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Abstract

Objective:

To evaluate the safety, efficacy, and durability of multiple sclerosis (MS) disease stabilization after high-dose immunosuppressive therapy (HDIT) and autologous hematopoietic cell transplantation (HCT).

Methods:

High-Dose Immunosuppression and Autologous Transplantation for Multiple Sclerosis (HALT-MS) is a phase II clinical trial of HDIT/HCT for patients with relapsing-remitting (RR) MS who experienced relapses with disability progression (Expanded Disability Status Scale [EDSS] 3.0–5.5) while on MS disease-modifying therapy. The primary endpoint was event-free survival (EFS), defined as survival without death or disease activity from any one of: disability progression, relapse, or new lesions on MRI. Participants were evaluated through 5 years posttransplant. Toxicities were reported using the National Cancer Institute Common Terminology Criteria for Adverse Events (AE).

Results:

Twenty-five participants were evaluated for transplant and 24 participants underwent HDIT/HCT. Median follow-up was 62 months (range 12–72). EFS was 69.2% (90% confidence interval [CI] 50.2–82.1). Progression-free survival, clinical relapse-free survival, and MRI activity-free survival were 91.3% (90% CI 74.7%–97.2%), 86.9% (90% CI 69.5%–94.7%), and 86.3% (90% CI 68.1%–94.5%), respectively. AE due to HDIT/HCT were consistent with expected toxicities and there were no significant late neurologic adverse effects noted. Improvements were noted in neurologic disability with a median change in EDSS of −0.5 (interquartile range −1.5 to 0.0; p = 0.001) among participants who survived and completed the study.

Conclusion:

HDIT/HCT without maintenance therapy was effective for inducing long-term sustained remissions of active RRMS at 5 years.

ClinicalTrials.gov identifier:

NCT00288626.

Classification of evidence:

This study provides Class IV evidence that participants with RRMS experienced sustained remissions with toxicities as expected from HDIT/HCT.
Multiple sclerosis (MS) is an autoimmune disease resulting in demyelination and loss of CNS neurons. The High-Dose Immunosuppression and Autologous Transplantation for Multiple Sclerosis (HALT-MS) clinical trial was initiated in participants with relapsing-remitting MS (RRMS); that is, with active CNS inflammation relatively early in the disease course.1 We hypothesized that high-dose immunosuppressive therapy (HDIT) and autologous hematopoietic cell transplantation (HCT) would remove disease-causing cells and induce a reset of the immune system, thereby controlling disease.2,3 Participants had substantial disability progression (Expanded Disability Status Scale [EDSS] 3.0–5.5) and failure of MS disease-modifying therapy (DMT) to control disease activity. At 3 years after HDIT/HCT and, importantly, with no posttransplant immunosuppressive therapy administered, event-free survival (EFS) was 78%,1 defined as absence of progression, relapse activity, or new MRI lesions. Further, peritransplant adverse events (AE) were consistent with those routinely observed after HDIT/HCT,1 and treatment-related mortality was zero.1 In this report, outcomes of participants followed at least 5 years are described.
Outcomes at 5 years for participants in the HALT-MS clinical trial compare favorably to results from nontransplant studies that enrolled participants with less severe MS and followed them for only 2–3 years.4 HALT-MS is among the first MS treatment clinical trials to use a composite endpoint for EFS that is comparable, but not identical, to no evidence of MS disease activity (NEDA) (including MRI activity, relapse, or progression of disability)4,5 as the primary endpoint. Advantages of the composite endpoint include that (1) it is a sensitive indicator of MS disease activity as compared to either relapse activity or progression of disability alone and (2) it facilitates comparison of HDIT/HCT to other MS DMT.4 For current Food and Drug Administration (FDA)–approved therapies for MS, including glatiramer acetate or interferon-β-1a (first-line treatments6), or natalizumab or alemtuzumab (second-line treatments6), NEDA levels of 19%, 21%, 37%, and 39%, respectively, were observed with follow-up of 2–3 years after initiation of study treatment.58 In an observational clinical cohort in which participants received no or multiple different therapies, NEDA was maintained at 1 year in 46%, but at 7 years in only 7% of participants with MS.9

METHODS

Details of the patient population, procedures, evaluations, and study design have been reported.1

Patients.

Eligible patients were 18–60 years of age and had MS by McDonald criteria10 with (1) RRMS; (2) EDSS11 3.0–5.5 at baseline; (3) lesions on brain MRI consistent with MS; (4) disease duration <15 years; and (5) failure of DMT, defined as ≥2 clinical relapses over 18 months while on therapy and associated with EDSS increase (by 1.0 for EDSS of 3.0–3.5 or by 0.5 for EDSS of 4.0–5.5 and sustained ≥4 weeks). Eligibility was determined by a MS Review Panel (MSRP).1

Standard protocol approvals, registrations, and patient consent.

The clinical study (protocol ITN033AI; BB-IND 12164; type II DMF BB-IND 118211) was approved by institutional review boards at participating sites and participants provided written informed consent. The clinicaltrials.gov registration number is NCT00288626.

Study design.

This is a prospective, open-label, single-arm, multicenter phase II clinical trial.

Procedures.

Autologous peripheral blood stem cells were collected, CD34-selected, and stored as described.1 High-dose chemotherapy was carmustine (BCNU) 300 mg/m2 on day −6, etoposide 200 mg/m2 and cytarabine 200 mg/m2 daily from day −5 to −2, and melphalan 140 mg/m2 on day −1 (BEAM).1,12 Rabbit antithymocyte globulin (2.5 mg/kg/d) was administered on days −2 and −1. On day 0, CD34+ hematopoietic progenitor cells were thawed and infused. Filgrastim (5 μg/kg/d) was administered from day +5 until recovery of blood counts. Prednisone was administered (0.5 mg/kg/d) from day +7 to +21 and then tapered over 2 weeks to prevent engraftment syndrome. Supportive care was administered as described.13

Primary endpoint and study evaluations.

The primary endpoint was time until treatment failure or EFS during 5 years post-HCT, defined as the first event of death or disease activity from any one of: (1) disability progression, (2) relapse, or (3) new lesions on MRI. Disability progression was defined as a change in EDSS performed at least 6 months after transplant of >0.5 as compared to EDSS at baseline and confirmed 3 months later.1 Relapse was defined as new neurologic symptoms lasting over 48 hours. The MRI endpoint was 2 or more gadolinium-enhancing or new T2-weighted lesions at 1 year or longer after transplant. The Multiple Sclerosis Functional Composite (MSFC) and the Multiple Sclerosis Impact Scale (MSIS-29) were performed before mobilization of stem cells, at +6 months, and then annually to end of study. Participants were contacted by telephone between annual visits at an interval of 3 months and if there were new neurologic symptoms, they were evaluated.
Brain MRI was performed at screening post-MSRP, baseline, +2 months, +6 months, and then annually to +5 years, on scanners with 1.5T field strength. Scans were analyzed centrally (NeuroRx, Montreal, Canada). The brain MRI at +2 months was the post-treatment reference scan for assessment of treatment failure. The pretreatment screening scan was the reference for brain volume changes.
Toxicities were reported by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. AE ≥ grade 2 were recorded from 3 to 5 years of the study.
Oligoclonal bands (OCB) were identified/quantified by 2 independent experienced readers following isoelectric focusing on agarose and in-gel enzyme-enhanced immunostaining using an FDA-approved method (Sebia [Norcross, GA] Isofocusing Gel), following consensus guidelines.14 Total immunoglobulin G (IgG) concentrations were measured in CSF and serum specimens to allow normalization of the concentration of IgG applied to each gel lane. Participant paired CSF and serum samples from baseline, 2 years, and 4 years posttransplant were assayed on the same gel for accurate comparison of bands. Bands visualized in CSF but not in paired serum specimens were denoted as CSF-specific. Disappearance/resolution of CSF-specific bands and appearance of novel CSF-specific bands in the +2 years and +4 years specimens as compared to the baseline sample of each participant were recorded. Analyses were performed in a CLIA-certified laboratory (Department of Laboratory Medicine, University of Washington, Seattle).

