence of rebound character. In contrast, 35% of first-line DMD quitters had mild recurrent disease activity, and no one exhibited rebound.

CONCLUSIONS: Withdrawal of a first-line DMD after prolonged treatment in middle-aged MS patients with stable disease appears to be relatively safe, while natalizumab withdrawal in a similar group of patients cannot be safely done without starting alternative therapy.

OBJECTIVES:

Magnetic resonance imaging (MRI) of the brain and spinal cord is the gold standard for assessing disease activity in multiple sclerosis (MS). MRI is an excellent instrument for determination of accumulated damage to the brain and spinal cord, but tells us little about ongoing tissue damage. In this study, biomarkers of oligodendrocyte, axonal and astrocyte injury were related to MRI and clinical findings and used to assess tissue damage in MS.

MATERIALS AND METHODS:

Cerebrospinal fluid from 44 patients with relapsing-remitting MS, 20 with secondary progressive MS and 15 controls were investigated with ELISA to determine levels of myelin basic protein (MBP), neurofilament light (NFL) and glial fibrillary acidic protein (GFAp). Patients underwent MRI of the brain and spinal cord, and gadolinium enhancing lesions, T1 lesions and T2 lesions were counted.

RESULTS:

Patients in clinical relapse and patients with nonsymptomatic gadolinium enhancing lesions had high levels of MBP and NFL, indicating ongoing damage to oligodendrocytes and axons. The level of MBP dropped quickly within a week from the onset of a relapse, whereas NFL remained elevated for several weeks and GFAp slowly rose during the course of a relapse. Relapsing-remitting MS patients without gadolinium enhancing lesions had values of MBP, NFL and GFAp similar to controls, while patients with secondary progressive disease had moderately increased values of all biomarkers.

CONCLUSIONS:

Analysis of MBP, NFL and GFAp provides direct means to measure tissue damage and is a useful addition to our methods for evaluation of MS.

BACKGROUND: Autologous haematopoietic stem cell transplantation (HSCT) is a viable option for treatment of aggressive multiple sclerosis (MS). No randomised controlled trial has been performed, and thus, experiences from systematic and sustained follow-up of treated patients constitute important information about safety and efficacy. In this observational study, we describe the characteristics and outcome of the Swedish patients treated with HSCT for MS.

METHODS: Neurologists from the major hospitals in Sweden filled out a follow-up form with prospectively collected data. Fifty-two patients were identified in total; 48 were included in the study and evaluated for safety and side effects; 41 patients had at least 1 year of follow-up and were further analysed for clinical and radiological outcome. In this cohort, 34 patients (83%) had relapsing-remitting MS, and mean follow-up time was 47 months.

RESULTS: At 5 years, relapse-free survival was 87%; MRI event-free survival 85%; expanded disability status scale (EDSS) score progression-free survival 77%; and disease-free survival (no relapses, no new MRI lesions and no EDSS progression) 68%. Presence of gadolinium-enhancing lesions prior to HSCT was associated with a favourable outcome (disease-free survival 79% vs 46%, p=0.028). There was no mortality. The most common long-term side effects were herpes zoster reactivation (15%) and thyroid disease (8.4%).

CONCLUSIONS: HSCT is a very effective treatment of inflammatory active MS and can be performed with a high degree of safety at experienced centres.

BACKGROUND: Treatment of multiple sclerosis (MS) with natalizumab during pregnancy is not recommended due to potential risks for the foetus. Despite strong advice accidental pregnancies occur.

CASE: A 32-year old woman with MS since the age of 26 was treated with natalizumab since January 2008. Treatment was stopped April 2011 due to pregnancy plans, but was restarted following an MS relapse. The patient was thoroughly informed about potential foetal risks, but nevertheless she one year later disclosed that she was pregnant in gestational week 15. Treatment was continued, since the first trimester had passed. The pregnancy course was normal and a healthy daughter was born at full gestational term.

CONCLUSIONS: This is the second known case where natalizumab treatment continued throughout the whole gestational period.

In this cross-sectional study, we wanted to identify key cytokines characteristic of different stages of multiple sclerosis (MS). To this end, cerebrospinal fluid from patients with MS was investigated with a multiplexed fluorescent bead-based immunoassay. In total 43 cytokines were assessed and related to clinical and imaging data. Increased levels of CCL22, CXCL10 and sCD40L characterized relapsing-remitting MS patients with the presence of gadolinium-enhancing lesions; decreased CCL2 and increased CXCL1 and CCL5 were typical of relapsing-remitting MS patients irrespectively of the presence of gadolinium-enhancing lesions. These homogenous patterns of cytokine activation do not conform to conventional Th1/Th2/Th17 responses.