Statistics.

EFS was calculated using the Kaplan-Meier method to assess the composite primary endpoint. Similar analyses were conducted for the individual components of disability progression, clinical relapse, new MRI lesions, and death to produce progression-free, relapse-free, MRI activity-free, and overall survival estimates. Follow-up for any component was not censored by earlier events so that each has an interpretation independent of the other components. Standard errors were derived using the Greenwood formula and used to generate 90% confidence intervals (CIs).
Secondary outcomes included change in T1 and T2 lesion volumes, total brain volume, EDSS, MSFC, and MSIS. Each component of the MSFC was transformed into a Z score using the National MS Society Task Force Database reference population.15 Significant change from baseline was tested using the Wilcoxon signed-rank test. The screening measurement was used as the reference for percent change in brain volume, while the baseline visit was used for all other endpoints. A limitation of this study is that for secondary outcomes no corrections have been made for multiple comparisons, as this pilot study was hypothesis-generating and not a formal test of specific hypotheses.
All analyses were performed using SAS version 9.3 (Cary, NC) or higher. Datasets for the analyses are available through TrialShare, a public website managed by the Immune Tolerance Network (https://www.itntrialshare.org/HALTMS_5yr.url).

Primary research question.

To assess the 5-year durability of disease stabilization in patients with MS after HDIT and autologous HCT.

Classification of evidence.

This study provides Class IV evidence that participants with RRMS experienced sustained remissions with toxicities as expected from HDIT/HCT.

RESULTS

Patient characteristics.

Twenty-five patients were consented and 24 patients underwent HDIT/HCT (figure 1, and figure e-1 and table e-1 at Neurology.org). The 25 entering participants had median age 37 years (interquartile range [IQR] 31–42), with 17 (68%) women. Disease duration was 4.9 years (median; IQR 2.5–7.3); baseline EDSS was 4.5 (median; IQR, 4.0–5.0). Participants had previously failed 3 (median; IQR 2–4) nontransplant MS medications.
Figure 1 Patient-level pretransplant characteristics and outcomes
Patient-level pretransplant characteristics and study outcomes are presented for the 24 transplanted participants. Time is measured in months relative to day 0, the day of graft infusion. The eligibility window is defined as the period of time beginning 18 months prior to the screening visit. At screening, the number of relapses, as defined in the protocol, that occurred during the eligibility window were identified retrospectively and documented in the clinical database, for the purpose of determining eligibility. The period of screening to transplant is defined as the time from determination of protocol eligibility until day 0. To obtain a more complete understanding of the events that occurred during the time from screening to day 0, we retrospectively investigated reports of multiple sclerosis (MS) attack, to determine if the participant had met the protocol definition of relapse, or if the event was a less severe MS worsening event. MS worsening is a new neurologic sign or symptom that does not meet criteria for relapse, and was documented only during the period from screening to day 0. Patients 2, 6, 14, 15, 19, and 22 experienced an Expanded Disability Status Scale (EDSS) increase of at least 0.5 during the period of screening to transplant. Study completion for some participants occurred beyond the 28-day visit window for the year 5 visit, due to scheduling difficulties. The participant flow diagram is presented as figure e-1 in the current publication. A total of 18 participants completed the year 4 assessment and 17 participants completed the year 5 assessment. MS disease activity is reduced for participants posttransplant as compared to prior to treatment. DMT = disease-modifying therapy.

Adverse events.

AEs to 3 years after transplant were described,1 and were consistent with toxic effects associated with HDIT/HCT, including predominantly cytopenias and infections; no acute treatment-related neurologic AE were observed.1 Beyond 3 years post-HCT, 15 grade 3 AEs occurred (table 1); no grade 4 AEs were observed.
Table 1 Adverse events (AEs) by time of occurrencea
Two participants had disease progression and died (grade 5 AE) at >2.5 years and >3.5 years after transplant and were reported.1 A third participant also had disease progression at 15 months and died at 4.5 years post-HCT. No information was available on the events leading up to death. The final cause of death was cardiopulmonary arrest. No death was attributed to transplant.

Evaluation of disease.

The estimated EFS probability was 73.8% (90% CI 55.0%–85.7%) at 4 years and 69.2% (90% CI 50.2%–82.1%) at 5 years. Of 24 participants transplanted, 7 did not maintain EFS by close of follow-up (figure 2, A–B and table e-2) by an increase in EDSS >0.5 (n = 2), clinical relapse (n = 3), or development of new MRI lesions (n = 2). The 5-year progression-free survival was 91.3% (90% CI 74.7%–97.2%), relapse-free survival was 86.9% (90% CI 69.5%–94.7%), MRI activity-free survival was 86.3% (90% CI 68.1%–94.5%), and overall survival was 86.3% (90% CI 68.3%–94.5%) (figure 2, C–F, and table e-2).
Figure 2 Neurologic outcomes: Composite primary endpoint and components
Kaplan-Meier plots of the probability an event will not occur were calculated. The number of participants at risk is presented at each time point along the x axis. Short vertical bars on the curves indicate censored data. Participants who withdrew early were censored at the date of last follow-up. (A) Event-free survival (without death or disease activity from any one of: loss of neurologic function, relapse, or new lesions on MRI). (B) Summary of all primary endpoint and subsequent events by participant with type and time of event since transplant. Primary endpoint events are bolded and starred. (C) Progression-free survival (increased Expanded Disability Status Scale [EDSS] greater than 0.5 from baseline). (D) Relapse-free survival. (E) MRI activity-free survival (presence of 2 or more independent multiple sclerosis lesions indicated on MRI). Note that the MRI event that occurred at 11.9 months was not a primary endpoint event, but rather an event that occurred subsequently after the participant met primary endpoint via clinical relapse at 5.1 months. (F) Overall survival. For each of the 3 deaths, the participant had previously met primary endpoint. In the analysis of the individual components comprising event-free survival (C–F), follow-up for any component was not censored by earlier events (see text).
Three of 24 participants transplanted did not maintain EFS due to clinical relapse, at 5.1, 22.2, and 32.6 months. However, for all participants, including those failing to maintain EFS, relapse activity was reduced posttransplant as compared to pretreatment (figure 1).
The EDSS score, for participants who survived and completed the study, improved after transplant with a median change from baseline of −0.50 (IQR −1.5 to 0.0) at 5 years (p = 0.001; figure 3A and table e-3). Specifically, as compared to baseline pretransplant, 15 participants had improvement (≥0.5 decrease) in EDSS, 5 remained stable (no change), and 4 progressed (≥0.5 increase) at the time of their last EDSS assessment, with 2 failing to maintain EFS due to progression at 15.2 and 18.9 months. The MSFC improved from baseline (figure 3, B–E, and table e-3) by 1 year and this persisted through 3 years after transplant, but by year 5 significant improvement was not sustained (p = 0.303). MSIS-29 quality of life (QoL) was improved at 3 years; however, only a trend towards improvement was noted at the end of the study (median −8.50; IQR −23 to 3.5; p = 0.091) (figure 3F and table e-3).
Figure 3 Clinical outcomes
(A) Expanded Disability Status Scale (EDSS). (B) Multiple Sclerosis Functional Composite (MSFC). (C) MSFC component: 3-second Paced Auditory Serial Addition test (PASAT-3). (D) MSFC component: 9-Hole Peg Test. Average of trials from the dominant and nondominant hands. (E) MSFC component: Timed 25-Foot Walk Test. (F) Quality of life: 29-Item Multiple Sclerosis Impact Scale (MSIS-29). The p values from a Wilcoxon signed-rank test are presented at each postbaseline visit along the x-axis assessing the change from baseline. The p value in the MSFC components in panels C through E assesses a change in the component Z score from baseline. The median component Z scores can be found in table e-3.

MRI assessments.

Two participants failed to maintain EFS at 45.6 and 48.4 months posttransplant due to development of new brain gadolinium-enhancing lesions or T2 lesions (figure 4, A and B). For all participants, T2 lesion volume decreased during follow-up starting at 6 months; at 5 years, there was still a decrease (p < 0.001) (figure 4C). T1 lesion volume demonstrated a median increase from baseline and at year 5 remained different from zero (p = 0.015) (figure 4D). Brain volume was decreased at 6 months as compared to baseline, but subsequently appeared to stabilize (figure 4E). Thus, while brain volume at the end of the study was decreased compared to baseline, there was no change in brain volume from year 3 to the end of the study.
Figure 4 MRI studies
(A) New gadolinium-enhancing (GD+) lesions occurring after transplant. The GD + lesions as seen at years 3 and 4 are 2 different GD+ lesions observed in the same participant, and thus this individual met primary endpoint. (B) New T2 lesions since previous visit. The new T2 lesions seen at year 4 are in one individual, who met primary endpoint. (C) T2 lesion volume (mL) change from baseline. There was a decrease in T2 lesion volume at year 5 (p < 0.001). (D) T1 lesion volume (mL) change from baseline. There was an increase in T1 lesion volume at year 5 (p = 0.015). (E) Percentage of change in brain volume from screening. At year 5, brain volume was significantly decreased compared to baseline (p < 0.001); however, there was stabilization in brain volume from year 3 to 5 (p = 0.311) after transplant.

OCB evaluation.

To investigate the effect of transplant on presence of OCB in the CSF, participant samples were analyzed at baseline and at 2 and 4 years post-HCT. There was persistence but a reduction in OCB number in the CSF at 2 years (figure e-2), with a reduction of CSF IgG levels after transplant.

DISCUSSION

In this 5-year analysis of HDIT/HCT without posttransplant maintenance therapy for participants with highly active RRMS in the HALT-MS study, 69.2% of participants remained event-free without evidence of relapse, disability progression, or new MRI lesions. These outcomes are highly promising, as compared to non-HCT treatments,4 and consistent with other contemporary investigations of autologous HCT for similarly afflicted individuals.1621
Highly active RRMS is the target population for contemporary investigations of HDIT/HCT for MS. Uniquely, among participants involved in earlier exploratory studies, those with RRMS demonstrated favorable responses, including some who experienced improved EDSS, while those with advanced primary progressive MS or secondary progressive MS (SPMS) continued to experience disability progression, possibly due to an irreversible neurodegenerative process with progression resulting from earlier immunologic injury.12,2225
Outcomes of HDIT with autologous HCT are similar across contemporary clinical trials including HALT-MS with regard to inducing sustained remissions and stability of neurologic function in participants with RRMS.4 For other contemporary investigations in which disease activity-free survival was determined, with events consisting of death or disease activity from any one of EDSS progression, relapse activity, or new MRI lesions, 68% of participants at 5 years in the Swedish experience,16 68% of participants at 4 years at Northwestern University,17 and 69.6% of participants at 3 years in the Canadian study18 remained event-free. Further, in the Canadian study, none of 24 participants experienced relapses or new MRI activity and only 7 of 24 participants (29%) experienced further disability progression at a median follow-up of 6.7 years.18 For 25 participants with RRMS reported from Italy, relapse-free survival was 70% and progression-free survival was 71% at 5 years.19
As detailed in our interim report, AEs observed in the HALT-MS study were consistent with those routinely observed after HDIT/HCT.1 AEs recorded at 4 and 5 years were not related to the transplant and, in general, were not considered severe. A third death occurred at 4.5 years posttransplant due to cardiorespiratory arrest; the 2 deaths reported previously1 were also late posttransplant at >2.5 and >3.5 years. These participants had all experienced worsening of MS, and no death was related to the study treatment.
In other contemporary studies of HDIT/HCT for RRMS, mortality has been 0%–4%.1619,21,26 Regarding treatment-related mortality, 1 death among 24 participants in the Canadian study18 and 2 deaths among 74 participants in the Italian experience were attributed to transplant-related complications (a third death in that series also occurred within 3 months of transplant but was attributed to other causes).19 One death occurred among 151 participants at Northwestern University, at 30 months posttransplant, from hypertensive cardiovascular disease.17 Overall survival in these studies has otherwise been 100% for the Autologous Stem Cell Transplantation International MS Trial (ASTIMS) randomized study (9 participants received transplant)21 and for the Swedish prospective observational study of 48 participants.16 These data are consistent with the recent EBMT registry report of 100-day, treatment-related mortality of 2% (for 345 MS cases), which was observed to be lower in experienced centers.26 In comparison, in a nontransplant group of patients with MS with EDSS of 3.5–5.5, MS-related mortality was 19% at 20 years of follow-up.27 In another report of non-transplant patients with MS with an EDSS of 3.0–5.5, mortality was 22% at 15 years.28 Although there were no treatment-related deaths in the HALT-MS study, there is a significant risk associated with transplant and patients require counseling regarding this.
The primary goal of HDIT/HCT in the HALT-MS clinical trial was to suppress active disease and prevent further disability. In addition, we note that participants who survived and completed the study experienced a median improvement in EDSS by a score of 0.5. In the contemporary Italian experience, 8 of 25 (31%) participants with RRMS experienced improvement of >1 EDSS point at 6–12 months after HDIT/HCT, compared with 1 of 36 with SPMS.19 At Northwestern University, it was noted that 17 of 21 (81%) participants with RRMS had an EDSS improvement of at least 1 point at a mean of 37 months post-HCT.20 In a larger study that included RRMS and SPMS from the same group, the baseline EDSS was 4.0, which improved to 2.5 at 4 years after HDIT/HCT.17 Therefore, patients with RRMS and relatively low EDSS scores may have more potential for recovery of neurologic function as compared to those with greater disability.
A markedly reduced risk of recurrent or new lesions on MRI has been observed for contemporary studies of HDIT/HCT for RRMS. This is important because appearance of new MRI lesions has been demonstrated to be correlated with relapse activity29 and with progression.30 For HALT-MS, a decrease in T2 lesion volume was observed through 5 years, and only 2 participants failed to maintain EFS by developing new lesions late after transplant. In the ASTIMS randomized study, HDIT/HCT significantly reduced MRI activity as compared to treatment with mitoxantrone.21 In the Italian experience, only 2 of 24 participants with MRI assessments at 1–2 years post-HCT had new gadolinium-enhancing lesions.19 At Northwestern University, there was a significant reduction in new gadolinium-enhancing lesions and T2 lesion volume after transplant.17 Of note, participants with active inflammation on MRI at baseline had a lower risk of progression after HDIT/HCT, as compared to those without inflammation.16,19,31
In the HALT-MS study, participants had stabilization of brain volume at 3 years through study conclusion at 5 years, consistent with attenuation of brain tissue loss following resolution of brain inflammation. A significant decrease in brain volume early after HDIT/HCT was noted in earlier studies, raising concern for brain atrophy, possibly due to high-dose chemotherapy.32,33 However, in 3 other contemporary studies, at time points beyond 2 years the rate of brain volume loss was observed to decrease, approaching normal for age.18,34,35
The MSIS was used in the HALT-MS study to measure function and QoL, and showed improvement during the first 3 years after transplant, with a trend towards improvement that did not maintain significance at 5 years. At Northwestern University, using the Short Form–36, a similar analysis demonstrated improvement at 4 years but not at 5 years,17 with the smaller number of participants available at 5 years possibly resulting in a loss of significance.
Investigation of the immunologic status of participants in the HALT-MS study with sustained remission at 5 years post-HCT vs those with disease activity may contribute to understanding mechanisms of disease in MS. We have shown that dominant CD4+ T-cell clones present pre-HCT were undetectable at 1 year post-HCT, whereas dominant CD8+ clones were not removed.3 Furthermore, participants who failed to respond to treatment had less diversity in their T-cell repertoire.3 Additional studies are currently underway.
Accumulating evidence supports preemptive treatment to prevent MS disease activity, to achieve best long-term outcomes.9,36,37 For patients failing first-line treatments, significantly more potent options are becoming available.6,37 We suggest that HDIT/HCT may be a reasonable consideration for such patients. Prospective clinical trials comparing HDIT/HCT to other approaches are needed.38 HDIT/HCT may represent a potential therapeutic option for patients with RRMS who fail conventional immunotherapy.

GLOSSARY

AE
adverse event
ASTIMS
Autologous Stem Cell Transplantation International MS Trial
CI
confidence interval
CTCAE
Common Terminology Criteria for Adverse Events
DMT
disease-modifying therapy
EDSS
Expanded Disability Status Scale
EFS
event-free survival
FDA
Food and Drug Administration
HALT-MS
High-Dose Immunosuppression and Autologous Transplantation for Multiple Sclerosis
HCT
hematopoietic cell transplantation
HDIT
high-dose immunosuppressive therapy
IgG
immunoglobulin G
IQR
interquartile range
MS
multiple sclerosis
MSFC
Multiple Sclerosis Functional Composite
MSIS
Multiple Sclerosis Impact Scale
MSRP
Multiple Sclerosis Review Panel
NEDA
no evidence of disease activity
OCB
oligoclonal bands
QoL
quality of life
RRMS
relapsing-remitting multiple sclerosis
SPMS
secondary progressive multiple sclerosis

ACKNOWLEDGMENT

The authors thank the participants and their families for their involvement in this study; the research nurses, clinical coordinators, and data technicians for their contributions to patient care and conduct of the protocol; and the Data and Safety Monitoring Board of this study.

Data Supplement

Neurology® data supplements are not copyedited before publication. Published editorials and translations have been copyedited. © 2017 American Academy of Neurology. Files in this Data Supplement:

Supplementary Material

File (nash_842.pdf)
File (supplemental_data.pdf)

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Information & Authors

Information

Published In

Neurology®
Volume 88Number 9February 28, 2017
Pages: 842-852
PubMed: 28148635

Publication History

Received: July 13, 2016
Accepted: December 9, 2016
Published online: February 1, 2017
Published in print: February 28, 2017

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Disclosure

R. Nash reports no disclosures relevant to the manuscript. G. Hutton receives research support from Biogen Idec, Novartis, MedImmune, Genzyme, Hoffman-LaRoche, and Opexa Therapeutics, and personal fees from Genentech and Sanofi. M. Racke receives funding from the National Institutes of Health and funding for clinical trials from Actelion, Genentech/Roche, and Novartis. He is on the editorial boards of the Annals of Neurology, the Annals of Clinical and Translational Neurology, JAMA Neurology, Therapeutic Advances in Neurologic Disorders, and the Journal of Neuroimmunology (Editor-in-Chief). He has received consultant fees from Abbvie, EMD Serono, Genentech/Roche, Novartis, Teva Neuroscience, and TG Therapeutics. U. Popat reports no disclosures relevant to the manuscript. S. Devine has received grants from NHLBI and NCI. K. Steinmiller and L. Griffith report no disclosures relevant to the manuscript. P. Muraro has received travel support and speaker honoraria from Novartis, Bayer HealthCare, Bayer Pharma, Biogen Idec, Merck-Serono, and Sanofi Aventis; and received research support from the Medical Research Council UK, UK Multiple Sclerosis Society, UK Stem Cell Foundation, and Italian Multiple Sclerosis Foundation (FISM). H. Openshaw and P. Sayre report no disclosures relevant to the manuscript. O. Stuve serves on the editorial boards of JAMA Neurology, Multiple Sclerosis Journal, and Therapeutic Advances in Neurologic Disorders; receives grant support from Teva Pharmaceuticals and Opexa Therapeutics; and is funded by a Merit Review grant (federal award document number [FAIN] I01BX001674) from the US Department of Veterans Affairs, Biomedical Laboratory Research and Development. Dr. Stuve has served on data monitoring committees for Pfizer and Sanofi-Aventis without monetary compensation. Dr. Stuve collaborated with Medscape on educational initiatives, represented Novartis in front of a Scientific Advisory Group at the European Medicines Agency (EMA), and has advised Genentech and Sanofi-Aventis. Dr. Stuve has participated in a Teva-sponsored meeting, consulted for Navigant Consulting, and received travel support from Pfizer. D. Arnold receives payments to NeuroRx Research from NIH/NIAID and ITN and personal fees for consulting from Acorda, Biogen, Hoffman LaRoche, MedImmune, Mitsubishi, Novartis, Receptos, and Sanofi-Aventis; grants from Biogen and Novartis; and an equity interest in NeuroRx Research, which was the image analysis center for this trial. M. Wener receives grant support from BioRad, consultation fees from Cellgene & MedImmune, and royalties from UpToDate and Medical Training Software. G. Georges reports no disclosures relevant to the manuscript. A. Wundes received grants from Biogen Idec and personal fees from Biogen Idec and Acorda Therapeutics. G. Kraft is a member of the Acorda Therapeutics AXoN Advisory Council. J. Bowen receives grant support from N01AI15416, NIH/NIAID; personal fees and research contracts from Acorda Therapeutics, Biogen IDEC, EMD Serono, Novartis, and Genzyme; research contracts from Alexion, Avanir, Genentech, GlaxoSmithKline, Sanofi-Aventis, Osmotica, Roche, Xenoport, Opexa, and Allergan; consults for Teva Neuroscience; and is a stockholder in Amgen. Go to Neurology.org for full disclosures.

Study Funding

This work was sponsored by the Division of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious Diseases (DAIT-NIAID), NIH, and conducted by the Immune Tolerance Network (ITN) (UM1 AI 109565) and DAIT-NIAID–funded statistical and clinical coordinating centers (UM2 AI 117870). The funding organization and sponsor, DAIT, NIAID, NIH, participated in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and the decision to submit the manuscript for publication. Baxter Healthcare Corporation, Deerfield, IL, supplied the Isolex 300i Magnetic Cell Selection System machines, Disposable Sets, and CD34 Reagent Kits used for the HALT-MS clinical trial to DAIT, NIAID, without charge. The opinions expressed are those of the authors and do not represent the position of the National Institute of Allergy and Infectious Diseases, the NIH, or the US Government.

Authors

Affiliations & Disclosures

Richard A. Nash, MD
From the Colorado Blood Cancer Institute (R.A.N.), Denver; Baylor College of Medicine (G.J.H.), Houston, TX; Ohio State University (M.K.R., S.M.D.), Columbus; MD Anderson Cancer Research Center (U.P.), Houston, TX; Rho, Inc. (K.C.S.), Chapel Hill, NC; National Institute of Allergy and Infectious Diseases (L.M.G.), National Institutes of Health, Bethesda, MD; Division of Brain Sciences (P.A.M.), Imperial College London, UK; City of Hope National Medical Center (H.O.), Duarte, CA; Immune Tolerance Network (P.H.S.), University of California San Francisco; University of Texas Southwestern (O.S.), Dallas; NeuroRx (D.L.A.), McGill University, Montreal, Canada; Fred Hutchinson Cancer Research Center (G.E.G.), University of Washington (M.H.W., A.W., G.H.K.); and Swedish Hospital Medical Center (J.D.B.), Seattle, WA.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
Speaker Honoraria 2016 Consortium of MS Centers $500
Editorial Boards:
1.
NONE
Patents:
1.
Canine GM-CSF cloning
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
Employment: Colorado Blood Cancer Institute (private practice). There is no relationship to this manuscript.
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
This is a manuscript about high-dose therapy and autologous hematopoietic cell transplantation for MS. There may be financial gain if we do more transplants for MS. The sponsor for the study was the NIH so there would be no financial gain for the sponsor.
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
Study was sponsored by the NIH and the Immune Tolerance Network. I had research grants from the NIH while I was at the Fred Hutchinson Cancer Research Center.
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
George J. Hutton, MD
From the Colorado Blood Cancer Institute (R.A.N.), Denver; Baylor College of Medicine (G.J.H.), Houston, TX; Ohio State University (M.K.R., S.M.D.), Columbus; MD Anderson Cancer Research Center (U.P.), Houston, TX; Rho, Inc. (K.C.S.), Chapel Hill, NC; National Institute of Allergy and Infectious Diseases (L.M.G.), National Institutes of Health, Bethesda, MD; Division of Brain Sciences (P.A.M.), Imperial College London, UK; City of Hope National Medical Center (H.O.), Duarte, CA; Immune Tolerance Network (P.H.S.), University of California San Francisco; University of Texas Southwestern (O.S.), Dallas; NeuroRx (D.L.A.), McGill University, Montreal, Canada; Fred Hutchinson Cancer Research Center (G.E.G.), University of Washington (M.H.W., A.W., G.H.K.); and Swedish Hospital Medical Center (J.D.B.), Seattle, WA.
Disclosure
Scientific Advisory Boards:
1.
Biogen Idec, Novartis, Genentech, Genzyme
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
Biogen Idec
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
Research support: Genzyme, Biogen Idec, Novartis, Opexa Therapeutics, Hoffmann La Roche, MedImmune
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Michael K. Racke, MD
From the Colorado Blood Cancer Institute (R.A.N.), Denver; Baylor College of Medicine (G.J.H.), Houston, TX; Ohio State University (M.K.R., S.M.D.), Columbus; MD Anderson Cancer Research Center (U.P.), Houston, TX; Rho, Inc. (K.C.S.), Chapel Hill, NC; National Institute of Allergy and Infectious Diseases (L.M.G.), National Institutes of Health, Bethesda, MD; Division of Brain Sciences (P.A.M.), Imperial College London, UK; City of Hope National Medical Center (H.O.), Duarte, CA; Immune Tolerance Network (P.H.S.), University of California San Francisco; University of Texas Southwestern (O.S.), Dallas; NeuroRx (D.L.A.), McGill University, Montreal, Canada; Fred Hutchinson Cancer Research Center (G.E.G.), University of Washington (M.H.W., A.W., G.H.K.); and Swedish Hospital Medical Center (J.D.B.), Seattle, WA.
Disclosure
Scientific Advisory Boards:
1.
(1) Accelerated Cure Project (1)National Multiple Sclerosis Society Research Programs Advisory Committee (2) Amarantus, Inc.
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
(1) JAMA Neurology, editorial board, 2002-present (2) Journal of Neuroimmunology, Editor-in-Chief, 2010- present (3) Therapeutic Advances for Neurologic Disorders, editorial board, 2008-present (4) Annals of Neurology, editorial board, 2016 (5) Annals of Clinical and Translational Neurology, 2015- present
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
(1) Novartis (2) Teva Neuroscience (3) EMD Serono (4) Genentech/Roche (5) Abbvie (6) TG Therapeutics
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
(1) Biogen (2) Genentech/Roche (3) Novartis (4) Actelion (5) Alkermes (6) Sun Pharma (7) TG Therapeutics
Research Support, Government Entities:
1.
(1) National Institutes of Health and Immune tolerance Network, Richard Nash, Protocol Chair, A Phase II Study of High-Dose Immunosuppressive Therapy (HDIT) Using Carmustine, Etoposide, Cytarabine, and Melphalan (BEAM) + Thymoglobulin, and Autologous CD34+ Hematopoietic Stem Cell Transplant (HCT) for the Treatment of Poor Prognosis Multiple Sclerosis, site PI, 2008-2016 (2) National Institutes of Health NeuroNEXT 2014-present
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
(1) National Multiple Sclerosis Society (2) Foundation of Consortium of Multiple Sclerosis Centers
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Uday Popat, MD
From the Colorado Blood Cancer Institute (R.A.N.), Denver; Baylor College of Medicine (G.J.H.), Houston, TX; Ohio State University (M.K.R., S.M.D.), Columbus; MD Anderson Cancer Research Center (U.P.), Houston, TX; Rho, Inc. (K.C.S.), Chapel Hill, NC; National Institute of Allergy and Infectious Diseases (L.M.G.), National Institutes of Health, Bethesda, MD; Division of Brain Sciences (P.A.M.), Imperial College London, UK; City of Hope National Medical Center (H.O.), Duarte, CA; Immune Tolerance Network (P.H.S.), University of California San Francisco; University of Texas Southwestern (O.S.), Dallas; NeuroRx (D.L.A.), McGill University, Montreal, Canada; Fred Hutchinson Cancer Research Center (G.E.G.), University of Washington (M.H.W., A.W., G.H.K.); and Swedish Hospital Medical Center (J.D.B.), Seattle, WA.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Steven M. Devine, MD
From the Colorado Blood Cancer Institute (R.A.N.), Denver; Baylor College of Medicine (G.J.H.), Houston, TX; Ohio State University (M.K.R., S.M.D.), Columbus; MD Anderson Cancer Research Center (U.P.), Houston, TX; Rho, Inc. (K.C.S.), Chapel Hill, NC; National Institute of Allergy and Infectious Diseases (L.M.G.), National Institutes of Health, Bethesda, MD; Division of Brain Sciences (P.A.M.), Imperial College London, UK; City of Hope National Medical Center (H.O.), Duarte, CA; Immune Tolerance Network (P.H.S.), University of California San Francisco; University of Texas Southwestern (O.S.), Dallas; NeuroRx (D.L.A.), McGill University, Montreal, Canada; Fred Hutchinson Cancer Research Center (G.E.G.), University of Washington (M.H.W., A.W., G.H.K.); and Swedish Hospital Medical Center (J.D.B.), Seattle, WA.
Disclosure
Scientific Advisory Boards:
1.
Incyte,Neovii
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
Sanofi
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Kaitlyn C. Steinmiller, MS
From the Colorado Blood Cancer Institute (R.A.N.), Denver; Baylor College of Medicine (G.J.H.), Houston, TX; Ohio State University (M.K.R., S.M.D.), Columbus; MD Anderson Cancer Research Center (U.P.), Houston, TX; Rho, Inc. (K.C.S.), Chapel Hill, NC; National Institute of Allergy and Infectious Diseases (L.M.G.), National Institutes of Health, Bethesda, MD; Division of Brain Sciences (P.A.M.), Imperial College London, UK; City of Hope National Medical Center (H.O.), Duarte, CA; Immune Tolerance Network (P.H.S.), University of California San Francisco; University of Texas Southwestern (O.S.), Dallas; NeuroRx (D.L.A.), McGill University, Montreal, Canada; Fred Hutchinson Cancer Research Center (G.E.G.), University of Washington (M.H.W., A.W., G.H.K.); and Swedish Hospital Medical Center (J.D.B.), Seattle, WA.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Linda M. Griffith, MD, MHS, PhD
From the Colorado Blood Cancer Institute (R.A.N.), Denver; Baylor College of Medicine (G.J.H.), Houston, TX; Ohio State University (M.K.R., S.M.D.), Columbus; MD Anderson Cancer Research Center (U.P.), Houston, TX; Rho, Inc. (K.C.S.), Chapel Hill, NC; National Institute of Allergy and Infectious Diseases (L.M.G.), National Institutes of Health, Bethesda, MD; Division of Brain Sciences (P.A.M.), Imperial College London, UK; City of Hope National Medical Center (H.O.), Duarte, CA; Immune Tolerance Network (P.H.S.), University of California San Francisco; University of Texas Southwestern (O.S.), Dallas; NeuroRx (D.L.A.), McGill University, Montreal, Canada; Fred Hutchinson Cancer Research Center (G.E.G.), University of Washington (M.H.W., A.W., G.H.K.); and Swedish Hospital Medical Center (J.D.B.), Seattle, WA.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Paolo A. Muraro, MD, PhD
From the Colorado Blood Cancer Institute (R.A.N.), Denver; Baylor College of Medicine (G.J.H.), Houston, TX; Ohio State University (M.K.R., S.M.D.), Columbus; MD Anderson Cancer Research Center (U.P.), Houston, TX; Rho, Inc. (K.C.S.), Chapel Hill, NC; National Institute of Allergy and Infectious Diseases (L.M.G.), National Institutes of Health, Bethesda, MD; Division of Brain Sciences (P.A.M.), Imperial College London, UK; City of Hope National Medical Center (H.O.), Duarte, CA; Immune Tolerance Network (P.H.S.), University of California San Francisco; University of Texas Southwestern (O.S.), Dallas; NeuroRx (D.L.A.), McGill University, Montreal, Canada; Fred Hutchinson Cancer Research Center (G.E.G.), University of Washington (M.H.W., A.W., G.H.K.); and Swedish Hospital Medical Center (J.D.B.), Seattle, WA.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
Dr. Muraro has received travel support and speaker honoraria from Novartis, Bayer HealthCare, Bayer Pharma, Biogen Idec, Merck-Serono and Sanofi Aventis.
Editorial Boards:
1.
Guest Editor, PLOS Medicine
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
Funder: Medical Research Council Type of grant: Patient Research Cohort Initiative Title: Rapidly evolving multiple sclerosis: opening the window of therapeutic opportunity Duration: 3 years PI: Muraro Co-applicants: Dr J Chataway, Professor G Giovannoni, Dr O Malik, Dr R Nicholas, Professor R Reynolds, Dr K Schmierer and Dr A Waldman Status: awarded 5.6.08 Starting date: 31/3/09 Reference number: G0800679
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
Funder: UK Multiple Sclerosis Society / UK Stem Cell Foundation Type of grant: Collaborative Project Grant Title: A phase II trial of autologous mesenchymal stem cell transplantation in highly active multiple sclerosis ? Duration: 3 years PI: Muraro Co-applicants: Chandran, Dazzi, Miller, Nicholas Collaborators: Malik, Scott, Lowdell Status: Awarded April 2011 Reference number: Funder: UK Multiple Sclerosis Society Type of grant: Project Grant Title: Immunological mechanisms of autologous hematopoietic stem cell transplantation for treatment of severe multiple sclerosis Duration: 3 years PI: Muraro Co-applicants: Prof D Altmann Status: Awarded September 2010 Reference number: 938/10 Funder: Italian Multiple Sclerosis Foundation (FISM) Type of grant: Project Grant Title: Functional relevance of haematopoietic stem cell mobilisation following therapeutic alpha 4-integrin blockade in multiple sclerosis Duration: 2 years PI: Muraro Collaborators: Nicholas, Malik, Dazzi, Mattoscio Status: Awarded January 2011 Funder: Italian Multiple Sclerosis Foundation (FISM) Type of grant: Research grant Title: Identification of early prognostic factors affecting the long-term outcome in MS Proposed duration: 2 years PI: Muraro Status: awarded 12.12.08 Starting date: 1/4/09
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Harry Openshaw, MD
From the Colorado Blood Cancer Institute (R.A.N.), Denver; Baylor College of Medicine (G.J.H.), Houston, TX; Ohio State University (M.K.R., S.M.D.), Columbus; MD Anderson Cancer Research Center (U.P.), Houston, TX; Rho, Inc. (K.C.S.), Chapel Hill, NC; National Institute of Allergy and Infectious Diseases (L.M.G.), National Institutes of Health, Bethesda, MD; Division of Brain Sciences (P.A.M.), Imperial College London, UK; City of Hope National Medical Center (H.O.), Duarte, CA; Immune Tolerance Network (P.H.S.), University of California San Francisco; University of Texas Southwestern (O.S.), Dallas; NeuroRx (D.L.A.), McGill University, Montreal, Canada; Fred Hutchinson Cancer Research Center (G.E.G.), University of Washington (M.H.W., A.W., G.H.K.); and Swedish Hospital Medical Center (J.D.B.), Seattle, WA.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Peter H. Sayre, MD
From the Colorado Blood Cancer Institute (R.A.N.), Denver; Baylor College of Medicine (G.J.H.), Houston, TX; Ohio State University (M.K.R., S.M.D.), Columbus; MD Anderson Cancer Research Center (U.P.), Houston, TX; Rho, Inc. (K.C.S.), Chapel Hill, NC; National Institute of Allergy and Infectious Diseases (L.M.G.), National Institutes of Health, Bethesda, MD; Division of Brain Sciences (P.A.M.), Imperial College London, UK; City of Hope National Medical Center (H.O.), Duarte, CA; Immune Tolerance Network (P.H.S.), University of California San Francisco; University of Texas Southwestern (O.S.), Dallas; NeuroRx (D.L.A.), McGill University, Montreal, Canada; Fred Hutchinson Cancer Research Center (G.E.G.), University of Washington (M.H.W., A.W., G.H.K.); and Swedish Hospital Medical Center (J.D.B.), Seattle, WA.
Disclosure
Scientific Advisory Boards:
1.
(1) Scientific advisory board, Shire (2) Data safety monitoring board, Caladrius
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Olaf Stuve, MD, PhD
From the Colorado Blood Cancer Institute (R.A.N.), Denver; Baylor College of Medicine (G.J.H.), Houston, TX; Ohio State University (M.K.R., S.M.D.), Columbus; MD Anderson Cancer Research Center (U.P.), Houston, TX; Rho, Inc. (K.C.S.), Chapel Hill, NC; National Institute of Allergy and Infectious Diseases (L.M.G.), National Institutes of Health, Bethesda, MD; Division of Brain Sciences (P.A.M.), Imperial College London, UK; City of Hope National Medical Center (H.O.), Duarte, CA; Immune Tolerance Network (P.H.S.), University of California San Francisco; University of Texas Southwestern (O.S.), Dallas; NeuroRx (D.L.A.), McGill University, Montreal, Canada; Fred Hutchinson Cancer Research Center (G.E.G.), University of Washington (M.H.W., A.W., G.H.K.); and Swedish Hospital Medical Center (J.D.B.), Seattle, WA.
Disclosure
Scientific Advisory Boards:
1.
Genzyme, Novartis
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
Travel support from Teva Thera
Editorial Boards:
1.
JAMA Neurology Therapeutic Advances in Neurological Disorders Clinical and Experimental Immunology MS Journal
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
Huron Navigant Consulting
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
Teva Pharmaceuticals Opexa Therapeutics
Research Support, Government Entities:
1.
Merit Review grant (federal award document number (FAIN) I01BX001674) from the United States (U.S.) Department of Veterans Affairs, Biomedical Laboratory Research and Development
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Douglas L. Arnold, MD
From the Colorado Blood Cancer Institute (R.A.N.), Denver; Baylor College of Medicine (G.J.H.), Houston, TX; Ohio State University (M.K.R., S.M.D.), Columbus; MD Anderson Cancer Research Center (U.P.), Houston, TX; Rho, Inc. (K.C.S.), Chapel Hill, NC; National Institute of Allergy and Infectious Diseases (L.M.G.), National Institutes of Health, Bethesda, MD; Division of Brain Sciences (P.A.M.), Imperial College London, UK; City of Hope National Medical Center (H.O.), Duarte, CA; Immune Tolerance Network (P.H.S.), University of California San Francisco; University of Texas Southwestern (O.S.), Dallas; NeuroRx (D.L.A.), McGill University, Montreal, Canada; Fred Hutchinson Cancer Research Center (G.E.G.), University of Washington (M.H.W., A.W., G.H.K.); and Swedish Hospital Medical Center (J.D.B.), Seattle, WA.
Disclosure
Scientific Advisory Boards:
1.
Adelphi, Acorda Therapeutics, Biogen, Genentech, Genzyme, Hoffman LaRoche, Medday, Novartis, Pfizer, Receptos, Roche, Sanofi-Aventis
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
Genzyme, travel support
Editorial Boards:
1.
NONE
Patents:
1.
Method of evaluating the efficacy of drug on brain nerve cells
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
Biogen, Novartis
Research Support, Government Entities:
1.
CIHR 15630 co-PI 2007 2012 CIHR 84360 co-PI 2007-2012 CIHR 84367 PI 2007-2012 CIHR 111169 coPI 2011-2014 CIHR 43871 co-PI 2010-2015
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
Multiple Sclerosis Society of Canada Multiple Sclerosis Research Foundation
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NeuroRx Research, 2002-2013
Legal Proceedings:
1.
NONE
Mark H. Wener, MD
From the Colorado Blood Cancer Institute (R.A.N.), Denver; Baylor College of Medicine (G.J.H.), Houston, TX; Ohio State University (M.K.R., S.M.D.), Columbus; MD Anderson Cancer Research Center (U.P.), Houston, TX; Rho, Inc. (K.C.S.), Chapel Hill, NC; National Institute of Allergy and Infectious Diseases (L.M.G.), National Institutes of Health, Bethesda, MD; Division of Brain Sciences (P.A.M.), Imperial College London, UK; City of Hope National Medical Center (H.O.), Duarte, CA; Immune Tolerance Network (P.H.S.), University of California San Francisco; University of Texas Southwestern (O.S.), Dallas; NeuroRx (D.L.A.), McGill University, Montreal, Canada; Fred Hutchinson Cancer Research Center (G.E.G.), University of Washington (M.H.W., A.W., G.H.K.); and Swedish Hospital Medical Center (J.D.B.), Seattle, WA.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
1. American College of Rheumatology, honorarium for webinar. 2. American College of Rheumatology, honorarium for symposium/lecture 3. Association of Medical Laboratory Immunologists, honorarium for symposium/lecture 4. New York State Rheumatology Association, honorarium for symposium/lecture 5. Washington Rheumatology Association, honorarium for symposium/lecture
Editorial Boards:
1.
1. UpToDate, author since 2006 and section editor, 2011 to present 2. Rheumatology, editorial board, 2014 to present 3. Arthritis Research & Therapy, editorial board, 2016
Patents:
1.
1. Method for measuring thyroglobulin using immunoaffinity and mass spectroscopy
Publishing Royalties:
1.
1. UpToDate chapters and editing, Wolters Kluwer, 2007 to present 2. Autoimmune Tutor and other on-line tutorials, Medical Laboratory Solutions, 1995 to present
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
1. Celgene Corp, short-term consultant
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
1. University of Washington Department of Laboratory Medicine, perform clinical testing for oligoclonal bands in CSF (estimate 1% of effort).
Research Support, Commercial Entities:
1.
1. Boehringer Ingelheim Pharmaceuticals, Inc., support for clinical trial for scleroderma lung disease.
Research Support, Government Entities:
1.
NIH, either directly or indirectly, through collaborative research projects as co-director of Analytic Core of the Nutrition and Obesity Research Center, director of dried blood spot biomarker lab, etc.
Research Support, Academic Entities:
1.
Collaborations with investigators at UCLA, University of Chicago, Harvard, University of Michigan, others. None pertain to the present project.
Research Support, Foundations and Societies:
1.
Puget Sound Chapter, Scleroderma Foundation
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
George E. Georges, MD
From the Colorado Blood Cancer Institute (R.A.N.), Denver; Baylor College of Medicine (G.J.H.), Houston, TX; Ohio State University (M.K.R., S.M.D.), Columbus; MD Anderson Cancer Research Center (U.P.), Houston, TX; Rho, Inc. (K.C.S.), Chapel Hill, NC; National Institute of Allergy and Infectious Diseases (L.M.G.), National Institutes of Health, Bethesda, MD; Division of Brain Sciences (P.A.M.), Imperial College London, UK; City of Hope National Medical Center (H.O.), Duarte, CA; Immune Tolerance Network (P.H.S.), University of California San Francisco; University of Texas Southwestern (O.S.), Dallas; NeuroRx (D.L.A.), McGill University, Montreal, Canada; Fred Hutchinson Cancer Research Center (G.E.G.), University of Washington (M.H.W., A.W., G.H.K.); and Swedish Hospital Medical Center (J.D.B.), Seattle, WA.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Annette Wundes, MD
From the Colorado Blood Cancer Institute (R.A.N.), Denver; Baylor College of Medicine (G.J.H.), Houston, TX; Ohio State University (M.K.R., S.M.D.), Columbus; MD Anderson Cancer Research Center (U.P.), Houston, TX; Rho, Inc. (K.C.S.), Chapel Hill, NC; National Institute of Allergy and Infectious Diseases (L.M.G.), National Institutes of Health, Bethesda, MD; Division of Brain Sciences (P.A.M.), Imperial College London, UK; City of Hope National Medical Center (H.O.), Duarte, CA; Immune Tolerance Network (P.H.S.), University of California San Francisco; University of Texas Southwestern (O.S.), Dallas; NeuroRx (D.L.A.), McGill University, Montreal, Canada; Fred Hutchinson Cancer Research Center (G.E.G.), University of Washington (M.H.W., A.W., G.H.K.); and Swedish Hospital Medical Center (J.D.B.), Seattle, WA.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
Multiple Sclerosis Association of America (MSAA), speaker honoraria
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
Biogen Idec
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
National Multiple Sclerosis Society (NMSS), institutional fellowship training grant
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
George H. Kraft, MD
From the Colorado Blood Cancer Institute (R.A.N.), Denver; Baylor College of Medicine (G.J.H.), Houston, TX; Ohio State University (M.K.R., S.M.D.), Columbus; MD Anderson Cancer Research Center (U.P.), Houston, TX; Rho, Inc. (K.C.S.), Chapel Hill, NC; National Institute of Allergy and Infectious Diseases (L.M.G.), National Institutes of Health, Bethesda, MD; Division of Brain Sciences (P.A.M.), Imperial College London, UK; City of Hope National Medical Center (H.O.), Duarte, CA; Immune Tolerance Network (P.H.S.), University of California San Francisco; University of Texas Southwestern (O.S.), Dallas; NeuroRx (D.L.A.), McGill University, Montreal, Canada; Fred Hutchinson Cancer Research Center (G.E.G.), University of Washington (M.H.W., A.W., G.H.K.); and Swedish Hospital Medical Center (J.D.B.), Seattle, WA.
Disclosure
Scientific Advisory Boards:
1.
(1)Acorda Therapeutics, Axon Council
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
(1)Acorda Therapeutics, Speakers Bureau
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
James D. Bowen, MD
From the Colorado Blood Cancer Institute (R.A.N.), Denver; Baylor College of Medicine (G.J.H.), Houston, TX; Ohio State University (M.K.R., S.M.D.), Columbus; MD Anderson Cancer Research Center (U.P.), Houston, TX; Rho, Inc. (K.C.S.), Chapel Hill, NC; National Institute of Allergy and Infectious Diseases (L.M.G.), National Institutes of Health, Bethesda, MD; Division of Brain Sciences (P.A.M.), Imperial College London, UK; City of Hope National Medical Center (H.O.), Duarte, CA; Immune Tolerance Network (P.H.S.), University of California San Francisco; University of Texas Southwestern (O.S.), Dallas; NeuroRx (D.L.A.), McGill University, Montreal, Canada; Fred Hutchinson Cancer Research Center (G.E.G.), University of Washington (M.H.W., A.W., G.H.K.); and Swedish Hospital Medical Center (J.D.B.), Seattle, WA.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
Acorda Therapeutics, Biogen IDEC, EMD Serono, Genentech, Novartis, Teva
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
Acorda Therapeutics, Biogen IDEC, EMD Serono, Genzyme, Genentech, Novartis, Teva
Speakers' Bureaus:
1.
Acorda Therapeutics, Biogen IDEC, EMD Serono, Genentech, Novartis, Teva
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
Acorda Therapeutics, Alexion, Allergan, Biogen IDEC, Genzyme, Genentech, Glaxo Smith Kline, Novartis, Roche, Sanofi-Aventis
Research Support, Government Entities:
1.
NINDS Grant #U10NS077309 Co-investigator, 5 years National Institute on Aging Grant #U01AG006781, Co- investigator, 5 years NIH/NIAID, managed by ITN Subcontract to N01 AI15416, co-investigator, 5 years
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
Amgen
Legal Proceedings:
1.
NONE

Notes

Correspondence to Dr. Nash: [email protected]
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. The Article Processing Charge was funded by The Immune Tolerance Network, which is funded by NIH/NIAID.

Author Contributions

Richard A. Nash: study concept or design, drafting of manuscript, study supervision or coordination, acquisition of data, analysis or interpretation of the data, critical revision of the manuscript for important intellectual content. George J. Hutton: acquisition of data, analysis or interpretation of the data, critical revision of the manuscript for important intellectual content. Michael K. Racke: acquisition of data, analysis or interpretation of the data, critical revision of the manuscript for important intellectual content. Uday Popat: acquisition of data, analysis or interpretation of the data, critical revision of the manuscript for important intellectual content. Steven M. Devine: acquisition of data, analysis or interpretation of the data, critical revision of the manuscript for important intellectual content. Kaitlyn C. Steinmiller (Rho, Inc.): statistical analysis, drafting of manuscript, analysis or interpretation of the data, critical revision of the manuscript for important intellectual content. Linda M. Griffith: study concept or design, drafting of manuscript, study supervision or coordination, analysis or interpretation of the data, critical revision of the manuscript for important intellectual content. Paolo A. Muraro: study concept or design, analysis or interpretation of the data, critical revision of the manuscript for important intellectual content. Harry Openshaw: study concept or design, analysis or interpretation of the data, critical revision of the manuscript for important intellectual content. Peter H. Sayre (ITN): study concept or design, study supervision or coordination, analysis or interpretation of the data, critical revision of the manuscript for important intellectual content. Olaf Stuve: analysis or interpretation of the data, critical revision of the manuscript for important intellectual content. Douglas L. Arnold (NeuroRx): study concept or design, study supervision or coordination, acquisition of data, analysis or interpretation of the data, critical revision of the manuscript for important intellectual content. Mark H. Wener: acquisition of data, analysis or interpretation of the data, critical revision of the manuscript for important intellectual content. George E. Georges: acquisition of data, analysis or interpretation of the data, critical revision of the manuscript for important intellectual content. Annette Wundes: acquisition of data, analysis or interpretation of the data, critical revision of the manuscript for important intellectual content. George H. Kraft: study concept or design, acquisition of data, analysis or interpretation of the data, critical revision of the manuscript for important intellectual content. James D. Bowen: study concept or design, acquisition of data, analysis or interpretation of the data, critical revision of the manuscript for important intellectual content. Dr. Richard A. Nash and Kaitlyn Steinmiller had full access to all study data and take responsibility for integrity of the data and accuracy of the data analysis.

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